convenes

The verbatim transcript of the Sponsored Workshop

on Thimerosal Vaccines held Wednesday, August

12th, 1999, at the National Institutes of Health,

Lister Hill Auditorium, Bethesda, Maryland.

2

PARTICIPANTS (by group, in alphabetical order)........... 4

VI. REDUCING AND ELIMINATING THIMEROSAL IN VACCINES

A. Opportunities and Challenges

1. Manufacturing Issues

Chris Adlam.................................. 14

2. Regulatory Issues

Norman Baylor................................ 33

3. The European Issues

Mary Teeling................................. 56

B. Immunization Issues During the Transition

to Thimerosal-Free Vaccines

1. Transitional Public Health Service

Immunization Options

Roger Bernier................................ 82

2. Implementing Transitional Immunization Options

American Academy of Pediatrics Perspective

Jon Abramson................................. 99

National Coalition for Adult Immunization

Perspective

Peggy Webster............................... 106

Institute for Vaccine Safety Perspective

Neal Halsey................................. 111

Infectious Disease Society of America

Perspective

Bruce Gellen................................ 127

Association for State and Territorial

Health Officials Perspective

Claire Hannon............................... 132

3

VI. FILLING THE GAPS: DEVELOPING A RESEARCH AGENDA

A. The Gaps

Regina Rabinovich........................... 165

B. Priorities for a Research Agenda

Tom Clarkson................................ 183

Michael Gerber.............................. 188

Alison Mawle................................ 193

Peter Paradiso.............................. 198

John Risher................................. 202

Bernard Schwetz............................. 207

VIII. WORKSHOP SUMMARY

Jerome Klein.................................... 233

ADJOURN -- END OF WORKSHOP.............................. 238

4

(By Group, in Alphabetical Order)

Allen Albright

Food and Drug Administration

Juan Archiniega

Food and Drug Administration

Deborah A. Ball

Thom Ballsier

Norman Baylor

Food and Drug Administration

Roger Bernier

National Immunization Program

Robert Breiman

National Immunization Program

Carolyn Buxton Bridges

National Center for Infectious Diseases

Druscilla Burns

Food and Drug Administration

Felecia Butler

Merck and Company, Inc.

Gerald Calver

VDBB&R

Lynn Cates

Department of Health and Human Services

Nancy Cherry

VRBPAC

Helen Cicirello

North American Vaccine

Thomas Clarkson

5

University of Rochester

John Clements

World Health Organization

Richard Clover

Advisory Committee on Immunization Practices

Janice Cordell

National Institutes of Health

José Corderi

George Counts

National Institutes of Health

Dack Dalrymple

Bailey & Dalrymple, LLC

John Daugherty

National Institutes of Health

Robert S. Daum

VRBPAC

Christopher De Rosa

ATSDR

Carolyn Deal

Food and Drug Administration

Paul Dominowski

PFIZER, Inc.

Filip Dubovsky

National Institutes of Health

William Egan

Food and Drug Administration

Theodore Eickhoff

VRBPAC

Renata Engler

Walter Reed Army Medical Center

Jeffery Englhardt

Eli Lilly & Company

6

Elaine Esber

Food and Drug Administration

Geoffrey Evans

Health Resources and Services Administration

Lydia Falk

Food and Drug Administration

Michael Favorou

Centers for Disease Control

Theresa Finn

Food and Drug Administration

Alan Fix

University of Maryland School of Medicine

Jim Froeschle

Pasteur Mérieux Connaught

Maryann Gallagher

Food and Drug Administration

Antonia Geber

Food and Drug Administration

Michael Gerber

National Institutes of Health

T. W. Glickson

Karen Goldenthal

Food and Drug Administration

Jesse Goodman

Food and Drug Administration

Fernando Guerra

Advisory Committee on Immunization Practices

Ken Guito

Debra Hackett

SmithKline Beecham

Neal Halsey

7

John Hopkins University

Claire Hannan

Alabama Department of Health

Karen Hendricks

American Academy of Pediatrics

Thomas Hoffman

Food and Drug Administration

Susan Homire

Alan Horowitz

Institute for Safe Medication Practices

Barbara Howe

SmithKline Beecham

Deborah Jansen

Virginia Johnson

Food and Drug Administration

Rohit Katal

Samuel Katz

Infectious Diseases Society of America

Clare Khan

SmithKline Beecham

Edwin Kilbourne

Centers for Disease Control

Robert Kilgore

Marketing and Business Development

Kwang Sik Kim

VRBPAC

Jerome Klein

Boston University School of Medicine

Cynthia Kleppinger

Food and Drug Administration

Linda Lambert

8

National Institutes of Health

Len Lavenda

Pasteur Mérieux Connaught

9

Jack Love

Wyeth-Lederle Vaccines

George Lucier

National Institutes of Health

Kathryn Mahaffey

United States EPA

Laura Martin

Wyeth-AQyerts Pharmaceuticals

Dean Mason

National Immunization Program

Eric Mast

Centers for Disease Control

Alison Mawle

Centers for Disease Control

Joan May

Food and Drug Administration

Gerhard Mayer

Marketing and Business Development

Kent McClure

The Animal Health Institute

Pamela McInnes

National Immunization Program

Roberta McKee

Merck and Company, Inc.

Loris McVittie

Food and Drug Administration

Carlton Meschievitz

Pasteur Mérieux Connaught

Walter Orenstein

Centers for Disease Control

Peter Patriarca

Food and Drug Administration

10

Robert Pless

Stanley Plotkin, M.D.

Pasteur Mérieux Connaught

Alicia Postema

National Vaccine Program Office

Douglas Pratt

Food and Drug Administration

Regina Rabinovich

National Institutes of Health

William Raub

Department of Health and Human Services

Gopa Raychaurdhuri

Food and Drug Administration

Martin Reers

Chiron Berhing

Margaret Rennels

ACIP

Barbara Reynolds

Paul Richman

Food and Drug Administration

John Risher

Patricia Rohan

Food and Drug Administration

David Ryan

CSL Research and Development Limited

Ronald Salerno

Merck and Company, Inc.

Edwin Schaart

Pasteur Mérieux Connaught

David H. Schofield

SmithKline Beecham

11

Ben Schwartz

National Immunization Program

Becky Sheets

Food and Drug Administration

Natalie Smith

CADHS

Rick Smith

Pasteur Mérieux Connaught

Dixie Snider

Centers for Disease Control

Mary Teeling

Ireland Medicines Board

Kirsten Vadheim

Merck and Company, Inc.

