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Hoe zelfvoorzien<strong>in</strong>g <strong>in</strong> stabiele<br />
plasmaderivaten voor België<br />
verzekeren?<br />
<strong>KCE</strong> <strong>report</strong>s 120A<br />
Federaal Kenn<strong>is</strong>centrum voor de Gezondheidszorg<br />
Centre fédéral d’expert<strong>is</strong>e des so<strong>in</strong>s de santé<br />
2009
Het Federaal Kenn<strong>is</strong>centrum voor de Gezondheidszorg<br />
Voorstell<strong>in</strong>g : Het Federaal Kenn<strong>is</strong>centrum voor de Gezondheidszorg <strong>is</strong> een<br />
parastatale, opgericht door de programma-wet van 24 december 2002<br />
(artikelen 262 tot 266) die onder de bevoegdheid valt van de M<strong>in</strong><strong>is</strong>ter<br />
van Volksgezondheid en Sociale Zaken. Het Centrum <strong>is</strong> belast met het<br />
real<strong>is</strong>eren van beleidsondersteunende studies b<strong>in</strong>nen de sector van de<br />
gezondheidszorg en de ziekteverzeker<strong>in</strong>g.<br />
Raad van Bestuur<br />
Effectieve leden : Pierre Gillet (Voorzitter), Dirk Cuypers (Ondervoorzitter), Jo De<br />
Cock (Ondervoorzitter), Frank Van Massenhove (Ondervoorzitter),<br />
Yolande Avondtroodt, Jean-Pierre Baeyens, Ri de Ridder, Olivier De<br />
Stexhe, Peter Degadt, Daniel Devos, Jean-Noël God<strong>in</strong>, Flor<strong>is</strong> Goyens,<br />
Jef Maes, Pascal Mertens, Raf Mertens, Marc Moens, Franço<strong>is</strong> Perl,<br />
Marco Schetgen, Yves Smeets, Patrick Verertbruggen, Michel Foulon,<br />
Myriam Hub<strong>in</strong>on<br />
Plaatsvervangers : Rita Cuypers, Chr<strong>is</strong>tiaan De Coster, Benoît Coll<strong>in</strong>, Lambert Stamatak<strong>is</strong>,<br />
Karel Vermeyen, Katrien Kesteloot, Bart Ooghe, Frederic Lernoux,<br />
Anne Vanderstappen, Paul Palsterman, Geert Messiaen, Anne Remacle,<br />
Roland Lemeye, Annick Poncé, Pierre Smiets, Jan Bertels, Cather<strong>in</strong>e<br />
Lucet, Ludo Meyers, Olivier Thonon.<br />
Reger<strong>in</strong>gscomm<strong>is</strong>sar<strong>is</strong> : Roger Yves<br />
Directie<br />
Algemeen Directeur a.i. : Jean-Pierre Closon<br />
Contact<br />
Federaal Kenn<strong>is</strong>centrum voor de Gezondheidszorg (<strong>KCE</strong>)<br />
Adm<strong>in</strong><strong>is</strong>tratief Centrum Kruidtu<strong>in</strong>, Doorbuild<strong>in</strong>g (10e verdiep<strong>in</strong>g)<br />
Kruidtu<strong>in</strong>laan 55<br />
B-1000 Brussel<br />
Belgium<br />
Tel: +32 [0]2 287 33 88<br />
Fax: +32 [0]2 287 33 85<br />
Email : <strong>in</strong>fo@kce.fgov.be<br />
Web : http://www.kce.fgov.be
Hoe zelfvoorzien<strong>in</strong>g <strong>in</strong><br />
stabiele plasmaderivaten voor<br />
België verzekeren?<br />
<strong>KCE</strong> rapporten 120A<br />
LEONARD CHRISTIAN, HANQUET GERMAINE, SENN ARNAUD, HUYBRECHTS MICHEL<br />
Federaal Kenn<strong>is</strong>centrum voor de gezondheidszorg<br />
Centre fédéral d’expert<strong>is</strong>e des so<strong>in</strong>s de santé<br />
2009
<strong>KCE</strong> <strong>report</strong>s 120A<br />
Titel: Hoe zelfvoorzien<strong>in</strong>g <strong>in</strong> stabiele plasmaderivaten voor België verzekeren?<br />
Auteurs: Chr<strong>is</strong>tian Léonard, Germa<strong>in</strong>e Hanquet, Arnaud Senn, Michel Huybrechts<br />
Reviewer: Jean-Pierre Closon (<strong>KCE</strong>)<br />
Externe experten: Marc Van De Casteele (RIZIV), Walter Bontez (Federaal Agentschap voor<br />
Geneesmiddelen en Gezondheidsproducten), Peter Van den Bergh (UCL<br />
St Luc), Pierrette Seeldrayers (CHU Charleroi), David Tuerl<strong>in</strong>ckx (UCL<br />
Mont God<strong>in</strong>ne), Jutte van der Werff (AZ VUB), Isabelle Meyts (UZ<br />
Leuven), Filomeen Haerynck (UZ Gent), Wim Robberecht (UZ Leuven),<br />
Pierre Philippet (CHC Liège), Al<strong>in</strong>a Ferster (HUDERF), Thierry Burnouf<br />
(HPPS), André De Swaef (Inami), Jean-Claude Osselaer (UCL Mont<br />
God<strong>in</strong>ne)<br />
Aknowledgements: Claire Michèle Farber (Erasme), Chr<strong>is</strong>tophe Chantra<strong>in</strong> (UCL St Luc), Wim<br />
Stevens (UIA), Danièle Sontag (Service Francophone du Sang), Olivier<br />
Bertrand (Service Francophone du Sang), Véronique Deneys (Service<br />
Francophone du Sang), Dom<strong>in</strong>ique-Marie Wouters (Association<br />
Externe validatoren:<br />
Francophone des Pharmaciens Hospitaliers), de Vlaamse Verenig<strong>in</strong>g voor<br />
Ziekenhu<strong>is</strong>apothekers (VZA) en de Belg<strong>is</strong>che ziekenhuizapothekers die<br />
deelnamen aan de enquête over immunoglobul<strong>in</strong>es, Leo Hertogs<br />
(commercieel directeur CAF-DCF), Patrick Robert, <strong>The</strong> Market<strong>in</strong>g<br />
Research Bureau Inc, - MRB , Orange CT, USA, Charles Waller, Plasma<br />
Prote<strong>in</strong> <strong>The</strong>rapeutics Association – PPTA – European Office , Brussels,<br />
Belgium, Prof. Dr. Philippe Vandekerckhove (Afgevaardigd Bestuurder -<br />
Rode Kru<strong>is</strong> Vlaanderen)<br />
Rosita Van Maele, Michel Delforges, Thierry Schneider<br />
Conflicts of <strong>in</strong>terest: R Van Maele was tot 2006 rev<strong>is</strong>or voor het Rode Kru<strong>is</strong> Vlaanderen. T<br />
Burnouf werkt als adv<strong>is</strong>eur <strong>in</strong> het dome<strong>in</strong> van de fractioner<strong>in</strong>g (met<br />
<strong>in</strong>begrip van het CAF-DCF), D Tuerl<strong>in</strong>ckx <strong>is</strong> verantwoordelijk voor een<br />
studie over immunoglobul<strong>in</strong>es, I Meyts werd betaald voor haar bijdrage<br />
aan een artikel met betrekk<strong>in</strong>g tot dit onderwerp, M Delforge <strong>is</strong> vast<br />
benoemd <strong>in</strong> zijn functie van fundamenteel wetenschappelijk onderzoeker<br />
en wordt gef<strong>in</strong>ancierd door het CAF-DCF.<br />
D<strong>is</strong>claimer: De externe experten hebben aan het wetenschappelijke rapport<br />
meegewerkt dat daarna aan de validatoren werd voorgelegd. De validatie<br />
van het rapport volgt uit een consensus of een meerderheidsstem tussen<br />
de validatoren. Alleen het <strong>KCE</strong> <strong>is</strong> verantwoordelijk voor de eventuele<br />
resterende verg<strong>is</strong>s<strong>in</strong>gen of onvolledigheden alsook voor de aanbevel<strong>in</strong>gen<br />
aan de overheid.<br />
Lay-out: Ine Verhulst<br />
Brussel, 24 november 2009<br />
Studie n° 2008-30<br />
Dome<strong>in</strong>: Health Services Research (HSR)<br />
MeSH: Blood Coagulation Factors ; Immunoglobul<strong>in</strong>s ; Serum Album<strong>in</strong> ; Plasma ; Red Cross ; Blood<br />
Banks ; supply and d<strong>is</strong>tribution<br />
NLM classification : WH 450<br />
Taal: Nederlands, Engels<br />
Formaat: Adobe® PDF (A4)<br />
Wettelijk depot: D/2009/10.273/57<br />
Elke gedeeltelijke reproductie van dit document <strong>is</strong> toegestaan mits bronvermeld<strong>in</strong>g.<br />
Dit document <strong>is</strong> beschikbaar van op de website van het Federaal Kenn<strong>is</strong>centrum voor de<br />
gezondheidszorg.<br />
Hoe refereren naar dit document?<br />
Léonard C, Hanquet G, Senn A, Huybrechts M. Hoe zelfvoorzien<strong>in</strong>g <strong>in</strong> stabiele plasmaderivaten voor<br />
België verzekeren Health Services Research (HSR). Brussel: Federaal Kenn<strong>is</strong>centrum voor de<br />
Gezondheidszorg (<strong>KCE</strong>). 2009. <strong>KCE</strong> Reports 120A. D/2009/10.273/57
<strong>KCE</strong> Reports 120A Plasma i<br />
VOORWOORD<br />
Geneesmiddelen worden gewoonlijk gemaakt op bas<strong>is</strong> van stoffen die <strong>in</strong> bijna<br />
onbeperkte hoeveelheden <strong>in</strong> de natuur worden aangetroffen. Dit geldt echter niet voor<br />
de meeste plasmaderivaten die onmogelijk op een andere manier kunnen worden<br />
geproduceerd dan door fractioner<strong>in</strong>g van menselijk plasma. De hoeveelheden van dit<br />
plasma zijn beperkt tot wat kan worden verzameld bij donoren.<br />
Omdat stabiele plasmaderivaten vaak de enige mogelijke remedie vormen voor bepaalde<br />
ernstige ziekten, <strong>is</strong> het begrijpelijk dat de gezondheids<strong>in</strong>stanties willen weten welke<br />
voorzorgsmaatregelen nodig zijn om ervoor te zorgen dat een voldoende bevoorrad<strong>in</strong>g<br />
van het land kan worden gegarandeerd, reken<strong>in</strong>g houdend met de beperkte bron.<br />
Deze vraag werd aan het <strong>KCE</strong> gesteld en dat gaf zich al snel rekenschap van de<br />
complexiteit van het probleem dat niet alleen samenhangt met de omstandigheden van<br />
de <strong>in</strong>zamel<strong>in</strong>g (door vrijwillige donoren en grat<strong>is</strong>), maar ook met problemen van<br />
f<strong>in</strong>ancieel evenwicht van de verschillende actoren en het gebrek aan transparantie op<br />
dat gebied. We zijn nochtans kunnen starten op bas<strong>is</strong> van voorheen reeds uitgevoerde<br />
audits.<br />
Wij danken iedereen die ons geholpen heeft om meer duidelijkheid te krijgen, en vooral<br />
de ziekenhuizen die massaal op onze enquête hebben gereageerd. Wij hopen dat wij de<br />
beleidsmakers voldoende ideeën kunnen aanreiken zodat ze tot oploss<strong>in</strong>gen kunnen<br />
komen die zowel voldoende, als kosteneffectief zijn.<br />
Jean-Pierre Closon<br />
Algemeen Directeur a.i.
ii Plasma <strong>KCE</strong> Reports 120A<br />
CONTEXT<br />
Samenvatt<strong>in</strong>g<br />
Bloed zorgt voor het transport van levensnoodzakelijke stoffen bij mensen, maar uit<br />
bloed kunnen ook derivaten worden gehaald die bij de behandel<strong>in</strong>g van bepaalde<br />
aandoen<strong>in</strong>gen bij andere personen worden gebruikt, zoals bij immuundeficiëntie en<br />
hemofilie. Deze derivaten zijn het resultaat van een fractioner<strong>in</strong>gsproces van het plasma.<br />
Plasma <strong>is</strong> het vloeibare bestanddeel van het bloed. Het <strong>is</strong> transparant geel van kleur en<br />
bestaat voor 90% uit water en voor de rest uit immunoglobul<strong>in</strong>en (hieraan zullen we<br />
een deel van dit rapport wijden), uit album<strong>in</strong>e, coagulatiefactoren en lipoproteïnen. Dit<br />
plasma wordt verkregen ofwel door de scheid<strong>in</strong>g van de bloedcellen uit vol bloed, ofwel<br />
door plasmaferese, een proces waarbij het plasma uit het bloed van een donor wordt<br />
verwijderd, maar de bloedcellen aan de donor worden teruggegeven.<br />
In België wordt alle bloed en plasma <strong>in</strong>gezameld door voornamelijk het Rode Kru<strong>is</strong> en<br />
door enkele kle<strong>in</strong>ere onafhankelijke centra. In overeenstemm<strong>in</strong>g met de geldende<br />
reglementer<strong>in</strong>g <strong>in</strong> de Europese Unie worden de donoren niet vergoed. Het <strong>in</strong>gezamelde<br />
plasma wordt verkocht aan de Centrale Afdel<strong>in</strong>g voor Fractioner<strong>in</strong>g (CAF) a , een bedrijf<br />
dat de fractioner<strong>in</strong>g uitvoert.<br />
De meeste Europese landen verbruiken veel meer plasmaderivaten dan kunnen worden<br />
gehaald uit het bloed en het plasma dat bij hun burgers wordt <strong>in</strong>gezameld. Voor dit<br />
surplus moeten ze zich dus bevoorraden bij fractioner<strong>in</strong>gsbedrijven die hun plasma <strong>in</strong><br />
het buitenland aankopen. Indien het buitenlandse plasma zou ontbreken of alleen tegen<br />
buitensporige prijzen zou kunnen worden aangekocht, kunnen de <strong>in</strong>voerende landen <strong>in</strong><br />
de problemen komen. Dit <strong>is</strong> vooral belangrijk omdat plasmaderivaten onontbeerlijk zijn<br />
voor de behandel<strong>in</strong>g van sommige ernstige ziekten. Vandaar de vraag die aan het <strong>KCE</strong><br />
werd gesteld <strong>in</strong> verband met de zelfvoorzien<strong>in</strong>g van België op gebied van plasma en<br />
stabiele plasmaderivaten en van de voorzorgsmaatregelen die moeten worden genomen<br />
om het r<strong>is</strong>ico van schaarste zoveel mogelijk te beperken.<br />
ONDERZOEKSVRAGEN<br />
Om deze problematiek te verduidelijken, hebben wij getracht een antwoord te geven<br />
op volgende vragen:<br />
Op het gebied van aanbod:<br />
• Hoe en <strong>in</strong> welke hoeveelheden wordt plasma <strong>in</strong>gezameld <strong>in</strong> België en <strong>in</strong><br />
andere landen? Welke evoluties worden hierbij opgemerkt? Welke subsidies<br />
worden toegekend om een voldoende <strong>in</strong>zamel<strong>in</strong>g te garanderen?<br />
• Hoe gebeurt de omzett<strong>in</strong>g van het <strong>in</strong> België <strong>in</strong>gezamelde plasma <strong>in</strong> stabiele<br />
plasmaderivaten? Welke hoeveelheden worden geproduceerd? Hoe wordt<br />
dit proces gef<strong>in</strong>ancierd?<br />
Op het gebied van vraag:<br />
• Wat zijn de med<strong>is</strong>che <strong>in</strong>dicaties voor een behandel<strong>in</strong>g met stabiele<br />
plasmaderivaten? Welke hoeveelheden zijn nodig om deze <strong>in</strong>dicaties te<br />
behandelen en welke zijn de <strong>in</strong> België verbruikte hoeveelheden? Welke<br />
trends kunnen <strong>in</strong> de volgende jaren worden voorzien?<br />
Op het gebied van de zekerheid qua dekk<strong>in</strong>g van de vraag:<br />
• Wat moet men onder zekerheid van dekk<strong>in</strong>g verstaan <strong>in</strong> de algemene z<strong>in</strong>?<br />
Welk niveau van dekk<strong>in</strong>g wil men <strong>in</strong> België en <strong>in</strong> andere landen bereiken?<br />
• Welk zijn de verschillende mogelijke stappen die kunnen worden gezet om<br />
het gekozen dekk<strong>in</strong>gsniveau zo dicht mogelijk te kunnen benaderen?<br />
a In het Frans: Département Central de Fractionnement (DCF). In het beg<strong>in</strong> was dit een afdel<strong>in</strong>g van het<br />
Rode Kru<strong>is</strong>. Op dit moment <strong>is</strong> dit een mult<strong>in</strong>ationale commerciële ondernem<strong>in</strong>g, waar<strong>in</strong> het Rode Kru<strong>is</strong><br />
slechts een m<strong>in</strong>derheidsaandeelhouder <strong>is</strong>.
<strong>KCE</strong> Reports 120A Plasma iii<br />
METHODOLOGIE<br />
We hebben specifieke methodologieën toegepast op elk van de drie thema’s die <strong>in</strong> dit<br />
rapport aan bod komen.<br />
Wat betreft de vragen op het gebied van het aanbod:<br />
Om de <strong>in</strong>gezamelde plasmahoeveelheden te kunnen bepalen, vroegen we de gegevens<br />
op bij de Belg<strong>is</strong>che <strong>in</strong>zamelpunten. De gegevens verkregen bij het Rode Kru<strong>is</strong> en de<br />
CAF - DCF werden getoetst aan de gegevens van een audit van deze twee <strong>in</strong>stell<strong>in</strong>gen<br />
om zo de plasmahoeveelheden die werden verkocht en gekocht en hun prijzen te<br />
bepalen. Dank zij de gegevens van het RIZIV en een enquête bij de ziekenhuizen<br />
konden we de totale hoeveelheid plasmaderivaten die <strong>in</strong> België werden verkocht<br />
bepalen. Hierbij maakten we onderscheid tussen de derivaten die werden geleverd door<br />
CAF - DCF en die geleverd door buitenlandse commerciële bedrijven.<br />
We hebben de evolutie van de aantal stabiele plasmaderivaten die door het CAF-DCF<br />
geproduceerd en verkocht werden bestudeerd en vergeleken met de hoeveelheden<br />
plasma die werden aangekocht van het Rode Kru<strong>is</strong>.<br />
De <strong>in</strong>terne documenten van het Rode Kru<strong>is</strong>, evenals de audit waaraan het werd<br />
onderworpen, lieten ons toe om de kosten van zijn activiteiten te evalueren, met name<br />
van de plasmaferese. Dit was nl. de manier van plasma-<strong>in</strong>zamel<strong>in</strong>g die als onvoldoende<br />
rendabel werd bestempeld. De prijzen die door het RK werden gekregen, werden<br />
vergeleken met de <strong>in</strong>ternationale prijzen om de mogelijke w<strong>in</strong>st voor het RK te<br />
evalueren <strong>in</strong>dien het zijn plasma op de <strong>in</strong>ternationale markt zou verkopen.<br />
Wat betreft de vragen op het gebied van de vraag:<br />
Het onderzoek richtte zich vooral op de immunoglobul<strong>in</strong>es (IG) omdat dit het<br />
plasmaderivaat <strong>is</strong> dat het meest bepalend <strong>is</strong> voor de vraag. De praktijkrichtlijnen die van<br />
kracht zijn <strong>in</strong> België en <strong>in</strong> andere geïndustrial<strong>is</strong>eerde landen werden geanalyseerd. Een<br />
literatuuroverzicht met nadruk op systemat<strong>is</strong>che reviews, bestudeerde de<br />
doeltreffendheid van immunoglobul<strong>in</strong>es voor de <strong>in</strong>dicaties die gewoonlijk <strong>in</strong> de nationale<br />
aanbevel<strong>in</strong>gen werden vermeld om kwantitatief het gebruik te kunnen verklaren en te<br />
voorzien voor de toekomst. Een analyse werd gemaakt van de kenmerken van het<br />
verbruik <strong>in</strong> andere geïndustrial<strong>is</strong>eerde landen om zo te bepalen welke <strong>in</strong>dicaties,<br />
waarvoor gebleken <strong>is</strong> dat de IG doeltreffend zijn, het grootste deel van het verbruik van<br />
IG voor hun reken<strong>in</strong>g namen. Wat betreft het verbruik <strong>in</strong> België werden drie gebieden<br />
onderzocht:<br />
• De globale gegevens voor verbruik <strong>in</strong> België, gebaseerd op de gegevens van<br />
het RIZIV (2004-2007) en op een enquête bij de apotheken van de Belg<strong>is</strong>che<br />
ziekenhuizen (2008) lieten toe om het “reële” verbruik te bestuderen <strong>in</strong><br />
termen van voorgeschreven en/of terugbetaalde globale hoeveelheden <strong>in</strong><br />
België.<br />
• De uitsplits<strong>in</strong>g van de hoeveelheden voorgeschreven per ziekenhu<strong>is</strong> en per<br />
med<strong>is</strong>ch special<strong>is</strong>me, evenals de huidige med<strong>is</strong>che praktijken, werden<br />
bestudeerd via een enquête bij de apotheken en via een tweede enquête bij<br />
10 universitaire immuno-hematolog<strong>is</strong>che diensten.<br />
• Een theoret<strong>is</strong>che schatt<strong>in</strong>g van de hoeveelheden IG nodig om de 12 erkende<br />
<strong>in</strong>dicaties die 74% van alle IG’s <strong>in</strong> de andere landen verbruikten, werd<br />
uitgevoerd op bas<strong>is</strong> van epidemiolog<strong>is</strong>che gegevens uit België of uit de<br />
buurlanden, en van de praktijken <strong>in</strong> de Belg<strong>is</strong>che of <strong>in</strong>ternationale centra.<br />
Wat betreft de vragen op gebied van zekerheid van dekk<strong>in</strong>g van de vraag:<br />
De Belg<strong>is</strong>che maatregelen om zelfvoorzien<strong>in</strong>g voor stabiele plasmaderivaten te<br />
verzekeren werden onderzocht.. Door ook te zoeken <strong>in</strong> de grijze literatuur en via<br />
directe contacten <strong>in</strong> het buitenland konden we de bevoorrad<strong>in</strong>gssystemen, van<br />
<strong>in</strong>zamel<strong>in</strong>g tot verbruik, <strong>in</strong> meerdere landen <strong>in</strong> het buitenland beschrijven (Frankrijk,<br />
Duitsland, Australië, Canada).
iv Plasma <strong>KCE</strong> Reports 120A<br />
RESULTATEN<br />
Wat betreft het concept van zekerheid van dekk<strong>in</strong>g<br />
De Belg<strong>is</strong>che reglementer<strong>in</strong>g geeft geen omschrijv<strong>in</strong>g van de hoeveelheid stabiele<br />
bloedproducten van menselijke oorsprong die <strong>in</strong> België zouden moeten worden<br />
geproduceerd <strong>in</strong>dien men zelfvoorzienend wil zijn. Een kon<strong>in</strong>klijk besluit uit 1998<br />
verklaart alleen dat, om de zelfvoorzien<strong>in</strong>g en de kwaliteit van de bevoorrad<strong>in</strong>g <strong>in</strong><br />
stabiele bloedproducten van humane oorsprong voor het land te garanderen, de prijs<br />
van een liter plasma die door het Rode Kru<strong>is</strong> aan de CAF – DCF wordt verkocht, zal<br />
worden gesubsidieerd, en dat een College van rev<strong>is</strong>oren elk jaar aan de Federale<br />
Overheids Dienst Gezondheidszorg het aantal verkochte liters zal meedelen om de<br />
subsidie correct te kunnen berekenen. Dit College stelt dat een hoeveelheid die<br />
overeenkomt met 60% van het verbruik plus een quaranta<strong>in</strong>evoorraad van 180 dagen,<br />
subsidieerbaar zijn. Hieruit wordt impliciet afgeleid dat België zelfvoorzienend <strong>is</strong>, maar<br />
wij hebben geen enkele wetenschappelijke rechtvaardig<strong>in</strong>g van deze hoeveelheid, noch<br />
van de duur van de quaranta<strong>in</strong>e (de periode tijdens dewelke het plasma moet worden<br />
bewaard vooraleer gefractioneerd te worden) kunnen v<strong>in</strong>den. Deze quaranta<strong>in</strong>eperiode<br />
steeg van 50 dagen naar 180 dagen <strong>in</strong> de periode tussen 1998 en 2006 zonder dat er<br />
iets vanuit het standpunt van med<strong>is</strong>che veiligheid deze verhog<strong>in</strong>g rechtvaardigt. Meer<br />
zelfs, nieuwe technieken voor biolog<strong>is</strong>che controle zouden kunnen toelaten deze<br />
quaranta<strong>in</strong>e periode significant te verkorten.. Het lijkt er dus sterk op dat <strong>in</strong> België over<br />
de concepten van zelfvoorzien<strong>in</strong>g en quaranta<strong>in</strong>e nooit echt werd nagedacht en ze ook<br />
nooit omschreven werden.<br />
Op <strong>in</strong>ternationaal niveau v<strong>in</strong>den we evenm<strong>in</strong> een nauwkeurige officiële rechtvaardig<strong>in</strong>g<br />
van wat meer correct “een mate van onafhankelijkheid” zou moeten worden genoemd.<br />
In Australië lijkt volledige onafhankelijkheid een impliciete doelstell<strong>in</strong>g te zijn, zelfs al<br />
wordt aanvaard om een beroep te doen op buitenlandse firma’s voor precieze en<br />
gerichte behoeften. In Frankrijk vertegenwoordigt de zelfvoorzien<strong>in</strong>g – omschreven als<br />
het deel vertegenwoordigd door de omzet van de nationale operator LFB (Laboratoire<br />
França<strong>is</strong> de Fractionnement et de Biotechnologie) <strong>in</strong> de totale omzet van de betrokken<br />
branche op de nationale markt – 75% voor de plasmaproducten, maar met variaties die<br />
afhangen van het onderzochte product (bv. : 60% voor de IG). Het doel vastgelegd bij<br />
het LFB <strong>is</strong> om een productieniveau te bereiken dat <strong>in</strong> staat <strong>is</strong> om mogelijk aan 100% van<br />
de noden van de Franse patiënten tegemoet te komen <strong>in</strong> 2011. Hoewel het LFB de<br />
enige operator <strong>is</strong> voor het fractioneren van het plasma geleverd door het Etabl<strong>is</strong>sement<br />
França<strong>is</strong> du Sang, bezit het niet het monopolie voor de verkoop van plasmaproducten<br />
en blijft het concurreren met de andere bedrijven die op de Franse markt aanwezig zijn.<br />
Wat betreft de <strong>in</strong>zamel<strong>in</strong>g van plasma<br />
Elk land ontwikkelt eigen strategieën voor het <strong>in</strong> voldoende hoeveelheden <strong>in</strong>zamelen<br />
van plasma. Om het geven van plasma te bevorderen wordt <strong>in</strong> Frankrijk en Duitsland<br />
vooral gemikt op de leeftijdsgroep van 18-25 jaar en op samenwerk<strong>in</strong>g met de<br />
universiteiten, evenals op het regelmatig opvolgen van de donoren (zeer doeltreffend)<br />
en de standaard<strong>is</strong>er<strong>in</strong>g van de donaties om de volume per donatie te verhogen. Het<br />
Etabl<strong>is</strong>sement França<strong>is</strong> de Sang heeft zich er contractueel toe verbonden om de<br />
plasmalever<strong>in</strong>gen aan het LFB te verhogen. In Duitsland wordt gebruik gemaakt van<br />
commerciële logica (80% van de donaties) en de donoren worden f<strong>in</strong>ancieel beloond<br />
(tot 25 euro/maximum bepaald door de wet). In Australië worden de <strong>in</strong>zamel<strong>in</strong>g, de<br />
bevoorrad<strong>in</strong>g <strong>in</strong> derivaten en de contracten beheerd door de National Blood Authority.<br />
In België, op bas<strong>is</strong> van de beschikbare gegevens, wordt plasmaferese stilaan afgebouwd<br />
door het Rode Kru<strong>is</strong> dat zelfs sommige centra voor plasmaferese heeft gesloten,<br />
blijkbaar omdat plasmaferese beschouwd wordt als onvoldoende rendabel. Deze<br />
rendabiliteit <strong>is</strong> tenm<strong>in</strong>ste gedeeltelijk afhankelijk van de manier waarop de vaste kosten<br />
aan het geheel van de activiteiten worden toegewezen.
<strong>KCE</strong> Reports 120A Plasma v<br />
Elke liter plasma afkomstig uit plasmaferese en verkocht <strong>in</strong> het kader van zelfvoorzien<strong>in</strong>g<br />
levert het RK een subsidie van 24,79 euro op zodat het dit plasma aan een lagere prijs<br />
aan de CAF - DCF kan verkopen. Het RK krijgt eveneens subsidie om de kosten van de<br />
NAT-testen (Nucleic Acid Tests) te dekken; deze testen worden op bloedafnamen<br />
uitgevoerd om bepaalde virussen op te sporen. De betal<strong>in</strong>g van verbruiksgoederen aan<br />
de firma die deze tests op de markt brengt <strong>is</strong> we<strong>in</strong>ig transparant en laat toe testen te<br />
factureren die niet werkelijk werden uitgevoerd.<br />
Wat betreft de omzett<strong>in</strong>g van plasma <strong>in</strong> stabiele derivaten:<br />
De CAF-DCF zorgt voor de fractioner<strong>in</strong>g van alle plasma dat op het Belg<strong>is</strong>ch<br />
grondgebied wordt aangekocht <strong>in</strong> partnerschap met drie ondernem<strong>in</strong>gen (Duits, Frans<br />
en Nederlands). De precieze afspraken tussen deze partners zijn niet publiek<br />
beschikbaar. Onze bereken<strong>in</strong>gen tonen aan dat verhoud<strong>in</strong>g tussen de hoeveelheid<br />
plasmaderivaten geproduceerd <strong>in</strong> België en de hoeveelheid plasma die door het CAF-<br />
DCF wordt gefractioneerd erg variabel <strong>is</strong> over de jaren. Deze variabiliteit lijkt<br />
gekoppeld aan de verander<strong>in</strong>g van de b<strong>in</strong>nenlandse vraag en het marktaandeel van CAF-<br />
DCF. Voor bepaalde plasmaderivaten en bepaalde jaren beschikt het CAF-DCF over<br />
meer plasma dan nodig om de hoeveelheden te produceren zijn ook die verkocht<br />
kunnen worden.<br />
Wat betreft het verbruik van de stabiele derivaten:<br />
Immunoglobul<strong>in</strong>en (IG) zijn de derivaten waarvoor de grootste hoeveelheden plasma<br />
nodig zijn om aan de therapeut<strong>is</strong>che behoeften te voldoen. De IG vertegenwoordigen<br />
ook de meeste uitgaven voor stabiele derivaten (33,4 miljoen euro of 62% van het totaal<br />
aan stabiele derivaten <strong>in</strong> 2006), hun verbruik stijgt voortdurend en het aantal <strong>in</strong>dicaties<br />
waarvoor de IG worden gebruikt, blijft ook toenemen. In België zijn er nu 13 <strong>in</strong>dicaties<br />
waarvoor IG worden terugbetaald. Een analyse van het voorschrijven van IG <strong>in</strong> de<br />
Belg<strong>is</strong>che ziekenhuizen werd uitgevoerd. Hieruit blijkt dat vier special<strong>is</strong>men 92% van de<br />
IG voorschreven <strong>in</strong> 2008 (<strong>in</strong>terne geneeskunde, neurologie, pneumologie en pediatrie).<br />
We stellen vast dat er een grote heterogeniteit bestaat bij het voorschrijven van IG<br />
tussen ziekenhuizen onderl<strong>in</strong>g, met name bij de pneumologen. Het hoge aantal<br />
voorschriften voor IG <strong>in</strong> pneumologie (16% van het totaal), vooral <strong>in</strong> enkele nietuniversitaire<br />
ziekenhuizen, kan niet worden verklaard door terugbetaalde <strong>in</strong>dicaties,<br />
behalve voor bepaalde immuundeficiënties met terugkomende bacteriële<br />
longontstek<strong>in</strong>gen die behandeld zouden worden door pneumologen; deze voorschriften<br />
werden <strong>in</strong> andere landen zelden vastgesteld . Wat betreft de toekomstige evolutie van<br />
de vraag kon nog geen enkel model worden omschreven: sommige factoren zouden de<br />
vraag kunnen doen stijgen, zoals mogelijke nieuwe <strong>in</strong>dicaties en de verhog<strong>in</strong>g van de<br />
prevalentie van bepaalde ziekten die vooral bejaarden treffen; andere factoren zouden<br />
ze kunnen doen dalen, zoals een beperk<strong>in</strong>g van het voorschrijven bij bekende <strong>in</strong>dicaties<br />
en de ontwikkel<strong>in</strong>g van alternatieve therapieën voor huidige <strong>in</strong>dicaties voor IG’s.<br />
De <strong>in</strong> België terugbetaalde <strong>in</strong>dicaties werden vergeleken met die aanbevolen en/of<br />
terugbetaald <strong>in</strong> vijf andere landen (Frankrijk, Verenigd Kon<strong>in</strong>krijk (VK), Nederland,<br />
Canada en Australië), Tabel 1. Belg<strong>is</strong>che aanbevel<strong>in</strong>gen over het gebruik van<br />
immunoglobul<strong>in</strong>en worden momenteel uitgewerkt aan de Hoge Gezondheidsraad<br />
(CSS/HGR).
vi Plasma <strong>KCE</strong> Reports 120A<br />
Tabel 1: Indicaties waarvoor het gebruik van immunoglobul<strong>in</strong>en <strong>in</strong> België<br />
wordt terugbetaald, onder specifieke voorwaarden.<br />
Terugbetaalde <strong>in</strong>dicaties <strong>in</strong> België Andere landen die IG aanbevelen voor<br />
de behandel<strong>in</strong>g van deze <strong>in</strong>dicatie*<br />
Primaire immunodeficiëntiesyndromen Frankrijk, VK, Nederland, Canada, Australië<br />
Myeloom en chron<strong>is</strong>che lymfat<strong>is</strong>che leukemie (met Frankrijk, VK, Nederland, Canada, Australië<br />
ernstige secundaire hypogammaglobul<strong>in</strong>emie en<br />
terugkerende <strong>in</strong>fecties)<br />
Idiopat<strong>is</strong>che trombocytopen<strong>is</strong>che purpura Frankrijk, VK, Nederland, Canada, Australië<br />
AIDS bij k<strong>in</strong>deren Frankrijk, Nederland, Canada, Australië<br />
Syndroom van Guilla<strong>in</strong>-barré Frankrijk, VK, Nederland, Canada, Australië<br />
Ziekte van Kawasaki Frankrijk, VK, Nederland, Canada, Australië<br />
Preventie van <strong>in</strong>fecties bij patiënten die een allogene Frankrijk, VK, Nederland, Australië<br />
beenmergtransplantatie ondergaan<br />
Behandel<strong>in</strong>g van seps<strong>is</strong> bij prematuren Nederland, Australië (preventie <strong>in</strong> Frankrijk)<br />
Behandel<strong>in</strong>g van seps<strong>is</strong> tijdens de neonatale periode Frankrijk, Australië<br />
Behandel<strong>in</strong>g van Streptokokken tox<strong>is</strong>che shock Frankrijk, VK, Australië<br />
syndroom<br />
Chron<strong>is</strong>che <strong>in</strong>flammatoire demyel<strong>in</strong><strong>is</strong>erende<br />
Frankrijk, VK, Canada, Australië<br />
polyradiculoneuropathie<br />
Multifocale motorneuropathie Frankrijk, VK, Canada, Australië<br />
*: Bronnen: Nationale richtlijnen <strong>in</strong> het Verenigd Kon<strong>in</strong>krijk, Australië en Canada; lijst<br />
gepubliceerd door het Agence frança<strong>is</strong>e de sécurité sanitaire des produits de santé (Afssaps) en<br />
door de Haute Autorité de Santé en France ; <strong>in</strong>dicaties toegestaan door het College ter<br />
Beoordel<strong>in</strong>g van Geneesmiddelen <strong>in</strong> Nederland.<br />
Er bestaan niet terugbetaalde <strong>in</strong>dicaties <strong>in</strong> België waarvoor een overzicht van de<br />
wetenschappelijke literatuur toonde aan dat immunoglobul<strong>in</strong>en voor deze <strong>in</strong>dicaties<br />
nuttig konden zijn. Er bestaan echter andere doeltreffende therapieën voor de meeste<br />
van deze pathologieën.<br />
BEPERKINGEN<br />
De eerste beperk<strong>in</strong>g van dit rapport hangt samen met de gegevens die wij hebben<br />
kunnen verzamelen. We waren niet <strong>in</strong> staat om gegevens over de <strong>in</strong> 2004-2007 nietterugbetaalde<br />
immunoglobul<strong>in</strong>en te verzamelen; voor 2008 zijn de gegevens die werden<br />
verkregen van de ziekenhu<strong>is</strong>apotheken vollediger, maar het <strong>is</strong> onduidelijk <strong>in</strong> welke mate<br />
het gebruik <strong>in</strong> schrijnende gevallen van immunoglobul<strong>in</strong>en <strong>in</strong> de gegevens van alle<br />
ondervraagde ziekenhuizen <strong>is</strong> opgenomen; volgens deskundigen zou dit een aanzienlijk<br />
deel kunnen uitmaken van het verbruik wat er dus zou kunnen toe leiden dat we het<br />
gebruik van IG en dus ook de reële vraag onderschatten.<br />
De tweede beperk<strong>in</strong>g hangt samen met het gebrek aan controle van de toewijz<strong>in</strong>g van<br />
de structurele kosten van het Rode Kru<strong>is</strong> aan de activiteit van plasmaferese. Een andere<br />
manier om de kosten te boeken zou het mogelijk kunnen maken het f<strong>in</strong>anciële tekort te<br />
verm<strong>in</strong>deren of zelfs volledig op te heffen.<br />
De derde beperk<strong>in</strong>g hangt samen met de prijsvariabiliteit van het plasma <strong>in</strong> tijd en<br />
ruimte op de <strong>in</strong>ternationale markt. Deze variabiliteit maakt het onmogelijk om duidelijke<br />
conclusies te trekken over de mogelijke baten <strong>in</strong> geval van verkoop van plasma op de<br />
<strong>in</strong>ternationale markt.
<strong>KCE</strong> Reports 120A Plasma vii<br />
AANBEVELINGEN<br />
Voor de def<strong>in</strong>itie van zelfvoorzien<strong>in</strong>g<br />
• Het voldoen aan de impliciet aanvaarde behoeften heeft als gevolg dat België<br />
gedeeltelijk afhankelijk <strong>is</strong> van de <strong>in</strong>ternationale markt. Deze afhankelijkheid<br />
zou het gevolg moeten zijn van een bewuste politieke keuze gebaseerd op<br />
een r<strong>is</strong>icoanalyse die reken<strong>in</strong>g houdt met de <strong>in</strong>ternationale prijzen, het<br />
<strong>in</strong>ternationale aanbod en vraag en de capaciteiten van het RK en de CAF -<br />
DCF om positief te reageren op een eventuele stijg<strong>in</strong>g van de b<strong>in</strong>nenlandse<br />
vraag.<br />
• We bevelen aan het aantal voorziene quaranta<strong>in</strong>e dagen voor de biolog<strong>is</strong>che<br />
veiligheid te verlagen.<br />
Voor de <strong>in</strong>zamel<strong>in</strong>g van plasma<br />
• Indien de overheid zou besluiten de mate van onafhankelijkheid voor de<br />
bevoorrad<strong>in</strong>g <strong>in</strong> derivaten te vergroten, zou het nuttig zijn zich te <strong>in</strong>spireren<br />
op de talrijke beleidsmaatregelen die <strong>in</strong> het buitenland worden gebruikt, en<br />
op de overweg<strong>in</strong>gen die op het niveau van de EU bestaan. Daarom bevelen<br />
we aan:<br />
o om zich bij de rekruter<strong>in</strong>g meer te richten op bepaalde<br />
leeftijdsgroepen en om zich bij voorkeur te richten op<br />
jongvolwassenen (18-25);<br />
o om een regelmatige opvolg<strong>in</strong>g van de donoren te garanderen en, meer<br />
<strong>in</strong> het algemeen, een goed beheer hiervan door het <strong>in</strong>zamelcentra;<br />
o om <strong>in</strong>tensieve sensibil<strong>is</strong>er<strong>in</strong>gscampagnes op te zetten;<br />
o om op techn<strong>is</strong>ch gebied te waken over een echte standaard<strong>is</strong>er<strong>in</strong>g en<br />
optimal<strong>is</strong>er<strong>in</strong>g van de <strong>in</strong>zamelpraktijken.<br />
• Om donoren eerlijk en rechtvaardig te behandelen zou voor iedereen, en <strong>in</strong><br />
het bijzonder voor alle werknemers, zowel bij de overheid als privé, de<br />
voordelen verbonden aan het geven van bloed of plasma <strong>in</strong> de toekomst gelijk<br />
moeten worden.<br />
• Wegens het we<strong>in</strong>ig transparante systeem voor de facturatie van de NAT<br />
(Nucleic Acid Tests) en hun subsidiër<strong>in</strong>g, wordt een real<strong>is</strong>t<strong>is</strong>che bepal<strong>in</strong>g van<br />
deze subsidies, die beter reken<strong>in</strong>g houdt met de reële kosten gedragen door<br />
het RK, aanbevolen, ofwel om deze kosten rechtstreeks <strong>in</strong> de prijs van het<br />
bloed door te rekenen.<br />
Voor het verbruik van stabiele plasmaderivaten<br />
• In verband met de grote variabiliteit die werd vastgesteld <strong>in</strong> de praktijk, en<br />
vooral <strong>in</strong> sommige perifere centra bevelen we aan :<br />
o richtlijnen te ontwikkelen voor het voorschrijven van IG en voor<br />
behandelalternatieven; (een dergelijk <strong>in</strong>itiatief <strong>is</strong> recent opgestart bij<br />
HGR/CSS)<br />
o dat het voorschrijven en de opvolg<strong>in</strong>g voor het gebruik van IG op<br />
lange termijn <strong>in</strong> handen wordt gegeven van special<strong>is</strong>ten en<br />
referentiecentra zoals nu al het geval <strong>is</strong> voor het gebruik van factor<br />
VIII (overeenkomst voor de hemofiliecentra).<br />
• Bovendien bevelen we aan om de opvolg<strong>in</strong>g van het voorschrift te verbeteren<br />
door het creëren van bijvoorbeeld een reg<strong>is</strong>ter van patiënten die met IG<br />
worden behandeld op de lange termijn, en door het geven van feedback aan<br />
de voorschrijvers met gebruik van benchmark<strong>in</strong>g.
viii Plasma <strong>KCE</strong> Reports 120A<br />
Voor een betere transparantie van de activiteiten en de reken<strong>in</strong>gen van de<br />
gesubsidieerde organ<strong>is</strong>men<br />
Een subsidiërende overhead moet het gebruik van de subsidies die ze geeft direct of<br />
<strong>in</strong>direct kunnen controleren. Bijgevolg,<br />
• Bevelen we aan het verder zetten van de subsidier<strong>in</strong>g van de prijs van het<br />
plasma dat aan CAF-DCF verkocht te koppelen aan een transparante<br />
communicatie<br />
o over de f<strong>in</strong>anciële stromen, de plasma volumes en de<br />
volumes plasmaderivaten die via het CAF-DCF en zijn<br />
buitenlandse partners passeren<br />
o over de precieze voorwaarden van het contract tussen<br />
CAF-DCF en zijn partners voor het directe en <strong>in</strong>directe<br />
gebruik van plasma dat <strong>in</strong> België werd verzameld,<br />
om te kunnen nagaan <strong>in</strong> hoeverre deze subsidies nuttig zijn b<strong>in</strong>nen een<br />
duidelijke gedef<strong>in</strong>ieerde politiek van zelfvoorzien<strong>in</strong>g.<br />
• Bevelen we ook aan een grondige audit van de reken<strong>in</strong>gen van het RK uit te<br />
voeren om de kostenstructuur van de plasmaferese activiteiten nauwkeurig <strong>in</strong><br />
kaart te brengen en om zo de eventueel noodzakelijke m<strong>in</strong>imale subsidie vast<br />
te leggen om deze activiteit f<strong>in</strong>ancieel <strong>in</strong> evenwicht te brengen en zo tot het<br />
gewenste niveau van plasma <strong>in</strong>zamel<strong>in</strong>g te komen.
<strong>KCE</strong> Reports 120 Plasma 1<br />
Scientific <strong>summary</strong><br />
Table of contents<br />
SCIENTIFIC SUMMARY ........................................................................................................... 1<br />
GLOSSARY ................................................................................................................................. 3<br />
1 INTRODUCTION ............................................................................................................ 5<br />
1.1 CONTEXT ..................................................................................................................................................... 5<br />
1.2 RESEARCH QUESTIONS ........................................................................................................................... 5<br />
2 SUPPLY OF PLASMA DERIVATIVES .......................................................................... 6<br />
2.1 COLLECTION OF PLASMA ...................................................................................................................... 6<br />
2.1.1 Legal and ethical framework .......................................................................................................... 6<br />
2.1.2 Plasma collection <strong>in</strong> Belgium ........................................................................................................ 12<br />
2.1.3 Plasma collection <strong>in</strong> other countries .......................................................................................... 22<br />
2.2 TRANSFORMATION OF PLASMA INTO PLASMA DERIVATIVES ............................................... 29<br />
2.2.1 Quick overview of fractionation process .................................................................................. 29<br />
2.2.2 <strong>The</strong> worldwide supply of plasma products .............................................................................. 32<br />
2.2.3 <strong>The</strong> supply of plasma stable derivatives <strong>in</strong> Belgium ................................................................. 34<br />
2.3 LIMITATIONS ............................................................................................................................................. 39<br />
3 DEMAND FOR PLASMA DERIVATIVES: THE CASE OF IMMUNOGLOBULINS<br />
.......................................................................................................................................... 40<br />
3.1 USE OF PLASMA DERIVATIVES IN BELGIUM .................................................................................... 40<br />
3.1.1 Methods ............................................................................................................................................ 40<br />
3.1.2 Results .............................................................................................................................................. 40<br />
3.1.3 <strong>The</strong> case of immunoglobul<strong>in</strong>s ...................................................................................................... 42<br />
3.2 INDICATIONS FOR IMMUNOGLOBULINS ...................................................................................... 43<br />
3.2.1 Recommendations for the use of immunoglobul<strong>in</strong>s................................................................ 43<br />
3.2.2 Evidence review on immunoglobul<strong>in</strong> effectiveness ................................................................. 49<br />
3.3 CONSUMPTION OF IMMUNOGLOBULINS ..................................................................................... 70<br />
3.3.1 Consumption <strong>in</strong> other countries ................................................................................................ 70<br />
3.3.2 Consumption <strong>in</strong> Belgium ............................................................................................................... 74<br />
3.3.3 Estimation of IG quantities to treat the ma<strong>in</strong> <strong>in</strong>dications ...................................................... 86<br />
3.3.4 Expected trends <strong>in</strong> consumption ................................................................................................ 97<br />
4 SELF SUFFICIENCY OF BELGIUM ............................................................................ 98<br />
4.1 WHAT ARE THE RISKS AT WORLDWIDE LEVEL ? ........................................................................ 98<br />
4.1.1 Plasma collection: Key role of the North American Region ................................................. 98<br />
4.1.2 Worldwide demand for plasma products / Focus on IVIG (2000-2008) .......................... 100<br />
4.1.3 Potential changes <strong>in</strong> demand structure .................................................................................... 100<br />
4.2 CONCEPT OF SELF SUFFICIENCY ..................................................................................................... 101<br />
4.2.1 In Belgium ....................................................................................................................................... 101<br />
4.2.2 In other countries ........................................................................................................................ 103<br />
4.3 HOW TO STAY OR BECOME SELF SUFFICIENT .......................................................................... 111<br />
4.3.1 Strategies to decrease IG use: lessons learned ...................................................................... 111<br />
4.3.2 Strategies to decrease IG use: what could be applied <strong>in</strong> Belgium ...................................... 115<br />
4.3.3 Increas<strong>in</strong>g the capacities of collect<strong>in</strong>g plasma ......................................................................... 115<br />
4.3.4 Transparency and better control of the supply of derivatives ........................................... 116<br />
4.4 CONCLUSIONS ....................................................................................................................................... 117<br />
5 APPENDICES ............................................................................................................... 118<br />
APPENDIX 1: ETHICAL DIMENSION OF DONATION: QUICK OVERVIEW .................................... 118<br />
APPENDIX 2 : SEARCH TERMS ........................................................................................................................ 120<br />
APPENDIX 3: GRADE CRITERIA FOR ASSIGNING GRADE OF EVIDENCE ...................................... 121<br />
APPENDIX 4: IMMUNO-HAEMATOLOGICAL SURVEY ........................................................................... 122<br />
APPENDIX 5: POTENTIAL CHANGES IN DEMAND VOLUME: FOCUS ON TWO EMERGING<br />
COUNTRIES .............................................................................................................................................. 124
2 Plasma <strong>KCE</strong> Reports 120<br />
APPENDIX 6: FRANCE: PLASMA COLLECTION WITHIN THE EFS ..................................................... 127<br />
APPENDIX 7: GERMANY: PLASMA COLLECTION WITHIN THE GERMAN RED CROSS AND BY<br />
OTHER STAKEHOLDERS ...................................................................................................................... 129<br />
APPENDIX 8: AUSTRALIA: INSTITUTIONAL ASPECTS ........................................................................... 135<br />
6 REFERENCES ............................................................................................................... 137
<strong>KCE</strong> Reports 120 Plasma 3<br />
GLOSSARY<br />
AD Alzheimer’s d<strong>is</strong>ease<br />
AFSSAPS Agence França<strong>is</strong>e de Sécurité Sanitaire des Produits de Santé<br />
ARCBS Australian Red Cross Blood Service<br />
BMT Bone marrow transplantation<br />
CAA Coronary artery aneurysms<br />
CAF-DCF Centrale Afdel<strong>in</strong>g voor Fractioner<strong>in</strong>g - Département Central de Fractionnement<br />
CFS Chronic fatigue syndrome<br />
CIDP Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyradiculoneuropathy<br />
CLL Chronic lymphocytic leukaemia<br />
CMV Cytomegalovirus<br />
CR Croix Rouge<br />
DRK Deutsches Rotes Kreuz (German Red Cross)<br />
EFS Etabl<strong>is</strong>sement França<strong>is</strong> du Sang<br />
FNAIT Fetal or neonatal allo-immune thrombocytopenia<br />
HAART Highly active antiretroviral therapy<br />
HSTC Hematopoietic stem cell transplantation<br />
IBM<br />
IG<br />
Inclusion body myosit<strong>is</strong><br />
Immunoglobul<strong>in</strong>s. In th<strong>is</strong> <strong>report</strong>, IG <strong>is</strong> used to describe pooled polyvalent human<br />
immunoglobul<strong>in</strong>, that can be adm<strong>in</strong><strong>is</strong>tered <strong>in</strong>travenously or subcutaneously; IG<br />
does not cover hyperimmune or specific immunoglobul<strong>in</strong>s.<br />
ITP Idiopathic thrombocytopenic purpura<br />
IVIG Intravenous polyvalent immunoglobul<strong>in</strong>s<br />
LEMS Lambert-Eaton myasthenic syndrome<br />
LFB Laboratoire França<strong>is</strong> de Fractionnement et de Biotechnologie<br />
MG Myasthenia grav<strong>is</strong><br />
MM Multiple myeloma<br />
MMN Multifocal motor neuropathy<br />
MS Multiple scleros<strong>is</strong><br />
NAT Nucleic Acid Test<br />
NBA National Blood Authority (Australia)<br />
NIHDI National Institute for Health and D<strong>is</strong>ability Insurance<br />
PID Primary immune deficiencies<br />
PPMS Primary progressive multiple scleros<strong>is</strong><br />
PPTA Plasma Prote<strong>in</strong> <strong>The</strong>rapeutics Association<br />
RCT Randomized control trial<br />
RP Recovered Plasma<br />
RRMS Relaps<strong>in</strong>g remitt<strong>in</strong>g multiple scleros<strong>is</strong><br />
RSV Respiratory Syncitial Virus<br />
SCIG Immunoglobul<strong>in</strong>s for sub-cutaneous adm<strong>in</strong><strong>is</strong>tration<br />
SFS Service Francophone du Sang<br />
SID Secondary immune deficiencies<br />
SIPLA Study on the Safety of Long-term Intensive Plasmapheres<strong>is</strong> <strong>in</strong> Donors (Germany)<br />
SP Source Plasma<br />
SPMS Secondary progressive multiple scleros<strong>is</strong>
4 Plasma <strong>KCE</strong> Reports 120<br />
STC Stem cell transplant<br />
TFG Transfusionsgesetz (German regulation on transfusion and blood-related <strong>is</strong>sues)<br />
VDB Vlaamse Dienst voor het Bloed
<strong>KCE</strong> Reports 120 Plasma 5<br />
1 INTRODUCTION<br />
1.1 CONTEXT<br />
Blood transports elements that are essential to life <strong>in</strong> <strong>in</strong>dividuals, but it can also be used<br />
to produce derivatives that are used <strong>in</strong> the treatment of specific d<strong>is</strong>orders <strong>in</strong> others<br />
such as immunodeficiency and haemophilia. <strong>The</strong>se derivates are produced by a process<br />
called plasma fractionation. Plasma <strong>is</strong> the transparent yellow<strong>is</strong>h liquid part of the blood,<br />
composed of 90% water and the rest of immunoglobul<strong>in</strong>s (a part of th<strong>is</strong> <strong>report</strong> <strong>is</strong><br />
devoted to their consumption), album<strong>in</strong>, coagulation factors and lipoprote<strong>in</strong>s. Th<strong>is</strong><br />
plasma <strong>is</strong> obta<strong>in</strong>ed either by separation of the red blod cells follow<strong>in</strong>g a whole blood<br />
donation, or by plasmapheres<strong>is</strong>, a process used to <strong>is</strong>olate the plasma from the blood of<br />
a donor, which reta<strong>in</strong>s the red blood cells.<br />
In Belgium, all of the blood and plasma <strong>is</strong> collected by the Red Cross and a few<br />
<strong>in</strong>dependent centres. <strong>The</strong> donors are not paid, <strong>in</strong> accordance <strong>with</strong> the rules <strong>in</strong> force <strong>in</strong><br />
the European Union. <strong>The</strong> collected plasma <strong>is</strong> sold to a company <strong>in</strong> Belgium, which<br />
performs the fractionation.<br />
<strong>The</strong> majority of European countries consume a greater quantity of derivatives than can<br />
be extracted from the blood and plasma collected from their citizens. <strong>The</strong>y must<br />
therefore obta<strong>in</strong> other supplies from fractionation companies that buy plasma abroad. If<br />
th<strong>is</strong> foreign plasma should one day be <strong>in</strong> short supply or only be <strong>available</strong> at exorbitant<br />
prices, import<strong>in</strong>g countries may f<strong>in</strong>d themselves <strong>in</strong> difficulty. Th<strong>is</strong> difficulty <strong>is</strong><br />
exacerbated by the fact that plasma derivatives are vital for the treatment certa<strong>in</strong><br />
serious illnesses, hence the question posed to the <strong>KCE</strong> of self-sufficiency for Belgium <strong>in</strong><br />
plasma and plasma derivatives and the precautions to be taken to reduce as far as<br />
possible the r<strong>is</strong>k of a shortfall <strong>in</strong> supplies.<br />
1.2 RESEARCH QUESTIONS<br />
To clarify the <strong>is</strong>sue, we <strong>in</strong>tend to answer the follow<strong>in</strong>g questions:<br />
Concern<strong>in</strong>g supply:<br />
• How and <strong>in</strong> what quantities <strong>is</strong> plasma collected <strong>in</strong> Belgium and <strong>in</strong> other<br />
countries? What trends have been observed? What subsidies are<br />
provided to ensure that enough <strong>is</strong> collected?<br />
• How are derivative products manufactured from the plasma collected <strong>in</strong><br />
Belgium? What are the quantities produced? How <strong>is</strong> it f<strong>in</strong>anced?<br />
Concern<strong>in</strong>g demand:<br />
• Which medical <strong>in</strong>dications are treated <strong>with</strong> plasma stable derivatives ?<br />
Which amounts are required to treat these conditions and which<br />
amounts are consumed <strong>in</strong> Belgium? Which trends can we expect over<br />
the com<strong>in</strong>g years?<br />
Concern<strong>in</strong>g security of coverage of demand:<br />
• What it meant by security of coverage <strong>in</strong> general? What level of coverage<br />
do we seek to achieve <strong>in</strong> Belgium and <strong>in</strong> other countries?<br />
• What different approaches could be used to achieve optimally the desired<br />
level of coverage?
6 Plasma <strong>KCE</strong> Reports 120<br />
2 SUPPLY OF PLASMA DERIVATIVES<br />
2.1 COLLECTION OF PLASMA<br />
2.1.1 Legal and ethical framework<br />
Plasma donation and collection processes have to abide by specific rules, both from a<br />
sanitary and ethical po<strong>in</strong>t of view.<br />
As a human product, collection and use of plasma are subject to specific rules, <strong>with</strong> a<br />
view to protect<strong>in</strong>g patient safety, and also donor’s security. Moreover specificity of<br />
plasma <strong>is</strong> that they stem from human donation. In the current state of science, artificial<br />
plasma as such cannot be produced, and the supply of plasma cannot be guaranteed.<br />
<strong>The</strong>refore donation <strong>is</strong> of paramount importance.<br />
However, one must clearly d<strong>is</strong>t<strong>in</strong>gu<strong>is</strong>h one the one hand donation and collection that<br />
rema<strong>in</strong> <strong>in</strong> the hands of each national system and on the other hand the global market of<br />
plasma-derived products, that <strong>is</strong> subject to free competition between private firms.<br />
For all these reasons, a very strict and specific legal and ethical framework has been<br />
def<strong>in</strong>ed. Given the high level of economic <strong>in</strong>tegration between EU economies <strong>in</strong> the field<br />
of plasma-derived products, but also the common expectations of EU citizens, these<br />
rules have been set out on the EU level.<br />
2.1.1.1 European and <strong>in</strong>ternational context: which impact?<br />
EU regulatory framework on blood and blood products<br />
More prec<strong>is</strong>ely, the key regulatory texts of the EU legal framework cover the follow<strong>in</strong>g<br />
subjects:<br />
QUALITY ISSUES: 2 DIRECTIVES<br />
Directive 2002/98/EC (27 January 2003) 1 sett<strong>in</strong>g standards of quality and safety for<br />
the collection, test<strong>in</strong>g, process<strong>in</strong>g, storage, and d<strong>is</strong>tribution of human blood and blood<br />
components and amend<strong>in</strong>g directive 2001/83/EC. Th<strong>is</strong> directive focuses on the follow<strong>in</strong>g<br />
aspects: prov<strong>is</strong>ions for establ<strong>is</strong>hments, quality management, haemovigilance, quality and<br />
safety of blood (and blood components), <strong>report</strong><strong>in</strong>g requirements, etc…<br />
Directive 2004/33/ EC (22 March 2004) 2 implement<strong>in</strong>g directive 2002/98 as<br />
regards certa<strong>in</strong> technical requirements for blood and blood components. Th<strong>is</strong> directive<br />
<strong>is</strong> also of paramount importance, as the appendixes l<strong>is</strong>t the key requirements for the<br />
practical organization of blood donation: def<strong>in</strong>ition of terms and concepts, eligibility<br />
criteria for donors, storage and d<strong>is</strong>tribution conditions, quality/safety requirements.<br />
TRACEABILITY REQUIREMENTS: 1 DIRECTIVE<br />
Directive 2005/61/ EC (30 September 2005) 3 implement<strong>in</strong>g directive 2002/98 of<br />
the European Parliament and of the Council as regards traceability requirements and<br />
notification of serious adverse events reactions and events.<br />
QUALITY SYSTEM FOR BLOOD ESTABLISHMENTS: 1 DIRECTIVE<br />
Directive 2005/62/ EC (30 September 2005) 4 implement<strong>in</strong>g directive 2002/98 of<br />
the European Parliament and of the Council as regards Community standards and<br />
specifications relat<strong>in</strong>g to a quality system for blood establ<strong>is</strong>hments.<br />
However, the <strong>is</strong>sue of self-sufficiency as such has not been addressed by the EU<br />
regulation so far and has been left to each country’s d<strong>is</strong>cretion. Besides, as far as plasma<br />
products are concerned, some further explanation <strong>is</strong> required, <strong>in</strong> terms of legal status.<br />
Indeed, it <strong>is</strong> a thorny and complex problem both from an <strong>in</strong>tellectual and political po<strong>in</strong>t<br />
of view.
<strong>KCE</strong> Reports 120 Plasma 7<br />
Focus: status of plasma products <strong>with</strong> regard to the EU leg<strong>is</strong>lation<br />
Legal status of plasma-derived products rema<strong>in</strong>s a sensitive and delicate subject both<br />
from a legal and political po<strong>in</strong>t of view.<br />
<strong>The</strong> ma<strong>in</strong> <strong>is</strong>sue <strong>is</strong> to have a clear view on the legal nature of blood products, to be<br />
specific of plasma-derived products. Whereas these products are blood products or<br />
drugs might have far-reach<strong>in</strong>g consequences, especially <strong>in</strong> terms of freedom of<br />
circulation.<br />
Until now, no case law of the European Court of Justice has been identified on the legal<br />
status of blood or plasma products, as such.<br />
<strong>The</strong> problem has really not been solved and the arguments l<strong>is</strong>ted below must be<br />
considered <strong>with</strong> great care, and might be challenged by the ECJ <strong>in</strong> the future. To some<br />
extent, one can rely on a body of legal evidence, consider<strong>in</strong>g the spirit of the ex<strong>is</strong>t<strong>in</strong>g<br />
EU leg<strong>is</strong>lation on blood and blood products.<br />
Directive 2004/33/ EC (22 March 2004) mentioned above sets out <strong>in</strong> Annex I a<br />
long and prec<strong>is</strong>e l<strong>is</strong>t of what <strong>is</strong> considered as “blood” and “blood components”, to<br />
which the directive’s requirements are applicable.<br />
Directive 2001/83 /EC (6 November 2001) on medic<strong>in</strong>al products: it <strong>is</strong> clearly<br />
stated <strong>in</strong> th<strong>is</strong> directive that “medic<strong>in</strong>al products derived from human blood or human<br />
plasma” can resort to “album<strong>in</strong>, coagulat<strong>in</strong>g factors and immunoglobul<strong>in</strong> of human<br />
orig<strong>in</strong>”. We can easily draw the conclusion that all these products are considered as<br />
medic<strong>in</strong>al products.<br />
One can easily <strong>in</strong>fer from the directives mentioned above that products that are l<strong>is</strong>ted<br />
<strong>in</strong> the Directive are blood products (and not pharmaceutical drugs) and are a matter for<br />
the EU Blood and Blood products leg<strong>is</strong>lation. Likew<strong>is</strong>e, one can also <strong>in</strong>fer that products<br />
resort<strong>in</strong>g to human plasma (alone or comb<strong>in</strong>ed <strong>with</strong> other substances) that are sold by<br />
pharmaceutical firms, after completion of the fractionation process, must be considered<br />
as drugs.<br />
Nonetheless, plasma fractionation <strong>is</strong> an extremely long and complex process, and the<br />
range of plasma-derived products <strong>is</strong> very wide. <strong>The</strong>refore, a “grey zone” can be<br />
identified between blood and blood-components and plasma-derived drugs as described<br />
<strong>in</strong> the previous paragraph. <strong>The</strong> ma<strong>in</strong> <strong>is</strong>sue <strong>is</strong> to def<strong>in</strong>e accurate criteria to d<strong>is</strong>t<strong>in</strong>gu<strong>is</strong>h<br />
“blood components” and “pharmaceutical drugs” and to draw a border between both<br />
concepts. Th<strong>is</strong> <strong>is</strong> not an easy task, from a purely conceptual and legal po<strong>in</strong>t of view.<br />
For lack of regulatory def<strong>in</strong>ition (or official case law of the European Court of Justice),<br />
several EU Directives on health-related subjects can provide us <strong>with</strong> <strong>in</strong>terest<strong>in</strong>g clues on<br />
that po<strong>in</strong>t, <strong>in</strong> several texts especially EU Regulation (EC) 1394/2007 on advanced<br />
therapies (13 November 2007) on advanced therapy medic<strong>in</strong>al products (amend<strong>in</strong>g<br />
Directive 2001/83 and Regulation 726/2004). <strong>The</strong> latter regulation deals <strong>with</strong> advanced<br />
therapies resort<strong>in</strong>g to cells or t<strong>is</strong>sues. One of the key <strong>is</strong>sues of th<strong>is</strong> regulation <strong>is</strong> to<br />
identify products that can be considered as “medic<strong>in</strong>al products”. To th<strong>is</strong> end, the<br />
regulation (Art.2 Def<strong>in</strong>itions) resorts to the concept of “eng<strong>in</strong>eered products” (as<br />
opposed to non eng<strong>in</strong>eered products).<br />
To be more specific only cells or t<strong>is</strong>sues that undergo “substantial manipulations” can be<br />
considered as “advance therapy medic<strong>in</strong>al products”. Given that cl<strong>in</strong>ical practice or<br />
scientific literature do not give a clear-cut def<strong>in</strong>ition of th<strong>is</strong> concept, th<strong>is</strong> regulation sets<br />
out a l<strong>is</strong>t of practices (Annex I) that are not considered as “substantial manipulations”.<br />
In practical terms, such practices as centrifugation, sterilization, filter<strong>in</strong>g, and freez<strong>in</strong>g<br />
can be considered as “substantial manipulations” as such.<br />
<strong>The</strong>n, a second criterion <strong>is</strong> used <strong>in</strong> the Directive, to be specific the volume of<br />
production: the scope of the regulation clearly refers to the rout<strong>in</strong>e <strong>in</strong>dustrial<br />
production of medic<strong>in</strong>al products (<strong>with</strong> a view to putt<strong>in</strong>g them on the market), and not<br />
to custom-made treatments. Thus, a product that <strong>is</strong> used <strong>with</strong><strong>in</strong> a hospital <strong>in</strong> compliance<br />
<strong>with</strong> a medical prescription and delivered to a patient <strong>is</strong> clearly excluded from the scope<br />
of the regulation, s<strong>in</strong>ce it <strong>is</strong> not considered as a medic<strong>in</strong>al product.
8 Plasma <strong>KCE</strong> Reports 120<br />
In the light of these criteria, only products that comply <strong>with</strong> these two criteria should<br />
be considered as “medic<strong>in</strong>al products”. However, one must rema<strong>in</strong> cautious on that<br />
po<strong>in</strong>t, and keep th<strong>is</strong> legal <strong>is</strong>sue under scrut<strong>in</strong>y.<br />
Apart from purely regulatory subjects, the EU level also plays a strategic role <strong>in</strong> the<br />
promotion of voluntary unpaid donation, <strong>in</strong> order to identify avenues worth explor<strong>in</strong>g<br />
to improve EU countries’ self-sufficiency, <strong>with</strong><strong>in</strong> the ethical and regulatory framework<br />
described above. Th<strong>is</strong> EU will play an important role over the next years.<br />
EU policy and ongo<strong>in</strong>g projects on promotion of voluntary unpaid donation<br />
SURVEY OF THE EU COMMISSION (DG SANCO) ON PROMOTION OF UNPAID<br />
DONATION<br />
One of the key <strong>is</strong>sues for political dec<strong>is</strong>ion-makers, but also for practical organization of<br />
blood and plasma donation <strong>is</strong> the lucrative or unpaid nature of donation. Th<strong>is</strong> takes us<br />
back to ethical notions, and to a philosophical and political debate.<br />
Some countries like the United States clearly opted for remuneration of donation,<br />
whereas others - like Canada and EU countries - opted for non remuneration of<br />
donation. <strong>The</strong> EU level formally recorded that donation <strong>is</strong> unpaid. With<strong>in</strong> th<strong>is</strong> ethical<br />
framework, the EU level organized an <strong>in</strong>-depth enquiry to learn more on ex<strong>is</strong>t<strong>in</strong>g<br />
practices on unpaid donation across Member States.<br />
A Europe-wide survey has been launched by the EU-Comm<strong>is</strong>sion (DG Sanco) 5 a few<br />
years ago on that subject, and a <strong>summary</strong> <strong>report</strong> has been <strong>is</strong>sued on 17 th May 2006.<br />
Across Member States, practices can vary on two po<strong>in</strong>ts: Interpretation of the pr<strong>in</strong>ciple<br />
of “unpaid donation” and Promotion of donation itself.<br />
Interpretation of the pr<strong>in</strong>ciple of “unpaid donation”: from a political and ethical po<strong>in</strong>t of<br />
view, the pr<strong>in</strong>ciple of “unpaid donation” <strong>is</strong> the cornerstone of the donation systems, all<br />
over the EU. However, th<strong>is</strong> pr<strong>in</strong>ciple does not exclude “f<strong>in</strong>ancial compensation” for<br />
donors <strong>in</strong> some countries (or <strong>in</strong> specific <strong>in</strong>stitutions <strong>with</strong><strong>in</strong> these countries, depend<strong>in</strong>g<br />
on their own political options). <strong>The</strong> amount of th<strong>is</strong> f<strong>in</strong>ancial compensation <strong>is</strong> kept below<br />
a specific threshold set out by leg<strong>is</strong>lation, and the nature of expenses covered (and not<br />
covered) by th<strong>is</strong> compensation (travel expenses, car park, etc..) <strong>is</strong> generally set out very<br />
prec<strong>is</strong>ely by the country’s leg<strong>is</strong>lation.<br />
Germany <strong>is</strong> a traditional example on that po<strong>in</strong>t: as expla<strong>in</strong>ed further <strong>in</strong> the <strong>report</strong>, many<br />
German <strong>in</strong>stitutions <strong>in</strong>volved <strong>in</strong> donation - especially private <strong>in</strong>stitutions <strong>in</strong>volved <strong>in</strong><br />
plasma donation- apply f<strong>in</strong>ancial compensation as an <strong>in</strong>centive for donors. <strong>The</strong> amount<br />
of th<strong>is</strong> compensation can reach € 25 for each donation (maximum amount set out by<br />
the German leg<strong>is</strong>lation).<br />
As a result of th<strong>is</strong> compensation mechan<strong>is</strong>m and depend<strong>in</strong>g on the frequency of<br />
donation, regular donors are apt to receive a yearly amount of money, that <strong>is</strong> far from<br />
be<strong>in</strong>g nom<strong>in</strong>al (around 1000 €).<br />
Promotion of donation itself: a very wide range of media and <strong>in</strong>stitutions have been<br />
used or mobil<strong>is</strong>ed to support donation:<br />
• Information campaigns resort<strong>in</strong>g to traditional media (leaflets, posters,<br />
press) or modern media, especially <strong>in</strong>ternet.<br />
• Special events on donation: World blood donor day or other events<br />
focus<strong>in</strong>g on donation.<br />
• Specific Student and secondary schools’ pupils awareness: <strong>in</strong> many<br />
Member States, ra<strong>is</strong><strong>in</strong>g awareness of th<strong>is</strong> age group <strong>is</strong> of paramount for<br />
further recruitment of donors.<br />
FURTHER DEVELOPMENTS ON THAT SUBJECT ON THE EU LEVEL: SHARING BEST<br />
PRACTICES BETWEEN MEMBER STATES<br />
In the light of these f<strong>in</strong>d<strong>in</strong>gs, the EU Comm<strong>is</strong>sion decided to carry out a new study on<br />
best practices for promotion of voluntary unpaid, <strong>in</strong> order to share best practices<br />
between Member States. <strong>The</strong> f<strong>in</strong>d<strong>in</strong>gs of th<strong>is</strong> new study should be <strong>available</strong> <strong>in</strong> early<br />
2010.
<strong>KCE</strong> Reports 120 Plasma 9<br />
Two technical European projects have been designed and implemented on donation:<br />
“DOMAINE” / Donor Management <strong>in</strong> Europe focus<strong>in</strong>g on recruitment, retention and<br />
long-term management of donors and “Optimal Blood Use” focus<strong>in</strong>g on the cl<strong>in</strong>ical and<br />
technical use of blood components. <strong>The</strong>se projects are all the more important as they<br />
will be completed <strong>in</strong> 2010 and should deliver helpful <strong>in</strong>formation on best practices on<br />
these subjects.<br />
“DOMAINE”: Donor Management <strong>in</strong> Europe: http://www.doma<strong>in</strong>eeurope.eu/Home/tabid/36/Default.aspx<br />
DOMAINE (Donor Management IN Europe) <strong>is</strong> a European project, <strong>in</strong> which blood<br />
establ<strong>is</strong>hments from 14 European member states and one patient-driven organ<strong>is</strong>ation<br />
jo<strong>in</strong> their forces on donor management. DOMAINE aims to create a safe and sufficient<br />
blood supply, by compar<strong>in</strong>g and recommend<strong>in</strong>g good donor management practice. Even<br />
if 14 Member States play a lead<strong>in</strong>g role as partners countries, surveys obviously covers<br />
European practices, ie all EU countries, and a small number of European non-EU<br />
countries (as a whole 34 countries).<br />
Th<strong>is</strong> project does not deal specifically <strong>with</strong> plasma donation. However, pr<strong>in</strong>ciples of<br />
donor management are apt to be applied to plasma donation as well.<br />
<strong>The</strong> whole range of donor management <strong>is</strong>sues will be addressed: donor recruitment<br />
strategies, donor retention strategies, deferral procedures and blood bank policy<br />
regard<strong>in</strong>g patients requir<strong>in</strong>g long-term transfusion.<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> EU concept of unpaid donation, opposable to all EU countries, does not<br />
exclude f<strong>in</strong>ancial compensation. Interpretation of th<strong>is</strong> latter concept may<br />
vary across Member States. Exchange of best practices on unpaid donation<br />
will also be <strong>available</strong> over the next years.<br />
• Noticeable d<strong>is</strong>crepancies have been identified <strong>in</strong> donor’s management but<br />
also <strong>in</strong> the use of blood and plasma across EU countries. <strong>The</strong> EU level’s<br />
objective <strong>is</strong> to support harmonization of practices. As a result, a<br />
contribution <strong>is</strong> expected from 2010 onwards: Manual on donor management,<br />
Manual on the rational use of blood and plasma.<br />
2.1.1.2 Contribution to the ethical debate on donation<br />
Over the last decades, blood and plasma donation has ra<strong>is</strong>ed very specific ethical<br />
questions for the follow<strong>in</strong>g reasons:<br />
• Blood and plasma products are human products and not <strong>in</strong>dustryproduced<br />
drugs.<br />
• Donation <strong>is</strong> based on a voluntary and <strong>in</strong>dividual act (at least <strong>in</strong> western<br />
countries).<br />
• Donation does not meet supply/demand rules <strong>in</strong> the traditional economic<br />
sense.<br />
• Specific ethical problems may appear both on the donor’s and user’s side.<br />
• Ethical frameworks of donation systems have a major impact on selfsufficiency,<br />
as shown <strong>in</strong>ter allia by the Canadian experience (see below).<br />
Ma<strong>in</strong> ethical dimensions of blood donation<br />
In Europe, many reflections have been conducted for several decades on blood and<br />
plasma donation and over the last years the University of Vienna <strong>in</strong> Austria<br />
(http://www.medicalethics.at/) , has conducted an <strong>in</strong>-depth reflection on that subject.
