Plasma protein product safety and Creutzfeldt-Jakob disease (CJD)

Introduction
A recent publication in the Emerging Infectious Diseases journal (published online on June 12, 2017) describes two individuals with bleeding disorders who were diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD) (1). The authors of this scientific report have not established a causal link between the treatment with clotting factors and the development of sporadic CJD and concluded that “the occurrence of these cases may simply reflect a chance event in the context of systematic surveillance for CJD in large populations”.

No sCJD case was reported in previous years in the United Kingdom (UK) or any other country in patient populations treated for bleeding disorders with plasma-derived clotting factors.

Background
The scientific publication describes two female patients, one with Hemophilia B and the other with von Willebrand disease, who were diagnosed in their 60-ies as dying from sporadic CJD. Both individuals were treated for decades with plasma-derived and recombinant clotting factor concentrates as well as large numbers of transfused blood components collected in the UK. They were identified as a result of many years of extensive surveillance carried out by the National CJD Research and Surveillance Unit, UK (2).

To address possible concerns of persons with bleeding disorders it is important to highlight the following:

  • Sporadic CJD is a neurological disorder that occurs in older persons with an incidence of about one (1) case per one million (1 000 000) persons per year (3).
  • The causative agent of sporadic CJD is not a virus or bacterium but a prion protein that, after changing its normal shape, can initiate the development of disease of the brain (4).
  • Sporadic CJD is not the same as variant Creutzfeldt-Jakob Disease (vCJD) that is presumably caused by eating beef products contaminated with bovine spongiform encephalopathy, more commonly known as “mad cow disease” (5).
  • Based on large epidemiological studies in the United States (US) by the American Red Cross (6), as well as in the UK (7) and France (8) sporadic CJD is NOT considered transmissible by blood transfusion.
  • To ensure pathogen safety of plasma collected for fractionation, strict deferral criteria are used as a precautionary measure for selection of donors according to regulatory requirements (9-11). These include deferral of donors with risks for vCJD, family history of CJD and those who were treated with human pituitary-derived medicinal products (e.g. human growth hormone) or had surgeries involving dura mater transplants.
  • Multiple complex manufacturing steps that are used in the production of plasma-derived medicinal products, such as precipitation, adsorption, chromatography and filtration, have shown scientifically proven capacity to remove prions. The effectiveness of these processes has been demonstrated by several studies, including those conducted by PPTA member companies (12-19).
  • According to the assessment of regulatory and health authorities in the European Union [European Medicines Agency (EMA) (9)] and in the US [Food and Drug Administration (FDA) (10)] current cumulative epidemiological evidence does not support transmission of CJD by plasma-derived medicinal products.
  • Systematic surveillance for CJD is in place in Europe (2, 20, 21) as well as in the USA (22) to ensure that any new information on CJD is addressed and assessed appropriately.

Conclusion
PPTA agrees with the author’s conclusion that “occurrence of these cases may simply reflect a chance event in the context of systematic surveillance for CJD in large populations" and PPTA sees no reason for additional concern.

 

For further information, please contact Julie Birkofer
Email:
jbirkofer@pptaglobal.org
Phone: +1.443.433.1117

