October 31, 2005

Bethesda, Maryland


Topic 2:           Labeling Claims for Filters Intended to Remove TSE Infectivity from Blood Components


Issue:              FDA seeks the advice of the Committee on the minimal scientific criteria for validation of a claim for reducing TSE infectivity in blood products by filtration.




Concerns about the potential transmission of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products emerged soon after the first report of the disease in 1996 (Will, RG. Lancet 1996; 347:921-25).  Precautionary measures were subsequently introduced by many nations to protect against transfusion transmission of vCJD.  Many countries, including the USA, adopted precautionary blood donor deferral policies for individuals who had lived in or traveled to regions endemic for BSE for substantial periods of time.  Additionally, based on theoretical considerations, leukoreduction was instituted as a possible added safeguard in the UK and in some other countries where bovine spongiform enecephalopathy (BSE) was prevalent. 


Leukoreduction of blood components can be achieved by collection of the products with an apheresis instrument capable of preparing a blood product with low leukocyte content or by filtration with specific filters that reduce leukocyte content of blood products.  Transfusion of leukoreduced blood has been shown to reduce the incidence of transfusion associated febrile nonhemolytic reactions, alloimmunization of platelet recipients and transmission of cytomegalovirus (CMV).  In the US a blood product labeled as leukoreduced has to have less than 5 x10 6 leukocytes while in Europe this cutoff is at 1 x 106 leukocytes.  Although leukoreduction of blood products is associated with several beneficial outcomes, so far no filter manufacturer has made claims that use of their filter will lead to such benefits. 


In 2003, a patient in the UK was diagnosed with vCJD that appeared to have been transmitted by a transfusion of non-leukodepleted red cells six years earlier from a donor who developed vCJD three years after the donation (Llewelyn CA. Lancet 2004; 363:417-21). In August 2004, a case of preclinical vCJD was reported in a patient who had received non-leukodepleted red blood cells from a donor who developed vCJD 18 months after donation (Peden AH. Lancet 2004; 364:527-529). The recipient died from a non-neurological disease five years after receiving the blood transfusion. Protease-resistant prion protein (PrPsc) was detected in the spleen and in a cervical lymph node but not in the brain. The patient was heterozygous for methionine and valine at codon 129 of the prion-protein-encoding gene (PRNP), suggesting that susceptibility to vCJD infection is not confined to methionine homozygous PRNP genotype, as had been previously suggested. These findings may increase the estimated number of future vCJD cases to be expected in the UK (Peden, AH. Lancet 2004; 364:527-529) and other countries.


In 1999, UK authorities implemented universal leukoreduction as a precaution against transmission of vCJD by transfusion of blood. This measure was based on an assumption—taken from a limited amount of research with animals experimentally infected with the agents of transmissible spongiform encephalopathies (TSEs)—that most of the infectivity in human blood would be associated with white blood cells (Williamson ML. Br J Haematol 2000; 110: 256-272). Even then, findings in blood of TSE-infected mice and hamsters suggested that at least 40% of the infectivity might be plasma-associated (Rohwer et al. unpublished). In agreement with this observation, other investigators found no loss of infectivity when TSE-infected plasma was passed through some leukocyte reduction filters (Brown P. Transfusion 1998; 38:810-816). Similarly, no significant removal of abnormal scrapie-type prion protein (PrPsc) was detected when units of human whole blood, spiked with microsomal fractions from a TSE-infected brain, were passed through leukoreduction filters from commercial sources (Prowse, CV. Vox Sang 2000; 79: 248).


Gregori et al. recently reported studies attempting to assess how effectively leukoreduction had reduced TSE infectivity in components of blood from hamsters that had been experimentally infected with the scrapie agent. Their data indicated that leukoreduction removed only 42% of the TSE infectivity present in whole blood. The authors concluded that leukoreduction using the filter studied had been insufficient to remove most of the infectivity from an infected blood unit and that substantial amounts of the transmissible agent remained in plasma (Gregori, L. Lancet 2004; 364:529-531).