10 Plasma <strong>KCE</strong> Reports 120<br />
THE REFLECTION ON ETHICAL DIMENSION OF STEPS:<br />
1. Ma<strong>in</strong> specificities of blood and plasma donation<br />
<strong>The</strong> ma<strong>in</strong> traits of blood and plasma donation have been identified by Richard Titmuss<br />
and officially set out <strong>in</strong> the follow<strong>in</strong>g article “Why give to strangers?“ Lancet 16 January<br />
1971 6 and h<strong>is</strong> book titled “<strong>The</strong> gift relationship: from human blood to social policy” (last<br />
edition 1997) 7 . <strong>The</strong> most specific traits of th<strong>is</strong> “Gift relationship” <strong>is</strong> its potentially onesided<br />
and not reward<strong>in</strong>g dimension of th<strong>is</strong> donation:<br />
• Physically uncomfortable<br />
• Anonymous and not reward<strong>in</strong>g (<strong>in</strong>dividually)<br />
• Potentially one-sided dimension (donor can be excluded from a future<br />
donation)<br />
• Absence of donation does not <strong>in</strong>volve any sanction<br />
• <strong>The</strong> use of donated blood depends on a large number of people<br />
• For the donor, donation <strong>is</strong> no great or def<strong>in</strong>itive loss whereas for the<br />
recipient, it can be a matter of life and death<br />
For all the reasons mentioned above blood and plasma donation can be considered as a<br />
very specific k<strong>in</strong>d of gift, not to be compared <strong>with</strong> other k<strong>in</strong>d of donations or “gift<br />
relationships”. Moreover blood and plasma donation as such entail specific symbolic<br />
dimensions (Myth of Blood). Further details: see Appendix<br />
2. Ma<strong>in</strong> learn<strong>in</strong>gs<br />
It <strong>is</strong> important to underl<strong>in</strong>e that h<strong>in</strong>der<strong>in</strong>g factors for donation must be considered <strong>in</strong><br />
close connection <strong>with</strong> the <strong>in</strong>dividuals’ past attitude towards donation (ie ever donors or<br />
non donors).<br />
<strong>The</strong> collection regimes may have an impact on donors’ motivation and donators’<br />
profiles. In practice, it often <strong>in</strong>volves a split between two donors profile. <strong>The</strong>refore, it<br />
<strong>is</strong> of key importance to bear <strong>in</strong> m<strong>in</strong>d that such subjects as f<strong>in</strong>ancial compensation cannot<br />
be considered separately from other subjects. <strong>in</strong> countries were compensation <strong>is</strong><br />
applied, plasma donors are generally younger, more educated, and less <strong>in</strong>volved <strong>in</strong><br />
professional life than whole blood donors. Conversely, <strong>in</strong> countries where no f<strong>in</strong>ancial<br />
compensation <strong>is</strong> provided any clear d<strong>is</strong>t<strong>in</strong>ction, <strong>in</strong> terms of donors’ profile, has been<br />
identified so far.<br />
MAXIMIZATION OF THE USE OF THE DONATED BLOOD AS AN ETHICAL IMPERATIVE<br />
Consensual prerequ<strong>is</strong>ites can be easily set out as follows, basically for purely practical<br />
reasons:<br />
- Plasma <strong>is</strong> a scarce resource (plasma as raw material <strong>is</strong> not <strong>in</strong>dustry-produced)<br />
- Plasma fractionation rema<strong>in</strong>s a complex and costly process. <strong>The</strong>refore it <strong>in</strong>volves very<br />
specific imperatives for stakeholders, more prec<strong>is</strong>ely:<br />
• Facilitat<strong>in</strong>g plasma collection (br<strong>in</strong>g<strong>in</strong>g down actual or potential barriers to<br />
donation)<br />
• Handl<strong>in</strong>g plasma and plasma-derived products cautiously<br />
• D<strong>is</strong>tribut<strong>in</strong>g burdens and benefits fairly to all participants of the collection<br />
and supply cha<strong>in</strong><br />
• Needs of the population are not always easy to meet (self-sufficiency<br />
<strong>is</strong>sue).<br />
ETHICS OF THE PLASMA ORGANIZATION<br />
Ethical dimension can work both ways: as clearly expla<strong>in</strong>ed by Healy 8 , “Collection<br />
regimes do not simply <strong>in</strong>crease or decrease the donation rate along a slid<strong>in</strong>g scale. <strong>The</strong>y<br />
shape the k<strong>in</strong>d of activity that blood donation <strong>is</strong>. How you organize a blood supply<br />
system not only affects how much you collect and who you get it from, it shapes the<br />
character of donation”.
<strong>KCE</strong> Reports 120 Plasma 11<br />
<strong>The</strong>refore, it <strong>is</strong> of key importance to consider blood or plasma collection system not<br />
only from a technical po<strong>in</strong>t of view, but also from an ethical po<strong>in</strong>t of view, s<strong>in</strong>ce each<br />
option – whatever it <strong>is</strong>- <strong>is</strong> apt to have a major impact on the ethical dimension on<br />
donation and thus on donors’ behaviour and <strong>in</strong>directly on donors’ motivation as such.<br />
Given th<strong>is</strong> background, four options can theoretically be considered:<br />
• A purely market-driven system: not affordable so far given the<br />
<strong>in</strong>stitutional European context described above. Besides it would require<br />
the fitt<strong>in</strong>g <strong>in</strong>vestments.<br />
• A solidarity-driven system: requires a strong social bond and can be easily<br />
implemented <strong>in</strong> smaller communities. In fact only strongly bound<br />
communities whose members identify themselves <strong>with</strong> the same core<br />
values can perform such a system and rely on it..<br />
• A purely-voluntary system: “gift-fet<strong>is</strong>h<strong>is</strong>m”. However such a system does<br />
not seem to be reliable, as a matter of pr<strong>in</strong>ciple.<br />
Us<strong>in</strong>g <strong>in</strong>centives but reta<strong>in</strong><strong>in</strong>g the “gift-like” features of the donation: the latter option<br />
money as such <strong>is</strong> not an <strong>in</strong>centive, but th<strong>is</strong> does not exclude f<strong>in</strong>ancial compensation. <strong>The</strong><br />
latter option which <strong>is</strong> used <strong>in</strong> Austria or Germany for plasma donation ra<strong>is</strong>es specific<br />
problems as they can be seen as “borderl<strong>in</strong>e systems” from a purely ethical po<strong>in</strong>t of<br />
view. Clear-cut d<strong>is</strong>t<strong>in</strong>ction between of <strong>in</strong>centive Vs remuneration <strong>is</strong> not always easy to<br />
make.<br />
<strong>The</strong> pr<strong>in</strong>ciple of voluntary unpaid donation<br />
Over the last decades, all the key <strong>in</strong>stitutions <strong>in</strong>volved <strong>in</strong> blood and plasma donation<br />
have reasserted that profit as such must not be a motive for donation. Step by step, the<br />
pr<strong>in</strong>ciple of unpaid donation has been ethical standard for the countries of the European<br />
Union. Th<strong>is</strong> pr<strong>in</strong>ciple <strong>is</strong> officially mentioned by foremost <strong>in</strong>ternational <strong>in</strong>stitutions, and<br />
thus accepted by Member States of these <strong>in</strong>stitutions:<br />
• International Red Cross and Red Crescent Societies / Core resolutions<br />
and guidel<strong>in</strong>es on voluntary non remunerated blood donation: “F<strong>in</strong>ancial<br />
profit must never be a motive for the donors or those responsible for<br />
collect<strong>in</strong>g the donation. Voluntary, non remunerated donors should<br />
always be encouraged”<br />
• Council of Europe / Art 2 of the European Conference N. R (95) 14:<br />
“Donation <strong>is</strong> considered as voluntary and non remunerated” (even if small<br />
tokens, refreshments, and reimbursement of travel costs are compatible<br />
<strong>with</strong> voluntary non remunerated donation).<br />
• World Health Organization: “Safe blood donors are the cornerstone of<br />
safe and adequate supply of blood and blood products. <strong>The</strong> safest blood<br />
donors are voluntary non remunerated blood donors from low-r<strong>is</strong>k<br />
populations”.<br />
• Charter of Fundamental Rights of the European Union (Art 3): <strong>The</strong> right<br />
to the <strong>in</strong>tegrity of the person <strong>in</strong>volves “<strong>The</strong> prohibition on mak<strong>in</strong>g the<br />
human body and its parts as such a source of f<strong>in</strong>ancial ga<strong>in</strong>”.<br />
• Eventually, EU Directive 2002/98 Art 20 (opposable to all EU Member<br />
States) officially states that “Voluntary and unpaid blood donation are a<br />
factor which can contribute to high safety standards for blood and blood<br />
components and therefore to the protection of human health”.<br />
What emerges from all these statements <strong>is</strong> that blood and blood components are a<br />
subject of great ethical importance for the <strong>in</strong>ternational and EU level. From an ethical<br />
po<strong>in</strong>t of view, the pr<strong>in</strong>ciple of voluntary unpaid donation <strong>is</strong> now accepted as the<br />
cornerstone of the donation policy <strong>in</strong> all EU countries. Th<strong>is</strong> <strong>is</strong> a key difference <strong>with</strong><br />
other countries –especially the United States- where blood and plasma donation can be<br />
remunerated (even if it <strong>is</strong> not always remunerated).
12 Plasma <strong>KCE</strong> Reports 120<br />
<strong>The</strong> pr<strong>in</strong>ciple of unpaid donation <strong>is</strong> of key importance for the practical and technical<br />
organization of blood donation, as the ma<strong>in</strong> po<strong>in</strong>ts of the EU ethical and regulatory<br />
framework should rema<strong>in</strong> stable over the next years.<br />
Key po<strong>in</strong>ts<br />
• Pr<strong>in</strong>ciples underp<strong>in</strong>n<strong>in</strong>g blood and plasma donation are specific to th<strong>is</strong> k<strong>in</strong>d<br />
of donation. Mak<strong>in</strong>g the best use of donated blood or plasma can be seen as<br />
an ethical duty.<br />
• Ethical donation <strong>is</strong> not contradictory <strong>with</strong> a concept of compensation or<br />
other <strong>in</strong>centives, <strong>with</strong><strong>in</strong> strict limits.<br />
• It must be borne <strong>in</strong> m<strong>in</strong>d that <strong>in</strong> countries were compensation <strong>is</strong> applied,<br />
plasma donors are generally younger, more educated, and less <strong>in</strong>volved <strong>in</strong><br />
professional life than whole blood donors. Conversely, <strong>in</strong> countries where no<br />
f<strong>in</strong>ancial compensation <strong>is</strong> provided no clear d<strong>is</strong>t<strong>in</strong>ction, <strong>in</strong> terms of donors’<br />
profile, has been identified so far.<br />
2.1.2 Plasma collection <strong>in</strong> Belgium<br />
2.1.2.1 Current legal framework<br />
In Belgium, as <strong>in</strong> any country, blood and plasma donation can be considered as an<br />
<strong>in</strong>dividual gift or a good deed, based on personal motives and/or beliefs (altru<strong>is</strong>m or any<br />
philosophical or religious belief) but also as a collective commitment, especially <strong>in</strong> a<br />
professional context.<br />
For th<strong>is</strong> reason, mak<strong>in</strong>g public <strong>in</strong>stitutions and private firms (SMEs or bigger firms)<br />
aware of th<strong>is</strong> problem and mobiliz<strong>in</strong>g their employees for blood donation has been one<br />
of the most important m<strong>is</strong>sions of the Red Cross over the last decades.<br />
However, the situation of the employees <strong>is</strong> utterly different, whether they work <strong>in</strong> a<br />
private or a public context.<br />
Private Law Contracts<br />
<strong>The</strong> Belgian Private Work Contract Act (3 rd July 1978) sets out all the key rules<br />
concern<strong>in</strong>g the rights and duties of employers and employees. Th<strong>is</strong> Act addresses the<br />
different types of contract (worker’s contract, employee’s contract, sales<br />
representative, etc…) and covers the whole range of traditional work law <strong>is</strong>sues.<br />
However, it rema<strong>in</strong>s silent about possible leave or days off for blood or plasma<br />
donation. Legally speak<strong>in</strong>g, specific prov<strong>is</strong>ions, measures or arrangements can be set out<br />
only <strong>in</strong> the policies and procedures of each firm, but actual implementation of these<br />
measures (or arrangements) <strong>is</strong> left to the employer’s d<strong>is</strong>cretion.<br />
<strong>The</strong> employees are generally allowed, <strong>in</strong> th<strong>is</strong> exceptional case, to leave the office just for<br />
the time spent for donation, (generally between 1 and 2 hours) but may be requested to<br />
make up for the “time lost” (“lost” from the employer’s po<strong>in</strong>t of view).<br />
In practice, blood or plasma collection <strong>is</strong> often performed by the Red Cross’s teams<br />
dur<strong>in</strong>g or around a lunch pause, and employees hardly ever benefit from specific leave<br />
for donation.<br />
Public Law Contracts<br />
Virtually all the Belgian public law <strong>in</strong>stitutions have set out specific prov<strong>is</strong>ions, measures<br />
or arrangements <strong>in</strong> the employee’s contracts to enable them to benefit from specific<br />
leave or days off for “philanthropic purposes” which covers, <strong>in</strong>ter allia, blood and<br />
plasma donation (as well as bone marrow and t<strong>is</strong>sue donation). However, regulatory<br />
rules vary widely across <strong>in</strong>stitutions and regions, as described below:
<strong>KCE</strong> Reports 120 Plasma 13<br />
FRENCH-SPEAKING INSTITUTIONS<br />
First Example – Wallonian Civil Servants [18 DECEMBER 2003 - Arrêté du<br />
Gouvernement wallon portant le Code de la fonction publique wallonne (Art 383)].<br />
1. On the day of donation, one day off (blood donation) or one half day (plasma<br />
donation) <strong>is</strong> awarded to the employee.<br />
2. One additional day (blood donation) or one-half additional day (plasma or<br />
platelet donation) <strong>is</strong> also awarded to the employee, whenever donation <strong>is</strong><br />
performed dur<strong>in</strong>g office hours and when the day after donation <strong>is</strong> a work day.<br />
Second example – French-Speak<strong>in</strong>g Community / Semi-public Institution [5 DECEMBER<br />
2008 - Arrêté du Gouvernement de la Communauté frança<strong>is</strong>e fixant le statut<br />
adm<strong>in</strong><strong>is</strong>tratif et pécuniaire du personnel de Wallonie-Bruxelles International (Art 316)].<br />
1. On the day of donation, one day off (blood donation) or one half day (plasma<br />
donation) <strong>is</strong> awarded to the employee.<br />
2. One additional day (blood donation) or one half additional day (plasma or<br />
platelet donation) <strong>is</strong> also awarded to the employee, whenever donation <strong>is</strong><br />
performed dur<strong>in</strong>g office hours and when the day after donation <strong>is</strong> a work day.<br />
Third example – French-Speak<strong>in</strong>g Community / Governmental and Audiov<strong>is</strong>ual<br />
Institutions [2 JUNE 2004. - Arrêté du Gouvernement de la Communauté frança<strong>is</strong>e<br />
relatif aux congés et aux absences des agents des Services du Gouvernement de la<br />
Communauté frança<strong>is</strong>e, du Conseil supérieur de l'Audiov<strong>is</strong>uel et des organ<strong>is</strong>mes<br />
d'<strong>in</strong>térêt public relevant du Comité de Secteur XVII (Art.42)].<br />
On the day of donation, one day off for blood or plasma donation <strong>is</strong> awarded to the<br />
employee. If the donation takes place dur<strong>in</strong>g off-duty hours (i.e. between the end of<br />
workday and midnight) the day off <strong>is</strong> awarded on the day follow<strong>in</strong>g donation.<br />
DUTCH SPEAKING INSTITUTIONS<br />
Flem<strong>is</strong>h Region [13 JANUARY 2006. - Arrêté du Gouvernement flamand fixant le statut<br />
du personnel des services des autorités flamandes (Art 79)].<br />
Employees can be awarded a one day leave for blood, plasma or platelet donation,<br />
(<strong>with</strong><strong>in</strong> the limit of 1 day per month).<br />
FEDERAL LEVEL<br />
Federal level: “Day-Off or leave for philanthropic purposes” [9 December 1999. –<br />
Circulaire n° 487 relative à l'octroi d'une d<strong>is</strong>pense de service pour le don de sang, de<br />
plaquettes et de plasma sangu<strong>in</strong> (Art.42)].<br />
As a general rule, one day off for blood, platelet or plasma donation <strong>is</strong> awarded to the<br />
employee (Maximum: 4 days yearly). As far as plasma donation <strong>is</strong> concerned, employees<br />
are allowed to start the work day 1h54 later or to leave the office 1h54 sooner than<br />
usual.<br />
Key po<strong>in</strong>ts<br />
• From a purely legal po<strong>in</strong>t of view, there are no specific <strong>in</strong>centives to get<br />
private firms’ employees <strong>in</strong>volved <strong>in</strong>to donation<br />
• Conversely, regulatory framework <strong>is</strong> more favourable to public law<br />
employees, but rewards are utterly status-dependant.
14 Plasma <strong>KCE</strong> Reports 120<br />
2.1.2.2 Collected Quantities<br />
N<strong>in</strong>ety six percent of the blood and plasma donations <strong>in</strong> Belgium are collected by the<br />
Red Cross, which has been placed under the responsibility of the Belgian Red Cross<br />
s<strong>in</strong>ce its <strong>in</strong>ception <strong>in</strong> 1935. Four non Red Cross blood centres, at Charleroi Hospital<br />
and UCL Hospital Mont-God<strong>in</strong>ne, AZ S<strong>in</strong>t-Jan Brugge and the Service militaire du sang<br />
account for the rema<strong>in</strong><strong>in</strong>g blood collections. All donations are made by voluntary noncompensated<br />
donors, although some donors (from public sector) may receive time off<br />
work <strong>in</strong> addition to the time for donation. Although the Red Cross collects donations<br />
by plasmapheres<strong>is</strong> (source plasma), the bigger part of plasma <strong>in</strong>tended for fractionation<br />
<strong>is</strong> recovered plasma (from whole blood donations). Th<strong>is</strong> <strong>report</strong> focuses solely on the<br />
two organizations which form the “transfusion service”: <strong>The</strong> SFS = le Service<br />
Francophone du Sang and the VDB = De Vlaamse Dienst voor het Bloed.<br />
Table 1 and figure 1 show the trend <strong>in</strong> donations of whole blood and plasmapheres<strong>is</strong><br />
from 2000 to 2008. We note that the overall number of donations of whole blood <strong>is</strong><br />
very stable between the start and end of the period under review. However, th<strong>is</strong><br />
stability between these two dates (2000 and 2008) obscures the fall at the start of the<br />
period (from 513 762 donations <strong>in</strong> 2000 to 503 247 <strong>in</strong> 2003 and the strong growth (+<br />
4.7%) <strong>in</strong> 2004. S<strong>in</strong>ce then, the number of donations fell aga<strong>in</strong> before recover<strong>in</strong>g <strong>in</strong> 2008.<br />
Compar<strong>in</strong>g the trend <strong>in</strong> the French-speak<strong>in</strong>g section of the Red Cross (SFS) <strong>with</strong> that of<br />
the <strong>Dutch</strong>-speak<strong>in</strong>g section (VDB), we f<strong>in</strong>d a contrast<strong>in</strong>g situation result<strong>in</strong>g <strong>in</strong> stability<br />
from a reduction of more than 11 000 units for the VDB offset by a r<strong>is</strong>e of almost<br />
11 000 units for the SFS, which <strong>is</strong> partially artificial as it follows the <strong>in</strong>tegration of two<br />
<strong>in</strong>dependent centres by the SFS (the transfusion centre <strong>in</strong> Brussels <strong>in</strong> 2003 and the<br />
Hust<strong>in</strong> centre <strong>in</strong> 2004) <strong>in</strong> the SFS activities. As for the number of plasmapheres<strong>is</strong><br />
donations, the trend <strong>is</strong> clearly downwards, -56% for the VDB and -63% for the SFS over<br />
the period <strong>in</strong> question as a whole. It seems that the drop <strong>in</strong> the number of donations of<br />
source plasma <strong>is</strong> l<strong>in</strong>ked to the closure of plasmapheres<strong>is</strong> centres. Globally, the number<br />
of donors <strong>is</strong> quite stable dur<strong>in</strong>g the last three years (+ 2%), result<strong>in</strong>g from a comb<strong>in</strong>ation<br />
of a decreas<strong>in</strong>g for the VDB (-1.5%) and a substantial <strong>in</strong>creas<strong>in</strong>g for the SFS (+9%).<br />
Table 1: Number of donations collected by SFS and VDB and number of<br />
donors<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
Number of donations whole<br />
blood SFS 162.101 155.083 151.835 159.083 173.602 167.902 161.499 162.474 173.083<br />
Number of donations whole<br />
blood VDB 351.661 346.036 344.370 344.145 353.337 353.017 349.483 337.246 340.237<br />
Total number of donations<br />
whole blood 513.762 501.119 496.205 503.228 526.939 520.919 510.982 499.720 513.320<br />
Number of donations<br />
plasmapheres<strong>is</strong> SFS 44.569 44.515 37.791 36.106 34.691 20.538 17.013 17.021 16.315<br />
Number of donations<br />
plasmapheres<strong>is</strong> VDB 122.518 120.653 128.727 118.700 115.898 100.654 72.167 60.962 53.568<br />
Total number of donations<br />
plasmapheres<strong>is</strong> 167.087 165.168 166.518 154.806 150.589 121.192 89.180 77.983 69.883<br />
Number of donations<br />
cytapheres<strong>is</strong> SFS 10.776 10.155 9.994 9.995 12.066 11.921 10.293 8.861 8.582<br />
Number of donations<br />
cytapheres<strong>is</strong> VDB 7.768 8.623 8.884 7.403 13.662 13.489 12.512 13.107 13.164<br />
Total number of donations<br />
cytapheres<strong>is</strong> 18.544 18.778 18.878 17.398 25.728 25.410 22.805 21.968 21.746<br />
Number of donors whole blood<br />
SFS 91.422 91.009 98.953 89.767 85.654 82.972 80.628 82.353 87.875<br />
Number of donors whole blood<br />
VDB 160.048 158.901 156.684 155.992 155.881 153.508 156.810 150.187 154.426<br />
Total number of donors whole<br />
blood 251.470 249.910 255.637 245.759 241.535 236.480 237.438 232.540 242.301<br />
Source : SFS & VDB
<strong>KCE</strong> Reports 120 Plasma 15<br />
Number of donations<br />
Figure 1: Number of donations collected by SFS and VDB<br />
600.000<br />
500.000<br />
400.000<br />
300.000<br />
200.000<br />
100.000<br />
0<br />
Source : SFS & VDB<br />
513.762 513.317<br />
167.087<br />
69.883<br />
Whole blood VDB<br />
Plasmapheres<strong>is</strong> VDB<br />
Whole blood SFS<br />
Plasmapheres<strong>is</strong> SFS<br />
Total Blood<br />
Total plasmapheres<strong>is</strong><br />
In the follow<strong>in</strong>g table we present the evolution of the volume of plasma collected by the<br />
SFS and the VDB dur<strong>in</strong>g the period 2000-2008. <strong>The</strong> plasma from whole blood <strong>is</strong><br />
decreas<strong>in</strong>g <strong>in</strong> volume <strong>with</strong> 14.5% and the plasma from plasmapheres<strong>is</strong> <strong>is</strong> decreas<strong>in</strong>g <strong>in</strong><br />
volume <strong>with</strong> 41.4%. Globally, the total volume of plasma decreases <strong>with</strong> 24.6%<br />
Table 2: Volume of plasma <strong>in</strong> litres collected by SFS and VDB<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
Volume of plasma from whole blood<br />
SFS 36.148 38.643 35.304 39.529 36.762 35.350 34.565 35.461 37.164<br />
Volume of plasma from whole blood<br />
VDB 89.326 86.014 88.061 84.639 79.393 73.340 70.526 70.533 70.139<br />
Volume of plasma from whole blood<br />
SFS + VDB 125.474 124.657 123.365 124.168 116.155 108.690 105.091 105.994 107.303<br />
Volume of plasma from<br />
plasmapheres<strong>is</strong> & cytapheres<strong>is</strong> SFS 16.662 18.428 17.339 14.932 23.814 17.825 13.642 13.499 13.255<br />
Volume of plasma from<br />
plasmapheres<strong>is</strong> & cytapheres<strong>is</strong> VDB 60.390 59.380 57.526 52.983 70.362 60.243 43.583 36.626 32.069<br />
Volume of plasma from plasmapheres.<br />
& cytapheres. SFS + VDB 77.052 77.808 74.865 67.915 94.176 78.068 57.225 50.125 45.324<br />
Total volume of plasma collected by<br />
SFS + VDB 202.526 202.465 198.230 192.083 210.331 186.758 162.316 156.119 152.627<br />
Source : SFS & VDB<br />
It seems that the collection of plasma <strong>is</strong> a quite flexible activity. Indeed <strong>in</strong> 2004-2005,<br />
the demand has <strong>in</strong>creased and SFS and VDB have collected more plasma from<br />
plasmapheres<strong>is</strong> to meet the <strong>in</strong>creased demand.
16 Plasma <strong>KCE</strong> Reports 120<br />
Table 3: Rate of evolution of the volume of plasma dur<strong>in</strong>g the period 2000 -<br />
2008<br />
2000 ‐ 2008<br />
Volume of plasma from whole blood SFS 2,8%<br />
Volume of plasma from whole blood VDB -21,5%<br />
Volume of plasma from whole blood SFS + VDB -14,5%<br />
Volume of plasma from plasmapheres<strong>is</strong> SFS -20,4%<br />
Volume of plasma from plasmapheres<strong>is</strong> VDB -46,9%<br />
Volume of plasma from plasmapheres<strong>is</strong> SFS + VDB -41,2%<br />
Total volume of plasma collected by SFS + VDB -24,6%<br />
Source : SFS & VDB<br />
We have calculated the average volume of donation of plasma for the recovered plasma<br />
(RP) and the source plasma (SP). <strong>The</strong> first one shows a relatively constant trend,<br />
around 0.210 ml per donation for the SFS. Th<strong>is</strong> volume has lightly decreased for VDB<br />
(0.254 <strong>in</strong> 2000 and 0.206 <strong>in</strong> 2008). <strong>The</strong> average volume of plasma from plasmapheres<strong>is</strong><br />
has strongly <strong>in</strong>creased s<strong>in</strong>ce 2004 for the two sections of the Red Cross.<br />
We also noticed that the average number of donations of whole blood per donor <strong>is</strong><br />
stable (Table 4), for the VDB and the SFS, dur<strong>in</strong>g the 2003-2008 period (around 2.2)<br />
(<strong>The</strong> average number of donations was obta<strong>in</strong>ed by divid<strong>in</strong>g the number of donations by<br />
the number of donors). Nevertheless, the evolution <strong>is</strong> different concern<strong>in</strong>g the average<br />
number of plasmapheres<strong>is</strong> donations. Whereas th<strong>is</strong> number rema<strong>in</strong>ed stable for the SFS<br />
(5.7), it decreased for the VDB (7.0 <strong>in</strong> 2003 and 4.5 <strong>in</strong> 2008).<br />
<strong>The</strong> figures presented do not make differences between the volume of plasma collected<br />
from plasmapheres<strong>is</strong> and the volume of plasma collected from cytapheres<strong>is</strong>. <strong>The</strong>se two<br />
k<strong>in</strong>ds of plasma are considered as source plasma and are sold to the CAF – DCF.<br />
F<strong>in</strong>ally, we present the average volume of plasma per donation for the RP and the SP.<br />
For the VDB, we received directly these average volumes per year. For the SFS, we<br />
have calculated the average by subtract<strong>in</strong>g the assumed volume of plasma collected by<br />
cytapheres<strong>is</strong> (hypothes<strong>is</strong> of 200 ml per donation) of the total volume of source plasma<br />
collected. <strong>The</strong> results are quite similar to those of the VDB. <strong>The</strong> <strong>in</strong>crease <strong>in</strong> the<br />
average volume s<strong>in</strong>ce 2004 <strong>is</strong> noticeable for the two sections of the Red Cross.<br />
It seems that the substantial <strong>in</strong>crease of SP collection <strong>in</strong> 2004 <strong>is</strong> the result of at least<br />
two factors:<br />
• A switch of practices concern<strong>in</strong>g the ‘therapeutic plasma’<br />
• A response to a <strong>in</strong>crease of the <strong>in</strong>ternational demand by a <strong>in</strong>crease of the<br />
average volume per donation<br />
Until 2004, the plasma used by hospitals for therapeutic purposes (used <strong>in</strong> the<br />
treatment of some bleed<strong>in</strong>gs) stemmed from plasmapheres<strong>is</strong> plasma, which was<br />
delivered by the Red Cross. From 2004 onwards, the Red Cross was authorized to<br />
manufacture th<strong>is</strong> therapeutic plasma, straight from its own whole blood. As a result of<br />
th<strong>is</strong> regulatory change:<br />
• <strong>The</strong> correspond<strong>in</strong>g volume of whole blood was tapped by the Red Cross<br />
(from the ex<strong>is</strong>t<strong>in</strong>g collected volume), <strong>in</strong> order to manufacture th<strong>is</strong><br />
therapeutic plasma.<br />
• Likew<strong>is</strong>e, the volume of plasmapheres<strong>is</strong> plasma, which was formerly<br />
delivered to hospitals for therapeutic purposes, was then transferred to<br />
the CAF-DCF.<br />
Th<strong>is</strong> switch <strong>in</strong> practices <strong>is</strong> probably one of the factors expla<strong>in</strong><strong>in</strong>g the sudden r<strong>is</strong>e <strong>in</strong> the<br />
volume of plasmapheres<strong>is</strong> plasma delivered to the CAF-DCF, and simultaneously the<br />
sudden decrease <strong>in</strong> the volume of whole blood plasma delivered to the CAF-DCF <strong>in</strong> the<br />
year 2004. An other factor <strong>is</strong> the change <strong>in</strong> global demand, as shown for the 2004-2005<br />
<strong>in</strong>crease (Table 2).
<strong>KCE</strong> Reports 120 Plasma 17<br />
Table 4: Average volume of plasma per donation and average number of<br />
donations per donor<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
Average number of donations per donor of<br />
whole blood (SFS) 1,77 1,70 1,53 1,77 2,03 2,02 2,00 1,97 1,97<br />
Average number of donations per donor of<br />
whole blood (VDB) 2,20 2,18 2,20 2,21 2,27 2,30 2,23 2,25 2,20<br />
Average number of donations per donor of<br />
plasmapherese (SFS) 6,08 4,73 5,71 5,65 5,73<br />
Average number of donations per donor of<br />
plasmapherese (VDB) 7,00 6,28 6,33 6,50 6,40 6,29 5,51 5,36 4,51<br />
Average volume (ml) of plasma per donation of<br />
whole blood (SFS) 0,223 0,249 0,233 0,248 0,212 0,211 0,214 0,218 0,215<br />
Average volume (ml) of plasma per donation of<br />
whole blood (VDB) 0,254 0,249 0,256 0,246 0,225 0,208 0,202 0,209 0,206<br />
Average volume (ml) of plasma per donation of<br />
plasmapherese (SFS) 0,325 0,368 0,406 0,358 0,617 0,752 0,681 0,689 0,707<br />
Average volume (ml) of plasma per donation of<br />
plasmapherese (VDB) 0,493 0,492 0,447 0,446 0,607 0,599 0,604 0,601 0,599<br />
Source : SFS & VDB<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> Red Cross collects 96% of all blood and plasma <strong>in</strong> Belgium<br />
• <strong>The</strong> number of donors of whole blood <strong>is</strong> relatively stable for the <strong>Dutch</strong>speak<strong>in</strong>g<br />
community and slightly up <strong>in</strong> the French-speak<strong>in</strong>g community<br />
• <strong>The</strong> fall <strong>in</strong> the number of donations collected ma<strong>in</strong>ly affects source plasma (-<br />
58% between 2000 and 2008)<br />
• In 2008, the number of donations of whole blood showed a slight upturn for<br />
the <strong>Dutch</strong>-speak<strong>in</strong>g community and confirmation of the r<strong>is</strong>e <strong>in</strong> the Frenchspeak<strong>in</strong>g<br />
community<br />
• <strong>The</strong> total volume of plasma has strongly decreased between 2000 and 2008,<br />
by - 24 % (- 14 % for RP and - 41 % for SP)<br />
• If the number of donation of plasmapheres<strong>is</strong> per donor has decreased s<strong>in</strong>ce<br />
2000, the volume per donation has strongly <strong>in</strong>creased s<strong>in</strong>ce 2004<br />
2.1.2.3 <strong>The</strong> price of plasma<br />
<strong>The</strong> plasma (from plasmapheres<strong>is</strong>, cytapheres<strong>is</strong> (SP) and whole blood (RP)) <strong>is</strong> sold by<br />
the Red Cross to a fractionation company – the CAF-DCF (Centrale Afdel<strong>in</strong>g voor<br />
Fractioner<strong>in</strong>g - Département Central de Fractionnement) – at a mutually agreed price<br />
and quantity each year. Th<strong>is</strong> agreement, dat<strong>in</strong>g back to 26 February 1998, also sets out<br />
the technical criteria for delivery a . <strong>The</strong> price of the RP purchased by the CAF – DCF<br />
has rema<strong>in</strong>ed unchanged s<strong>in</strong>ce 1998 (53.30 euros). In 1998, the CAF – DCF was<br />
granted a price cut for the purchase of SP s<strong>in</strong>ce 1998 (53.3 euros <strong>in</strong> place of 78.09<br />
euros), <strong>in</strong> order to protect its competitiveness on the <strong>in</strong>ternational market and to<br />
ensure the fund<strong>in</strong>g of the technological progress of its activities. In 2003, the price was<br />
<strong>in</strong>creased.<br />
a In compliance <strong>with</strong> the 5 July 1994 Law , it <strong>is</strong> a matter of confirm<strong>in</strong>g that plasma must stem, as a matter<br />
of pr<strong>in</strong>ciple, from voluntary and non remunerated donors
18 Plasma <strong>KCE</strong> Reports 120<br />
Year<br />
Table 5 shows the trend <strong>in</strong> the price of RP and SP from 1997 to 2007 <strong>with</strong> which we<br />
compare the trend <strong>in</strong> <strong>in</strong>ternational prices found <strong>in</strong> an unpubl<strong>is</strong>hed PPTA document.<br />
Over the years for which data are <strong>available</strong> (2002, 2003, 2004 and 2006, 2007), it<br />
appears that the price of RP sold by the Red Cross to the CAF-DCF (53.07 euros)<br />
represents a very competitive price compared <strong>with</strong> the prices be<strong>in</strong>g paid on the<br />
<strong>in</strong>ternational market. As a corollary, th<strong>is</strong> price represents a loss of potential revenue<br />
for the Red Cross. For SP, the situation prior to 2003 (given the <strong>in</strong>ternational price <strong>in</strong><br />
2002) cannot have been profitable for the Red Cross. After the r<strong>is</strong>e <strong>in</strong> price <strong>in</strong> 2003,<br />
from 53.30 to 78.09, the situation has improved: the amount received by the RC (price<br />
+ subsidy, see next section) <strong>is</strong> systematically higher than the <strong>in</strong>ternational price,<br />
accord<strong>in</strong>g to the sources of Table 5.<br />
In view of the small difference between the <strong>in</strong>ternational price and the amount received<br />
by the Red Cross (price + subsidy), it <strong>is</strong> vital to confirm th<strong>is</strong> analys<strong>is</strong> by compar<strong>in</strong>g it<br />
<strong>with</strong> other sources of <strong>in</strong>ternational prices. In Table 6, we show an average price of<br />
source plasma amounts to 106 euros.<br />
As highlighted by Verhaegen, 9 the r<strong>is</strong>e <strong>in</strong> price agreed <strong>in</strong> 2003 should correspond to reestabl<strong>is</strong>h<strong>in</strong>g<br />
of the competitive position of the CAF-DCF, which had completed its<br />
<strong>in</strong>vestment <strong>in</strong> build<strong>in</strong>gs (construction on the site at Neder-Over-Heembeeck).<br />
However, reta<strong>in</strong><strong>in</strong>g the subsidy for the Red Cross was <strong>with</strong>out doubts l<strong>in</strong>ked to the<br />
<strong>in</strong>adequate price paid by the CAF-DCF to cover the cost of plasma collection. <strong>The</strong><br />
validity of the above results depends critically on <strong>in</strong>ternational prices. Dur<strong>in</strong>g a meet<strong>in</strong>g<br />
of external experts, we obta<strong>in</strong>ed different <strong>in</strong>formation that <strong>in</strong>ternational prices were<br />
around 75 euros for RP and 90 euros for SP, <strong>in</strong>clud<strong>in</strong>g the price of the NAT test (see<br />
below). Other sources 10 appear to confirm that the price paid by the CAF-DCF for<br />
whole blood plasma <strong>is</strong> well below the <strong>in</strong>ternational price and that the average price that<br />
the Red Cross could obta<strong>in</strong> for plasma from plasmapheres<strong>is</strong> <strong>is</strong> slightly higher than the<br />
price it currently receives, <strong>in</strong>clud<strong>in</strong>g the subsidy (Table 6).<br />
Table 5: Plasma prices from 1998 to 2007<br />
Price of recovered plasma Price of source plasma<br />
paid by<br />
CAF<br />
received by<br />
Red Cross<br />
International<br />
price (PPTA)<br />
paid by<br />
CAF<br />
received by<br />
Red Cross<br />
International<br />
price (PPTA)<br />
1997 53.30 53.30 78.09 78.09<br />
1998 53.30 53.30 53.30 78.09<br />
1999 53.30 53.30 53.30 78.09<br />
2000 53.30 53.30 53.30 78.09<br />
2001 53.30 53.30 53.30 78.09<br />
2002 53.30 53.30 90.78 53.30 78.09 100.00<br />
2003 53.30 53.30 70.04 78.09 102.88 100.00<br />
2004 53.30 53.30 65.20 78.09 102.88 85.88<br />
2005 53.30 53.30 78.09 102.88 79.00<br />
2006 53.30 53.30 81.01 78.09 102.88 87.51<br />
2007 53.30 53.30 60.65 78.09 102.88 98.55<br />
1 Source: International Blood/Plasma News; June 2002<br />
2 Source: International Blood/Plasma News; June 2003 – conversion: www.oanda.com<br />
3 Source: International Blood/Plasma News; January 2004 – US-based suppliers, NOT Polymerase<br />
Cha<strong>in</strong> Reaction (PCR) tested<br />
4 Source: International Blood/Plasma News; April 2005 – not Nucleic Acid Test (NAT)<br />
5 Source: International Blood/Plasma News; March 2006<br />
6 Source: International Blood/Plasma News; January 2007 – NAT tested
<strong>KCE</strong> Reports 120 Plasma 19<br />
Table 6: Price of plasma from whole blood and from plasmapheres<strong>is</strong> <strong>in</strong> 2009<br />
(prices <strong>in</strong> euro us<strong>in</strong>g a conversion rate of 1 euro = 1.4 USD)<br />
Type of plasma and country Average price Lower end Upper end<br />
Whole blood USA frozen <strong>with</strong><strong>in</strong> 120h<br />
(the most usual)<br />
79 € 75 € 82 €<br />
Whole blood USA frozen <strong>with</strong><strong>in</strong> 24h 86 € 82 € 89 €<br />
Whole blood only Germany 8h and<br />
Austria<br />
Significant variations<br />
depend<strong>in</strong>g on suppliers<br />
95 € 110 €<br />
Plasmapheres<strong>is</strong> USA 106 € 100 € 114 €<br />
Plasmapheres<strong>is</strong> Germany (comparable<br />
figures)<br />
(Source: 10)<br />
Key Po<strong>in</strong>ts<br />
106 € 100 € 114 €<br />
• <strong>The</strong> Red Cross sells the collected source plasma to the CAF – DCF at a price<br />
determ<strong>in</strong>ed <strong>in</strong> a contract between the two <strong>in</strong>stitutions<br />
• We cannot determ<strong>in</strong>e if the price received <strong>is</strong> higher or lower than the price<br />
determ<strong>in</strong>ed by the demand and supply of plasma on the <strong>in</strong>ternational<br />
market<br />
2.1.2.4 Subsidy for source plasma<br />
S<strong>in</strong>ce 1998, the Red Cross receives a subsidy of 24.79 euros per litre of source plasma<br />
(from plasmapheras<strong>is</strong> and cytapheras<strong>is</strong>) sold to the CAF-DCF. <strong>The</strong> subsidy <strong>is</strong> f<strong>in</strong>anced<br />
by a supplement of 0.10% paid on compulsory car <strong>in</strong>surance premiums.<br />
<strong>The</strong>se prov<strong>is</strong>ions therefore make a sometimes considerable d<strong>is</strong>t<strong>in</strong>ction between the<br />
price on the Belgian market and the price on the <strong>in</strong>ternational market. As showed <strong>in</strong><br />
table 5, the Red Cross receives a fixed subsidy per liter of source plasma<br />
(plasmapheres<strong>is</strong> and cytapheras<strong>is</strong> plasma) sold to the CAF-DCF. <strong>The</strong> received subsidy<br />
had to offset a reduction <strong>in</strong> the sale price of the same amount.<br />
Key po<strong>in</strong>ts<br />
• S<strong>in</strong>ce 1998, the CAF – DCF benefits from a reduction of the price of source<br />
plasma<br />
• To compensate th<strong>is</strong> reduction, the Red Cross receives a subsidy from the<br />
State<br />
2.1.2.5 Subsidy for NAT test<strong>in</strong>g<br />
<strong>The</strong> transfusion establ<strong>is</strong>hments receive a budget that covers the cost of nucleic acid<br />
tests (NAT) HIV1 and HCV test<strong>in</strong>g on whole blood donations. <strong>The</strong> budget takes the<br />
form of a prov<strong>is</strong>ion that <strong>is</strong> subsequently topped up or clawed back depend<strong>in</strong>g on the<br />
number of tests actually performed. <strong>The</strong>se budgets are determ<strong>in</strong>ed by Royal Decrees.<br />
<strong>The</strong> establ<strong>is</strong>hments concerned are the two sections of the Red Cross, the non-profit<br />
organ<strong>is</strong>ation ‘transfusion du sang’ <strong>in</strong> Charleroi, the non-profit organ<strong>is</strong>ation<br />
‘Etabl<strong>is</strong>sement de transfusion de Mont-God<strong>in</strong>ne’ and the AZ S<strong>in</strong>t-Jan <strong>in</strong> Bruges. <strong>The</strong><br />
f<strong>in</strong>al balance of the subsidy granted, to be received or reimbursed, <strong>is</strong> calculated on the<br />
total number of successful samples collected, effectively carried out and tested us<strong>in</strong>g the<br />
NAT tests for HIV1 and HCV.
20 Plasma <strong>KCE</strong> Reports 120<br />
Th<strong>is</strong> number of units collected and testes must be justified by the <strong>in</strong>voices relat<strong>in</strong>g to<br />
these tests and certified by an <strong>in</strong>ternal or external auditor. <strong>The</strong> def<strong>in</strong>itive balance of the<br />
<strong>in</strong>stitutions <strong>is</strong> calculated follow<strong>in</strong>g the subm<strong>is</strong>sion of the support<strong>in</strong>g documents, which<br />
are sent to the Federal Agency for Medic<strong>in</strong>es and Health Products. In 2007, a sum of<br />
14.00 EUR was paid for each test actually conducted. <strong>The</strong> Royal Decree states that the<br />
subsidies granted can under no circumstances exceed the real costs <strong>in</strong>curred.<br />
<strong>The</strong> remuneration procedure def<strong>in</strong>ed for the NAT test licence <strong>is</strong> as follows: systematic<br />
collection of royalties for the test manufacturer - reflect<strong>in</strong>g the number of usable<br />
results; for example if a s<strong>in</strong>gle test <strong>is</strong> used for 10 pouches of blood (pool test<strong>in</strong>g), the<br />
number of royalties will be equal to ten although only one test has been used if negative<br />
result). In addition, the subsidy depends on the number of units successfully collected<br />
and the number of tests certified <strong>in</strong> an <strong>in</strong>voice. As mentioned above, these are l<strong>in</strong>ked to<br />
the number of usable results and not necessarily to the number of units used as<br />
reagents. Th<strong>is</strong> means that if a pool<strong>in</strong>g process <strong>is</strong> used (which seems to be the case for<br />
the Red Cross), the amount of the subsidies may be d<strong>is</strong>sociated from the number of<br />
reagents purchased. For the Red Cross, the system of pool test<strong>in</strong>g may lead to a sav<strong>in</strong>g<br />
<strong>in</strong> manpower.<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> collectors of whole blood receive a specific subsidy for the NAT tests to<br />
detect HIV1 and HCV<br />
• <strong>The</strong> Red Cross uses a system of pool<strong>in</strong>g to carry out these tests, likely sav<strong>in</strong>g<br />
<strong>in</strong> manpower<br />
• <strong>The</strong> firm sell<strong>in</strong>g these tests receives royalties <strong>in</strong> function of the number of<br />
usable tests (not necessarily of the number of tests carried out)<br />
2.1.2.6 Cost of plasmapheres<strong>is</strong><br />
Year<br />
We found the costs associated <strong>with</strong> the collection of plasma from plasmaphaeres<strong>is</strong> <strong>in</strong> an<br />
<strong>in</strong>ternal SFS <strong>report</strong>. Unfortunately, we did not have the opportunity to consult the<br />
same <strong>report</strong>s for the VDB.<br />
Table 7: Costs SFS associated <strong>with</strong> the collection of 1 liter plasma from<br />
plasmapheres<strong>is</strong><br />
Donor<br />
manag<br />
Direct cost Organ<strong>is</strong>ation<br />
Total<br />
Total<br />
Collection Labo D<strong>is</strong>tribution<br />
costs<br />
direct<br />
1997 2.68 49.75 15.39 1.64 69.46 20.62 90.08<br />
1998 4.04 50.25 13.76 0.77 68.82 17.75 86.57<br />
1999 4.66 52.11 17.07 0.77 74.61 20.97 95.58<br />
2000 5.97 53.69 15.02 0.92 75.60 20.15 95.75<br />
2001 7.09 62.32 16.19 1.19 86.79 23.19 109.98<br />
2002 3.37 65.49 19.03 1.37 89.26 17.94 107.20<br />
2003 5.22 67.62 27.10 1.35 101.29 16.92 118.21<br />
2004 7.53 67.29 27.30 1.06 103.18 24.79 127.97<br />
2005 8.73 67.56 27.28 1.33 104.90 26.96 131.86<br />
2006 10.25 72.72 28.85 1.42 113.24 31.40 144.64<br />
2007 9.12 78.51 29.26 1.25 118.14 35.37 153.51<br />
(Source: SFS – <strong>in</strong>ternal <strong>report</strong>s)<br />
If we subtract the subsidies from the total costs, we can compare the SFS net cost to<br />
the price received.
<strong>KCE</strong> Reports 120 Plasma 21<br />
Table 8: Compar<strong>is</strong>on of total costs m<strong>in</strong>us subsidies <strong>with</strong> prices of plasma<br />
from plasmapheres<strong>is</strong><br />
Year Total costs Subsidies<br />
Total costs<br />
m<strong>in</strong>us subsidies<br />
Price received<br />
1997 90.08 0.00 90.08 78.09<br />
1998 86.57 24.79 61.78 78.09<br />
1999 95.58 24.79 70.79 78.09<br />
2000 95.75 24.79 70.96 78.09<br />
2001 109.98 24.79 85.19 78.09<br />
2002 107.20 24.79 82.41 78.09<br />
2003 118.21 24.79 93.42 102.88<br />
2004 127.97 25.19 102.78 102.88<br />
2005 131.86 28.17 103.69 102.88<br />
2006 144.64 30.35 114.29 102.88<br />
2007 153.51 33.01 120.50 102.88<br />
For the subsidies, we have taken the data from the <strong>in</strong>ternal <strong>report</strong>s of the SFS for the<br />
years 2004 to 2007. For the previous years, <strong>in</strong> the absence of such data <strong>in</strong> the abovementioned<br />
<strong>report</strong>s, we have used the official data, which fix the subsidy at 24.79 euros.<br />
<strong>The</strong> head<strong>in</strong>gs for costs specific to plasmapheres<strong>is</strong> (donor management, collection and<br />
laboratory) are constantly r<strong>is</strong><strong>in</strong>g. <strong>The</strong> organ<strong>is</strong>ation costs <strong>in</strong> 2007 constitute 23% of total<br />
costs; given that these costs are allocated to all organ<strong>is</strong>ation costs for ‘plasmapheres<strong>is</strong>’, a<br />
part of the negative result of the compar<strong>is</strong>on between costs and prices for th<strong>is</strong> activity<br />
may require d<strong>is</strong>cussion concern<strong>in</strong>g th<strong>is</strong> allocation. If a smaller part of the organ<strong>is</strong>ation<br />
costs was allocated to plasmapheres<strong>is</strong>, the total costs would be reduced accord<strong>in</strong>gly.<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> difference between the cost of a litre of plasma from plasmapheres<strong>is</strong><br />
and the price received for th<strong>is</strong> litre of plasma depends on the allocation of<br />
the structure costs on th<strong>is</strong> activity<br />
• We did not receive the cost structure used by the VDB
22 Plasma <strong>KCE</strong> Reports 120<br />
2.1.3 Plasma collection <strong>in</strong> other countries<br />
2.1.3.1 Plasma collection <strong>in</strong> Germany<br />
General Po<strong>in</strong>ts<br />
Blood and plasma donation are organized <strong>with</strong><strong>in</strong> a strict legal framework def<strong>in</strong>ed by law.<br />
<strong>The</strong> Transfusion Act (Transfusionsgesetz- TFG) 11 sets out the key pr<strong>in</strong>ciples and rules<br />
that blood donation must follow: donor selection, <strong>in</strong>formation, blood tests and blood<br />
quality control, f<strong>in</strong>ancial compensation, epidemiology data, data protection, follow-up of<br />
blood donations.<br />
Pr<strong>in</strong>ciple of unpaid donation and f<strong>in</strong>ancial compensation<br />
Concern<strong>in</strong>g f<strong>in</strong>ancial <strong>is</strong>sues, the key pr<strong>in</strong>ciple <strong>is</strong> that blood donation <strong>in</strong> general (full blood<br />
and/or plasma) must rema<strong>in</strong> unpaid. However, f<strong>in</strong>ancial compensation can be awarded<br />
to the donor (“may”, as it <strong>is</strong> not mandatory), provided it <strong>is</strong> directly and clearly<br />
connected <strong>with</strong> donation-related costs, <strong>in</strong> practice: travel costs, car park, and time spent<br />
for donation.<br />
<strong>The</strong> maximum amount of th<strong>is</strong> f<strong>in</strong>ancial compensation has been set out by the German<br />
leg<strong>is</strong>lation, ie 25€. However, as expla<strong>in</strong>ed further <strong>in</strong> th<strong>is</strong> <strong>report</strong>, each <strong>in</strong>stitution enjoys a<br />
complete freedom <strong>in</strong> th<strong>is</strong> field: whereas some do reward donors (eg: Private Plasma<br />
donation centres), some other do not (eg: German Red Cross Institutions). <strong>The</strong> amount<br />
of the compensation <strong>is</strong> left to each <strong>in</strong>stitution’s d<strong>is</strong>cretion, <strong>with</strong><strong>in</strong> the limit of 25€.<br />
Free Competition between <strong>in</strong>stitutions of blood and plasma donation<br />
Unlike <strong>in</strong> other countries, blood donation <strong>is</strong> not organized on a monopoly bas<strong>is</strong>. Public<br />
and private <strong>in</strong>stitutions are allowed to compete <strong>with</strong> each other, <strong>in</strong> the field of blood<br />
donation and plasma donation alike. Three <strong>in</strong>stitutions have emerged <strong>in</strong> the field of<br />
donation: University-hospitals, German Red Cross Institutions, and Private Donation<br />
Centres.<br />
However, it <strong>is</strong> also important to underl<strong>in</strong>e that these <strong>in</strong>stitutions, although compet<strong>in</strong>g<br />
<strong>with</strong> each other <strong>in</strong> day-to-day donation are required to cooperate <strong>with</strong> each other <strong>in</strong><br />
case of shortage (mutual delivery of blood, plasma, or blood and plasma products).<br />
Th<strong>is</strong> support service was already implemented on the field <strong>in</strong> 2007, when 300 000<br />
pockets of Red Cells Concentrate have been shipped by the Red Cross to the<br />
University-Hospital donation centres.<br />
In practice, as expla<strong>in</strong>ed further <strong>in</strong> th<strong>is</strong> <strong>report</strong>, plasma collection as such <strong>is</strong> largely<br />
performed by purely private or <strong>in</strong>dustry-driven <strong>in</strong>stitutions.<br />
Cl<strong>in</strong>ical Issues: German Guidel<strong>in</strong>es of 2005 on plasmapheres<strong>is</strong> and ongo<strong>in</strong>g studies<br />
(SIPLA Studies)<br />
Specific “Richtl<strong>in</strong>ien” (mandatory guidel<strong>in</strong>es) have been <strong>is</strong>sued, and titled: “Guidel<strong>in</strong>es<br />
for the Collection of blood and blood components and utilization of blood products<br />
(haemotherapy)” Establ<strong>is</strong>hed by the German Order of Doctors and agreed <strong>with</strong> the<br />
Paul-Ehrlich Institut, pursuant to the Transfusion Act 12 .<br />
<strong>The</strong>se guidel<strong>in</strong>es have been def<strong>in</strong>ed by the National Order of Doctors and the Paul<br />
Ehrlich Institut. However, <strong>in</strong> today’s form, these guidel<strong>in</strong>es are not considered as utterly<br />
sat<strong>is</strong>factory by most stakeholders, and a specific work<strong>in</strong>g group has been set out, and<br />
specific studies have been carried out (“Study on the Safety of Long-Term Intensive<br />
Plasmapheres<strong>is</strong> <strong>in</strong> Donors” also known as SIPLA I, and SIPLA II Studies”), <strong>in</strong> order to<br />
formulate new propositions on specific po<strong>in</strong>ts, and to improve the volume of donations,<br />
while ensur<strong>in</strong>g the protection of the donor’s health.
<strong>KCE</strong> Reports 120 Plasma 23<br />
Role of the German Red Cross (DRK) compared to private firms <strong>in</strong> the plasma<br />
collection <strong>in</strong>dustry<br />
Accord<strong>in</strong>g to the German leg<strong>is</strong>lation, free competition <strong>is</strong> allowed between a large<br />
number of <strong>in</strong>stitutions, public and private alike. Today’s picture of plasma collection <strong>in</strong><br />
Germany <strong>is</strong> very specific as purely private firms or <strong>in</strong>stitutions have been more and<br />
more <strong>in</strong>volved <strong>in</strong> th<strong>is</strong> field, over the last years. <strong>The</strong>se private firms resort to clearly<br />
customer-oriented and profit-centred strategies.<br />
An <strong>in</strong>-depth survey conducted by Robert Koch Institute on d<strong>is</strong>tribution of plasma<br />
collection <strong>in</strong> 2006. Th<strong>is</strong> survey focused on the number of plasma repeat donors. It<br />
clearly showed that the number of donors from <strong>in</strong>dustry-driven centres and private<br />
centres amount for more than 81.6% of the total number of plasma repeat donors. <strong>The</strong><br />
number of plasma repeat donors from the Red Cross <strong>is</strong> much smaller (10.4%). So <strong>is</strong> the<br />
number of repeat donors from Federal or municipal centres (8%).<br />
Consider<strong>in</strong>g the volume of plasma delivered for fractionation, approximately half of th<strong>is</strong><br />
volume comes from plasmapheres<strong>is</strong>. Th<strong>is</strong> <strong>is</strong> of key importance, as private centres<br />
(<strong>in</strong>dustry-driven centres or private donation centres) design specific strategies target<strong>in</strong>g<br />
plasma donors, whereas the Red Cross did not (ma<strong>in</strong>ly for h<strong>is</strong>torical reasons).<br />
All pr<strong>in</strong>ciples and rules detailed <strong>in</strong> the Appendix (see Appendix “Germany”) relat<strong>in</strong>g to<br />
the German Red Cross – especially the campaign and <strong>in</strong>formation material – are <strong>in</strong> use<br />
both for full blood and plasma collection. Indeed, no specific campaign has been<br />
designed for plasma donation as such, unlike <strong>in</strong> the <strong>in</strong>dustry-driven or private donation<br />
centres.<br />
Demographic dimension of plasma donation <strong>in</strong> Germany: survey of Robert Koch<br />
<strong>in</strong>stitute<br />
<strong>The</strong> first objective of the survey was to conduct an <strong>in</strong>-depth analys<strong>is</strong> the demographic<br />
profile of plasma donors <strong>in</strong> Germany especially concern<strong>in</strong>g d<strong>is</strong>tribution of age groups<br />
among plasma donors, <strong>in</strong> each type of <strong>in</strong>stitutions (Website: http://www.rki.de/ ).<br />
<strong>The</strong> f<strong>in</strong>al objective of the survey was to analyze the possible impact of demographic<br />
changes of the German population on plasma donation over the next decades.<br />
D<strong>is</strong>tribution of age groups for blood donors highlights the crucial role of young people<br />
<strong>in</strong> plasma donation, ie people younger than 44 and among them those below 25. As<br />
shown on the graph below d<strong>is</strong>tribution of age groups <strong>is</strong> clearly uneven:<br />
Table 9: D<strong>is</strong>tribution of Donors 2006 Source: Robert Koch Institute<br />
Age 18-24 25-34 35-44 45-54 55-68<br />
New<br />
donors<br />
2006 %<br />
Repeat<br />
Donors<br />
2006 %<br />
51 24 15 7 2<br />
37 25 21 15 2<br />
Over the next decades, the German general population will undergo major changes,<br />
especially <strong>in</strong> terms of age structure. <strong>The</strong> objective of the survey was to make a quick<br />
synthes<strong>is</strong> on the ma<strong>in</strong> demographic trends and to analyze their impact on the donors<br />
population. In l<strong>in</strong>e <strong>with</strong> the German regulation and the guidel<strong>in</strong>es mentioned above, the<br />
“Population <strong>with</strong><strong>in</strong> the donor age limits” <strong>is</strong> def<strong>in</strong>ed as people between 18 and 68.<br />
Based on the data of the German stat<strong>is</strong>tical office (Destat<strong>is</strong>) the size of th<strong>is</strong> population<br />
will evolve as below:
24 Plasma <strong>KCE</strong> Reports 120<br />
Figure 2: Demographic prospects <strong>in</strong> Germany 2006-2031 (Age d<strong>is</strong>tribution)<br />
Source: German Federal Stat<strong>is</strong>tical Office<br />
Divergence between these both trends has been clearly highlighted by Robert Koch<br />
Institute as an age<strong>in</strong>g population means an <strong>in</strong>crease of potential recipients. On the long<br />
term, it could ra<strong>is</strong>e major problems <strong>in</strong> terms of supply/demand. In order to prevent<br />
shortfalls <strong>in</strong> plasma supply, it <strong>is</strong> clear that the number of donors should be ra<strong>is</strong>ed over<br />
the whole population of potential donors (ie 18-68). Emphas<strong>is</strong> should also be laid on<br />
retention of donors. Private centres and <strong>in</strong>dustry-driven centres will face major<br />
difficulties unless they recruit a much large number of donors <strong>in</strong> higher age groups<br />
(above 35) than they do today.<br />
Further <strong>in</strong>formation on donation campaign and demographic <strong>is</strong>sues <strong>in</strong> Appendix<br />
“Germany”<br />
Key po<strong>in</strong>ts<br />
• Maxim<strong>is</strong>ation of <strong>in</strong>dividual donation volume <strong>is</strong> one of the key <strong>is</strong>sues of<br />
ongo<strong>in</strong>g studies <strong>in</strong> Germany.<br />
• Consider<strong>in</strong>g plasma delivered for fractionation, plasmapheres<strong>is</strong> plays an<br />
important role, and <strong>is</strong> largely performed by private centres.<br />
• Plasma donors’ profile <strong>is</strong> quite specific: younger, more-educated, less<br />
<strong>in</strong>volved <strong>in</strong> professional life, and less often married.<br />
• “Real World” communication campaigns and practical follow-up of donors<br />
<strong>with</strong> modern techniques are of key importance to improve retention of<br />
donors. Interface <strong>with</strong> the education system <strong>is</strong> also of paramount<br />
importance.<br />
• Great attention <strong>is</strong> paid to the demographic dimension to adjust recruitment<br />
and retention policy accord<strong>in</strong>gly.
<strong>KCE</strong> Reports 120 Plasma 25<br />
2.1.3.2 Plasma collection <strong>in</strong> France<br />
H<strong>is</strong>torical Background<br />
For h<strong>is</strong>torical reasons, collection and fractionation activities have been clearly split<br />
between two different <strong>in</strong>stitutions:<br />
• Etabl<strong>is</strong>sement França<strong>is</strong> du Sang (EFS) for collection and vigilance activities<br />
(and other specific activities / see below)<br />
• Laboratoire França<strong>is</strong> de Fractionnement et de Biotechnologie (LFB) for<br />
fractionation activities, market<strong>in</strong>g of plasma-derived products, and<br />
Biotechnology R&D.<br />
In their own respective fields of activity, each of these <strong>in</strong>stitutions enjoys a monopoly.<br />
For practical reasons, both <strong>in</strong>stitutions have to work <strong>in</strong> connection under the<br />
superv<strong>is</strong>ion of public authorities. However, they are matters for different legal statuses.<br />
Safety and security requirements<br />
<strong>The</strong> AFSSAPS – Agence França<strong>is</strong>e de Sécurité Sanitaire des Produits de Santé French<br />
Agency for the Safety of Health Products (Dec<strong>is</strong>ion of 6 November 2006) <strong>is</strong> <strong>in</strong> charge of<br />
set<strong>in</strong>g out security rules, def<strong>in</strong><strong>in</strong>g and d<strong>is</strong>sem<strong>in</strong>at<strong>in</strong>g best practices, but also ensur<strong>in</strong>g<br />
propoer monitor<strong>in</strong>g of blood and plasma-derived products (see further).<br />
EU legal requirements are obviously applicable <strong>in</strong> the field of blood donation, quality and<br />
safety, as described above <strong>in</strong> the <strong>report</strong><br />
Legal status and m<strong>is</strong>sions of the Etabl<strong>is</strong>sement França<strong>is</strong> du Sang -EFS<br />
LEGAL STATUS<br />
<strong>The</strong> EFS has been created <strong>in</strong> 2000, <strong>is</strong> a public-law body and compr<strong>is</strong>es one national head<br />
office and 17 regional branches. Key members of its Board of Adm<strong>in</strong><strong>is</strong>tration are<br />
representatives of the Department of Health, M<strong>in</strong><strong>is</strong>try of F<strong>in</strong>ance, and M<strong>in</strong><strong>is</strong>try of<br />
Research. Representatives of the Health Care Insurance Funds are also members of the<br />
Board. While be<strong>in</strong>g a public <strong>in</strong>stitution one must notice that the EFS does not receive<br />
any public subsidy (most of its resources stem from the sale of labile products to<br />
hospitals) See website:<br />
http://www.dondusang.net/rewrite/head<strong>in</strong>g/1.htm?idRubrique=1) .<br />
THE MISSIONS OF THE EFS<br />
<strong>The</strong>se m<strong>is</strong>sions have been set out by the French leg<strong>is</strong>lation as follows:<br />
• Collection of blood and plasma: See also Appendix “France” on collection<br />
<strong>is</strong>sues<br />
• Ensur<strong>in</strong>g self-sufficiency<br />
• Vigilance activities: ensur<strong>in</strong>g actual application of safety and quality<br />
requirements, especially good practices set out by the AFSSAPS<br />
mentioned above.<br />
• Implement<strong>in</strong>g highly-skilled technical and research activities <strong>in</strong> connection<br />
<strong>with</strong> blood/t<strong>is</strong>sue: stem cells bank, bone marrow transplants, placental<br />
blood, etc…<br />
• Delivery of labile products to hospitals for transfusion purposes<br />
• Delivery of plasma to the LFB for fractionation purposes (official delivery<br />
targets)<br />
• International cooperation activities
26 Plasma <strong>KCE</strong> Reports 120<br />
Legal Status and m<strong>is</strong>sions of the Laboratoire França<strong>is</strong> de Fractionnement et de<br />
Biotechnologie - LFB<br />
LEGAL STATUS<br />
In 2005, LFB (formerly public-law structure) has been transformed <strong>in</strong>to a private-law<br />
firm (Edict of 28 July 2005) 13 . However, key members of the Board of Adm<strong>in</strong><strong>is</strong>tration<br />
are representatives of public authorities (Department of Health, M<strong>in</strong><strong>is</strong>try of F<strong>in</strong>ance),<br />
and the majority of the LFB’s shares rema<strong>in</strong>s <strong>in</strong> the hands of public stakeholders only.<br />
In today’s form, LFB <strong>is</strong> a hold<strong>in</strong>g company that controls two subsidiary companies:<br />
• LFB Biomédicaments (specialized <strong>in</strong> plasma fractionation and market<strong>in</strong>g of<br />
plasma-derived products).<br />
• LFB Biotechnologies (specialized <strong>in</strong> Biotechnology R&D)<br />
THE MISSIONS OF THE LFB<br />
LFB <strong>is</strong> specialized <strong>in</strong> the follow<strong>in</strong>g fields:<br />
• Immunology: primary immune deficiency, secondary immune deficiency,<br />
Kawasaki d<strong>is</strong>ease, Guilla<strong>in</strong>-Barré syndrome, etc..<br />
• Hemostasy / Clott<strong>in</strong>g factors: ma<strong>in</strong>ly von Willbrand and haemophilia<br />
• Anaesthesia / Resuscitation products<br />
• RD activities <strong>in</strong> the field of Biotechnology:<br />
• International activities: as most private firms of th<strong>is</strong> <strong>in</strong>dustry, LFB <strong>is</strong> also<br />
committed <strong>in</strong> <strong>in</strong>ternational activities, especially <strong>in</strong> plasma fractionation. As<br />
described below <strong>in</strong> the <strong>report</strong>, it plays an important role on the Brazilian<br />
market, as it will ass<strong>is</strong>t Brazilian stakeholders <strong>in</strong> sett<strong>in</strong>g up plasma<br />
fractionation facilities, and a susta<strong>in</strong>able supply cha<strong>in</strong>.<br />
Connection between the EFS towards the LFB<br />
As far as delivery of plasma <strong>is</strong> concerned, specific targets are fixed between EFS and LFB<br />
whereby, the volume of plasma to be delivered by EFS to the FFB <strong>is</strong> officially set out 14 .<br />
<strong>The</strong>se targets are opposable to the EFS. <strong>The</strong>refore, the key strategic objective of the<br />
latter <strong>is</strong> to keep up <strong>with</strong> the evolution of LFB supply needs. Delivery targets have<br />
evolved and will evolve as below (liters):<br />
Figure 3: EFS Delivery targets to LFB (2005-2011)<br />
Source: EFS Corporate data<br />
Th<strong>is</strong> key driver for the EFS <strong>is</strong> basically to <strong>in</strong>crease its plasma supply <strong>in</strong> order to meet the<br />
EFS needs, which thus <strong>in</strong>volves an <strong>in</strong>-depth reflection on the whole collection strategy<br />
and processes. Besides, the sale price of the plasma <strong>is</strong> fixed nationally by the<br />
Department of Health. Over the last years, it was reduced from 155 € to 135€ <strong>in</strong> 2007,<br />
and to 105€ <strong>in</strong> 2008. For all these reasons, the EFS steadily needs to improve its<br />
productivity (<strong>in</strong> terms of process) and also the total volume of collected plasma.<br />
In 2008:
<strong>KCE</strong> Reports 120 Plasma 27<br />
• 73% of plasma delivered to LFB stems from traditional whole blood<br />
technique.<br />
• 27% from other techniques: plasmapheres<strong>is</strong>, comb<strong>in</strong>ed apheres<strong>is</strong>, and<br />
mixed platelets concentrates (MPC).<br />
Cost control and EFS processes<br />
Costs Issues<br />
As mentioned above the EFS has to reach very demand<strong>in</strong>g delivery targets, under strict<br />
constra<strong>in</strong>ts, especially unilateral sale prices fix<strong>in</strong>g by the Departement of Health.<br />
<strong>The</strong>refore, the EFS <strong>is</strong> compelled to deliver an <strong>in</strong>creas<strong>in</strong>g volume of blood to LFB 630<br />
000 liters <strong>in</strong> 2006; 1,1 Millions liters scheduled for 2011.<br />
<strong>The</strong> ma<strong>in</strong> problems for EFS managers are obviously to ensure overall f<strong>in</strong>ancial balance of<br />
collection activities, but also to avoid d<strong>is</strong>crepancies between the collection costs of<br />
blood and plasma. One of ma<strong>in</strong> driver for EFS’s dec<strong>is</strong>ion makers <strong>is</strong> to cut down<br />
apherese plasma production costs, step by step, thanks to an <strong>in</strong>creased collection of<br />
actually collected plasma and a rationalization of collection techniques.<br />
DISTRIBUTION BETWEEN APHERESE PLASMA AND RECOVERED PLASMA<br />
In 2007, around 20% of plasma comes from apherese plasma whereas 80% rema<strong>in</strong>s<br />
recovered plasma. <strong>The</strong> objective of the EFS <strong>is</strong> to ra<strong>is</strong>e the share of apherese plama over<br />
the next year, for technical reasons (ma<strong>in</strong>ly <strong>in</strong>creased frequency of donations).<br />
Frequency of donation <strong>is</strong> all the more important as the proportion of donors <strong>in</strong> the<br />
French population rema<strong>in</strong>s low (around 4% of the overall population). However, one<br />
must bear <strong>in</strong> m<strong>in</strong>d that cost breakdown between apherese plasma and recovered<br />
plasma rema<strong>in</strong>s very different:<br />
• Costs of Apherese Plasma<br />
• 58% connected <strong>with</strong> collection step<br />
• 42% connected <strong>with</strong> process<strong>in</strong>g, vigilance, and quality-control<br />
• Costs of Recovered Plasma<br />
• 22% connected <strong>with</strong> collection step<br />
• 78% connected <strong>with</strong> process<strong>in</strong>g, vigilance, and quality-control<br />
Hence, th<strong>is</strong> policy will call for specific efforts and rationalization of the collection step<br />
itself as it accounts for the major part of the costs mentioned above. Rationalization can<br />
be understood as a systematic use of accurate processes and techniques, but also a<br />
better use of human resources, as described below.<br />
CLINICAL PRACTICES AND HUMAN RESOURCES<br />
Volume of <strong>in</strong>dividual donations<br />
Across the country, cl<strong>in</strong>ical practices rema<strong>in</strong> uneven, <strong>in</strong> the field of blood and plasma<br />
collection. As a practical matter, the volume of <strong>in</strong>dividual plasma collection may vary<br />
across donation centres and regions. Over the next years, one of the key <strong>is</strong>sues (from a<br />
purely technical po<strong>in</strong>t of view) <strong>is</strong> to make sure that field practices are <strong>in</strong> l<strong>in</strong>e <strong>with</strong> official<br />
requirements set out by the EFS, and to standardize these practices. By do<strong>in</strong>g so, the<br />
volume of <strong>in</strong>dividual collection could be ra<strong>is</strong>ed significantly.<br />
Plasmapherese techniques<br />
Until now, 60% of apherese <strong>is</strong> performed <strong>is</strong> as a simple apherese and 40% <strong>is</strong> performed<br />
<strong>with</strong> an additive solution. Three measures will be implemented over the next years to<br />
maximize and to standardize the rentability of plasmapherese techniques:<br />
• <strong>The</strong> more <strong>in</strong>tensive use of MPC as additive solutions<br />
• <strong>The</strong> automation of the production of the MPC
28 Plasma <strong>KCE</strong> Reports 120<br />
Human resources <strong>is</strong>sues<br />
<strong>The</strong> nurses’ rate of activity <strong>is</strong> also a concern for the EFS: <strong>in</strong> practice, th<strong>is</strong> rate <strong>is</strong><br />
relatively low (<strong>in</strong> average around 55%), due to an <strong>in</strong>accurate d<strong>is</strong>tribution of donation<br />
centres across the country and/or an <strong>in</strong>adequate organization of collection, especially<br />
consider<strong>in</strong>g the French sociological profile. In practice the use of donation rooms has<br />
not been rationalized yet, and the total amount of donor accommodation <strong>in</strong> donation<br />
rooms <strong>is</strong> often not fully used.<br />
Pr<strong>in</strong>ciples on cost rationalization<br />
Dec<strong>is</strong>ion makers of the EFS have identified several key measures to improve cost<br />
efficiency of the donation system. All of these measures are not equally profitable for<br />
the donation system, but they all br<strong>in</strong>g a helpful contribution to the smooth runn<strong>in</strong>g of<br />
the whole process and to the best use of donated blood.<br />
<strong>The</strong> follow<strong>in</strong>g measures l<strong>is</strong>ted below have been ranked from the most profitable to the<br />
less profitable (from a cost / efficiency po<strong>in</strong>t of view) consider<strong>in</strong>g today’s workforce.<br />
• Rationaliz<strong>in</strong>g the use of donation rooms and ra<strong>is</strong><strong>in</strong>g the nurses’ rate of<br />
activity: which <strong>in</strong>volves a restructur<strong>in</strong>g of donation facilities and a better<br />
d<strong>is</strong>tribution of donation. Th<strong>is</strong> will automatically ra<strong>is</strong>e the nurses’ rate of<br />
activity<br />
• Implementation of apherese <strong>with</strong> additive solution: th<strong>is</strong> technique will<br />
improve <strong>in</strong>dividual rentability of blood donations<br />
• Unify<strong>in</strong>g and ra<strong>is</strong><strong>in</strong>g the volume of <strong>in</strong>dividual donation<br />
Communication Campaigns: Further Information <strong>in</strong> Appendix “France : Plasma<br />
collection <strong>with</strong><strong>in</strong> the framework of EFS”<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> French system comb<strong>in</strong>es public law and private law rules <strong>in</strong> the field of<br />
collection, fractionation and supply. Plasma collection <strong>is</strong> not supported by<br />
public subsidies, and the sale price of plasma <strong>is</strong> fixed by the national health<br />
authorities. Delivery targets of the EFS will be ra<strong>is</strong>ed gradually over the next<br />
years.<br />
• EFS’s communication policy targets students and young adults.<br />
• <strong>The</strong> ma<strong>in</strong> driver for the collection centres <strong>is</strong> to improve HR management, to<br />
<strong>in</strong>crease <strong>in</strong>dividual collection volume, and to realize economies of scale.
