FDA Transmissible Spongiform Encephalopathies Advisory Committee and Vaccines and Related Biological Products Advisory Committee - Joint Meeting

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FOOD AND DRUG ADMINISTRATION

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE

AND

VACCINES AND RELATED BIOLOGICAL PRODUCTS

ADVISORY COMMITTEE

+ + + + +

JOINT MEETING

+ + + + +

THURSDAY

JULY 27, 2000

The joint committee met in open session at 9:23 a.m. in the Versailles Ballrooms I, II and III of the Holiday Inn, Bethesda, Maryland, Dr. Paul Brown, Chairman of the TSEAC, and Dr. Harry Greenberg, Chair of VRBPAC, presiding.

PRESENT:

PAUL W. BROWN, M.D. Joint Committee Chair

HARRY B. GREENBERG, M.D. Joint Committee Co-Chair

ERMIAS D. BELAY, M.D. TSEAC

DAVID C. BOLTON, Ph.D. TSEAC

DONALD S. BURKE, M.D. TSEAC

DEAN O. CLIVER, Ph.D. TSEAC

ROBERT S. DAUM, M.D. VRBPAC

MARY K. ESTES, Ph.D. VRBPAC

BRUCE EWENSTEIN, M.D., PhD TSEAC

LISA A. FERGUSON, D.V.M. TSEAC

PATRICIA FERRIERI, M.D. Temporary Voting Member

BARBARA LOE FISHER VRBPAC Consumer Rep

DIANE E. GRIFFIN, M.D., PhD VRBPAC

ALICE S. HUANG VRBPAC

KWANG SIK KIM, M.D. VRBPAC

STEVE KOHL, M.D. VRBPAC

PETER G. LURIE, M.D. TSEAC

JOHN F. MODLIN, M.D. Temporary Voting Member

PRESENT: (continued)

MARTIN MYERS, M.D. Temporary Voting Member

PEDRO PICCARDO, M.D. TSEAC

RAYMOND P. ROOS, M.D. TSEAC

DIXIE SNIDER, JR., M.D.,PhD VRBPAC

DAVID S. STEPHENS, M.D. VRBPAC

SHIRLEY JEAN WALKER TSEAC Consumer Rep

ELIZABETH WILLIAMS, DVM,PhD TSEAC

I-N-D-E-X

Page

Administrative Announcements 4

W. Freas, PhD, Executive Secretary, TSEAC

Welcome: Paul Brown, MD, Committee Chair 10

Harry Greenberg, MD, Co-Chair

Introduction 13

W. Egan, PhD, Acting Dir., OVRR, FDA

Overview of U.S. Vaccination Program 25

Walter Orenstein, CDC

BSE Overview 44

D. Asher, MD, CBER, FDA

Studies of BSE Infectivity in Tissues of 72

Cattle: Gerald Wells, United Kingdom

Current Research Overview: 84

John Wilesmith, BVSc, United Kingdom

European Union Presentation: 106

Professor Jean-Hugues Trouvin and

Dr. Roland Dobbelaer, London

Bacterial Vaccines: Overview of Manufacturing 125

and Risk Assessment: Willie Vann, PhD, CBER

Viral Vaccines: Overview of Manufacturing & 133

Risk Assessment: Ira Berkower, OVRR, CBER

Manufacturers Comments/Presentations:

SmithKline Beecham: Dr. Clare Kahn 151

Dr. R. Bradley, CBE, BSE Consultant 153

Aventis Pasteur, Dr. Jeffrey Almond 172

Comments from Other Manufacturers 178

Open public hearing 178

Discussion/presentation of "Questions 183

for the Committee"

P-R-O-C-E-E-D-I-N-G-S

(9:23 a.m.)

DR. FREAS: Could I ask you to take your seats, please. We will begin. We are behind on the time schedule. If you take your seats, we are going to go ahead and resume this committee meeting.

I would like to welcome the public to the open session of this joint meeting of the Transmissible Spongiform Encephalopathies Advisory Committee and the Vaccines and Related Biological Products Advisory Committee.

At this time, for the members of the public, I would like to go around and introduce the members of the committees seated at the tables. I will start on the righthand side of the room. The first nine individuals are members of the Vaccines and Related Biological Products Advisory Committee, and if they would raise their hands when I call their name, I would appreciate it.

At the end of the table is Dr. Dixie Snider, who is Associate Director for Science, Centers for Disease Control and Prevention.

In the next chair is Dr. Mary Estes, the Professor of Molecular Virology, Baylor College of Medicine.

In the next chair Dr. Steve Kohl, Adjunct Professor, Department of Pediatrics, Oregon Health Sciences University.

In the next is Dr. Alice Huang, Senior Counselor for External Relations, California Institute of Technology.

Next is Dr. Robert Daum, Professor of Pediatrics, University of Chicago Children's Hospital.

in the next chair is our Consumer Representative for the Vaccines Advisory Committee. That is Ms. Barbara Low Fisher, Co-founder and President, National Vaccine Information Center, Vienna, Virginia.

In the next chair is Dr. David Stephens, Professor of Medicine, Microbiology and Immunology, Emory University School of Medicine.

Next is Dr. Diane Griffin, Professor and Chair, Molecular, Microbiology and Immunology, Johns Hopkins University.

Next is Dr. Kwang Sik Kim, Division Chief, Pediatric Infectious Disease Division, Johns Hopkins University.

Next is a temporary member for today's meeting, and that is Dr. John Modlin, Professor of Pediatrics and Medicine, Dartmouth-Hitchcock medical Center.

Around the corner of the table is another temporary voting member for today, Dr. Patricia Ferrieri, Professor, Departments of Laboratory Medicine, Pathology and Pediatrics, University of Minnesota.

Next is another temporary voting member for today, Dr. Martin Myers, Acting Director, National Vaccine Program Office, Centers for Disease Control and Prevention.

Next is the Chairman of the Vaccines and Related biological Products Advisory Committee who is acting as Co-Chair for today's meeting, and that is Dr. Harry Greenberg, the Grant Professor of Medicine, Microbiology and Immunology, Senior Associate Dean for Research, Stanford University Medical School.

In the next chair is the Chairman of the TSE Advisory Committee and the Chairman of today's meeting. That is Dr. Paul Brown, Medical Director, Laboratory of the Central Nervous System Studies, National Institute of Neurological Disorders and Stroke.

In the next chair is Dr. Raymond Roos, Chairman, Department of Neurology, University of Chicago.

At the corner of the table is Dr. Peter Lurie, Medical Researcher for Public Citizen's Health Resource Group, Washington, D.C.

Next is the Consumer Representative for the TSE Advisory Committee. That is Ms. Shirley Walker, Vice President of Health and Human Services, Dallas Urban League.

Next is Dr. Bruce Ewenstein, Clinical Director, Hematology Division, Brigham and Women's Hospital.

Next is Dr. Ermias Belay, Medical Epidemiologist, Centers for Disease Control and Prevention.

Next is Dr. David Bolton, head of the Laboratory of Molecular Structure and Function, New York State Institute for Basic Research.

Next is Dr. Pedro Piccardo, Associate Professor, Indiana University Hospital.

Next is Dr. Lisa Ferguson, Senior Staff Veterinarian, U.S. Department of Agriculture.

Next is Dr. Donald Burke, Director, Center for Immunization Research, Johns Hopkins University.

Next is Dr. Dean Cliver, Professor, School of Veterinary Medicine, University of California, Davis.

At the end of the table, Dr. Elizabeth Williams, Professor, Department of Veterinary Service, University of Wyoming.

There are three standing members that are not attending today. They are Dr. Stan Prusiner, Dr. Jeffrey McCullough, and Dr. Walter Faggett.

I would now like to read into the record the official conflict of interest statement for this meeting.

The following announcement is made part of the public record to preclude even the appearance of a conflict of interest at this meeting. Pursuant to the authority granted under the committee charter, the Director, Center for Biologics Evaluation and Research has appointed Doctors Linda Detwiler, Patricia Ferrieri, and Martin Myers as temporary voting members.

In addition, the Senior Associate Commissioner of FDA has appointed Dr. John Modlin as a temporary voting member.

Based on the agenda made available, it has been determined that the agenda addresses general matters issues only. General matters waivers have been approved by the agency for all special government employees participating for this meeting.

The general nature of the matters to be discussed by the committee will not have a unique and distinct effect on any of the participants' personal or imputed financial interests. In regards to FDA's invited guests, the agency has determined that the services of these guests are essential.

The following reported interests are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by these guests:

Dr. Ronald Dobbelaer is employed by the Biological Standardization Scientific Institute of Public Health, Louis Pasteur, in Brussels, Belgium.

Dr. Walter Orenstein is employed as the Director of the National Immunization Program at the Centers for Disease Control and Prevention.

Dr. Suzette Priola is employed at the Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH.

Dr. Jean-Hugues Trouvin is employed by the Department of Biologics, APSS, APS, in France.

Dr. Gerald Wells is employed at the Veterinary Laboratories Agency in Weybridge, United Kingdom.

Dr. John Wilesmith is employed at the Veterinary Laboratories Agency in Weybridge, United Kingdom.

in the event that discussions involve specific products or specific firms for which FDA participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted on the public record.

A copy of the waivers are available by written request under the Freedom of Information Act. With respect to all other meeting participants, we ask in the interest of fairness that you address any current or previous financial involvement with any firm whose products you may wish to comment upon.

So ends the reading of the conflict of interest statement. Dr. Brown, I turn the microphone over to you.

CHAIRMAN BROWN: Thank you, Bill. Welcome, everyone, to this meeting. I thought I would open by telling you a little story that might have consequences for the members of my committee.

I sent a little review of the whole BSE new variant CJD problem to the journal Neurology about two months ago, and I'd like to read the committee the one paragraph review by a reviewer of this submission.

"I feel that the amount of novel information is equal to zero and that this short paper does nothing more, in addition to providing some questionable justification for the arbitrary decision made by the panel of which Paul Brown was president of the Federal Drug Administration to defer blood donations from donors that have resided in Great Britain for more than six months. That particular decision rested and continues to rest on a very weak scientific background, and the attempts by Dr. Brown to defend that position in the present paper remain rather unconvincing."

So you can see that the participation on these committees is not without its own risk.

The background information which was supplied as a summary for the present meeting is a very lucid and concise document, and I'd like to read three or four paragraphs that seem to me to have generated this meeting at this time, and they are extracted from this background summary information. But I think the chronology is important.

In a letter to manufacturers in December of 1993, the FDA recommended that bovine materials from BSE countries should not be used in biological products.

Second statement: Uncertainties about BSE-free status of certain countries led to the inclusion of all of Europe in the list maintained by the USDA. There has been no general guidance issued advising manufacturers on how to proceed in the event that a country used as a source of bovine derived materials is subsequently added to the USDA list.

Third statement in April 2000: CBER sent a letter to manufacturers including the recommendation that bovine derived materials from countries in which BSE is known to exist or from countries whose BSE status is unknown not be used in the manufacture of biological products.

The last statement: The FDA has recommended that bovine derived materials from countries in which BSE is known to exist or from countries whose BSE status is unknown not be used in the manufacture of biological products. The agency has learned that this recommendation for U.S. licensed biological products has not been universally followed by vaccine manufacturers.

I think the chronology of those four statements will set the scene for why this particular meeting exists.

We have a number of presentations from speakers invited by the FDA this morning. They will be followed by comments and presentations by two of the manufacturers, and these are not the manufacturers implied in the last statement that I mentioned. Finally, we will have an open public hearing and discussion and presentation of a number of questions which the FDA would like discussed by this committee.

Today there will be no formal voting on any of the questions. There will be discussion only, and we will be sure and cover specifically two or three items which the FDA is particularly interested in having opinions about.

I now invite as the first presentation this morning introductory remarks by Dr. Egan from the FDA. Dr. Egan.

DR. EGAN: Thank you very much. Good morning. On behalf of the Office of Vaccines Research and Review, I'd like to welcome the members of the Transmissible Spongiform Encephalopathy and the Vaccines and Related Biological Products Advisory Committees to this joint meeting and to express my gratitude to all of you for being here, and in many cases rearranging your schedules to do so.

I'd like to take a few minutes to provide the background and history for this meeting and an outline of what we hope to accomplish today. I will also go over the questions for discussion. There are no issues, however, on which we have asked for a formal vote.

The potential for contamination of biological products with the agent of bovine spongiform encephalopathy, BSE, has been a concern of the Center for Biologics Evaluation and Research and the Office of Vaccines Research and Review for many years.

CBER has recommended that bovine derived materials from countries in which BSE is known to exist or whose BSE status is unknown but suspect not be used in the manufacture of biological products. Manufacturers have been referred to the USDA listing for the BSE status of a particular country. Recommendations, however, were not offered by FDA on how to respond to changes in the USDA list that would affect existing vaccines as new countries are added.

The appearance of new variant Creutzfeldt-Jakob Disease in the United Kingdom and its attribution to oral exposure to the infectious agent of BSE have raised concerns regarding the potential for human exposure to the BSE agent that might result from the use of bovine derived materials in the manufacture of vaccines.

No evidence exists that any case of variant CJD has resulted from the administration of a vaccine product. However, the theoretical risk of disease that might result from contaminated vaccines needs to be considered.

Earlier this year during the review of a regulatory submission, we learned that CBER's aforementioned policy on the sourcing of bovine products has not been universally followed. This finding prompted the Office of Vaccines to conduct a general review of all licensed vaccines.

The requested in depth review of sourcing of bovine materials for vaccines has been completed by nearly all manufacturers and submitted to the Office of Vaccines. Personnel within the Office of Vaccines have been reviewing these responses, and that review is essentially complete. A few uncertainties remain, and these are being looked into further. The uncertainties that remain, however, do not present any new type of issue.

Let me be more specific now about the nature of the issues regarding the sourcing and use of bovine materials. Fetal calf serum sourced from the United Kingdom prepared during the mid-1980s has been used in the preparation of certain cell and viral seed banks.

Beef broths prepared from skeletal muscle or skeletal muscle plus pancreatic tissue that were sourced from Europe, specifically Germany, Denmark, the Netherlands and Poland, have been used in bacterial fermentations.

Polygeline prepared from bovine bones sourced from Germany, Italy, Austria, and Switzerland has been used in the preparation of a master bacterial seed bank.

Bovine hemin has been used as a component of a bacterial culture medium.

Several other bovine derived materials of European source have been used in the preparation of bacterial seeds.

This listing that I've just given fairly well covers the range of all issues. We have not considered milk derived products such as amino acids or lactose or tallow derivatives such as glycerol to be problematic, now have we considered bovine materials sourced prior to 1980 to be problematic.

The affected bovine materials would be classified as Category III and IV materials in the European Union scheme. That is, materials having low or no demonstrated infectivity. The European categorization scheme is based on scrapie infectivity in sheep and goats, and the European Union has noted that infectivity in BSE infected cattle appears to be much more restrictive.

The experimental data on BSE infectivity that we would really like to have is, to our knowledge, not in the literature. There are a number of assumptions that must be made in making estimates of risk for these issues.

Moreover, the experimental data that does exist, in many cases, only establishes a boundary, for example, that the infectivity of a particular material is less than a certain number of units, although that material's infectivity could be orders of magnitude less than the experimentally demonstrated limit.

There are limits to how much material can be injected into animals. We recognize that one cannot prove absolutely no infectivity, but we certainly would have desired lower limits to have been determined.

In the presentations by Doctors Vann and Berkower later this morning, we will be presenting risk calculations that incorporate a number of these assumptions and that reflect these boundaries. They are very, to us, conservative estimates.

Differing risk evaluation, depending on the assumptions that are made, will lead to differing conclusions, and your own evaluations may differ markedly from ours. That is why we are here today. We seek your expert opinion in defining potential risk.

For a number of these issues, manufacturers have agreed to and have begun to take corrective actions. For example, manufacturers have committed to changing beef sources for bacterial fermentation broths and culture medium components. Additionally, several manufacturers have indicated a willingness to re-derive cell or seed banks as necessary.

Now since manufacturers are taking these corrective actions, why are we then here? The answer is primarily that corrective actions take time. New materials such as beef broths need to be made and qualified, and following qualification new batches of vaccines need to be manufactured, formulated, and tested. For some products, this will take on the order of one year. Realistically then, we do not expect new products to be able to reach the market until the fall of next year.

Additionally, we are seeking guidance from the committee on the need to re-derive master seeds, not working seeds but the master seeds. We are requesting an estimate of risk, if any, that these products might pose, and your expert opinions for forming an interim policy for the use of the existing vaccines.

We are, moreover, requesting your opinions on dealing with investigational products that have similar issues regarding bovine sourcing, and in this context we need to consider both new vaccines as well as currently licensed vaccines that are components of an investigational product -- for example, a new combination vaccine.

Let me now go over the questions that we would like you to consider. I will clarify these questions, if needed, so that discussions on the following presentations can be appropriately focused.

In the first question we are asking the committee to please discuss the potential risk presented by the use of bovine derived materials sourced from Europe, including the United Kingdom, in currently licensed vaccines.

In this discussion we would like you to please comment on the various risk estimates that have been presented to the committee, and in this discussion to please include: Preparation of bacterial and viral, master and working seeds, preparation of master and working cell banks -- for example, the use of fetal calf serum; to consider to include fermentation processes -- for example, the use of bovine derived media components; the formulation of the final products -- for example, the use of gelatin in their formulation; and additionally in this discussion, please include some risk assessment for bovine materials sourced at differing times from differing European countries, U.K., Germany, France, etcetera.

As a second question for discussion or point for discussion, we would like the following: The following item pertains to currently licensed U.S. vaccines that contain bovine derived material obtained from Europe, including the United Kingdom. We would like the committee to please discuss those circumstances, if any, under which FDA should take specific regulatory actions regarding these vaccines.

Some examples of regulatory actions which are available to the FDA include product recall, modification of the package insert or issuance of a "Dear Doctor", "Dear Health Care Provider" letter or some combination.

Finally, question 3: This item pertains to investigational -- that is, non-U.S. licensed -- vaccines that contain bovine derived materials obtained from Europe, including the United Kingdom. This includes certain investigational vaccines used under IND that contain currently licensed vaccines as components, such as components of a new combination vaccine. In addition, this includes the usual investigational vaccines without previous U.S. licensed components.

In the presentations by CBER personnel this morning, Dr. Asher will provide an overview of BSE epidemiology and FDA policy, and Doctors Vann and Berkower will provide overviews of the manufacturing process for bacterial and viral vaccines respectively, indicating points in the process where bovine source materials have been used and approximate amounts of these materials.

Estimates of risk from bovine source materials will also be presented by Doctors Vann and Berkower for these viral -- for these bacterial and viral vaccines.

I'll try to answer any questions that you might have at this time.

CHAIRMAN BROWN: Does the committee have any questions for Dr. Egan? Thank you, Dr. Egan.

DR. LURIE: Can you explain as far as possible when it was that the problem that we are here addressing came to the attention of the FDA, and how it was that -- Well, why don't you answer that question first.

DR. EGAN: It first came to our attention or to our attention within OVRR of these issues around March of 2000. So a few months ago.

DR. LURIE: I wonder if you can just react to my concern about this. My concern is that it's taken some four months to put together a meeting to discuss this issue, which I think is risky on the part of FDA in that it invites a period of percolating of sometimes not accurate scientific information in the general public.

So I'm wondering why it took quite so long to call this meeting.

DR. EGAN: I think there were a number of issues that were involved. First, we were trying to get some initial assessments for risk on our own from the manufacturers and evaluate those, and then to work on trying to get a review of all vaccines, having all the manufacturers go over all vaccines so that we could present a comprehensive list of issues to the committee.

Then there are some times that it takes to prepare materials for the committee, our own presentations and other materials to get to the committee, and there is some time that it takes to announce the committee meeting in the Federal Register and have sufficient time for the public.

I understand that you do regard that as lengthy.

DR. LURIE: I guess my reaction to that is -- I mean, among the list of options, perhaps not a likely one but among the options that you listed was the option of recall. It sort of seems somehow contradictory to be having the meeting four months later where the subject is recall.

It seems to me that a clear message from taking as long as it took to put the meeting together is that, you know, there is little risk. Now that may be true, but I guess that's the point that I'd like to drive home. It seems that it's taken a wile.

Let me ask you another question. In the very important December 17, 1993, document -- I don't know if you were at the agency at the time in which FDA wrote to the manufacturers of FDA regulated products -- the statement is we request that bovine derived materials from cattle which resided or originated from countries where BSE has been diagnosed, etcetera, etcetera, not be used in the manufacturer of FDA regulated products intended for administration to humans.

What about that statement, if anything, seems unclear to you?

DR. EGAN: I think the statement is clear.

DR. LURIE: Yeah. So do I. And my next question is: Later in the same letter comes the following statement: The agency is considering rulemaking to restrict the use of bovine derived materials from BSE countries. This is in December of 1993.

Can you tell us what the fate of that consideration was?

DR. EGAN: I don't believe -- There was not rulemaking by the agency.

DR. LURIE: Can you explain why?

DR. EGAN: No, I cannot.

DR. LURIE: Does that seem to you, in retrospect, to have been a mistake?

DR. EGAN: You know, I think that's probably an issue that we could debate a lot about whether rulemaking is required or whether the existing flexibilities that exist with the agency to deal with it are sufficient. I could probably give you personal opinions.

CHAIRMAN BROWN: Can we come back to this perhaps in the open discussion rather than linger on with Dr. Egan? I think these are kinds of questions that would be equally appropriate in the discussion.

DR. LURIE: It's only that he's at the microphone.

DR. EGAN: Yes. To answer your first question, yes, I was at the agency in 1993, but in a different capacity.

CHAIRMAN BROWN: Thank you very much, Dr. Egan. We now will have an overview of the U.S. vaccination program presented by Dr. Orenstein from the Centers for Disease Control. Dr. Orenstein.

DR. ORENSTEIN: Thank you very much. I don't know whether -- I guess it's through a computer presentation rather than slides. Okay, we have both here.

DR. FREAS: It's your choice.

DR. ORENSTEIN: Okay. Well, if somebody will run the computer, I'll just talk about next slides.

The title of my talk is an Overview of the U.S. Vaccination Program, and I've been asked by the FDA to review the benefits of and, hence, needs for vaccines in the U.S. As you review potential risks of vaccines today, it's important to place any risk evaluation in context with the benefits in order to formulate the most appropriate policies. Can I have the next slide, please.

Last year as we came to the end of the Twentieth Century, CDC looked back on what it considered were ten great public health achievements. Among those ten great public health achievements of the Twentieth Century, vaccination was listed and, in fact, was the first of a series of ten articles on major public health triumphs during the Twentieth Century. Next slide, please.

Vaccines are considered one of the most cost effective measures of preventive health. In 1995 Tengs, et al. published an analysis of 310 life saving health care sector interventions. of those 310 publications, six involved vaccines -- Six of the 45 identified were cost savings that were vaccine related. All published childhood cost/benefit or cost effectiveness analyses showed society saved money for childhood vaccination, and this doesn't include some unpublished information or later evaluations. Next slide, please.

We have achieved some of the highest immunization rates in this country for routine childhood immunization. For most of our vaccines among 19- to 35-month-old children, a median age of 27 months, we have coverage rates of 90 percent or higher. For hepatitis B we are approaching 90 percent, at 88 percent, and varicella vaccine, which is a newly licensed vaccine in '95 recommended for universal use in '96, we are beginning to see exponential increases in coverage with approaching 60 percent in our last measurements. Next slide, please.

This is a slide updated from an April 1999 MMWR article that looks at, for eight vaccine preventable diseases or, in the case of congenital rubella, a complication, what their representative annual Twentieth Century morbidity taken from data or estimates during the early to the mid-Twentieth Century and what happened in 1999.

What we've achieved is 95.9 percent or greater reductions in all of these diseases, and for many of them through rounding we get to minus-100 percent. To highlight a few, diphtheria as a disease is virtually gone in this country, although the organism persists, and we do run risks if vaccination levels fall of a return of diphtheria.

Measles, which I'll cover in more detail, we believe, is no longer circulating in the United States. Rubella is essentially gone in the United States. It is now primarily a disease of Hispanic populations, Hispanic populations who grew up in countries that at the time were not practicing rubella vaccination. And hemophilus influenza Type B, which at one point is estimated to have caused 12,000 cases of meningitis and 20,000 cases of invasive disease, is now, when it occurs, often a grand rounds case. People are brought around to see such a rare illness. Next slide, please.

This is to remind us of what used to occur in this country. This is a slide form the Rancho de los Amigos Hospital in Los Angelos during the 1950s showing a ward full of persons on iron lungs or Drinker respirators. During the 1950s, we had an average of about 16,000 paralytic cases a year in the United States, and over 1800 deaths. Next slide, please.

This slide shows what has happened with polio in the United States, first with the introduction of inactivated vaccine and then oral vaccine. Polio has been eliminated in the United States. The last indigenously acquired cases of polio in the U.S. occurred in 1979. There have been no wild virus induced polio cases since 1979 acquired within the U.S.

Nevertheless, we continue to be at risk of polio. While there is a worldwide eradication effort underway, we still have about 30 countries in the world that are endemic for polio, and the World Health Organization estimates that roughly 20 will still be endemic by the end of this year. Hence, if polio vaccinations drop, we run the risk of a return of epidemics of polio. Next slide, please.

This is a slide classically taken from Krugman and Sam Katz and others showing the clinical course of measles. I put this in here to show that measles is not a trivial disease. A typical case often had fever between 103 to 105 degrees, multiple systemic symptoms including conjunctivitis or photophobia, coryza, and often a severe, intense cough. Next slide, please.

To further emphasize that measles is not a trivial disease, these are cases reported to CDC between 1985 and 1992, showing that 29 percent had at least one complication, including diarrhea, ear infections, pneumonia, about one in 1,000 with severe encephalitis, and about one in 500 who died.

About 18 percent of the cases were hospitalized, and we learned during a resurgence how young physicians who had not seen measles were really misled by the toxicity, and we heard anecdote after anecdote of kids without complications being admitted to hospitals, because the kids looked so toxic, and they were suspecting something else was going on. Next slide, please.

This shows you what has happened with measles in the United States. Vaccine was licensed in 1963. We've seen a dramatic reduction, but we've had three major outbreaks of measles in the United States, the last between 1989 and 1991 in which we had over 55,000 cases, over 11,000 hospitalizations, and officially reported 102 deaths from measles during that period.

We have now achieved substantially higher vaccination coverage than we had at that time, and we believe all measles in the U.S. today is not endemic circulating measles but measles from foreign importations with limited domestic spread. Next slide, please.

This slide doesn't show up. It would show in the slides. But let me put it -- We still run the threat of reintroduction of measles and, if coverage falls, of measles epidemics. During the three-year period 1997 to 1999, there were 116 international importations of measles into the U.S. They infected 32 states and the District of Columbia, and infected 78 counties. There's a clear need and a clear threat for measles vaccine, and a clear threat for the reintroduction of measles. Next slide, please.

We often give statistics and numbers, and I'd like to, with your forbearance, read a clinical description. This was put together by Lloyd Olson from Indiana University in 1975 of pertussis to put in perspective, I think, one of the best clinical descriptions:

"The child possessed of a coughing fit is a pitiful sight, all the more so as the observer is helpless to alleviate or terminate the attack. Each attack consists of ten to 30 forceful coughs per spasm, and into each cough the patient appears to concentrate all his energy. He leans forward or, if standing, stands with legs spread grasping the nearest object and leaning far forward, tongue protruded to the utmost, saliva and mucous streaming from nose and mouth, eyes bulging with tears streaming, his entire body racked with the total exertion of each cough." Next slide, please.

"The coughing continues in a staccato series. The face becomes more and more cyanotic. The neck bulges with venous congestion, and still the attack continues. Finally, when it seems certain that death is imminent, a final cough appears to clear offending secretions and mucous from the upper airway, and the first opportunity to inspire is offered. With a massive effort, inspiration ensues. Air rushes into the lungs against a still narrowed glottis, and a characteristic whoop is produced." Next slide, please.

Apart from the complicating conditions which occur in some patients with pertussis, the major danger from the disease is during severe coughing paroxysms during which prolonged hypoxia may lead to irreversible changes in the CNS or even death. The greatest mortality via this mechanism occurs in infants.

This shows you what has happened with pertussis in the United States, first with whole cell pertussis vaccines, showing a major acceleration in the decline of pertussis, and now in cellular vaccines. We've seen pertussis increasing recently in the United States, and this involves particularly young adults and adolescents who are a reservoir of continuing transmission.

If immunization levels fall, I think we can be certain that we will again see epidemics of pertussis without the need for international importations. Next slide, please.

To put it perspective the concerns about pertussis, this is data from Japan, but it was seen in the United Kingdom and Sweden. In Japan there was extreme concern about the safety of the whole cell vaccines after two deaths followed whole cell vaccination. The pertussis vaccination program was suspended for a time, then reinstituted at two years of age, but not very effectively.

Again, this was after two deaths following vaccine. There was a major epidemic of pertussis in which 41 deaths were reported, and it was only through reintroduction of a cellular vaccine, first at two years of age and then at younger ages, that have led to major control of pertussis in Japan. Next slide, please.

I'd like to move now to varicella. The CDC has estimated that roughly everybody got varicella in the pre-vaccine era. That's about 4 million cases per year, about 11,000 hospitalizations per year, about 105 deaths per year, about one on average per week in children. The majority of deaths and hospitalizations did not occur in persons with risk factors, but in those who were healthy children and healthy adults. Next slide, please.

These are data from a sentinel surveillance project CDC funded in Antelope Valley, California, West Philadelphia, and Travis County, Texas, where immunization coverage, as best we can measure it in the trial population, varies from about six to 80 percent or so.

What you can see here, if you look at the bottom line, is an overall reduction in reported cases of varicella, ranging from 77.5 percent to 84.3 percent. The other thing of interest is that a program targeted toward children is having a major impact on circulation of varicella in all age groups, including older adolescents and adults. Next slide, please.

What's gratifying is we're not only seeing a decrease in reported cases, but we're seeing a major decrease in hospitalizations, shown here by the blue bars, and on the rates of hospitalizations, shown here in red. Next slide, please.