Current considerations:


FDA’s TSEAC concluded, on June 2, 2000, that the then current scientific data were insufficient to support reliance on leukocyte reduction to reduce the infectivity of CJD and vCJD agents potentially present in blood components—at that time still only a theoretical possibility. TSEAC did not recommend leukoreduction in addition to or as a substitute for FDA’s precautionary blood donor deferral policy.




Since the last review of leukoreduction by the TSEAC, the recognition of two presumptive transfusion-transmitted cases of vCJD in the UK has established with high likelihood that transmission of vCJD by blood transfusion can occur (Wilson, K. Lancet 2004; 477-479).   Additionally, during the past year, the Council of Europe has granted their “mark” to a leukoreduction filter, acknowledging that a manufacturer had presented data in support of a claim that the filter had reduced the risk of transmitting vCJD by blood (  Pall Corporation is the first manufacturer to obtain a CE Mark in Europe for reduction of prions in blood products (Leukotrap Affinity Prion Reduction filter), which, the company has stated, “may reduce the risk of vCJD through blood transfusion” (  There are at present no devices that have been licensed in the US for the purpose of removing TSE infectivity from blood or a blood component.


FDA remains very concerned about the risk from blood products derived from donors with asymptomatic vCJD, and possibly other forms of CJD.  FDA wishes to assess whether, when used in combination with donor deferral policies already in place (or under consideration), clearance of TSE agents from blood by newer filters, including leukocyte reduction filters, is likely to contribute substantially to the safety of blood, blood components or plasma derivatives.  Consequently, FDA seeks to clarify the scientific criteria that would be appropriate for approval of filters (or other methods) labeled with a claim to reduce prions in blood or blood components.


Evaluation of the potential efficacy of filtration devices or other techniques to remove pathogens from contaminated blood is not unique to TSE agents. FDA has reviewed a number of methods purported to reduce the risk of transmitting bacteria and viruses present in donor blood. Criteria FDA used for evaluating such methods may be of some value in similar review of methods to remove TSE agents from blood; those criteria have been summarized in by the FDA at - 07-09-2004 and in an ICH consensus document (Fed Reg 1998;  However, any attempt to apply the criteria used to review previous methods for reduction of other infectious agents is limited by the present scientific uncertainties regarding the interpretation of TSE clearance studies, which include the following:

FDA Proposal

Based on these considerations, FDA proposes that the following minimal scientific criteria should be applied in validation of candidate submissions to FDA for claims of reducing TSE infectivity in blood and blood components by leukoreduction filters:


·            Demonstration of a reduction of endogenous TSE infectivity by bioassay in two animal models (rodent and sheep)


i) The study should use a full-scale blood unit and leukoreduction filter.

ii) The infectivity should be from BSE or vCJD strains of TSE disease.

iii) Reduction of PrPres content by filtration will be considered is as supportive data but not sufficient to obtain a claim.


·          Each study should be done at two separate sites to minimize issues of cross contamination and differences in laboratory practice. 


·          Study size should be sufficient to support a statistically valid conclusion on the ability of the filter to decrease endogenous infectivity in a blood product.



Based on the results of the animal studies, FDA currently would consider clearing filters with the following labeling:


This filter has been shown to reduce transmission of TSE infectivity by transfusion in an animal model.  Due to lack of feasibility, studies have not been performed to validate this claim in a human population.


Questions for the Committee


FDA asks the TSEAC to consider whether, in addition to blood donor and plasma donor suitability policies that currently are recommended, the safety of blood products might be enhanced by use of leukoreduction filters validated to remove TSE agents from blood or blood components.  More specifically, we ask the committee to address the following questions:


1)      Are the FDA’s proposed minimal criteria for validation of TSE infectivity reduction by filtration adequate and appropriate?


In particular, please comment on the following elements of the FDA’s proposed criteria:


2)   Please comment on FDA’s proposed labeling for a filter that meets appropriate criteria for a claim to reduce TSE infectivity in blood or blood components.