Paul Varughese

Health Canada

Peter Vigliarolo

Conney/Waters Group

Fred Vogel

Pasteur Mérieux Connaught

John Vose

Pasteur Mérieux Connaught

Luba Vujcic

Food and Drug Administration

Beth Waters

Cooney/Waters Group

Peggy Webster

National Coalition of Adult Immunization

David Wonnacott

Merck and Company, Inc.

Laura York

Wyeth-Lederle Vaccines

12

Adelle Young

Infectious Diseases Society of America

13

Robert Zeldin

Merck and Company, Inc.

Kathryn Zoon

Food and Drug Administration

14

NANCY LEE & ASSOCIATES

mentioned yesterday that if there are others who wanted 4

to give perspectives on the immunization options 5

through the transitions, we were underwhelmed. So 6

there's still -- it's not too late. If other people 7

would like to give a perspective, if they would contact 8

Dr. Modlin at the break. 9

Dr. Rabinovich has asked that those of you who are in 10

the panel on the research priorities, if you would 11

contact her at the -- if you could get together briefly 12

at the break this morning. 13

Our moderator for today is Dr. John Modlin, who is 14

Professor of Pediatrics and Medicine, and, more 15

recently, the Acting Chair of Pediatrics at Dartmouth, 16

and he's also Chair of the Advisory Committee on 17

Immunization Practices, and he'll moderate today's 18

session. 19

we begin, just one or two quick housekeeping issues. 21

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NANCY LEE & ASSOCIATES

Number one, Nancy Cherry and her staff have very 1

graciously agreed to help us with taxicabs. So those 2

of you who will be taking cabs to the airport directly 3

from the center here, if you would check with either 4

Nancy or one of her staff members out at the table, 5

either at the break or at lunchtime, they will be happy 6

to arrange a cab for you. 7

Secondly, Harry Greenberg clearly set the standard 8

yesterday by finishing up early. Those of you who 9

attend the ACIP meetings know that I also have an 10

obsession for staying on time and sticking to the 11

agenda. So I will warn today's speakers of that in 12

advance, and you all are so warned. 13

Yesterday we heard how this problem with thimerosal in 14

vaccines has developed. We learned more about mercury 15

toxicity from some very excellent background 16

presentations. Today the focus will be on where we go 17

from here. We don't have all the data that we'd like 18

to have. We still need to make some important 19

decisions in the near future, and this is certainly the 20

case for vaccine manufacturers, it's a case for the 21

16

NANCY LEE & ASSOCIATES

FDA, it's a case for advisory committees, and we will 1

hear from representatives from all of these groups 2

today. We'll also hear from a representative, one of 3

our European colleagues, on how they have chosen to 4

deal with this issue. 5

So to begin with, I will introduce the first speaker 6

for today, who will be Dr. Chris Adlam. Dr. Adlam is 7

Associate Director of Regulatory Affairs at SmithKline 8

Beecham Biologicals, and he will be presenting the 9

manufacturing issues under the "Opportunities and 10

Challenges" section of this symposium. 11

Dr. Adlam? 12

Thank you, Mr. Chairman, for that introduction. 14

What I should like to do today is to expand on some of 15

the points made by earlier speakers, with particular 16

reference to the manufacturing issues surrounding the 17

use of thimerosal in vaccines and, as Dr. Modlin 18

pointed out, moving a little bit to the future as to 19

where we might be going. So, as you see, Opportunities 20

and Challenges is the thrust of this part of the 21

17

NANCY LEE & ASSOCIATES

meeting. 1

Thimerosal is used in two different areas in the 2

manufacturing process, and the first, which is the main 3

concern of this meeting, is, of course, its use in 4

final containers of vaccine as a preservative. 5

Now, the reason it is used in that situation is, of 6

course, to guard against contamination which might be 7

introduced during the filling process. 8

The second area, though, where it's still used is in 9

vaccine development; for example, where we need to 10

produce pilot batches of product for testing purposes, 11

or we may require to validate equipment, scale up 12

equipment, for example, but also, we still use 13

thimerosal in full-scale manufacturing processes for 14

some vaccines, and particularly where the method of 15

antigen purification, for example, might be complex, 16

and where manufacturing people may consider that there 17

would be potential risk for contamination if a 18

preservative wasn't present. 19

Now, historically, thimerosal has been used as a 20

blanket cover for most liquid-inactivated vaccines, but 21

18

NANCY LEE & ASSOCIATES

as techniques have improved in manufacturing and the 1

concept of good manufacturing practices over the years 2

has come to the forefront, companies have reviewed 3

their use of thimerosal and, indeed, have come under 4

pressure from environmental agencies to reduce the 5

quantities of thimerosal that they use in their vaccine 6

manufacturing processes. 7

So why are preservatives still used in vaccines? We've 8

heard some of these points raised yesterday. As we've 9

heard, multi-dose containers, we have to have a 10

preservative there to guard against the potential 11

contamination when multiple punctures of a multi-dose 12

container are made. 13

I won't deal on point two very much because Dr. 14

Clements gave an excellent overview of the particular 15

problems faced by the international agencies. As we 16

have heard, they have particular problems, which, of 17

course, vaccine companies, most of whom these days are 18

international, have to address. 19

It's worth making the point, though, that if we have to 20

remove thimerosal for, if you like, developed country 21

19

NANCY LEE & ASSOCIATES

markets, we still will have to make a second product 1

containing the preservative for multi-dose containers 2

in the international markets. So that is, of course, 3

an added cost to the industry. 4

Finally, and to my mind most important, is that 5

although quality of manufacture has greatly improved 6

over the last 20 years -- Good manufacturing practices 7

have, of course, improved out of sight since I first 8

joined the industry -- and the data and figures that 9

were shown in terms of numbers of filling lots that 10

were contaminated yesterday, these would of, course, 11

not be tolerated by today's standards. Nevertheless, 12

it has to be said that good manufacturing practice 13