<strong>KCE</strong> Reports 120 Plasma 29<br />
2.2 TRANSFORMATION OF PLASMA INTO PLASMA<br />
DERIVATIVES<br />
2.2.1 Quick overview of fractionation process<br />
S<strong>in</strong>ce the early 1940s the method of manufactur<strong>in</strong>g plasma, <strong>in</strong>itially developed by Pr<br />
Edw<strong>in</strong> J. Cohn, has been <strong>in</strong>fluenced by multiple factors, which over the years have<br />
forced the <strong>in</strong>dustry to adapt production <strong>in</strong> such a way that the optimal use of plasma – a<br />
human source - rema<strong>in</strong>s to be the lead<strong>in</strong>g objective. As already mentioned above,<br />
human plasma, <strong>is</strong> a unique biological material. Plasma fractionation, a “crack<strong>in</strong>g” process<br />
(cf. petroleum “crack<strong>in</strong>g”) used to prepare therapeutic prote<strong>in</strong>s, <strong>is</strong> and rema<strong>in</strong>s a<br />
complex process. Human plasma derived prote<strong>in</strong> products have unique character<strong>is</strong>tics<br />
l<strong>in</strong>ked to the orig<strong>in</strong> of the start<strong>in</strong>g raw material. Human plasma exhibits a complex<br />
biochemical nature due to its high prote<strong>in</strong> content, close to 60 g per litre, and to the<br />
diversity of its prote<strong>in</strong> components.<br />
Figure 4: Blood composition<br />
White cells<br />
& platelets<br />
8%<br />
Red cells<br />
42%<br />
Blood<br />
Plasma<br />
50%<br />
Plasma<br />
Prote<strong>in</strong><br />
Other<br />
7%<br />
3%<br />
Water<br />
90%<br />
Coagulation<br />
Factors<br />
1% 1%<br />
Globul<strong>in</strong>s<br />
15%<br />
Prote<strong>in</strong><br />
Other<br />
24%<br />
Album<strong>in</strong><br />
60%<br />
Below <strong>is</strong> a l<strong>is</strong>t of the best-known of those prote<strong>in</strong>s which are commercially <strong>available</strong>,<br />
although one should note that the order does not reflect the relative importance of the<br />
prote<strong>in</strong>s.<br />
IVIG:<br />
Album<strong>in</strong><br />
<strong>in</strong>travenous immunoglobul<strong>in</strong><br />
Factor VIII: coagulation factor<br />
Factor IX: coagulation factor<br />
AT-III: anti-thromb<strong>in</strong> III<br />
IMGG: <strong>in</strong>tra-muscular gammaglobul<strong>in</strong><br />
A1-AT: alpha-1 anti-tryps<strong>in</strong><br />
Fibr<strong>in</strong> sealant<br />
IMGG anti-D:<br />
Up to 25 others<br />
<strong>in</strong>tra-muscular gammaglobul<strong>in</strong> anti-Rh factor
30 Plasma <strong>KCE</strong> Reports 120<br />
2.2.1.1 Developmental nature of production<br />
Although the plasma derivatives <strong>in</strong>dustry cont<strong>in</strong>ues to use the Cohn procedure,<br />
developed <strong>in</strong> the early 1940s by Professor E. Cohn, the products now obta<strong>in</strong>ed by th<strong>is</strong><br />
method bear little resemblance to those obta<strong>in</strong>ed dur<strong>in</strong>g the early stages of the plasma<br />
derivatives <strong>in</strong>dustry. <strong>The</strong> Cohn procedure cons<strong>is</strong>ts, fundamentally, of the precipitation<br />
of the various prote<strong>in</strong>s by means of changes to pH and salt concentration levels, <strong>with</strong><br />
the prote<strong>in</strong>s be<strong>in</strong>g separated out by centrifugation. In order to prevent the prote<strong>in</strong>s<br />
from be<strong>in</strong>g denatured, the work <strong>is</strong> conducted at low temperatures and ethanol <strong>is</strong> added<br />
at various concentrations. While th<strong>is</strong> <strong>in</strong>itial prote<strong>in</strong> fractionation stage has been<br />
ma<strong>in</strong>ta<strong>in</strong>ed, what has changed <strong>is</strong> the process of purify<strong>in</strong>g the prote<strong>in</strong>s <strong>in</strong> order to obta<strong>in</strong><br />
a safer, purer end product.<br />
Figure 5: Schema of fractionation methods (Source: unpubl<strong>is</strong>hed document<br />
of PPTA – Plasma Prote<strong>in</strong> <strong>The</strong>rapeutics Association)<br />
2.2.1.2 Progress <strong>in</strong> purification<br />
<strong>The</strong> Cohn procedure does not produce therapeutic prote<strong>in</strong>s <strong>in</strong> a pure state, and it has<br />
therefore been necessary to add purification stages which, <strong>in</strong> addition to purify<strong>in</strong>g the<br />
prote<strong>in</strong>s, elim<strong>in</strong>ate the contam<strong>in</strong>ants added dur<strong>in</strong>g fractionation (ethanol and salts).<br />
<strong>The</strong>se purification stages vary depend<strong>in</strong>g on the character<strong>is</strong>tics of the Cohn fraction to<br />
be purified and the nature of the product be<strong>in</strong>g obta<strong>in</strong>ed. In the case of FVIII or antihaemophiliac<br />
factor, the development of aff<strong>in</strong>ity chromatography techniques (whether<br />
us<strong>in</strong>g monoclonal antibodies or hepar<strong>in</strong>) has allowed the development of FVIII <strong>with</strong> far<br />
higher purity levels than the first FVIII used <strong>in</strong> the treatment of haemophilia. Another<br />
significant advantage <strong>is</strong> that the <strong>in</strong>fusion volume of FVIII which now needs to be<br />
adm<strong>in</strong><strong>is</strong>tered <strong>is</strong> considerably lower, <strong>with</strong> result<strong>in</strong>g improvements <strong>in</strong> patient comfort and<br />
quality of life.
<strong>KCE</strong> Reports 120 Plasma 31<br />
Figure 6: Fractionation Techniques and Available Products (Source:<br />
unpubl<strong>is</strong>hed document of PPTA – Plasma Prote<strong>in</strong> <strong>The</strong>rapeutics Association)<br />
Each of the aff<strong>in</strong>ity chromatography systems described above also requires 2 highly<br />
purified, but different, FVIII products. Purification us<strong>in</strong>g monoclonal antibodies (anti-FVIII<br />
antibodies produced <strong>in</strong> mouse cells and bound to the chromatography matrix) allows a<br />
very pure FVIII to be obta<strong>in</strong>ed. In contrast, if aff<strong>in</strong>ity chromatography <strong>with</strong> hepar<strong>in</strong> <strong>is</strong><br />
used, both FVIII and von Willebrand Factor are obta<strong>in</strong>ed. VWF protects the FVIII<br />
molecule and <strong>is</strong> used <strong>in</strong> the treatment of immuno-<strong>in</strong>tolerance <strong>in</strong> haemophiliacs who<br />
have developed anti-Factor VIII antibodies, and can also be used to treat patients <strong>with</strong><br />
von Willebrand Factor deficit.<br />
Immunoglobul<strong>in</strong>s are another group of products where the new purification techniques<br />
have led to unforeseen therapeutic progress. Orig<strong>in</strong>ally, immunoglobul<strong>in</strong>s could only be<br />
adm<strong>in</strong><strong>is</strong>tered <strong>in</strong>tramuscularly, but th<strong>is</strong> method h<strong>in</strong>dered the adm<strong>in</strong><strong>is</strong>tration of sufficient<br />
quantities of immunoglobul<strong>in</strong>s, thereby br<strong>in</strong>g<strong>in</strong>g <strong>in</strong>to question their therapeutic utility.<br />
<strong>The</strong> use of different purification stages – precipitation <strong>with</strong> polyethylene glycol, glyc<strong>in</strong>e<br />
etc. – and different aff<strong>in</strong>ity chromatography systems has made it possible to obta<strong>in</strong><br />
<strong>in</strong>travenous immunoglobul<strong>in</strong>s (IVIG). Th<strong>is</strong> has meant that sufficient therapeutic doses<br />
can be adm<strong>in</strong><strong>is</strong>tered to patients, allow<strong>in</strong>g not just patients <strong>with</strong> primary<br />
immunodeficiency’s to benefit from such treatments (patients suffer<strong>in</strong>g from<br />
immunoglobul<strong>in</strong> production deficit), but also other patients <strong>with</strong> auto-immune illnesses,<br />
together <strong>with</strong> some who have neurological d<strong>is</strong>eases.<br />
2.2.1.3 Progress <strong>in</strong> safety<br />
Because the plasma fractionation <strong>in</strong>dustry uses plasma as its raw material, many viral<br />
illnesses carried <strong>in</strong> the plasma can be transmitted through transfusions of the end<br />
product. In order to prevent the r<strong>is</strong>k of further viral transm<strong>is</strong>sion, the <strong>in</strong>dustry<br />
developed a series of safety procedures which covered the donor, the plasma and the<br />
product. An <strong>in</strong>terest<strong>in</strong>g example <strong>in</strong> the development <strong>in</strong> viral safety can be found <strong>in</strong> the<br />
technical and scientific advances <strong>in</strong> the field of viral DNA detection (NAT techniques)<br />
which complement and improve upon the old viral marker techniques which used ELISA<br />
technology. <strong>The</strong> old techniques were based on detect<strong>in</strong>g antibodies to different viruses.<br />
However, as there <strong>is</strong> a variable time period (known as the ‘w<strong>in</strong>dow period’) between<br />
<strong>in</strong>itial <strong>in</strong>fection and the production of antibodies depend<strong>in</strong>g on the virus type, there <strong>is</strong> a<br />
danger that plasma <strong>with</strong> a low viral load which has tested negative us<strong>in</strong>g ELISA<br />
techniques can still be used <strong>in</strong> plasma fractionation.
32 Plasma <strong>KCE</strong> Reports 120<br />
NAT technology for viral DNA detection has dramatically reduced th<strong>is</strong> w<strong>in</strong>dow period.<br />
Negative results from the subsequent application of NAT technology to the plasma pool<br />
for a range of viruses (HCV, HIV, Parvo B19, HBV, etc.) provide assurance that the<br />
<strong>in</strong>itial viral load <strong>in</strong> the plasma pool <strong>is</strong> zero or very low.<br />
2.2.2 <strong>The</strong> worldwide supply of plasma products<br />
2.2.2.1 Corporate structure of the market of plasma products<br />
Restructur<strong>in</strong>g of the sector of plasma products<br />
Consider<strong>in</strong>g the <strong>in</strong>creas<strong>in</strong>g and vital needs of plasma products <strong>in</strong> most western<br />
countries, and simultaneously the uncerta<strong>in</strong> level of donation, purchasers of plasma<br />
products – ie hospitals, and more generally health care <strong>in</strong>stitutions – can feel <strong>in</strong> an<br />
<strong>in</strong>ferior position towards the plasma fractionation <strong>in</strong>dustry.<br />
<strong>The</strong> evolution of medical practices and also the political pressure of patient associations<br />
on health authorities do not leave them much room for manoeuvre. <strong>The</strong>refore it <strong>is</strong><br />
important to analyze the recent evolution of th<strong>is</strong> <strong>in</strong>dustry to have a clear idea on the<br />
purchasers’ actual negotiation power.<br />
MAIN SPECIFICITIES OF THIS INDUSTRY SINCE THE NINETIES: FUSIONS AND MARKET<br />
CONSOLIDATION<br />
In 1996, the number of global stakeholders <strong>in</strong> the n<strong>in</strong>eties was relatively high: almost 40<br />
companies (or non profit organ<strong>is</strong>ations) were identified worldwide <strong>in</strong> the plasma<br />
fractionation <strong>in</strong>dustry. Follow<strong>in</strong>g several merger waves, only 20 companies still ex<strong>is</strong>t<br />
today.<br />
Among these 20 companies some of them do not play a noticeable role on the global<br />
market because of their size or because of regulatory barriers that still <strong>is</strong>olate their<br />
domestic market from the <strong>in</strong>ternational market. Hence, only a very small number of<br />
companies can be considered as real “global players” <strong>in</strong> terms of economic weight: and<br />
market share.<br />
CURRENT SITUATION (2003-2005)<br />
Worldwide, only five private companies still play an important role (>5%) on the global<br />
market. Non profit organizations are also important stakeholders; however some of<br />
them enjoy a monopoly, based on a specific national regulation.<br />
Table 10: Global firms on the plasma product <strong>in</strong>dustry<br />
2003 2005<br />
Baxter 18.4% 19.5%<br />
State ruled or on Profit 23.1% 16.5%<br />
Organ<strong>is</strong>ations<br />
CSL-Behr<strong>in</strong>g 15.8% 17.1%<br />
Talecr<strong>is</strong> / Bayer 14.2% 13.8%<br />
Octapharma 5.7% 7.1%<br />
Grifols 7.6% 6.1%<br />
CSL/ZLB / Bioplasma 6% 1.6%<br />
Other 9.1% 18.2%<br />
Total 100% 100%
<strong>KCE</strong> Reports 120 Plasma 33<br />
GEOGRAPHICAL DIMENSION OF THIS INDUSTRY:<br />
Table 11: Geographical dimension of the plasma product <strong>in</strong>dustry<br />
‘MM US$ Oceania Africa South Middle Asia- Europe North World<br />
America East Pacific<br />
America Total<br />
Baxter 13.22 8.77 174.12 26.31 74.81 557.20 1230 2084.4<br />
CSL-Behr<strong>in</strong>g 116.54 13.08 72.4 39.2 191.54 539.98 929.74 1902.47<br />
Talecr<strong>is</strong> 0 5.12 19.3 15.37 55.58 128.65 925.79 1149.81<br />
Octapharma 24.5 32.25 98.78 96.75 23.07 382.98 205.75 864.08<br />
Grifols 0 1.53 40.59 4.60 16.66 413.59 270.65 747.63<br />
Leav<strong>in</strong>g aside non profit or public organ<strong>is</strong>ations (the strategy of which <strong>is</strong> largely<br />
connected <strong>with</strong> specific national regulations), private companies’ strategies <strong>is</strong> obviously<br />
guided by f<strong>in</strong>ancial prospects and expected profits on each geographical area. In that<br />
respect, the North-American area rema<strong>in</strong>s the most attractive geographical area for<br />
plasma fractionation firms.<br />
<strong>The</strong>refore, European buyers are apt to compete <strong>with</strong> American ones, and a harsh<br />
competition could ar<strong>is</strong>e at any time between them <strong>with</strong> two possible consequences:<br />
punctual supply shortage and/or sharp <strong>in</strong>crease <strong>in</strong> the prices of plasma-derived products.<br />
Capital structure: Four profiles identified<br />
As far as capital structure <strong>is</strong> concerned, one must notice that four profiles of capital<br />
structure have emerged, generally due to specific and deliberate corporate strategies. In<br />
other cases, (public <strong>in</strong>stitutions or other structures comm<strong>is</strong>sioned by public authorities)<br />
capital structure <strong>is</strong> closely connected <strong>with</strong> the monopoly status of the <strong>in</strong>stitution or<br />
specific national regulations.<br />
PROFILE 1: PRIVATE OWNED FIRMS (OCTAPHARMA AND GRIFOLS)<br />
<strong>The</strong>se two firms are relatively close situations from th<strong>is</strong> po<strong>in</strong>t of view: Octapharma <strong>is</strong> as<br />
a private-owned firm, and so <strong>is</strong> Grifols. In both cases, other stakeholders (especially<br />
banks) can play an important role <strong>in</strong> capital structure. However, private and family<br />
stakeholders rema<strong>in</strong> the key <strong>in</strong>vestors <strong>in</strong> both cases and key stakeholders often rema<strong>in</strong><br />
deeply connected <strong>with</strong> the national or even regional economy (Switzerland / Catalonia).<br />
PROFILE 2: NATIONAL STATE-CONTROLLED FIRMS OR INSTITUTIONS (LFB)<br />
In several western countries, fractionation firms enjoy a monopoly as def<strong>in</strong>ed by a<br />
specific regulation (generally for h<strong>is</strong>torical or cultural reasons). In th<strong>is</strong> case, the firm <strong>is</strong><br />
either owned or controlled by public stakeholders, ie governmental <strong>in</strong>stitutions or<br />
<strong>in</strong>stitutions comm<strong>is</strong>sioned by the government.<br />
LFB <strong>in</strong> France <strong>is</strong> a traditional example: it enjoys a monopoly <strong>in</strong> plasma fractionation<br />
based on a French specific regulation. Before 2005, LFB used to be a public-law<br />
<strong>in</strong>stitution. S<strong>in</strong>ce then, it has been transformed <strong>in</strong>to a private law hold<strong>in</strong>g company<br />
(legally a Ltd company) divided <strong>in</strong>to two subsidiary companies: one focus<strong>in</strong>g on<br />
Biotechnology, one focus<strong>in</strong>g on Plasma fractionation. <strong>The</strong> capital of both subsidiary<br />
companies <strong>is</strong> state-controlled. Key members of the Board of Adm<strong>in</strong><strong>is</strong>tration are<br />
government’s representatives (M<strong>in</strong><strong>is</strong>try of F<strong>in</strong>ance, M<strong>in</strong><strong>is</strong>try of Health).<br />
PROFILE 3: FOREIGN-OWNED FIRMS (CSL-BEHRING)<br />
CSL-Behr<strong>in</strong>g <strong>is</strong> a very specific case: it was orig<strong>in</strong>ally a German firm, CSL Behr<strong>in</strong>g became<br />
a subsidiary of CSL Limited, a biopharmaceutical company headquartered <strong>in</strong> Melbourne,<br />
Australia. From a f<strong>in</strong>ancial po<strong>in</strong>t of view, about 90% of the shares are now controlled by<br />
Australian stakeholders. <strong>The</strong>refore, even if CSL-Behr<strong>in</strong>g’s ma<strong>in</strong> facilities and RD centres<br />
are still located <strong>in</strong> Europe, it <strong>is</strong> under the control of foreign-based <strong>in</strong>stitutions.
34 Plasma <strong>KCE</strong> Reports 120<br />
PROFILE 4: TRADITIONAL PRIVATE FIRMS (US FIRMS: BAXTER, TALECRIS)<br />
<strong>The</strong>se firms’ capital structure <strong>is</strong> more traditional, as their capital <strong>is</strong> owned by private<br />
stakeholders (eg: Telecr<strong>is</strong> <strong>is</strong> owned by private equity groups Cerberus Partners and<br />
Ampersand Ventures).<br />
In may 2009, CSL tried to take over the US firm Talecr<strong>is</strong> mentioned above. However,<br />
the US Federal Trade Comm<strong>is</strong>sion recommended legal actions to block the purchase of<br />
Talecr<strong>is</strong> by CSL, on antitrust grounds. US public authorities, especially the new<br />
American adm<strong>in</strong><strong>is</strong>tration, seems to keep a vigilant eye on th<strong>is</strong> <strong>in</strong>dustry, especially on<br />
merg<strong>in</strong>g of bus<strong>in</strong>ess, whenever it <strong>is</strong> apt to have an impact on the American<br />
Ma<strong>in</strong> learn<strong>in</strong>gs for dec<strong>is</strong>ion-makers:<br />
• <strong>The</strong> capital ownership of the lead<strong>in</strong>g global firms of the plasma<br />
fractionation <strong>in</strong>dustry <strong>is</strong> unlikely to evolve over the next years and th<strong>is</strong><br />
<strong>in</strong>dustry, <strong>in</strong> today’s form, seems to be blocked.<br />
• Restructur<strong>in</strong>g of the plasma fractionation <strong>in</strong>dustry: the recent merg<strong>in</strong>g of<br />
bus<strong>in</strong>esses and the <strong>in</strong>creas<strong>in</strong>g weight of each firm (considered <strong>in</strong>dividually)<br />
can be seen as a rather negative evolution for the purchasers’ negotiation<br />
power.<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> recent merg<strong>in</strong>g of bus<strong>in</strong>esses has <strong>in</strong>volved a high concentration of<br />
fractionation activities. Given th<strong>is</strong> context, the negotiation power of<br />
purchasers (d<strong>is</strong>regard<strong>in</strong>g public or private status) <strong>is</strong> gett<strong>in</strong>g weaker.<br />
• In the context of a global fractionation <strong>in</strong>dustry, any change <strong>in</strong> the<br />
prescription habits or authorization of drugs of one country <strong>is</strong> apt to have an<br />
impact on the production flows of any other country. Great attention must<br />
be paid to the US policy on that po<strong>in</strong>t.<br />
2.2.3 <strong>The</strong> supply of plasma stable derivatives <strong>in</strong> Belgium<br />
2.2.3.1 Who are the suppliers<br />
<strong>The</strong> plasma collected by the Belgian Red Cross Blood Services - source plasma (SP) as<br />
well as recovered plasma (RP) - <strong>is</strong> sent to CAF-DCF for fractionation b . CAF-DCF <strong>is</strong> the<br />
exclusive manufacturer of plasma derivatives based on plasma collected <strong>in</strong> Belgium. All<br />
locally produced derivatives are <strong>in</strong>tended to be used <strong>with</strong><strong>in</strong> the country. <strong>The</strong> CAF-DCF<br />
was h<strong>is</strong>torically an <strong>in</strong>tegral part of the Belgian Red Cross up to the 23 December 1997.<br />
From that date, the <strong>in</strong>dependent CAF-DCF was set up as a cooperative company <strong>with</strong><br />
limited liability. Today the owners of the shares are:<br />
• the Sanqu<strong>in</strong> Bloodsupply Foundation (Nl) 50.02%,<br />
• the Laboratoire frança<strong>is</strong> du fractionnement et des biotechnologies, LFB<br />
(Fr), a limited company created <strong>in</strong> July 2005 and fully owned by the French<br />
State 24.99% and<br />
• the Belgian Red Cross 24.99%.<br />
Besides that, CAF-DCF has signed a cooperation contract <strong>with</strong> the German company<br />
Biotest for the fractionation of <strong>in</strong>termediate plasma products <strong>in</strong>to immunoglobul<strong>in</strong>s.<br />
CAF-DCF also fractionates for <strong>in</strong>ternational firms, its total fractionation capacity <strong>is</strong><br />
centered between 500.000 and 550.000 kilo of plasma<br />
b Except for a limited amount that <strong>is</strong> transformed <strong>in</strong>to fresh frozen plasma, used to treat specific<br />
hemorrhagic situations and some coagulation d<strong>is</strong>orders
<strong>KCE</strong> Reports 120 Plasma 35<br />
It <strong>is</strong> surpr<strong>is</strong><strong>in</strong>g to f<strong>in</strong>d that the capital of the company <strong>with</strong> a monopoly on the<br />
fractionation of plasma collected <strong>in</strong> Belgium <strong>is</strong> ma<strong>in</strong>ly <strong>in</strong> the hands of foreign partners.<br />
Grant<strong>in</strong>g a monopoly to an enterpr<strong>is</strong>e only makes sense if, <strong>in</strong> exchange for th<strong>is</strong><br />
monopoly, the enterpr<strong>is</strong>e <strong>in</strong> question fulfils a m<strong>is</strong>sion of collective <strong>in</strong>terest, and if the<br />
authority that granted th<strong>is</strong> monopoly can control what use <strong>is</strong> made of it. In th<strong>is</strong><br />
particular case, control of the CAF-DCF by the public authorities <strong>is</strong> difficult, verg<strong>in</strong>g on<br />
the impossible, given the m<strong>in</strong>ority stake held by the Belgian partner. In addition, it seems<br />
that there <strong>is</strong> no agreement or norm b<strong>in</strong>d<strong>in</strong>g the CAF-DCF <strong>in</strong> terms of the organ<strong>is</strong>ation<br />
and <strong>in</strong>tended use of its output.<br />
It should also be noted that the Board of Adm<strong>in</strong><strong>is</strong>tration of CAF-DCF cons<strong>is</strong>ts as well of<br />
suppliers (CR) as clients (e.g. Sanqu<strong>in</strong>), hav<strong>in</strong>g diverg<strong>in</strong>g <strong>in</strong>terests.<br />
2.2.3.2 Quantities fractionated by CAF-DCF<br />
<strong>The</strong> follow<strong>in</strong>g table presents the quantities of plasma (RP & SP) purchased by CAF-DCF<br />
from all collectors, as well as the quantities really used for fractionation each year by<br />
the CAF-DCF.<br />
Table 12: Purchased and fractionated quantities (2000-2008)<br />
<strong>in</strong> litres<br />
Plasma purchased by CAF<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
(source: Federal Agency<br />
for Medic<strong>in</strong>es)<br />
219.552 218.200 213.869 205.578 220.163 195.945 179.553 167.634 163.089<br />
Plasma fractionated by<br />
CAF (source: CAF-DCF)<br />
Differences (calculated by<br />
<strong>KCE</strong>)<br />
190.964 192.648 206.015 212.827 210.578 178.249 182.149 170.497 159.421<br />
28.588 25.552 7.854 -7.249 9.585 17.696 -2.596 -2.863 3.668<br />
CAF-DCF <strong>report</strong>ed a quite strait competition on the Belgian market and the underly<strong>in</strong>g<br />
reduction of plasma collection to expla<strong>in</strong> the constant reduction of fractionated plasma.<br />
It must be noted that, overall, CAF-DCF fractionates a smaller volume than the actually<br />
purchased volume. Strategic stocks are then constituted, which can prove helpful<br />
whenever quantities of collected plasma are not sufficient to fulfill the demand. In 2003,<br />
2006 and 2007, we observe that stocks had to be tapped. Th<strong>is</strong> tapp<strong>in</strong>g of the stock <strong>is</strong><br />
confirmed by the audit <strong>report</strong>s of Verhaegen 9 and PWC 15 .<br />
Availability of strategic stocks at the end of each year have been communicated by CAF-<br />
DCF and recorded on the first l<strong>in</strong>e of the table below. If we add to the yearly recorded<br />
strategic stock, the volume of plasma bought to the Red Cross the follow<strong>in</strong>g year - but<br />
not fractionated, and if we subtract the strategic stock recorded at the end of the<br />
follow<strong>in</strong>g year, we calculate a yearly balance, shown on the last l<strong>in</strong>e of the table below.<br />
Table 13: Stocks and balances (2000-2008)<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
Stategic stock 78.010 81.095 86.684 83.170 76.673 90.819 58.588 48.342 34.803<br />
Purchased - fractionated 28.588 25.552 7.854 -7.249 9.585 17.696 -2.596 -2.863 3.668<br />
Balances 22.467 2.265 -3.735 16.082 3.550 29.635 7.383 17.207<br />
Calculated by <strong>KCE</strong> and based on CAF-DCF data<br />
Accord<strong>in</strong>g to CAF-DCF, it <strong>is</strong> normal that the yearly variations <strong>in</strong> the volume of the<br />
strategic stock do not correspond to the differences between the volume of purchased<br />
plasma and the one of fractionated plasma. Indeed, losses may occur along the process<br />
e.g. when test<strong>in</strong>g reveals that a batch of plasma <strong>is</strong> <strong>in</strong>fected, as well as production losses -<br />
or even volumes of plasma put <strong>in</strong>to quarant<strong>in</strong>e for test<strong>in</strong>g purposes, and thus not<br />
recorded onto the strategic stock. However the volume of « lost » quantities may<br />
greatly vary from a year to another. No prec<strong>is</strong>e element could be collected concern<strong>in</strong>g<br />
the orig<strong>in</strong> of these variations.
36 Plasma <strong>KCE</strong> Reports 120<br />
2.2.3.3 Produced and sold quantities<br />
Plasma fractionated by<br />
CAF-DCF <strong>in</strong> litres<br />
Album<strong>in</strong> produced by<br />
CAF-DCF <strong>in</strong> Belgium <strong>in</strong><br />
kg<br />
Album<strong>in</strong> sold by CAF-<br />
DCF <strong>in</strong> Belgium <strong>in</strong> kg<br />
Number gr produced<br />
album<strong>in</strong> for 1 litre plasma<br />
(calculated by <strong>KCE</strong>)<br />
Production of album<strong>in</strong> if<br />
the yield equals 25,29<br />
gr/litre<br />
Album<strong>in</strong> produced by<br />
CAF-DCF <strong>in</strong> Belgium <strong>in</strong><br />
kg<br />
Based on the availability of volumes of plasma fractionated by CAF-DCF, volumes of<br />
derivatives manufactured from th<strong>is</strong> plasma, and yearly volume of sales, we can make the<br />
follow<strong>in</strong>g analys<strong>is</strong>.<br />
<strong>The</strong> first f<strong>in</strong>d<strong>in</strong>g <strong>is</strong> the bear<strong>is</strong>h trend for the sale of specific derivatives. <strong>The</strong> r<strong>is</strong>k of (and<br />
fear for) d<strong>is</strong>ease transmitted by plasma derivatives has probably contributed to the<br />
variations <strong>in</strong> the amounts of derivatives sold. For <strong>in</strong>stance, the r<strong>is</strong>k for Creutzfeld Jacob<br />
or other transm<strong>is</strong>sible d<strong>is</strong>ease has contributed the <strong>in</strong>creas<strong>in</strong>g use of recomb<strong>in</strong>ant<br />
coagulation factors to treat hemophilia, and subsequent decreas<strong>in</strong>g use of plasma<br />
derived factors. Indeed <strong>in</strong> 2004, the Belgian authorities have <strong>report</strong>ed that Belgian<br />
hemophilic patients had received coagulation factors prepared from a European plasma<br />
pool that could have been contam<strong>in</strong>ated <strong>with</strong> prions. c<br />
We will focus the follow<strong>in</strong>g analys<strong>is</strong> on album<strong>in</strong> and immunoglobul<strong>in</strong>s.<br />
Album<strong>in</strong><br />
<strong>The</strong> first calculus cons<strong>is</strong>ts <strong>in</strong> divid<strong>in</strong>g the number of litres of fractionated plasma by the<br />
number of actually produced grams of album<strong>in</strong>. Th<strong>is</strong> ratio <strong>is</strong> decreas<strong>in</strong>g s<strong>in</strong>ce 2001 even<br />
if the level of 2008 shows a weak <strong>in</strong>crease.<br />
Table 14: Calculation of number of grams obta<strong>in</strong>ed from 1 litre of plasma<br />
(2000-2008)<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
190.964 192.648 206.015 212.827 210.578 178.249 182.149 170.497 159.421<br />
4.679 4.873 4.755 4.873 5.005 4.264 2.419 2.607 3.085<br />
4.640 4.860 5.040 4.780 4.730 3.570 2.740 2.450 2.750<br />
24,50 25,29 23,08 22,90 23,77 23,92 13,28 15,29 19,35<br />
Source: CAF-DCF for the three first l<strong>in</strong>es of the table<br />
As from 2003 the <strong>in</strong>termediate album<strong>in</strong> rich fraction <strong>is</strong> sent to Sanqu<strong>in</strong> ( 9 p. 12) for<br />
ref<strong>in</strong><strong>in</strong>g and packag<strong>in</strong>g. Accord<strong>in</strong>g to Verhaegen 9 , the overall cost of th<strong>is</strong> process<strong>in</strong>g<br />
totals 3.1 million euros <strong>in</strong> 2003 and 4.6 million euros <strong>in</strong> 2004. We calculated the<br />
volume that could have been produced, if the album<strong>in</strong>/plasma ratio had rema<strong>in</strong>ed<br />
identical to the one of 2001 for the reviewed years.<br />
Table 15: Calculation of the potential production of album<strong>in</strong>s (2000-2008)<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
4.829 4.872 5.210 5.382 5.326 4.508 4.607 4.312 4.022<br />
4.679 4.872 4.755 4.873 5.005 4.264 2.419 2.607 3.085<br />
Differences 150 0 455 509 321 244 2.188 1.705 1.272<br />
Thanks to th<strong>is</strong> calculus, we observe that between 0,15 and 2,18 supplementary tons of<br />
album<strong>in</strong> per year could have been produced, technically speak<strong>in</strong>g. However, l<strong>in</strong>e 3 of<br />
table 14 shows that no purchasers could be found for such volumes on the Belgian<br />
market. Hence, CAF-DCF had no <strong>in</strong>terest to produce more album<strong>in</strong>s. <strong>The</strong> production<br />
of album<strong>in</strong> follows the demand on the Belgian market. <strong>The</strong> real yield for fractionation of<br />
album<strong>in</strong>s ivaries between 24,6 and 25,6 gram per kilo of plasma.<br />
c Service public fédéral Santé publique. Communiqué de presse du 23 novembre 2004.
<strong>KCE</strong> Reports 120 Plasma 37<br />
Plasma fractionated by<br />
CAF<br />
IG produced by CAF‐DCF<br />
<strong>in</strong> Belgium <strong>in</strong> gr<br />
Th<strong>is</strong> Belgian demand <strong>is</strong> function of the nature of the competition between firms present<br />
on the market and of an <strong>in</strong>ternational underly<strong>in</strong>g reduction of album<strong>in</strong> demand. Th<strong>is</strong> <strong>is</strong><br />
confirmed by a recent Australian Report of CSL where we can read that ‘In Australia<br />
the amount of album<strong>in</strong> <strong>is</strong>sued per annum over the period 1994-95 to 2004-5 has<br />
<strong>in</strong>creased by an average annual growth rate of ca. 1.4%, as shown <strong>in</strong>, although <strong>in</strong> the last<br />
five years th<strong>is</strong> value has been higher at ca. 2.3%. In contrast, the growth <strong>in</strong> plasma<br />
collections has been ca. 6% per annum over the same period and if all of th<strong>is</strong> plasma had<br />
been converted <strong>in</strong>to product then Australia would have accumulated a substantial<br />
excess of album<strong>in</strong> over requirements. Recogniz<strong>in</strong>g th<strong>is</strong> situation, CSL was <strong>in</strong>structed to<br />
limit the production of album<strong>in</strong> from 1999-00 onward <strong>in</strong> order to balance supply <strong>with</strong><br />
demand. As a consequence of th<strong>is</strong> policy the latest data from 2004-05 <strong>in</strong>dicates that<br />
Australia can meet demand for album<strong>in</strong> by convert<strong>in</strong>g only about 60% of the <strong>available</strong><br />
plasma <strong>in</strong>to f<strong>in</strong><strong>is</strong>hed album<strong>in</strong> product’. 16 <strong>The</strong> same phenomenon occurred <strong>in</strong> Belgium<br />
and a proportion of collected plasma <strong>is</strong> then sold to foreign firms under the form of<br />
<strong>in</strong>termediate products.<br />
<strong>The</strong> case of immunoglobul<strong>in</strong>s<br />
<strong>The</strong> trend identified for IG <strong>is</strong> opposed to the trend for album<strong>in</strong>: it shows that s<strong>in</strong>ce<br />
2004 the quantities of IG sold by the CAF-DCF follow a r<strong>is</strong><strong>in</strong>g path despite the fall <strong>in</strong><br />
collection. Th<strong>is</strong> r<strong>is</strong>e <strong>in</strong> sales volume might be partly expla<strong>in</strong>ed by the desertion of the<br />
Belgian market by one firm around 2004.<br />
Table 16: Calculation of number of grams obta<strong>in</strong>ed from 1 litre of plasma<br />
(2000-2008)<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
190.964 192.648 206.015 212.827 210.578 178.249 182.149 170.497 159.421<br />
171.000 185.000 118.000 340.000 379.000 456.000 455.000 531.000 636.000<br />
IG sold by CAF‐DCF <strong>in</strong><br />
Belgium <strong>in</strong> gr<br />
Number of gr of<br />
122.000 151.000 170.000 298.000 393.000 389.000 462.000 490.000 543.000<br />
produced IG for 1 litre<br />
plasma<br />
0,90 0,96 0,57 1,60 1,80 2,56 2,50 3,11 3,99<br />
Source: CAF-DCF for the tree first l<strong>in</strong>es of the table<br />
<strong>The</strong> calculated ratios present a constant <strong>in</strong>crease s<strong>in</strong>ce 2000. <strong>The</strong>se ratios are calculated<br />
as if all the fractionated plasma was used to produce immunoglobul<strong>in</strong>s. CAF-DCF<br />
<strong>report</strong>ed that the quantities of fractionated plasma used for a given derivative <strong>is</strong> always<br />
determ<strong>in</strong>ed by the demand. <strong>The</strong> <strong>report</strong>ed technical yield by the CAF-DCF <strong>is</strong> 2,7 gr/L<br />
plasma for the period 2000-2002. S<strong>in</strong>ce 2003, the CAF-DCF used a very perform<strong>in</strong>g<br />
technology to produce the Multigam. Dur<strong>in</strong>g the period 2003-2007, the yield was equal<br />
to 4,2 gr/L. In 2008, the use of the nanofiltration caused a light reduction of the yield to<br />
3,9 gr/L. In 2008, the ratio <strong>is</strong> exactly the same as the reference mentioned <strong>in</strong> an<br />
unpubl<strong>is</strong>hed document of PPTA (3.98 g/L). Nevertheless it seems that the world’s best<br />
fractionation operators should obta<strong>in</strong> a constant yield of 5.3 g/L (CSL reference).<br />
However, as we do not have at our d<strong>is</strong>posal the right data to determ<strong>in</strong>e the prec<strong>is</strong>e<br />
content of the yields identified <strong>in</strong> other countries, th<strong>is</strong> compar<strong>is</strong>on must be considered<br />
<strong>with</strong> care.<br />
Th<strong>is</strong> evolution shows CAF-DCF’s responsiveness to demand and also its capacity to<br />
ra<strong>is</strong>e its production at a faster pace than the one of demand.
38 Plasma <strong>KCE</strong> Reports 120<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> production of plasma derivatives <strong>is</strong> not carried out only by the CAF-<br />
DCF, which has concluded agreements <strong>with</strong> foreign firms to carry out a part<br />
of the process<br />
• Relatively large volumes of plasma purchased by CAF-DCF do not<br />
contribute at all to the fractionation process. <strong>The</strong>se volumes seem to vary<br />
greatly over the years, and th<strong>is</strong> phenomenon has not been clarified.<br />
• <strong>The</strong> CAF-DCF seems to experience overcapacity for specific stable<br />
derivatives. In spite of the decrease of the volumes of purchased plasma, it<br />
produces more than it actually sells on the Belgian market. A proportion of<br />
collected plasma (under the form of <strong>in</strong>termediate product) <strong>is</strong> sometimes<br />
dedicated to the production for foreign markets.<br />
• Trad<strong>in</strong>g as well as production agreements, concluded between CAF-DCF<br />
partners, are not transparent towards the public authority, although th<strong>is</strong><br />
f<strong>in</strong>ancially supports CAF-DCF through subsidized plasma prices.<br />
2.2.3.4 Position of CAF-DCF on the <strong>in</strong>ternational market<br />
<strong>The</strong> <strong>in</strong>vestments made by the CAF-DCF, notably <strong>in</strong> a new build<strong>in</strong>g <strong>in</strong> Neder-Over-<br />
Hembeek, enable the company to manufacture quality products that have resulted <strong>in</strong><br />
foreign companies tak<strong>in</strong>g hold<strong>in</strong>gs <strong>in</strong> the capital of the CAF-DCF. Nevertheless, the<br />
CAF-DCF rema<strong>in</strong>s a very small enterpr<strong>is</strong>e on the world stage and its f<strong>in</strong>ancial situation<br />
<strong>is</strong> precarious, despite the <strong>in</strong>direct subsidies it receives through the price that it pays for<br />
plasma to the Red Cross.<br />
An audit carried out <strong>in</strong> 2006 had already highlighted the difficult f<strong>in</strong>ancial situation of the<br />
CAF-DCF. 9 Accord<strong>in</strong>g to th<strong>is</strong> audit, the results of th<strong>is</strong> enterpr<strong>is</strong>e <strong>in</strong> Belgium were <strong>in</strong><br />
the red for the entire period under review (2000 – 2005) and the positive results of<br />
foreign operations were not enough to offset the losses made <strong>in</strong> Belgium. As from<br />
2003, the purchases column saw a substantial <strong>in</strong>crease due to the r<strong>is</strong>e <strong>in</strong> the price of<br />
plasma from plasmapheres<strong>is</strong> (+37%). Two other cost head<strong>in</strong>gs were also to blame for<br />
the deterioration <strong>in</strong> the f<strong>in</strong>ancial situation of the CAF-DCF dur<strong>in</strong>g the period <strong>in</strong><br />
question: ‘special orders’ and ‘purchases of stable derivatives’. <strong>The</strong> r<strong>is</strong>e <strong>in</strong> the head<strong>in</strong>g<br />
‘special orders’ follows the closure of the former CAF fractionation factory <strong>in</strong> Ixelles.<br />
As from 2004, the plasma was fractionated <strong>in</strong>to <strong>in</strong>termediate products <strong>in</strong> the factory at<br />
Neder-Over-Heembeek. <strong>The</strong> <strong>in</strong>termediate products are then sent to foreign partners<br />
for f<strong>in</strong>er fractionation. S<strong>in</strong>ce 2002 the preparation of factor VIII has been carried out by<br />
the French company LFB. S<strong>in</strong>ce 2003 the album<strong>in</strong> has been produced by Sanqu<strong>in</strong> <strong>in</strong> the<br />
Netherlands. As for the r<strong>is</strong>e <strong>in</strong> the head<strong>in</strong>g ‘purchases of stable derivatives’, it results<br />
from a comb<strong>in</strong>ation of two factors: the purchase of PPSB by Sanqu<strong>in</strong> follow<strong>in</strong>g the r<strong>is</strong>e<br />
<strong>in</strong> demand for th<strong>is</strong> product and the manufacture of Multigam (immunoglobul<strong>in</strong>s) by the<br />
firm Biotest, which receives the <strong>in</strong>termediate products from the CAF-DCF and sends<br />
them back as the f<strong>in</strong><strong>is</strong>hed product.<br />
Accord<strong>in</strong>g to the audit conducted by F. Verhaegen, th<strong>is</strong> negative f<strong>in</strong>ancial situation<br />
should improve significantly <strong>with</strong> the removal of the compulsory levy on the<br />
pharmaceutical firms.<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> CAF-DCF <strong>is</strong> a high technology firm but rather small on the world-wide<br />
scale.<br />
• <strong>The</strong> f<strong>in</strong>ancial situation of the CAF-DCF, structurally negative between 2000<br />
and 2005, recovered thanks to the removal of the levy on pharmaceutical<br />
products, from which plasma derivatives are currently exempt
<strong>KCE</strong> Reports 120 Plasma 39<br />
2.3 LIMITATIONS<br />
<strong>The</strong> subject we are deal<strong>in</strong>g <strong>with</strong> <strong>is</strong> sensitive <strong>in</strong> more than one respect. Firstly, the<br />
products <strong>in</strong> question constitute, for a number of medical conditions, the only possible<br />
therapy at the present time. In addition, the data concern<strong>in</strong>g the price and the quantities<br />
collected and produced concern actors that play an important role <strong>in</strong> th<strong>is</strong> sector. It <strong>is</strong><br />
therefore essential to have validated data <strong>in</strong> order to be able to draw relevant<br />
conclusions. It <strong>is</strong> also essential to identify the reasons why caution <strong>is</strong> necessary <strong>in</strong> the<br />
formulation of certa<strong>in</strong> f<strong>in</strong>d<strong>in</strong>gs and conclusions, and we present here the limitations of<br />
our analys<strong>is</strong>.<br />
<strong>The</strong> first limitation concerns the cost of plasmapheres<strong>is</strong>. We have seen that the<br />
allocation of organ<strong>is</strong>ation costs to th<strong>is</strong> activity, compared <strong>with</strong> the other activities of the<br />
Red Cross, could have a dec<strong>is</strong>ive effect on the real cost of the activity <strong>in</strong> question.<br />
<strong>The</strong> second limitation <strong>is</strong> related to the profitability of plasmapheres<strong>is</strong>. We are not <strong>in</strong> a<br />
position to establ<strong>is</strong>h <strong>with</strong> certa<strong>in</strong>ty the price at which the Red Cross could sell, or could<br />
have sold, plasma on the <strong>in</strong>ternational market. <strong>The</strong> various data collected show that we<br />
cannot be sure of the profitability of such an approach because of the variability of<br />
prices <strong>in</strong> time and space.
40 Plasma <strong>KCE</strong> Reports 120<br />
3 DEMAND FOR PLASMA DERIVATIVES: THE<br />
CASE OF IMMUNOGLOBULINS<br />
Th<strong>is</strong> chapter aims at describ<strong>in</strong>g the quantities of plasma derivatives used <strong>in</strong> Belgium, how<br />
they are used and what are the future trends <strong>in</strong> consumption. <strong>The</strong> purpose <strong>is</strong> to<br />
subsequently compare quantities used and quantities supplied.<br />
S<strong>in</strong>ce polyvalent immunoglobul<strong>in</strong> (IG) <strong>is</strong> the plasma derivative considered as the market<br />
driver for plasma procurement, we have focused most of our research on IG. 17 In a first<br />
phase, we have studied the <strong>in</strong>dications for IG use: we have compared the<br />
recommendations for IG use <strong>in</strong> Belgium and <strong>in</strong> other <strong>in</strong>dustrialized countries and<br />
reviewed the scientific evidence on IG effectiveness. In a second phase, we have<br />
analyzed the quantities of IG that are used <strong>in</strong> Belgium and <strong>in</strong> other countries, the<br />
amounts that would be required to treat the ma<strong>in</strong> <strong>in</strong>dications and how can IG<br />
consumption be rationalized and reduced.<br />
3.1 USE OF PLASMA DERIVATIVES IN BELGIUM<br />
3.1.1 Methods<br />
3.1.2 Results<br />
We collected data on the use of plasma derivatives <strong>in</strong> Belgium to determ<strong>in</strong>e the<br />
quantities and expenses <strong>in</strong>volved <strong>in</strong> the recent years, as well as to identify recent trends.<br />
<strong>The</strong> National Institute for Health and D<strong>is</strong>ability Insurance (NIHDI or INAMI/RIZIV)<br />
provided us <strong>with</strong> national data on reimbursed plasma derivatives for the period 2004-<br />
2006 <strong>with</strong> the follow<strong>in</strong>g relevant <strong>in</strong>formation: hospital, ward (<strong>in</strong>patient or outpatient),<br />
trimester, category of reimbursement, ATC code 5 (J06BA01 et J06BA02), number of<br />
packages and price. <strong>The</strong>se data have been checked for cons<strong>is</strong>tence between the number<br />
of items and the expenses. <strong>The</strong> yearly quantities of each derivative have been computed<br />
<strong>in</strong> grams or <strong>in</strong>ternational units (IU) by year and by type of producer, categorized <strong>in</strong><br />
CAF-DCF (Centrale Afdel<strong>in</strong>g voor Fractioner<strong>in</strong>g - Département Central de<br />
Fractionnement) or non CAF-DCF.<br />
We had no access to data on non-reimbursed plasma derivatives and derivatives used<br />
for compassionate use.<br />
<strong>The</strong> yearly amounts of the ma<strong>in</strong> reimbursed derivatives are presented <strong>in</strong> Table 17.<br />
Recomb<strong>in</strong>ant coagulation factors, obta<strong>in</strong>ed us<strong>in</strong>g recomb<strong>in</strong>ant DNA technology, are also<br />
mentioned (<strong>in</strong> italic). Though they are not derived from plasma, their evolution<br />
<strong>in</strong>fluences the trends <strong>in</strong> plasma derived factors.<br />
Over the period 2004-2006, the follow<strong>in</strong>g trends <strong>in</strong> consumption are observed: human<br />
factors VIII and IX are decreas<strong>in</strong>g by more than half (-61% and -56% respectively),<br />
parallel to an <strong>in</strong>crease <strong>in</strong> recomb<strong>in</strong>ant factors; von Willebrand factors are doubl<strong>in</strong>g; the<br />
use of FEIBA and sub-cutaneous immunoglobul<strong>in</strong>s are emerg<strong>in</strong>g; and <strong>in</strong>travenous<br />
immunoglobul<strong>in</strong>s have <strong>in</strong>creased by 11%. <strong>The</strong> consumption of CAF-DCF products has<br />
been compared to those from other producers on the Belgian market: all CAF-DCF<br />
products show a sharp decrease <strong>in</strong> quantities, except for immunoglobul<strong>in</strong>s (+18%) and<br />
PPSB (+16%). Th<strong>is</strong> decrease can not be exclusively expla<strong>in</strong>ed by the <strong>in</strong>crease <strong>in</strong><br />
recomb<strong>in</strong>ant product use.
<strong>KCE</strong> Reports 120 Plasma 41<br />
Table 17: Ma<strong>in</strong> plasma derivatives and recomb<strong>in</strong>ant factors reimbursed by<br />
the National Institute for Health and D<strong>is</strong>ability Insurance (NIHDI) <strong>in</strong> kU or<br />
grams<br />
Plasma derivatives and equivalents 2004 2005 2006<br />
PPSB CAF 5.193 kU 5.825 kU 6.013 kU<br />
Fact VIII 43.606 kU 52.153 kU 58.148 kU<br />
Fact VIII-human CAF 4.049 kU 3.404 kU 1.598 kU<br />
Fact VIII-recomb<strong>in</strong>ant<br />
Factor Eight Inhibitor Bypass<strong>in</strong>g<br />
39.557 kU 48.749 kU 56.550 kU<br />
Activity (FEIBA) 65 kU 206 kU 839 kU<br />
Factor IX-human 2.069 kU 1.293 kU 908 kU<br />
Factor IX-human CAF 1.921 kU 1.045 kU 602 kU<br />
Factor IX-human not-CAF 148 kU 248 kU 306 kU<br />
Factor IX-recomb<strong>in</strong>ant 1.825 kU 3.537 kU 4.789 kU<br />
Fact VII-human CAF 101 kU 110 kU 24 kU<br />
Factor VIIa-recomb<strong>in</strong>ant 375.324 kU 265.866 kU 127.588 kU<br />
Von Willebrand +/- Fact VIII 2.011 kU 3.978 kU 4.605 kU<br />
von Willebrand +/- Fact VIII CAF 1.226 kU 1.001 kU 829 kU<br />
von Willebrand +/- Fact VIII not-CAF 785 kU 2.978 kU 3.776 kU<br />
Factor XIII-human 13 kU 11 kU 9 kU<br />
Alb & SSPP 4.599.557 gr 4.904.672 gr 4.224.990 gr<br />
Alb & SSPP CAF 4.416.990 gr 3.543.800 gr 2.479.800 gr<br />
Alb & SSPP not-CAF 182.568 gr 1.360.873 gr 1.745.190 gr<br />
SC Immunoglobul<strong>in</strong>s polyvalent 0 gr 115 gr 3.604 gr<br />
IV Immunoglobul<strong>in</strong>s polyvalent 749.559 gr 773.486 gr 828.546 gr<br />
IV Immunoglobul<strong>in</strong>s polyvalent CAF 353.058 gr 356.314 gr 416.363 gr<br />
IV Immunoglobul<strong>in</strong>s polyvalent not-CAF 396.501 gr 417.172 gr 412.183 gr<br />
Antithromb<strong>in</strong>e III 803 kU 1.112 kU 721 kU<br />
Fragm<strong>in</strong> 0 kU 0 kU 0 kU<br />
C prote<strong>in</strong> 0 kU 0 kU 0 kU<br />
Table 18 presents the national expenses <strong>in</strong> plasma derivatives and recomb<strong>in</strong>ant factors<br />
by year, the changes <strong>in</strong> expenses over the 3 year period (<strong>in</strong> percent <strong>in</strong>crease compared<br />
to 2004) and the proportion of each product expense related to the total expenses for<br />
all derivatives (recomb<strong>in</strong>ant <strong>in</strong>cluded). <strong>The</strong> cost of human derivatives stayed relatively<br />
stable over the 3 years, while the cost of recomb<strong>in</strong>ant <strong>in</strong>creased by 35% (mostly due to<br />
an 43% <strong>in</strong>crease <strong>in</strong> Factor VIII recomb<strong>in</strong>ant). <strong>The</strong> trends <strong>in</strong> human derivative expenses<br />
follows the same patterns than the trends <strong>in</strong> quantities reimbursed. All together, plasma<br />
derivatives and recomb<strong>in</strong>ant factors represented <strong>in</strong> 2006 3% of all drug expenses from<br />
the health budget.<br />
In 2006, the cost of recomb<strong>in</strong>ant products represented 52% of total expenses, <strong>with</strong><br />
recomb<strong>in</strong>ant Factor VIII alone represent<strong>in</strong>g 48% of all expenses. Among human<br />
derivatives, the highest expense was due to <strong>in</strong>travenous immunoglobul<strong>in</strong>s (33.4 millions<br />
€ or 62% of human derivatives), followed by album<strong>in</strong> and SSPP (12.2 millions € or 23%<br />
of human derivatives).
42 Plasma <strong>KCE</strong> Reports 120<br />
Table 18: Plasma derivatives and recomb<strong>in</strong>ant factors reimbursed by the<br />
NIHDI <strong>in</strong> euros<br />
Increase<br />
(%)<br />
from % of<br />
2004 to total<br />
Plasma derivative 2004 2005 2006 2006 (2006)<br />
PPSB CAF 3.085.617 3.460.927 3.538.650 +15% 3%<br />
Fact VIII 40.985.245 49.261.250 55.007.814 +34% 49%<br />
Fact VIII-human CAF 3.641.669 3.346.896 1.529.897 ‐58% 1%<br />
Fact VIII-recomb<strong>in</strong>ant 37.343.576 45.914.354 53.477.916 +43% 48%<br />
FEIBA 44.564 141.977 578.834 +1199% 1%<br />
Factor IX-human 1.300.125 804.461 541.869 ‐58% 0%<br />
Factor IX-human CAF 1.220.440 671.533 378.548 ‐69% 0%<br />
Factor IX-human not-CAF 79.685 132.928 163.321 +105% 0%<br />
Factor IX-recomb<strong>in</strong>ant 1.482.492 2.866.969 3.639.488 +145% 3%<br />
Fact VII-human CAF 47.712 52.041 11.280 ‐76% 0%<br />
Factor VIIa-recomb<strong>in</strong>ant 4.606.335 3.262.395 1.565.229 ‐66% 1%<br />
von Willebrand +/- Fact VIII 838.996 1.246.384 1.335.818 +59% 1%<br />
von Willebrand +/- Fact VIII CAF 651.254 531.557 439.080 ‐33%<br />
von Willebrand +/- Fact VIII not-CAF 187.741 714.826 896.738 +378%<br />
Factor XIII-human 3.941 4.751 4.034 +2% 0%<br />
Alb & SSPP 13.578.166 14.248.444 12.200.319 ‐10% 11%<br />
Alb & SSPP CAF 13.061.558 10.499.273 7.416.617 ‐43% 7%<br />
Alb & SSPP not-CAF 516.470 3.749.154 4.783.694 +826% 4%<br />
Other plasma prote<strong>in</strong> fractions 138 17 8 ‐94% 0%<br />
SC Immunoglobul<strong>in</strong>s polyvalent 0 5.231 165.310 ‐ 0%<br />
IV Immunoglobul<strong>in</strong>s polyvalent 30.448.581 31.498.645 33.450.863 +10% 30%<br />
IV Immunoglobul<strong>in</strong>s polyvalent CAF 14.137.200 14.262.430 16.485.695 +17% 15%<br />
IV Immunoglobul<strong>in</strong>s polyv. not-CAF 16.311.381 17.236.216 16.965.168 +4% 15%<br />
Antithromb<strong>in</strong>e III 446.735 566.246 377.277 ‐16% 0%<br />
Total all products 96.868.647 107.419.738 112.416.793 +5% 100%<br />
Total human derivatives 53,436,244 55,376,020 53,734,159 +1% 48%<br />
Total recomb<strong>in</strong>ant factors 43,432,403 52,043,718 58,682,633 +35% 52%<br />
3.1.3 <strong>The</strong> case of immunoglobul<strong>in</strong>s<br />
<strong>The</strong> rema<strong>in</strong><strong>in</strong>g of th<strong>is</strong> chapter focuses on polyvalent immunoglobul<strong>in</strong>s (IG). Demand <strong>in</strong><br />
immunoglobul<strong>in</strong>s <strong>is</strong> the highest among all derivatives when consider<strong>in</strong>g the amount of<br />
plasma required to produce it. Its use cont<strong>in</strong>ues to grow as the number of cl<strong>in</strong>ical<br />
<strong>in</strong>dications for IG keeps <strong>in</strong>creas<strong>in</strong>g. Th<strong>is</strong> <strong>in</strong>creased demand resulted <strong>in</strong> severe product<br />
shortages <strong>in</strong> the late 1990’s <strong>in</strong> the US and a number of other countries, impact<strong>in</strong>g IG<br />
supply <strong>in</strong> Belgium. In addition, IG <strong>is</strong> important <strong>in</strong> terms of amounts <strong>in</strong>volved and budget<br />
impact <strong>in</strong> Belgium, represent<strong>in</strong>g 62% of expenses <strong>in</strong> human plasma derivatives <strong>in</strong> 2006.<br />
In th<strong>is</strong> chapter, IG <strong>is</strong> used to describe pooled polyvalent human immunoglobul<strong>in</strong>, that<br />
can be adm<strong>in</strong><strong>is</strong>tered <strong>in</strong>travenously or subcutaneously; IG does not cover hyperimmune<br />
or specific immunoglobul<strong>in</strong>s.<br />
Polyvalent IG are used to treat a wide range of d<strong>is</strong>eases due to three major therapeutic<br />
properties: IG can replace or supplement antibodies <strong>in</strong> immunodeficiency d<strong>is</strong>eases, <strong>in</strong><br />
order to restore normal humoral immune function; IG has an immunomodulatory<br />
action <strong>in</strong> various autoimmune conditions and <strong>in</strong>flammatory d<strong>is</strong>eases; and IG may be used<br />
as prophylax<strong>is</strong> or therapeutic adjunct aga<strong>in</strong>st some <strong>in</strong>fectious agents <strong>in</strong> patients <strong>with</strong><br />
normal immune humoral function. After IG was shown to be effective <strong>in</strong> the treatment<br />
of auto-immune and <strong>in</strong>flammatory d<strong>is</strong>orders, the l<strong>is</strong>t of d<strong>is</strong>ease for which it <strong>is</strong> used has<br />
grown rapidly.
<strong>KCE</strong> Reports 120 Plasma 43<br />
3.2 INDICATIONS FOR IMMUNOGLOBULINS<br />
Th<strong>is</strong> section aims at identify<strong>in</strong>g the d<strong>is</strong>eases requir<strong>in</strong>g significant amounts of<br />
immunoglobul<strong>in</strong>s, to enable <strong>in</strong>terpretation of IG amounts consumed or calculation of<br />
amounts required. We describe and compare the recommendations for IG use <strong>in</strong><br />
Belgium and <strong>in</strong> five other <strong>in</strong>dustrialized countries. Based on the <strong>in</strong>dications that are<br />
<strong>in</strong>cluded <strong>in</strong> at least one country (29 <strong>in</strong>dications), we present a review of the scientific<br />
evidence on IG effectiveness to date.<br />
Warn<strong>in</strong>g: In th<strong>is</strong> document, the term <strong>in</strong>dication <strong>is</strong> used to refer to a d<strong>is</strong>ease or<br />
syndrome for which immunoglobul<strong>in</strong> (IG) <strong>is</strong> used or considered to be used. It does not<br />
stand for “authorized <strong>in</strong>dication” or “licensed <strong>in</strong>dication”, which refers to the<br />
<strong>in</strong>dications proposed by the manufacturer and authorized by the drug regulatory<br />
authority.<br />
3.2.1 Recommendations for the use of immunoglobul<strong>in</strong>s<br />
<strong>The</strong> recommendations on which d<strong>is</strong>eases can be treated <strong>with</strong> polyvalent<br />
3.2.1.1<br />
immunoglobul<strong>in</strong>s vary per country, as well as the status of the recommendations.<br />
A few countries have developed full evidence-based guidel<strong>in</strong>es, such as Canada and the<br />
United K<strong>in</strong>gdom (UK), extend<strong>in</strong>g recommendations beyond the labelled <strong>in</strong>dications;<br />
other countries, such as Belgium, did not develop guidel<strong>in</strong>es yet but have legally def<strong>in</strong>ed<br />
a l<strong>is</strong>t of reimbursed <strong>in</strong>dications; for others countries, such as the Netherlands, a l<strong>is</strong>t of<br />
“labelled” <strong>in</strong>dications <strong>is</strong> presented (i.e. <strong>in</strong>dications approved by the regulatory drug<br />
agency). As a consequence, the legal status of these recommendations differs per<br />
country.<br />
Recommendations <strong>in</strong> Belgium<br />
In Belgium, official recommendations for IG use have not been yet publ<strong>is</strong>hed, but<br />
guidel<strong>in</strong>es for IG use are currently under development by the Health Council<br />
(CSS/HGR). <strong>The</strong> only sources for guidance on IG use are the l<strong>is</strong>t of <strong>in</strong>dications that are<br />
authorized <strong>in</strong> Belgium for each IG brand product (labelled <strong>in</strong>dications) and the l<strong>is</strong>t of<br />
reimbursed <strong>in</strong>dications and criteria for reimbursement for each <strong>in</strong>dication, stated <strong>in</strong> the<br />
law (Table 19):<br />
• <strong>The</strong> authorized <strong>in</strong>dications vary per brand product and over time.<br />
• <strong>The</strong> <strong>in</strong>dications and criteria for which IG are reimbursed by the<br />
INAMI/RIZIV are described <strong>in</strong> the Royal Decree from 21 December 2001,<br />
<strong>with</strong> last modification stated <strong>in</strong> the M<strong>in</strong><strong>is</strong>terial Decree from 15 July 2008. d<br />
Intravenous immunoglobul<strong>in</strong>s<br />
In Belgium, several brands or pharmaceutical specialities of <strong>in</strong>travenous immunoglobul<strong>in</strong>s<br />
(IVIG) are reg<strong>is</strong>tered. Though reimbursed <strong>in</strong>dications vary per brand product, the<br />
follow<strong>in</strong>g pathologies are considered <strong>in</strong> the decree and summarized <strong>in</strong> Table 19:<br />
1. Haematological <strong>in</strong>dications<br />
• Primary immune deficiency conditions: agammaglobul<strong>in</strong>emia;<br />
hypogammaglobul<strong>in</strong>emia <strong>with</strong> specific criteria; congenital deficiency <strong>in</strong> antipolysaccharidic<br />
antibodies (provid<strong>in</strong>g specific criteria are met)<br />
• Secondary immune deficiency:<br />
o Multiple myeloma and chronic lymphocytic leukaemia <strong>with</strong> severe<br />
hypogammaglobul<strong>in</strong>emia and recurrent <strong>in</strong>fections<br />
o Prevention of <strong>in</strong>fections <strong>in</strong> patients hav<strong>in</strong>g an allogenic bone marrow<br />
transplant<br />
o Paediatric AIDS<br />
o Treatment of septicaemia <strong>in</strong> preterm <strong>in</strong>fants and neonates<br />
d Arrêté m<strong>in</strong><strong>is</strong>tériel du 18 juillet 2008 modifiant la l<strong>is</strong>te jo<strong>in</strong>te à l'arrêté royal du 21 décembre 2001 fixant<br />
les procédures, déla<strong>is</strong> et conditions en matière d'<strong>in</strong>tervention de l'assurance obligatoire so<strong>in</strong>s de santé et<br />
<strong>in</strong>demnités dans le coût des spécialités pharmaceutiques (MB 18 JUILLET 2008 DEUXIEME EDITION).
44 Plasma <strong>KCE</strong> Reports 120<br />
• Idiopathic thrombocytopenic purpura: <strong>in</strong> children and <strong>in</strong> adults present<strong>in</strong>g<br />
a high r<strong>is</strong>k of bleed<strong>in</strong>g or for those await<strong>in</strong>g surgery<br />
2. Neurological <strong>in</strong>dications<br />
• Guilla<strong>in</strong>-Barré syndrome, <strong>with</strong> specific criteria<br />
• Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyradiculoneuropathy (CIDP), <strong>with</strong><br />
specific criteria<br />
• Multifocal motor neuropathy (MMN), <strong>with</strong> specific criteria<br />
3. Other <strong>in</strong>dications<br />
• Kawasaki d<strong>is</strong>ease<br />
• Treatment of the toxic shock syndrome (TSS) due to streptococcal<br />
<strong>in</strong>fections<br />
Table 19: Indications and reimbursement by pharmaceutical specialty of<br />
<strong>in</strong>travenous immunoglobul<strong>in</strong>s, Belgium, as of October 2008<br />
Indications / brand product Sandoglobul<strong>in</strong> Multigam® Gammagard®<br />
of immunoglobul<strong>in</strong><br />
®<br />
a Octagam®<br />
Nanogam®<br />
Primary immune deficiency<br />
conditions (specified)<br />
I, R I, R I, R I, R<br />
Multiple myeloma and chronic<br />
lymphocytic leukaemia<br />
I, R I, R I, R I, R<br />
Paediatric AIDS R I, R I, R I, R<br />
Idiopathic thrombocytopenic<br />
purpura<br />
I, R I, R I, R I, R<br />
Guilla<strong>in</strong>-Barré syndrome I, R I, R I, R I, R<br />
Kawasaki d<strong>is</strong>ease R I, R R I, R<br />
Allogenous bone marrow<br />
transplant<br />
I, R I, R I, R I, R<br />
Treatment of septicaemia <strong>in</strong><br />
preterm and neonates<br />
R I, R (2002)<br />
Treatment of toxic shock<br />
syndrome due to streptococcal<br />
<strong>in</strong>fection<br />
I, R<br />
Chronic <strong>in</strong>flammatory<br />
demyel<strong>in</strong>at<strong>in</strong>g<br />
polyradiculoneuropathy<br />
I, R (2002) I, R (2003)<br />
Multifocal motor neuropathy I, R (2002) R (2008)<br />
Rheumatoid polyarthrit<strong>is</strong> I<br />
For humoral immune deficiency I (R for above<br />
I (R for above<br />
follow<strong>in</strong>g cytostatic treatment <strong>in</strong>dications)<br />
<strong>in</strong>dications)<br />
I: <strong>in</strong>cluded <strong>in</strong> <strong>in</strong>dications<br />
R: reimbursed <strong>in</strong>dication (date of <strong>in</strong>troduction of reimbursement)<br />
a: <strong>in</strong>terpretation of the <strong>in</strong>dications that are labelled <strong>in</strong> these general terms: “used <strong>in</strong> the<br />
substitution treatment of primary and secondary immune deficiencies, as for the prevention of<br />
<strong>in</strong>fections result<strong>in</strong>g from these immune deficiencies. Used <strong>in</strong> the aim of modify<strong>in</strong>g or controll<strong>in</strong>g<br />
the immune response <strong>in</strong> many d<strong>is</strong>eases.”<br />
<strong>The</strong> l<strong>is</strong>t of reimbursed <strong>in</strong>dications per brand product has also evolved over time. <strong>The</strong><br />
neurological <strong>in</strong>dications CIDP and MMN have been added <strong>in</strong> the l<strong>is</strong>t of reimbursed<br />
<strong>in</strong>dications <strong>in</strong> July 2002 for Sandoglobul<strong>in</strong>® and later for Multigam® (CIDP <strong>in</strong> 2004 and<br />
MMN <strong>in</strong> 2008). For each patient <strong>with</strong> CIDP or MMN, there <strong>is</strong> a maximum<br />
reimbursement of 9 g/kg per patient every 6 months, after a positive cl<strong>in</strong>ical evaluation.
<strong>KCE</strong> Reports 120 Plasma 45<br />
Subcutaneous immunoglobul<strong>in</strong>s<br />
Sub-cutaneous immunoglobul<strong>in</strong>s, Subcuvia® and Vivaglob<strong>in</strong>®, are reimbursed for the<br />
follow<strong>in</strong>g <strong>in</strong>dications:<br />
• Primary immune deficiency conditions: agammaglobul<strong>in</strong>emia,<br />
hypogammaglobul<strong>in</strong>emia <strong>with</strong> specific criteria, congenital deficiency <strong>in</strong> antipolysaccharidic<br />
antibodies <strong>with</strong> specific criteria<br />
• Multiple myeloma and chronic lymphocytic leukaemia.<br />
3.2.1.2 Recommendations <strong>in</strong> other countries<br />
<strong>The</strong> recommendations for IG use <strong>in</strong> terms of which cl<strong>in</strong>ical <strong>in</strong>dications can be treated<br />
<strong>with</strong> IG are presented for five other <strong>in</strong>dustrialized countries and compared to Belgium<br />
<strong>in</strong> Table 20.<br />
In Canada, the UK and Australia, guidel<strong>in</strong>es are clearly stat<strong>in</strong>g that “IG therapy <strong>is</strong> not<br />
<strong>in</strong>dicated” for specific conditions, described as “No” <strong>in</strong> the table, when applicable.<br />
<strong>The</strong> sources of these recommendations on IG use are described below:<br />
1. In Canada, detailed national guidel<strong>in</strong>es cover<strong>in</strong>g the haematological and<br />
neurological <strong>in</strong>dications have been publ<strong>is</strong>hed <strong>in</strong> four articles <strong>in</strong> the journal<br />
Transfusion Medic<strong>in</strong>e Reviews <strong>in</strong> 2007. 18-21 <strong>The</strong>y have been elaborated by a<br />
special committee, based on scientific evidence and us<strong>in</strong>g expert panels.<br />
2. In the United K<strong>in</strong>gdom, evidence-based guidel<strong>in</strong>es from the Department of<br />
Health have been elaborated and the most updated version <strong>is</strong> dated May<br />
2008. 17 Besides a l<strong>is</strong>t of recommendations on IG use, a l<strong>is</strong>t of “grey<br />
<strong>in</strong>dications” has been establ<strong>is</strong>hed: grey <strong>in</strong>dications are those “for which the<br />
evidence base <strong>is</strong> weak, <strong>in</strong> many cases because the d<strong>is</strong>ease <strong>is</strong> rare, and for<br />
which IVIG treatment should be considered on a case by case bas<strong>is</strong>,<br />
priorit<strong>is</strong>ed aga<strong>in</strong>st other compet<strong>in</strong>g demands”. Th<strong>is</strong> comprehensive l<strong>is</strong>t of<br />
grey <strong>in</strong>dications <strong>is</strong> not <strong>in</strong>cluded <strong>in</strong> the table unless the d<strong>is</strong>ease was l<strong>is</strong>ted <strong>in</strong><br />
other country recommendations, and grey <strong>in</strong>dications are <strong>in</strong>dicated <strong>with</strong> a<br />
“(3)”, see Table 3 legend. Th<strong>is</strong> guidel<strong>in</strong>e also <strong>in</strong>cludes a short l<strong>is</strong>t of<br />
<strong>in</strong>dications for which IVIG <strong>is</strong> not recommended (<strong>in</strong>dicated as “No” <strong>in</strong> the<br />
table).<br />
3. In the Netherlands, labelled <strong>in</strong>dications are described <strong>in</strong> a document for<br />
prescribers from the Medic<strong>in</strong>es Evaluation Board (2003). e<br />
4. In France, full recommendations have not been yet establ<strong>is</strong>hed at national<br />
level. Each IG specialty has a limited l<strong>is</strong>t of authorized <strong>in</strong>dications; <strong>in</strong> addition,<br />
a wider l<strong>is</strong>t of d<strong>is</strong>eases for which IG <strong>is</strong> recommended has been publ<strong>is</strong>hed by<br />
the “Comm<strong>is</strong>sion de la Transparence”, “Haute Autorité de Santé” (HAS) for<br />
specific products, and from the Drug Agency (AFSSAPS) for IG <strong>in</strong> general <strong>in</strong><br />
its document «Proposition de hiérarch<strong>is</strong>ation des <strong>in</strong>dications des<br />
immunoglobul<strong>in</strong>es huma<strong>in</strong>es <strong>in</strong>trave<strong>in</strong>euses (IgIV) en situation de tension<br />
forte sur les approv<strong>is</strong>ionnements pour le marché frança<strong>is</strong>, 06/05/2008 ».f<br />
Cl<strong>in</strong>ical <strong>in</strong>dications have been categorized per level of priority <strong>in</strong> several<br />
groups, to identify patients that should receive IG <strong>in</strong> a context of shortage.<br />
On one hand, the <strong>in</strong>dications <strong>in</strong>cluded <strong>in</strong> the market<strong>in</strong>g authorizations<br />
(Autor<strong>is</strong>ation de M<strong>is</strong>e sur le Marché or AMM) have been classified <strong>in</strong> priority<br />
groups: priority <strong>in</strong>dications; <strong>in</strong>dications to keep for vital emergencies or after<br />
failure of alternative treatment; and non-priority <strong>in</strong>dications (that can wait till<br />
shortage end). On the other hand, a l<strong>is</strong>t of d<strong>is</strong>eases non <strong>in</strong>cluded <strong>in</strong> the AMM<br />
e Medic<strong>in</strong>es Evaluation Board. http://db.cbg-meb.nl/IB-teksten/h16942.pdf<br />
f AFSSAPS. Proposition de Hiérarch<strong>is</strong>ation des <strong>in</strong>dications des IgIV reconnues dans l'AMM, d<strong>is</strong>ponible dans<br />
la circulaire DGS/PP/DHOS/E2/AFSSaPS/2008/92 du 14/03/2008 relative à la surveillance des<br />
approv<strong>is</strong>ionnements en immunoglobul<strong>in</strong>es huma<strong>in</strong>es normales et à la gestion des situations de tension. 6<br />
June 2008. Available on http://www.afssaps.fr/Infos-de-securite/Autres-mesures-de-securite/Propositionde-hierarch<strong>is</strong>ation-des-<strong>in</strong>dications-des-immunoglobul<strong>in</strong>es-huma<strong>in</strong>es-<strong>in</strong>trave<strong>in</strong>euses-IgIV-en-situation-detension-forte-sur-les-approv<strong>is</strong>ionnements-pour-le-marche-franca<strong>is</strong>2<br />
Accessed January 2009.