References

  1. Urwin P, Thanigaikumar K, Ironside JW, Molesworth A, Knight RS, Hewitt PE, Llewelyn C, Mackenzie J, Will RG. Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom. Em Inf Dis. 2017; 6: 893-7. https://wwwnc.cdc.gov/eid/article/23/6/16-1884_article.
  2. The National CJD Research and Surveillance Unit, University of Edinburgh, UK. http://www.cjd.ed.ac.uk
  3. Holman RC, Belay ED, Christensen KY, Maddox RA, Minino AM, Folkema AM, Haberling DL, Hammett TA, Kochanek KD, Sejvar JJ, Schonberger LB. Human prion diseases in the United States. PLoS One. 2010 Jan 1;5(1):e8521. doi: 10.1371/journal.pone.0008521.
  4. Colby DW, Prusiner SB. Prions. Cold Spring Harb Perspect Biol. 2011 Jan 1;3(1):a006833. doi: 10.1101/cshperspect.a006833. Review.
  5. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature. 1997;389:498–501. http://dx.doi.org/10.1038/39057
  6. Crowder LA, Schonberger LB, Dodd RY, Steele WR. Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk. Transfusion. 2017 Apr 25. doi: 10.1111/trf.14145.
  7. Urwin PJ, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang. 2016;110:310–6. http://dx.doi.org/10.1111/vox.12371.
  8. Martin M, Trouvin JH. Risk of transmission of Creutzfeldt-Jakob disease via blood and blood products. The French risk-analysis over the last 15 years. Transfus Clin Biol. 2013 Sep;20(4):398-404. doi: 10.1016/j.tracli.2013.06.001. Epub 2013 Jul 30.
  9. European Medicines Agency. CHMP position statement on Creutzfeldt-Jakob disease and plasma-derived and urine-derived medicinal products. London, 23 June 2011.
  10. The Food and Drug Administration. Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products. Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research May 2010. Updated January 2016.
  11. COMMISSION DIRECTIVE 2004/33/EC of 22 March 2004 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components. Published in the Official Journal of the European Union on 30 March 2004
  12. Foster PR. Removal of TSE agents from blood products. Vox Sang 2004; 87 Suppl 2: 7-10.
  13. Lee DC, Stenland CJ, Miller JL, Cai K, Ford EK, Gilligan KJ, Hartwell RC, Terry JC, Rubenstein R, Fournel M, Petteway SR Jr. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion. 2001 Apr;41(4):449-55.
  14. Groener A, Schäfer W, Vey M. Removal of Prions by the Manufacturing Process of Haemate® P/Humate-P®. Blood 2005 106:4171
  15. Groener A, Groschupchup M, Vey M. Efficient Reduction of Prions by the Manufacturing Process of a VWF/FVIII Product. Blood 2008 112:995;
  16. Cai K, Gröner A, Dichtelmüller HO, Fabbrizzi F, Flechsig E, Gajardo R, von Hoegen I, Jorquera JI, Kempf C, Kreil TR, Lee DC, Moscardini M, Pölsler G, Roth NJ. 2013 Sep;53(9):1894-905. doi: 10.1111/trf.12050. Epub 2012 Dec 17.
  17. Diez JM, Caballero S, Belda F, Otegui M, Gajardo R, Jorquera JI. Capacity of the manufacturing process of Flebogamma(®) DIF, a new human high purity intravenous immunoglobulin, to remove a TSE model-agent. Biologicals. 2010 Nov;38(6):670-4. doi: 10.1016/j.biologicals.2010.08.003. Epub 2010 Sep 22.
  18. Diez JM, Caballero S, Belda FJ, Otegui M, Gajardo R, Jorquera JI. Elimination capacity of a TSE-model agent in the manufacturing process of Alphanate/Fanhdi, a human factor VIII/VWF complex concentrate. Haemophilia. 2009 Nov;15(6):1249-57. doi: 10.1111/j.1365-2516.2009.02067.x. Epub 2009 Jun 26.
  19. Herring S. Grifols' factor IX concentrates: new findings in biochemical characteristics and safety profiles. Haemophilia. 2010 Jul;16 Suppl 6:3-8. doi: 10.1111/j.1365-2516.2010.02299.x.
  20. Creutzfeldt-Jakob Disease International Surveillance Network. http://www.eurocjd.ed.ac.uk/
  21. United Kingdom Haemophilia Centres Doctor's Organization (UKHCDO). http://www.ukhcdo.org/patient-information/
  22. National Prion Disease Pathology Surveillance Center (NPDPSC), Case Western Reserve University, Cleveland, Ohio, USA. http://case.edu/med/pathology/centers/npdpsc/