remains pretty good but not 100 percent perfect. 14

And to expand on that just a little, it should be borne 15

in mind that today's vaccines, in contrast to those of 16

20 years ago, contain highly purified antigens and that 17

these products may go through very many stages in the 18

purification cycle. Sophisticated equipment, column 19

chromatography would be used, where as, of course, 20 20

years ago these techniques were just considered totally 21

20

NANCY LEE & ASSOCIATES

unnecessary for vaccine manufacture. 1

As many as nine or ten bulks, different bulk antigens 2

would have to be stored. Aseptically -- They would 3

have to be blended together aseptically to make a 4

modern multi-component combination vaccine. 5

Elimination of preservatives then, even from mono-dose 6

vaccine presentations, is a serious step, and the 7

appropriate tests and validations have to be done to 8

make sure that the resulting vaccine remains safe and 9

efficacious. 10

Why thimerosal? Many people have said, as we've heard, 11

it's been around a long time, and the industry is very 12

used to using it. Up to now, the only concern with 13

this material has been down to the occasional 14

hypersensitivity reaction, which is seen, but I think 15

it's worth saying that in contrast to the use of 16

topical pharmaceuticals containing mercury, where, as 17

we've heard yesterday, sensitizations may occur, this 18

is a very rare event in injectable vaccines containing 19

thimerosal. 20

We have numbers within our company of reports of this 21

21

NANCY LEE & ASSOCIATES

type of sensitization which run somewhere between 1 and 1

3 million doses administered and 1 in 20 million doses 2

administered. So we're talking of a very rare event, 3

and the majority of those cases are not life- 4

threatening sensitizations. 5

And secondly, of course, as we heard yesterday again, 6

thimerosal is a very potent substance and does its job 7

extremely well. And we heard about the spiking 8

experiments that companies have to do with all new 9

vaccines to prove that the preservative in the 10

container does the job that it's supposed to do in 11

knocking back potential contaminating organisms. 12

So what are the alternatives open to the industry as we 13

move away from the age of thimerosal? Of course, the 14

first option is to eliminate even from mono-dose 15

vaccines -- we can't do it for multi-dose, but we could 16

eliminate from mono-dose vaccines all preservatives and 17

to rely on good manufacturing practices. 18

This is a laudable objective, and it may be, indeed, 19

possible for some products and some processes, and it 20

certainly is a road down which the FDA is pushing the 21

22

NANCY LEE & ASSOCIATES

companies. However, as I've stated already, we should 1

maintain caution when we do this, if indeed we're not 2

to replace one set of problems with another. 3

And the second option, which I have to say is the one 4

we as a company have taken so far, is to use an 5

alternative to thimerosal as the preservative in the 6

vaccine. Now, if you talk to manufacturing people, 7

it's clear that they always prefer to maintain a 8

preservative in their vaccine box and vaccine 9

presentations, for obvious reasons. 10

This slide just lists the vaccines produced by 11

SmithKline Beecham Biologicals and which are 12

commercialized in the U.S. together with their 13

preservatives. And as you can see, only the earliest 14

licensed product, which is the hepatitis B vaccine 15

licensed back in -- launched in 1989, contains 16

thimerosal. And since that time, it has been a 17

decision within the company to move away from 18

thimerosal and to use the alternative 2-phenoxyethanol. 19

And as we heard, again, a little bit on this substance 20

yesterday, it has an excellent safety record and is 21

23

NANCY LEE & ASSOCIATES

pretty good as a preservative. 1

The second point I'd like to make from this slide is 2

that there has been a conscious effort on behalf of the 3

industry to move to combination products containing 4

many antigens. And, of course, the more we can do 5

that, the fewer injections that will need to be given 6

to the children, and, of course, the less the amount of 7

preservative that will have to be given. So this is, I 8

think, if you like, an opportunity there and also a 9

challenge to develop this kind of product. 10

Now, as far as the vaccines that are commercialized 11

which contain thimerosal, as we heard, companies have 12

been approached by the agencies and are in discussion 13

with agencies, both in the U.S. and in Europe, as to 14

what their plans are for reducing or eliminating 15

thimerosal. And like other companies, I would guess, 16

we have submitted our plans for removing thimerosal as 17

a preservative from this vaccine. 18

So to conclude this brief résumé and by returning a 19

little bit to the title of this part of the talk, 20

"Opportunities and Challenges," as I've said, I think 21

24

NANCY LEE & ASSOCIATES

one of the first opportunities and challenges, if you 1

like, lies in the continued development of new multi- 2

component products, which, of course, will result in 3

fewer injections that need to be given, which, as we're 4

all aware, is a good thing. 5

The second challenge, I think -- And this is a 6

challenge for both the industry and the regulators -- 7

would be: how can we speed up the production of good 8

solid dossiers to support these changes and how can we 9

get them through the agency review period in as short a 10

time as possible? And I think we're all exercising our 11

minds along those particular areas, as I said, in 12

discussions with various agencies on this particular 13

topic. 14

And thirdly and finally, of course, all of objectives - 15

- our main objective is to continue to improve the 16

efficacy and the safety of all of our vaccines. 17

So I think I'd like just to leave it there, Mr. 18

Chairman, and if there are questions, either take them 19

now or at the end of this section. 20

Thank you. 21

25

NANCY LEE & ASSOCIATES

(APPLAUSE) 1

Dr. Adlam. Are there? Yes, Dr. Egan? 3

the -- 6

You commented on possibly -- about the use of 8

preservative even in a single-dose vials. Could you 9

expand a little bit on what you feel is the need or the 10

advisability of having preservatives in them and what 11

kind of levels? Thank you. 12

bit of a contentious issue. I think we would all like 14

to be able to say that we can remove all preservatives 15

