The report is available in English with a French summary - KCE

Comment assurer l’autosuffisance 

de la Belgique en dérivés 

stables du plasma? 

KCE reports 120B 

Federaal Kenniscentrum voor de Gezondheidszorg 

Centre fédéral d’expertise des soins de santé 

2009

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Comment assurer 

l’autosuffisance de la Belgique 

en dérivés stables du plasma ? 


LEONARD CHRISTIAN, HANQUET GERMAINE, SENN ARNAUD, HUYBRECHTS MICHEL 

Federaal Kenniscentrum voor de gezondheidszorg 

Centre fédéral d’expertise des soins de santé 

2009


Titre: Comment assurer l’autosuffisance de la Belgique en dérivés stables du 

plasma? 

Auteurs: Christian Léonard, Germaine Hanquet, Arnaud Senn et Michel 

Huybrechts 

Relecture: Jean-Pierre Closon (KCE) 

Experts externes: Marc Van De Casteele (INAMI), Walter Bontez (Agence Fédérale des 

médicaments et des produits de santé), Peter Van den Bergh (UCL St 

Luc), Pierrette Seeldrayers (CHU Charleroi), David Tuerlinckx (UCL 

Mont Godinne), Jutte van der Werff (AZ VUB), Isabelle Meyts (UZ 

Leuven), Filomeen Haerynck (UZ Gent), Wim Robberecht (UZ Leuven), 

Pierre Philippet (CHC Liège), Alina Ferster (HUDERF), Thierry Burnouf 

(HPPS), André De Swaef (Inami), Jean-Claude Osselaer (UCL Mont 

Godinne), 

Remerciements: Claire Michèle Farber (Erasme), Christophe Chantrain (UCL St Luc), Wim 

Stevens (UIA), Danièle Sontag (Service Francophone du Sang), Olivier 

Bertrand (Service Francophone du Sang), Véronique Deneys (Service 

Francophone du Sang), Dominique-Marie Wouters (Association 

Validateurs externes: 

Francophone des Pharmaciens Hospitaliers), le Vlaamse Vereniging voor 

Ziekenhuisapothekers (VZA) et les pharmaciens des hôpitaux belges qui 

ont participé à l’enquête sur les immunoglobulines, Leo Hertogs 

(directeur commercial CAF-DCF), Patrick Robert, The Marketing 

Research Bureau Inc, - MRB , Orange CT, USA, Charles Waller, Plasma 

Protein Therapeutics Association – PPTA – European Office , Brussels, 

Belgium, Prof. Dr. Philippe Vandekerckhove (Administrateur délégué - 

Rode Kruis Vlaanderen) 

Rosita Van Maele, Michel Delforge et Thierry Schneider 

Conflits d’intérêt: R. Van Maele a été réviseur auprès de la Rode Kruis Vlaanderen jusqu’en 

2006. T. Burnouf travaille dans la consultance dans le domaine du 

fractionnement (y compris pour le CAF-DCF), D. Tuerlinckx est 

responsable d’une étude sur les immunoglobulines, I. Meyts a été 

sponsorisée pour sa contribution à un article relatif au sujet et M. 

Delforge est titulaire d’un poste en recherche fondamentale sponsorisée 

par le CAF-DCF. 

Disclaimer : Les experts externes ont collaboré au rapport scientifique qui a ensuite 

été soumis aux validateurs. La validation du rapport résulte d’un 

consensus ou d’un vote majoritaire entre les validateurs. Le KCE reste 

seul responsable des erreurs ou omissions qui pourraient subsister de 

même que des recommandations faites aux autorités publiques. 

Mise en Page: Ine Verhulst 

Bruxelles, 24 novembre 2009 

Etude n° 2008-30 

Domaine: Health Services Research (HSR) 

MeSH: Blood Coagulation Factors ; Immunoglobulins ; Serum Albumin ; Plasma ; Red Cross ; Blood 

Banks ; supply and distribution 

NLM classification : WH 450 

Langage: français, anglais 

Format: Adobe® PDF (A4) 

Dépôt légal: D/2009/10.273/58 

La reproduction partielle de ce document est autorisée à condition que la source soit mentionnée. Ce 

document est disponible en téléchargement sur le site Web du Centre fédéral d’expertise des soins 

de santé. 

Comment citer ce rapport? 

Léonard C, Hanquet G, Senn A, Huybrechts M. Comment assurer l’autosuffisance de la Belgique en 

dérivés stables du plasma? Health Services Research (HSR). Bruxelles: Centre fédéral d’expertise des 

soins de santé (KCE). 2009. KCE Reports 120B. D/2009/10.273/58

KCE Reports 120B Plasma i 

PRÉFACE 

Les médicaments sont généralement fabriqués à partir de substances que l’on trouve 

dans la nature en quantités quasi illimitées. Il n’en va pas de même pour la majorité des 

dérivés plasmatiques qu’il est impossible de fabriquer d’une autre manière que par 

fractionnement de plasma humain dont la quantité est limitée à ce qui a pu être collecté 

auprès de donneurs. 

Comme les dérivés stables du plasma sont parfois les seuls remèdes possibles à des 

maladies graves, on comprend que les autorités de santé s’enquièrent des précautions 

nécessaires pour garantir un approvisionnement suffisant du pays compte tenu de ce 

facteur limitant à la source. 

Interrogé à ce sujet, le KCE s’est rapidement rendu compte de la complexité du 

problème liée aussi bien aux conditions de collecte (volontariat et gratuité des dons) 

qu’aux problèmes d’équilibre financier des différents acteurs et au peu de transparence 

à ce sujet. Nous avons cependant pu repartir d’audits déjà effectués. 

Nous remercions tous ceux qui nous ont aidés à y voir plus clair et en particulier les 

hôpitaux qui ont répondu massivement à notre enquête. Nous espérons avoir ouvert 

suffisamment de voies pour aider les décideurs à mettre en place des solutions à la fois 

sûres et coût-efficaces. 

Jean-Pierre Closon 

Directeur général a.i.

ii Plasma KCE Reports 120B 

CONTEXTE 

Résumé 

Le sang assure le transport d’éléments essentiels à la vie chez la personne, mais il 

permet aussi de produire des dérivés qui interviennent dans le traitement d’affections 

particulières chez d’autres personnes tels que les immunodéficiences et l’hémophilie. 

Ces dérivés résultent d’un processus de fractionnement du plasma. Le plasma est la 

partie liquide du sang de couleur transparente et jaune, composée à 90 % d’eau et pour 

le reste d’immunoglobulines (à la consommation desquelles nous consacrons une partie 

de ce rapport), d’albumine, de facteurs de coagulation et de lipoprotéines. Ce plasma 

est obtenu soit par séparation des cellules sanguines à la suite d’un don de sang total, 

soit par plasmaphérèse, processus qui consiste à isoler le plasma du sang d’un donneur 

qui conserve ainsi ses cellules sanguines. 

En Belgique, la totalité du sang et du plasma est collectée par la Croix Rouge et 

quelques petits centres indépendants. Les donneurs ne sont pas rémunérés 

conformément aux règles en vigueur dans l’Union Européenne. Le plasma collecté est 

vendu au Département Central de Fractionnement (DCF) a , une entreprise qui en 

effectue le fractionnement. 

La plupart des pays européens consomment une quantité plus grande de produits 

dérivés que ce que l’on peut extraire du sang et du plasma collectés auprès de leurs 

citoyens. Ils doivent donc s’approvisionner pour le surplus auprès de fractionneurs qui 

achètent du plasma à l’étranger. Si ce plasma étranger venait un jour à manquer ou à 

n’être plus vendu qu’à des prix exorbitants, les pays importateurs pourraient se trouver 

en difficulté. Difficulté d’autant plus importante que les dérivés plasmatiques sont 

indispensables pour soigner certaines maladies graves, D’où la question posée au KCE 

de l’auto suffisance de la Belgique en plasma et dérivés stables du plasma et des 

précautions à prendre pour réduire au maximum le risque de pénurie. 

QUESTIONS DE RECHERCHE 

Pour éclairer cette problématique, nous avons tenté de répondre aux questions de 

recherche suivantes: 

A propos de l’offre: 

• Comment et en quelles quantités le plasma est il collecté en Belgique et dans 

d’autres pays? Quelles sont les évolutions observées? Quels subsides sont 

accordés pour assurer une collecte suffisante? 

• Comment se passe la transformation du plasma recueilli en Belgique en 

produits dérivés stables? Quelles sont les quantités produites? Comment le 

processus est-il financé? 

A propos de la demande: 

• Quelles sont les indications médicales traitées avec des dérivés stables du 

plasma ? Quelles quantités sont nécessaires pour traiter ces indications et 

quelles sont les quantités consommées en Belgique? Quelles tendances peuton 

prévoir dans les prochaines années? 

A propos de la sécurité de couverture de la demande : 

• Que faut-il entendre par sécurité de couverture d’une manière générale ? 

Quel niveau de couverture cherche-t-on à atteindre en Belgique et dans 

d’autres pays? 

• Quelles sont les différentes démarches possibles pour atteindre de façon 

optimale un niveau de couverture choisi? 

a En néerlandais: Centrale Afdeling voor Fractionering (CAF). Au départ, il s’agissait d’un département de la 

Croix Rouge. Aujourd’hui, il s’agit d’une entreprise commerciale multi nationale, dans laquelle la Croix 

Rouge n’est plus qu’un actionnaire minoritaire.

KCE Reports 120B Plasma iii 

MÉTHODOLOGIE 

Nous avons adopté des méthodologies spécifiques à chacun des trois thèmes traités 

dans ce rapport. 

En ce qui concerne les questions relatives à l’offre : 

Afin de déterminer les quantités de plasma collectées, nous avons recueilli des données 

auprès des collecteurs belges. Des données fournies par la Croix-Rouge et le CAF- 

DCF ont été recoupées avec des données issues d’un audit de ces deux institutions afin 

de déterminer les quantités de plasma vendues et achetées et leurs prix. Les données 

INAMI et une enquête auprès des hôpitaux nous ont permis de déterminer les quantités 

totales de produits dérivés vendues en Belgique, en distinguant celles fournies par le 

CAF – DCF et celles fournies par des firmes commerciales étrangères. 

Nous avons étudié l’évolution des quantités de dérivés stables produites et vendues par 

le CAF-DCF et les avons mises en regard des quantités de plasma qu’il achète à la Croix 

Rouge. . Des documents internes de la Croix-Rouge ainsi que l’audit dont elle a été 

l’objet nous ont permis d’évaluer les coûts de ses activités et notamment de la 

plasmaphérèse qui constitue le mode de collecte de plasma dont la rentabilité était 

supposée insuffisante. Les prix perçus par la CR ont été comparés aux prix 

internationaux afin d’évaluer le gain potentiel pour la CR de vendre son plasma sur le 

marché international. 

En ce qui concerne les questions relatives à la demande : 

La recherche s’est concentrée sur les immunoglobulines (IG), qui représentent le dérivé 

plasmatique le plus déterminant de la demande. Les recommandations de bonne 

pratique en vigueur en Belgique et dans d’autres pays industrialisés ont été analysées. 

Une revue de la littérature, centrée sur les revues systématiques, s’est penchée sur 

l’efficacité des immunoglobulines pour les indications généralement reprises dans les 

recommandations nationales en vue de pouvoir expliquer et prévoir les quantités 

consommées. Les caractéristiques de consommation d’autres pays industrialisés ont été 

analysées pour déterminer quelles indications, pour lesquelles les IG ont montré une 

efficacité, représentaient la plus grande partie de la consommation en IG. En ce qui 

concerne la consommation en Belgique, trois domaines ont été examinés: 

• Les données globales de consommation belge, basées sur les données de 

l’Inami (2004-2007) et sur une enquête auprès des pharmacies des hôpitaux 

belges (2008), ont permis d’étudier les consommations « réelles » en terme 

de quantités globales prescrites et/ou remboursées en Belgique. 

• Les distributions des quantités prescrites par hôpital et par spécialité 

médicale, ainsi que les pratiques médicales en cours, ont été étudiées à 

travers l’enquête auprès des pharmacies et une deuxième enquête auprès de 

services universitaires d’immuno-hématologie. 

• Une estimation théorique des quantités d’IG nécessaire pour traiter les 11 

indications reconnues qui ont consommé 74% des IG dans les autres pays a 

été réalisée sur base des données épidémiologiques belges ou des pays 

voisins, ainsi que des pratiques dans les centres belges ou internationaux. 

En ce qui concerne les questions relatives à la sécurité de couverture de la 

demande: 

Les dispositions prises en Belgique pour assurer son auto suffisance en dérivés stables 

du plasma, ont été analysées. Une recherche dans la littérature grise et des contacts 

étrangers nous ont permis de décrire les systèmes d’approvisionnement, de la collecte à 

la consommation, dans plusieurs pays étrangers (France, Allemagne, Australie, Canada).

iv Plasma KCE Reports 120B 

RÉSULTATS 

En ce qui concerne le concept de sécurité de couverture 

La réglementation belge ne définit pas la proportion de produits sanguins stables 

d’origine humaine qui doit être produite en Belgique pour garantir son auto suffisance. 

Un arrêté royal de 1998 précise seulement que pour garantir l’auto suffisance et la 

qualité de l’approvisionnement du pays en produits sanguins stables d’origine humaine, 

le prix du litre de plasma vendu par la Croix Rouge au CAF-DCF sera subsidié et qu’un 

Collège de réviseurs transmettra chaque année au SPF le nombre de litres vendus en 

vue de calculer correctement le subside. Dans les faits, ce Collège observe qu’une 

quantité équivalente à 60% de la consommation plus un stock de quarantaine de 180 

jours sont subsidiables. On en déduit implicitement que la Belgique est ainsi auto 

suffisante mais nous n’avons trouvé aucune justification scientifique de cette proportion 

ni de la durée de la quarantaine (période pendant laquelle le plasma doit être conservé 

avant d’être fractionné). Celle-ci est passée de 50 à 180 jours entre 1998 à 2006 sans 

que rien ne justifie cette hausse d’un point de vue de la sécurité médicale. Au contraire, 

de nouvelles techniques d’analyse biologique permettent de réduire la quarantaine de 

façon drastique. Il semble donc que les concepts d’autosuffisance et de quarantaine 

n’ont jamais été vraiment réfléchis et définis en Belgique. 

Au niveau international, on ne retrouve pas non plus de justification officielle précise de 

ce qu’il serait plus exact d’appeler un ‘degré d’indépendance’. En Australie, 

l’indépendance complète semble être une finalité implicite même si il est accepté d’avoir 

recours aux firmes étrangères pour des besoins précis et ponctuels. En France, 

l’autosuffisance - définie comme la part représentée par le chiffre d’affaires de 

l’opérateur national LFB dans le chiffre d’affaires total de la branche considérée sur le 

marché national - représente 75% pour les produits plasmatiques mais avec des 

variations selon les produits considérés (par ex : 60% pour les IG). L’objectif fixé au LFB 

(Laboratoire Français de Fractionnement et de Biotechnologie) est d’atteindre un niveau 

de production capable de couvrir potentiellement 100 % des besoins des patients 

français en 2011. Toutefois, si LFB est le seul opérateur à fractionner le plasma livré par 

l’Etablissement Français du Sang, il ne détient pas pour autant le monopole de vente des 

produits plasmatiques et reste en concurrence avec les autres entreprises présentes sur 

le marché français. 

En ce qui concerne la collecte du plasma 

Chaque pays développe des stratégies particulières pour collecter le plasma en quantités 

suffisantes. En France et en Allemagne, afin de favoriser le don de plasma, l’accent est 

mis sur les 18-25 ans et la collaboration avec les universités ainsi que sur le suivi régulier 

des donneurs (très efficace) et la standardisation des dons de manière à augmenter le 

volume par don. L’Etablissement Français de Sang s’est engagé contractuellement à 

augmenter ses livraisons de plasma au LFB. En Allemagne, la logique commerciale 

prévaut (80% des dons) et les dons sont compensés financièrement (jusqu’à 25 euros / 

limite fixée par la loi). En Australie, la collecte, l’approvisionnement en produits dérivés 

et les contrats sont gérés par la National Blood Authority. 

En Belgique, sur base des données disponibles, la plasmaphérèse est une activité en 

perte de vitesse à la Croix-Rouge qui a même fermé certains centres de plasmaphérèse. 

Peut être la plasmaphérèse n’est elle pas jugée suffisamment rentable ? Cette rentabilité 

est toutefois fonction, au moins partiellement, du mode d’affectation de coûts fixes à 

l’ensemble des activités. 

Chaque litre de plasma issu de plasmaphérèse et vendu dans le cadre de l’autosuffisance 

donne droit à un subside de 24,79 euros versé à la CR, de façon à lui permettre de 

vendre ce plasma au CAF – DCF à un prix plus bas. La CR reçoit également un subside 

afin de couvrir le coût des tests NAT (Nucleic Acid Tests), effectués sur les 

prélèvements de sang, qui détectent la présence éventuelle de certains virus. Le 

paiement des consommables à la firme qui les commercialise est peu transparent et 

permet de facturer des tests qui n’auraient pas été effectués réellement.

KCE Reports 120B Plasma v 

En ce qui concerne la transformation du plasma en produits dérivés stables : 

Le CAF – DCF assure le fractionnement de tout le plasma acheté sur le territoire en 

partenariat avec trois entreprises (allemande, française et hollandaise). Les conventions 

de partenariat ne sont pas rendues publiques. Nos calculs montrent que le rapport 

entre les quantités de dérivés produites et les quantités de plasma fractionné par le 

CAF-DCF, est très variable d’une année à l’autre. Cette variabilité semble liée aux 

modifications de la demande intérieure et à la part de marché du CAF-DCF. Pour 

certains dérivés et certaines années, le CAF-DCF dispose de plus de plasma qu’il n’est 

nécessaire pour produire les quantités qu’il parvient à vendre. 

En ce qui concerne la consommation des produits dérivés stables : 

Les immunoglobulines (IG) sont les dérivés qui nécessitent les plus grandes quantités de 

plasma pour répondre aux besoins thérapeutiques. Les IG représentent aussi la majorité 

des dépenses en dérivés stables (33.4 millions € ou 62% du total des dérivés stables en 

2006), leur consommation augmente de manière continue et le nombre d’indications 

pour lesquelles les IG sont utilisées ne cesse d’augmenter. En Belgique, les IG sont 

actuellement remboursées pour 13 indications. Une analyse de la prescription d’IG dans 

les hôpitaux belges a été réalisée. Il en ressort que les prestataires de quatre spécialités 

ont prescrit 92% des IG en 2008 (médecine interne, neurologie, pneumologie et 

pédiatrie). On observe une grande hétérogénéité de la prescription entre les hôpitaux, 

en particulier en pneumologie. La prescription élevée d’IG en pneumologie (16% du 

total), prédominante dans quelques hôpitaux non universitaires, ne peut être reliée aux 

indications remboursées en Belgique, à l’exception de certaines déficiences immunitaires 

présentant des infections respiratoires bactériennes répétées qui seraient traitées par 

des pneumologues; ce phénomène a également été rarement observé dans d’autres 

pays. En ce qui concerne l’évolution future de la demande, aucun modèle n’a pu être 

défini : certains facteurs pourraient augmenter la demande, comme des nouvelles 

indications potentielles et l’augmentation de prévalence de certaines maladies affectant 

surtout les personnes âgées ; d’autres facteurs pourraient la diminuer, comme une 

limitation de la prescription aux indications reconnues et le développement de thérapies 

alternatives pour les indications actuelles des IG. 

Les indications remboursées en Belgique ont été comparées à celles recommandées 

et/ou remboursées dans cinq autres pays (France, Royaume Uni (RU), Pays Bas, Canada 

et Australie), Table 1. Des recommandations belges sur l’utilisation des 

immunoglobulines sont actuellement en cours d’élaboration au Conseil Supérieur de la 

Santé (CSS/HGR).

vi Plasma KCE Reports 120B 

Table 1: Indications pour lesquelles l’utilisation d’immunoglobulines est 

remboursée en Belgique, sous certains critères définis. 

Indications remboursées en Belgique Autres pays recommandant les IG dans 

le traitement de cette indication* 

Syndromes d’immunodéficience primaire France, RU, Pays Bas, Canada, Australie 

Myélome et leucémie lymphoïde chronique (avec France, RU, Pays Bas, Canada, Australie 

hypogammaglobulinémie secondaire sévère et infections 

récidivantes) 

Purpura thrombocytopénique idiopathique France, RU, Pays Bas, Canada, Australie 

SIDA pédiatrique France, Pays Bas, Canada, Australie 

Syndrome de Guillain-Barré France, RU, Pays Bas, Canada, Australie 

Maladie de Kawasaki France, RU, Pays Bas, Canada, Australie 

Prévention des infections chez des patients subissant France, RU, Pays Bas, Australie 

une transplantation allogène de moelle osseuse 

Traitement de septicémie chez des prématurés Pays Bas, Australie (prévention en France) 

Traitement de septicémie pendant la période néonatale France, Australie 

Le traitement du syndrome du choc toxique d’origine France, RU, Australie 

streptococcique. 

La polyradiculoneuropathie démyélinisante 

France, RU, Canada, Australie 

inflammatoire chronique 

La neuropathie motrice multifocale France, RU, Canada, Australie 

*: Sources: Guidelines nationaux au Royaume Uni, Australie et Canada; liste publiée par l’Agence 

française de sécurité sanitaire des produits de santé (Afssaps) et la Haute Autorité de Santé en 

France; indications autorisées par le Medicine Evaluation Board aux Pays Bas. 

LIMITATIONS 

Il existe des indications, pour lesquelles les IG ne sont pas remboursées en Belgique, 

mais pour lesquelles une revue de la littérature scientifique a montré que les 

immunoglobulines pouvaient apporter une amélioration. Cependant, d’autres thérapies 

efficaces existent pour la plupart de ces pathologies. 

La première des limitations de ce rapport est liée aux données que nous avons pu 

récolter. Nous n’avons pas pu recueillir de données sur les immunoglobulines non 

remboursées en 2004-2007. Pour 2008, les données rapportées par les pharmacies 

hospitalières sont plus complètes mais nous ignorons si l’utilisation d’immunoglobulines 

à usage compassionnel est inclue dans les données de tous les hôpitaux interrogés. 

Celles-ci pourraient représenter une proportion significative des consommations 

d’après certains experts, et nous amèneraient donc à sous-estimer systématiquement 

les consommations en IG et donc la demande réelle. 

La deuxième limitation est liée à l’absence de vérification de l’affectation des coûts de 

structure de la Croix Rouge à l’activité de plasmaphérèse. Une autre forme de 

ventilation des coûts serait donc susceptible de réduire le déficit financier, voire de le 

supprimer. 

La troisième limitation est liée à la variabilité du prix du plasma dans le temps et l’espace 

sur le marché international. Cette variabilité empêche de tirer des conclusions claires 

sur les gains potentiels en cas de vente du plasma sur le marché international

KCE Reports 120B Plasma vii 

RECOMMANDATIONS 

En ce qui concerne la définition de l’autosuffisance 

• Le niveau implicite de couverture des besoins admis en Belgique entraîne une 

dépendance partielle à l’égard du marché international. Cette dépendance 

devrait résulter d’un choix politique conscient basé sur une analyse de risques 

tenant compte des prix internationaux, de l’offre et de la demande 

internationales et des capacités de la CR et du CAF – DCF à répondre 

positivement à une hausse éventuelle de la demande intérieure. 

• Il est recommandé de revoir à la baisse le nombre de jours requis par la 

quarantaine pour sécurité biologique. 

En ce qui concerne la collecte de plasma 

• Si l’autorité publique décidait d’augmenter le degré d’indépendance de 

l’approvisionnement en produits dérivés, il serait utile de s’inspirer des 

nombreuses politiques mises au point à l’étranger et sur les réflexions 

existant au niveau de l’UE. Ainsi, il est recommandé : 

o de mieux cibler le recrutement notamment en termes de tranches 

d’âge et de cibler les jeunes adultes (18-25) en priorité ; 

o d’assurer un suivi régulier des donneurs, et de façon plus générale une 

bonne gestion de celui-ci par l’organisme de collecte ; 

o de procéder à des campagnes intensives de sensibilisation ; 

o sur le plan technique, de veiller à une véritable standardisation et 

optimisation des pratiques de collecte. 

• Dans une optique d’équité, l’ensemble des donneurs et en particulier les 

travailleurs, devraient être traités de la même manière, notamment en 

uniformisant progressivement les avantages octroyés en cas de don de sang 

ou de plasma. 

• En raison d’un système peu transparent relatif à la facturation des tests NAT 

(Nucleic Acid Tests) et à leur subsidiation, il est recommandé de procéder à 

une détermination des subsides qui tienne mieux compte des coûts réels 

supportés par la CR ou de vérifier la possibilité d’inclure le coût de ces tests 

dans le prix du sang. 

En ce qui concerne la consommation de dérivés stables du plasma 

• La variabilité des pratiques constatées - surtout dans des centres 

périphériques - invite à recommander 

o la production de guidelines au sujet de la prescription d’IG et de 

traitements alternatifs (une initiative en ce sens est en cours au 

CSS/HGR) ; 

o de privilégier une prescription et un suivi par des spécialistes et des 

centres de références pour le traitement par IG au long cours, comme 

cela est prévu pour l’usage du facteur VIII (convention pour les centres 

d’hémophilie). 

• Il est recommandé aussi d’améliorer le suivi de la prescription par 

l’établissement par exemple d’un registre ou d’une base de données des 

patients traités par IG au long cours, et par la transmission de feedbacks aux 

prescripteurs avec l’utilisation de benchmarking.

viii Plasma KCE Reports 120B 

En ce qui concerne la transparence des activités et des comptes des 

organismes subsidiés 

Une autorité subsidiante doit pouvoir contrôler l’utilisation des subsides qu’elle octroie 

directement ou indirectement. Par conséquent: 

• Il est recommandé de lier la poursuite de la subsidiation du prix du plasma 

vendu au CAF-DCF à une communication transparente 

o des flux financiers et en volumes relatifs au plasma et aux 

produits dérivés qui transitent par le CAF-DCF et ses 

partenaires étrangers 

o Des termes du contrat qui lie le CAF-DCF à ses 

partenaires concernant l’utilisation directe ou indirecte du 

plasma collecté en Belgique 

de manière à pouvoir vérifier l’utilité des subsides dans le cadre d’une 

politique d’auto suffisance clairement définie; 

• Il est également recommandé de mener un audit approfondi des comptes de 

la CR afin de déterminer avec précision la structure des coûts de l’activité de 

plasmaphérèse et d’en déduire le subside minimal éventuellement nécessaire 

pour assurer que cette activité soit financièrement en équilibre, et ainsi 

soutenir la collecte du niveau souhaité de plasma source.

KCE Reports 120 Plasma 1 

Scientific summary 

Table of contents 

SCIENTIFIC SUMMARY ........................................................................................................... 1 

GLOSSARY ................................................................................................................................. 3 

1 INTRODUCTION ............................................................................................................ 5 

1.1 CONTEXT ..................................................................................................................................................... 5 

1.2 RESEARCH QUESTIONS ........................................................................................................................... 5 

2 SUPPLY OF PLASMA DERIVATIVES .......................................................................... 6 

2.1 COLLECTION OF PLASMA ...................................................................................................................... 6 

2.1.1 Legal and ethical framework .......................................................................................................... 6 

2.1.2 Plasma collection in Belgium ........................................................................................................ 12 

2.1.3 Plasma collection in other countries .......................................................................................... 22 

2.2 TRANSFORMATION OF PLASMA INTO PLASMA DERIVATIVES ............................................... 29 

2.2.1 Quick overview of fractionation process .................................................................................. 29 

2.2.2 The worldwide supply of plasma products .............................................................................. 32 

2.2.3 The supply of plasma stable derivatives in Belgium ................................................................. 34 

2.3 LIMITATIONS ............................................................................................................................................. 39 

3 DEMAND FOR PLASMA DERIVATIVES: THE CASE OF IMMUNOGLOBULINS 

.......................................................................................................................................... 40 

3.1 USE OF PLASMA DERIVATIVES IN BELGIUM .................................................................................... 40 

3.1.1 Methods ............................................................................................................................................ 40 

3.1.2 Results .............................................................................................................................................. 40 

3.1.3 The case of immunoglobulins ...................................................................................................... 42 

3.2 INDICATIONS FOR IMMUNOGLOBULINS ...................................................................................... 43 

3.2.1 Recommendations for the use of immunoglobulins................................................................ 43 

3.2.2 Evidence review on immunoglobulin effectiveness ................................................................. 49 

3.3 CONSUMPTION OF IMMUNOGLOBULINS ..................................................................................... 70 

3.3.1 Consumption in other countries ................................................................................................ 70 

3.3.2 Consumption in Belgium ............................................................................................................... 74 

3.3.3 Estimation of IG quantities to treat the main indications ...................................................... 86 

3.3.4 Expected trends in consumption ................................................................................................ 97 

4 SELF SUFFICIENCY OF BELGIUM ............................................................................ 98 

4.1 WHAT ARE THE RISKS AT WORLDWIDE LEVEL ? ........................................................................ 98 

4.1.1 Plasma collection: Key role of the North American Region ................................................. 98 

4.1.2 Worldwide demand for plasma products / Focus on IVIG (2000-2008) .......................... 100 

4.1.3 Potential changes in demand structure .................................................................................... 100 

4.2 CONCEPT OF SELF SUFFICIENCY ..................................................................................................... 101 

4.2.1 In Belgium ....................................................................................................................................... 101 

4.2.2 In other countries ........................................................................................................................ 103 

4.3 HOW TO STAY OR BECOME SELF SUFFICIENT .......................................................................... 111 

4.3.1 Strategies to decrease IG use: lessons learned ...................................................................... 111 

4.3.2 Strategies to decrease IG use: what could be applied in Belgium ...................................... 115 

4.3.3 Increasing the capacities of collecting plasma ......................................................................... 115 

4.3.4 Transparency and better control of the supply of derivatives ........................................... 116 

4.4 CONCLUSIONS ....................................................................................................................................... 117 

5 APPENDICES ............................................................................................................... 118 

APPENDIX 1: ETHICAL DIMENSION OF DONATION: QUICK OVERVIEW .................................... 118 

APPENDIX 2 : SEARCH TERMS ........................................................................................................................ 120 

APPENDIX 3: GRADE CRITERIA FOR ASSIGNING GRADE OF EVIDENCE ...................................... 121 

APPENDIX 4: IMMUNO-HAEMATOLOGICAL SURVEY ........................................................................... 122 

APPENDIX 5: POTENTIAL CHANGES IN DEMAND VOLUME: FOCUS ON TWO EMERGING 

COUNTRIES .............................................................................................................................................. 124

2 Plasma KCE Reports 120 

APPENDIX 6: FRANCE: PLASMA COLLECTION WITHIN THE EFS ..................................................... 127 

APPENDIX 7: GERMANY: PLASMA COLLECTION WITHIN THE GERMAN RED CROSS AND BY 

OTHER STAKEHOLDERS ...................................................................................................................... 129 

APPENDIX 8: AUSTRALIA: INSTITUTIONAL ASPECTS ........................................................................... 135 

6 REFERENCES ............................................................................................................... 137


GLOSSARY 

AD Alzheimer’s disease 

AFSSAPS Agence Française de Sécurité Sanitaire des Produits de Santé 

ARCBS Australian Red Cross Blood Service 

BMT Bone marrow transplantation 

CAA Coronary artery aneurysms 

CAF-DCF Centrale Afdeling voor Fractionering - Département Central de Fractionnement 

CFS Chronic fatigue syndrome 

CIDP Chronic inflammatory demyelinating polyradiculoneuropathy 

CLL Chronic lymphocytic leukaemia 

CMV Cytomegalovirus 

CR Croix Rouge 

DRK Deutsches Rotes Kreuz (German Red Cross) 

EFS Etablissement Français du Sang 

FNAIT Fetal or neonatal allo-immune thrombocytopenia 

HAART Highly active antiretroviral therapy 

HSTC Hematopoietic stem cell transplantation 

IBM 

IG 

Inclusion body myositis 

Immunoglobulins. In this report, IG is used to describe pooled polyvalent human 

immunoglobulin, that can be administered intravenously or subcutaneously; IG 

does not cover hyperimmune or specific immunoglobulins. 

ITP Idiopathic thrombocytopenic purpura 

IVIG Intravenous polyvalent immunoglobulins 

LEMS Lambert-Eaton myasthenic syndrome 

LFB Laboratoire Français de Fractionnement et de Biotechnologie 

MG Myasthenia gravis 

MM Multiple myeloma 

MMN Multifocal motor neuropathy 

MS Multiple sclerosis 

NAT Nucleic Acid Test 

NBA National Blood Authority (Australia) 

NIHDI National Institute for Health and Disability Insurance 

PID Primary immune deficiencies 

PPMS Primary progressive multiple sclerosis 

PPTA Plasma Protein Therapeutics Association 

RCT Randomized control trial 

RP Recovered Plasma 

RRMS Relapsing remitting multiple sclerosis 

RSV Respiratory Syncitial Virus 

SCIG Immunoglobulins for sub-cutaneous administration 

SFS Service Francophone du Sang 

SID Secondary immune deficiencies 

SIPLA Study on the Safety of Long-term Intensive Plasmapheresis in Donors (Germany) 

SP Source Plasma 

SPMS Secondary progressive multiple sclerosis


STC Stem cell transplant 

TFG Transfusionsgesetz (German regulation on transfusion and blood-related issues) 

VDB Vlaamse Dienst voor het Bloed


1 INTRODUCTION 

1.1 CONTEXT 

Blood transports elements that are essential to life in individuals, but it can also be used 

to produce derivatives that are used in the treatment of specific disorders in others 

such as immunodeficiency and haemophilia. These derivates are produced by a process 

called plasma fractionation. Plasma is the transparent yellowish liquid part of the blood, 

composed of 90% water and the rest of immunoglobulins (a part of this report is 

devoted to their consumption), albumin, coagulation factors and lipoproteins. This 

plasma is obtained either by separation of the red blod cells following a whole blood 

donation, or by plasmapheresis, a process used to isolate the plasma from the blood of 

a donor, which retains the red blood cells. 

In Belgium, all of the blood and plasma is collected by the Red Cross and a few 

independent centres. The donors are not paid, in accordance with the rules in force in 

the European Union. The collected plasma is sold to a company in Belgium, which 

performs the fractionation. 

The majority of European countries consume a greater quantity of derivatives than can 

be extracted from the blood and plasma collected from their citizens. They must 

therefore obtain other supplies from fractionation companies that buy plasma abroad. If 

this foreign plasma should one day be in short supply or only be available at exorbitant 

prices, importing countries may find themselves in difficulty. This difficulty is 

exacerbated by the fact that plasma derivatives are vital for the treatment certain 

serious illnesses, hence the question posed to the KCE of self-sufficiency for Belgium in 

plasma and plasma derivatives and the precautions to be taken to reduce as far as 

possible the risk of a shortfall in supplies. 

1.2 RESEARCH QUESTIONS 

To clarify the issue, we intend to answer the following questions: 

Concerning supply: 

• How and in what quantities is plasma collected in Belgium and in other 

countries? What trends have been observed? What subsidies are 

provided to ensure that enough is collected? 

• How are derivative products manufactured from the plasma collected in 

Belgium? What are the quantities produced? How is it financed? 

Concerning demand: 

• Which medical indications are treated with plasma stable derivatives ? 

Which amounts are required to treat these conditions and which 

amounts are consumed in Belgium? Which trends can we expect over 

the coming years? 

Concerning security of coverage of demand: 

• What it meant by security of coverage in general? What level of coverage 

do we seek to achieve in Belgium and in other countries? 

• What different approaches could be used to achieve optimally the desired 

level of coverage?


2 SUPPLY OF PLASMA DERIVATIVES 

2.1 COLLECTION OF PLASMA 

2.1.1 Legal and ethical framework 

Plasma donation and collection processes have to abide by specific rules, both from a 

sanitary and ethical point of view. 

As a human product, collection and use of plasma are subject to specific rules, with a 

view to protecting patient safety, and also donor’s security. Moreover specificity of 

plasma is that they stem from human donation. In the current state of science, artificial 

plasma as such cannot be produced, and the supply of plasma cannot be guaranteed. 

Therefore donation is of paramount importance. 

However, one must clearly distinguish one the one hand donation and collection that 

remain in the hands of each national system and on the other hand the global market of 

plasma-derived products, that is subject to free competition between private firms. 

For all these reasons, a very strict and specific legal and ethical framework has been 

defined. Given the high level of economic integration between EU economies in the field 

of plasma-derived products, but also the common expectations of EU citizens, these 

rules have been set out on the EU level. 

2.1.1.1 European and international context: which impact? 

EU regulatory framework on blood and blood products 

More precisely, the key regulatory texts of the EU legal framework cover the following 

subjects: 

QUALITY ISSUES: 2 DIRECTIVES 

Directive 2002/98/EC (27 January 2003) 1 setting standards of quality and safety for 

the collection, testing, processing, storage, and distribution of human blood and blood 

components and amending directive 2001/83/EC. This directive focuses on the following 

aspects: provisions for establishments, quality management, haemovigilance, quality and 

safety of blood (and blood components), reporting requirements, etc… 

Directive 2004/33/ EC (22 March 2004) 2 implementing directive 2002/98 as 

regards certain technical requirements for blood and blood components. This directive 

is also of paramount importance, as the appendixes list the key requirements for the 

practical organization of blood donation: definition of terms and concepts, eligibility 

criteria for donors, storage and distribution conditions, quality/safety requirements. 

TRACEABILITY REQUIREMENTS: 1 DIRECTIVE 

Directive 2005/61/ EC (30 September 2005) 3 implementing directive 2002/98 of 

the European Parliament and of the Council as regards traceability requirements and 

notification of serious adverse events reactions and events. 

QUALITY SYSTEM FOR BLOOD ESTABLISHMENTS: 1 DIRECTIVE 

Directive 2005/62/ EC (30 September 2005) 4 implementing directive 2002/98 of 

the European Parliament and of the Council as regards Community standards and 

specifications relating to a quality system for blood establishments. 

However, the issue of self-sufficiency as such has not been addressed by the EU 

regulation so far and has been left to each country’s discretion. Besides, as far as plasma 

products are concerned, some further explanation is required, in terms of legal status. 

Indeed, it is a thorny and complex problem both from an intellectual and political point 

of view.


Focus: status of plasma products with regard to the EU legislation 

Legal status of plasma-derived products remains a sensitive and delicate subject both 

from a legal and political point of view. 

The main issue is to have a clear view on the legal nature of blood products, to be 

specific of plasma-derived products. Whereas these products are blood products or 

drugs might have far-reaching consequences, especially in terms of freedom of 

circulation. 

Until now, no case law of the European Court of Justice has been identified on the legal 

status of blood or plasma products, as such. 

The problem has really not been solved and the arguments listed below must be 

considered with great care, and might be challenged by the ECJ in the future. To some 

extent, one can rely on a body of legal evidence, considering the spirit of the existing 

EU legislation on blood and blood products. 

Directive 2004/33/ EC (22 March 2004) mentioned above sets out in Annex I a 

long and precise list of what is considered as “blood” and “blood components”, to 

which the directive’s requirements are applicable. 

Directive 2001/83 /EC (6 November 2001) on medicinal products: it is clearly 

stated in this directive that “medicinal products derived from human blood or human 

plasma” can resort to “albumin, coagulating factors and immunoglobulin of human 

origin”. We can easily draw the conclusion that all these products are considered as 

medicinal products. 

One can easily infer from the directives mentioned above that products that are listed 

in the Directive are blood products (and not pharmaceutical drugs) and are a matter for 

the EU Blood and Blood products legislation. Likewise, one can also infer that products 

resorting to human plasma (alone or combined with other substances) that are sold by 

pharmaceutical firms, after completion of the fractionation process, must be considered 

as drugs. 

Nonetheless, plasma fractionation is an extremely long and complex process, and the 

range of plasma-derived products is very wide. Therefore, a “grey zone” can be 

identified between blood and blood-components and plasma-derived drugs as described 

in the previous paragraph. The main issue is to define accurate criteria to distinguish 

“blood components” and “pharmaceutical drugs” and to draw a border between both 

concepts. This is not an easy task, from a purely conceptual and legal point of view. 

For lack of regulatory definition (or official case law of the European Court of Justice), 

several EU Directives on health-related subjects can provide us with interesting clues on 

that point, in several texts especially EU Regulation (EC) 1394/2007 on advanced 

therapies (13 November 2007) on advanced therapy medicinal products (amending 

Directive 2001/83 and Regulation 726/2004). The latter regulation deals with advanced 

therapies resorting to cells or tissues. One of the key issues of this regulation is to 

identify products that can be considered as “medicinal products”. To this end, the 

regulation (Art.2 Definitions) resorts to the concept of “engineered products” (as 

opposed to non engineered products). 

To be more specific only cells or tissues that undergo “substantial manipulations” can be 

considered as “advance therapy medicinal products”. Given that clinical practice or 

scientific literature do not give a clear-cut definition of this concept, this regulation sets 

out a list of practices (Annex I) that are not considered as “substantial manipulations”. 

In practical terms, such practices as centrifugation, sterilization, filtering, and freezing 

can be considered as “substantial manipulations” as such. 

Then, a second criterion is used in the Directive, to be specific the volume of 

production: the scope of the regulation clearly refers to the routine industrial 

production of medicinal products (with a view to putting them on the market), and not 

to custom-made treatments. Thus, a product that is used within a hospital in compliance 

with a medical prescription and delivered to a patient is clearly excluded from the scope 

of the regulation, since it is not considered as a medicinal product.


In the light of these criteria, only products that comply with these two criteria should 

be considered as “medicinal products”. However, one must remain cautious on that 

point, and keep this legal issue under scrutiny. 

Apart from purely regulatory subjects, the EU level also plays a strategic role in the 

promotion of voluntary unpaid donation, in order to identify avenues worth exploring 

to improve EU countries’ self-sufficiency, within the ethical and regulatory framework 

described above. This EU will play an important role over the next years. 

EU policy and ongoing projects on promotion of voluntary unpaid donation 

SURVEY OF THE EU COMMISSION (DG SANCO) ON PROMOTION OF UNPAID 

DONATION 

One of the key issues for political decision-makers, but also for practical organization of 

blood and plasma donation is the lucrative or unpaid nature of donation. This takes us 

back to ethical notions, and to a philosophical and political debate. 

Some countries like the United States clearly opted for remuneration of donation, 

whereas others - like Canada and EU countries - opted for non remuneration of 

donation. The EU level formally recorded that donation is unpaid. Within this ethical 

framework, the EU level organized an in-depth enquiry to learn more on existing 

practices on unpaid donation across Member States. 

A Europe-wide survey has been launched by the EU-Commission (DG Sanco) 5 a few 

years ago on that subject, and a summary report has been issued on 17 th May 2006. 

Across Member States, practices can vary on two points: Interpretation of the principle 

of “unpaid donation” and Promotion of donation itself. 

Interpretation of the principle of “unpaid donation”: from a political and ethical point of 

view, the principle of “unpaid donation” is the cornerstone of the donation systems, all 

over the EU. However, this principle does not exclude “financial compensation” for 

donors in some countries (or in specific institutions within these countries, depending 

on their own political options). The amount of this financial compensation is kept below 

a specific threshold set out by legislation, and the nature of expenses covered (and not 

covered) by this compensation (travel expenses, car park, etc..) is generally set out very 

precisely by the country’s legislation. 

Germany is a traditional example on that point: as explained further in the report, many 

German institutions involved in donation - especially private institutions involved in 

plasma donation- apply financial compensation as an incentive for donors. The amount 

of this compensation can reach € 25 for each donation (maximum amount set out by 

the German legislation). 

As a result of this compensation mechanism and depending on the frequency of 

donation, regular donors are apt to receive a yearly amount of money, that is far from 

being nominal (around 1000 €). 

Promotion of donation itself: a very wide range of media and institutions have been 

used or mobilised to support donation: 

• Information campaigns resorting to traditional media (leaflets, posters, 

press) or modern media, especially internet. 

• Special events on donation: World blood donor day or other events 

focusing on donation. 

• Specific Student and secondary schools’ pupils awareness: in many 

Member States, raising awareness of this age group is of paramount for 

further recruitment of donors. 

FURTHER DEVELOPMENTS ON THAT SUBJECT ON THE EU LEVEL: SHARING BEST 

PRACTICES BETWEEN MEMBER STATES 

In the light of these findings, the EU Commission decided to carry out a new study on 

best practices for promotion of voluntary unpaid, in order to share best practices 

between Member States. The findings of this new study should be available in early 

2010.


Two technical European projects have been designed and implemented on donation: 

“DOMAINE” / Donor Management in Europe focusing on recruitment, retention and 

long-term management of donors and “Optimal Blood Use” focusing on the clinical and 

technical use of blood components. These projects are all the more important as they 

will be completed in 2010 and should deliver helpful information on best practices on 

these subjects. 

“DOMAINE”: Donor Management in Europe: http://www.domaineeurope.eu/Home/tabid/36/Default.aspx 

DOMAINE (Donor Management IN Europe) is a European project, in which blood 

establishments from 14 European member states and one patient-driven organisation 

join their forces on donor management. DOMAINE aims to create a safe and sufficient 

blood supply, by comparing and recommending good donor management practice. Even 

if 14 Member States play a leading role as partners countries, surveys obviously covers 

European practices, ie all EU countries, and a small number of European non-EU 

countries (as a whole 34 countries). 

This project does not deal specifically with plasma donation. However, principles of 

donor management are apt to be applied to plasma donation as well. 

The whole range of donor management issues will be addressed: donor recruitment 

strategies, donor retention strategies, deferral procedures and blood bank policy 

regarding patients requiring long-term transfusion. 

Key points 

• The EU concept of unpaid donation, opposable to all EU countries, does not 

exclude financial compensation. Interpretation of this latter concept may 

vary across Member States. Exchange of best practices on unpaid donation 

will also be available over the next years. 

