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Blood Safety Summary - January 1998

DATE: February 17, 1998

TO: Interested Parties

FROM: Stephen D. Nightingale, NM, Executive Secretary Advisory Committee on Blood Safety and Availability

SUBJECT: Summary of Third Meeting Advisory committee on Blood Safety and Availability

Hubert H. Humphrey Building, Room 800

200 Independence Ave., SW

Washington, DC 20201

January 29 and 30, 1998

Voting members present were Dr. Arthur Caplan, Chair; Mr. Larry Allen, Dr. James AuBuchon, Dr. Michael Busch, Dr. Ronald Gilcher, Dr. Edward Gomperts, Dr. Fernando Guerra, Dr. Paul Haas, Dr. William Hoots, Ms. Carolyn Jones, Dr. Dana Kuhn, Ms. Tricia O'Connor, Dr. John Penner, Dr. Jane Piliavin, Dr. Eugene Schiff, Dr. Marian Secundy, and Mr. John Walsh. Non-voting members present were Dr. Mary Chamberland, Dr. Eric Goosby, Dr. David Feigal, Dr. Paul McCurdy, and Dr. David Snyder. Dr. Kristine Moore, Consultant to the Committee, was also present, as were Stephen Nightingale, MD, Executive Secretary, and CDR Lawrence McMurtry, Deputy Executive Secretary.

The meeting opened with Dr. John Eisenberg, Acting Assistant Secretary for Health, reading a letter from the Secretary to Dr. Caplan. The text of the letter is as follows:

Dear Dr. Caplan:

Thank you for your thoughtful recommendations for persons inadvertently exposed to

hepatitis C through blood transfusion. Your recommendations have greatly assisted the Department's extensive review of this matter.

"I support your recommendation for the use of direct notification efforts to reach those individuals who received a transfusion from a donor who later tested positive for hepatitis by a confirmed second generation screening test. I also support your recommendation for a public and provider education effort directed at those who received blood before this second generation screening test was available. This education effort will also benefit others at risk for hepatitis C, regardless of the source of their risk."

In addition, I intend to go beyond your recommendations. I consider these steps to be only the first phase of a comprehensive plan to address this significant public health problem. It is my intention to reach effectively as many people at risk as we can. Todays decision will allow us to move immediately to address concerns among transfusion recipients at greatest risk. At the same time, we will educate the public at large, evaluate our efforts, and take even more steps to address unmet needs as we identify them.

I am directing the Public Health Service Blood Safety Committee, chaired by the Blood Safety Director, to meet regularly to review progress in these efforts and make appropriate recommendations for further action. We will keep you informed of our progress.

Sincerely,

Donna E. Shalala

Dr. Robert Rohwer, Veterans Administration Hospital, Baltimore, MD, then discussed animal models of Creutzfeldt-Jacob Disease (CJD) and the relevance of these animal models to the human disease. He noted that prior experiments at NIH have failed to demonstrate transmission of CJD from the blood of affected humans to primates. He also noted that claims of transmission of CJD from the blood affected humans to rodents are not widely accepted.

Dr. Rohwers experiments use brain tissue from sheep with scrapie, a transmissible spongiform encephalopathy (TSE) which has clinical and pathological features similar to human CJD Hamsters inoculated with this sheep brain tissue develop a TSE referred to as hamster-adapted scrapie. When the hamster develops signs of hamster-adapted scrapie, roughly two months after inoculation, it is sacrificed. The first 2 cc of blood from the sacrificed hamster are transfused into a healthy hamster, and the remainder of the blood (or blood fractions such as buffy coat or plasma fractions such as Cohn Fraction V) is inoculated in 50 micro liter aliquots directly into the brain of other healthy hamster.

Dr. Rohwer has observed that intracerebral inoculation transmitted CJD in 22 of 22 hamsters. However, transfusion transmitted CJD in only 1 of these 22 hamsters. Furthermore, subsequent experiments have so far failed to demonstrate transmission by transfusion. These experiments have also demonstrated intracerebral transmission by whole plasma and Cohn plasma fractions I, I- U, and III, but not by Cohn Fractions IV or V. Intracerebral transmission was also demonstrated when human blood spiked with brain tissue from affected hamsters was used instead of blood from an affected hamster.

Dr. Rohwer then discussed the probability that a human transfusion donor would subsequently develop CJD, which is the incidence per mi4lion population per year (1) times the incubation period of the disease (40 years): 40 per million donors or I per 25,000 donors. Since the average pool size for plasma fractions is about 30,000, it is virtually certain that recipients of that pool will be exposed to blood from someone who will subsequently develop CJD.

Dr. Rohwer concluded by emphasizing the apparent differences between classic human CJD, the animal model he was studying, and "new variant" (nv) CJD. Classic CJD appears to have been present for hundreds of years; nvCJD only recently jumped species from cows, where it produces bovine spongiform encephalopathy (BSE) or Mad Cow disease, to humans. Dr. Rohwer did not feel that extrapolating work done on classic CJD or his animal TSE models to nvCJD was warranted.

In the following discussion, Dr. Rohwer discussed the possibility of 'intraspecies recycling,"a situation in which affected blood donors would die before they developed symptoms of a disease, increasing the incidence of silent transmission. If this has actually happened, however, the incidence of new cases should be increasing. In the case of classical CJD this has not been observed; in nvCJD it is not yet clear whether this is happening or not.