The last disease I want to talk about is hepatitis A. Hepatitis A is again not a trivial disease. It consists generally of a pro-germ of fever, malaise, loss of appetite, nausea, abdominal discomfort, and jaundice. Next slide, please.

The CDC estimates that approximately 100 persons die each year in the absence of a vaccination program from fulminant hepatitis A. While the usual illness resolves within two months, about ten to 15 percent have relapsing illness up to six months. About 11 to 22 percent are hospitalized, and the cost per case, even for children, is not insubstantial, in children ranging, from CDC estimates from our hepatitis group, from $433 to $1492 per case.

The total cost estimated and published in the ACIP statement on hepatitis A was approximately $100 million. Next slide, please.

What you can see here with hepatitis A in the Indian population where coverage rates for hepatitis A vaccine in children have ranged from about 60 to 80 percent is a marked drop in hepatitis A to the point that hepatitis A in the American Indian population is now similar to the overall U.S. population. Next slide, please.

The last point I want to make deals with the immunization schedule. At the present time, we routinely vaccinate children in the United States against 11 vaccine-preventable diseases in a number of areas at high risk for hepatitis A, 12 areas.

What this means is a substantial number of injections and a substantial number of doses of vaccines that are needed for young children. In fact, if you cut off at 18 months of age, it now requires 16 to 20 injections, 16 to 20 doses, to fully immunize a child by 18 months of age.

This is a major challenge for parents, for health care providers. In some cases, five injections are being given at a single visit, and clearly, combination vaccines, if deemed to be safe and effective, would be very, very important in trying to assure everybody benefits from these vaccines. Next slide, which is the last.

So in summary then, vaccines are one of the greatest achievements of public health. Most vaccine-preventable diseases are at or near record low levels. There is an ever present threat of vaccine-preventable diseases, both within this country and from abroad, and therefore, there is a need for maintaining high vaccination coverage levels. Thank you.

CHAIRMAN BROWN: Than you very much, Dr. Orenstein, for this very upbeat presentation on the utility of vaccines, which many of us, I think, probably were not fully aware of.

Any questions for Dr. Orenstein? Yes, Dr. Modlin?

DR. KIM: Kwang Sik Kim. In the context of what we are discussing today, can you somehow elaborate whether indeed vaccine safety, the safety of vaccines per se, has been any contributing factor to achieving or maintaining high vaccine coverage?

DR. ORENSTEIN: I think the issue of vaccine safety is critical, and I think there's a critical need to assure the public and the physicians and nurses and others who give vaccines that vaccines are safe. I think there has been a substantial commitment to improving of what we already consider a very safe schedule.

This includes the move from oral polio vaccine to inactivated polio vaccine, from whole cell pertussis vaccines to acellular vaccines, and a variety of others. So, yes, I agree. It's critical that vaccines need to be safe and have a special standard for safety.

CHAIRMAN BROWN: Sorry, Dr. Kim. Dr. Modlin's sign is in my sight line right in front of you. So forgive me. Any other questions? Yes?

DR. STEPHENS: Walt, to you on the spot a little bit more, does NIP have an opinion about the issue directly for this committee?

DR. ORENSTEIN: I think not at this point. Clearly, I think we're here to hear the information and learn more about it.

CHAIRMAN BROWN: Thanks very much, Dr. Orenstein. The last -- One more question. All right.

DR. HUANG: Alice Huang. I have both a specific and a general question, the specific one being whether the varicella vaccine protects against shingles, with what we know about that.

The second general question is would you talk a little bit about herd immunity and the importance of that in vaccination.

DR. ORENSTEIN: In terms of shingles, the available data that we have show that the incidence rate of shingles following vaccination is substantially lower than what would be expected from natural virus.

Clearly, we haven't had the extreme long term follow-up, but at least in the childhood population I think the data are quite good that the risk is extremely small. It's not zero, and there have been vaccine viruses isolated from patients with shingles. The Japanese also are seeing a decrease.

I don't know, John, if you wanted to comment more on it. I'm not as familiar with the Japanese data. Then I'll come back to the herd immunity.

DR. MODLIN: Just very quickly, Alice, the Japanese, who have been using the Yoka strain for the longest, I think, have the longest experience. They recently have published data on that now is about a 20-year follow-up for some vaccinees that suggests -- that substantiate just what Walt said, that the incidence of Zostra amongst the vaccinees has been lower than one would have otherwise expected.

DR. GREENBERG: Greenberg. There is a large cooperative study in the VA system currently evaluating whether vaccination of people over the age of 60 or 65, people who would have been exposed to wild type varicella, would benefit and are likely to be protected by vaccination, which might have been your question.

So that -- The answer to that is unknown at the present.

DR. ORENSTEIN: The data I was quoting is really some estimates of risk of zostra, particularly in the childhood population and what we've seen and experienced in reports of cases.

In terms of herd immunity, we feel it's absolutely critical in terms of protecting the population. We know that there are populations that cannot be vaccinated, such as those with immune deficiency disorders or, if vaccinated, do not make adequate immune response, and they are protected through herd immunity.

We have achieved our measles successes without having to have 100 percent immunity in the population. I think that a number of groups derive benefit from vaccination that may not be vaccinated. They include one -- I mentioned those who medically cannot receive vaccines, for whatever reason or cannot mount an adequate immune response.

There are people with religious beliefs who do not desire immunization or do not feel -- feel immunization goes against their religious beliefs. They are benefitting by herd immunity, and those that refuse vaccination at the present time benefitting by herd immunity.

CHAIRMAN BROWN: Last question from Ms. Fisher.

MS. FISHER: Dr. Orenstein, as the head of the immunization program for the CDC, do you support strict guidelines for manufacturers to make sure that there is no transmission of BSE to American babies through vaccines using bovine sources for production?

DR. ORENSTEIN: I think that there should be guidelines for manufacturers, and I think that, to the extent possible, that risk needs to be as close to zero as possible, hopefully zero. But I think, with all of these things, we're going to have to weigh risks and benefits.

My hope is it's zero, and I think that we ought to try and go for zero, but with other vaccines we have to weigh the risks and benefits, and I think we need to understand what the magnitude of risk would be in order to put that into the equation of a risk-benefit evaluation.

CHAIRMAN BROWN: A postscript from Dr. Ewenstein.

DR. EWENSTEIN: Thanks. Have you tried to -- Well, I guess there are two parts to this. One, for the many vaccines that we've talked about, are there multiple sources, (a)? (b) Have you tried to project, without trying to infer anything from the question, what the impact would be on various, let's say, periods of time when a vaccine was not available what the impact would be on the resurgence of diseases that you've described?

DR. ORENSTEIN: If we could go back -- I don't know if you can go back to the schedules, because you have to go vaccine by vaccine. There are four suppliers right now of DTAP vaccine. There is a single supplier of inactivated polio vaccine. There are three suppliers, I believe, of Hib vaccine. There is one supplier of MMR vaccine, one supplier of varicella vaccine, two suppliers of hepatitis A, one supplier of pneumococcal conjugate vaccine. Did I leave any out? I think that covers them all.

In terms of the impact, it's very difficult to project. It would depend, clearly, on how soon vaccine could be reinstituted. The longer we go, the more the risk.

I would presume there would need to be some accumulation of susceptibles. How long that would have to be and in which populations is very difficult, because these are sort of stochastic kinds of things. It's difficult to know when or whom is going to introduce disease in which population.

CHAIRMAN BROWN: Please?

DR. DAUM: Bob Daum from the University of Chicago. As an infectitious disease practitioner, with many older, less expensive antimicrobials, we are now experiencing severe shortages because manufacturers just don't seem to be willing to make them anymore.

I'm sort of wondering whether you would be willing to comment on potential strain in this system where we as a practicing community, a medical community, need manufacturers to make these vaccines, because the government really isn't in that business right now, and what the impacts would be of actual threatened or perceived shortages of vaccines, in your view, on the vaccination program in this country.

DR. ORENSTEIN: Well, I think -- Thanks, Bob. I think, in my opinion, if we lose some of these vaccines, for whatever reason, I think we are going to see a return of some of these epidemic diseases. So I think we do need to weigh risks and benefits when we make any decisions about this.

I think it's not to maximize the benefits or minimize the risks, but I think they need to be weighed as fairly as possible in an overall policy decision. I think that I've tried to demonstrate that doing without vaccines is not without cost. There is a cost to society and a cost to the health of the public, and I think we just need to balance those to make sure we derive the maximum health and the maximum benefit.

CHAIRMAN BROWN: Well, I don't think I'll thank Dr. Orenstein anymore. We'll just have continuing questions. So go ahead.

DR. KOHL: I'm going to push you, Walt, a little harder. If this committee or the FDA agrees on a product recall of specific vaccines, has the CDC prepared any scenarios of what the impact would be?

DR. ORENSTEIN: We have not. We'd need to know which vaccines, and we would need to know the magnitude of that in order to do that. So we have not.

CHAIRMAN BROWN: Dr. Orenstein, you'll be here the whole day, won't you?

DR. ORENSTEIN: Yes, I will.

CHAIRMAN BROWN: So in general discussion, if any of these questions come up that Dr. Orenstein can answer, he will still be here, and we can continue to ask him. Thank you.

The next presentation and the last one before our morning break will be given by Dr. David Asher from the FDA.

DR. ASHER: Thank you, Dr. Brown. Good morning. I'd just like to add here that, in addition to other duties, I'm CBER's representative on the FDA TSE Intercenter Working Group, and one of the issues that we are concerned about is the development of an appropriate regulation concerning TSEs.

I will review FDA policies concerning BSE and the safety of regulated products, beginning with the first expressions of concern in 1991, soon followed by recommendations that manufacturers not use most bovine derived materials from countries with BSE, which remains today the policy of the FDA as well as of our sister agency, the U.S. Department of Agriculture.

Since we know that those recommendations were not always followed, I will also address briefly several factors affecting the risk that the use of bovine derived materials from various countries in manufacturing vaccines might result in transmission of BSE to recipients, an event that has not been demonstrated and the likelihood of which seems quite remote, but which might be catastrophic, should it occur.

Of course, there are precedents for accidental transmission of TSEs by veterinary vaccines and by human peptide hormones, though both products are quite unlike those to be discussed today.

Several factors to consider in estimates to risk are related to the source of bovine materials: The temporal risk, that is, the years when cattle in a country were infected; the geographic risk, that a country has BSE in its native cattle and the BSE rates in that country; and the tissue risk, the likelihood that various tissues of an infected animal contain the BSE agent.

I'm very grateful to the SSC, the Scientific Steering Committee, of the European Commission's Health and Consumer Protection Directorate General for recently issuing a number of valuable opinions addressing those issues.

Also to consider in evaluating the theoretical risks are details of manufacturing and end use of vaccines that I can discuss only very briefly.

We are concerned only with bovine derived materials, those from other ruminants being negligible in CBER regulated vaccines, and of the animal TSEs, only BSE has been convincingly associated with a human disease, new variant CJD with its unique constellation of findings, listed here, several of which are BSE-like. FDA's concern about the potential transmissibility of animal TSEs to humans predates the first description of VCJD in 1996.

Today we are mainly concerned about four bovine components used to manufacture vaccines: Serum collected from fetal and older animals in a high prevalence country during years when many cattle were infected; a derivative of gelatin prepared from the bones of cattle in several low prevalence countries; and bovine pancreatic extracts in meat broth, also from cattle in low prevalence countries.

For many years, FDA regulations have required that cultures used to manufacture biologics be free from extraneous organisms. Except for the so called ruminant feed ban of 1997, the FDA has issued no additional rule specifically regulating TSE safety. However, beginning in 1991 the agency has sent a number of letters to manufacturers of regulated products and issued published guidance expressing concern about the potential danger of ruminant TSEs for humans.

In May of 1991 the CBER Director first articulated concern for the safety of biologics and asked manufacturers to review sources of bovine and ovine materials that they used not only as active ingredients and excipients, but also as in-process reagents, including enzymes and cell culture components like serum and its derivatives.

In July 1993, CBER provided manufacturers with a recently revised "Points to Consider" document specifically recommending that bovine serum and other additives in cell culture media used for production of biologics be free of the BSE agent.

Later in 1993, CBER and other FDA centers sent letters published the following year recommending that most bovine components in regulated products not be sourced from animals in BSE countries, and noting that the USDA maintains a list of such countries.

I must add here that the FDA did not consider the possibility that a product prepared with components derived from cattle in a country not on the BSE list might still be in inventory when the country was added to the list later.

In 1996 following the recognition of VCJD, the Deputy Commissioner of Food and Drugs sent letters to manufacturers of regulated drugs, devices and biologics requesting that they take whatever steps are necessary to assure all concerned that they were not using bovine materials from BSE countries in the manufacture of products for humans, and stating again that the USDA maintains the list of BSE countries.

Finally, in April of this year, the CBER Director repeated that recommendation, clarifying that manufacture of biologics includes preparation of master and working seeds and cell banks, and pointing out that the USDA BSE list includes not only countries that have actually recognized BSE in native cattle, but also countries where the USDA has been unable to assure the FDA that BSE does not exist, the so called BSE suspect countries or status unknown countries, and reiterating the steps that CBER expects manufacturers to take.

As some members of the TSE Advisory Committee will recall, in 1994 bovine gelatin was temporarily excluded from FDA's recommendation against sourcing from BSE countries, but after process validation attempts failed to eliminate TSE agent during scaled down production of gelatin, and FDA learned that some brain, spinal cord and dorsal ganglia probably contaminated the starting material for bovine bone gelatin, the agency, endorsed by advice from the committee, again recommended against the use of bovine gelatin from BSE countries in injectable, implantable and ophthalmic products, and suggested increased precautions for oral and topical gelatin.

The TSE Advisory committee also has reviewed bovine tallow derivatives, and was generally reassured about the safety of such reagents from any source. Revised FDA policies concerning tallow derivatives are in development now.

Besides gelatin and tallow, all other bovine components are either covered by FDA's general BSE guidance or have been considered case by case.

USDA regulations, intended to protect animal health and only indirectly protecting human health, prohibit the importation not only of ruminant meat and meat products from BSE countries but also offal, glands and blood. Bovine gelatin not for human consumption or industrial use is similarly restricted.

Bovine serum -- next slide, please -- Ruminant serum from BSE countries can be imported under USDA permit so long as the Administrator of the Animal and Plant Health Inspection Service determines that it will only be used under circumstances that will prevent introduction of BSE into animals, and the USDA permit does not authorize exposing any animal to that ruminant serum, even species not known to be susceptible to TSEs. The capitalization here is the USDA's, not mine, and it indicates their level of concern about the safety of the material.

Most important, in December of 1997, published the following month, the USDA, having learned about earlier widespread exports of cattle and meat and bonemeal from the U.K. into many parts of Europe, prohibited the importation of ruminants and most ruminant products from all of Europe as a precaution, expanding the BSE list.

Now I will briefly review some information useful to estimate the theoretical risk posed by the bovine materials of concern today, starting with temporal risk.

To date BSE has been recognized only in cattle born in ten European countries, listed here in approximate order of the earliest birth cohort affected. The vast majority of recognized cases have been, and still are, in the U.K., which has reported over 176,000 to date, almost 2300 last year.

In the U.K. diseases affected some cattle born as early as the 1970s, peaking in cohorts born in the late 1980s when the USDA estimates that as many as .5 percent of all cattle there may have been infected.

The disease then appeared in cohorts of cattle born in France, Ireland, Portugal and Switzerland in the mid-1980s, and those born a decade later in the Benelux countries and in Liechtenstein and Denmark. The EC's SSC now suspects that there must also be some native cattle infected with BSE in Germany, Italy and Spain, although those countries have not recognized the disease.

BSE cases peaked in the U.K. near the end of 1992. They may have peaked in Switzerland more recently. The situation in other countries is not yet clear.

The SSC recently released a helpful estimate of the probability that cattle in a given country have been infected with the BSE agent and the probable current incidence in each of 25 countries that provided information, the geographic BSE risk estimate or GBR.

The GBR depends on a number of factors, including numbers of cattle in a country, imports and feeding of meat and bonemeal, rendering and recycling of meat and bonemeal within the country, elimination of specified risk materials, so called SRM, from carcasses, surveillance for BSE, and cattle culling practices.

The quality of TSE surveillance is especially important, since passive confirmation of disease in sick animals alone misses at least 50 percent of infected animals, while active examination of brains of apparently healthy older animals provides a more realistic estimate of incidence.

Both the intensity of BSE challenge -- that is, the exposure of animals to imported contaminated meat and bonemeal and to recycled meat and bone meal -- and stability, the effectiveness of national control efforts to remove infected animals, and contaminated products from the environment influence the risk that cattle are infected.

The overall SSC assessments were based not only on information provided by national authorities, but also on results of EC inspections, U.K. trade figures, and realistic worst case assumptions.

The current GBR, which seems inevitably destined for modification, recognizes four risk categories of country, from the highest, Roman Numeral IV which includes only the U.K. and Portugal, and a lower risk category III, probably to be further stratified, which includes all other countries known to have BSE in native cattle, plus the three suspect European countries.

Nine countries, including the USA, are considered to be in Category II. They are probably free of BSE, but have a history of importing cattle from the U.K., rendering some carcass into meat and bonemeal, and possibly feeding it to native cattle. The U.S. feed ban was put into effect only in August of 1997.

Four countries in Category I are considered BSE-free, although one may be reconsidered because of its imports from a category III country. Of course, many countries did not provide information to the SSC, but all those of concern to the FDA today except one did respond.

The third element of risk associated with source is the tissue risk, which will be reviewed in detail by later speakers today. Thus far, only neural tissues and intestines of cattle have been convincingly demonstrated to contain BSE agent. However, in the U.K. and in some other parts of Europe, lymphoid tissues are also removed from beef carcasses as a precaution, because those tissues are consistently infectitious in sheep and goats with scrapie.

The EC has a system to estimate the risk that a given tissue of a ruminant with a TSE, including cattle with BSE, may be infectitious. Unfortunately, this system, in contrast to the GBR, assigns the lowest number, most recently an Arabic numeral, to the highest risk tissue. Tissues in the two highest risk categories are listed here.

Note that the four bovine materials of concern today, shown here bolded, are all derived form tissues in either low risk Category III or in the no-detectable infectivity category IV, which we prefer to call minimal risk tissues.

Just a warning: Experience looking for infectivity in a variety of tissues form human CJD patients assayed by intracerebral inoculation of monkeys illustrates that small sample sizes can yield misleading results. Note here that CJD infectivity was found in only a modest fraction of kidneys, livers and spleens tested. Those would be tissue risk categories III and IV in the European system for cattle.

Testing of a small number of specimens with the use of less sensitive animal models might have failed to detect infectivity in those tissues. I hope that today's more recent information from the U.K. Ministry of Agriculture, Fisheries and Foods BSE pathogenesis study may serve to increase our confidence in the EC BSE tissue risk estimates.

Now for a short digression. What has led regulatory authorities to recommend taking such apparently extravagant precautionary steps for sourcing -- for example, the U.K.'s including lymphoid tissues among the specified risk material to be removed from older calves, the U.K.'s decision not to use its own blood donors' plasma for fractionation, and the FDA's repeated requests not to use most bovine materials from BSE countries?

The precautions may seem excessive, considering that there are, as we have heard, no actual scientific data showing that any of those materials is infected. However, those decisions reflect the uncertainty of the risk involved.

The basis for such decisions has been codified in the European Union as the "Precautionary Principle," which asserts the right of a society to respond preemptively to an uncertain risk while awaiting better scientific information.

In that regard, a recent opinion by the SSC expresses well FDA's thinking about minimal BSE risk tissues, noting that there is little doubt that under certain circumstances humans or animals could be exposed to the BSE agent by consuming ruminant blood products, and that this risk may be reduced or eliminated by a combination of various strategies, including source bovine blood from BSE-free areas or closed herds.

The SSC noted further that potential infectivity in bovine blood, and presumably in other minimal risk tissues, might result not only from some as yet undetected intrinsic infectivity to the tissue, presumably at low levels and perhaps infrequent, but also from potential extrinsic infectivity due to contamination of the blood with high risk tissue, either by slaughter or blood collection techniques.

There are a number of factors that should serve to mitigate greatly the risk of transmitting BSE, even if the country of origin had the disease in some cattle: all material from health, inspected animals, especially animals from well controlled and documented herds; a documented history that the animals had never been fed meat and bonemeal; source animals for the material too young to be in the later stages of the BSE incubation period, as in the United Kingdom's 30-month scheme; and potential cross-contamination of low and minimal risk tissues with specified risk materials reduced by using slaughter techniques unlikely to embolize brain tissue or to allow its leakage; and by careful removal and disposal of risk material at the point of slaughter.

Risk is also affected by the manufacturing process, although often to an uncertain degree, and you will hear more today about the potential effects of dilution, partition, and possible reduction of infectivity by heat in various production steps.

Additional, Sue Priola of the NIH is here today and available to comment on the theoretical, albeit unlikely, possibility that the BSE agent might replicate in some cell cultures.

The last element of risk to be considered in a traditional analysis is the end use of the product. Here we must recognize that vaccines at issue are all administered by intramuscular injection, a route that's more effective in transmitting most infections, including TSEs, than is the oral route to which transmission of new variant CJD has already been attributed.

I need not remind you that vaccinated children pose special concerns for caregivers, manufacturers, and for regulators. Children have a whole lifetime to incubate a slow infection. They are generally healthy, and they are especially vulnerable in that they are legally unable to give informed consent for treatments that they receive as much to protect others as themselves.

Their parents' continued confidence in the safety of vaccines will be necessary if our nation is to achieve universal immunization. Vulnerable people undergoing non-voluntary preventive treatments that contribute to the general welfare are entitled to receive the highest level of fiduciary protection.

The public might reasonably understand that protection to include the most careful possible sourcing of all components of vaccines at all stages of production.

When, due to misunderstandings, FDA precautionary recommendations concerning that subsourcing were not followed in the manufacture of vaccines, the obvious great benefit afforded by the product may outweigh any remote theoretical risk of harm to the recipients. However, the agency would generally expect deviations from these recommendations to be corrected as soon as feasible, and for the situation to be disclosed to the public. Thank you.

CHAIRMAN BROWN: Are there any questions for Dr. Asher? Yes?

DR. BELAY: David, can you expand a little bit on what you call extrinsic infectivity, where that infectivity comes from and whether or not there have been any measures taken in European countries to mitigate that infectivity that could end up in low infectivity?

DR. ASHER: The two possible sources of extrinsic infectivity in a low risk tissue come from the slaughter technique used and the tissue collection technique. The slaughter technique of greatest concern of those in which air is introduced into the cranial vault which is known to produce embolization of brain tissue, not only into lung, but it's now been documented into other tissues as well, though not specifically into muscle.

Less invasive pithing -- that is, the procedure of putting a rod through an entry wound into the skull and disrupting brain -- is also known to produce embolization. Less damaging slaughter techniques are less likely to produce embolization.

Information on slaughter techniques in the European Union may be available to the USDA. Perhaps Lisa Ferguson would like to comment on that.

CHAIRMAN BROWN: Well, before we have other comments, there is a document which has just been completed by the European Community with extraordinarily graphic descriptions of slaughter processes, and Dr. Bradley this afternoon, who is speaking, might want to -- if you have further questions about it -- give you more details, because he and I and a number of other people participated on the committee that drew up this document.

In general, slaughtering is done by captive bolt, which basically is a bullet on the end of a -- a bullet that never leaves permanently the pistol, and it's traumatic, but it has been relatively infrequently associated with any cerebral emboli.

The use of air injection and of pithing are both currently being discouraged, if not banned -- air injection -- as a guideline by the European Community. So this method of slaughter is on the way out, but has been used in some countries of the Western world during the period at which BSE was occurring.

DR. ASHER: The answer to the second question was during the collection of blood, particularly not fetal blood but from older animals, there is an opportunity for brain tissue exiting from a cranial wound to enter the blood.

The point I was making was that, if such techniques are avoided, the chance of extrinsic contamination is much reduced, and those would be mitigating factors.

DR. GREENBERG: Do you have some estimate of the likelihood that a country like the United States actually has BSE circulating and just below the level of detectability? What should be the level of assurance that BSE is geographically restricted to various areas?

DR. ASHER: The U.S. Department of Agriculture has an active surveillance program, and I gave up counting when they reached more than 7,000 brains from suspect animals, all of which had been negative. Perhaps Lisa has the latest figure on that, and estimate of the probability for this country.

It seems quite remote at the moment.

DR. FERGUSON: Yes. I would agree that it does seem quite remote. We've had a fairly strong surveillance program in place since 1990, including what we would term both passive and active surveillance. We're not looking strictly at central nervous system cases that are presented, although those, obviously, are included, but we are also sampling what we call downer cows. In Europe they are more often referred to as fallen stock.

These are animals that are -- and they can't stand, for whatever reason. In many cases, it's not a CNS type reason, but we are sampling from both of those populations all animals.

Over the ten years that we've been doing the surveillance -- I looked at our figures yesterday, and through May of this year it was over 10,700. At one point in time we did an estimate of essentially our confidence interval that we would find a one in a million case. I think it was like a 95 percent confidence interval, with our targeting in the adult population.

CHAIRMAN BROWN: Yes, and that one in a million figure, Dr. Greenberg, is one to keep in mind. It's entirely possible that cattle, sheep, pigs, chickens, fish and every other species known has a sporadic occurrence of CJD at the same rate that occurs in humans, one in a million.

What we can say is -- What we can't say is we don't know if that occurs. What we can say is that, if it does occur, it doesn't seem to cause a problem. Dave?

DR. ASHER: I would only want to comment. Regardless of whether one subscribes to the theory of spontaneous generation of the disease agent, the ruminant feed band is specifically designed to reduce or eliminate the recycling of any infective material, which is what clearly caused, as we'll hear later in the morning -- clearly caused the epidemic of BSE in the United Kingdom.

DR. ROOS: Ray Roos. David, you presented the SSC data regarding BSE in European countries. Now there is also a USDA list that you commented on.

DR. ASHER: Yes.

DR. ROOS: I'm wondering about the relationship of those two, since we are going to be asked to comment later about countries and origins of bovine material.

DR. ASHER: The USDA has what I would consider a more conservative list in that all of Europe, including the low risk countries, at the moment are prohibited, and it's on the USDA list that the FDA relies.

Now the USDA has allowed for the possibility of European countries being reinstated by the provision to the USDA of reassuring information. To my knowledge, since January 1998 when the interim regulation was published, no European country has actually been reinstated, and it's on that USDA position that the FDA, obviously, relies.

CHAIRMAN BROWN: Let me clarify that. I think the question was: Is the FDA using the USDA list as its list of BSE-free, possible BSE occurring countries?

DR. ASHER: Yes.

CHAIRMAN BROWN: And has that information been included -- that is, specifically included -- to the most recent letters to the manufacturer, so that there's no question that, if the FDA list currently might not include Country X but the USDA list does include Country X that it's been specifically communicated to the manufacturers that the USDA list essentially supersedes dated FDA lists?

DR. ASHER: The USDA -- The FDA has repeatedly noted that we rely on the USDA list. For the purposes of these discussions, though, there really is no difference, since all countries of concern today with the exception of one are Categories III or IV or "status unknown" in the European system. So it's really not a major discrepancy.

DR. ROOS: And the USDA list corresponds to the SSC tables that you have presented and, if not, which do we follow, David?

DR. ASHER: USDA is the agency to which the FDA since the beginning of this outbreak has turned for authoritative advice on BSE. The requirements of Europe are quite different, because they already have BSE in a number of countries, and in North America, so far as we known with the exception of one imported case in Canada, we do not.

So that the criteria for being listed in this country are much stricter than they would be in Europe, and the way the list was developed is different. In this country the list was developed as a precaution to protect animals and us. In Europe it was an attempt to estimate how much disease is present in a given country.

CHAIRMAN BROWN: So FDA guidance, which is what we're here to consider, is based on the USDA list, current. Yes?

DR. SNIDER: With regard to that issue, it seems to me the EU SSC list, as you stated, is more conservative as it relates to European countries, but then I guess part of the disconnect is that in Category II the SSC includes not only countries like Austria which USDA prohibits imports, but also countries like USA and Canada and would only include in Category I Argentina, New Zealand, Paraguay and Norway.

So one of the things we would have to struggle with is again, if we wanted -- if the principle is to try to be as conservative and protective as possible, are we talking about excluding USA and Canada as well?

DR. ASHER: No, we are not. Of course, the SSC list I cited for information and because today's issue is a European issue, not because we have any obligatory reliance upon that list, which we do not.

Let me point out that the USDA list is a "yes or no" list.

DR. SNIDER: Well, today's issue, but as it was pointed out by Bill Freas earlier, we are supposed to be talking about this from a very generic standpoint, not from particular manufacturers' sources of products, you know, today, but from now on.

I guess part of the concern is -- Now if for a variety of reasons, whether they are scientific, whether they are economic, whether they are political, countries start jumping around from one list to another, that's going to create some havoc, both for those of us trying to advise FDA and for FDA and for manufacturers.

So I think it's important to try to understand the basis for classifying countries as being places where we can obtain safe products, and I'm not questioning the U.S. being safe. I'm just having trouble trying to understand why we ban from Austria and don't ban from the U.S. because what's the USDA's basis for saying that when the SSC comes up with similar classification for those two countries. That's all.

DR. FERGUSON: Could I clarify -- I think it might be helpful -- some of USDA's actions and what we did in the interim rule that was published at that time, what we have done in the intervening time and probably what is predicted in the future.

When we initially published our interim rule where we extended the restrictions to all of Europe, that was a very conservative action, and we took that because we did not know exactly what the status was in Europe. There were publications out at that point in time that really made allegations about severe underreporting of BSE in Europe.

So we took that action. At the time we took the action, we also provided for any country to give us information that addressed various factors, and we would consider that information. If, through that evaluation, we decided that country was not a risk, then we would go through further regulatory processes and take them back off the list.

So we did get information from various countries, and we went through some evaluation processes with those. About the time we got that done, there were several other factors that intervened.

We contracted with Harvard to do a risk assessment internally, which is still in process, but also about the same time the Scientific Steering Committee decided to go through their similar process. Actually, the factors that they were looking at were very similar to the factors that we were looking at.

You know, obviously, with this disease you're going to have the same things come into play. So even though we had initially done some evaluation, once we knew that the SSC was going through this, and we were somewhat familiar with the SSC's process, we decided we would sit back and wait and see what their final determination was.