• Noticeable discrepancies have been identified in donor’s management but 

also in the use of blood and plasma across EU countries. The EU level’s 

objective is to support harmonization of practices. As a result, a 

contribution is expected from 2010 onwards: Manual on donor management, 

Manual on the rational use of blood and plasma. 

2.1.1.2 Contribution to the ethical debate on donation 

Over the last decades, blood and plasma donation has raised very specific ethical 

questions for the following reasons: 

• Blood and plasma products are human products and not industryproduced 

drugs. 

• Donation is based on a voluntary and individual act (at least in western 

countries). 

• Donation does not meet supply/demand rules in the traditional economic 

sense. 

• Specific ethical problems may appear both on the donor’s and user’s side. 

• Ethical frameworks of donation systems have a major impact on selfsufficiency, 

as shown inter allia by the Canadian experience (see below). 

Main ethical dimensions of blood donation 

In Europe, many reflections have been conducted for several decades on blood and 

plasma donation and over the last years the University of Vienna in Austria 

(http://www.medicalethics.at/) , has conducted an in-depth reflection on that subject.


THE REFLECTION ON ETHICAL DIMENSION OF STEPS: 

1. Main specificities of blood and plasma donation 

The main traits of blood and plasma donation have been identified by Richard Titmuss 

and officially set out in the following article “Why give to strangers?“ Lancet 16 January 

1971 6 and his book titled “The gift relationship: from human blood to social policy” (last 

edition 1997) 7 . The most specific traits of this “Gift relationship” is its potentially onesided 

and not rewarding dimension of this donation: 

• Physically uncomfortable 

• Anonymous and not rewarding (individually) 

• Potentially one-sided dimension (donor can be excluded from a future 

donation) 

• Absence of donation does not involve any sanction 

• The use of donated blood depends on a large number of people 

• For the donor, donation is no great or definitive loss whereas for the 

recipient, it can be a matter of life and death 

For all the reasons mentioned above blood and plasma donation can be considered as a 

very specific kind of gift, not to be compared with other kind of donations or “gift 

relationships”. Moreover blood and plasma donation as such entail specific symbolic 

dimensions (Myth of Blood). Further details: see Appendix 

2. Main learnings 

It is important to underline that hindering factors for donation must be considered in 

close connection with the individuals’ past attitude towards donation (ie ever donors or 

non donors). 

The collection regimes may have an impact on donors’ motivation and donators’ 

profiles. In practice, it often involves a split between two donors profile. Therefore, it 

is of key importance to bear in mind that such subjects as financial compensation cannot 

be considered separately from other subjects. in countries were compensation is 

applied, plasma donors are generally younger, more educated, and less involved in 

professional life than whole blood donors. Conversely, in countries where no financial 

compensation is provided any clear distinction, in terms of donors’ profile, has been 

identified so far. 

MAXIMIZATION OF THE USE OF THE DONATED BLOOD AS AN ETHICAL IMPERATIVE 

Consensual prerequisites can be easily set out as follows, basically for purely practical 

reasons: 

- Plasma is a scarce resource (plasma as raw material is not industry-produced) 

- Plasma fractionation remains a complex and costly process. Therefore it involves very 

specific imperatives for stakeholders, more precisely: 

• Facilitating plasma collection (bringing down actual or potential barriers to 

donation) 

• Handling plasma and plasma-derived products cautiously 

• Distributing burdens and benefits fairly to all participants of the collection 

and supply chain 

• Needs of the population are not always easy to meet (self-sufficiency 

issue). 

ETHICS OF THE PLASMA ORGANIZATION 

Ethical dimension can work both ways: as clearly explained by Healy 8 , “Collection 

regimes do not simply increase or decrease the donation rate along a sliding scale. They 

shape the kind of activity that blood donation is. How you organize a blood supply 

system not only affects how much you collect and who you get it from, it shapes the 

character of donation”.


Therefore, it is of key importance to consider blood or plasma collection system not 

only from a technical point of view, but also from an ethical point of view, since each 

option – whatever it is- is apt to have a major impact on the ethical dimension on 

donation and thus on donors’ behaviour and indirectly on donors’ motivation as such. 

Given this background, four options can theoretically be considered: 

• A purely market-driven system: not affordable so far given the 

institutional European context described above. Besides it would require 

the fitting investments. 

• A solidarity-driven system: requires a strong social bond and can be easily 

implemented in smaller communities. In fact only strongly bound 

communities whose members identify themselves with the same core 

values can perform such a system and rely on it.. 

• A purely-voluntary system: “gift-fetishism”. However such a system does 

not seem to be reliable, as a matter of principle. 

Using incentives but retaining the “gift-like” features of the donation: the latter option 

money as such is not an incentive, but this does not exclude financial compensation. The 

latter option which is used in Austria or Germany for plasma donation raises specific 

problems as they can be seen as “borderline systems” from a purely ethical point of 

view. Clear-cut distinction between of incentive Vs remuneration is not always easy to 

make. 

The principle of voluntary unpaid donation 

Over the last decades, all the key institutions involved in blood and plasma donation 

have reasserted that profit as such must not be a motive for donation. Step by step, the 

principle of unpaid donation has been ethical standard for the countries of the European 

Union. This principle is officially mentioned by foremost international institutions, and 

thus accepted by Member States of these institutions: 

• International Red Cross and Red Crescent Societies / Core resolutions 

and guidelines on voluntary non remunerated blood donation: “Financial 

profit must never be a motive for the donors or those responsible for 

collecting the donation. Voluntary, non remunerated donors should 

always be encouraged” 

• Council of Europe / Art 2 of the European Conference N. R (95) 14: 

“Donation is considered as voluntary and non remunerated” (even if small 

tokens, refreshments, and reimbursement of travel costs are compatible 

with voluntary non remunerated donation). 

• World Health Organization: “Safe blood donors are the cornerstone of 

safe and adequate supply of blood and blood products. The safest blood 

donors are voluntary non remunerated blood donors from low-risk 

populations”. 

• Charter of Fundamental Rights of the European Union (Art 3): The right 

to the integrity of the person involves “The prohibition on making the 

human body and its parts as such a source of financial gain”. 

• Eventually, EU Directive 2002/98 Art 20 (opposable to all EU Member 

States) officially states that “Voluntary and unpaid blood donation are a 

factor which can contribute to high safety standards for blood and blood 

components and therefore to the protection of human health”. 

What emerges from all these statements is that blood and blood components are a 

subject of great ethical importance for the international and EU level. From an ethical 

point of view, the principle of voluntary unpaid donation is now accepted as the 

cornerstone of the donation policy in all EU countries. This is a key difference with 

other countries –especially the United States- where blood and plasma donation can be 

remunerated (even if it is not always remunerated).


The principle of unpaid donation is of key importance for the practical and technical 

organization of blood donation, as the main points of the EU ethical and regulatory 

framework should remain stable over the next years. 


• Principles underpinning blood and plasma donation are specific to this kind 

of donation. Making the best use of donated blood or plasma can be seen as 

an ethical duty. 

• Ethical donation is not contradictory with a concept of compensation or 

other incentives, within strict limits. 

• It must be borne in mind that in countries were compensation is applied, 

plasma donors are generally younger, more educated, and less involved in 

professional life than whole blood donors. Conversely, in countries where no 

financial compensation is provided no clear distinction, in terms of donors’ 

profile, has been identified so far. 

2.1.2 Plasma collection in Belgium 

2.1.2.1 Current legal framework 

In Belgium, as in any country, blood and plasma donation can be considered as an 

individual gift or a good deed, based on personal motives and/or beliefs (altruism or any 

philosophical or religious belief) but also as a collective commitment, especially in a 

professional context. 

For this reason, making public institutions and private firms (SMEs or bigger firms) 

aware of this problem and mobilizing their employees for blood donation has been one 

of the most important missions of the Red Cross over the last decades. 

However, the situation of the employees is utterly different, whether they work in a 

private or a public context. 

Private Law Contracts 

The Belgian Private Work Contract Act (3 rd July 1978) sets out all the key rules 

concerning the rights and duties of employers and employees. This Act addresses the 

different types of contract (worker’s contract, employee’s contract, sales 

representative, etc…) and covers the whole range of traditional work law issues. 

However, it remains silent about possible leave or days off for blood or plasma 

donation. Legally speaking, specific provisions, measures or arrangements can be set out 

only in the policies and procedures of each firm, but actual implementation of these 

measures (or arrangements) is left to the employer’s discretion. 

The employees are generally allowed, in this exceptional case, to leave the office just for 

the time spent for donation, (generally between 1 and 2 hours) but may be requested to 

make up for the “time lost” (“lost” from the employer’s point of view). 

In practice, blood or plasma collection is often performed by the Red Cross’s teams 

during or around a lunch pause, and employees hardly ever benefit from specific leave 

for donation. 

Public Law Contracts 

Virtually all the Belgian public law institutions have set out specific provisions, measures 

or arrangements in the employee’s contracts to enable them to benefit from specific 

leave or days off for “philanthropic purposes” which covers, inter allia, blood and 

plasma donation (as well as bone marrow and tissue donation). However, regulatory 

rules vary widely across institutions and regions, as described below:


FRENCH-SPEAKING INSTITUTIONS 

First Example – Wallonian Civil Servants [18 DECEMBER 2003 - Arrêté du 

Gouvernement wallon portant le Code de la fonction publique wallonne (Art 383)]. 

1. On the day of donation, one day off (blood donation) or one half day (plasma 

donation) is awarded to the employee. 

2. One additional day (blood donation) or one-half additional day (plasma or 

platelet donation) is also awarded to the employee, whenever donation is 

performed during office hours and when the day after donation is a work day. 

Second example – French-Speaking Community / Semi-public Institution [5 DECEMBER 

2008 - Arrêté du Gouvernement de la Communauté française fixant le statut 

administratif et pécuniaire du personnel de Wallonie-Bruxelles International (Art 316)]. 

1. On the day of donation, one day off (blood donation) or one half day (plasma 

donation) is awarded to the employee. 

2. One additional day (blood donation) or one half additional day (plasma or 

platelet donation) is also awarded to the employee, whenever donation is 

performed during office hours and when the day after donation is a work day. 

Third example – French-Speaking Community / Governmental and Audiovisual 

Institutions [2 JUNE 2004. - Arrêté du Gouvernement de la Communauté française 

relatif aux congés et aux absences des agents des Services du Gouvernement de la 

Communauté française, du Conseil supérieur de l'Audiovisuel et des organismes 

d'intérêt public relevant du Comité de Secteur XVII (Art.42)]. 

On the day of donation, one day off for blood or plasma donation is awarded to the 

employee. If the donation takes place during off-duty hours (i.e. between the end of 

workday and midnight) the day off is awarded on the day following donation. 

DUTCH SPEAKING INSTITUTIONS 

Flemish Region [13 JANUARY 2006. - Arrêté du Gouvernement flamand fixant le statut 

du personnel des services des autorités flamandes (Art 79)]. 

Employees can be awarded a one day leave for blood, plasma or platelet donation, 

(within the limit of 1 day per month). 

FEDERAL LEVEL 

Federal level: “Day-Off or leave for philanthropic purposes” [9 December 1999. – 

Circulaire n° 487 relative à l'octroi d'une dispense de service pour le don de sang, de 

plaquettes et de plasma sanguin (Art.42)]. 

As a general rule, one day off for blood, platelet or plasma donation is awarded to the 

employee (Maximum: 4 days yearly). As far as plasma donation is concerned, employees 

are allowed to start the work day 1h54 later or to leave the office 1h54 sooner than 

usual. 


• From a purely legal point of view, there are no specific incentives to get 

private firms’ employees involved into donation 

• Conversely, regulatory framework is more favourable to public law 

employees, but rewards are utterly status-dependant.


2.1.2.2 Collected Quantities 

Ninety six percent of the blood and plasma donations in Belgium are collected by the 

Red Cross, which has been placed under the responsibility of the Belgian Red Cross 

since its inception in 1935. Four non Red Cross blood centres, at Charleroi Hospital 

and UCL Hospital Mont-Godinne, AZ Sint-Jan Brugge and the Service militaire du sang 

account for the remaining blood collections. All donations are made by voluntary noncompensated 

donors, although some donors (from public sector) may receive time off 

work in addition to the time for donation. Although the Red Cross collects donations 

by plasmapheresis (source plasma), the bigger part of plasma intended for fractionation 

is recovered plasma (from whole blood donations). This report focuses solely on the 

two organizations which form the “transfusion service”: The SFS = le Service 

Francophone du Sang and the VDB = De Vlaamse Dienst voor het Bloed. 

Table 1 and figure 1 show the trend in donations of whole blood and plasmapheresis 

from 2000 to 2008. We note that the overall number of donations of whole blood is 

very stable between the start and end of the period under review. However, this 

stability between these two dates (2000 and 2008) obscures the fall at the start of the 

period (from 513 762 donations in 2000 to 503 247 in 2003 and the strong growth (+ 

4.7%) in 2004. Since then, the number of donations fell again before recovering in 2008. 

Comparing the trend in the French-speaking section of the Red Cross (SFS) with that of 

the Dutch-speaking section (VDB), we find a contrasting situation resulting in stability 

from a reduction of more than 11 000 units for the VDB offset by a rise of almost 

11 000 units for the SFS, which is partially artificial as it follows the integration of two 

independent centres by the SFS (the transfusion centre in Brussels in 2003 and the 

Hustin centre in 2004) in the SFS activities. As for the number of plasmapheresis 

donations, the trend is clearly downwards, -56% for the VDB and -63% for the SFS over 

the period in question as a whole. It seems that the drop in the number of donations of 

source plasma is linked to the closure of plasmapheresis centres. Globally, the number 

of donors is quite stable during the last three years (+ 2%), resulting from a combination 

of a decreasing for the VDB (-1.5%) and a substantial increasing for the SFS (+9%). 

Table 1: Number of donations collected by SFS and VDB and number of 

donors 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

Number of donations whole 

blood SFS 162.101 155.083 151.835 159.083 173.602 167.902 161.499 162.474 173.083 

Number of donations whole 

blood VDB 351.661 346.036 344.370 344.145 353.337 353.017 349.483 337.246 340.237 

Total number of donations 

whole blood 513.762 501.119 496.205 503.228 526.939 520.919 510.982 499.720 513.320 

Number of donations 

plasmapheresis SFS 44.569 44.515 37.791 36.106 34.691 20.538 17.013 17.021 16.315 


plasmapheresis VDB 122.518 120.653 128.727 118.700 115.898 100.654 72.167 60.962 53.568 


plasmapheresis 167.087 165.168 166.518 154.806 150.589 121.192 89.180 77.983 69.883 


cytapheresis SFS 10.776 10.155 9.994 9.995 12.066 11.921 10.293 8.861 8.582 


cytapheresis VDB 7.768 8.623 8.884 7.403 13.662 13.489 12.512 13.107 13.164 


cytapheresis 18.544 18.778 18.878 17.398 25.728 25.410 22.805 21.968 21.746 

Number of donors whole blood 

SFS 91.422 91.009 98.953 89.767 85.654 82.972 80.628 82.353 87.875 

Number of donors whole blood 

VDB 160.048 158.901 156.684 155.992 155.881 153.508 156.810 150.187 154.426 

Total number of donors whole 

blood 251.470 249.910 255.637 245.759 241.535 236.480 237.438 232.540 242.301 

Source : SFS & VDB



Figure 1: Number of donations collected by SFS and VDB 

600.000 

500.000 

400.000 

300.000 

200.000 

100.000 

0 

Source : SFS & VDB 

513.762 513.317 

167.087 

69.883 

Whole blood VDB 

Plasmapheresis VDB 

Whole blood SFS 

Plasmapheresis SFS 

Total Blood 

Total plasmapheresis 

In the following table we present the evolution of the volume of plasma collected by the 

SFS and the VDB during the period 2000-2008. The plasma from whole blood is 

decreasing in volume with 14.5% and the plasma from plasmapheresis is decreasing in 

volume with 41.4%. Globally, the total volume of plasma decreases with 24.6% 

Table 2: Volume of plasma in litres collected by SFS and VDB 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

Volume of plasma from whole blood 

SFS 36.148 38.643 35.304 39.529 36.762 35.350 34.565 35.461 37.164 


VDB 89.326 86.014 88.061 84.639 79.393 73.340 70.526 70.533 70.139 


SFS + VDB 125.474 124.657 123.365 124.168 116.155 108.690 105.091 105.994 107.303 

Volume of plasma from 

plasmapheresis & cytapheresis SFS 16.662 18.428 17.339 14.932 23.814 17.825 13.642 13.499 13.255 

Volume of plasma from 

plasmapheresis & cytapheresis VDB 60.390 59.380 57.526 52.983 70.362 60.243 43.583 36.626 32.069 

Volume of plasma from plasmapheres. 

& cytapheres. SFS + VDB 77.052 77.808 74.865 67.915 94.176 78.068 57.225 50.125 45.324 

Total volume of plasma collected by 

SFS + VDB 202.526 202.465 198.230 192.083 210.331 186.758 162.316 156.119 152.627 


It seems that the collection of plasma is a quite flexible activity. Indeed in 2004-2005, 

the demand has increased and SFS and VDB have collected more plasma from 

plasmapheresis to meet the increased demand.


Table 3: Rate of evolution of the volume of plasma during the period 2000 - 

2008 

2000 ‐ 2008 

Volume of plasma from whole blood SFS 2,8% 

Volume of plasma from whole blood VDB -21,5% 

Volume of plasma from whole blood SFS + VDB -14,5% 

Volume of plasma from plasmapheresis SFS -20,4% 

Volume of plasma from plasmapheresis VDB -46,9% 

Volume of plasma from plasmapheresis SFS + VDB -41,2% 

Total volume of plasma collected by SFS + VDB -24,6% 


We have calculated the average volume of donation of plasma for the recovered plasma 

(RP) and the source plasma (SP). The first one shows a relatively constant trend, 

around 0.210 ml per donation for the SFS. This volume has lightly decreased for VDB 

(0.254 in 2000 and 0.206 in 2008). The average volume of plasma from plasmapheresis 

has strongly increased since 2004 for the two sections of the Red Cross. 

We also noticed that the average number of donations of whole blood per donor is 

stable (Table 4), for the VDB and the SFS, during the 2003-2008 period (around 2.2) 

(The average number of donations was obtained by dividing the number of donations by 

the number of donors). Nevertheless, the evolution is different concerning the average 

number of plasmapheresis donations. Whereas this number remained stable for the SFS 

(5.7), it decreased for the VDB (7.0 in 2003 and 4.5 in 2008). 

The figures presented do not make differences between the volume of plasma collected 

from plasmapheresis and the volume of plasma collected from cytapheresis. These two 

kinds of plasma are considered as source plasma and are sold to the CAF – DCF. 

Finally, we present the average volume of plasma per donation for the RP and the SP. 

For the VDB, we received directly these average volumes per year. For the SFS, we 

have calculated the average by subtracting the assumed volume of plasma collected by 

cytapheresis (hypothesis of 200 ml per donation) of the total volume of source plasma 

collected. The results are quite similar to those of the VDB. The increase in the 

average volume since 2004 is noticeable for the two sections of the Red Cross. 

It seems that the substantial increase of SP collection in 2004 is the result of at least 

two factors: 

• A switch of practices concerning the ‘therapeutic plasma’ 

• A response to a increase of the international demand by a increase of the 

average volume per donation 

Until 2004, the plasma used by hospitals for therapeutic purposes (used in the 

treatment of some bleedings) stemmed from plasmapheresis plasma, which was 

delivered by the Red Cross. From 2004 onwards, the Red Cross was authorized to 

manufacture this therapeutic plasma, straight from its own whole blood. As a result of 

this regulatory change: 

• The corresponding volume of whole blood was tapped by the Red Cross 

(from the existing collected volume), in order to manufacture this 

therapeutic plasma. 

• Likewise, the volume of plasmapheresis plasma, which was formerly 

delivered to hospitals for therapeutic purposes, was then transferred to 

the CAF-DCF. 

This switch in practices is probably one of the factors explaining the sudden rise in the 

volume of plasmapheresis plasma delivered to the CAF-DCF, and simultaneously the 

sudden decrease in the volume of whole blood plasma delivered to the CAF-DCF in the 

year 2004. An other factor is the change in global demand, as shown for the 2004-2005 

increase (Table 2).


Table 4: Average volume of plasma per donation and average number of 

donations per donor 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

Average number of donations per donor of 

whole blood (SFS) 1,77 1,70 1,53 1,77 2,03 2,02 2,00 1,97 1,97 


whole blood (VDB) 2,20 2,18 2,20 2,21 2,27 2,30 2,23 2,25 2,20 


plasmapherese (SFS) 6,08 4,73 5,71 5,65 5,73 


plasmapherese (VDB) 7,00 6,28 6,33 6,50 6,40 6,29 5,51 5,36 4,51 

Average volume (ml) of plasma per donation of 

whole blood (SFS) 0,223 0,249 0,233 0,248 0,212 0,211 0,214 0,218 0,215 


whole blood (VDB) 0,254 0,249 0,256 0,246 0,225 0,208 0,202 0,209 0,206 


plasmapherese (SFS) 0,325 0,368 0,406 0,358 0,617 0,752 0,681 0,689 0,707 


plasmapherese (VDB) 0,493 0,492 0,447 0,446 0,607 0,599 0,604 0,601 0,599 



• The Red Cross collects 96% of all blood and plasma in Belgium 

• The number of donors of whole blood is relatively stable for the Dutchspeaking 

community and slightly up in the French-speaking community 

• The fall in the number of donations collected mainly affects source plasma (- 

58% between 2000 and 2008) 

• In 2008, the number of donations of whole blood showed a slight upturn for 

the Dutch-speaking community and confirmation of the rise in the Frenchspeaking 

community 

• The total volume of plasma has strongly decreased between 2000 and 2008, 

by - 24 % (- 14 % for RP and - 41 % for SP) 

• If the number of donation of plasmapheresis per donor has decreased since 

2000, the volume per donation has strongly increased since 2004 

2.1.2.3 The price of plasma 

The plasma (from plasmapheresis, cytapheresis (SP) and whole blood (RP)) is sold by 

the Red Cross to a fractionation company – the CAF-DCF (Centrale Afdeling voor 

Fractionering - Département Central de Fractionnement) – at a mutually agreed price 

and quantity each year. This agreement, dating back to 26 February 1998, also sets out 

the technical criteria for delivery a . The price of the RP purchased by the CAF – DCF 

has remained unchanged since 1998 (53.30 euros). In 1998, the CAF – DCF was 

granted a price cut for the purchase of SP since 1998 (53.3 euros in place of 78.09 

euros), in order to protect its competitiveness on the international market and to 

ensure the funding of the technological progress of its activities. In 2003, the price was 

increased. 

a In compliance with the 5 July 1994 Law , it is a matter of confirming that plasma must stem, as a matter 

of principle, from voluntary and non remunerated donors


Year 

Table 5 shows the trend in the price of RP and SP from 1997 to 2007 with which we 

compare the trend in international prices found in an unpublished PPTA document. 

Over the years for which data are available (2002, 2003, 2004 and 2006, 2007), it 

appears that the price of RP sold by the Red Cross to the CAF-DCF (53.07 euros) 

represents a very competitive price compared with the prices being paid on the 

international market. As a corollary, this price represents a loss of potential revenue 

for the Red Cross. For SP, the situation prior to 2003 (given the international price in 

2002) cannot have been profitable for the Red Cross. After the rise in price in 2003, 

from 53.30 to 78.09, the situation has improved: the amount received by the RC (price 

+ subsidy, see next section) is systematically higher than the international price, 

according to the sources of Table 5. 

In view of the small difference between the international price and the amount received 

by the Red Cross (price + subsidy), it is vital to confirm this analysis by comparing it 

with other sources of international prices. In Table 6, we show an average price of 

source plasma amounts to 106 euros. 

As highlighted by Verhaegen, 9 the rise in price agreed in 2003 should correspond to reestablishing 

of the competitive position of the CAF-DCF, which had completed its 

investment in buildings (construction on the site at Neder-Over-Heembeeck). 

However, retaining the subsidy for the Red Cross was without doubts linked to the 

inadequate price paid by the CAF-DCF to cover the cost of plasma collection. The 

validity of the above results depends critically on international prices. During a meeting 

of external experts, we obtained different information that international prices were 

around 75 euros for RP and 90 euros for SP, including the price of the NAT test (see 

below). Other sources 10 appear to confirm that the price paid by the CAF-DCF for 

whole blood plasma is well below the international price and that the average price that 

the Red Cross could obtain for plasma from plasmapheresis is slightly higher than the 

price it currently receives, including the subsidy (Table 6). 

Table 5: Plasma prices from 1998 to 2007 

Price of recovered plasma Price of source plasma 

paid by 

CAF 

received by 

Red Cross 

International 

price (PPTA) 

paid by 

CAF 

received by 

Red Cross 

International 

price (PPTA) 

1997 53.30 53.30 78.09 78.09 

1998 53.30 53.30 53.30 78.09 

1999 53.30 53.30 53.30 78.09 

2000 53.30 53.30 53.30 78.09 

2001 53.30 53.30 53.30 78.09 

2002 53.30 53.30 90.78 53.30 78.09 100.00 

2003 53.30 53.30 70.04 78.09 102.88 100.00 

2004 53.30 53.30 65.20 78.09 102.88 85.88 

2005 53.30 53.30 78.09 102.88 79.00 

2006 53.30 53.30 81.01 78.09 102.88 87.51 

2007 53.30 53.30 60.65 78.09 102.88 98.55 

1 Source: International Blood/Plasma News; June 2002 

2 Source: International Blood/Plasma News; June 2003 – conversion: www.oanda.com 

3 Source: International Blood/Plasma News; January 2004 – US-based suppliers, NOT Polymerase 

Chain Reaction (PCR) tested 

4 Source: International Blood/Plasma News; April 2005 – not Nucleic Acid Test (NAT) 

5 Source: International Blood/Plasma News; March 2006 

6 Source: International Blood/Plasma News; January 2007 – NAT tested


Table 6: Price of plasma from whole blood and from plasmapheresis in 2009 

(prices in euro using a conversion rate of 1 euro = 1.4 USD) 

Type of plasma and country Average price Lower end Upper end 

Whole blood USA frozen within 120h 

(the most usual) 

79 € 75 € 82 € 

Whole blood USA frozen within 24h 86 € 82 € 89 € 

Whole blood only Germany 8h and 

Austria 

Significant variations 

depending on suppliers 

95 € 110 € 

Plasmapheresis USA 106 € 100 € 114 € 

Plasmapheresis Germany (comparable 

figures) 

(Source: 10) 

Key Points 

106 € 100 € 114 € 

• The Red Cross sells the collected source plasma to the CAF – DCF at a price 

determined in a contract between the two institutions 

• We cannot determine if the price received is higher or lower than the price 

determined by the demand and supply of plasma on the international 

market 

2.1.2.4 Subsidy for source plasma 

Since 1998, the Red Cross receives a subsidy of 24.79 euros per litre of source plasma 

(from plasmapherasis and cytapherasis) sold to the CAF-DCF. The subsidy is financed 

by a supplement of 0.10% paid on compulsory car insurance premiums. 

These provisions therefore make a sometimes considerable distinction between the 

price on the Belgian market and the price on the international market. As showed in 

table 5, the Red Cross receives a fixed subsidy per liter of source plasma 

(plasmapheresis and cytapherasis plasma) sold to the CAF-DCF. The received subsidy 

had to offset a reduction in the sale price of the same amount. 


• Since 1998, the CAF – DCF benefits from a reduction of the price of source 

plasma 

• To compensate this reduction, the Red Cross receives a subsidy from the 

State 

2.1.2.5 Subsidy for NAT testing 

The transfusion establishments receive a budget that covers the cost of nucleic acid 

tests (NAT) HIV1 and HCV testing on whole blood donations. The budget takes the 

form of a provision that is subsequently topped up or clawed back depending on the 

number of tests actually performed. These budgets are determined by Royal Decrees. 

The establishments concerned are the two sections of the Red Cross, the non-profit 

organisation ‘transfusion du sang’ in Charleroi, the non-profit organisation 

‘Etablissement de transfusion de Mont-Godinne’ and the AZ Sint-Jan in Bruges. The 

final balance of the subsidy granted, to be received or reimbursed, is calculated on the 

total number of successful samples collected, effectively carried out and tested using the 

NAT tests for HIV1 and HCV.


This number of units collected and testes must be justified by the invoices relating to 

these tests and certified by an internal or external auditor. The definitive balance of the 

institutions is calculated following the submission of the supporting documents, which 

are sent to the Federal Agency for Medicines and Health Products. In 2007, a sum of 

14.00 EUR was paid for each test actually conducted. The Royal Decree states that the 

subsidies granted can under no circumstances exceed the real costs incurred. 

The remuneration procedure defined for the NAT test licence is as follows: systematic 

collection of royalties for the test manufacturer - reflecting the number of usable 

results; for example if a single test is used for 10 pouches of blood (pool testing), the 

number of royalties will be equal to ten although only one test has been used if negative 

result). In addition, the subsidy depends on the number of units successfully collected 

and the number of tests certified in an invoice. As mentioned above, these are linked to 

the number of usable results and not necessarily to the number of units used as 

reagents. This means that if a pooling process is used (which seems to be the case for 

the Red Cross), the amount of the subsidies may be dissociated from the number of 

reagents purchased. For the Red Cross, the system of pool testing may lead to a saving 

in manpower. 


• The collectors of whole blood receive a specific subsidy for the NAT tests to 

detect HIV1 and HCV 

• The Red Cross uses a system of pooling to carry out these tests, likely saving 

in manpower 

• The firm selling these tests receives royalties in function of the number of 

usable tests (not necessarily of the number of tests carried out) 

2.1.2.6 Cost of plasmapheresis 

Year 

We found the costs associated with the collection of plasma from plasmaphaeresis in an 

internal SFS report. Unfortunately, we did not have the opportunity to consult the 

same reports for the VDB. 

Table 7: Costs SFS associated with the collection of 1 liter plasma from 

plasmapheresis 

Donor 

manag 

Direct cost Organisation 

Total 

Total 

Collection Labo Distribution 

costs 

direct 

1997 2.68 49.75 15.39 1.64 69.46 20.62 90.08 

1998 4.04 50.25 13.76 0.77 68.82 17.75 86.57 

1999 4.66 52.11 17.07 0.77 74.61 20.97 95.58 

2000 5.97 53.69 15.02 0.92 75.60 20.15 95.75 

2001 7.09 62.32 16.19 1.19 86.79 23.19 109.98 

2002 3.37 65.49 19.03 1.37 89.26 17.94 107.20 

2003 5.22 67.62 27.10 1.35 101.29 16.92 118.21 

2004 7.53 67.29 27.30 1.06 103.18 24.79 127.97 

2005 8.73 67.56 27.28 1.33 104.90 26.96 131.86 

2006 10.25 72.72 28.85 1.42 113.24 31.40 144.64 

2007 9.12 78.51 29.26 1.25 118.14 35.37 153.51 

(Source: SFS – internal reports) 

If we subtract the subsidies from the total costs, we can compare the SFS net cost to 

the price received.


Table 8: Comparison of total costs minus subsidies with prices of plasma 

from plasmapheresis 

Year Total costs Subsidies 

Total costs 

minus subsidies 

Price received 

1997 90.08 0.00 90.08 78.09 

1998 86.57 24.79 61.78 78.09 

1999 95.58 24.79 70.79 78.09 

2000 95.75 24.79 70.96 78.09 

2001 109.98 24.79 85.19 78.09 

2002 107.20 24.79 82.41 78.09 

2003 118.21 24.79 93.42 102.88 

2004 127.97 25.19 102.78 102.88 

2005 131.86 28.17 103.69 102.88 

2006 144.64 30.35 114.29 102.88 

2007 153.51 33.01 120.50 102.88 

For the subsidies, we have taken the data from the internal reports of the SFS for the 

years 2004 to 2007. For the previous years, in the absence of such data in the abovementioned 

reports, we have used the official data, which fix the subsidy at 24.79 euros. 

The headings for costs specific to plasmapheresis (donor management, collection and 

laboratory) are constantly rising. The organisation costs in 2007 constitute 23% of total 

costs; given that these costs are allocated to all organisation costs for ‘plasmapheresis’, a 

part of the negative result of the comparison between costs and prices for this activity 

may require discussion concerning this allocation. If a smaller part of the organisation 

costs was allocated to plasmapheresis, the total costs would be reduced accordingly. 


• The difference between the cost of a litre of plasma from plasmapheresis 

and the price received for this litre of plasma depends on the allocation of 

the structure costs on this activity 

• We did not receive the cost structure used by the VDB


2.1.3 Plasma collection in other countries 

2.1.3.1 Plasma collection in Germany 

General Points 

Blood and plasma donation are organized within a strict legal framework defined by law. 

The Transfusion Act (Transfusionsgesetz- TFG) 11 sets out the key principles and rules 

that blood donation must follow: donor selection, information, blood tests and blood 

quality control, financial compensation, epidemiology data, data protection, follow-up of 

blood donations. 

Principle of unpaid donation and financial compensation 

Concerning financial issues, the key principle is that blood donation in general (full blood 

and/or plasma) must remain unpaid. However, financial compensation can be awarded 

to the donor (“may”, as it is not mandatory), provided it is directly and clearly 

connected with donation-related costs, in practice: travel costs, car park, and time spent 

for donation. 

The maximum amount of this financial compensation has been set out by the German 

legislation, ie 25€. However, as explained further in this report, each institution enjoys a 

complete freedom in this field: whereas some do reward donors (eg: Private Plasma 

donation centres), some other do not (eg: German Red Cross Institutions). The amount 

of the compensation is left to each institution’s discretion, within the limit of 25€. 

Free Competition between institutions of blood and plasma donation 

Unlike in other countries, blood donation is not organized on a monopoly basis. Public 

and private institutions are allowed to compete with each other, in the field of blood 

donation and plasma donation alike. Three institutions have emerged in the field of 

donation: University-hospitals, German Red Cross Institutions, and Private Donation 

Centres. 

However, it is also important to underline that these institutions, although competing 

with each other in day-to-day donation are required to cooperate with each other in 

case of shortage (mutual delivery of blood, plasma, or blood and plasma products). 

This support service was already implemented on the field in 2007, when 300 000 

pockets of Red Cells Concentrate have been shipped by the Red Cross to the 

University-Hospital donation centres. 

In practice, as explained further in this report, plasma collection as such is largely 

performed by purely private or industry-driven institutions. 

Clinical Issues: German Guidelines of 2005 on plasmapheresis and ongoing studies 

(SIPLA Studies) 

Specific “Richtlinien” (mandatory guidelines) have been issued, and titled: “Guidelines 

for the Collection of blood and blood components and utilization of blood products 

(haemotherapy)” Established by the German Order of Doctors and agreed with the 

Paul-Ehrlich Institut, pursuant to the Transfusion Act 12 . 

These guidelines have been defined by the National Order of Doctors and the Paul 

Ehrlich Institut. However, in today’s form, these guidelines are not considered as utterly 

satisfactory by most stakeholders, and a specific working group has been set out, and 

specific studies have been carried out (“Study on the Safety of Long-Term Intensive 

Plasmapheresis in Donors” also known as SIPLA I, and SIPLA II Studies”), in order to 

formulate new propositions on specific points, and to improve the volume of donations, 

while ensuring the protection of the donor’s health.


Role of the German Red Cross (DRK) compared to private firms in the plasma 

collection industry 

According to the German legislation, free competition is allowed between a large 

number of institutions, public and private alike. Today’s picture of plasma collection in 

Germany is very specific as purely private firms or institutions have been more and 

more involved in this field, over the last years. These private firms resort to clearly 

customer-oriented and profit-centred strategies. 

An in-depth survey conducted by Robert Koch Institute on distribution of plasma 

collection in 2006. This survey focused on the number of plasma repeat donors. It 

clearly showed that the number of donors from industry-driven centres and private 

centres amount for more than 81.6% of the total number of plasma repeat donors. The 

number of plasma repeat donors from the Red Cross is much smaller (10.4%). So is the 

number of repeat donors from Federal or municipal centres (8%). 

Considering the volume of plasma delivered for fractionation, approximately half of this 

volume comes from plasmapheresis. This is of key importance, as private centres 

(industry-driven centres or private donation centres) design specific strategies targeting 

plasma donors, whereas the Red Cross did not (mainly for historical reasons). 

All principles and rules detailed in the Appendix (see Appendix “Germany”) relating to 

the German Red Cross – especially the campaign and information material – are in use 

both for full blood and plasma collection. Indeed, no specific campaign has been 

designed for plasma donation as such, unlike in the industry-driven or private donation 

centres. 

Demographic dimension of plasma donation in Germany: survey of Robert Koch 

institute 

The first objective of the survey was to conduct an in-depth analysis the demographic 

profile of plasma donors in Germany especially concerning distribution of age groups 

among plasma donors, in each type of institutions (Website: http://www.rki.de/ ). 

The final objective of the survey was to analyze the possible impact of demographic 

changes of the German population on plasma donation over the next decades. 

Distribution of age groups for blood donors highlights the crucial role of young people 

in plasma donation, ie people younger than 44 and among them those below 25. As 

shown on the graph below distribution of age groups is clearly uneven: 

Table 9: Distribution of Donors 2006 Source: Robert Koch Institute 

Age 18-24 25-34 35-44 45-54 55-68 

New 

donors 

2006 % 

Repeat 

Donors 

2006 % 

51 24 15 7 2 

37 25 21 15 2 

Over the next decades, the German general population will undergo major changes, 

especially in terms of age structure. The objective of the survey was to make a quick 

synthesis on the main demographic trends and to analyze their impact on the donors 

population. In line with the German regulation and the guidelines mentioned above, the 

“Population within the donor age limits” is defined as people between 18 and 68. 

Based on the data of the German statistical office (Destatis) the size of this population 

will evolve as below:


Figure 2: Demographic prospects in Germany 2006-2031 (Age distribution) 

Source: German Federal Statistical Office 

Divergence between these both trends has been clearly highlighted by Robert Koch 

Institute as an ageing population means an increase of potential recipients. On the long 

term, it could raise major problems in terms of supply/demand. In order to prevent 

shortfalls in plasma supply, it is clear that the number of donors should be raised over 

the whole population of potential donors (ie 18-68). Emphasis should also be laid on 

retention of donors. Private centres and industry-driven centres will face major 

difficulties unless they recruit a much large number of donors in higher age groups 

(above 35) than they do today. 

Further information on donation campaign and demographic issues in Appendix 

“Germany” 


• Maximisation of individual donation volume is one of the key issues of 

ongoing studies in Germany. 

• Considering plasma delivered for fractionation, plasmapheresis plays an 

important role, and is largely performed by private centres. 

• Plasma donors’ profile is quite specific: younger, more-educated, less 

involved in professional life, and less often married. 

• “Real World” communication campaigns and practical follow-up of donors 

with modern techniques are of key importance to improve retention of 

donors. Interface with the education system is also of paramount 

importance. 

• Great attention is paid to the demographic dimension to adjust recruitment 

and retention policy accordingly.


2.1.3.2 Plasma collection in France 

Historical Background 

For historical reasons, collection and fractionation activities have been clearly split 

between two different institutions: 

• Etablissement Français du Sang (EFS) for collection and vigilance activities 

(and other specific activities / see below) 

• Laboratoire Français de Fractionnement et de Biotechnologie (LFB) for 

fractionation activities, marketing of plasma-derived products, and 

Biotechnology R&D. 

In their own respective fields of activity, each of these institutions enjoys a monopoly. 

For practical reasons, both institutions have to work in connection under the 

supervision of public authorities. However, they are matters for different legal statuses. 

Safety and security requirements 

The AFSSAPS – Agence Française de Sécurité Sanitaire des Produits de Santé French 

Agency for the Safety of Health Products (Decision of 6 November 2006) is in charge of 

seting out security rules, defining and disseminating best practices, but also ensuring 

propoer monitoring of blood and plasma-derived products (see further). 

EU legal requirements are obviously applicable in the field of blood donation, quality and 

safety, as described above in the report 

Legal status and missions of the Etablissement Français du Sang -EFS 

LEGAL STATUS 

The EFS has been created in 2000, is a public-law body and comprises one national head 

office and 17 regional branches. Key members of its Board of Administration are 

representatives of the Department of Health, Ministry of Finance, and Ministry of 

Research. Representatives of the Health Care Insurance Funds are also members of the 

Board. While being a public institution one must notice that the EFS does not receive 

any public subsidy (most of its resources stem from the sale of labile products to 

hospitals) See website: 

http://www.dondusang.net/rewrite/heading/1.htm?idRubrique=1) . 

THE MISSIONS OF THE EFS 

These missions have been set out by the French legislation as follows: 

• Collection of blood and plasma: See also Appendix “France” on collection 

issues 

• Ensuring self-sufficiency 

• Vigilance activities: ensuring actual application of safety and quality 

requirements, especially good practices set out by the AFSSAPS 

mentioned above. 

• Implementing highly-skilled technical and research activities in connection 

with blood/tissue: stem cells bank, bone marrow transplants, placental 

blood, etc… 

• Delivery of labile products to hospitals for transfusion purposes 

• Delivery of plasma to the LFB for fractionation purposes (official delivery 

targets) 

• International cooperation activities


Legal Status and missions of the Laboratoire Français de Fractionnement et de 

Biotechnologie - LFB 

LEGAL STATUS 

In 2005, LFB (formerly public-law structure) has been transformed into a private-law 

firm (Edict of 28 July 2005) 13 . However, key members of the Board of Administration 

are representatives of public authorities (Department of Health, Ministry of Finance), 

and the majority of the LFB’s shares remains in the hands of public stakeholders only. 

In today’s form, LFB is a holding company that controls two subsidiary companies: 

• LFB Biomédicaments (specialized in plasma fractionation and marketing of 

plasma-derived products). 

• LFB Biotechnologies (specialized in Biotechnology R&D) 

THE MISSIONS OF THE LFB 

LFB is specialized in the following fields: 

• Immunology: primary immune deficiency, secondary immune deficiency, 

Kawasaki disease, Guillain-Barré syndrome, etc.. 

• Hemostasy / Clotting factors: mainly von Willbrand and haemophilia 

• Anaesthesia / Resuscitation products 

• RD activities in the field of Biotechnology: 

• International activities: as most private firms of this industry, LFB is also 

committed in international activities, especially in plasma fractionation. As 

described below in the report, it plays an important role on the Brazilian 

market, as it will assist Brazilian stakeholders in setting up plasma 

fractionation facilities, and a sustainable supply chain. 

Connection between the EFS towards the LFB 

As far as delivery of plasma is concerned, specific targets are fixed between EFS and LFB 

whereby, the volume of plasma to be delivered by EFS to the FFB is officially set out 14 . 

These targets are opposable to the EFS. Therefore, the key strategic objective of the 

latter is to keep up with the evolution of LFB supply needs. Delivery targets have 

evolved and will evolve as below (liters): 

Figure 3: EFS Delivery targets to LFB (2005-2011) 

Source: EFS Corporate data 

This key driver for the EFS is basically to increase its plasma supply in order to meet the 

EFS needs, which thus involves an in-depth reflection on the whole collection strategy 

and processes. Besides, the sale price of the plasma is fixed nationally by the 

Department of Health. Over the last years, it was reduced from 155 € to 135€ in 2007, 

and to 105€ in 2008. For all these reasons, the EFS steadily needs to improve its 

productivity (in terms of process) and also the total volume of collected plasma. 

In 2008:


• 73% of plasma delivered to LFB stems from traditional whole blood 

technique. 

• 27% from other techniques: plasmapheresis, combined apheresis, and 

mixed platelets concentrates (MPC). 

Cost control and EFS processes 

Costs Issues 

As mentioned above the EFS has to reach very demanding delivery targets, under strict 

constraints, especially unilateral sale prices fixing by the Departement of Health. 

Therefore, the EFS is compelled to deliver an increasing volume of blood to LFB 630 

000 liters in 2006; 1,1 Millions liters scheduled for 2011. 

The main problems for EFS managers are obviously to ensure overall financial balance of 

collection activities, but also to avoid discrepancies between the collection costs of 

blood and plasma. One of main driver for EFS’s decision makers is to cut down 

apherese plasma production costs, step by step, thanks to an increased collection of 

actually collected plasma and a rationalization of collection techniques. 

DISTRIBUTION BETWEEN APHERESE PLASMA AND RECOVERED PLASMA 

In 2007, around 20% of plasma comes from apherese plasma whereas 80% remains 

recovered plasma. The objective of the EFS is to raise the share of apherese plama over 

the next year, for technical reasons (mainly increased frequency of donations). 

Frequency of donation is all the more important as the proportion of donors in the 

French population remains low (around 4% of the overall population). However, one 

must bear in mind that cost breakdown between apherese plasma and recovered 

plasma remains very different: 

• Costs of Apherese Plasma 

• 58% connected with collection step 

• 42% connected with processing, vigilance, and quality-control 

• Costs of Recovered Plasma 

• 22% connected with collection step 

• 78% connected with processing, vigilance, and quality-control 

Hence, this policy will call for specific efforts and rationalization of the collection step 

itself as it accounts for the major part of the costs mentioned above. Rationalization can 

be understood as a systematic use of accurate processes and techniques, but also a 

better use of human resources, as described below. 

CLINICAL PRACTICES AND HUMAN RESOURCES 

Volume of individual donations 

Across the country, clinical practices remain uneven, in the field of blood and plasma 

collection. As a practical matter, the volume of individual plasma collection may vary 

across donation centres and regions. Over the next years, one of the key issues (from a 

purely technical point of view) is to make sure that field practices are in line with official 

requirements set out by the EFS, and to standardize these practices. By doing so, the 

volume of individual collection could be raised significantly. 

