Unofficial Summary

for the

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE Meeting on

December 15, 2006

This summary provides an unofficial overview of the December 15, 2006, TSEAC meeting until official transcripts are available.

The committee received an update from Dr. Weinstein, FDA on the status of FDA’s initiative on communication of the potential exposure to vCJD risk from an investigational product, plasma derived Factor XI that was manufactured from UK donor plasma)

Topic I. FDA’s risk assessment for potential exposure to vCJD in human plasma-derived antihemophilic factor (FVIII) products and communication materials.

Issue: FDA prepared a risk assessment of the potential, but unproven, risk related to pdFVIII products, which are used by some patients with the blood clotting disorders hemophilia A and von Willebrand’s disease. The risk of the potential of pdFVIII products to transmit vCJD, the agent which causes the human form of “Mad Cow Disease,” is highly uncertain, but appears likely to be extremely small. FDA presented the risk assessment to the TSEAC to seek advice on key message points, and appropriate ways to communicate the risk assessment information to physicians, patients, and the general public.

Dr. Dorothy Scott introduced FDA’s overall risk management strategy for potential exposure to vCJD in plasma derivatives. The multitiered approach to risk management includes deferral of blood and plasma donors who may be at increased risk of vCJD exposure, recommendations to recall any products containing a donation from a vCJD patient, evaluation of submitted TSE clearance studies from manufacturers for labeling, risk communication through labeling, and development of paradigms for licensure of vCJD blood tests and for devices that remove TSE agents from blood or plasma. Dr. Steven Anderson then presented the FVIII risk assessment and interpretation. Dr. Mark Weinstein discussed FDA’s approach and documents that were developed to communicate this information to IND holders and the general public. In this effort he obtained individual input from patient advocates from the following organizations: National Hemophilia Foundation (Mr. Val Bias) Hemophilia Federation of America (Ms. Janice Hamilton) Committee of Ten Thousand (Dr. Richard Colvin) and the World Federation of Hemophilia (Mr. Mark Skinner) These advocates are current Special Government Employees (SGEs) who received the risk assessment and key points documents prior to the meeting and were asked for their input. They assisted in the development of the revised Key Message Points document that was distributed at the TSEAC meeting. These SGEs made presentations, which included requests for: a continuous process of risk evaluation and communication; appropriate education of all patients and health care providers regarding the risks involved; and assurance that the risk assessment information be worded so as not to cause unnecessary fear or impair access to medical services. They reminded the Committee of the events in 1980 when HIV was transmitted through blood transfusions in spite of early assurances from various parties. They also asked FDA to continue working with consumer advocacy organizations during this process. A request was made that leukocyte reduction technology be universally utilized and more efforts be made to develop a test of vCJD in blood and blood products.

During the morning Open Public Hearing, Mr. Corey Dubin, President, Committee of Ten Thousand, requested that more studies be conducted in order to better understand the risk of vCJD and there be more cooperation by government agencies involved with the oversight and surveillance efforts aimed at reducing the risk of further spread of vCJD. He also requested if any blood product recipients become infected with vCJD from taking blood products, that they should be compensated by industry for their medical expenses.

Questions to the Committee

1. Does the Committee have any comments on the technical aspects of FDA’s risk assessment, including the risk estimates and uncertainties, for pdFVIII from US donors?

Committee members expressed concerns regarding the risk assessment. Their concern included possible under reporting and undetected cases of vCJD in addition to silent carriers, and long incubation times of vCJD.

Members stated that there were uncertainties regarding the input parameters used in the risk assessment model. They stated that with time and more data future updating the model will improve its accuracy.

A major concern involved the clearance studies which were used to determine the log reduction of the TSE agent in the manufacture of these products (which was a major risk driver of the risk assessment model). Concerns involved the relevance of current models and spiking procedures used, and the ensuing uncertainties in applying the data obtained to predictions of plasma derivative infectivity in humans. Some of the uncertainties addressed by committee members were: that human to human transmission could be more efficient than cow to human transmission, the relative efficiency of i.c. vs. i.v. routes of transmission with respect to assessing infectivity in animals and humans and the possibility that subinfectious doses of TSE agents could accumulate to result in an infection in humans.

Members stated that spiking experiments were a step in the right direction however additional studies need to be performed.

Members stated that it is important to proceed with efforts to obtain the best available scientific data and encourage more scientific studies of TSE clearance, especially those using human infectious agents as spiking materials.