Actually, as it turns out, they were getting more information than we were. Obviously, they had a bit more access. So we were very interested to see if there was additional information that showed up in their reports that we were not privy to.

As it turns out, probably our risk estimations were very close. They were very similar, you know, the large groups of countries falling into different categories, yeah. So even though at this point in time our list has not changed on a regulatory basis, it very likely will change, because we've made that obligation initially, is if we estimate the risk of a country to be acceptable, then we will go ahead and take them off the list.

CHAIRMAN BROWN: Yes. And let me just add to this discussion and perhaps terminate it. This committee is not being charged with validating the decisions made by USDA and a variety of other organizations as to the relative risk of a country. What we're being asked to do is to give -- that is to say, given a category of BSE possibility versus non-BSE possibility, to move on to whether or not we think that it's a risk or not.

So we're just going to make the assumption that the USDA and other organizations are doing the best they can in making a valid estimate of the risk. We are going to move beyond that and just accept that, and then talk about whether it's a good thing or not.

DR. KOHL: I think some clarification for me, in particular, and the audience, possibly in general, might be helpful.

It seems that the USDA has put out much more stringent kinds of regulations and actually bans on certain animal products, whereas the FDA has, it appears, made recommendations without apparently enforcing them.

I'm not sure how that happened, and I presume it's based on what would happen when you withdraw certain kinds of products. But if that could be clarified for us, it might help put this into some kind of context.

CHAIRMAN BROWN: Dave, do you want to clarify it now, if possible, or shall we wait until this afternoon in general discussion?

DR. ASHER: Yes, it sounds like it has a large element of compliance involved. All I can say is that you have to keep in mind that guidance -- failure to follow guidance is not per se a violation unless the underlying regulation or a statute is violated.

When one finds out that there has not been compliance with guidance, there are only a number of things that you can do, absent an immediate public health emergency. One of them is to assert that failure to follow the guidance is a failure of following GMP, good manufacturing processes. Another would be to convene a meeting, a meeting like this.

CHAIRMAN BROWN: I'm going to terminate this discussion now. It's eleven o'clock. We're running one hour behind schedule. We will reconvene at 11:15.

(Whereupon, the foregoing matter went off the record at 11:01 a.m. and went back on the record at 11:16 a.m.)

CHAIRMAN BROWN: We have three presentations between now and the lunch break, and the first will be given by Dr. Gerald Wells, who has been a consultant -- well, he is now a consultant veterinary pathologist, but he's worked for years and years and years at the Veterinary Laboratories Agency, New Haw, the United Kingdom. Dr. Wells.

I might also add, just by way of introduction, it was Dr. Wells who made the initial diagnosis of BSE in the United Kingdom. Gerry?

DR. WELLS: Thank you very much, Paul. In this presentation I'd like to provide a background on the studies which have provided some estimates of the presence of infectivity in tissues of cattle with BSE, either those cattle in the clinical phase of the disease or, more importantly, I'd like to consider those at various stages in the pathogenesis, during the pathogenesis.

This presentation is not, by any means, comprehensive of the transmissibility studies of BSE, but concentrates on the most recent observations. All the studies that I'm going to discuss are funded by the U.K.'s Ministry of Agriculture, Fisheries and Food, and the standards of the new Food Standards Agency.

The pathogenesis of the TSEs in general gets its reputation initially from work that was carried out on scrapie of sheep, particularly by Hadlow and others, and the dogma regarding scrapie is that by parenteral routes or oral routes of infection, by non-neural routes, there is a lymphoreticular phase of infectivity prior to neuro-invasion.

That has led to, as we've seen already today, categorization of various levels of infectivity that occur in the different tissues in sheep, with Category I high infectivity in brain and spinal cord, medium maybe in lymphoreticular tissues, and then Category III in another series of tissues, and finally no detectable infectivity in Category IV tissues.

Bioassays were carried out in conventional RIII mice of the infectivity in tissues of naturally infected cattle, clinically affected with BSE. Infectivity has been found in those studies only in brain, cervical spinal cord, the terminal part of the spinal cord, and retina, all central nervous system tissues.

No infectivity was found in 51 tissues, but this indicates here approximately a total number of assays of 100, that the number of animals sampled per tissue is variable, and in most cases extremely limited.

With the occurrence of BSE has been the accompanying geographically and contemporaneously associated occurrence of disease in several other species. So this in itself has given a clue to the fact that the BSE agent does not deal -- does not occur with the same sort of frequency in species as scrapie, in other words has a different species range to that of scrapie.

Here are species that have been shown by bioassay to contain the same --

CHAIRMAN BROWN: Can we get someone to focus this slide projector, please?

DR. WELLS: -- the same agent as BSE here, Greater Kudu, the domestic cat, and the association of these species in Britain with exposure to meat and bonemeal products and the exposure of exotic species of cats to products of the bovine carcass, probably as raw meat material or spinal cord material from half-necks.

So with the occurrence of BSE, various studies indicated the -- In the early course of BSE, various studies indicated that there was a feasibility of carrying out a pathogenesis study of BSE actually in cattle. Certainly, the lesion profile in cattle, the lesion profile in mice and the biological characteristics of the disease in mice indicated that we were probably dealing with a single agent.

Furthermore, the apparent homogeneity of the PrP gene throughout the cattle population indicated that we could carry out a pathogenesis study with reasonable degree of predictability of results, of uniform results in the pest animals, providing a sufficient dose of agent was given.

So a pathogenesis experiment, which has been alluded to already, was set up, the objective being to determine the temporal and spatial development of infectivity and pathology following oral exposure of cows to a single 100 gram dose of affected cattle brain homogenate.

The protocol: Thirty cows in total, not a large experiment by some of the later standards, but all the number of cattle that could be housed in the facilities available at that time. Thirty cattle dosed orally at four months with the 100 gram brain stem material, and then groups killed sequentially at intervals through to 14 months.

The inoculum consisted of a pooled brain stems from 75 cases of BSE, and the material was sourced in 1991. The inoculum was assayed in RIII mice with an incubation period of 373 days, indicating that it was not the highest titer material, but probably equates to a titer of somewhere about 104 in RIII mice.

The tissue is inoculated into mice from each kill of the sequential kill study in cattle. I'll just very quickly go through the series. This was the tissues, the neural tissues, inoculated, and neuromuscular tissues, including triceps, masseter, longissimus dorsi, absternocapellicus muscles.

Lymphoreticular tissues were, obviously, included, and spleen, thymus, tonsil, and a range of regional lymph nodes and lymphonodes from the viscera. Alimentary tissues comprised tongue, salivary glands, pillar of the rumen, pyloric region of the stomach, portions of the wall of the duodenum, the distal ileum including pars patches, the spiral colon, not necessarily including lymphoid tissue, pancreas and liver.

A few other tissues were also selected for inoculation into mice, including kidney, lung, a portion of lung, respiratory epithelium from the nasal chamber, the left ventricle of the heart muscle, blood and bone marrow.

The results of the early assays showed infectivity confined entirely to the distal ileum. Here, if you can see that, the infectivity denoted by the red dots against an incubation period in mice here, in RIII mice, showed first at six months post-inoculation, and showed a decreasing mean incubation period up to 14 months and sort of plateaued out at 18 months.

No infectivity was found during the other sequential kills of the study until infectivity was detected in the central nervous system at 32 months after exposure.

Clinical disease was first apparent in cattle at 35 months, and here also parts of the peripheral nervous system, the dorsal root ganglia, and the trigeminal ganglia were involved and, interestingly, bone marrow infectivity was detected at 38 months post-exposure.

Also in this clinical period of disease, infectivity was again detected in the distal ileum here in the three final kill sequences, and we'll come to that in the next slide.

Ignore the term interim here. These are, in fact, now final results of bioassay here in C57 black mice from the distal ileum of cattle killed between 36 and 40 months PI.

Here we can see -- Again, ignore the coloring here, because these are now final results in all kills. Here the number of positive mice over the number of mice surviving wherein the first mice was confirmed positive, so any one of two here, at 942 days for the 12 and nine over 19 at 40 months.

A decreasing mean incubation period in the mice, but the incubation periods are close to the limit of detectability of infectivity, probably denoting limiting dilutions of infectivity in that tissue.

Just a quick look at the bioassay results of infectivity in the bone marrow of cattle 38 months post-inoculation, the only time point at which infectivity was detected in this tissue.

The clinical status of the mice: Only two out of 16 in the group at this incubation period of days -- two out of 16 were also histopathologically positive, but on application of PrP immunocytochemistry to the mouse brains, a further -- that should be six -- a further four animals became positive, again with incubation periods close to indicating limiting dilutions of infectivity.

In summary then, the original part of the study of the pathogenesis of experimental BSE in cattle showed clinical signs occurring initially at 35 months post-exposure; abnormal PrP from 32 months post-exposure; vacuolar changes in the central nervous system of the cattle only from 36 months post-exposure; and infectivity in the CNS again from 32 months and in the peripheral nervous system also from 32 months, and infectivity in the distal ileum from six to 18 months; and this hiatus here where no infectivity was detected until it again appeared, but at a much lower concentration, from 36 to 40 months.

A further number of tissues were taken from the same pathogenesis study at two particular time periods, 18 months pi and 32 months pi. These were tissues which had potential significance to medical procedures, and those tissues were heart valve, pericardium, aorta, skin, collagen, and bone, and collagen taken from the Achilles tendon. Those were all negative, and that study is completed.

Just to go back now to some older studies that were carried by Marsh and Hadlow before I introduce the next experiment: These studies indicate the value of within-species assays.

Since many of the -- All the assays we've been talking about so far are from cattle to mice, using the most effective route of exposure, the i.c. or sometimes the i.c. plus i.p. route; but here with TME tissues -- tissues from TME experimentally infected TME mink, when assayed in mink, show relatively higher titers than if they were assayed across a species barrier.

Notably, skeletal muscle -- this is one of the very few observations of indicating any infectivity in skeletal muscle in TSEs.

So the next study was to compare the titration of infectivity within species, cattle to cattle, compared with a titration of infectivity in the most efficient conventional mouse model for primary inoculation, which was in RIII mice.

The injection in mice was by -- in cattle, rather, was by a semi-stereotactic method into the brain stem, and the needle was withdrawn during inoculation to deposit the 1 ml of 10-1 inoculant along the needle track.

The objectives of the study, as I've stated: to measure the underestimation of infectivity titer of BSE when titrated across a species barrier in mice, and to produce an approximate dosing incubation curve of infectivity of brain from BSE-affected cattle.

The design of this study was six groups of four cows were inoculated i.c. at four months with a single dilution of BSE brain pool using a tenfold dilutions from 103 down to 108. Parallel titration was carried out in RIII mice i.p. with a range of 10-1 to 10-6 dilutions.

This gives results to November of '98, but interestingly, now the experiment has been terminated at 86 months post-inoculation, and the results in terms of numbers per group affected have not changed. So unlike some titrations, we have a rather messy result in that we have three groups here with an incomplete tape.

The mouse titration was completed, obviously, long before the cattle titration, and the titration -- the Karber titer in mice is 103.3, relatively low.

The results of the comparative titration showed that the Karber titer of bovine brain stem pool, five cases of BSE went into the pool. In RIII mice, as we said, 103.3; in the cattle, 106.

Side by side with this comparative titration there was a study carried out where a pool of lymph nodes and a pool of spleen tissues from the same five cases was inoculated at a 10-1 dilution into mice and in cattle.

The good news is that the Fresian/Holstein cattle were negative at the endpoint of the study, 86 months p.i., and at the end of this presentation I'll show you a dose response curve calculation for this part of the study. In RIII mice, negative again at the endpoint of 700 days.

So the conclusion from the comparative titration study is that the underestimate of infectivity titer of BSE brain tissue titrated across a species barrier in mice is around 102.7 -- in other words, 500-fold, somewhat less than the previous more pessimistic estimates of a thousandfold.

The spleen or lymph node pool from confirmed cases of BSE clearly must contain less than 10-1 log 10 i.c. LD50 gram.

So taking tissues from the pathogenesis study, we have now or sometime back now started a study in which we have titrated the tissues from the pathogenesis study or selected tissues in cattle to determine infectivity in a range of these tissues at different time points from the original pathogenesis study.

The only results of that study to date are three positive groups, the distal ileum taken at ten months post-inoculation with an incubation period of close to two years, distal ileum at 18 months here, definitely at two years, and caudal medulla and spinal cord pooled from the animals at 32 months, again as expected, an incubation period here, which is indicating a fairly low titer.

If we now look, finally, at the estimated dose response curve of bovine brain from cases of BSE after i.c. inoculation, here the data only goes up to 39 months, but this is the projected dose response curve at limiting dilutions, and here we can see that around the two-year those cattle in the previous slide will have an approximate titer in cattle of 102.

There I'd like to leave it and just to say that, clearly, from these experiments there is no evidence as yet of infectivity in any of the tissues that we are concerned with in this session today. Thank you.

CHAIRMAN BROWN: Thank you very much, Dr. Wells. I think we'll go on immediately to the next presentation, given by Dr. John Wilesmith, veterinarian and head of the Epidemiology Department at Weybridge.

Again, by way of introduction, Dr. Wilesmith was responsible for, I think it's fair to say, unraveling the mystery of the epidemiology of BSE in a very timely way, and I think the United Kingdom and all people concerned with these diseases should be very grateful both to Dr. Wells and to Dr. Wilesmith. John?

DR. WILESMITH: Thank you very much, Mr. Chairman. That's very kind.

What I've got to say to you is probably not very much new today. Most of the studies I've been involved in, the epidemiological research has, obviously, been more concerned with the animal side in this pool, sorting out that side. But there have been some, hopefully, important things which have been related to human health, both in BSE and also perhaps FSE, the feline spongiform encephalopathy epidemic.

I'm going to concentrate on BSE, and it's going to be sort of bits and pieces perhaps which, hopefully, are of some relevance. The title, you'll be pleased to hear, is longer than the talk.

Well, the first thing I wanted to say is something about the sort of update on past control measures and onsets of exposure, and then say a little bit about the current status of the epidemic.

I'll restrict my comments now about the European situation to a very few words, because that's really been covered, and then finally I was prompted, rally, to say something about the large cohort study which was completed in 1997 and started up in '89, because I gather that has had some sort of interpretations with respect to the risks of calf fetal serum. So we'll go through in that order.

Well, you've seen the epidemic already, and this takes you up to March 2000 for the confirmed cases, and this is by month and year of onset. The epidemic does appear, as you see, to be going away. But coming back to the, as it were, beginning, there have been a number of things that we were interested in, and that's when, you know, was BSE a new disease and could we identify when the first cases were, and could we determine when the onset of effective exposure was?

The rest of the interest, really, has been then throughout the epidemic of trying to determine what the effects of the interventions have been, and of trying to determine whether there is any other means of infection other than the food borne source or the feed borne source, I should say. So I'm going to say a little bit about those with some relevance to the sort of human health aspects.

Well, there's been a lot of work going on right from the beginning in terms of trying to get some idea of when this thing started. I think we really have got some fix, and it does look as this whole thing started around April '85 in terms of clinical disease, and that comes, really, from my initial epidemiological studies and also Gerald's sort of review of archive material, and we keep getting back to April '85. I'm not saying there weren't cases before, but that seems to be the substantive start of the whole thing.

When it comes to the onset of exposure, then we did some fairly simple modeling way, way back in 1987. That suggested that we had this sort of sudden onset of effective exposure at least to cause the clinical epidemic in '81-82.

Now we've done all sorts of things in between, and myself and others have sort of modeled this, and they come up with a similar date. We've recently sort of taken the whole of the epidemic and done some rather large and grandiose sort of spatio-temporal analyses, and we seem to have substantiated that.

So to summarize what I've just said is that we had this initial suggestion of the winter, if you like, of '81-82 as exposure starting. The modeling studies seem to have supported this time, and having done a great deal more at trying to get to grips with this, it does seem that this all fits together without being too tautological and going around the same houses in these studies.

So if one needs any confidence about sourcing and dates, then that might give the committee some assistance.

In terms of the intervention measures, these are probably really irrelevant maybe to the human side of things, but because we are looking at the ruminant derived protein ban in July '88 and the SBO ban, the specified bovine offal ban, in November 1990. Of course, the SBO ban for humans was the year before in September 1989.

To give you a flavor of what's perhaps been happening in the animals in terms of immediate effects -- by immediate, I mean in the first 12 months after their introduction -- again a number of efforts have been made to look at this, but this is the results of the really sort of survivorship analyses in some detail which we completed recently. Hopefully, the papers will be published shortly.

The ruminant protein ban had a 67 -- or produced a 67 percent reduction in the first 12 months after that ban. Not perfect, because as you all know, there were some imperfections in terms of the SBO ban itself and also we have this problem of continued cross-contamination, particularly in mills before the -- hopefully, before the August 1996 total ban on mammalian protein being fed to animals.

The other one which may be convertible to what the effects of the SBO ban in humans are is that we had a 46 percent reduction in risk in the first 12 months following that ban.

Personally, I think one care needs to be taken in that. People have got a little bit worried perhaps in terms of the human risks because of that figure, but my view is that I think the noncompliance with the SBO ban was probably more hazardous to the animal population than the human population. But that perhaps gives some sort of start to the whole thing.

In terms of exposure windows, this has been something of interest to those people who have been trying to model variant CJD, and this perhaps is a little bit crude. But we started off by thinking that the main exposure window was between 1985-89.

Obviously, there's scatter around both ends of that because of the preclinical cases pre-'85, and if the SBO ban was not as perfect as perhaps it might have been, there might be something happening after '89. But that seems to be the high risk period.

The '85 start-up is quite interesting in terms of some of the exposures to other species in that it does seem that, although we have incomplete ascertainment for the cats, the domestic cats, the ones that we see at the beginning of their epidemic would have also been exposed in '85, and it does seem to indicate this quite -- indicates the build-up of infection in the circulating meat and bonemeal in animal products at that time.

The epidemic had really driven the propagation that occurred to get really high prevalences of infection in that circulating material.

The other is a minor point, and perhaps for consideration in terms of vaccines, but it's still interesting that we can't find out what the exposure of the human population was in terms of CNS, brain and spinal cord, and that contained in mechanically recovered meat. It really is quite difficult, and we probably know more about the feeding of animals than the feeding of humans.

Back to the epidemic curve, there are a number of things going on in terms of monitoring this decline in the epidemic. We have a number of problems that the critics sort of have fun with in that currently in terms of reported cases we are getting around about 20 to 30 a week, of which on average 25 percent will be negative histopathologically.

If we look at the 1996-born suspects reported, then we have nearly 200 of those reported, and we only have two positives. This is an unprecedented negative range, and it leads people to say that this is -- you know, we are now seeing BSE II. In fact, it's just a fiction, really, of the surveillance system, and we will, hopefully, see these negatives coming in. However, there's also people wanting confirmation that this epidemic is going away.

Surveillance has been mentioned in the European context, and I'll come back to that. But just to put you in the picture of what's going on, in the first three months of 1999 we conducted an over-30 months scheme survey of the OTMS animals.

We actually pointed the survey to the animals greater than five, just to get a bit more power in the whole survey. You can see that we took a sample of just over 4,000 animals, which was me estimating what we might actually find, given the current diagnostic tests.

Well, we did find .45 percent of animals histopath positive. The survey was designed to detect half a percent. So that wasn't too bad.

On the new tests which may be of interest, we did process these samples or colleagues in Switzerland did process these samples by the prionix check test, and that did not reveal any additional positive animals. It entirely matched using a blind technique. They were not told which were the histopathologically positive animals. They just matched the histopath animals, which was quite interesting.

In terms of further tests then, we are using a Delphia technology which was developed by Jim Hope and colleagues in the Institute of Animal Health in Britain, together with colleagues in the VLA, and we are still processing these samples.

It's now been sort of set up for survey use. It's not actually being alternated, but we are processing these. It is interesting to see what these tests are actually detecting.

The Delphia may actually be somewhat better than the others at detecting preclinical infection. It's a complicated business, and we seem to be learning more and more.

CHAIRMAN BROWN: John, were the histopathologically positive animals clinically ill or were they clinically healthy?

DR. WILESMITH: Sorry. These were clinically normal animals.

CHAIRMAN BROWN: Normal?

DR. WILESMITH: Yes. There were 18 of them, if you want some expansion. There were 18 to make up that prevalence, and going back to the farms, 17 of the farms, 17 of the 18 farms had all had cases before. There was no indication that these animals were being shipped off, and there's no financial advantage for them to be done so.

As a follow-up, an additional survey to try and get this sort of independent assessment of the decline, we started in May 15. We don't have any results yet. As I say, we're trying to get this independent assessment of the decline and, hopefully, allow for evaluation of the Delphia.

I should say the Delphia is a post-mortem test of brain or spinal cord, and it will also allow me to see if we can actually work out the sample size for the next survey in 2001. It is likely that this is going to exceed the resources, because it could get into the hundreds of thousands, and unless some automation of testing goes on, we might not achieve that.

Turning back to Brussels and what Brussels now are requiring from one of the more recent amendments to one of these Commission decisions -- The Commission decision number, if you collect them, is 98/272, and this is about surveillance for BSE, and it is enforcing all member states to do surveys on fallen stock, and they are designed to detect - I think it's a half-percent prevalence with 95 percent confidence.

This is not estimating prevalence. It's detecting the presence. I think that will be important. Some of the results of that surveillance will be important in making some further assessments of the geographical BSE risk assessments that I was involved in and have already been alluded to, to actually see precisely -- not precisely, but estimate somehow better when these countries became exposed, when things started happening and so on.

So it's not ideal for the British situation to take fallen stock. I would prefer to go on with the over-30 months abattoir survey, but that's the decision that's been made, and it will, hopefully, reveal some interesting results.

France, as you probably gathered from the press, have already started on this and are in the process of trying to collect 44,000 such animals over a period of 12 months.

Right. Back to the epidemic curve. All I wanted to say was, in terms of the future incidents which people still are quite interested in, the predictions are actually going quite well. You can see that we have some 95 percent confidence intervals for 2000 and 2001, and all I can advise is to look at the righthand end of those confidence intervals, because those seem to be the ones that are nearest.

So we've more or less got a 50 percent reduction in decline in the epidemic, which is much as expected from the intervention on the food-borne source.

Now I was going to say something about BSE in Europe and other countries. I'll try and keep it brief, especially as what the Chairman has advised on this issue of the geographical BSE risk assessment. But it is true that we did write a paper a few years ago on the risks of exporting British animals to member states.

This caused -- The paper caused a certain amount of commotion. It was unfortunate, because everybody sort of thought that we were criticizing their animal surveillance.

I wrote the last three paragraphs of the discussion of that paper fairly carefully, and it was actually saying that you didn't really need to detect BSE. You could do a decent risk assessment and consider control measures, irrespective of whether you had found it or not. However, that was ignored, and it started into a battle on import figures and quality of surveillance.

Since that, as you've learned, the SSC stimulated this very, very large project to look at the geographical risk assessment, and just to put it in perspective, this project, if you like, was initiated because of the need to perhaps persuade other member states to put in SRM bounds, which they were reluctant to do because of the cost and so on, and the countries are saying why should we do this when we think our risks are low.

That is the background to it. I think, in terms of interpreting some of it, summaries, as far as I know, are on the SFC's Web site. The full risk assessments should be available. They might even be available on the Web site since I came away, but they will require -- If you need to look to see when significant risks might have been present in any country, you may need to read those risk assessments in a little bit more detail.

All I will say is that the one thing that we have learned from that exercise is that, really, most, if not all, of the European member states were capable of propagating the BSE agent once seeded, and that is a change from what everybody was trying to claim, that it wouldn't happen with us.

That might sound critical, but it was a kind of feeling of denial that has been prevalent in the past, and I think the risk assessment has been useful. It may be a bit delayed, and I hope that it's useful to answer the question about categories of countries.

I think, when you get to the ones and twos, you shouldn't worry too much whether you're in I or II. It's quite subtle in terms of that sort of categorization. Again, I can only point you to read the details. So I'm not going to say anymore about that.

Just to finish off, Mr. Chairman, I'd just like to say something about this cohort study which has been criticized in all sorts of manners, and people have had expectations of it more than it really deserved. This is the basic plan.

What we were trying to do here was to get in a simple epidemiological way a population estimate to determine whether there was a maternal risk, a maternally associated risk.

That is, where offspring of BSE confirmed cases more at risk than offspring of dams which did not have clinical BSE in their lifetime? Was there a difference between those two lots of animals? So nothing to do with how long were they with their mum and so on. It was much simpler than that.

So what we did, we used the BSE database, because we had been recording all these details about offspring and so on from the beginning, and we went out to the naturally affected herds, and we purchased classically the pairs of animals, born in the same herd, in the same season, an they had to be castrated or virgin heifers.

We started this in July '89, purchasing them. We actually ran out of animals in December 1989. We had exhausted the population, and this is another thing that people don't quite appreciate. We did not have an infinite population to go at. We were buying these animals, and they weren't that common.

So we have one -- One of the pairs is an offspring of a confirmed case, and the other is the offspring of a normal dam. That is, she lived until six years of age without getting clinical BSE. We maintained these animals in their pairs on three of the old farms -- that's what the ADAS really means -- until seven years of age unless death or the need to slaughter intervened.

Anything suspected casualty or when they got to seven, they were all looked at histologically by Gerald and his team, all blind. What it says on the bottom lefthand corner -- you probably can't read -- is that the last animal reached seven in November 1996. So very expensive, but actually was quite a straightforward hypothesis or objective.

Now just to put this a little bit in words, the objective of the cohort study was to provide this estimate of the risk of offspring of confirmed cases of BSE of developing BSE themselves compared to the offspring of BSE unaffected animals. Ever so simple.

The study was not concerned specifically with maternal transmission. So the study could not really identify or even suggest perhaps the mechanisms involved in any positive maternal effect observed. So I don't want to get this out of context. I don't want to labor the point, really, either. But it is important to realize what the limits of this big study were.

Well, the results have been published, and this is just really the summary table, giving you the -- The results have been published. As you have seen, there was a risk difference between the two groups of 9.7 percent.

In summary, if you want a summary statement of that, then it means that offspring of animals born to confirmed cases in the last six months of their incubation period probably have a ten percent risk of BSE. That has been used, actually, the results of that.

Although such effect is really true of maternal transmission, it couldn't maintain the epidemic. Nonetheless, an offspring CO was commenced in 1998 and is proceeding prospectively.

So we've got this apparent ten percent risk for offspring of clinically affected cows born during the last six months of the dam's incubation period. The results cannot confirm the occurrence of maternal transmission, only this apparent maternal effect. There's a great debate, as some of you will know, then about the whole business of maternal transmission.

There was no evidence for a reduced age of onset of clinical signs produced in the offspring and, therefore, reduced incubation period, suggesting that they probably got it as calves, and further research is required to investigate the hypothesis of the maternal effect, notably its presence in the absence of a feed-borne source.

I'm afraid that's not going to be possible, because of the offspring CO, and we've not been able to do any further studies. I'm afraid it will remain as it stands in terms of BSE.

Thank you, Mr. Chairman.

CHAIRMAN BROWN: Thank you very much, Dr. Wilesmith. If there are a maximum of three questions that might be posed for either Dr. Wells or Dr. Wilesmith, we will ask for them now. Well, that's four. Seems the Vaccine Committee is the aggressive part of this joint meeting.

DR. HUANG: I'm Alice Huang. I think that for risk assessment as well as for surveillance, one of the most important questions we have here before us is an understanding of the assays that are being used.

I have here, from what I understand, that certainly between infectivity doses and species in cows or in mice that there's a 10-2-103 there. However, I would like to know, first, in the RIII mice, are they special? Can they be improved by genetic manipulation?

Also, what is a Delphia test, and what is the prionics test? I think all those would be helpful to clarify.

DR. WELLS: On the question of the mice, RIII mice and C-57 mice, they are the short incubation period, the homozygous sync gene or the short incubation PRP gene mice that are used -- the conventional mice that are used for all the assays and part of the panel of conventional mice strains that are used for assays of both scrapie and BSE.

You're quite right that there are studies now that have carried out transgenic studies of infectivity in transgenics. But I'm not aware of any of these that have actually standardized the procedure to a degree that would enable us to use them in a routine manner.

CHAIRMAN BROWN: Yes?

DR. GRIFFIN: Well, have they been directly compared? Are they more sensitive than RIII or Black 6 mice? I mean, is that direct comparison --

CHAIRMAN BROWN: Maybe Gerry knows more than I do, but to the best of my knowledge, the RIII mouse remains the most sensitive assay animal with the shortest incubation period.

DR. GRIFFIN; So transgenesis into that mouse does not improve things.

DR. WELLS: That's our primary transmission.

DR. GRIFFIN: I think the real question is -- I mean, I have the same question as Alice's. What's the sensitivity of the assays, all these various assays, and can they be improved; because it sounds like that's really a limiting factor in trying to --

CHAIRMAN BROWN: That is, the question goes to whether or not the demonstrated tissues or the tissues that have been demonstrated to be infectious could be, shall we say, the tip of the iceberg.

DR. GRIFFIN: Exactly.

CHAIRMAN BROWN: There might be low levels of infectivity that haven't been picked up yet. Right. Well, I think the answer to the question is maybe not the tip of the iceberg, but certainly low levels of infectivity might be present, if you are assaying in any species that is not the host species.

On the other hand, you have seen evidence presented in which the species barrier has been eliminated by using cattle as the assay animal, and the results of those rather extensive assays are very optimistic. That is, you can't get better than cattle and cattle.

DR. HUANG: How about the prionics test and the Delphia test?

CHAIRMAN BROWN: Go ahead, John.

DR. WILESMITH: I'm not an expert on these tests. These are two of four tests which were put through an EU evaluation. I use the word carefully, not a validation. Briefly, the prionics is in kit form, and it's basically in an ELISA format. Okay?

The prionics uses this Delphia technology which I really am light on, but developed by a company called Wallach, and it's this rapid -- sort of detecting this rapid fluorescence that one gets from the test system.

So they are basically trying to detect various forms of PrP-SC, and that's the interesting bit, I think, that we're learning from these tests, because they are all actually detecting different forms, aggregated and progenase K resistant. I think we might actually get some information from comparing these tests on, if you like, the pathogenesis of the development of abnormal forms of PrP.