from mono-dose containers, and this is -- as I said, 16

they are laudable objective to try to achieve. My only 17

caveat to that is, as I say, I think we have to very 18

careful that it can be achieved. I mean, as you're 19

well aware, all companies will submit media fill 20

control data to the agency. These -- This information 21

26

NANCY LEE & ASSOCIATES

is out there. We can look at it and we can see whether 1

we are yet in a position to totally remove all 2

preservatives from the vaccine. In terms of quantity, 3

we use the standard quantities of 2-phenoxyethanol in 4

these more recent products. 5

It's a point for debate. We could discuss that, I 6

think, the advisability of dropping it out, keeping it 7

in, but it's something which we should be, in my view, 8

careful -- It should be approached carefully on a case- 9

by-case basis. 10

I thank you for bringing the issue of combination 12

vaccines up. WHO is firmly in favor of developing 13

strategies which will enable developing countries to 14

use combination vaccines for the sorts of reasons 15

you've identified. 16

My question is: What opportunities do you think 17

developing countries will have for producing 18

combination vaccines, bearing in mind their desire so 19

often to have local production? What are your ideas on 20

the possibility of technology transfer and local 21

27

NANCY LEE & ASSOCIATES

filling, for instance? 1

company, are involved already in discussions on 3

technology transfer in certain areas of the world, and 4

I think this is an area that will continue to expand. 5

I mean, there is no question that putting a combination 6

vaccine together is not just a straightforward mixing 7

of antigens and away you go. I mean, as we're well 8

aware, it's a lot more complex than that, and there are 9

interactions between antigens. We have to confirm that 10

the combinations are compatible with each other and 11

that there is no enhancement in the -- no enhancing the 12

problems associated with safety which could result. 13

And so there's a lot of work to be done, which, in a 14

developing country context, is quite a significant 15

task. But as far as technology transfer, I don't think 16

any of the companies are against that kind of 17

arrangement. 18

Are there any special issues for producing 21

28

NANCY LEE & ASSOCIATES

preservative-free single-dose vaccines for vaccines 1

produced in eggs or viruses grown in eggs? 2

would look at. If you think about it, what you're 4

doing when you make an inactivated influenza vaccine is 5

to process and purify your influenza antigen from eggs, 6

as you say, from embryonated eggs. Now, that is a 7

whole lot of very rich protein that you have around, 8

plus the fact can you be sure that each one of those 9

eggs does not carry a contaminate of one sort or 10

another. We know, for example, that hens' eggs in the 11

outside world -- Of course, we don't use farmyard eggs 12

to make these vaccines, okay? 13

But, nevertheless, the theoretical possibility is still 14

there that you may have the odd egg with the odd 15

contaminate. Okay? And if you have that, then you 16

have to have something in your system to prevent that 17

becoming a real problem in the final vaccine. 18

So I think that's an excellent example along the lines 19

of the ones that I was -- the protein there, and there 20

may be others. 21

29

NANCY LEE & ASSOCIATES

Chicago. 3

I'd like to make a comment and hear your response to 4

it. It seems to me that no matter what strategy is 5

involved from these considerations, whether it's better 6

reliance on PMP or identification of an alternative 7

preservative, that we're going to be giving what 8

results from this new policy to millions and millions 9

of people. Therefore, with a hopefully very low rate, 10

problems are going to occur if it's good medical 11

practice. As you pointed out in your slide, it's not 12

100 percent. There's going to be instances of 13

contamination. I'm certain of that. If it's a new 14

preservative and we give it to millions and millions of 15

people, someone somewhere will have a reaction to it, 16

and it will happen and we'll gather at workshops like 17

this to discuss what to do about that. 18

It seems to me that no matter how try to minimize this 19

problem -- nd minimize it we must because it's not 20

acceptable to have an overly reactive (inaudible) -- 21

30

NANCY LEE & ASSOCIATES

we're never going to get it to zero. I wonder -- We 1

live in an era now of numerator amplification where one 2

side (inaudible), it instantly becomes -- CNN helps do 3

that and some of our support groups help do that. It 4

just becomes instantly news all over the place. 5

I wonder if the proper way to think about this is to 6

just realize that we're not going to ever solve this 7

problem with taking the side effect or toxicity rates 8

to zero. We're going to pick the method to get it as 9

low as we possible can and then also have an education 10

campaign that says, you know, there's no free lunch in 11

this world. We have a wonderful preventative strategy 12

here, we're offering it to all children, and in the 13

end, like any medical intervention, there are rare 14

occasional problems. 15

I don't -- I don't know that we've really come to grips 16

with accepting that there will be residual benefits and 17

really focusing on it as an educational intervention or 18

alternative. I'm not meaning to belittle the 19

importance of toxicity here, but it just seems to me 20

the rate isn't ever going to be zero. 21

31

NANCY LEE & ASSOCIATES

would all agree with that. I mean, as you say, there 2

isn't one single medicament that's out there that's 3

going to be completely safe and free. I mean, if you 4

drink 15 liters of water, you're probably going to die, 5

you know? So that's a philosophical discussion. I 6

think what it does raise -- excuse me, Dr. Modlin -- 7

What it does raise, though, is the important issues of 8

communication, and I see on the agenda that we have 9

somebody that will be addressing that. But I think 10

that's obviously a key portion so that the right 11

messages are given so that the general public is 12

properly advised and knows, if you like, what the risks 13

and benefits are for all of these procedures. 14

questions. 16

First, if I understood you correctly, and I'd like to 17

know if I did understand correctly, that combination 18

vaccines present us with both a plus and a minus in 19