Plasmapherese techniques 

Until now, 60% of apherese is performed is as a simple apherese and 40% is performed 

with an additive solution. Three measures will be implemented over the next years to 

maximize and to standardize the rentability of plasmapherese techniques: 

• The more intensive use of MPC as additive solutions 

• The automation of the production of the MPC


Human resources issues 

The nurses’ rate of activity is also a concern for the EFS: in practice, this rate is 

relatively low (in average around 55%), due to an inaccurate distribution of donation 

centres across the country and/or an inadequate organization of collection, especially 

considering the French sociological profile. In practice the use of donation rooms has 

not been rationalized yet, and the total amount of donor accommodation in donation 

rooms is often not fully used. 

Principles on cost rationalization 

Decision makers of the EFS have identified several key measures to improve cost 

efficiency of the donation system. All of these measures are not equally profitable for 

the donation system, but they all bring a helpful contribution to the smooth running of 

the whole process and to the best use of donated blood. 

The following measures listed below have been ranked from the most profitable to the 

less profitable (from a cost / efficiency point of view) considering today’s workforce. 

• Rationalizing the use of donation rooms and raising the nurses’ rate of 

activity: which involves a restructuring of donation facilities and a better 

distribution of donation. This will automatically raise the nurses’ rate of 

activity 

• Implementation of apherese with additive solution: this technique will 

improve individual rentability of blood donations 

• Unifying and raising the volume of individual donation 

Communication Campaigns: Further Information in Appendix “France : Plasma 

collection within the framework of EFS” 


• The French system combines public law and private law rules in the field of 

collection, fractionation and supply. Plasma collection is not supported by 

public subsidies, and the sale price of plasma is fixed by the national health 

authorities. Delivery targets of the EFS will be raised gradually over the next 

years. 

• EFS’s communication policy targets students and young adults. 

• The main driver for the collection centres is to improve HR management, to 

increase individual collection volume, and to realize economies of scale.


2.2 TRANSFORMATION OF PLASMA INTO PLASMA 

DERIVATIVES 

2.2.1 Quick overview of fractionation process 

Since the early 1940s the method of manufacturing plasma, initially developed by Pr 

Edwin J. Cohn, has been influenced by multiple factors, which over the years have 

forced the industry to adapt production in such a way that the optimal use of plasma – a 

human source - remains to be the leading objective. As already mentioned above, 

human plasma, is a unique biological material. Plasma fractionation, a “cracking” process 

(cf. petroleum “cracking”) used to prepare therapeutic proteins, is and remains a 

complex process. Human plasma derived protein products have unique characteristics 

linked to the origin of the starting raw material. Human plasma exhibits a complex 

biochemical nature due to its high protein content, close to 60 g per litre, and to the 

diversity of its protein components. 

Figure 4: Blood composition 

White cells 

& platelets 

8% 

Red cells 

42% 

Blood 

Plasma 

50% 

Plasma 

Protein 

Other 

7% 

3% 

Water 

90% 

Coagulation 

Factors 

1% 1% 

Globulins 

15% 

Protein 

Other 

24% 

Albumin 

60% 

Below is a list of the best-known of those proteins which are commercially available, 

although one should note that the order does not reflect the relative importance of the 

proteins. 

IVIG: 


intravenous immunoglobulin 

Factor VIII: coagulation factor 

Factor IX: coagulation factor 

AT-III: anti-thrombin III 

IMGG: intra-muscular gammaglobulin 

A1-AT: alpha-1 anti-trypsin 

Fibrin sealant 

IMGG anti-D: 

Up to 25 others 

intra-muscular gammaglobulin anti-Rh factor


2.2.1.1 Developmental nature of production 

Although the plasma derivatives industry continues to use the Cohn procedure, 

developed in the early 1940s by Professor E. Cohn, the products now obtained by this 

method bear little resemblance to those obtained during the early stages of the plasma 

derivatives industry. The Cohn procedure consists, fundamentally, of the precipitation 

of the various proteins by means of changes to pH and salt concentration levels, with 

the proteins being separated out by centrifugation. In order to prevent the proteins 

from being denatured, the work is conducted at low temperatures and ethanol is added 

at various concentrations. While this initial protein fractionation stage has been 

maintained, what has changed is the process of purifying the proteins in order to obtain 

a safer, purer end product. 

Figure 5: Schema of fractionation methods (Source: unpublished document 

of PPTA – Plasma Protein Therapeutics Association) 

2.2.1.2 Progress in purification 

The Cohn procedure does not produce therapeutic proteins in a pure state, and it has 

therefore been necessary to add purification stages which, in addition to purifying the 

proteins, eliminate the contaminants added during fractionation (ethanol and salts). 

These purification stages vary depending on the characteristics of the Cohn fraction to 

be purified and the nature of the product being obtained. In the case of FVIII or antihaemophiliac 

factor, the development of affinity chromatography techniques (whether 

using monoclonal antibodies or heparin) has allowed the development of FVIII with far 

higher purity levels than the first FVIII used in the treatment of haemophilia. Another 

significant advantage is that the infusion volume of FVIII which now needs to be 

administered is considerably lower, with resulting improvements in patient comfort and 

quality of life.


Figure 6: Fractionation Techniques and Available Products (Source: 

unpublished document of PPTA – Plasma Protein Therapeutics Association) 

Each of the affinity chromatography systems described above also requires 2 highly 

purified, but different, FVIII products. Purification using monoclonal antibodies (anti-FVIII 

antibodies produced in mouse cells and bound to the chromatography matrix) allows a 

very pure FVIII to be obtained. In contrast, if affinity chromatography with heparin is 

used, both FVIII and von Willebrand Factor are obtained. VWF protects the FVIII 

molecule and is used in the treatment of immuno-intolerance in haemophiliacs who 

have developed anti-Factor VIII antibodies, and can also be used to treat patients with 

von Willebrand Factor deficit. 

Immunoglobulins are another group of products where the new purification techniques 

have led to unforeseen therapeutic progress. Originally, immunoglobulins could only be 

administered intramuscularly, but this method hindered the administration of sufficient 

quantities of immunoglobulins, thereby bringing into question their therapeutic utility. 

The use of different purification stages – precipitation with polyethylene glycol, glycine 

etc. – and different affinity chromatography systems has made it possible to obtain 

intravenous immunoglobulins (IVIG). This has meant that sufficient therapeutic doses 

can be administered to patients, allowing not just patients with primary 

immunodeficiency’s to benefit from such treatments (patients suffering from 

immunoglobulin production deficit), but also other patients with auto-immune illnesses, 

together with some who have neurological diseases. 

2.2.1.3 Progress in safety 

Because the plasma fractionation industry uses plasma as its raw material, many viral 

illnesses carried in the plasma can be transmitted through transfusions of the end 

product. In order to prevent the risk of further viral transmission, the industry 

developed a series of safety procedures which covered the donor, the plasma and the 

product. An interesting example in the development in viral safety can be found in the 

technical and scientific advances in the field of viral DNA detection (NAT techniques) 

which complement and improve upon the old viral marker techniques which used ELISA 

technology. The old techniques were based on detecting antibodies to different viruses. 

However, as there is a variable time period (known as the ‘window period’) between 

initial infection and the production of antibodies depending on the virus type, there is a 

danger that plasma with a low viral load which has tested negative using ELISA 

techniques can still be used in plasma fractionation.


NAT technology for viral DNA detection has dramatically reduced this window period. 

Negative results from the subsequent application of NAT technology to the plasma pool 

for a range of viruses (HCV, HIV, Parvo B19, HBV, etc.) provide assurance that the 

initial viral load in the plasma pool is zero or very low. 

2.2.2 The worldwide supply of plasma products 

2.2.2.1 Corporate structure of the market of plasma products 

Restructuring of the sector of plasma products 

Considering the increasing and vital needs of plasma products in most western 

countries, and simultaneously the uncertain level of donation, purchasers of plasma 

products – ie hospitals, and more generally health care institutions – can feel in an 

inferior position towards the plasma fractionation industry. 

The evolution of medical practices and also the political pressure of patient associations 

on health authorities do not leave them much room for manoeuvre. Therefore it is 

important to analyze the recent evolution of this industry to have a clear idea on the 

purchasers’ actual negotiation power. 

MAIN SPECIFICITIES OF THIS INDUSTRY SINCE THE NINETIES: FUSIONS AND MARKET 

CONSOLIDATION 

In 1996, the number of global stakeholders in the nineties was relatively high: almost 40 

companies (or non profit organisations) were identified worldwide in the plasma 

fractionation industry. Following several merger waves, only 20 companies still exist 

today. 

Among these 20 companies some of them do not play a noticeable role on the global 

market because of their size or because of regulatory barriers that still isolate their 

domestic market from the international market. Hence, only a very small number of 

companies can be considered as real “global players” in terms of economic weight: and 

market share. 

CURRENT SITUATION (2003-2005) 

Worldwide, only five private companies still play an important role (>5%) on the global 

market. Non profit organizations are also important stakeholders; however some of 

them enjoy a monopoly, based on a specific national regulation. 

Table 10: Global firms on the plasma product industry 

2003 2005 

Baxter 18.4% 19.5% 

State ruled or on Profit 23.1% 16.5% 

Organisations 

CSL-Behring 15.8% 17.1% 

Talecris / Bayer 14.2% 13.8% 

Octapharma 5.7% 7.1% 

Grifols 7.6% 6.1% 

CSL/ZLB / Bioplasma 6% 1.6% 

Other 9.1% 18.2% 

Total 100% 100%


GEOGRAPHICAL DIMENSION OF THIS INDUSTRY: 

Table 11: Geographical dimension of the plasma product industry 

‘MM US$ Oceania Africa South Middle Asia- Europe North World 

America East Pacific 

America Total 

Baxter 13.22 8.77 174.12 26.31 74.81 557.20 1230 2084.4 

CSL-Behring 116.54 13.08 72.4 39.2 191.54 539.98 929.74 1902.47 

Talecris 0 5.12 19.3 15.37 55.58 128.65 925.79 1149.81 

Octapharma 24.5 32.25 98.78 96.75 23.07 382.98 205.75 864.08 

Grifols 0 1.53 40.59 4.60 16.66 413.59 270.65 747.63 

Leaving aside non profit or public organisations (the strategy of which is largely 

connected with specific national regulations), private companies’ strategies is obviously 

guided by financial prospects and expected profits on each geographical area. In that 

respect, the North-American area remains the most attractive geographical area for 

plasma fractionation firms. 

Therefore, European buyers are apt to compete with American ones, and a harsh 

competition could arise at any time between them with two possible consequences: 

punctual supply shortage and/or sharp increase in the prices of plasma-derived products. 

Capital structure: Four profiles identified 

As far as capital structure is concerned, one must notice that four profiles of capital 

structure have emerged, generally due to specific and deliberate corporate strategies. In 

other cases, (public institutions or other structures commissioned by public authorities) 

capital structure is closely connected with the monopoly status of the institution or 

specific national regulations. 

PROFILE 1: PRIVATE OWNED FIRMS (OCTAPHARMA AND GRIFOLS) 

These two firms are relatively close situations from this point of view: Octapharma is as 

a private-owned firm, and so is Grifols. In both cases, other stakeholders (especially 

banks) can play an important role in capital structure. However, private and family 

stakeholders remain the key investors in both cases and key stakeholders often remain 

deeply connected with the national or even regional economy (Switzerland / Catalonia). 

PROFILE 2: NATIONAL STATE-CONTROLLED FIRMS OR INSTITUTIONS (LFB) 

In several western countries, fractionation firms enjoy a monopoly as defined by a 

specific regulation (generally for historical or cultural reasons). In this case, the firm is 

either owned or controlled by public stakeholders, ie governmental institutions or 

institutions commissioned by the government. 

LFB in France is a traditional example: it enjoys a monopoly in plasma fractionation 

based on a French specific regulation. Before 2005, LFB used to be a public-law 

institution. Since then, it has been transformed into a private law holding company 

(legally a Ltd company) divided into two subsidiary companies: one focusing on 

Biotechnology, one focusing on Plasma fractionation. The capital of both subsidiary 

companies is state-controlled. Key members of the Board of Administration are 

government’s representatives (Ministry of Finance, Ministry of Health). 

PROFILE 3: FOREIGN-OWNED FIRMS (CSL-BEHRING) 

CSL-Behring is a very specific case: it was originally a German firm, CSL Behring became 

a subsidiary of CSL Limited, a biopharmaceutical company headquartered in Melbourne, 

Australia. From a financial point of view, about 90% of the shares are now controlled by 

Australian stakeholders. Therefore, even if CSL-Behring’s main facilities and RD centres 

are still located in Europe, it is under the control of foreign-based institutions.


PROFILE 4: TRADITIONAL PRIVATE FIRMS (US FIRMS: BAXTER, TALECRIS) 

These firms’ capital structure is more traditional, as their capital is owned by private 

stakeholders (eg: Telecris is owned by private equity groups Cerberus Partners and 

Ampersand Ventures). 

In may 2009, CSL tried to take over the US firm Talecris mentioned above. However, 

the US Federal Trade Commission recommended legal actions to block the purchase of 

Talecris by CSL, on antitrust grounds. US public authorities, especially the new 

American administration, seems to keep a vigilant eye on this industry, especially on 

merging of business, whenever it is apt to have an impact on the American 

Main learnings for decision-makers: 

• The capital ownership of the leading global firms of the plasma 

fractionation industry is unlikely to evolve over the next years and this 

industry, in today’s form, seems to be blocked. 

• Restructuring of the plasma fractionation industry: the recent merging of 

businesses and the increasing weight of each firm (considered individually) 

can be seen as a rather negative evolution for the purchasers’ negotiation 

power. 


• The recent merging of businesses has involved a high concentration of 

fractionation activities. Given this context, the negotiation power of 

purchasers (disregarding public or private status) is getting weaker. 

• In the context of a global fractionation industry, any change in the 

prescription habits or authorization of drugs of one country is apt to have an 

impact on the production flows of any other country. Great attention must 

be paid to the US policy on that point. 

2.2.3 The supply of plasma stable derivatives in Belgium 

2.2.3.1 Who are the suppliers 

The plasma collected by the Belgian Red Cross Blood Services - source plasma (SP) as 

well as recovered plasma (RP) - is sent to CAF-DCF for fractionation b . CAF-DCF is the 

exclusive manufacturer of plasma derivatives based on plasma collected in Belgium. All 

locally produced derivatives are intended to be used within the country. The CAF-DCF 

was historically an integral part of the Belgian Red Cross up to the 23 December 1997. 

From that date, the independent CAF-DCF was set up as a cooperative company with 

limited liability. Today the owners of the shares are: 

• the Sanquin Bloodsupply Foundation (Nl) 50.02%, 

• the Laboratoire français du fractionnement et des biotechnologies, LFB 

(Fr), a limited company created in July 2005 and fully owned by the French 

State 24.99% and 

• the Belgian Red Cross 24.99%. 

Besides that, CAF-DCF has signed a cooperation contract with the German company 

Biotest for the fractionation of intermediate plasma products into immunoglobulins. 

CAF-DCF also fractionates for international firms, its total fractionation capacity is 

centered between 500.000 and 550.000 kilo of plasma 

b Except for a limited amount that is transformed into fresh frozen plasma, used to treat specific 

hemorrhagic situations and some coagulation disorders


It is surprising to find that the capital of the company with a monopoly on the 

fractionation of plasma collected in Belgium is mainly in the hands of foreign partners. 

Granting a monopoly to an enterprise only makes sense if, in exchange for this 

monopoly, the enterprise in question fulfils a mission of collective interest, and if the 

authority that granted this monopoly can control what use is made of it. In this 

particular case, control of the CAF-DCF by the public authorities is difficult, verging on 

the impossible, given the minority stake held by the Belgian partner. In addition, it seems 

that there is no agreement or norm binding the CAF-DCF in terms of the organisation 

and intended use of its output. 

It should also be noted that the Board of Administration of CAF-DCF consists as well of 

suppliers (CR) as clients (e.g. Sanquin), having diverging interests. 

2.2.3.2 Quantities fractionated by CAF-DCF 

The following table presents the quantities of plasma (RP & SP) purchased by CAF-DCF 

from all collectors, as well as the quantities really used for fractionation each year by 

the CAF-DCF. 

Table 12: Purchased and fractionated quantities (2000-2008) 

in litres 

Plasma purchased by CAF 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

(source: Federal Agency 

for Medicines) 

219.552 218.200 213.869 205.578 220.163 195.945 179.553 167.634 163.089 

Plasma fractionated by 

CAF (source: CAF-DCF) 

Differences (calculated by 

KCE) 

190.964 192.648 206.015 212.827 210.578 178.249 182.149 170.497 159.421 

28.588 25.552 7.854 -7.249 9.585 17.696 -2.596 -2.863 3.668 

CAF-DCF reported a quite strait competition on the Belgian market and the underlying 

reduction of plasma collection to explain the constant reduction of fractionated plasma. 

It must be noted that, overall, CAF-DCF fractionates a smaller volume than the actually 

purchased volume. Strategic stocks are then constituted, which can prove helpful 

whenever quantities of collected plasma are not sufficient to fulfill the demand. In 2003, 

2006 and 2007, we observe that stocks had to be tapped. This tapping of the stock is 

confirmed by the audit reports of Verhaegen 9 and PWC 15 . 

Availability of strategic stocks at the end of each year have been communicated by CAF- 

DCF and recorded on the first line of the table below. If we add to the yearly recorded 

strategic stock, the volume of plasma bought to the Red Cross the following year - but 

not fractionated, and if we subtract the strategic stock recorded at the end of the 

following year, we calculate a yearly balance, shown on the last line of the table below. 

Table 13: Stocks and balances (2000-2008) 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

Stategic stock 78.010 81.095 86.684 83.170 76.673 90.819 58.588 48.342 34.803 

Purchased - fractionated 28.588 25.552 7.854 -7.249 9.585 17.696 -2.596 -2.863 3.668 

Balances 22.467 2.265 -3.735 16.082 3.550 29.635 7.383 17.207 

Calculated by KCE and based on CAF-DCF data 

According to CAF-DCF, it is normal that the yearly variations in the volume of the 

strategic stock do not correspond to the differences between the volume of purchased 

plasma and the one of fractionated plasma. Indeed, losses may occur along the process 

e.g. when testing reveals that a batch of plasma is infected, as well as production losses - 

or even volumes of plasma put into quarantine for testing purposes, and thus not 

recorded onto the strategic stock. However the volume of « lost » quantities may 

greatly vary from a year to another. No precise element could be collected concerning 

the origin of these variations.


2.2.3.3 Produced and sold quantities 


CAF-DCF in litres 

Albumin produced by 

CAF-DCF in Belgium in 

kg 

Albumin sold by CAF- 

DCF in Belgium in kg 

Number gr produced 

albumin for 1 litre plasma 

(calculated by KCE) 

Production of albumin if 

the yield equals 25,29 

gr/litre 

Albumin produced by 

CAF-DCF in Belgium in 

kg 

Based on the availability of volumes of plasma fractionated by CAF-DCF, volumes of 

derivatives manufactured from this plasma, and yearly volume of sales, we can make the 

following analysis. 

The first finding is the bearish trend for the sale of specific derivatives. The risk of (and 

fear for) disease transmitted by plasma derivatives has probably contributed to the 

variations in the amounts of derivatives sold. For instance, the risk for Creutzfeld Jacob 

or other transmissible disease has contributed the increasing use of recombinant 

coagulation factors to treat hemophilia, and subsequent decreasing use of plasma 

derived factors. Indeed in 2004, the Belgian authorities have reported that Belgian 

hemophilic patients had received coagulation factors prepared from a European plasma 

pool that could have been contaminated with prions. c 

We will focus the following analysis on albumin and immunoglobulins. 


The first calculus consists in dividing the number of litres of fractionated plasma by the 

number of actually produced grams of albumin. This ratio is decreasing since 2001 even 

if the level of 2008 shows a weak increase. 

Table 14: Calculation of number of grams obtained from 1 litre of plasma 

(2000-2008) 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

190.964 192.648 206.015 212.827 210.578 178.249 182.149 170.497 159.421 

4.679 4.873 4.755 4.873 5.005 4.264 2.419 2.607 3.085 

4.640 4.860 5.040 4.780 4.730 3.570 2.740 2.450 2.750 

24,50 25,29 23,08 22,90 23,77 23,92 13,28 15,29 19,35 

Source: CAF-DCF for the three first lines of the table 

As from 2003 the intermediate albumin rich fraction is sent to Sanquin ( 9 p. 12) for 

refining and packaging. According to Verhaegen 9 , the overall cost of this processing 

totals 3.1 million euros in 2003 and 4.6 million euros in 2004. We calculated the 

volume that could have been produced, if the albumin/plasma ratio had remained 

identical to the one of 2001 for the reviewed years. 

Table 15: Calculation of the potential production of albumins (2000-2008) 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

4.829 4.872 5.210 5.382 5.326 4.508 4.607 4.312 4.022 

4.679 4.872 4.755 4.873 5.005 4.264 2.419 2.607 3.085 

Differences 150 0 455 509 321 244 2.188 1.705 1.272 

Thanks to this calculus, we observe that between 0,15 and 2,18 supplementary tons of 

albumin per year could have been produced, technically speaking. However, line 3 of 

table 14 shows that no purchasers could be found for such volumes on the Belgian 

market. Hence, CAF-DCF had no interest to produce more albumins. The production 

of albumin follows the demand on the Belgian market. The real yield for fractionation of 

albumins ivaries between 24,6 and 25,6 gram per kilo of plasma. 

c Service public fédéral Santé publique. Communiqué de presse du 23 novembre 2004.



CAF 

IG produced by CAF‐DCF 

in Belgium in gr 

This Belgian demand is function of the nature of the competition between firms present 

on the market and of an international underlying reduction of albumin demand. This is 

confirmed by a recent Australian Report of CSL where we can read that ‘In Australia 

the amount of albumin issued per annum over the period 1994-95 to 2004-5 has 

increased by an average annual growth rate of ca. 1.4%, as shown in, although in the last 

five years this value has been higher at ca. 2.3%. In contrast, the growth in plasma 

collections has been ca. 6% per annum over the same period and if all of this plasma had 

been converted into product then Australia would have accumulated a substantial 

excess of albumin over requirements. Recognizing this situation, CSL was instructed to 

limit the production of albumin from 1999-00 onward in order to balance supply with 

demand. As a consequence of this policy the latest data from 2004-05 indicates that 

Australia can meet demand for albumin by converting only about 60% of the available 

plasma into finished albumin product’. 16 The same phenomenon occurred in Belgium 

and a proportion of collected plasma is then sold to foreign firms under the form of 

intermediate products. 

The case of immunoglobulins 

The trend identified for IG is opposed to the trend for albumin: it shows that since 

2004 the quantities of IG sold by the CAF-DCF follow a rising path despite the fall in 

collection. This rise in sales volume might be partly explained by the desertion of the 

Belgian market by one firm around 2004. 

Table 16: Calculation of number of grams obtained from 1 litre of plasma 

(2000-2008) 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

190.964 192.648 206.015 212.827 210.578 178.249 182.149 170.497 159.421 

171.000 185.000 118.000 340.000 379.000 456.000 455.000 531.000 636.000 

IG sold by CAF‐DCF in 

Belgium in gr 

Number of gr of 

122.000 151.000 170.000 298.000 393.000 389.000 462.000 490.000 543.000 

produced IG for 1 litre 

plasma 

0,90 0,96 0,57 1,60 1,80 2,56 2,50 3,11 3,99 

Source: CAF-DCF for the tree first lines of the table 

The calculated ratios present a constant increase since 2000. These ratios are calculated 

as if all the fractionated plasma was used to produce immunoglobulins. CAF-DCF 

reported that the quantities of fractionated plasma used for a given derivative is always 

determined by the demand. The reported technical yield by the CAF-DCF is 2,7 gr/L 

plasma for the period 2000-2002. Since 2003, the CAF-DCF used a very performing 

technology to produce the Multigam. During the period 2003-2007, the yield was equal 

to 4,2 gr/L. In 2008, the use of the nanofiltration caused a light reduction of the yield to 

3,9 gr/L. In 2008, the ratio is exactly the same as the reference mentioned in an 

unpublished document of PPTA (3.98 g/L). Nevertheless it seems that the world’s best 

fractionation operators should obtain a constant yield of 5.3 g/L (CSL reference). 

However, as we do not have at our disposal the right data to determine the precise 

content of the yields identified in other countries, this comparison must be considered 

with care. 

This evolution shows CAF-DCF’s responsiveness to demand and also its capacity to 

raise its production at a faster pace than the one of demand.



• The production of plasma derivatives is not carried out only by the CAF- 

DCF, which has concluded agreements with foreign firms to carry out a part 

of the process 

• Relatively large volumes of plasma purchased by CAF-DCF do not 

contribute at all to the fractionation process. These volumes seem to vary 

greatly over the years, and this phenomenon has not been clarified. 

• The CAF-DCF seems to experience overcapacity for specific stable 

derivatives. In spite of the decrease of the volumes of purchased plasma, it 

produces more than it actually sells on the Belgian market. A proportion of 

collected plasma (under the form of intermediate product) is sometimes 

dedicated to the production for foreign markets. 

• Trading as well as production agreements, concluded between CAF-DCF 

partners, are not transparent towards the public authority, although this 

financially supports CAF-DCF through subsidized plasma prices. 

2.2.3.4 Position of CAF-DCF on the international market 

The investments made by the CAF-DCF, notably in a new building in Neder-Over- 

Hembeek, enable the company to manufacture quality products that have resulted in 

foreign companies taking holdings in the capital of the CAF-DCF. Nevertheless, the 

CAF-DCF remains a very small enterprise on the world stage and its financial situation 

is precarious, despite the indirect subsidies it receives through the price that it pays for 

plasma to the Red Cross. 

An audit carried out in 2006 had already highlighted the difficult financial situation of the 

CAF-DCF. 9 According to this audit, the results of this enterprise in Belgium were in 

the red for the entire period under review (2000 – 2005) and the positive results of 

foreign operations were not enough to offset the losses made in Belgium. As from 

2003, the purchases column saw a substantial increase due to the rise in the price of 

plasma from plasmapheresis (+37%). Two other cost headings were also to blame for 

the deterioration in the financial situation of the CAF-DCF during the period in 

question: ‘special orders’ and ‘purchases of stable derivatives’. The rise in the heading 

‘special orders’ follows the closure of the former CAF fractionation factory in Ixelles. 

As from 2004, the plasma was fractionated into intermediate products in the factory at 

Neder-Over-Heembeek. The intermediate products are then sent to foreign partners 

for finer fractionation. Since 2002 the preparation of factor VIII has been carried out by 

the French company LFB. Since 2003 the albumin has been produced by Sanquin in the 

Netherlands. As for the rise in the heading ‘purchases of stable derivatives’, it results 

from a combination of two factors: the purchase of PPSB by Sanquin following the rise 

in demand for this product and the manufacture of Multigam (immunoglobulins) by the 

firm Biotest, which receives the intermediate products from the CAF-DCF and sends 

them back as the finished product. 

According to the audit conducted by F. Verhaegen, this negative financial situation 

should improve significantly with the removal of the compulsory levy on the 

pharmaceutical firms. 


• The CAF-DCF is a high technology firm but rather small on the world-wide 

scale. 

• The financial situation of the CAF-DCF, structurally negative between 2000 

and 2005, recovered thanks to the removal of the levy on pharmaceutical 

products, from which plasma derivatives are currently exempt


2.3 LIMITATIONS 

The subject we are dealing with is sensitive in more than one respect. Firstly, the 

products in question constitute, for a number of medical conditions, the only possible 

therapy at the present time. In addition, the data concerning the price and the quantities 

collected and produced concern actors that play an important role in this sector. It is 

therefore essential to have validated data in order to be able to draw relevant 

conclusions. It is also essential to identify the reasons why caution is necessary in the 

formulation of certain findings and conclusions, and we present here the limitations of 

our analysis. 

The first limitation concerns the cost of plasmapheresis. We have seen that the 

allocation of organisation costs to this activity, compared with the other activities of the 

Red Cross, could have a decisive effect on the real cost of the activity in question. 

The second limitation is related to the profitability of plasmapheresis. We are not in a 

position to establish with certainty the price at which the Red Cross could sell, or could 

have sold, plasma on the international market. The various data collected show that we 

cannot be sure of the profitability of such an approach because of the variability of 

prices in time and space.


3 DEMAND FOR PLASMA DERIVATIVES: THE 

CASE OF IMMUNOGLOBULINS 

This chapter aims at describing the quantities of plasma derivatives used in Belgium, how 

they are used and what are the future trends in consumption. The purpose is to 

subsequently compare quantities used and quantities supplied. 

Since polyvalent immunoglobulin (IG) is the plasma derivative considered as the market 

driver for plasma procurement, we have focused most of our research on IG. 17 In a first 

phase, we have studied the indications for IG use: we have compared the 

recommendations for IG use in Belgium and in other industrialized countries and 

reviewed the scientific evidence on IG effectiveness. In a second phase, we have 

analyzed the quantities of IG that are used in Belgium and in other countries, the 

amounts that would be required to treat the main indications and how can IG 

consumption be rationalized and reduced. 

3.1 USE OF PLASMA DERIVATIVES IN BELGIUM 

3.1.1 Methods 

3.1.2 Results 

We collected data on the use of plasma derivatives in Belgium to determine the 

quantities and expenses involved in the recent years, as well as to identify recent trends. 

The National Institute for Health and Disability Insurance (NIHDI or INAMI/RIZIV) 

provided us with national data on reimbursed plasma derivatives for the period 2004- 

2006 with the following relevant information: hospital, ward (inpatient or outpatient), 

trimester, category of reimbursement, ATC code 5 (J06BA01 et J06BA02), number of 

packages and price. These data have been checked for consistence between the number 

of items and the expenses. The yearly quantities of each derivative have been computed 

in grams or international units (IU) by year and by type of producer, categorized in 

CAF-DCF (Centrale Afdeling voor Fractionering - Département Central de 

Fractionnement) or non CAF-DCF. 

We had no access to data on non-reimbursed plasma derivatives and derivatives used 

for compassionate use. 

The yearly amounts of the main reimbursed derivatives are presented in Table 17. 

Recombinant coagulation factors, obtained using recombinant DNA technology, are also 

mentioned (in italic). Though they are not derived from plasma, their evolution 

influences the trends in plasma derived factors. 

Over the period 2004-2006, the following trends in consumption are observed: human 

factors VIII and IX are decreasing by more than half (-61% and -56% respectively), 

parallel to an increase in recombinant factors; von Willebrand factors are doubling; the 

use of FEIBA and sub-cutaneous immunoglobulins are emerging; and intravenous 

immunoglobulins have increased by 11%. The consumption of CAF-DCF products has 

been compared to those from other producers on the Belgian market: all CAF-DCF 

products show a sharp decrease in quantities, except for immunoglobulins (+18%) and 

PPSB (+16%). This decrease can not be exclusively explained by the increase in 

recombinant product use.


Table 17: Main plasma derivatives and recombinant factors reimbursed by 

the National Institute for Health and Disability Insurance (NIHDI) in kU or 

grams 

Plasma derivatives and equivalents 2004 2005 2006 

PPSB CAF 5.193 kU 5.825 kU 6.013 kU 

Fact VIII 43.606 kU 52.153 kU 58.148 kU 

Fact VIII-human CAF 4.049 kU 3.404 kU 1.598 kU 

Fact VIII-recombinant 

Factor Eight Inhibitor Bypassing 

39.557 kU 48.749 kU 56.550 kU 

Activity (FEIBA) 65 kU 206 kU 839 kU 

Factor IX-human 2.069 kU 1.293 kU 908 kU 

Factor IX-human CAF 1.921 kU 1.045 kU 602 kU 

Factor IX-human not-CAF 148 kU 248 kU 306 kU 

Factor IX-recombinant 1.825 kU 3.537 kU 4.789 kU 

Fact VII-human CAF 101 kU 110 kU 24 kU 

Factor VIIa-recombinant 375.324 kU 265.866 kU 127.588 kU 

Von Willebrand +/- Fact VIII 2.011 kU 3.978 kU 4.605 kU 

von Willebrand +/- Fact VIII CAF 1.226 kU 1.001 kU 829 kU 

von Willebrand +/- Fact VIII not-CAF 785 kU 2.978 kU 3.776 kU 

Factor XIII-human 13 kU 11 kU 9 kU 

Alb & SSPP 4.599.557 gr 4.904.672 gr 4.224.990 gr 

Alb & SSPP CAF 4.416.990 gr 3.543.800 gr 2.479.800 gr 

Alb & SSPP not-CAF 182.568 gr 1.360.873 gr 1.745.190 gr 

SC Immunoglobulins polyvalent 0 gr 115 gr 3.604 gr 

IV Immunoglobulins polyvalent 749.559 gr 773.486 gr 828.546 gr 

IV Immunoglobulins polyvalent CAF 353.058 gr 356.314 gr 416.363 gr 

IV Immunoglobulins polyvalent not-CAF 396.501 gr 417.172 gr 412.183 gr 

Antithrombine III 803 kU 1.112 kU 721 kU 

Fragmin 0 kU 0 kU 0 kU 

C protein 0 kU 0 kU 0 kU 

Table 18 presents the national expenses in plasma derivatives and recombinant factors 

by year, the changes in expenses over the 3 year period (in percent increase compared 

to 2004) and the proportion of each product expense related to the total expenses for 

all derivatives (recombinant included). The cost of human derivatives stayed relatively 

stable over the 3 years, while the cost of recombinant increased by 35% (mostly due to 

an 43% increase in Factor VIII recombinant). The trends in human derivative expenses 

follows the same patterns than the trends in quantities reimbursed. All together, plasma 

derivatives and recombinant factors represented in 2006 3% of all drug expenses from 

the health budget. 

In 2006, the cost of recombinant products represented 52% of total expenses, with 

recombinant Factor VIII alone representing 48% of all expenses. Among human 

derivatives, the highest expense was due to intravenous immunoglobulins (33.4 millions 

€ or 62% of human derivatives), followed by albumin and SSPP (12.2 millions € or 23% 

of human derivatives).


Table 18: Plasma derivatives and recombinant factors reimbursed by the 

NIHDI in euros 

Increase 

(%) 

from % of 

2004 to total 

Plasma derivative 2004 2005 2006 2006 (2006) 

PPSB CAF 3.085.617 3.460.927 3.538.650 +15% 3% 

Fact VIII 40.985.245 49.261.250 55.007.814 +34% 49% 

Fact VIII-human CAF 3.641.669 3.346.896 1.529.897 ‐58% 1% 

Fact VIII-recombinant 37.343.576 45.914.354 53.477.916 +43% 48% 

FEIBA 44.564 141.977 578.834 +1199% 1% 

Factor IX-human 1.300.125 804.461 541.869 ‐58% 0% 

Factor IX-human CAF 1.220.440 671.533 378.548 ‐69% 0% 

Factor IX-human not-CAF 79.685 132.928 163.321 +105% 0% 

Factor IX-recombinant 1.482.492 2.866.969 3.639.488 +145% 3% 

Fact VII-human CAF 47.712 52.041 11.280 ‐76% 0% 

Factor VIIa-recombinant 4.606.335 3.262.395 1.565.229 ‐66% 1% 

von Willebrand +/- Fact VIII 838.996 1.246.384 1.335.818 +59% 1% 

von Willebrand +/- Fact VIII CAF 651.254 531.557 439.080 ‐33% 

von Willebrand +/- Fact VIII not-CAF 187.741 714.826 896.738 +378% 

Factor XIII-human 3.941 4.751 4.034 +2% 0% 

Alb & SSPP 13.578.166 14.248.444 12.200.319 ‐10% 11% 

Alb & SSPP CAF 13.061.558 10.499.273 7.416.617 ‐43% 7% 

Alb & SSPP not-CAF 516.470 3.749.154 4.783.694 +826% 4% 

Other plasma protein fractions 138 17 8 ‐94% 0% 

SC Immunoglobulins polyvalent 0 5.231 165.310 ‐ 0% 

IV Immunoglobulins polyvalent 30.448.581 31.498.645 33.450.863 +10% 30% 

IV Immunoglobulins polyvalent CAF 14.137.200 14.262.430 16.485.695 +17% 15% 

IV Immunoglobulins polyv. not-CAF 16.311.381 17.236.216 16.965.168 +4% 15% 

Antithrombine III 446.735 566.246 377.277 ‐16% 0% 

Total all products 96.868.647 107.419.738 112.416.793 +5% 100% 

Total human derivatives 53,436,244 55,376,020 53,734,159 +1% 48% 

Total recombinant factors 43,432,403 52,043,718 58,682,633 +35% 52% 

3.1.3 The case of immunoglobulins 

The remaining of this chapter focuses on polyvalent immunoglobulins (IG). Demand in 

immunoglobulins is the highest among all derivatives when considering the amount of 

plasma required to produce it. Its use continues to grow as the number of clinical 

indications for IG keeps increasing. This increased demand resulted in severe product 

shortages in the late 1990’s in the US and a number of other countries, impacting IG 

supply in Belgium. In addition, IG is important in terms of amounts involved and budget 

impact in Belgium, representing 62% of expenses in human plasma derivatives in 2006. 

In this chapter, IG is used to describe pooled polyvalent human immunoglobulin, that 

can be administered intravenously or subcutaneously; IG does not cover hyperimmune 

or specific immunoglobulins. 

Polyvalent IG are used to treat a wide range of diseases due to three major therapeutic 

properties: IG can replace or supplement antibodies in immunodeficiency diseases, in 

order to restore normal humoral immune function; IG has an immunomodulatory 

action in various autoimmune conditions and inflammatory diseases; and IG may be used 

as prophylaxis or therapeutic adjunct against some infectious agents in patients with 

normal immune humoral function. After IG was shown to be effective in the treatment 

of auto-immune and inflammatory disorders, the list of disease for which it is used has 

grown rapidly.


3.2 INDICATIONS FOR IMMUNOGLOBULINS 

This section aims at identifying the diseases requiring significant amounts of 

immunoglobulins, to enable interpretation of IG amounts consumed or calculation of 

amounts required. We describe and compare the recommendations for IG use in 

Belgium and in five other industrialized countries. Based on the indications that are 

included in at least one country (29 indications), we present a review of the scientific 

evidence on IG effectiveness to date. 

Warning: In this document, the term indication is used to refer to a disease or 

syndrome for which immunoglobulin (IG) is used or considered to be used. It does not 

stand for “authorized indication” or “licensed indication”, which refers to the 

indications proposed by the manufacturer and authorized by the drug regulatory 

authority. 

3.2.1 Recommendations for the use of immunoglobulins 

The recommendations on which diseases can be treated with polyvalent 

3.2.1.1 

immunoglobulins vary per country, as well as the status of the recommendations. 

A few countries have developed full evidence-based guidelines, such as Canada and the 

United Kingdom (UK), extending recommendations beyond the labelled indications; 

other countries, such as Belgium, did not develop guidelines yet but have legally defined 

a list of reimbursed indications; for others countries, such as the Netherlands, a list of 

“labelled” indications is presented (i.e. indications approved by the regulatory drug 

agency). As a consequence, the legal status of these recommendations differs per 

country. 

Recommendations in Belgium 

In Belgium, official recommendations for IG use have not been yet published, but 

guidelines for IG use are currently under development by the Health Council 

(CSS/HGR). The only sources for guidance on IG use are the list of indications that are 

authorized in Belgium for each IG brand product (labelled indications) and the list of 

reimbursed indications and criteria for reimbursement for each indication, stated in the 

law (Table 19): 

• The authorized indications vary per brand product and over time. 

• The indications and criteria for which IG are reimbursed by the 

INAMI/RIZIV are described in the Royal Decree from 21 December 2001, 

with last modification stated in the Ministerial Decree from 15 July 2008. d 

Intravenous immunoglobulins 

In Belgium, several brands or pharmaceutical specialities of intravenous immunoglobulins 

(IVIG) are registered. Though reimbursed indications vary per brand product, the 

following pathologies are considered in the decree and summarized in Table 19: 

1. Haematological indications 

• Primary immune deficiency conditions: agammaglobulinemia; 

hypogammaglobulinemia with specific criteria; congenital deficiency in antipolysaccharidic 

antibodies (providing specific criteria are met) 

• Secondary immune deficiency: 

o Multiple myeloma and chronic lymphocytic leukaemia with severe 

hypogammaglobulinemia and recurrent infections 

o Prevention of infections in patients having an allogenic bone marrow 

transplant 

o Paediatric AIDS 

o Treatment of septicaemia in preterm infants and neonates 

d Arrêté ministériel du 18 juillet 2008 modifiant la liste jointe à l'arrêté royal du 21 décembre 2001 fixant 

les procédures, délais et conditions en matière d'intervention de l'assurance obligatoire soins de santé et 

indemnités dans le coût des spécialités pharmaceutiques (MB 18 JUILLET 2008 DEUXIEME EDITION).


• Idiopathic thrombocytopenic purpura: in children and in adults presenting 

a high risk of bleeding or for those awaiting surgery 

2. Neurological indications 

• Guillain-Barré syndrome, with specific criteria 

• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), with 

specific criteria 

• Multifocal motor neuropathy (MMN), with specific criteria 

3. Other indications 

• Kawasaki disease 

• Treatment of the toxic shock syndrome (TSS) due to streptococcal 

infections 

Table 19: Indications and reimbursement by pharmaceutical specialty of 

intravenous immunoglobulins, Belgium, as of October 2008 

Indications / brand product Sandoglobulin Multigam® Gammagard® 

of immunoglobulin 

® 

a Octagam® 

Nanogam® 

Primary immune deficiency 

conditions (specified) 

I, R I, R I, R I, R 

Multiple myeloma and chronic 

lymphocytic leukaemia 


Paediatric AIDS R I, R I, R I, R 

Idiopathic thrombocytopenic 

purpura 


Guillain-Barré syndrome I, R I, R I, R I, R 

Kawasaki disease R I, R R I, R 

Allogenous bone marrow 

transplant 


Treatment of septicaemia in 

preterm and neonates 

R I, R (2002) 

Treatment of toxic shock 

syndrome due to streptococcal 

infection 

I, R 

Chronic inflammatory 

demyelinating 

polyradiculoneuropathy 

I, R (2002) I, R (2003) 

Multifocal motor neuropathy I, R (2002) R (2008) 

Rheumatoid polyarthritis I 

For humoral immune deficiency I (R for above 

I (R for above 

following cytostatic treatment indications) 

indications) 

I: included in indications 

R: reimbursed indication (date of introduction of reimbursement) 

a: interpretation of the indications that are labelled in these general terms: “used in the 

substitution treatment of primary and secondary immune deficiencies, as for the prevention of 

infections resulting from these immune deficiencies. Used in the aim of modifying or controlling 

the immune response in many diseases.” 

The list of reimbursed indications per brand product has also evolved over time. The 

neurological indications CIDP and MMN have been added in the list of reimbursed 

indications in July 2002 for Sandoglobulin® and later for Multigam® (CIDP in 2004 and 

MMN in 2008). For each patient with CIDP or MMN, there is a maximum 

reimbursement of 9 g/kg per patient every 6 months, after a positive clinical evaluation.


Subcutaneous immunoglobulins 

Sub-cutaneous immunoglobulins, Subcuvia® and Vivaglobin®, are reimbursed for the 

following indications: 

• Primary immune deficiency conditions: agammaglobulinemia, 

hypogammaglobulinemia with specific criteria, congenital deficiency in antipolysaccharidic 

antibodies with specific criteria 

• Multiple myeloma and chronic lymphocytic leukaemia. 

3.2.1.2 Recommendations in other countries 

The recommendations for IG use in terms of which clinical indications can be treated 

with IG are presented for five other industrialized countries and compared to Belgium 

in Table 20. 

In Canada, the UK and Australia, guidelines are clearly stating that “IG therapy is not 

indicated” for specific conditions, described as “No” in the table, when applicable. 

The sources of these recommendations on IG use are described below: 

1. In Canada, detailed national guidelines covering the haematological and 

neurological indications have been published in four articles in the journal 

Transfusion Medicine Reviews in 2007. 18-21 They have been elaborated by a 

special committee, based on scientific evidence and using expert panels. 

2. In the United Kingdom, evidence-based guidelines from the Department of 

Health have been elaborated and the most updated version is dated May 

2008. 17 Besides a list of recommendations on IG use, a list of “grey 

indications” has been established: grey indications are those “for which the 

evidence base is weak, in many cases because the disease is rare, and for 

which IVIG treatment should be considered on a case by case basis, 

prioritised against other competing demands”. This comprehensive list of 

grey indications is not included in the table unless the disease was listed in 

other country recommendations, and grey indications are indicated with a 

“(3)”, see Table 3 legend. This guideline also includes a short list of 

indications for which IVIG is not recommended (indicated as “No” in the 

table). 

3. In the Netherlands, labelled indications are described in a document for 

prescribers from the Medicines Evaluation Board (2003). e 

4. In France, full recommendations have not been yet established at national 

level. Each IG specialty has a limited list of authorized indications; in addition, 

a wider list of diseases for which IG is recommended has been published by 

the “Commission de la Transparence”, “Haute Autorité de Santé” (HAS) for 

specific products, and from the Drug Agency (AFSSAPS) for IG in general in 

its document «Proposition de hiérarchisation des indications des 

immunoglobulines humaines intraveineuses (IgIV) en situation de tension 

forte sur les approvisionnements pour le marché français, 06/05/2008 ».f 

Clinical indications have been categorized per level of priority in several 

groups, to identify patients that should receive IG in a context of shortage. 