46 Plasma <strong>KCE</strong> Reports 120<br />
has been classified <strong>in</strong> 5 groups and publ<strong>is</strong>hed by the AFSSAPS, based on the<br />
expert recommendations. g In total, 8 groups of d<strong>is</strong>eases are def<strong>in</strong>ed, and how<br />
to apply these priority levels <strong>is</strong> not clearly described.<br />
5. In Australia, the “Criteria for the cl<strong>in</strong>ical use of <strong>in</strong>travenous immunoglobul<strong>in</strong><br />
<strong>in</strong> Australia” has been <strong>is</strong>sued by the Australian health M<strong>in</strong><strong>is</strong>ters’ conference <strong>in</strong><br />
December 2007. 22 It <strong>is</strong> <strong>in</strong>tended to be regularly updated, and rev<strong>is</strong>ions are<br />
periodically <strong>is</strong>sued on http://www.nba.gov.au/ivig/pdf/criteria-rev<strong>is</strong>ions.pdf<br />
(last update February 2009). It also set up several groups of d<strong>is</strong>eases for<br />
priority sett<strong>in</strong>g: 1. Conditions for which IVIg has an establ<strong>is</strong>hed therapeutic<br />
role; 2. conditions for which IVIg has an emerg<strong>in</strong>g therapeutic role: 3.<br />
conditions for which IVIg <strong>is</strong> used <strong>in</strong> exceptional circumstances; 4. conditions<br />
for which IVIg use <strong>is</strong> not <strong>in</strong>dicated.<br />
As previously said, the legal status of these recommendations differs per country, due<br />
to the difference between sources describ<strong>in</strong>g them.<br />
Based on the compar<strong>is</strong>on of national recommendations (Table 20), the follow<strong>in</strong>g<br />
conclusions on <strong>in</strong>dication for IG can be drawn:<br />
• IG <strong>is</strong> recommended <strong>in</strong> all countries for a number of d<strong>is</strong>eases, <strong>in</strong> a<br />
cons<strong>is</strong>tent way: primary immune deficiencies, multiple myeloma and<br />
chronic lymphocytic leukaemia for selected situations, idiopathic<br />
thrombocytopenic purpura, Kawasaki d<strong>is</strong>ease and selected neurological<br />
d<strong>is</strong>eases such as Guilla<strong>in</strong> Barré syndrome. It should be noted that the<br />
recommendations publ<strong>is</strong>hed <strong>in</strong> the Netherlands <strong>in</strong>clude only a limited<br />
number of <strong>in</strong>dications because only reimbursed <strong>in</strong>dications are l<strong>is</strong>ted; th<strong>is</strong><br />
does not precludes that IG use <strong>is</strong> accepted for other d<strong>is</strong>eases.<br />
• In many <strong>in</strong>dications, IG <strong>is</strong> only recommended <strong>in</strong> “selected” cases of a<br />
given d<strong>is</strong>ease, accord<strong>in</strong>g to specific criteria described by each country.<br />
Criteria <strong>in</strong>clude cl<strong>in</strong>ical variables, severity or level of d<strong>is</strong>ability, age,<br />
biological criteria (e.g. serum Ig levels) or therapeutic response to other<br />
treatments. For <strong>in</strong>stance, IG <strong>is</strong> only recommended for multiple scleros<strong>is</strong><br />
and dermatomyosit<strong>is</strong> cases show<strong>in</strong>g failure or contra-<strong>in</strong>dications to<br />
standard treatment.<br />
• However for many other d<strong>is</strong>eases, recommendations for the use of IG are<br />
not cons<strong>is</strong>tent across countries. In most of these d<strong>is</strong>eases, the <strong>available</strong><br />
evidence on IG effectiveness <strong>is</strong> either not <strong>available</strong>, of low level,<br />
<strong>in</strong>cons<strong>is</strong>tent across studies, or only show a marg<strong>in</strong>al benefit.<br />
Key po<strong>in</strong>ts<br />
• In these six <strong>in</strong>dustrialized countries, IG <strong>is</strong> recommended for a def<strong>in</strong>ed<br />
number of d<strong>is</strong>eases <strong>in</strong> a cons<strong>is</strong>tent way.<br />
• In many <strong>in</strong>dications, IG <strong>is</strong> only recommended <strong>in</strong> “selected” cases and the<br />
criteria for IG treatment vary per country.<br />
• In a number of d<strong>is</strong>eases, IG <strong>is</strong> not recommended on a cons<strong>is</strong>tent way across<br />
countries. Th<strong>is</strong> mostly concern d<strong>is</strong>eases <strong>with</strong> an auto-immune component,<br />
for which the <strong>available</strong> evidence <strong>is</strong> either of low level or only shows marg<strong>in</strong>al<br />
benefit.<br />
g Comité d’Evaluation et de Diffusion des Innovations Techniques” (CEDIT) of the “Ass<strong>is</strong>tance Publique des<br />
Hôpitaux de Par<strong>is</strong>. Proposition de Hiérarch<strong>is</strong>ation des <strong>in</strong>dications hors AMM des IgIV réal<strong>is</strong>ée par le<br />
Comité d'experts IgIV du Cedit de l'AP-HP, dans l'attente de la publication par l'Afssaps prévue d'ici f<strong>in</strong><br />
Ju<strong>in</strong> 2008 des référentiels de bon usage sur les IgIV, qui déf<strong>in</strong>iront les situations temporairement<br />
acceptables justifiant la m<strong>is</strong>e en place d'un protocole thérapeutique temporaire. Available on<br />
http://www.afssaps.fr/Infos-de-securite/Autres-mesures-de-securite/Proposition-de-hierarch<strong>is</strong>ation-des<strong>in</strong>dications-des-immunoglobul<strong>in</strong>es-huma<strong>in</strong>es-<strong>in</strong>trave<strong>in</strong>euses-IgIV-en-situation-de-tension-forte-sur-lesapprov<strong>is</strong>ionnements-pour-le-marche-franca<strong>is</strong>2
<strong>KCE</strong> Reports 120 Plasma 47<br />
Table 20: Recommendations for <strong>in</strong>travenous immunoglobul<strong>in</strong>s use <strong>in</strong> six selected countries<br />
Indications Belgium a Canada b <strong>The</strong> UK b Netherlands c France d Australia b<br />
Immuno-haematological <strong>in</strong>dications<br />
Idiopathic thrombocytopenic<br />
purpura<br />
Yes, selected (1) Yes (1) Yes, selected Yes (1) Yes, selected (1) Yes, selected<br />
Primary immune deficiency<br />
conditions<br />
Secondary immune deficiencies:<br />
Yes, selected (1) Yes (1) Yes, long term Yes, selected (1) Yes (1) Yes, selected<br />
- <strong>in</strong> general<br />
Not mentioned Yes (1)<br />
Yes (3)<br />
Not mentioned Yes (1)<br />
Yes <strong>in</strong> general, for<br />
selected conditions<br />
Yes, selected (1) Yes, selected (2) Yes, selected Yes, <strong>in</strong> CLL (1) Yes, selected (1) Yes, selected<br />
- multiple myeloma, chronic<br />
lymphocytic leukaemia<br />
- Allogenous bone marrow<br />
transplant<br />
- paediatric HIV/AIDS<br />
- <strong>in</strong> solid organ transplant<br />
- septicaemia <strong>in</strong> neonates<br />
- <strong>in</strong>fections <strong>in</strong> preterm and/or low<br />
birth weight<br />
Isoimmune haemolytic jaundice <strong>in</strong><br />
neonates<br />
Alloimmune thrombocytopenia,<br />
foetal and neonatal<br />
Yes (1)<br />
No but labelled Yes if low IgG Yes (1)<br />
Yes (1)<br />
Yes, selected<br />
Yes (1) Yes, selected (2) No Yes (1) Yes, selected (1) Yes, selected<br />
Not mentioned NA For CMV<br />
pneumonit<strong>is</strong><br />
For rejection (3)<br />
Yes, kidney (1) Yes (kidney) (3) Yes, selected<br />
Yes treatment (1) NA No Not mentioned Yes (3) Yes but (3)<br />
Preterm, to treat NA NA Yes (
48 Plasma <strong>KCE</strong> Reports 120<br />
Myasthenia grav<strong>is</strong> Not mentioned Yes, selected (2) Yes, selected Not mentioned Yes (3) Yes, selected<br />
Dermatomyosit<strong>is</strong> Not mentioned Yes, selected (2) Yes, selected Not mentioned Yes (3) Yes, selected<br />
Inclusion body myosit<strong>is</strong> Not mentioned No No Not mentioned Yes, selected (3) Yes, selected<br />
Stiff person syndrome<br />
Other <strong>in</strong>dications<br />
Not mentioned Yes, selected (2) Yes, selected Not mentioned Yes (3) Yes, selected<br />
Kawasaki d<strong>is</strong>ease Yes (1) Yes (1) Yes Yes (1) Yes, selected (1) Yes<br />
Treat<strong>in</strong>g septic shock and/or Yes, streptococcus NA Yes, selected Not mentioned Yes, streptococcus Yes, streptococcus<br />
necrotiz<strong>in</strong>g fasciit<strong>is</strong><br />
(1)<br />
(3)<br />
staphylococcus<br />
Viral myocardit<strong>is</strong> <strong>in</strong> children Not mentioned NA Not mentionned Not mentioned Not mentioned Yes but (3)<br />
Yes: Immunoglobul<strong>in</strong> use <strong>is</strong> recommended<br />
No: recommendations state that IG <strong>is</strong> not <strong>in</strong>dicated for that d<strong>is</strong>ease<br />
Selected: Immunoglobul<strong>in</strong> use <strong>is</strong> recommended or reimbursed for th<strong>is</strong> <strong>in</strong>dication <strong>in</strong> selected cases; criteria have been establ<strong>is</strong>hed for recommendation or reimbursement.<br />
NA: non <strong>available</strong>, mean<strong>in</strong>g that recommendations on th<strong>is</strong> <strong>in</strong>dication have not been publ<strong>is</strong>hed yet<br />
Not mentionned: th<strong>is</strong> <strong>in</strong>dication <strong>is</strong> not mentionned <strong>in</strong> exhaustive guidel<strong>in</strong>es or l<strong>is</strong>t of <strong>in</strong>dications<br />
RRMS: relaps<strong>in</strong>g remitt<strong>in</strong>g multiple scleros<strong>is</strong><br />
a: reimbursed <strong>in</strong>dications<br />
b: from national guidel<strong>in</strong>es<br />
c: from labelled <strong>in</strong>dications, accord<strong>in</strong>g to the Medic<strong>in</strong>e Evaluation Board<br />
d: from the “Comm<strong>is</strong>sion de la Transparence », “Haute Autorité de Santé” (HAS), Av<strong>is</strong> 19 juillet 2006 and from AFSSAPS « Proposition de hiérarch<strong>is</strong>ation des <strong>in</strong>dications des<br />
immunoglobul<strong>in</strong>es huma<strong>in</strong>es <strong>in</strong>trave<strong>in</strong>euses (IgIV) en situation de tension forte sur les approv<strong>is</strong>ionnements pour le marché frança<strong>is</strong>, 06/05/2008 ».<br />
(1): Labelled use (or reg<strong>is</strong>tered use or use <strong>in</strong>cluded <strong>in</strong> the market<strong>in</strong>g authorization)<br />
(2): Off-label use (i.e. not <strong>in</strong>cluded <strong>in</strong> the reg<strong>is</strong>tered <strong>in</strong>dications) but IG use <strong>is</strong> recommended for th<strong>is</strong> d<strong>is</strong>ease <strong>in</strong> the guidel<strong>in</strong>es<br />
(3): Use of IG <strong>is</strong> only recommended for th<strong>is</strong> d<strong>is</strong>ease <strong>in</strong> specific cases: after failure of other therapies or <strong>in</strong> vital emergencies (France); considered on a case by case bas<strong>is</strong> <strong>in</strong> the<br />
UK, priorit<strong>is</strong>ed aga<strong>in</strong>st other compet<strong>in</strong>g demands (grey <strong>in</strong>dications); or <strong>in</strong> exceptional circumstances - urgent or life-threaten<strong>in</strong>g circumstances, or <strong>in</strong> circumstances <strong>in</strong> which<br />
significant morbidity would be expected and other cl<strong>in</strong>ically appropriate standard therapies have been exhausted or are contra<strong>in</strong>dicated (Australia).
<strong>KCE</strong> Reports 120 Plasma 49<br />
3.2.2 Evidence review on immunoglobul<strong>in</strong> effectiveness<br />
3.2.2.1 Background<br />
3.2.2.2 Methods<br />
<strong>The</strong> mechan<strong>is</strong>ms of action of polyvalent immunoglobul<strong>in</strong>s (IG) are complex and not<br />
totally elucidated today, aside of their use <strong>in</strong> correct<strong>in</strong>g immunodeficiencies. In<br />
immunodeficiency d<strong>is</strong>eases, polyvalent IG <strong>is</strong> given to restore normal humoral immune<br />
function by <strong>in</strong>creas<strong>in</strong>g antibody levels. In autoimmune d<strong>is</strong>orders and some <strong>in</strong>flammatory<br />
d<strong>is</strong>eases, it <strong>is</strong> assumed to have a rapid immunomodulatory action, by neutraliz<strong>in</strong>g<br />
circulat<strong>in</strong>g auto-antibodies, modulat<strong>in</strong>g the production of <strong>in</strong>flammatory cytok<strong>in</strong>es,<br />
<strong>in</strong>terfer<strong>in</strong>g <strong>in</strong> complement activation, and a few other mechan<strong>is</strong>ms. In the long term, it<br />
also regulates the production of antibodies and cytok<strong>in</strong>es. Th<strong>is</strong> evidence review does<br />
not cover the IG mechan<strong>is</strong>ms of action but it reviews the effectiveness of IG <strong>in</strong> treat<strong>in</strong>g<br />
a number of d<strong>is</strong>eases.<br />
Scope<br />
As more than 100 <strong>in</strong>dications have been considered for IG use, th<strong>is</strong> literature review<br />
focuses on the <strong>in</strong>dications that contribute to address the research question. We<br />
selected <strong>in</strong>dications for which IG are reimbursed or recommended by national<br />
authorities and/or likely to consume significant amounts of IG and/or have been covered<br />
<strong>in</strong> systematic reviews. We <strong>in</strong>cluded the follow<strong>in</strong>g d<strong>is</strong>eases (see Table 21):<br />
• <strong>in</strong>dications reimbursed <strong>in</strong> Belgium<br />
• d<strong>is</strong>eases for which IG <strong>is</strong> recommended <strong>in</strong> five comparable <strong>in</strong>dustrialized<br />
countries (France, Netherlands, UK, Canada and Australia)<br />
• other d<strong>is</strong>eases covered by Cochrane systematic reviews <strong>in</strong>clud<strong>in</strong>g IG<br />
effectiveness<br />
• d<strong>is</strong>eases under <strong>in</strong>vestigation that may consume high amounts of IG<br />
Twenty-n<strong>in</strong>e <strong>in</strong>dications have thus been selected for th<strong>is</strong> literature review:<br />
Haematological d<strong>is</strong>eases<br />
1. Primary immune deficiency conditions<br />
2. Secondary immune deficiencies:<br />
• Multiple myeloma and chronic lymphocytic leukaemia<br />
• Allogenic bone marrow or stem cell transplant<br />
• Prophylax<strong>is</strong> <strong>in</strong> solid organ transplant<br />
• Suspected or proven <strong>in</strong>fections <strong>in</strong> neonates<br />
• Preterm and/or low birth weight <strong>in</strong>fants<br />
• Paediatric HIV/AIDS<br />
3. Idiopathic thrombocytopenic purpura<br />
4. Isoimmune haemolytic jaundice <strong>in</strong> neonates<br />
5. Fetal allo-immune thrombocytopenia<br />
Neurological and neuro-muscular d<strong>is</strong>eases<br />
1. Guilla<strong>in</strong>-Barré syndrome (and variants)<br />
2. Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyradiculoneuropathy<br />
3. Multifocal motor neuropathy<br />
4. Paraprote<strong>in</strong>-associated peripheral neuropathies<br />
5. Multiple scleros<strong>is</strong><br />
6. Lambert-Eaton myasthenic syndrome (LEMS)
50 Plasma <strong>KCE</strong> Reports 120<br />
7. Myasthenia grav<strong>is</strong><br />
8. Dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong><br />
9. Inclusion body myosit<strong>is</strong><br />
10. Stiff person syndrome<br />
11. Neuromyelit<strong>is</strong> optica<br />
Other d<strong>is</strong>eases<br />
1. Kawasaki d<strong>is</strong>ease<br />
2. For treat<strong>in</strong>g seps<strong>is</strong> and septic shock<br />
3. Viral myocardit<strong>is</strong><br />
4. For treat<strong>in</strong>g respiratory syncitial virus <strong>in</strong>fection<br />
D<strong>is</strong>eases under <strong>in</strong>vestigation<br />
1. Chronic fatigue syndrome<br />
2. Alzheimer d<strong>is</strong>ease<br />
Search strategy<br />
<strong>The</strong> search for evidence synthes<strong>is</strong> was focused on systematic reviews. Systematic<br />
reviews identified were subsequently updated <strong>with</strong> orig<strong>in</strong>al RCT publ<strong>is</strong>hed <strong>in</strong> Medl<strong>in</strong>e or<br />
Embase, after the last literature search. For d<strong>is</strong>eases not covered by a systematic<br />
review, publ<strong>is</strong>hed randomized controlled trials (RCT) were considered. <strong>The</strong> date of<br />
search was November 2008 and an update was performed <strong>in</strong> June 2009.<br />
Databases used were the Cochrane review database, the database of abstracts of<br />
reviews of effects (DARE) <strong>in</strong> the Centre for Reviews and D<strong>is</strong>sem<strong>in</strong>ation database (CRD)<br />
(http://www.crd.york.ac.uk/crdweb/), Medl<strong>in</strong>e and Embase. Search terms are described<br />
<strong>in</strong> appendix.<br />
Selection of studies<br />
Evidence synthes<strong>is</strong> studies were eligible if they reviewed the literature systematically on<br />
the cl<strong>in</strong>ical efficacy of polyvalent immunoglobul<strong>in</strong>s (adm<strong>in</strong><strong>is</strong>trated <strong>in</strong>travenously or<br />
subcutaneously), on cl<strong>in</strong>ically relevant outcomes regard<strong>in</strong>g morbidity / mortality /<br />
d<strong>is</strong>ability due to these d<strong>is</strong>eases.<br />
Orig<strong>in</strong>al studies were eligible if they were random<strong>is</strong>ed controlled trials publ<strong>is</strong>hed after<br />
the last systematic review search, or after 1998 if no systematic review was found.<br />
Studies publ<strong>is</strong>hed <strong>in</strong> Engl<strong>is</strong>h, <strong>Dutch</strong>, French and Span<strong>is</strong>h were considered. When no<br />
systematic reviews or randomized controlled trial were found on the d<strong>is</strong>ease of<br />
<strong>in</strong>terest, observational studies cover<strong>in</strong>g the effectiveness of IG publ<strong>is</strong>hed after 1998<br />
were described for <strong>in</strong>formation. Cost-effectiveness studies were also <strong>in</strong>cluded.<br />
Controlled trials on other <strong>in</strong>terventions such as specific immunoglobul<strong>in</strong>s, oral or <strong>in</strong>tramuscular<br />
adm<strong>in</strong><strong>is</strong>tration, and on other health conditions than those l<strong>is</strong>ted under<br />
“Scope” were excluded.<br />
In addition, the eligible references or related articles of the systematic reviews were<br />
searched for any m<strong>is</strong>s<strong>in</strong>g publication, when evidence was lack<strong>in</strong>g or conflict<strong>in</strong>g.
<strong>KCE</strong> Reports 120 Plasma 51<br />
Search results<br />
COCHRANE SYSTEMATIC REVIEWS<br />
N<strong>in</strong>eteen Cochrane Systematic Reviews (last versions) were found on the effectiveness<br />
of immunoglobul<strong>in</strong>s <strong>in</strong> treat<strong>in</strong>g the follow<strong>in</strong>g d<strong>is</strong>eases: multiple myeloma, chronic<br />
lymphocytic leukaemia, bone marrow/stem cell transplant, <strong>is</strong>oimmune haemolytic<br />
jaundice <strong>in</strong> neonates, fetomaternal alloimmune thrombocytopenia, CMV prophylax<strong>is</strong> <strong>in</strong><br />
solid organ transplant, severe <strong>in</strong>fections <strong>in</strong> neonates, for prevent<strong>in</strong>g <strong>in</strong>fection <strong>in</strong> preterm<br />
and low birth weight babies, Guilla<strong>in</strong>-Barré syndrome, chronic <strong>in</strong>flammatory<br />
demyel<strong>in</strong>at<strong>in</strong>g polyradiculoneuropathy, multifocal motor neuropathy, multiple scleros<strong>is</strong>,<br />
paraprote<strong>in</strong>-associated peripheral neuropathies, Lambert-Eaton myasthenic syndrome,<br />
myasthenia grav<strong>is</strong>, dermatomyosit<strong>is</strong>, Kawasaki d<strong>is</strong>ease, treat<strong>in</strong>g seps<strong>is</strong> and septic shock,<br />
viral myocardit<strong>is</strong> and treat<strong>in</strong>g respiratory syncitial virus <strong>in</strong>fection.<br />
CRD DATABASE<br />
We found 105 references on immunoglobul<strong>in</strong>s, <strong>in</strong>clud<strong>in</strong>g 30 which focused on<br />
polyvalent immunoglobul<strong>in</strong>s. <strong>The</strong>se <strong>in</strong>cluded 28 systematic reviews (<strong>in</strong>clud<strong>in</strong>g the 19<br />
Cochrane reviews), 1 guidel<strong>in</strong>e and 1 <strong>report</strong> which fitted the selection criteria.<br />
Appra<strong>is</strong>al of evidence<br />
Relevant papers were reviewed to identify the best evidence to answer the key cl<strong>in</strong>ical<br />
questions. Th<strong>is</strong> process <strong>in</strong>volved selection of relevant studies; assessment of study<br />
quality; synthes<strong>is</strong> of the results; and grad<strong>in</strong>g of the evidence.<br />
<strong>The</strong> critical appra<strong>is</strong>al was done for systematic reviews and additional studies. A level of<br />
evidence (high, moderate or low) was assigned to each body of evidence accord<strong>in</strong>g to<br />
the GRADE methodology, as described by the GRADE work<strong>in</strong>g group (see Appendix). 23
52 Plasma <strong>KCE</strong> Reports 120<br />
Table 21: Summary of evidence f<strong>in</strong>d<strong>in</strong>gs and evidence levels per d<strong>is</strong>ease<br />
D<strong>is</strong>ease / syndrome Ma<strong>in</strong> f<strong>in</strong>d<strong>in</strong>gs Evidence<br />
Primary immune deficiency<br />
conditions<br />
Secondary immune deficiencies:<br />
- multiple myeloma and chronic<br />
lymphocytic leukaemia<br />
- <strong>in</strong> stem cell/bone marrow<br />
transplant (BMT/HSCT)<br />
- <strong>in</strong> solid organ transplant<br />
- for suspected or proven<br />
<strong>in</strong>fection <strong>in</strong> neonates<br />
Large reduction <strong>in</strong> <strong>in</strong>fection severity and <strong>in</strong>cidence <strong>in</strong> XLA, CVID and<br />
agammaglobul<strong>in</strong>emia. No clear benefit <strong>in</strong> specific antibody deficiencies.<br />
IG significantly decreased documented <strong>in</strong>fections and may be considered <strong>in</strong> patients<br />
<strong>with</strong> hypogammaglobul<strong>in</strong>emia and recurrent <strong>in</strong>fections. No impact on mortality.<br />
IG prophylax<strong>is</strong> significantly reduced the r<strong>is</strong>k for <strong>in</strong>terstitial pneumonia after<br />
BMT/HSCT <strong>in</strong> two meta-analyses. IG also significantly reduced the <strong>in</strong>cidence of<br />
CMV pneumonia <strong>in</strong> one meta-analys<strong>is</strong>.<br />
Reduction <strong>in</strong> CMV deaths but no significant reduction of CMV d<strong>is</strong>ease and overall<br />
mortality. Antivirals are effective.<br />
In highly sensitized patients, RCT showed some benefit of IG after transplant but no<br />
significant reduction <strong>in</strong> rejection rates<br />
IG given to neonates <strong>with</strong> proven <strong>in</strong>fection reduced overall mortality <strong>in</strong> 5 metaanalyses.<br />
Reduction <strong>in</strong> mortality <strong>in</strong> neonates <strong>with</strong> suspected <strong>in</strong>fections <strong>is</strong> less clear.<br />
- <strong>in</strong> preterm / low birth weight IG given to <strong>in</strong> preterm and/or low birth weight <strong>in</strong>fants only marg<strong>in</strong>ally reduced<br />
seps<strong>is</strong> and serious <strong>in</strong>fections (by 3-4%), and had no effect on mortality.<br />
level<br />
Comment on level of evidence<br />
Moderate Observational studies and 1 RCT<br />
show<strong>in</strong>g dose-response gradient<br />
High Meta-analys<strong>is</strong> of 10 RCT<br />
Moderate Two meta-analyses of >30 RCT, old<br />
RCT, different results, poor<br />
Moderate<br />
Moderate<br />
directness (BMT treatment evolved)<br />
- Meta-analys<strong>is</strong> of 37 RCT <strong>with</strong> poor<br />
study quality<br />
- 3 small RCT, <strong>in</strong>cons<strong>is</strong>tent results<br />
across RCT<br />
Meta-analys<strong>is</strong> of 9 RCT but sparsity<br />
and <strong>in</strong>cons<strong>is</strong>tent results <strong>with</strong> the<br />
former Cochrane meta-analys<strong>is</strong><br />
High Meta-analys<strong>is</strong> of 19 RCT, 5000<br />
<strong>in</strong>fants, confirm 3 previous metaanalyses<br />
Moderate Several RCT before HAART, lack<br />
- <strong>in</strong> paediatric HIV/AIDS IG decreases <strong>in</strong>cidence of <strong>in</strong>fections and hospital adm<strong>is</strong>sions.<br />
But limited use due to HAART and AB prophylax<strong>is</strong>.<br />
directness<br />
Idiopathic thrombocytopenic - In children <strong>with</strong> acute ITP, IG has higher and quicker effectiveness than no Moderate Meta-analys<strong>is</strong> of 28 RCT but low<br />
purpura (ITP)<br />
treatment or steroids. IG role <strong>in</strong> chronic childhood ITP could not be establ<strong>is</strong>hed.<br />
- In adult ITP, IG may be more effective than steroids <strong>in</strong> the short term. For chronic<br />
ITP, the advantage of IG over other therapies <strong>is</strong> not establ<strong>is</strong>hed.<br />
quality and sparsity<br />
Isoimmune haemolytic d<strong>is</strong>ease <strong>in</strong> IG significantly reduced the need for exchange transfusion and phototherapy. Moderate Meta-analys<strong>is</strong> of 3 small not bl<strong>in</strong>ded<br />
neonates<br />
RCT<br />
Fetal allo-immune<br />
Observational studies suggest a benefit of IG <strong>in</strong> FNAIT. IG added to predn<strong>is</strong>olone Low 26 observational studies, 2 RCTs of<br />
thrombocytopenia (FNAIT) has no higher effectiveness than IG alone<br />
IG added to steroids<br />
Guilla<strong>in</strong>-Barré syndrome (and In severe GBS, IG hastens recovery as much as plasma exchange, but no RCT Moderate In adults, meta-analys<strong>is</strong> of 5 RCT<br />
variants)<br />
compared IG <strong>with</strong> supportive care or placebo. In children, limited evidence suggests for adults, compar<strong>in</strong>g IG to PE; directness<br />
that IG hastens recovery compared <strong>with</strong> supportive care alone.<br />
low for questioned.<br />
children 3 small trials <strong>in</strong> children
<strong>KCE</strong> Reports 120 Plasma 53<br />
CIDP IG improves d<strong>is</strong>ability for up 24-48 weeks compared to placebo, but <strong>is</strong> not more<br />
effective than plasma exchange and predn<strong>is</strong>olone. Unclear which treatment <strong>is</strong> more<br />
effective.<br />
Multifocal motor neuropathy IG showed a significant effect on muscle strength and a non-significant improvement<br />
Paraprote<strong>in</strong>-associated<br />
peripheral neuropathies<br />
Multiple scleros<strong>is</strong><br />
- Relaps<strong>in</strong>g remitt<strong>in</strong>g (RRMS)<br />
- Primary progressive (PPMS)<br />
- Secondary progressive (SPMS)<br />
Lambert-Eaton myasthenic<br />
syndrome<br />
High Meta-analys<strong>is</strong> of 5 RCT vs. placebo,<br />
2 RCT vs. other treatments.<br />
Moderate Meta-analys<strong>is</strong> of 4 RCT, but small<br />
<strong>in</strong> d<strong>is</strong>ability<br />
size and sparse data<br />
In IgM associated neuropathies, IG may produce some short-term benefit.<br />
Moderate Review of 2 small RCT, but quality<br />
In IgG and IgA d<strong>is</strong>ease, evidence on IG effectiveness <strong>is</strong> <strong>in</strong>sufficient.<br />
problems<br />
Low Small observational studies<br />
In RRMS, IG reduced d<strong>is</strong>ease progression and MRI lesions.<br />
Moderate Several meta-analyses, 15 RCT.<br />
IG delayed d<strong>is</strong>ease progression <strong>in</strong> PPMS.<br />
Incons<strong>is</strong>tent results <strong>in</strong> the last and<br />
No effect on d<strong>is</strong>ease progression <strong>in</strong> SPMS.<br />
IG reduced the rate of relapses <strong>in</strong> the post-partum period.<br />
larger mult<strong>in</strong>ational RCT on RRMS.<br />
IG improved functional capacities and muscle strength <strong>in</strong> a small RCT Low Review but 1 small RCT<br />
Myasthenia grav<strong>is</strong> IG <strong>is</strong> more effective than placebo or as effective as other treatments for severe<br />
exacerbation and worsen<strong>in</strong>g, but th<strong>is</strong> benefit was not shown <strong>in</strong> mild and moderate<br />
d<strong>is</strong>ease.<br />
Dermatomyosit<strong>is</strong> and<br />
polymyosit<strong>is</strong><br />
Inclusion body myosit<strong>is</strong> IG did not improve muscle strength <strong>in</strong> IBM patients but significantly improved<br />
swallow<strong>in</strong>g functions <strong>in</strong> one study<br />
Moderate Review of 6 RCT but one had<br />
<strong>in</strong>cons<strong>is</strong>tent results<br />
IG improved symptoms and muscle strength and was more effective than placebo Moderate Review w/ 1 RCT, 1 non controlled<br />
trial, observational studies<br />
Moderate 3 small RCT (N=47)<br />
Stiff person syndrome IG improved stiffness and sensitivity scores Moderate 1 small RCT<br />
Neuromyelit<strong>is</strong> optica <strong>The</strong> effectiveness of IG <strong>in</strong> neuromyelit<strong>is</strong> optica has not been shown. Low Few case series<br />
Kawasaki d<strong>is</strong>ease IG showed significant decrease <strong>in</strong> new coronary artery abnormalities, fever and<br />
hospitalization compared to placebo.<br />
High Meta-analys<strong>is</strong> of 16 RCT<br />
Viral myocardit<strong>is</strong> <strong>in</strong> children and Limited evidence does not show a benefit of IG over placebo for the management Moderate Review <strong>with</strong> 1 RCT, results<br />
adults<br />
of presumed viral myocardit<strong>is</strong> <strong>in</strong> adults. <strong>The</strong>re <strong>is</strong> no evidence for paediatric cases for adults <strong>in</strong>cons<strong>is</strong>tent <strong>with</strong> open studies<br />
Treat<strong>in</strong>g seps<strong>is</strong> and septic shock IG used as an adjuvant therapy reduces mortality compared to placebo or no<br />
adjuvant therapy <strong>in</strong> 3 recent meta-analyses.<br />
High 3 meta-analyses (11-20 RCT each)<br />
Treat<strong>in</strong>g RSV <strong>in</strong>fection No significant benefit of IG treatment added to supportive care, compared <strong>with</strong> Moderate Review of 4 RCT, heterogeneity of<br />
supportive care alone.<br />
outcomes<br />
Alzheimer d<strong>is</strong>ease (AD) Evidence <strong>is</strong> lack<strong>in</strong>g on the effectiveness of IG Low 2 small case series<br />
Chronic fatigue syndrome No conclusion can be drawn on the effect of IG <strong>in</strong> CFS as the evidence <strong>is</strong><br />
conflict<strong>in</strong>g. <strong>The</strong> larger trial showed no effect, <strong>with</strong> 70-80% of adverse events.<br />
Moderate 3 RCT but <strong>in</strong>cons<strong>is</strong>tent results
54 Plasma <strong>KCE</strong> Reports 120<br />
3.2.2.3 Immuno-hematological d<strong>is</strong>eases<br />
A <strong>summary</strong> of evidence f<strong>in</strong>d<strong>in</strong>gs and levels of evidence for IG use <strong>is</strong> presented <strong>in</strong> Table<br />
21.<br />
Primary immune deficiencies<br />
Primary immunodeficiency d<strong>is</strong>orders (PID) result from <strong>in</strong>tr<strong>in</strong>sic defects of the immune<br />
system, <strong>in</strong> contrast to immune d<strong>is</strong>orders that are secondary to <strong>in</strong>fection, chemotherapy<br />
or immunosuppressive therapy. Individuals <strong>with</strong> PID are prone to recurrent bacterial<br />
<strong>in</strong>fections, typically <strong>in</strong> respiratory and gastro-<strong>in</strong>test<strong>in</strong>al tracts, or protozoal, fungal and<br />
viral <strong>in</strong>fections, of vary<strong>in</strong>g severity. Deficiencies of various components of the immune<br />
system have been identified, and more than 200 different PID are currently recognized<br />
by the WHO. In Europe, the PID requir<strong>in</strong>g IG replacement that are the most commonly<br />
diagnosed are: the common variable immunodeficiency (CVID) - revealed at adulthood,<br />
X-l<strong>in</strong>ked agammaglobul<strong>in</strong>emia (XLA), other agammaglobul<strong>in</strong>emia, W<strong>is</strong>kott-Aldrich<br />
syndrome, severe comb<strong>in</strong>ed immunodeficiency, hyper-IgM syndromes and severe<br />
hypogammaglobul<strong>in</strong>emia <strong>with</strong> recurrent and severe bacterial <strong>in</strong>fections. 24 In most of the<br />
cases <strong>with</strong> severe antibody deficiency (IgG
<strong>KCE</strong> Reports 120 Plasma 55<br />
• IG reduces the <strong>in</strong>cidence and severity of <strong>in</strong>fection <strong>in</strong> patients <strong>with</strong><br />
agammaglobul<strong>in</strong>emia and severe hypo-gammaglobul<strong>in</strong>emia.<br />
• Effectiveness of IG <strong>in</strong> milder hypogammaglobul<strong>in</strong>emia, IgG subclass<br />
deficiency and impaired polysaccharide responsiveness <strong>is</strong> unclear.<br />
• <strong>The</strong> route of adm<strong>in</strong><strong>is</strong>tration (IV or SC) does not <strong>in</strong>fluence treatment<br />
effectiveness.<br />
Secondary immune deficiencies<br />
In many patients, the immune deficiency <strong>is</strong> a direct consequence of a decreased antibody<br />
production due to cancers of the haematopoietic system, such as multiple myeloma or<br />
chronic lymphocytic leukaemia, cytotoxic chemotherapy, immunosuppressive therapy to<br />
prevent transplants rejection, very low weight etc.<br />
<strong>The</strong> effectiveness of IG <strong>in</strong> treat<strong>in</strong>g the conditions lead<strong>in</strong>g to secondary immune<br />
deficiency varies per pathology. It has only been well studied for specific pathologies,<br />
such as multiple myeloma, chronic lymphocytic leukaemia and stem cell transplants (see<br />
below). For hypo-gammaglobul<strong>in</strong>emia related to other d<strong>is</strong>eases or drug therapy, no<br />
evidence on the benefit of IG treatment was found. However, most guidel<strong>in</strong>es<br />
recommend the use of IG – besides antimicrobial prophylax<strong>is</strong> – to decrease the r<strong>is</strong>k of<br />
<strong>in</strong>fection <strong>in</strong> cases <strong>with</strong> the same criteria than those set for PID requir<strong>in</strong>g IG<br />
supplementation: IgG levels under reference range and severe or recurrent bacterial<br />
<strong>in</strong>fections that are unresponsive to prophylactic antibiotics etc. 17, 22 .<br />
Multiple myeloma and chronic lymphocytic leukaemia<br />
Multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) are rare proliferative<br />
d<strong>is</strong>orders that lead to a higher <strong>in</strong>cidence of serious bacterial <strong>in</strong>fections, such as<br />
pneumonias and ur<strong>in</strong>ary tract <strong>in</strong>fections. Factors underly<strong>in</strong>g the <strong>in</strong>creased susceptibility<br />
to <strong>in</strong>fections are many and complex. A major factor <strong>is</strong> the decreased capacity to<br />
produce potent immunoglobul<strong>in</strong>s, often reflected by a certa<strong>in</strong> degree of hypogammaglobul<strong>in</strong>emia<br />
observed <strong>in</strong> the majority of patients. In MM, the immunodeficiency<br />
<strong>is</strong> ma<strong>in</strong>ly caused by abnormal Ig production and impairment of the primary immune<br />
response. 41 Infections and its consequences (<strong>in</strong>clud<strong>in</strong>g renal failure) are the major cause<br />
of morbidity and mortality <strong>in</strong> both d<strong>is</strong>eases. Up to 65% of CLL patients die from<br />
<strong>in</strong>fection-related events and MM cases have a fatality rate of 30%. Many treatment<br />
strategies ex<strong>is</strong>t for MM and CLL; IG <strong>is</strong> ma<strong>in</strong>ly used as prophylactic agent to prevent<br />
<strong>in</strong>fections, mostly <strong>in</strong> recurrent life threaten<strong>in</strong>g <strong>in</strong>fections. 42<br />
A Cochrane review updated <strong>in</strong> 2009 <strong>in</strong>cluded ten RCT <strong>in</strong>volv<strong>in</strong>g MM or CLL patients<br />
<strong>with</strong> hypogammaglobul<strong>in</strong>emia and recurrent <strong>in</strong>fections, and the meta-analys<strong>is</strong> comb<strong>in</strong>ed<br />
studies from both d<strong>is</strong>eases. 43 It showed that no benefit of IG could be demonstrated <strong>in</strong><br />
terms of mortality, but IG significantly decreased the r<strong>is</strong>k of cl<strong>in</strong>ically documented<br />
<strong>in</strong>fections by 51% (RR 0.49, 95% CI 0.39-0.61), and significantly reduced the occurrence<br />
of microbiologically documented <strong>in</strong>fections as compared to controls (RR 0.71, 95% CI<br />
0.53-0.95). Authors concluded that IG use may be considered <strong>in</strong> MM and CLL patients<br />
<strong>with</strong> hypogammaglobul<strong>in</strong>emia and recurrent <strong>in</strong>fections, for the reduction of cl<strong>in</strong>ically<br />
documented <strong>in</strong>fections.<br />
Another systematic review, conducted by the same group, <strong>in</strong>cluded n<strong>in</strong>e of the 10 RCT<br />
<strong>in</strong>volv<strong>in</strong>g CLL and MM patients, and presented similar f<strong>in</strong>d<strong>in</strong>gs and conclusions. 44<br />
A 2005 systematic review on the cost of d<strong>is</strong>ease <strong>in</strong>cluded cost-effectiveness studies. 45 It<br />
only found one cost effectiveness study on IG, publ<strong>is</strong>hed <strong>in</strong> 1991, thus excluded from<br />
th<strong>is</strong> review. 46<br />
IG significantly decreased documented <strong>in</strong>fections <strong>in</strong> CLL and MM patients but<br />
had no impact on mortality. IG <strong>is</strong> considered <strong>in</strong> patients <strong>with</strong> documented<br />
hypogammaglobul<strong>in</strong>emia and recurrent <strong>in</strong>fections.
56 Plasma <strong>KCE</strong> Reports 120<br />
Bone marrow transplantation and hematopoietic stem cell transplantation<br />
Bone marrow transplantation (BMT) and hematopoietic stem cell transplantation<br />
(HSCT) comprom<strong>is</strong>e the immune system of patients due to the adm<strong>in</strong><strong>is</strong>tration of high<br />
doses of chemo-radiotherapy prior to <strong>in</strong>fusion of the donor stem cells. 44 Multiple<br />
immunological deficiencies, <strong>in</strong>clud<strong>in</strong>g T- and B-cell abnormalities and<br />
hypogammaglobul<strong>in</strong>emia, pred<strong>is</strong>pose patients to a high r<strong>is</strong>k of develop<strong>in</strong>g <strong>in</strong>fections. As<br />
the <strong>in</strong>cidence of CMV seropositivity <strong>in</strong> the general population <strong>is</strong> high, CMV reactivation<br />
and subsequent d<strong>is</strong>ease becomes a significant prognostic factor of morbidity and<br />
mortality <strong>in</strong> BMT/HSTC. Even though antiviral agents can <strong>in</strong>hibit the viral replication <strong>in</strong><br />
vivo, they have not been able to treat CMV <strong>in</strong>terstitial pneumonia effectively. Th<strong>is</strong><br />
period of immunological <strong>in</strong>competence usually lasts from six to 12 months. <strong>The</strong>se<br />
abnormalities are less prom<strong>in</strong>ent <strong>in</strong> autologous than <strong>in</strong> allogenic transplantations.<br />
Systematic reviews of evidence are contradictory, despite numerous RCT on th<strong>is</strong> area,<br />
as many of them have divergent f<strong>in</strong>d<strong>in</strong>gs.<br />
On one hand, the Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2008 <strong>in</strong>cluded 30 RCT <strong>with</strong> 4223<br />
patients receiv<strong>in</strong>g prophylax<strong>is</strong> after BMT/HSCT. 43 Twenty-one RCT evaluated polyvalent<br />
IG or compared it to CMV hyper-immune IG. <strong>The</strong> analys<strong>is</strong> did not d<strong>is</strong>t<strong>in</strong>gu<strong>is</strong>h between<br />
allogenic or autologous transplantation. When polyvalent IG was compared to control,<br />
there was no difference <strong>in</strong> all-cause mortality. IG significantly reduced the r<strong>is</strong>k for<br />
<strong>in</strong>terstitial pneumonia but <strong>in</strong>creased the r<strong>is</strong>k for veno-occlusive d<strong>is</strong>ease and adverse<br />
events. Th<strong>is</strong> review concluded that rout<strong>in</strong>e prophylax<strong>is</strong> <strong>with</strong> IG <strong>is</strong> not supported by<br />
<strong>available</strong> evidence for these patients.<br />
On the other hand, a meta-analys<strong>is</strong> of 12 RCT <strong>in</strong>volv<strong>in</strong>g 1282 patients was conducted <strong>in</strong><br />
1993 and showed that IG reduced all cause mortality (though <strong>with</strong> borderl<strong>in</strong>e<br />
significance), CMV pneumonia and non-CMV <strong>in</strong>terstitial pneumonia. 47 Three of the trials<br />
were not RCT and the Cochrane review excluded several of them for methodological<br />
reasons; however, th<strong>is</strong> review allocated a quality weight for data analys<strong>is</strong>.<br />
A major limitation of both reviews <strong>is</strong> that the majority of RCTs are old (patients treated<br />
<strong>in</strong> the 80’s and 90’s) while techniques and treatment for patients undergo<strong>in</strong>g<br />
transplantation for haematological malignancies have changed considerably over the last<br />
two decades, such as the use of non-myeloablative treatment. Th<strong>is</strong> may expla<strong>in</strong> the<br />
divergence <strong>in</strong> conclusions between the two meta-analyses. In addition, several RCT<br />
concluded that IG was not found to be beneficial <strong>in</strong> autologous BMT recipients. Despite<br />
the controversy about the benefit of IG <strong>in</strong> HSCT/BMT, th<strong>is</strong> agent <strong>is</strong> still recommended<br />
<strong>in</strong> most transplantation protocols <strong>in</strong> many countries. Some authors suggest that IG<br />
should be reserved for patients who are hypo-gammaglobul<strong>in</strong>aemic after BMT. 48<br />
IG prophylax<strong>is</strong> significantly reduced the r<strong>is</strong>k for <strong>in</strong>terstitial pneumonia after<br />
BMT/HSCT <strong>in</strong> two meta-analyses. IG also significantly reduced the <strong>in</strong>cidence of<br />
CMV pneumonia <strong>in</strong> one meta-analys<strong>is</strong>.
<strong>KCE</strong> Reports 120 Plasma 57<br />
Solid organ transplant<br />
IG may be <strong>in</strong>dicated for two ma<strong>in</strong> problems encountered <strong>in</strong> solid organ transplant<br />
(SOT) recipients:<br />
• On one hand, immunosuppression after SOT <strong>is</strong> associated <strong>with</strong> <strong>in</strong>creased<br />
r<strong>is</strong>k of opportun<strong>is</strong>tic <strong>in</strong>fections, particularly dur<strong>in</strong>g the 6-month posttransplant<br />
period when viral <strong>in</strong>fections are most prevalent. 49<br />
Cytomegalovirus (CMV) <strong>is</strong> a major cause of d<strong>is</strong>ease and death <strong>in</strong> SOT<br />
recipients dur<strong>in</strong>g th<strong>is</strong> period, <strong>with</strong> an overall <strong>in</strong>cidence of 30% to 50%.<br />
CMV also has the propensity to establ<strong>is</strong>h lifelong ’latency’ <strong>in</strong>fection <strong>in</strong> the<br />
host after the <strong>in</strong>itial <strong>in</strong>fection has resolved. <strong>The</strong>refore, SOT recipients may<br />
be <strong>in</strong>fected either by exogenous virus or by reactivation of latent virus if<br />
they were CMV positive pre-transplant. Those at highest r<strong>is</strong>k of<br />
symptomatic CMV d<strong>is</strong>ease are thus CMV sero-negative patients who<br />
receive organs from CMV sero-positive donors, and CMV sero-positive<br />
patients on heavily immunosuppressive regimens. CMV <strong>is</strong> also associated<br />
<strong>with</strong> <strong>in</strong>creased r<strong>is</strong>k of allograft <strong>in</strong>jury and rejection, opportun<strong>is</strong>tic<br />
<strong>in</strong>fections and late onset malignancies. Two ma<strong>in</strong> strategies to prevent<br />
CMV d<strong>is</strong>ease ex<strong>is</strong>t: prophylax<strong>is</strong> of all organ recipients <strong>with</strong> antiviral<br />
medications and/or immunoglobul<strong>in</strong>s called ’pre-emptive therapy’ for highr<strong>is</strong>k<br />
groups, such as patients receiv<strong>in</strong>g anti-lymphocyte antibody<br />
preparations.<br />
• On the other hand, one-third of patients await<strong>in</strong>g renal allograft transplant<br />
have high levels of pre-formed anti-HLA antibodies, and are called highlysensitized<br />
patients. 50, 51 If transplanted, these patients experience an<br />
<strong>in</strong>crease number of rejection ep<strong>is</strong>odes and have poorer graft survival.<br />
Over the past several years, high doses of IG have been used to help<br />
improve transplantation rates <strong>in</strong> th<strong>is</strong> group. 52<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2007 <strong>in</strong>cluded 37 RCT on the effectiveness of IG on<br />
CMV r<strong>is</strong>k and d<strong>is</strong>ease. 53 Studies look<strong>in</strong>g at the efficacy of polyvalent IG and CMV<br />
hyperimmune IG were comb<strong>in</strong>ed as no difference between the two groups could be<br />
detected. <strong>The</strong>re was no significant difference <strong>in</strong> the r<strong>is</strong>k for CMV d<strong>is</strong>ease, CMV <strong>in</strong>fection<br />
and all-cause mortality <strong>with</strong> IG compared <strong>with</strong> placebo/no treatment. However, IG<br />
significantly reduced the r<strong>is</strong>k of death from CMV d<strong>is</strong>ease (RR 0.33, 95% CI 0.14-0.80).<br />
Add<strong>in</strong>g IG to antiviral medication did not affect the r<strong>is</strong>k for CMV d<strong>is</strong>ease, CMV <strong>in</strong>fection<br />
or all-cause mortality, compared to antivirals alone. <strong>The</strong> authors concluded that there<br />
are currently no <strong>in</strong>dications for IG <strong>in</strong> the prophylax<strong>is</strong> of CMV d<strong>is</strong>ease <strong>in</strong> SOT recipients,<br />
consider<strong>in</strong>g that the efficacy of several antiviral medications (valganciclovir, ganciclovir,<br />
acyclovir, valganciclovir) have been demonstrated <strong>in</strong> reduc<strong>in</strong>g CMV d<strong>is</strong>ease, CMV<br />
<strong>in</strong>fection, all-cause and CMV related mortality and opportun<strong>is</strong>tic <strong>in</strong>fections.<br />
In highly sensitized patients, no systematic review was found, but three RCT <strong>in</strong>volv<strong>in</strong>g<br />
kidney transplants <strong>in</strong> patients at r<strong>is</strong>k for rejection were retrieved. A first RCT was<br />
conducted <strong>in</strong> 41 patients hav<strong>in</strong>g received a second kidney transplant and treated <strong>with</strong><br />
immunosuppressant. 54 Daily IG was added to the treatment of 21 patients on the first 5<br />
days after transplantation. <strong>The</strong> number of acute rejection ep<strong>is</strong>odes and <strong>in</strong>cidence of<br />
CMV <strong>in</strong>fection were similar but the 5-year survival rate was significantly higher <strong>in</strong> the IG<br />
group compared to the control group. A second RCT, <strong>in</strong>volv<strong>in</strong>g 30 patients <strong>with</strong><br />
confirmed steroid-res<strong>is</strong>tant rejections, compared the effectiveness of IG versus<br />
monoclonal anti-CD3. 55 <strong>The</strong> <strong>in</strong>cidence of rejections after treatment was lower <strong>in</strong> the IG<br />
group compared to the other group but not significantly (46% vs. 75%, p=0.4). Patient<br />
survival rates and graft survival were not significantly different <strong>in</strong> the two groups.
58 Plasma <strong>KCE</strong> Reports 120<br />
A third RCT, conducted <strong>in</strong> 101 patients <strong>with</strong> end-stage renal d<strong>is</strong>ease and <strong>in</strong>volv<strong>in</strong>g 27<br />
kidney transplants, showed that IG was effective <strong>in</strong> reduc<strong>in</strong>g anti-HLA antibody levels,<br />
improv<strong>in</strong>g kidney transplant rates <strong>in</strong> highly sensitized patients compared to placebo, and<br />
decreased wait<strong>in</strong>g time to graft. 51 <strong>The</strong>re was however no significant decrease <strong>in</strong> graft<br />
survival rates and patient survival <strong>in</strong> the IG group compared to placebo and allograft<br />
rejection was significantly higher <strong>in</strong> the IG group. <strong>The</strong> authors concluded that IG pretreatment<br />
should improve the transplant potential for highly sensitized patients <strong>with</strong><br />
end-stage renal d<strong>is</strong>ease await<strong>in</strong>g kidney transplantation, especially those res<strong>is</strong>tant to<br />
other therapies.<br />
• IG, used alone or <strong>with</strong> antivirals, for the prophylax<strong>is</strong> of CMV d<strong>is</strong>ease <strong>in</strong> SOT<br />
recipients did not decrease the r<strong>is</strong>k of CMV d<strong>is</strong>ease and overall mortality<br />
compared to placebo, or to antivirals alone, <strong>in</strong> a meta-analys<strong>is</strong> of 30 RCT. IG<br />
reduced the r<strong>is</strong>k of death from CMV d<strong>is</strong>ease compared to placebo. Antiviral<br />
medications are effective.<br />
• In highly sensitized patients, three RCT suggested some benefit of IG<br />
treatment after transplant but failed to show a significant reduction of<br />
transplant rejection.<br />
Suspected or proven <strong>in</strong>fection <strong>in</strong> neonates<br />
As endogenous synthes<strong>is</strong> of immunoglobul<strong>in</strong>s does not beg<strong>in</strong> until about 24 weeks after<br />
birth, neonates are at high r<strong>is</strong>k for morbidity and mortality from <strong>in</strong>fections acquired <strong>in</strong><br />
utero, as well as from exposure to <strong>in</strong>fectious sources <strong>in</strong> neonatal <strong>in</strong>tensive care units. 56<br />
Seps<strong>is</strong> <strong>is</strong> an important cause of neonatal death and bra<strong>in</strong> damage. Though effective<br />
antibiotic treatment <strong>is</strong> essential for seps<strong>is</strong>, adjuvant therapies such as IG may offer an<br />
additional strategy. <strong>The</strong> rationale for IG treatment for neonatal <strong>in</strong>fections <strong>is</strong> based on<br />
the evidence that it provides IgG that can b<strong>in</strong>d to cell surface receptors, provide<br />
opsonic activity, activate complement, promote antibody dependent cytotoxicity and<br />
improve neutrophilic chemolum<strong>in</strong>escence.<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2004 <strong>in</strong>cluded 9 RCT <strong>in</strong>volv<strong>in</strong>g 553 neonates <strong>with</strong><br />
suspected <strong>in</strong>fection. 57 Six studies <strong>report</strong>ed on mortality and results showed a reduction<br />
<strong>in</strong> mortality follow<strong>in</strong>g IG treatment <strong>in</strong> cases <strong>with</strong> suspected <strong>in</strong>fection of borderl<strong>in</strong>e<br />
stat<strong>is</strong>tical significance. Treatment <strong>with</strong> IG <strong>in</strong> cases of subsequently proven <strong>in</strong>fection did<br />
result <strong>in</strong> a stat<strong>is</strong>tically significant reduction <strong>in</strong> mortality (RR 0.55, 95% CI: 0.31-0.98).<br />
However, the authors po<strong>in</strong>ts that these f<strong>in</strong>d<strong>in</strong>gs are <strong>in</strong> contrast <strong>with</strong> a previous<br />
Cochrane meta-analys<strong>is</strong> (from the same author) that showed the reverse relationship<br />
(significant reduction <strong>in</strong> mortality <strong>in</strong> suspected <strong>in</strong>fections and non significant reduction <strong>in</strong><br />
proven <strong>in</strong>fections). 58 <strong>The</strong> review also mentions that four former meta-analyses showed<br />
stat<strong>is</strong>tically significant reductions <strong>in</strong> mortality follow<strong>in</strong>g IG treatment for neonatal seps<strong>is</strong>,<br />
up to a six-fold decrease (p=0.007) when IG <strong>is</strong> adm<strong>in</strong><strong>is</strong>tered <strong>in</strong> addition to standard<br />
therapies.<br />
IG given to neonates <strong>with</strong> proven <strong>in</strong>fections reduced overall mortality <strong>in</strong> five<br />
meta-analyses. However, the effectiveness of IG to reduce mortality <strong>in</strong><br />
neonates <strong>with</strong> suspected <strong>in</strong>fections was not always significant.<br />
Preterm / low birth weight <strong>in</strong>fants<br />
As maternal transfer of IG to the foetus occurs ma<strong>in</strong>ly after 32 weeks of gestation and<br />
endogenous synthes<strong>is</strong> does not beg<strong>in</strong> until about 24 weeks after birth, the preterm<br />
<strong>in</strong>fant <strong>is</strong> especially vulnerable to <strong>in</strong>fectious sources. 57 Indeed, nosocomial <strong>in</strong>fections<br />
cont<strong>in</strong>ue to be a significant cause of morbidity and mortality among preterm and/or low<br />
birth weight <strong>in</strong>fants. Due to the mechan<strong>is</strong>ms above described, IG was considered to<br />
have the potential of prevent<strong>in</strong>g or alter<strong>in</strong>g the course of nosocomial <strong>in</strong>fections. 59
<strong>KCE</strong> Reports 120 Plasma 59<br />
A Cochrane review on IG for prevent<strong>in</strong>g <strong>in</strong>fections <strong>in</strong> preterm (
60 Plasma <strong>KCE</strong> Reports 120<br />
bleed<strong>in</strong>g occurrence. In some countries, IG <strong>is</strong> used as the first l<strong>in</strong>e<br />
treatment (e.g. France) and <strong>in</strong> other countries as a second l<strong>in</strong>e or as one<br />
of the treatment options.<br />
• In adults: Adult ITP usually has an <strong>in</strong>sidious onset and <strong>is</strong> typically a chronic<br />
d<strong>is</strong>ease. Its <strong>in</strong>cidence <strong>in</strong>creases <strong>with</strong> age. IG <strong>is</strong> usually recommended <strong>in</strong><br />
cases <strong>with</strong> r<strong>is</strong>k of serious bleed<strong>in</strong>g, as part of a multi-modal therapy.<br />
Other treatments <strong>in</strong>clude <strong>in</strong>travenous steroids, anti-D immune globul<strong>in</strong>,<br />
v<strong>in</strong>cr<strong>is</strong>t<strong>in</strong>e, platelet transfusions and factor VIIa. However,<br />
recommendations for chronic ITP widely vary per guidel<strong>in</strong>e.<br />
A systematic literature review was publ<strong>is</strong>hed <strong>in</strong> 2008 as part of a health technology<br />
assessment undertaken by the Canadian drug agency. 62 It <strong>in</strong>cluded 28 RCT: 15 RCT<br />
among children <strong>with</strong> acute ITP, 4 RCT among children <strong>with</strong> chronic d<strong>is</strong>ease, 7 RCT<br />
among adult ITP and 2 RCT among mixed populations. IG was compared <strong>with</strong> steroids,<br />
anti-D immunoglobul<strong>in</strong>, modified or different doses of IVIG, or close observation. <strong>The</strong><br />
review only <strong>in</strong>cluded Engl<strong>is</strong>h language publications.<br />
• In children: In one trial that compared IG <strong>with</strong> close observation, IG was<br />
associated <strong>with</strong> earlier improvements <strong>in</strong> platelet counts. IG also showed<br />
higher effectiveness compared <strong>with</strong> steroids for early recovery of<br />
thrombocytopenia <strong>in</strong> acute ITP. <strong>The</strong> advantage of IG over anti-D<br />
immunoglobul<strong>in</strong> <strong>is</strong> uncerta<strong>in</strong> due to sparse evidence. <strong>The</strong> optimal dose of<br />
IG has not been establ<strong>is</strong>hed. <strong>The</strong>re was <strong>in</strong>sufficient evidence to determ<strong>in</strong>e<br />
if specific subgroups of children <strong>with</strong> acute ITP may receive preferential<br />
benefit from IG treatment. <strong>The</strong> role of IG <strong>in</strong> chronic childhood ITP could<br />
not be establ<strong>is</strong>hed, because evidence from scant, poorly designed, and<br />
poorly <strong>report</strong>ed RCT could not be synthesized.<br />
• In adults: Two RCT compared IG <strong>with</strong> steroids <strong>in</strong> adults <strong>with</strong> newly<br />
diagnosed ITP: <strong>in</strong> one, no advantage for IG was found; <strong>in</strong> the other study,<br />
IG was more effective than steroids for the short-term improvement of<br />
thrombocytopenia and gave a more rapid and susta<strong>in</strong>ed response. 63 IG<br />
was associated <strong>with</strong> more severe adverse events that prolonged<br />
hospitalization. <strong>The</strong> review concluded that sparse evidence <strong>in</strong>dicates that<br />
IG may be more efficacious than high dose corticosteroids <strong>in</strong> improv<strong>in</strong>g<br />
platelet counts <strong>in</strong> the short term, though its effect on cl<strong>in</strong>ical outcomes<br />
rema<strong>in</strong>s <strong>in</strong>determ<strong>in</strong>ate. Limited evidence could not demonstrate the<br />
superiority of a 2 g/kg dose of IVIG over a 1 g/kg dose; a dose of 1 g/kg,<br />
however, may be better than a dose of 0.5 g/kg. For the long-term<br />
management of adult ITP, data were <strong>in</strong>sufficient and studies were<br />
heterogeneous, prevent<strong>in</strong>g any conclusion on whether IG has an<br />
advantage over other treatments.<br />
A US study compared the cost-effectiveness of IG, anti-D, methylpredn<strong>is</strong>olone and<br />
predn<strong>is</strong>one. 64 <strong>The</strong>rapies <strong>with</strong> IG and methylpredn<strong>is</strong>olone were less effective and more<br />
expensive than anti-D and predn<strong>is</strong>one, respectively. However, th<strong>is</strong> analys<strong>is</strong> has been<br />
debated by many authors, as it <strong>is</strong> based on several questionable assumptions; for<br />
<strong>in</strong>stance, they assumed that all ITP patients received treatment, all children responded<br />
65, 66<br />
to the <strong>in</strong>itial management strategy, and IG <strong>is</strong> not more effective than steroids.<br />
A more recent Ch<strong>in</strong>ese systematic review of studies publ<strong>is</strong>hed between 1990 and 2007<br />
showed that the use of steroids provided additional life years and was more costeffective<br />
compared <strong>with</strong> IG, but that transferability of results to other countries was<br />
low. 62
<strong>KCE</strong> Reports 120 Plasma 61<br />
• In children <strong>with</strong> acute ITP, evidence suggests that IG improves more rapidly<br />
platelet counts than no treatment or steroids. <strong>The</strong> role of IG <strong>in</strong> chronic<br />
childhood ITP could not be establ<strong>is</strong>hed.<br />
• In adult ITP, sparse evidence <strong>in</strong>dicates that IG may be more efficacious than<br />
steroids <strong>in</strong> improv<strong>in</strong>g platelet counts <strong>in</strong> the short term, though its effect on<br />
cl<strong>in</strong>ical outcomes <strong>is</strong> unclear. For long term treatment of chronic ITP, studies<br />
did not allow to determ<strong>in</strong>e the benefit of IG and its advantage over other<br />
treatments.<br />
Fetal/Neonatal allo-immune thrombocytopenia<br />
Fetal or neonatal allo-immune thrombocytopenia (FNAIT) accounts for 27% of cases of<br />
severe foetal and neonatal thrombocytopenia and <strong>is</strong> the most frequent cause of<br />
foetal/neonatal <strong>in</strong>tracranial haemorrhage. 67 FNAIT occurs when the mother produces<br />
antibodies aga<strong>in</strong>st fetal platelet-specific antigens that the foetus has <strong>in</strong>herited from the<br />
father. <strong>The</strong>se antibodies may easily cross the placenta as early as the 14th week of<br />
gestation and cause fetal thrombocytopenia. Transfer of antibodies <strong>in</strong>creases as<br />
gestation progresses, until a maximum level <strong>is</strong> atta<strong>in</strong>ed <strong>in</strong> the late third trimester. Its<br />
<strong>in</strong>cidence <strong>is</strong> estimated to be one <strong>in</strong> 1000-2000 births. <strong>The</strong> recommended antenatal<br />
therapy, aim<strong>in</strong>g at prevent<strong>in</strong>g <strong>in</strong>tracranial haemorrhage, ma<strong>in</strong>ly cons<strong>is</strong>ts of maternal<br />
<strong>in</strong>fusions of IG, <strong>with</strong> or <strong>with</strong>out steroids, or <strong>in</strong>trauter<strong>in</strong>e transfusion of antigen<br />
compatible platelets. 68 Steroids are often used <strong>in</strong> the management of refractory cases.<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2005 identified one RCT <strong>in</strong>volv<strong>in</strong>g 54 pregnant women.<br />
However, th<strong>is</strong> trial only compared <strong>in</strong>travenous IG plus steroids <strong>with</strong> <strong>in</strong>travenous IG<br />
alone, thus not cover<strong>in</strong>g the research question. 68 A systematic review publ<strong>is</strong>hed after<br />
the Cochrane search period identified an additional RCT, publ<strong>is</strong>hed <strong>in</strong> 2007, compar<strong>in</strong>g<br />
aga<strong>in</strong> the effectiveness of IG plus predn<strong>is</strong>one to IG alone <strong>in</strong> 73 women. 69 No RCT<br />
compar<strong>in</strong>g IG to placebo has been found, likely because IG <strong>is</strong> currently the first l<strong>in</strong>e<br />
treatment <strong>in</strong> most sett<strong>in</strong>gs. However, 26 observational studies on IG efficacy have<br />
suggested an improvement <strong>in</strong> cl<strong>in</strong>ical outcome and probable reduction <strong>in</strong> r<strong>is</strong>k for<br />
<strong>in</strong>tracranial haemorrhage. Though no meta-analys<strong>is</strong> wad performed and <strong>in</strong> spite of the<br />
drawbacks of observational studies, most of current practice <strong>is</strong> based <strong>in</strong> their f<strong>in</strong>d<strong>in</strong>gs. 68<br />
Though no RCT have been conducted to study the IG effectiveness <strong>in</strong><br />
fetal/feonatal allo-immune thrombocytopenia, data from observational studies<br />
suggested a benefit of IG.<br />
Isoimmune haemolytic jaundice <strong>in</strong> neonates<br />
Both rhesus factor and ABO <strong>in</strong>compatibilities between maternal and fetal or neonatal<br />
cells can result <strong>in</strong> autoimmune haemolytic d<strong>is</strong>ease of the new-born. <strong>The</strong> use of anti-D<br />
prophylax<strong>is</strong> <strong>in</strong> rhesus negative women has led to a marked decl<strong>in</strong>e <strong>in</strong> haemolytic d<strong>is</strong>ease<br />
of the newborn. However, anti-D immunoglobul<strong>in</strong> does not always prevent sensitization<br />
as a high proportion of haemolytic d<strong>is</strong>ease of the newborn <strong>is</strong> caused by antibodies to<br />
antigens other than D. 70 Exchange transfusion and phototherapy have traditionally been<br />
used to treat affected newborn <strong>in</strong>fants. However, exchange transfusion <strong>is</strong> related to<br />
<strong>in</strong>creased mortality and morbidity. New therapies, aim<strong>in</strong>g at reduc<strong>in</strong>g the need for<br />
exchange transfusion, <strong>in</strong>clude IG.<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2002 <strong>in</strong>cluded three RCT, <strong>in</strong>volv<strong>in</strong>g 189 term and<br />
preterm <strong>in</strong>fants <strong>with</strong> rhesus and ABO <strong>in</strong>compatibility. <strong>The</strong> use of exchange transfusion<br />
decreased significantly <strong>in</strong> the IG treated group, <strong>with</strong> a lower mean number of exchange<br />
transfusions per <strong>in</strong>fant. None of the studies assessed long term outcomes. Authors<br />
considered that the applicability of the results <strong>is</strong> limited. A more recent systematic<br />
review publ<strong>is</strong>hed <strong>in</strong> 2003 <strong>in</strong>cluded 4 RCT to compare neonatal IG plus phototherapy to<br />
phototherapy alone. 71 It also found that fewer <strong>in</strong>fants <strong>in</strong> the IG group required exchange<br />
transfusion. <strong>The</strong> IG group also required lower duration of phototherapy and shorter<br />
hospital stays than the control group.<br />
In <strong>is</strong>oimmune haemolytic d<strong>is</strong>ease <strong>in</strong> <strong>in</strong>fants, IG reduced the need for exchange<br />
transfusion and phototherapy and lead to shorter hospital stays.