So they are in use and so on, and the prionics is the most attractive if you want to process a lot of samples, but it's no better than a good pathologist.

CHAIRMAN BROWN: If you want to make the Swiss rich, prionics is the test. As a matter of fact, they are all good tests, and several of them depend on an ELISA format with refinements of detectability. Some would argue that the Western blot remains the gold standard. Immunohistochemistry, in some cases, in different studies you get a little -- you get an occasional positive immunohistochemically that doesn't turn up in a Western; vice versa.

There is an immunoblot. There is another technique now which takes formalin-fixed tissue and converts it into a kind of immunoblot. There are a half-dozen different technologies out there, and they have varying degrees of sensitivity, but in general the sensitivity is certainly equal to the same tests used on conventional infectious agents.

DR. ALMOND: Mr. Chairman, could I just add that I was on the EU committee that was established to validate those four tests. The validation was carried out by the importation of 1,000 clean brains from one of the clean countries, and that they were randomly mixed blind with 250 brains that were provided from confirmed cases from MAF in London.

Three of the four tests identified 100 percent of the positives and all of the negatives as such in the way the material was presented. So they were very good tests.

The only caveat we should add, which John has already alluded to, is that these animals from which the positive brains were taken were all clinically sick animals and, of course, therefore, terminal. They had been confirmed by histopathology.

None of the tests were assessed in terms of their ability to detect preclinical animals. However, each of the tests were tested with dilutions of brain macerate where the dilution was of an infected brain by uninfected brain. Some of the tests did rather better than the others in terms of the dilution to which you would still get a positive with those brain macerates.

It was absolutely clear that what was required to follow up on those tests was a diagnosis of the animals that were in the pathogenesis study that Gerald Wells described, so you could then assess how the tests were performing on preclinical animals. In that sense, the sort of comparison that John talked about will be useful at the moment. But as far as the tests today are concerned, they have only really been tested on clinically sick animals.

CHAIRMAN BROWN: Yes. The other part -- We're going to have to stop again, but the other part of the question, of course, is we're talking now about optimum tissue, brain tissue. When you're talking about muscle, when you're talking about plasma, you may be in a somewhat different situation, and none of these tests are as sensitive as a bioassay in detecting very low levels of infectivity. I mean, that's a fact.

All right. We'll move on now to the final -- not the final, actually -- to a presentation about the European Union approach and perspective. I have two speakers listed. The first is Professor Jean-Hugues Trouvin.

DR. TROUVIN: Thank you, Chairman. I would indeed like to present to the committee the way the question of BSE has been answered in Europe since the early 1990s. This has essentially been done by presenting the European guidelines on minimizing the risk of transmitting the BSE and TSE. After my presentation my colleague, Dr. Dobbelaer, will expand and apply the EU approach to the vaccine. Next slide, please.

In this presentation I would like essentially to present the guidelines, the three scientific criteria which are used, some additional measures, discuss also some aspects of the guideline, and then the concrete. Next slide.

The European guideline was issued first in 1991 at the very beginning of the epidemic in Great Britain. The revision of the guideline took place at several locations, but the most significant revision was in 1999 when the guideline became an essential part of the EU regulation regarding TSE requirements in medicinal products.

Originally dedicated to cover strictly the BSE question, the scope of the guideline has been now adapted to cover all TSEs in animal species, particularly ruminants. However, this guideline does not cover the human form of spongiform encephalopathy, and thus excludes products of human origin. For this presentation I will refer only to the BSE aspect.

The guideline covers all types of material derived from ruminants which can be used in medicinal products either as active substances or excipients or even in-process reagents during the manufacturing process. In other words, all the necessary measures to minimize the risk of TSE in products entering the pharmaceutical industry should apply, whatever the use of the product. Next slide.

As stated in the guideline, the aim of the document is to clearly identify the necessary information for assessing the TSE risk for a given product. Basically, three pieces of information should be considered: The origin of the animals (geographical parameter); the nature of the tissue collected and used; and the products and process or processes.

This clearly shows at the very beginning of the guideline that the risk evaluation is and should be a multi-parameter approach which also takes into consideration the nature and use of the final product. Next slide.

Let's now go to these three criteria. The first criterion deals with sourcing. It is well acknowledged in the guideline that this is the most important criterion. This criterion, obviously, is directly linked with the status of the country regarding BSE cases, and the guideline envisages, thus, three situations and states that the most satisfactory source is from countries which have no reported cases of BSE. However, the guideline does envisage the situation where materials can be sourced from countries where cases of BSE have occurred.

In this case, additional safety criteria have to be in place in these countries. Needless to say that sourcing from countries where there is a high incidence of BSE should not be envisaged. This recommendation has been made in 1991 and, obviously, is valid essentially for the risk for the beginning of the outbreak of BSE in the U.K.

The guideline envisages also the possibility to make use of well monitored herd, whatever it is located and wherever it is located. As we got now the so called BSE status for a given country, it is important to mention that the OIE criteria are those recommended and used in the guideline.

The BSE status is a very difficult matter, as essentially it does not only rely on the number of cases reported or detected in a given country, but takes also into consideration many other parameters and other risk factors. Next slide.

The second criterion to be taken into consideration is the nature of the tissue collected. As the committee knows, it is necessary to consider the tissue distribution of infectivity. Depending of the tissue, the risk of collecting an infectious material is thus largely different.

It is important for that to remind the WHO classification -- next slide -- which envisages four categories of tissues, depending on the level of infectivity. This has already been mentioned by Dr. Egan and Dr. Wells.

First -- There are two points on this slide to be considered. The first point is that most, if not all, the bovine derived materials we are dealing with today are classified in Category III, i.e., with low infectivity, or in Category IV where no infectivity is detectable, at least with the limits of detection of the test.

The second point in this slide is that specifically for BSE this classification is a worst case scenario as, in fact, as already mentioned, infectivity distribution in affected cattle seem to be restricted essentially to the central nervous system and some part of the digestive tract. Next slide.

Another point to be considered for the tissue aspect deals with the risk of cross-contamination during collection of the considered tissue. Cross-contamination is a well known source of risk which, obviously, has to be carefully checked in the collection procedures. Next slide.

Another criterion which has also to be taken on board when assessing the risk is the age of animals. Infectivity, as you know, replicates and accumulates in certain tissues, and it is thus logic, as already shown, to collect from as young animal as possible.

This criteria is, unfortunately, not always applicable, depending on the type of tissue you wish to collect.

In summary for this tissue aspect, it is important to note that, even if the source is in a BSE country, the risk of collecting infected tissues is, obviously, depending on several other parameters and factors such as the tissue itself, the age of animal, and the risk of contamination, not only based on the geographical origin. Next slide.

The third criterion to be considered deals with the manufacturing process. In fact, this notion of manufacturing process encompasses two aspects, the manufacturing process from which the concerned bovine derived material is obtained and the manufacturing process in which the concerned material is used.

For the process which give rise to the concerned bovine derived material, it is important to mention that some processes can be very "soft," e.g., the collection and processing of the fetal calf serum can be very "harsh."

This is the case for, for example, tallow derivative. I know this is not the subject of today, or even the gelatin, but clearly this process has to be taken into consideration in the risk assessment.

The second process we have also to consider is the manufacturing process in which the material is used. It is also important to mention this process, as it can provide further safety measures, for example, via dilution, via partitioning, and so on.

This is essentially true for bovine derived materials which are used in the production of vaccine, and this point will be illustrated by Dr. Dobbelaer. The guideline, however, does recognize the spatial resistance of the agent to the inactivation process, which is clearly a limiting factor in the safety of those products.

Having gone through the criteria which have to be considered in the BSE risk assessment, I would now like to discuss some of them before concluding this presentation. Next slide.

This slide just to sum up the three criteria which should be considered in the BSE risk assessment. Again, and clearly, this is a combination of factors which contribute to the safety of the final product. Next slide.

I think it's necessary to take a few minutes, if possible, to discuss the geographical criteria. As already mentioned, the BSE status for a given country is often based on the incidence of clinical cases declared or detected in this country. However, it is necessary to acknowledge that incidence is largely depending on the quality of the surveillance system and also depending on many other risk factors in the concerned country, as illustrated in the OID criteria.

There is essentially -- As already mentioned by Dr. Asher, there is in Europe a new proposal to introduce a concept of geographical BSE GBR. From this concept -- next slide -- it is possible to classify countries according to their risk of having BSE cases diagnosed on their territory.

Without entering into detail of this classification, it is worth noting that USA and Canada, as already mentioned, would be considered as being in Class II, and most of the European countries are considered in Class III. This is to say that the geographical criterion is essentially fluctuating, and the number of cases declared should not be considered as an absolute proof of safety.

What would be the confusion for a given product declared safe because sourced in a country where no BSE cases have been reported if the day after the BSE status changes with one or more cases declared? Should the change in the BSE status be a significant and sufficient reason to consider that the safety of the concerned product is no longer guaranteed? Next slide.

In addition to that, and even if we consider the BSE status as of paramount importance, are the technical problems such as traceability and certificate of origin should also be mentioned. So, clearly, it seems to be reasonable to conclude for this geographical criterion, as explained in the EU guideline, that the geographical criterion cannot be considered as the only safety criterion. It is a necessary criteria, but certainly not an absolute yes or no and sufficient criteria. Next slide.

The geographical criterion is only one of the parameters to be considered. The EU guideline proposes, in fact, a multi-parameter evaluation where each criterion contributes to the overall safety assessment. Once again, no single approach alone will necessarily establish the safety of the product. This is a combined approach which is necessary in the risk assessment. Next slide.

In this multi-parameter approach other factors should also be considered in the risk assessment, such as quantity, route of administration, etcetera. Next slide.

The guideline is also encouraging the manufacturer to try to get rid of the use of such animal derived material. This is an easily understandable recommendation. However, this recommendation today should not be considered as being in conflict with the current situation where some products are still making use of bovine derived material.

This recommendation is essentially applicable at the development stage of a new product, and we have to acknowledge the current situation that, in some cases, bovine derived materials may still be required because of their special characteristics, as will be explained by Dr. Dobbelaer for vaccine. But this also for many other biological products and even recombinant processes.

Another point which should be mentioned, the last point in the guideline, deals with the quality assurance system. This concept of traceability is also applicable at any stage of the process and contributes to the confidence in the final safety of the product.

In conclusion -- next slide -- Chairman, it's important to remind that, based on the criteria laid down in the EU guideline, all concerned medicinal products, including vaccines, have been reviewed and judged satisfactory in Europe. This review has been also a good experience to show that the risk assessment should indeed take into consideration a number of factors, and should not be restricted to the geographical origin alone.

Finally, this multi-parameter approach is necessary, particularly if one considered the possible evolution of the TSE status worldwide, which makes the geographical origin a very fragile and critical criterion. Thank you for your attention.

CHAIRMAN BROWN: Thank you, Dr. Trouvin. Dr. Dobbelaer has the second part of this presentation.

DR. DOBBELAER: Thank you, Mr. Chairman. Through you, Mr. Chairman, I would like to thank the organizers to allow me to be part of this decision making, very important decision making which, in my opinion, will -- and it has not been said explicitly today -- will have not only an impact on the U.S. situation but also on the situation in the European Union, and not only in these two continents, but even worldwide, since the very same vaccines and the very same substances we are discussing today are used in worldwide in vaccines.

What I would like together with you is very quickly go over the processes which are used to make bacterial and viral vaccines. I will not dwell very long on that, since it will also be the subject in a more detailed way by William Vann and Ira Berkower.

Then I will emphasize from these production processes what are the quantities of substances of ruminant origin which are to be expected in the final product, and I will also give you a very brief and, I admit, incomplete overview of the different substances of ruminant origin which may be used in production of vaccines, to then come to a conclusion and present the European position which is, in fact, the result of the assessment, an ongoing assessment of individual products and which has recently been consolidated in a general CPMP commission survey. If I could have the next slide.

This is just to remember the audience that vaccines may consist of either bacterial cells -- the examples here are live oral typhoid vaccine, inactivated whole cell pertussis vaccine -- may contain purified bacterial cell products like diphtheria, tetanus toxoids, acellular pertussis antigens, recombinant hepatitis B vaccine, Hemophilus b vaccine, or may consist of live purified inactivated viral vaccines produced in mammalian cells, such as measles, mumps, rubella, varicella and inactivated poliomyelitis vaccine. If I can have the next slide.

This is a very simplified diagram which shows the production process of a bacterial vaccine, and colored red are the stages at which substances of ruminant origin may be used.

Just to tell you that one very -- Well, first I have to make a restriction, in that in some cases a material from ruminant origin are also used in later stages of the production, such as Tween 80 during purification and gelatin derivatives as excipients or stabilizers in the final product. But I think I can say safely that the tallow derivatives and the gelatin derivatives are products which can additionally benefit from their production process to evaluate their safety.

Just to stress the importance, the main issue of this slide is that one quantity of seed material yields, in fact, tens of thousands of vaccine doses, and substances of animal origin used in the initial stages of production are, as stated by Jean-Hugues Trouvin, diluted out, in particular those which are used in the seed lot.

Just to give an example, if you take a 1 ml seed, which is first inoculated into a 20 ml pre-culture which is then transferred to another pre-culture of 20 liters, which is then transferred to a fermenter of 1000 liters, the overall dilution factor of the seed is one over 20 million.

Furthermore, I think it can safely be stated as well that the cells which are used for, for instance, virus vaccine production or bacterial cells, are not known to replicate the agents of BSE.

The next slide summarizes the production of viral vaccines, and essentially it is the same message I wanted to give. As a difference with the bacterial vaccines production, here eukaryotic mammalian and avian cells are needed to support virus growth.

I'm going to mention it here. I didn't mention it for the bacterial vaccines. One very important aspect in the production of bacterial and virus vaccines is the use of seed lots and cell banks which provide a constant and reliable source for vaccine production over many, many years. In fact, many of the cell banks and seed lots have been produced and have been the source material to help ensure production consistency for 20 or 30 years.

Again, also in viral vaccines I made this simplified distinction between the different colors. Also in viral vaccines in later stages some substances of ruminant origin may be used, but the point I wanted to make is that, especially for substances used at the level of seed material, the dilution factor also in the case of viral vaccines may be very large, and the dilution factor for a serum used in a cell bank, for instance, is 10-8, which is 100 million times.

Again, the cells used for vaccine production, the mammalian and avian cells used for vaccine production, exclude neural cells and are not known to support prion growth. Next slide.

This is just to give you an idea of the order of magnitude of residual quantities of substances of ruminant origin which may be found at the level of the finished product of some vaccines.

Just to give you an idea, in the bacterial culture systems where 1 ml seed would be inoculated, etcetera, just the same reasoning I just gave you in pre-culture and in fermenter culture, the dilution factor would be, as I said, 20 millions. One can expect quantities up to 100 nanograms per single human dose in a bacterial vaccine which would use the substance of ruminant origin during the fermentation stage. Next slide, please.

This is to give you an idea of the substances which are used. Not mentioned are amino acids, for instance, and also I should mention that, as I already did, some of these products may be used at stages which are different from the ones stated in the slide. But the main message is that most of these products are used in the introduction of seed lots and cell banks. These are the very initial stages of vaccine production.

As I probably already staged, products such as lactose and gelatin derivatives may also be used in the formulation of some of the vaccines. Formulation is the very -- well, the last but one stage of vaccine production.

The key message I wanted to give here, that as has been more convincingly demonstrated in previous talks, none of these substances have demonstrated BSE infectivity in studies from naturally or experimentally infected cattle. Next slide, please.

As has been the case, I think, at CBER-FDA, the evaluation process as far as TSE risk is concerned of dosiers for marketing authorization has been an ongoing process since the very appearance of BSE in the U.K., and it has also been a growing process.

I think I can safely state that all EU authorities and all EU manufacturers, as we believe is the case for all authorities and vaccine manufacturers in the U.S. and on the global level, have always been aware and are concerned with the microbiological quantity of biological medical products in general and vaccines in particular.

I think it is particularly true for the TSE issue and its potential ramifications into the field of biological medicinal products such as vaccines and blood and plasma derivatives. From the very beginning of the BSE epidemic in the U.K. in the later parts of the Eighties, all parties concerned have taken measures to minimize the transmission of the disease to animals and man.

We believe that in the field of medicinal products in general and vaccines in particular, these measures have been very effective, and applying the scientific principles which are laid down in the EU CPMP guideline which has been explained to you by Jean-Hugues Trouvin, and which is now binding EU legislation, and the scientific principles which are used in the -- applying these in the risk assessment and risk management related to vaccines has indeed minimized the risk to theoretical levels.

I just wanted to finish by stating that EU authorities currently see no benefit in additional measures. Should such measures be imposed by other authorities, EU authorities would feel them not to be associated with -- much more -- sorry -- to be associated with risk perception and not with a real risk.

My final slide is certainly not intending to prove that vaccines cannot transmit BSE or prions in terms of the CJD or variant CJD, but this is just to show that, if you classify the cases of variant CJD by year of birth, then one can safely say that vaccines have not been associated with the VCJD epidemic in the U.K., as all have been vaccinated with vaccines -- well, some of them at least, long before appearance of BSE.

So I think I'll conclude here. Thank you.

CHAIRMAN BROWN: Thank you very much, Dr. Dobbelaer. What we are going to do now is break for lunch, and we are going to have the two brief bacterial and viral vaccine overviews immediately following lunch.

We are going to pick up probably a good half-hour of time early this afternoon, and I hope to pick up another 15 minutes at lunch, because it should be possible for us to reconvene at 1:30 rather than an hour from now. At 1:30.

Before you go out, Bill Freas will tell you about lunch arrangements.

DR. FREAS: In order for us to get back here at 1:30, there is a table reserved in the restaurant downstairs for the TSE members. You are more than welcome to use that table if you so choose. Hopefully, the service will be a little faster.

Some of the Vaccine Advisory Committee members have ordered box lunches. If you would see Nancy Cherry out in the hallway, she will assist you with your lunch. So we're going different directions at this time. See you at 1:30.

(Whereupon. the foregoing matter went off the record at 12:47 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:36 p.m.)

CHAIRMAN BROWN: It would be much better if I had one of those little bells that you bang, bang; but if I keep talking for a few minutes, probably everybody else will stop. Could we please have some quiet, and could people take their seats, because we would like to start the afternoon session as close to our late time as possible.

As I mentioned before the lunch break, we will now have two very brief presentations on viral and bacterial vaccines. That will be followed by presentations from the industry for public consumption. We already had a closed meeting at eight o'clock which dealt with any particularly proprietary aspects of the manufacture of vaccine.

So without further ado, we will now hear form Dr. Willie Vann. Could we have some quiet over here on the right, please, the FDA group. Dr. Vann, please.

DR. VANN: Today I will present an overview of the manufacturing and a risk assessment of bacterial vaccines. In order to estimate the potential risk of contamination of bacterial vaccines with the BSE agent, we first considered how bacterial vaccines were made and where bovine derived material is likely to enter the process.

A generalized scheme of how bacterial vaccines are made is outlined in the first slide. The scheme and the calculations that follow are based on our review of currently licensed bacterial vaccines in the United States.

The production of a bacterial vaccine begins with the preparation of a master seed or reference culture, followed by the preparation of a working seed or working culture. The master seed is a well characterized reference culture from which all bacterial cultures used in the manufacture of a particular vaccine component are derived. Next slide.

The working culture is derived from the master seed, and is stored in aliquots to be used for routine production of batches of vaccine. An aliquot of the working seed is used to generate an inoculum for the fermentation process. Next slide.

The fermentation step is the growth phase where bacterial culture is expanded and produces antigens for vaccine production. The antigen for the vaccines are recovered from the culture, purified and converted into a final container product.

The preparation of an entry of master seed and working seed cultures in the process involves significant dilution of the culture which can range from 10-2 to 10-3 for a given step. Next slide.

After review of current practices in the manufacture of bacterial vaccines licensed in the United States, only a few components were identified with the potential for the introduction of BSE agents via bovine derived material. These manufacturing components given in this slide are media components and stabilizers for seed culture storage.

The media components are primarily bovine derived broths. The stabilizer of polygeline is used for the long term storage of the master seed. Next slide.

This slide outlines the points at which bovine derived material would enter the manufacturing process. Thus, the potential for entry of BSE agent would be in either of three places, the master seed culture, the working seed culture, or the fermentation broth.

Because of the small amount of media introduced into the seed culture steps, due to the high dilution, these steps are considered to be less -- have less of a potential risk than at the fermentation step. Approximately one to 10 milligrams of protein derived culture media is introduced at either of these seed steps prior to fermentation.

The potential risk is increased for the use of bovine derived material in the fermentation broth, because of the large amount of media required for fermentation in a batch. A fermentation broth requires hundreds of grams to several kilograms of media protein. Next slide.

The next important issue to consider is the potential infectivity of the bovine derived material used in the preparation of the media. We have used in our estimation the infectivity categories outlined by the European Union which have been generally adopted for the estimation of the risk of BSE in culture media.

For our risk calculations we have relied on data supplied and published by European Union committees, and on the methods published by Bader, et al., in 1998. These latter methods were the results of deliberations of the BSE Committee of the Pharmaceutical Research and Manufacturers of America.

The European Union system has four categories of infectivity, the most infectious for BSE agent being Category I which includes nervous tissue, and the least being Category IV. The infectivities given in this table are based on values published by the PhRMA BSE Committee.

In the next slide is given a list of media components -- of media containing bovine derived material used in the manufacture of bacterial vaccines and the EU categories of the tissues used in the manufacture of these media. All of the bovine derived material used for bacterial vaccines are derived from either Category III or Category IV tissues.

Thus, in our estimation we have used a theoretical mixture of Category III and Category IV materials. The assumptions that we used to make our risk estimate are given in the next slide.

First, we do not assume a species barrier. Secondly, the conditions that we are considering is where the bovine tissues are sourced from a country in Europe other than the U.K. Because variations in butchering practice methods for the preparation of bovine muscle tissue could result in contamination with nervous tissue, we have done the calculation for two scenarios.

The first scenario assumes that the skeletal muscle is free of contamination from Category I tissues. The second assumes a .01 percent contamination with Category I nervous tissue. This is equivalent to approximately a tenth of the spinal cord per cow. This latter scenario provides a worst case based on our current review of manufacturing where a small amount of Category I material could enter the manufacturing process.

We used these assumptions and the information outlined above to calculate a risk assessment based on the method outlined in the Bader article. This method is outlined in the next slide.

The potential risk of an infected animal used in manufacturing is given by the regional risk of an animal -- of an infected adult animal. This value and the number of animals used per batch of media are used to calculate the risk of a batch of vaccine being contaminated by an infected animal.

The infectivity of the bovine tissue is estimated next. This estimate relies on the estimated infectivity of appropriate tissues from an infected cow. The estimations given in the next slide are based on the German quantitative system, since infection with Category III and Category IV bovine materials has never been observed.

The German system uses scrapie by analogy as a model to estimate relative infectivities. Thus, these values could be a likely overestimation of the infectivity of the bovine tissues. Next slide.

The species barrier in this equation is one, since we do not assume a species barrier. The estimated number of infections per contaminated batch is then calculated by multiplying this value by the correction for the route of administration and the process reduction factor.

The route of administration is intramuscular, which is 100 times less infective than intracerebral, for which the infectivities in the previous table was generated.

The major process reduction step is autoclaving of the bacterial growth media, which is assumed to be tenfold. All media containing bovine derived material are autoclaved prior to use. This autoclaving step and the low level of purification accounts for the reduction of risk due to process. In the last equation we are assuming a batch size of one million doses of vaccine. Next slide.

For our potential risk calculation, we have used two theoretical tissue compositions for calculating human infectivity. Both theoretical mixtures contain Category III and Category IV derived materials.

In scenario one, the skeletal muscle added to the broth is free of contamination with Category I nervous tissue. In scenario two, it is assumed that the equivalent of one-tenth of a spinal cord contaminates the skeletal muscle from one cow.

Since the largest amount of bovine derived material that could potentially be introduced into the process is in the fermentation broth, we have outlined these calculations using the above method in the next slide for fermentation broth.

In this calculation we used the risk of an infected animal for Europe of 10-4 or one in every 10,000 cows. This value is arrived at using the EU scheme by multiplying the incidence in the worst case country by a factor of ten to obtain a potential risk. Since we are assuming that only one cow is used per batch, the risk of a contaminating batch is one times 10-4.

The estimated infectivity is based on our theoretical media composition. The estimated number of infections per contaminated batch is reduced by a process factor of 20, mainly due to autoclaving.

Finally, the risk of a contaminated dose based on use of bovine fermentation broth is 5 x 10-10. This is one in every 2 billion doses. For scenario two, the potential risk is increased to 10-8.

In the next slide is given an estimate of the risk for the use of bovine broth in master seed or working seed using the same assumptions. In the latter case, the risk is very small, one in every 200 billion doses, even when one assumes a 0.1 percent mixture of Category I nervous tissue with the Category IV material.

The values that we have presented in this assessment are, in our judgment, a realistic worst case scenario. Thank you. Thanks to the other guys who helped me.

CHAIRMAN BROWN: That was, in fact, a conclusion, Dr. Vann?

DR. VANN: That was, in fact, my conclusion.

CHAIRMAN BROWN: Okay. Well, we thank you very much, and we will now move on to a similar parallel discussion or presentation of viral vaccines by Dr. Berkower. Both Dr. Vann and Dr. Berkower are in CBER, which is part of the FDA.

DR. BERKOWER: Today I discuss the potential risk of BSE contamination in viral vaccines. The main risk of BSE contamination comes from bovine material added to the culture medium used for growing cells and virus.

FDA review has determined that fetal calf serum from the United Kingdom has been used to make certain viral vaccines. This fetal calf serum was obtained at a time when the BSE epidemic was just getting underway in the U.K. USDA has estimated the incidence of BSE in adult cattle at that time as about one in 200.

Other data presented today have suggested that maternal-fetal transmission was on the order of ten percent, resulting in one calf in 2,000 becoming infected. Since the fetal calf serum is often pooled in lots typically of the size 1500, it is quite possible that some fetal calf serum from an infected calf could be included in the pool used for vaccine production. Next slide.

This slide shows typical steps in vaccine production where bovine material is used. Vaccine production proceeds along two paths, here and here, which converge at the bottom, resulting in production of the vaccine. On the right, virus from the original isolate is expanded first to the master seed and then to the working seed where it is ready to be used in the production.

At each step in this expansion fetal calf serum and cells are used to grow the virus, here and here. Thus, if the calf serum or the cells are contaminated, they could contaminate the growing virus.

On the left side cells are grown from the cell source up to a large scale, and then frozen to make the working cell bank. Typically, the working cell bank may include as many as 1,000 vials of cells. At the start of a production run, a manufacturer would thaw one vial and expand that to a bioreactor size infected with the virus and produce viral antigen, which is then subject to pretty limited steps of purification and/or inactivation to produce the final vaccine.

As shown on this slide, fetal calf serum from the U.K. has entered the production process at steps marked one and two in red. So U.K. fetal calf serum was used to produce the working cell bank. About 5 mls of U.K. fetal calf serum were used to make each vial of the working cell bank. These cells are then -- The one vial is then used to make a production lot, which is typically on the order of 500,000 doses of vaccine. So 5 mls makes 500,000 doses.

The question is: If these 5 mls of fetal calf serum became contaminated with the BSE agent, what would be the risk of BSE coming through to the final product? Note then that each ml of fetal calf serum at the working cell bank is used to make 100,000 doses of vaccine.

In order to calculate this risk -- next slide -- we made certain assumptions about BSE. First, we assumed that one in 2,000 fetal calves was infected. Second, we assumed that each ml of fetal calf serum from this calf contained approximately less than one infectious dose of BSE.

This estimate is based on partially completed experiments in which cell concentrates made from cow blood -- that is, buffy coats -- were shown to be noninfectious cow to cow. Noninfectivity of 1 ml could certainly represent less than one infectious dose per ml or it could actually be less than one infectious dose per ml, but we have conservatively assumed less than one.

Third, we assumed that the number of BSE agents introduced at the top of the process I just showed you on the previous slide would equal the number that came through into the vaccine. Thus, the risk would be the input number of BSE agents divided over the number of doses given.

We have allowed no risk reduction for purification, because in many cases the purification is minimal, or for species barrier which is basically unknown in the case of BSE from cow to man. We have, however, allowed a factor of 200 for reduced transmission by the intramuscular route.

Given these assumptions -- next slide -- we can calculate the risk of BSE getting into vaccines as the product of four separate risk factors shown on this slide.

The first is we assumed less than one infectious unit per ml of fetal calf serum. The second was we know that the infectious unit is diluted into a pool of 2,000 normals. Third, we know that the cells from one ml of fetal calf serum make approximately 100,000 doses of vaccine in a typical production scheme, giving us a factor of 10-5. Fourth, we have allowed a 200-fold reduction for the route of administration. Those are our four factors.

Multiplying those four together gives us a cumulative risk of infection per dose as .25 x 10-10. This means one BSE infectious dose per 40 billion vaccine doses.

Now each of our assumptions comes with its own uncertainty, and some of these would be rather large. Next slide.

First, we assumed the incidence of BSE in cows to be one in 200 in the early years of the epidemic in the U.K. That is, in the mid-1980s. This is based on estimates of the USDA.

Second, we've assumed that transmission from the mother to fetal calf was about ten percent, based on the study of Wilesmith presented earlier, although others have challenged this estimate.

Third, the infectivity of fetal calf serum from an infected calf may be significantly less than one per ml, as I said, because the experiments have basically shown that transmission was not detected when approximately 1 ml was used in a sensitive bioassay.

Fourth, there may be additional risk reduction factors which we have not allowed for, such as a species barrier between cow and man.

Fifth, partial purification of vaccine may contribute a little more. We have allowed no reduction for purification, because the purification scheme was not designed to remove BSE agent and has never been shown to remove it.

Finally, our overall estimate obtained by multiplying values with large errors could itself vary over a very large range.

In summary -- the next slide -- we estimate the risk of BSE transmission as less than one BSE infectious dose in 40 billion vaccine doses for viral vaccines made with U.K. fetal calf serum in the mid-1980s.

CHAIRMAN BROWN: Thank you, Dr. Berkower. Question? Yes?