terms of a preservative, that is, that you would have 20

to give a smaller amount of -- per antigen that you 21

32

NANCY LEE & ASSOCIATES

were using, but because of the complexity of the 1

manufacturing process, it might be more important to 2

include a preservative when making a combination 3

vaccine. 4

And secondly, assuming at least from SmithKline 5

Beecham's standpoint, that preservative is 2- 6

phenoxyethanol. Are there any concerns about that? 7

Since your company has started to move in that 8

direction, have there been any concerns about reactions 9

or long-term toxicity and so forth from any 10

toxicologists or others you might have consulted? 11

combinations, and I think you're right there. 13

Obviously, the more complex the manufacturing process 14

is, the more pressure there would be, I would say, to 15

include some kind of preservative in the vaccine. So I 16

think that analysis that you made there is correct. 17

In terms of 2-phenoxyethanol, it is fairly widely used, 18

not just by us, but by others and in the pharmaceutical 19

arena. It has a pretty clean tox profile as a 20

material, and it's fairly effective at doing its job. 21

33

NANCY LEE & ASSOCIATES

Of course, we don't yet have 60 years experience with 1

it -- That's a given -- but it's -- it looks to be very 2

effective, and it is accepted by the agencies involved 3

with preservatives. 4

I also wanted to focus on your use of 2-phenoxyethanol. 6

Yesterday we heard from a couple of the speakers, when 7

looking at the in vitro tests with the USP agents that 8

it performed less well than thimerosal. So I was 9

wondering what type of testing has been done 10

specifically that suggests that it's adequate as a 11

preservative, and your company clearly has made a 12

decision that it, indeed, is adequate to accomplish 13

that particular function. 14

With respect to the adverse -- the potential adverse 15

reactions, you spoke in very general terms about what's 16

known, but I think one of the things that we've learned 17

from thimerosal is that even in a product that has been 18

used for 60 years that there hasn't been a lot of 19

research about its use. So I would expand on Dixie's 20

question and say, well, if the safety profile, quote, 21

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NANCY LEE & ASSOCIATES

"looks good," what research has actually been done and 1

are there areas? Are there gaps where we need to look 2

further to get a better understanding of potential 3

toxicity? 4

phenoxyethanol as all other preservatives, in fact, it 6

seems does satisfy the -- for example, the USP 7

regulations surrounding the use of preservatives in 8

vaccines. 9

It's true that as I said we don't have 60 years' 10

experience with this material. There have been studies 11

done. There is a literature on 2-phenoxyethanol. It's 12

probably outside the -- you know, without having 13

another symposium on 2-phenoxyethanol. Nevertheless, 14

there's a significant body of information. But you're 15

quite right, we don't have 60 years experience with 16

this material. 17

As far a thimerosal is concerned, I think that the fact 18

that 60 years has gone by with it being used as a -- as 19

a useful product has probably meant that people haven't 20

spent a great deal of time going back over the old 21

35

NANCY LEE & ASSOCIATES

data, which is what we heard yesterday. 1

Now, this meeting and recent -- recent interest -- 2

resurgence of interest in the topic may stimulate some 3

of this research, and I guess that's going to be a 4

situation to be discussed in this afternoon's session 5

as to where we go with thimerosal, 2-phenoxyethanol, 6

and maybe future alternative preservatives. 7

The statements of the Academy of Pediatrics and the CDC 10

about thimerosal are to eliminate or reduce use, and 11

I'd like to focus on the second part of that phrase. 12

By reduce, my interpretation is that the number of 13

products that are thimerosal-containing will be 14

diminished. But is it feasible to take some of the 15

products that have thimerosal and reduce the 16

concentration such that it might be more acceptable in 17

terms of the theoretical toxicity? 18

You could say, well, we have X amount of thimerosal in 20

this product, can we reduce it by half and still have a 21

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safe effective product? I mean, I think those -- or 1

couldn't we eliminate it completely? Can we 2

substitute? These are the kinds of debates that are 3

being held now with the agency in this particular area 4

for particular products, and, you know, the discussions 5

continue, and there will be, you know, discussions 6

along what will be needed to show that your product is 7

still efficacious if we remove or we reduce thimerosal, 8

and goes -- Those questions have to be addressed on a 9

case-by-case basis and data has -- will have to be 10

supplied. 11

And that's nice headway to the introduction of our next 13

speaker who is Dr. Norman Baylor. Dr. Baylor is the 14

Associate Director for Regulatory Policy for CBER at 15

the Food and Drug Administration. 16

Dr. Baylor? 17

some of the regulatory issues involved in reducing and 19

eliminating thimerosal in vaccines. 20

Before I begin, I would like to emphasize a few points. 21

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As stated yesterday by Dr. Egan, the FDA has not 1

banned the use of thimerosal as a preservative in 2

vaccines. Secondly, there's no evidence -- no evidence 3

has been presented that would suggest that the amount 4

of thimerosal in individual vaccines is unsafe. 5

Lastly, our goal or objective is to assist in 6

decreasing the exposure of humans to mercury-containing 7

compounds by reducing or eliminating, where feasible, 8

thimerosal from vaccines, and this is also stated or an 9

objective of the Food and Drug Administration 10

Modernization Act of 1997. 11

Basically, the regulatory issues involved in reducing 12

and eliminating thimerosal from vaccines is no 13

different than the regulatory concerns of making any 14

other manufacturing change to a vaccine. I think the 15

issue here is, what are the implications involved in 16

removing thimerosal at this time and also for reducing 17

the amount of thimerosal. 18

The options that we have, there are basically three 19

that we can choose from. I think Dr. Adlam touched on 20

these. 21

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The first is to eliminate the use of thimerosal as a 1