On one hand, the indications included in the marketing authorizations 

(Autorisation de Mise sur le Marché or AMM) have been classified in priority 

groups: priority indications; indications to keep for vital emergencies or after 

failure of alternative treatment; and non-priority indications (that can wait till 

shortage end). On the other hand, a list of diseases non included in the AMM 

e Medicines Evaluation Board. http://db.cbg-meb.nl/IB-teksten/h16942.pdf 

f AFSSAPS. Proposition de Hiérarchisation des indications des IgIV reconnues dans l'AMM, disponible dans 

la circulaire DGS/PP/DHOS/E2/AFSSaPS/2008/92 du 14/03/2008 relative à la surveillance des 

approvisionnements en immunoglobulines humaines normales et à la gestion des situations de tension. 6 

June 2008. Available on http://www.afssaps.fr/Infos-de-securite/Autres-mesures-de-securite/Propositionde-hierarchisation-des-indications-des-immunoglobulines-humaines-intraveineuses-IgIV-en-situation-detension-forte-sur-les-approvisionnements-pour-le-marche-francais2 

Accessed January 2009.


has been classified in 5 groups and published by the AFSSAPS, based on the 

expert recommendations. g In total, 8 groups of diseases are defined, and how 

to apply these priority levels is not clearly described. 

5. In Australia, the “Criteria for the clinical use of intravenous immunoglobulin 

in Australia” has been issued by the Australian health Ministers’ conference in 

December 2007. 22 It is intended to be regularly updated, and revisions are 

periodically issued on http://www.nba.gov.au/ivig/pdf/criteria-revisions.pdf 

(last update February 2009). It also set up several groups of diseases for 

priority setting: 1. Conditions for which IVIg has an established therapeutic 

role; 2. conditions for which IVIg has an emerging therapeutic role: 3. 

conditions for which IVIg is used in exceptional circumstances; 4. conditions 

for which IVIg use is not indicated. 

As previously said, the legal status of these recommendations differs per country, due 

to the difference between sources describing them. 

Based on the comparison of national recommendations (Table 20), the following 

conclusions on indication for IG can be drawn: 

• IG is recommended in all countries for a number of diseases, in a 

consistent way: primary immune deficiencies, multiple myeloma and 

chronic lymphocytic leukaemia for selected situations, idiopathic 

thrombocytopenic purpura, Kawasaki disease and selected neurological 

diseases such as Guillain Barré syndrome. It should be noted that the 

recommendations published in the Netherlands include only a limited 

number of indications because only reimbursed indications are listed; this 

does not precludes that IG use is accepted for other diseases. 

• In many indications, IG is only recommended in “selected” cases of a 

given disease, according to specific criteria described by each country. 

Criteria include clinical variables, severity or level of disability, age, 

biological criteria (e.g. serum Ig levels) or therapeutic response to other 

treatments. For instance, IG is only recommended for multiple sclerosis 

and dermatomyositis cases showing failure or contra-indications to 

standard treatment. 

• However for many other diseases, recommendations for the use of IG are 

not consistent across countries. In most of these diseases, the available 

evidence on IG effectiveness is either not available, of low level, 

inconsistent across studies, or only show a marginal benefit. 


• In these six industrialized countries, IG is recommended for a defined 

number of diseases in a consistent way. 

• In many indications, IG is only recommended in “selected” cases and the 

criteria for IG treatment vary per country. 

• In a number of diseases, IG is not recommended on a consistent way across 

countries. This mostly concern diseases with an auto-immune component, 

for which the available evidence is either of low level or only shows marginal 

benefit. 

g Comité d’Evaluation et de Diffusion des Innovations Techniques” (CEDIT) of the “Assistance Publique des 

Hôpitaux de Paris. Proposition de Hiérarchisation des indications hors AMM des IgIV réalisée par le 

Comité d'experts IgIV du Cedit de l'AP-HP, dans l'attente de la publication par l'Afssaps prévue d'ici fin 

Juin 2008 des référentiels de bon usage sur les IgIV, qui définiront les situations temporairement 

acceptables justifiant la mise en place d'un protocole thérapeutique temporaire. Available on 

http://www.afssaps.fr/Infos-de-securite/Autres-mesures-de-securite/Proposition-de-hierarchisation-desindications-des-immunoglobulines-humaines-intraveineuses-IgIV-en-situation-de-tension-forte-sur-lesapprovisionnements-pour-le-marche-francais2


Table 20: Recommendations for intravenous immunoglobulins use in six selected countries 

Indications Belgium a Canada b The UK b Netherlands c France d Australia b 

Immuno-haematological indications 


purpura 

Yes, selected (1) Yes (1) Yes, selected Yes (1) Yes, selected (1) Yes, selected 


conditions 

Secondary immune deficiencies: 

Yes, selected (1) Yes (1) Yes, long term Yes, selected (1) Yes (1) Yes, selected 

- in general 

Not mentioned Yes (1) 

Yes (3) 

Not mentioned Yes (1) 

Yes in general, for 

selected conditions 

Yes, selected (1) Yes, selected (2) Yes, selected Yes, in CLL (1) Yes, selected (1) Yes, selected 

- multiple myeloma, chronic 


- Allogenous bone marrow 

transplant 

- paediatric HIV/AIDS 

- in solid organ transplant 

- septicaemia in neonates 

- infections in preterm and/or low 

birth weight 

Isoimmune haemolytic jaundice in 

neonates 

Alloimmune thrombocytopenia, 

foetal and neonatal 

Yes (1) 

No but labelled Yes if low IgG Yes (1) 

Yes (1) 

Yes, selected 

Yes (1) Yes, selected (2) No Yes (1) Yes, selected (1) Yes, selected 

Not mentioned NA For CMV 

pneumonitis 

For rejection (3) 

Yes, kidney (1) Yes (kidney) (3) Yes, selected 

Yes treatment (1) NA No Not mentioned Yes (3) Yes but (3) 

Preterm, to treat NA NA Yes (


Myasthenia gravis Not mentioned Yes, selected (2) Yes, selected Not mentioned Yes (3) Yes, selected 

Dermatomyositis Not mentioned Yes, selected (2) Yes, selected Not mentioned Yes (3) Yes, selected 

Inclusion body myositis Not mentioned No No Not mentioned Yes, selected (3) Yes, selected 

Stiff person syndrome 

Other indications 

Not mentioned Yes, selected (2) Yes, selected Not mentioned Yes (3) Yes, selected 

Kawasaki disease Yes (1) Yes (1) Yes Yes (1) Yes, selected (1) Yes 

Treating septic shock and/or Yes, streptococcus NA Yes, selected Not mentioned Yes, streptococcus Yes, streptococcus 

necrotizing fasciitis 

(1) 

(3) 

staphylococcus 

Viral myocarditis in children Not mentioned NA Not mentionned Not mentioned Not mentioned Yes but (3) 

Yes: Immunoglobulin use is recommended 

No: recommendations state that IG is not indicated for that disease 

Selected: Immunoglobulin use is recommended or reimbursed for this indication in selected cases; criteria have been established for recommendation or reimbursement. 

NA: non available, meaning that recommendations on this indication have not been published yet 

Not mentionned: this indication is not mentionned in exhaustive guidelines or list of indications 

RRMS: relapsing remitting multiple sclerosis 

a: reimbursed indications 

b: from national guidelines 

c: from labelled indications, according to the Medicine Evaluation Board 

d: from the “Commission de la Transparence », “Haute Autorité de Santé” (HAS), Avis 19 juillet 2006 and from AFSSAPS « Proposition de hiérarchisation des indications des 

immunoglobulines humaines intraveineuses (IgIV) en situation de tension forte sur les approvisionnements pour le marché français, 06/05/2008 ». 

(1): Labelled use (or registered use or use included in the marketing authorization) 

(2): Off-label use (i.e. not included in the registered indications) but IG use is recommended for this disease in the guidelines 

(3): Use of IG is only recommended for this disease in specific cases: after failure of other therapies or in vital emergencies (France); considered on a case by case basis in the 

UK, prioritised against other competing demands (grey indications); or in exceptional circumstances - urgent or life-threatening circumstances, or in circumstances in which 

significant morbidity would be expected and other clinically appropriate standard therapies have been exhausted or are contraindicated (Australia).


3.2.2 Evidence review on immunoglobulin effectiveness 

3.2.2.1 Background 

3.2.2.2 Methods 

The mechanisms of action of polyvalent immunoglobulins (IG) are complex and not 

totally elucidated today, aside of their use in correcting immunodeficiencies. In 

immunodeficiency diseases, polyvalent IG is given to restore normal humoral immune 

function by increasing antibody levels. In autoimmune disorders and some inflammatory 

diseases, it is assumed to have a rapid immunomodulatory action, by neutralizing 

circulating auto-antibodies, modulating the production of inflammatory cytokines, 

interfering in complement activation, and a few other mechanisms. In the long term, it 

also regulates the production of antibodies and cytokines. This evidence review does 

not cover the IG mechanisms of action but it reviews the effectiveness of IG in treating 

a number of diseases. 

Scope 

As more than 100 indications have been considered for IG use, this literature review 

focuses on the indications that contribute to address the research question. We 

selected indications for which IG are reimbursed or recommended by national 

authorities and/or likely to consume significant amounts of IG and/or have been covered 

in systematic reviews. We included the following diseases (see Table 21): 

• indications reimbursed in Belgium 

• diseases for which IG is recommended in five comparable industrialized 

countries (France, Netherlands, UK, Canada and Australia) 

• other diseases covered by Cochrane systematic reviews including IG 

effectiveness 

• diseases under investigation that may consume high amounts of IG 

Twenty-nine indications have thus been selected for this literature review: 

Haematological diseases 

1. Primary immune deficiency conditions 

2. Secondary immune deficiencies: 

• Multiple myeloma and chronic lymphocytic leukaemia 

• Allogenic bone marrow or stem cell transplant 

• Prophylaxis in solid organ transplant 

• Suspected or proven infections in neonates 

• Preterm and/or low birth weight infants 

• Paediatric HIV/AIDS 

3. Idiopathic thrombocytopenic purpura 

4. Isoimmune haemolytic jaundice in neonates 

5. Fetal allo-immune thrombocytopenia 

Neurological and neuro-muscular diseases 

1. Guillain-Barré syndrome (and variants) 

2. Chronic inflammatory demyelinating polyradiculoneuropathy 

3. Multifocal motor neuropathy 

4. Paraprotein-associated peripheral neuropathies 

5. Multiple sclerosis 

6. Lambert-Eaton myasthenic syndrome (LEMS)


7. Myasthenia gravis 

8. Dermatomyositis and polymyositis 

9. Inclusion body myositis 

10. Stiff person syndrome 

11. Neuromyelitis optica 

Other diseases 

1. Kawasaki disease 

2. For treating sepsis and septic shock 

3. Viral myocarditis 

4. For treating respiratory syncitial virus infection 

Diseases under investigation 

1. Chronic fatigue syndrome 

2. Alzheimer disease 

Search strategy 

The search for evidence synthesis was focused on systematic reviews. Systematic 

reviews identified were subsequently updated with original RCT published in Medline or 

Embase, after the last literature search. For diseases not covered by a systematic 

review, published randomized controlled trials (RCT) were considered. The date of 

search was November 2008 and an update was performed in June 2009. 

Databases used were the Cochrane review database, the database of abstracts of 

reviews of effects (DARE) in the Centre for Reviews and Dissemination database (CRD) 

(http://www.crd.york.ac.uk/crdweb/), Medline and Embase. Search terms are described 

in appendix. 

Selection of studies 

Evidence synthesis studies were eligible if they reviewed the literature systematically on 

the clinical efficacy of polyvalent immunoglobulins (administrated intravenously or 

subcutaneously), on clinically relevant outcomes regarding morbidity / mortality / 

disability due to these diseases. 

Original studies were eligible if they were randomised controlled trials published after 

the last systematic review search, or after 1998 if no systematic review was found. 

Studies published in English, Dutch, French and Spanish were considered. When no 

systematic reviews or randomized controlled trial were found on the disease of 

interest, observational studies covering the effectiveness of IG published after 1998 

were described for information. Cost-effectiveness studies were also included. 

Controlled trials on other interventions such as specific immunoglobulins, oral or intramuscular 

administration, and on other health conditions than those listed under 

“Scope” were excluded. 

In addition, the eligible references or related articles of the systematic reviews were 

searched for any missing publication, when evidence was lacking or conflicting.


Search results 

COCHRANE SYSTEMATIC REVIEWS 

Nineteen Cochrane Systematic Reviews (last versions) were found on the effectiveness 

of immunoglobulins in treating the following diseases: multiple myeloma, chronic 

lymphocytic leukaemia, bone marrow/stem cell transplant, isoimmune haemolytic 

jaundice in neonates, fetomaternal alloimmune thrombocytopenia, CMV prophylaxis in 

solid organ transplant, severe infections in neonates, for preventing infection in preterm 

and low birth weight babies, Guillain-Barré syndrome, chronic inflammatory 

demyelinating polyradiculoneuropathy, multifocal motor neuropathy, multiple sclerosis, 

paraprotein-associated peripheral neuropathies, Lambert-Eaton myasthenic syndrome, 

myasthenia gravis, dermatomyositis, Kawasaki disease, treating sepsis and septic shock, 

viral myocarditis and treating respiratory syncitial virus infection. 

CRD DATABASE 

We found 105 references on immunoglobulins, including 30 which focused on 

polyvalent immunoglobulins. These included 28 systematic reviews (including the 19 

Cochrane reviews), 1 guideline and 1 report which fitted the selection criteria. 

Appraisal of evidence 

Relevant papers were reviewed to identify the best evidence to answer the key clinical 

questions. This process involved selection of relevant studies; assessment of study 

quality; synthesis of the results; and grading of the evidence. 

The critical appraisal was done for systematic reviews and additional studies. A level of 

evidence (high, moderate or low) was assigned to each body of evidence according to 

the GRADE methodology, as described by the GRADE working group (see Appendix). 23


Table 21: Summary of evidence findings and evidence levels per disease 

Disease / syndrome Main findings Evidence 


conditions 


- multiple myeloma and chronic 


- in stem cell/bone marrow 

transplant (BMT/HSCT) 

- in solid organ transplant 

- for suspected or proven 

infection in neonates 

Large reduction in infection severity and incidence in XLA, CVID and 

agammaglobulinemia. No clear benefit in specific antibody deficiencies. 

IG significantly decreased documented infections and may be considered in patients 

with hypogammaglobulinemia and recurrent infections. No impact on mortality. 

IG prophylaxis significantly reduced the risk for interstitial pneumonia after 

BMT/HSCT in two meta-analyses. IG also significantly reduced the incidence of 

CMV pneumonia in one meta-analysis. 

Reduction in CMV deaths but no significant reduction of CMV disease and overall 

mortality. Antivirals are effective. 

In highly sensitized patients, RCT showed some benefit of IG after transplant but no 

significant reduction in rejection rates 

IG given to neonates with proven infection reduced overall mortality in 5 metaanalyses. 

Reduction in mortality in neonates with suspected infections is less clear. 

- in preterm / low birth weight IG given to in preterm and/or low birth weight infants only marginally reduced 

sepsis and serious infections (by 3-4%), and had no effect on mortality. 

level 

Comment on level of evidence 

Moderate Observational studies and 1 RCT 

showing dose-response gradient 

High Meta-analysis of 10 RCT 

Moderate Two meta-analyses of >30 RCT, old 

RCT, different results, poor 

Moderate 

Moderate 

directness (BMT treatment evolved) 

- Meta-analysis of 37 RCT with poor 

study quality 

- 3 small RCT, inconsistent results 

across RCT 

Meta-analysis of 9 RCT but sparsity 

and inconsistent results with the 

former Cochrane meta-analysis 

High Meta-analysis of 19 RCT, 5000 

infants, confirm 3 previous metaanalyses 

Moderate Several RCT before HAART, lack 

- in paediatric HIV/AIDS IG decreases incidence of infections and hospital admissions. 

But limited use due to HAART and AB prophylaxis. 

directness 

Idiopathic thrombocytopenic - In children with acute ITP, IG has higher and quicker effectiveness than no Moderate Meta-analysis of 28 RCT but low 

purpura (ITP) 

treatment or steroids. IG role in chronic childhood ITP could not be established. 

- In adult ITP, IG may be more effective than steroids in the short term. For chronic 

ITP, the advantage of IG over other therapies is not established. 

quality and sparsity 

Isoimmune haemolytic disease in IG significantly reduced the need for exchange transfusion and phototherapy. Moderate Meta-analysis of 3 small not blinded 

neonates 

RCT 

Fetal allo-immune 

Observational studies suggest a benefit of IG in FNAIT. IG added to prednisolone Low 26 observational studies, 2 RCTs of 

thrombocytopenia (FNAIT) has no higher effectiveness than IG alone 

IG added to steroids 

Guillain-Barré syndrome (and In severe GBS, IG hastens recovery as much as plasma exchange, but no RCT Moderate In adults, meta-analysis of 5 RCT 

variants) 

compared IG with supportive care or placebo. In children, limited evidence suggests for adults, comparing IG to PE; directness 

that IG hastens recovery compared with supportive care alone. 

low for questioned. 

children 3 small trials in children


CIDP IG improves disability for up 24-48 weeks compared to placebo, but is not more 

effective than plasma exchange and prednisolone. Unclear which treatment is more 

effective. 

Multifocal motor neuropathy IG showed a significant effect on muscle strength and a non-significant improvement 

Paraprotein-associated 

peripheral neuropathies 

Multiple sclerosis 

- Relapsing remitting (RRMS) 

- Primary progressive (PPMS) 

- Secondary progressive (SPMS) 

Lambert-Eaton myasthenic 

syndrome 

High Meta-analysis of 5 RCT vs. placebo, 

2 RCT vs. other treatments. 

Moderate Meta-analysis of 4 RCT, but small 

in disability 

size and sparse data 

In IgM associated neuropathies, IG may produce some short-term benefit. 

Moderate Review of 2 small RCT, but quality 

In IgG and IgA disease, evidence on IG effectiveness is insufficient. 

problems 

Low Small observational studies 

In RRMS, IG reduced disease progression and MRI lesions. 

Moderate Several meta-analyses, 15 RCT. 

IG delayed disease progression in PPMS. 

Inconsistent results in the last and 

No effect on disease progression in SPMS. 

IG reduced the rate of relapses in the post-partum period. 

larger multinational RCT on RRMS. 

IG improved functional capacities and muscle strength in a small RCT Low Review but 1 small RCT 

Myasthenia gravis IG is more effective than placebo or as effective as other treatments for severe 

exacerbation and worsening, but this benefit was not shown in mild and moderate 

disease. 

Dermatomyositis and 

polymyositis 

Inclusion body myositis IG did not improve muscle strength in IBM patients but significantly improved 

swallowing functions in one study 

Moderate Review of 6 RCT but one had 

inconsistent results 

IG improved symptoms and muscle strength and was more effective than placebo Moderate Review w/ 1 RCT, 1 non controlled 

trial, observational studies 

Moderate 3 small RCT (N=47) 

Stiff person syndrome IG improved stiffness and sensitivity scores Moderate 1 small RCT 

Neuromyelitis optica The effectiveness of IG in neuromyelitis optica has not been shown. Low Few case series 

Kawasaki disease IG showed significant decrease in new coronary artery abnormalities, fever and 

hospitalization compared to placebo. 

High Meta-analysis of 16 RCT 

Viral myocarditis in children and Limited evidence does not show a benefit of IG over placebo for the management Moderate Review with 1 RCT, results 

adults 

of presumed viral myocarditis in adults. There is no evidence for paediatric cases for adults inconsistent with open studies 

Treating sepsis and septic shock IG used as an adjuvant therapy reduces mortality compared to placebo or no 

adjuvant therapy in 3 recent meta-analyses. 

High 3 meta-analyses (11-20 RCT each) 

Treating RSV infection No significant benefit of IG treatment added to supportive care, compared with Moderate Review of 4 RCT, heterogeneity of 

supportive care alone. 

outcomes 

Alzheimer disease (AD) Evidence is lacking on the effectiveness of IG Low 2 small case series 

Chronic fatigue syndrome No conclusion can be drawn on the effect of IG in CFS as the evidence is 

conflicting. The larger trial showed no effect, with 70-80% of adverse events. 

Moderate 3 RCT but inconsistent results


3.2.2.3 Immuno-hematological diseases 

A summary of evidence findings and levels of evidence for IG use is presented in Table 

21. 

Primary immune deficiencies 

Primary immunodeficiency disorders (PID) result from intrinsic defects of the immune 

system, in contrast to immune disorders that are secondary to infection, chemotherapy 

or immunosuppressive therapy. Individuals with PID are prone to recurrent bacterial 

infections, typically in respiratory and gastro-intestinal tracts, or protozoal, fungal and 

viral infections, of varying severity. Deficiencies of various components of the immune 

system have been identified, and more than 200 different PID are currently recognized 

by the WHO. In Europe, the PID requiring IG replacement that are the most commonly 

diagnosed are: the common variable immunodeficiency (CVID) - revealed at adulthood, 

X-linked agammaglobulinemia (XLA), other agammaglobulinemia, Wiskott-Aldrich 

syndrome, severe combined immunodeficiency, hyper-IgM syndromes and severe 

hypogammaglobulinemia with recurrent and severe bacterial infections. 24 In most of the 

cases with severe antibody deficiency (IgG


• IG reduces the incidence and severity of infection in patients with 

agammaglobulinemia and severe hypo-gammaglobulinemia. 

• Effectiveness of IG in milder hypogammaglobulinemia, IgG subclass 

deficiency and impaired polysaccharide responsiveness is unclear. 

• The route of administration (IV or SC) does not influence treatment 

effectiveness. 

Secondary immune deficiencies 

In many patients, the immune deficiency is a direct consequence of a decreased antibody 

production due to cancers of the haematopoietic system, such as multiple myeloma or 

chronic lymphocytic leukaemia, cytotoxic chemotherapy, immunosuppressive therapy to 

prevent transplants rejection, very low weight etc. 

The effectiveness of IG in treating the conditions leading to secondary immune 

deficiency varies per pathology. It has only been well studied for specific pathologies, 

such as multiple myeloma, chronic lymphocytic leukaemia and stem cell transplants (see 

below). For hypo-gammaglobulinemia related to other diseases or drug therapy, no 

evidence on the benefit of IG treatment was found. However, most guidelines 

recommend the use of IG – besides antimicrobial prophylaxis – to decrease the risk of 

infection in cases with the same criteria than those set for PID requiring IG 

supplementation: IgG levels under reference range and severe or recurrent bacterial 

infections that are unresponsive to prophylactic antibiotics etc. 17, 22 . 

Multiple myeloma and chronic lymphocytic leukaemia 

Multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) are rare proliferative 

disorders that lead to a higher incidence of serious bacterial infections, such as 

pneumonias and urinary tract infections. Factors underlying the increased susceptibility 

to infections are many and complex. A major factor is the decreased capacity to 

produce potent immunoglobulins, often reflected by a certain degree of hypogammaglobulinemia 

observed in the majority of patients. In MM, the immunodeficiency 

is mainly caused by abnormal Ig production and impairment of the primary immune 

response. 41 Infections and its consequences (including renal failure) are the major cause 

of morbidity and mortality in both diseases. Up to 65% of CLL patients die from 

infection-related events and MM cases have a fatality rate of 30%. Many treatment 

strategies exist for MM and CLL; IG is mainly used as prophylactic agent to prevent 

infections, mostly in recurrent life threatening infections. 42 

A Cochrane review updated in 2009 included ten RCT involving MM or CLL patients 

with hypogammaglobulinemia and recurrent infections, and the meta-analysis combined 

studies from both diseases. 43 It showed that no benefit of IG could be demonstrated in 

terms of mortality, but IG significantly decreased the risk of clinically documented 

infections by 51% (RR 0.49, 95% CI 0.39-0.61), and significantly reduced the occurrence 

of microbiologically documented infections as compared to controls (RR 0.71, 95% CI 

0.53-0.95). Authors concluded that IG use may be considered in MM and CLL patients 

with hypogammaglobulinemia and recurrent infections, for the reduction of clinically 

documented infections. 

Another systematic review, conducted by the same group, included nine of the 10 RCT 

involving CLL and MM patients, and presented similar findings and conclusions. 44 

A 2005 systematic review on the cost of disease included cost-effectiveness studies. 45 It 

only found one cost effectiveness study on IG, published in 1991, thus excluded from 

this review. 46 

IG significantly decreased documented infections in CLL and MM patients but 

had no impact on mortality. IG is considered in patients with documented 

hypogammaglobulinemia and recurrent infections.


Bone marrow transplantation and hematopoietic stem cell transplantation 

Bone marrow transplantation (BMT) and hematopoietic stem cell transplantation 

(HSCT) compromise the immune system of patients due to the administration of high 

doses of chemo-radiotherapy prior to infusion of the donor stem cells. 44 Multiple 

immunological deficiencies, including T- and B-cell abnormalities and 

hypogammaglobulinemia, predispose patients to a high risk of developing infections. As 

the incidence of CMV seropositivity in the general population is high, CMV reactivation 

and subsequent disease becomes a significant prognostic factor of morbidity and 

mortality in BMT/HSTC. Even though antiviral agents can inhibit the viral replication in 

vivo, they have not been able to treat CMV interstitial pneumonia effectively. This 

period of immunological incompetence usually lasts from six to 12 months. These 

abnormalities are less prominent in autologous than in allogenic transplantations. 

Systematic reviews of evidence are contradictory, despite numerous RCT on this area, 

as many of them have divergent findings. 

On one hand, the Cochrane review published in 2008 included 30 RCT with 4223 

patients receiving prophylaxis after BMT/HSCT. 43 Twenty-one RCT evaluated polyvalent 

IG or compared it to CMV hyper-immune IG. The analysis did not distinguish between 

allogenic or autologous transplantation. When polyvalent IG was compared to control, 

there was no difference in all-cause mortality. IG significantly reduced the risk for 

interstitial pneumonia but increased the risk for veno-occlusive disease and adverse 

events. This review concluded that routine prophylaxis with IG is not supported by 

available evidence for these patients. 

On the other hand, a meta-analysis of 12 RCT involving 1282 patients was conducted in 

1993 and showed that IG reduced all cause mortality (though with borderline 

significance), CMV pneumonia and non-CMV interstitial pneumonia. 47 Three of the trials 

were not RCT and the Cochrane review excluded several of them for methodological 

reasons; however, this review allocated a quality weight for data analysis. 

A major limitation of both reviews is that the majority of RCTs are old (patients treated 

in the 80’s and 90’s) while techniques and treatment for patients undergoing 

transplantation for haematological malignancies have changed considerably over the last 

two decades, such as the use of non-myeloablative treatment. This may explain the 

divergence in conclusions between the two meta-analyses. In addition, several RCT 

concluded that IG was not found to be beneficial in autologous BMT recipients. Despite 

the controversy about the benefit of IG in HSCT/BMT, this agent is still recommended 

in most transplantation protocols in many countries. Some authors suggest that IG 

should be reserved for patients who are hypo-gammaglobulinaemic after BMT. 48 

IG prophylaxis significantly reduced the risk for interstitial pneumonia after 

BMT/HSCT in two meta-analyses. IG also significantly reduced the incidence of 

CMV pneumonia in one meta-analysis.


Solid organ transplant 

IG may be indicated for two main problems encountered in solid organ transplant 

(SOT) recipients: 

• On one hand, immunosuppression after SOT is associated with increased 

risk of opportunistic infections, particularly during the 6-month posttransplant 

period when viral infections are most prevalent. 49 

Cytomegalovirus (CMV) is a major cause of disease and death in SOT 

recipients during this period, with an overall incidence of 30% to 50%. 

CMV also has the propensity to establish lifelong ’latency’ infection in the 

host after the initial infection has resolved. Therefore, SOT recipients may 

be infected either by exogenous virus or by reactivation of latent virus if 

they were CMV positive pre-transplant. Those at highest risk of 

symptomatic CMV disease are thus CMV sero-negative patients who 

receive organs from CMV sero-positive donors, and CMV sero-positive 

patients on heavily immunosuppressive regimens. CMV is also associated 

with increased risk of allograft injury and rejection, opportunistic 

infections and late onset malignancies. Two main strategies to prevent 

CMV disease exist: prophylaxis of all organ recipients with antiviral 

medications and/or immunoglobulins called ’pre-emptive therapy’ for highrisk 

groups, such as patients receiving anti-lymphocyte antibody 

preparations. 

• On the other hand, one-third of patients awaiting renal allograft transplant 

have high levels of pre-formed anti-HLA antibodies, and are called highlysensitized 

patients. 50, 51 If transplanted, these patients experience an 

increase number of rejection episodes and have poorer graft survival. 

Over the past several years, high doses of IG have been used to help 

improve transplantation rates in this group. 52 

A Cochrane review published in 2007 included 37 RCT on the effectiveness of IG on 

CMV risk and disease. 53 Studies looking at the efficacy of polyvalent IG and CMV 

hyperimmune IG were combined as no difference between the two groups could be 

detected. There was no significant difference in the risk for CMV disease, CMV infection 

and all-cause mortality with IG compared with placebo/no treatment. However, IG 

significantly reduced the risk of death from CMV disease (RR 0.33, 95% CI 0.14-0.80). 

Adding IG to antiviral medication did not affect the risk for CMV disease, CMV infection 

or all-cause mortality, compared to antivirals alone. The authors concluded that there 

are currently no indications for IG in the prophylaxis of CMV disease in SOT recipients, 

considering that the efficacy of several antiviral medications (valganciclovir, ganciclovir, 

acyclovir, valganciclovir) have been demonstrated in reducing CMV disease, CMV 

infection, all-cause and CMV related mortality and opportunistic infections. 

In highly sensitized patients, no systematic review was found, but three RCT involving 

kidney transplants in patients at risk for rejection were retrieved. A first RCT was 

conducted in 41 patients having received a second kidney transplant and treated with 

immunosuppressant. 54 Daily IG was added to the treatment of 21 patients on the first 5 

days after transplantation. The number of acute rejection episodes and incidence of 

CMV infection were similar but the 5-year survival rate was significantly higher in the IG 

group compared to the control group. A second RCT, involving 30 patients with 

confirmed steroid-resistant rejections, compared the effectiveness of IG versus 

monoclonal anti-CD3. 55 The incidence of rejections after treatment was lower in the IG 

group compared to the other group but not significantly (46% vs. 75%, p=0.4). Patient 

survival rates and graft survival were not significantly different in the two groups.


A third RCT, conducted in 101 patients with end-stage renal disease and involving 27 

kidney transplants, showed that IG was effective in reducing anti-HLA antibody levels, 

improving kidney transplant rates in highly sensitized patients compared to placebo, and 

decreased waiting time to graft. 51 There was however no significant decrease in graft 

survival rates and patient survival in the IG group compared to placebo and allograft 

rejection was significantly higher in the IG group. The authors concluded that IG pretreatment 

should improve the transplant potential for highly sensitized patients with 

end-stage renal disease awaiting kidney transplantation, especially those resistant to 

other therapies. 

• IG, used alone or with antivirals, for the prophylaxis of CMV disease in SOT 

recipients did not decrease the risk of CMV disease and overall mortality 

compared to placebo, or to antivirals alone, in a meta-analysis of 30 RCT. IG 

reduced the risk of death from CMV disease compared to placebo. Antiviral 

medications are effective. 

• In highly sensitized patients, three RCT suggested some benefit of IG 

treatment after transplant but failed to show a significant reduction of 

transplant rejection. 

Suspected or proven infection in neonates 

As endogenous synthesis of immunoglobulins does not begin until about 24 weeks after 

birth, neonates are at high risk for morbidity and mortality from infections acquired in 

utero, as well as from exposure to infectious sources in neonatal intensive care units. 56 

Sepsis is an important cause of neonatal death and brain damage. Though effective 

antibiotic treatment is essential for sepsis, adjuvant therapies such as IG may offer an 

additional strategy. The rationale for IG treatment for neonatal infections is based on 

the evidence that it provides IgG that can bind to cell surface receptors, provide 

opsonic activity, activate complement, promote antibody dependent cytotoxicity and 

improve neutrophilic chemoluminescence. 

A Cochrane review published in 2004 included 9 RCT involving 553 neonates with 

suspected infection. 57 Six studies reported on mortality and results showed a reduction 

in mortality following IG treatment in cases with suspected infection of borderline 

statistical significance. Treatment with IG in cases of subsequently proven infection did 

result in a statistically significant reduction in mortality (RR 0.55, 95% CI: 0.31-0.98). 

However, the authors points that these findings are in contrast with a previous 

Cochrane meta-analysis (from the same author) that showed the reverse relationship 

(significant reduction in mortality in suspected infections and non significant reduction in 

proven infections). 58 The review also mentions that four former meta-analyses showed 

statistically significant reductions in mortality following IG treatment for neonatal sepsis, 

up to a six-fold decrease (p=0.007) when IG is administered in addition to standard 

therapies. 

IG given to neonates with proven infections reduced overall mortality in five 

meta-analyses. However, the effectiveness of IG to reduce mortality in 

neonates with suspected infections was not always significant. 

Preterm / low birth weight infants 

As maternal transfer of IG to the foetus occurs mainly after 32 weeks of gestation and 

endogenous synthesis does not begin until about 24 weeks after birth, the preterm 

infant is especially vulnerable to infectious sources. 57 Indeed, nosocomial infections 

continue to be a significant cause of morbidity and mortality among preterm and/or low 

birth weight infants. Due to the mechanisms above described, IG was considered to 

have the potential of preventing or altering the course of nosocomial infections. 59


A Cochrane review on IG for preventing infections in preterm (


bleeding occurrence. In some countries, IG is used as the first line 

treatment (e.g. France) and in other countries as a second line or as one 

of the treatment options. 

• In adults: Adult ITP usually has an insidious onset and is typically a chronic 

disease. Its incidence increases with age. IG is usually recommended in 

cases with risk of serious bleeding, as part of a multi-modal therapy. 

Other treatments include intravenous steroids, anti-D immune globulin, 

vincristine, platelet transfusions and factor VIIa. However, 

recommendations for chronic ITP widely vary per guideline. 

A systematic literature review was published in 2008 as part of a health technology 

assessment undertaken by the Canadian drug agency. 62 It included 28 RCT: 15 RCT 

among children with acute ITP, 4 RCT among children with chronic disease, 7 RCT 

among adult ITP and 2 RCT among mixed populations. IG was compared with steroids, 

anti-D immunoglobulin, modified or different doses of IVIG, or close observation. The 

review only included English language publications. 

• In children: In one trial that compared IG with close observation, IG was 

associated with earlier improvements in platelet counts. IG also showed 

higher effectiveness compared with steroids for early recovery of 

thrombocytopenia in acute ITP. The advantage of IG over anti-D 

immunoglobulin is uncertain due to sparse evidence. The optimal dose of 

IG has not been established. There was insufficient evidence to determine 

if specific subgroups of children with acute ITP may receive preferential 

benefit from IG treatment. The role of IG in chronic childhood ITP could 

not be established, because evidence from scant, poorly designed, and 

poorly reported RCT could not be synthesized. 

• In adults: Two RCT compared IG with steroids in adults with newly 

diagnosed ITP: in one, no advantage for IG was found; in the other study, 

IG was more effective than steroids for the short-term improvement of 

thrombocytopenia and gave a more rapid and sustained response. 63 IG 

was associated with more severe adverse events that prolonged 

hospitalization. The review concluded that sparse evidence indicates that 

IG may be more efficacious than high dose corticosteroids in improving 

platelet counts in the short term, though its effect on clinical outcomes 

remains indeterminate. Limited evidence could not demonstrate the 

superiority of a 2 g/kg dose of IVIG over a 1 g/kg dose; a dose of 1 g/kg, 

however, may be better than a dose of 0.5 g/kg. For the long-term 

management of adult ITP, data were insufficient and studies were 

heterogeneous, preventing any conclusion on whether IG has an 

advantage over other treatments. 

A US study compared the cost-effectiveness of IG, anti-D, methylprednisolone and 

prednisone. 64 Therapies with IG and methylprednisolone were less effective and more 

expensive than anti-D and prednisone, respectively. However, this analysis has been 

debated by many authors, as it is based on several questionable assumptions; for 

instance, they assumed that all ITP patients received treatment, all children responded 

65, 66 

to the initial management strategy, and IG is not more effective than steroids. 

A more recent Chinese systematic review of studies published between 1990 and 2007 

showed that the use of steroids provided additional life years and was more costeffective 

compared with IG, but that transferability of results to other countries was 

low. 62


• In children with acute ITP, evidence suggests that IG improves more rapidly 

platelet counts than no treatment or steroids. The role of IG in chronic 

childhood ITP could not be established. 

• In adult ITP, sparse evidence indicates that IG may be more efficacious than 

steroids in improving platelet counts in the short term, though its effect on 

clinical outcomes is unclear. For long term treatment of chronic ITP, studies 

did not allow to determine the benefit of IG and its advantage over other 

treatments. 

Fetal/Neonatal allo-immune thrombocytopenia 

Fetal or neonatal allo-immune thrombocytopenia (FNAIT) accounts for 27% of cases of 

severe foetal and neonatal thrombocytopenia and is the most frequent cause of 

foetal/neonatal intracranial haemorrhage. 67 FNAIT occurs when the mother produces 

antibodies against fetal platelet-specific antigens that the foetus has inherited from the 

father. These antibodies may easily cross the placenta as early as the 14th week of 

gestation and cause fetal thrombocytopenia. Transfer of antibodies increases as 

gestation progresses, until a maximum level is attained in the late third trimester. Its 

incidence is estimated to be one in 1000-2000 births. The recommended antenatal 

therapy, aiming at preventing intracranial haemorrhage, mainly consists of maternal 

infusions of IG, with or without steroids, or intrauterine transfusion of antigen 

compatible platelets. 68 Steroids are often used in the management of refractory cases. 

A Cochrane review published in 2005 identified one RCT involving 54 pregnant women. 

However, this trial only compared intravenous IG plus steroids with intravenous IG 

alone, thus not covering the research question. 68 A systematic review published after 

the Cochrane search period identified an additional RCT, published in 2007, comparing 

again the effectiveness of IG plus prednisone to IG alone in 73 women. 69 No RCT 

comparing IG to placebo has been found, likely because IG is currently the first line 

treatment in most settings. However, 26 observational studies on IG efficacy have 

suggested an improvement in clinical outcome and probable reduction in risk for 

intracranial haemorrhage. Though no meta-analysis wad performed and in spite of the 

drawbacks of observational studies, most of current practice is based in their findings. 68 

Though no RCT have been conducted to study the IG effectiveness in 

fetal/feonatal allo-immune thrombocytopenia, data from observational studies 

suggested a benefit of IG. 

Isoimmune haemolytic jaundice in neonates 

Both rhesus factor and ABO incompatibilities between maternal and fetal or neonatal 

cells can result in autoimmune haemolytic disease of the new-born. The use of anti-D 

prophylaxis in rhesus negative women has led to a marked decline in haemolytic disease 

of the newborn. However, anti-D immunoglobulin does not always prevent sensitization 

as a high proportion of haemolytic disease of the newborn is caused by antibodies to 

antigens other than D. 70 Exchange transfusion and phototherapy have traditionally been 

used to treat affected newborn infants. However, exchange transfusion is related to 

increased mortality and morbidity. New therapies, aiming at reducing the need for 

exchange transfusion, include IG. 

A Cochrane review published in 2002 included three RCT, involving 189 term and 

preterm infants with rhesus and ABO incompatibility. The use of exchange transfusion 

decreased significantly in the IG treated group, with a lower mean number of exchange 

transfusions per infant. None of the studies assessed long term outcomes. Authors 

considered that the applicability of the results is limited. A more recent systematic 

review published in 2003 included 4 RCT to compare neonatal IG plus phototherapy to 

phototherapy alone. 71 It also found that fewer infants in the IG group required exchange 

transfusion. The IG group also required lower duration of phototherapy and shorter 

hospital stays than the control group. 

In isoimmune haemolytic disease in infants, IG reduced the need for exchange 

transfusion and phototherapy and lead to shorter hospital stays.


3.2.2.4 Neurological and neuro-muscular disorders 

A summary of evidence findings and levels of evidence for IG use is presented in Table 

21. 

Guillain-Barré syndrome and variants 

Guillain-Barré syndrome is an acute disease of the peripheral nerves. It causes the rapid 

development of weakness and usually numbness of the limbs and often the facial, 

swallowing and breathing muscles. Between 3.5 and 12% patients die of complications 

during the acute stage. Recovery takes several weeks or months. One year after onset, 

12% patients still require aid to walk and 62% still notice its effect on their or their 

carers’ lives three to six years later. 72 , 73 

A Cochrane review, updated in 2004, has shown that plasma exchange significantly 

hastens recovery. 74 A Cochrane review on IG, updated in 2006, did not find any trial 

comparing IG with placebo in adults. 73 It included 6 RCT comparing IG with plasma 

exchange. A meta-analysis of 5 of these RCT, involving 536 patients (mostly adults) with 

severe disease and using disability grades, showed that IG started within two weeks 

from onset hastens recovery as much as plasma exchange. Treatment with IG was 

significantly more likely to be completed than plasma exchange. Giving IG after plasma 

exchange did not confer significant extra benefit. One study showed a trend toward 

higher improvement with high-dose (2.4g/kg) compared to low-dose IG (1.2g/kg). 

Three trials compared IG to supportive care or steroids in children, involving 75 

participants. Results suggested that IG hastens recovery compared with supportive care, 

but this was only found significant in two studies, including an open trial in which the 

further analysis of raw data a found significant association when using disability grade 

(outcome not selected by the trial). The third study involved only 18 participants and 

lacked power. This suggests that IG hastens recovery in children, compared with 

supportive care alone. 

A 1999 study compared the cost-effectiveness of plasma exchange and IG in the 

treatment of Guillain Barré disease. 75 Trials comparing the effectiveness of plasma 

exchange and IG for the treatment of acute Guillain-Barré syndrome showed insufficient 

evidence that one therapy was more effective than the other. The study determined 

that plasma exchange was almost $4,000 less costly per patient than IG but that further 

research is required to determine the impact of patient and physician preferences. No 

recent cost-effectiveness analysis has been found. 

• In adult Guillain Barré cases, IG hastens recovery as much as plasma 

exchange - which has been shown to be more effective than supportive care 

alone. 

• In paediatric cases, limited evidence suggests that IG hastens recovery 

compared to supportive care alone. 

Chronic inflammatory demyelinating polyradiculoneuropathy 

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive 

or relapsing weakness and numbness of the limbs, developing over at least two months. 

It may cause prolonged disability and even death. It is often considered to be a chronic 

variant of GBS. CIDP can occur at any age, with a peak prevalence in the sixth and 

seventh decade and a lower prevalence among children. 76 Three therapies have 

demonstrated beneficial effect in RCT: corticosteroids, plasma exchange and IG. 

A Cochrane review updated in 2009 included 7 RCT with 287 participants. 76 These 

trials were homogeneous and the overall quality was high. In the 5 RCT comparing IG 

against placebo, a significantly higher proportion of participants improved in disability 

within one month after IG treatment as compared with placebo (RR 2.4, 95% CI 1.7- 

3.4). One large RCT included in this review had a long-term follow up and indicated 

that IG improves disability more than placebo over 24 and 48 weeks. 77


Two small trials compared IG with prednisolone and plasma exchange respectively, and 

showed no difference in improvement in disability in the IG group compared to the 

other therapy. There were no statistically significant differences in frequencies of side 

effects between the three types of treatment. Based on this evidence, the authors 

concluded that IG improves disability for at least two to six weeks compared with 

placebo, with a number needed to treat of 3. Since IG, plasma exchange and 

prednisolone seem to be equally effective, it is currently uncertain which of these 

treatments should be the first choice. 

Cost-effectiveness studies comparing the alternative treatments were also retrieved. A 

multinational study (including Belgium) aimed at analyzing incremental cost-effectiveness 

of IG compared to prednisolone to treat CIDP. 78 IG was shown to be substantially 

more expensive than prednisolone (3754€ over a 6 week period) and did not reduce 

disability substantially compared to prednisolone. But IG did result in greater 

improvement in health-related quality of life. The probability of IVIG being cost-effective 

in comparison with prednisolone was 50% or above only if one QALY was valued at 

over 250,000€. The impact of later side-effects of prednisolone on long term costs and 

quality of life are likely to reduce the cost per QALY of IG treatment. 

In patients with CIDP, IG improves disability for at least two to six weeks 

compared with placebo, but showed no difference in effectiveness compared to 

plasma exchange and prednisolone. Further cost-effectiveness studies are 

required. 

Multifocal motor neuropathy 

Multifocal motor neuropathy (MMN) is a rare disease marked by a slow progression of 

motor weakness, often distal, asymmetric and involving the forearms, without sensory 

impairment. Consensus statements assert that IG is the only safe treatment for MMN 

patients. Steroids and plasma exchanges are not effective and may even exacerbate the 


A Cochrane systematic review published in 2005 included 4 RCT involving 34 patients. 79 

Strength improved in 78% of patients treated with IG and only 4% of placebo-treated 

patients. Disability improved in a higher proportion of patients treated with IG (78%) 

than with placebo (14%) but the difference was statistically not significant. Authors 

concluded that limited evidence from RCT shows that IG has a beneficial effect on 

strength. IG has been so far the only therapy showing significant improvement in MMN. 

In patients with multifocal motor neuropathy (MMN), IG showed a significant 

effect on muscle strength and a non-significant improvement in disability in 

small trials. No other treatment has proven effective for MMN. 

Paraprotein associated polyneuropathy 

The paraprotein associated polyneuropathy is another auto-immune neuropathy with 

demyelination, characterized by a slow progression and a sensory predominance. 

However, it may produce eventual disabling motor symptoms. The condition is 

associated with a monoclonal paraprotein, an immunoglobulin molecule produced by 

bone marrow cells, that is present in excess and is often non-functional. 80 , 81 This 

paraprotein may belong to one of these three classes: IgG, IgA or IgM. 

A Cochrane review on IgG and IgA paraproteinemic peripheral neuropathy, published in 

2007, included only one RCT on plasma exchange. 80 This review also identified several 

small observational studies showing a beneficial response in some of the patients treated 

with IG. Another 2006 Cochrane review examined the efficacy of immunotherapy in 

IgM paraprotein-associated demyelinating neuropathy. 81 It included two RCT comparing 

IG with placebo and concluded that IG may produce some short-term benefit: a trial 

involving 22 participants showed a significant improvement in overall disability with IG 

over placebo at four weeks; 82 a small trial of 11 patients showed a modest improvement 

in strength in 18% of patients. 83 As other therapies such as steroids have been shown 

beneficial in this disease in open trials, some reviews recommend that IG be considered 

but not continued if acute benefit is not observed. 27


• In patients with IgM paraprotein-associated demyelinating neuropathy, IG 

produced short-term benefit, such as reduced disability and improved 

muscle strength. 