Dr. Lawrence Schonberger, Centers for Disease Control and Prevention, Atlanta, GA, then reviewed the epidemiology of classic human CJD. He presented the data in support of the CDC position that the risk of transmission of classic CJD by blood transfusion is small and remains theoretical. No such transmissions have been confirmed so far. Surveillance has been sufficient to identify transmission of CJD by human growth hormone and by dura mater grafts and stereotactic EEG equipment. Case-control studies do not identify blood transfusion as a risk factor for CJD. The reported incidence of CJD has not increased from 1979 to 1995, and the preliminary 1996 figure of 218 CJD cases is within the previous range. No hemophiliacs have as yet been found to have CJD. No one who has received blood from a donor who subsequently developed CJD has so far developed CJD.

Dr. Schonberger stated that there are legitimate concerns about the appropriateness of current CJD withdrawal policies. The vast majority of product is used before withdrawal is ordered, the cost is substantial, and shortages are created.

The discussion following this presentation focused on whether CJD was under recognized, particularly in those with comorbid conditions such as hemophilia and, specifically, ADDS.

Dr. Robert Will, National Creutzfeldt-Jacob Surveillance Unit, Edinburgh, Scotland, UK, then discussed nvCJD. nvCJD differs from classic CJD in that nvCJD has a younger age at onset, shorter incubation time, predominantly psychiatric and sensory manifestations, a characteristic atypical electroencephalogram, distinct neuropathology, and lymphoreticular extracranial involvement. The epidemiologic link of nvCJD to BSE is being confirmed by animal experiments in which material from both nvCJD and BSE causes the same distinct lesions. These observations form the basis of the UK decision to withdraw blood products if a donor subsequently develops nvCJD, but not if a donor subsequently develops classic CJD.

Dr. Clarence Gibbs, National Institutes of Health, Bethesda, NM, then discussed present directions of research on TSEs. Dr. Gibbs enumerated the human and animal TSES; the latter include, in addition to BSE and scrapie, mink encephalopathy and chronic wasting disease of deer and elk. The NIH supports studies of the pathogenesis of TSES, including the work for which Dr. Stanley Prusiner recently received the Nobel Prize. The NIH also supports work on development of diagnostic tests for human and animal TSES.

After a lunch break, Dr. Lola Lopes (University of Iowa, Iowa City, IA) presented data that individuals confronted with risky choices are influenced by the shape of the distribution of the various possible outcomes and not just by the mean of all possible outcomes. She then discussed her research on the hypothesis that varying responses of different individuals to risky choice can be explained by differences along an axis between security and potential, and along a different axis called aspiration. Finally she discussed differences in estimates of risk between experts and the public at large, and she pointed out that these differences were less when the public had confidence in experts in that particular area.

Dr. Mark Weinstein (Food and Drug Administration, Rockville, NM) then described current FDA policies regarding TSES. He reviewed the December 11, 1996 FDA memorandum which requires that all products for injection be retrieved and destroyed if a donor is subsequently found to have CID or be at risk for CJD unless that risk is a single family member with CJD, in which case plasma derivatives using plasma from that donor can be used for injection. Recipient notification is left to the discretion of others. He also reviewed the recommendations of the FDA Transmissible Spongiform Encephalopathy Advisory Committee meeting of October 6 and 7, 1997, which were exceptions to withdrawals should be considered only for life- or health- sustaining products in short supply, that albumin could be exempted from withdrawals only when used as an excipient for a non-vaccine or non-plasma product, and that decisions about manufacturing process reagents could be made on a case-by-case basis. Dr. Weinstein then gave examples of how these policies were currently being translated into practice.

After a recess, the Advisory Committee heard presentations from David Cavenaugh, Committee of Ten Thousand; Jan Hamilton, Hemophilia Federation; Jerry Winkelstein, MD, h-nmune Deficiency Foundation; Donald Colbum, National Hemophilia Foundation; Roslyn Romtovian, NM, American Society of Clinical Pathology; Richard Davey, NM, American Red Cross; Barry Wenz, Pall Corporation; Margaret A. Somerville, Consultant to Pall Corporation; Paul Just, Premier, Inc,; Jason Babilak, International Plasma Producers Industry Association.

A brief discussion of the framework for subsequent discussion by the Committee was followed by adjournment.

On January 30, 1998, Dr. Edward Gomperts described processes by which recombinant products are produced in industrial quantities.

The Committee then held an extensive discussion. The following recommendations were proposed and approved:

We recommend that the Public Health Service coordinate an effort to develop a report within six months that will address issues of existing and emerging transmissible spongiform encephalopathies. The report should make specific reference to

Food borne transmission, particularly through consumption of central nervous system tissues;

latrogenic transmission; and

Transmission through transfusion of blood components and plasma derivatives.

National and international surveillance of transmission in both humans and animals, education of providers and the public, needed resources for research, prevention strategies, and efforts in other countries also should be addressed in this report.

2. We recommend that the Public Health Service, professional groups, and patient advocates emphasize the importance of postmortem examination to the protection of the public health, and that they support the training of physicians to recognize new pathological patterns of emerging disease in autopsy tissues.

3. We recommend nationwide standardization of procedures for screening donors at risk for transmissible spongiform encephalopathies.

4. We recommend that the National Institute of Health specify its needs for research and infrastructure support necessary to promote research on the transmissible spongiform encephalopathies, with particular reference to human and animal tests which can discriminate among these conditions within each species.

5. We recommend that during the next year the Food and Drug Administration work with industry and appropriate consumer groups to relax current Creutzfeldt-Jacob disease guidelines on quarantine and withdrawal of blood products to the extent necessary to relieve product shortages.

The Committee then turned to Old Business. There was a brief discussion of the Secretarys letter to the Chairman of the Committee. The Committee requested a report prior to its next meeting about the implementation of the Secretarys initiative regarding hepatitis C and blood safety.

Then Committee then turned to New Business. The Committee made a several recommendations for future agenda items, including the suggestion that it should address the issue of shortages of blood products in more detail. The meeting was then adjourned.