preservative in vaccines -- That gets into the issue of 2

single-dose vials versus multiple-dose vials, and I'll 3

touch on that a little bit further in a minute -- or we 4

can substitute alternative preservatives for 5

thimerosal, and the third option is to reduce the 6

amount of thimerosal in vaccines. This option, the 7

last option, will involve using criteria other than 8

those outlined in the U.S. Pharmacopeia. 9

However, there's another option which I did not list on 10

my slide -- on the slide, and that option is to 11

continue to use the current concentration of thimerosal 12

in vaccines, albeit, at this time, this would require a 13

justification from the manufacturers to the Agency as 14

to why they felt it's necessary to continue the use of 15

thimerosal in its present concentration in a given 16

vaccine. 17

For all of these options, the regulatory requirements 18

will differ slightly for each of these. As Dr. Egan 19

mentioned in his talk yesterday, there are no 20

regulatory requirements to include a preservative in a 21

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NANCY LEE & ASSOCIATES

vaccine contained within a single dose or a single-dose 1

vial. However, vaccines that are filled in multiple- 2

dose vials do require, by regulation, the use of a 3

preservative with the exception of some live viral 4

vaccines. The elimination of thimerosal from multiple- 5

dose vials will require the exclusive use of single- 6

dose vials or the replacement of thimerosal with an 7

alternative preservative. 8

If we begin with the assumption that manufacturers will 9

continue to use multiple-dose vials for vaccines, then 10

we must assume that thimerosal will either be replaced 11

or the amount used will be reduced as I stated in my 12

outline earlier in the options. Let us begin with the 13

substitution of an alternative compound for thimerosal. 14

One must first determine where in the manufacturing 15

process the thimerosal is used, and I think Dr. Adlam 16

also touched on this. thimerosal may be used as a 17

bacteriostatic agent in the production process. So in 18

processing the various steps involved in manufacturing 19

may require the use of some type of preservative, and 20

in this case, perhaps thimerosal as a bacteriostatic 21

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NANCY LEE & ASSOCIATES

agent. This is the case with some of the influenza 1

vaccines. The use of thimerosal may also be used as an 2

inactivating agent, and an example of that would be 3

whole cell pertussis vaccine. 4

Then thimerosal is also, as we all know and why we're 5

here, is used as a preservative and that preservative 6

may be in bulk/final containment or it be in the 7

diluent. 8

In other words, the replacement of thimerosal with an 9

alternative compound will depend on how and where the 10

thimerosal is used in the manufacturing process. In 11

turn, the regulatory requirements for substituting an 12

alternative compound for thimerosal will depend upon 13

whether the compound is used solely as a preservative 14

or as a bacteriostatic agent for in-process 15

manufacturing or as an inactivating agent. 16

Now, looking at the regulatory -- further into the 17

regulatory requirements, I think it's necessary to 18

explain a little bit about how the regulatory process 19

works. The regulatory reporting category for a 20

manufacturing change will depend upon whether the 21

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NANCY LEE & ASSOCIATES

substitution of thimerosal results in a complete 1

formulation change in the final product or whether the 2

removal or substitution of thimerosal is, for example, 3

only for a buffer used to reconstitute a vaccine. So 4

the reporting categories will be different. We have 5

what is known as a prior approval supplement. The 6

prior approval manufacturing supplement has a maximum 7

review time, and emphasizing the review time, of six 8

months, although we have a target of reviewing a 9

percentage of those in four months. Then the other 10

extreme is a minor manufacturing change where you could 11

have distribution of that product containing that 12

change within thirty days or after a thirty-day period 13

if the Agency -- if the manufacturer does not hear from 14

the Agency that there are problems. 15

So what I'm getting at here is depending on the type of 16

change, that removing this thimerosal from the product, 17

depending on where you remove it, it will dictate how 18

much or how long the review time will be. In other 19

words, if it's a new formulation, that's a full prior 20

approval supplement. Whereas, if your formulation does 21

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NANCY LEE & ASSOCIATES

not contain thimerosal and you are only adding the 1

thimerosal to a buffer that's to be used to 2

reconstitute the vaccine, that may be a lesser change 3

that will require less time. 4

So prior approval supplement versus changes being 5

effected in thirty days, the timing on 6

the -- depending on where and how the thimerosal is used 7

will dictate the review time. 8

Preclinical data may be necessary for some of these 9

changes, including reproductive and toxicological 10

studies on new compounds, compounds that we have no 11

experience with, may require repro/tox studies. Data 12

on the compatibility of the new compound with other 13

components in the vaccine will definitely be required, 14

but depending on where in the process, the amount of 15

data, again, will be dictated by that. 16

Of course, validation of the bacteriostatic and 17

bacteriocidal type of properties of the new compound, 18

as well as inhibition of yeast and fungi will have to 19

be -- data will have to be submitted to support the use 20

of the new or alternative preservative. 21

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In addition, batch analysis of consistency lots will be 1

required to be submitted to support a change of 2

removing thimerosal. Stability data will also be 3

required and, preferably, we require real-time 4

stability data for those submissions. Again, all of 5

this we're going to try to work with the companies to 6

work out the amount of data that's needed and what's 7

available from the manufacturers. Stability data would 8

also be required when you're changing from a multi-dose 9

vial to a single-dose vial or syringe. 10

Also, human clinical data may be necessary if the 11

result of the substitution of a new compound for 12

thimerosal results in a new formulation or a new 13

product. In some of our old products, we can see where 14

that product may change significantly. We may require 15

human clinical data. Now, the amount of the human 16

clinical data, again, we would have to work with the 17

manufacturers in designing protocols to decide how much 18

of this would be necessary. 19

Now, in some cases, thimerosal may not be easily 20

replaced by an alternative preservative. An option 21

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NANCY LEE & ASSOCIATES

would be to reduce the amount of thimerosal in a 1

vaccine, especially if exclusive production of single- 2

dose vials is not an option. 3

But, basically, the regulatory requirements for 4

reducing the amount of thimerosal are the same as those 5

for substituting an alternative preservative. However, 6

most important here is the validation of the inhibition 7

of microorganisms using the reduced concentration of 8

thimerosal, as well as stability data supporting the 9

desired shelf life of the final product. Now, some of 10

the options we could take here is by -- Well, let me 11

back up. 12

Most importantly, as I stated, the manufacturers would 13

have to validate the reduced amount of thimerosal has a 14

given effect, i.e., bacteriostatic/bacteriocidal, on -- 15

with the given preservative. Now, those would not meet 16

the USP requirements, but as stated yesterday, we're 17

not really bound by the USP requirements. The USP 18

requirements are accepted, but we would work with the 19

manufacturer to -- and look at the validation data, and 20

what we may come -- we may come to a point where we 21

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NANCY LEE & ASSOCIATES

would reduce the shelf life on that product. So if you 1

had a thirty-month dating period and you could validate 2

-- you could substitute or reduce the amount of 3

thimerosal and shorten that dating period, that would 4

be an option also. 5

So, in summary, the regulatory requirements for the 6

elimination, substitution, or reduction of thimerosal 7

in vaccines must be determined for each individual 8

vaccine on a case-by-case basis. The FDA has 9

recommended that each manufacturer discuss with the 10

Agency how they intend to address the issue of 11

thimerosal used in all of their vaccines prior to 12

submitting supplements to the Agency for review and the 13

FDA is committed to expediting the review of these 14

submissions. 15

Thank you. 16

(APPLAUSE) 17

of Pediatrics. It would seem to me that scientifically 20

what had to happen prior to all of this is that as for 21

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each vaccine you were figuring out how much thimerosal 1

was needed that there is data on the lower side of what 2

was finally put in there that would tell us that. I 3

mean, I can't believe that people would pick a number 4

and did the studies just with that concentration and 5

didn't do (inaudible) factors. 6

what we're -- When we receive the data, we're looking 8

at -- we've going to evaluate that data on the safety 9

and efficacy of that vaccine. So looking at the amount 10

of thimerosal and -- Again, some of these products were 11

licensed decades ago and the review was somewhat 12

different, but, even then, there was concern about the 13

toxicity of these compounds. So we did look at that in 14

the whole package, but I think also that you have to -- 15

the point that was made yesterday about the 16

requirements in the United States versus Europe, some 17

of those requirements, some of the Pharmacopeia 18

requirements in Europe are higher. And looking at what 19

the manufacturers are going through, producing multiple 20

formulations for the world or taking the option of 21

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NANCY LEE & ASSOCIATES

producing one formulation and that formulation happens 1

to have a slightly higher amount of thimerosal than 2

needed for the U.S. or to be the beat the USP, as long 3

as it's safe and effective, we're going to -- we're not 4

going to disapprove that vaccine, but, you know, we are 5

going to look at the toxicity. I think the bar is much 6

higher now than it was when some of these old vaccines 7

were approved. 8

Disease Society. 13

There may not be a blanket answer to this, but when you 14

have -- when you use thimerosal in the process, does it 15

necessarily stay in the end product? 16

quite careful in your introductory remarks about -- I 19

may have not quoted this perfectly, but you said 20

there's no evidence presented that thimerosal in 21

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individual vaccines is unsafe. You were cautious to 1