• In IgG and IgA paraproteinemic neuropathy, evidence on IG effectiveness is 

insufficient. 

Multiple sclerosis 

Multiple sclerosis (MS) is a disorder of the central nervous system with progressive 

deterioration of neurological functions caused by autoimmune, inflammatory and 

neurodegenerative mechanisms. The course of the disease is relapsing remitting (called 

RRMS) initially in 80-85% of all MS patients. A minority of patients (10-15%) have a 

chronic progressive course from the beginning, without typical relapses and remissions, 

termed primary progressive MS or PPMS. In most patients, the disease progresses to a 

stage with steady deterioration, known as secondary chronic progressive MS or 

SPMS. 84 , 85 

A Cochrane systematic review included only 2 RCT out of the 10 RCT on RRMS cases 

that were eligible, due to methodological issues or studies being in progress, and did not 

perform any meta-analysis. 86 Another review was published in 2008 and performed a 

meta-analysis based on 4 RCT. 87 Nine additional RCT published after the last Cochrane 

review update (Jan 2003) have been retrieved. All findings are relatively consistent 

across studies and are presented below by type of MS. 

1. RRMS: The two literature reviews have evaluated IG effectiveness compared 

to placebo in treating RRMS, and three additional RCT have been published. 

• The 2008 review included four RCT, involving 265 RRMS patients. 87 A 

meta-analysis of the 4 RCT showed a significant reduction in relapse rate, 

proportion of relapse-free patients and changes of disability scores in the 

groups treated with IG compared to placebo. 88,89, 90 A small RCT 

comparing two doses to placebo also found a significant reduction in 

groups treated with IG. 91 A small RCT assessing Magnetic Resonance 

Imaging (MRI) impact on 26 patients showed a significant reduction in MRI 

lesions. 90 

• The 2003 Cochrane review was based on two of these RCT, involving 

168 RRMS participants, and found a significant reduction in relapse rate 

and an increased time to first relapse during IG treatment. 

• One recent multi-national RCT, published after the two reviews and 

involving 127 patients from 30 European and US sites, showed no 

beneficial effect of IG at doses of 0.2 to 0.4g/kg as compared to placebo in 

RRMS patients after a year period. 92 Authors could not explain why these 

results contrast with other findings, except for an overly optimistic 

sample size calculation. 

• Two RCT involving 19 and 76 patients with MS and acute relapses found 

that IG combined to prednisolone was not more effective in the 

treatment of relapses than prednisolone alone. 93,94 

2. PPMS: A small RCT published after the search period of the two reviews and 

involving 34 patients with PPMS showed that IG significantly reduced disease 

progression as measured by clinical indicators, compared to placebo. 84 

3. SPMS: Three RCT, involving a total of 585 SPMS patients, consistently 

showed no significant effect of IG on disease progression, relapses or MRI 

lesions compared to placebo. 84,95,96, 97 No meta-analysis was performed as only 

one RCT was included in the 2008 review (though no exclusion criteria was 

stated). 

4. Post-partum relapses: The risk of MS relapses is increased in the post-partum 

period and the other available therapies are not recommended during 

pregnancy or lactation. Several non-controlled trial or retrospective studies 

on IG treatment suggested that the exacerbation rate in the treated group


was lower than in a reference population. 98, 99 A multi-national RCT in 9 EU 

countries including Belgium, comparing two doses in the 6 months postpartum 

(but not to placebo), did not show significant differences in outcome 

between the two doses. 100 Despite the lack of RCT comparing IG to placebo, 

many authors conclude that IG can be considered as an optional treatment to 

reduce the increased rate of relapses in this period, because no alternative 

treatment with proven efficacy is available. 

5. In patients with clinically isolated syndrome: An RCT evaluated the 

occurrence of a second attack in 91 MS cases after a first neurological event 

suggestive of demyelinating disease. Among patients in the IG group, the 

incidence of a second attack and disease activity as measured by brain MRI 

significantly reduced compared to placebo. 101 

6. Dosage: all RCT but one used a dose ranging 0.15-0.4g/kg monthly. A single 

study used 2g/kg but did not yield higher efficacy rates. 90 A study comparing 

two dose treatment (0.2 and 0.4g/kg/month) for the treatment of RRMS 

could not show any significant differences between the effects of the two 

doses. 92 

A systematic review searched clinical and cost effectiveness studies on 

immunomodulatory drugs for MS, but did not find any cost-effectiveness study including 

IG. 102 

• In RRMS disease, IG has shown beneficial effects on disease progression and 

on magnetic resonance imaging (MRI) lesions (moderate). Combined to 

prednisolone, IG was not more effective in the treatment of relapses than 

prednisolone alone (high). The ideal dose and the effect on long term 

disability have not been well studied. IG is considered as one of the options 

for the treatment of RRMS. 

• In PPMS patients, IG delayed disease progression in one RCT (moderate). 

• In SPMS disease, IG had no significant effect on disease progression or MRI 

lesions (high). 

• IG reduced the increased rate of relapses in the post-partum period in open 

studies and is considered as an optional treatment (low). 

Lambert-Eaton myasthenic syndrome 

Lambert-Eaton myasthenic syndrome or LEMS is a rare autoimmune disorder of 

neuromuscular transmission, most commonly seen as a paraneoplasic syndrome (60% of 

patients). It is characterized by proximal muscle weakness, ocular symptoms, bulbar 

symptoms and autonomic dysfunction. LEMS often responds to steroids or other 

immunosuppressant. 

A Cochrane review published in 2005 included only 1 RCT assessing the use of IG in 

LEMS cases. 103 Significant improvement in limb muscle strength, vital capacity and 

drinking time was observed compared to placebo, but was short term and declined 

after 8 weeks. The review concluded that IG can be considered as an alternative 

treatment to steroids and immunosupressants for LEMS. 

A small RCT showed that IG improved functional capacities and muscle 

strength in Lambert-Eaton myasthenic syndrome on the short term


Myasthenia gravis 

Myasthenia gravis (MG) is an autoimmune disease, characterized by weakness and 

fatigability of muscle changing over shorter or longer periods. Acute exacerbations (or 

crisis) may be life-threatening because of swallowing difficulties or respiratory failure. 104 

Prevalences tend to increase with time, partly due to ageing of the population combined 

to higher prevalence in the elderly, and better diagnosis. 105 Current treatment includes 

anticholinesterase drugs, thymectomy, steroids, immunosupressants, plasma exchange 

and IVIG. 

A Cochrane review updated in 2008 included 6 RCT. 106 A placebo controlled trial 

involving 51 patients provided evidence for the effectiveness of IG in MG worsening, 

while another small study involving 15 mild or moderate MG cases found no significant 

difference in efficacy after six weeks compared to placebo. Two studies, one involving 

87 participants with exacerbation and another small study involved 12 participants with 

moderate or severe MG, showed no significant difference between IG and plasma 

exchange, after two and four weeks respectively. No significant difference in the efficacy 

of IG and methylprednisolone was shown in a study including 33 patients with moderate 

exacerbations. A large RCT showed no significant difference in efficacy between two 

doses for MG exacerbations (1 and 2g/kg). An open study of 10 severe MG patients 

unresponsive to common treatment showed that IG induced and maintained remission 

with sparing of the dose of immunosuppressive treatments. Gajdos et al. concluded that 

there is no convincing evidence to support the routine use of IG as maintenance 

therapy. Several reviews recommend IG for myasthenic crisis that are unresponsive to 

other agents, for severe exacerbations until other immunosuppressive treatments 

achieve stabilization, or as an option to stabilize patients before surgery. 107,108 The best 

IG dose in MG remains unclear, ranging 1-2g/kg. 

IG is more effective than placebo and as effective as other therapies (plasma 

exchange and steroids) for severe MG exacerbation and MG worsening, but this 

benefit was not shown in mild and moderate disease. Most RCT studied MG 

with exacerbations. 

Dermatomyositis and polymyositis 

Dermatomyositis and polymyositis are idiopathic inflammatory myopathies, 

characterized by chronic inflammation of skeletal muscle which can result in persisting 

muscle weakness with significant disability. 109 Dermatomyositis also affects the skin, 

results in skin abnormalities, while polymyositis may have occasional pulmonary 

involvement. Both diseases generally responds to steroid or immunosuppressive drugs 

but the optimal therapy remains unclear, and a number of patients are resistant or only 

partially responsive to these therapies. 110 

A Cochrane review published in 2005 included one small RCT on IG compared to 

placebo, involving 15 patients with dermatomyositis. 109 It showed that IG was 

significantly superior to placebo in improving muscle strength, neuromuscular symptoms 

and skin rash. 111 Other therapies did not show clear benefit. The RCT concluded that 

IG is an effective second-line therapy for patients with dermatomyositis that 

incompletely respond to steroids and immunosupressants. A non-controlled trial and 

several observational studies confirmed the IG benefit in dermatomyositis and 

polymyositis. 112,113 

IG improved symptoms and muscle strength in dermatomyositis. 

Inclusion body myositis 

Inclusion body myositis (IBM) is the most common inflammatory myopathy in elderly 

patients. It is characterized by a slow chronic progressive and painless asymmetric 

weakness, with involvement of distal muscles with atrophy. Corticosteroids and 

immunosupressants are not successful. Treatment remains difficult as there is no or 

very little response to immunotherapy. 108


Three RCT involving 47 patients showed similar results. 108 A placebo controlled RCT 

involving 19 patients showed an improvement in muscle strength in the group treated 

by IG compared to placebo, but the differences were not statistically significant, except 

for the muscles used for swallowing. 114 A second study showed similar results. 115 A third 

study compared IG (2g/kg) added to prednisolone to prednisolone alone. 116 After 3 

months of treatment, there was no significant difference in muscle strength between the 

two groups. Despite these negative findings, many reviews recommend a short course 

of IG (2g/kg) as trial because no other treatment is effective. 27,107 

IG did not improve muscle strength in patients with inclusion body myositis 

patients but significantly improved swallowing functions in one study 

Stiff person syndrome 

The stiff person syndrome is a rare disorder of the nervous central system 

characterized by severe and episodic muscle rigidity and spasms. The cause is unknown 

but most patients are associated with high levels of antibodies directed against a specific 

enzyme, the glutamic acid decarboxylase, which is responsible for the synthesis of a 

major neurotransmitter (gamma amino butyric acid). 

A single RCT conducted in 1996-99, involving 16 patients with Stiff person syndrome 

comparing IG to placebo, showed that IG significantly reduces muscle stiffness and 

occurrence of spasms in this disease compared to placebo. 117 The duration of the 

beneficial effect of IG varied from 6 weeks to one year. Three open studies have 

suggested the same effectiveness and improvement in quality of life. 118 , 119 , 120 IG is now 

considered to be the treatment of choice in many countries because other therapies 

only produce modest improvement in symptoms. 

IG significantly reduced muscle stiffness and occurrence of spasms in Stiff 

person syndrome 

Neuromyelitis optica 

Neuromyelitis optica is a demyelinating disease of the spinal cord and optic nerves that 

manifest by recurrent attacks, and tends to have a poor prognosis. There is no proven 

effective treatment, although relapses are commonly treated with steroids; patients with 

recurrent attacks may be managed with immunosupressants. 121 IG has been considered 

as a possible treatment because the disease is antibody mediated. 

There are a few case studies, involving 1 to 2 cases, suggesting that monthly IG may be 

effective in preventing relapses. 121,122 However, no RCT or other observational studies 

were found. More recent studies have rather focused on the effectiveness of rituximab, 

as it appears to reduce the frequency of attacks, with subsequent stabilization or 

improvement in disability. 123,124 

There is no evidence on the effectiveness of IG in neuromyelitis optica, and 

limited evidence suggested the effectiveness of rituximab 

3.2.2.5 Evidence on other medical conditions 

Kawasaki disease 

The Kawasaki syndrome is an acute vasculitis affecting infants and young children, 

involving the coronary arteries. Its aetiology is unknown. The main complications are 

coronary artery aneurysms (CAA) that may occur from the second week of illness 

during the convalescent stage. 

A Cochrane review published in 2003 included 16 RCT involving children with Kawasaki 

disease. 125 Results of the meta-analyses of IG versus placebo showed a statistically 

significant decrease in new CAA in favour of IG plus salicylate over salicylate alone, in 

favour of a single high dose regime over 4 or 5 day low dose regime. There was also a 

significant decrease in duration of fever and duration of hospitalization in cases treated 

with IG, with no statistically significant increase in adverse events.


Authors concluded that children fulfilling the diagnostic criteria for Kawasaki disease 

should be treated with high dose IG within 10 days of onset of symptoms. An RCT 

published after the Cochrane search period, comparing the effectiveness of IG at 

different doses, showed that a lower dose (1g/kg) was as effective as the standard 2g/kg 

dose. 126 

A Canadian study compared the cost-effectiveness of aspirin, low doses of IG 

(0.4g/kg/day for 4 days) and high doses of IG (2g/kg single dose). 127 It concluded that a 

single high dose is preferred because it results in both lower costs and lower rates of 

new CAA. A study in Japan came to the same conclusion, though it limited the high 

dose therapy to patients with specific criteria (Harada score). 128 

In Kawasaki disease, IG showed a significant decrease in new coronary artery 

abnormalities, fever and hospitalization, compared to placebo. A lower dose 

(1g/kg) is as effective as a high dose (2g/kg). A high single dose (2g/kg) is more 

cost-effective than a lower dose (0.4g/kg/day) for 4 days. 

Viral myocarditis in children and adults 

Acute myocarditis is a disease that occurs in all age groups. In young patients, it is the 

most common cause of heart failure requiring cardiac transplantation. 129 It is presumed 

to usually start as a viral infection, although autoimmune and idiopathic forms also 

occur. It remains unclear if the primary problem is most the ongoing damage from a 

virus, a post infectious inflammatory reaction, or a combination of both. However, 

immunosuppressive therapy was not shown efficacious in previous RCT. As IG has both 

antiviral and immunomodulatory effects and is an important therapy for Kawasaki 

disease, IG has been used in children with new-onset myocarditis. 

A Cochrane systematic review published in 2005 included only one RCT involving 62 

adult patients with presumed viral myocarditis. 129 Clinical improvement and incidence of 

death were not significantly different in patients receiving IG compared with the placebo 

group, due to the high rate of spontaneous recovery. The favourable prognosis with 

conventional therapy may explain the apparent improvement reported in uncontrolled 

studies. 129 These findings contrast with case series and a study comparing cases treated 

with IG to recent historical controls, which reported significant improvements in left 

ventricular function in cases treated with IG. 130,131,132 Authors concluded that evidence 

from this trial does not support the use of IG for the management of adults with 

presumed viral myocarditis. There are no randomized paediatric trials. 

Evidence from one trial did not show a benefit of IG for the management of 

presumed viral myocarditis in adults. There is no evidence for paediatric cases. 

Treating sepsis and septic shock 

Despite the development of new antibiotics and advances in the management of 

critically ill adults with severe infections, the mortality rate from septic shock remains 

very high, ranging from 21 to 72%. 133,134 Because of its broad and potent activity against 

bacterial products and host cytokines, polyclonal intravenous immunoglobulin has been 

investigated as an adjunctive therapy for treating severe infections. 

Several Cochrane systematic reviews have been published on this topic. The most 

recent one (2002) included 11 RCT involving 492 patients treated with polyvalent IG. 133 

Overall mortality was reduced in patients who received polyclonal IG compared to 

placebo or no intervention (RR=0.64; 95% CI 0.51-0.80). Polyclonal IG also reduced 

mortality from septic shock in a pooled analysis from 3 RCT. Several other systematic 

reviews and meta-analyses have been published after this Cochrane review. The two 

most recent meta-analyses searched literature till March and May 2006 and included 14 

and 20 RCT respectively, comparing IG for the adjunctive treatment of severe sepsis 

and septic shock with placebo or no treatment. 134,135 Though only 5 RCT were common 

to the three reviews, the two meta-analyses found similar and significant reduction in 

mortality in patients treated with IG compared to placebo or no intervention (RR=0.66; 

95% CI 0.53-0.83 and RR=0.74; 95% CI, 0.62-0.89). 134,135


Severe sepsis or septic shock cases receiving a higher dose (total dose 1g/kg or more) 

and treated for longer than 2 days were strongly associated with this survival 

benefit. 134,135 

IG used as an adjuvant therapy in patients with sepsis and septic shock reduced 

mortality compared with placebo or no intervention. This survival benefit was 

consistently observed in three large meta-analyses. 

Treating Respiratory Syncitial Virus infections 

Infection with the Respiratory Syncitial Virus (RSV) is a common cause of childhood 

bronchiolitis and pneumonia, and can cause severe disease in children between two to 

eight months. In older age groups, RSV may cause simple upper respiratory tract illness. 

Nearly all children have had at least one infection by the age of 3 years. No cure exists 

for RSV infections. Prophylactic use of IG products with high anti-RSV antibody titres or 

monoclonal anti-RSV antibody have proved beneficial when given monthly in selected 

high-risk infants, 136 but are not discussed in this section on polyvalent IG. Several studies 

have also assessed the effectiveness of providing IG for children admitted to hospital for 

severe RSV infection as treatment. 

A Cochrane review published in 2006 evaluated the treatment of RSV infections with 

several types of IG, including polyvalent IG, IG with high anti-RSV antibody titres and 

humanised monoclonal antibody to RSV. 137 It included four publications, and no RCT 

demonstrated statistically significant benefit of IG treatment added to supportive care, 

compared with supportive care alone. No meta-analysis was possible due to the wide 

heterogeneity of the outcomes assessed. No RCT published after the review period 

were found. The available evidence thus does not support a role of IG for the treatment 

of RSV infection, with the doses used in the studies. 

No significant benefit of IG treatment added to supportive care has been shown 

for the treatment of RSV infections, compared with supportive care alone. 

3.2.2.6 Medical conditions under investigation 

Alzheimer disease 

Alzheimer’s disease (AD) is the most common cause of dementia and accounts for 

more than half of the dementia cases. One of the major manifestations of AD is the 

presence of abundant plaques in the brain tissues of the affected individuals, due to 

deposits of an amyloid-beta peptide (AbP). The dominant theory states that 

overproduction of AbP, or failure to clear this peptide, leads to the neuronal damage. 138 

Preliminary studies have suggested that IG therapy has several positive effects on 

patients with AD, by lowering the level of soluble AbP in the brain. 139 However, no RCT 

was found; IG was only shown to have positive effect on AD patients in two small and 

non-controlled trials. The first trial involved 5 AD patients with IG monthly for six 

months and showed a drop in CSF AbP (by 30%) and an increase in plasma AbP (by 

23%), together with a stabilization in cognitive decline in all the patients. 140 Another 18month 

study in 8 patients with mild AD receiving IG led to transient increases in plasma 

levels of AbP. 141 The CSF AbP levels decreased after six months of IG therapy and, after 

three months without IG, increased to their pre-treatment baseline levels. These 

findings indicate that no definite statement on the effects of IG in AD can be made. 

Many other agents for passive immunotherapy are under study, mostly monoclonal 

antibodies against Ab or investigative vaccines. A phase III trial of pooled human 

immunoglobulin has been recently launched but no details are available. 142 

Evidence is lacking on the effectiveness of IG in the treatment of Alzheimer 

Disease


Chronic fatigue syndrome 

The Chronic fatigue syndrome (CFS) is a condition characterised by severe, disabling 

fatigue in the absence of exertion, and is marked by a dramatic decline in activity level. 

Currently, the aetiology of CFS remains unknown. 

The beneficial effect of IG for CFS patients is controversial. Three RCTs obtained mixed 

results: a RCT conducted in 1990 found improvements in symptom scores and 

functional capacity at three months; 143 a second found improvement in immune 

indicators but not in symptom and functional measures, 144 the third trial was more 

recent and larger (involving 99 adult patients). 145 It found no effect of treatment, but 

reported adverse reactions in 70-80% patients, with no relationship to IG treatment. It 

concluded that IG cannot be recommended as a therapy for CFS. 

There is conflicting evidence on the effect of IG in CFS, but the larger and more 

recent trial showed no effect, with a high rate of adverse events. 

3.3 CONSUMPTION OF IMMUNOGLOBULINS 

3.3.1 Consumption in other countries 

Few studies investigating IG use and its trends are available. No study has been found on 

IG consumption in European countries. However, eight studies with quantitative data 

on recent IG use per indication were found from Australia, Canada, New Zealand and 

the US. 146,147,148,149,150,151,152,153 . 

3.3.1.1 Consumption by medical speciality and indication 

The results of the four studies analyzing prescription data after 2000 are described 

below. 146,147-149 . The distribution of the total quantities of IG used, by indication and 

major specialty, is shown in Table 22, based on the four studies analyzing IG use per 

indication. Though variations are observed across studies, the majority of IG was 

prescribed by two clinical specialities: neurology, which consume in average one third of 

total IG amount; and immuno-haematology, which consume around half of the total 

amount. An exception to this pattern was the Massachusset general hospital (US) where 

a very high consumption in neurology (71%) is biasing other relative estimates. 

Table 22: Distribution of the total amount of immunoglobulin used per 

disease in four studies in three countries, 2000-2004 (New Zealand, Canada, 

US). Weighted average of the four studies. 

Studies New Zealand Toronto 

Massach 

US 

Canada 

Atlantic 

Weighted 

average 

Diseases/year 2004 2000 2004 2003-04 

Guillain-Barré syndrome 6% 5% 3% 4% 5% 

Chronic inflammatory demyelinating polyneuropathy 13% 9% 12% 19% 

Multifocal motor neuropathy 3% 3% 62% 

8% 4% 

Relapsing-remitting multiple sclerosis 3% 3% 

Myasthenia gravis 2% 1% 4% 5% 3% 

Dermatomyositis 2% 2% 2% 2% 

Total neurology - muscular 25% 20% 71% 35% 32% 

Idiopathic thrombocytopenic purpura 9% 16% 8% 17% 13% 

Primary immune deficiencies 32% 15% 9% 15% 19% 

Secondary immune deficiency in general 15% 19% 9% 10% 14% 

- Chronic lymphocytic leukaemia 5% 1% 4% 

- Multiple myeloma 1% 1% 

- Bone marrow / stem cell transplant 8% 19% 4% 11% 

- Children with HIV 1% 1% 

- solid organ transplants 2% 1% 4% 2% 

Acute leukaemia in childhood 4% 4% 

Autoimmune haemolytic anaemia 2% 1% 2% 

Total immuno-hemato 60% 51% 27% 42% 48% 

Kawasaki disease in children 0% 1% 0% 

Toxic shock syndrome 3% 2% 1% 2% 

Others 15% 27% 1% 22% 17% 

Total amount IG 101.496 g 100.208 g 48.230 g 65.240 g 315.174 g


The analysis of IG distribution per indication shows that a few diseases treated with 

long term maintenance IG consume a high proportion of the total IG amount. Among 

the neurological indications, chronic inflammatory demyelinating polyneuropathy (CIDP) 

accounts for the highest consumption per disease (19% of total use in average), and 

combined with multifocal motor neuropathy (MMN) consumed as much as 62% of the 

IG amount in Massachusset, while it represents 11-20% in other studies. Among the 

immuno-haematological indications, the main consumers are primary and secondary 

immune deficiencies (PID and SID), representing together 34% of total use (ranging 18- 

47%). Idiopathic thrombocytopenic purpura (ITP) and stem cell transplants (included in 

secondary immune deficiencies) represents 13 and 11% of total IG use respectively but 

this proportion widely varies across countries, reflecting diverging views on the IG use 

for these indications. 

Similar geographical variations were observed across Canadian regions (Tonronto vs. 

146, 148, 151 

Atlantic regions), as well as across Australian regions. 

Some other specialties or indications were responsible for a high IG use, which 

contrasted with the recommendations in use. For instance, the Toronto study showed 

an unexpectedly high amount of IG used for infectious diseases (18%) and dermatology 

(7%). 148 Unexpected patterns of IG use were also observed in specific regions: in the 

New Zealand study, one region was an extraordinarily high user of IG for obstetric 

purposes, using 11-fold more IG per capita in this category than the other regions, and 

also used large amounts for respiratory and rheumatic diseases. Another region used 

more IG for cardiological diagnoses than all other regions combined. 149 The Toronto 

study also noticed that individual physicians with specific clinical interest were 

responsible for large proportions of the total IG prescribed. 148 A high number of 

patients received IG as a single dose, for other indications that those commonly 

accepted; each patient consumed relatively little IG but made up of nearly one-third of 

all patients treated. Most of these single-use patients probably represents empirical use 

of IG in which a clinician attempts to rescue a seriously ill patient for whom there are 

few other treatments available, or when physicians are confronted with an undefined 

medical problem, such as a peripheral neuropathy. This pattern was also suggested by 

the Canadian Atlantic study. 146 

The distribution of the total number of patients treated with IG per disease (Table 23) 

suggests a similar distribution. However, the proportion of patients treated for 

neurological disorders tends to be lower than the respective proportion of IG use, 

especially in Massachusset where 39% cases with neurological disorder consume 71% of 

total IG use. This is due to the high amount of IG used for the long term immunomodulatory 

treatment of neurological indications such as CIDP and MMN: the dosage 

ranges 1-2g/kg body weight (vs. 0.3-0.6g for PID and 0.8-1g for ITP) and these patients 

are mostly adults. 

The average IG amount used to treat a case with a defined disease is presented in Table 

24. It indeed confirms the (non significantly) higher average dose per patient used to 

treat the neurological diseases (ranging 173-486g per patient) as compared to immunohaematological 

indications (ranging 90-302g per patient). Diseases ranking the highest in 

IG use per patient (weighted average) were dermatomyositis, multiple sclerosis, CIDP, 

MMN, stem cell transplant, acute leukaemia and solid organ transplants. Primary and 

other secondary immune deficiencies are consuming lower amounts per case (ranging 

150-229g per patient), due to the lower dosage per kg used for IG supplementation.


Table 23: Distribution of the number of cases treated with immunoglobulins, 

per disease, in four studies in three countries, 2000-2004 (New Zealand, 

Canada, US). 

New 

Massach Canada Total 

Studies Zealand Toronto US Atlantic cases 


Guillain-Barré syndrome 7% 11% 4% 5% 106 

Chronic inflammatory demyelinating polyneuropathy 10% 11% 7% 149 

Multifocal motor neuropathy 3% 1% 29% 3% 27 

Relapsing-remitting multiple sclerosis 2% 6 

Myasthenia gravis 2% 2% 5% 5% 44 

Dermatomyositis 1% 1% 1% 12 

Total neurology - muscular 23% 26% 39% 22% 24% 

Idiopathic thrombocytopenic purpura 12% 15% 10% 15% 190 

Primary immune deficiencies 30% 6% 13% 19% 253 

Secondary immune deficiency in general 18% 8% 61 

- Chronic lymphocytic leukaemia 5% 24 

- Multiple myeloma 1% 5 

- Bone marrow / stem cell transplant 5% 15% 7% 113 

- Children with HIV 1% 2 

- solid organ transplants 1% 1% 7 

Acute leukaemia in childhood 3% 12 

Autoimmune haemolytic anaemia 3% 1% 14 

Total immuno-hemato 56% 39% 45% 50% 48% 

Kawasaki disease in children 0% 3% 11 

Toxic shock syndrome 

Others 

4% 2% 1% 24 

Total amount IG 457 429 194 339 1419 

Table 24: Immunoglobulin amount used per patient, per year and per 

disease, in four studies in three countries, 2000-2004 (New Zealand, Canada, 

US). Weighted average of the four studies. 

Studies 

New 

Zealand Toronto 

Massach 

US 

Canada 

Atlantic 

Weighted 

average 


Guillain-Barré syndrome 188 g 160 g 190 g 174 g 173 g 

Chronic inflammatory demyelinating polyneuropathy 297 g 182 g 348 g 

Multifocal motor neuropathy 248 g 708 g 530 g 

486 g 

Relapsing-remitting multiple sclerosis 354 g 354 g 

Myasthenia gravis 219 g 169 g 190 g 200 g 198 g 

Dermatomyositis 439 g 490 g 453 g 

Idiopathic thrombocytopenic purpura 170 g 243 g 190 g 217 g 210 g 

Primary immune deficiencies 


239 g 233 g 170 g 229 g 

- Chronic lymphocytic leukaemia 

- Multiple myeloma 

219 g 219 g 

- Bone marrow / stem cell transplant 342 g 287 g 302 g 

- Children with HIV 150 g 150 g 

- solid organ transplants 426 g 80 g 286 g 

Acute leukaemia in childhood 299 g 299 g 

Autoimmune haemolytic anaemia 166 g 10 g 146 g 

Kawasaki disease in children 20 g 52 g 51 g 

Toxic shock syndrome 160 g 120 g 87 g 140 g


3.3.1.2 Trends over time 

An increase in overall IG consumption has been described worldwide. For instance, 

annual utilisation in Australia rose by an average of 14.8% from 1994-95 to 2004-05. 16 In 

Canada, the IG use has steadily risen since 1990, at a mean annual rate of 12.5%. 146 

However, only a few studies have analyzed the distribution of IG use per indication (or 

specialty) over time. An unpublished US study shows that the weight of each medical 

specialty has undergone noticeable changes within a 5-year period of time (2002-2007, 

Table 25). The Toronto study reported that dermatological conditions increased from 

0% of annual consumption in 1995 to 16% by 2000, and this was linked to the 

establishment of specialized dermatological clinics. 148 

This suggests that diversification in IG use or IG demand, resulting from either newly 

approved indications or changes in prescription practices, may appear in any country in 

a relatively short period of time. 

Table 25: Distribution of the total amount of immunoglobulin used per 

medical specialty in the US, 2002-2007 

Medical Specialty 2002 2007 

Allergy Immunology 19,0% 21,6% 

Rheumatology Nephrology 2,1% 7,8% 

Dermatology 6,3% 7,6% 

Neurology 20,2% 22,0% 

Hematology 30,8% 11,3% 

Cardiology 0,0% 3,4% 

Obstetrics Gynecology 0,0% 6,7% 

Infectious Diseases 14,1% 10,0% 

Ophtalmology 2,0% 9,1% 

Others 5,5% 0,0% 

Source: presentation of Marketing Research Bureau/ IPPC-PPTA Congress 3-4 March 2009 

3.3.1.3 Unlabelled use of immunoglobulin 

Several studies compared the proportion of IG used or the proportion of patients 

treated with IG for an unlabelled indication, as defined in each country (Table 26). 146 It is 

noteworthy that these unlabelled indications represented more than half of the total 

number of patients receiving IG (52-64%) in all studies. However, most of these IG 

administrations were scientifically accepted and often included in the national 

recommendations, in accordance with the last guidelines. This concept of labelled and 

unlabelled indication for IG is thus no longer related to the concept of scientifically 

proven benefit. In Canada (Atlantic Provinces), the introduction of detailed 

recommendations did not impact on the proportion of IG administered for unlabelled 

indications, at least in the first year. 146 

Table 26: Use of immunoglobulins for unlabeled indications in the US and 

Canada, 2000-2005. 

Country % total (year) Comments 

US, 12 academic 

centres 

52% patients (Chen, 2000) Drug authority allows all uses 

US, Massachusset 54% patients (Darabi, 2004) Drug authority allows all uses 

hospital 

Canada, Atlantic 

provinces 

64% of IVIG amount 

(Constantine 2005) 

Study pre and post recommendations



• In other industrialized countries, around half of the total amount of 

immunoglobulins is used to treat immuno-haematological diseases, and 

around one third is used to treat neurological and neuro-muscular diseases. 

• Some specialities or indications that are usually not included in 

recommendations consume an unexpectedly high amount of IG, with large 

variations across hospitals and geographical areas. Individual physicians or 

clinics may impact on large proportions of the total IG prescribed 

• A few diseases consume a high proportion of the total IG. For instance, four 

diseases (chronic inflammatory demyelinating polyneuropathy, primary and 

secondary immune deficiencies and idiopathic thrombocytopenic purpura) 

consumed in average two third of the total IG amount. Three of these 

diseases require long term treatment with IG. 

3.3.2 Consumption in Belgium 

3.3.2.1 Methods 

Data on IG use in Belgium were collected from two sources: 

1. Data on the period January 2004 - June 2007 from the National Institute for 

Health and Disability Insurance (INAMI/RIZIV) on the IG amounts 

reimbursed, per quarter; 

2. Data on the year 2008 on IG used by hospitals (reimbursed or not) and 

collected by an ad-hoc survey. 

The KCE carried out a survey in March-June 2009 addressed to all pharmacists 

responsible for hospital pharmacies in Belgium, with the collaboration of the two 

regional associations of hospital pharmacists. We requested data on the amount of each 

IG brand product (per label and dosage) used in 2008, by medical specialty of the 

prescriber, based on the last three numbers of the INAMI/RIZIV codes. All nonresponding 

hospitals that had consumed >1 500 gr or spent >60 000€ for IG in 2006 

were then contacted personally. 

Data were then analyzed by summing all brand products expressed in grams. 

Distribution per hospital, medical specialties and type of producer (CAF and non-CAF) 

are presented. Though data come from two non-fully comparable sources, we have 

compared data over the 2004-2008 period to identify trends. 

Information on the indications for which IG has been prescribed is not available. This 

survey does not aim at assessing the relevance of IG prescription in hospitals. 

3.3.2.2 Overall IG amounts used in 2004-2008 

INAMI/RIZIV data for the 2004-2006 period have been presented under “Use of plasma 

derivatives in Belgium” and are compared below to the 2008 data (Figure 7). 

The KCE received data on 2008 IG amounts used from 102 hospitals reporting a total 

use of 919.6 kg of IG, all products combined. These 102 hospitals represent a response 

rate of 82% on the 125 hospitals that reported IG use in 2006 and accounted for as 

much as 99% of national IG use in 2006.


Figure 7: Yearly quantities of IG consumed during the period 2004-2008 

1,000,000 gr 

800,000 gr 

600,000 gr 

400,000 gr 

200,000 gr 

0 gr 

IG amount 

trend (linear) 

2004 2005 2006 2007 2008 

Sources: INAMI (2004-2006) and KCE survey (2008) 

Figure 7 shows the yearly increase of IG consumed over the period 2004-2008 and its 

linear trend. Data on 2007 are only available for the first two quarter of 2007. It must 

be noted that the two data sources are not fully comparable: 2004-2006 data cover 

reimbursed IG data provided by INAMI/RIZIV in all Belgian hospitals; 2008 data 

collected by the survey cover reimbursed and non-reimbursed IG reported by Belgian 

hospitals representing 99% of IG use in 2006. However, we observed that the 2008 

estimate fits with the linear trend on the 2004-2006 data. 

Figure 8 presents the evolution (per quarter) of intravenous IG (IVIG) used, per 

producer (CAF-DCF and other producers). The systematically lower consumption in 

the third quarter may be explained by the discontinuation of IG supplementation in mild 

immune deficiencies during summer (see Patterns of use). The proportion of CAF-DCF 

IVIG used increased over the period (except in 2007) to reach 54.4% of all IVIG in the 

second quarter of 2008. 

In Figure 9, the IG consumption over the years 2004, 2006 and 2008 is compared for 

the 20 hospitals showing the highest IG consumption. The absolute amounts of IG used 

are not compared across hospitals by level of activity, by lack of suitable criteria or 

indicator. But the comparison of trends across hospitals show divergences in IG 

consumption trends over this 5 year period: some hospitals have nearly doubled their 

IG use (hospitals 10, 12 and 17), others showed a milder increase or a relative 

stabilization of IG use, and a minority of them have decreased IG use from 2004 to 

2008.


Figure 8: Quantities of IG consumed in 2004-2008, per quarter and producer 

gr per quarter 

125.000 gr 

100.000 gr 

75.000 gr 

50.000 gr 

25.000 gr 

90.000 gr 

80.000 gr 

70.000 gr 

60.000 gr 

50.000 gr 

40.000 gr 

30.000 gr 

20.000 gr 

10.000 gr 

0 gr 

Consumption of polyvalent IV Immunoglobulins 

Sources: INAMI (2004–2007 first half-year) and KCE survey (2008) 

Figure 9: Evolution of the consumption of IG (2004 – 2006 – 2008) in the 20 

Belgian hospitals with highest consumption 

0 gr 

3.3.2.3 Amounts prescribed per medical speciality in 2008 

121.227 gr 

101.322 gr 

20041 20043 20051 20053 20061 20063 20071 2008 Quarter 

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 

Based on the last three numbers of the INAMI/RIZIV code for prescribers, we have 

analyzed 2008 IG prescription by medical specialty. 

Table 27 indicates that four major specialities prescribed 92% of the IG 2008 amount: 

internists (all sub-specialties confounded) prescribed around half of IG, neurologists 

around one quarter, pneumologists one sixth and paediatricians 6%. 

CAF 

not-CAF 

2004 

2006 

2008


Figure 10: Quantities of immunoglobulins prescribed by medical specialty in 

2008, Belgium 

54.602 gr 

Source : KCE Survey 2009 

149.506 gr 

215.582 gr 

425.644 gr 

Internist (058 & 580) 

Neurodegenerative care 

(76/77 & 760/770) 

Paediatrician (69 & 690) 

Pulmonologist (62 & 620) 

Other specialities 

The prescription by medical specialty shows variations between the university / 

academic hospitals (UZGent, UZA, KULeuven, AZ-VUB, UCL St Luc and Mont- 

Godinne, Erasme and Children Hospital Reine Fabiola, CHU-Liège) and the other 

hospitals (als but 23% in other hospitals. 

Table 27). The widest discrepancy is observed in the distribution of IG prescribed by 

lung specialists: it represents 2% of all IG prescribed in academic hospitals but 23% in 

other hospitals. 

Table 27: Amounts of immunoglobulins prescribed by medical specialty in 

2008, academic vs. non-academic hospitals 

Use in 

academic 

hospitals 

% of total 

amount in 

academic 

% of total 

amount in 

other 

hospitals 

Use in all % of total 

Use in other 

Specialty 

hospitals amount 

hospitals 

N hospitals 102 8 94 

Internists 425.644 gr 46% 148.067 gr 50% 277.578 gr 44% 

Neurology and related 215.582 gr 23% 89.818 gr 31% 125.764 gr 20% 

Paediatricians 54.602 gr 6% 26.898 gr 9% 27.704 gr 4% 

Pneumologists 149.506 gr 16% 6.030 gr 2% 143.476 gr 23% 

Other specialities 74.338 gr 8% 22.948 gr 8% 51.390 gr 8% 

Total reported 919.672 gr 100% 293.761 gr 100% 625.912 gr 100% 

In order to further investigate these differences, we have also compared the total 

amount prescribed by hospital and medical specialty, as well as the proportion it 

represents on the total IG amount prescribed in each hospital. The tables below per 

specialty present in the first line the consumption in all academic hospital together, per 

linguistic regime (for the Flemish part: UZGent, UZA, KULeuven and AZ-VUB and for 

the French-speaking part: UCL St Luc and Mont-Godinne, Erasme and Children Hospital 

Reine Fabiola, CHU-Liège); the following lines present, by hospital and linguistic regime, 

the consumption in the hospitals with highest IG amount, in decreasing order.


Table 28: Amounts of immunoglobulins prescribed by internists in 2008 and 

proportion of the total amount prescribed per hospital 

Flemish French-speaking 

Amount % Amount % 

All academic general internists 108.25 kg 57.1% 39.82 kg 38.3% 

23.74 kg 77.9% 11.73 kg 91,0% 

23.61 kg 88.4% 9.37 kg 92,7% 

19.60 kg 78.7% 7.90 kg 45,8% 

7.44 kg 40.7% 7.12 kg 54,4% 

7.13 kg 60.3% 5.78 kg 64,5% 

6.72 kg 78.2% 5.46 kg 76,4% 

5.82 kg 52.9% 5.33 kg 40,7% 

5.19 kg 15.6% 5.27 kg 72,3% 

5.16 kg 37.7% 4.89 kg 61,8% 

3.83 kg 52.0% 4.80 kg 58,9% 

3.73 kg 36.6% 4.44 kg 61,2% 

3.63 kg 19.4% 4.39 kg 68,4% 

3.26 kg 72.7% 3.77 kg 63,5% 

3.09 kg 25.3% 3.18 kg 70,5% 

2.62 kg 62.9% 2.40 kg 34,0% 

2.39 kg 7.3% 2.11 kg 42,6% 

2.37 kg 46.6% 2.10 kg 36,0% 

2.02 kg 24.9% 1.92 kg 70,1% 

2.02 kg 75.7% 1.65 kg 51,4% 

All Belgian general internists 425.594 kg 46.3% 

Table 29: Amounts of immunoglobulins prescribed by neurologists & neuropsychiatrists 

in 2008 and proportion of the total amount prescribed per 

hospital 


All academic neurologists & neuropsychiatrists 


43.41 kg 22.9% 46.41 kg 44.6% 

18.65 kg 57.2% 3.84 kg 22.2% 

9.43 kg 58.4% 2.95 kg 22.5% 

6.99 kg 65.7% 2.64 kg 29.5% 

4.60 kg 13.8% 2.52 kg 51.0% 

4.01 kg 32.9% 2.07 kg 35.4% 

3.63 kg 33.0% 1.97 kg 15.0% 

3.56 kg 11.7% 1.87 kg 52.2% 

3.46 kg 18.9% 1.47 kg 60.2% 

3.00 kg 29.4% 1.40 kg 19.2% 

2.96 kg 75.8% 1.33 kg 16.4% 

2.39 kg 9.6% 1.22 kg 17.1% 

2.26 kg 53.7% 1.22 kg 20.5% 

2.20 kg 47.8% 

All Belgian neurologists & 

neuropsychiatrists 215.58 kg 23.4% 

Table 28 and Table 29 show variations in amounts prescribed and proportion these 

represent in each hospital for the specialities internal medicine and neurology. 

However, no conclusion can be drawn as we did not compare these values with the 

number of cases requiring IG and treated in these hospitals.


Table 30: Amounts of immunoglobulins prescribed by lung specialists in 2008 

and proportion of the total amount prescribed per hospital 



All academic pulmonologists 4.57 kg 2.4% 1.46 kg 1.4% 

21.09 kg 63.4% 4.29 kg 60.7% 

12.32 kg 65.9% 2.83 kg 21.6% 

10.94 kg 33.6% 2.13 kg 29.4% 

10.23 kg 93,7% 1.95 kg 23.9% 

7.62 kg 55.7% 1.37 kg 7.9% 

6.40 kg 70.8% 

6.03 kg 66.1% 

5.42 kg 33.6% 

5.35 kg 29.3% 

4.23 kg 52.1% 

3.31 kg 32.5% 

2.35 kg 59.1% 

2.26 kg 59.5% 

2.25 kg 54.8% 

2.24 kg 7.4% 

2.06 kg 17.4% 

2.04 kg 7.6% 

All Belgian lung specialists 149.51 kg 16.3% 

In Table 30, we observe a severe discrepancy between the prescription of IG by lung 

specialists in academic and the prescription in non-academic hospitals: the Flemish 

hospital where lung specialists prescribed the highest IG amount accounted for 21.1 kg 

or 4.6 times the amount consumed in all university hospitals combined. The Frenchspeaking 

hospital having prescribed most IG in pneumology, consumed three times the 

amount prescribed in all French-speaking university hospitals. In both hospitals, IG 

prescribed by pneumologists represented more than 60% of the IG prescribed for the 

whole hospital, while this proportion represents 1.4% and 2.4% in academic hospitals. 

This high prescription for lung disease is especially noticeable in Flanders: in at least 11 

non-academic hospitals, over 50% of the total IG is prescribed by pneumologists. This 

prescription pattern and high IG use in pneumology cannot be unexplained by current 

reimbursed indications, as no respiratory pathology is included in the current 

indications for IG, except for agammaglobulinemia and hypogammaglobulinemia with 

repeated bacterial infections that may affect the respiratory tract. Experts reported that 

IG is frequently prescribed in some peripheral hospitals for other immune deficiencies, 

such as isolated Ig G subclasses deficiencies without recurrent infections and without 

abnormal antibody response after pneumococcal vaccination. However, these patients 

are neither an indication for IG nor is IG reimbursed for these situations. It should also 

be noted that the criteria for IG reimbursement clearly state that “IG are not 

reimbursed if the IgG/IgG2/IgG3 deficiency is due to a long term treatment with 

steroids, for instance as in the chronic obstructive pulmonary disease”. 

In a few other specialties, similar patterns are also observed, to a lower extent: a high 

level of heterogeneity in prescription is seen across hospitals and some hospitals are 

prescribing significant IG amount in some specialties for which no indication is 

reimbursed or usually recommended based on evidence; for instance, in surgery, 

obstetrics, gynaecology and gastro-enterology.