DR, GRIFFIN: It seems to me, especially for the virus vaccines, the biggest assumption that we're making wasn't on your list, and that's that there is no evidence that the agent can replicate at all in the cells that are being used to produce the vaccine.

I'd just like to know what kind of data we have for that assumption.

DR. BERKOWER: Well, there has been experience in getting BSE agent to replicate -- or I should say, TSE agents to replicate in cell culture. These have worked entirely on cells of neural origin, such as neural blastomas. They have not worked on cells that would typically be used for vaccine production.

DR. GRIFFIN: How hard have people tried? In general, you get a system that works. That's what you work with, but going to the apposite or, you know, can you really not do it in another kind of cell is a different problem.

DR. BERKOWER: There are a number of things that could be done that have not been done to assess the ability of TSE agents to grow on the cells that are used for viral vaccine production. For example, they could simply try and infect the actual cells that were used or they could measure the PrP status of the cells that were used at the end of a fermenter run or -- There are many other things that could be done. Those are two that I would like to see.

As Dr. Egan said at the start of this, there are many factors that we would like to know which we don't know at this time.

CHAIRMAN BROWN: The answer is correct. We did in our own laboratory many, many years ago all kinds of cell culture efforts with a number of human -- not BSE but a number of human TSEs, and they just diluted out over a few passages. They simply don't replicate in cell cultures typically.

DR. GRIFFIN: Right. Now I appreciate that, but I think that's still a little bit different question than could they possibly, and does BSE, because it does cross species barriers a little more easily than some of the other TSEs, in my understanding.

CHAIRMAN BROWN: Well, I don't know if that's true. It certainly crossed the human species barrier.

DR. GRIFFIN: Well, that's the one we are most worried about.

CHAIRMAN BROWN: The most important, yes. Exactly. So if we're using, say, human cells, it may be that they are more facilitated by that than, for example, a strain of scrapie. I think maybe that's what you're talking about.

DR. GRIFFIN: Exactly. And we know that they go into non-human primates as well, and those are frequently the source of the kinds of cells that are used in viral vaccines.

CHAIRMAN BROWN: Is Dr. Sue Priola in the room? I understand that she might have some information about cell cultures. Please.

DR. PRIOLA: Well, I don't think I can add much to what Dr. Brown said, but historically the only cells that have been susceptible are either neuronal in nature or fiberglass. There's been reports of fiberglass.

Those experiments have all been done with rodent models of scrapie. There's only one instance that I can recall of sheep infectivity being passed into culture. Other than that, no work has been done with BSE that I'm aware of.

So in addition to the difficulty of getting the agent into the cells, it's very difficult to maintain it. As Dr. Brown said, you tend to lose it very quickly and, when it does get in, it's at very low levels.

CO-CHAIRMAN GREENBERG: I would just add that this experiment is different yet again, because it's a co-cultivation with a virus. Nobody in the right mind would do that experiment in their laboratory, but the virus could facilitate as well as interfere with transmission in cell culture.

In each case, it would be a different virus. So it would be complicated to figure it out.

DR. GRIFFIN: Right. But you could do some kinds of experiments, like even co-cult with a neuroblastoma cell line or something that you knew was very susceptible or the most susceptible to your agent of interest.

CHAIRMAN BROWN: Ray Bradley or any representatives from the United Kingdom, are you aware of any effort, any attempt, anything that is going on right now with respect to attempting to grow specifically the BSE agent in any cell culture?

DR. BRADLEY: Nothing that I'm aware of in the master program at all.

CHAIRMAN BROWN: Okay.

DR. BRADLEY: If I could just comment briefly on the bioassay in cattle from tissues from cattle of buffy coat, you suggested that those studies were completed.

DR. BERKOWER: I think I said incomplete.

DR. BRADLEY: Sorry.

DR. BERKOWER: I said partially complete. That's what I said. I have it right here.

DR. WELLS: If I could just give some detail on that partial completion, basically, we have assays from the pathogenesis study at six months post-exposure, 18 months, 26 months, and 32 months. Only the material from the 32 months has reached 43 months p.i. which, you know, might be assumed to be a reasonable incubation period, if it was going to -- if disease was going to occur.

The others are all below 20 months, which would be somewhere -- unless we're going to say that there is above 103 cattle units in there, then we can't draw conclusions from that.

DR. BERKOWER: Okay. I'd like to just repeat what you said. If you do assays in mice where there's a species barrier of 103 and you can't even inject a ml, but let's say you did because you did a lot of mice, you could say it was less than 1,000 per ml. That's the best you could say. That's what you just said.

Also I was aware of the buffy coat from the animals when they first lit up the brain in your pathology study, pathogenesis study, being used; and I know they are a little under four years and that the animals are okay at this point. I believe it's four cows that it's been assayed in.

DR. WELLS: That's right.

DR. BERKOWER: Four cows. Yes, and the way I calculated the less than one per ml is that a buffy coat is roughly a tenfold concentrate, that to use it in the brain it was diluted roughly tenfold an the volume injected in the brain, obviously, was about one ml. So it's about one ml worth of cells, which would be roughly equivalent, if this were scrapie and if it was Dr. Brown's experiments, to one ml of serum.

DR. PRIOLA: Dr. Brown, may I make one more brief comment?

CHAIRMAN BROWN: Yes. Sure.

DR. PRIOLA: When these infections are successful in tissue culture, it usually takes an extremely high level of infectivity to get it to go, that usually they are very inefficient. At the lower multiplicity of infection you go, the less efficient the process. So in most cases, you have to start out with quite high levels.

CHAIRMAN BROWN: Dr. Almond, you had your hand up a minute ago.

DR. MODLIN: Actually, I wanted to pursue exactly the same line of questioning that Diane just did, and I think I had just about all my questions answered except just to point out that in this system the fermentation in cell culture for a virus, presumably polio virus or whatever, is going to be very short. It's going to be a matter of just a few days, and here we're talking about an agent that requires presumably an incubation period of much, much longer than that, even in cell culture, to detect it.

I guess that was a question. How long does it take -- How long do you have to maintain it in cell culture before you can detect it in your most sensitive system?

CHAIRMAN BROWN: Well, what typically happens is, if you inoculate it progressively over a matter of one or two or three passages, it disappears rather than replicates, and the question -- the reverse question, how long does a successful take require, I will defer to you.

DR. PRIOLA: You can detect the protease resistant form of the prion protein in our hands after a day, if you overlay the homogenate. But to get a successful infection, you usually have to wait 30 days to ensure that it's replicating, but if it's present at the first pass, it may be present at -- you know, on pass three and pass five. It might be present continuously or it might be lost by passage two. It's unpredictable.

CHAIRMAN BROWN: So like everything else, the answer helps a great deal.

DR. GRIFFIN: Well, but the point is that that's how long it takes for you to detect it. But if the infection is successful, it's successful on the first few hours. I mean, you know -- I mean, it's there or it's not there, and then how long it takes to build up to the point of detectability in whatever assay you are using is another issue.

DR. BERKOWER: Can I just say one thing on this? So in our calculations we had a little thing we called prion equals prion-out or BSE-out. We didn't assume that it grew, and we didn't assume that it just disappeared. We assumed that it hung onto the cells, was not washed off during the typical incubation period, and that's sort of -- I think that's about what everyone has said.

CHAIRMAN BROWN: Dr. Almond, last comment on this?

DR. ALMOND: Just to echo your comments, Mr. Chairman. In my laboratory we also tried very hard to establish prions in cell culture, and we worked, in fact, with Sue Priola on some aspects of that. We didn't manage it. But the point I wanted to make was that a lot of cell cultures that have been kept and maintained in U.K. laboratories over the last 20 years will inevitably have used U.K. sera.

I don't know of any evidence that when you look at those cells, you detect any PrPSE in any of them. In fact, it's very hard to detect PrP at all in those cells. I think that probably points to the fact that it really is not easy to infect these cells with prions.

Chris Berkett is probably the person at the U.K. program that's most experienced working with these so called SMB cells, which were derived from a scrapie mouse brain back in the 1970s. He has managed to do some work with those cells, but I spoke to him recently, and it's clear that he also has great difficulty in infecting cells.

CHAIRMAN BROWN: And you have the other problem, that PrP detection is typically infinitely less sensitive than a bioassay. So what you would really be obliged to do would be to bioassay all your cell systems. Dr. Roos?

DR. ROOS: I just wondered how common it might be that one contaminated the fetal calf serum during its collection, for example, with instruments that might have been used for slaughter and contact with central nervous system tissue, especially when we go back to the early years in the BSE epidemic.

CHAIRMAN BROWN: Ray Bradley, could you make a comment with respect to the potential risk of cross-contamination in a slaughterhouse during the period in question, 1980 to '95?

DR. BRADLEY: Well, I can only, Mr. Chairman, answer the basic information. When one collects fetal calf serum, if one was collecting it, of course, the cow is already dead. The uterus is removed, and then the fetus from that uterus is taken away, and there would be no possibility of cross-contamination, I think, with central nervous tissue in the normal method that people would utilize to collect this.

Of course, the qualities of collection, going back very historically, could not be necessarily claimed to be the same as they are today, but I haven't got any possibility of commenting on that, never having done it. But I think actual cross-contamination with central nervous tissue would be most improbable, even central nervous system from the calf, because this would not be opened or touched in any way.

CHAIRMAN BROWN: Is that okay, Ray?

DR. ROOS: I assume that the instruments that might have been used on the central nervous system of the mother is also perhaps used in the collection of the fetal calf serum. Am I correct?

DR. BRADLEY: I'm sorry. I just missed the first part of your question.

DR. ROOS: I'm assuming that the instruments used to collect that fetal calf serum might be the same that could have been contaminated with the central nervous system of the mother.

DR. BRADLEY: No, certainly not. I would think that would be most unlikely. Well, it would be, I think, not possible, certainly in the modern ear, because the --

DR. ROOS: No, I meant --

DR. BRADLEY: Historically?

DR. ROOS: Yes.

DR. BRADLEY: I do not think that there would be any practical connection between those instruments. I mean, we are talking here about trying to collect a sterile product, forgetting all about BSE. Those who are involved in this procedure do take very, very careful precautions to prevent any form of cross-contamination, whether it be bacterial, environmental, viral or anything.

The methodologies used now involve sterile equipment, disposable equipment, cardiac puncture, in an environment which is essentially divorced from the central nervous tissue in the slaughter hall. This would not be permitted to be done in the slaughter hall. So there would be no connection. They would be different personnel trained for different purposes.

DR. ROOS: I don't want to belabor this, but I want to go back 15 years ago. It just wasn't clear to me. So the instrument that is used to collect the fetal calf serum would not have been used with respect to the mother and the mother's tissue. Is that what you're saying? Totally different --

DR. BRADLEY: Exactly.

DR. ROOS: -- sterile, newly packaged scalpel?

DR. BRADLEY: Exactly. In order to --

CHAIRMAN BROWN: Yes, that's what he said.

DR. BRADLEY: In order to collect the blood, you would use a needle. A needle would not be involved at any point in the slaughter. So just from practical common sense, it wouldn't be done. But I cannot speak from personal knowledge of that procedure historically.

CHAIRMAN BROWN: Bearing in mind, of course, that a slaughterhouse is not a P3 facility.

Thank you. We now have presentations from two manufacturers of vaccines, and the first will be from SmithKline Beecham Pharmaceuticals, and Dr. Clare Kahn will introduce the subject, which will be followed by a presentation from a gentleman who you now are familiar with, Dr. Ray Bradley.

DR. KAHN: Good afternoon, members of the committees, ladies and gentlemen. I'm Clare Kahn, and Vice President, North American Regulatory Affairs, responsible for vaccines and representing SmithKline Beecham.

We have a generic presentation for you today, and to deliver this it's my pleasure to introduce to you Dr. Ray Bradley, CBE. He will broadly review the topic of TSE risk from bovine derived materials, making special reference to all of the considerations for their use in vaccine manufacture as raised by the agency for today's discussion.

Dr. Bradley served as head of the pathology at the Central Veterinary Laboratory, now called the Veterinary and Laboratory Agency, in the U.K.'s Ministry of Agriculture, Fisheries and Food, or MAFF, from 1983 to 1991. These were seminal years in the history of BSE.

During this time BSE was discovered. Dr. Bradley initiated and collaborated the initial BSE research program, and he was heavily involved in national and international issues for BSE and other animal TSEs.

Dr. Bradley served as the BSE coordinator for MAFF from '91 to '95, and since that time he has served as an independent BSE consultant to WHO, OIE, EC, U.K., and the Argentine and the U.S. governments' committees and expert committees and expert consultation.

In his consultancy with SBE, Dr. Bradley has conducted a comprehensive review of BSE risk from bovine derived materials, and also review of the provenance and TSE risk in starting materials of bovine origin used by SBE in vaccine production for worldwide markets.

So now it's my pleasure to call upon Dr. Bradley to present to you on the TSE risk from source materials derived from cattle and used in the manufacture of vaccines for human use.

DR. BRADLEY: Mr. Chairman, members of the committees, ladies and gentlemen, good afternoon or, if you're from Europe, good evening. If I could have the next slide, please.

The objectives of my talk are to discuss the TSE risk from source materials derived from cattle used in the preparation of master working seeds and cell banks, fermentation processes, and in the formulation of final products.

First of all, just a recapitulation and reminder of where BSE occurs. The red countries are those with cases in native-born cattle, and those in blue are countries with BSE in only imported cattle. Next slide, please.

Here is a reminder of the epidemic curve for the U.K. based on annual report cases, and I refer to the large number of BSE cases in the U.K., 176,000. By comparison, throughout the rest of the world the total number is some 1300. Next slide, please.

Once you have BSE in a country, there are possibilities to export it in incubating healthy live cattle. That has been done by accident, of course, from the U.K. to various countries which are quite widely dispersed, as you see, but very small numbers of animals which in themselves present very low risk, provided they are detected and destroyed. Next slide, please.

However, it is not just cattle which actually present the risk. The other risk comes from the export of meat and bonemeal contaminated with BSE material. As you can see, from the U.K. quite large quantities and meat and bonemeal were exported for the European Union. Even a small amount was exported to the North America, just 12.3 tons, in 1984-85, which was, of course, a risk period.

From other countries with BSE, there's a lot less certainty as to how many cattle and how much meat and bonemeal might have been exported elsewhere. Next slide, please.

The next point I want to make is the importance of the factors governing transmission of transmissible spongiform encephalopathies. There are three factors, the dose, the route of exposure and the species barrier, which clearly comes into play once you cross a barrier between two different species.

The dose is the mass or volume multiplied by the titer in unit mass. In regard to the route of exposure, there are widely differing efficiencies of different routes. Most of the talks that you've had today and much of mine will be referring to transmissions done by the intracerebral route, which is the most efficient of all.

The oral route is the least efficient, and the intramuscular route is rather closer to this end of the scale than it is to this one. Next slide, please. Sorry, could I just go back? The species barrier is determined by two features or two factors, firstly the strain of the agent and, secondly, the variation in the PrP gene sequence between the donor and recipient species. Next slide, please.

So the summary from the geographical risk from cattle with TSE: We can say that the risk could be derived from two sources, exogenous sources and endogenous sources. Exogenous sources include importation of infected cattle or meat and bonemeal, and endogenous sources means genesis of TSE in cattle from any species and recycling it via the feed in meat and bonemeal.

To conclude on this slide, the precise geographical destination of cattle and meat and bonemeal exported from all countries with BSE is uncertain. Thus, the analysis of risk of TSE infectivity by type of tissue is of fundamental importance. Next slide, please.

So that's what I want to pass to now. As you have heard from Mr. Wells, in natural cases of BSE there is a very restricted distribution of agent infectivity to the central nervous tissue and included in the retina and spinal cord and brain. Next slide, please.

However, when one challenges mice by the efficient intracerebral route, including the intraperitoneal route at the same time, we find a whole range of tissues in which no detectable infectivity can be found. They are listed here. Mr. Wells mentioned 51 tissues on this slide.

I draw attention to those in blue, which I'm going to talk about in a little more detail, because these are tissues which are used as starting materials for manufacture of vaccines. I will also draw attention to the negative transmission studies from a series of male and female reproductive tissues and including fetal calf blood. Next slide, please, and the next.

Mr. Wells has elegantly explained his pathogenesis study to you, and this is a summary slide giving the essential data from which I wish to draw one or two clear points.

First, that only the distal ileum shows infectivity at early stages of incubation. Second, in the other tissues marked in red, which do show infectivity, none of them show infectivity more than three months before the clinical onset of disease. So this window period that's been mentioned is very small. Finally, a whole range of tissues, which I'll deal with in a little more detail later, show no detectable infectivity after bioassay in mice at any stage of either preclinical or clinical disease. Next slide, please.

The specific items I wish to consider are listed here, and I'll deal with them in turn. Independent judgment that milk is safe after consideration of the results of transmission and epidemiological studies have been determined by the WHO, the OIE, the EC, and the U.K. SEAC. They have evaluated the data and concluded, in a nutshell, that milk is safe. The USDA has no restrictions on the importation of milk, presumably coming to the same conclusion. Next, please.

Now to summarize the results from all the collective studies that have been done on blood. First of all, in natural BSE in cattle in this column and then in experimental BSE in cattle in the second column, I've listed here not just blood itself but other tissues which are closely associated with blood such as spleen, lymph nodes and bone marrow.

So in natural BSE, not one of these tissues has shown any detectable infectivity when tested in mice, and of the two that have already been tested in cattle, Mr. Wells reported this morning by intracerebral inoculation, the most efficient route, no detectable infectivity there either.

When we come to the experimental BSE, the pathogenesis study, again buffy coat was bioassayed. It shows no detectable infectivity. Likewise for these other tissues during incubation, including the bone marrow during incubation, and the buffy coat has bee bioassayed in cattle, although that has not yet been completed. It has so far gone for three and a half years, as you see here, and the animals are still alive and healthy, giving us confidence but not absolute, complete reassurance at this point in time. Next slide, please.

I now pass to muscle and pancreas. To summarize these two issues which have been part of the concern, skeletal muscle and pancreas from cattle affected with natural BSE have shown no detectable infectivity after bioassay in susceptible mice. Furthermore, BSE infectivity has not been detected in skeletal muscle or pancreas at any stage of incubation of experimental BSE, also following bioassay in susceptible mice. Next, please.

Now passing to derivatives of gelatin which, as source material, start from bovine bone, and I'm speaking here specifically about polygeline. There is no detectable inherent infectivity in the raw material from clinically healthy animals that is, in bones. However, the TSE risks in bones historically used for gelatin manufacture may not have been negligible due to the contamination or possible contamination with central nervous system tissue. But -- and this is an important "but" -- the process in producing polygeline involves an important clearance factor of many logs of loss of infectivity. Next slide, please.

So the conclusions from this are that no BSE infectivity has been detected in skeletal muscle, pancreas, spleen, blood or any component of blood of cattle or bovine fetuses in natural or experimental BSE or in the milk in natural BSE. There is no epidemiological evidence that bovine milk, blood or any blood component carries BSE infectivity.

Here is an important point to stress. BSE is different from scrapie. In the early days of this epidemic, we were less certain about that. We are now sure that it is not the same as scrapie, and we cannot use the data for scrapie to make the risk assessments if we have new data generated from the species and tissues in question.

The WHO and CPMP classifications based on observations of scrapie in sheep and goats showing low infectivity Category III for pancreas and medium infectivity Category II for spleen are, therefore, not applicable to cattle potentially or actually infected with the BSE agent. Next slide, please.

I now want to come to the more concluding part of my talk in regard to possible in utero maternal transmission of BSE. Next.

I think it's very important indeed for you, particularly if you are not veterinarians, to understand what we mean by maternal transmission. It means transmission from dam to offspring at one of three stages, in utero -- and this is the point at which fetal calf serum would be sourced.

So the subsequent other two forms of maternal transmission such as infectivity getting to the fetus during parturition or in the immediate post-parturient period do not count. This is the only one that has to be proved to show if there was an infectivity here, and I shall try to demonstrate there is not. Next, please.

In regard to maternal transmission, the cohort study and the case controlled study that Mr. Wilesmith mentioned this morning did not address the question of occurrence of infectivity in fetal calf blood. That was not a defect of the design. It was never intended, and so it could not report on that feature.

Neither study demonstrated the existence of maternal transmission in the absence of a feed-borne source, a very important feature. Neither study demonstrated the occurrence of in utero maternal transmission, the only one which could potentially incriminate any risk factor in fetal calf serum. Next slide, please.

In regard to the general points about maternal transmission of BSE, in the U.K. in no case has the observed annual incidence of BSE in offspring of confirmed cases exceeded the expected incidence from the feed-borne source alone. In the EU outside of the U.K., I've mentioned that we have had outside there 1283 cases of confirmed BSE. No case of BSE has been reported in the offspring of a case. So that figure is zero.

In Switzerland, an even more thorough study was done. Brains from 182 offspring of BSE cases have been examined microscopically and for the presence of prion protein. No evidence of BSE was found in any case. Next slide.

So the summary on this: No infectivity has been found in any reproductive tissue, whether male or female. Cohort and case controlled study are not designed to determine infectivity in fetal calf serum. No studies have demonstrated maternal transmission in the absence of a feed-borne source, and the results of these studies do not contradict any of the evidence supporting the absence of detectable BSE infectivity in fetal calf serum. Next, please.

My last slide and conclusion is, therefore, that the assessment of TSE risk in the starting materials of ruminant origin that are used for the manufacture of vaccines has revealed no evidence for a degree of risk that is higher than negligible. Thank you.

CHAIRMAN BROWN: Thanks very much, Dr. Bradley.

DR. KOHL: I think it's a very important presentation, and I'd like to verify or possibly challenge a couple of points.

Clarify for me the bone marrow experience. We were told this morning, I believe, that several bone marrows were positive during, I think, the latest stage of BSE.

DR. BRADLEY: I'm just going to put the slide up which will answer your question. This is the pathogenesis study. Let me wait for the slide. And bone marrow is listed here, and you see that the bone marrow is a singleton positive result which occurred in the clinical phase of disease from which we do not collect, and there is a paper written by Mr. Wells and his colleagues giving the possible explanations for this.

I wouldn't wish to go into the detail on that at the moment, but if that's helpful to you.

DR. KOHL: That is. On your other slide, the bone marrow was referring to during incubation. Is that correct?

DR. BRADLEY: I'm sorry?

DR. KOHL: Your other slide which said bone marrows were negative is referring to the incubation period?

DR. BRADLEY: Yes. This one, there's no infectivity in incubation, no case --

CHAIRMAN BROWN: Do you have a follow-up? That's okay, Ray. Go ahead.

DR. KOHL: Now on the cohort study which was presented this morning there was a ten percent risk of -- I'm not going to say transmission, but of BSE in offspring of infected cows. In that study, as reported in our briefing document, the relative risk was 3.4 percent -- 3.4 relative risk between offspring of infected cows compared to offspring of non-infected cows.

DR. BRADLEY; Yes.

DR. KOHL: Now you've told us and everybody else has told us that milk is not infectious. Is that correct?

DR. BRADLEY: Yes, no detectable infectivity in bovine milk.

DR. KOHL: Okay. So we can disregard the infectivity from mother to child or to infant by milk.

DR. BRADLEY: No.

DR. KOHL: Well, either it is or it isn't.

DR. BRADLEY: That's not -- You are assuming that could be the only post-natal origin.

DR. KOHL: I'm just talking about milk. Milk is not infectious.

DR. BRADLEY: Okay.

DR. KOHL: Is that right?

DR. BRADLEY: Yes.

DR. KOHL: Okay. And these cows, the infected babies or whatever you call calves, and the non-infected calves -- I'm a pediatrician -- are kept -- My understanding is they are kept on the same farms, fed the same food, and in the same environment. So presumably, the risk of transmission to these calves in the post-partum period is similar.

So I am left with the assumption that either this relative risk of 3.4 is due to intrapartum transmission, in which case the fetal calf serum would not be affected since there is no partum period when you collect fetal calf, or due to in utero transmission.

Now I agree with you that the studies don't prove that it's in utero transmission, but one can definitely not assume in that study -- in fact, in any study so far -- that there is no intrauterine transmission.

DR. BRADLEY: Well, I think there's several points I should make. The first point, and I think Mr. Wilesmith made it very well, was that he said his study did not demonstrate maternal transmission. It demonstrated there was a maternal factor involved in the different observations that were made in the two groups of animals.

DR. KOHL: Well, I'd like you to describe any maternal factor other than breast milk, intrapartum infection or intrauterine infection. As a pediatrician, my area of expertise is congenital infections, and I've published a bit on that, and I'm not aware of any other maternal factor.

DR. BRADLEY: Okay. In the course of the study, just to indicate -- and Mr. Wilesmith can perhaps chip in if I've got the major fact wrong -- that the calves that we used, the 600 calves, were pairs, of course. But they were not collected at birth from farms and then moved to the environment on the experimental farms in which we looked after them.

So they stayed on their natal farms for some period, sometimes for a year, perhaps longer. So that's the first point, before they were all collected together on the three separate farms, but kept as a pair.

The calves were collected from three birth cohorts, and during the course of these birth cohorts the risk from BSE from feed diminished. If you analyze the figures in the cohort study, there was an equivalent decline or a similar decline in the incidence of BSE as you got further away from the feed ban which was in place.

Thus, there is an association of a reducing risk with time associated potentially with feed. So let's just see how that maternal factor could operate. It could operate on the basis that some particular animals eat more. So they had a greater opportunity to consume infected feed, if there was any infected feed, and that I'm speaking of on their farm of origin before they came to the Ministry farms. I don't know if that will go any distance to answer your question.

If I may, Larry, could I just ask John to add something to that, because it was his experiment.

DR. WILESMITH: Ill try and clarify this. One of the things that is of interest is that what I did in terms of the design of the study was to take account of this continuing feed-borne risk.

There is one thing that I can do to try and put this study in perspective which would help rule out the feed-borne source for those dams, would be to look at the remainder of the cohorts which we didn't purchase -- They were left on the farm -- to see what happened to them.

In other words, if one had a case of so called maternally associated case, were those more likely to occur on farms in which those birth cohorts had also had other cases but in animals unrelated to cases. So there is that one thing.

So in terms of the maternal risk factors, as I say, the presence -- You know, that may only be there in the presence of the feed-borne source, and it may be untangleable. But it's just that all that we can say at the moment is we do not know of any kind of biological mechanisms that this thing is happening through. Theoretically, yes; but practically, no.

CHAIRMAN BROWN: Dr. Lurie had a question. Then, you know, we are getting so close to the discussion period and our speakers will all be here that I would very much like to get to it as quickly as possible, and then when we have questions that require the expertise of the people who have addressed us, we can ask them questions at that time. Peter?

DR. LURIE: This is a question for Dr. Kahn. As you know, on December 17, 1993, the FDA wrote to a number of drug companies insisting that they no longer source their bovine derived materials from cattle which have resided in BSE countries.

I'm going to make the hypothetical assumptions that the fact that your company has made a presentation and flown in an expert from Britain that you're here for a reason that may be related to your having produced one of those vaccines. And assuming that my hypothetical assumption is correct, my question is: Why did you ignore the December 17, 1993, FDA letter?

DR. KAHN: I'm sorry, I missed the very end of your question?

DR. LURIE: Assuming the hypothetical stated, my question was why did your company ignore the December 17, 1993, letter?

DR. FREAS: Dr. Kahn, before you respond, to prevent me from reading the conflict of interest statement over again, we are not allowed as a committee to discuss individual manufacturers or individual products. We have to talk in generic terms. So her answer has to be in a generic term for all manufacturers, not for her specific company.

CHAIRMAN BROWN: Is that possible to do, Dr. Kahn? If it's not, we'll finesse the whole thing.

DR. KAHN: I just want to say, and I'm sure this is common with other manufacturers, that we take all such letters and guidance and recommendations, as these were, seriously, and we have recommendations from multiple countries' regulatory bodies.

Our policy -- I'm sure this is common with others -- is to move away from any risk or perception of risk, and even perception of risk can be a problem today. I can say that, even as early as 1990, we made the concerted decision to make all bulk manufacturing, all routine manufacturing steps -- the serum would be sourced from countries which include New Zealand, Australia, and go away from any country that would be listed or a risk country.

Other materials would have come from Europe and other countries which were non-BSE. There's an evolution in the list of countries that are causing a problem. So we are always looking for ways to come into line.

Now having said that, for some of the source materials, assumptions were made by our company. Maybe they are considered unwarranted today, but they were made in full, good faith of disclosure and the fact that the starting materials are non-infective. I think the non-infectivity of starting materials is the cornerstone for what you do in vaccine manufacture, and very important to us.

We have written, shared all of this information with the agency, and I can honestly -- and we also, by the way, improved traceability, decreased the chances of cross-contamination in collection. All those things were put into place as soon as any hint of a risk was mentioned from the Eighties.

SB is working very closely right now with FDA to evaluate and to implement any changes that are considered necessary to address even the perception of risk.

DR. LURIE: So you did ignore it then.

DR. KAHN: No, we don't ignore their letters.

CHAIRMAN BROWN: I think that this is a very pointed question, and what we want is blunt questions, and I think if we want to talk generically and globally, that's fine. But we can't have this dialogue with respect to SmithKline and you.

DR. LURIE; I mean, I guess the overall point, though, is that it's very difficult for this committee to make any kind of real assessment of risk. I understand we're not voting on anything, but it's difficult even to discuss in the absence of our knowledge of what vaccines are an issue, what numbers of vaccines have been injected into people, what numbers of vaccines remain on the shelf, how long it would take for particular vaccines to replenish, you know, what the lag time would be. And all of this is beyond a theoretical discussion, and it only becomes real and our deliberations only become of much use, it seems to me, at the point that that sort of information is available.

CHAIRMAN BROWN: Well, Peter, you've been on the committee long enough to know that we never make decisions based on scientific evidence, and we're not going to start today. Thank you, Dr. Kahn.

An even shorter presentation now by Dr. Jeffrey Almond, who represents Aventis Pasteur.

DR. ALMOND: Thank you, Mr. Chairman, and it's an interesting turn that the questions have taken. I would like to say that I agree with Ray Bradley in his analysis, and one thing that I did with Ray was to work very closely with him -- could I have the first slide, please? We have a technological failure. I think the guy from SmithKline turned my slides off.