62 Plasma <strong>KCE</strong> Reports 120<br />
3.2.2.4 Neurological and neuro-muscular d<strong>is</strong>orders<br />
A <strong>summary</strong> of evidence f<strong>in</strong>d<strong>in</strong>gs and levels of evidence for IG use <strong>is</strong> presented <strong>in</strong> Table<br />
21.<br />
Guilla<strong>in</strong>-Barré syndrome and variants<br />
Guilla<strong>in</strong>-Barré syndrome <strong>is</strong> an acute d<strong>is</strong>ease of the peripheral nerves. It causes the rapid<br />
development of weakness and usually numbness of the limbs and often the facial,<br />
swallow<strong>in</strong>g and breath<strong>in</strong>g muscles. Between 3.5 and 12% patients die of complications<br />
dur<strong>in</strong>g the acute stage. Recovery takes several weeks or months. One year after onset,<br />
12% patients still require aid to walk and 62% still notice its effect on their or their<br />
carers’ lives three to six years later. 72 , 73<br />
A Cochrane review, updated <strong>in</strong> 2004, has shown that plasma exchange significantly<br />
hastens recovery. 74 A Cochrane review on IG, updated <strong>in</strong> 2006, did not f<strong>in</strong>d any trial<br />
compar<strong>in</strong>g IG <strong>with</strong> placebo <strong>in</strong> adults. 73 It <strong>in</strong>cluded 6 RCT compar<strong>in</strong>g IG <strong>with</strong> plasma<br />
exchange. A meta-analys<strong>is</strong> of 5 of these RCT, <strong>in</strong>volv<strong>in</strong>g 536 patients (mostly adults) <strong>with</strong><br />
severe d<strong>is</strong>ease and us<strong>in</strong>g d<strong>is</strong>ability grades, showed that IG started <strong>with</strong><strong>in</strong> two weeks<br />
from onset hastens recovery as much as plasma exchange. Treatment <strong>with</strong> IG was<br />
significantly more likely to be completed than plasma exchange. Giv<strong>in</strong>g IG after plasma<br />
exchange did not confer significant extra benefit. One study showed a trend toward<br />
higher improvement <strong>with</strong> high-dose (2.4g/kg) compared to low-dose IG (1.2g/kg).<br />
Three trials compared IG to supportive care or steroids <strong>in</strong> children, <strong>in</strong>volv<strong>in</strong>g 75<br />
participants. Results suggested that IG hastens recovery compared <strong>with</strong> supportive care,<br />
but th<strong>is</strong> was only found significant <strong>in</strong> two studies, <strong>in</strong>clud<strong>in</strong>g an open trial <strong>in</strong> which the<br />
further analys<strong>is</strong> of raw data a found significant association when us<strong>in</strong>g d<strong>is</strong>ability grade<br />
(outcome not selected by the trial). <strong>The</strong> third study <strong>in</strong>volved only 18 participants and<br />
lacked power. Th<strong>is</strong> suggests that IG hastens recovery <strong>in</strong> children, compared <strong>with</strong><br />
supportive care alone.<br />
A 1999 study compared the cost-effectiveness of plasma exchange and IG <strong>in</strong> the<br />
treatment of Guilla<strong>in</strong> Barré d<strong>is</strong>ease. 75 Trials compar<strong>in</strong>g the effectiveness of plasma<br />
exchange and IG for the treatment of acute Guilla<strong>in</strong>-Barré syndrome showed <strong>in</strong>sufficient<br />
evidence that one therapy was more effective than the other. <strong>The</strong> study determ<strong>in</strong>ed<br />
that plasma exchange was almost $4,000 less costly per patient than IG but that further<br />
research <strong>is</strong> required to determ<strong>in</strong>e the impact of patient and physician preferences. No<br />
recent cost-effectiveness analys<strong>is</strong> has been found.<br />
• In adult Guilla<strong>in</strong> Barré cases, IG hastens recovery as much as plasma<br />
exchange - which has been shown to be more effective than supportive care<br />
alone.<br />
• In paediatric cases, limited evidence suggests that IG hastens recovery<br />
compared to supportive care alone.<br />
Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyradiculoneuropathy<br />
Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyradiculoneuropathy (CIDP) causes progressive<br />
or relaps<strong>in</strong>g weakness and numbness of the limbs, develop<strong>in</strong>g over at least two months.<br />
It may cause prolonged d<strong>is</strong>ability and even death. It <strong>is</strong> often considered to be a chronic<br />
variant of GBS. CIDP can occur at any age, <strong>with</strong> a peak prevalence <strong>in</strong> the sixth and<br />
seventh decade and a lower prevalence among children. 76 Three therapies have<br />
demonstrated beneficial effect <strong>in</strong> RCT: corticosteroids, plasma exchange and IG.<br />
A Cochrane review updated <strong>in</strong> 2009 <strong>in</strong>cluded 7 RCT <strong>with</strong> 287 participants. 76 <strong>The</strong>se<br />
trials were homogeneous and the overall quality was high. In the 5 RCT compar<strong>in</strong>g IG<br />
aga<strong>in</strong>st placebo, a significantly higher proportion of participants improved <strong>in</strong> d<strong>is</strong>ability<br />
<strong>with</strong><strong>in</strong> one month after IG treatment as compared <strong>with</strong> placebo (RR 2.4, 95% CI 1.7-<br />
3.4). One large RCT <strong>in</strong>cluded <strong>in</strong> th<strong>is</strong> review had a long-term follow up and <strong>in</strong>dicated<br />
that IG improves d<strong>is</strong>ability more than placebo over 24 and 48 weeks. 77
<strong>KCE</strong> Reports 120 Plasma 63<br />
Two small trials compared IG <strong>with</strong> predn<strong>is</strong>olone and plasma exchange respectively, and<br />
showed no difference <strong>in</strong> improvement <strong>in</strong> d<strong>is</strong>ability <strong>in</strong> the IG group compared to the<br />
other therapy. <strong>The</strong>re were no stat<strong>is</strong>tically significant differences <strong>in</strong> frequencies of side<br />
effects between the three types of treatment. Based on th<strong>is</strong> evidence, the authors<br />
concluded that IG improves d<strong>is</strong>ability for at least two to six weeks compared <strong>with</strong><br />
placebo, <strong>with</strong> a number needed to treat of 3. S<strong>in</strong>ce IG, plasma exchange and<br />
predn<strong>is</strong>olone seem to be equally effective, it <strong>is</strong> currently uncerta<strong>in</strong> which of these<br />
treatments should be the first choice.<br />
Cost-effectiveness studies compar<strong>in</strong>g the alternative treatments were also retrieved. A<br />
mult<strong>in</strong>ational study (<strong>in</strong>clud<strong>in</strong>g Belgium) aimed at analyz<strong>in</strong>g <strong>in</strong>cremental cost-effectiveness<br />
of IG compared to predn<strong>is</strong>olone to treat CIDP. 78 IG was shown to be substantially<br />
more expensive than predn<strong>is</strong>olone (3754€ over a 6 week period) and did not reduce<br />
d<strong>is</strong>ability substantially compared to predn<strong>is</strong>olone. But IG did result <strong>in</strong> greater<br />
improvement <strong>in</strong> health-related quality of life. <strong>The</strong> probability of IVIG be<strong>in</strong>g cost-effective<br />
<strong>in</strong> compar<strong>is</strong>on <strong>with</strong> predn<strong>is</strong>olone was 50% or above only if one QALY was valued at<br />
over 250,000€. <strong>The</strong> impact of later side-effects of predn<strong>is</strong>olone on long term costs and<br />
quality of life are likely to reduce the cost per QALY of IG treatment.<br />
In patients <strong>with</strong> CIDP, IG improves d<strong>is</strong>ability for at least two to six weeks<br />
compared <strong>with</strong> placebo, but showed no difference <strong>in</strong> effectiveness compared to<br />
plasma exchange and predn<strong>is</strong>olone. Further cost-effectiveness studies are<br />
required.<br />
Multifocal motor neuropathy<br />
Multifocal motor neuropathy (MMN) <strong>is</strong> a rare d<strong>is</strong>ease marked by a slow progression of<br />
motor weakness, often d<strong>is</strong>tal, asymmetric and <strong>in</strong>volv<strong>in</strong>g the forearms, <strong>with</strong>out sensory<br />
impairment. Consensus statements assert that IG <strong>is</strong> the only safe treatment for MMN<br />
patients. Steroids and plasma exchanges are not effective and may even exacerbate the<br />
d<strong>is</strong>ease.<br />
A Cochrane systematic review publ<strong>is</strong>hed <strong>in</strong> 2005 <strong>in</strong>cluded 4 RCT <strong>in</strong>volv<strong>in</strong>g 34 patients. 79<br />
Strength improved <strong>in</strong> 78% of patients treated <strong>with</strong> IG and only 4% of placebo-treated<br />
patients. D<strong>is</strong>ability improved <strong>in</strong> a higher proportion of patients treated <strong>with</strong> IG (78%)<br />
than <strong>with</strong> placebo (14%) but the difference was stat<strong>is</strong>tically not significant. Authors<br />
concluded that limited evidence from RCT shows that IG has a beneficial effect on<br />
strength. IG has been so far the only therapy show<strong>in</strong>g significant improvement <strong>in</strong> MMN.<br />
In patients <strong>with</strong> multifocal motor neuropathy (MMN), IG showed a significant<br />
effect on muscle strength and a non-significant improvement <strong>in</strong> d<strong>is</strong>ability <strong>in</strong><br />
small trials. No other treatment has proven effective for MMN.<br />
Paraprote<strong>in</strong> associated polyneuropathy<br />
<strong>The</strong> paraprote<strong>in</strong> associated polyneuropathy <strong>is</strong> another auto-immune neuropathy <strong>with</strong><br />
demyel<strong>in</strong>ation, characterized by a slow progression and a sensory predom<strong>in</strong>ance.<br />
However, it may produce eventual d<strong>is</strong>abl<strong>in</strong>g motor symptoms. <strong>The</strong> condition <strong>is</strong><br />
associated <strong>with</strong> a monoclonal paraprote<strong>in</strong>, an immunoglobul<strong>in</strong> molecule produced by<br />
bone marrow cells, that <strong>is</strong> present <strong>in</strong> excess and <strong>is</strong> often non-functional. 80 , 81 Th<strong>is</strong><br />
paraprote<strong>in</strong> may belong to one of these three classes: IgG, IgA or IgM.<br />
A Cochrane review on IgG and IgA paraprote<strong>in</strong>emic peripheral neuropathy, publ<strong>is</strong>hed <strong>in</strong><br />
2007, <strong>in</strong>cluded only one RCT on plasma exchange. 80 Th<strong>is</strong> review also identified several<br />
small observational studies show<strong>in</strong>g a beneficial response <strong>in</strong> some of the patients treated<br />
<strong>with</strong> IG. Another 2006 Cochrane review exam<strong>in</strong>ed the efficacy of immunotherapy <strong>in</strong><br />
IgM paraprote<strong>in</strong>-associated demyel<strong>in</strong>at<strong>in</strong>g neuropathy. 81 It <strong>in</strong>cluded two RCT compar<strong>in</strong>g<br />
IG <strong>with</strong> placebo and concluded that IG may produce some short-term benefit: a trial<br />
<strong>in</strong>volv<strong>in</strong>g 22 participants showed a significant improvement <strong>in</strong> overall d<strong>is</strong>ability <strong>with</strong> IG<br />
over placebo at four weeks; 82 a small trial of 11 patients showed a modest improvement<br />
<strong>in</strong> strength <strong>in</strong> 18% of patients. 83 As other therapies such as steroids have been shown<br />
beneficial <strong>in</strong> th<strong>is</strong> d<strong>is</strong>ease <strong>in</strong> open trials, some reviews recommend that IG be considered<br />
but not cont<strong>in</strong>ued if acute benefit <strong>is</strong> not observed. 27
64 Plasma <strong>KCE</strong> Reports 120<br />
• In patients <strong>with</strong> IgM paraprote<strong>in</strong>-associated demyel<strong>in</strong>at<strong>in</strong>g neuropathy, IG<br />
produced short-term benefit, such as reduced d<strong>is</strong>ability and improved<br />
muscle strength.<br />
• In IgG and IgA paraprote<strong>in</strong>emic neuropathy, evidence on IG effectiveness <strong>is</strong><br />
<strong>in</strong>sufficient.<br />
Multiple scleros<strong>is</strong><br />
Multiple scleros<strong>is</strong> (MS) <strong>is</strong> a d<strong>is</strong>order of the central nervous system <strong>with</strong> progressive<br />
deterioration of neurological functions caused by autoimmune, <strong>in</strong>flammatory and<br />
neurodegenerative mechan<strong>is</strong>ms. <strong>The</strong> course of the d<strong>is</strong>ease <strong>is</strong> relaps<strong>in</strong>g remitt<strong>in</strong>g (called<br />
RRMS) <strong>in</strong>itially <strong>in</strong> 80-85% of all MS patients. A m<strong>in</strong>ority of patients (10-15%) have a<br />
chronic progressive course from the beg<strong>in</strong>n<strong>in</strong>g, <strong>with</strong>out typical relapses and rem<strong>is</strong>sions,<br />
termed primary progressive MS or PPMS. In most patients, the d<strong>is</strong>ease progresses to a<br />
stage <strong>with</strong> steady deterioration, known as secondary chronic progressive MS or<br />
SPMS. 84 , 85<br />
A Cochrane systematic review <strong>in</strong>cluded only 2 RCT out of the 10 RCT on RRMS cases<br />
that were eligible, due to methodological <strong>is</strong>sues or studies be<strong>in</strong>g <strong>in</strong> progress, and did not<br />
perform any meta-analys<strong>is</strong>. 86 Another review was publ<strong>is</strong>hed <strong>in</strong> 2008 and performed a<br />
meta-analys<strong>is</strong> based on 4 RCT. 87 N<strong>in</strong>e additional RCT publ<strong>is</strong>hed after the last Cochrane<br />
review update (Jan 2003) have been retrieved. All f<strong>in</strong>d<strong>in</strong>gs are relatively cons<strong>is</strong>tent<br />
across studies and are presented below by type of MS.<br />
1. RRMS: <strong>The</strong> two literature reviews have evaluated IG effectiveness compared<br />
to placebo <strong>in</strong> treat<strong>in</strong>g RRMS, and three additional RCT have been publ<strong>is</strong>hed.<br />
• <strong>The</strong> 2008 review <strong>in</strong>cluded four RCT, <strong>in</strong>volv<strong>in</strong>g 265 RRMS patients. 87 A<br />
meta-analys<strong>is</strong> of the 4 RCT showed a significant reduction <strong>in</strong> relapse rate,<br />
proportion of relapse-free patients and changes of d<strong>is</strong>ability scores <strong>in</strong> the<br />
groups treated <strong>with</strong> IG compared to placebo. 88,89, 90 A small RCT<br />
compar<strong>in</strong>g two doses to placebo also found a significant reduction <strong>in</strong><br />
groups treated <strong>with</strong> IG. 91 A small RCT assess<strong>in</strong>g Magnetic Resonance<br />
Imag<strong>in</strong>g (MRI) impact on 26 patients showed a significant reduction <strong>in</strong> MRI<br />
lesions. 90<br />
• <strong>The</strong> 2003 Cochrane review was based on two of these RCT, <strong>in</strong>volv<strong>in</strong>g<br />
168 RRMS participants, and found a significant reduction <strong>in</strong> relapse rate<br />
and an <strong>in</strong>creased time to first relapse dur<strong>in</strong>g IG treatment.<br />
• One recent multi-national RCT, publ<strong>is</strong>hed after the two reviews and<br />
<strong>in</strong>volv<strong>in</strong>g 127 patients from 30 European and US sites, showed no<br />
beneficial effect of IG at doses of 0.2 to 0.4g/kg as compared to placebo <strong>in</strong><br />
RRMS patients after a year period. 92 Authors could not expla<strong>in</strong> why these<br />
results contrast <strong>with</strong> other f<strong>in</strong>d<strong>in</strong>gs, except for an overly optim<strong>is</strong>tic<br />
sample size calculation.<br />
• Two RCT <strong>in</strong>volv<strong>in</strong>g 19 and 76 patients <strong>with</strong> MS and acute relapses found<br />
that IG comb<strong>in</strong>ed to predn<strong>is</strong>olone was not more effective <strong>in</strong> the<br />
treatment of relapses than predn<strong>is</strong>olone alone. 93,94<br />
2. PPMS: A small RCT publ<strong>is</strong>hed after the search period of the two reviews and<br />
<strong>in</strong>volv<strong>in</strong>g 34 patients <strong>with</strong> PPMS showed that IG significantly reduced d<strong>is</strong>ease<br />
progression as measured by cl<strong>in</strong>ical <strong>in</strong>dicators, compared to placebo. 84<br />
3. SPMS: Three RCT, <strong>in</strong>volv<strong>in</strong>g a total of 585 SPMS patients, cons<strong>is</strong>tently<br />
showed no significant effect of IG on d<strong>is</strong>ease progression, relapses or MRI<br />
lesions compared to placebo. 84,95,96, 97 No meta-analys<strong>is</strong> was performed as only<br />
one RCT was <strong>in</strong>cluded <strong>in</strong> the 2008 review (though no exclusion criteria was<br />
stated).<br />
4. Post-partum relapses: <strong>The</strong> r<strong>is</strong>k of MS relapses <strong>is</strong> <strong>in</strong>creased <strong>in</strong> the post-partum<br />
period and the other <strong>available</strong> therapies are not recommended dur<strong>in</strong>g<br />
pregnancy or lactation. Several non-controlled trial or retrospective studies<br />
on IG treatment suggested that the exacerbation rate <strong>in</strong> the treated group
<strong>KCE</strong> Reports 120 Plasma 65<br />
was lower than <strong>in</strong> a reference population. 98, 99 A multi-national RCT <strong>in</strong> 9 EU<br />
countries <strong>in</strong>clud<strong>in</strong>g Belgium, compar<strong>in</strong>g two doses <strong>in</strong> the 6 months postpartum<br />
(but not to placebo), did not show significant differences <strong>in</strong> outcome<br />
between the two doses. 100 Despite the lack of RCT compar<strong>in</strong>g IG to placebo,<br />
many authors conclude that IG can be considered as an optional treatment to<br />
reduce the <strong>in</strong>creased rate of relapses <strong>in</strong> th<strong>is</strong> period, because no alternative<br />
treatment <strong>with</strong> proven efficacy <strong>is</strong> <strong>available</strong>.<br />
5. In patients <strong>with</strong> cl<strong>in</strong>ically <strong>is</strong>olated syndrome: An RCT evaluated the<br />
occurrence of a second attack <strong>in</strong> 91 MS cases after a first neurological event<br />
suggestive of demyel<strong>in</strong>at<strong>in</strong>g d<strong>is</strong>ease. Among patients <strong>in</strong> the IG group, the<br />
<strong>in</strong>cidence of a second attack and d<strong>is</strong>ease activity as measured by bra<strong>in</strong> MRI<br />
significantly reduced compared to placebo. 101<br />
6. Dosage: all RCT but one used a dose rang<strong>in</strong>g 0.15-0.4g/kg monthly. A s<strong>in</strong>gle<br />
study used 2g/kg but did not yield higher efficacy rates. 90 A study compar<strong>in</strong>g<br />
two dose treatment (0.2 and 0.4g/kg/month) for the treatment of RRMS<br />
could not show any significant differences between the effects of the two<br />
doses. 92<br />
A systematic review searched cl<strong>in</strong>ical and cost effectiveness studies on<br />
immunomodulatory drugs for MS, but did not f<strong>in</strong>d any cost-effectiveness study <strong>in</strong>clud<strong>in</strong>g<br />
IG. 102<br />
• In RRMS d<strong>is</strong>ease, IG has shown beneficial effects on d<strong>is</strong>ease progression and<br />
on magnetic resonance imag<strong>in</strong>g (MRI) lesions (moderate). Comb<strong>in</strong>ed to<br />
predn<strong>is</strong>olone, IG was not more effective <strong>in</strong> the treatment of relapses than<br />
predn<strong>is</strong>olone alone (high). <strong>The</strong> ideal dose and the effect on long term<br />
d<strong>is</strong>ability have not been well studied. IG <strong>is</strong> considered as one of the options<br />
for the treatment of RRMS.<br />
• In PPMS patients, IG delayed d<strong>is</strong>ease progression <strong>in</strong> one RCT (moderate).<br />
• In SPMS d<strong>is</strong>ease, IG had no significant effect on d<strong>is</strong>ease progression or MRI<br />
lesions (high).<br />
• IG reduced the <strong>in</strong>creased rate of relapses <strong>in</strong> the post-partum period <strong>in</strong> open<br />
studies and <strong>is</strong> considered as an optional treatment (low).<br />
Lambert-Eaton myasthenic syndrome<br />
Lambert-Eaton myasthenic syndrome or LEMS <strong>is</strong> a rare autoimmune d<strong>is</strong>order of<br />
neuromuscular transm<strong>is</strong>sion, most commonly seen as a paraneoplasic syndrome (60% of<br />
patients). It <strong>is</strong> characterized by proximal muscle weakness, ocular symptoms, bulbar<br />
symptoms and autonomic dysfunction. LEMS often responds to steroids or other<br />
immunosuppressant.<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2005 <strong>in</strong>cluded only 1 RCT assess<strong>in</strong>g the use of IG <strong>in</strong><br />
LEMS cases. 103 Significant improvement <strong>in</strong> limb muscle strength, vital capacity and<br />
dr<strong>in</strong>k<strong>in</strong>g time was observed compared to placebo, but was short term and decl<strong>in</strong>ed<br />
after 8 weeks. <strong>The</strong> review concluded that IG can be considered as an alternative<br />
treatment to steroids and immunosupressants for LEMS.<br />
A small RCT showed that IG improved functional capacities and muscle<br />
strength <strong>in</strong> Lambert-Eaton myasthenic syndrome on the short term
66 Plasma <strong>KCE</strong> Reports 120<br />
Myasthenia grav<strong>is</strong><br />
Myasthenia grav<strong>is</strong> (MG) <strong>is</strong> an autoimmune d<strong>is</strong>ease, characterized by weakness and<br />
fatigability of muscle chang<strong>in</strong>g over shorter or longer periods. Acute exacerbations (or<br />
cr<strong>is</strong><strong>is</strong>) may be life-threaten<strong>in</strong>g because of swallow<strong>in</strong>g difficulties or respiratory failure. 104<br />
Prevalences tend to <strong>in</strong>crease <strong>with</strong> time, partly due to age<strong>in</strong>g of the population comb<strong>in</strong>ed<br />
to higher prevalence <strong>in</strong> the elderly, and better diagnos<strong>is</strong>. 105 Current treatment <strong>in</strong>cludes<br />
antichol<strong>in</strong>esterase drugs, thymectomy, steroids, immunosupressants, plasma exchange<br />
and IVIG.<br />
A Cochrane review updated <strong>in</strong> 2008 <strong>in</strong>cluded 6 RCT. 106 A placebo controlled trial<br />
<strong>in</strong>volv<strong>in</strong>g 51 patients provided evidence for the effectiveness of IG <strong>in</strong> MG worsen<strong>in</strong>g,<br />
while another small study <strong>in</strong>volv<strong>in</strong>g 15 mild or moderate MG cases found no significant<br />
difference <strong>in</strong> efficacy after six weeks compared to placebo. Two studies, one <strong>in</strong>volv<strong>in</strong>g<br />
87 participants <strong>with</strong> exacerbation and another small study <strong>in</strong>volved 12 participants <strong>with</strong><br />
moderate or severe MG, showed no significant difference between IG and plasma<br />
exchange, after two and four weeks respectively. No significant difference <strong>in</strong> the efficacy<br />
of IG and methylpredn<strong>is</strong>olone was shown <strong>in</strong> a study <strong>in</strong>clud<strong>in</strong>g 33 patients <strong>with</strong> moderate<br />
exacerbations. A large RCT showed no significant difference <strong>in</strong> efficacy between two<br />
doses for MG exacerbations (1 and 2g/kg). An open study of 10 severe MG patients<br />
unresponsive to common treatment showed that IG <strong>in</strong>duced and ma<strong>in</strong>ta<strong>in</strong>ed rem<strong>is</strong>sion<br />
<strong>with</strong> spar<strong>in</strong>g of the dose of immunosuppressive treatments. Gajdos et al. concluded that<br />
there <strong>is</strong> no conv<strong>in</strong>c<strong>in</strong>g evidence to support the rout<strong>in</strong>e use of IG as ma<strong>in</strong>tenance<br />
therapy. Several reviews recommend IG for myasthenic cr<strong>is</strong><strong>is</strong> that are unresponsive to<br />
other agents, for severe exacerbations until other immunosuppressive treatments<br />
achieve stabilization, or as an option to stabilize patients before surgery. 107,108 <strong>The</strong> best<br />
IG dose <strong>in</strong> MG rema<strong>in</strong>s unclear, rang<strong>in</strong>g 1-2g/kg.<br />
IG <strong>is</strong> more effective than placebo and as effective as other therapies (plasma<br />
exchange and steroids) for severe MG exacerbation and MG worsen<strong>in</strong>g, but th<strong>is</strong><br />
benefit was not shown <strong>in</strong> mild and moderate d<strong>is</strong>ease. Most RCT studied MG<br />
<strong>with</strong> exacerbations.<br />
Dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong><br />
Dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong> are idiopathic <strong>in</strong>flammatory myopathies,<br />
characterized by chronic <strong>in</strong>flammation of skeletal muscle which can result <strong>in</strong> pers<strong>is</strong>t<strong>in</strong>g<br />
muscle weakness <strong>with</strong> significant d<strong>is</strong>ability. 109 Dermatomyosit<strong>is</strong> also affects the sk<strong>in</strong>,<br />
results <strong>in</strong> sk<strong>in</strong> abnormalities, while polymyosit<strong>is</strong> may have occasional pulmonary<br />
<strong>in</strong>volvement. Both d<strong>is</strong>eases generally responds to steroid or immunosuppressive drugs<br />
but the optimal therapy rema<strong>in</strong>s unclear, and a number of patients are res<strong>is</strong>tant or only<br />
partially responsive to these therapies. 110<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2005 <strong>in</strong>cluded one small RCT on IG compared to<br />
placebo, <strong>in</strong>volv<strong>in</strong>g 15 patients <strong>with</strong> dermatomyosit<strong>is</strong>. 109 It showed that IG was<br />
significantly superior to placebo <strong>in</strong> improv<strong>in</strong>g muscle strength, neuromuscular symptoms<br />
and sk<strong>in</strong> rash. 111 Other therapies did not show clear benefit. <strong>The</strong> RCT concluded that<br />
IG <strong>is</strong> an effective second-l<strong>in</strong>e therapy for patients <strong>with</strong> dermatomyosit<strong>is</strong> that<br />
<strong>in</strong>completely respond to steroids and immunosupressants. A non-controlled trial and<br />
several observational studies confirmed the IG benefit <strong>in</strong> dermatomyosit<strong>is</strong> and<br />
polymyosit<strong>is</strong>. 112,113<br />
IG improved symptoms and muscle strength <strong>in</strong> dermatomyosit<strong>is</strong>.<br />
Inclusion body myosit<strong>is</strong><br />
Inclusion body myosit<strong>is</strong> (IBM) <strong>is</strong> the most common <strong>in</strong>flammatory myopathy <strong>in</strong> elderly<br />
patients. It <strong>is</strong> characterized by a slow chronic progressive and pa<strong>in</strong>less asymmetric<br />
weakness, <strong>with</strong> <strong>in</strong>volvement of d<strong>is</strong>tal muscles <strong>with</strong> atrophy. Corticosteroids and<br />
immunosupressants are not successful. Treatment rema<strong>in</strong>s difficult as there <strong>is</strong> no or<br />
very little response to immunotherapy. 108
<strong>KCE</strong> Reports 120 Plasma 67<br />
Three RCT <strong>in</strong>volv<strong>in</strong>g 47 patients showed similar results. 108 A placebo controlled RCT<br />
<strong>in</strong>volv<strong>in</strong>g 19 patients showed an improvement <strong>in</strong> muscle strength <strong>in</strong> the group treated<br />
by IG compared to placebo, but the differences were not stat<strong>is</strong>tically significant, except<br />
for the muscles used for swallow<strong>in</strong>g. 114 A second study showed similar results. 115 A third<br />
study compared IG (2g/kg) added to predn<strong>is</strong>olone to predn<strong>is</strong>olone alone. 116 After 3<br />
months of treatment, there was no significant difference <strong>in</strong> muscle strength between the<br />
two groups. Despite these negative f<strong>in</strong>d<strong>in</strong>gs, many reviews recommend a short course<br />
of IG (2g/kg) as trial because no other treatment <strong>is</strong> effective. 27,107<br />
IG did not improve muscle strength <strong>in</strong> patients <strong>with</strong> <strong>in</strong>clusion body myosit<strong>is</strong><br />
patients but significantly improved swallow<strong>in</strong>g functions <strong>in</strong> one study<br />
Stiff person syndrome<br />
<strong>The</strong> stiff person syndrome <strong>is</strong> a rare d<strong>is</strong>order of the nervous central system<br />
characterized by severe and ep<strong>is</strong>odic muscle rigidity and spasms. <strong>The</strong> cause <strong>is</strong> unknown<br />
but most patients are associated <strong>with</strong> high levels of antibodies directed aga<strong>in</strong>st a specific<br />
enzyme, the glutamic acid decarboxylase, which <strong>is</strong> responsible for the synthes<strong>is</strong> of a<br />
major neurotransmitter (gamma am<strong>in</strong>o butyric acid).<br />
A s<strong>in</strong>gle RCT conducted <strong>in</strong> 1996-99, <strong>in</strong>volv<strong>in</strong>g 16 patients <strong>with</strong> Stiff person syndrome<br />
compar<strong>in</strong>g IG to placebo, showed that IG significantly reduces muscle stiffness and<br />
occurrence of spasms <strong>in</strong> th<strong>is</strong> d<strong>is</strong>ease compared to placebo. 117 <strong>The</strong> duration of the<br />
beneficial effect of IG varied from 6 weeks to one year. Three open studies have<br />
suggested the same effectiveness and improvement <strong>in</strong> quality of life. 118 , 119 , 120 IG <strong>is</strong> now<br />
considered to be the treatment of choice <strong>in</strong> many countries because other therapies<br />
only produce modest improvement <strong>in</strong> symptoms.<br />
IG significantly reduced muscle stiffness and occurrence of spasms <strong>in</strong> Stiff<br />
person syndrome<br />
Neuromyelit<strong>is</strong> optica<br />
Neuromyelit<strong>is</strong> optica <strong>is</strong> a demyel<strong>in</strong>at<strong>in</strong>g d<strong>is</strong>ease of the sp<strong>in</strong>al cord and optic nerves that<br />
manifest by recurrent attacks, and tends to have a poor prognos<strong>is</strong>. <strong>The</strong>re <strong>is</strong> no proven<br />
effective treatment, although relapses are commonly treated <strong>with</strong> steroids; patients <strong>with</strong><br />
recurrent attacks may be managed <strong>with</strong> immunosupressants. 121 IG has been considered<br />
as a possible treatment because the d<strong>is</strong>ease <strong>is</strong> antibody mediated.<br />
<strong>The</strong>re are a few case studies, <strong>in</strong>volv<strong>in</strong>g 1 to 2 cases, suggest<strong>in</strong>g that monthly IG may be<br />
effective <strong>in</strong> prevent<strong>in</strong>g relapses. 121,122 However, no RCT or other observational studies<br />
were found. More recent studies have rather focused on the effectiveness of rituximab,<br />
as it appears to reduce the frequency of attacks, <strong>with</strong> subsequent stabilization or<br />
improvement <strong>in</strong> d<strong>is</strong>ability. 123,124<br />
<strong>The</strong>re <strong>is</strong> no evidence on the effectiveness of IG <strong>in</strong> neuromyelit<strong>is</strong> optica, and<br />
limited evidence suggested the effectiveness of rituximab<br />
3.2.2.5 Evidence on other medical conditions<br />
Kawasaki d<strong>is</strong>ease<br />
<strong>The</strong> Kawasaki syndrome <strong>is</strong> an acute vasculit<strong>is</strong> affect<strong>in</strong>g <strong>in</strong>fants and young children,<br />
<strong>in</strong>volv<strong>in</strong>g the coronary arteries. Its aetiology <strong>is</strong> unknown. <strong>The</strong> ma<strong>in</strong> complications are<br />
coronary artery aneurysms (CAA) that may occur from the second week of illness<br />
dur<strong>in</strong>g the convalescent stage.<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2003 <strong>in</strong>cluded 16 RCT <strong>in</strong>volv<strong>in</strong>g children <strong>with</strong> Kawasaki<br />
d<strong>is</strong>ease. 125 Results of the meta-analyses of IG versus placebo showed a stat<strong>is</strong>tically<br />
significant decrease <strong>in</strong> new CAA <strong>in</strong> favour of IG plus salicylate over salicylate alone, <strong>in</strong><br />
favour of a s<strong>in</strong>gle high dose regime over 4 or 5 day low dose regime. <strong>The</strong>re was also a<br />
significant decrease <strong>in</strong> duration of fever and duration of hospitalization <strong>in</strong> cases treated<br />
<strong>with</strong> IG, <strong>with</strong> no stat<strong>is</strong>tically significant <strong>in</strong>crease <strong>in</strong> adverse events.
68 Plasma <strong>KCE</strong> Reports 120<br />
Authors concluded that children fulfill<strong>in</strong>g the diagnostic criteria for Kawasaki d<strong>is</strong>ease<br />
should be treated <strong>with</strong> high dose IG <strong>with</strong><strong>in</strong> 10 days of onset of symptoms. An RCT<br />
publ<strong>is</strong>hed after the Cochrane search period, compar<strong>in</strong>g the effectiveness of IG at<br />
different doses, showed that a lower dose (1g/kg) was as effective as the standard 2g/kg<br />
dose. 126<br />
A Canadian study compared the cost-effectiveness of aspir<strong>in</strong>, low doses of IG<br />
(0.4g/kg/day for 4 days) and high doses of IG (2g/kg s<strong>in</strong>gle dose). 127 It concluded that a<br />
s<strong>in</strong>gle high dose <strong>is</strong> preferred because it results <strong>in</strong> both lower costs and lower rates of<br />
new CAA. A study <strong>in</strong> Japan came to the same conclusion, though it limited the high<br />
dose therapy to patients <strong>with</strong> specific criteria (Harada score). 128<br />
In Kawasaki d<strong>is</strong>ease, IG showed a significant decrease <strong>in</strong> new coronary artery<br />
abnormalities, fever and hospitalization, compared to placebo. A lower dose<br />
(1g/kg) <strong>is</strong> as effective as a high dose (2g/kg). A high s<strong>in</strong>gle dose (2g/kg) <strong>is</strong> more<br />
cost-effective than a lower dose (0.4g/kg/day) for 4 days.<br />
Viral myocardit<strong>is</strong> <strong>in</strong> children and adults<br />
Acute myocardit<strong>is</strong> <strong>is</strong> a d<strong>is</strong>ease that occurs <strong>in</strong> all age groups. In young patients, it <strong>is</strong> the<br />
most common cause of heart failure requir<strong>in</strong>g cardiac transplantation. 129 It <strong>is</strong> presumed<br />
to usually start as a viral <strong>in</strong>fection, although autoimmune and idiopathic forms also<br />
occur. It rema<strong>in</strong>s unclear if the primary problem <strong>is</strong> most the ongo<strong>in</strong>g damage from a<br />
virus, a post <strong>in</strong>fectious <strong>in</strong>flammatory reaction, or a comb<strong>in</strong>ation of both. However,<br />
immunosuppressive therapy was not shown efficacious <strong>in</strong> previous RCT. As IG has both<br />
antiviral and immunomodulatory effects and <strong>is</strong> an important therapy for Kawasaki<br />
d<strong>is</strong>ease, IG has been used <strong>in</strong> children <strong>with</strong> new-onset myocardit<strong>is</strong>.<br />
A Cochrane systematic review publ<strong>is</strong>hed <strong>in</strong> 2005 <strong>in</strong>cluded only one RCT <strong>in</strong>volv<strong>in</strong>g 62<br />
adult patients <strong>with</strong> presumed viral myocardit<strong>is</strong>. 129 Cl<strong>in</strong>ical improvement and <strong>in</strong>cidence of<br />
death were not significantly different <strong>in</strong> patients receiv<strong>in</strong>g IG compared <strong>with</strong> the placebo<br />
group, due to the high rate of spontaneous recovery. <strong>The</strong> favourable prognos<strong>is</strong> <strong>with</strong><br />
conventional therapy may expla<strong>in</strong> the apparent improvement <strong>report</strong>ed <strong>in</strong> uncontrolled<br />
studies. 129 <strong>The</strong>se f<strong>in</strong>d<strong>in</strong>gs contrast <strong>with</strong> case series and a study compar<strong>in</strong>g cases treated<br />
<strong>with</strong> IG to recent h<strong>is</strong>torical controls, which <strong>report</strong>ed significant improvements <strong>in</strong> left<br />
ventricular function <strong>in</strong> cases treated <strong>with</strong> IG. 130,131,132 Authors concluded that evidence<br />
from th<strong>is</strong> trial does not support the use of IG for the management of adults <strong>with</strong><br />
presumed viral myocardit<strong>is</strong>. <strong>The</strong>re are no randomized paediatric trials.<br />
Evidence from one trial did not show a benefit of IG for the management of<br />
presumed viral myocardit<strong>is</strong> <strong>in</strong> adults. <strong>The</strong>re <strong>is</strong> no evidence for paediatric cases.<br />
Treat<strong>in</strong>g seps<strong>is</strong> and septic shock<br />
Despite the development of new antibiotics and advances <strong>in</strong> the management of<br />
critically ill adults <strong>with</strong> severe <strong>in</strong>fections, the mortality rate from septic shock rema<strong>in</strong>s<br />
very high, rang<strong>in</strong>g from 21 to 72%. 133,134 Because of its broad and potent activity aga<strong>in</strong>st<br />
bacterial products and host cytok<strong>in</strong>es, polyclonal <strong>in</strong>travenous immunoglobul<strong>in</strong> has been<br />
<strong>in</strong>vestigated as an adjunctive therapy for treat<strong>in</strong>g severe <strong>in</strong>fections.<br />
Several Cochrane systematic reviews have been publ<strong>is</strong>hed on th<strong>is</strong> topic. <strong>The</strong> most<br />
recent one (2002) <strong>in</strong>cluded 11 RCT <strong>in</strong>volv<strong>in</strong>g 492 patients treated <strong>with</strong> polyvalent IG. 133<br />
Overall mortality was reduced <strong>in</strong> patients who received polyclonal IG compared to<br />
placebo or no <strong>in</strong>tervention (RR=0.64; 95% CI 0.51-0.80). Polyclonal IG also reduced<br />
mortality from septic shock <strong>in</strong> a pooled analys<strong>is</strong> from 3 RCT. Several other systematic<br />
reviews and meta-analyses have been publ<strong>is</strong>hed after th<strong>is</strong> Cochrane review. <strong>The</strong> two<br />
most recent meta-analyses searched literature till March and May 2006 and <strong>in</strong>cluded 14<br />
and 20 RCT respectively, compar<strong>in</strong>g IG for the adjunctive treatment of severe seps<strong>is</strong><br />
and septic shock <strong>with</strong> placebo or no treatment. 134,135 Though only 5 RCT were common<br />
to the three reviews, the two meta-analyses found similar and significant reduction <strong>in</strong><br />
mortality <strong>in</strong> patients treated <strong>with</strong> IG compared to placebo or no <strong>in</strong>tervention (RR=0.66;<br />
95% CI 0.53-0.83 and RR=0.74; 95% CI, 0.62-0.89). 134,135
<strong>KCE</strong> Reports 120 Plasma 69<br />
Severe seps<strong>is</strong> or septic shock cases receiv<strong>in</strong>g a higher dose (total dose 1g/kg or more)<br />
and treated for longer than 2 days were strongly associated <strong>with</strong> th<strong>is</strong> survival<br />
benefit. 134,135<br />
IG used as an adjuvant therapy <strong>in</strong> patients <strong>with</strong> seps<strong>is</strong> and septic shock reduced<br />
mortality compared <strong>with</strong> placebo or no <strong>in</strong>tervention. Th<strong>is</strong> survival benefit was<br />
cons<strong>is</strong>tently observed <strong>in</strong> three large meta-analyses.<br />
Treat<strong>in</strong>g Respiratory Syncitial Virus <strong>in</strong>fections<br />
Infection <strong>with</strong> the Respiratory Syncitial Virus (RSV) <strong>is</strong> a common cause of childhood<br />
bronchiolit<strong>is</strong> and pneumonia, and can cause severe d<strong>is</strong>ease <strong>in</strong> children between two to<br />
eight months. In older age groups, RSV may cause simple upper respiratory tract illness.<br />
Nearly all children have had at least one <strong>in</strong>fection by the age of 3 years. No cure ex<strong>is</strong>ts<br />
for RSV <strong>in</strong>fections. Prophylactic use of IG products <strong>with</strong> high anti-RSV antibody titres or<br />
monoclonal anti-RSV antibody have proved beneficial when given monthly <strong>in</strong> selected<br />
high-r<strong>is</strong>k <strong>in</strong>fants, 136 but are not d<strong>is</strong>cussed <strong>in</strong> th<strong>is</strong> section on polyvalent IG. Several studies<br />
have also assessed the effectiveness of provid<strong>in</strong>g IG for children admitted to hospital for<br />
severe RSV <strong>in</strong>fection as treatment.<br />
A Cochrane review publ<strong>is</strong>hed <strong>in</strong> 2006 evaluated the treatment of RSV <strong>in</strong>fections <strong>with</strong><br />
several types of IG, <strong>in</strong>clud<strong>in</strong>g polyvalent IG, IG <strong>with</strong> high anti-RSV antibody titres and<br />
human<strong>is</strong>ed monoclonal antibody to RSV. 137 It <strong>in</strong>cluded four publications, and no RCT<br />
demonstrated stat<strong>is</strong>tically significant benefit of IG treatment added to supportive care,<br />
compared <strong>with</strong> supportive care alone. No meta-analys<strong>is</strong> was possible due to the wide<br />
heterogeneity of the outcomes assessed. No RCT publ<strong>is</strong>hed after the review period<br />
were found. <strong>The</strong> <strong>available</strong> evidence thus does not support a role of IG for the treatment<br />
of RSV <strong>in</strong>fection, <strong>with</strong> the doses used <strong>in</strong> the studies.<br />
No significant benefit of IG treatment added to supportive care has been shown<br />
for the treatment of RSV <strong>in</strong>fections, compared <strong>with</strong> supportive care alone.<br />
3.2.2.6 Medical conditions under <strong>in</strong>vestigation<br />
Alzheimer d<strong>is</strong>ease<br />
Alzheimer’s d<strong>is</strong>ease (AD) <strong>is</strong> the most common cause of dementia and accounts for<br />
more than half of the dementia cases. One of the major manifestations of AD <strong>is</strong> the<br />
presence of abundant plaques <strong>in</strong> the bra<strong>in</strong> t<strong>is</strong>sues of the affected <strong>in</strong>dividuals, due to<br />
deposits of an amyloid-beta peptide (AbP). <strong>The</strong> dom<strong>in</strong>ant theory states that<br />
overproduction of AbP, or failure to clear th<strong>is</strong> peptide, leads to the neuronal damage. 138<br />
Prelim<strong>in</strong>ary studies have suggested that IG therapy has several positive effects on<br />
patients <strong>with</strong> AD, by lower<strong>in</strong>g the level of soluble AbP <strong>in</strong> the bra<strong>in</strong>. 139 However, no RCT<br />
was found; IG was only shown to have positive effect on AD patients <strong>in</strong> two small and<br />
non-controlled trials. <strong>The</strong> first trial <strong>in</strong>volved 5 AD patients <strong>with</strong> IG monthly for six<br />
months and showed a drop <strong>in</strong> CSF AbP (by 30%) and an <strong>in</strong>crease <strong>in</strong> plasma AbP (by<br />
23%), together <strong>with</strong> a stabilization <strong>in</strong> cognitive decl<strong>in</strong>e <strong>in</strong> all the patients. 140 Another 18month<br />
study <strong>in</strong> 8 patients <strong>with</strong> mild AD receiv<strong>in</strong>g IG led to transient <strong>in</strong>creases <strong>in</strong> plasma<br />
levels of AbP. 141 <strong>The</strong> CSF AbP levels decreased after six months of IG therapy and, after<br />
three months <strong>with</strong>out IG, <strong>in</strong>creased to their pre-treatment basel<strong>in</strong>e levels. <strong>The</strong>se<br />
f<strong>in</strong>d<strong>in</strong>gs <strong>in</strong>dicate that no def<strong>in</strong>ite statement on the effects of IG <strong>in</strong> AD can be made.<br />
Many other agents for passive immunotherapy are under study, mostly monoclonal<br />
antibodies aga<strong>in</strong>st Ab or <strong>in</strong>vestigative vacc<strong>in</strong>es. A phase III trial of pooled human<br />
immunoglobul<strong>in</strong> has been recently launched but no details are <strong>available</strong>. 142<br />
Evidence <strong>is</strong> lack<strong>in</strong>g on the effectiveness of IG <strong>in</strong> the treatment of Alzheimer<br />
D<strong>is</strong>ease
70 Plasma <strong>KCE</strong> Reports 120<br />
Chronic fatigue syndrome<br />
<strong>The</strong> Chronic fatigue syndrome (CFS) <strong>is</strong> a condition character<strong>is</strong>ed by severe, d<strong>is</strong>abl<strong>in</strong>g<br />
fatigue <strong>in</strong> the absence of exertion, and <strong>is</strong> marked by a dramatic decl<strong>in</strong>e <strong>in</strong> activity level.<br />
Currently, the aetiology of CFS rema<strong>in</strong>s unknown.<br />
<strong>The</strong> beneficial effect of IG for CFS patients <strong>is</strong> controversial. Three RCTs obta<strong>in</strong>ed mixed<br />
results: a RCT conducted <strong>in</strong> 1990 found improvements <strong>in</strong> symptom scores and<br />
functional capacity at three months; 143 a second found improvement <strong>in</strong> immune<br />
<strong>in</strong>dicators but not <strong>in</strong> symptom and functional measures, 144 the third trial was more<br />
recent and larger (<strong>in</strong>volv<strong>in</strong>g 99 adult patients). 145 It found no effect of treatment, but<br />
<strong>report</strong>ed adverse reactions <strong>in</strong> 70-80% patients, <strong>with</strong> no relationship to IG treatment. It<br />
concluded that IG cannot be recommended as a therapy for CFS.<br />
<strong>The</strong>re <strong>is</strong> conflict<strong>in</strong>g evidence on the effect of IG <strong>in</strong> CFS, but the larger and more<br />
recent trial showed no effect, <strong>with</strong> a high rate of adverse events.<br />
3.3 CONSUMPTION OF IMMUNOGLOBULINS<br />
3.3.1 Consumption <strong>in</strong> other countries<br />
Few studies <strong>in</strong>vestigat<strong>in</strong>g IG use and its trends are <strong>available</strong>. No study has been found on<br />
IG consumption <strong>in</strong> European countries. However, eight studies <strong>with</strong> quantitative data<br />
on recent IG use per <strong>in</strong>dication were found from Australia, Canada, New Zealand and<br />
the US. 146,147,148,149,150,151,152,153 .<br />
3.3.1.1 Consumption by medical speciality and <strong>in</strong>dication<br />
<strong>The</strong> results of the four studies analyz<strong>in</strong>g prescription data after 2000 are described<br />
below. 146,147-149 . <strong>The</strong> d<strong>is</strong>tribution of the total quantities of IG used, by <strong>in</strong>dication and<br />
major specialty, <strong>is</strong> shown <strong>in</strong> Table 22, based on the four studies analyz<strong>in</strong>g IG use per<br />
<strong>in</strong>dication. Though variations are observed across studies, the majority of IG was<br />
prescribed by two cl<strong>in</strong>ical specialities: neurology, which consume <strong>in</strong> average one third of<br />
total IG amount; and immuno-haematology, which consume around half of the total<br />
amount. An exception to th<strong>is</strong> pattern was the Massachusset general hospital (US) where<br />
a very high consumption <strong>in</strong> neurology (71%) <strong>is</strong> bias<strong>in</strong>g other relative estimates.<br />
Table 22: D<strong>is</strong>tribution of the total amount of immunoglobul<strong>in</strong> used per<br />
d<strong>is</strong>ease <strong>in</strong> four studies <strong>in</strong> three countries, 2000-2004 (New Zealand, Canada,<br />
US). Weighted average of the four studies.<br />
Studies New Zealand Toronto<br />
Massach<br />
US<br />
Canada<br />
Atlantic<br />
Weighted<br />
average<br />
D<strong>is</strong>eases/year 2004 2000 2004 2003-04<br />
Guilla<strong>in</strong>-Barré syndrome 6% 5% 3% 4% 5%<br />
Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyneuropathy 13% 9% 12% 19%<br />
Multifocal motor neuropathy 3% 3% 62%<br />
8% 4%<br />
Relaps<strong>in</strong>g-remitt<strong>in</strong>g multiple scleros<strong>is</strong> 3% 3%<br />
Myasthenia grav<strong>is</strong> 2% 1% 4% 5% 3%<br />
Dermatomyosit<strong>is</strong> 2% 2% 2% 2%<br />
Total neurology - muscular 25% 20% 71% 35% 32%<br />
Idiopathic thrombocytopenic purpura 9% 16% 8% 17% 13%<br />
Primary immune deficiencies 32% 15% 9% 15% 19%<br />
Secondary immune deficiency <strong>in</strong> general 15% 19% 9% 10% 14%<br />
- Chronic lymphocytic leukaemia 5% 1% 4%<br />
- Multiple myeloma 1% 1%<br />
- Bone marrow / stem cell transplant 8% 19% 4% 11%<br />
- Children <strong>with</strong> HIV 1% 1%<br />
- solid organ transplants 2% 1% 4% 2%<br />
Acute leukaemia <strong>in</strong> childhood 4% 4%<br />
Autoimmune haemolytic anaemia 2% 1% 2%<br />
Total immuno-hemato 60% 51% 27% 42% 48%<br />
Kawasaki d<strong>is</strong>ease <strong>in</strong> children 0% 1% 0%<br />
Toxic shock syndrome 3% 2% 1% 2%<br />
Others 15% 27% 1% 22% 17%<br />
Total amount IG 101.496 g 100.208 g 48.230 g 65.240 g 315.174 g
<strong>KCE</strong> Reports 120 Plasma 71<br />
<strong>The</strong> analys<strong>is</strong> of IG d<strong>is</strong>tribution per <strong>in</strong>dication shows that a few d<strong>is</strong>eases treated <strong>with</strong><br />
long term ma<strong>in</strong>tenance IG consume a high proportion of the total IG amount. Among<br />
the neurological <strong>in</strong>dications, chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyneuropathy (CIDP)<br />
accounts for the highest consumption per d<strong>is</strong>ease (19% of total use <strong>in</strong> average), and<br />
comb<strong>in</strong>ed <strong>with</strong> multifocal motor neuropathy (MMN) consumed as much as 62% of the<br />
IG amount <strong>in</strong> Massachusset, while it represents 11-20% <strong>in</strong> other studies. Among the<br />
immuno-haematological <strong>in</strong>dications, the ma<strong>in</strong> consumers are primary and secondary<br />
immune deficiencies (PID and SID), represent<strong>in</strong>g together 34% of total use (rang<strong>in</strong>g 18-<br />
47%). Idiopathic thrombocytopenic purpura (ITP) and stem cell transplants (<strong>in</strong>cluded <strong>in</strong><br />
secondary immune deficiencies) represents 13 and 11% of total IG use respectively but<br />
th<strong>is</strong> proportion widely varies across countries, reflect<strong>in</strong>g diverg<strong>in</strong>g views on the IG use<br />
for these <strong>in</strong>dications.<br />
Similar geographical variations were observed across Canadian regions (Tonronto vs.<br />
146, 148, 151<br />
Atlantic regions), as well as across Australian regions.<br />
Some other specialties or <strong>in</strong>dications were responsible for a high IG use, which<br />
contrasted <strong>with</strong> the recommendations <strong>in</strong> use. For <strong>in</strong>stance, the Toronto study showed<br />
an unexpectedly high amount of IG used for <strong>in</strong>fectious d<strong>is</strong>eases (18%) and dermatology<br />
(7%). 148 Unexpected patterns of IG use were also observed <strong>in</strong> specific regions: <strong>in</strong> the<br />
New Zealand study, one region was an extraord<strong>in</strong>arily high user of IG for obstetric<br />
purposes, us<strong>in</strong>g 11-fold more IG per capita <strong>in</strong> th<strong>is</strong> category than the other regions, and<br />
also used large amounts for respiratory and rheumatic d<strong>is</strong>eases. Another region used<br />
more IG for cardiological diagnoses than all other regions comb<strong>in</strong>ed. 149 <strong>The</strong> Toronto<br />
study also noticed that <strong>in</strong>dividual physicians <strong>with</strong> specific cl<strong>in</strong>ical <strong>in</strong>terest were<br />
responsible for large proportions of the total IG prescribed. 148 A high number of<br />
patients received IG as a s<strong>in</strong>gle dose, for other <strong>in</strong>dications that those commonly<br />
accepted; each patient consumed relatively little IG but made up of nearly one-third of<br />
all patients treated. Most of these s<strong>in</strong>gle-use patients probably represents empirical use<br />
of IG <strong>in</strong> which a cl<strong>in</strong>ician attempts to rescue a seriously ill patient for whom there are<br />
few other treatments <strong>available</strong>, or when physicians are confronted <strong>with</strong> an undef<strong>in</strong>ed<br />
medical problem, such as a peripheral neuropathy. Th<strong>is</strong> pattern was also suggested by<br />
the Canadian Atlantic study. 146<br />
<strong>The</strong> d<strong>is</strong>tribution of the total number of patients treated <strong>with</strong> IG per d<strong>is</strong>ease (Table 23)<br />
suggests a similar d<strong>is</strong>tribution. However, the proportion of patients treated for<br />
neurological d<strong>is</strong>orders tends to be lower than the respective proportion of IG use,<br />
especially <strong>in</strong> Massachusset where 39% cases <strong>with</strong> neurological d<strong>is</strong>order consume 71% of<br />
total IG use. Th<strong>is</strong> <strong>is</strong> due to the high amount of IG used for the long term immunomodulatory<br />
treatment of neurological <strong>in</strong>dications such as CIDP and MMN: the dosage<br />
ranges 1-2g/kg body weight (vs. 0.3-0.6g for PID and 0.8-1g for ITP) and these patients<br />
are mostly adults.<br />
<strong>The</strong> average IG amount used to treat a case <strong>with</strong> a def<strong>in</strong>ed d<strong>is</strong>ease <strong>is</strong> presented <strong>in</strong> Table<br />
24. It <strong>in</strong>deed confirms the (non significantly) higher average dose per patient used to<br />
treat the neurological d<strong>is</strong>eases (rang<strong>in</strong>g 173-486g per patient) as compared to immunohaematological<br />
<strong>in</strong>dications (rang<strong>in</strong>g 90-302g per patient). D<strong>is</strong>eases rank<strong>in</strong>g the highest <strong>in</strong><br />
IG use per patient (weighted average) were dermatomyosit<strong>is</strong>, multiple scleros<strong>is</strong>, CIDP,<br />
MMN, stem cell transplant, acute leukaemia and solid organ transplants. Primary and<br />
other secondary immune deficiencies are consum<strong>in</strong>g lower amounts per case (rang<strong>in</strong>g<br />
150-229g per patient), due to the lower dosage per kg used for IG supplementation.
72 Plasma <strong>KCE</strong> Reports 120<br />
Table 23: D<strong>is</strong>tribution of the number of cases treated <strong>with</strong> immunoglobul<strong>in</strong>s,<br />
per d<strong>is</strong>ease, <strong>in</strong> four studies <strong>in</strong> three countries, 2000-2004 (New Zealand,<br />
Canada, US).<br />
New<br />
Massach Canada Total<br />
Studies Zealand Toronto US Atlantic cases<br />
D<strong>is</strong>eases/year 2004 2000 2004 2003-04<br />
Guilla<strong>in</strong>-Barré syndrome 7% 11% 4% 5% 106<br />
Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyneuropathy 10% 11% 7% 149<br />
Multifocal motor neuropathy 3% 1% 29% 3% 27<br />
Relaps<strong>in</strong>g-remitt<strong>in</strong>g multiple scleros<strong>is</strong> 2% 6<br />
Myasthenia grav<strong>is</strong> 2% 2% 5% 5% 44<br />
Dermatomyosit<strong>is</strong> 1% 1% 1% 12<br />
Total neurology - muscular 23% 26% 39% 22% 24%<br />
Idiopathic thrombocytopenic purpura 12% 15% 10% 15% 190<br />
Primary immune deficiencies 30% 6% 13% 19% 253<br />
Secondary immune deficiency <strong>in</strong> general 18% 8% 61<br />
- Chronic lymphocytic leukaemia 5% 24<br />
- Multiple myeloma 1% 5<br />
- Bone marrow / stem cell transplant 5% 15% 7% 113<br />
- Children <strong>with</strong> HIV 1% 2<br />
- solid organ transplants 1% 1% 7<br />
Acute leukaemia <strong>in</strong> childhood 3% 12<br />
Autoimmune haemolytic anaemia 3% 1% 14<br />
Total immuno-hemato 56% 39% 45% 50% 48%<br />
Kawasaki d<strong>is</strong>ease <strong>in</strong> children 0% 3% 11<br />
Toxic shock syndrome<br />
Others<br />
4% 2% 1% 24<br />
Total amount IG 457 429 194 339 1419<br />
Table 24: Immunoglobul<strong>in</strong> amount used per patient, per year and per<br />
d<strong>is</strong>ease, <strong>in</strong> four studies <strong>in</strong> three countries, 2000-2004 (New Zealand, Canada,<br />
US). Weighted average of the four studies.<br />
Studies<br />
New<br />
Zealand Toronto<br />
Massach<br />
US<br />
Canada<br />
Atlantic<br />
Weighted<br />
average<br />
D<strong>is</strong>eases/year 2004 2000 2004 2003-04<br />
Guilla<strong>in</strong>-Barré syndrome 188 g 160 g 190 g 174 g 173 g<br />
Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyneuropathy 297 g 182 g 348 g<br />
Multifocal motor neuropathy 248 g 708 g 530 g<br />
486 g<br />
Relaps<strong>in</strong>g-remitt<strong>in</strong>g multiple scleros<strong>is</strong> 354 g 354 g<br />
Myasthenia grav<strong>is</strong> 219 g 169 g 190 g 200 g 198 g<br />
Dermatomyosit<strong>is</strong> 439 g 490 g 453 g<br />
Idiopathic thrombocytopenic purpura 170 g 243 g 190 g 217 g 210 g<br />
Primary immune deficiencies<br />
Secondary immune deficiencies:<br />
239 g 233 g 170 g 229 g<br />
- Chronic lymphocytic leukaemia<br />
- Multiple myeloma<br />
219 g 219 g<br />
- Bone marrow / stem cell transplant 342 g 287 g 302 g<br />
- Children <strong>with</strong> HIV 150 g 150 g<br />
- solid organ transplants 426 g 80 g 286 g<br />
Acute leukaemia <strong>in</strong> childhood 299 g 299 g<br />
Autoimmune haemolytic anaemia 166 g 10 g 146 g<br />
Kawasaki d<strong>is</strong>ease <strong>in</strong> children 20 g 52 g 51 g<br />
Toxic shock syndrome 160 g 120 g 87 g 140 g
<strong>KCE</strong> Reports 120 Plasma 73<br />
3.3.1.2 Trends over time<br />
An <strong>in</strong>crease <strong>in</strong> overall IG consumption has been described worldwide. For <strong>in</strong>stance,<br />
annual util<strong>is</strong>ation <strong>in</strong> Australia rose by an average of 14.8% from 1994-95 to 2004-05. 16 In<br />
Canada, the IG use has steadily r<strong>is</strong>en s<strong>in</strong>ce 1990, at a mean annual rate of 12.5%. 146<br />
However, only a few studies have analyzed the d<strong>is</strong>tribution of IG use per <strong>in</strong>dication (or<br />
specialty) over time. An unpubl<strong>is</strong>hed US study shows that the weight of each medical<br />
specialty has undergone noticeable changes <strong>with</strong><strong>in</strong> a 5-year period of time (2002-2007,<br />
Table 25). <strong>The</strong> Toronto study <strong>report</strong>ed that dermatological conditions <strong>in</strong>creased from<br />
0% of annual consumption <strong>in</strong> 1995 to 16% by 2000, and th<strong>is</strong> was l<strong>in</strong>ked to the<br />
establ<strong>is</strong>hment of specialized dermatological cl<strong>in</strong>ics. 148<br />
Th<strong>is</strong> suggests that diversification <strong>in</strong> IG use or IG demand, result<strong>in</strong>g from either newly<br />
approved <strong>in</strong>dications or changes <strong>in</strong> prescription practices, may appear <strong>in</strong> any country <strong>in</strong><br />
a relatively short period of time.<br />
Table 25: D<strong>is</strong>tribution of the total amount of immunoglobul<strong>in</strong> used per<br />
medical specialty <strong>in</strong> the US, 2002-2007<br />
Medical Specialty 2002 2007<br />
Allergy Immunology 19,0% 21,6%<br />
Rheumatology Nephrology 2,1% 7,8%<br />
Dermatology 6,3% 7,6%<br />
Neurology 20,2% 22,0%<br />
Hematology 30,8% 11,3%<br />
Cardiology 0,0% 3,4%<br />
Obstetrics Gynecology 0,0% 6,7%<br />
Infectious D<strong>is</strong>eases 14,1% 10,0%<br />
Ophtalmology 2,0% 9,1%<br />
Others 5,5% 0,0%<br />
Source: presentation of Market<strong>in</strong>g Research Bureau/ IPPC-PPTA Congress 3-4 March 2009<br />
3.3.1.3 Unlabelled use of immunoglobul<strong>in</strong><br />
Several studies compared the proportion of IG used or the proportion of patients<br />
treated <strong>with</strong> IG for an unlabelled <strong>in</strong>dication, as def<strong>in</strong>ed <strong>in</strong> each country (Table 26). 146 It <strong>is</strong><br />
noteworthy that these unlabelled <strong>in</strong>dications represented more than half of the total<br />
number of patients receiv<strong>in</strong>g IG (52-64%) <strong>in</strong> all studies. However, most of these IG<br />
adm<strong>in</strong><strong>is</strong>trations were scientifically accepted and often <strong>in</strong>cluded <strong>in</strong> the national<br />
recommendations, <strong>in</strong> accordance <strong>with</strong> the last guidel<strong>in</strong>es. Th<strong>is</strong> concept of labelled and<br />
unlabelled <strong>in</strong>dication for IG <strong>is</strong> thus no longer related to the concept of scientifically<br />
proven benefit. In Canada (Atlantic Prov<strong>in</strong>ces), the <strong>in</strong>troduction of detailed<br />
recommendations did not impact on the proportion of IG adm<strong>in</strong><strong>is</strong>tered for unlabelled<br />
<strong>in</strong>dications, at least <strong>in</strong> the first year. 146<br />
Table 26: Use of immunoglobul<strong>in</strong>s for unlabeled <strong>in</strong>dications <strong>in</strong> the US and<br />
Canada, 2000-2005.<br />
Country % total (year) Comments<br />
US, 12 academic<br />
centres<br />
52% patients (Chen, 2000) Drug authority allows all uses<br />
US, Massachusset 54% patients (Darabi, 2004) Drug authority allows all uses<br />
hospital<br />
Canada, Atlantic<br />
prov<strong>in</strong>ces<br />
64% of IVIG amount<br />
(Constant<strong>in</strong>e 2005)<br />
Study pre and post recommendations
74 Plasma <strong>KCE</strong> Reports 120<br />
Key po<strong>in</strong>ts<br />
• In other <strong>in</strong>dustrialized countries, around half of the total amount of<br />
immunoglobul<strong>in</strong>s <strong>is</strong> used to treat immuno-haematological d<strong>is</strong>eases, and<br />
around one third <strong>is</strong> used to treat neurological and neuro-muscular d<strong>is</strong>eases.<br />
• Some specialities or <strong>in</strong>dications that are usually not <strong>in</strong>cluded <strong>in</strong><br />
recommendations consume an unexpectedly high amount of IG, <strong>with</strong> large<br />
variations across hospitals and geographical areas. Individual physicians or<br />
cl<strong>in</strong>ics may impact on large proportions of the total IG prescribed<br />
• A few d<strong>is</strong>eases consume a high proportion of the total IG. For <strong>in</strong>stance, four<br />
d<strong>is</strong>eases (chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyneuropathy, primary and<br />
secondary immune deficiencies and idiopathic thrombocytopenic purpura)<br />
consumed <strong>in</strong> average two third of the total IG amount. Three of these<br />
d<strong>is</strong>eases require long term treatment <strong>with</strong> IG.<br />
3.3.2 Consumption <strong>in</strong> Belgium<br />
3.3.2.1 Methods<br />
Data on IG use <strong>in</strong> Belgium were collected from two sources:<br />
1. Data on the period January 2004 - June 2007 from the National Institute for<br />
Health and D<strong>is</strong>ability Insurance (INAMI/RIZIV) on the IG amounts<br />
reimbursed, per quarter;<br />
2. Data on the year 2008 on IG used by hospitals (reimbursed or not) and<br />
collected by an ad-hoc survey.<br />
<strong>The</strong> <strong>KCE</strong> carried out a survey <strong>in</strong> March-June 2009 addressed to all pharmac<strong>is</strong>ts<br />
responsible for hospital pharmacies <strong>in</strong> Belgium, <strong>with</strong> the collaboration of the two<br />
regional associations of hospital pharmac<strong>is</strong>ts. We requested data on the amount of each<br />
IG brand product (per label and dosage) used <strong>in</strong> 2008, by medical specialty of the<br />
prescriber, based on the last three numbers of the INAMI/RIZIV codes. All nonrespond<strong>in</strong>g<br />
hospitals that had consumed >1 500 gr or spent >60 000€ for IG <strong>in</strong> 2006<br />
were then contacted personally.<br />
Data were then analyzed by summ<strong>in</strong>g all brand products expressed <strong>in</strong> grams.<br />
D<strong>is</strong>tribution per hospital, medical specialties and type of producer (CAF and non-CAF)<br />
are presented. Though data come from two non-fully comparable sources, we have<br />
compared data over the 2004-2008 period to identify trends.<br />
Information on the <strong>in</strong>dications for which IG has been prescribed <strong>is</strong> not <strong>available</strong>. Th<strong>is</strong><br />
survey does not aim at assess<strong>in</strong>g the relevance of IG prescription <strong>in</strong> hospitals.<br />
3.3.2.2 Overall IG amounts used <strong>in</strong> 2004-2008<br />
INAMI/RIZIV data for the 2004-2006 period have been presented under “Use of plasma<br />
derivatives <strong>in</strong> Belgium” and are compared below to the 2008 data (Figure 7).<br />
<strong>The</strong> <strong>KCE</strong> received data on 2008 IG amounts used from 102 hospitals <strong>report</strong><strong>in</strong>g a total<br />
use of 919.6 kg of IG, all products comb<strong>in</strong>ed. <strong>The</strong>se 102 hospitals represent a response<br />
rate of 82% on the 125 hospitals that <strong>report</strong>ed IG use <strong>in</strong> 2006 and accounted for as<br />
much as 99% of national IG use <strong>in</strong> 2006.
<strong>KCE</strong> Reports 120 Plasma 75<br />
Figure 7: Yearly quantities of IG consumed dur<strong>in</strong>g the period 2004-2008<br />
1,000,000 gr<br />
800,000 gr<br />
600,000 gr<br />
400,000 gr<br />
200,000 gr<br />
0 gr<br />
IG amount<br />
trend (l<strong>in</strong>ear)<br />
2004 2005 2006 2007 2008<br />
Sources: INAMI (2004-2006) and <strong>KCE</strong> survey (2008)<br />
Figure 7 shows the yearly <strong>in</strong>crease of IG consumed over the period 2004-2008 and its<br />
l<strong>in</strong>ear trend. Data on 2007 are only <strong>available</strong> for the first two quarter of 2007. It must<br />
be noted that the two data sources are not fully comparable: 2004-2006 data cover<br />
reimbursed IG data provided by INAMI/RIZIV <strong>in</strong> all Belgian hospitals; 2008 data<br />
collected by the survey cover reimbursed and non-reimbursed IG <strong>report</strong>ed by Belgian<br />
hospitals represent<strong>in</strong>g 99% of IG use <strong>in</strong> 2006. However, we observed that the 2008<br />
estimate fits <strong>with</strong> the l<strong>in</strong>ear trend on the 2004-2006 data.<br />
Figure 8 presents the evolution (per quarter) of <strong>in</strong>travenous IG (IVIG) used, per<br />
producer (CAF-DCF and other producers). <strong>The</strong> systematically lower consumption <strong>in</strong><br />
the third quarter may be expla<strong>in</strong>ed by the d<strong>is</strong>cont<strong>in</strong>uation of IG supplementation <strong>in</strong> mild<br />
immune deficiencies dur<strong>in</strong>g summer (see Patterns of use). <strong>The</strong> proportion of CAF-DCF<br />
IVIG used <strong>in</strong>creased over the period (except <strong>in</strong> 2007) to reach 54.4% of all IVIG <strong>in</strong> the<br />
second quarter of 2008.<br />
In Figure 9, the IG consumption over the years 2004, 2006 and 2008 <strong>is</strong> compared for<br />
the 20 hospitals show<strong>in</strong>g the highest IG consumption. <strong>The</strong> absolute amounts of IG used<br />
are not compared across hospitals by level of activity, by lack of suitable criteria or<br />
<strong>in</strong>dicator. But the compar<strong>is</strong>on of trends across hospitals show divergences <strong>in</strong> IG<br />
consumption trends over th<strong>is</strong> 5 year period: some hospitals have nearly doubled their<br />
IG use (hospitals 10, 12 and 17), others showed a milder <strong>in</strong>crease or a relative<br />
stabilization of IG use, and a m<strong>in</strong>ority of them have decreased IG use from 2004 to<br />
2008.
76 Plasma <strong>KCE</strong> Reports 120<br />
Figure 8: Quantities of IG consumed <strong>in</strong> 2004-2008, per quarter and producer<br />
gr per quarter<br />
125.000 gr<br />
100.000 gr<br />
75.000 gr<br />
50.000 gr<br />
25.000 gr<br />
90.000 gr<br />
80.000 gr<br />
70.000 gr<br />
60.000 gr<br />
50.000 gr<br />
40.000 gr<br />
30.000 gr<br />
20.000 gr<br />
10.000 gr<br />
0 gr<br />
Consumption of polyvalent IV Immunoglobul<strong>in</strong>s<br />
Sources: INAMI (2004–2007 first half-year) and <strong>KCE</strong> survey (2008)<br />
Figure 9: Evolution of the consumption of IG (2004 – 2006 – 2008) <strong>in</strong> the 20<br />
Belgian hospitals <strong>with</strong> highest consumption<br />
0 gr<br />
3.3.2.3 Amounts prescribed per medical speciality <strong>in</strong> 2008<br />
121.227 gr<br />
101.322 gr<br />
20041 20043 20051 20053 20061 20063 20071 2008 Quarter<br />
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20<br />
Based on the last three numbers of the INAMI/RIZIV code for prescribers, we have<br />
analyzed 2008 IG prescription by medical specialty.<br />
Table 27 <strong>in</strong>dicates that four major specialities prescribed 92% of the IG 2008 amount:<br />
<strong>in</strong>tern<strong>is</strong>ts (all sub-specialties confounded) prescribed around half of IG, neurolog<strong>is</strong>ts<br />
around one quarter, pneumolog<strong>is</strong>ts one sixth and paediatricians 6%.<br />
CAF<br />
not-CAF<br />
2004<br />
2006<br />
2008
<strong>KCE</strong> Reports 120 Plasma 77<br />
Figure 10: Quantities of immunoglobul<strong>in</strong>s prescribed by medical specialty <strong>in</strong><br />
2008, Belgium<br />
54.602 gr<br />
Source : <strong>KCE</strong> Survey 2009<br />
149.506 gr<br />
215.582 gr<br />
425.644 gr<br />
Intern<strong>is</strong>t (058 & 580)<br />
Neurodegenerative care<br />
(76/77 & 760/770)<br />
Paediatrician (69 & 690)<br />
Pulmonolog<strong>is</strong>t (62 & 620)<br />
Other specialities<br />
<strong>The</strong> prescription by medical specialty shows variations between the university /<br />
academic hospitals (UZGent, UZA, KULeuven, AZ-VUB, UCL St Luc and Mont-<br />
God<strong>in</strong>ne, Erasme and Children Hospital Re<strong>in</strong>e Fabiola, CHU-Liège) and the other<br />
hospitals (als but 23% <strong>in</strong> other hospitals.<br />
Table 27). <strong>The</strong> widest d<strong>is</strong>crepancy <strong>is</strong> observed <strong>in</strong> the d<strong>is</strong>tribution of IG prescribed by<br />
lung special<strong>is</strong>ts: it represents 2% of all IG prescribed <strong>in</strong> academic hospitals but 23% <strong>in</strong><br />
other hospitals.<br />
Table 27: Amounts of immunoglobul<strong>in</strong>s prescribed by medical specialty <strong>in</strong><br />
2008, academic vs. non-academic hospitals<br />
Use <strong>in</strong><br />
academic<br />
hospitals<br />
% of total<br />
amount <strong>in</strong><br />
academic<br />
% of total<br />
amount <strong>in</strong><br />
other<br />
hospitals<br />
Use <strong>in</strong> all % of total<br />
Use <strong>in</strong> other<br />
Specialty<br />
hospitals amount<br />
hospitals<br />
N hospitals 102 8 94<br />
Intern<strong>is</strong>ts 425.644 gr 46% 148.067 gr 50% 277.578 gr 44%<br />
Neurology and related 215.582 gr 23% 89.818 gr 31% 125.764 gr 20%<br />
Paediatricians 54.602 gr 6% 26.898 gr 9% 27.704 gr 4%<br />
Pneumolog<strong>is</strong>ts 149.506 gr 16% 6.030 gr 2% 143.476 gr 23%<br />
Other specialities 74.338 gr 8% 22.948 gr 8% 51.390 gr 8%<br />
Total <strong>report</strong>ed 919.672 gr 100% 293.761 gr 100% 625.912 gr 100%<br />
In order to further <strong>in</strong>vestigate these differences, we have also compared the total<br />
amount prescribed by hospital and medical specialty, as well as the proportion it<br />
represents on the total IG amount prescribed <strong>in</strong> each hospital. <strong>The</strong> tables below per<br />
specialty present <strong>in</strong> the first l<strong>in</strong>e the consumption <strong>in</strong> all academic hospital together, per<br />
l<strong>in</strong>gu<strong>is</strong>tic regime (for the Flem<strong>is</strong>h part: UZGent, UZA, KULeuven and AZ-VUB and for<br />
the French-speak<strong>in</strong>g part: UCL St Luc and Mont-God<strong>in</strong>ne, Erasme and Children Hospital<br />
Re<strong>in</strong>e Fabiola, CHU-Liège); the follow<strong>in</strong>g l<strong>in</strong>es present, by hospital and l<strong>in</strong>gu<strong>is</strong>tic regime,<br />
the consumption <strong>in</strong> the hospitals <strong>with</strong> highest IG amount, <strong>in</strong> decreas<strong>in</strong>g order.
78 Plasma <strong>KCE</strong> Reports 120<br />
Table 28: Amounts of immunoglobul<strong>in</strong>s prescribed by <strong>in</strong>tern<strong>is</strong>ts <strong>in</strong> 2008 and<br />
proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h French-speak<strong>in</strong>g<br />
Amount % Amount %<br />
All academic general <strong>in</strong>tern<strong>is</strong>ts 108.25 kg 57.1% 39.82 kg 38.3%<br />
23.74 kg 77.9% 11.73 kg 91,0%<br />
23.61 kg 88.4% 9.37 kg 92,7%<br />
19.60 kg 78.7% 7.90 kg 45,8%<br />
7.44 kg 40.7% 7.12 kg 54,4%<br />
7.13 kg 60.3% 5.78 kg 64,5%<br />
6.72 kg 78.2% 5.46 kg 76,4%<br />
5.82 kg 52.9% 5.33 kg 40,7%<br />
5.19 kg 15.6% 5.27 kg 72,3%<br />
5.16 kg 37.7% 4.89 kg 61,8%<br />
3.83 kg 52.0% 4.80 kg 58,9%<br />
3.73 kg 36.6% 4.44 kg 61,2%<br />
3.63 kg 19.4% 4.39 kg 68,4%<br />
3.26 kg 72.7% 3.77 kg 63,5%<br />
3.09 kg 25.3% 3.18 kg 70,5%<br />
2.62 kg 62.9% 2.40 kg 34,0%<br />
2.39 kg 7.3% 2.11 kg 42,6%<br />
2.37 kg 46.6% 2.10 kg 36,0%<br />
2.02 kg 24.9% 1.92 kg 70,1%<br />
2.02 kg 75.7% 1.65 kg 51,4%<br />
All Belgian general <strong>in</strong>tern<strong>is</strong>ts 425.594 kg 46.3%<br />
Table 29: Amounts of immunoglobul<strong>in</strong>s prescribed by neurolog<strong>is</strong>ts & neuropsychiatr<strong>is</strong>ts<br />
<strong>in</strong> 2008 and proportion of the total amount prescribed per<br />
hospital<br />
Flem<strong>is</strong>h French-speak<strong>in</strong>g<br />
All academic neurolog<strong>is</strong>ts & neuropsychiatr<strong>is</strong>ts<br />
Amount % Amount %<br />
43.41 kg 22.9% 46.41 kg 44.6%<br />
18.65 kg 57.2% 3.84 kg 22.2%<br />
9.43 kg 58.4% 2.95 kg 22.5%<br />
6.99 kg 65.7% 2.64 kg 29.5%<br />
4.60 kg 13.8% 2.52 kg 51.0%<br />
4.01 kg 32.9% 2.07 kg 35.4%<br />
3.63 kg 33.0% 1.97 kg 15.0%<br />
3.56 kg 11.7% 1.87 kg 52.2%<br />
3.46 kg 18.9% 1.47 kg 60.2%<br />
3.00 kg 29.4% 1.40 kg 19.2%<br />
2.96 kg 75.8% 1.33 kg 16.4%<br />
2.39 kg 9.6% 1.22 kg 17.1%<br />
2.26 kg 53.7% 1.22 kg 20.5%<br />
2.20 kg 47.8%<br />
All Belgian neurolog<strong>is</strong>ts &<br />
neuropsychiatr<strong>is</strong>ts 215.58 kg 23.4%<br />
Table 28 and Table 29 show variations <strong>in</strong> amounts prescribed and proportion these<br />
represent <strong>in</strong> each hospital for the specialities <strong>in</strong>ternal medic<strong>in</strong>e and neurology.<br />
However, no conclusion can be drawn as we did not compare these values <strong>with</strong> the<br />
number of cases requir<strong>in</strong>g IG and treated <strong>in</strong> these hospitals.
<strong>KCE</strong> Reports 120 Plasma 79<br />
Table 30: Amounts of immunoglobul<strong>in</strong>s prescribed by lung special<strong>is</strong>ts <strong>in</strong> 2008<br />
and proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h French-speak<strong>in</strong>g<br />
Amount % Amount %<br />
All academic pulmonolog<strong>is</strong>ts 4.57 kg 2.4% 1.46 kg 1.4%<br />
21.09 kg 63.4% 4.29 kg 60.7%<br />
12.32 kg 65.9% 2.83 kg 21.6%<br />
10.94 kg 33.6% 2.13 kg 29.4%<br />
10.23 kg 93,7% 1.95 kg 23.9%<br />
7.62 kg 55.7% 1.37 kg 7.9%<br />
6.40 kg 70.8%<br />
6.03 kg 66.1%<br />
5.42 kg 33.6%<br />
5.35 kg 29.3%<br />
4.23 kg 52.1%<br />
3.31 kg 32.5%<br />
2.35 kg 59.1%<br />
2.26 kg 59.5%<br />
2.25 kg 54.8%<br />
2.24 kg 7.4%<br />
2.06 kg 17.4%<br />
2.04 kg 7.6%<br />
All Belgian lung special<strong>is</strong>ts 149.51 kg 16.3%<br />
In Table 30, we observe a severe d<strong>is</strong>crepancy between the prescription of IG by lung<br />
special<strong>is</strong>ts <strong>in</strong> academic and the prescription <strong>in</strong> non-academic hospitals: the Flem<strong>is</strong>h<br />
hospital where lung special<strong>is</strong>ts prescribed the highest IG amount accounted for 21.1 kg<br />
or 4.6 times the amount consumed <strong>in</strong> all university hospitals comb<strong>in</strong>ed. <strong>The</strong> Frenchspeak<strong>in</strong>g<br />
hospital hav<strong>in</strong>g prescribed most IG <strong>in</strong> pneumology, consumed three times the<br />
amount prescribed <strong>in</strong> all French-speak<strong>in</strong>g university hospitals. In both hospitals, IG<br />
prescribed by pneumolog<strong>is</strong>ts represented more than 60% of the IG prescribed for the<br />
whole hospital, while th<strong>is</strong> proportion represents 1.4% and 2.4% <strong>in</strong> academic hospitals.<br />
Th<strong>is</strong> high prescription for lung d<strong>is</strong>ease <strong>is</strong> especially noticeable <strong>in</strong> Flanders: <strong>in</strong> at least 11<br />
non-academic hospitals, over 50% of the total IG <strong>is</strong> prescribed by pneumolog<strong>is</strong>ts. Th<strong>is</strong><br />
prescription pattern and high IG use <strong>in</strong> pneumology cannot be unexpla<strong>in</strong>ed by current<br />
reimbursed <strong>in</strong>dications, as no respiratory pathology <strong>is</strong> <strong>in</strong>cluded <strong>in</strong> the current<br />
<strong>in</strong>dications for IG, except for agammaglobul<strong>in</strong>emia and hypogammaglobul<strong>in</strong>emia <strong>with</strong><br />
repeated bacterial <strong>in</strong>fections that may affect the respiratory tract. Experts <strong>report</strong>ed that<br />
IG <strong>is</strong> frequently prescribed <strong>in</strong> some peripheral hospitals for other immune deficiencies,<br />
such as <strong>is</strong>olated Ig G subclasses deficiencies <strong>with</strong>out recurrent <strong>in</strong>fections and <strong>with</strong>out<br />
abnormal antibody response after pneumococcal vacc<strong>in</strong>ation. However, these patients<br />
are neither an <strong>in</strong>dication for IG nor <strong>is</strong> IG reimbursed for these situations. It should also<br />
be noted that the criteria for IG reimbursement clearly state that “IG are not<br />
reimbursed if the IgG/IgG2/IgG3 deficiency <strong>is</strong> due to a long term treatment <strong>with</strong><br />
steroids, for <strong>in</strong>stance as <strong>in</strong> the chronic obstructive pulmonary d<strong>is</strong>ease”.<br />
In a few other specialties, similar patterns are also observed, to a lower extent: a high<br />
level of heterogeneity <strong>in</strong> prescription <strong>is</strong> seen across hospitals and some hospitals are<br />
prescrib<strong>in</strong>g significant IG amount <strong>in</strong> some specialties for which no <strong>in</strong>dication <strong>is</strong><br />
reimbursed or usually recommended based on evidence; for <strong>in</strong>stance, <strong>in</strong> surgery,<br />
obstetrics, gynaecology and gastro-enterology.