2. Does the Committee agree that the Key Points and Additional Information as described:

a) capture the essential points of the risk assessment,

b) provide a suitable and understandable interpretation of the results?

TSEAC members stated that the revised Key Points document captured the essential points of RA and provided a suitable interpretation.

3. Please comment on the communication strategy regarding the risk assessment and its interpretation.

Summary of major comments and suggestions from committee members:

Key points should have less emphasis on negative factors and should include what FDA is doing now to ensure the protection of the blood supply and also address the benefits of these products so the risk could be evaluated along with the benefit.

The Key Points document should start off with positive points before emphasizing the risk.

The Key Points document needs a clearer message to health care providers so that treatment of the hemophilia community will not be adversely affected in terms of access to care.

The document should describe what vCJD is in lay terms and should explain why only Factor VIII and not other products, such as Factor IX, were not included in the assessment.

The document should state what other steps FDA has taken to help diminish the risk of vCJD in products, and include FDA’s commitment to reassess the risk when additional scientific information becomes available.

The document should provide contact information for healthcare providers and others if there is a suspected vCJD case.

The document should state why US and UK policy is different and why U.S. products have a lower risk than the UK products did.

A member raised the question whether additional audiences beyond the hemophilia community and direct care providers should be addressed in future risk assessment communications.

When communicating the risk FDA needs to be proactive so that the patient population continues to receive health care in all tiers of the health care system. The risk communication message must be communicated so that as many patients as possible receive it. About 70% of people with clotting disorders are associated with hemophilia treatment centers, and that other means would be needed to inform the remaining 30% of patients.

Dr. Epstein thanked everyone at the meeting and stated that additional written comments would be welcome. FDA will continue to revise and further develop its risk communication.

Topic II. Levels of TSE clearance in the manufacture of plasma-derived FVIII

Issue: FDA asked the Committee for advice on whether a minimum TSE agent reduction factor, demonstrated in laboratory-based experimental models, would enhance vCJD safety of the products.

Dr. Scott summarized the discussions of the September 19, 2006 TSEAC meeting and then Dr. Thomas Kreil from Baxter Bioscience, speaking for the Plasma Protein Therapeutics Association, updated the Committee on information from manufacturers on clearance studies.

There were two open public hearing speakers in the afternoon. David Cavanaugh, Government Relations, COTT, expressed his concern regarding the industry clearance studies and assumptions. He emphasized that reliable and accurate information is needed regarding the safety of these products. Chris Temple expressed his concern regarding reporting of the incidence of BSE in this country and the lack of incentive for farmers to comply with reporting and proper disposal procedures for sick cattle.

Questions for the Committee

1. Based on available scientific knowledge, please discuss whether a minimum TSE agent reduction factor, demonstrated using an exogenous (spiking) model in scaled-down manufacturing experiments, would enhance vCJD safety of the products.

While the committee was encouraged that members of industry are studying TSE clearance in their products, and that many reported clearance levels of 4 log₁₀ or greater, some members expressed misgivings about the ability of Prp-res to serve as a surrogate marker for infectivity, and also about additivity of clearance steps, if not empirically demonstrated. Members expressed the ongoing concern that the experimental spiking models may not bear relevance to human blood.

There was general agreement that spiking experiments enhance understanding of product safety. However, the Committee felt that sufficient data was not available to allow establishment of a minimum log reduction. The Committee requested more efforts by industry to do more studies and to consider modifications of manufacturing that could reduce infectivity. Dr. Kreil replied that modifications to manufacturing processes would require FDA approval and may require a new product application that would then have to be approved by FDA.

Initial vote on Question 1: 9 yes votes, 2 no votes, 5 members abstained.

The question was then reworded as follows: (Question 1- revised). Based on available scientific knowledge, would a minimum TSE agent reduction factor, measured by bioassay, demonstrated using an exogenous (spiking) model in scaled-down manufacturing experiments, enhance vCJD safety of the products.

Vote on revised question 1. Unanimous yes votes, two members abstained.

2. If the Committee identifies a minimum TSE reduction factor that would enhance vCJD safety what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:

a.Labeling that would differentiate the higher clearance products from other products;

b. Recommending addition of TSE clearance steps to the manufacturing method;

c. Performance of TSE clearance experiments using endogenous infectivity models;

d. Any other actions?

Since the Committee could not identify a minimum TSE reduction factor, there was no vote on this question, and the meeting was adjourned.

Please refer to the Committee Transcripts for a detailed account of the meeting.