CHAIRMAN BROWN: Can you make your points without visual aids, Jeffrey, or is that not --

DR. ALMOND: Yes. I can start making several points without the slide.

I was about to say that I worked very closely with Ray Bradley, because he, as he indicated on his slide or during his introduction, was the coordinator for the MAFF research program in the U.K. I was coordinator for the Research Councils, the Biotechnology and Biological Sciences Research Council of Great Britain, during their research campaign, and I was coordinator of that for a period of eight years and worked very closely with Ray.

I was also a member of the Spongiform Encephalopathies Advisory Committee of the U.K. and, of course, was heavily involved with all of our friends here today from the U.K. during the very heady days of 1996 and through there where we first observed new variant CJD.

I am now, however, Senior Vice President of Research and Development to Aventis Pasteur, and it seems that this subject, of course, is a broad one, and comes with me wherever I go.

I wanted to say that in Aventis Pasteur our approach to this over several years has been, as we indicate on this slide, to check all of our processes for the production of all of our vaccines on the U.S. market at the stages of the primary or master seed lots -- and we've heard about that this morning and I've picked a few slides out that relate to where they come in, but you all know that -- the working seed lots, the primary cell banks, the working cell banks, and the industrial scale production, the purification and its effects, and of course, the final formulation. Next slide, please.

We consider every ingredient of every solution, growth medium, purification process, excipient, etcetera, at every stage of its preparation to identify materials of ruminant origin.

We then ask questions about the species of the animal concerned, the geographical origin of those animals, the date of the preparation of the material and, of course, the crucial date is the first of January 1980. Before that, we assume no risk whatsoever. After that, that is about an incubation time away from the first appearance of -- or the first diagnosis of BSE, as Gerald Wells informed us, in December 1986.

We also look, of course, at the processes used in the derivation of materials, bearing full mind of the fact that in some cases, such as the treatment of tallow, there are very harsh processes that would destroy any infectivity.

This is not a trivial task to check all of these things, and it does involve not only checking our own records but tracing our sources and contracting suppliers of sometimes 25 years ago, and obtaining from them a original specification details of all the materials used. That has been part of our program to assess any risks that might have been present from the BSE epidemic. Next slide, please.

For any calculations that we then have carried out, we work on theoretical risks from those components, and where we have made those calculations, our assessment has been very similar to what you've heard about from Doctors Vann and Berkower.

In fact, I had a substantial experience of carrying out these risk assessments from SEAC where we looked at risk assessments of a range of things from blood and blood products through even the ash coming out of power stations where infected carcasses were being burned. So the methods that we have used are very similar to those described.

What one does in those cases is assume a U.K. origin as a worst case scenario, estimate the relative risks to the date of the process, bearing in mind what I said earlier about the date, estimate the dilution factors where appropriate in the process, estimate inactivation of the agent by process steps in the manufacture, estimate the extent of removal or clearance of the BSE agent by purification of the vaccine active ingredients, and then assign a numerical theoretical risk to the final vaccine dose.

When one does that, we have no concerns about any of our products. It gives levels which are substantially ahead of those that we heard of before in terms of the numerical value. In other words, zero risk to all intents and purposes with very large numbers of safety errors.

So while we at Aventis Pasteur agree with most scientific experts that the risk for bovine materials in vaccines remains theoretical, we are taking steps to address concerns, and we have made progress in this direction with the goal of eliminating bovine source material where possible or by using safe sources, if removal is not technically feasible.

It has to be remembered that, for some cell culture types, there is no good alternative to calf serum. It is quite difficult to grow those cells in the absence of calf serum, and if you try, your yields of the vaccine virus will plummet substantially, and at the present time it is not technically feasible to totally remove those bovine products.

We are committed to supplying vaccines that are safe, efficacious and in full compliance with the regulatory requirements, and we are confident, as I reiterate, that our existing products meet these standards, and there is no clinical or scientific evidence suggesting that the use of bovine source materials in vaccines presents any safety risk.

My final slide just makes the point that we believe that it is important to maintain public confidence in vaccines and in immunization, and that even a theoretical risk must be taken seriously, if it undermines public confidence.

The greatest danger that we see is the possible return of vaccine-preventable diseases caused by doubts about the safety of vaccines. That's why we are anxious to do the risk assessment and make sure that our vaccines are safe.

We are, of course, committed to working with all public health community organizations to maintain confidence in the safety of vaccination. Thank you.

CHAIRMAN BROWN: Thank you, too, Dr. Almond. Are there any representatives from other vaccine manufacturing firms in the audience who wish at this time to make a statement? If not, we now have an open public hearing, and we are aware of two individuals who have notified us that they wish to speak.

the first is Mr. John M. Clymer who is Director of External Affairs at the Albert B. Sabin Vaccine Institute. Mr. Clymer.

Well, barring Mr. Clymer's presence, we will go on and see if the second representative is here. That's Ms. Lynn Tylczak, I think it might be pronounced, who was going to speak on the importance of vaccination. Yes, she is here. How do you pronounce your name?

MS. TYLCZAK: It's Tylczak, rhymes with "smile back." T as in Tiger, y is in yak, l as in llama, c as in camel, z as in zebra, a as in aardvark, k as in kangeroo.

CHAIRMAN BROWN: Obviously, you've had a great many questions to that effect. Please go ahead.

MS. TYLCZAK: Thank you. Good afternoon, members of the committee. I apologize. My knees are shaking. The last time I spoke in front of this many people, I got married. So cut me a little skack.

My name is Lynn Tylczak, and I'm the Communications Director for PKIDs, Parents of Kids with Infectious Diseases. We are a national nonprofit with two missions. First, we assist the families of children affected by infectious diseases. Second, we educate the public about infectious diseases and various methods of prevention, including immunizations.

I am here to speak on behalf of those families whose children suffer from vaccine-preventable diseases. In the past few years, we have been contacted by folks from all over the country who want straight talk about childhood immunizations. These moms and dads have heard contradictory statements in the media and on the Internet, and they don't know what to believe. They want to know the truth.

As your committee ponders the issues before it today and what, if any, action should be taken to address them, we only ask that you continue to do what you have done in the past, follow the science to find the answers.

As parents, we support childhood immunizations. It is critical for the protection of our children to maintain high rates of coverage. Too many of our families have children living with horrible diseases, diseases that could have been prevented with a simple shot.

Some of our parents even know the pain of losing a child to one of these preventable diseases. They agonize over the "if only." If only they had gotten their child vaccinated.

We all want what's best for the kids. Vaccines should not be brought onto the market until research shows that they are safe and effective. After vaccines are in use, the scientific community should continue to look for ways to improve their safety and increase their efficacy.

That said, we ask that care be taken to avoid creating fear and misunderstanding among concerned parents. Vaccines save lives. There is a big difference between inference and information, certainty and circumstances, coincidences and causal links. Let science do its job. Let it save our children. Thank you.

CHAIRMAN BROWN: Thank you very much, Ms. Tylczak. Is there anyone else in the audience who would like at this time to make a public statement on the topic before the committee? That being so, the open public hearing aspect has been concluded, and in spite of the fact that we started an hour late, we are now 20 minutes ahead of time.

Now the fun begins. As I said at the beginning -- Let's see. Before I do this, I've been asked if Dr. Schoenberger from the CDC would get up and at least -- and not "at least," but put on the record a statement about the presence or absence of cases of new variant CJD in this country, the United States. Larry?

DR. SCHOENBERGER: Yes. We've been conducting surveillance of CJD in the country, at least since 1979 and, of course, have paid even greater than usual attention since the report of the emergence of new variant CJD in 1996 from the U.K.

I can tell you that we have not had any documented cases of new variant CJD in the United States. We are fortunate in looking for new variant CJD versus regular CJD in that there are some major differences in the age group that is affected, and that has made our job a bit easier in that respect.

As many of you may know from some of the previous slides, new variant CJD affects a much younger age group than normal CJD. The mean age for regular CJD is in the order of 68, whereas the mean age for the new variant CJD is more like 27-28 years.

In fact, we've been dropping with time with teenagers and so on. We haven't had a single case in the United States of CJD in teenagers. We've got very good evidence on all the very young cases, which constitute perhaps 60 percent or so of the cases in the United Kingdom, and all of them have been ruled out with either tissues or very specific types of investigation.

We also have an ongoing -- There is no case in the U.K. of a case over 55 years of age at death, and we have an active surveillance now of looking at all cases under 55 for clinical and pathologic evidence.

So we are pretty confident that we do not have new variant CJD in the United States, and I gather that's what they wanted to get on the record.

There was a question earlier about what other factors in that cohort study of calves that might be different between those that have a dam that's infected with BSE versus those who have a dam that's not. In these diseases, I believe genetics do play a role.

One possibility is that there is some increased susceptibility that is evident in the calf whose mother had BSE.

CHAIRMAN BROWN: Thank you, Dr. Schoenberger.

We have three questions that were phrased. They look a little complicated in the way that they were put together. In fact, they are not, but that will require a slight reorganization of the questions.

Before I try to reorganize those for you, I'd like to give you just very briefly my read on this issue as a way of trying to orient and focus the discussion which, in this particular case, is very vulnerable to being dilatory.

I think the first fact is that we are looking at levels of infectivity which, if present, are very, very low, and the consequence of that is we are looking at risk that is very, very low.

I think the committee would share with me the idea that the only thing worse than the death of a child is the death of a child that could be prevented. Having said that, and having listened to the lady who spoke, that is a two-edged knife. One can die from BSE or one can die from a vaccine-preventable disease.

So the discussion will invariably involve a trade-off, as it always does, between what is at present a theoretical risk versus what would certainly be a real risk. In risk assessment in this particular instance, I don't think there probably are four. There are probably three elements, and you've heard about them all.

One is the source. One is the tissue, and one is the processing. We probably haven't heard too much about processing, because that tends to be proprietary. But let me give you an example of the kind of thinking that might go into the source and the tissue.

The worst thing would be, for example, that material were taken from a sick animal in the United Kingdom. An alternative would be -- and that would be a Category I. Another would be a Category II or III country where you had a misdiagnosis of an animal that actually had the disease or you took material from an animal that was perfectly healthy but was incubating the disease.

None of the estimates of risk that you've heard today can be precisely quantified, and I don't think the committee should get too exercised and to put too fine a point on a number here or a number there. The fact is that every risk analysis that you've heard or you will ever hear has serious lacunae.

So we will not be able to put a number on any risk estimate under any circumstances this afternoon.

In terms of the tissue, we all know that brain is the worst, and nothing, to the best of my knowledge, originates in brain that goes into a vaccine. With respect to serum, fetal calf serum or any other kind of serum, or other tissues, you have heard that the evidence presented to date indicates that there is no detectable infectivity.

That also is a two-edged sword, and the functional word is detectable. Certainly, any level of infectivity in cattle is very, very, very low. But arguing from a rodent model, for example, in which serum had very low levels of infectivity, it required 30, 40, 60 and 100 animals assayed to detect the infectivity.

So the fact that you've got four or five cows used as an assay for a tissue such as fetal calf serum cannot -- you cannot conclude from that that the serum from any cow with this disease is not infectious. All you can conclude is that, if there is infectivity, it is at an extremely low level, which is no surprise.

The third point is processing, about which we haven't heard too much. We know from studies of TSE over the years that these agents are phenomenally resistant to most conventional means of inactivation. For example, usual heat and formaldehyde treatment is totally ineffective in inactivating these agents.

There is, however, a process step which is used in many biologicals which removes, rather than inactivates, infectivity. That is chromatography or filtration. Depth filtration and chromatography of any stripe, we know, removes up to three logs of infectivity.

So if those steps are present in the processing procedure, they would be a further safeguard.

With those comments, I would also mention one other thing, that dilution is totally irrelevant. One infectious unit is one infectious unit, and will infect one person by definition, and it doesn't matter whether it's in vial A or vial 1,000-A. It's still there. You cannot, so far as we know, dilute out infectivity, not in this disease.

The questions that we've been asked to address have been divided into considerations of licensed vaccines and investigational vaccines. I think, for the first part of the discussion, we should just ignore that, because the only reason for making that distinction is because the FDA would have different options in terms of what they might do, depending on what kinds of advice they get, and they have given an example of that.

For example, in a licensed vaccine they could take regulatory action. They could do product recall, package inserts, "Dear Doctor" letters. Whereas, with investigational vaccines the options would include things like stopping a clinical trial. It would also include regulatory action or modification of the informed consent.

So, really, it doesn't matter if you get sick and you are under investigation or if you get sick and you've been vaccinated, from the point of estimating risk. It really is divided only because of the options that the FDA would have that would be appropriate.

CO-CHAIRMAN GREENBERG: Can I just intervene for a second? The risks are the same. The benefits vary. So presumably, in a licensed vaccine there's an established benefit, and in an investigational vaccine there's something that is not established. That's why it's being investigated.

I think that's why the FDA separated them, at least for the VRBPAC committee. We are very used to thinking of licensed versus investigational. So that might be a difference.

We heard this wonderful story of polio. It would be a great concern to stop polio vaccination at the moment. An investigational vaccine for there is no efficacy shown, I would be much more free to stop giving.

CHAIRMAN BROWN: Right. Well, you've blown my train of thought out of the water. I don't think, actually, we are disagreeing. That's another reason why they are different, but in terms of risk considerations, it's the same topic.

So we are now going to talk about risk considerations, and the FDA has organized risk considerations particularly along the following lines, and you've heard them repeated several times in the course of the day.

They are interested in our consideration of master and working seeds, of master and working cell banks, and of the use of calf serum and, particularly, fetal calf serum. They have actually organized it according to the chronology of making vaccines. These would be the earliest steps; second, the process of fermentation; third, the process of formulation.

Those same considerations apply both to licensed and investigational vaccines. So I am now going to open the discussion, and if it wanders too far from the point, I'll try and direct it a little bit, but I'm hoping I won't have to do that.

Who would like to initiate the discussion? Yes?

DR. KIM: Before I answer these questions, I'd like to ask one question. That is: We heard about the infection models using cows and mice, and is there any data available whether the age of the animal make difference? For example, younger animals would be more susceptible to this disease following inoculation?

CHAIRMAN BROWN: I should add that we don't -- We can ask questions. We can attract people. We can make comments. We can do almost anything we want, and we have all of the presenters who are still here. If a question is asked by a member of the committee, whether or not it's directed to a specific presenter, if the presenter has information that would bear on it, I would hope they would raise their hand and let me know.

To the best of my knowledge, the age of an animal is not a factor in susceptibility, but I could be corrected.

DR. WILESMITH: I think we do have some evidence of an age dependent susceptibility, but not absolute in that it does appear that calves as a group are more susceptible than adults.

We do have difficulty of looking at that in the field, because there is a break in the majority of cattle's feeding patterns. So during their sort of 12-month to almost two and a half years, they are hardly fed any concentrate. So we don't get a good look at it. But the drill in the studies that we have performed at CBO, now VLA, have involved the exposure of calves at four months of age, which is the time at which we think naturally infection takes place.

CHAIRMAN BROWN: Is that too much different, talking to the pediatricians in the group now, from virtually every infectious -- I mean, infectious diseases typically seem to -- Well, younger people seem -- No, not at all? Sorry, forget it. It's true in animal experiments, but --

DR. WELLS: Just to add a point to John's, simply that the inoculation of cattle in the cattle bioassays at around to four to six months is largely an operational problem, in that we have to source them, get them in, and overcome any respiratory disease when they are mixed and so on before we can put them onto experiment with a reasonable assurance that they are going to survive through to the long term.

CHAIRMAN BROWN: So, finally, the answer, Dr. Kim, I think, to your question is there is marginal evidence that younger calves are more susceptible to BSE. Please?

DR. SNIDER: On that point, I think, as many of us know, clearly, there are infectious diseases that are more common in infants and young children than they are in older children. In some cases, that has to do with the fact that -- not necessarily -- the children are more susceptible than older children. But the agent is so common in population that, when young children encounter it for the first time, they just have a higher incidence.

In other cases, since humans are one of the species that are not born with the most mature immune systems, they are susceptible, more susceptible to certain infectious diseases. But again, how that would translate for TSEs, I don't think -- I certainly don't have a clue.

With regard to answer the first question, I wonder, Paul, if you or others could make some statement about PrP and how that protein behaves or how you might expect it to behave during some of the processes that are going on early in the manufacturing process. Do we know -- You indicated something about chromatography. Could you sort of elaborate more on some of the physical/chemical characteristics of --

CHAIRMAN BROWN: I'll say a couple of things, and then I'll let Dave Bolton complement what I say, just in terms of removal.

This is -- The word sticky is usually used. It's an aggregated protein which tends to adhere to matrices, and that is why it is taken out when material is run through a matrix, whether it be a depth column filter or a chromatography column.

It can be removed as well by very high speed ultra-centrifugation, if that happens to be one of the steps -- partly removed, not totally removed. There is a strong but not universal consensus that PrP is, in fact, the infectious agent, not just a part of it. It's one or the other.

So PrP and infectivity from the point of view of tracking can be considered one and the same thing. So what PrP does, there goes also the infectivity under almost all circumstances. Therefore, whether you detect PrP or detect infectivity, by and large, one indicates the other, and you can either try and measure PrP or bioassay for infectivity.

As I've indicated, and I'm sure Dave will agree, current tests which are an improvement, vast improvement, over tests that were in use several years ago, including the Western blot, have now instead of reaching a point where you need 10,000 molecules of PrP to make one infectious unit, you can now detect, oh, somewhere between -- You can detect infectivity at a level of about 100 to 1,000 the dilution of PrP.

So PrP is still a much less sensitive detection method than a bioassay, but it is getting better and better. Dave?

DR. SNIDER: What about adherence to cell membrane --

CHAIRMAN BROWN: I'm sorry?

DR. SNIDER: -- solubility in water versus lipid solubility?

CHAIRMAN BROWN: I could get into it, but Dave, you're here. Why don't you do that?

DR. BOLTON: Paul covered a lot of that. one thing about PrP is it really depends on what strain of the agent you're looking at.

A lot of the biophysical characterization of PrP prions have been done with the 263K strain from hamsters, and that behaves very differently, say, than some of the other mouse strains or even other hamster strains like the TME agents adapted in the hamster.

So -- I haven't done work directly with the BSE agent. So it's difficult to say how that would behave. I'm not sure if anybody here has expertise on handling that. But in general, PrP is very hydrophobic. It does tend to cling to things, particularly it will be taken up by cells and may remain in cells for some period of time, although the replication rate is quite slow.

So although you may have the original agent sticking to cells and remaining with the cells and not being degraded, the likelihood that it will double in amount even over a short period of time is very small.

CHAIRMAN BROWN: Just for those on the committee, the Vaccines Committee, who were not aware of it, Dr. Bolton is one of the people who discovered PrP and has been a pioneer in its characterization ever since. That's why I defer to him.

DR. CLIVER: Another -- We were talking about doable experiments. We have fairly circumscribed host systems for our virus vaccines. I heard the varicella mentioned for the inactivated polio vaccine. I don't know whether FRHK-4 is used for the hepatitis A vaccine or not.

When we talk about introducing prions hypothetically with calf serum, even though I personally am satisfied that isn't going to be in calf serum, we are not really going to replicate those prions. We are only going to have a replicating system, if indeed either of those monkey kidney cell lines is producing prions as a matter of course; because the viruses, particularly the polio virus, will shut down DNA-dependent RNA synthesis.

So cell-specific proteins probably aren't going to expressed for long after polio virus cuts in as an infectious agent. So having said all that, if the prions aren't being expressed by the host cells in a condition that would allow them to be refolded under the influence of the introduced hypothetically prions from the calf serum, why there is no way for multiplication to take place.

This strikes me as something that could be easily enough determined, not at this sitting, mind you, but not a great problem experimentally, compared to some of the other undoables that we are confronting here.

CHAIRMAN BROWN: Dave, is that -- I mean, I could envision the consequence of this. Well, just looking, you couldn't do it in cell culture, because you don't have an assay that's sensitive enough.

DR. BOLTON: Not at this time

CHAIRMAN BROWN: No. You might be able to do it in vivo. That is to say, you could inoculate a strain of BSE, say, into a variety of different species which are the source of a variety of cell lines. You could then possibly -- possibly -- determine whether or not those organs by bioassay were infected.

If you didn't have any -- If, for example, you inoculated BSE into a green monkey and then, when the green monkey got sick, you would take his kidney, because green monkey kidney cells might be used in tissue culture, and then you would assay the kidney to see whether or not there was any infectivity; and if there were or if there weren't, it would give you maybe a clue as to whether or not it would work. But to try and do molecular biology to see whether or not the protein folded in the normal cell -- how are you going to do it, if it's not infected?

DR. CLIVER: The recipe for vaccines does not start with catch a monkey.

CHAIRMAN BROWN: All right. I used green monkey as an example. Use any species and cell that you want.

DR. CLIVER: There are cell lines that have been established for over 20 years. You can produce any given quantity of that cell line.

CHAIRMAN BROWN: Okay.

DR. CLIVER: My point is that they -- First of all, they've got to have a gene for prion production, which should be determined.

CHAIRMAN BROWN: They have to have -- I'm sorry, what?

DR. CLIVER: They have to have a gene -- In order to produce prions --

CHAIRMAN BROWN: Well, that's 100 percent. So that's a done deed.

DR. CLIVER: Well, but not necessarily.

DR. BOLTON: But they don't necessarily express it. I think that's one of the problems.

DR. CLIVER: One of the questions is, is that gene expressed.

CHAIRMAN BROWN: Well, I turn it over to Dave. Can you design an experiment, Dave, that will satisfy our member?

DR. BOLTON: We shouldn't make this too complicated. If you take, basically, the fastest model of prion replication, in vivo in the best possible conditions, you have an incubation time of somewhere around 60 to 65 days.

The doubling rate, if you calculate that out, is somewhere between five to seven days. So when you look at that versus a cell doubling rate in culture, you can see why the past history of cell culture in prion diseases has destroyed many careers, I think. It just doesn't work out very well in cells that are expressing PrP at a normal level.

I think that, you know, perhaps for those of us who work on prion disease, it would be much better if we could get a cell line that would efficiently replicate prions, but it isn't happening now, and I think that -- So it's unlikely that that would be a great concern of contaminating the cell line with prions and having the prions be a major problem down the line in production of the working stocks and the final vaccine.

CHAIRMAN BROWN: If I understood Dr. Cliver's proposal, the first element of it was to see whether or not a given cell had the machinery to convert a prion. Is that doable?

DR. BOLTON: Sure. Those are absolutely doable. If you look at -- Well, we looked at a few cell lines. There are a lot of cell lines that are normally used in propagating viruses just don't make very much PrP. So even if you try to pull it out of the cells by PCR, they are in very, very small amounts.

Each cell line that's used could be checked by PCR, for example, to see how much PrP it's making, and of course, the next step would be to check to see -- Let's see, you've got the vero cell, which is monkey cell -- can you, in fact, convert that PrP to a PrP scrapie.

Again in this case, you would have to look at PrP rez, the protease-resistant form, unless you want to do bioassays back into green monkeys to find out if it could convert -- say, inoculating with BSE agent into the cell line, would you get conversion?

Those are certainly doable experiments. They would be quite expensive. And it would for what?

DR. CLIVER: I'm just saying we need to get away from the conception that somehow or other prions are going to propagate in the cell culture in consequence of having perhaps been present in the calf serum that went into the medium.

If there aren't prions there that can be converted to the Rez configuration, they are not going to propagate. There's not propagation as such in the introduced prions in those cell cultures.

DR. BOLTON: There's somewhat of maybe a dichotomy here. If you look in the normal animal, PrPC is made in many, many different tissues, including heart and skeletal muscle and lymphocytes and a lot of different tissues besides the brain. But it's a curious fact that when you try to propagate prions in these other tissues, it doesn't seem to work.

It seems to work really well in central nervous system tissue and not very well in anywhere else. So right now in the absence of actual data, my guess would be that propagating prions accidentally in cell cultures would not be a problem, but there is a clear path to obtaining that real information, although it would be time consuming and somewhat expensive, but that information could be had.

DR. CLIVER: But you can't propagate polio virus in a monkey's kidney either. Yet we're doing a very good job of propagating polio virus in cells derived long ago from monkey kidneys.

So I think appeal to the original monkey is probably not very useful in this case. We don't know how the cells that we now call the vero line were selected from one fortunate or unfortunate but not immortal African green monkey.

So I think it's better to focus on the line as we now use it and not think so much about whatever was swinging from a tree 25 years ago.

CO-CHAIRMAN GREENBERG: I'm going to switch away from the topic that I don't know anything about, propagating prions, except my own, and try to get back to the question.

It seems to me, Paul said it very clearly. The risk in fetal calf serum -- I think I'm just going to assume that all of you around the table heard exactly what I heard, that the risk is going to be very low, but potential -- there is potentially some risk.

The question that I come up with is it sounds like, if you use fetal calf serum from a country or geography where there is no disease, you've lowered that risk, that potential risk, a fair amount more than if you used it from a place like the U.K.

I don't see a convincing reason, given the world surplus of cattle, that we need to say we need to maintain our ability to use -- I don't have a good rationale for saying why I want to use fetal bovine serum from the U.K. or from France or reserve the right to do that, when I have this universe of cattle out there that would lower the risk.

So now I haven't addressed things that are already in the freezer that were made in the past, but to start things I would say I can see no reason in a go-forward way that one would ever use serum from those countries. But I could be convinced otherwise.

DR. SNIDER: I would agree with that, Harry, and I think that I would go further in terms of thinking then about the stuff that is in the freezer and say let's get rid of that, too, but not at the expense of having -- in a radical manner that would expose kids to the risk of vaccine-preventable diseases. But then the questions I was posing earlier were because I was trying to think more broadly and strategically about this issue for the future, because I don't know what's going to happen.

I don't understand these set of infectious diseases very well, and I don't know what's going to happen in Australia or New Zealand or the United States with regard to TSEs. I hope that what's been put in place will prevent those from occurring, but in case we're wrong about that, one of the things I was trying to get at is, is there a way to develop a process that would remove prions and then the folks also getting into a discussion, is there a way to sensitively determine that you have removed them or that they are not there, and shouldn't we be moving in the direction of trying to find those methods for manufacture and for analyzing materials?

CO-CHAIRMAN GREENBERG: I'm in agreement, Dixie. Now I'm going to stop right now. But given that, I guess it's Dr. Trouvin who spoke for the EU. So I must be missing something, because one of the things that he says, materials may also be sourced from countries where low numbers of indigenous cases have occurred.

So that's an EU point of view, and I don't understand the rationale for that point of view. Why give yourself that out? Is he here?

CHAIRMAN BROWN: Dr. Trouvin? Is he still in the audience? Yes.

CO-CHAIRMAN GREENBERG: So did you understand my question?

DR. TROUVIN: Yes. The rationale: It's clear that, first of all, we have to consider whether there is even the risk in using such tissue or such fluid. If there is a -- that there is no risk that the level of risk is theoretical, then why to add an additional criteria such as the geographical region for which, even for this criterion, you cannot have an absolute assurance even of the origin for a country.

CO-CHAIRMAN GREENBERG: Okay. So that's what I thought you were thinking, actually. So I disagree with that rationale. Unless you could tell me compelling reasons that fetal calf serum in Austria was 100th the cost of getting it from New Zealand, I don't see a reason to support the Austrian fetal calf serum industry, you know, saying that, well, I don't think there's any risk at this point of serum being contaminated or you show your 10-20 slide.

From my standpoint -- and this is the last I'll say -- listening to all this, it looked to me like we're never going to get past it until we have better assays the feeling that there's some incredibly small risk of transmission from fetal calf serum where there is this disease in the cattle in that country.

Since we have a way of avoiding that risk, why not do it? I'm done.

CHAIRMAN BROWN: Yes. I think I'll have just a second. We are really always talking about the same question in different dress. That is, even if I know that, let's say, a chicken had the flu and I know that chicken flu is absolutely not a human pathogen, given the choice between that chicken --

DR. FERRIERI: Be careful.

CHAIRMAN BROWN: -- and a chicken without--

DR. FERRIERI: You're in very dangerous grounds, really. Don't talk chicken flu with our group.

CHAIRMAN BROWN: -- I would still prefer a healthy chicken. I'm not trying to get into questions about whether chicken flu is a pathogen for humans or not. It just came to the top of my head, but the principle is there. If I have something which has a disease for which there is absolutely not a shred of evidence that it's a human pathogen, and I still know it has the disease, and there's a choice between that and something that doesn't have the disease or something, it's just human nature to want the one that's healthy. That's a fact. go ahead.

DR. KOHL: It's sometimes nice not to know too much about some things. So as you said earlier in a different way, the science doesn't become a barrier.

We're balancing two major problems. One is an incredibly small risk of a terrible disease, and we've heard different analyses today going from 1018 or 1010. They are really teeny, but one is much, much higher than the other, and next week it may be 105. I don't know, but there is a risk.

Obviously, as Harry has said, as Dr. Brown said, if we can move to a less risky system, we ought to do it, and I don't see why we are not doing it. Now we are not doing it, because the other component is something we haven't heard much about or something that is not forthcoming at this meeting, unfortunately. What is the risk right now of moving to a safer situation where we don't use any material that was sourced from BSE countries?

That's where we need to know how quickly the manufacturers can shift over, and whether there is any kind of a production lag, and whether there will be uncovered children, because that's a real risk. I don't want to see measles or polio in this country, or more pertussis.

So that piece of the equation we desperately need, either from the CDC or from the manufacturers, and several of us have asked that question and it's not been forthcoming.

CHAIRMAN BROWN: I have something to say, but I'll hold off, because we have two other comments, at least. Yes, please?

DR. DAUM: I would actually like to hear responses to Kohl's comment. He mentioned that he's sure that there is a risk. I'm not convinced after what I've heard today that there is a risk that we can actually measure, but I am concerned about the safety of the vaccine supply that we put into children.

So if there might be a risk, I'm almost willing to stipulate that there is for the sake of this discussion. But I would like to temper that with Dr. Orenstein's presentation this morning and a piece of information that I've calculated while we've been talking.

It seems to me that the highest risk that's been presented today is about one child or one dose in 40 billion being infectious. If that's true, and the U.S. birth cohort is about 4 million, and each child gets ten injections of this stuff, it would take about 1,000 years at that point to have one child get an infected dose.