80 Plasma <strong>KCE</strong> Reports 120<br />
Table 31: Amounts of immunoglobul<strong>in</strong>s prescribed by paediatricians <strong>in</strong> 2008<br />
and proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
All academic paediatricians 14.61 kg 7.7% 12.28 kg 11.8%<br />
2.44 kg 9.8% 3.05 kg 17.7%<br />
0.96 kg 5.9% 1.82 kg 23.0%<br />
0.96 kg 5.2% 1.54 kg 11.8%<br />
0.89 kg 7.5% 1.00 kg 7.6%<br />
0.84 kg 11.4% 0.66 kg 20.5%<br />
0.61 kg 1.9% 0.56 kg 7.7%<br />
0.58 kg 7.1% 0.51 kg 5.7%<br />
0.53 kg 2.8% 0.50 kg 6.8%<br />
All Belgian paediatricians 54.62 kg 5.9%<br />
Table 32: Amounts of immunoglobul<strong>in</strong>s prescribed by rheumatolog<strong>is</strong>ts <strong>in</strong><br />
2008 and proportion of the total amount prescribed per hospital<br />
All academic<br />
rheumatolog<strong>is</strong>tss<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
2.52 kg 1.3% 0.20 kg 0.2%<br />
4.45 kg 36.5% 2.19 kg 61.5%<br />
1.51 kg 4.5%<br />
1.42 kg 12.9%<br />
1.21 kg 35.7%<br />
1.06 kg 36.0%<br />
All Belgian<br />
rheumatolog<strong>is</strong>ts 18.89 kg 2.1%<br />
Table 33: Amounts of immunoglobul<strong>in</strong>s prescribed <strong>in</strong> <strong>in</strong>tensive care units for<br />
adults <strong>in</strong> 2008 and proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
All academic IC units for adults 4.04 kg 2.5% 2.92 kg 3.8%<br />
1.47 kg 4.6% 0.83 kg 17.1%<br />
0.63 kg 10.7% 0.65 kg 6.7%<br />
All Belgian IC units for adults 20.55 kg 2.5%<br />
Table 34: Amounts of immunoglobul<strong>in</strong>s prescribed by gastro-enterolog<strong>is</strong>ts <strong>in</strong><br />
2008 and proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
All academic gastroenterolog<strong>is</strong>ts 2.09 kg 1.1% 0.54 kg 0.5%<br />
1.11 kg 12.1%<br />
0.63 kg 7.8%<br />
All Belgian gastroenterolog<strong>is</strong>ts 7.71 kg 0.8%<br />
Table 35: Amounts of immunoglobul<strong>in</strong>s prescribed by surgeons <strong>in</strong> 2008 and<br />
proportion of the total amount prescribed per hospital<br />
All academic general<br />
surgeons<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
1.47 kg 0.8% 1.37 kg 1.3%<br />
2.37 kg 18,0%<br />
All Belgian general<br />
surgeons 6.50 kg 0.7%
<strong>KCE</strong> Reports 120 Plasma 81<br />
Table 36: Amounts of immunoglobul<strong>in</strong>s prescribed by hospital general<br />
practitionners (GPs) <strong>in</strong> 2008 and proportion of the total amount prescribed<br />
per hospital<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
All GPs <strong>in</strong> academic hospitals 1.98 kg 1.0% 0.16 kg 0.2%<br />
1.03 kg 92.3%<br />
1.02 kg 15.8%<br />
All Belgian general practitioners <strong>in</strong><br />
hospitals 5.56 kg 0.6%<br />
Table 37: Amounts of immunoglobul<strong>in</strong>s prescribed by cardiolog<strong>is</strong>ts <strong>in</strong> 2008<br />
and proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
All academic cardiolog<strong>is</strong>ts 3.11 kg 1.6% 0.50 kg 0.5%<br />
0.64 kg 16.1%<br />
All Belgian cardiolog<strong>is</strong>ts 6.46 kg 0.7%<br />
Table 38: Amounts of immunoglobul<strong>in</strong>s prescribed by gynecolog<strong>is</strong>ts <strong>in</strong> 2008<br />
and proportion of the total amount prescribed per hospital<br />
Flem<strong>is</strong>h Flem<strong>is</strong>h French French<br />
All academic gynecolog<strong>is</strong>ts 0.96 kg 0.3% 0.00 kg 0.0%<br />
0.24 kg 12.2% 0.77 kg 4.4%<br />
0.19 kg 1.0% 0.23 kg 3.9%<br />
All Belgian gynecolog<strong>is</strong>ts 3.04 kg 0.3%<br />
3.3.2.4 D<strong>is</strong>cussion on IG consumption<br />
Data on IG consumption <strong>in</strong> Belgium <strong>in</strong>dicate similar patterns than those found <strong>in</strong> other<br />
countries: IG consumption <strong>is</strong> <strong>in</strong>creas<strong>in</strong>g over time, four ma<strong>in</strong> specialties consume the<br />
majority of IG, the use of IG <strong>is</strong> heterogeneous across hospitals and some hospitals<br />
consume a high IG amount <strong>in</strong> specialties that are not related to the authorized or<br />
reimbursed <strong>in</strong>dications.<br />
Two additional f<strong>in</strong>d<strong>in</strong>gs <strong>in</strong> Belgium have been revealed by the <strong>KCE</strong> survey:<br />
1. A high amount of IG <strong>is</strong> prescribed by lung special<strong>is</strong>ts, though th<strong>is</strong> cannot be<br />
justified by current reimbursed <strong>in</strong>dications or <strong>available</strong> evidence, as no<br />
respiratory pathology <strong>is</strong> <strong>in</strong>cluded <strong>in</strong> the current <strong>in</strong>dications for IG (except for<br />
specific immune deficiencies <strong>with</strong> repeated respiratory tract <strong>in</strong>fections). Th<strong>is</strong><br />
was not observed <strong>in</strong> any of the academic hospitals but was predom<strong>in</strong>ant <strong>in</strong> 11<br />
Flem<strong>is</strong>h and one Walloon hospitals. At <strong>in</strong>ternational level, th<strong>is</strong> was only<br />
<strong>report</strong>ed <strong>in</strong> one region <strong>in</strong> the New Zealand study. As we did not have access<br />
to data on IG consumption per <strong>in</strong>dication, we could not expla<strong>in</strong> th<strong>is</strong><br />
prescription <strong>with</strong> <strong>available</strong> data. Th<strong>is</strong> f<strong>in</strong>d<strong>in</strong>g deserves further <strong>in</strong>vestigation.<br />
2. <strong>The</strong> survey showed wide variations <strong>in</strong> prescription patterns between<br />
academic and non-academic hospitals. A major f<strong>in</strong>d<strong>in</strong>g <strong>is</strong> that a number of<br />
non-academic hospitals prescribe significant IG amounts for four other<br />
specialties (surgery, obstetrics, gynaecology and gastro-enterology) that are<br />
not related to reimbursed <strong>in</strong>dications - or to other <strong>in</strong>dications for which a<br />
benefit of IG has been proven. Th<strong>is</strong> unexpectedly high IG use <strong>is</strong> not observed<br />
<strong>in</strong> academic hospitals. Unexpected patterns of IG use <strong>in</strong> some hospitals or<br />
geographical areas were also observed <strong>in</strong> New Zealand where one region<br />
used 11-fold more IG per capita for obstetric purposes than the other<br />
regions. <strong>The</strong> Toronto study also noticed that <strong>in</strong>dividual physicians <strong>with</strong><br />
specific cl<strong>in</strong>ical <strong>in</strong>terest were responsible for large proportions of the total IG<br />
prescribed.<br />
<strong>The</strong> reasons for the overall <strong>in</strong>crease <strong>in</strong> IG consumption over the recent years could not<br />
be <strong>in</strong>vestigated based on these Belgian data. We had no access to data allow<strong>in</strong>g us to<br />
determ<strong>in</strong>e for which <strong>in</strong>dications IG has been prescribed over time.
82 Plasma <strong>KCE</strong> Reports 120<br />
For <strong>in</strong>stance, a growth <strong>in</strong> IG used <strong>in</strong> neurology was expected <strong>with</strong> the gradual<br />
<strong>in</strong>troduction of CIDP and MMN <strong>in</strong> the l<strong>is</strong>t of reimbursed <strong>in</strong>dications over 2002-2008<br />
(Table 19), but th<strong>is</strong> could not be verified. It <strong>is</strong> remarkable to observe that a few<br />
hospitals have decreased their IG consumption while others have doubled it over a 5<br />
year period.<br />
3.3.2.5 Patterns of use<br />
In order to understand IG use <strong>in</strong> Belgium and help determ<strong>in</strong>e the IG amount that would<br />
be required to treat the most IG consum<strong>in</strong>g <strong>in</strong>dications, two expert meet<strong>in</strong>gs and a<br />
survey were organized. <strong>The</strong> aim was to assess current practices <strong>in</strong> Belgium regard<strong>in</strong>g<br />
the character<strong>is</strong>tics of patients treated, the dosage used, the frequency of IG treatment<br />
<strong>in</strong> ma<strong>in</strong>tenance therapy and the expected trends <strong>in</strong> IG use.<br />
In immuno-haematological d<strong>is</strong>eases<br />
A survey was undertaken among 10 ma<strong>in</strong> centres adm<strong>in</strong><strong>is</strong>ter<strong>in</strong>g IG for immunodeficiencies.<br />
Questionnaires were addressed to paediatricians and haematolog<strong>is</strong>ts to<br />
obta<strong>in</strong> <strong>in</strong>formation on how IG are used <strong>in</strong> Belgium. We requested 2008 data on the<br />
number of patients treated per reimbursed <strong>in</strong>dication, number of IG adm<strong>in</strong><strong>is</strong>trations and<br />
usual dosage for the reimbursed <strong>in</strong>dications. Responses were received from 7 hospitals,<br />
and 6 hospitals provided the data requested. Survey results were presented to an<br />
expert committee and d<strong>is</strong>cussed. <strong>The</strong> questionnaires are provided <strong>in</strong> appendix.<br />
Collected questionnaires covered 846 cases, <strong>in</strong>clud<strong>in</strong>g 562 cases <strong>with</strong> an immunological<br />
or haematological d<strong>is</strong>ease or a Kawasaki d<strong>is</strong>ease: 186 cases <strong>with</strong> primary immune<br />
deficiency (PID) under ma<strong>in</strong>tenance treatment, 148 transplant cases, 75 ITP cases, 58<br />
cases <strong>with</strong> MM or CLL, 31 Kawasaki d<strong>is</strong>ease cases, 37 neonates treated <strong>with</strong> IG for<br />
<strong>in</strong>fection or severe ABO <strong>in</strong>compatibility and 27 cases <strong>with</strong> other immune deficiencies.<br />
Among these cases, 338 were children (154 PID, 36 transplants, 53 ITP, 31 Kawasaki<br />
d<strong>is</strong>ease, 37 neonates and 27 other immune deficiencies).<br />
No cases treated <strong>with</strong> IG for septic shock syndrome were <strong>report</strong>ed, though th<strong>is</strong> <strong>is</strong> a<br />
reimbursed <strong>in</strong>dication for IG. Based on several assumptions, we estimated that all these<br />
cases - <strong>with</strong> the exclusion of neurological <strong>in</strong>dications - accounted for a total IG use of<br />
108 kg <strong>in</strong> 2008, represent<strong>in</strong>g around 12% of total national use <strong>in</strong> 2008.<br />
DOSAGE PER INDICATION<br />
Results showed that similar dosage of IG supplementation per kg body weight are<br />
adm<strong>in</strong><strong>is</strong>tered <strong>in</strong> all centres to PID cases (around 0.4g), <strong>in</strong> accordance <strong>with</strong> guidel<strong>in</strong>es<br />
publ<strong>is</strong>hed by the Primary Immune deficiency Belgian group, 34 and for transplant cases.<br />
But dosage for other <strong>in</strong>dications showed wide variations. In ITP, doses ranged 0.8-2g/kg;<br />
two hospitals use a dose of 0.8g/kg <strong>in</strong> children as it has shown similar efficacy than<br />
higher doses <strong>in</strong> a recent study. In Kawasaki d<strong>is</strong>ease, dose ranged 1 to 2g/kg but 2g was<br />
the most frequent. For the other <strong>in</strong>dications, only one or two centres <strong>report</strong>ed cases<br />
and no conclusion can be drawn.<br />
FREQUENCY OF TREATMENT<br />
<strong>The</strong> annual frequency and duration of <strong>in</strong>travenous IG (IVIG) adm<strong>in</strong><strong>is</strong>trations per patient<br />
requir<strong>in</strong>g long term treatment also showed differences across centres:<br />
• For PID, the frequency of IVIG adm<strong>in</strong><strong>is</strong>tration varied from an average of<br />
6.4 to 14.3 per year <strong>in</strong> 2008. However, centres <strong>report</strong><strong>in</strong>g a lower<br />
frequency had many patients switch<strong>in</strong>g from IV to SC adm<strong>in</strong><strong>is</strong>tration <strong>in</strong><br />
2008 and a more documented monitor<strong>in</strong>g. In addition, the frequency <strong>in</strong> IG<br />
adm<strong>in</strong><strong>is</strong>tration depends on the type of immune deficiency: patient <strong>with</strong><br />
severe antibody deficiencies must receive treatment all year long, mostly<br />
every 3-4 weeks, requir<strong>in</strong>g 12-14 adm<strong>in</strong><strong>is</strong>trations per year; while <strong>in</strong><br />
transient or mild hypogammaglobul<strong>in</strong>emia <strong>with</strong> recurrent severe<br />
<strong>in</strong>fections, IG treatment can be stopped dur<strong>in</strong>g summer.
<strong>KCE</strong> Reports 120 Plasma 83<br />
• For bone marrow or stem cell transplant, the frequency of adm<strong>in</strong><strong>is</strong>tration<br />
averaged 10.8 per year, rang<strong>in</strong>g 2.6-12.9. In general <strong>in</strong> children, treatment<br />
<strong>is</strong> adm<strong>in</strong><strong>is</strong>tered before transplant and dur<strong>in</strong>g at least 3 months, mostly 6<br />
months and up to 1-2 years <strong>in</strong> cases of pers<strong>is</strong>tent B-cell abnormalities.<br />
However, the recent decrease <strong>in</strong> myeloablative transplants, due to an<br />
<strong>in</strong>crease <strong>in</strong> non-myeloablative techniques, has decreased the level and<br />
duration of secondary immune deficiency - and the consequent IG needs.<br />
Th<strong>is</strong> <strong>is</strong> mostly described <strong>in</strong> adult patients.<br />
• For ITP, the frequency of adm<strong>in</strong><strong>is</strong>tration was not <strong>available</strong> <strong>in</strong> most<br />
hospitals but was 1.4 per case <strong>in</strong> average <strong>in</strong> 3 hospitals.<br />
• In Kawasaki d<strong>is</strong>ease, the frequency of adm<strong>in</strong><strong>is</strong>tration could not be<br />
establ<strong>is</strong>hed based on <strong>available</strong> data, but experts adv<strong>is</strong>ed the adm<strong>in</strong><strong>is</strong>tration<br />
of a s<strong>in</strong>gle dose, followed by a 2nd dose <strong>in</strong> a few patients <strong>in</strong> which<br />
<strong>in</strong>flammatory signs and symptoms are still present.<br />
WHICH CASES SHOULD BE TREATED WITH IG<br />
<strong>The</strong> proportion of patients receiv<strong>in</strong>g IG for each of these <strong>in</strong>dications <strong>in</strong> Belgium was<br />
difficult to assess <strong>in</strong> th<strong>is</strong> survey, as cl<strong>in</strong>icians could not always collect data on the total<br />
number of cases that v<strong>is</strong>ited their centre.<br />
For bone marrow or stem cell transplant, paediatricians considered that nearly all<br />
paediatric cases require IG supplementation; <strong>in</strong> adults, only a selected subgroup of<br />
patients hav<strong>in</strong>g a symptomatic secondary immunodeficiency follow<strong>in</strong>g the transplant can<br />
benefit from IG treatment, and th<strong>is</strong> should be decided on an <strong>in</strong>dividual bas<strong>is</strong>.<br />
Secondary immune deficiencies due to the use of therapies deplet<strong>in</strong>g B-cells or impair<strong>in</strong>g<br />
B-cell response (eg. some anticancer drugs) and <strong>in</strong>duc<strong>in</strong>g symptomatic<br />
hypogammaglobul<strong>in</strong>emia are also medical conditions for which IG may be necessary.<br />
Experts proposed that cases <strong>with</strong> secondary hypogammaglobul<strong>in</strong>emia be treated <strong>with</strong> IG<br />
dur<strong>in</strong>g for the period of the hypogammaglobul<strong>in</strong>emia, irrespective of its cause. Th<strong>is</strong> <strong>is</strong><br />
l<strong>in</strong>e <strong>with</strong> the approach of PID cases, though the treatment would be mostly limited to a<br />
period of 6-12 months.<br />
ESTIMATION OF AMOUNTS<br />
<strong>The</strong> amount of IG used for each immuno-haematological <strong>in</strong>dication <strong>in</strong> these centres has<br />
been estimated, based on the assumption of an average 75kg body weight per adult, 25<br />
kg per child and 4 kg per neonate. Under these assumptions, treatment of PID patients<br />
would represent 61% of the total IG use for immuno-haematological <strong>in</strong>dications, CLL<br />
and MM 14% and transplants 10%. However, these estimates are biased by a better<br />
response rate among paediatricians as compared to haematolog<strong>is</strong>ts treat<strong>in</strong>g adult cases.<br />
USE OF SUB-CUTANEOUS IG<br />
Subcutaneous adm<strong>in</strong><strong>is</strong>tration of IG was used for PID <strong>in</strong> 5 out of the 6 hospitals and used<br />
to treat 44% of the PID paediatric cases <strong>in</strong> average. Th<strong>is</strong> practice was predom<strong>in</strong>ant <strong>in</strong><br />
two hospitals where 48-71% of PID children received SC adm<strong>in</strong><strong>is</strong>tration, and <strong>is</strong> a<br />
grow<strong>in</strong>g practice <strong>in</strong> the other paediatric wards of these centres. Expert paediatricians<br />
consider that SC adm<strong>in</strong><strong>is</strong>tration <strong>is</strong> a first choice for long-term treatment as it improves<br />
quality of life of the patient and <strong>is</strong> more effective to control immunodeficiencies, as IG<br />
levels are better ma<strong>in</strong>ta<strong>in</strong>ed <strong>with</strong> weekly <strong>in</strong>fusions. In adult cases however, only two out<br />
of four hospitals were us<strong>in</strong>g SC adm<strong>in</strong><strong>is</strong>tration, and th<strong>is</strong> concerned 14 and 44% of the<br />
PID adult cases.<br />
In neurological d<strong>is</strong>eases<br />
In order to know the current use of IG <strong>in</strong> Belgium for the neurological and neuromuscular<br />
<strong>in</strong>dications consum<strong>in</strong>g large amounts of IG, an expert meet<strong>in</strong>g was organized.<br />
<strong>The</strong> criteria for IG treatment, proportion of cases treated, dosage and frequency of IG<br />
treatment were d<strong>is</strong>cussed, based on <strong>in</strong>formation found <strong>in</strong> the scientific literature and<br />
the Belgian situation. <strong>The</strong> survey also collected data on 284 IG adm<strong>in</strong><strong>is</strong>trations for<br />
neurological cases (Guilla<strong>in</strong> Barré d<strong>is</strong>ease, CIDP and MMN).
84 Plasma <strong>KCE</strong> Reports 120<br />
However, results should be taken <strong>with</strong> caution as data were only provided by 3<br />
hospitals and were not exhaustive for each hospital (focus on paediatrics). <strong>The</strong> ma<strong>in</strong><br />
f<strong>in</strong>d<strong>in</strong>gs are summarized below:<br />
• For Guilla<strong>in</strong> Barré syndrome, dosage and frequency described <strong>in</strong> the<br />
literature <strong>is</strong> also applied <strong>in</strong> Belgium. In the above mentioned survey, only<br />
34 cases were <strong>report</strong>ed by 3 hospitals, and data on adult cases were only<br />
<strong>report</strong>ed by one hospital. IG dosage ranged 1 to 2g/kg <strong>in</strong> the 3 hospitals.<br />
• For CIDP, the Moniteur Belge / Belg<strong>is</strong>ch Staatblad (MB/BS) stipulates that<br />
the first l<strong>in</strong>e treatment <strong>is</strong> steroids, and only patients <strong>with</strong> contra<strong>in</strong>dications<br />
or treatment failure to steroids should receive IG. Experts<br />
estimate that about two-third of CIDP patients receive IG treatment. Th<strong>is</strong><br />
proportion also depends on the cl<strong>in</strong>ician expert<strong>is</strong>e; unnecessary IG<br />
treatment has been observed <strong>in</strong> patients referred by peripheral centres to<br />
the university centres. Dosage also ranges 1 to 2g/kg. <strong>The</strong> current<br />
practice <strong>is</strong> to rapidly decrease the <strong>in</strong>itial dose accord<strong>in</strong>g to the cl<strong>in</strong>ical<br />
response, then to reach a m<strong>in</strong>imal ma<strong>in</strong>tenance dose. Th<strong>is</strong> dose be<strong>in</strong>g<br />
patient-dependant, no strict guidel<strong>in</strong>e can be establ<strong>is</strong>hed. <strong>The</strong> upper limit<br />
<strong>in</strong> IG quantities accepted for reimbursement <strong>in</strong> the MB/BS (9g/kg per<br />
semester) <strong>is</strong> considered by experts as too low to treat some specific<br />
cases. Treatment requires good knowledge of the d<strong>is</strong>ease and its cl<strong>in</strong>ical<br />
manifestations.<br />
• For MMN, a higher proportion of cases are treated because mild d<strong>is</strong>ease<br />
<strong>is</strong> less frequent and there <strong>is</strong> no alternative treatment. <strong>The</strong> dose also needs<br />
to be adapted to the cl<strong>in</strong>ical response, and the treatment <strong>is</strong> more difficult<br />
to adjust than for CIDP. It may require <strong>in</strong>creas<strong>in</strong>g doses and decreas<strong>in</strong>g<br />
treatment <strong>in</strong>tervals, especially <strong>in</strong> the long term, due to a known decl<strong>in</strong>e of<br />
treatment effectiveness after prolonged treatment. However a few<br />
patients may have susta<strong>in</strong>ed rem<strong>is</strong>sion and even stop treatment. <strong>The</strong><br />
average dose usually varies from 0.4 to 1g/kg.<br />
• IgM paraprote<strong>in</strong> demyel<strong>in</strong>at<strong>in</strong>g neuropathies are treated <strong>with</strong> IG if they fit<br />
<strong>with</strong> the criteria establ<strong>is</strong>hed for CIDP. <strong>The</strong>se cases represent 5-10% of<br />
CIDP cases.<br />
• In multiple scleros<strong>is</strong> (MS), IG <strong>is</strong> ma<strong>in</strong>ly used <strong>in</strong> the pre and post-partum<br />
period to reduce relapses. IG may also be used <strong>in</strong> the few MS cases <strong>with</strong><br />
relaps<strong>in</strong>g-remitt<strong>in</strong>g cases that do not respond to steroids; one s<strong>in</strong>gle<br />
treatment <strong>is</strong> given <strong>in</strong> case of relapse. Some private <strong>in</strong>surance companies<br />
are cover<strong>in</strong>g the costs. Th<strong>is</strong> concerns a very small number of cases. All<br />
together, the proportion of all MS cases that are treated <strong>with</strong> IG <strong>is</strong><br />
estimated to range 0-3%, as observed <strong>in</strong> other countries.<br />
• In myasthenia grav<strong>is</strong> (MG), IG <strong>is</strong> only used <strong>in</strong> cases that do not respond to<br />
other treatments (plasma exchange and immunosuppressive therapy).<br />
Though IG has replaced plasma exchange as a first l<strong>in</strong>e treatment <strong>in</strong> many<br />
countries, IG <strong>is</strong> not reimbursed for th<strong>is</strong> d<strong>is</strong>ease <strong>in</strong> Belgium - or only by the<br />
solidarity fund when criteria are met. However, due to a lack of expert<strong>is</strong>e<br />
<strong>in</strong> th<strong>is</strong> rare d<strong>is</strong>ease, experts fear that IG would be overused if<br />
reimbursement for MG would be <strong>in</strong>troduced.<br />
• In dermatomyosit<strong>is</strong> and <strong>in</strong>clusion body myosit<strong>is</strong>, IG use for th<strong>is</strong> d<strong>is</strong>ease <strong>is</strong><br />
limited and relatively similar to myasthenia grav<strong>is</strong>.<br />
• Stiff person syndrome <strong>is</strong> a rare d<strong>is</strong>ease, but experts estimated that there<br />
may be around 20 patients <strong>in</strong> Belgium. Plasma exchange <strong>is</strong> the first<br />
treatment option.
<strong>KCE</strong> Reports 120 Plasma 85<br />
3.3.2.6 Limitations<br />
A major limitation of th<strong>is</strong> analys<strong>is</strong> of IG prescription <strong>is</strong> that we have no data <strong>in</strong> 2004-<br />
2006 on non reimbursed IG. Likew<strong>is</strong>e, it <strong>is</strong> unclear whether the IG quantities <strong>report</strong>ed<br />
by hospitals <strong>in</strong>clude IG prescribed for compassionate use. Accord<strong>in</strong>g to some experts,<br />
compassionate use may represent a significant proportion of IG consumption. Th<strong>is</strong> <strong>is</strong><br />
likely result<strong>in</strong>g <strong>in</strong> an underestimation of overall IG consumption.<br />
Another limitation of th<strong>is</strong> survey and expert meet<strong>in</strong>g <strong>is</strong> the lack of representativeness of<br />
the Belgium situation: it only <strong>in</strong>volved cl<strong>in</strong>icians work<strong>in</strong>g <strong>in</strong> large university centres and a<br />
small numbers of experts (only paediatricians for the immuno-haematological<br />
<strong>in</strong>dications) could attend. Problems of higher dose, higher frequency and non-<strong>in</strong>dicated<br />
IG therapy have been <strong>report</strong>ed <strong>in</strong> peripheral hospitals or practices, but <strong>available</strong> data did<br />
not allow <strong>in</strong>vestigat<strong>in</strong>g th<strong>is</strong> hypothes<strong>is</strong>.<br />
However, prescription patterns per specialty tend to confirm th<strong>is</strong> hypothes<strong>is</strong>. Experts<br />
<strong>report</strong>ed that th<strong>is</strong> may be due to the lack of experience among peripheral cl<strong>in</strong>icians, as<br />
the low frequency of these d<strong>is</strong>eases result that non-specialized cl<strong>in</strong>icians rarely<br />
encounter these d<strong>is</strong>eases, added to the fact that strict diagnos<strong>is</strong> criteria are mostly not<br />
required for the reimbursement of IG. Experts also <strong>report</strong>ed a strong lobby from the<br />
plasma <strong>in</strong>dustry to use IG for most hypogammaglobul<strong>in</strong>emia. Th<strong>is</strong> implies that the<br />
estimation of IG quantities based on th<strong>is</strong> survey <strong>is</strong> likely to underestimate the real IG<br />
use.<br />
Key po<strong>in</strong>ts<br />
• IG consumption <strong>is</strong> <strong>in</strong>creas<strong>in</strong>g over time <strong>in</strong> Belgium as <strong>in</strong> other countries.<br />
However, <strong>in</strong>dividual hospitals show diverg<strong>in</strong>g trends: a few hospitals have<br />
decrease their IG consumption while other have doubled it over a 5 year<br />
period.<br />
• Four ma<strong>in</strong> specialties prescribe 92% of the total IG amount prescribed <strong>in</strong><br />
Belgium: <strong>in</strong>ternal medic<strong>in</strong>e (46%), neurology and related d<strong>is</strong>eases (23%), lung<br />
d<strong>is</strong>ease (16%) and paediatrics (6%). <strong>The</strong> high prescription of IG by lung<br />
special<strong>is</strong>ts was neither expected nor <strong>report</strong>ed by studies <strong>in</strong> other countries;<br />
th<strong>is</strong> was only found <strong>in</strong> non-academic hospitals but accounted for a significant<br />
amount of IG use.<br />
• We observed huge variations <strong>in</strong> IG prescriptions across Belgian hospitals, as<br />
also <strong>report</strong>ed <strong>in</strong> other countries. Some non-academic hospitals consume a<br />
high IG amount <strong>in</strong> specialties that are not related to the <strong>in</strong>dications<br />
reimbursed. Experts also <strong>report</strong>ed an over-use of IG for specific immune<br />
deficiencies and peripheral neuropathies <strong>in</strong> peripheral hospitals, where<br />
cl<strong>in</strong>icians may be less familiar to these d<strong>is</strong>eases due to their low prevalence.<br />
• For most immune deficiencies and neurological d<strong>is</strong>orders, academic centres<br />
<strong>report</strong>ed similar practices regard<strong>in</strong>g who should be treated and the dosage.<br />
For two <strong>in</strong>dications, stem cell transplants and idiopathic thrombocytopenic<br />
purpura, practices differed regard<strong>in</strong>g which patients are treated, length of<br />
treatment and dosage.<br />
• <strong>The</strong> long term treatment of these rare immune deficiencies and peripheral<br />
neuropathies requires a good knowledge of the d<strong>is</strong>ease to adapt IG dosage<br />
and frequency of treatment to the cl<strong>in</strong>ical response.<br />
• <strong>The</strong> use of sub-cutaneous IG <strong>is</strong> emerg<strong>in</strong>g for PID cases and was used for 44%<br />
of PID patients <strong>in</strong> academic centres <strong>in</strong> 2008, ma<strong>in</strong>ly for paediatric cases.
86 Plasma <strong>KCE</strong> Reports 120<br />
3.3.3 Estimation of IG quantities to treat the ma<strong>in</strong> <strong>in</strong>dications<br />
<strong>The</strong> objective of th<strong>is</strong> exerc<strong>is</strong>e was to estimate the needs <strong>in</strong> plasma derivatives that<br />
would be required <strong>in</strong> Belgium to treat the ma<strong>in</strong> <strong>in</strong>dications.<br />
3.3.3.1 Methodology<br />
Th<strong>is</strong> estimation represents the theoretical quantities that are required yearly, based on<br />
two assumptions: <strong>in</strong>dications are clearly def<strong>in</strong>ed, all cases are correctly diagnosed, and<br />
patients under long term IG treatment are receiv<strong>in</strong>g IG all year long, <strong>with</strong>out<br />
<strong>in</strong>terruption.<br />
Selection of d<strong>is</strong>eases<br />
Based on the literature review and the recommendations for IG use <strong>in</strong> Belgium and<br />
other countries, we have selected a first l<strong>is</strong>t of 22 d<strong>is</strong>eases <strong>in</strong> which evidence shows a<br />
benefit of IG, or <strong>in</strong> which sufficient evidence on IG benefit <strong>is</strong> not <strong>available</strong> but for which<br />
IG therapy <strong>is</strong> recommended <strong>in</strong> most <strong>in</strong>dustrialized countries (Table 37).<br />
Table 39: D<strong>is</strong>eases for which IG treatment has a proven benefit and/or <strong>is</strong><br />
recommended <strong>in</strong> EU countries: selection for the estimation of IG quantities<br />
Indications Selected for IG estimation<br />
Idiopathic thrombocytopenic purpura Yes<br />
Primary immune deficiency conditions Yes<br />
Multiple myeloma Yes<br />
Chronic lymphocytic leukaemia Yes<br />
Allogenic stem cell transplant Yes<br />
Paediatric HIV/AIDS No (few cases)<br />
Prophylax<strong>is</strong> <strong>in</strong> solid organ transplant No<br />
Prevention of treatment of <strong>in</strong>fections <strong>in</strong> neonates No (small amounts - low weight)<br />
In preterm and/or low birth weight No (small amounts - low weight)<br />
Isoimmune haemolytic jaundice <strong>in</strong> neonates No (small amounts - low weight)<br />
Guilla<strong>in</strong>-Barré syndrome (and variants) Yes<br />
CIDP Yes<br />
Multifocal motor neuropathy Yes<br />
Multiple scleros<strong>is</strong> (relaps<strong>in</strong>g remitt<strong>in</strong>g) Yes<br />
Paraprote<strong>in</strong>-associated peripheral neuropathies No (<strong>in</strong>frequent d<strong>is</strong>ease)<br />
Lambert-Eaton myasthenic syndrome No (<strong>in</strong>frequent d<strong>is</strong>ease)<br />
Myasthenia grav<strong>is</strong> Yes<br />
Dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong> Yes<br />
Inclusion body myosit<strong>is</strong> No (no <strong>available</strong> data and low use)<br />
Stiff person syndrome No (<strong>in</strong>frequent d<strong>is</strong>ease)<br />
Kawasaki d<strong>is</strong>ease Yes<br />
Treat<strong>in</strong>g seps<strong>is</strong> and septic shock No (few cases treated <strong>in</strong> Belgium)<br />
Based on the analys<strong>is</strong> of the IG amounts used to treat these d<strong>is</strong>eases <strong>in</strong> other countries<br />
(see above), we have selected the 12 d<strong>is</strong>eases that are consum<strong>in</strong>g the highest amount of<br />
IG and accounted for respectively 88%, 80% and 68% of total IG use <strong>in</strong> the US<br />
(Massachusset), New Zealand and Canada (Toronto). Further estimations of IG<br />
quantities have been limited to these 12 d<strong>is</strong>eases.<br />
Data on d<strong>is</strong>ease frequency and IG use per d<strong>is</strong>ease<br />
As data on the number of cases treated for each of these d<strong>is</strong>eases were mostly not<br />
<strong>available</strong> <strong>in</strong> Belgian databases, we have extracted the follow<strong>in</strong>g <strong>in</strong>dicators from studies<br />
conducted <strong>in</strong> other countries:<br />
• <strong>The</strong> yearly <strong>in</strong>cidence and/or prevalence rate, depend<strong>in</strong>g whether the<br />
treatment <strong>is</strong> applied once or as long term ma<strong>in</strong>tenance therapy: <strong>in</strong>cidence<br />
rate was searched when treatment <strong>is</strong> adm<strong>in</strong><strong>is</strong>tered once or twice per<br />
patient; prevalence rate was used for ma<strong>in</strong>tenance treatment. For d<strong>is</strong>ease<br />
present<strong>in</strong>g an acute and a chronic form, both <strong>in</strong>cidence and prevalence<br />
were used.
<strong>KCE</strong> Reports 120 Plasma 87<br />
• <strong>The</strong> proportion of patients treated <strong>with</strong> IG, per d<strong>is</strong>ease.<br />
• <strong>The</strong> dosage used per treatment (g/kg) and the frequency of treatment<br />
(per patient or per year for ma<strong>in</strong>tenance treatment).<br />
<strong>The</strong> source studies were selected accord<strong>in</strong>g to the follow<strong>in</strong>g criteria: studies <strong>in</strong>clud<strong>in</strong>g<br />
data from 1995 onwards, hav<strong>in</strong>g a large study population size (>1 million <strong>in</strong>habitants<br />
mostly), and carried out <strong>in</strong> Western EU countries - or <strong>in</strong> other <strong>in</strong>dustrialized countries<br />
when other EU studies were not <strong>available</strong>. When d<strong>is</strong>ease rates vary significantly per<br />
geographical area (e.g. prevalence of multiple scleros<strong>is</strong> vary<strong>in</strong>g <strong>with</strong> latitude), we have<br />
only consider studies conducted <strong>in</strong> similar geographical areas.<br />
<strong>The</strong> values found for the proportion of patient treated <strong>with</strong> IG, the dosage used per<br />
treatment and the frequency of treatment were d<strong>is</strong>cussed and validated <strong>in</strong> two expert<br />
meet<strong>in</strong>gs. For a few <strong>in</strong>dications, the annual numbers of cases were found <strong>in</strong> Belgian<br />
databases (e.g. transplants). Similarly, the dosage and frequency of adm<strong>in</strong><strong>is</strong>tration<br />
obta<strong>in</strong>ed through the survey <strong>in</strong> Belgian hospitals were used when considered as<br />
methodologically reliable and representative, based on expert op<strong>in</strong>ion and <strong>in</strong>formation<br />
on current practice.<br />
Estimation of the annual IG amounts per d<strong>is</strong>ease<br />
<strong>The</strong> annual IG quantities estimated to treat these 12 d<strong>is</strong>eases <strong>in</strong> Belgium were calculated<br />
based on the follow<strong>in</strong>g:<br />
• Data from other countries were aggregated to produce averages for<br />
<strong>in</strong>cidence or prevalence rate, proportion of patients treated and<br />
frequency of treatment, after be<strong>in</strong>g weighted by survey size (“weighted<br />
average”).<br />
• <strong>The</strong> expected annual number of cases under treatment <strong>in</strong> Belgium was<br />
calculated by multiply<strong>in</strong>g the weighted average of the <strong>in</strong>cidence or<br />
prevalence rate by the Belgian population size (per age group when<br />
relevant) and by the proportion of patients treated <strong>with</strong> IG.<br />
• <strong>The</strong> IG amount used per patient and per year was obta<strong>in</strong>ed by multiply<strong>in</strong>g<br />
the average dosage per treatment (<strong>in</strong> g/kg) by the average body weight<br />
(per age group when relevant) and the frequency of treatment (when<br />
multiple doses are given), named as “method A”. An alternative<br />
estimation (method B) was based on the average IG amounts per case and<br />
per year found <strong>in</strong> studies from other countries (weighted average), see<br />
Table 24.<br />
• <strong>The</strong> annual quantities needed to treat each d<strong>is</strong>ease were obta<strong>in</strong>ed by<br />
multiply<strong>in</strong>g the annual number of patients under treatment by the IG<br />
amount used per patient (by method A and B).<br />
Estimates found for the above <strong>in</strong>dicators are described below. <strong>The</strong> annual IG quantities<br />
estimated to treat these 12 d<strong>is</strong>eases <strong>in</strong> Belgium are described <strong>in</strong> Table 40 and below.<br />
3.3.3.2 Estimates per d<strong>is</strong>ease<br />
Idiopathic Thrombocytopenic Purpura<br />
Idiopathic thrombocytopenic purpura (ITP) can present as acute or chronic d<strong>is</strong>ease;<br />
chronic d<strong>is</strong>ease <strong>is</strong> def<strong>in</strong>ed by a duration of ITP for more than 6 months. Studies on the<br />
<strong>in</strong>cidence of acute and chronic ITP show variations <strong>in</strong> case def<strong>in</strong>ition (especially <strong>in</strong> terms<br />
of threshold for platelet count) and age studied. <strong>The</strong>se directly <strong>in</strong>fluences <strong>in</strong>cidence<br />
estimates as a very sensitive threshold for platelet counts overestimates the frequency<br />
of cl<strong>in</strong>ical ITP, and the frequency of chronic ITP <strong>in</strong>creases <strong>with</strong> age.<br />
IN CHILDREN<br />
Three studies <strong>in</strong> Norway, Germany and Nordic countries, estimated the <strong>in</strong>cidence rate<br />
of acute ITP <strong>in</strong> children us<strong>in</strong>g similar criteria (bleed<strong>in</strong>g +/- platelet count
88 Plasma <strong>KCE</strong> Reports 120<br />
<strong>The</strong> proportion of acute ITP that had evolved <strong>in</strong>to chronic ITP was estimated <strong>in</strong> four<br />
studies <strong>in</strong> Norway, France, Denmark and Nordic countries <strong>in</strong> 1996-99 and ranged 18-<br />
33% (average 26%). 155, 156,157,158 We then extrapolated the <strong>in</strong>cidence rate of chronic ITP<br />
at 0.8 per 100,000 <strong>in</strong> children
<strong>KCE</strong> Reports 120 Plasma 89<br />
In Belgium, a survey cover<strong>in</strong>g 6 centres for paediatric PID and 3 centres for adult PID<br />
<strong>report</strong>ed a total of 437 PID cases under follow up, but th<strong>is</strong> figure <strong>is</strong> also <strong>in</strong>complete.<br />
Among these, 263 have received IG treatment <strong>in</strong> 2008. In order to estimate the total<br />
number of PID cases treated <strong>in</strong> Belgium, we have used as proxy the proportion of all<br />
Belgian bone marrow transplants that were conducted <strong>in</strong> these centres, as <strong>report</strong>ed to<br />
the INAMI/RIZIV. Though the proportion of transplants <strong>is</strong> not directly l<strong>in</strong>ked to the<br />
proportion of PID treated, th<strong>is</strong> was considered as a proxy of specialized immunological<br />
activity of these centres. <strong>The</strong> 6 centres provid<strong>in</strong>g data on paediatric cases and the 3<br />
centres provid<strong>in</strong>g data on adult cases represent respectively 34% and 29% of all marrow<br />
transplants <strong>in</strong> 2007. <strong>The</strong> number of PID cases under treatment <strong>is</strong> thus estimated at 806<br />
cases. In Belgian centres surveyed, the dosage ranged 0.3-0.5g/kg and most centres used<br />
0.4g/kg. <strong>The</strong> annual number of IVIG treatment per year ranged 6.4-14.4 per year for<br />
children (average 11.3) and 12.0-13.3 per year for adults (average 11.8). <strong>The</strong> amount of<br />
IG required for SC adm<strong>in</strong><strong>is</strong>tration has been estimated as equivalent to those required<br />
for IV adm<strong>in</strong><strong>is</strong>tration.<br />
Multiple myeloma (MM)<br />
In Belgium, a range of 617-690 new cases of MM were <strong>report</strong>ed per year to the cancer<br />
reg<strong>is</strong>try <strong>in</strong> 2004-2008 and the <strong>in</strong>cidence <strong>is</strong> <strong>in</strong>creas<strong>in</strong>g <strong>with</strong> age. Prevalence data are not<br />
<strong>available</strong> from Belgium or other EU countries. We used the 2006 age-specific<br />
prevalence rates <strong>report</strong>ed among the white population <strong>in</strong> the US and extrapolated to<br />
the Belgian population by age-group. 8 A number of 2390 prevalent cases of MM are<br />
estimated. Th<strong>is</strong> figure may be an underestimation of the Belgian situation because the<br />
MM <strong>in</strong>cidence rates <strong>in</strong> the US are slightly lower than the Belgian <strong>in</strong>cidence rates.<br />
<strong>The</strong> proportion of MM patients treated was not documented <strong>in</strong> the literature, but<br />
expert advice provided a range of 10-15%, based on experience.<br />
<strong>The</strong> survey among immuno-haematolog<strong>is</strong>ts collected data on MM from one Belgian<br />
university hospital only. <strong>The</strong> dosage of 0.4g/kg was similar to the recommendations of<br />
other countries and <strong>in</strong> average 10 treatments were provided per case and year.<br />
Chronic lymphocytic leukaemia (CLL)<br />
National data are not <strong>available</strong> on the <strong>in</strong>cidence or prevalence of CLL but 636 new<br />
cases of lymphoid leukaemia (acute and chronic) were <strong>report</strong>ed <strong>in</strong> 2008. No prevalence<br />
data were found from other countries. <strong>The</strong> proportion of patients treated was also not<br />
<strong>available</strong>.<br />
As for MM, the survey among immuno-haematolog<strong>is</strong>ts collected data on MM from one<br />
Belgian university hospital only. <strong>The</strong> dosage was 0.4g/kg and an average of 10 treatments<br />
was provided per case and year.<br />
Due to the lack of data, IG amounts required to treat CLL cases could not be<br />
calculated.<br />
Allogenous bone marrow or stem cell transplant (SCT)<br />
<strong>The</strong> number of bone marrow transplants <strong>is</strong> collected by the INAMI/RIZIV <strong>in</strong> the<br />
framework of the convention <strong>with</strong> transplant centres. In 2007, 284 allogenous<br />
transplants were recorded, and the 2005-07 data show a gradual <strong>in</strong>crease <strong>in</strong> the number<br />
of allogenous SCT (+31% <strong>in</strong> 2 years). <strong>The</strong> number of transplant was then estimated at<br />
320 for 2008, assum<strong>in</strong>g a l<strong>in</strong>ear trend from 2005 to 2007. However, th<strong>is</strong> number may be<br />
underestimated as hospitals that are not <strong>in</strong>cluded <strong>in</strong> the Convention may also perform<br />
allogenous SCT (INAMI, personal communication).<br />
8 Estimated US cancer prevalence counts at on Jan 1, 2006 by Race/Ethnicity, Sex and Years S<strong>in</strong>ce<br />
Diagnos<strong>is</strong>. National Cancer Institute: Surveillance Epidemiology and End Results Cancer Stat<strong>is</strong>tics Review<br />
1975 – 2006.<br />
http://seer.cancer.gov/csr/1975_2006/browse_csr.php?section=18&page=sect_18_table.18.html
90 Plasma <strong>KCE</strong> Reports 120<br />
<strong>The</strong> proportion of SCT cases receiv<strong>in</strong>g IG supplementation has not been found <strong>in</strong> the<br />
scientific publications. In Belgium, it varies across centres, type of transplant and age<br />
group. <strong>The</strong> <strong>in</strong>crease <strong>in</strong> non-myeloablative SCT, ma<strong>in</strong>ly <strong>in</strong> adults, has likely decrease the<br />
IG needs <strong>in</strong> th<strong>is</strong> group. <strong>The</strong> pr<strong>in</strong>ciple <strong>is</strong> that IG treatment should be adm<strong>in</strong><strong>is</strong>tered <strong>in</strong><br />
cases of severe antibody deficiency and thus tailored to the patient. Among children, the<br />
consensus among paediatricians dur<strong>in</strong>g the expert consultation was that most paediatric<br />
cases require IG supplementation, as post-SCT humoral immunodeficiency <strong>is</strong> common.<br />
Among adults, experts consider that the prophylactic and pre-emptive use of antibiotics,<br />
antifungal and antiviral drugs has replaced the rout<strong>in</strong>e use of IVIG, and that only patients<br />
hav<strong>in</strong>g a (transient) symptomatic secondary immunodeficiency should receive IVIG, on<br />
an <strong>in</strong>dividual bas<strong>is</strong>.<br />
Based on compar<strong>is</strong>on between survey results and INAMI data sources on allogenous<br />
BMT, we estimated that 33% of all allogenous SCT (children and adult confounded)<br />
receive IG supplementation.<br />
<strong>The</strong> dosage used <strong>in</strong> Belgium ranges 0.2-0.5g/kg, <strong>with</strong> the majority of centres us<strong>in</strong>g<br />
0.4g/kg. In the Netherlands, treatment scheme was 0.5g/kg per week (before transplant)<br />
then followed by 0.5g/kg per month as ma<strong>in</strong>tenance dose; <strong>in</strong> France, 0.4-0.6g/kg as<br />
load<strong>in</strong>g dose followed by 0.3g/kg. In most studies, IG prophylax<strong>is</strong> was given for 3<br />
months and the maximum period of adm<strong>in</strong><strong>is</strong>tration was 1 year. Most guidel<strong>in</strong>es<br />
recommend cont<strong>in</strong>u<strong>in</strong>g IG after transplant until reconstitution of B cell and antibody<br />
production has been achieved. We estimated that IG treatments were adm<strong>in</strong><strong>is</strong>tered <strong>in</strong><br />
average 12 times per year, based on the survey results (10.8 <strong>in</strong> children and 12 <strong>in</strong><br />
adults).<br />
Guilla<strong>in</strong>-Barré Syndrome (GBS)<br />
Five epidemiological studies, conducted <strong>in</strong> the period 1992-2000 <strong>in</strong> the UK, Italy (2<br />
studies), Spa<strong>in</strong> and Sweden were selected for the estimation of <strong>in</strong>cidence rate. 164,165,166,167,<br />
168<br />
A German study based on hospital records has been excluded as the methods did<br />
not <strong>in</strong>clude validation of diagnos<strong>is</strong>; 169 <strong>in</strong>deed, such studies were shown to over-estimate<br />
d<strong>is</strong>ease <strong>in</strong>cidence. 167 Most studies <strong>report</strong>ed similar values, suggest<strong>in</strong>g that GBS occur<br />
evenly, at least throughout the Western hem<strong>is</strong>phere: the <strong>in</strong>cidence rate ranged 1.26-<br />
1.63 per 100,000 <strong>in</strong> the five studies, and the weighted average <strong>is</strong> 1.42 per 100,000.<br />
In four studies conducted <strong>in</strong> Italy, Spa<strong>in</strong> and Sweden (two studies) <strong>in</strong> the period 1996-<br />
1999 and <strong>in</strong>volv<strong>in</strong>g a total of 343 cases, the proportion of GBS cases treated <strong>with</strong> IG<br />
165, 166, 170, 171<br />
ranged 65-82% <strong>with</strong> a weighted average at 75%.<br />
<strong>The</strong> dosage was 2 g/kg per treatment <strong>in</strong> all studies and reviews. Only one <strong>Dutch</strong><br />
publication described the proportion of cases requir<strong>in</strong>g a second treatment from two<br />
studies, which amounted at 7% of the GBS cases <strong>in</strong>itially treated. 172<br />
Chronic <strong>in</strong>flammatory demyel<strong>in</strong>at<strong>in</strong>g polyneuropathy (CIDP)<br />
Two EU studies (Italy and England) and an Australian study calculated the CIDP<br />
prevalence, which ranged 1.9-3.6. 173,174,175 <strong>The</strong>se differences are expla<strong>in</strong>ed by a lack of<br />
diagnostic gold standard or clear diagnostic criteria. <strong>The</strong> weighted averaged <strong>in</strong>cidence<br />
rate was calculated at 2.7 per 100,000.<br />
<strong>The</strong> proportion of all CIDP cases that were treated <strong>with</strong> long term IG were estimated<br />
<strong>in</strong> 3 studies from France (2 studies) and the UK, publ<strong>is</strong>hed <strong>in</strong> 2007-2008, and ranged 51-<br />
63%. 175 , 176 , 177 <strong>The</strong> weighted average was 56%.<br />
<strong>The</strong> dosage ranged 0.4-2g/kg <strong>in</strong> studies and national recommendations. In Belgium, the<br />
maximum reimbursed dose ranges 0.25-2g/kg <strong>with</strong> a maximum of 9g/kg/6 months. <strong>The</strong><br />
practice for CIDP (and MMN) <strong>is</strong> to start at 2g/kg dose and rapidly decrease the dose<br />
accord<strong>in</strong>g to the cl<strong>in</strong>ical response, to reach a m<strong>in</strong>imal ma<strong>in</strong>tenance dose; it has been<br />
estimated at 1.5g/kg <strong>in</strong> average. <strong>The</strong> median <strong>in</strong>terval for IVIG adm<strong>in</strong><strong>is</strong>tration <strong>in</strong> studies<br />
was 3 weeks (frequency of 17.3 per year).
<strong>KCE</strong> Reports 120 Plasma 91<br />
Multifocal motor neuropathy (MMN)<br />
Epidemiological data on MMN prevalence are scarce: only two EU prevalence studies<br />
from England and the Netherlands were found <strong>in</strong> conference abstracts, <strong>with</strong> very similar<br />
values. 178 <strong>The</strong> average could not be weighted for study size as the number of cases was<br />
m<strong>is</strong>s<strong>in</strong>g <strong>in</strong> the Engl<strong>is</strong>h study. <strong>The</strong> 2008 prevalence was respectively 0.53 and 0.58 per<br />
100,000 <strong>in</strong> England and the Netherlands, and the average <strong>in</strong>cidence rate calculated at<br />
0.56 per 100,000.<br />
Data on the proportion of all MMN cases that were treated <strong>with</strong> IG were found <strong>in</strong> 3<br />
recent EU studies, conducted <strong>in</strong> the UK, the Netherlands and France and publ<strong>is</strong>hed <strong>in</strong><br />
2007-2008. 179,178,180 Th<strong>is</strong> proportion ranged 51-76% and the weighted average was 66%.<br />
<strong>The</strong> dosage was 2 g/kg per treatment <strong>in</strong> all studies, though the maximum reimbursed <strong>in</strong><br />
Belgium ranges 0.25-2g/kg <strong>with</strong> a maximum of 9g/kg/6 months. <strong>The</strong> median <strong>in</strong>terval for<br />
IVIG adm<strong>in</strong><strong>is</strong>tration <strong>in</strong> studies was 3 weeks (frequency of 17.3 per year). However, the<br />
annual IG amount used to treat one case widely varied across studies, rang<strong>in</strong>g 248g <strong>in</strong><br />
New Zealand to 1728g <strong>in</strong> the UK. 149,179<br />
Multiple scleros<strong>is</strong> (MS)<br />
Several epidemiological studies on MS prevalence <strong>in</strong> Europe were found but showed<br />
very diverg<strong>in</strong>g values. Due to an observed North-South gradient <strong>in</strong> prevalence, our<br />
analys<strong>is</strong> was limited to countries or regions hav<strong>in</strong>g a latitude similar to Belgium and a<br />
population of >2 millions <strong>in</strong>habitants to decrease the <strong>in</strong>accuracies due to small numbers<br />
of cases. Only studies us<strong>in</strong>g the Poser criteria for MS diagnos<strong>is</strong> and validation of<br />
diagnos<strong>is</strong> were selected. Studies based on community surveys and self <strong>report</strong>ed cases<br />
were excluded.<br />
A survey was conducted <strong>in</strong> Flanders <strong>in</strong> 1991 but was excluded as it did not fit <strong>in</strong><br />
<strong>in</strong>clusion period. 181 Indeed prevalence <strong>is</strong> <strong>in</strong>creas<strong>in</strong>g over time, likely due to improved<br />
diagnos<strong>is</strong> and unknown factors. <strong>The</strong> two selected studies were conducted <strong>in</strong> France and<br />
Austria and the prevalence for def<strong>in</strong>ite and probable cases was 120 and 99 per 100,000<br />
respectively, <strong>with</strong> a weighted average at 103 per 100,000. 182,183<br />
Immunoglobul<strong>in</strong>s may be used for very specific MS cases, i.e. <strong>in</strong> cases of relapses that<br />
are res<strong>is</strong>tant to other treatment, when other therapies are not tolerated, as well as <strong>in</strong><br />
the post-partum for the prevention of relapses. No studies were found on the<br />
proportion of MS patients that are treated <strong>with</strong> IG. Experts estimate that 0-3% of MS<br />
patients are treated <strong>with</strong> IG for treatment (or prevention) of relapses. Consider<strong>in</strong>g that<br />
IG are mostly used for the prevention of post-partum relapses, that women <strong>in</strong> postpartum<br />
represent 1.1% of the Belgian population and that a large European prospective<br />
study estimated that 28% of pregnant women experience a relapse <strong>in</strong> the 3 months<br />
post-partum, we can assume that a maximum 0.31% of MS cases could benefit from<br />
IG. 184 IG <strong>is</strong> not reimbursed <strong>in</strong> Belgium for th<strong>is</strong> d<strong>is</strong>ease but some private <strong>in</strong>surance might<br />
reimburse it.<br />
<strong>The</strong> doses used ranged 0.15-2g/kg/month, <strong>with</strong> no superiority of a given dose shown.<br />
An observational Austrian study among pregnant women calculated that an average<br />
dose of 0.24 g/kg/month was given. 85 <strong>The</strong> mean treatment duration was 3.4 +/- 1.8 years<br />
and the mean time to first relapse <strong>with</strong> IG therapy was 247 days (median 199 days) <strong>in</strong><br />
the first 2 years.<br />
Myasthenia grav<strong>is</strong><br />
Studies on myasthenia grav<strong>is</strong> (MG) prevalence showed very different values, depend<strong>in</strong>g<br />
on the diagnostic criteria. Three studies conducted <strong>in</strong> Sweden, the Netherlands and<br />
England <strong>in</strong> 1997-1999 estimated a prevalence rang<strong>in</strong>g 11.9-14.1 per 100,000. 105 , 185 , 186 A<br />
study <strong>in</strong> Greece was excluded because MG cases were limited to those hav<strong>in</strong>g<br />
antibodies aga<strong>in</strong>st the acetylchol<strong>in</strong>e receptor, which represented only 79% of total cases<br />
<strong>in</strong> both the <strong>Dutch</strong> and the Engl<strong>is</strong>h studies. <strong>The</strong> weighted average of the three selected<br />
studies was 12.7 per 100,000. However, th<strong>is</strong> estimate probably underestimates the<br />
current figure as prevalence <strong>in</strong>creases over the years, due to the age<strong>in</strong>g of population<br />
comb<strong>in</strong>ed to a higher prevalence found among the elderly.
92 Plasma <strong>KCE</strong> Reports 120<br />
<strong>The</strong> proportion of MG cases treated <strong>with</strong> long term IG was not found. <strong>The</strong> 1997 Engl<strong>is</strong>h<br />
study described 3% patients be<strong>in</strong>g under plasma exchange therapy (the golden standard<br />
for myasthenic cr<strong>is</strong><strong>is</strong> at that time). 185 S<strong>in</strong>ce th<strong>is</strong> therapy has often been replaced by IG <strong>in</strong><br />
recent years, we estimated that 3% MG patient would be treated <strong>with</strong> IG, and experts<br />
considered th<strong>is</strong> estimate to be valid for the Belgian situation.<br />
<strong>The</strong> dosage was 2g/kg <strong>in</strong> most studies and national recommendations, but a study<br />
compar<strong>in</strong>g a dose of 1g vs. 2g/kg body weight suggested that 1g/kg may be sufficient.<br />
<strong>The</strong>re <strong>is</strong> no evidence to support IG use as a long-term treatment, thus a s<strong>in</strong>gle<br />
treatment <strong>in</strong> case of cr<strong>is</strong><strong>is</strong> or exacerbations was assumed.<br />
Dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong><br />
Dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong> cases were not d<strong>is</strong>t<strong>in</strong>gu<strong>is</strong>hed as both d<strong>is</strong>eases are<br />
idiopathic <strong>in</strong>flammatory myopathies, usually studied together. Only one recent study<br />
estimat<strong>in</strong>g the prevalence of dermatomyosit<strong>is</strong> and polymyosit<strong>is</strong> was identified,<br />
conducted <strong>in</strong> Canada <strong>in</strong> a population of 7.5 million <strong>in</strong>habitants, and found a 2003<br />
prevalence at 21.5/100,000. 187 Older estimates from the USA and Japan ranged 5.0-6.3<br />
per 100,000 <strong>in</strong> 1960-1987 but are considered to underestimate the true d<strong>is</strong>ease<br />
prevalence. 188<br />
Data on the proportion of dermatomyosit<strong>is</strong> patients treated was only found <strong>in</strong> an older<br />
cohort study on juvenile dermatomyosit<strong>is</strong> <strong>in</strong> Canada, represent<strong>in</strong>g 9% of cases, and<br />
cannot be used to extrapolate to other age groups. 189 ) It <strong>is</strong> only known that IG <strong>is</strong> only<br />
needed <strong>in</strong> special cases and seems the treatment of choice <strong>in</strong> severe myosit<strong>is</strong> <strong>with</strong><br />
dysphagia. 190<br />
<strong>The</strong> dosage was 2g/kg every 3-6 weeks <strong>in</strong> most studies. Data on practice <strong>in</strong> Belgium<br />
have not been found. In the 15 patients <strong>in</strong>cluded <strong>in</strong> the only RCT conducted so far, the<br />
frequency of treatment varied from every 3 to 6 weeks (average 4 weeks) and two<br />
patients could stop IG treatment. 110<br />
As no data are <strong>available</strong> on the proportion of cases treated, th<strong>is</strong> d<strong>is</strong>ease has not been<br />
<strong>in</strong>cluded <strong>in</strong> the calculation. However, as we know that the treatment of<br />
dermatomyosit<strong>is</strong> cases represented 2% of total amount of IG used <strong>in</strong> the three studies<br />
<strong>in</strong> other countries (Table 22), the same proportion of the total IG amount has been<br />
assumed <strong>in</strong> Belgium.<br />
Kawasaki d<strong>is</strong>ease<br />
<strong>The</strong> <strong>in</strong>cidence of Kawasaki d<strong>is</strong>ease (KD) was estimated <strong>in</strong> Denmark, Sweden and New<br />
Zealand, while other recent studies were based on rates of hospitalization for<br />
KD. 191,192,193 Incidence among children
<strong>KCE</strong> Reports 120 Plasma 93<br />
Based on these methods and the assumptions described under table 40, we have<br />
estimated that 576 kg (method A) and 483 kg (method B) of IG would be annually<br />
needed to treat these 11 d<strong>is</strong>eases, thus not <strong>in</strong>clud<strong>in</strong>g CLL. Th<strong>is</strong> would represent<br />
respectively 70% (A) and 59% (B) of the IG amount reimbursed <strong>in</strong> 2006 based on<br />
INAMI/RIZIV data (Table 41).<br />
Though we have not used stat<strong>is</strong>tical tests given the high <strong>in</strong>tr<strong>in</strong>sic uncerta<strong>in</strong>ty around<br />
some estimates and assumptions, the proportion of total IG use that would be required<br />
to treat these 11 d<strong>is</strong>eases <strong>is</strong> lower than calculated <strong>in</strong> the 4 studies, for both methods A<br />
and B: these 11 d<strong>is</strong>eases consumed 75%, 68%, 88% and 72% of the total IG amount <strong>in</strong><br />
New Zealand, Toronto (Canada), Massachusset (US) and the Canadian Atlantic<br />
prov<strong>in</strong>ces, <strong>with</strong> a weighted average of 74%. If we compare our estimates to the annual<br />
IG amount <strong>report</strong>ed by Belgian hospitals <strong>in</strong> 2008 (919.6 kg, <strong>KCE</strong> survey), th<strong>is</strong><br />
proportion would be even lower, represent<strong>in</strong>g 63% (A) and 53% (B) of total amount.<br />
Our estimation suggests that a higher proportion of IG <strong>is</strong> used for other <strong>in</strong>dications<br />
than those <strong>in</strong>cluded here, compared to other countries. In other studies, 12% to 32% of<br />
total IG amounts was consumed by the rema<strong>in</strong><strong>in</strong>g <strong>in</strong>dications, while th<strong>is</strong> would<br />
represent as much as 37% (A) and 41% (B) <strong>in</strong> Belgium. Th<strong>is</strong> <strong>is</strong> not surpr<strong>is</strong><strong>in</strong>g when we<br />
observed that, <strong>in</strong> Belgium, already 16% of IG has been prescribed by lung special<strong>is</strong>ts <strong>in</strong><br />
2008.<br />
However conclusions on the yearly amount of IG required <strong>in</strong> Belgium cannot be based<br />
on th<strong>is</strong> exerc<strong>is</strong>e, as th<strong>is</strong> estimation has many methodological limitations.<br />
3.3.3.4 Limitations<br />
<strong>The</strong> ma<strong>in</strong> limitations to th<strong>is</strong> estimation that we have identified are:<br />
• Th<strong>is</strong> method has probably underestimated the number of cases under IG<br />
treatment for several d<strong>is</strong>eases: First, our calculations were based on data<br />
from scientific studies, where all cases were verified for adherence <strong>with</strong><br />
def<strong>in</strong>ed case def<strong>in</strong>ition and criteria; <strong>in</strong> a real life sett<strong>in</strong>g, many more cases<br />
are likely to be treated. For <strong>in</strong>stance, we estimated that 150 cases of<br />
Guillla<strong>in</strong> Barré occur every year <strong>in</strong> Belgium, based on <strong>in</strong>cidence from<br />
neighbour<strong>in</strong>g countries, while RCM/MKG data for code ICD9CM 357-0 <strong>in</strong><br />
2000-2007 show annual numbers rang<strong>in</strong>g 609-717 cases. Second, many<br />
studies were based on old data from the n<strong>in</strong>eties and probably<br />
underestimated d<strong>is</strong>ease rate as the prevalence of several d<strong>is</strong>eases <strong>is</strong><br />
known to <strong>in</strong>crease <strong>with</strong> time, due to population age<strong>in</strong>g and improved<br />
diagnostic.<br />
• Th<strong>is</strong> estimation could not <strong>in</strong>clude cases of CLL.<br />
• We have found several other <strong>in</strong>cons<strong>is</strong>tencies when compar<strong>in</strong>g our<br />
estimates to other Belgian data, which may be due to the assumptions<br />
used or the lack of representativeness of practices <strong>in</strong> the centres<br />
surveyed. Th<strong>is</strong> was ma<strong>in</strong>ly observed for bone marrow transplant (BMT)<br />
where we likely underestimated the number of cases under treatment:<br />
the proportion of transplant cases treated <strong>with</strong> IG <strong>is</strong> based on data from<br />
two university hospitals and may be higher <strong>in</strong> other hospitals. Indeed, 56<br />
transplant cases under treatment were <strong>report</strong>ed <strong>in</strong> the survey from 4<br />
paediatric wards and an adult ward, while our overall estimate of BMT<br />
treated <strong>with</strong> IG <strong>in</strong> the whole Belgium <strong>is</strong> 105. Th<strong>is</strong> was also suggested by<br />
the lower proportion of total IG amount used <strong>in</strong> BMT <strong>in</strong> Belgium<br />
compared to other studies (3-4% vs. 11%). <strong>The</strong> number of ITP cases<br />
under IG treatment extrapolated from <strong>in</strong>cidence rates from other studies<br />
did not correspond to the number <strong>report</strong>ed by Belgian centres (52 cases<br />
under treatment are <strong>report</strong>ed from 5 university hospitals vs. 49 for all<br />
Belgium based on other studies).<br />
• Data on IG use are compared to four studies from three non-European<br />
countries (US, Canada, New Zealand), where IG use was <strong>report</strong>ed to be<br />
high.
94 Plasma <strong>KCE</strong> Reports 120<br />
• Many estimates were based on the Belgian survey and expert meet<strong>in</strong>gs,<br />
which may not be representative of the overall Belgian situation.<br />
In spite of the limitations due to th<strong>is</strong> method, we reach the same overall conclusions<br />
than the studies based on real IG consumption: the highest IG use <strong>is</strong> observed for<br />
immuno-haematological d<strong>is</strong>orders (41-43% of IG amount) but covers as much as 1545<br />
cases, compared to neuro-muscular d<strong>is</strong>eases which may consume 25-28% of total IG<br />
amount but only covers 367 cases. <strong>The</strong> d<strong>is</strong>eases likely to consume the highest amount<br />
of IG are: primary immune deficiencies, CIDP, MM, ITP and MMN.<br />
Key po<strong>in</strong>ts<br />
• Based on theoretical needs and assumptions, we estimated that from 483 to<br />
576 kg of IG would be annually needed to treat the 11 <strong>in</strong>dications consum<strong>in</strong>g<br />
the highest amount of IG <strong>in</strong> Belgium, exclud<strong>in</strong>g CLL. Th<strong>is</strong> would represent<br />
53-63% of the total IG amount prescribed <strong>in</strong> Belgium <strong>in</strong> 2008. Compared to<br />
studies from other countries (Canada, New Zealand and the US), th<strong>is</strong><br />
represents a lower proportion of the total IG amount to treat these<br />
d<strong>is</strong>eases.<br />
• Th<strong>is</strong> compar<strong>is</strong>on suggests that <strong>in</strong> Belgium, a higher proportion of IG <strong>is</strong> used<br />
to treat the rema<strong>in</strong><strong>in</strong>g <strong>in</strong>dications (37-41% <strong>in</strong> Belgium vs. 12-32% <strong>in</strong> the other<br />
countries). Part of th<strong>is</strong> difference may be expla<strong>in</strong>ed by the 16% of total IG<br />
that has been prescribed by lung special<strong>is</strong>ts <strong>in</strong> 2008.<br />
• However conclusions on the yearly amount of IG required <strong>in</strong> Belgium cannot<br />
be based on th<strong>is</strong> exerc<strong>is</strong>e, as th<strong>is</strong> estimation has many methodological<br />
limitations and probably underestimates the amount that would be required<br />
<strong>in</strong> a “real life” sett<strong>in</strong>g.
<strong>KCE</strong> Reports 120 Plasma 95<br />
D<strong>is</strong>ease / medical condition<br />
Table 40: <strong>The</strong>oretical estimation of annual amounts of immunoglobul<strong>in</strong>s needed to cover the treatment of 11 d<strong>is</strong>eases <strong>in</strong> Belgium<br />
Incidence Prevalence<br />
rate (per rate (case N patients<br />
100,000/year) per 100,000) considered<br />
Based on the follow<strong>in</strong>g assumptions:<br />
Population figures:<br />
Population Belgium (2007): 10.547.958<br />
Population children < 15 years (2007): 1.796.916<br />
Population adults (> 15 years) 2007: 8.751.042<br />
Average body weight:<br />
Adults: 75,0 kg<br />
Children: 25,0 kg<br />
Whole population: 50,0 kg<br />
A B C D E F G H<br />
% patients<br />
treated w/<br />
IVIG/SCIG<br />
N patients<br />
treated per<br />
year<br />
N treatments<br />
per patient<br />
year*<br />
Dose per<br />
treatment<br />
(g/kg)<br />
Amount per<br />
patient per<br />
treatment (g)<br />
Amount per<br />
patient per<br />
year (g) A<br />
Amount per<br />
patient per<br />
year (g) B<br />
IG amount <strong>in</strong><br />
g per year<br />
(A)<br />
Idiopathic thrombocytopenic purpura (all) see detail see detail 323 see detail see detail see detail 210 32.850<br />
- ITP <strong>in</strong> children (
96 Plasma <strong>KCE</strong> Reports 120<br />
Table 41: Estimation of the proportion of immunoglobul<strong>in</strong>s needed (or used) to treat 11 d<strong>is</strong>eases <strong>in</strong> Belgium and <strong>in</strong> 4 studies<br />
D<strong>is</strong>ease / medical condition<br />
IG amount <strong>in</strong><br />
g per year<br />
(A)<br />
Idiopathic thrombocytopenic purpura (all) 32.850<br />
- ITP <strong>in</strong> children (
<strong>KCE</strong> Reports 120 Plasma 97<br />
3.3.4 Expected trends <strong>in</strong> consumption<br />
We have identified a few trends and scientific progresses that may <strong>in</strong>fluence future<br />
trends <strong>in</strong> IG use and consumption, to help predict future trends.<br />
1. <strong>The</strong> number of allogenic bone marrow transplants performed <strong>in</strong> Belgium <strong>is</strong><br />
<strong>in</strong>creas<strong>in</strong>g from year to year, from 216 <strong>in</strong> 2005 to 284 <strong>in</strong> 2007 (+31% <strong>in</strong> 2<br />
years). In Europe, a study estimated a more conservative 13% r<strong>is</strong>e <strong>in</strong> bone<br />
marrow transplants to be expected from 2005 to 2010. 194 Th<strong>is</strong> would imply<br />
an <strong>in</strong>creased IG use over time. However, the <strong>in</strong>crease <strong>in</strong> non-myeloablative<br />
transplants <strong>in</strong> adults, <strong>with</strong> a consequent lower level and shorter duration of<br />
hypogammaglobul<strong>in</strong>emia, would tend to decrease IG needs.<br />
2. <strong>The</strong> prognos<strong>is</strong> of patients <strong>with</strong> MM has improved significantly dur<strong>in</strong>g the last<br />
three decades, result<strong>in</strong>g <strong>in</strong> <strong>in</strong>creased survival. 195 Th<strong>is</strong> will likely <strong>in</strong>crease the<br />
d<strong>is</strong>ease prevalence and related needs <strong>in</strong> IG. But alternative therapies for MM<br />
and CLL are also <strong>in</strong>creas<strong>in</strong>gly used and th<strong>is</strong> may result <strong>in</strong> decreased needs <strong>in</strong><br />
IG supplementation.<br />
3. <strong>The</strong> prevalence of multiple scleros<strong>is</strong> and myasthenia grav<strong>is</strong> <strong>is</strong> <strong>in</strong>creas<strong>in</strong>g <strong>with</strong><br />
time, due to age<strong>in</strong>g of the population and better diagnostic tools, and could<br />
result <strong>in</strong> <strong>in</strong>creas<strong>in</strong>g IG needs.<br />
4. Alternative treatments for ITP and for the prevention of <strong>in</strong>fections <strong>in</strong><br />
transplant are under development. Some therapies are arriv<strong>in</strong>g on the market<br />
(e.g. Rituximab and Romiplost<strong>in</strong>e) could potentially decrease IG use for these<br />
<strong>in</strong>dications.<br />
5. Many studies are conducted to test alternative treatment that would allow<br />
decreas<strong>in</strong>g or even stopp<strong>in</strong>g IG ma<strong>in</strong>tenance treatment <strong>in</strong> CIDP cases. If<br />
successful and <strong>available</strong>, these therapies would decrease IG use for th<strong>is</strong><br />
d<strong>is</strong>ease.<br />
6. Alzheimer d<strong>is</strong>ease, any auto-immune d<strong>is</strong>ease, asthma and some other<br />
frequent d<strong>is</strong>eases related to immunity and for which no alternative treatment<br />
has shown efficacy, may be considered by some physicians as new <strong>in</strong>dications<br />
for IG. Th<strong>is</strong> may represent a problem before any RCT could demonstrate the<br />
efficacy - or lack of efficacy - of IG for these d<strong>is</strong>eases.