Table 31: Amounts of immunoglobulins prescribed by paediatricians in 2008 


Flemish Flemish French French 

All academic paediatricians 14.61 kg 7.7% 12.28 kg 11.8% 

2.44 kg 9.8% 3.05 kg 17.7% 

0.96 kg 5.9% 1.82 kg 23.0% 

0.96 kg 5.2% 1.54 kg 11.8% 

0.89 kg 7.5% 1.00 kg 7.6% 

0.84 kg 11.4% 0.66 kg 20.5% 

0.61 kg 1.9% 0.56 kg 7.7% 

0.58 kg 7.1% 0.51 kg 5.7% 

0.53 kg 2.8% 0.50 kg 6.8% 

All Belgian paediatricians 54.62 kg 5.9% 

Table 32: Amounts of immunoglobulins prescribed by rheumatologists in 

2008 and proportion of the total amount prescribed per hospital 

All academic 

rheumatologistss 


2.52 kg 1.3% 0.20 kg 0.2% 

4.45 kg 36.5% 2.19 kg 61.5% 

1.51 kg 4.5% 

1.42 kg 12.9% 

1.21 kg 35.7% 

1.06 kg 36.0% 

All Belgian 

rheumatologists 18.89 kg 2.1% 

Table 33: Amounts of immunoglobulins prescribed in intensive care units for 

adults in 2008 and proportion of the total amount prescribed per hospital 


All academic IC units for adults 4.04 kg 2.5% 2.92 kg 3.8% 

1.47 kg 4.6% 0.83 kg 17.1% 

0.63 kg 10.7% 0.65 kg 6.7% 

All Belgian IC units for adults 20.55 kg 2.5% 

Table 34: Amounts of immunoglobulins prescribed by gastro-enterologists in 

2008 and proportion of the total amount prescribed per hospital 


All academic gastroenterologists 2.09 kg 1.1% 0.54 kg 0.5% 

1.11 kg 12.1% 

0.63 kg 7.8% 

All Belgian gastroenterologists 7.71 kg 0.8% 

Table 35: Amounts of immunoglobulins prescribed by surgeons in 2008 and 

proportion of the total amount prescribed per hospital 

All academic general 

surgeons 


1.47 kg 0.8% 1.37 kg 1.3% 

2.37 kg 18,0% 

All Belgian general 

surgeons 6.50 kg 0.7%


Table 36: Amounts of immunoglobulins prescribed by hospital general 

practitionners (GPs) in 2008 and proportion of the total amount prescribed 

per hospital 


All GPs in academic hospitals 1.98 kg 1.0% 0.16 kg 0.2% 

1.03 kg 92.3% 

1.02 kg 15.8% 

All Belgian general practitioners in 

hospitals 5.56 kg 0.6% 

Table 37: Amounts of immunoglobulins prescribed by cardiologists in 2008 



All academic cardiologists 3.11 kg 1.6% 0.50 kg 0.5% 

0.64 kg 16.1% 

All Belgian cardiologists 6.46 kg 0.7% 

Table 38: Amounts of immunoglobulins prescribed by gynecologists in 2008 



All academic gynecologists 0.96 kg 0.3% 0.00 kg 0.0% 

0.24 kg 12.2% 0.77 kg 4.4% 

0.19 kg 1.0% 0.23 kg 3.9% 

All Belgian gynecologists 3.04 kg 0.3% 

3.3.2.4 Discussion on IG consumption 

Data on IG consumption in Belgium indicate similar patterns than those found in other 

countries: IG consumption is increasing over time, four main specialties consume the 

majority of IG, the use of IG is heterogeneous across hospitals and some hospitals 

consume a high IG amount in specialties that are not related to the authorized or 

reimbursed indications. 

Two additional findings in Belgium have been revealed by the KCE survey: 

1. A high amount of IG is prescribed by lung specialists, though this cannot be 

justified by current reimbursed indications or available evidence, as no 

respiratory pathology is included in the current indications for IG (except for 

specific immune deficiencies with repeated respiratory tract infections). This 

was not observed in any of the academic hospitals but was predominant in 11 

Flemish and one Walloon hospitals. At international level, this was only 

reported in one region in the New Zealand study. As we did not have access 

to data on IG consumption per indication, we could not explain this 

prescription with available data. This finding deserves further investigation. 

2. The survey showed wide variations in prescription patterns between 

academic and non-academic hospitals. A major finding is that a number of 

non-academic hospitals prescribe significant IG amounts for four other 

specialties (surgery, obstetrics, gynaecology and gastro-enterology) that are 

not related to reimbursed indications - or to other indications for which a 

benefit of IG has been proven. This unexpectedly high IG use is not observed 

in academic hospitals. Unexpected patterns of IG use in some hospitals or 

geographical areas were also observed in New Zealand where one region 

used 11-fold more IG per capita for obstetric purposes than the other 

regions. The Toronto study also noticed that individual physicians with 

specific clinical interest were responsible for large proportions of the total IG 

prescribed. 

The reasons for the overall increase in IG consumption over the recent years could not 

be investigated based on these Belgian data. We had no access to data allowing us to 

determine for which indications IG has been prescribed over time.


For instance, a growth in IG used in neurology was expected with the gradual 

introduction of CIDP and MMN in the list of reimbursed indications over 2002-2008 

(Table 19), but this could not be verified. It is remarkable to observe that a few 

hospitals have decreased their IG consumption while others have doubled it over a 5 

year period. 

3.3.2.5 Patterns of use 

In order to understand IG use in Belgium and help determine the IG amount that would 

be required to treat the most IG consuming indications, two expert meetings and a 

survey were organized. The aim was to assess current practices in Belgium regarding 

the characteristics of patients treated, the dosage used, the frequency of IG treatment 

in maintenance therapy and the expected trends in IG use. 

In immuno-haematological diseases 

A survey was undertaken among 10 main centres administering IG for immunodeficiencies. 

Questionnaires were addressed to paediatricians and haematologists to 

obtain information on how IG are used in Belgium. We requested 2008 data on the 

number of patients treated per reimbursed indication, number of IG administrations and 

usual dosage for the reimbursed indications. Responses were received from 7 hospitals, 

and 6 hospitals provided the data requested. Survey results were presented to an 

expert committee and discussed. The questionnaires are provided in appendix. 

Collected questionnaires covered 846 cases, including 562 cases with an immunological 

or haematological disease or a Kawasaki disease: 186 cases with primary immune 

deficiency (PID) under maintenance treatment, 148 transplant cases, 75 ITP cases, 58 

cases with MM or CLL, 31 Kawasaki disease cases, 37 neonates treated with IG for 

infection or severe ABO incompatibility and 27 cases with other immune deficiencies. 

Among these cases, 338 were children (154 PID, 36 transplants, 53 ITP, 31 Kawasaki 

disease, 37 neonates and 27 other immune deficiencies). 

No cases treated with IG for septic shock syndrome were reported, though this is a 

reimbursed indication for IG. Based on several assumptions, we estimated that all these 

cases - with the exclusion of neurological indications - accounted for a total IG use of 

108 kg in 2008, representing around 12% of total national use in 2008. 

DOSAGE PER INDICATION 

Results showed that similar dosage of IG supplementation per kg body weight are 

administered in all centres to PID cases (around 0.4g), in accordance with guidelines 

published by the Primary Immune deficiency Belgian group, 34 and for transplant cases. 

But dosage for other indications showed wide variations. In ITP, doses ranged 0.8-2g/kg; 

two hospitals use a dose of 0.8g/kg in children as it has shown similar efficacy than 

higher doses in a recent study. In Kawasaki disease, dose ranged 1 to 2g/kg but 2g was 

the most frequent. For the other indications, only one or two centres reported cases 

and no conclusion can be drawn. 

FREQUENCY OF TREATMENT 

The annual frequency and duration of intravenous IG (IVIG) administrations per patient 

requiring long term treatment also showed differences across centres: 

• For PID, the frequency of IVIG administration varied from an average of 

6.4 to 14.3 per year in 2008. However, centres reporting a lower 

frequency had many patients switching from IV to SC administration in 

2008 and a more documented monitoring. In addition, the frequency in IG 

administration depends on the type of immune deficiency: patient with 

severe antibody deficiencies must receive treatment all year long, mostly 

every 3-4 weeks, requiring 12-14 administrations per year; while in 

transient or mild hypogammaglobulinemia with recurrent severe 

infections, IG treatment can be stopped during summer.


• For bone marrow or stem cell transplant, the frequency of administration 

averaged 10.8 per year, ranging 2.6-12.9. In general in children, treatment 

is administered before transplant and during at least 3 months, mostly 6 

months and up to 1-2 years in cases of persistent B-cell abnormalities. 

However, the recent decrease in myeloablative transplants, due to an 

increase in non-myeloablative techniques, has decreased the level and 

duration of secondary immune deficiency - and the consequent IG needs. 

This is mostly described in adult patients. 

• For ITP, the frequency of administration was not available in most 

hospitals but was 1.4 per case in average in 3 hospitals. 

• In Kawasaki disease, the frequency of administration could not be 

established based on available data, but experts advised the administration 

of a single dose, followed by a 2nd dose in a few patients in which 

inflammatory signs and symptoms are still present. 

WHICH CASES SHOULD BE TREATED WITH IG 

The proportion of patients receiving IG for each of these indications in Belgium was 

difficult to assess in this survey, as clinicians could not always collect data on the total 

number of cases that visited their centre. 

For bone marrow or stem cell transplant, paediatricians considered that nearly all 

paediatric cases require IG supplementation; in adults, only a selected subgroup of 

patients having a symptomatic secondary immunodeficiency following the transplant can 

benefit from IG treatment, and this should be decided on an individual basis. 

Secondary immune deficiencies due to the use of therapies depleting B-cells or impairing 

B-cell response (eg. some anticancer drugs) and inducing symptomatic 

hypogammaglobulinemia are also medical conditions for which IG may be necessary. 

Experts proposed that cases with secondary hypogammaglobulinemia be treated with IG 

during for the period of the hypogammaglobulinemia, irrespective of its cause. This is 

line with the approach of PID cases, though the treatment would be mostly limited to a 

period of 6-12 months. 

ESTIMATION OF AMOUNTS 

The amount of IG used for each immuno-haematological indication in these centres has 

been estimated, based on the assumption of an average 75kg body weight per adult, 25 

kg per child and 4 kg per neonate. Under these assumptions, treatment of PID patients 

would represent 61% of the total IG use for immuno-haematological indications, CLL 

and MM 14% and transplants 10%. However, these estimates are biased by a better 

response rate among paediatricians as compared to haematologists treating adult cases. 

USE OF SUB-CUTANEOUS IG 

Subcutaneous administration of IG was used for PID in 5 out of the 6 hospitals and used 

to treat 44% of the PID paediatric cases in average. This practice was predominant in 

two hospitals where 48-71% of PID children received SC administration, and is a 

growing practice in the other paediatric wards of these centres. Expert paediatricians 

consider that SC administration is a first choice for long-term treatment as it improves 

quality of life of the patient and is more effective to control immunodeficiencies, as IG 

levels are better maintained with weekly infusions. In adult cases however, only two out 

of four hospitals were using SC administration, and this concerned 14 and 44% of the 

PID adult cases. 

In neurological diseases 

In order to know the current use of IG in Belgium for the neurological and neuromuscular 

indications consuming large amounts of IG, an expert meeting was organized. 

The criteria for IG treatment, proportion of cases treated, dosage and frequency of IG 

treatment were discussed, based on information found in the scientific literature and 

the Belgian situation. The survey also collected data on 284 IG administrations for 

neurological cases (Guillain Barré disease, CIDP and MMN).


However, results should be taken with caution as data were only provided by 3 

hospitals and were not exhaustive for each hospital (focus on paediatrics). The main 

findings are summarized below: 

• For Guillain Barré syndrome, dosage and frequency described in the 

literature is also applied in Belgium. In the above mentioned survey, only 

34 cases were reported by 3 hospitals, and data on adult cases were only 

reported by one hospital. IG dosage ranged 1 to 2g/kg in the 3 hospitals. 

• For CIDP, the Moniteur Belge / Belgisch Staatblad (MB/BS) stipulates that 

the first line treatment is steroids, and only patients with contraindications 

or treatment failure to steroids should receive IG. Experts 

estimate that about two-third of CIDP patients receive IG treatment. This 

proportion also depends on the clinician expertise; unnecessary IG 

treatment has been observed in patients referred by peripheral centres to 

the university centres. Dosage also ranges 1 to 2g/kg. The current 

practice is to rapidly decrease the initial dose according to the clinical 

response, then to reach a minimal maintenance dose. This dose being 

patient-dependant, no strict guideline can be established. The upper limit 

in IG quantities accepted for reimbursement in the MB/BS (9g/kg per 

semester) is considered by experts as too low to treat some specific 

cases. Treatment requires good knowledge of the disease and its clinical 

manifestations. 

• For MMN, a higher proportion of cases are treated because mild disease 

is less frequent and there is no alternative treatment. The dose also needs 

to be adapted to the clinical response, and the treatment is more difficult 

to adjust than for CIDP. It may require increasing doses and decreasing 

treatment intervals, especially in the long term, due to a known decline of 

treatment effectiveness after prolonged treatment. However a few 

patients may have sustained remission and even stop treatment. The 

average dose usually varies from 0.4 to 1g/kg. 

• IgM paraprotein demyelinating neuropathies are treated with IG if they fit 

with the criteria established for CIDP. These cases represent 5-10% of 

CIDP cases. 

• In multiple sclerosis (MS), IG is mainly used in the pre and post-partum 

period to reduce relapses. IG may also be used in the few MS cases with 

relapsing-remitting cases that do not respond to steroids; one single 

treatment is given in case of relapse. Some private insurance companies 

are covering the costs. This concerns a very small number of cases. All 

together, the proportion of all MS cases that are treated with IG is 

estimated to range 0-3%, as observed in other countries. 

• In myasthenia gravis (MG), IG is only used in cases that do not respond to 

other treatments (plasma exchange and immunosuppressive therapy). 

Though IG has replaced plasma exchange as a first line treatment in many 

countries, IG is not reimbursed for this disease in Belgium - or only by the 

solidarity fund when criteria are met. However, due to a lack of expertise 

in this rare disease, experts fear that IG would be overused if 

reimbursement for MG would be introduced. 

• In dermatomyositis and inclusion body myositis, IG use for this disease is 

limited and relatively similar to myasthenia gravis. 

• Stiff person syndrome is a rare disease, but experts estimated that there 

may be around 20 patients in Belgium. Plasma exchange is the first 

treatment option.


3.3.2.6 Limitations 

A major limitation of this analysis of IG prescription is that we have no data in 2004- 

2006 on non reimbursed IG. Likewise, it is unclear whether the IG quantities reported 

by hospitals include IG prescribed for compassionate use. According to some experts, 

compassionate use may represent a significant proportion of IG consumption. This is 

likely resulting in an underestimation of overall IG consumption. 

Another limitation of this survey and expert meeting is the lack of representativeness of 

the Belgium situation: it only involved clinicians working in large university centres and a 

small numbers of experts (only paediatricians for the immuno-haematological 

indications) could attend. Problems of higher dose, higher frequency and non-indicated 

IG therapy have been reported in peripheral hospitals or practices, but available data did 

not allow investigating this hypothesis. 

However, prescription patterns per specialty tend to confirm this hypothesis. Experts 

reported that this may be due to the lack of experience among peripheral clinicians, as 

the low frequency of these diseases result that non-specialized clinicians rarely 

encounter these diseases, added to the fact that strict diagnosis criteria are mostly not 

required for the reimbursement of IG. Experts also reported a strong lobby from the 

plasma industry to use IG for most hypogammaglobulinemia. This implies that the 

estimation of IG quantities based on this survey is likely to underestimate the real IG 

use. 


• IG consumption is increasing over time in Belgium as in other countries. 

However, individual hospitals show diverging trends: a few hospitals have 

decrease their IG consumption while other have doubled it over a 5 year 

period. 

• Four main specialties prescribe 92% of the total IG amount prescribed in 

Belgium: internal medicine (46%), neurology and related diseases (23%), lung 

disease (16%) and paediatrics (6%). The high prescription of IG by lung 

specialists was neither expected nor reported by studies in other countries; 

this was only found in non-academic hospitals but accounted for a significant 

amount of IG use. 

• We observed huge variations in IG prescriptions across Belgian hospitals, as 

also reported in other countries. Some non-academic hospitals consume a 

high IG amount in specialties that are not related to the indications 

reimbursed. Experts also reported an over-use of IG for specific immune 

deficiencies and peripheral neuropathies in peripheral hospitals, where 

clinicians may be less familiar to these diseases due to their low prevalence. 

• For most immune deficiencies and neurological disorders, academic centres 

reported similar practices regarding who should be treated and the dosage. 

For two indications, stem cell transplants and idiopathic thrombocytopenic 

purpura, practices differed regarding which patients are treated, length of 

treatment and dosage. 

• The long term treatment of these rare immune deficiencies and peripheral 

neuropathies requires a good knowledge of the disease to adapt IG dosage 

and frequency of treatment to the clinical response. 

• The use of sub-cutaneous IG is emerging for PID cases and was used for 44% 

of PID patients in academic centres in 2008, mainly for paediatric cases.


3.3.3 Estimation of IG quantities to treat the main indications 

The objective of this exercise was to estimate the needs in plasma derivatives that 

would be required in Belgium to treat the main indications. 

3.3.3.1 Methodology 

This estimation represents the theoretical quantities that are required yearly, based on 

two assumptions: indications are clearly defined, all cases are correctly diagnosed, and 

patients under long term IG treatment are receiving IG all year long, without 

interruption. 

Selection of diseases 

Based on the literature review and the recommendations for IG use in Belgium and 

other countries, we have selected a first list of 22 diseases in which evidence shows a 

benefit of IG, or in which sufficient evidence on IG benefit is not available but for which 

IG therapy is recommended in most industrialized countries (Table 37). 

Table 39: Diseases for which IG treatment has a proven benefit and/or is 

recommended in EU countries: selection for the estimation of IG quantities 

Indications Selected for IG estimation 

Idiopathic thrombocytopenic purpura Yes 

Primary immune deficiency conditions Yes 

Multiple myeloma Yes 

Chronic lymphocytic leukaemia Yes 

Allogenic stem cell transplant Yes 

Paediatric HIV/AIDS No (few cases) 

Prophylaxis in solid organ transplant No 

Prevention of treatment of infections in neonates No (small amounts - low weight) 

In preterm and/or low birth weight No (small amounts - low weight) 

Isoimmune haemolytic jaundice in neonates No (small amounts - low weight) 

Guillain-Barré syndrome (and variants) Yes 

CIDP Yes 

Multifocal motor neuropathy Yes 

Multiple sclerosis (relapsing remitting) Yes 

Paraprotein-associated peripheral neuropathies No (infrequent disease) 

Lambert-Eaton myasthenic syndrome No (infrequent disease) 

Myasthenia gravis Yes 

Dermatomyositis and polymyositis Yes 

Inclusion body myositis No (no available data and low use) 

Stiff person syndrome No (infrequent disease) 

Kawasaki disease Yes 

Treating sepsis and septic shock No (few cases treated in Belgium) 

Based on the analysis of the IG amounts used to treat these diseases in other countries 

(see above), we have selected the 12 diseases that are consuming the highest amount of 

IG and accounted for respectively 88%, 80% and 68% of total IG use in the US 

(Massachusset), New Zealand and Canada (Toronto). Further estimations of IG 

quantities have been limited to these 12 diseases. 

Data on disease frequency and IG use per disease 

As data on the number of cases treated for each of these diseases were mostly not 

available in Belgian databases, we have extracted the following indicators from studies 

conducted in other countries: 

• The yearly incidence and/or prevalence rate, depending whether the 

treatment is applied once or as long term maintenance therapy: incidence 

rate was searched when treatment is administered once or twice per 

patient; prevalence rate was used for maintenance treatment. For disease 

presenting an acute and a chronic form, both incidence and prevalence 

were used.


• The proportion of patients treated with IG, per disease. 

• The dosage used per treatment (g/kg) and the frequency of treatment 

(per patient or per year for maintenance treatment). 

The source studies were selected according to the following criteria: studies including 

data from 1995 onwards, having a large study population size (>1 million inhabitants 

mostly), and carried out in Western EU countries - or in other industrialized countries 

when other EU studies were not available. When disease rates vary significantly per 

geographical area (e.g. prevalence of multiple sclerosis varying with latitude), we have 

only consider studies conducted in similar geographical areas. 

The values found for the proportion of patient treated with IG, the dosage used per 

treatment and the frequency of treatment were discussed and validated in two expert 

meetings. For a few indications, the annual numbers of cases were found in Belgian 

databases (e.g. transplants). Similarly, the dosage and frequency of administration 

obtained through the survey in Belgian hospitals were used when considered as 

methodologically reliable and representative, based on expert opinion and information 

on current practice. 

Estimation of the annual IG amounts per disease 

The annual IG quantities estimated to treat these 12 diseases in Belgium were calculated 

based on the following: 

• Data from other countries were aggregated to produce averages for 

incidence or prevalence rate, proportion of patients treated and 

frequency of treatment, after being weighted by survey size (“weighted 

average”). 

• The expected annual number of cases under treatment in Belgium was 

calculated by multiplying the weighted average of the incidence or 

prevalence rate by the Belgian population size (per age group when 

relevant) and by the proportion of patients treated with IG. 

• The IG amount used per patient and per year was obtained by multiplying 

the average dosage per treatment (in g/kg) by the average body weight 

(per age group when relevant) and the frequency of treatment (when 

multiple doses are given), named as “method A”. An alternative 

estimation (method B) was based on the average IG amounts per case and 

per year found in studies from other countries (weighted average), see 

Table 24. 

• The annual quantities needed to treat each disease were obtained by 

multiplying the annual number of patients under treatment by the IG 

amount used per patient (by method A and B). 

Estimates found for the above indicators are described below. The annual IG quantities 

estimated to treat these 12 diseases in Belgium are described in Table 40 and below. 

3.3.3.2 Estimates per disease 

Idiopathic Thrombocytopenic Purpura 

Idiopathic thrombocytopenic purpura (ITP) can present as acute or chronic disease; 

chronic disease is defined by a duration of ITP for more than 6 months. Studies on the 

incidence of acute and chronic ITP show variations in case definition (especially in terms 

of threshold for platelet count) and age studied. These directly influences incidence 

estimates as a very sensitive threshold for platelet counts overestimates the frequency 

of clinical ITP, and the frequency of chronic ITP increases with age. 

IN CHILDREN 

Three studies in Norway, Germany and Nordic countries, estimated the incidence rate 

of acute ITP in children using similar criteria (bleeding +/- platelet count


The proportion of acute ITP that had evolved into chronic ITP was estimated in four 

studies in Norway, France, Denmark and Nordic countries in 1996-99 and ranged 18- 

33% (average 26%). 155, 156,157,158 We then extrapolated the incidence rate of chronic ITP 

at 0.8 per 100,000 in children


In Belgium, a survey covering 6 centres for paediatric PID and 3 centres for adult PID 

reported a total of 437 PID cases under follow up, but this figure is also incomplete. 

Among these, 263 have received IG treatment in 2008. In order to estimate the total 

number of PID cases treated in Belgium, we have used as proxy the proportion of all 

Belgian bone marrow transplants that were conducted in these centres, as reported to 

the INAMI/RIZIV. Though the proportion of transplants is not directly linked to the 

proportion of PID treated, this was considered as a proxy of specialized immunological 

activity of these centres. The 6 centres providing data on paediatric cases and the 3 

centres providing data on adult cases represent respectively 34% and 29% of all marrow 

transplants in 2007. The number of PID cases under treatment is thus estimated at 806 

cases. In Belgian centres surveyed, the dosage ranged 0.3-0.5g/kg and most centres used 

0.4g/kg. The annual number of IVIG treatment per year ranged 6.4-14.4 per year for 

children (average 11.3) and 12.0-13.3 per year for adults (average 11.8). The amount of 

IG required for SC administration has been estimated as equivalent to those required 

for IV administration. 

Multiple myeloma (MM) 

In Belgium, a range of 617-690 new cases of MM were reported per year to the cancer 

registry in 2004-2008 and the incidence is increasing with age. Prevalence data are not 

available from Belgium or other EU countries. We used the 2006 age-specific 

prevalence rates reported among the white population in the US and extrapolated to 

the Belgian population by age-group. 8 A number of 2390 prevalent cases of MM are 

estimated. This figure may be an underestimation of the Belgian situation because the 

MM incidence rates in the US are slightly lower than the Belgian incidence rates. 

The proportion of MM patients treated was not documented in the literature, but 

expert advice provided a range of 10-15%, based on experience. 

The survey among immuno-haematologists collected data on MM from one Belgian 

university hospital only. The dosage of 0.4g/kg was similar to the recommendations of 

other countries and in average 10 treatments were provided per case and year. 

Chronic lymphocytic leukaemia (CLL) 

National data are not available on the incidence or prevalence of CLL but 636 new 

cases of lymphoid leukaemia (acute and chronic) were reported in 2008. No prevalence 

data were found from other countries. The proportion of patients treated was also not 

available. 

As for MM, the survey among immuno-haematologists collected data on MM from one 

Belgian university hospital only. The dosage was 0.4g/kg and an average of 10 treatments 

was provided per case and year. 

Due to the lack of data, IG amounts required to treat CLL cases could not be 

calculated. 

Allogenous bone marrow or stem cell transplant (SCT) 

The number of bone marrow transplants is collected by the INAMI/RIZIV in the 

framework of the convention with transplant centres. In 2007, 284 allogenous 

transplants were recorded, and the 2005-07 data show a gradual increase in the number 

of allogenous SCT (+31% in 2 years). The number of transplant was then estimated at 

320 for 2008, assuming a linear trend from 2005 to 2007. However, this number may be 

underestimated as hospitals that are not included in the Convention may also perform 

allogenous SCT (INAMI, personal communication). 

8 Estimated US cancer prevalence counts at on Jan 1, 2006 by Race/Ethnicity, Sex and Years Since 

Diagnosis. National Cancer Institute: Surveillance Epidemiology and End Results Cancer Statistics Review 

1975 – 2006. 

http://seer.cancer.gov/csr/1975_2006/browse_csr.php?section=18&page=sect_18_table.18.html


The proportion of SCT cases receiving IG supplementation has not been found in the 

scientific publications. In Belgium, it varies across centres, type of transplant and age 

group. The increase in non-myeloablative SCT, mainly in adults, has likely decrease the 

IG needs in this group. The principle is that IG treatment should be administered in 

cases of severe antibody deficiency and thus tailored to the patient. Among children, the 

consensus among paediatricians during the expert consultation was that most paediatric 

cases require IG supplementation, as post-SCT humoral immunodeficiency is common. 

Among adults, experts consider that the prophylactic and pre-emptive use of antibiotics, 

antifungal and antiviral drugs has replaced the routine use of IVIG, and that only patients 

having a (transient) symptomatic secondary immunodeficiency should receive IVIG, on 

an individual basis. 

Based on comparison between survey results and INAMI data sources on allogenous 

BMT, we estimated that 33% of all allogenous SCT (children and adult confounded) 

receive IG supplementation. 

The dosage used in Belgium ranges 0.2-0.5g/kg, with the majority of centres using 

0.4g/kg. In the Netherlands, treatment scheme was 0.5g/kg per week (before transplant) 

then followed by 0.5g/kg per month as maintenance dose; in France, 0.4-0.6g/kg as 

loading dose followed by 0.3g/kg. In most studies, IG prophylaxis was given for 3 

months and the maximum period of administration was 1 year. Most guidelines 

recommend continuing IG after transplant until reconstitution of B cell and antibody 

production has been achieved. We estimated that IG treatments were administered in 

average 12 times per year, based on the survey results (10.8 in children and 12 in 

adults). 

Guillain-Barré Syndrome (GBS) 

Five epidemiological studies, conducted in the period 1992-2000 in the UK, Italy (2 

studies), Spain and Sweden were selected for the estimation of incidence rate. 164,165,166,167, 

168 

A German study based on hospital records has been excluded as the methods did 

not include validation of diagnosis; 169 indeed, such studies were shown to over-estimate 

disease incidence. 167 Most studies reported similar values, suggesting that GBS occur 

evenly, at least throughout the Western hemisphere: the incidence rate ranged 1.26- 

1.63 per 100,000 in the five studies, and the weighted average is 1.42 per 100,000. 

In four studies conducted in Italy, Spain and Sweden (two studies) in the period 1996- 

1999 and involving a total of 343 cases, the proportion of GBS cases treated with IG 

165, 166, 170, 171 

ranged 65-82% with a weighted average at 75%. 

The dosage was 2 g/kg per treatment in all studies and reviews. Only one Dutch 

publication described the proportion of cases requiring a second treatment from two 

studies, which amounted at 7% of the GBS cases initially treated. 172 

Chronic inflammatory demyelinating polyneuropathy (CIDP) 

Two EU studies (Italy and England) and an Australian study calculated the CIDP 

prevalence, which ranged 1.9-3.6. 173,174,175 These differences are explained by a lack of 

diagnostic gold standard or clear diagnostic criteria. The weighted averaged incidence 

rate was calculated at 2.7 per 100,000. 

The proportion of all CIDP cases that were treated with long term IG were estimated 

in 3 studies from France (2 studies) and the UK, published in 2007-2008, and ranged 51- 

63%. 175 , 176 , 177 The weighted average was 56%. 

The dosage ranged 0.4-2g/kg in studies and national recommendations. In Belgium, the 

maximum reimbursed dose ranges 0.25-2g/kg with a maximum of 9g/kg/6 months. The 

practice for CIDP (and MMN) is to start at 2g/kg dose and rapidly decrease the dose 

according to the clinical response, to reach a minimal maintenance dose; it has been 

estimated at 1.5g/kg in average. The median interval for IVIG administration in studies 

was 3 weeks (frequency of 17.3 per year).


Multifocal motor neuropathy (MMN) 

Epidemiological data on MMN prevalence are scarce: only two EU prevalence studies 

from England and the Netherlands were found in conference abstracts, with very similar 

values. 178 The average could not be weighted for study size as the number of cases was 

missing in the English study. The 2008 prevalence was respectively 0.53 and 0.58 per 

100,000 in England and the Netherlands, and the average incidence rate calculated at 

0.56 per 100,000. 

Data on the proportion of all MMN cases that were treated with IG were found in 3 

recent EU studies, conducted in the UK, the Netherlands and France and published in 

2007-2008. 179,178,180 This proportion ranged 51-76% and the weighted average was 66%. 

The dosage was 2 g/kg per treatment in all studies, though the maximum reimbursed in 

Belgium ranges 0.25-2g/kg with a maximum of 9g/kg/6 months. The median interval for 

IVIG administration in studies was 3 weeks (frequency of 17.3 per year). However, the 

annual IG amount used to treat one case widely varied across studies, ranging 248g in 

New Zealand to 1728g in the UK. 149,179 

Multiple sclerosis (MS) 

Several epidemiological studies on MS prevalence in Europe were found but showed 

very diverging values. Due to an observed North-South gradient in prevalence, our 

analysis was limited to countries or regions having a latitude similar to Belgium and a 

population of >2 millions inhabitants to decrease the inaccuracies due to small numbers 

of cases. Only studies using the Poser criteria for MS diagnosis and validation of 

diagnosis were selected. Studies based on community surveys and self reported cases 

were excluded. 

A survey was conducted in Flanders in 1991 but was excluded as it did not fit in 

inclusion period. 181 Indeed prevalence is increasing over time, likely due to improved 

diagnosis and unknown factors. The two selected studies were conducted in France and 

Austria and the prevalence for definite and probable cases was 120 and 99 per 100,000 

respectively, with a weighted average at 103 per 100,000. 182,183 

Immunoglobulins may be used for very specific MS cases, i.e. in cases of relapses that 

are resistant to other treatment, when other therapies are not tolerated, as well as in 

the post-partum for the prevention of relapses. No studies were found on the 

proportion of MS patients that are treated with IG. Experts estimate that 0-3% of MS 

patients are treated with IG for treatment (or prevention) of relapses. Considering that 

IG are mostly used for the prevention of post-partum relapses, that women in postpartum 

represent 1.1% of the Belgian population and that a large European prospective 

study estimated that 28% of pregnant women experience a relapse in the 3 months 

post-partum, we can assume that a maximum 0.31% of MS cases could benefit from 

IG. 184 IG is not reimbursed in Belgium for this disease but some private insurance might 

reimburse it. 

The doses used ranged 0.15-2g/kg/month, with no superiority of a given dose shown. 

An observational Austrian study among pregnant women calculated that an average 

dose of 0.24 g/kg/month was given. 85 The mean treatment duration was 3.4 +/- 1.8 years 

and the mean time to first relapse with IG therapy was 247 days (median 199 days) in 

the first 2 years. 

Myasthenia gravis 

Studies on myasthenia gravis (MG) prevalence showed very different values, depending 

on the diagnostic criteria. Three studies conducted in Sweden, the Netherlands and 

England in 1997-1999 estimated a prevalence ranging 11.9-14.1 per 100,000. 105 , 185 , 186 A 

study in Greece was excluded because MG cases were limited to those having 

antibodies against the acetylcholine receptor, which represented only 79% of total cases 

in both the Dutch and the English studies. The weighted average of the three selected 

studies was 12.7 per 100,000. However, this estimate probably underestimates the 

current figure as prevalence increases over the years, due to the ageing of population 

combined to a higher prevalence found among the elderly.


The proportion of MG cases treated with long term IG was not found. The 1997 English 

study described 3% patients being under plasma exchange therapy (the golden standard 

for myasthenic crisis at that time). 185 Since this therapy has often been replaced by IG in 

recent years, we estimated that 3% MG patient would be treated with IG, and experts 

considered this estimate to be valid for the Belgian situation. 

The dosage was 2g/kg in most studies and national recommendations, but a study 

comparing a dose of 1g vs. 2g/kg body weight suggested that 1g/kg may be sufficient. 

There is no evidence to support IG use as a long-term treatment, thus a single 

treatment in case of crisis or exacerbations was assumed. 

Dermatomyositis and polymyositis 

Dermatomyositis and polymyositis cases were not distinguished as both diseases are 

idiopathic inflammatory myopathies, usually studied together. Only one recent study 

estimating the prevalence of dermatomyositis and polymyositis was identified, 

conducted in Canada in a population of 7.5 million inhabitants, and found a 2003 

prevalence at 21.5/100,000. 187 Older estimates from the USA and Japan ranged 5.0-6.3 

per 100,000 in 1960-1987 but are considered to underestimate the true disease 

prevalence. 188 

Data on the proportion of dermatomyositis patients treated was only found in an older 

cohort study on juvenile dermatomyositis in Canada, representing 9% of cases, and 

cannot be used to extrapolate to other age groups. 189 ) It is only known that IG is only 

needed in special cases and seems the treatment of choice in severe myositis with 

dysphagia. 190 

The dosage was 2g/kg every 3-6 weeks in most studies. Data on practice in Belgium 

have not been found. In the 15 patients included in the only RCT conducted so far, the 

frequency of treatment varied from every 3 to 6 weeks (average 4 weeks) and two 

patients could stop IG treatment. 110 

As no data are available on the proportion of cases treated, this disease has not been 

included in the calculation. However, as we know that the treatment of 

dermatomyositis cases represented 2% of total amount of IG used in the three studies 

in other countries (Table 22), the same proportion of the total IG amount has been 

assumed in Belgium. 

Kawasaki disease 

The incidence of Kawasaki disease (KD) was estimated in Denmark, Sweden and New 

Zealand, while other recent studies were based on rates of hospitalization for 

KD. 191,192,193 Incidence among children


Based on these methods and the assumptions described under table 40, we have 

estimated that 576 kg (method A) and 483 kg (method B) of IG would be annually 

needed to treat these 11 diseases, thus not including CLL. This would represent 

respectively 70% (A) and 59% (B) of the IG amount reimbursed in 2006 based on 

INAMI/RIZIV data (Table 41). 

Though we have not used statistical tests given the high intrinsic uncertainty around 

some estimates and assumptions, the proportion of total IG use that would be required 

to treat these 11 diseases is lower than calculated in the 4 studies, for both methods A 

and B: these 11 diseases consumed 75%, 68%, 88% and 72% of the total IG amount in 

New Zealand, Toronto (Canada), Massachusset (US) and the Canadian Atlantic 

provinces, with a weighted average of 74%. If we compare our estimates to the annual 

IG amount reported by Belgian hospitals in 2008 (919.6 kg, KCE survey), this 

proportion would be even lower, representing 63% (A) and 53% (B) of total amount. 

Our estimation suggests that a higher proportion of IG is used for other indications 

than those included here, compared to other countries. In other studies, 12% to 32% of 

total IG amounts was consumed by the remaining indications, while this would 

represent as much as 37% (A) and 41% (B) in Belgium. This is not surprising when we 

observed that, in Belgium, already 16% of IG has been prescribed by lung specialists in 

2008. 

However conclusions on the yearly amount of IG required in Belgium cannot be based 

on this exercise, as this estimation has many methodological limitations. 

3.3.3.4 Limitations 

The main limitations to this estimation that we have identified are: 

• This method has probably underestimated the number of cases under IG 

treatment for several diseases: First, our calculations were based on data 

from scientific studies, where all cases were verified for adherence with 

defined case definition and criteria; in a real life setting, many more cases 

are likely to be treated. For instance, we estimated that 150 cases of 

Guilllain Barré occur every year in Belgium, based on incidence from 

neighbouring countries, while RCM/MKG data for code ICD9CM 357-0 in 

2000-2007 show annual numbers ranging 609-717 cases. Second, many 

studies were based on old data from the nineties and probably 

underestimated disease rate as the prevalence of several diseases is 

known to increase with time, due to population ageing and improved 

diagnostic. 

• This estimation could not include cases of CLL. 

• We have found several other inconsistencies when comparing our 

estimates to other Belgian data, which may be due to the assumptions 

used or the lack of representativeness of practices in the centres 

surveyed. This was mainly observed for bone marrow transplant (BMT) 

where we likely underestimated the number of cases under treatment: 

the proportion of transplant cases treated with IG is based on data from 

two university hospitals and may be higher in other hospitals. Indeed, 56 

transplant cases under treatment were reported in the survey from 4 

paediatric wards and an adult ward, while our overall estimate of BMT 

treated with IG in the whole Belgium is 105. This was also suggested by 

the lower proportion of total IG amount used in BMT in Belgium 

compared to other studies (3-4% vs. 11%). The number of ITP cases 

under IG treatment extrapolated from incidence rates from other studies 

did not correspond to the number reported by Belgian centres (52 cases 

under treatment are reported from 5 university hospitals vs. 49 for all 

Belgium based on other studies). 

• Data on IG use are compared to four studies from three non-European 

countries (US, Canada, New Zealand), where IG use was reported to be 

high.


• Many estimates were based on the Belgian survey and expert meetings, 

which may not be representative of the overall Belgian situation. 

In spite of the limitations due to this method, we reach the same overall conclusions 

than the studies based on real IG consumption: the highest IG use is observed for 

immuno-haematological disorders (41-43% of IG amount) but covers as much as 1545 

cases, compared to neuro-muscular diseases which may consume 25-28% of total IG 

amount but only covers 367 cases. The diseases likely to consume the highest amount 

of IG are: primary immune deficiencies, CIDP, MM, ITP and MMN. 


• Based on theoretical needs and assumptions, we estimated that from 483 to 

576 kg of IG would be annually needed to treat the 11 indications consuming 

the highest amount of IG in Belgium, excluding CLL. This would represent 

53-63% of the total IG amount prescribed in Belgium in 2008. Compared to 

studies from other countries (Canada, New Zealand and the US), this 

represents a lower proportion of the total IG amount to treat these 

diseases. 

• This comparison suggests that in Belgium, a higher proportion of IG is used 

to treat the remaining indications (37-41% in Belgium vs. 12-32% in the other 

countries). Part of this difference may be explained by the 16% of total IG 

that has been prescribed by lung specialists in 2008. 

• However conclusions on the yearly amount of IG required in Belgium cannot 

be based on this exercise, as this estimation has many methodological 

limitations and probably underestimates the amount that would be required 

in a “real life” setting.


Disease / medical condition 

Table 40: Theoretical estimation of annual amounts of immunoglobulins needed to cover the treatment of 11 diseases in Belgium 

Incidence Prevalence 

rate (per rate (case N patients 

100,000/year) per 100,000) considered 

Based on the following assumptions: 

Population figures: 

Population Belgium (2007): 10.547.958 

Population children < 15 years (2007): 1.796.916 

Population adults (> 15 years) 2007: 8.751.042 

Average body weight: 

Adults: 75,0 kg 

Children: 25,0 kg 

Whole population: 50,0 kg 

A B C D E F G H 

% patients 

treated w/ 

IVIG/SCIG 

N patients 

treated per 

year 

N treatments 

per patient 

year* 

Dose per 

treatment 

(g/kg) 

Amount per 

patient per 

treatment (g) 

Amount per 

patient per 

year (g) A 

Amount per 

patient per 

year (g) B 

IG amount in 

g per year 

(A) 

Idiopathic thrombocytopenic purpura (all) see detail see detail 323 see detail see detail see detail 210 32.850 

- ITP in children (


Table 41: Estimation of the proportion of immunoglobulins needed (or used) to treat 11 diseases in Belgium and in 4 studies 

Disease / medical condition 

IG amount in 

g per year 

(A) 

Idiopathic thrombocytopenic purpura (all) 32.850 

- ITP in children (


3.3.4 Expected trends in consumption 

We have identified a few trends and scientific progresses that may influence future 

trends in IG use and consumption, to help predict future trends. 

1. The number of allogenic bone marrow transplants performed in Belgium is 

increasing from year to year, from 216 in 2005 to 284 in 2007 (+31% in 2 

years). In Europe, a study estimated a more conservative 13% rise in bone 

marrow transplants to be expected from 2005 to 2010. 194 This would imply 

an increased IG use over time. However, the increase in non-myeloablative 

transplants in adults, with a consequent lower level and shorter duration of 

hypogammaglobulinemia, would tend to decrease IG needs. 

2. The prognosis of patients with MM has improved significantly during the last 

three decades, resulting in increased survival. 195 This will likely increase the 

disease prevalence and related needs in IG. But alternative therapies for MM 

and CLL are also increasingly used and this may result in decreased needs in 

IG supplementation. 

3. The prevalence of multiple sclerosis and myasthenia gravis is increasing with 

time, due to ageing of the population and better diagnostic tools, and could 

result in increasing IG needs. 

4. Alternative treatments for ITP and for the prevention of infections in 

transplant are under development. Some therapies are arriving on the market 

(e.g. Rituximab and Romiplostine) could potentially decrease IG use for these 

indications. 

5. Many studies are conducted to test alternative treatment that would allow 

decreasing or even stopping IG maintenance treatment in CIDP cases. If 

successful and available, these therapies would decrease IG use for this 


6. Alzheimer disease, any auto-immune disease, asthma and some other 

frequent diseases related to immunity and for which no alternative treatment 

has shown efficacy, may be considered by some physicians as new indications 

for IG. This may represent a problem before any RCT could demonstrate the 

efficacy - or lack of efficacy - of IG for these diseases.


4 SELF SUFFICIENCY OF BELGIUM 

4.1 WHAT ARE THE RISKS AT WORLDWIDE LEVEL ? 

4.1.1 Plasma collection: Key role of the North American Region 

Over the last years, total volume of plasma available worldwide for fractionation has 

slightly increased (22.3 million litres in 2000, 21.4 million litres in 2005) and reached 

26.5 million litres in 2007, broken down as below: 

• 17.9 million of apherese plasma (9.2 million in 2000 ; 13.7 in 2005) 

• 8.6 million of recovered plasma (13.2 million in 2000 ; 7.7 in 2005) 

Of the 26.5 million of plasma mentioned above: 

• 15 million are collected in the North American region (56%) 

• 6.4 million are collected in the European Region (24%) 

These ratios have remained stable since 2000. 

Of the 17.9 million litres of apherese plasma mentioned above, 

• 12.5 million are collected in the North American region (70%). 

• 2.1 million are collected in the European Region (12%) 

Figure 11: Shares in Global Collection of Plasma 

Other Regions 

20% 

Europ. Union 

24% 

Source: Marketing Research Bureau 

North America 

56%


Figure 12: Focus: Shares in Global Collection of Plasmapherese 

Europ. Union 

12% 

Other Regions 

18% 


North America 

70% 

From a geographical point of view, North America clearly remains the key stakeholder 

in plasma collection. Conversely, one must bear in mind that Europe remains the key 

stakeholder in the fractionation industry. 

As explained above, more than 50% of plasma collected worldwide is collected in North 

America (mainly in the USA). This ration reaches 70% for apherese plasma. 

Plasma donation and collection in the USA (as well as blood donation and collection in 

general) is based on purely private and commercial principles. Donor selection is 

organized on a risk-management basis, and blood donation is paid. This ethical and 

organisational framework is largely different from the European one. 

In practice, a large part of the plasma collected in the United States needs to be 

exported to Europe in order to be processed, and re-imported into the United States 

for clinical use. Therefore, it is also of paramount importance to underline that Europebased 

fractionation facilities are often devoted to the supply of the world market, 

especially the American one. In other words, European fractionation capacity is largely 

devoted to the needs of non European (especially US) patients. 

In order to fulfil the American patients’ needs, it is vital for American stakeholders to 

secure the supply of plasma products, the latter being largely produced by Europe-based 

companies. This may lead American stakeholders to implement specific corporate 

strategies (especially long term supply contracts) or even purchase strategies in Europe. 

For obvious reasons, these strategies are implemented, with a view to improving the 

American patients (whatever the needs of the European patients may be). 

Should a shortage of plasma products appear (eg sharp and quick raise in global needs 

due to new indications), potential competition between American patients’ needs and 

European patients’ needs could be clearly identified. 

Moreover, as mentioned below, any change in the use of plasma products, especially 

indications in the USA (or even changes in prescription habits) is likely to have an 

impact on the US demand and then indirectly on the European fractionation industry. 

Basically, considering today’s situation of American and European plasma fractionation 

industry, the main concern of American stakeholders is to secure the stream of plasma 

products across the Atlantic. As a practical matter, if US health authorities decided to 

restrict export of their own raw plasma, European countries would not be in the 

position to fulfil immediately the needs of European patients.


4.1.2 Worldwide demand for plasma products / Focus on IVIG (2000-2008) 

Percentage 

60 

50 

40 

30 

20 

10 

0 

Over the last years, global demand for polyvalent Intravenous immune-globulin has 

raised firmly and steadily. 

Whereas global demand for polyvalent IVIG amounted to ca 47 000 tons in 2000, it 

reached more than 82 000 tons in 2008.(ie an increase by 75% in an eight-year period of 

time). 

In 2007, the share of the European Region in the global demand amounted to 25%, 

whereas the one of the North American Region reached 45%. 