So that I want risks to be zero, but I do want to call attention to the fact that we're dealing with exponential numbers here, 10-10, 10-18. These are incredibly low numbers, and I think this calculation gives some sense of where the actual risk to an individual child is. However, I, like everybody else here, want it to be zero.

I think that Dr. Greenberg's comments would go a long way, if it's feasible from a manufacturing perspective and FDA perspective, would go along way toward acknowledging this committee discussed this; this committee had appropriate concern about it; and took a reasonable step without all the information that we need to define things to drop that risk a whole lot further.

So I would like to hear whether out-sourcing the serum to -- the serum source to a country where there is no disease at the present time, while a lot of the missing science gets filled in, can be accomplished.

CHAIRMAN BROWN: I think probably no one -- go ahead.

DR. EGAN: Could I just address a couple of the issues that have come up. With regard to the manufacturing, the actual production of the vaccine, fetal calf sera is sourced from countries such as the U.S., Australia and New Zealand. No materials from Europe are used in the actual -- you know, the production.

What we are referring to here are the master seeds and the working seeds. Those can't be changed. What we're talking about is, first of all, whether or not we need to change the master seed, which will take some time -- it's doable -- with regard to the fermentation and the use of bovine broths.

All of those sources, you know, are being -- have been changed and are being changed, and the issue is what to do in this interim, this period of about a year, while new lots of vaccines would be produced, formulated and tested and released.

So there is not a continued use of fetal calf serum from U.K. and Europe in the production. The fetal calf serum refers back to these master and working cell banks.

CHAIRMAN BROWN: I may not understand. What I interpret you to say -- to mean is that, say a year from now, all of these things that are being addressed in the questions will have been taken care of. That is to say, working seeds and master seeds will be changed. Fetal calf serum will be resourced, ta-da-da-da. What do we do in the year -- in this coming year? I mean, what are the options? Are we going to --

DR. EGAN: Yes. I meant not necessarily certain for the fermentation and the use of the beef broths that we've heard discussed by Dr. Vann and by others. Those will be changed, and it will probably be on the order of a year to have new vaccines from them on the market.

If manufacturers have to change the master seeds, I think that will take longer to re-derive those.

CHAIRMAN BROWN: Well, let me ask you and the committee a question then. Let's suppose that one of the seeds, whether it be a working seed or a master seed, was prepared, let's just for fun say, in 1985, and amongst the materials to which it was exposed in the course of its being produced was a meat broth sourced from the U.K. which, I think, we've heard today, if I'm not mistaken, might have been the squish from mechanically recovered meat which would include spinal ganglia and spinal cord.

What you're asking is what do we do with that master seed now, or what do we do -- You're saying it's going to be replaced but in a year, and so I guess what you're asking is what do we do with the vaccines that have been produced from this master seed, that are still in circulation? I mean, is that the question?

DR. EGAN: Yes, as well as whether the committee feels there's a significant risk from the master seeds to warrant replacing them. I think some of the estimates that you heard from us on, you know, the risk assessments that we did for the master seeds were on the order of 10-18.

CHAIRMAN BROWN: So you're not saying that all of the manufacturers are going to replace their master seeds. You're asking us to recommend or talk about whether or not we think it should be done.

DR. EGAN: Yes. The fermentation process, use of bovine derived material -- that is being done now. That is taken care of.

CHAIRMAN BROWN: All right. The fermentation process and bovine derived media -- that's being done. The master and working seeds is still at issue. Is that right?

DR. EGAN: Yes.

CHAIRMAN BROWN: And the formulation of the final product.

DR. EGAN: And the issue there was the use of fetal calf serum.

CHAIRMAN BROWN: Right. Comments? Discussion? Yes?

DR. BURKE: I have a question that would be a generic question for the manufacturers. It seems almost an oxymoron to say that you can replace a master seed and still have the same vaccine. Most of the time when you change a master seed, you're changing a fundamental property of a vaccine.

To say that that could then continue to be licensed under the previous Phase I, II, III and efficacy seems almost incompatible, to me. I would ask my colleagues at both the FDA and the manufacturers, do I understand this correctly, that a change in a master seed would almost by definition mean a need to relicense, in which case it would be impossible.

CHAIRMAN BROWN: Yes, Catch-22.

DR. BURKE: This is a question. I'm asking both the FDA and the manufacturers.

CHAIRMAN BROWN: Okay. Do you have a choice of first response?

DR. BURKE: I'd like to hear from both.

CHAIRMAN BROWN: FDA first or it doesn't matter?

DR. BURKE: I defer to the Chair.

CHAIRMAN BROWN: FDA, as long as you're standing up.

DR. EGAN: Yeah. I mean, the change in the master seed is extraordinarily difficult, and I guess we're talking about, in the case of viral vaccines, re-deriving the seed from clones, if they exist, or plaque purifications. Again for bacterial vaccines, again trying to do purifications through growing up, dilution, pulling out single colonies, you know, isolating it, regrowing it again and again.

CHAIRMAN BROWN: And the same thing doesn't apply to working seeds. Working seeds are not a problem.

DR. EGAN: The working seeds are not a problem, because you just re-derive a whole bunch of those with the masters, and that can be done.

DR. FERRIERI: But what would you be requiring to do? Would you be requiring the manufacturers to submit for all the new trials? I don't think that's what you would be requiring them to do, is it?

DR. EGAN: Submit for -- You mean new clinical trials? Would it require a new IND?

DR. FERRIERI: Are you going to need to go through all the Phase I, II and III?

DR. EGAN: No, I don't think so.

CHAIRMAN BROWN: So what you're saying is that, supposing -- just supposing the committee felt very strongly that all of the master seeds ought to be replaced. You are saying that the FDA approval of such master seeds would not be a standard approval process?

DR. EGAN: Well, it would have to be a supplement that would be submitted to the license. It would have to be dated to show the identity to the original material.

DR. BURKE: How would you guaranty identity?

DR. EGAN: Well, I think this is a bridge that we're going to have to cross. I'm not -- You know, in some case it could be through sequencing.

CHAIRMAN BROWN: Dr. Ewenstein?

DR. EWENSTEIN: Well, I wanted to contrast what we are trying to do today to --

CHAIRMAN BROWN: Yes, any of the manufacturers, please.

MR. STEPHENNE: Yes. Jean Stephenne, SmithKline Beecham. I would like to make a few clarifications.

The first one, I don't think that any manufacturer is using any serum coming from BSE country. So that's the first point, and I think there has been confusion during the discussion about that.

So as you know, when we manufacture vaccine, we start from the working seed. We grow the cells, and we use bovine serum. This bovine serum since 1990 has been changed to the source which are non-BSE countries. So I want to avoid the confusion there.

Secondly, when you manufacture vaccine, you need master seed and you need working cell bank. Then if you look back to the history, what has happened in the Seventies or Eighties when these vaccine were developed, that's really the fruit of research. Right? So it has been years of research to develop these vaccine.

So if today you take, for example, MRC5 cell line, which I use for production of hepatitis A vaccine, this cell line were discovered in the U.K. and developed in the U.K., and they have a certain history, and you cannot change that history, which means you have to go back to the master cell line. That's the only thing you can do, but you cannot terminate all the history.

Two, when you look to history, let's say ten years ago the way we were controlling productible bioengineering is totally different than what we are doing today, which means that the manufacturer of amino acid has changed the process also during the last 20 years and the last ten years.

Why? Because attention has been given to BSE, which means when you speak about fetal calf serum, you need also to speak about other ingredients, for example, gelatin-derived product, whether gelatin produced 20 years ago is safe as bovine serum?

So it means we need to address working cell bank and working seed virus. Can you change it? Yes, we can do it, and the process is ongoing and in discussion with health authorities.

Then can you change your master seed? For us, it's a new development. It is the development of a new vaccine, because I don't think that someone can guaranty that we'll do all the in vitro tests to prove that the vaccine you have done and the new strain you have done is similar to what you have used in the past. So you have to re-do everything.

So I think we need to in the discussion phrase, what do we use in routine production? Can we change a working cell bank? Then what do we do for the master cell virus or cell bank? And when addressing that, I think that's a question which must be addressed for all manufacturers, not the European manufacturer.

Why? Because who can guaranty that 20 years ago a U.S. manufacturer who was buying U.S. serum or was buying U.S. amino acid was -- there was no certificate of origin. There was, I would say, less control of manufacture of these products than today. So I think we have to address it globally as the whole industry. Thank you.

CHAIRMAN BROWN: Thank you very much. Dr. Ferrieri?

DR. FERRIERI: I think nothing stirs our blood more than the possibility of adventitious agents in our vaccines and the enormous problems that this imposes on manufacturers as well as the potential for undermining our vaccination effort and the confidence of parents and consumers on behalf of recipients of vaccines.

I feel a bit compromised today, as Dr. Lurie had mentioned earlier, in not being able to ask certain very specific questions. So I think that I'll try to stay away from anything controversial.

From a theoretical standpoint, I don't understand why we can't test these master seeds and at least have some confidence that using the best assays that might be available, that we might feel secure that they do not display any infectivity potential.

I applaud the manufacturers who have presented their plans to replace all bovine sources, but realistically, we know that there may be some aspects of the whole process that will not be able to be replaced.

So based on everything I've heard today, I do not see -- and I'm fairly conservative and very interested in the safety of all that we do here, but I don't see that there is anything we've heard that impugns the integrity of vaccines that are on the shelf to any significant extent at all, and that we need to solve the problem and move forward.

We have solved other problems of a tougher nature within the past five years at the VRBP Advisory Committee, and this one will be solved as well. I guess I'm an optimist and know that CBER and all of you will be able to meet the kinds of requirements that we need. But I don't think we should be overhysterical about the current problem and that the current master seeds are likely to be pretty intact.

CHAIRMAN BROWN: You raise an interesting issue. The next one is Dr. Ewenstein, but the issue is today, is there anything that the FDA might do, from the committee's perspective, about risk on the shelf, so to speak, versus the future, and what might be done in terms of a word that we haven't heard so far today but this committee is very familiar with, validation tests. For example, taking a master seed, spiking it with a bovine strain, processing it, and then inoculating the final product into the most susceptible host, which would be a cow or a bovinized transgenic mouse.

That's a kind of two-year experiment, but two years or three years from now, as is usual in these discussions, we may have the information that we need now, but at least it would be something.

Other comments and questions? Dr. Ewenstein?

DR. EWENSTEIN: Well, I was beginning to say I wanted to contrast what we were trying to do today to what we did in the donor deferral question. I think there at least we had the ability to look at the risks and the benefits, and we tried to find a point at which we would not seriously interrupt the blood supply while trying to reduce a theoretical risk.

I think we're accepting the fact now that we don't have that other side of the equation today, and we can only suspect that the impact of losing these vaccines for one or more years would be large, but we have no specific number on that.

I don't think we've heard anything today that would justify a large risk on the loss of the vaccines. I think it should also be put into context that you have to compare the risk of catching TSE through a vaccine, if you will, to the real risks that we already know exist that we're willing to balance, and that includes idiosyncratic reactions and allergic reactions and -- well, we heard about shingles and the like.

So these vaccines are never going to be risk-free, as is true of anything in medicine, and I don't think we heard anything today that would raise what we're talking about here with TSE above the risks that we know we are already taking.

All of that said, I think that, if there are things that can be done in the interim -- the manufacturers have talked about some of the things that they've been done -- that they are doing, rather, that have been done. I would encourage that, and I would hope that the FDA would enforce the guidance to that degree.

I suspect that the sensitive test that we're looking for for TSE is going to come around before we could perhaps develop the new vaccines that have been at least theoretically discussed, and that we are likely to get to the answer more quickly that way than we are to start from scratch in developing all new vaccines.

DR. MODLIN: I'd like to agree with the last two comments almost completely. I think there's a fair amount of room here. I was going through the same calculations that Dr. Daum was with respect to the likelihood of observing a case anytime in the near future, and it appears to be so remote that I think that there's a considerable amount of room and confidence that there is -- we can take, I wouldn't say a casual approach to it. That's the wrong word to use, but can have some confidence that considering the alternatives, considering the alternative of seeing the return of vaccine-preventable diseases even in a small number of children, which would be likely or certainly be a much higher probability event than, I think -- I would take a measured, thoughtful but direct approach that Dr. Ferrieri suggested.

That is to test what we can test and derive what information we can from that, and then to proceed further. I would just point out that one of the vaccines that was under discussion today is IPV. If the WHO eradication effort continues to go as successfully as it has in the past, there's a likelihood that -- or use of IPV that we'll be using in the future will be finite and that we, you know, hopefully, will never have an opportunity to see whether IPV, no matter how it's manufactured, is associated with an adverse event from adventitial reagent.

So I think a measured approach to assessing what risk we can and taking the steps to remove what we can to reduce the risk makes a lot of sense. But I certainly would not encourage anything else.

DR. ROOS: I think we have safe vaccines now with respect to perceived dangers of spongiform encephalopathies, and what we really have is perhaps a perceived risk. It would be great to get rid of that perceived risk, but the question is what's the downside of making new master lots of cells and virus seed.

It sounds to me, first, as if there are going to be regulatory issues that are going to be rather onerous, that there will be difficulties establishing secure, safe cells. That is, the histories of these cells may be controversial, the fact that there is perhaps mysterious histories about some of the lots that were used in any of these cells sometime in the past.

I think the third issue, which is an important one, is that these new cells and virus seeds won't really have the history of safety with respect to many other viruses and adventitial agents that we presently know with vaccines today.

So there's a tradeoff here in potentially getting virus that has no -- that is less likely to have fetal bovine serum from a U.K. source, but the tradeoff is that we really don't have the safety record for these new established vaccines. So I think that, in order to decrease perceived risk here, we may be taking new risks that are unknown.

CHAIRMAN BROWN: Just a second. Ms. Fisher, did you have a question that I haven't been paying attention to?

MS. FISHER: I do have a comment. I think that Dr. Berkower summed it up best, at least for me as a consumer rep, when he said there are many factors we would like to know but don't know at this time. What I've learned here today is that when bovine derived materials are used in vaccine production, especially materials from countries where BSE is known to exist, there is at least a theoretical risk of TSE transmission and that this risk is made more possible by the technology limitations to detect adventitious agents.

I think that, if there is a risk, even a theoretical risk, from a consumer's standpoint that you have to tell the people who are using the product. There has to be full public disclosure, and I would encourage the FDA to look at requiring the manufacturers to have something in the product manufacturer insert to reflect this theoretical risk.

CHAIRMAN BROWN: Thank you. That is an interesting issue. Of course, it's one of the FDA options to be able to do it, and I'm sure as a consumer rep you recognize that the likely reaction -- and I'm all for public disclosure -- of a letter which says "Dear Doctor, it has come to our attention recently that this vaccine contains fetal bovine serum that was processed from Great Britain which has, as you know, killed a number of people from mad cow disease. We thought you ought to know -- You know, you wonder whether or not the risk is sufficient even to cause this much anxiety, because it does.

MS. FISHER: It may be a difficult thing to address, but I don't think that -- I think the public trust is important and, if you're truthful with the public and forthcoming with the public all along the way, then there are no surprises for anybody in the future.

I think that people cannot be elitist and decide what is best for other people. You have to have full public disclosure about even a theoretical risk, and I think in the long run it's going to serve the vaccine program better than to basically have people be finding out that we knew but didn't tell.

CHAIRMAN BROWN: Yes. I, a hundred percent, absolutely agree with that, and it's a long process of education and people have to -- You have to take the flak for a while until people understand that when you're telling them that there is a theoretical risk, that that's exactly what you mean, there's a theoretical risk. And they gradually begin to appreciate the remoteness of that risk and, therefore, accept it. But I agree that it's entirely better to do it that way, accept the reaction you're going to get from that subset of the population that always at zero risk as the only alternative, and gradually they will come to understand that there really wasn't any risk, but still --

MS. FISHER: At least you were honest. At least you were above-board.

CHAIRMAN BROWN: Yes, right, exactly. At least you were above-board. Go ahead, please.

DR. LURIE: I think those are very important points. Let me just make one sort of introductory point and then follow up on Ms. Fisher's point.

As I see the very worst case scenario here, which is not, of course, the only one, and Dr. Vann's presentation, the fermenter under the worst scenario -- and again, it is the worst scenario -- is a five times 10-8 probability of a single dose being infected. That's one in 20 million. It's not one in 40 billion, and one in 20 million -- Again, we don't know how many vaccine doses, because we don't know which vaccines, etcetera, etcetera -- points I've made before.

Certainly, that doesn't take very long for 20 million shots to be administered in this country. But having said that, I think that Ms. Fisher's point is absolutely right on. I think that the fact of -- There are two reasons to disclose. One is a moral one, that the patient would like to know and, I believe, has the right to know about a risk like this.

Certainly, I would like to know if I had been exposed to a minimal risk or not. So I think that's a moral issue, and I do think we should steer away from paternalistic ideas about what is best for patients. I think that's the sort of thing this country has been leading the world in moving away from.

The second point is, frankly, a political one. The fact of the matter is that in this room today there are a number of members of the press, and they are going to write stories about this, and those stories are going to be on the Internet by tomorrow, and they are going to be out there for people to talk about.

It is going to do no good for this committee or the public health or for public confidence in vaccines for that kind of stuff to be out there and we taking a position that somehow patients should not be adequately informed in some fashion.

So I think that, for political reasons as well as moral reasons, we do inform. The question to me is not so much whether to inform, because it's informing via Reuters and the AMA News versus informing by the FDA, the manufacturers or the doctor. That's really the question.

So I think the question we should be asking is how to inform, and my own feeling is that a letter to doctors explaining this can be written. It would be difficult to do, but I'm sure the FDA can write a letter that will explain how small the risk is, but still provide the information to doctors who will need to be answering the questions posed by the patients who read about this on the Internet tomorrow.

CHAIRMAN BROWN: Well, as this is one of the options that the FDA has and the question has come up, I think we should clear the decks and ask for any other comments about this particular issue. That is to say, shall we say, quote/unquote, "informed consent." Dr. Ewenstein?

DR. EWENSTEIN: Well, I agree that the facts are already out there essentially, as you are saying, and I think that adding it to the package insert, as long as it's put in the right context, makes a lot of sense.

I'm wondering really whether a "Dear Doctor" letter which has a certain amount of urgency attached to it isn't overkill, and I think it's also important that we not just be a neutral filter. At the risk of sounding somewhat elitist, it is our job to make recommendations and to put things in context, and to put information out there without a recommendation is really betraying the trust that, I think, we have here to make a recommendation.

I think that it should be stated that, although there is this theoretical risk, that the best calculations that we can put forth -- and I am somewhat encouraged that, although there is a wide range, that none of the calculations, whether they be from industry or from various government or impartial sources, one might say, exceed, I think, by any of our calculations the benefits, and by a very wide margin.

I think it's important that it be stated that way, just as when giving a vaccine it wouldn't be fair -- forget the TSE risk -- to say this is a risk-free thing. Okay? If somebody asks you, you would have to be honest and say that rarely people have severe reactions, but extremely rarely, and not to the point where we stop giving vaccinations.

I just think it needs to be put alongside a recommendation that no change in practice is indicated.

CHAIRMAN BROWN: I have a sense that the entire committee feels essentially as Dr. Ewenstein just expressed. Is there any dissenting view? If there's not, I think the FDA has one answer from today's discussion, and now we will have another comment. Yes?

DR. HUANG: No, I completely agree with the last speaker, but I think this is the right time to say that it's terribly important as we look at the data that's been presented today that we recognize that there is still a lot to be found out, and although some of the experiments that have been suggested, I would say, are really trying to prove the negative and that we go out and ask people to spend their whole careers trying to prove the negative, that's not going to work very well.

However, there are a few areas that have come out today which, I think, it's important to stress, and some of it has been discussed at great length and others have not.

There are three areas which I think are extremely important. That is: Understanding inactivation of the prion material; providing -- continuing the surveillance that we have had in the animal population; and improving the diagnosis.

I think that there are areas which we can pursue very effectively that will help in surveillance, help in inactivation, and improved diagnosis.

CHAIRMAN BROWN: Inactivation may be a dead issue, in a sense. I mean, there's been a tremendous amount of work over the past 30 years on inactivation, and the bottom line is that virtually anything that inactivates this agent will inactivate the biological activity of anything that it's in.

So that's probably not the most fruitful line of future research to follow. Surveillance, certainly, will be continued, and as you've heard, some of the European countries are now doing pilot studies or beyond pilot studies of fairly sensitive tests for the detection of infectivity in cattle.

I guess that's what you're really talking about, diagnosis. Right? The diagnosis of BSE?

DR. HUANG: Well, Mr. Chairman, I might suggest that, for instance, in terms of inactivation that now that we know the sequence, we might have specific proteases or specific sequence binding small molecules. There are ways of looking at that.

I think also, in terms of diagnosis, the whole area of chaperon and interaction of floating proteins with chaperons is worth pursuing. There are areas now in molecular biology that offer whole new avenues, and even quite specifically, when we think about the genetic restriction that we know about now with PrP gene, that that area can be pursued in detail as well.

So these are just a few that come to mind. I'm sure there will be others that I haven't thought about.

CHAIRMAN BROWN: I really think the diagnosis of BSE is up to speed. I mean, cattle that die and are examined histopathologically and who die or that die from the disease test positive by current tests.

DR. HUANG: Well, yes, I think that that is a good test, but it takes, what, 36 months?

CHAIRMAN BROWN: No. That takes -- That's a PrP detection test. It takes 36 hours. It's a good test.

DR. HUANG: You mean cattle die in 36 hours?

CHAIRMAN BROWN: I'm sorry?

DR. GRIFFIN: You're talking about cattle that are ill.

CHAIRMAN BROWN: Not necessarily, not necessarily.

DR. FERRIERI; In surveillance of herds, you would be doing that.

CHAIRMAN BROWN: That's right. That's what they are doing.

DR. FERRIERI: And so this is early. I mean, this is how they are monitored, and I want to add that we not be complacent about the purity of what may come out of Australia and New Zealand, etcetera, and that we continue to have molecular monitoring so that we do not make any false assumptions, if products are used from non-European countries.

DR. PICCARDO: I agree with that. I think it's --

CHAIRMAN BROWN: That's Dr. Piccardo.

DR. PICCARDO: Sorry. I agree with that, because as the discussion moves, we have to rely more and more on countries that we suppose are BSE-free. I mean, if they say they are BSE-free, okay, we'll believe them, but there should be somehow a monitor system that keeps the standard very high, because we rely more and more on those. So yes, I agree with that.

CHAIRMAN BROWN: We should remind the committee that Dr. Piccardo's home of record is Argentina. Another question?

DR. PICCARDO: Actually, that has nothing to do with what I just said. Actually, if the people from my country hear what I just said, probably they will kill me.

CHAIRMAN BROWN: Hold on just a second. Yes, Dr. Almond?

DR. ALMOND: I would just like to echo what Alice Huang said concerning inactivation. One area that I think is very poorly investigated is the effect of acid hydrolysis on prions. I know that -- I spoke to David Taylor recently who, of course, has done a lot of the inactivation studies, and the effect of acid hydrolysis is very poorly studied on prions.

Now that -- We know it's a protein molecule. We know the peptide bond is susceptible to acid hydrolysis. We know that acid hydrolysis is actually used in the preparation of a lot of bacteriological growth media, including, for example, casein hydrolysate, but also things like thioglycollate, hemin and so on involve acid hydrolysis steps.

There is one poster which describes this, and it looks like hot acid really knocks the hell out of prions, actually. Ray may know something about that poster, but I think more studies along those lines would be interesting and might serve a great reassurance, at least on the bacteriological growth media side, that are those media so treated, the risk from prions goes away.

CHAIRMAN BROWN: We do have information about one strain, which is a relatively resistant strain, which is the hamster strain, an that's unaffected by pH-1. I don't know if --

DR. ALMOND: I think the observations are that cold acid does nothing, but hot acid certainly seems to. And it's hot acid -- The heat -- When you do an amino acid analysis of a protein typically, of course, is by a chemist with heat with acid overnight, and you smash the protein down to amino acids and do your amino acid hydrolysis.

CHAIRMAN BROWN: Is boiling acid compatible with vaccine biological activity?

DR. ALMOND: I just remind you that casein hydrolysis --

CHAIRMAN BROWN: I know. I'm not being smart. I'm asking a question. Is a vaccine --

DR. ALMOND: Well, what you are providing in a bacteriological growth media is a source of amino acid is a source of peptide is a source of protein. It doesn't need to be intact, and certainly the acid hydrolyses that you do use on that just smash the proteins, and that's quite clear in things like casein hydrolysis being a case in point, and thioglycollate broth as well.

So if you are providing nutrient to a bacterium, then that's fine. Of course, you couldn't do it on calf serum.

CHAIRMAN BROWN: That's what I say. This has to do with the nutrient media, not the bacteria.

DR. ALMOND: Absolutely, on the nutrient media that you feed them with, where it enters into the process. You, obviously, couldn't do it on the calf sera. Wouldn't expect it to survive, but certainly on the nutrient source for the bacteria, that would be a good place to start looking.

CHAIRMAN BROWN: Right. This is a subset of what you were asking, Dr. Huang. Instead of trying to knock out the agent, we knock out the possibility that the agent might exist in media to which it's been exposed. In other words, that you know that the media at least that contacts whatever it is you're making a vaccine from cannot be infectious.

DR. HUANG: Right. In that case, you are knocking out the agent from a nutrient source. I think that there are other methods that one can approach of knocking out the agent from the final product.

CHAIRMAN BROWN: Yes. Two of the most important things or useful things in general are one normal sodium hydroxide -- pretty tough -- and 6 to 8 moler urea, which oddly enough, does not destroy the biological activity of human growth hormone.

So there are surprises. Yes, in the back? I think your compatriot there had priority.

DR. SLAOUI: I just want to share with the experts around the table --

CHAIRMAN BROWN: Could you identify yourself, please, again?

DR. SLAOUI: Sorry. Moncef Slaoui from SmithKline Beecham.

I'd like to share with the committee again a real life experiment, because rightly so, many experts have stressed how fully sensitive or eventually fully sensitive the detection methods that are available today out there to assess the infectivity of the components involved in vaccine manufacturing.

Well, if we consider fetal calf serum, I'd like to share with you a real life experiment in which 29 million doses of bovine vaccine have been manufactured using amounts of fetal calf serum sourced from the U.K. between 1985 and 1988, i.e., at the time where the epidemic was growing, and it had been inoculated in -- actually 26.5 million doses inoculated outside of the U.K. in bovine. There has not been a single case reported of vaccine-associated BSE.

I can't think of a larger real life experiment assessing whether fetal calf serum or actually cow serum or adult bovine serum involved in vaccine manufacturing in amounts that are orders of magnitude higher than what we are discussing here can be reinoculated in cattle. So I think that's probably very relevant to the discussion.

CHAIRMAN BROWN: That's very interesting. It ought to go into a letter to Lancet.

DR. SNIDER: How good is the vaccine adverse effects reporting system in cattle? I hope it's better than it is in people.

CHAIRMAN BROWN: Can you identify yourself, and repeat the question, please?

DR. SNIDER: This is Dixie Snider of CDC. The question is how good is the vaccine adverse effects reporting system in cattle? I hope it's better than it is in humans, because although that experience is reassuring, unless there's some real active surveillance, I'm not sure that the results are really all that helpful.

DR. SLAOUI: I think your point is very relevant, and of course, the 26.5 million doses have been distributed in countries of Europe where BSE surveillance was happening at that time, and have continued to happen beyond that time, because of course, the cattle that are recipients of vaccine between 1988 and 1990 have continued to live over the years beyond that; and 2.5 million doses were distributed in the U.K. during which time at that period surveillance was certainly very maximum.

Not a single case has been associated with vaccination. There is a publication on association between vaccination and BSE in bovine in the U.K.

CHAIRMAN BROWN: That would be an interesting observation to make in the U.K. Can you tell me, for example, in a country with as much BSE as the U.K., that you can actually tell us that not a single cow died of BSE that had been vaccinated?

DR. SLAOUI: No. I mean, again this is statistics, but I think Dr. Ray Bradley said that there was about 1300 cases of BSE reported over the years outside of the U.K. and, if I believe, over 100,000 cases reported in the U.K. over that period.

So that gives an order of magnitude. Now can we go back and trace every single cow that have been receiving of those 26.5 million doses of vaccine? The answer is no, because nothing was designed in that regard. But the size of that experiment is, of course, outstanding in comparison to any experiments you could do in real life.

CHAIRMAN BROWN: I think you would have to do a little data analysis. I mean, you're assuming that, for us to buy that wholesale, it would mean -- it would exclude the possibility that only, say, a small portion of the doses might have, in fact, contained an infectious dose. So that this spread, this difference -- Unless you could show that there was a clear difference between unvaccinated and vaccinated BSE cattle that died, I don't see that that's useful.

DR. SLAOUI: Well, epidemics of BSE outside of the U.K. --

CHAIRMAN BROWN: Outside of the U.K. is a different matter.

DR. SLAOUI: Right.

CHAIRMAN BROWN: But you were saying in the U.K. as well.

DR. SLAOUI: No, I'm sorry. 26.5 million doses were distributed outside of the U.K.

DR. ASHER How many lived past five years?

DR. SLAOUI: Unknown, but I think the comment -- The comment is as many as in natural bovine industry keeping animals out there, immunizing them, and some of them reaching the age at which they manifest BSE clinical disease. The sheer numbers should allow for, you know, a normal distribution.

CHAIRMAN BROWN: Go ahead.

DR. BURKE: I think this line of reasoning is actually excellent. Tt's one of the few places that we may be able to get some data without the issue of the host species barrier that may be clouding a lot of our interpretations.

You don't need to focus on the U.K. You should focus on the United States --

CHAIRMAN BROWN: Oh, exactly. I mean, U.K. is off limits, but other European countries.

DR. BURKE: Where it has not been seen. If we find that there have been millions and millions of doses of vaccines that have been prepared with fetal calf serum derived from the U.K. and used in these countries which have yet to recognize a single case of BSE in the animal population, that would, I think -- I would find that very useful as a reassuring step.

CHAIRMAN BROWN: Yes, I agree.