98 Plasma <strong>KCE</strong> Reports 120<br />
4 SELF SUFFICIENCY OF BELGIUM<br />
4.1 WHAT ARE THE RISKS AT WORLDWIDE LEVEL ?<br />
4.1.1 Plasma collection: Key role of the North American Region<br />
Over the last years, total volume of plasma <strong>available</strong> worldwide for fractionation has<br />
slightly <strong>in</strong>creased (22.3 million litres <strong>in</strong> 2000, 21.4 million litres <strong>in</strong> 2005) and reached<br />
26.5 million litres <strong>in</strong> 2007, broken down as below:<br />
• 17.9 million of apherese plasma (9.2 million <strong>in</strong> 2000 ; 13.7 <strong>in</strong> 2005)<br />
• 8.6 million of recovered plasma (13.2 million <strong>in</strong> 2000 ; 7.7 <strong>in</strong> 2005)<br />
Of the 26.5 million of plasma mentioned above:<br />
• 15 million are collected <strong>in</strong> the North American region (56%)<br />
• 6.4 million are collected <strong>in</strong> the European Region (24%)<br />
<strong>The</strong>se ratios have rema<strong>in</strong>ed stable s<strong>in</strong>ce 2000.<br />
Of the 17.9 million litres of apherese plasma mentioned above,<br />
• 12.5 million are collected <strong>in</strong> the North American region (70%).<br />
• 2.1 million are collected <strong>in</strong> the European Region (12%)<br />
Figure 11: Shares <strong>in</strong> Global Collection of Plasma<br />
Other Regions<br />
20%<br />
Europ. Union<br />
24%<br />
Source: Market<strong>in</strong>g Research Bureau<br />
North America<br />
56%
<strong>KCE</strong> Reports 120 Plasma 99<br />
Figure 12: Focus: Shares <strong>in</strong> Global Collection of Plasmapherese<br />
Europ. Union<br />
12%<br />
Other Regions<br />
18%<br />
Source: Market<strong>in</strong>g Research Bureau<br />
North America<br />
70%<br />
From a geographical po<strong>in</strong>t of view, North America clearly rema<strong>in</strong>s the key stakeholder<br />
<strong>in</strong> plasma collection. Conversely, one must bear <strong>in</strong> m<strong>in</strong>d that Europe rema<strong>in</strong>s the key<br />
stakeholder <strong>in</strong> the fractionation <strong>in</strong>dustry.<br />
As expla<strong>in</strong>ed above, more than 50% of plasma collected worldwide <strong>is</strong> collected <strong>in</strong> North<br />
America (ma<strong>in</strong>ly <strong>in</strong> the USA). Th<strong>is</strong> ration reaches 70% for apherese plasma.<br />
Plasma donation and collection <strong>in</strong> the USA (as well as blood donation and collection <strong>in</strong><br />
general) <strong>is</strong> based on purely private and commercial pr<strong>in</strong>ciples. Donor selection <strong>is</strong><br />
organized on a r<strong>is</strong>k-management bas<strong>is</strong>, and blood donation <strong>is</strong> paid. Th<strong>is</strong> ethical and<br />
organ<strong>is</strong>ational framework <strong>is</strong> largely different from the European one.<br />
In practice, a large part of the plasma collected <strong>in</strong> the United States needs to be<br />
exported to Europe <strong>in</strong> order to be processed, and re-imported <strong>in</strong>to the United States<br />
for cl<strong>in</strong>ical use. <strong>The</strong>refore, it <strong>is</strong> also of paramount importance to underl<strong>in</strong>e that Europebased<br />
fractionation facilities are often devoted to the supply of the world market,<br />
especially the American one. In other words, European fractionation capacity <strong>is</strong> largely<br />
devoted to the needs of non European (especially US) patients.<br />
In order to fulfil the American patients’ needs, it <strong>is</strong> vital for American stakeholders to<br />
secure the supply of plasma products, the latter be<strong>in</strong>g largely produced by Europe-based<br />
companies. Th<strong>is</strong> may lead American stakeholders to implement specific corporate<br />
strategies (especially long term supply contracts) or even purchase strategies <strong>in</strong> Europe.<br />
For obvious reasons, these strategies are implemented, <strong>with</strong> a view to improv<strong>in</strong>g the<br />
American patients (whatever the needs of the European patients may be).<br />
Should a shortage of plasma products appear (eg sharp and quick ra<strong>is</strong>e <strong>in</strong> global needs<br />
due to new <strong>in</strong>dications), potential competition between American patients’ needs and<br />
European patients’ needs could be clearly identified.<br />
Moreover, as mentioned below, any change <strong>in</strong> the use of plasma products, especially<br />
<strong>in</strong>dications <strong>in</strong> the USA (or even changes <strong>in</strong> prescription habits) <strong>is</strong> likely to have an<br />
impact on the US demand and then <strong>in</strong>directly on the European fractionation <strong>in</strong>dustry.<br />
Basically, consider<strong>in</strong>g today’s situation of American and European plasma fractionation<br />
<strong>in</strong>dustry, the ma<strong>in</strong> concern of American stakeholders <strong>is</strong> to secure the stream of plasma<br />
products across the Atlantic. As a practical matter, if US health authorities decided to<br />
restrict export of their own raw plasma, European countries would not be <strong>in</strong> the<br />
position to fulfil immediately the needs of European patients.
100 Plasma <strong>KCE</strong> Reports 120<br />
4.1.2 Worldwide demand for plasma products / Focus on IVIG (2000-2008)<br />
Percentage<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
Over the last years, global demand for polyvalent Intravenous immune-globul<strong>in</strong> has<br />
ra<strong>is</strong>ed firmly and steadily.<br />
Whereas global demand for polyvalent IVIG amounted to ca 47 000 tons <strong>in</strong> 2000, it<br />
reached more than 82 000 tons <strong>in</strong> 2008.(ie an <strong>in</strong>crease by 75% <strong>in</strong> an eight-year period of<br />
time).<br />
In 2007, the share of the European Region <strong>in</strong> the global demand amounted to 25%,<br />
whereas the one of the North American Region reached 45%.<br />
In f<strong>in</strong>ancial terms, the demand of the European Region reached 762 million US dollars<br />
(20% of the global demand), whereas the one of the North American Region amounted<br />
to 2199 million US dollars (57% of the global demand).<br />
Figure 13: Global collection and Demand of IVIG<br />
North<br />
America<br />
European<br />
Union<br />
Source: Market<strong>in</strong>g Research Bureau<br />
Other<br />
Regions<br />
4.1.3 Potential changes <strong>in</strong> demand structure<br />
Share <strong>in</strong> Global Collection %<br />
Share <strong>in</strong> Global Demand %<br />
North America European Union Other Regions<br />
Share <strong>in</strong> Global Demand % 45 25 30<br />
Share <strong>in</strong> Global Collection % 56 24 20<br />
Indications have evolved over the last years. <strong>The</strong>refore, it <strong>is</strong> important to stress that<br />
these evolutions have had an impact (or even a major) on the demand of plasma<br />
products. It rema<strong>in</strong>s difficult to forecast evolution of consumption prec<strong>is</strong>ely, as different<br />
factors must be taken <strong>in</strong>to account: research progress and new evidence-based<br />
<strong>in</strong>dications, but also d<strong>is</strong>sem<strong>in</strong>ation of premature and non evidence-based practices or<br />
expert op<strong>in</strong>ions.<br />
Further <strong>in</strong>formation <strong>in</strong> Appendix “Emerg<strong>in</strong>g Countries” on the Brazilian and the Ch<strong>in</strong>ese<br />
market
<strong>KCE</strong> Reports 120 Plasma 101<br />
Key po<strong>in</strong>ts<br />
• <strong>The</strong> North American region (especially the United States) rema<strong>in</strong>s the<br />
“World’s plasma collector” whereas Europe rema<strong>in</strong>s the “World’s plasma<br />
fractionator”.<br />
• <strong>The</strong> ma<strong>in</strong> concern of the American stakeholders <strong>is</strong> to secure the supply for<br />
plasma products, by different means (long term supply contracts, control of<br />
fractionation capacities), whereas the fulfill<strong>in</strong>g of European patients<br />
simultaneously requires large imports of American plasma.<br />
• Should US health authorities decide to restrict export of their own raw<br />
plasma, European patients would be put <strong>in</strong> a predicament. Any change of<br />
American practices (new <strong>in</strong>dications or change <strong>in</strong> prescription habits) must<br />
be kept under close scrut<strong>in</strong>y as it could lead to a similar deadlock.<br />
Conversely, American patients need to rely on the EU fractionation <strong>in</strong>dustry<br />
to fulfil their own needs.<br />
• Emerg<strong>in</strong>g countries are likely to play an ever greater role on the world<br />
market, which means greater competition between purchasers.<br />
4.2 CONCEPT OF SELF SUFFICIENCY<br />
4.2.1 In Belgium<br />
Belgian regulations do not def<strong>in</strong>e the proportion of plasma derivatives that must be<br />
produced <strong>in</strong> Belgium to m<strong>in</strong>im<strong>is</strong>e the r<strong>is</strong>k of shortages of plasma derivatives. A Royal<br />
Decree of 18 June 1998 simply states that <strong>in</strong> order to ensure self-sufficiency and the<br />
quality of the supplies of stable blood products of human orig<strong>in</strong>, the price of a litre of<br />
plasma, manufactured by plasmapheres<strong>is</strong> and sold by the Red Cross to the CAF-DCF,<br />
will be subsid<strong>is</strong>ed and that a firm of auditors will communicate each year to the SPF the<br />
number of litres sold <strong>in</strong> order to calculate correctly the subsidy.<br />
S<strong>in</strong>ce the quantity guarantee<strong>in</strong>g self-sufficiency <strong>is</strong> not explicitly stated <strong>in</strong> the decree, it<br />
transpires from verbal explanations gathered that the auditor i deems that self-sufficiency<br />
<strong>is</strong> achieved if the CAF-DCF provides<br />
• “a level of production cover<strong>in</strong>g 60% of the average national consumption<br />
of the ma<strong>in</strong> plasma-derived products – i.e. Factor VIII, Album<strong>in</strong>, and IVIG -<br />
<strong>in</strong> normal sanitary and epidemiological conditions, and consider<strong>in</strong>g<br />
approved <strong>in</strong>dications”<br />
• “a quarant<strong>in</strong>e stock cover<strong>in</strong>g 90 days of average national consumption for<br />
the three ma<strong>in</strong> products mentioned above”. In practice, th<strong>is</strong> stock<br />
compr<strong>is</strong>es 8000 bottles of Album<strong>in</strong>, 1 million doses of Factor VIII, and<br />
50kg of IVIG.<br />
Th<strong>is</strong> quantity <strong>is</strong> shown on the first l<strong>in</strong>e of the table below. PWC then deducts from th<strong>is</strong><br />
quantity the number of litres of non-subsid<strong>is</strong>ed plasma (RP) (l<strong>in</strong>e 2) and adds to it the<br />
number of litres taken from stocks (l<strong>in</strong>e 4) to calculate the number of litres to be<br />
subsid<strong>is</strong>ed (l<strong>in</strong>e 5).<br />
i Th<strong>is</strong> role <strong>is</strong> assumed by the firm PricewaterhouseCoopers. See ‘Plasma from plasmapheres<strong>is</strong> required for<br />
self-sufficiency <strong>in</strong> Belgium <strong>in</strong> 2008’ PWC
1<br />
2<br />
3<br />
102 Plasma <strong>KCE</strong> Reports 120<br />
Table 42: Volumes of plasma bought by CAF-DCF and subsidized <strong>in</strong> Belgium<br />
between 2000 and 2008<br />
Type of plasma 2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
Quantities of plasma<br />
necessary for self<br />
sufficiency<br />
Recovered plasma<br />
bought by CAF –<br />
DCF from all<br />
collectors<br />
Source plasma<br />
bought by CAF –<br />
DCF from all<br />
collectors<br />
196,479 197,527 210,564 212,827 243,795 202,24 182,149 170,497 157,472<br />
140,451 138,141 136,348 135,141 123,78 115,896 113,731 114,375 106,923<br />
56,028 59,386 74,216 68,087 96,024 80,25 59,751 50,488 42,592<br />
4 Intake from stock 8,667 5,634 7,957<br />
5<br />
Source plasma<br />
subsidized<br />
56,028 59,386 74,216 77,686 120,015 86,344 68,418 56,122 50,549<br />
Source: PWC<br />
Note that the quantities of source plasma purchased by the CAF-DCF from the SFS and<br />
VDB accord<strong>in</strong>g to PWC are not the same as those received by the Federal Agency for<br />
Medic<strong>in</strong>es :<br />
Table 43: Compar<strong>is</strong>on of quantities purchased by the CAF and collected by<br />
SFS-VDB<br />
2000 2001 2002 2003 2004 2005 2006 2007 2008<br />
SP purchased by CAF from SFS + VDB (source: PWC)<br />
Sp purchased by CAF from SFS + VDB (source: Federal<br />
n.a. n.a. n.a. 68.087 96.024 80.250 59.751 50.488 42.592<br />
Agency for Drug) 76.561 77.736 74.865 67.908 93.860 78.052 59.462 50.125 45.324<br />
SP collected by SFS + VDB (source: SFS & VDB)<br />
77.052 77.808 74.865 67.915 94.176 78.068 57.225 50.125 45.324<br />
But these quantities are approximately the same than the collected quantities except for<br />
2006. We didn’t receive any explanation for th<strong>is</strong> difference of 2.237 litres (i.e. 3.9% of<br />
the total volume of SP collected <strong>in</strong> 2006).<br />
It clearly emerges that the term self-sufficiency <strong>is</strong> no longer adequate to describe the<br />
data from these calculations. PWC starts <strong>with</strong> a total quantity of plasma, which <strong>is</strong> the<br />
quantity that the CAF-DCF would have to buy to supply a quantity of derivatives over<br />
and above those supplied by commercial firms <strong>in</strong> Belgium. It <strong>is</strong> important to understand<br />
that the total market for plasma derivatives <strong>is</strong> not divided between the ex<strong>is</strong>t<strong>in</strong>g vendors<br />
<strong>in</strong> a fixed d<strong>is</strong>tribution pattern. It <strong>is</strong> the <strong>in</strong>terplay of competition that determ<strong>in</strong>es the<br />
quantities that the CAF-DCF and the other foreign commercial vendors will sell dur<strong>in</strong>g<br />
a given year to the various hospitals. Th<strong>is</strong> clearly establ<strong>is</strong>hes that self-sufficiency only<br />
relates to a part of Belgian consumption, which results from competition between the<br />
firms operat<strong>in</strong>g <strong>in</strong> the market.<br />
It appears that the authority has no clear <strong>in</strong>tention of achiev<strong>in</strong>g total <strong>in</strong>dependence. But<br />
does the coverage of 60%, extended to 180 days, which seems somewhat arbitrary,<br />
truly reflect a reasonable r<strong>is</strong>k? Nobody knows. We also f<strong>in</strong>d no scientific justification for<br />
the quarant<strong>in</strong>e period (dur<strong>in</strong>g which the plasma must be kept before fractionation).<br />
Th<strong>is</strong> was extended from 50 to 180 days between 1998 and 2006 <strong>with</strong> no justification for<br />
th<strong>is</strong> extension from the standpo<strong>in</strong>t of medical safety. It therefore appears that the<br />
concepts of self-sufficiency and quarant<strong>in</strong>e have never been properly considered and<br />
def<strong>in</strong>ed <strong>in</strong> Belgium.
<strong>KCE</strong> Reports 120 Plasma 103<br />
Key po<strong>in</strong>ts<br />
• Free competition has led to a market d<strong>is</strong>tribution of 60-40 between the<br />
CAF-DCF and the other firms produc<strong>in</strong>g blood derivatives<br />
• <strong>The</strong>re does not appear to have been any d<strong>is</strong>cussion of whether or not th<strong>is</strong><br />
d<strong>is</strong>tribution <strong>is</strong> optimal from the standpo<strong>in</strong>t of secur<strong>in</strong>g coverage of our needs<br />
4.2.2 In other countries<br />
4.2.2.1 In Australia<br />
Australian official def<strong>in</strong>ition of Self-sufficiency<br />
<strong>The</strong> promotion of national self-sufficiency <strong>in</strong> respect of blood and blood products <strong>is</strong> a<br />
policy aim of Australia’s Commonwealth, state and territory governments. <strong>The</strong><br />
Australian Health M<strong>in</strong><strong>is</strong>ters’ Conference Policy Statement on National Self Sufficiency <strong>in</strong><br />
the Supply of Blood and Blood Products, <strong>is</strong>sued <strong>in</strong> April 2006 196 , def<strong>in</strong>es self-sufficiency<br />
as: “Australia striv<strong>in</strong>g to source blood components and plasma from <strong>with</strong><strong>in</strong> Australia to<br />
meet appropriate cl<strong>in</strong>ical demand”.<br />
Self-Sufficiency objective and National Blood Agreement<br />
All Australian, State and Territory Governments are signatories to the National Blood<br />
Agreement 2003, which sets out, the policy objectives and aims for Australia’s national<br />
blood sector, which are:<br />
• provide an adequate, safe, secure and affordable supply of blood<br />
products,blood related products and blood related services;<br />
• promote safe, high quality management and use of blood products, blood<br />
related products and blood related services <strong>in</strong> Australia.<br />
<strong>The</strong>refore all stakeholders are clearly committed <strong>in</strong> the field implementation of selfsufficiency<br />
policy.<br />
However, national self-sufficiency objective does not preclude Australia from import<strong>in</strong>g<br />
blood or plasma products <strong>in</strong> a narrow range of circumstances, ie where there <strong>is</strong> an<br />
<strong>in</strong>ability to meet cl<strong>in</strong>ical needs through the domestic supply, and where supply cha<strong>in</strong><br />
r<strong>is</strong>ks must be addressed. <strong>The</strong> Australian Health M<strong>in</strong><strong>is</strong>ters’ Conference statement<br />
acknowledged that Australia <strong>is</strong> (and has never been) not totally self-sufficient <strong>in</strong> plasma<br />
products and derivatives.<br />
<strong>The</strong>refore the agreement signed between health authorities and CSL-Limited also gave<br />
room for some flexibility on the matter of import of plasma products and derivatives,<br />
<strong>with</strong><strong>in</strong> a strict framework that:<br />
• ensures adequacy of supply to Australian patients <strong>in</strong> need;<br />
• m<strong>in</strong>imizes the supply security and product safety r<strong>is</strong>ks to patients;<br />
• ensures affordability of products to the Australian health sector; and<br />
• recognizes the practicalities of production and d<strong>is</strong>tribution.<br />
Self sufficiency and Australian national blood policy<br />
<strong>The</strong> Australian example has been selected, s<strong>in</strong>ce Australia <strong>is</strong> the only western country<br />
that has succeeded <strong>in</strong> sett<strong>in</strong>g up a comprehensive blood and plasma policy, from a<br />
• practical po<strong>in</strong>t of view : organization of donation, collection, fractionation<br />
of blood and plasma<br />
• legal po<strong>in</strong>t of view : strong <strong>in</strong>terface between suppliers and health<br />
authorities<br />
• cl<strong>in</strong>ical po<strong>in</strong>t of view : <strong>in</strong>terface between cl<strong>in</strong>ical practices and supply<br />
policy.
104 Plasma <strong>KCE</strong> Reports 120<br />
It must be outl<strong>in</strong>ed that such a policy requires an unfail<strong>in</strong>g and long-last<strong>in</strong>g political<br />
commitment of the national health authorities. In Australia th<strong>is</strong> policy th<strong>is</strong> policy has<br />
been <strong>in</strong>itiated <strong>in</strong> the fifties: the Commonwealth Serum Laboratories (hereafter “CSL”)<br />
orig<strong>in</strong>ally founded <strong>in</strong> 1916 commenced production of fractionated products <strong>in</strong> 1953,<br />
thanks to the Australian Government’s support. CSL was later privatized and merged<br />
<strong>with</strong> Behr<strong>in</strong>g.<br />
<strong>The</strong> Australian policy was elaborated step by step, and <strong>in</strong> 1995 the Commonwealth<br />
Review of the Australian Blood and Blood Product System identified the need for a<br />
s<strong>in</strong>gle, <strong>in</strong>tegrated, blood supply agency <strong>in</strong> Australia <strong>with</strong> a view to enhanc<strong>in</strong>g the safety,<br />
efficacy,and adequacy of supply of blood and blood products. As a result of that, the<br />
separate state and territory blood services comb<strong>in</strong>ed to form the Australian Red Cross<br />
Blood Service <strong>in</strong> 1996.<br />
<strong>The</strong> Review of the Australian Blood Bank<strong>in</strong>g and Plasma sector, which was completed <strong>in</strong><br />
2001, recommended the establ<strong>is</strong>hment of an authority to provide national management<br />
and oversight of Australia’s blood system. Follow<strong>in</strong>g th<strong>is</strong> review, the National Blood<br />
Authority (hereafter “NBA”) was set up <strong>in</strong> 2003.<br />
Background: Australian adm<strong>in</strong><strong>is</strong>trative structure<br />
ROLE OF THE NATIONAL BLOOD AUTHORITY<br />
Australian blood and blood products policy (especially <strong>in</strong> the field of plasma products)<br />
has been centralized and rationalized every angle: one s<strong>in</strong>gle public body <strong>is</strong> entrusted to<br />
manage the whole Australian policy. <strong>The</strong> National Blood Authority <strong>is</strong> a statutory and<br />
overarch<strong>in</strong>g agency establ<strong>is</strong>hed under the National Blood Authority Act 2003 . <strong>The</strong><br />
NBA <strong>is</strong> central to Australia’s national blood and plasma policy. <strong>The</strong> most important and<br />
<strong>in</strong>terest<strong>in</strong>g character<strong>is</strong>tic of the NBA <strong>is</strong> that it covers the whole scope of th<strong>is</strong> policy:<br />
• Coord<strong>in</strong>ation of demand and supply plann<strong>in</strong>g of blood and blood products<br />
and purchase those products on behalf of Health authorities<br />
• Negotiation and follow-up of the contracts <strong>with</strong> suppliers of blood, blood<br />
products and blood services, <strong>in</strong>clud<strong>in</strong>g development of a national pric<strong>in</strong>g<br />
schedule.<br />
• Implementation of an efficient blood use based on evidence-based<br />
pr<strong>in</strong>ciples and good cl<strong>in</strong>ical practice. (<strong>in</strong>cl. <strong>in</strong>formation and advice to<br />
governments ).<br />
• Coord<strong>in</strong>ation of the development of the National Health and Medical<br />
Research Council’s Cl<strong>in</strong>ical Practice Guidel<strong>in</strong>es for the Use of Blood<br />
Components.<br />
• Follow-up of legal <strong>is</strong>sues<br />
Further <strong>in</strong>formation <strong>is</strong> provided on <strong>in</strong>stitutional aspects (NBA and other <strong>in</strong>stitutions <strong>in</strong><br />
the appendix).<br />
Access to plasma derivatives: key po<strong>in</strong>ts<br />
APPROVAL PROCESS AS DESIGNED UNTIL MARCH 2008<br />
Access to plasma-derived products has been rationalized and must abide by a specific<br />
cl<strong>in</strong>ical and adm<strong>in</strong><strong>is</strong>trative process. Processes may vary across the Australian States<br />
(some of them be<strong>in</strong>g more demand<strong>in</strong>g or than others); however, the key po<strong>in</strong>t of the<br />
Australian policy <strong>is</strong> to rationalize the use of plasma derived products (especially IVIG<br />
which represents two-thirds of Australia’s demand <strong>in</strong> th<strong>is</strong> field) both for ethical reasons<br />
(optimal use of donated blood) but also for practical reasons (avoid<strong>in</strong>g shortage).<br />
From a purely cl<strong>in</strong>ical po<strong>in</strong>t of view <strong>in</strong>dications have been grouped <strong>in</strong>to three groups<br />
depend<strong>in</strong>g on the level of cl<strong>in</strong>ical accuracy:<br />
• Category 1: <strong>in</strong>dications for which strong evidence of IVIg benefit has been<br />
identified.<br />
• Category 2: <strong>in</strong>dications for which evidence of th<strong>is</strong> benefit <strong>is</strong> <strong>in</strong>conclusive<br />
for the follow<strong>in</strong>g reasons:
<strong>KCE</strong> Reports 120 Plasma 105<br />
• Conflict<strong>in</strong>g evidence<br />
• Low level of evidence<br />
• Little research, especially for rare conditions<br />
Category 3: <strong>in</strong>dications for which there <strong>is</strong> conv<strong>in</strong>c<strong>in</strong>g evidence that IVIg br<strong>in</strong>gs no<br />
benefit. A strong f<strong>in</strong>ancial connection has been establ<strong>is</strong>hed between accuracy of<br />
<strong>in</strong>dications – as described above – and fund<strong>in</strong>g policy. In short, prescription of Category<br />
1 IVIg <strong>is</strong> funded on the bas<strong>is</strong> of a specific cost-shar<strong>in</strong>g arrangement, called Australia’s<br />
National Blood Agreement ie 63% by the Australian Government (national level) and<br />
37% by the State / Territory level. Prescription of imported IVIg products outside of<br />
Category 1 are not co-funded, and IVIg products must be purchased at full price by<br />
prescribers (hospitals) directly from the relevant manufacturer which are responsible<br />
for production of IVIg. Hence, there <strong>is</strong> a f<strong>in</strong>ancial <strong>in</strong>centive for an evidence-based and<br />
rational use of IVIg products.<br />
<strong>The</strong> ARCBS approved requests that meet category 1. If <strong>in</strong>sufficient <strong>in</strong>formation was<br />
provided by the cl<strong>in</strong>ician to the ARCBS, the request was forwarded to the local IVIG<br />
Work<strong>in</strong>g Group. Th<strong>is</strong> IVIG Work<strong>in</strong>g Group cons<strong>is</strong>ted of 8 cl<strong>in</strong>icians, represent<strong>in</strong>g<br />
specialities who had an <strong>in</strong>terest <strong>in</strong> IVIG <strong>is</strong>sues, and made the f<strong>in</strong>al dec<strong>is</strong>ion (approval or<br />
not).<br />
In March 2008 (ongo<strong>in</strong>g reform), the new “Criteria for the cl<strong>in</strong>ical use of <strong>in</strong>travenous<br />
immunoglobul<strong>in</strong> <strong>in</strong> Australia” (hereafter “Criteria”) have been officially <strong>is</strong>sued by the<br />
Australian. In short, the conditions are categor<strong>is</strong>ed <strong>in</strong> the Criteria under those for<br />
which IVIG has:<br />
• An establ<strong>is</strong>hed therapeutic role<br />
• An emerg<strong>in</strong>g therapeutic role<br />
• A use <strong>in</strong> exceptional circumstances<br />
• Conditions for which IVIG <strong>is</strong> not <strong>in</strong>dicated<br />
Supply contracts <strong>with</strong> CSL-Ltd: Plasma Products Agreement and other<br />
contractual arrangements 197<br />
BACKGROUND<br />
In 1994 CSL became a public company limited by shares and taken to be reg<strong>is</strong>tered<br />
under the Companies Act 1981 (Cwlth). At th<strong>is</strong> time, certa<strong>in</strong> leg<strong>is</strong>lative obligations were<br />
imposed upon CSL Limited, <strong>in</strong> l<strong>in</strong>e <strong>with</strong> the Commonwealth Serum Laboratories Act<br />
1961 (CSL Act), as described below:<br />
• Provide that CSL Limited <strong>is</strong> to rema<strong>in</strong> Australian-controlled.<br />
• CSL <strong>is</strong> also required to ma<strong>in</strong>ta<strong>in</strong> a reg<strong>is</strong>ter of foreign-held vot<strong>in</strong>g shares<br />
and must provide th<strong>is</strong> reg<strong>is</strong>ter, or a copy thereof, to the M<strong>in</strong><strong>is</strong>ter if<br />
requested to do so by the M<strong>in</strong><strong>is</strong>ter, <strong>in</strong> writ<strong>in</strong>g.<br />
• Require CSL, when manufactur<strong>in</strong>g plasma products from Australiandonated<br />
plasma, to produce those products <strong>in</strong> Australia.<br />
• Prohibit CSL from d<strong>is</strong>pos<strong>in</strong>g of its manufactur<strong>in</strong>g facility at<br />
Broadmeadows, which may not be sold or encumbered <strong>with</strong>out<br />
M<strong>in</strong><strong>is</strong>terial perm<strong>is</strong>sion.<br />
• Provide for court orders where the Commonwealth can show that CSL <strong>is</strong><br />
breach<strong>in</strong>g, or threaten<strong>in</strong>g to breach, a contractual obligation.<br />
An <strong>in</strong>d-depth analys<strong>is</strong> of fractionation arrangements had been carried out and<br />
completed <strong>in</strong> 2006 196 . In today’s form – Plasma Products Agreement mentioned above -<br />
relationship between CSL-Ltd and Australian health authorities can be summarized as a<br />
close partnership based on a monopoly for fractionation <strong>in</strong> exchange for strict and<br />
demand<strong>in</strong>g performance and safety standards 164 (see table below):
106 Plasma <strong>KCE</strong> Reports 120<br />
Table 44: <strong>The</strong> Plasma Products Agreement between CSL-Ltd and the<br />
Australian National Blood Authority<br />
Head<strong>in</strong>g Content<br />
Section A: Interpretation and Term Def<strong>in</strong>itions, rules of <strong>in</strong>terpretation<br />
Section B: Relationship Management Relationship between the parties, Contacts and notices,<br />
Management meet<strong>in</strong>gs and reviews, Public Affairs<br />
Management, Variations to the Deed, CSL contracts <strong>with</strong><br />
other Nat. Blood Suppliers<br />
Section C: Products / Services Obligations Prov<strong>is</strong>ion of products (quantity; notice obligations, etc..)<br />
Exclusive right to fractionate plasma, Report<strong>in</strong>g obligations,<br />
Obligations under <strong>The</strong>rapeutic Goods Act, CSL general<br />
obligations (as a manufacturer and where CSL <strong>is</strong> not a<br />
manufacturer)<br />
Product compliance and return,<br />
Performance requirements for goods and services<br />
Section D: Payment Obligations Payments by the NBA, Invoic<strong>in</strong>g obligations, Recovery of<br />
money by the NBA,<br />
Section E: Ownership Issues Possession of products, Intellectual property, Moral rights<br />
Section F: Protection of Information Confidentiality, Data security, Privacy, Conf. of Interest<br />
Section G: Treatment of R<strong>is</strong>ks R<strong>is</strong>k Manag. Warranties, Indemnities, Undertak<strong>in</strong>gs,<br />
Insurance, Supply cont<strong>in</strong>uity plans & options<br />
Section H: Other Requirements of CSL Records, Access to <strong>in</strong>formation & Prem<strong>is</strong>es, Audit.<br />
Section I: Term<strong>in</strong>ation and D<strong>is</strong>putes Term<strong>in</strong>. for default, for change of policy, Handover<br />
obligations, D<strong>is</strong>pute Resolution,<br />
Section J: M<strong>is</strong>cellaneous Assignment (by CSL, by NBA), Execution of separate<br />
documents.<br />
CSL Limited <strong>is</strong> also <strong>in</strong> charge of ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g the National Reserve of plasma products for<br />
the NBA, under a contractual arrangement separate to the PPA.<br />
4.2.2.2 In France<br />
French Approach of self-sufficiency<br />
In France, there <strong>is</strong> no official and legal def<strong>in</strong>ition of “self-sufficiency” as such. However, a<br />
general approach of th<strong>is</strong> concept could be def<strong>in</strong>ed as the turnover of LFB (national<br />
fractionator enjoy<strong>in</strong>g the monopoly of EFS plasma fractionation) compared to the total<br />
turnover of fractionators operat<strong>in</strong>g <strong>in</strong> France. One must bear <strong>in</strong> m<strong>in</strong>d that the plasma<br />
product market <strong>is</strong> subject to competition. LFB must therefore compete <strong>with</strong> other firms<br />
(Baxter, Octapharma, etc…).<br />
Consider<strong>in</strong>g th<strong>is</strong> approach, it must be outl<strong>in</strong>ed that LFB meets 75% of the needs of the<br />
French market. However, it must be underl<strong>in</strong>ed that LFB corporate objective <strong>is</strong> to be <strong>in</strong><br />
the position to fulfil 100% of these needs <strong>in</strong> 2011 (specific <strong>in</strong>vestments have been<br />
planned accord<strong>in</strong>gly).<br />
Another important po<strong>in</strong>t <strong>is</strong> the very last update of the French regulation framework. In<br />
Summer 2009, the new French Law on Health Care organization (Loi Hôpital Patients<br />
Santé et Territoire – Loi HPST) officially stated that fulfill<strong>in</strong>g the French patients’ needs<br />
must be LFB’s priority (<strong>in</strong> return of its monopoly of EFS plasma fractionation).<br />
Supply of blood and plasma-derived products: the French monitor<strong>in</strong>g system<br />
Follow<strong>in</strong>g the shortage of Factor VIII <strong>in</strong> France <strong>in</strong> 2000-2001 (and consequential<br />
problems for haemophilia patients), the French Department of Health decided to set up<br />
a long-term monitor<strong>in</strong>g system -National Steer<strong>in</strong>g Committee- to address th<strong>is</strong> specific<br />
k<strong>in</strong>d of problems. <strong>The</strong> latter has been organized s<strong>in</strong>ce 2001 (by means of a Department<br />
of Health’s Circular dated 28 June 2001) under the leadership of the AFSSAPS Agence<br />
França<strong>is</strong>e de Sécurité Sanitaire des Produits de Santé– French Agency for the Safety of<br />
Health Products.<br />
Follow<strong>in</strong>g the meet<strong>in</strong>gs of these groups, and depend<strong>in</strong>g on the likelihood of shortage of<br />
plasma derivatives, national official recommendations – <strong>in</strong>clud<strong>in</strong>g priority orders - can be<br />
officially set out and publ<strong>is</strong>hed by the AFSSAPS and to rationalize the use of these<br />
products accord<strong>in</strong>gly (eg: Fibr<strong>in</strong>ogene-derived products <strong>in</strong> December 2008 and the<br />
follow<strong>in</strong>g months).
<strong>KCE</strong> Reports 120 Plasma 107<br />
As far as IVIG products are concerned, a specific steer<strong>in</strong>g group has been set up to<br />
organize rout<strong>in</strong>e monitor<strong>in</strong>g of IVIG products supply. All relevant private and public<br />
stakeholders are <strong>in</strong>volved: representatives of the Department of Health, several<br />
representatives of pharmac<strong>is</strong>ts (<strong>in</strong>cl. the French Pharmaceutical Association), Networks<br />
of heath care establ<strong>is</strong>hments, cl<strong>in</strong>ical experts, but also the lead<strong>in</strong>g fractionation firms on<br />
the French market.<br />
Supply and storage <strong>is</strong>sues are d<strong>is</strong>cussed every angle: data collection on consumption and<br />
supply, cl<strong>in</strong>ical dimension, <strong>in</strong>dustrial problems etc…<strong>The</strong> m<strong>in</strong>utes of these meet<strong>in</strong>gs are<br />
not public doma<strong>in</strong> and they rema<strong>in</strong> confidential. However, th<strong>is</strong> rout<strong>in</strong>e monitor<strong>in</strong>g<br />
system plays a key-role <strong>in</strong> shortage prevention and also covers the <strong>in</strong>terface between<br />
public dec<strong>is</strong>ion-makers and private fractionation <strong>in</strong>dustry on that matters.<br />
4.2.2.3 In Germany<br />
Quantity<br />
Collected<br />
(Liters)<br />
German approach of self-sufficiency<br />
As stated by Art 4.7 of the German Transfusion Act “Compensation <strong>is</strong> also an aspect of<br />
self-sufficiency. Should it not be allowed to pay a compensation, th<strong>is</strong> would cause a<br />
highly v<strong>is</strong>ible loss of donors. Th<strong>is</strong> would be counter-productive to the aim of selfsufficiency”.<br />
“Blood and Plasma donors may receive a compensation for the donation<br />
time and effort. However, th<strong>is</strong> compensation must not become a payment”.<br />
However, from a purely legal and conceptual po<strong>in</strong>t there <strong>is</strong> no one s<strong>in</strong>gle def<strong>in</strong>ition of<br />
“self-sufficiency” as such, but several ratios followed up on the national level by the Paul<br />
Ehrlich Institut thanks to a centralized data collection system.<br />
<strong>The</strong> key objective of the German Health Authorities <strong>is</strong> to have a clear overview of<br />
plasma quantities actually <strong>available</strong> for fractionation and also to analyze the German<br />
<strong>in</strong>dustry’s actual capacity to fractionate the German plasma.<br />
As often underl<strong>in</strong>ed by the Paul Ehrlich Institut’s experts, <strong>in</strong>creas<strong>in</strong>g plasma collection <strong>is</strong><br />
not an end <strong>in</strong> itself. A sensible approach requires a specific follow-op of plasma<br />
collection but also a specific monitor<strong>in</strong>g of the German actual fractionation capacity for<br />
the whole range of plasma products meet<strong>in</strong>g the German patients’ demand.<br />
Practical follow-up of self-sufficiency <strong>is</strong>sues<br />
Th<strong>is</strong> data collection system <strong>is</strong> a regulatory obligation, based on Article 21 and 22 of the<br />
German National Transfusion Act (“Transfusionsgesetz” <strong>in</strong> German).<br />
• Blood and plasma collectors (Red Cross, Private Centres, Municipal<br />
Centres, German Army) are subject to th<strong>is</strong> specific <strong>report</strong><strong>in</strong>g obligation,<br />
but also:<br />
• Fractionation <strong>in</strong>dustry : all firms act<strong>in</strong>g on the German market<br />
• On the demand side: panel doctors and hospitals and specialized health<br />
care establ<strong>is</strong>hments.<br />
Th<strong>is</strong> <strong>report</strong><strong>in</strong>g system refers to a specific data set, set out by the German regulation<br />
mentioned above. <strong>The</strong>refore, the German health authorities are <strong>in</strong> the position to<br />
organize a follow-up of a specific range of rout<strong>in</strong>e <strong>in</strong>dicators and to have a clear<br />
overview of Germany’s situation <strong>in</strong> terms of self-sufficiency.<br />
SUPPLY SIDE<br />
In practice all the concerned data are validated, sorted and entered onto the Paul<br />
Ehrlich Institut’s data bases. Consider<strong>in</strong>g our subject, one of the most accurate<br />
monitor<strong>in</strong>g tool <strong>is</strong> the “Balance Sheet” that records the follow<strong>in</strong>g flows (2006 Data):<br />
Loss Expiry<br />
(Manufactu<br />
rer)<br />
Total<br />
Export<br />
Total<br />
Import<br />
Quantity<br />
Available on<br />
the German<br />
Market<br />
Fractionat<br />
ion <strong>in</strong><br />
Germany<br />
2 143 205 154 881 5 990 1 001 911 609 584 1 750 878 1 201 613
108 Plasma <strong>KCE</strong> Reports 120<br />
Thanks to th<strong>is</strong> follow-up of imports, the Institute can have a clear view of Germany’s<br />
situation for the whole range of plasma products, <strong>in</strong>clud<strong>in</strong>g those that are not<br />
manufactured <strong>in</strong> Germany.<br />
DEMAND SIDE<br />
A specific follow-up <strong>is</strong> also rout<strong>in</strong>ely carried out by the Paul Ehrlich Institut.<br />
- One of the self sufficiency key <strong>in</strong>dicators <strong>is</strong> the follow<strong>in</strong>g: “Quantities manufactured <strong>in</strong><br />
Germany relat<strong>in</strong>g to consumption <strong>in</strong> Germany”. Based on th<strong>is</strong> approach, the self-sufficiency<br />
ratios are:<br />
• Factor VIII from plasma : above 100%<br />
• Factor IX from plasma: 66%<br />
• IG (normal): 99%<br />
• IG (specific / Anti D): 94%<br />
• IG (other specific IGs): Above 100%<br />
Among all plasma products, some are not manufactured <strong>in</strong> Germany, but imports are<br />
subject to a prec<strong>is</strong>e follow-up. Consumption of each plasma product <strong>is</strong> also subject to a<br />
prec<strong>is</strong>e follow-up. However, <strong>in</strong> spite of th<strong>is</strong> follow-up mechan<strong>is</strong>m, the Paul Ehrlich<br />
Institute had to admit that there <strong>is</strong> some uncerta<strong>in</strong>ty about reliability of data on the<br />
latter subject.<br />
Recent strengthen<strong>in</strong>g of supply capacity <strong>in</strong> Germany (2000-2008)<br />
A DYNAMIC COLLECTION POLICY<br />
As a whole, the situation of Germany has evolved quite positively over the last ten<br />
years. Plasma actually collected <strong>in</strong> Germany has ra<strong>is</strong>ed from 1.5 million litters <strong>in</strong> 2000 to<br />
2.5 million litters <strong>in</strong> 2008.<br />
A SURGE IN PLASMA FRACTIONATION CAPACITY<br />
<strong>The</strong> amount of plasma actually fractionated <strong>in</strong> Germany has ra<strong>is</strong>ed accord<strong>in</strong>gly: 750 000<br />
litters <strong>in</strong> 2004, 1.2 Million litres <strong>in</strong> 2006 (see above), and 2 Million litres <strong>in</strong> 2008.<br />
4.2.2.4 In Canada<br />
Canadian h<strong>is</strong>torical background<br />
H<strong>is</strong>torically, gratuity of donation of blood and plasma has been considered as the<br />
underp<strong>in</strong>n<strong>in</strong>g pr<strong>in</strong>ciple of the whole Canadian donation system. In the n<strong>in</strong>eties, a major<br />
public health scandal called the “ta<strong>in</strong>ted blood scandal” seriously underm<strong>in</strong>ed the public<br />
and the donors’ trust <strong>in</strong> the donation <strong>in</strong>stitutions, especially the Canadian Red Cross.<br />
In compliance <strong>with</strong> the conclusions of the Krever Comm<strong>is</strong>sion of Inquiry of 1997 (see<br />
below), the Canadian Red Cross eventually transferred its blood and plasma services to<br />
the newly founded “Canadian Blood Services- CBS” (and Héma-Québec for th<strong>is</strong> latter<br />
prov<strong>in</strong>ce).<br />
Canadian Reflection on the ethical framework<br />
As mentioned above, the Krever Comm<strong>is</strong>sion of Inquiry conducted an <strong>in</strong>-depth analys<strong>is</strong><br />
of the whole donation system and <strong>is</strong>sued key statements (1997) on the pr<strong>in</strong>ciples that<br />
must underp<strong>in</strong> the future Canadian donation system (the follow<strong>in</strong>g po<strong>in</strong>ts are official<br />
statements):<br />
• “Donors of blood and plasma should not be paid, except <strong>in</strong> rare<br />
circumstances”<br />
• “Significant efforts must be made to ensure that blood products used <strong>in</strong><br />
Canada are made from unpaid donors”<br />
• “Plasma must be collected <strong>in</strong> sufficient quantities <strong>in</strong> Canada to meet<br />
domestic needs for blood products”<br />
• “Safety should be paramount”
<strong>KCE</strong> Reports 120 Plasma 109<br />
Follow<strong>in</strong>g these pr<strong>in</strong>ciples, gratuity of donation rema<strong>in</strong>ed untouched but security and<br />
quantitative aspects of plasma supply were also underl<strong>in</strong>ed. However, further pr<strong>in</strong>ciples<br />
also had to be taken <strong>in</strong>to account as set out by the Found<strong>in</strong>g Memorandum of<br />
Understand<strong>in</strong>g (1997):<br />
• Ensur<strong>in</strong>g access to a safe, secure and affordable supply of blood, blood<br />
products and alternatives, and supports their appropriate use.<br />
• Address<strong>in</strong>g <strong>in</strong>ventory imbalances (shortages / surpluses) to m<strong>in</strong>imize<br />
waste and ensure adequate supply<br />
• Consider<strong>in</strong>g dec<strong>is</strong>ion mak<strong>in</strong>g <strong>in</strong> a health r<strong>is</strong>k management framework<br />
which places on an equal foot<strong>in</strong>g the three critical elements of cost,<br />
benefit and r<strong>is</strong>k.<br />
<strong>The</strong>refore the newly founded donation system – ie the Canadian Blood Services to<br />
which the Red Cross donation activities were transferred – had to pursue several goals<br />
<strong>in</strong> the same time:<br />
• Ensur<strong>in</strong>g blood safety, which <strong>is</strong> of paramount importance consider<strong>in</strong>g the<br />
Canadian h<strong>is</strong>torical background. More generally it <strong>is</strong> an objective as such<br />
for any country.<br />
• Improv<strong>in</strong>g level of self-sufficiency <strong>is</strong> also an objective as such, from a public<br />
health and from a political po<strong>in</strong>t of view.<br />
• Increas<strong>in</strong>g volume of domestic donation for blood and plasma, which <strong>is</strong><br />
strongly connected <strong>with</strong> the previous po<strong>in</strong>t.<br />
• Ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g gratuity of donation, as a key ethical option.<br />
• Reduc<strong>in</strong>g r<strong>is</strong>k of supply d<strong>is</strong>ruption (especially <strong>in</strong> the field of IVIG) to avoid<br />
any danger for patients’ safety.<br />
Today’s situation of Canada <strong>in</strong> terms of IVIG self-sufficiency:<br />
In 2008-2009, Canada will be about:<br />
• 28% sufficient <strong>in</strong> IVIG (made from Canadian Plasma)<br />
• 72% of the IVIG d<strong>is</strong>tributed to Canadian hospitals comes from plasma<br />
collected commercially <strong>in</strong> the US<br />
<strong>The</strong>refore, Canada has to face two thorny problems simultaneously: security (as<br />
described above) but also a poor level of self-sufficiency, and thus possible d<strong>is</strong>ruption <strong>in</strong><br />
plasma (especially IVIG) supply. Once aga<strong>in</strong> th<strong>is</strong> situation <strong>is</strong> quite close to the Belgian<br />
one.<br />
Th<strong>is</strong> situation ra<strong>is</strong>ed several questions: the adequate of national self-sufficiency , the<br />
ways and means to reach th<strong>is</strong> level of self-sufficiency.<br />
Canadian strategy<br />
At the end of the reflection process, the official target of 100% Self-sufficiency through<br />
domestic collection and supply was eventually abandoned for Canadian Blood Services<br />
for the follow<strong>in</strong>g reasons:<br />
• It would require huge <strong>in</strong>vestments (18 new plasma centres <strong>with</strong><strong>in</strong> the next<br />
7 years)<br />
• It would not be cost efficient as Canadian production costs rema<strong>in</strong> much<br />
higher than the US ones.<br />
• It <strong>is</strong> not scientifically justified <strong>in</strong> terms of blood safety<br />
For all the reasons mentioned above, the official self-sufficiency target has been rev<strong>is</strong>ed<br />
downwards to 40%. A wide range of options had been orig<strong>in</strong>ally considered to close<br />
th<strong>is</strong> gap (28% to 40%): ra<strong>is</strong><strong>in</strong>g the level of domestic collection, improv<strong>in</strong>g processes,<br />
etc… Today’s Canadian strategy can thus be described as a “sufficiency aimed at<br />
optimally reduc<strong>in</strong>g r<strong>is</strong>k of IVIG supply d<strong>is</strong>ruption”. In practice it can be described as a<br />
“policy-mix”. In practice, several measures were implemented <strong>in</strong> the same time:<br />
• Improvement of collection methodology
110 Plasma <strong>KCE</strong> Reports 120<br />
Key po<strong>in</strong>ts<br />
• Re<strong>in</strong>troduction of source plasma collection at some sites, when required<br />
• Increased volume per collection<br />
• Usage of platelet additive solutions<br />
• Improvement of fractionation capacities: seek<strong>in</strong>g to have two<br />
fractionators licensed for Canadian plasma<br />
• <strong>The</strong>re <strong>is</strong> no universal def<strong>in</strong>ition of “self-sufficiency” but all selected countries<br />
have conducted an <strong>in</strong>-depth reflection on th<strong>is</strong> concept, <strong>in</strong> connection <strong>with</strong><br />
other subjects.<br />
• All selected countries have set up a monitor<strong>in</strong>g system of self-sufficiency<br />
ratios, or at least a centralized data collection on the subject.<br />
• Clear connection between self-sufficiency and remuneration <strong>is</strong>sues must be<br />
born <strong>in</strong> m<strong>in</strong>d.<br />
• Australian policy <strong>is</strong> probably the most comprehensive policy as it has<br />
establ<strong>is</strong>hed a close connection between th<strong>is</strong> dimension and all related <strong>is</strong>sues<br />
<strong>with</strong><strong>in</strong> the framework of the National Blood Authority, which covers all<br />
aspects of blood and plasma supply.<br />
• A short synthetic table of foreign policies <strong>in</strong> d<strong>is</strong>played <strong>in</strong> the table below.<br />
Table 45: Summary<br />
Germany France Canada Australia<br />
Ethical<br />
F<strong>in</strong>ancial<br />
Non-<br />
Non-<br />
Nonframework<br />
Compensation<br />
allowed (Max:25€)<br />
to collector’s<br />
d<strong>is</strong>cretion<br />
Remunerated Remunerated Remunerated<br />
Collection Free Competition: EFS monopoly Canada Blood Red Cross<br />
Red Cr.,Private Delivery targets Service monopoly<br />
to LFB monopoly<br />
Fractionation Several <strong>in</strong>stitutions LFB Monopoly Two<br />
CSL Ltd<br />
on fraction. of fractionators Monopoly on<br />
EFS plasma (but expected around fractionation and<br />
no monopoly on 2014 sales (import if<br />
sales)<br />
un<strong>available</strong>)<br />
Self-Sufficiency Self-Sufficiency LFB Turnover Official def<strong>in</strong>ition Official def<strong>in</strong>ition<br />
Approach<br />
national ratios<br />
ratio<br />
Self-Sufficiency Regulatory data Rout<strong>in</strong>e and Rout<strong>in</strong>e and N.B.A.:<br />
follow-up<br />
collection compulsory data compulsory data All self-sufficiency<br />
Public annual<br />
<strong>report</strong>s<br />
collection collection aspects<br />
Self-Sufficiency Policy mix Policy mix Policy mix NBA policy:<br />
strategy<br />
Increas.collection Increas<strong>in</strong>g Increas<strong>in</strong>g All aspects:<br />
(demo. approach) collection collection, collection ,<br />
and fractionation Increas<strong>in</strong>g LFB- fractionation fractionation,<br />
capacity ; control of fractionation capacity ; contract <strong>with</strong><br />
consumption capacity ; control control of CSL Ltd and<br />
of consumption consumption consumption
<strong>KCE</strong> Reports 120 Plasma 111<br />
4.3 HOW TO STAY OR BECOME SELF SUFFICIENT<br />
<strong>The</strong>re <strong>is</strong> no answer to the question of self sufficiency <strong>in</strong> terms of figures <strong>in</strong> th<strong>is</strong> <strong>report</strong>.<br />
Th<strong>is</strong> <strong>is</strong> a political choice to be made <strong>in</strong> the light of the r<strong>is</strong>k-aversion of Belgian dec<strong>is</strong>ionmakers.<br />
<strong>The</strong> fundamental question <strong>is</strong> to determ<strong>in</strong>e the desired level of <strong>in</strong>dependence.<br />
Supply security considerations must govern th<strong>is</strong> choice. For th<strong>is</strong> we need to determ<strong>in</strong>e<br />
whether the trend <strong>in</strong> demand <strong>in</strong> countries deemed to have a high level of consumption<br />
could lead to a shortage of derivative products. Such a r<strong>is</strong>k could also result if the<br />
collection <strong>in</strong> these countries no longer covered their own requirements for derivatives.<br />
Price levels and volatility are another r<strong>is</strong>k factor to be considered. Be<strong>in</strong>g more<br />
dependent on foreign supplies could mean suffer<strong>in</strong>g substantial price variations, which<br />
are the first adjustment variable affect<strong>in</strong>g variations <strong>in</strong> supply and demand. Beyond a<br />
certa<strong>in</strong> level of shortage, there are fears that simple purchas<strong>in</strong>g power may no longer be<br />
enough.<br />
To m<strong>in</strong>im<strong>is</strong>e the cost of production for Belgian plasma derivatives for a given level of<br />
coverage, we could strive for:<br />
• A reduction <strong>in</strong> the demand for these products<br />
• An <strong>in</strong>creas<strong>in</strong>g of the capacities of collect<strong>in</strong>g plasma<br />
• Transparency and better control of the supply of derivatives<br />
4.3.1 Strategies to decrease IG use: lessons learned<br />
4.3.1.1 Experience from other countries<br />
Several countries, confronted to <strong>in</strong>creased IG consumption, shortage or r<strong>is</strong>k of<br />
shortage, and grow<strong>in</strong>g cost, have publ<strong>is</strong>hed the measures that they planned or have<br />
undertaken to improve the supply and demand balance.(Hume, Anderson, TMR 2007;<br />
Constant<strong>in</strong>e 2007, UK DOH National Immunoglobul<strong>in</strong> Database Update j , Australia k ).<br />
However, very few studies have evaluated the impact of these measures.<br />
Table 45 summarized the overall strategies used <strong>in</strong> different countries. We focus here<br />
on the reduction of IG use. <strong>The</strong> ma<strong>in</strong> measures taken or proposed <strong>in</strong>clude:<br />
Classify<strong>in</strong>g <strong>in</strong>dications <strong>in</strong> priority groups for IG treatment<br />
A l<strong>is</strong>t of <strong>in</strong>dications for which IG can be used has been def<strong>in</strong>ed <strong>in</strong> most countries. In<br />
addition, a few countries such as France, the UK and Australia, that experienced<br />
shortage (or its r<strong>is</strong>k), have decided on prioritization of IG use and classified <strong>in</strong>dications<br />
(labeled or not) <strong>in</strong>to groups or higher and lower priority. However, th<strong>is</strong> classification<br />
has been applied <strong>in</strong> many different ways:<br />
• In Australia, very clear categories for priority sett<strong>in</strong>g have been<br />
establ<strong>is</strong>hed: 1. Conditions for which IG has an establ<strong>is</strong>hed therapeutic<br />
role; 2. conditions for which IVIg has an emerg<strong>in</strong>g therapeutic role; 3.<br />
conditions for which IVIg are used <strong>in</strong> exceptional circumstances; 4.<br />
conditions for which IVIg use <strong>is</strong> not <strong>in</strong>dicated.<br />
• In the UK, three well def<strong>in</strong>ed categories have been establ<strong>is</strong>hed, coded by<br />
colour (red, blue and grey), to facilitate the cl<strong>in</strong>ician understand<strong>in</strong>g of the<br />
level of priority.<br />
• In France, the drug agency (AFSSAPS) def<strong>in</strong>ed 7 groups, us<strong>in</strong>g different<br />
levels of priority, d<strong>is</strong>t<strong>in</strong>gu<strong>is</strong>h<strong>in</strong>g labeled and non labeled <strong>in</strong>dications, <strong>with</strong><br />
no clear rationale; the priority of each group of <strong>in</strong>dications above the<br />
others <strong>is</strong> not always clear. l<br />
j Source: National Immunoglobul<strong>in</strong> Database Update. DOH.<br />
http://www.dh.gov.uk/en/Publicationsandstat<strong>is</strong>tics/Publications/PublicationsPolicyAndGuidance/DH_09767<br />
0<br />
k Source: Criteria for the cl<strong>in</strong>ical use of <strong>in</strong>travenous immunoglobul<strong>in</strong> <strong>in</strong> Australia. Australian Health<br />
M<strong>in</strong><strong>is</strong>ters’ Conference. December 2007.<br />
l Source: AFSSAPS: http://www.afssaps.fr/Infos-de-securite/Autres-mesures-de-securite/Proposition-dehierarch<strong>is</strong>ation-des-<strong>in</strong>dications-des-immunoglobul<strong>in</strong>es-huma<strong>in</strong>es-<strong>in</strong>trave<strong>in</strong>euses-IgIV-en-situation-detension-forte-sur-les-approv<strong>is</strong>ionnements-pour-le-marche-franca<strong>is</strong>2
112 Plasma <strong>KCE</strong> Reports 120<br />
A difficulty <strong>with</strong> th<strong>is</strong> system <strong>is</strong> that the rationale beh<strong>in</strong>d the choice of classification <strong>is</strong> not<br />
always stated or made clear, the categories need to be regulary updated, and the<br />
application of th<strong>is</strong> priorization <strong>is</strong> not always described: <strong>in</strong> the absence of shortage,<br />
should a patient from a last priority group receive IG or not?<br />
Establ<strong>is</strong>h<strong>in</strong>g guidel<strong>in</strong>es and criteria for use<br />
<strong>The</strong> Canada, Australia and the UK have <strong>in</strong>vested important resources and time to<br />
produce guidel<strong>in</strong>es, based on evidence and consensus sessions among experts:<br />
• <strong>The</strong> Canadian Blood Services and the National Adv<strong>is</strong>ory Committee on<br />
Blood and Blood Products began <strong>in</strong> 2004 to develop detailed and evidence<br />
based guidel<strong>in</strong>es for the use of IVIG <strong>in</strong> hematological and neurological<br />
conditions. <strong>The</strong> results of th<strong>is</strong> work are publ<strong>is</strong>hed <strong>in</strong> a supplement of the<br />
journal Transfusion Medic<strong>in</strong>e Reviews <strong>in</strong> 2007. 18-21<br />
• In Australia, the “Criteria for the Cl<strong>in</strong>ical Use of Intravenous<br />
Immunoglobul<strong>in</strong>” was developed <strong>in</strong> 2004-2007, based on evidence<br />
identified through systematic reviews of the literature and the op<strong>in</strong>ions of<br />
cl<strong>in</strong>ical experts. <strong>The</strong> cl<strong>in</strong>ical criteria are conta<strong>in</strong>ed <strong>with</strong><strong>in</strong> condition proforma<br />
and have been set out to cover four major <strong>is</strong>sues: l<strong>is</strong>t of <strong>in</strong>dications<br />
for IG use; qualify<strong>in</strong>g criteria, exclusion criteria and review criteria. 22<br />
• In the UK, as part of the “Demand Management Programme”, National<br />
Cl<strong>in</strong>ical Guidel<strong>in</strong>es for the appropriate use of IVIG have been produced<br />
based on <strong>available</strong> evidence and expert op<strong>in</strong>ion <strong>in</strong> the period 2006-2008.<br />
After literature review and expert review, <strong>in</strong>terested bodies reg<strong>is</strong>tered as<br />
“Stakeholders” provided comments on the document. Regular updates<br />
are ensured, at least yearly.<br />
• In France, the CEDIT has <strong>is</strong>sued recommendations that are widely used.<br />
National guidel<strong>in</strong>es are also expected at national level, based on the<br />
CEDIT work. l<br />
• In Australia, the concept of ‘criteria for use’ constitutes a more directive<br />
framework for dec<strong>is</strong>ions about the use of a particular treatment, as<br />
opposed to the concept of “guidel<strong>in</strong>es” that usually refer to the<br />
management of conditions rather than to the use of specific therapeutic<br />
products such as IVIG. 22 <strong>The</strong> latter term has been selected to describe the<br />
circumstances, based on evidence and cl<strong>in</strong>ical experience, under which the<br />
cl<strong>in</strong>ical use of IVIG <strong>is</strong> considered appropriate <strong>in</strong> Australia.<br />
It should be noted that <strong>in</strong> each country, the production of guidel<strong>in</strong>es has cost a<br />
considerable amount of time (around 3 years), <strong>in</strong> literature review and negotiations <strong>with</strong><br />
experts and stakeholders. Guidel<strong>in</strong>es also need to be regularly updated.<br />
Only one study assessed the impact of guidel<strong>in</strong>es on IG use. In the Atlantic region of<br />
Canada, a study compared IVIG use between a basel<strong>in</strong>e phase (2003-2004) before<br />
guidel<strong>in</strong>e use, and after implementation of “optimization tools” (2005). In the second<br />
period, they found a 7% decrease <strong>in</strong> IG use, contrast<strong>in</strong>g <strong>with</strong> the previous annual r<strong>is</strong>es<br />
(7% <strong>in</strong> 2002-03 to 2003-04 and 10% from 2003-04 to 2004-05). 146<br />
Limit<strong>in</strong>g prescription of IG to specific groups<br />
In the UK under the “Comm<strong>is</strong>sion<strong>in</strong>g Policy”, all immunoglobul<strong>in</strong> must be prescribed by<br />
a consultant <strong>with</strong> special<strong>is</strong>t knowledge of its use; no GP may prescribe. Prescribers must<br />
monitor future communications on any r<strong>is</strong>ks to supply and understand the mechan<strong>is</strong>m<br />
for handl<strong>in</strong>g any shortages.
<strong>KCE</strong> Reports 120 Plasma 113<br />
Improv<strong>in</strong>g awareness of cl<strong>in</strong>icians and patients<br />
Two countries mention the <strong>in</strong>formation to cl<strong>in</strong>icians <strong>in</strong> their plan: France planned to<br />
implement <strong>in</strong>formation to pharmac<strong>is</strong>ts and prescribe. m In the UK, the demand<br />
management programme states that patients should be fully <strong>in</strong>formed of arrangements<br />
for their treatment and the implications of any supply shortages.<br />
Improv<strong>in</strong>g evaluation of use and monitor<strong>in</strong>g<br />
Several countries have <strong>in</strong>itiated a reg<strong>is</strong>try for patients under IG treatment or a national<br />
database. However, no further <strong>in</strong>formation <strong>is</strong> <strong>available</strong> on the application of these<br />
systems and its impact.<br />
• In the UK, the “Comm<strong>is</strong>sion<strong>in</strong>g Policy” stated that all patients should be<br />
logged <strong>with</strong> the national immunoglobul<strong>in</strong> database and their data provided.<br />
All patients receiv<strong>in</strong>g long-term immunoglobul<strong>in</strong> should be reviewed<br />
annually to assess d<strong>is</strong>ease activity and determ<strong>in</strong>e the best therapeutic<br />
option.<br />
• In Australia, <strong>The</strong> national Blood Agency has also <strong>in</strong>cluded <strong>in</strong> its plans the<br />
development of a system to collect data that will provide <strong>in</strong>formation<br />
about the effectiveness of IVIG therapy. 22 Th<strong>is</strong> <strong>in</strong>formation was planned to<br />
be assessed by experts and used to <strong>in</strong>form future reviews of th<strong>is</strong> “criteria<br />
for use”. However, we have no <strong>in</strong>formation on whether th<strong>is</strong> strategy has<br />
been effectively implemented.<br />
• In some Canadian regions, such as the Atlantic Prov<strong>in</strong>ces, a work<strong>in</strong>g group<br />
was created to monitor IVIG use and a reg<strong>is</strong>try of IVIG was created.<br />
Assessment of <strong>in</strong>dication appropriateness <strong>is</strong> determ<strong>in</strong>ed based on<br />
guidel<strong>in</strong>es, and feedback <strong>report</strong>s are d<strong>is</strong>tributed to stakeholders.<br />
• France launched a data collection on IVIG consumption per <strong>in</strong>dication, to<br />
evaluate the appropriateness of IVIG use <strong>in</strong> cl<strong>in</strong>ical practice.<br />
Other lessons learned<br />
In the US, a shortage <strong>in</strong> IVIG occurred <strong>in</strong> 1997. 198 <strong>The</strong> authorities <strong>in</strong>formed the medical<br />
community but did not respond to the shortage <strong>in</strong> a timely of effective manner. Instead,<br />
it took a passive role, leav<strong>in</strong>g IVIG manufacturers and d<strong>is</strong>tributors, health care<br />
<strong>in</strong>stitutions, and cl<strong>in</strong>icians to fend for themselves. Regulatory steps and<br />
recommendations were made but after prolonged debate. No updated national<br />
recommendation on appropriate use of IVIG has been <strong>is</strong>sued. Institutions have<br />
developed their own guidel<strong>in</strong>es to restrict the use of IVIG for off-label conditions.<br />
Guidel<strong>in</strong>es varied substantially across <strong>in</strong>stitutions. Consequently IVIG was d<strong>is</strong>tributed at<br />
often extremely elevated prices and not accord<strong>in</strong>g to the criteria of need and urgency.<br />
<strong>The</strong> shortage likely had an uneven impact on patients, based on the relative market<br />
strength of the health care <strong>in</strong>stitutions <strong>in</strong> which they received care and the <strong>in</strong>dividual<br />
patient's ability to absorb the <strong>in</strong>creas<strong>in</strong>g out-of-pocket costs of scarce IVIG.<br />
Overall impact of strategies to reduce IG use<br />
Several countries are conduct<strong>in</strong>g audits <strong>in</strong> hospitals (eg. the UK and the US) but few<br />
countries have evaluated the overall impact of their set of strategies on IG<br />
consumption.<br />
In France, the last <strong>available</strong> consumption data from the “Hôpitaux de Par<strong>is</strong>”, follow<strong>in</strong>g<br />
the CEDIT guidel<strong>in</strong>es and prioritization, date from 2005 and show an <strong>in</strong>crease <strong>in</strong> IVIG<br />
use (+18%). Th<strong>is</strong> <strong>in</strong>crease <strong>is</strong> however lower than the <strong>in</strong>crease observed at national level<br />
(+24%). n<br />
m http://cedit.aphp.fr/servlet/siteCedit?Dest<strong>in</strong>ation=reco&numArticle=02.02/Re4/07<br />
n Recommandation 2007 relative à l’util<strong>is</strong>ation des immunoglobul<strong>in</strong>es huma<strong>in</strong>es normales (<strong>in</strong>trave<strong>in</strong>euses<br />
polyvalentes (IgIV) et sous-cutanées) avec bilan des consommations en 2005 à l’AP-HP, accessed on<br />
http://cedit.aphp.fr/servlet/siteCedit?Dest<strong>in</strong>ation=reco&numArticle=02.02/Re4/07
114 Plasma <strong>KCE</strong> Reports 120<br />
In the UK, prelim<strong>in</strong>ary analys<strong>is</strong> of the national immunoglobul<strong>in</strong> database (first 9 months)<br />
has been publ<strong>is</strong>hed but there <strong>is</strong> no compar<strong>is</strong>on pre and post-<strong>in</strong>tervention. o<br />
Table 46: Summary of measures proposed to prevent or control IG shortage<br />
<strong>in</strong> 6 countries<br />
Country, Reduce use Improve supply Improve evaluation /<br />
period<br />
monitor<strong>in</strong>g of<br />
use/supply<br />
France (AFFSAPS Guidel<strong>in</strong>es on IVIG use Not covered Data collection on IG<br />
and CEDIT, Priority l<strong>is</strong>ts for <strong>in</strong>dications<br />
use per <strong>in</strong>dication group<br />
1991-2008) (7 categories)<br />
Information for prescribers<br />
Canada, 2004-07 Detailed guidel<strong>in</strong>es on IVIG Not covered Evaluation of IG use per<br />
use<br />
<strong>in</strong>dication (per region)<br />
<strong>The</strong> UK, Detailed guidel<strong>in</strong>es<br />
Not covered National IG database to<br />
Comm<strong>is</strong>sion<strong>in</strong>g Priority l<strong>is</strong>t (red, blue, grey)<br />
reg<strong>is</strong>ter each patient<br />
policy<br />
Fund<strong>in</strong>g for IG l<strong>in</strong>ked to data<br />
prov<strong>is</strong>ion<br />
Prescription limited to<br />
special<strong>is</strong>t (no GP)<br />
Audit of trusts<br />
Australia Limit <strong>in</strong>dications and Increas<strong>in</strong>g the manufacture <strong>in</strong><br />
rationalize use: criteria for Australia<br />
use<br />
Import<strong>in</strong>g IVIg from overseas<br />
Priority l<strong>is</strong>ts (4 groups) suppliers<br />
US, 1997 198 None. Improve appropriate Encouraged producers to Monthly data from<br />
use at local level.<br />
<strong>in</strong>crease supplies<br />
producers, but not<br />
effective<br />
4.3.1.2 Experiences from Belgium<br />
In Belgium, the Health Council (CSS/HGR) has developed guidel<strong>in</strong>es for the use of red<br />
blood cells <strong>in</strong> January 2007, p and for the use of frozen plasma <strong>in</strong> 2007. q After the<br />
guidel<strong>in</strong>es were <strong>is</strong>sued, the consumption of both products decreased. Guidel<strong>in</strong>es on the<br />
use of immunoglobul<strong>in</strong>s are currently be<strong>in</strong>g developed at the Health Council and should<br />
be <strong>available</strong> <strong>in</strong> the near future.<br />
In the late n<strong>in</strong>eties, the BIOMED project used the technique of “benchmark<strong>in</strong>g”<br />
(restitution of data document<strong>in</strong>g <strong>in</strong>dividual performance and compar<strong>is</strong>on of these data<br />
<strong>with</strong> the group average or <strong>with</strong> external references) to impact on the red cell<br />
transfusion. After the thorough restitution of data and <strong>with</strong>out the <strong>in</strong>troduction of new<br />
regulations or guidel<strong>in</strong>es, time was given to the participants to improve their practices,<br />
by us<strong>in</strong>g the strategies they deemed most appropriate for their local situation. Data<br />
collected 2.5 years later showed that the use of blood and blood products decreased<br />
markedly: a reduction of the order of 20%-25% was achieved over a 2 to 3 year period.<br />
<strong>The</strong> reduction of red cell transfusion has been obta<strong>in</strong>ed <strong>with</strong>out any change <strong>in</strong><br />
hematocrits at any time dur<strong>in</strong>g hospital stay for any surgical procedure. 199<br />
o National Immunoglobul<strong>in</strong> Database Update. April 2009.<br />
http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_097668.pdf<br />
p CSS/HGR. AVIS DU CONSEIL SUPERIEUR D’HYGIENE. Guide d’<strong>in</strong>dications transfusionnelles pour les<br />
globules rouges. 10 janvier 2007 CSH n° 8085.<br />
https://portal.health.fgov.be/pls/portal/docs/PAGE/INTERNET_PG/HOMEPAGE_MENU/ABOUTUS1_MENU/INSTITU<br />
TIONSAPPARENTEES1_MENU/HOGEGEZONDHEIDSRAAD1_MENU/ADVIEZENENAANBEVELINGEN1_MENU/A<br />
DVIEZENENAANBEVELINGEN1_DOCS/CSH8085_INDICATIONS_TRANSFUSIONNELLES_GLOBULES_ROUGES<br />
_FR.PDF<br />
q AVIS DU CONSEIL SUPERIEUR D’HYGIENE. Guide d’<strong>in</strong>dications transfusionnelles pour le plasma fra<strong>is</strong><br />
congelé. 7 février 2007. CSH n° 8157
<strong>KCE</strong> Reports 120 Plasma 115<br />
4.3.2 Strategies to decrease IG use: what could be applied <strong>in</strong> Belgium<br />
Overall, the follow<strong>in</strong>g measures could be considered for implementation <strong>in</strong> Belgium:<br />
• Def<strong>in</strong><strong>in</strong>g a l<strong>is</strong>t of <strong>in</strong>dications for IG use, based on <strong>available</strong> evidence and<br />
expert panels. A l<strong>is</strong>t of reimbursed <strong>in</strong>dications <strong>is</strong> already def<strong>in</strong>ed and<br />
regularly updated <strong>in</strong> Belgium, but several <strong>in</strong>dications which have shown a<br />
benefit based on evidence are not <strong>in</strong>cluded (see Chapter II). It <strong>is</strong> unclear<br />
how these d<strong>is</strong>eases are currently treated <strong>in</strong> Belgium, and it <strong>is</strong> possible that<br />
significant amounts of IG are given under compassionate use.<br />
• Classify<strong>in</strong>g these <strong>in</strong>dications <strong>in</strong> priority groups for IG treatment (high<br />
priority, low priority). However, establ<strong>is</strong>h<strong>in</strong>g these priorities must be<br />
based on evidence and requires consensus and regular update. <strong>The</strong><br />
application of these classifications <strong>in</strong> practice (how to treat these patients)<br />
<strong>is</strong> not always clear. In some countries, patients from the low priority<br />
group may be treated <strong>with</strong> IG unless there <strong>is</strong> a IG shortage.<br />
• Establ<strong>is</strong>h<strong>in</strong>g guidel<strong>in</strong>es and criteria for use. In countries where guidel<strong>in</strong>es<br />
have been developed as a response to IG shortage, th<strong>is</strong> has requested<br />
important resources <strong>in</strong> terms of persons, time required (2-3 years) and<br />
expert panels and consensus. In Belgium, the Health Council <strong>is</strong> <strong>in</strong> the<br />
process of develop<strong>in</strong>g guidel<strong>in</strong>es that should be <strong>is</strong>sued at end of 2009. <strong>The</strong><br />
Belgian experience <strong>with</strong> similar guidel<strong>in</strong>es (for the use of red cell<br />
transfusion and fresh frozen plasma) has shown positive results <strong>in</strong> terms<br />
of practice and reduction of consumption. It should be noted that<br />
guidel<strong>in</strong>es also need to be regularly updated.<br />
• Limit<strong>in</strong>g prescription of IG to specific groups of prescribers. In Belgium, a<br />
high IG amount <strong>is</strong> prescribed by ass<strong>is</strong>tants <strong>in</strong> specialization (<strong>in</strong> academic<br />
hospitals) and a IG amounts are sometimes prescribed by peripheral<br />
hospitals for specialties that should <strong>in</strong> pr<strong>in</strong>ciple not use significant<br />
amounts. An option would be to limit the <strong>in</strong>itiation and superv<strong>is</strong>ion of IG<br />
treatment to a number of “IG reference centres”, follow<strong>in</strong>g the same<br />
model than the centres for haemophilia centres or for bone marrow<br />
transplants, through convention <strong>with</strong> the INAMI/RIZIV.<br />
• Improv<strong>in</strong>g awareness of cl<strong>in</strong>icians and patients. In Belgium, cl<strong>in</strong>icians have<br />
access to evidence based literature, but receive no direct <strong>in</strong>formation on<br />
the cost of IG and the r<strong>is</strong>k of shortage; good <strong>in</strong>formation on these aspects<br />
could help decrease the prescription of IG for the <strong>in</strong>dications <strong>in</strong> which no<br />
benefit has been proven.<br />
• Improv<strong>in</strong>g evaluation of use and monitor<strong>in</strong>g. A reg<strong>is</strong>try for patients under<br />
long term IG treatment or a national data bas<strong>is</strong> could be a tool to allow a<br />
better monitor<strong>in</strong>g of IG use and assess <strong>in</strong>dication appropriateness based<br />
on guidel<strong>in</strong>es. Th<strong>is</strong> data collection could also be used for a<br />
“benchmark<strong>in</strong>g” method, which has been successfully used for red cell<br />
transfusion <strong>in</strong> Belgium <strong>in</strong> the late n<strong>in</strong>eties (see above).<br />
4.3.3 Increas<strong>in</strong>g the capacities of collect<strong>in</strong>g plasma<br />
A major part of the cost of collect<strong>in</strong>g plasma doubtless stems from the difficulty <strong>in</strong><br />
f<strong>in</strong>d<strong>in</strong>g donors and the efforts made to seek out and persuade them. It seems selfevident<br />
that a greater number of donors would allow economies of scale <strong>in</strong> the<br />
collection of plasma and might result <strong>in</strong> collect<strong>in</strong>g more than <strong>is</strong> required to cover the<br />
needs of Belgium as def<strong>in</strong>ed by the concept of self-sufficiency <strong>in</strong> the Royal Decree of 18<br />
June 1998. <strong>The</strong> Red Cross could then export at a market price higher than the price it<br />
sells to the CAF-DCF. <strong>The</strong> subsidies could then be reduced accord<strong>in</strong>gly.