In financial terms, the demand of the European Region reached 762 million US dollars 

(20% of the global demand), whereas the one of the North American Region amounted 

to 2199 million US dollars (57% of the global demand). 

Figure 13: Global collection and Demand of IVIG 

North 

America 

European 

Union 


Other 

Regions 

4.1.3 Potential changes in demand structure 

Share in Global Collection % 

Share in Global Demand % 

North America European Union Other Regions 

Share in Global Demand % 45 25 30 

Share in Global Collection % 56 24 20 

Indications have evolved over the last years. Therefore, it is important to stress that 

these evolutions have had an impact (or even a major) on the demand of plasma 

products. It remains difficult to forecast evolution of consumption precisely, as different 

factors must be taken into account: research progress and new evidence-based 

indications, but also dissemination of premature and non evidence-based practices or 

expert opinions. 

Further information in Appendix “Emerging Countries” on the Brazilian and the Chinese 

market



• The North American region (especially the United States) remains the 

“World’s plasma collector” whereas Europe remains the “World’s plasma 

fractionator”. 

• The main concern of the American stakeholders is to secure the supply for 

plasma products, by different means (long term supply contracts, control of 

fractionation capacities), whereas the fulfilling of European patients 

simultaneously requires large imports of American plasma. 

• Should US health authorities decide to restrict export of their own raw 

plasma, European patients would be put in a predicament. Any change of 

American practices (new indications or change in prescription habits) must 

be kept under close scrutiny as it could lead to a similar deadlock. 

Conversely, American patients need to rely on the EU fractionation industry 

to fulfil their own needs. 

• Emerging countries are likely to play an ever greater role on the world 

market, which means greater competition between purchasers. 

4.2 CONCEPT OF SELF SUFFICIENCY 

4.2.1 In Belgium 

Belgian regulations do not define the proportion of plasma derivatives that must be 

produced in Belgium to minimise the risk of shortages of plasma derivatives. A Royal 

Decree of 18 June 1998 simply states that in order to ensure self-sufficiency and the 

quality of the supplies of stable blood products of human origin, the price of a litre of 

plasma, manufactured by plasmapheresis and sold by the Red Cross to the CAF-DCF, 

will be subsidised and that a firm of auditors will communicate each year to the SPF the 

number of litres sold in order to calculate correctly the subsidy. 

Since the quantity guaranteeing self-sufficiency is not explicitly stated in the decree, it 

transpires from verbal explanations gathered that the auditor i deems that self-sufficiency 

is achieved if the CAF-DCF provides 

• “a level of production covering 60% of the average national consumption 

of the main plasma-derived products – i.e. Factor VIII, Albumin, and IVIG - 

in normal sanitary and epidemiological conditions, and considering 

approved indications” 

• “a quarantine stock covering 90 days of average national consumption for 

the three main products mentioned above”. In practice, this stock 

comprises 8000 bottles of Albumin, 1 million doses of Factor VIII, and 

50kg of IVIG. 

This quantity is shown on the first line of the table below. PWC then deducts from this 

quantity the number of litres of non-subsidised plasma (RP) (line 2) and adds to it the 

number of litres taken from stocks (line 4) to calculate the number of litres to be 

subsidised (line 5). 

i This role is assumed by the firm PricewaterhouseCoopers. See ‘Plasma from plasmapheresis required for 

self-sufficiency in Belgium in 2008’ PWC

1 

2 

3 


Table 42: Volumes of plasma bought by CAF-DCF and subsidized in Belgium 

between 2000 and 2008 

Type of plasma 2000 2001 2002 2003 2004 2005 2006 2007 2008 

Quantities of plasma 

necessary for self 

sufficiency 

Recovered plasma 

bought by CAF – 

DCF from all 

collectors 

Source plasma 

bought by CAF – 

DCF from all 

collectors 

196,479 197,527 210,564 212,827 243,795 202,24 182,149 170,497 157,472 

140,451 138,141 136,348 135,141 123,78 115,896 113,731 114,375 106,923 

56,028 59,386 74,216 68,087 96,024 80,25 59,751 50,488 42,592 

4 Intake from stock 8,667 5,634 7,957 

5 

Source plasma 

subsidized 

56,028 59,386 74,216 77,686 120,015 86,344 68,418 56,122 50,549 

Source: PWC 

Note that the quantities of source plasma purchased by the CAF-DCF from the SFS and 

VDB according to PWC are not the same as those received by the Federal Agency for 

Medicines : 

Table 43: Comparison of quantities purchased by the CAF and collected by 

SFS-VDB 

2000 2001 2002 2003 2004 2005 2006 2007 2008 

SP purchased by CAF from SFS + VDB (source: PWC) 

Sp purchased by CAF from SFS + VDB (source: Federal 

n.a. n.a. n.a. 68.087 96.024 80.250 59.751 50.488 42.592 

Agency for Drug) 76.561 77.736 74.865 67.908 93.860 78.052 59.462 50.125 45.324 

SP collected by SFS + VDB (source: SFS & VDB) 

77.052 77.808 74.865 67.915 94.176 78.068 57.225 50.125 45.324 

But these quantities are approximately the same than the collected quantities except for 

2006. We didn’t receive any explanation for this difference of 2.237 litres (i.e. 3.9% of 

the total volume of SP collected in 2006). 

It clearly emerges that the term self-sufficiency is no longer adequate to describe the 

data from these calculations. PWC starts with a total quantity of plasma, which is the 

quantity that the CAF-DCF would have to buy to supply a quantity of derivatives over 

and above those supplied by commercial firms in Belgium. It is important to understand 

that the total market for plasma derivatives is not divided between the existing vendors 

in a fixed distribution pattern. It is the interplay of competition that determines the 

quantities that the CAF-DCF and the other foreign commercial vendors will sell during 

a given year to the various hospitals. This clearly establishes that self-sufficiency only 

relates to a part of Belgian consumption, which results from competition between the 

firms operating in the market. 

It appears that the authority has no clear intention of achieving total independence. But 

does the coverage of 60%, extended to 180 days, which seems somewhat arbitrary, 

truly reflect a reasonable risk? Nobody knows. We also find no scientific justification for 

the quarantine period (during which the plasma must be kept before fractionation). 

This was extended from 50 to 180 days between 1998 and 2006 with no justification for 

this extension from the standpoint of medical safety. It therefore appears that the 

concepts of self-sufficiency and quarantine have never been properly considered and 

defined in Belgium.



• Free competition has led to a market distribution of 60-40 between the 

CAF-DCF and the other firms producing blood derivatives 

• There does not appear to have been any discussion of whether or not this 

distribution is optimal from the standpoint of securing coverage of our needs 

4.2.2 In other countries 

4.2.2.1 In Australia 

Australian official definition of Self-sufficiency 

The promotion of national self-sufficiency in respect of blood and blood products is a 

policy aim of Australia’s Commonwealth, state and territory governments. The 

Australian Health Ministers’ Conference Policy Statement on National Self Sufficiency in 

the Supply of Blood and Blood Products, issued in April 2006 196 , defines self-sufficiency 

as: “Australia striving to source blood components and plasma from within Australia to 

meet appropriate clinical demand”. 

Self-Sufficiency objective and National Blood Agreement 

All Australian, State and Territory Governments are signatories to the National Blood 

Agreement 2003, which sets out, the policy objectives and aims for Australia’s national 

blood sector, which are: 

• provide an adequate, safe, secure and affordable supply of blood 

products,blood related products and blood related services; 

• promote safe, high quality management and use of blood products, blood 

related products and blood related services in Australia. 

Therefore all stakeholders are clearly committed in the field implementation of selfsufficiency 

policy. 

However, national self-sufficiency objective does not preclude Australia from importing 

blood or plasma products in a narrow range of circumstances, ie where there is an 

inability to meet clinical needs through the domestic supply, and where supply chain 

risks must be addressed. The Australian Health Ministers’ Conference statement 

acknowledged that Australia is (and has never been) not totally self-sufficient in plasma 

products and derivatives. 

Therefore the agreement signed between health authorities and CSL-Limited also gave 

room for some flexibility on the matter of import of plasma products and derivatives, 

within a strict framework that: 

• ensures adequacy of supply to Australian patients in need; 

• minimizes the supply security and product safety risks to patients; 

• ensures affordability of products to the Australian health sector; and 

• recognizes the practicalities of production and distribution. 

Self sufficiency and Australian national blood policy 

The Australian example has been selected, since Australia is the only western country 

that has succeeded in setting up a comprehensive blood and plasma policy, from a 

• practical point of view : organization of donation, collection, fractionation 

of blood and plasma 

• legal point of view : strong interface between suppliers and health 

authorities 

• clinical point of view : interface between clinical practices and supply 

policy.


It must be outlined that such a policy requires an unfailing and long-lasting political 

commitment of the national health authorities. In Australia this policy this policy has 

been initiated in the fifties: the Commonwealth Serum Laboratories (hereafter “CSL”) 

originally founded in 1916 commenced production of fractionated products in 1953, 

thanks to the Australian Government’s support. CSL was later privatized and merged 

with Behring. 

The Australian policy was elaborated step by step, and in 1995 the Commonwealth 

Review of the Australian Blood and Blood Product System identified the need for a 

single, integrated, blood supply agency in Australia with a view to enhancing the safety, 

efficacy,and adequacy of supply of blood and blood products. As a result of that, the 

separate state and territory blood services combined to form the Australian Red Cross 

Blood Service in 1996. 

The Review of the Australian Blood Banking and Plasma sector, which was completed in 

2001, recommended the establishment of an authority to provide national management 

and oversight of Australia’s blood system. Following this review, the National Blood 

Authority (hereafter “NBA”) was set up in 2003. 

Background: Australian administrative structure 

ROLE OF THE NATIONAL BLOOD AUTHORITY 

Australian blood and blood products policy (especially in the field of plasma products) 

has been centralized and rationalized every angle: one single public body is entrusted to 

manage the whole Australian policy. The National Blood Authority is a statutory and 

overarching agency established under the National Blood Authority Act 2003 . The 

NBA is central to Australia’s national blood and plasma policy. The most important and 

interesting characteristic of the NBA is that it covers the whole scope of this policy: 

• Coordination of demand and supply planning of blood and blood products 

and purchase those products on behalf of Health authorities 

• Negotiation and follow-up of the contracts with suppliers of blood, blood 

products and blood services, including development of a national pricing 

schedule. 

• Implementation of an efficient blood use based on evidence-based 

principles and good clinical practice. (incl. information and advice to 

governments ). 

• Coordination of the development of the National Health and Medical 

Research Council’s Clinical Practice Guidelines for the Use of Blood 

Components. 

• Follow-up of legal issues 

Further information is provided on institutional aspects (NBA and other institutions in 

the appendix). 

Access to plasma derivatives: key points 

APPROVAL PROCESS AS DESIGNED UNTIL MARCH 2008 

Access to plasma-derived products has been rationalized and must abide by a specific 

clinical and administrative process. Processes may vary across the Australian States 

(some of them being more demanding or than others); however, the key point of the 

Australian policy is to rationalize the use of plasma derived products (especially IVIG 

which represents two-thirds of Australia’s demand in this field) both for ethical reasons 

(optimal use of donated blood) but also for practical reasons (avoiding shortage). 

From a purely clinical point of view indications have been grouped into three groups 

depending on the level of clinical accuracy: 

• Category 1: indications for which strong evidence of IVIg benefit has been 

identified. 

• Category 2: indications for which evidence of this benefit is inconclusive 

for the following reasons:


• Conflicting evidence 

• Low level of evidence 

• Little research, especially for rare conditions 

Category 3: indications for which there is convincing evidence that IVIg brings no 

benefit. A strong financial connection has been established between accuracy of 

indications – as described above – and funding policy. In short, prescription of Category 

1 IVIg is funded on the basis of a specific cost-sharing arrangement, called Australia’s 

National Blood Agreement ie 63% by the Australian Government (national level) and 

37% by the State / Territory level. Prescription of imported IVIg products outside of 

Category 1 are not co-funded, and IVIg products must be purchased at full price by 

prescribers (hospitals) directly from the relevant manufacturer which are responsible 

for production of IVIg. Hence, there is a financial incentive for an evidence-based and 

rational use of IVIg products. 

The ARCBS approved requests that meet category 1. If insufficient information was 

provided by the clinician to the ARCBS, the request was forwarded to the local IVIG 

Working Group. This IVIG Working Group consisted of 8 clinicians, representing 

specialities who had an interest in IVIG issues, and made the final decision (approval or 

not). 

In March 2008 (ongoing reform), the new “Criteria for the clinical use of intravenous 

immunoglobulin in Australia” (hereafter “Criteria”) have been officially issued by the 

Australian. In short, the conditions are categorised in the Criteria under those for 

which IVIG has: 

• An established therapeutic role 

• An emerging therapeutic role 

• A use in exceptional circumstances 

• Conditions for which IVIG is not indicated 

Supply contracts with CSL-Ltd: Plasma Products Agreement and other 

contractual arrangements 197 

BACKGROUND 

In 1994 CSL became a public company limited by shares and taken to be registered 

under the Companies Act 1981 (Cwlth). At this time, certain legislative obligations were 

imposed upon CSL Limited, in line with the Commonwealth Serum Laboratories Act 

1961 (CSL Act), as described below: 

• Provide that CSL Limited is to remain Australian-controlled. 

• CSL is also required to maintain a register of foreign-held voting shares 

and must provide this register, or a copy thereof, to the Minister if 

requested to do so by the Minister, in writing. 

• Require CSL, when manufacturing plasma products from Australiandonated 

plasma, to produce those products in Australia. 

• Prohibit CSL from disposing of its manufacturing facility at 

Broadmeadows, which may not be sold or encumbered without 

Ministerial permission. 

• Provide for court orders where the Commonwealth can show that CSL is 

breaching, or threatening to breach, a contractual obligation. 

An ind-depth analysis of fractionation arrangements had been carried out and 

completed in 2006 196 . In today’s form – Plasma Products Agreement mentioned above - 

relationship between CSL-Ltd and Australian health authorities can be summarized as a 

close partnership based on a monopoly for fractionation in exchange for strict and 

demanding performance and safety standards 164 (see table below):


Table 44: The Plasma Products Agreement between CSL-Ltd and the 

Australian National Blood Authority 

Heading Content 

Section A: Interpretation and Term Definitions, rules of interpretation 

Section B: Relationship Management Relationship between the parties, Contacts and notices, 

Management meetings and reviews, Public Affairs 

Management, Variations to the Deed, CSL contracts with 

other Nat. Blood Suppliers 

Section C: Products / Services Obligations Provision of products (quantity; notice obligations, etc..) 

Exclusive right to fractionate plasma, Reporting obligations, 

Obligations under Therapeutic Goods Act, CSL general 

obligations (as a manufacturer and where CSL is not a 

manufacturer) 

Product compliance and return, 

Performance requirements for goods and services 

Section D: Payment Obligations Payments by the NBA, Invoicing obligations, Recovery of 

money by the NBA, 

Section E: Ownership Issues Possession of products, Intellectual property, Moral rights 

Section F: Protection of Information Confidentiality, Data security, Privacy, Conf. of Interest 

Section G: Treatment of Risks Risk Manag. Warranties, Indemnities, Undertakings, 

Insurance, Supply continuity plans & options 

Section H: Other Requirements of CSL Records, Access to information & Premises, Audit. 

Section I: Termination and Disputes Termin. for default, for change of policy, Handover 

obligations, Dispute Resolution, 

Section J: Miscellaneous Assignment (by CSL, by NBA), Execution of separate 

documents. 

CSL Limited is also in charge of maintaining the National Reserve of plasma products for 

the NBA, under a contractual arrangement separate to the PPA. 

4.2.2.2 In France 

French Approach of self-sufficiency 

In France, there is no official and legal definition of “self-sufficiency” as such. However, a 

general approach of this concept could be defined as the turnover of LFB (national 

fractionator enjoying the monopoly of EFS plasma fractionation) compared to the total 

turnover of fractionators operating in France. One must bear in mind that the plasma 

product market is subject to competition. LFB must therefore compete with other firms 

(Baxter, Octapharma, etc…). 

Considering this approach, it must be outlined that LFB meets 75% of the needs of the 

French market. However, it must be underlined that LFB corporate objective is to be in 

the position to fulfil 100% of these needs in 2011 (specific investments have been 

planned accordingly). 

Another important point is the very last update of the French regulation framework. In 

Summer 2009, the new French Law on Health Care organization (Loi Hôpital Patients 

Santé et Territoire – Loi HPST) officially stated that fulfilling the French patients’ needs 

must be LFB’s priority (in return of its monopoly of EFS plasma fractionation). 

Supply of blood and plasma-derived products: the French monitoring system 

Following the shortage of Factor VIII in France in 2000-2001 (and consequential 

problems for haemophilia patients), the French Department of Health decided to set up 

a long-term monitoring system -National Steering Committee- to address this specific 

kind of problems. The latter has been organized since 2001 (by means of a Department 

of Health’s Circular dated 28 June 2001) under the leadership of the AFSSAPS Agence 

Française de Sécurité Sanitaire des Produits de Santé– French Agency for the Safety of 

Health Products. 

Following the meetings of these groups, and depending on the likelihood of shortage of 

plasma derivatives, national official recommendations – including priority orders - can be 

officially set out and published by the AFSSAPS and to rationalize the use of these 

products accordingly (eg: Fibrinogene-derived products in December 2008 and the 

following months).


As far as IVIG products are concerned, a specific steering group has been set up to 

organize routine monitoring of IVIG products supply. All relevant private and public 

stakeholders are involved: representatives of the Department of Health, several 

representatives of pharmacists (incl. the French Pharmaceutical Association), Networks 

of heath care establishments, clinical experts, but also the leading fractionation firms on 

the French market. 

Supply and storage issues are discussed every angle: data collection on consumption and 

supply, clinical dimension, industrial problems etc…The minutes of these meetings are 

not public domain and they remain confidential. However, this routine monitoring 

system plays a key-role in shortage prevention and also covers the interface between 

public decision-makers and private fractionation industry on that matters. 

4.2.2.3 In Germany 

Quantity 

Collected 

(Liters) 

German approach of self-sufficiency 

As stated by Art 4.7 of the German Transfusion Act “Compensation is also an aspect of 

self-sufficiency. Should it not be allowed to pay a compensation, this would cause a 

highly visible loss of donors. This would be counter-productive to the aim of selfsufficiency”. 

“Blood and Plasma donors may receive a compensation for the donation 

time and effort. However, this compensation must not become a payment”. 

However, from a purely legal and conceptual point there is no one single definition of 

“self-sufficiency” as such, but several ratios followed up on the national level by the Paul 

Ehrlich Institut thanks to a centralized data collection system. 

The key objective of the German Health Authorities is to have a clear overview of 

plasma quantities actually available for fractionation and also to analyze the German 

industry’s actual capacity to fractionate the German plasma. 

As often underlined by the Paul Ehrlich Institut’s experts, increasing plasma collection is 

not an end in itself. A sensible approach requires a specific follow-op of plasma 

collection but also a specific monitoring of the German actual fractionation capacity for 

the whole range of plasma products meeting the German patients’ demand. 

Practical follow-up of self-sufficiency issues 

This data collection system is a regulatory obligation, based on Article 21 and 22 of the 

German National Transfusion Act (“Transfusionsgesetz” in German). 

• Blood and plasma collectors (Red Cross, Private Centres, Municipal 

Centres, German Army) are subject to this specific reporting obligation, 

but also: 

• Fractionation industry : all firms acting on the German market 

• On the demand side: panel doctors and hospitals and specialized health 

care establishments. 

This reporting system refers to a specific data set, set out by the German regulation 

mentioned above. Therefore, the German health authorities are in the position to 

organize a follow-up of a specific range of routine indicators and to have a clear 

overview of Germany’s situation in terms of self-sufficiency. 

SUPPLY SIDE 

In practice all the concerned data are validated, sorted and entered onto the Paul 

Ehrlich Institut’s data bases. Considering our subject, one of the most accurate 

monitoring tool is the “Balance Sheet” that records the following flows (2006 Data): 

Loss Expiry 

(Manufactu 

rer) 

Total 

Export 

Total 

Import 

Quantity 

Available on 

the German 

Market 

Fractionat 

ion in 

Germany 

2 143 205 154 881 5 990 1 001 911 609 584 1 750 878 1 201 613


Thanks to this follow-up of imports, the Institute can have a clear view of Germany’s 

situation for the whole range of plasma products, including those that are not 

manufactured in Germany. 

DEMAND SIDE 

A specific follow-up is also routinely carried out by the Paul Ehrlich Institut. 

- One of the self sufficiency key indicators is the following: “Quantities manufactured in 

Germany relating to consumption in Germany”. Based on this approach, the self-sufficiency 

ratios are: 

• Factor VIII from plasma : above 100% 

• Factor IX from plasma: 66% 

• IG (normal): 99% 

• IG (specific / Anti D): 94% 

• IG (other specific IGs): Above 100% 

Among all plasma products, some are not manufactured in Germany, but imports are 

subject to a precise follow-up. Consumption of each plasma product is also subject to a 

precise follow-up. However, in spite of this follow-up mechanism, the Paul Ehrlich 

Institute had to admit that there is some uncertainty about reliability of data on the 

latter subject. 

Recent strengthening of supply capacity in Germany (2000-2008) 

A DYNAMIC COLLECTION POLICY 

As a whole, the situation of Germany has evolved quite positively over the last ten 

years. Plasma actually collected in Germany has raised from 1.5 million litters in 2000 to 

2.5 million litters in 2008. 

A SURGE IN PLASMA FRACTIONATION CAPACITY 

The amount of plasma actually fractionated in Germany has raised accordingly: 750 000 

litters in 2004, 1.2 Million litres in 2006 (see above), and 2 Million litres in 2008. 

4.2.2.4 In Canada 

Canadian historical background 

Historically, gratuity of donation of blood and plasma has been considered as the 

underpinning principle of the whole Canadian donation system. In the nineties, a major 

public health scandal called the “tainted blood scandal” seriously undermined the public 

and the donors’ trust in the donation institutions, especially the Canadian Red Cross. 

In compliance with the conclusions of the Krever Commission of Inquiry of 1997 (see 

below), the Canadian Red Cross eventually transferred its blood and plasma services to 

the newly founded “Canadian Blood Services- CBS” (and Héma-Québec for this latter 

province). 

Canadian Reflection on the ethical framework 

As mentioned above, the Krever Commission of Inquiry conducted an in-depth analysis 

of the whole donation system and issued key statements (1997) on the principles that 

must underpin the future Canadian donation system (the following points are official 

statements): 

• “Donors of blood and plasma should not be paid, except in rare 

circumstances” 

• “Significant efforts must be made to ensure that blood products used in 

Canada are made from unpaid donors” 

• “Plasma must be collected in sufficient quantities in Canada to meet 

domestic needs for blood products” 

• “Safety should be paramount”


Following these principles, gratuity of donation remained untouched but security and 

quantitative aspects of plasma supply were also underlined. However, further principles 

also had to be taken into account as set out by the Founding Memorandum of 

Understanding (1997): 

• Ensuring access to a safe, secure and affordable supply of blood, blood 

products and alternatives, and supports their appropriate use. 

• Addressing inventory imbalances (shortages / surpluses) to minimize 

waste and ensure adequate supply 

• Considering decision making in a health risk management framework 

which places on an equal footing the three critical elements of cost, 

benefit and risk. 

Therefore the newly founded donation system – ie the Canadian Blood Services to 

which the Red Cross donation activities were transferred – had to pursue several goals 

in the same time: 

• Ensuring blood safety, which is of paramount importance considering the 

Canadian historical background. More generally it is an objective as such 

for any country. 

• Improving level of self-sufficiency is also an objective as such, from a public 

health and from a political point of view. 

• Increasing volume of domestic donation for blood and plasma, which is 

strongly connected with the previous point. 

• Maintaining gratuity of donation, as a key ethical option. 

• Reducing risk of supply disruption (especially in the field of IVIG) to avoid 

any danger for patients’ safety. 

Today’s situation of Canada in terms of IVIG self-sufficiency: 

In 2008-2009, Canada will be about: 

• 28% sufficient in IVIG (made from Canadian Plasma) 

• 72% of the IVIG distributed to Canadian hospitals comes from plasma 

collected commercially in the US 

Therefore, Canada has to face two thorny problems simultaneously: security (as 

described above) but also a poor level of self-sufficiency, and thus possible disruption in 

plasma (especially IVIG) supply. Once again this situation is quite close to the Belgian 

one. 

This situation raised several questions: the adequate of national self-sufficiency , the 

ways and means to reach this level of self-sufficiency. 

Canadian strategy 

At the end of the reflection process, the official target of 100% Self-sufficiency through 

domestic collection and supply was eventually abandoned for Canadian Blood Services 

for the following reasons: 

• It would require huge investments (18 new plasma centres within the next 

7 years) 

• It would not be cost efficient as Canadian production costs remain much 

higher than the US ones. 

• It is not scientifically justified in terms of blood safety 

For all the reasons mentioned above, the official self-sufficiency target has been revised 

downwards to 40%. A wide range of options had been originally considered to close 

this gap (28% to 40%): raising the level of domestic collection, improving processes, 

etc… Today’s Canadian strategy can thus be described as a “sufficiency aimed at 

optimally reducing risk of IVIG supply disruption”. In practice it can be described as a 

“policy-mix”. In practice, several measures were implemented in the same time: 

• Improvement of collection methodology



• Reintroduction of source plasma collection at some sites, when required 

• Increased volume per collection 

• Usage of platelet additive solutions 

• Improvement of fractionation capacities: seeking to have two 

fractionators licensed for Canadian plasma 

• There is no universal definition of “self-sufficiency” but all selected countries 

have conducted an in-depth reflection on this concept, in connection with 

other subjects. 

• All selected countries have set up a monitoring system of self-sufficiency 

ratios, or at least a centralized data collection on the subject. 

• Clear connection between self-sufficiency and remuneration issues must be 

born in mind. 

• Australian policy is probably the most comprehensive policy as it has 

established a close connection between this dimension and all related issues 

within the framework of the National Blood Authority, which covers all 

aspects of blood and plasma supply. 

• A short synthetic table of foreign policies in displayed in the table below. 

Table 45: Summary 

Germany France Canada Australia 

Ethical 

Financial 

Non- 

Non- 

Nonframework 

Compensation 

allowed (Max:25€) 

to collector’s 

discretion 

Remunerated Remunerated Remunerated 

Collection Free Competition: EFS monopoly Canada Blood Red Cross 

Red Cr.,Private Delivery targets Service monopoly 

to LFB monopoly 

Fractionation Several institutions LFB Monopoly Two 

CSL Ltd 

on fraction. of fractionators Monopoly on 

EFS plasma (but expected around fractionation and 

no monopoly on 2014 sales (import if 

sales) 

unavailable) 

Self-Sufficiency Self-Sufficiency LFB Turnover Official definition Official definition 

Approach 

national ratios 

ratio 

Self-Sufficiency Regulatory data Routine and Routine and N.B.A.: 

follow-up 

collection compulsory data compulsory data All self-sufficiency 

Public annual 

reports 

collection collection aspects 

Self-Sufficiency Policy mix Policy mix Policy mix NBA policy: 

strategy 

Increas.collection Increasing Increasing All aspects: 

(demo. approach) collection collection, collection , 

and fractionation Increasing LFB- fractionation fractionation, 

capacity ; control of fractionation capacity ; contract with 

consumption capacity ; control control of CSL Ltd and 

of consumption consumption consumption


4.3 HOW TO STAY OR BECOME SELF SUFFICIENT 

There is no answer to the question of self sufficiency in terms of figures in this report. 

This is a political choice to be made in the light of the risk-aversion of Belgian decisionmakers. 

The fundamental question is to determine the desired level of independence. 

Supply security considerations must govern this choice. For this we need to determine 

whether the trend in demand in countries deemed to have a high level of consumption 

could lead to a shortage of derivative products. Such a risk could also result if the 

collection in these countries no longer covered their own requirements for derivatives. 

Price levels and volatility are another risk factor to be considered. Being more 

dependent on foreign supplies could mean suffering substantial price variations, which 

are the first adjustment variable affecting variations in supply and demand. Beyond a 

certain level of shortage, there are fears that simple purchasing power may no longer be 

enough. 

To minimise the cost of production for Belgian plasma derivatives for a given level of 

coverage, we could strive for: 

• A reduction in the demand for these products 

• An increasing of the capacities of collecting plasma 

• Transparency and better control of the supply of derivatives 

4.3.1 Strategies to decrease IG use: lessons learned 

4.3.1.1 Experience from other countries 

Several countries, confronted to increased IG consumption, shortage or risk of 

shortage, and growing cost, have published the measures that they planned or have 

undertaken to improve the supply and demand balance.(Hume, Anderson, TMR 2007; 

Constantine 2007, UK DOH National Immunoglobulin Database Update j , Australia k ). 

However, very few studies have evaluated the impact of these measures. 

Table 45 summarized the overall strategies used in different countries. We focus here 

on the reduction of IG use. The main measures taken or proposed include: 

Classifying indications in priority groups for IG treatment 

A list of indications for which IG can be used has been defined in most countries. In 

addition, a few countries such as France, the UK and Australia, that experienced 

shortage (or its risk), have decided on prioritization of IG use and classified indications 

(labeled or not) into groups or higher and lower priority. However, this classification 

has been applied in many different ways: 

• In Australia, very clear categories for priority setting have been 

established: 1. Conditions for which IG has an established therapeutic 

role; 2. conditions for which IVIg has an emerging therapeutic role; 3. 

conditions for which IVIg are used in exceptional circumstances; 4. 

conditions for which IVIg use is not indicated. 

• In the UK, three well defined categories have been established, coded by 

colour (red, blue and grey), to facilitate the clinician understanding of the 

level of priority. 

• In France, the drug agency (AFSSAPS) defined 7 groups, using different 

levels of priority, distinguishing labeled and non labeled indications, with 

no clear rationale; the priority of each group of indications above the 

others is not always clear. l 

j Source: National Immunoglobulin Database Update. DOH. 

http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_09767 

0 

k Source: Criteria for the clinical use of intravenous immunoglobulin in Australia. Australian Health 

Ministers’ Conference. December 2007. 

l Source: AFSSAPS: http://www.afssaps.fr/Infos-de-securite/Autres-mesures-de-securite/Proposition-dehierarchisation-des-indications-des-immunoglobulines-humaines-intraveineuses-IgIV-en-situation-detension-forte-sur-les-approvisionnements-pour-le-marche-francais2


A difficulty with this system is that the rationale behind the choice of classification is not 

always stated or made clear, the categories need to be regulary updated, and the 

application of this priorization is not always described: in the absence of shortage, 

should a patient from a last priority group receive IG or not? 

Establishing guidelines and criteria for use 

The Canada, Australia and the UK have invested important resources and time to 

produce guidelines, based on evidence and consensus sessions among experts: 

• The Canadian Blood Services and the National Advisory Committee on 

Blood and Blood Products began in 2004 to develop detailed and evidence 

based guidelines for the use of IVIG in hematological and neurological 

conditions. The results of this work are published in a supplement of the 

journal Transfusion Medicine Reviews in 2007. 18-21 

• In Australia, the “Criteria for the Clinical Use of Intravenous 

Immunoglobulin” was developed in 2004-2007, based on evidence 

identified through systematic reviews of the literature and the opinions of 

clinical experts. The clinical criteria are contained within condition proforma 

and have been set out to cover four major issues: list of indications 

for IG use; qualifying criteria, exclusion criteria and review criteria. 22 

• In the UK, as part of the “Demand Management Programme”, National 

Clinical Guidelines for the appropriate use of IVIG have been produced 

based on available evidence and expert opinion in the period 2006-2008. 

After literature review and expert review, interested bodies registered as 

“Stakeholders” provided comments on the document. Regular updates 

are ensured, at least yearly. 

• In France, the CEDIT has issued recommendations that are widely used. 

National guidelines are also expected at national level, based on the 

CEDIT work. l 

• In Australia, the concept of ‘criteria for use’ constitutes a more directive 

framework for decisions about the use of a particular treatment, as 

opposed to the concept of “guidelines” that usually refer to the 

management of conditions rather than to the use of specific therapeutic 

products such as IVIG. 22 The latter term has been selected to describe the 

circumstances, based on evidence and clinical experience, under which the 

clinical use of IVIG is considered appropriate in Australia. 

It should be noted that in each country, the production of guidelines has cost a 

considerable amount of time (around 3 years), in literature review and negotiations with 

experts and stakeholders. Guidelines also need to be regularly updated. 

Only one study assessed the impact of guidelines on IG use. In the Atlantic region of 

Canada, a study compared IVIG use between a baseline phase (2003-2004) before 

guideline use, and after implementation of “optimization tools” (2005). In the second 

period, they found a 7% decrease in IG use, contrasting with the previous annual rises 

(7% in 2002-03 to 2003-04 and 10% from 2003-04 to 2004-05). 146 

Limiting prescription of IG to specific groups 

In the UK under the “Commissioning Policy”, all immunoglobulin must be prescribed by 

a consultant with specialist knowledge of its use; no GP may prescribe. Prescribers must 

monitor future communications on any risks to supply and understand the mechanism 

for handling any shortages.


Improving awareness of clinicians and patients 

Two countries mention the information to clinicians in their plan: France planned to 

implement information to pharmacists and prescribe. m In the UK, the demand 

management programme states that patients should be fully informed of arrangements 

for their treatment and the implications of any supply shortages. 

Improving evaluation of use and monitoring 

Several countries have initiated a registry for patients under IG treatment or a national 

database. However, no further information is available on the application of these 

systems and its impact. 

• In the UK, the “Commissioning Policy” stated that all patients should be 

logged with the national immunoglobulin database and their data provided. 

All patients receiving long-term immunoglobulin should be reviewed 

annually to assess disease activity and determine the best therapeutic 

option. 

• In Australia, The national Blood Agency has also included in its plans the 

development of a system to collect data that will provide information 

about the effectiveness of IVIG therapy. 22 This information was planned to 

be assessed by experts and used to inform future reviews of this “criteria 

for use”. However, we have no information on whether this strategy has 

been effectively implemented. 

• In some Canadian regions, such as the Atlantic Provinces, a working group 

was created to monitor IVIG use and a registry of IVIG was created. 

Assessment of indication appropriateness is determined based on 

guidelines, and feedback reports are distributed to stakeholders. 

• France launched a data collection on IVIG consumption per indication, to 

evaluate the appropriateness of IVIG use in clinical practice. 

Other lessons learned 

In the US, a shortage in IVIG occurred in 1997. 198 The authorities informed the medical 

community but did not respond to the shortage in a timely of effective manner. Instead, 

it took a passive role, leaving IVIG manufacturers and distributors, health care 

institutions, and clinicians to fend for themselves. Regulatory steps and 

recommendations were made but after prolonged debate. No updated national 

recommendation on appropriate use of IVIG has been issued. Institutions have 

developed their own guidelines to restrict the use of IVIG for off-label conditions. 

Guidelines varied substantially across institutions. Consequently IVIG was distributed at 

often extremely elevated prices and not according to the criteria of need and urgency. 

The shortage likely had an uneven impact on patients, based on the relative market 

strength of the health care institutions in which they received care and the individual 

patient's ability to absorb the increasing out-of-pocket costs of scarce IVIG. 

Overall impact of strategies to reduce IG use 

Several countries are conducting audits in hospitals (eg. the UK and the US) but few 

countries have evaluated the overall impact of their set of strategies on IG 

consumption. 

In France, the last available consumption data from the “Hôpitaux de Paris”, following 

the CEDIT guidelines and prioritization, date from 2005 and show an increase in IVIG 

use (+18%). This increase is however lower than the increase observed at national level 

(+24%). n 

m http://cedit.aphp.fr/servlet/siteCedit?Destination=reco&numArticle=02.02/Re4/07 

n Recommandation 2007 relative à l’utilisation des immunoglobulines humaines normales (intraveineuses 

polyvalentes (IgIV) et sous-cutanées) avec bilan des consommations en 2005 à l’AP-HP, accessed on 

http://cedit.aphp.fr/servlet/siteCedit?Destination=reco&numArticle=02.02/Re4/07


In the UK, preliminary analysis of the national immunoglobulin database (first 9 months) 

has been published but there is no comparison pre and post-intervention. o 

Table 46: Summary of measures proposed to prevent or control IG shortage 

in 6 countries 

Country, Reduce use Improve supply Improve evaluation / 

period 

monitoring of 

use/supply 

France (AFFSAPS Guidelines on IVIG use Not covered Data collection on IG 

and CEDIT, Priority lists for indications 

use per indication group 

1991-2008) (7 categories) 

Information for prescribers 

Canada, 2004-07 Detailed guidelines on IVIG Not covered Evaluation of IG use per 

use 

indication (per region) 

The UK, Detailed guidelines 

Not covered National IG database to 

Commissioning Priority list (red, blue, grey) 

register each patient 

policy 

Funding for IG linked to data 

provision 

Prescription limited to 

specialist (no GP) 

Audit of trusts 

Australia Limit indications and Increasing the manufacture in 

rationalize use: criteria for Australia 

use 

Importing IVIg from overseas 

Priority lists (4 groups) suppliers 

US, 1997 198 None. Improve appropriate Encouraged producers to Monthly data from 

use at local level. 

increase supplies 

producers, but not 

effective 

4.3.1.2 Experiences from Belgium 

In Belgium, the Health Council (CSS/HGR) has developed guidelines for the use of red 

blood cells in January 2007, p and for the use of frozen plasma in 2007. q After the 

guidelines were issued, the consumption of both products decreased. Guidelines on the 

use of immunoglobulins are currently being developed at the Health Council and should 

be available in the near future. 

In the late nineties, the BIOMED project used the technique of “benchmarking” 

(restitution of data documenting individual performance and comparison of these data 

with the group average or with external references) to impact on the red cell 

transfusion. After the thorough restitution of data and without the introduction of new 

regulations or guidelines, time was given to the participants to improve their practices, 

by using the strategies they deemed most appropriate for their local situation. Data 

collected 2.5 years later showed that the use of blood and blood products decreased 

markedly: a reduction of the order of 20%-25% was achieved over a 2 to 3 year period. 

The reduction of red cell transfusion has been obtained without any change in 

hematocrits at any time during hospital stay for any surgical procedure. 199 

o National Immunoglobulin Database Update. April 2009. 

http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_097668.pdf 

p CSS/HGR. AVIS DU CONSEIL SUPERIEUR D’HYGIENE. Guide d’indications transfusionnelles pour les 

globules rouges. 10 janvier 2007 CSH n° 8085. 

https://portal.health.fgov.be/pls/portal/docs/PAGE/INTERNET_PG/HOMEPAGE_MENU/ABOUTUS1_MENU/INSTITU 

TIONSAPPARENTEES1_MENU/HOGEGEZONDHEIDSRAAD1_MENU/ADVIEZENENAANBEVELINGEN1_MENU/A 

DVIEZENENAANBEVELINGEN1_DOCS/CSH8085_INDICATIONS_TRANSFUSIONNELLES_GLOBULES_ROUGES 

_FR.PDF 

q AVIS DU CONSEIL SUPERIEUR D’HYGIENE. Guide d’indications transfusionnelles pour le plasma frais 

congelé. 7 février 2007. CSH n° 8157


4.3.2 Strategies to decrease IG use: what could be applied in Belgium 

Overall, the following measures could be considered for implementation in Belgium: 

• Defining a list of indications for IG use, based on available evidence and 

expert panels. A list of reimbursed indications is already defined and 

regularly updated in Belgium, but several indications which have shown a 

benefit based on evidence are not included (see Chapter II). It is unclear 

how these diseases are currently treated in Belgium, and it is possible that 

significant amounts of IG are given under compassionate use. 

• Classifying these indications in priority groups for IG treatment (high 

priority, low priority). However, establishing these priorities must be 

based on evidence and requires consensus and regular update. The 

application of these classifications in practice (how to treat these patients) 

is not always clear. In some countries, patients from the low priority 

group may be treated with IG unless there is a IG shortage. 

• Establishing guidelines and criteria for use. In countries where guidelines 

have been developed as a response to IG shortage, this has requested 

important resources in terms of persons, time required (2-3 years) and 

expert panels and consensus. In Belgium, the Health Council is in the 

process of developing guidelines that should be issued at end of 2009. The 

Belgian experience with similar guidelines (for the use of red cell 

transfusion and fresh frozen plasma) has shown positive results in terms 

of practice and reduction of consumption. It should be noted that 

guidelines also need to be regularly updated. 

• Limiting prescription of IG to specific groups of prescribers. In Belgium, a 

high IG amount is prescribed by assistants in specialization (in academic 

hospitals) and a IG amounts are sometimes prescribed by peripheral 

hospitals for specialties that should in principle not use significant 

amounts. An option would be to limit the initiation and supervision of IG 

treatment to a number of “IG reference centres”, following the same 

model than the centres for haemophilia centres or for bone marrow 

transplants, through convention with the INAMI/RIZIV. 

• Improving awareness of clinicians and patients. In Belgium, clinicians have 

access to evidence based literature, but receive no direct information on 

the cost of IG and the risk of shortage; good information on these aspects 

could help decrease the prescription of IG for the indications in which no 

benefit has been proven. 

• Improving evaluation of use and monitoring. A registry for patients under 

long term IG treatment or a national data basis could be a tool to allow a 

better monitoring of IG use and assess indication appropriateness based 

on guidelines. This data collection could also be used for a 

“benchmarking” method, which has been successfully used for red cell 

transfusion in Belgium in the late nineties (see above). 

4.3.3 Increasing the capacities of collecting plasma 

A major part of the cost of collecting plasma doubtless stems from the difficulty in 

finding donors and the efforts made to seek out and persuade them. It seems selfevident 

that a greater number of donors would allow economies of scale in the 

collection of plasma and might result in collecting more than is required to cover the 

needs of Belgium as defined by the concept of self-sufficiency in the Royal Decree of 18 

June 1998. The Red Cross could then export at a market price higher than the price it 

sells to the CAF-DCF. The subsidies could then be reduced accordingly.


To attract a larger number of donors it would not be allowed to resort to paying for 

the blood or plasma collected. The principle of voluntary donation free of charge 

constitutes the essential ethical framework for all European countries. But the likes of 

advertising campaigns, benefits in kind and tax breaks could be considered and set up at 

a cost probably lower than that of the subsidies given to the Red Cross to arrive at the 

same result. 

In most European countries (see part 1 of this report), in particular France and 

Germany, it clearly emerges that a major effort has been made in recent years aimed at 

the priority age groups, namely 18-25 years, usually involving a close partnership with 

the schools and universities concerned. More generally, communication campaigns using 

a wide variety of media have been implemented, paying special attention to managing 

the donors over time in order to improve their loyalty. 

Germany has given special thought to the geographical location of plasma collection 

centres in relation to the profile of potential donors, in particular in terms of age. 

It is nevertheless necessary to reflect on the different treatment currently given to 

private sector and public sector employees. The quest for equal treatment of all 

donors could lead the authority to reduce the benefits, in terms of days of leave, 

granted to members of the public services and make donating blood and plasma totally 

charitable. This would open up the possibility of reconverting the resulting savings into 

campaigns promoting blood and plasma donation. 

Finally, a wide-raging debate in terms of demographic prospects has taken place in 

Germany in order to emphasise the importance of this dimension for the future 

satisfaction of the needs of the population. This debate will make possible better 

forecasting of the donor population. 

4.3.4 Transparency and better control of the supply of derivatives 

As we have already seen, it seems that the quantities of derivatives sold in Belgium by 

the CAF-DCF are below what the firm should be able to produce if she were using all 

the quantity of plasma sold to it by the Red Cross. There are various possible 

explanations for this situation, but the information available does not enable us to 

identify the correct ones, largely because of the complexity of the market and of the 

fractionation circuit implemented via agreements with foreign firms, the terms of which 

are not known to us. 

Given the indirect subsidy granted to the CAF-DCF via the below-market price at 

which plasma is sold to it, it would make sense to have public control over the terms 

and costs of its agreements with foreign partners. 

Relations between the organisations responsible for collection and fractionation are a 

delicate and complex subject in all western countries. 

France and Germany first sought to ensure standardisation of the technical collection 

process (in particular the volume of individual donations) in order to improve the 

volumes effectively delivered to the fractionation firms, with the same number of 

donors. 

Of all the countries studied, it is without doubt in Australia where the debate on 

contractual relations between the fractionator and the other actors involved has gone 

furthest. The contract binding the National Blood Authority and the fractionator (CSL- 

Ltd) covers all aspects of the relationship between the two partners, including the 

financial, logistical, technical (health security, risk management) and legal dimensions 

(ownership clause, appeal jurisdictions, etc.). This contractual relationship also takes 

into account that the National Blood Authority is responsible for all functions touching 

on the question of the supply and distribution of blood and plasma products within the 

country.


4.4 CONCLUSIONS 

The issue of the independence of supplies of plasma derivatives is fundamentally a 

political one, and the public authorities must define the degree of independence they 

wish to achieve and, as a corollary, the degree of insecurity that they are willing to 

accept. The substance of these choices would then determine the measures to be 

taken within the three fields of action identified in this report: plasma collection, the 

production of plasma derivatives and the consumption of these derivatives. Each of 

these fields concerns different actors that require specific instruments in order to move 

towards the collection of more plasma, more profitable transformation of plasma into 

derivatives, and consumption of derivatives more in step with recognised medical 

conditions. Maintaining or increasing our independence therefore requires the 

application of a combination of measures in these three fields. However, independently 

of any quest for a specific degree of independence, it would appear that consumption 

that satisfies the rules of good practice, collection at minimum cost and satisfactory 

yields from the fractionation process are basic requirements. The scale of each possible 

measure must be linked to established facts, in which respect it is important to take into 

account the limitations of any scientific study. In this case they concern international 

prices and certain data relating to the consumption of derivative products. For each of 

these limitations, further studies would make the results more robust, not forgetting 

the confidential nature of certain data, which will always be subject to some uncertainty. 