DR. BOLTON: But I want to get on record David Asher's point, and that is how many of those animals lived beyond five years. If we had that information, then we would really have something that was meaningful. I would recommend to the FDA that there be a specific effort to pull that data together, if possible. I think that would be helpful.

CHAIRMAN BROWN: Do you know if any of the vaccine went to really BSE-free countries like Australia and, I think it's fair to say, the USA?

DR. SLAOUI: I would like to say that we have shared with the agency this information that we are compiling and continue to compile, but you understand, for practical reasons, our company is no more having its animal health as part of SmithKline Beecham. It's been merged with another company, and finding back all the trace information for where the vaccines actually were delivered, etcetera. But these sale of tens of millions of doses were delivered across Europe and outside for many vaccines, some of which containing up to .15 milliliters of serum that were delivered either intranasally or subcutaneously or intramuscularly in countries, I am sure, in Europe where there has been no case of endogenous BSE reported.

CHAIRMAN BROWN: There was a question again or a comment.

DR. EGAN: Yes. I would just like to have a little bit of clarification from the committee. I think I heard a lot of expression for public disclosure of the issues around all of the different vaccines, but some -- I would like to know if that is the committee's consensus.

Second, I think I heard some people favoring or suggesting "Dear Doctor" letters and others thinking that that was maybe too much overkill and to change the package insert. That's going to come up in the second question, but I think we would appreciate some clarification on that or more discussion or additional opinions.

CHAIRMAN BROWN: You want more discussion on that? Well, it seems to me, the committee is uniform in its approval of some form of notification about this issue and the concept of finite risk. I think there was no dissenting opinion.

So the question now is in what form the committee might feel that would be most appropriate, and at least two options were a package insert addition to the fine print, a "Dear Doctor" letter. What are the other options the FDA has?

DR. EGAN: Well, those, I think, are the two major ones --

CHAIRMAN BROWN: Those are the two?

DR. EGAN: -- for disclosure. The "Dear Doctor" letter is very, very public. The package enclosure is limited to those who read the package enclosure.

CHAIRMAN BROWN: To those with very good eyesight, yes. What does the committee feel in terms of a choice between these two. Yes?

DE. BELAY: I'd like to know what the vaccine manufacturers feel about the disclosure issue, if somebody would comment on that.

CHAIRMAN BROWN: I'm sorry. I didn't understand.

DR. BELAY: I would like to know what the vaccine manufacturers would say about the disclosure issue.

CHAIRMAN BROWN: Okay. Before we do that, again the FDA. The "Dear Doctor" letter has nothing to do with the manufacturers. Right? That goes -- or does it? Does the manufacturer do that or does the FDA do it or who does that?

DR. EGAN: Either one could do that.

CHAIRMAN BROWN: Either one could do that.

DR. EGAN: The manufacturer can send a letter to those who purchase the vaccine, the vaccine purchasers.

CHAIRMAN BROWN: Okay. So we would like to hear at least from both manufacturers present what their viewpoint is about either one of these two options. Who wishes to speak? Yes?

DR. SLAOUI: Moncef Slaoui, SmithKline Beecham. I think I would like to reiterate what was said a little bit earlier and take a minute to do that.

CHAIRMAN BROWN: I'm sorry. What would you like to reiterate?

DR. SLAOUI: Reiterate what was said earlier.

CHAIRMAN BROWN: By whom?

DR. SLAOUI: By Mr. Jean Stephenne from SmithKline Beecham. I think the point to be considered regarding information is again to identify what is exactly the issue and where is the issue. To what vaccine does it relate? If we speak about seeds, master seeds and working seeds, having been historically in contact with bovine derived material from the U.K., for instance, in the mid-eighties -- right? If we speak about that, that means, clearly, there has been since, say, 1985 -- you use that number -- there has been no other contact with bovine derived material ever.

The key question becomes for every single vaccine out there -- not that one specifically or those ones that are today under discussion, but for every single vaccine out there for which the seeds, the working seeds, the master seeds, the banks, the working banks, the master banks, have been in culture.

In the mid-eighties, there is a very long risk, I think it was shown or could be shown again, of animal derived material or bovine derived materials that are involved in manufacturing of those seeds that were sourced in the mid-eighties, at time at which it is impossible to ascertain and trace and document that the bovine origin materials were not sourced from the U.K.

Because we are talking about risk factors here in the orders of the billions and the hundreds of billions or thousands of billions, the probability that those other components than fetal calf serum or feed broth coming also from bovine origin could have been, in part, sourced from the U.K. or in part processed in the manufacturing -- you know, at those manufacturer places in a place where U.K. derived material that have been used for something else was in those same recipients.

You know, we've been discussing these things earlier. How can we be confident that those things have not happened historically? We think that it is for that reason that, if this committee and the agency opts for an information on this point, the information ought to be generic to all vaccines; because, effectively, if the issue is related to the seeds, master seeds, we cannot exclude in a sure way -- again, we are talking about remote theoretical risks. We cannot exclude in a sure way that that's not present everywhere.

That's the point we would like to make, and I think that then raises the issue about the impact on perceptions of risk and perception of safety of vaccine and uptake of vaccines and immunization strategy and the impact on public health.

We would like again to reiterate, you know, real life experiment like the bovine vaccine I discussed, all the data that have been described and that scientifically documents that there is no identifiable risk associated with this vaccine -- one should really weigh the impacts.

CHAIRMAN BROWN: Well, it seems to me that the committee has already discounted exactly what you've said. They recognize that the risk may well be infinitesimal. My feeling was that the committee feels that, despite that -- and it's summed up by the words theoretical risk -- that they have already decided that theoretical risks deserve to be called as such and publicized in some way.

Again, the question was -- just a second, Peter. The question was: In what form should that information be conveyed? So let's move beyond your objections and say --

DR. SLAOUI: Well, I guess the comment then would be generic.

CHAIRMAN BROWN: -- if that is the committee's recommendation, what form would you prefer to see it in?

DR. SLAOUI: Well, I guess, really, the short answer then it has to be generic, because scientifically you cannot prove everything --

CHAIRMAN BROWN: Okay. I think it would be generic. I don't think it's the FDA's plan to identify vaccines A through D and leave vaccines E through Z untouched. As you say, there is a sufficient absence of information from archival vaccines so that nobody probably making a vaccine could guaranty that there wasn't this possibility of an infinitesimal risk by exposure to something that was produced between 1980 and 1990 in Great Britain.

On the other hand, if the FDA could be completely convinced, as you point out, that there are certain brands or vaccines even within a certain company that have no possibility of ever having been exposed to bovine products, than there is no point for information to be conveyed.

Peter?

DR. LURIE: First point: Package inserts are, you know, fine as far as they go, but the vast majority of patients don't see them. So I don't think that that's going to be an adequate effort on its own.

I strongly disagree with the notion that any notification should be generic. Obviously, it's in the self-interest of a pharmaceutical manufacturer who is really worried about his or her own vaccine to make sure that everybody is equally tarred, but the fact of the matter is that, even with the very difficult risk assessments that have been necessary in BSE, people have managed to divide things up into categories.

Here there are three potential categories, those were it is known that the companies disobeyed the guidance and obtained the materials at a point in time and from a place that was precluded by FDA. There is a second group where it's simply unknown, and that can be stated, and the third is, if there somehow is a way of convincingly stating where the entire -- where the master cell lines and the working cells come from.

It seems to me that it is wrong to go and tar everybody with the same brush, because there are some ways, however imperfect, of distinguishing between vaccines. I think that, to physicians and patients, it would be enormously helpful to know that, in fact, the vaccine that you are asking about happens to be the one with which we have greater or lesser certainty that the theoretical risk is still lower.

I can't see any reason for throwing everybody into the same pool here.

DR. SLAOUI: Well, I'd like to just make a comment and say my comments, of course, were purely scientifically driven, and I simply cannot make the difference between 18 logs and 16 logs and 15 logs. That's my comment to the experts.

DR. HUANG: And I also want to say I don't think a theoretical threat is tarring anybody, and we shouldn't be even using that term.

DR. LURIE: But the whole conversation here, all the conversation about how important vaccines are and all those presentations by Dr. Orenstein this morning are precisely aimed to point out that vaccines are important, which I agree with, because we are worried that this information is going to tar vaccines. I don't think it should. I'm with you.

I mean, I think that fundamentally there is not a substantial change in the known safety of vaccines today as opposed to yesterday. But we are worried about public perceptions here and, as long as we are, and as long as we have more rather than less information, I think we should impart it to the public.

DR. SNIDER: In terms of communicating it, I would not have an objection to a letter to physicians. But it seems to me that the communication, whatever form it takes, really needs to have the whole context. One of the important messages that needs to come out of this meeting is that we do not -- I don't believe any of us want the FDA to take action which will increase the incidence of vaccine preventable diseases in this country.

So one context, of course, is to emphasize the importance of continuing to vaccinate children against these diseases. That includes using vaccines that are currently on the shelf while, as I hear from the manufacturers, they continue to replace products that came from areas which represent a theoretical risk with products that come from areas that do not present such a risk.

For those -- and when they can do that without having to create a whole new vaccine. For those master lots, it seems to me, the question has been raised, and something that FDA should consider would be whether they can be tested, as has been suggested, if those master lots are going to be sitting around and continue to be used for some time.

Then as has been mentioned, there should be a commitment, I think, to continuing research on the part of manufacturers and FDA and others to identify new technologies which would help reduce the risk, either those technologies that improve the assays or those technologies which might remove the infectious agent.

All of that combined into a communication, I think, would be very educational for physicians, and then would help them in trying to communicate with their patients. Obviously, the communication would include the risk, some statements about the risk assessments that have been done.

To just have a short statement that there's a theoretical risk here without a context, I think, would be a terrible mistake.

CHAIRMAN BROWN: Coming from the floor?

DR. DeWILDER: Michael DeWilder from Aventis Pasteur. I want to address also this communication issue, but before doing that I'd like to reiterate our company commitment that we made very clear. This is to make all attempts that are technically feasible to remove materials of those type of origins, and this includes, actually, master seeds.

What I want to point out is the reason we do that is not because there is a risk associated with the use of those materials or the past use of those materials, but because we are doing it because there is nothing more important to us than the perception of vaccine safety, and indeed we refer to in Dr. Orenstein's talk and to the great catastrophe that would be linked to vaccine preventable diseases; because indeed there is no risk associated with the use of those materials, and you have the calculation that we have made, and you have the expert that you have consulted, and you have the expert that's spoken here today. Here is a fact; that's a number, whatever they are. He's using between 1010 and 1020, whatever, it doesn't matter, in a range which are actually equivalent to no risk.

I urge your committee and the agency to take this into consideration as they choose a way to communicate this to the community.

CHAIRMAN BROWN: Thank you. Now we have heard from both manufacturers, and we have Dr. Scott Ratzan who is a professional and an expert in the whole field of the communication of medical knowledge to the general public, who has something to say. Dr. Ratzan.

DR. RATZAN: Thank you, Dr. Brown. I do spend my life doing this type of activity, as I edit the peer review Journal of Health Communication and edited a book on the mad cow crisis, Health and the Public Good that was published in 1998 by University College, London Press and NYU Press.

I'm very interested in the sort of disconnection of what I heard of some of the data earlier today and what I'm hearing now in terms of something to communicate to the public. I heard something like one in 20 billion, and I know we are using logarithmic numbers.

One in 20 billion would be one second of my life, if I live 640 years. I mean, we are talking about some very, very low numbers that don't translate very well into the public.

What my major concern is, is what I think Dr. Modlin and Dr. Snider just said, what does this do for vaccine preventable deaths. We saw the bumps earlier in the morning in terms of the measles, in terms of what happened with over 100 deaths. As a father and a physician now, I think that we have a very conscionable task to look at how we communicate this to the public, and not jump to a conclusion of this or that.

These need to be tested. There's a science behind communication, and it makes me think of what Justice Potter Stewart said many years ago. Just because we have the right to do it doesn't mean it's the right thing to do.

I think that's where we're stepping in grounds in terms of dealing with theoretical risk here. I'm just trying to think of recent experiences. We saw what happened with thimerosal a year ago where we have four different academies now, AAFP, AAP, the CDC groups, FDA groups -- a lot of people back-peddling and saying there is no risk. It was only a precautionary measure.

We saw 79 percent of hospitals in this country change their policies in terms of childhood immunizations because of that statement that was made. In 1996 the SEAC committee similarly met in England and made a decision that they say there may be a link. They didn't have a communication person on that committee, and the House of Lords and the other groups that have looked back on it said that it was a major issue and a major mistake that they made in how $20 billion and many lives and livelihoods were lost in terms of the U.K. and Europe and the world.

I think this is a very serious discussion that needs to be made for moving from question 1, from yes, we agree with some theoretical risk which, again one in 20 billion -- two, are we going to communicate to a public, are we going to communicate to physicians, all who interpret risk very differently.

So I really implore the committee to try to think about that, not only take a scientific approach to the communication, but really take a scientific approach to look at the evidence on what the public needs to know, what physicians need to know, what policy makers need to know, and how we can continue to make healthy public policy in this area.

So I would be happy to answer questions in this regard, but I really hope that I've been able to impart that upon the committee today.

CHAIRMAN BROWN: Thank you very much. Yes?

DR. DAUM: I'd like to make a comment and then actually ask you a question. My comment is that I am, as I've been reminded today, a person in favor of full disclosure, and I am.

So that the question then becomes how. I totally agree with your comments and approach, as my earlier comment spoke to, and I don't think, therefore, that this should be product recall, which is one of the things we were asked to comment on.

I frankly don't think, with all respect to my colleague at CDC, that there should be a letter sent out to all doctors, because that's an alarming thing to have appear in your mailbox from the Food and Drug Association of the USA.

So I would say to you -- and I also don't think you should just slip something into the fine print of the package insert without letting someone know a little stinker is there. So the question is, in your experience -- you sound like a professional in this area -- how could we approach this?

I feel the need to say something. It's theoretical. I agree with your sense of how often it's going to occur totally. What could we do? What could they do?

DR. SNIDER: This is Dixie Snider. Yeah, we can hear from him, but you made a criticism of my comment, and I just want -- I thought it might be useful to have something to go along with their U.S. Today story that they were reading. That's all. Something that's authoritative from the FDA.

CHAIRMAN BROWN: I'm glad I'm the Chairman of this committee, not this committee.

DR. RATZAN: If I could try to answer that, there is a scientific nature to how do you look at communication. You don't overreact to infinitesimal risks, and at the same time you don't under-react when there is a real risk that's involved, because that does undermine the public trust.

What I heard today were some of the steps that were being taken by some of the manufacturers, the two that presented, that they are trying to embody the public trust in terms of their processes. I think more of the open nature, even meetings like this of being able to have advisory meetings, meetings also that might have the professional associations where you have opinion leaders who might be able to defuse the information appropriately.

A blanket communication -- We often say Marshall McCluhan, a Canadian scholar in media, said, if you try to reach everybody, you reach nobody. By doing that, it's really key in thinking about communicating with the people that need to know.

Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map. We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels.

So I'm answering in a circuitous way, because I think we've heard some of the right steps being taken today, the open hearing, some of the voluntary efforts that are being done in good faith by the manufacturers, and some of the other ways that continue to monitor the open disclosure. I think the surveillance systems that we've put in place not only here in the United States but now abroad in looking at BSE and looking at the CJD that we heard from CDC and others where the numbers are.

So I would say, by all means, keep the surveillance. Keep the voluntary efforts. Continue to focus upon the science, and communicate that appropriately on, whether it's a quarterly basis, or use the different channels, the Institute of Medicine channels that are out there.

I think there's a variety of different ways to do it, such as these expert committees as well. So, thank you.

CHAIRMAN BROWN: Thank you very much. Yes?

MS. FISHER: You may not want to communicate this theoretical risk to the public, but that doesn't mean it's the right thing to do. I think that part of what the National Childhood Injury Act of 1986 was all about, the safety provisions, was communicating risk to parents before they get their children vaccinated.

I think that, you know, the FDA's charge is to ensure the purity and potency of vaccines. It seems to me that the least that we can do at this juncture when we know something is to let the people know we know, rather than keeping it from them.

CHAIRMAN BROWN: Hold on, Dave. Shirley?

MS. WALKER: There's an old German proverb, "Don't point the devil on the wall; otherwise, he will jump off." I think the devil has already jumped off.

The inserts in the packets for pharmaceuticals are great. Notification to the doctor is great. But I represent something like 79,000 mothers who have children in Dallas County who we actively promote to get vaccinated.

So Monday morning when I go back to work, I'm going to have to tell someone, a percentage of these young mothers, that, hey, your child is at risk for whatever that minute amount is for CJD. So what do we do at this particular point? Do we remain mute and say nothing or do we promote and give some type of information?

So I am saying to FDA that we do need some kind of general information that we can impart to our constituents.

CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more comments in this discussion, and then in the event that a number of people on the committee may have to leave, there are two or three very specific questions that the FDA would like some discussion on, and I want to move to them. We've touched on some of them already, but if there's anything more to say on this -- Yes, go ahead.

DR. STEPHENS: I guess I'm really concerned that this discussion is kind of spinning out of control in terms of the risk. I must agree with the consumer advocate who spoke a minute ago --

CHAIRMAN BROWN: Dr. Ratzan.

DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a duty, in my view, to protect the vaccine system in this country. I think that this discussion has gotten to the point of at least suggesting that we believe that this is a significant problem. The data suggests that the risk is in the billions, that there have not -- there's not been a single case of new variant CJD in this country, despite the use of vaccines that have been manufactured in this way for years.

So I think the issue is we need public disclosure. That's not the question. I think we all are in agreement on this committee, but I think to emphasize this point where you're concerned about going back to your group of mothers and saying there's a risk -- I think that's something we don't want to send. That's a message we do not want to send.

CHAIRMAN BROWN: I opened this whole seminar with the notion that we're starting from a very, very small amount of infectivity, if there is any, and the corresponding risk was equally very, very small, if there is any, and that there is a tradeoff between, as several people have said, a theoretical risk and a real risk, which would be discrediting in some way vaccines or causing vaccine shortages or difficulties or refusal to get vaccines.

In other words, this is the tradeoff. Right at the outset, this was the scene that I hoped to set. But you're right. All of our committee discussion meetings tend to spin out of control at about this time of the afternoon, and sometimes it's in one direction, and sometimes it's in another direction.

I think the word risk has enlarged as the afternoon has progressed, and maybe we should shrink it down a little bit and get a little better perspective or a little different perspective. So I tend to agree with you. Let me --

DR. BOLTON: Paul, can I get in my comment?

CHAIRMAN BROWN: I'm sorry? Go ahead. I'm sorry, Dave.

DR. BOLTON: I agree that it wold be important to communicate known risks or even good estimates of risk to the public, but I'm not sure what that estimate would be at this point. I don't think that we really have enough information to communicate to the public and have it be meaningful and not simply scare people away.

I can't imagine the negative impact on the vaccine program in this country if parents started thinking that, if I vaccinate my child, he or she may come down with new variant CJD.

To me, the other way that we communicate is by action. It seems to me that there are actions that can be taken in terms of looking at the process of vaccine manufacture and where the real -- the greatest of the theoretical risks are. It seems to me that the viral/bacterial master seeds are really at the very lowest end, as are the master cell banks, and also trying to change those creates the biggest problem.

From that point on, from the working seeds on down through production, I think that the manufacturers have issues that they can address in terms of removing the use of at-risk bovine materials from that point on.

I guess my question to anybody at the FDA is: Are at-risk bovine materials currently in use at the -- certainly from the production step on, and even at the production of the working seeds and working cell lines, are they in use now, and how long before they will be phased out?

CHAIRMAN BROWN: I guess what you're -- to add to that, are the sources of anything currently coming from BSE designated countries?

DR. STEPHENS: When I say at risk, I really mean those bovine materials are coming from Europe or at-risk countries.

CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --

DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines there was bovine derived fermentation media where that skeletal muscle and pancreas derived from several European countries. I think it was Germany, Denmark, Poland, the Netherlands.

CHAIRMAN BROWN: Right. So they are currently in use in this country.

DR. EGAN: They have all agreed to -- That will be changed, but as I mentioned, by the time -- You know, they've gotten new sources, but that comes into new vaccines -- What?

DR. BOLTON: Is that the only material that's now sourced from at-risk countries?

DR. EGAN: That's used in the production. I think I also mentioned hemin. I think that was it, but I'd have to go back to it.

DR. BOLTON: So I guess my recommendation would be that the FDA work with the manufacturers to set a definite timeline to phase out all those materials. In terms of the master virus seeds and the bacterial stocks and the master cell lines, I think that the risk is so small as to be really counterproductive to try to change those, because the risk of changing the product by changing those is much, much greater than any risk that there would be from proceeding.

CHAIRMAN BROWN: One of the questions that the FDA specifically wanted some judgment on was: Is it necessary to re-derive bacterial master seeds? I mean, I'm getting the sense -- Every time I get the sense of something, the sense changes. You know, we had a consensus about informed consent, and now we have a consensus about not smother it, but be awfully, awfully, awfully careful.

Now I thought we had pretty much decided that, at least for current products, that it will not be necessary to re-derive bacterial master seeds. That was my sense. Dr. Huang?

DR. HUANG: I completely agree. I think that the derivation of new master seed stocks would be more dangerous than this perceived danger that we are facing now.

CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ from that opinion? All right. We have answered one definitive question that the FDA wanted to asked.

They also want an answer to a question I think should be very easy to answer. That is: Is 1980, form all that you have heard, an appropriate cutoff date before which one need not worry about anything in terms of sourcing of the products we are talking about?

We always worry about something, but 1980 -- is that an appropriate date before which not to be concerned? That's a pretty focused question. Is there anybody that feels that one should be concerned about products produced before 1980 from anywhere? Yes?

DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect to our blood donation pool in the United States, we were concerned about BSE and started with 1980.

CHAIRMAN BROWN: It has the merit of consistency as well. All right. That's two questions.

The third question they were concerned about was: Do we think that the small amount of fetal calf serum from the U.K. around 1985 used in the production of master cell banks constitutes a negligible or -- well, the phrase was "a negligible or a significant risk"? Again, a question about fetal calf serum, sourced from the U.K. in the middle of the 1980s, use in the production of master cell banks constitutes any kind of significant risk? Yes?

DR. CLIVER: May I start by saying negligible. We'll see if anybody disagrees.

CHAIRMAN BROWN: Do I hear significant? Negligible?

DR. BOLTON: I agree that it's negligible.

CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used for the production -- just for this specific purpose, used in the production of master cell banks? Well, that answers the three questions that you most wanted some judgment on. Dr. Ewenstein?

DR. EWENSTEIN: There was also the question about products that are still under investigation. I think, you know, we should address that. I think one of the comments before was, I think, right on the point. That is that it's different if you have a licensed drug or product that has, therefore, documented benefit versus recruited volunteers.

I think we should think about what we should answer for number 3. I think that it's appropriate to include again, with the correct caveat, about theoretical and negligibly small risk in a consent form. but I certainly wouldn't like to see all clinical trials stopped of such vaccines.

CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We haven't touched on that, and we might just continue that discussion a bit. Peter?

DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him correctly. I think that it is indeed a different situation. For one thing, not only is the benefit of the vaccine unknown, but for another, one actually does know the name of the patients, and one is personal contact with those patients on a semi-regular basis.

I think that the ethical responsibility toward those people is quite different than is owed to the population at large. In any event, there is simply no tracking, as far as I know, on the national level of exactly who receives what lot of what vaccine.

So I think it is distinguishable, and I think that personal notification is the way to go in the proper context.

CHAIRMAN BROWN: Let me ask a question of the people, especially, on the Vaccine side. In trials of vaccines, what kinds of risks are real? We're talking about a theoretical risk and notification. What kinds of risks in a vaccine trial actually happen? Anybody know?

I mean, it's nice to compare this theoretical risk against something that's a real risk.

DR. STEPHENS: Well, you certainly have risks of the local reactions to the vaccine. You have the intra-susception story with the rotaviruses as an example of a risk that did occur.

There are clear risks associated in a clinical trial with a vaccine.

CHAIRMAN BROWN: Or you could have, for example, an ampule or a batch that was contaminated with bacteria. I mean, that happens, certainly in -- not necessarily in vaccines, but in drugs and media.

DR. STEPHENS: That's less likely, but yes. I mean, there are a variety, and anyone participating in the clinical trial understands that there are risks. Some of them are known; some of them are not known.

CHAIRMAN BROWN: I'm sorry? Some of them are?

DR. STEPHENS: Some of them are known; some of them are not known with any kind of IND.

CHAIRMAN BROWN: Would it be a problem for this additional theoretical risk information to be tacked on? I assume, when they have informed consent -- I mean, I can tell you a story about informed consent that is very funny, but I won't.

Informed consent is almost always signed by volunteers, no matter what it says, and I assume that the addition of a theoretical risk of this nature added to an informed consent would not be a great difficulty, if it were properly communicated, properly worded.

DR. FERRIERI: Well, don't underestimate the impact of having additional material in informed consent. It adds a huge, huge amount of time to the explanations, and the more indefinite the risk is, the harder it is to communicate, in my opinion.

CHAIRMAN BROWN: Would it be fair to say that, if it turns out that the FDA chooses in some way to inform -- to get this information across to the recipients or at least the givers of vaccines to the recipients in the general public, if that decision is made, then consistency dictates that something also be said to recipients of investigational drugs.

DR. FERRIERI: Absolutely.

DR. STEPHENS: In consent forms, you try to list all of the things that you think might occur, and this could be one of those theoretical possibilities that would occur. So I think that that would be appropriate.

Again, going back to the emphasis, we are talking about a theoretical, in the billions risk in this particular setting.

CHAIRMAN BROWN: The story I was going to tell you: I had a tooth pulled many years ago by the Navy, and they had a consent form at the Navy hospital which listed in increasing order of seriousness the various complications, and the next to last line was death. The last line was "Other."

DR. FERRIERI: I'd like to revisit the issue of the communication and propose one possible avenue as a preliminary. That would be for FDA to write a brief one-page sort of "for your information based on our meeting" that would be submitted to JAMA. It reaches so many physicians, and it might defuse the issue of what they may read in the newspaper; and depending on what's on Web sites, parents will start coming in and asking questions before physicians will even have been aware of the issue perhaps.

Dr. DiAngelis, the editor, might be very interested in some sort of statement "for your information" as the thrust of it.

CHAIRMAN BROWN: I think that's a crackerjack idea. The JAMA -- After all, vaccination reaches the general public like no other form of therapy, and the JAMA probably has the widest distribution to that part of the medical community involved in vaccination.

So what does the FDA think about that? I see a head nodding. Good.

DR. EGAN: I think it's a good option.

CHAIRMAN BROWN: Peter?

DR. LURIE: I guess the day is getting late. I can feel my caffeine levels dropping. I guess it makes me want to think about prevention in a general way, and particularly how we can prevent ourselves from being in this particular situation that this committee has found itself today.

This really is an unnecessary situation we're in. In that sense, this meeting is unnecessary. And it's unnecessary, because there was inaction or improper action by two groups of players here.

The first is the FDA which threatened to produce a regulation, but instead provided a guidance which then provided them with no ability to enforce, if it were necessary.

I think the lesson here is for all the claims by some of the manufacturers who are here that they are doing the best they can to get rid of the BSE country sources for these vaccines, there are many vaccine manufacturers who aren't here today.

So if we are to prevent this from happening again, the first thing that needs to happen is we need to regulate, not provide guidances; because guidances can, and in this case were, ignored by the industry.

The industry takes the other responsibility for this. We have experts at the FDA who came to the conclusion that the right approach to this was to source the materials from non-BSE countries, and the industry has recklessly, in my view, decided simply to ignore that.

Had either of those two things been in place, we wouldn't be here today, and all of this discussion would have been unnecessary.

CHAIRMAN BROWN: Ms. Fisher?

MS. FISHER: I absolutely agree with you, and I think that the reason we are meeting today is exactly what you said. Therefore, I think the FDA has the duty to ask the vaccine manufacturers involved to put it in the product manufacturer insert. At the very least, that should be done.

I wasn't saying it should be, you know, put out in a physician's statement or a letter to physicians, but it should be in the product manufacturer insert.

DR. BOLTON: Paul, I have a question, I guess, for the vaccine group. That is, to put this in perspective, as what Paul had mentioned earlier, other real vaccine risks -- for example, the switch from the active attenuated polio vaccine to the inactivated vaccine was prompted by cases of paralytic polio.

How long did it take that action to occur from the time that it was first recognized to the time the switch was made?

CHAIRMAN BROWN: Can anybody in the audience answer that question?

DR. FERRIERI: Well, there is someone in the audience who could answer it best, and that's Dr. Katz.

CHAIRMAN BROWN: Dr. Katz.

DR. KATZ: Vaccine associated paralytic disease was probably first recognized in the late 1960s, but what you were doing was calculating a risk-benefit over the years of an effect that was about one in a million versus thousands of cases of polio. It wasn't until polio was controlled in this country that the issue became crystallized as when was it appropriate to take the risk of switching to an injectable vaccine which was less acceptable to the public in many ways, more difficult to administer, less available, contrary to the recommendations of the World Health Organization.

It took a good number of years from meetings in the 1980s until polio was declared eliminated from the Western Hemisphere in 1994 to convince the recommending committees to make that change.

DR. BOLTON: And I guess that, I think, emphasizes my point. That is that, in a real risk situation, it even can take years to take an action versus here where we have a very less than negligible theoretical risk. I don't think we should feel bad about moving slowly, and I think it's inappropriate, really, to talk about inappropriate actions on the part of you, the FDA, or the vaccine manufacturers.

I think people are moving at an appropriate speed and contemplating and thinking about these issues very carefully.

CHAIRMAN BROWN: Thank you. I will ask if anyone on either committee or the joint committee has anything that they have not said that they definitely want recorded as a public statement before I conclude the day's proceedings.

I think the FDA was very astute not to ask this committee to vote on any of the issues, but I think the FDA has received a great deal of pros and cons and discussion, and I think the meeting was very worthwhile, and thank you all for coming.

(Whereupon, the foregoing matter went off the record at 5:13 p.m.)

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FDA Transmissible Spongiform Encephalopathies Advisory Committee and Vaccines and Related Biological Products Advisory Committee - Joint Meeting