talk about individual vaccines. Do you -- Is there a 2

stance about the vaccination process, that there's a 3

feeling that as given currently that there's evidence 4

presented that thimerosal content overall in infants is 5

unsafe? 6

was trying to get out there is that this issue that 8

we're dealing with today and that we've been dealing 9

with revolves around the cumulative amount of 10

thimerosal, a mercury-containing compound, to 11

individuals receiving several vaccines, but if you look 12

at the vaccines individually, there are no -- whether 13

you look at EPA or FDA, there are no levels that are 14

exceeded on those vaccines. The issue comes about when 15

you administer a number of the vaccines, for instance, 16

when a child receives all the recommended vaccines on 17

time within the first six months. That's really the 18

issue we're dealing with. We're not really dealing 19

with -- I don't know if there's -- We, as an agency, 20

don't have concerns that there's something -- there's 21

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NANCY LEE & ASSOCIATES

an amount of a compound in these products that are 1

unsafe. It's the cumulative receipt. 2

question about the regulation to require a preservative 5

in multi-dose vials. Dr. Egan made the point yesterday 6

and you made it again today that we have multi-dose 7

vials of vaccines that do not contain preservative, 8

measles/mumps/rubella being perhaps the most obvious 9

example that a preservative would inactivate the 10

vaccine, but we do license that as a multi-dose vial 11

with no preservatives in it. 12

So is it another alternative for the manufacturer to 13

consider the multi-dose vial without a preservative 14

that has a very short shelf life after being entered 15

the first time? 16

have the current regulations, no. However, that is a 18

possibility if the manufacturers can validate that they 19

can actually make or produce a multi-dose vial without 20

a preservative and validate that that product would not 21

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NANCY LEE & ASSOCIATES

-- or would maintain its integrity as far as absence of 1

contamination. We could consider that. However, the 2

only way to consider that at this time is to eliminate 3

that regulation. As long as the regulation is on the 4

books, we have to have -- we have to require that, but 5

that's not something that can't be done. We've 6

eliminated regulations before. So . . . 7

for Safe Medication Practices. 10

As an entity that works in collaboration with USP 11

receiving medication errors, which, of course, we 12

forward to FDA as a med watch partner, over the years 13

we've received numerous incidences of adverse drug 14

events related to multi-dose vaccines, confusion with 15

(inaudible), cross-contamination up to, in one 16

incident, 468 patients. You had mentioned four 17

different alternatives that the Agency may do if I 18

understood your presentation. It seems to me that with 19

the sole exception of moving into a single-dose, 20

essentially a unit dose, those same problems that are 21

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reported to us and that have been reported to us are 1

likely to occur. 2

Having said that, do you foresee any agency activity in 3

terms of mandating the single-dose vials? 4

thimerosal or seeking an alternative? 7

mandating single-dose vials. To do that has a number 9

of implications and we feel that basically the -- with 10

the multi-dose vials in their current state, they're 11

safe. I mean, the manufacturers have validated that 12

with using the current preservatives in those products. 13

They maintain their integrity. 14

See, the complicated part here is we have no question 15

that the manufacturer can produce a vaccine in a multi- 16

dose vial or single-dose vial or any kind of vial 17

that's going to be sterile. The issue is when you get 18

out in the field. And we don't know if everyone is 19

practicing aseptic techniques. That's something we 20

can't control as an agency, but by requiring -- I mean, 21

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NANCY LEE & ASSOCIATES

that's part of the rationale for requiring 1

preservatives in multi-dose vials. We're trying to 2

address that issue, but we'll never be able to address 3

that issue across the board because we just can't -- we 4

cannot police aseptic techniques in the field. 5

have been discussed -- Dr. Engler from Walter Reed. I 8

was just wondering in the options why there's no 9

consideration of leaving the concentration of 10

thimerosal the same, but increasing the concentration 11

of the active antigen and giving a smaller dose, which 12

would also reduce the pain of the injection, facilitate 13

jet injector technology development, and would 14

potentially be a win/win. The half cc comes from the 15

era when syringes did not have small enough markings 16

and you couldn't readily measure more than a half cc. 17

From a clinical perspective, it seems we might move to 18

a new era considering we have tuberculin syringes. 19

again, it would have to be validated and if the data 21

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NANCY LEE & ASSOCIATES

supports it, I don't see why that -- you know, we would 1

definitely consider it. 2

may have missed something in the logic here and I just 5

need to clear -- 6

you want to just press the button that says "Request to 8

Speak." That may help. 9

I may have missed something, but I think you said at 11

the beginning that the FDA is committed to decreasing 12

or eliminating thimerosal from vaccines, and I'm just 13

sort of wondering, having listened to the discussion 14

now, whether the FDA has considered not doing that, 15

leaving the thimerosal situation as it is. And if the 16

answer is "no," exactly which piece of evidence are you 17

relying on to come to the conclusion that something 18

must be done? 19

did not rule that option out. 21

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manufacturers to do something about thimerosal or is 2

the Agency just having discussion at this point? 3

manufacturers what are they doing to address thimerosal 5

in vaccines. We sent out a letter this summer to all 6

vaccine manufacturers asking them to address this 7

issue. Again, our objective is to -- It's just like 8

anything. Our objective is to remove or to decrease 9

the exposure of humans to mercury. Thimerosal is a 10

mercury-containing compound. 11

So if that's feasible, and I did use that word in my 12

discussion, then we want to -- we want a dialogue with 13

the manufacturers to find out if that can be done. 14

it, an implication that that exposure is -- the 16

exposure to this kind of mercury compound is harmful? 17

mean, any -- If we lived in a perfect world, none of us 19

would want to be exposed to mercury. So if we have an 20

opportunity to decrease our exposure to mercury or any 21

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NANCY LEE & ASSOCIATES

other harmful chemical, we would do it. So we would 1

like to know from the manufacturers what are they doing 2

to address this issue. Can they address this issue? 3

We have not issued any mandates at this time and this 4

was not the purpose of (inaudible) in Section 413. It 5

was not to issue any kind of mandate. It was 6

exploratory. 7

that preservatives must have about bacteriostatic and 9

bacteriocidal activities, and the question to you is 10

that: Does FDA have any specific guidelines how to do 11

those assays? For example, if the compounds are being 12

be the way to reduce the concentration of 15

preservatives. 16

to be validated. If the manufacturers want to go that 18

route, they will have to validate -- I think the 19

guidance is in the USP. You can start with that and 20

then go back, but you have to validate the amount of 21

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preservative that you're going to use. In that 1

validation, what are the inhibitory properties 2

resulting from a reduced amount of preservative? And 3

then we, as an Agency, will decide whether that's 4

acceptable or not. In that decision, we may say, well, 5

we need to cut your -- based on the data that you've 6

accumulated, we need to cut your shelf life in half, or 7

whatever. 8

specifically -- 11

My question specifically is, if thimerosal is taken out 14

of a vaccine, I believe what you said is that stability 15

studies would be required because you've taken out the 16

preservative, although I'm not sure that affects the 17

stability, but you would require stability studies -- 18

clinical studies as well, in other words, to show that 21

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the material is still immunogenic and safe? 1