Nevertheless, it is not necessary to wait for certainty regarding every parameter before 

taking the necessary measures.


5 APPENDICES 

APPENDIX 1: ETHICAL DIMENSION OF 

DONATION: QUICK OVERVIEW 

REASONS FOR DONATING BLOOD AND PLASMA: EMPIRIC 

ANALYSIS 

A specific “motivation model” ie a motivation ethical framework has been identified and 

recently set out by Godin in one of his most recent articles [Godin et al “Factors 

explaining the intention to give blood among the general population Vox Sanguinis 

(2005) 89, 140-149 et al. 2005] 200 . In this Canadian study (Québec), all these factors 

where analyzed both in the “never donors” group (ie individuals who never donated) 

and in the “ever donors” group (individuals who donated, at least one). 

External variables (individual and collective alike) are apt to have an impact on 3 types of 

ethical factors: 

• Attitudes (cognitive attitudes, but also emotional attitudes) 

• Accepted norms: perceived behaviour control, moral norms as accepted 

in a specific country (at a specific time of history), and past experience of 

donation. 

• Controls (self-initiated controls or society-initiated controls) 

The three ethical factors mentioned above determine the “intention to donate”, which 

turns into actual behaviour (ie actual donation) provided resources are available to 

perform it. 

In both groups - “Ever donors” and “Never donors” – morals norms and perceived 

controls appeared as the most important factors. 

PRINCIPLES UNDERPINNING BLOOD DONATION 

Utilitarianism: doing what is good / decisions are made owing to the consequences of a 

specific behaviour. From a purely practical point of view, cost/effectiveness (both on the 

individual and social level) reasoning is the key principle underpinning decision-making 

processes. Therefore people should donate, regardless of their motives. Blood donation 

must be organized in such a way that maximizes rentability of donation (incentives, 

attractive and comfortable framework, etc…). 

Duty-Ethics: doing what must be done and motivated by fair intention. Donation is 

send and considered from the point of view of realization of each individual’s freedom. 

However, each individual’s behaviour “duty-ethical” behaviour is supposed to be 

considered and acknowledged as a general rule. 

Contract-Ethics: donation can be seen as a part of the whole social contract. The latter 

can be seen as a cluster of common rules defined for the same common benefit 

(solidarity). 

Virtue-Ethics: who can be considered as an “virtuous individual”. The whole concept 

of “virtue” is applied to the whole individual and not to specific behaviour or punctual 

act. Donation is the expression of mutual dependence between people. 

In short, and from an “ethical values” point of view, people must donate blood because: 

• It is useful 

• It is a duty 

• It is the expression of solidarity 

• It is a proof of virtue


FAVOURING AND HINDERING FACTORS 

Given the background mentioned above, favouring and hindering factors have obviously 

been identified in the very specific field of blood and plasma donation. 

Favouring factors: 

Hindering factors 

• Altruism 

• Role-identity 

• Social rules 

• Facilitating framework (logistics issues) as identified by Godin et al 2005, 

especially short distance between the potential donor’s home and the 

blood donation centre 

• Positive effects of the donation for the donor 

Perceived negative effect of donation and fears among potential donors about donation 

(fear of needles, fear of fainting experience, etc..) 

Logistic problems: long distance between the donor’s home and the donation centre, 

but also lack of intimacy. 

“Free-rider” behaviour, applied to donation as explained by David B. Johnson in the 

British Journal of Psychology 1982 201 , ie individual’s reluctance to donate because the 

individual contribution would have no effect no perceptible effect on the overall 

provision of blood and that the individual himself cannot be excluded from enjoying the 

benefits of the system (if case of need). 

Main learnings: people’s reluctance to donate is mainly explained by perceived 

psychological, physical or practical barriers and obstacles regarding donation (even the 

latter have little to do with reality). Therefore donation promotional strategies should 

be adapted accordingly and focus on elimination of these barriers. Strategies should 

obviously be adapted to each population group (donors and non donors). 

Profile of donors’ population 

Considering Austrian compensation policy, the profile of whole blood donors and the 

one of plasma donors (as identified by the research team) remains quite different. 

Plasma donors are in average: 

• younger (18-35 important age group) 

• more educated (students) 

• less apt to live in stable couples (single) 

• less involved in professional life (students, jobless), than whole blood 

donors.


Remuneration of donation / Empiric findings for Austria 

One must bear in mind that financial compensation is an extremely ambivalent and 

controversial issue, as it may be either a hindering or a factor, depending on the existing 

cultural and institutional framework of the country where donation is performed. 

As identified by the Austrian research team of the University of Vienna a change in 

remuneration policy would have a major impact on donors’ behaviour, ie: 

• should remuneration for whole blood donation be introduced, 84.3% of 

whole blood donors would stop donating whole blood 

• conversely, should remuneration for plasma donation be stopped 56.2% of 

plasma donors would stop donating plasma 

Likewise, it was clearly mentioned that donor’s motives for donation remain very 

different, especially towards the concept of altruism vs remuneration: For whole blood 

donors, altruism as such is an important motive for 88.2% for donation, whereas only 

50% of plasma donors feel concerned with this kind of motives. In the same time 52.1% 

of plasma donors clearly mention remuneration as one of the fix elements of their 

monthly incomes. 

APPENDIX 2 : SEARCH TERMS 

The following databases were searched, by using the following search terms: 

• Cochrane review database, with the search term “immunoglobulin$” 

• In the Centre for Reviews and Dissemination database (CRD) 

(http://www.crd.york.ac.uk/crdweb/), the database of abstracts of reviews 

of effects (DARE), with the search term “immunoglobulin$” 

• Medline and Embase with the following search terms (or their equivalent): 

("Immunoglobulins, Intravenous"[Mesh] AND "Randomized Controlled 

Trial "[Publication Type] AND (disease considered)” 

In addition, cost-effectiveness studies were retrieved by searching Medline and Embase 

by using the following search terms (or equivalent): "Cost-Benefit Analysis"[Mesh] AND 

"Immunoglobulins, Intravenous"[Mesh]


APPENDIX 3: GRADE CRITERIA FOR ASSIGNING 

GRADE OF EVIDENCE 

From “Grading quality of evidence and strength of recommendations”, GRADE 

Working Group, BMJ. 2004;328(7454):1490. 23 

CRITERIA FOR ASSIGNING GRADE OF EVIDENCE 

Type of evidence 

Decrease grade if: 

Increase grade if: 

Judgments about quality of evidence should be guided by a systematic review of available 

evidence. Reviewers should consider four key elements: study design, study quality, 

consistency, and directness (see below). Study design refers to the basic study design, 

which we have broadly categorized as observational studies and randomized trials. Study 

quality refers to the detailed study methods and execution. Consistency refers to the 

similarity of estimates of effect across studies. Directness refers to the extent to which 

the people, interventions, and outcome measures are similar to those of interest. 

Another type of indirect evidence arises when there are no direct comparisons of 

interventions and investigators must make comparisons across studies. 

Randomised trial = high 

Observational study = low 

Any other evidence = very low 

• Serious ( − 1) or very serious ( − 2) limitation to study quality 

• Important inconsistency ( − 1) 

• Some ( − 1) or major ( − 2) uncertainty about directness 

• Imprecise or sparse data ( − 1) 

• High probability of reporting bias ( − 1) 

• Strong evidence of association—significant relative risk of > 2 ( < 0.5) 

based on consistent evidence from two or more observational studies, 

with no plausible confounders (+1) 

• Very strong evidence of association—significant relative risk of > 5 ( < 

0.2) based on direct evidence with no major threats to validity (+2) 

• Evidence of a dose response gradient (+1) 

• All plausible confounders would have reduced the effect (+1)


APPENDIX 4: IMMUNO-HAEMATOLOGICAL 

SURVEY 

Use of immunoglobulins in the treatment of immune deficiencies 

and other diseases 

This information is asked by the KCE to project the future needs in immunoglobulins (IG) 

in Belgium. This work has been requested by INAMI/RIZIV to prevent future IG 

shortages. 

Your data will not be distributed to any other institution, and will not be used to assess 

appropriateness of IG use in Belgian centers. 

If you have any question about this survey or the project, you can contact: 

Dr Germaine Hanquet, KCE, 02/287.33.37, germaine.hanquet@kce.fgov.be 

Or Dr Michel Huybrechts, KCE, 02/287.33.42, michel.huybrechts@kce.fgov.be 

Thank you for your assistance! 

Name of the physician:…………………………………………………………………. 

Name of the Centre / Hospital:………………………………………………………… 

In the first column (total patients followed), please include all patients that were seen in 

your centre in 2008, regardless of treatment. 

1. For Primary Immune Deficiencies (PID) treated in your centre in 2008 

If this information is not available for 2008, please provide data from other periods and 

specify. 

Treatment with intravenous immunoglobulins 

Indications Total number patients Number of IG 

Average dose per 

followed in your perfusions 

perfusion in g/kg 

centre 

administered in 2008 (or usual dose) 

PID in adults 

PID in children 

Comments:………………………………………………………………………………. 

Treatment with subcutaneous immunoglobulins 

Indications Total number patients Number of IG 


followed in your perfusions prescribed perfusion in g/kg 

centre 

in 2008 

(or usual dose) 

PID in adults 

PID in children 

Comments:……………………………………………………………………………….


For other immune deficiencies treated in your centre in 2008 with intravenous IG 

Indications Total number 

patients followed 

Myeloma 

Chronic lymphocytic 

leukemia 

Prevention of infections in 

transplant 

Other immune deficiencies 

that required IG (please 

specify) 

Number IVIG 

treatments given 

in 2008 


treatment in g/kg 

(or usual dose) 

Comments:………………………………………………………………………………….. 

4. For other indications treated in your centre in 2008 with intravenous IG 

Indications Number IVIG treatments 

given in 2008 


purpura in children 


purpura in adults 

Guillain Barré syndrome 

Kawasaki syndrome 

Toxic shock syndrome 

Infections in neonates 

Others:……………… 

General comments: 

Do you wish to receive the KCE report once published? 

(it will also available be available on our website www.kce.fgov.be) 

Thank you for your time! 

Average dose per treatment 

in g/kg (or usual dose)


APPENDIX 5: POTENTIAL CHANGES IN DEMAND 

VOLUME: FOCUS ON TWO EMERGING 

COUNTRIES 

FOCUS ON THE BRAZILIAN MARKET 

Brazil’s demand of plasma-derived products 

In the early nineties, Brazilian plasma fractionation market was considered as a relatively 

minor one. However, due to the increasing demand of the population and the evolution 

of prescription habits, Brazil’s demand for plasma products surged dramatically between 

1992 and 2007, and more precisely over the last three years. 

Figure 14: Value of the Brazilian Fractionation Market - without 

recombinant - 1992-2007 (Mil.US $) 

Mil. US $ 

250 

200 

150 

100 

50 

Value of the Brazilian 

Fractionation Market ‐ 

without recombinant ‐ 

1992‐2007 (Mil.US $) 


0 

1992 1995 1998 2001 2004 2007 

46,9 80,4 164,2 112,5 129,5 227,6 

On this market, and despite the surge of the population’s needs and demand, no 

domestic company has emerged yet and Brazilian companies are virtually absent: in 

2007, sixteen foreign companies (profit and non profit) fractioned and sold almost 100% 

of plasma products, and four of them hold key positions (Baxter, Octapharma, CSL- 

Behring, BPL) as described below : 

Table 47: Key market Leaders in 2007 

Brazilian Plasma Fractionation Market / Key Market leaders in 2007 

(Percentage in total sales) 

Baxter Octapharma CSL-Behring BPL Other companies 

25% 23% 15% 10% 27% 

As far as IVIG is concerned, Octapharma is clearly the market leader (market share of 

42%). 

Structure of this market is mainly centred on IVIG and Factor VIII (incl. recombinant), as 

described below:


Table 48: Structure of the Brazilian market in 2007 

IVIG Factor VIII Albumin Other 

31% 20% 19% 30% 

Focus : Intravenous Immune Globulin Market (IVIG) market 

Within this market, IVIG demand has raised dramatically since 2001, as described 

below. 

The slower increase of demand between 2004 and 2007 (+21%) is mainly due to a 

political problem (see below). This very last figure of the table should not be 

representative of further development of the Brazilian market. 

Figure 15: Brazilian IVIG Market (Toushands of units) 1998-2007 

Units (1 unit=2.5g) 


Further foreseeable developments on the Brazilian market 

INSTITUTIONAL CONTEXT 

450 

400 

350 

300 

250 

200 

150 

100 

50 

0 

Brazilian IVIG Market 

(Toushands of units) 

1998‐2007 

1998 2001 2004 2007 

141 213 337 408 

Given Brazil’s absence of self-sufficiency, the Brazilian Federal Government, but also 

several federate states (eg State of Rio-de-Janeiro, State of Sao Paolo, etc..) launched 

international public tenders, in order to fulfil the population’s needs. Between 2003 and 

today some problems occurred in the supply of plasma products, mainly because of the 

2003 scandal also known as the “vampire scandal” that brought corruption and illegal 

arrangements to light, especially between the key stakeholders of the plasma market 

mentioned above. Following this scandal fractionation contract that expired in 2004 was 

renewed in 2007 only. This interruption in plasma products supply slowed down the 

evolution of Brazilian demand, but this was, by definition, a punctual phenomenon. 

Brazilian willing to reach some self-sufficiency is quite clear as it concluded an 

agreement with LFB to set up a fractionation plant in Brazil: a close and official 

partnership has been established between LFB and Brazilian state-controlled structure 

“Hemobras” to implement this project and rationalize the whole collection and supply 

chain. 

As a practical matter, the objective of this project is to set up a fractionation plant in 

northern Brazil, with a view to producing plasma-derived products, made from Brazilian 

plasma, in order to bring additional volumes of plasma products and thus improve 

Brazil’s situation in terms of self-sufficiency. 

However, this project will require some time, and self-sufficiency remains a very long 

term objective, and the level of import of plasma-derived products is likely to remain 

high over the next years.


ECONOMIC CONTEXT 

The sharp increase in the demand of such products as IVIG demand illustrates the 

evolution of prescription habits, but also the recent ability of Brazilian citizens to 

purchase these products, thanks to the improvement of the Brazilian economic 

situation. Should this economic trend remain stable over the next years, this evolution 

is likely to remain comparable for the next years. 

CLINICAL PRACTICES 

In comparison to the situation of west European countries and North America, 

consumption of IVIG per capita remains low: 5.7 g per thousand people. Should 

Brazilian practices conform progressively to the western standards, this consumption 

would obviously evolve accordingly and thus have a noticeable impact on Brazilian 

demand. 

FOCUS ON THE CHINESE MARKET 

Recent restructuring of the Chinese plasma fractionation industry has led to a reduction 

of domestic production of plasma products, from 4.5 to 3 million liters in 2006. This cut 

down in Chinese production capacity has led to imports of Albumin and recombinant 

factor VIII. Import of other plasma-derived products remains banned, due to the specific 

Chinese regulation framework. 

Clinical practices and coverage of medical expenditure are the main hindering factors 

for further development of the plasma market: 

• Such pathologies as haemophilia remain under-diagnosed (1000 patients 

officially diagnosed ; theoretical number of patients around 100 000) 

• Access to modern treatments (especially plasma products) remains 

difficult for the vas majority of the population for two reasons because of 

the absence or the lack of health care coverage and of the ban on import 

of most of plasma products. Therefore, many physicians still resort to 

cryoprecipitate, whole blood or even traditional medicine. 

Chinese ban on import of plasma products and its impact on the market remains a 

hindering factor for import of a wide-range of plasma products except for recombinant 

Factor VIII and Albumin. Given the increased awareness of innovative therapy, and 

simultaneously domestic suppliers’ difficulty to meet the Chinese population’s actual 

needs, it is clear that China will continue to import these two factors, at least over the 

very next years. However today’s Chinese legal framework, ie ban on import of IVIG is 

unlikely to change over the very next years.


APPENDIX 6: FRANCE: PLASMA COLLECTION 

WITHIN THE EFS 

KEY FIGURES ON DONATION: TODAY’S SITUATION 

The number of donors has reached 1.5 and the number of donations about 2.5 million 

(ie about 8000 donations daily in average). The blood collected in France has enabled to 

carry out treatment for 500 000 patients yearly. 

From a political point of view, the main strengths of the system are 

• The tradition of donation and republican public-spiritidness. 

• The indisputable visibility of the EFS. 

Conversely, the main limits of the system are 

• The relatively week proportion of donors (around 4% of the overall 

population). 

• The distribution of collection centres, which is largely a heritage of the 

past decades, but not always cost-efficient, considering today’s financial 

constraints. 

PRACTICAL ORGANISATION AND ACTUAL POLICIES: KEY 

POINTS 

The website of the EFS is centralized on the national level, but with regional windows. 

All relevant information is available on the website, and On-line booking is also available 

and user-friendly. Field blood and plasma collection is comparable to other countries’ 

practices, with 175 collection sites, fixed or mobile, distributed across the French 

territory, both in rural and urban areas. 

However, mobile collection remains important compared to fixed collection points: for 

this reasons, the use of human resources and facilities is not optimized in some places. 

Focus on young adults 

Apart from traditional campaigns (comparable to other countries’ campaigns) one of the 

key targets of the EFS has been to focus communication on the most relevant age 

groups, ie young people and young adults, who are apt to become future donors, and 

repeat donors. 

Given the crucial importance of this age group (18-26), a national competition was 

launched in 2008-2009. The main originality of this competition was to get this age 

group involved into the designing and the field organization of campaigns. After 

completion of these campaigns, the EFS has organized an in-depth evaluation of these 

campaigns, and rewarded the best campaigns. Three different awards have been defined 

and awarded accordingly, based on the following subjects: 

• Creativity award: the objective is to identify the most innovative 

campaign to raise students’ awareness of donation. 

• Interactivity award: the objective is to identify the campaign that 

resorted to widest range of media simultaneously (especially multimedia 

tools). 

• Pedagogy Award: the objective is to identify the most didactic 

campaign, and simultaneously the most faithful to the EFS values: voluntary 

and unpaid dimensions of donation, quality and best practices, non-profit 

dimension of EFS, etc.. 

This first step campaign is now complete. A last mailing of documents will be launched 

between November 2009 and April 2010, in close cooperation with the French 

University canteens.


As far as private firms are concerned EFS documents (thematic documents, general 

information on donation and blood products, and one specific poster “More than 

colleagues …Blood Donors”..) can be downloaded free of charge from the EFS website. 

However, the EFS recently laid emphasis on SMEs (ie firms employing lesser than 500 

employees): a specific mailing campaign has been launched, which addressed 50 000 

SMEs nationwide. The EFS obtained a positive answer from 500 SMEs (ie 1% of the 

target). These SMEs’ data and contact details have been entered onto the databases of 

the different branches of the EFS in order to organize close contacts and field 

cooperation in line with local priorities: Newsletter, routine information, etc… 

Larger firms (above 500 employees) should be the next target of the communication 

campaign over the next months. 

However, these efforts focus on blood donation in general and not on plasma donation 

specifically. 

Information delivered to the donor 

As in other EU countries, the EFS website provides with key information on governance 

and values of the EFS. It also provides technical information on the organization of 

blood / plasma donation in practice: On-line booking; Fixed collection centres and 

mobile collection. 

Clinical information is also available about blood groups, donation types, and the key 

steps of blood processing. 

French population’s awareness of plasma donation 

However, all information delivered to the donor remain very general and addresses 

whole blood and plasma donors alike. Plasmapheresis technique is mentioned on the 

website. However no specific emphasis is laid on that subject and no further 

information is provided on the technical and clinical dimensions of this technique. 

This situation should draw stakeholders’ attention, as only 60% of French people know 

that plasma can be donated: as demonstrated by a recent survey of Cerphi Association 

(Etude Cerphi – Troisième Edition – Donner son sang en France – Cécile Bazin & 

Jacques Malet – Mai 2006), 202 awareness of plasma donation and plasma donation 

techniques remains poor in France compared to other kinds of donations (whole blood 

but also platelets).


APPENDIX 7: GERMANY: PLASMA COLLECTION 

WITHIN THE GERMAN RED CROSS AND BY 

OTHER STAKEHOLDERS 

PLASMA COLLECTION WITHIN THE FRAMEWORK OF THE 

GERMAN RED CROSS (DRK) 

Selection, Follow-up and retention of donors 

Age-group targets 

In terms of target population people below 30 (and among them students and jobless 

people) are clearly the most important people to focus on for plasma donation, (see : 

Survey of Robert Koch Institute). The DRK has the contact details of all teachers 

working in relevant areas (ie sciences, biology) at its disposal. Hence, it has the 

possibility to contact them very easily. Specific material dedicated to high school pupils 

are: 

• High School magazine: “We are heroes” focusing on key scientific 

information and on the civic dimension of blood donation. 

• Experiment material: 6 different biology experiment packages on blood, 

blood functions, blood groups, etc...to be performed by pupils themselves 

in their classroom. 

• 12 scientific leaflets on: immune system, clotting process, blood groups, 

etc.. 

• Illustrated charts and posters on the main blood-related subjects. 

Practical follow-up of donors by the DRK 

Once a donor is identified and selected, his/her data are entered onto the DRK 

database, and he/she is subject to: 

• a precise personal data management (online updating system available) 

• a specific and very regular administrative follow-up: regular chasing of the 

donors is performed by E-mail, Mailings, regular phone recruiting. 

Focus: key messages of the advertising and communication campaign 

• No involvement of celebrities in the campaign: “No show-off models” is 

the first statement put forward on the website of the DRK. DRK’s 

campaign focused on ordinary people, real life situations, and real world 

objects. 

• Everyday life products and situations: the key messages first focus on the 

concept of shortage of renewable products and the trouble caused by this 

shortage, eg: the end of a toothpaste tube, the last match of the 

matchbox, the last drops of ink from a cartridge. 

Contrast between consumer products and blood (and blood products): For each of the 

concerned products, the message clearly refers to the possibility of buying the product 

easily and quickly (eg: “You will find ink cartridges in shops. But not blood”. Donate 

Blood / See below). By contrast with these products, specific nature of blood is clearly 

underlined, and thus the irreplaceable nature of blood donation.


Figure 16 :“Ink cartridge” Posters 

Source: German Red Cross Website 

• Connection between nature of blood and irreplaceable nature of blood 

donation 

Tone of the campaign: direct commands. One must underline that “Spende Blut” means 

“Give Blood” with informal “you”. 

Targeting the donors’ social life: important to stress is the ability of to stick to the 

specific traits of German social and cultural life. The DRK deliberately targeted students 

in its campaign and selected a “Stammtisch Picture” on one of its posters, to attract 

potential student donors. Note: The Stammtisch is an old tradition in German 

universities: debates on a wide range of subjects (literary, philosophical, or political). 

The slogan is “You will find philosophers everywhere. Not Blood. Donate Blood!” 

Figure 17: “Stammtisch” Poster 

Source: German Red Cross Website 

COLLECTION BY OTHER STAKEHOLDERS 

Whole Blood collection in Germany 

Table 49: Whole blood collection in Germany 

Institutions Contribution / Total 

amount of whole 

blood donation 

University Hospital – 

15-20% 

based Centres 

Red Cross 75-80% 

Private Centres Ca 5% (increasing)


Distribution of plasma collection in Germany: key role of the private sector 

Public/Private sector: plasma repeat donors (2006 figures) 

The overall number of plasma repeat donors was 128 000 in 2006 in Germany. Among 

them, 105 000 (ca 80%) stem from Private Industry driven and Private specialized 

centres. 

Figure 18: Plasma Collection in Germany / Repeat Donors 

Source: Robert Koch Institute 

Age Profile of plasma repeat donors 

Figure 19: Private Industry Centres / Repeat Donors - 2006 

20000 

15000 

10000 

5000 

0 

Municip‐ 

Centres 

8% 

Red Cross 

11% 


Priv‐Spec‐ 

Centres 

42% 

Priv‐Ind‐ 

Centres 

40% 

18‐24 25‐34 35‐44 45‐54 55‐68 

Female 

Male


Figure 20: Private Spec. Centres / Repeat Donors 2006 

25000 

20000 

15000 

10000 

5000 

0 


The age relationship described above has been clearly identified for private centres, but 

not for Municipal or Red Cross Centres. For the latter centres, age distribution is quite 

different and age relationship is much fuzzier, as mature people bring a noticeable 

contribution to donation. 

Figure 21: German Red Cross Centres - Nb of Repeat Donors 2006 

4000 

3500 

3000 

2500 

2000 

1500 

1000 

500 

0 


18‐24 25‐34 35‐44 45‐54 55‐68 

18‐24 25‐34 35‐44 45‐54 55‐68 

Female 

Male 

Female 

Male 

Location of the private centres 

Concerning plasmapheresis specifically, the German association of the plasma donation 

centres called Arge-Plasmapherese, founded 1997 (http://www.arge-plasmapherese.de/), 

delivers key information on that subject, especially on location of plasma centres: 

• Location of Red Cross centres and Municipal centres is largely due to 

historical reasons. Red Cross and Municipal Centres are few and their 

distribution across Germany is relatively even.


• Conversely, location of private and industry centres has been selected on 

rentability-oriented criteria over the last years: rather under privileged 

regions: of the 60 private plasmapheresis centres registered in 32 are 

located in the ex- Democratic Republic of Germany, 14 in North 

Rhineland – Westphalia. In other words 75% of these centres are often 

located close to universities. It must be outlined that they are generally 

located in small / medium sized towns both for financial reasons (lower 

start-up costs for the centre itself) and for practical reasons (Faster 

penetration with marketing activities, Possibility to achieve full capacity in 

a shorter period of time). 

Exemple of private plasma donation in Germany: Plasma Europe Service/ Biotest 

Size of the town 

Small towns are clearly privileged, and within each town, busy shopping streets and/or 

places close to university campuses and in any case easy to reach 

Location of Plasma Service Centres: Which regions ? 

All donation centres of this firm are located in the ex-German Democratic Republic or 

in North Rhineland – Westphalia (see Map below/ Source: Plasmaservice Website / 

www.plasmaservice.de) 

Distribution of Plasma Service Europe Centres in Germany / Corporate Data 

Other points on practical fitting out: Non hospital atmosphere, warm colours, 

Optimized distribution of beds across the donation room, Clear separation between 

donation rooms and manufacturing/freezing areas (restricted areas). 

FINANCIAL COMPENSATION 

Even within the same umbrella organization, the level of financial compensation may 

vary across centres. Within the organization we focused on, it ranges from 16 to 20 €. 

Therefore, this compensation is not just a compensation but also part of costs 

management. Specific financial compensation is provided to first donors: 38€ in most 

centres.


TIME MANAGEMENT AND COST STRUCTURE 

Tthe whole donation process (44 min) is divided into 4 steps 

- Step 1: Reception time Step 2: Medical interview 

- Step 3: Donation in donat. room Step 4: Plasma processing and data collection 

Cost Structure: see below 

Table 50: Cost Structure / Plasma Service Europe 

Budget Codes Average Costs 

Administrative Costs 4 € 

Renting and side costs 4.10 € - 5.50 € 

Personal / HR 23 – 28 € 

Advertising 1.70 € 

Maintenance Costs 2.30€ 

Capital Allowances 0.70€ 

Miscellaneous Expenses 2.60€ 

TOTAL 40.40 € – 46.80 € 

FINANCIAL 

COMPENSATION 

16-20 € 

TOTAL COSTS 56.40€ - 66.80€ 

Smooth running of this industry implies a noticeable “investment” in financial 

compensation (28% of the costs) and Human Resources to recruit and retain donors. 

However, financial compensation does not prevent these centres from being financially 

profitable and sustainable. 

Figure 22: Plasma Service Europe: Cost structure for plasma collection 

Miscellaneous 

4% 

Capital 

Allow. 

1% 

Maintenance 

4% 

Advertis. 

2% 

Source : Corporate Data 

Fin.Compensati 

on 

28% 

Admin. 

13% 

Hum‐Res 

40% 

Renting 

8%


APPENDIX 8: AUSTRALIA: INSTITUTIONAL 

ASPECTS 

ROLE OF THE DIFFERENT STAKEHOLDERS IN AUSTRALIA 

National Blood Authority 

Overarching and steering institution in charge of the Australian National blood and 

plasma policy (see core report). 

Australian Red Cross Blood Service (ARCBS) 

CSL Limited 

The ARCBS is responsible for the collection of blood and plasma from donors and the 

distribution of fresh plasma and some imported plasma products, to the health system. 

This firm plays a key role in the supply chain, as it is responsible for fractionating the 

plasma supplied by the ARCBS and providing plasma products back to the ARCBS for 

further distribution. CSL Limited has to assume on many points public law obligations, 

as commissioned by the NBA (even if CSL is not a public law body). 

Other pharmaceutical firms 

More punctually, other firms can be responsible for the supply and distribution of 

specific range of products, whenever these products are not produced in Australia or 

when the Australian domestic capacity is not in the position to meet the patients’ needs. 

Therapeutic Goods Administration (TGA) 

The TGA is an independent body that is responsible for regulating the whole sector in 

the field of efficacy, safety standards, and quality of blood and blood products. It is also 

entrusted with auditing of Good Manufacturing Practice and product recalls (see below / 

Contract between CSL and the NBA). 

Health care professionals and suppliers 

The latter stakeholders also play a role, even informally, in advising the NBA a number 

of formal or informal working groups and fora on technical subjects (eg: Professional 

Community Forum, NBA Fellows Program, and Clinical Advisory Council). 

MANAGEMENT OF SUPPLY: QUICK OVERVIEW 

On a routine basis, the NBA notifies the Australian Red Cross Blood Service annually of 

the volume of plasma to be supplied to CSL for fractionation. Under the terms of the 

Plasma Products Agreement (PPA), the NBA must give CSL the Annual Supply Estimate 

for a particular financial year by no later than the preceding 30 November. Although 

these forecasts are not binding on the NBA, it is required under the terms of the PPA 

to purchase 95% of the plasma products produced in accordance with the Confirmed 

Quarterly Requirements that the NBA furnishes to CSL six months in advance of each 

quarter. The NBA also needs to make sure that suppliers actually maintain reserve 

holdings of products, in order to ensure that timely and adequate supplies are available 

to meet clinical needs.


CRISIS AND RISK MANAGEMENT 

One of the day-to-day, but also strategic objectives of the NBA is to enhance the 

resilience and the responsiveness of the whole sector. The latter aspect is of great 

importance for Australia, as a specific crisis-management framework has been defined 

by the NBA. 

• Likelihood of a supply / demand crisis is identified by the NBA and 

entered onto a specific table [1: rare – 5: almost certain]. 

• Consequence of a crisis is also identified by the NBA and entered onto a 

specific table [1: Minor consequences / Buffer stock – 5: Catastrophe / 

Widespread national outage, Blood stocks below 24h]. 

Thanks to the combination of the two scales mentioned above, a risk matrix has been 

set up to assess the overall risk rate, ie the seriousness of the crisis. Following this risk 

assessment process, a specific framework has been set out to define preparation and 

mitigation of supply or demand crisis. The NBA has defined strategies to minimise the 

impact of such crises based on risk management plans in supply contracts, cooperation 

in supplier contingency planning, product reserves and contingent supply arrangements, 

promotion of best practice of blood and blood products and improvement in inventory 

management and reporting. Should these measures not be sufficient, further measures 

can be considered on the national level (Department of Health). 

KEY SUCCESS FACTORS FOR A RELIABLE SUPPLY POLICY 

• Providing the Australian governments (national and federate level) with 

accurate and timely information for decision-making. 

• Close and day-to-day partnership with suppliers, with a view to addressing 

supply chain gaps. 

• Close partnership with the clinical community to enhance the 

development of EB guidelines, standards, and programs for improving 

patient outcomes.


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Dépôt légal : D/2009/10.273/58

KCE reports 

1. Efficacité et rentabilité des thérapies de sevrage tabagique. D/2004/10.273/2. 

2. Etude relative aux coûts potentiels liés à une éventuelle modification des règles du droit de la 

responsabilité médicale (Phase 1). D/2004/10.273/4. 

3. Utilisation des antibiotiques en milieu hospitalier dans le cas de la pyélonéphrite aiguë. 

D/2004/10.273/6. 

4. Leucoréduction. Une mesure envisageable dans le cadre de la politique nationale de sécurité 

des transfusions sanguines. D/2004/10.273/8. 

5. Evaluation des risques préopératoires. D/2004/10.273/10. 

6. Validation du rapport de la Commission d’examen du sous financement des hôpitaux. 

D/2004/10.273/12. 

7. Recommandation nationale relative aux soins prénatals: Une base pour un itinéraire clinique de 

suivi de grossesses. D/2004/10.273/14. 

8. Systèmes de financement des médicaments hospitaliers: étude descriptive de certains pays 

européens et du Canada. D/2004/10.273/16. 

9. Feedback: évaluation de l'impact et des barrières à l'implémentation – Rapport de recherche: 

partie 1. D/2005/10.273/02. 

10. Le coût des prothèses dentaires. D/2005/10.273/04. 

11. Dépistage du cancer du sein. D/2005/10.273/06. 

12. Etude d’une méthode de financement alternative pour le sang et les dérivés sanguins labiles 

dans les hôpitaux. D/2005/10.273/08. 

13. Traitement endovasculaire de la sténose carotidienne. D/2005/10.273/10. 

14. Variations des pratiques médicales hospitalières en cas d’infarctus aigu du myocarde en 

Belgique. D/2005/10.273/12 

15. Evolution des dépenses de santé. D/2005/10.273/14. 


responsabilité médicale. Phase II : développement d'un modèle actuariel et premières 

estimations. D/2005/10.273/16. 

17. Evaluation des montants de référence. D/2005/10.273/18. 

18. Utilisation des itinéraires cliniques et guides de bonne pratique afin de déterminer de manière 

prospective les honoraires des médecins hospitaliers: plus facile à dire qu'à faire.. 

D/2005/10.273/20 

19. Evaluation de l'impact d'une contribution personnelle forfaitaire sur le recours au service 

d'urgences. D/2005/10.273/22. 

20. HTA Diagnostic Moléculaire en Belgique. D/2005/10.273/24, D/2005/10.273/26. 

21. HTA Matériel de Stomie en Belgique. D/2005/10.273.28. 

22. HTA Tomographie par Emission de Positrons en Belgique. D/2005/10.273/30. 

23. HTA Le traitement électif endovasculaire de l’anévrysme de l’aorte abdominale (AAA). 

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24. L'emploi des peptides natriurétiques dans l'approche diagnostique des patients présentant une 

suspicion de décompensation cardiaque. D/2005/10.273.35 

25. Endoscopie par capsule. D2006/10.273.02. 

26. Aspects médico-légaux des recommandations de bonne pratique médicale. D2006/10.273/06. 

27. Qualité et organisation des soins du diabète de type 2. D2006/10.273/08. 

28. Recommandations provisoires pour les évaluations pharmacoéconomiques en Belgique. 

D2006/10.273/11. 

29. Recommandations nationales Collège d’oncologie : A. cadre général pour un manuel 

d’oncologie B. base scientifique pour itinéraires cliniques de diagnostic et traitement, cancer 

colorectal et cancer du testicule. D2006/10.273/13. 

30. Inventaire des bases de données de soins de santé. D2006/10.273/15. 

31. Health Technology Assessment : l’antigène prostatique spécifique (PSA) dans le dépistage du 

cancer de la prostate. D2006/10.273/18. 

32. Feedback: évaluation de l'impact et des barrières à l'implémentation - Rapport de recherche: 

partie II. D2006/10.273/20. 

33. Effets et coûts de la vaccination des enfants Belges au moyen du vaccin conjugué 

antipneumococcique. D2006/10.273/22. 

34. Trastuzumab pour les stades précoces du cancer du sein. D2006/10.273/24.


responsabilité médicale – Phase III : affinement des estimations. D2006/10.273/27. 

36. Traitement pharmacologique et chirurgical de l'obésité. Prise en charge résidentielle des 

enfants sévèrement obèses en Belgique. D/2006/10.273/29. 

37. Health Technology Assessment Imagerie par Résonance Magnétique. D/2006/10.273/33. 

38. Dépistage du cancer du col de l’utérus et recherche du Papillomavirus humain (HPV). 

D/2006/10.273/36 

39. Evaluation rapide de technologies émergentes s'appliquant à la colonne vertébrale : 

remplacement de disque intervertébral et vertébro/cyphoplastie par ballonnet. 

D/2006/10.273/39. 

40. Etat fonctionnel du patient: un instrument potentiel pour le remboursement de la 

kinésithérapie en Belgique? D/2006/10.273/41. 

41. Indicateurs de qualité cliniques. D/2006/10.273/44. 

42. Etude des disparités de la chirurgie élective en Belgique. D/2006/10.273/46. 

43. Mise à jour de recommandations de bonne pratique existantes. D/2006/10.273/49. 

44. Procédure d'évaluation des dispositifs médicaux émergeants. D/2006/10.273/51. 

45. HTA Dépistage du Cancer Colorectal : état des lieux scientifique et impact budgétaire pour la 

Belgique. D/2006/10.273/54. 

46. Health Technology Assessment. Polysomnographie et monitoring à domicile des nourrissons 

en prévention de la mort subite. D/2006/10.273/60. 

47. L'utilisation des médicaments dans les maisons de repos et les maisons de repos et de soins 

Belges. D/2006/10.273/62 

48. Lombalgie chronique. D/2006/10.273/64. 

49. Médicaments antiviraux en cas de grippe saisonnière et pandémique. Revue de littérature et 

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50. Contributions personnelles en matière de soins de santé en Belgique. L'impact des suppléments. 

D/2006/10.273/69. 

51. Besoin de soins chroniques des personnes âgées de 18 à 65 ans et atteintes de lésions 

cérébrales acquises. D/2007/10.273/02. 

52. Rapid Assessment: Prévention cardiovasculaire primaire dans la pratique du médecin 

généraliste en Belgique. D/2007/10.273/04. 

53. Financement des soins Infirmiers Hospitaliers. D/2007/10 273/06 

54. Vaccination des nourrissons contre le rotavirus en Belgique. Analyse coût-efficacité 

55. Valeur en termes de données probantes des informations écrites de l’industrie pharmaceutique 

destinées aux médecins généralistes. D/2007/10.273/13 

56. Matériel orthopédique en Belgique: Health Technology Assessment. D/2007/10.273/15. 

57. Organisation et Financement de la Réadaptation Locomotrice et Neurologique en Belgique 

D/2007/10.273/19 

58. Le Défibrillateur Cardiaque Implantable.: un rapport d’évaluation de technologie de santé 

D/2007/10.273/22 

59. Analyse de biologie clinique en médecine général. D/2007/10.273/25 

60. Tests de la fonction pulmonaire chez l'adulte. D/2007/10.273/28 

61. Traitement de plaies par pression négative: une évaluation rapide. D/2007/10.273/31 

62. Radiothérapie Conformationelle avec Modulation d’intensité (IMRT). D/2007/10.273/33. 

63. Support scientifique du Collège d’Oncologie: un guideline pour la prise en charge du cancer du 

sein. D/2007/10.273/36. 

64. Vaccination HPV pour la prévention du cancer du col de l’utérus en Belgique: Health 

Technology Assessment. D/2007/10.273/42. 

65. Organisation et financement du diagnostic génétique en Belgique. D/2007/10.273/45. 

66. Drug Eluting Stents en Belgique: Health Technology Assessment. D/2007/10.273/48. 

67. Hadronthérapie. D/2007/10.273/51. 

68. Indemnisation des dommages résultant de soins de santé - Phase IV : Clé de répartition entre 

le Fonds et les assureurs. D/2007/10.273/53. 

69. Assurance de Qualité pour le cancer du rectum – Phase 1: Recommandation de bonne 

pratique pour la prise en charge du cancer rectal D/2007/10.273/55 

70. Etude comparative des programmes d’accréditation hospitalière en Europe. D/2008/10.273/02 

71. Recommandation de bonne pratique clinique pour cinq tests ophtalmiques. D/2008/10.273/05 

72. L’offre de médecins en Belgique. Situation actuelle et défis. D/2008/10.273/08

73. Financement du programme de soins pour le patient gériatrique dans l’hôpital 

classique : Définition et évaluation du patient gériatrique, fonction de liaison et évaluation d’un 

instrument pour un financement approprié. D/2008/10.273/12 

74. Oxygénothérapie Hyperbare: Rapid Assessment. D/2008/10.273/14. 

75. Guideline pour la prise en charge du cancer oesophagien et gastrique: éléments scientifiques à 

destination du Collège d’Oncologie. D/2008/10.273/17. 

76. Promotion de la qualité de la médecine générale en Belgique: status quo ou quo vadis ? 

D/2008/10.273/19. 

77. Orthodontie chez les enfants et adolescents D/2008/10.273/21 

78. Recommandations pour les évaluations pharmacoéconomiques en Belgique. D/2008/10.273/24. 

79. Remboursement des radioisotopes en Belgique. D/2008/10.273/27. 

80. Évaluation des effets du maximum à facturer sur la consommation et l’accessibilité financière 

des soins de santé. D/2008/10.273/36. 

81. Assurance de qualité pour le cancer rectal – phase 2: développement et test d’un ensemble 

d’indicateurs de qualité. D/2008/10.273/39 

82. Angiographie coronaire par tomodensitométrie 64-détecteurs chez les patients suspects de 

maladie coronarienne. D/2008/10.273/41 

83. Comparaison internationale des règles de remboursement et aspects légaux de la chirurgie 

plastique D/2008/10.273/44 

84. Les séjours psychiatriques de longue durée en lits T. D/2008/10.273/47 

85. Comparaison de deux systèmes de financement des soins de première ligne en Belgique. 

D/2008/10.273/50. 

86. Différenciation de fonctions dans les soins infirmiers :possibilités et limites D/2008/10.273/53 

87. Consommation de kinésithérapie et de médecine physique et de réadaptation en Belgique. 

D/2008/10.273/55 

88. Syndrome de Fatigue Chronique : diagnostic, traitement et organisation des soins. 

D/2008/10.273/59. 

89. Evaluation des certains nouveaux traitements du cancer de la prostate et de l’hypertrophie 

bénigne de la prostate. D/2008/10.273/62 

90. Médecine générale: comment promouvoir l’attraction et la rétention dans la profession ? 

D/2008/10.273/64. 

91. Appareils auditifs en Belgique: health technology assessment. D/2008/10.273/68 

92. Les infections nosocomiales en Belgique : Volet I, Etude Nationale de Prévalence. 

D/2008/10.273/71. 

93. Détection des événements indésirables dans les bases de données administratives. 

D/2008/10.273/74. 

94. Soins maternels intensifs (Maternal Intensive Care) en Belgique. D/2008/10.273/78. 

95. Implantation percutanée des valvules cardiaques dans le cas de maladies valvulaires congénitales 

et dégénératives: A rapid Health Technology Assessment. D/2007/10.273/80. 

96. Construction d’un index médical pour les contrats privés d’assurance maladie. 

D/2008/10.273/83. 

97. Centres de réadaptation ORL/PSY : groupes cibles, preuves scientifiques et organisation des 

soins. D/2009/10.273/85. 

98. Évaluation de programmes de vaccination généraux et ciblés contre l’hépatite A en Belgique. 

D/2008/10.273/89. 

99. Financement de l’hôpital de jour gériatrique. D/2008/10.273/91. 

100. Valeurs seuils pour le rapport coût-efficacité en soins de santé. D/2008/10.273/95. 

101. Enregistrement vidéo des interventions chirurgicales par endoscopie : une évaluation rapide. 

D/2008/10.273/98. 

102. Les infections nosocomiales en Belgique: Volet II: Impact sur la mortalité et sur les coûts. 

D/2009/10.273/100. 

103. Réformes dans l’organisation des soins de santé mentale : étude d’évaluation des ‘projets 

thérapeutiques’ - 1er rapport intermédiaire. D/2009/10.273/05. 

104. Chirurgie assistée par robot: health technology assessment. D/2009/10.273/08 

105. Soutien scientifique au Collège d’Oncologie: recommandations pour la pratique clinique dans la 

prise en charge du cancer du pancréas. D/2009/10.273/11 

106. Imagerie par résonance magnétique : analyse de coûts. D/2009/10.273/15 

107. Indemnisation des dommages résultant de soins de santé. Phase V: impact budgétaire de la 

transposition du système français en Belgique. D/2009/10.273/17

108. Le Tiotropium dans le traitement des BronchoPneumopathies Chroniques Obstructives: 

Health Technology Assessment. D/2009/10.273/19 

109. A propos de la valeur de l’EEG et des potentiels évoqués dans la pratique clinique. 

D/2009/10.273/22 

110. La tomographie par émission de positrons en Belgique: une mise à jour. D/2009/10.273/25 

111. Interventions pharmaceutiques et non pharmaceutiques dans la maladie d’Alzheimer : une 

évaluation rapide. D/2009/10.273/28 

112. Politiques relatives aux maladies orphelines et aux médicaments orphelins. D/2009/10.273/31 

113. Le volume des interventions chirurgicales et son impact sur le résultat : étude de faisabilité 

basée sur des données belges. D/2009/10.273/34. 

114. Valves endobronchiales dans le traitement de l’emphysème pulmonaire avancé: un rapid Health 

Technology Assessment. D/2009/10.273/38 

115. Organisation des soins palliatifs en Belgique. D/2009/10.273/41 

116. Evaluation rapide des implants inter-épineux et des vis pédiculaires pour la stabilisation 

dynamique de la colonne vertébrale lombaire. D/2009/10.273/45 

117. Utilisation des coagulomètres portables chez les patients sous anticoagulants oraux: Health 

technology Assesment. D/2009/10.273/48. 

118. Avantages, désavantages et faisabilité de l’introduction de programmes “P4Q” en Belgique. 

D/2009/10.273/51. 

119. Douleur cervicales atypiques: diagnostic et traitement. D/2009/10.273/55. 

120. Comment assurer l’autosuffisance de la Belgique en dérivés stables du plasma? 

D/2009/10.273/58.

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