116 Plasma <strong>KCE</strong> Reports 120<br />
To attract a larger number of donors it would not be allowed to resort to pay<strong>in</strong>g for<br />
the blood or plasma collected. <strong>The</strong> pr<strong>in</strong>ciple of voluntary donation free of charge<br />
constitutes the essential ethical framework for all European countries. But the likes of<br />
advert<strong>is</strong><strong>in</strong>g campaigns, benefits <strong>in</strong> k<strong>in</strong>d and tax breaks could be considered and set up at<br />
a cost probably lower than that of the subsidies given to the Red Cross to arrive at the<br />
same result.<br />
In most European countries (see part 1 of th<strong>is</strong> <strong>report</strong>), <strong>in</strong> particular France and<br />
Germany, it clearly emerges that a major effort has been made <strong>in</strong> recent years aimed at<br />
the priority age groups, namely 18-25 years, usually <strong>in</strong>volv<strong>in</strong>g a close partnership <strong>with</strong><br />
the schools and universities concerned. More generally, communication campaigns us<strong>in</strong>g<br />
a wide variety of media have been implemented, pay<strong>in</strong>g special attention to manag<strong>in</strong>g<br />
the donors over time <strong>in</strong> order to improve their loyalty.<br />
Germany has given special thought to the geographical location of plasma collection<br />
centres <strong>in</strong> relation to the profile of potential donors, <strong>in</strong> particular <strong>in</strong> terms of age.<br />
It <strong>is</strong> nevertheless necessary to reflect on the different treatment currently given to<br />
private sector and public sector employees. <strong>The</strong> quest for equal treatment of all<br />
donors could lead the authority to reduce the benefits, <strong>in</strong> terms of days of leave,<br />
granted to members of the public services and make donat<strong>in</strong>g blood and plasma totally<br />
charitable. Th<strong>is</strong> would open up the possibility of reconvert<strong>in</strong>g the result<strong>in</strong>g sav<strong>in</strong>gs <strong>in</strong>to<br />
campaigns promot<strong>in</strong>g blood and plasma donation.<br />
F<strong>in</strong>ally, a wide-rag<strong>in</strong>g debate <strong>in</strong> terms of demographic prospects has taken place <strong>in</strong><br />
Germany <strong>in</strong> order to emphas<strong>is</strong>e the importance of th<strong>is</strong> dimension for the future<br />
sat<strong>is</strong>faction of the needs of the population. Th<strong>is</strong> debate will make possible better<br />
forecast<strong>in</strong>g of the donor population.<br />
4.3.4 Transparency and better control of the supply of derivatives<br />
As we have already seen, it seems that the quantities of derivatives sold <strong>in</strong> Belgium by<br />
the CAF-DCF are below what the firm should be able to produce if she were us<strong>in</strong>g all<br />
the quantity of plasma sold to it by the Red Cross. <strong>The</strong>re are various possible<br />
explanations for th<strong>is</strong> situation, but the <strong>in</strong>formation <strong>available</strong> does not enable us to<br />
identify the correct ones, largely because of the complexity of the market and of the<br />
fractionation circuit implemented via agreements <strong>with</strong> foreign firms, the terms of which<br />
are not known to us.<br />
Given the <strong>in</strong>direct subsidy granted to the CAF-DCF via the below-market price at<br />
which plasma <strong>is</strong> sold to it, it would make sense to have public control over the terms<br />
and costs of its agreements <strong>with</strong> foreign partners.<br />
Relations between the organ<strong>is</strong>ations responsible for collection and fractionation are a<br />
delicate and complex subject <strong>in</strong> all western countries.<br />
France and Germany first sought to ensure standard<strong>is</strong>ation of the technical collection<br />
process (<strong>in</strong> particular the volume of <strong>in</strong>dividual donations) <strong>in</strong> order to improve the<br />
volumes effectively delivered to the fractionation firms, <strong>with</strong> the same number of<br />
donors.<br />
Of all the countries studied, it <strong>is</strong> <strong>with</strong>out doubt <strong>in</strong> Australia where the debate on<br />
contractual relations between the fractionator and the other actors <strong>in</strong>volved has gone<br />
furthest. <strong>The</strong> contract b<strong>in</strong>d<strong>in</strong>g the National Blood Authority and the fractionator (CSL-<br />
Ltd) covers all aspects of the relationship between the two partners, <strong>in</strong>clud<strong>in</strong>g the<br />
f<strong>in</strong>ancial, log<strong>is</strong>tical, technical (health security, r<strong>is</strong>k management) and legal dimensions<br />
(ownership clause, appeal jur<strong>is</strong>dictions, etc.). Th<strong>is</strong> contractual relationship also takes<br />
<strong>in</strong>to account that the National Blood Authority <strong>is</strong> responsible for all functions touch<strong>in</strong>g<br />
on the question of the supply and d<strong>is</strong>tribution of blood and plasma products <strong>with</strong><strong>in</strong> the<br />
country.
<strong>KCE</strong> Reports 120 Plasma 117<br />
4.4 CONCLUSIONS<br />
<strong>The</strong> <strong>is</strong>sue of the <strong>in</strong>dependence of supplies of plasma derivatives <strong>is</strong> fundamentally a<br />
political one, and the public authorities must def<strong>in</strong>e the degree of <strong>in</strong>dependence they<br />
w<strong>is</strong>h to achieve and, as a corollary, the degree of <strong>in</strong>security that they are will<strong>in</strong>g to<br />
accept. <strong>The</strong> substance of these choices would then determ<strong>in</strong>e the measures to be<br />
taken <strong>with</strong><strong>in</strong> the three fields of action identified <strong>in</strong> th<strong>is</strong> <strong>report</strong>: plasma collection, the<br />
production of plasma derivatives and the consumption of these derivatives. Each of<br />
these fields concerns different actors that require specific <strong>in</strong>struments <strong>in</strong> order to move<br />
towards the collection of more plasma, more profitable transformation of plasma <strong>in</strong>to<br />
derivatives, and consumption of derivatives more <strong>in</strong> step <strong>with</strong> recogn<strong>is</strong>ed medical<br />
conditions. Ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g or <strong>in</strong>creas<strong>in</strong>g our <strong>in</strong>dependence therefore requires the<br />
application of a comb<strong>in</strong>ation of measures <strong>in</strong> these three fields. However, <strong>in</strong>dependently<br />
of any quest for a specific degree of <strong>in</strong>dependence, it would appear that consumption<br />
that sat<strong>is</strong>fies the rules of good practice, collection at m<strong>in</strong>imum cost and sat<strong>is</strong>factory<br />
yields from the fractionation process are basic requirements. <strong>The</strong> scale of each possible<br />
measure must be l<strong>in</strong>ked to establ<strong>is</strong>hed facts, <strong>in</strong> which respect it <strong>is</strong> important to take <strong>in</strong>to<br />
account the limitations of any scientific study. In th<strong>is</strong> case they concern <strong>in</strong>ternational<br />
prices and certa<strong>in</strong> data relat<strong>in</strong>g to the consumption of derivative products. For each of<br />
these limitations, further studies would make the results more robust, not forgett<strong>in</strong>g<br />
the confidential nature of certa<strong>in</strong> data, which will always be subject to some uncerta<strong>in</strong>ty.<br />
Nevertheless, it <strong>is</strong> not necessary to wait for certa<strong>in</strong>ty regard<strong>in</strong>g every parameter before<br />
tak<strong>in</strong>g the necessary measures.
118 Plasma <strong>KCE</strong> Reports 120<br />
5 APPENDICES<br />
APPENDIX 1: ETHICAL DIMENSION OF<br />
DONATION: QUICK OVERVIEW<br />
REASONS FOR DONATING BLOOD AND PLASMA: EMPIRIC<br />
ANALYSIS<br />
A specific “motivation model” ie a motivation ethical framework has been identified and<br />
recently set out by God<strong>in</strong> <strong>in</strong> one of h<strong>is</strong> most recent articles [God<strong>in</strong> et al “Factors<br />
expla<strong>in</strong><strong>in</strong>g the <strong>in</strong>tention to give blood among the general population Vox Sangu<strong>in</strong><strong>is</strong><br />
(2005) 89, 140-149 et al. 2005] 200 . In th<strong>is</strong> Canadian study (Québec), all these factors<br />
where analyzed both <strong>in</strong> the “never donors” group (ie <strong>in</strong>dividuals who never donated)<br />
and <strong>in</strong> the “ever donors” group (<strong>in</strong>dividuals who donated, at least one).<br />
External variables (<strong>in</strong>dividual and collective alike) are apt to have an impact on 3 types of<br />
ethical factors:<br />
• Attitudes (cognitive attitudes, but also emotional attitudes)<br />
• Accepted norms: perceived behaviour control, moral norms as accepted<br />
<strong>in</strong> a specific country (at a specific time of h<strong>is</strong>tory), and past experience of<br />
donation.<br />
• Controls (self-<strong>in</strong>itiated controls or society-<strong>in</strong>itiated controls)<br />
<strong>The</strong> three ethical factors mentioned above determ<strong>in</strong>e the “<strong>in</strong>tention to donate”, which<br />
turns <strong>in</strong>to actual behaviour (ie actual donation) provided resources are <strong>available</strong> to<br />
perform it.<br />
In both groups - “Ever donors” and “Never donors” – morals norms and perceived<br />
controls appeared as the most important factors.<br />
PRINCIPLES UNDERPINNING BLOOD DONATION<br />
Utilitarian<strong>is</strong>m: do<strong>in</strong>g what <strong>is</strong> good / dec<strong>is</strong>ions are made ow<strong>in</strong>g to the consequences of a<br />
specific behaviour. From a purely practical po<strong>in</strong>t of view, cost/effectiveness (both on the<br />
<strong>in</strong>dividual and social level) reason<strong>in</strong>g <strong>is</strong> the key pr<strong>in</strong>ciple underp<strong>in</strong>n<strong>in</strong>g dec<strong>is</strong>ion-mak<strong>in</strong>g<br />
processes. <strong>The</strong>refore people should donate, regardless of their motives. Blood donation<br />
must be organized <strong>in</strong> such a way that maximizes rentability of donation (<strong>in</strong>centives,<br />
attractive and comfortable framework, etc…).<br />
Duty-Ethics: do<strong>in</strong>g what must be done and motivated by fair <strong>in</strong>tention. Donation <strong>is</strong><br />
send and considered from the po<strong>in</strong>t of view of realization of each <strong>in</strong>dividual’s freedom.<br />
However, each <strong>in</strong>dividual’s behaviour “duty-ethical” behaviour <strong>is</strong> supposed to be<br />
considered and acknowledged as a general rule.<br />
Contract-Ethics: donation can be seen as a part of the whole social contract. <strong>The</strong> latter<br />
can be seen as a cluster of common rules def<strong>in</strong>ed for the same common benefit<br />
(solidarity).<br />
Virtue-Ethics: who can be considered as an “virtuous <strong>in</strong>dividual”. <strong>The</strong> whole concept<br />
of “virtue” <strong>is</strong> applied to the whole <strong>in</strong>dividual and not to specific behaviour or punctual<br />
act. Donation <strong>is</strong> the expression of mutual dependence between people.<br />
In short, and from an “ethical values” po<strong>in</strong>t of view, people must donate blood because:<br />
• It <strong>is</strong> useful<br />
• It <strong>is</strong> a duty<br />
• It <strong>is</strong> the expression of solidarity<br />
• It <strong>is</strong> a proof of virtue
<strong>KCE</strong> Reports 120 Plasma 119<br />
FAVOURING AND HINDERING FACTORS<br />
Given the background mentioned above, favour<strong>in</strong>g and h<strong>in</strong>der<strong>in</strong>g factors have obviously<br />
been identified <strong>in</strong> the very specific field of blood and plasma donation.<br />
Favour<strong>in</strong>g factors:<br />
H<strong>in</strong>der<strong>in</strong>g factors<br />
• Altru<strong>is</strong>m<br />
• Role-identity<br />
• Social rules<br />
• Facilitat<strong>in</strong>g framework (log<strong>is</strong>tics <strong>is</strong>sues) as identified by God<strong>in</strong> et al 2005,<br />
especially short d<strong>is</strong>tance between the potential donor’s home and the<br />
blood donation centre<br />
• Positive effects of the donation for the donor<br />
Perceived negative effect of donation and fears among potential donors about donation<br />
(fear of needles, fear of fa<strong>in</strong>t<strong>in</strong>g experience, etc..)<br />
Log<strong>is</strong>tic problems: long d<strong>is</strong>tance between the donor’s home and the donation centre,<br />
but also lack of <strong>in</strong>timacy.<br />
“Free-rider” behaviour, applied to donation as expla<strong>in</strong>ed by David B. Johnson <strong>in</strong> the<br />
Brit<strong>is</strong>h Journal of Psychology 1982 201 , ie <strong>in</strong>dividual’s reluctance to donate because the<br />
<strong>in</strong>dividual contribution would have no effect no perceptible effect on the overall<br />
prov<strong>is</strong>ion of blood and that the <strong>in</strong>dividual himself cannot be excluded from enjoy<strong>in</strong>g the<br />
benefits of the system (if case of need).<br />
Ma<strong>in</strong> learn<strong>in</strong>gs: people’s reluctance to donate <strong>is</strong> ma<strong>in</strong>ly expla<strong>in</strong>ed by perceived<br />
psychological, physical or practical barriers and obstacles regard<strong>in</strong>g donation (even the<br />
latter have little to do <strong>with</strong> reality). <strong>The</strong>refore donation promotional strategies should<br />
be adapted accord<strong>in</strong>gly and focus on elim<strong>in</strong>ation of these barriers. Strategies should<br />
obviously be adapted to each population group (donors and non donors).<br />
Profile of donors’ population<br />
Consider<strong>in</strong>g Austrian compensation policy, the profile of whole blood donors and the<br />
one of plasma donors (as identified by the research team) rema<strong>in</strong>s quite different.<br />
Plasma donors are <strong>in</strong> average:<br />
• younger (18-35 important age group)<br />
• more educated (students)<br />
• less apt to live <strong>in</strong> stable couples (s<strong>in</strong>gle)<br />
• less <strong>in</strong>volved <strong>in</strong> professional life (students, jobless), than whole blood<br />
donors.
120 Plasma <strong>KCE</strong> Reports 120<br />
Remuneration of donation / Empiric f<strong>in</strong>d<strong>in</strong>gs for Austria<br />
One must bear <strong>in</strong> m<strong>in</strong>d that f<strong>in</strong>ancial compensation <strong>is</strong> an extremely ambivalent and<br />
controversial <strong>is</strong>sue, as it may be either a h<strong>in</strong>der<strong>in</strong>g or a factor, depend<strong>in</strong>g on the ex<strong>is</strong>t<strong>in</strong>g<br />
cultural and <strong>in</strong>stitutional framework of the country where donation <strong>is</strong> performed.<br />
As identified by the Austrian research team of the University of Vienna a change <strong>in</strong><br />
remuneration policy would have a major impact on donors’ behaviour, ie:<br />
• should remuneration for whole blood donation be <strong>in</strong>troduced, 84.3% of<br />
whole blood donors would stop donat<strong>in</strong>g whole blood<br />
• conversely, should remuneration for plasma donation be stopped 56.2% of<br />
plasma donors would stop donat<strong>in</strong>g plasma<br />
Likew<strong>is</strong>e, it was clearly mentioned that donor’s motives for donation rema<strong>in</strong> very<br />
different, especially towards the concept of altru<strong>is</strong>m vs remuneration: For whole blood<br />
donors, altru<strong>is</strong>m as such <strong>is</strong> an important motive for 88.2% for donation, whereas only<br />
50% of plasma donors feel concerned <strong>with</strong> th<strong>is</strong> k<strong>in</strong>d of motives. In the same time 52.1%<br />
of plasma donors clearly mention remuneration as one of the fix elements of their<br />
monthly <strong>in</strong>comes.<br />
APPENDIX 2 : SEARCH TERMS<br />
<strong>The</strong> follow<strong>in</strong>g databases were searched, by us<strong>in</strong>g the follow<strong>in</strong>g search terms:<br />
• Cochrane review database, <strong>with</strong> the search term “immunoglobul<strong>in</strong>$”<br />
• In the Centre for Reviews and D<strong>is</strong>sem<strong>in</strong>ation database (CRD)<br />
(http://www.crd.york.ac.uk/crdweb/), the database of abstracts of reviews<br />
of effects (DARE), <strong>with</strong> the search term “immunoglobul<strong>in</strong>$”<br />
• Medl<strong>in</strong>e and Embase <strong>with</strong> the follow<strong>in</strong>g search terms (or their equivalent):<br />
("Immunoglobul<strong>in</strong>s, Intravenous"[Mesh] AND "Randomized Controlled<br />
Trial "[Publication Type] AND (d<strong>is</strong>ease considered)”<br />
In addition, cost-effectiveness studies were retrieved by search<strong>in</strong>g Medl<strong>in</strong>e and Embase<br />
by us<strong>in</strong>g the follow<strong>in</strong>g search terms (or equivalent): "Cost-Benefit Analys<strong>is</strong>"[Mesh] AND<br />
"Immunoglobul<strong>in</strong>s, Intravenous"[Mesh]
<strong>KCE</strong> Reports 120 Plasma 121<br />
APPENDIX 3: GRADE CRITERIA FOR ASSIGNING<br />
GRADE OF EVIDENCE<br />
From “Grad<strong>in</strong>g quality of evidence and strength of recommendations”, GRADE<br />
Work<strong>in</strong>g Group, BMJ. 2004;328(7454):1490. 23<br />
CRITERIA FOR ASSIGNING GRADE OF EVIDENCE<br />
Type of evidence<br />
Decrease grade if:<br />
Increase grade if:<br />
Judgments about quality of evidence should be guided by a systematic review of <strong>available</strong><br />
evidence. Reviewers should consider four key elements: study design, study quality,<br />
cons<strong>is</strong>tency, and directness (see below). Study design refers to the basic study design,<br />
which we have broadly categorized as observational studies and randomized trials. Study<br />
quality refers to the detailed study methods and execution. Cons<strong>is</strong>tency refers to the<br />
similarity of estimates of effect across studies. Directness refers to the extent to which<br />
the people, <strong>in</strong>terventions, and outcome measures are similar to those of <strong>in</strong>terest.<br />
Another type of <strong>in</strong>direct evidence ar<strong>is</strong>es when there are no direct compar<strong>is</strong>ons of<br />
<strong>in</strong>terventions and <strong>in</strong>vestigators must make compar<strong>is</strong>ons across studies.<br />
Random<strong>is</strong>ed trial = high<br />
Observational study = low<br />
Any other evidence = very low<br />
• Serious ( − 1) or very serious ( − 2) limitation to study quality<br />
• Important <strong>in</strong>cons<strong>is</strong>tency ( − 1)<br />
• Some ( − 1) or major ( − 2) uncerta<strong>in</strong>ty about directness<br />
• Imprec<strong>is</strong>e or sparse data ( − 1)<br />
• High probability of <strong>report</strong><strong>in</strong>g bias ( − 1)<br />
• Strong evidence of association—significant relative r<strong>is</strong>k of > 2 ( < 0.5)<br />
based on cons<strong>is</strong>tent evidence from two or more observational studies,<br />
<strong>with</strong> no plausible confounders (+1)<br />
• Very strong evidence of association—significant relative r<strong>is</strong>k of > 5 ( <<br />
0.2) based on direct evidence <strong>with</strong> no major threats to validity (+2)<br />
• Evidence of a dose response gradient (+1)<br />
• All plausible confounders would have reduced the effect (+1)
122 Plasma <strong>KCE</strong> Reports 120<br />
APPENDIX 4: IMMUNO-HAEMATOLOGICAL<br />
SURVEY<br />
Use of immunoglobul<strong>in</strong>s <strong>in</strong> the treatment of immune deficiencies<br />
and other d<strong>is</strong>eases<br />
Th<strong>is</strong> <strong>in</strong>formation <strong>is</strong> asked by the <strong>KCE</strong> to project the future needs <strong>in</strong> immunoglobul<strong>in</strong>s (IG)<br />
<strong>in</strong> Belgium. Th<strong>is</strong> work has been requested by INAMI/RIZIV to prevent future IG<br />
shortages.<br />
Your data will not be d<strong>is</strong>tributed to any other <strong>in</strong>stitution, and will not be used to assess<br />
appropriateness of IG use <strong>in</strong> Belgian centers.<br />
If you have any question about th<strong>is</strong> survey or the project, you can contact:<br />
Dr Germa<strong>in</strong>e Hanquet, <strong>KCE</strong>, 02/287.33.37, germa<strong>in</strong>e.hanquet@kce.fgov.be<br />
Or Dr Michel Huybrechts, <strong>KCE</strong>, 02/287.33.42, michel.huybrechts@kce.fgov.be<br />
Thank you for your ass<strong>is</strong>tance!<br />
Name of the physician:………………………………………………………………….<br />
Name of the Centre / Hospital:…………………………………………………………<br />
In the first column (total patients followed), please <strong>in</strong>clude all patients that were seen <strong>in</strong><br />
your centre <strong>in</strong> 2008, regardless of treatment.<br />
1. For Primary Immune Deficiencies (PID) treated <strong>in</strong> your centre <strong>in</strong> 2008<br />
If th<strong>is</strong> <strong>in</strong>formation <strong>is</strong> not <strong>available</strong> for 2008, please provide data from other periods and<br />
specify.<br />
Treatment <strong>with</strong> <strong>in</strong>travenous immunoglobul<strong>in</strong>s<br />
Indications Total number patients Number of IG<br />
Average dose per<br />
followed <strong>in</strong> your perfusions<br />
perfusion <strong>in</strong> g/kg<br />
centre<br />
adm<strong>in</strong><strong>is</strong>tered <strong>in</strong> 2008 (or usual dose)<br />
PID <strong>in</strong> adults<br />
PID <strong>in</strong> children<br />
Comments:……………………………………………………………………………….<br />
Treatment <strong>with</strong> subcutaneous immunoglobul<strong>in</strong>s<br />
Indications Total number patients Number of IG<br />
Average dose per<br />
followed <strong>in</strong> your perfusions prescribed perfusion <strong>in</strong> g/kg<br />
centre<br />
<strong>in</strong> 2008<br />
(or usual dose)<br />
PID <strong>in</strong> adults<br />
PID <strong>in</strong> children<br />
Comments:……………………………………………………………………………….
<strong>KCE</strong> Reports 120 Plasma 123<br />
For other immune deficiencies treated <strong>in</strong> your centre <strong>in</strong> 2008 <strong>with</strong> <strong>in</strong>travenous IG<br />
Indications Total number<br />
patients followed<br />
Myeloma<br />
Chronic lymphocytic<br />
leukemia<br />
Prevention of <strong>in</strong>fections <strong>in</strong><br />
transplant<br />
Other immune deficiencies<br />
that required IG (please<br />
specify)<br />
Number IVIG<br />
treatments given<br />
<strong>in</strong> 2008<br />
Average dose per<br />
treatment <strong>in</strong> g/kg<br />
(or usual dose)<br />
Comments:…………………………………………………………………………………..<br />
4. For other <strong>in</strong>dications treated <strong>in</strong> your centre <strong>in</strong> 2008 <strong>with</strong> <strong>in</strong>travenous IG<br />
Indications Number IVIG treatments<br />
given <strong>in</strong> 2008<br />
Idiopathic thrombocytopenic<br />
purpura <strong>in</strong> children<br />
Idiopathic thrombocytopenic<br />
purpura <strong>in</strong> adults<br />
Guilla<strong>in</strong> Barré syndrome<br />
Kawasaki syndrome<br />
Toxic shock syndrome<br />
Infections <strong>in</strong> neonates<br />
Others:………………<br />
General comments:<br />
Do you w<strong>is</strong>h to receive the <strong>KCE</strong> <strong>report</strong> once publ<strong>is</strong>hed?<br />
(it will also <strong>available</strong> be <strong>available</strong> on our website www.kce.fgov.be)<br />
Thank you for your time!<br />
Average dose per treatment<br />
<strong>in</strong> g/kg (or usual dose)
124 Plasma <strong>KCE</strong> Reports 120<br />
APPENDIX 5: POTENTIAL CHANGES IN DEMAND<br />
VOLUME: FOCUS ON TWO EMERGING<br />
COUNTRIES<br />
FOCUS ON THE BRAZILIAN MARKET<br />
Brazil’s demand of plasma-derived products<br />
In the early n<strong>in</strong>eties, Brazilian plasma fractionation market was considered as a relatively<br />
m<strong>in</strong>or one. However, due to the <strong>in</strong>creas<strong>in</strong>g demand of the population and the evolution<br />
of prescription habits, Brazil’s demand for plasma products surged dramatically between<br />
1992 and 2007, and more prec<strong>is</strong>ely over the last three years.<br />
Figure 14: Value of the Brazilian Fractionation Market - <strong>with</strong>out<br />
recomb<strong>in</strong>ant - 1992-2007 (Mil.US $)<br />
Mil. US $<br />
250<br />
200<br />
150<br />
100<br />
50<br />
Value of the Brazilian<br />
Fractionation Market ‐<br />
<strong>with</strong>out recomb<strong>in</strong>ant ‐<br />
1992‐2007 (Mil.US $)<br />
Source: Market<strong>in</strong>g Research Bureau<br />
0<br />
1992 1995 1998 2001 2004 2007<br />
46,9 80,4 164,2 112,5 129,5 227,6<br />
On th<strong>is</strong> market, and despite the surge of the population’s needs and demand, no<br />
domestic company has emerged yet and Brazilian companies are virtually absent: <strong>in</strong><br />
2007, sixteen foreign companies (profit and non profit) fractioned and sold almost 100%<br />
of plasma products, and four of them hold key positions (Baxter, Octapharma, CSL-<br />
Behr<strong>in</strong>g, BPL) as described below :<br />
Table 47: Key market Leaders <strong>in</strong> 2007<br />
Brazilian Plasma Fractionation Market / Key Market leaders <strong>in</strong> 2007<br />
(Percentage <strong>in</strong> total sales)<br />
Baxter Octapharma CSL-Behr<strong>in</strong>g BPL Other companies<br />
25% 23% 15% 10% 27%<br />
As far as IVIG <strong>is</strong> concerned, Octapharma <strong>is</strong> clearly the market leader (market share of<br />
42%).<br />
Structure of th<strong>is</strong> market <strong>is</strong> ma<strong>in</strong>ly centred on IVIG and Factor VIII (<strong>in</strong>cl. recomb<strong>in</strong>ant), as<br />
described below:
<strong>KCE</strong> Reports 120 Plasma 125<br />
Table 48: Structure of the Brazilian market <strong>in</strong> 2007<br />
IVIG Factor VIII Album<strong>in</strong> Other<br />
31% 20% 19% 30%<br />
Focus : Intravenous Immune Globul<strong>in</strong> Market (IVIG) market<br />
With<strong>in</strong> th<strong>is</strong> market, IVIG demand has ra<strong>is</strong>ed dramatically s<strong>in</strong>ce 2001, as described<br />
below.<br />
<strong>The</strong> slower <strong>in</strong>crease of demand between 2004 and 2007 (+21%) <strong>is</strong> ma<strong>in</strong>ly due to a<br />
political problem (see below). Th<strong>is</strong> very last figure of the table should not be<br />
representative of further development of the Brazilian market.<br />
Figure 15: Brazilian IVIG Market (Toushands of units) 1998-2007<br />
Units (1 unit=2.5g)<br />
Source: Market<strong>in</strong>g Research Bureau<br />
Further foreseeable developments on the Brazilian market<br />
INSTITUTIONAL CONTEXT<br />
450<br />
400<br />
350<br />
300<br />
250<br />
200<br />
150<br />
100<br />
50<br />
0<br />
Brazilian IVIG Market<br />
(Toushands of units)<br />
1998‐2007<br />
1998 2001 2004 2007<br />
141 213 337 408<br />
Given Brazil’s absence of self-sufficiency, the Brazilian Federal Government, but also<br />
several federate states (eg State of Rio-de-Janeiro, State of Sao Paolo, etc..) launched<br />
<strong>in</strong>ternational public tenders, <strong>in</strong> order to fulfil the population’s needs. Between 2003 and<br />
today some problems occurred <strong>in</strong> the supply of plasma products, ma<strong>in</strong>ly because of the<br />
2003 scandal also known as the “vampire scandal” that brought corruption and illegal<br />
arrangements to light, especially between the key stakeholders of the plasma market<br />
mentioned above. Follow<strong>in</strong>g th<strong>is</strong> scandal fractionation contract that expired <strong>in</strong> 2004 was<br />
renewed <strong>in</strong> 2007 only. Th<strong>is</strong> <strong>in</strong>terruption <strong>in</strong> plasma products supply slowed down the<br />
evolution of Brazilian demand, but th<strong>is</strong> was, by def<strong>in</strong>ition, a punctual phenomenon.<br />
Brazilian will<strong>in</strong>g to reach some self-sufficiency <strong>is</strong> quite clear as it concluded an<br />
agreement <strong>with</strong> LFB to set up a fractionation plant <strong>in</strong> Brazil: a close and official<br />
partnership has been establ<strong>is</strong>hed between LFB and Brazilian state-controlled structure<br />
“Hemobras” to implement th<strong>is</strong> project and rationalize the whole collection and supply<br />
cha<strong>in</strong>.<br />
As a practical matter, the objective of th<strong>is</strong> project <strong>is</strong> to set up a fractionation plant <strong>in</strong><br />
northern Brazil, <strong>with</strong> a view to produc<strong>in</strong>g plasma-derived products, made from Brazilian<br />
plasma, <strong>in</strong> order to br<strong>in</strong>g additional volumes of plasma products and thus improve<br />
Brazil’s situation <strong>in</strong> terms of self-sufficiency.<br />
However, th<strong>is</strong> project will require some time, and self-sufficiency rema<strong>in</strong>s a very long<br />
term objective, and the level of import of plasma-derived products <strong>is</strong> likely to rema<strong>in</strong><br />
high over the next years.
126 Plasma <strong>KCE</strong> Reports 120<br />
ECONOMIC CONTEXT<br />
<strong>The</strong> sharp <strong>in</strong>crease <strong>in</strong> the demand of such products as IVIG demand illustrates the<br />
evolution of prescription habits, but also the recent ability of Brazilian citizens to<br />
purchase these products, thanks to the improvement of the Brazilian economic<br />
situation. Should th<strong>is</strong> economic trend rema<strong>in</strong> stable over the next years, th<strong>is</strong> evolution<br />
<strong>is</strong> likely to rema<strong>in</strong> comparable for the next years.<br />
CLINICAL PRACTICES<br />
In compar<strong>is</strong>on to the situation of west European countries and North America,<br />
consumption of IVIG per capita rema<strong>in</strong>s low: 5.7 g per thousand people. Should<br />
Brazilian practices conform progressively to the western standards, th<strong>is</strong> consumption<br />
would obviously evolve accord<strong>in</strong>gly and thus have a noticeable impact on Brazilian<br />
demand.<br />
FOCUS ON THE CHINESE MARKET<br />
Recent restructur<strong>in</strong>g of the Ch<strong>in</strong>ese plasma fractionation <strong>in</strong>dustry has led to a reduction<br />
of domestic production of plasma products, from 4.5 to 3 million liters <strong>in</strong> 2006. Th<strong>is</strong> cut<br />
down <strong>in</strong> Ch<strong>in</strong>ese production capacity has led to imports of Album<strong>in</strong> and recomb<strong>in</strong>ant<br />
factor VIII. Import of other plasma-derived products rema<strong>in</strong>s banned, due to the specific<br />
Ch<strong>in</strong>ese regulation framework.<br />
Cl<strong>in</strong>ical practices and coverage of medical expenditure are the ma<strong>in</strong> h<strong>in</strong>der<strong>in</strong>g factors<br />
for further development of the plasma market:<br />
• Such pathologies as haemophilia rema<strong>in</strong> under-diagnosed (1000 patients<br />
officially diagnosed ; theoretical number of patients around 100 000)<br />
• Access to modern treatments (especially plasma products) rema<strong>in</strong>s<br />
difficult for the vas majority of the population for two reasons because of<br />
the absence or the lack of health care coverage and of the ban on import<br />
of most of plasma products. <strong>The</strong>refore, many physicians still resort to<br />
cryoprecipitate, whole blood or even traditional medic<strong>in</strong>e.<br />
Ch<strong>in</strong>ese ban on import of plasma products and its impact on the market rema<strong>in</strong>s a<br />
h<strong>in</strong>der<strong>in</strong>g factor for import of a wide-range of plasma products except for recomb<strong>in</strong>ant<br />
Factor VIII and Album<strong>in</strong>. Given the <strong>in</strong>creased awareness of <strong>in</strong>novative therapy, and<br />
simultaneously domestic suppliers’ difficulty to meet the Ch<strong>in</strong>ese population’s actual<br />
needs, it <strong>is</strong> clear that Ch<strong>in</strong>a will cont<strong>in</strong>ue to import these two factors, at least over the<br />
very next years. However today’s Ch<strong>in</strong>ese legal framework, ie ban on import of IVIG <strong>is</strong><br />
unlikely to change over the very next years.
<strong>KCE</strong> Reports 120 Plasma 127<br />
APPENDIX 6: FRANCE: PLASMA COLLECTION<br />
WITHIN THE EFS<br />
KEY FIGURES ON DONATION: TODAY’S SITUATION<br />
<strong>The</strong> number of donors has reached 1.5 and the number of donations about 2.5 million<br />
(ie about 8000 donations daily <strong>in</strong> average). <strong>The</strong> blood collected <strong>in</strong> France has enabled to<br />
carry out treatment for 500 000 patients yearly.<br />
From a political po<strong>in</strong>t of view, the ma<strong>in</strong> strengths of the system are<br />
• <strong>The</strong> tradition of donation and republican public-spiritidness.<br />
• <strong>The</strong> <strong>in</strong>d<strong>is</strong>putable v<strong>is</strong>ibility of the EFS.<br />
Conversely, the ma<strong>in</strong> limits of the system are<br />
• <strong>The</strong> relatively week proportion of donors (around 4% of the overall<br />
population).<br />
• <strong>The</strong> d<strong>is</strong>tribution of collection centres, which <strong>is</strong> largely a heritage of the<br />
past decades, but not always cost-efficient, consider<strong>in</strong>g today’s f<strong>in</strong>ancial<br />
constra<strong>in</strong>ts.<br />
PRACTICAL ORGANISATION AND ACTUAL POLICIES: KEY<br />
POINTS<br />
<strong>The</strong> website of the EFS <strong>is</strong> centralized on the national level, but <strong>with</strong> regional w<strong>in</strong>dows.<br />
All relevant <strong>in</strong>formation <strong>is</strong> <strong>available</strong> on the website, and On-l<strong>in</strong>e book<strong>in</strong>g <strong>is</strong> also <strong>available</strong><br />
and user-friendly. Field blood and plasma collection <strong>is</strong> comparable to other countries’<br />
practices, <strong>with</strong> 175 collection sites, fixed or mobile, d<strong>is</strong>tributed across the French<br />
territory, both <strong>in</strong> rural and urban areas.<br />
However, mobile collection rema<strong>in</strong>s important compared to fixed collection po<strong>in</strong>ts: for<br />
th<strong>is</strong> reasons, the use of human resources and facilities <strong>is</strong> not optimized <strong>in</strong> some places.<br />
Focus on young adults<br />
Apart from traditional campaigns (comparable to other countries’ campaigns) one of the<br />
key targets of the EFS has been to focus communication on the most relevant age<br />
groups, ie young people and young adults, who are apt to become future donors, and<br />
repeat donors.<br />
Given the crucial importance of th<strong>is</strong> age group (18-26), a national competition was<br />
launched <strong>in</strong> 2008-2009. <strong>The</strong> ma<strong>in</strong> orig<strong>in</strong>ality of th<strong>is</strong> competition was to get th<strong>is</strong> age<br />
group <strong>in</strong>volved <strong>in</strong>to the design<strong>in</strong>g and the field organization of campaigns. After<br />
completion of these campaigns, the EFS has organized an <strong>in</strong>-depth evaluation of these<br />
campaigns, and rewarded the best campaigns. Three different awards have been def<strong>in</strong>ed<br />
and awarded accord<strong>in</strong>gly, based on the follow<strong>in</strong>g subjects:<br />
• Creativity award: the objective <strong>is</strong> to identify the most <strong>in</strong>novative<br />
campaign to ra<strong>is</strong>e students’ awareness of donation.<br />
• Interactivity award: the objective <strong>is</strong> to identify the campaign that<br />
resorted to widest range of media simultaneously (especially multimedia<br />
tools).<br />
• Pedagogy Award: the objective <strong>is</strong> to identify the most didactic<br />
campaign, and simultaneously the most faithful to the EFS values: voluntary<br />
and unpaid dimensions of donation, quality and best practices, non-profit<br />
dimension of EFS, etc..<br />
Th<strong>is</strong> first step campaign <strong>is</strong> now complete. A last mail<strong>in</strong>g of documents will be launched<br />
between November 2009 and April 2010, <strong>in</strong> close cooperation <strong>with</strong> the French<br />
University canteens.
128 Plasma <strong>KCE</strong> Reports 120<br />
As far as private firms are concerned EFS documents (thematic documents, general<br />
<strong>in</strong>formation on donation and blood products, and one specific poster “More than<br />
colleagues …Blood Donors”..) can be downloaded free of charge from the EFS website.<br />
However, the EFS recently laid emphas<strong>is</strong> on SMEs (ie firms employ<strong>in</strong>g lesser than 500<br />
employees): a specific mail<strong>in</strong>g campaign has been launched, which addressed 50 000<br />
SMEs nationwide. <strong>The</strong> EFS obta<strong>in</strong>ed a positive answer from 500 SMEs (ie 1% of the<br />
target). <strong>The</strong>se SMEs’ data and contact details have been entered onto the databases of<br />
the different branches of the EFS <strong>in</strong> order to organize close contacts and field<br />
cooperation <strong>in</strong> l<strong>in</strong>e <strong>with</strong> local priorities: Newsletter, rout<strong>in</strong>e <strong>in</strong>formation, etc…<br />
Larger firms (above 500 employees) should be the next target of the communication<br />
campaign over the next months.<br />
However, these efforts focus on blood donation <strong>in</strong> general and not on plasma donation<br />
specifically.<br />
Information delivered to the donor<br />
As <strong>in</strong> other EU countries, the EFS website provides <strong>with</strong> key <strong>in</strong>formation on governance<br />
and values of the EFS. It also provides technical <strong>in</strong>formation on the organization of<br />
blood / plasma donation <strong>in</strong> practice: On-l<strong>in</strong>e book<strong>in</strong>g; Fixed collection centres and<br />
mobile collection.<br />
Cl<strong>in</strong>ical <strong>in</strong>formation <strong>is</strong> also <strong>available</strong> about blood groups, donation types, and the key<br />
steps of blood process<strong>in</strong>g.<br />
French population’s awareness of plasma donation<br />
However, all <strong>in</strong>formation delivered to the donor rema<strong>in</strong> very general and addresses<br />
whole blood and plasma donors alike. Plasmapheres<strong>is</strong> technique <strong>is</strong> mentioned on the<br />
website. However no specific emphas<strong>is</strong> <strong>is</strong> laid on that subject and no further<br />
<strong>in</strong>formation <strong>is</strong> provided on the technical and cl<strong>in</strong>ical dimensions of th<strong>is</strong> technique.<br />
Th<strong>is</strong> situation should draw stakeholders’ attention, as only 60% of French people know<br />
that plasma can be donated: as demonstrated by a recent survey of Cerphi Association<br />
(Etude Cerphi – Tro<strong>is</strong>ième Edition – Donner son sang en France – Cécile Baz<strong>in</strong> &<br />
Jacques Malet – Mai 2006), 202 awareness of plasma donation and plasma donation<br />
techniques rema<strong>in</strong>s poor <strong>in</strong> France compared to other k<strong>in</strong>ds of donations (whole blood<br />
but also platelets).
<strong>KCE</strong> Reports 120 Plasma 129<br />
APPENDIX 7: GERMANY: PLASMA COLLECTION<br />
WITHIN THE GERMAN RED CROSS AND BY<br />
OTHER STAKEHOLDERS<br />
PLASMA COLLECTION WITHIN THE FRAMEWORK OF THE<br />
GERMAN RED CROSS (DRK)<br />
Selection, Follow-up and retention of donors<br />
Age-group targets<br />
In terms of target population people below 30 (and among them students and jobless<br />
people) are clearly the most important people to focus on for plasma donation, (see :<br />
Survey of Robert Koch Institute). <strong>The</strong> DRK has the contact details of all teachers<br />
work<strong>in</strong>g <strong>in</strong> relevant areas (ie sciences, biology) at its d<strong>is</strong>posal. Hence, it has the<br />
possibility to contact them very easily. Specific material dedicated to high school pupils<br />
are:<br />
• High School magaz<strong>in</strong>e: “We are heroes” focus<strong>in</strong>g on key scientific<br />
<strong>in</strong>formation and on the civic dimension of blood donation.<br />
• Experiment material: 6 different biology experiment packages on blood,<br />
blood functions, blood groups, etc...to be performed by pupils themselves<br />
<strong>in</strong> their classroom.<br />
• 12 scientific leaflets on: immune system, clott<strong>in</strong>g process, blood groups,<br />
etc..<br />
• Illustrated charts and posters on the ma<strong>in</strong> blood-related subjects.<br />
Practical follow-up of donors by the DRK<br />
Once a donor <strong>is</strong> identified and selected, h<strong>is</strong>/her data are entered onto the DRK<br />
database, and he/she <strong>is</strong> subject to:<br />
• a prec<strong>is</strong>e personal data management (onl<strong>in</strong>e updat<strong>in</strong>g system <strong>available</strong>)<br />
• a specific and very regular adm<strong>in</strong><strong>is</strong>trative follow-up: regular chas<strong>in</strong>g of the<br />
donors <strong>is</strong> performed by E-mail, Mail<strong>in</strong>gs, regular phone recruit<strong>in</strong>g.<br />
Focus: key messages of the advert<strong>is</strong><strong>in</strong>g and communication campaign<br />
• No <strong>in</strong>volvement of celebrities <strong>in</strong> the campaign: “No show-off models” <strong>is</strong><br />
the first statement put forward on the website of the DRK. DRK’s<br />
campaign focused on ord<strong>in</strong>ary people, real life situations, and real world<br />
objects.<br />
• Everyday life products and situations: the key messages first focus on the<br />
concept of shortage of renewable products and the trouble caused by th<strong>is</strong><br />
shortage, eg: the end of a toothpaste tube, the last match of the<br />
matchbox, the last drops of <strong>in</strong>k from a cartridge.<br />
Contrast between consumer products and blood (and blood products): For each of the<br />
concerned products, the message clearly refers to the possibility of buy<strong>in</strong>g the product<br />
easily and quickly (eg: “You will f<strong>in</strong>d <strong>in</strong>k cartridges <strong>in</strong> shops. But not blood”. Donate<br />
Blood / See below). By contrast <strong>with</strong> these products, specific nature of blood <strong>is</strong> clearly<br />
underl<strong>in</strong>ed, and thus the irreplaceable nature of blood donation.
130 Plasma <strong>KCE</strong> Reports 120<br />
Figure 16 :“Ink cartridge” Posters<br />
Source: German Red Cross Website<br />
• Connection between nature of blood and irreplaceable nature of blood<br />
donation<br />
Tone of the campaign: direct commands. One must underl<strong>in</strong>e that “Spende Blut” means<br />
“Give Blood” <strong>with</strong> <strong>in</strong>formal “you”.<br />
Target<strong>in</strong>g the donors’ social life: important to stress <strong>is</strong> the ability of to stick to the<br />
specific traits of German social and cultural life. <strong>The</strong> DRK deliberately targeted students<br />
<strong>in</strong> its campaign and selected a “Stammt<strong>is</strong>ch Picture” on one of its posters, to attract<br />
potential student donors. Note: <strong>The</strong> Stammt<strong>is</strong>ch <strong>is</strong> an old tradition <strong>in</strong> German<br />
universities: debates on a wide range of subjects (literary, philosophical, or political).<br />
<strong>The</strong> slogan <strong>is</strong> “You will f<strong>in</strong>d philosophers everywhere. Not Blood. Donate Blood!”<br />
Figure 17: “Stammt<strong>is</strong>ch” Poster<br />
Source: German Red Cross Website<br />
COLLECTION BY OTHER STAKEHOLDERS<br />
Whole Blood collection <strong>in</strong> Germany<br />
Table 49: Whole blood collection <strong>in</strong> Germany<br />
Institutions Contribution / Total<br />
amount of whole<br />
blood donation<br />
University Hospital –<br />
15-20%<br />
based Centres<br />
Red Cross 75-80%<br />
Private Centres Ca 5% (<strong>in</strong>creas<strong>in</strong>g)
<strong>KCE</strong> Reports 120 Plasma 131<br />
D<strong>is</strong>tribution of plasma collection <strong>in</strong> Germany: key role of the private sector<br />
Public/Private sector: plasma repeat donors (2006 figures)<br />
<strong>The</strong> overall number of plasma repeat donors was 128 000 <strong>in</strong> 2006 <strong>in</strong> Germany. Among<br />
them, 105 000 (ca 80%) stem from Private Industry driven and Private specialized<br />
centres.<br />
Figure 18: Plasma Collection <strong>in</strong> Germany / Repeat Donors<br />
Source: Robert Koch Institute<br />
Age Profile of plasma repeat donors<br />
Figure 19: Private Industry Centres / Repeat Donors - 2006<br />
20000<br />
15000<br />
10000<br />
5000<br />
0<br />
Municip‐<br />
Centres<br />
8%<br />
Red Cross<br />
11%<br />
Source: Robert Koch Institute<br />
Priv‐Spec‐<br />
Centres<br />
42%<br />
Priv‐Ind‐<br />
Centres<br />
40%<br />
18‐24 25‐34 35‐44 45‐54 55‐68<br />
Female<br />
Male
132 Plasma <strong>KCE</strong> Reports 120<br />
Figure 20: Private Spec. Centres / Repeat Donors 2006<br />
25000<br />
20000<br />
15000<br />
10000<br />
5000<br />
0<br />
Source: Robert Koch Institute<br />
<strong>The</strong> age relationship described above has been clearly identified for private centres, but<br />
not for Municipal or Red Cross Centres. For the latter centres, age d<strong>is</strong>tribution <strong>is</strong> quite<br />
different and age relationship <strong>is</strong> much fuzzier, as mature people br<strong>in</strong>g a noticeable<br />
contribution to donation.<br />
Figure 21: German Red Cross Centres - Nb of Repeat Donors 2006<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1500<br />
1000<br />
500<br />
0<br />
Source: Robert Koch Institute<br />
18‐24 25‐34 35‐44 45‐54 55‐68<br />
18‐24 25‐34 35‐44 45‐54 55‐68<br />
Female<br />
Male<br />
Female<br />
Male<br />
Location of the private centres<br />
Concern<strong>in</strong>g plasmapheres<strong>is</strong> specifically, the German association of the plasma donation<br />
centres called Arge-Plasmapherese, founded 1997 (http://www.arge-plasmapherese.de/),<br />
delivers key <strong>in</strong>formation on that subject, especially on location of plasma centres:<br />
• Location of Red Cross centres and Municipal centres <strong>is</strong> largely due to<br />
h<strong>is</strong>torical reasons. Red Cross and Municipal Centres are few and their<br />
d<strong>is</strong>tribution across Germany <strong>is</strong> relatively even.
<strong>KCE</strong> Reports 120 Plasma 133<br />
• Conversely, location of private and <strong>in</strong>dustry centres has been selected on<br />
rentability-oriented criteria over the last years: rather under privileged<br />
regions: of the 60 private plasmapheres<strong>is</strong> centres reg<strong>is</strong>tered <strong>in</strong> 32 are<br />
located <strong>in</strong> the ex- Democratic Republic of Germany, 14 <strong>in</strong> North<br />
Rh<strong>in</strong>eland – Westphalia. In other words 75% of these centres are often<br />
located close to universities. It must be outl<strong>in</strong>ed that they are generally<br />
located <strong>in</strong> small / medium sized towns both for f<strong>in</strong>ancial reasons (lower<br />
start-up costs for the centre itself) and for practical reasons (Faster<br />
penetration <strong>with</strong> market<strong>in</strong>g activities, Possibility to achieve full capacity <strong>in</strong><br />
a shorter period of time).<br />
Exemple of private plasma donation <strong>in</strong> Germany: Plasma Europe Service/ Biotest<br />
Size of the town<br />
Small towns are clearly privileged, and <strong>with</strong><strong>in</strong> each town, busy shopp<strong>in</strong>g streets and/or<br />
places close to university campuses and <strong>in</strong> any case easy to reach<br />
Location of Plasma Service Centres: Which regions ?<br />
All donation centres of th<strong>is</strong> firm are located <strong>in</strong> the ex-German Democratic Republic or<br />
<strong>in</strong> North Rh<strong>in</strong>eland – Westphalia (see Map below/ Source: Plasmaservice Website /<br />
www.plasmaservice.de)<br />
D<strong>is</strong>tribution of Plasma Service Europe Centres <strong>in</strong> Germany / Corporate Data<br />
Other po<strong>in</strong>ts on practical fitt<strong>in</strong>g out: Non hospital atmosphere, warm colours,<br />
Optimized d<strong>is</strong>tribution of beds across the donation room, Clear separation between<br />
donation rooms and manufactur<strong>in</strong>g/freez<strong>in</strong>g areas (restricted areas).<br />
FINANCIAL COMPENSATION<br />
Even <strong>with</strong><strong>in</strong> the same umbrella organization, the level of f<strong>in</strong>ancial compensation may<br />
vary across centres. With<strong>in</strong> the organization we focused on, it ranges from 16 to 20 €.<br />
<strong>The</strong>refore, th<strong>is</strong> compensation <strong>is</strong> not just a compensation but also part of costs<br />
management. Specific f<strong>in</strong>ancial compensation <strong>is</strong> provided to first donors: 38€ <strong>in</strong> most<br />
centres.
134 Plasma <strong>KCE</strong> Reports 120<br />
TIME MANAGEMENT AND COST STRUCTURE<br />
Tthe whole donation process (44 m<strong>in</strong>) <strong>is</strong> divided <strong>in</strong>to 4 steps<br />
- Step 1: Reception time Step 2: Medical <strong>in</strong>terview<br />
- Step 3: Donation <strong>in</strong> donat. room Step 4: Plasma process<strong>in</strong>g and data collection<br />
Cost Structure: see below<br />
Table 50: Cost Structure / Plasma Service Europe<br />
Budget Codes Average Costs<br />
Adm<strong>in</strong><strong>is</strong>trative Costs 4 €<br />
Rent<strong>in</strong>g and side costs 4.10 € - 5.50 €<br />
Personal / HR 23 – 28 €<br />
Advert<strong>is</strong><strong>in</strong>g 1.70 €<br />
Ma<strong>in</strong>tenance Costs 2.30€<br />
Capital Allowances 0.70€<br />
M<strong>is</strong>cellaneous Expenses 2.60€<br />
TOTAL 40.40 € – 46.80 €<br />
FINANCIAL<br />
COMPENSATION<br />
16-20 €<br />
TOTAL COSTS 56.40€ - 66.80€<br />
Smooth runn<strong>in</strong>g of th<strong>is</strong> <strong>in</strong>dustry implies a noticeable “<strong>in</strong>vestment” <strong>in</strong> f<strong>in</strong>ancial<br />
compensation (28% of the costs) and Human Resources to recruit and reta<strong>in</strong> donors.<br />
However, f<strong>in</strong>ancial compensation does not prevent these centres from be<strong>in</strong>g f<strong>in</strong>ancially<br />
profitable and susta<strong>in</strong>able.<br />
Figure 22: Plasma Service Europe: Cost structure for plasma collection<br />
M<strong>is</strong>cellaneous<br />
4%<br />
Capital<br />
Allow.<br />
1%<br />
Ma<strong>in</strong>tenance<br />
4%<br />
Advert<strong>is</strong>.<br />
2%<br />
Source : Corporate Data<br />
F<strong>in</strong>.Compensati<br />
on<br />
28%<br />
Adm<strong>in</strong>.<br />
13%<br />
Hum‐Res<br />
40%<br />
Rent<strong>in</strong>g<br />
8%
<strong>KCE</strong> Reports 120 Plasma 135<br />
APPENDIX 8: AUSTRALIA: INSTITUTIONAL<br />
ASPECTS<br />
ROLE OF THE DIFFERENT STAKEHOLDERS IN AUSTRALIA<br />
National Blood Authority<br />
Overarch<strong>in</strong>g and steer<strong>in</strong>g <strong>in</strong>stitution <strong>in</strong> charge of the Australian National blood and<br />
plasma policy (see core <strong>report</strong>).<br />
Australian Red Cross Blood Service (ARCBS)<br />
CSL Limited<br />
<strong>The</strong> ARCBS <strong>is</strong> responsible for the collection of blood and plasma from donors and the<br />
d<strong>is</strong>tribution of fresh plasma and some imported plasma products, to the health system.<br />
Th<strong>is</strong> firm plays a key role <strong>in</strong> the supply cha<strong>in</strong>, as it <strong>is</strong> responsible for fractionat<strong>in</strong>g the<br />
plasma supplied by the ARCBS and provid<strong>in</strong>g plasma products back to the ARCBS for<br />
further d<strong>is</strong>tribution. CSL Limited has to assume on many po<strong>in</strong>ts public law obligations,<br />
as comm<strong>is</strong>sioned by the NBA (even if CSL <strong>is</strong> not a public law body).<br />
Other pharmaceutical firms<br />
More punctually, other firms can be responsible for the supply and d<strong>is</strong>tribution of<br />
specific range of products, whenever these products are not produced <strong>in</strong> Australia or<br />
when the Australian domestic capacity <strong>is</strong> not <strong>in</strong> the position to meet the patients’ needs.<br />
<strong>The</strong>rapeutic Goods Adm<strong>in</strong><strong>is</strong>tration (TGA)<br />
<strong>The</strong> TGA <strong>is</strong> an <strong>in</strong>dependent body that <strong>is</strong> responsible for regulat<strong>in</strong>g the whole sector <strong>in</strong><br />
the field of efficacy, safety standards, and quality of blood and blood products. It <strong>is</strong> also<br />
entrusted <strong>with</strong> audit<strong>in</strong>g of Good Manufactur<strong>in</strong>g Practice and product recalls (see below /<br />
Contract between CSL and the NBA).<br />
Health care professionals and suppliers<br />
<strong>The</strong> latter stakeholders also play a role, even <strong>in</strong>formally, <strong>in</strong> adv<strong>is</strong><strong>in</strong>g the NBA a number<br />
of formal or <strong>in</strong>formal work<strong>in</strong>g groups and fora on technical subjects (eg: Professional<br />
Community Forum, NBA Fellows Program, and Cl<strong>in</strong>ical Adv<strong>is</strong>ory Council).<br />
MANAGEMENT OF SUPPLY: QUICK OVERVIEW<br />
On a rout<strong>in</strong>e bas<strong>is</strong>, the NBA notifies the Australian Red Cross Blood Service annually of<br />
the volume of plasma to be supplied to CSL for fractionation. Under the terms of the<br />
Plasma Products Agreement (PPA), the NBA must give CSL the Annual Supply Estimate<br />
for a particular f<strong>in</strong>ancial year by no later than the preced<strong>in</strong>g 30 November. Although<br />
these forecasts are not b<strong>in</strong>d<strong>in</strong>g on the NBA, it <strong>is</strong> required under the terms of the PPA<br />
to purchase 95% of the plasma products produced <strong>in</strong> accordance <strong>with</strong> the Confirmed<br />
Quarterly Requirements that the NBA furn<strong>is</strong>hes to CSL six months <strong>in</strong> advance of each<br />
quarter. <strong>The</strong> NBA also needs to make sure that suppliers actually ma<strong>in</strong>ta<strong>in</strong> reserve<br />
hold<strong>in</strong>gs of products, <strong>in</strong> order to ensure that timely and adequate supplies are <strong>available</strong><br />
to meet cl<strong>in</strong>ical needs.
136 Plasma <strong>KCE</strong> Reports 120<br />
CRISIS AND RISK MANAGEMENT<br />
One of the day-to-day, but also strategic objectives of the NBA <strong>is</strong> to enhance the<br />
resilience and the responsiveness of the whole sector. <strong>The</strong> latter aspect <strong>is</strong> of great<br />
importance for Australia, as a specific cr<strong>is</strong><strong>is</strong>-management framework has been def<strong>in</strong>ed<br />
by the NBA.<br />
• Likelihood of a supply / demand cr<strong>is</strong><strong>is</strong> <strong>is</strong> identified by the NBA and<br />
entered onto a specific table [1: rare – 5: almost certa<strong>in</strong>].<br />
• Consequence of a cr<strong>is</strong><strong>is</strong> <strong>is</strong> also identified by the NBA and entered onto a<br />
specific table [1: M<strong>in</strong>or consequences / Buffer stock – 5: Catastrophe /<br />
Widespread national outage, Blood stocks below 24h].<br />
Thanks to the comb<strong>in</strong>ation of the two scales mentioned above, a r<strong>is</strong>k matrix has been<br />
set up to assess the overall r<strong>is</strong>k rate, ie the seriousness of the cr<strong>is</strong><strong>is</strong>. Follow<strong>in</strong>g th<strong>is</strong> r<strong>is</strong>k<br />
assessment process, a specific framework has been set out to def<strong>in</strong>e preparation and<br />
mitigation of supply or demand cr<strong>is</strong><strong>is</strong>. <strong>The</strong> NBA has def<strong>in</strong>ed strategies to m<strong>in</strong>im<strong>is</strong>e the<br />
impact of such cr<strong>is</strong>es based on r<strong>is</strong>k management plans <strong>in</strong> supply contracts, cooperation<br />
<strong>in</strong> supplier cont<strong>in</strong>gency plann<strong>in</strong>g, product reserves and cont<strong>in</strong>gent supply arrangements,<br />
promotion of best practice of blood and blood products and improvement <strong>in</strong> <strong>in</strong>ventory<br />
management and <strong>report</strong><strong>in</strong>g. Should these measures not be sufficient, further measures<br />
can be considered on the national level (Department of Health).<br />
KEY SUCCESS FACTORS FOR A RELIABLE SUPPLY POLICY<br />
• Provid<strong>in</strong>g the Australian governments (national and federate level) <strong>with</strong><br />
accurate and timely <strong>in</strong>formation for dec<strong>is</strong>ion-mak<strong>in</strong>g.<br />
• Close and day-to-day partnership <strong>with</strong> suppliers, <strong>with</strong> a view to address<strong>in</strong>g<br />
supply cha<strong>in</strong> gaps.<br />
• Close partnership <strong>with</strong> the cl<strong>in</strong>ical community to enhance the<br />
development of EB guidel<strong>in</strong>es, standards, and programs for improv<strong>in</strong>g<br />
patient outcomes.
<strong>KCE</strong> Reports 120 Plasma 137<br />
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D/2005/10.273/21.<br />
20. HTA Moleculaire Diagnostiek <strong>in</strong> België. D/2005/10.273/23, D/2005/10.273/25.<br />
21. HTA Stomamateriaal <strong>in</strong> België. D/2005/10.273/27.<br />
22. HTA Positronen Em<strong>is</strong>sie Tomografie <strong>in</strong> België. D/2005/10.273/29.<br />
23. HTA De electieve endovasculaire behandel<strong>in</strong>g van het abdom<strong>in</strong>ale aorta aneurysma<br />
(AAA). D/2005/10.273/32.<br />
24. Het gebruik van natriuret<strong>is</strong>che peptides <strong>in</strong> de diagnost<strong>is</strong>che aanpak van patiënten met<br />
vermoeden van hartfalen. D/2005/10.273/34.<br />
25. Capsule endoscopie. D/2006/10.273/01.<br />
26. Medico–legale aspecten van kl<strong>in</strong><strong>is</strong>che praktijkrichtlijnen. D2006/10.273/05.<br />
27. De kwaliteit en de organ<strong>is</strong>atie van type 2 diabeteszorg. D2006/10.273/07.<br />
28. Voorlopige richtlijnen voor farmaco-econom<strong>is</strong>ch onderzoek <strong>in</strong> België. D2006/10.273/10.<br />
29. Nationale Richtlijnen College voor Oncologie: A. algemeen kader oncolog<strong>is</strong>ch<br />
kwaliteitshandboek B. wetenschappelijke bas<strong>is</strong> voor kl<strong>in</strong><strong>is</strong>che paden voor diagnose en<br />
behandel<strong>in</strong>g colorectale kanker en test<strong>is</strong>kanker. D2006/10.273/12.<br />
30. Inventar<strong>is</strong> van databanken gezondheidszorg. D2006/10.273/14.<br />
31. Health Technology Assessment prostate-specific-antigen (PSA) voor<br />
prostaatkankerscreen<strong>in</strong>g. D2006/10.273/17.<br />
32. Feedback : onderzoek naar de impact en barrières bij implementatie –<br />
Onderzoeksrapport : deel II. D/2006/10.273/19.<br />
33. Effecten en kosten van de vacc<strong>in</strong>atie van Belg<strong>is</strong>che k<strong>in</strong>deren met geconjugeerd<br />
pneumokokkenvacc<strong>in</strong>. D/2006/10.273/21.<br />
34. Trastuzumab bij vroegtijdige stadia van borstkanker. D/2006/10.273/23.<br />
35. Studie naar de mogelijke kosten van een eventuele wijzig<strong>in</strong>g van de rechtsregels <strong>in</strong>zake<br />
med<strong>is</strong>che aansprakelijkheid (fase III)- prec<strong>is</strong>er<strong>in</strong>g van de kostenram<strong>in</strong>g.<br />
D/2006/10.273/26.<br />
36. Farmacolog<strong>is</strong>che en chirurg<strong>is</strong>che behandel<strong>in</strong>g van obesitas. Residentiële zorg voor<br />
ernstig obese k<strong>in</strong>deren <strong>in</strong> België. D/2006/10.273/28.
37. HTA Magnet<strong>is</strong>che Resonantie Beeldvorm<strong>in</strong>g. D/2006/10.273/32.<br />
38. Baarmoederhalskankerscreen<strong>in</strong>g en testen op Human Papillomavirus (HPV).<br />
D/2006/10.273/35<br />
39. Rapid assessment van nieuwe wervelzuil technologieën : totale d<strong>is</strong>cusprothese en<br />
vertebro/ballon kyfoplastie. D/2006/10.273/38.<br />
40. Functioneel bilan van de patiënt als mogelijke bas<strong>is</strong> voor nomenclatuur van<br />
k<strong>in</strong>esitherapie <strong>in</strong> België? D/2006/10.273/40.<br />
41. Kl<strong>in</strong><strong>is</strong>che kwaliteits<strong>in</strong>dicatoren. D/2006/10.273/43.<br />
42. Studie naar praktijkverschillen bij electieve chirurg<strong>is</strong>che <strong>in</strong>grepen <strong>in</strong> België.<br />
D/2006/10.273/45.<br />
43. Herzien<strong>in</strong>g bestaande praktijkrichtlijnen. D/2006/10.273/48.<br />
44. Een procedure voor de beoordel<strong>in</strong>g van nieuwe med<strong>is</strong>che hulpmiddelen.<br />
D/2006/10.273/50.<br />
45. HTA Colorectale Kankerscreen<strong>in</strong>g: wetenschappelijke stand van zaken en budgetimpact<br />
voor België. D/2006/10.273/53.<br />
46. Health Technology Assessment. Polysomnografie en thu<strong>is</strong>monitor<strong>in</strong>g van zuigel<strong>in</strong>gen<br />
voor de preventie van wiegendood. D/2006/10.273/59.<br />
47. Geneesmiddelengebruik <strong>in</strong> de belg<strong>is</strong>che rusthuizen en rust- en verzorg<strong>in</strong>gstehuizen.<br />
D/2006/10.273/61<br />
48. Chron<strong>is</strong>che lage rugpijn. D/2006/10.273/63.<br />
49. Antivirale middelen bij seizoensgriep en grieppandemie. Literatuurstudie en ontwikkel<strong>in</strong>g<br />
van praktijkrichtlijnen. D/2006/10.273/65.<br />
50. Eigen betal<strong>in</strong>gen <strong>in</strong> de Belg<strong>is</strong>che gezondheidszorg. De impact van supplementen.<br />
D/2006/10.273/68.<br />
51. Chron<strong>is</strong>che zorgbehoeften bij personen met een niet- aangeboren hersenletsel (NAH)<br />
tussen 18 en 65 jaar. D/2007/10.273/01.<br />
52. Rapid Assessment: Cardiovasculaire Primaire Preventie <strong>in</strong> de Belg<strong>is</strong>che Hu<strong>is</strong>artspraktijk.<br />
D/2007/10.273/03.<br />
53. F<strong>in</strong>ancier<strong>in</strong>g van verpleegkundige zorg <strong>in</strong> ziekenhuizen. D/2007/10 273/06<br />
54. Kosten-effectiviteitsanalyse van rotavirus vacc<strong>in</strong>atie van zuigel<strong>in</strong>gen <strong>in</strong> België<br />
55. Evidence-based <strong>in</strong>houd van geschreven <strong>in</strong>formatie vanuit de farmaceut<strong>is</strong>che <strong>in</strong>dustrie aan<br />
hu<strong>is</strong>artsen. D/2007/10.273/12.<br />
56. Orthoped<strong>is</strong>ch Materiaal <strong>in</strong> België: Health Technology Assessment. D/2007/10.273/14.<br />
57. Organ<strong>is</strong>atie en F<strong>in</strong>ancier<strong>in</strong>g van Musculoskeletale en Neurolog<strong>is</strong>che Revalidatie <strong>in</strong> België.<br />
D/2007/10.273/18.<br />
58. De Implanteerbare Defibrillator: een Health Technology Assessment. D/2007/10.273/21.<br />
59. Laboratoriumtesten <strong>in</strong> de hu<strong>is</strong>artsgeneeskunde. D2007/10.273/24.<br />
60. Longfunctie testen bij volwassenen. D/2007/10.273/27.<br />
61. Vacuümgeass<strong>is</strong>teerde Wondbehandel<strong>in</strong>g: een Rapid Assessment. D/2007/10.273/30<br />
62. Intensiteitsgemoduleerde Radiotherapie (IMRT). D/2007/10.273/32.<br />
63. Wetenschappelijke ondersteun<strong>in</strong>g van het College voor Oncologie: een nationale<br />
praktijkrichtlijn voor de aanpak van borstkanker. D/2007/10.273/35.<br />
64. HPV Vacc<strong>in</strong>atie ter Preventie van Baarmoederhalskanker <strong>in</strong> België: Health Technology<br />
Assessment. D/2007/10.273/41.<br />
65. Organ<strong>is</strong>atie en f<strong>in</strong>ancier<strong>in</strong>g van genet<strong>is</strong>che diagnostiek <strong>in</strong> België. D/2007/10.273/44.<br />
66. Health Technology Assessment: Drug-Elut<strong>in</strong>g Stents <strong>in</strong> België. D/2007/10.273/47<br />
67. Hadrontherapie. D/2007/10.273/50.<br />
68. Vergoed<strong>in</strong>g van schade als gevolg van gezondheidszorg – Fase IV : Verdeelsleutel tussen<br />
het Fonds en de verzekeraars. D/2007/10.273/52.<br />
69. Kwaliteit van rectale kankerzorg – Fase 1: een praktijkrichtlijn voor rectale kanker<br />
D/2007/10.273/54.<br />
70. Vergelijkende studie van ziekenhu<strong>is</strong>accrediter<strong>in</strong>gs-programma’s <strong>in</strong> Europa<br />
D/2008/10.273/57.<br />
71. Aanbevel<strong>in</strong>gen voor het gebruik van vijf oftalmolog<strong>is</strong>che testen <strong>in</strong> de kl<strong>in</strong><strong>is</strong>che<br />
praktijk .D/2008/10.273/04<br />
72. Het aanbod van artsen <strong>in</strong> België. Huidige toestand en toekomstige uitdag<strong>in</strong>gen.<br />
D/2008/10.273/07
73. F<strong>in</strong>ancier<strong>in</strong>g van het zorgprogramma voor de geriatr<strong>is</strong>che patiënt <strong>in</strong> algemene<br />
ziekenhuizen: def<strong>in</strong>itie en evaluatie van een geriatr<strong>is</strong>che patiënt, def<strong>in</strong>itie van de <strong>in</strong>terne<br />
lia<strong>is</strong>ongeriatrie en evaluatie van de middelen voor een goede f<strong>in</strong>ancier<strong>in</strong>g.<br />
D/2008/10.273/11<br />
74. Hyperbare Zuurstoftherapie: Rapid Assessment. D/2008/10.273/13.<br />
75. Wetenschappelijke ondersteun<strong>in</strong>g van het College voor Oncologie: een nationale<br />
praktijkrichtlijn voor de aanpak van slokdarm- en maagkanker. D/2008/10.273/16.<br />
76. Kwaliteitsbevorder<strong>in</strong>g <strong>in</strong> de hu<strong>is</strong>artsenpraktijk <strong>in</strong> België: status quo of quo vad<strong>is</strong>?<br />
D/2008/10.273/18.<br />
77. Orthodontie bij k<strong>in</strong>deren en adolescenten. D/2008/10.273/20.<br />
78. Richtlijnen voor farmaco-econom<strong>is</strong>che evaluaties <strong>in</strong> België. D/2008/10.273/23.<br />
79. Terugbetal<strong>in</strong>g van radio<strong>is</strong>otopen <strong>in</strong> België. D/2008/10.273/26<br />
80. Evaluatie van de effecten van de maximumfactuur op de consumptie en f<strong>in</strong>anciële<br />
toegankelijkheid van gezondheidszorg. D/2008/10.273/35.<br />
81. Kwaliteit van rectale kankerzorg – phase 2: ontwikkel<strong>in</strong>g en test van een set van<br />
kwaliteits<strong>in</strong>dicatoren. D/2008/10.273/38<br />
82. 64-Slice computertomografie van de kransslagaders bij patiënten met vermoeden van<br />
coronaire hartziekte. D/2008/10.273/40<br />
83. Internationale vergelijk<strong>in</strong>g van terugbetal<strong>in</strong>gsregels en jurid<strong>is</strong>che aspecten van plast<strong>is</strong>che<br />
heelkunde. D/200810.273/43<br />
84. Langverblijvende psychiatr<strong>is</strong>che patiënten <strong>in</strong> T-bedden. D/2008/10.273/46<br />
85. Vergelijk<strong>in</strong>g van twee f<strong>in</strong>ancier<strong>in</strong>gssystemen voor de eerstelijnszorg <strong>in</strong> België.<br />
D/2008/10.273/49.<br />
86. Functiedifferentiatie <strong>in</strong> de verpleegkundige zorg: mogelijkheden en beperk<strong>in</strong>gen.<br />
D/2008/10.273/52.<br />
87. Het gebruik van k<strong>in</strong>esitherapie en van fys<strong>is</strong>che geneeskunde en revalidatie <strong>in</strong> België.<br />
D/2008/10.273/54.<br />
88. Chron<strong>is</strong>ch Vermoeidheidssyndroom: diagnose, behandel<strong>in</strong>g en zorgorgan<strong>is</strong>atie.<br />
D/2008/10.273/58.<br />
89. Rapid assessment van enkele nieuwe behandel<strong>in</strong>gen voor prostaatkanker en goedaardige<br />
prostaathypertrofie. D/2008/10.273/61<br />
90. Hu<strong>is</strong>artsgeneeskunde: aantrekk<strong>in</strong>gskracht en beroepstrouw bevorderen.<br />
D/2008/10.273/63<br />
91. Hoorapparaten <strong>in</strong> België: health technology assessment. D/2008/10.273/67<br />
92. Nosocomiale <strong>in</strong>fecties <strong>in</strong> België, deel 1: nationale prevalentiestudie. D/2008/10.273/70.<br />
93. Detectie van adverse events <strong>in</strong> adm<strong>in</strong><strong>is</strong>tratieve databanken. D/2008/10.273/73.<br />
94. Intensieve maternele verzorg<strong>in</strong>g (Maternal Intensive Care) <strong>in</strong> België. D/2008/10.273/77<br />
95. Percutane hartklep implantatie bij congenitale en degeneratieve klepletsels: A rapid<br />
Health Technology Assessment. D/2008/10.273/79<br />
96. Het opstellen van een med<strong>is</strong>che <strong>in</strong>dex voor private ziekteverzeker<strong>in</strong>gs-overeenkomsten.<br />
D/2008/10.273/82<br />
97. NOK/PSY revalidatiecentra: doelgroepen, wetenschappelijke evidentie en<br />
zorgorgan<strong>is</strong>atie. D/2009/10.273/84<br />
98. Evaluatie van universele en doelgroep hepatit<strong>is</strong> A vacc<strong>in</strong>atie opties <strong>in</strong> België.<br />
D/2008/10.273/88<br />
99. F<strong>in</strong>ancier<strong>in</strong>g van het geriatr<strong>is</strong>ch dagziekenhu<strong>is</strong>. D/2008/10.273/90<br />
100. Drempelwaarden voor kosteneffectiviteit <strong>in</strong> de gezondheidszorg. D/2008/10.273/94<br />
101. Videoreg<strong>is</strong>tratie van endoscop<strong>is</strong>che chirurg<strong>is</strong>che <strong>in</strong>terventies: rapid assessment.<br />
D/2008/10.273/97<br />
102. Nosocomiale Infecties <strong>in</strong> België: Deel II, Impact op Mortaliteit en Kosten.<br />
D/2009/10.273/99<br />
103. Hervorm<strong>in</strong>gen <strong>in</strong> de geestelijke gezondheidszorg: evaluatieonderzoek ‘therapeut<strong>is</strong>che<br />
projecten’ - eerste tussentijds rapport. D/2009/10.273/04.<br />
104. Robotgeass<strong>is</strong>teerde chirurgie: health technology assessment. D/2009/10.273/07<br />
105. Wetenschappelijke ondersteun<strong>in</strong>g van het College voor Oncologie: een nationale<br />
praktijkrichtlijn voor de aanpak van pancreaskanker. D/2009/10.273/10<br />
106. Magnet<strong>is</strong>che Resonantie Beeldvorm<strong>in</strong>g: kostenstudie. D/2009/10.273/14<br />
107. Vergoed<strong>in</strong>g van schade ten gevolge van gezondheidszorg – Fase V: Budgettaire impact<br />
van de omzett<strong>in</strong>g van het Franse systeem <strong>in</strong> België. D/2009/10.273/16
108. Tiotropium <strong>in</strong> de behandel<strong>in</strong>g van Chron<strong>is</strong>ch Obstructief Longlijden (COPD): Health<br />
Technology Assessment. D/2009/10.273/18<br />
109. De waarde van EEG en geëvokeerde potentialen <strong>in</strong> de kl<strong>in</strong><strong>is</strong>che praktijk.3<br />
D/2009/10.273/21<br />
110. Positron Em<strong>is</strong>sie Tomografie: een update. D/2009/10.273/24<br />
111. Medicamenteuze en niet-medicamenteuze <strong>in</strong>terventies voor de ziekte van Alzheimer,<br />
een rapid assessment. D/2009/10.273/27<br />
112. Beleid voor weesziekten en weesgeneesmiddelen. D/2009/10.273/30.<br />
113. Het volume van chirurg<strong>is</strong>che <strong>in</strong>grepen en de impact ervan op de uitkomst:<br />
haalbaarheidsstudie op bas<strong>is</strong> van Belg<strong>is</strong>che gegevens. D/2009/10.273/33.<br />
114. Endobronchiale kleppen bij de behandel<strong>in</strong>g van ernstig longemfyseem Een “rapid” Health<br />
Technology Assessment. D/2009/10.273/37.<br />
115. Organ<strong>is</strong>atie van palliatieve zorg <strong>in</strong> België. D/2009/10.273/40<br />
116. Rapid assessment van <strong>in</strong>tersp<strong>in</strong>ale implantaten en pedikelschroeven voor dynam<strong>is</strong>che<br />
stabil<strong>is</strong>atie van de lumbale wervelkolom. D/2009/10.273/44<br />
117. Gebruik van po<strong>in</strong>t-of care systemen bij patiënten met orale anticoagulatie: een Health<br />
Technology Assesment. D/2009/10.273/47<br />
118. Voordelen, nadelen en haalbaarheid van het <strong>in</strong>voeren van ‘Pay for Quality’ programma’s<br />
<strong>in</strong> België. D/2009/10.273/50.<br />
119. Aspecifieke nekpijn: diagnose en behandel<strong>in</strong>g. D/2009/10.273/54.<br />
120. Hoe zelfvoorzien<strong>in</strong>g <strong>in</strong> stabiele plasmaderivaten voor België verzekeren?<br />
D/2009/10.273/57.