The Transmissible Spongiform Encephalopathies Advisory Committee met June 12 in Gaithersburg, Md., to review FDA’s modified risk assessment for potential exposure to the infectious agent of variant Creutzfeldt-Jakob disease in U.S.-licensed plasma-derived factor VIII, or pdFVIII.
pdFVIII products are used by blood clotting disorder patients with von Willebrand disease and some patients with hemophilia A. The announcement in February 2009 by the U.K. Health Protection Agency, or HPA, of a probable case of preclinical vCJD in a man approximately 70 years of age with hemophilia prompted FDA to review the potential vCJD risk for U.S. users of U.S.-licensed pdFVIII products and current risk management strategies for such products. HPA reports indicated that postmortem examination of the brain found no neuropathological changes suggestive of vCJD; however, examination of the spleen revealed abnormal accumulations of prion protein typical of vCJD and not of other forms of CJD. The 70-year-old man had been treated 11 years earlier with U.K.-sourced pdFVIII from a “vCJD-implicated” lot — that is, a lot of pdFVIII manufactured from pooled plasma containing at least one donation from a person who later died of confirmed or probable vCJD.
A review of current FDA geographic donor deferral policies to reduce the risk of transmitting vCJD by blood, blood components and plasma derivatives; information on TSE clearance in the manufacture of pdFVIII; and an assessment of possible risks for plasma-derived products in the U.K. and U.S. were presented for the committee’s consideration and discussion.
FDA’s current risk management strategy for vCJD has evolved in response to emerging epidemiologic findings and basic scientific developments pertinent to the epidemic. The overall risk management strategy for vCJD includes the following:
Deferral of donors at increased risk of vCJD based on epidemiological data and withdrawal of certain products at increased vCJD risk.
Facilitating development, validation and information sharing (including product labeling), regarding manufacturing processes for the clearance of TSE from blood products.
Facilitating development of candidate donor screening and diagnostic tests for vCJD and other TSEs.
Risk assessment and communication to inform patients and physicians about the current scientific understanding regarding vCJD risk from the use of blood products and to help inform treatment decisions.
Results from the updated FDA 2009 vCJD pdFVIII Risk Assessment Model continue to indicate that the risk of vCJD infection from U.S.-licensed pdFVIII is likely to be extremely small but may not be zero. For U.S. plasma donors, the major source of vCJD risk is dietary exposure during travel and/or residence in the U.K., France or other European countries since 1980. Blood and plasma donor deferral criteria in place since 1999 have reduced the risk posed by donations from bovine spongiform encephalopathy-exposed and vCJD-exposed people. Manufacturing processes for human pdFVIII products are likely to reduce the quantity of vCJD agent, if present, but the level of reduction achieved by manufacturing steps is not known precisely.
Questions for the Committee
The TSEAC was asked to consider three questions, with a vote on one question.
1. Does the committee agree with the updated and new inputs to the FDA risk assessment model for U.S.-licensed pdFVIII?
The committee discussed this question and was in general agreement with the updated model.
2. Despite the finding of minimal additional risk in FDA’s modified risk assessment, should the recent report from the U.K. Health Protection Agency attributing a case of vCJD infection to treatment with U.K. pdFVIII alter FDA’s interpretation of the risk for U.S.-licensed preparations of pdFVIII?
The committee voted “no” unanimously.
3. Based on the available information, should FDA consider:
a. Recommending additional risk-reducing steps for manufacture of plasma derivatives (e.g., modifications to current donor deferral policies)?
b. Recommending revised warning labels for plasma derivatives?
c. Recommending modifications to FDA’s public communication (e.g., to Web postings) regarding the risk of vCJD associated with the use of FDA-licensed plasma derivatives?
The committee discussed but did not vote on question three. Suggestions to FDA included a) defer transfusion recipients from all BSE countries; b) strike “theoretical” from warning label but include that risk is very small as well as discriminate between CJD and vCJD; c) have more communication to alleviate confusion between CJD and vCJD, utilizing social networking tools