preservative is used will dictate whether we will -- 3

is, as a preservative? 6

formulation versus, say, you've made your final 9

formulation and you have in your diluent, we may not 10

require clinical data, but if it's in your final 11

formulation, we may require clinical data because your 12

final formulation has changed. But, again, that 13

statement does not go across the board about products. 14

We have to look at the individual product that you're 15

speaking of and determine it from there, determine how 16

you're adding -- or where the thimerosal is and the 17

parameters that are involved in incorporating that into 18

your final product. I mean, another example is you may 19

have the -- you may have a preservative in your bulk 20

and decide to leave that in, but as you're doing your 21

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final fill, you may remove that from your bulk at the 1

time of final fill and demonstrate that it's at a level 2

of -- or below the level of detection. 3

question that Dr. Myers has just made about multiple- 6

dose MMR vaccines, and I really offer this as a 7

comment. 8

I'm concerned that the meeting may be under a 9

misapprehension about such vaccine vials. At WHO, we 10

encourage countries to use the measles vaccine, which 11

is a multi-dose, ten-dose vial, but once the vaccine is 12

reconstituted, then it has -- we give strict training 13

that this vaccine must be discarded up to six hours 14

from the start of reconstitution and failure to do that 15

has, in many, many instances, resulted in 16

contamination, overgrowth of staph, and what is known 17

as the toxic shock syndrome. The tragedies that result 18

from that are the deaths of multiple -- two, three, or 19

six children at a time from overgrowth of staph in the 20

vaccine. 21

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So I would caution the enthusiastic procedure of multi- 1

dose MMR vaccines. 2

bit different issue than it is with perhaps some other 4

vaccines. 5

Are there others? Dr. Egan? 8

comment on the MMR vaccine itself. 10

First of all, it's a freeze-dried preparation. It does 11

contain some neomycin, a preservative, and perhaps the 12

representative from Merck can correct me, I believe the 13

package insert says that it must be utilized within 14

eight hours of reconstitution. So it's similar to the 15

WHO. I think it's eight and not six. 16

I appreciate your attempts to try and shed some light 18

on this challenging situation. If I can go back to 19

your option four, if I might, and expand on your 20

comments and Dr. Daum's comments. 21

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You see a potential for, I guess, a hybrid of that 1

situation where you could have a product such as flu 2

where you would produce single-dose vials for a very 3

specific population, women of childbearing potential, 4

pregnant mothers, and the occasional infant. You had a 5

multi-dose presentation that kept the existing level of 6

thimerosal. 7

what we're going to be faced with in the short run is 9

that situation anyhow, because as we move -- as 10

manufacturers move toward removing thimerosal from some 11

of their products, we're going to be in a situation 12

where there are going to be thimerosal-containing and 13

thimerosal-free products, the same products, same 14

manufacturer on the market at the same time. So we're 15

going to have a period where that's going to happen 16

anyhow. Now, whether we're going to prolong that 17

period, that's up for discussion. 18

Our next speaker is going to give us a perspective on 20

how our European colleagues have dealt with this issue 21

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very recently. She is Mary Teeling, who is Medical 1

Director of the Ireland Medical Boards. 2

Dr. Teeling, welcome. 3

Europe been looking at the issue of thimerosal for -- 5

We've been doing this, in fact, for a year and a half. 6

So it's a great honor and privilege for me to come 7

here to share with you our deliberations and, more 8

importantly, how we are coping and what we are doing on 9

an ongoing basis with thimerosal. 10

And thank you to Dr. Myers. And I did say to him that 11

I do have the facility, being a good Irish woman, to 12

use many words rather than a few, but I really didn't 13

think that my introduction was going to be as long as 14

this. 15

(LAUGHTER) 16

we do in Europe -- Because I think this is very 18

important and it's an important issue when we're 19

looking at thimerosal -- we have in Europe two methods 20

of licensing. Now, there are 15 member states in the 21

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European Union and each member state has its own 1

national agency. So you can imagine 15 FDAs, albeit 2

all different sizes and shapes. And that's important 3

because that means that it is possible to have a 4

national license for medicines, including vaccines. 5

We also have a European Agency for Evaluation of 6

Medicinal Products called the EMEA, and that is 7

responsible for community authorization. So that means 8

it's a one-stop shop. If you go the agency with a 9

particular type of medicine, you can get a license 10

that's valid in the 15 member states. 11

Now, it is important to note that the European system 12

of licensing, community licensing, is not available to 13

everything. For instance, it's not available to 14

existing authorized medicines unless they can show a 15

totally new indication. It's not available for 16

generics. It's obligatory for biotech products. And, 17

of course, with the combination vaccines containing 18

hepatitis B, that's important, because they will have 19

to use this system because they are biotechnology- 20

derived. 21

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Now, the European agency has two main arms. The first 1

is the Secretariat -- Quite an extensive secretary is 2

taken from all over the European Union, and these are 3

mostly people who will have worked in agencies within 4

the 15 member states -- and a scientific committee 5

called the Committee for Proprietary Medicinal 6

Products, the CPMP. Now, as I said, the CPMP is a 7

scientific committee. It's made up of two members per 8

member from each member state, but you leave your 9

national hat outside the door when you come into the 10

CPMP. It is a truly scientific committee where science 11

is evaluated. So national issues are not discussed at 12

the CPMP. 13

Now, if you were to ask me what the role of this 14

scientific committee is, I think you can get many, many 15

different views, but I think, in general, it's to 16

ensure the provision of safe and efficacious medicines 17

to the market place in a timely fashion. 18

Now, that's very important. I know the FDA have time 19

limits. In fact, Norman Baylor mentioned some time 20

limits before, and we have implemented time limits, 210 21

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NANCY LEE & ASSOCIATES

days from time of -- beginning of the authorization to 1

approval, positive opinion, or otherwise, from the 2

CPMP. And that's for the community licenses, for the 3

ones that get the European license. 4

Does the CPMP have any other role? Of course, it 5

does. It's a public health body, and so we look at 6

ongoing safety of marketed medicines. Now, these are 7

medicines that will around at national level, as well, 8

and if they're judged to be community interest issues, 9

then they are discussed by the CPMP. 10

And, of course, a very important point in today's world 11

is to ensure that the provision of adequate information 12

takes place to both health care professionals and to 13

the public. 14

And we have in Europe -- I think it's a totally 15

different system, but certainly over the last years we 16

have become far more transparent. We have a standard 17

method of provision of what's called a summary of 18

product characteristics, which is the health care 19

professional document, and also patient information 20

leaflets in user-friendly language. These are new -- 21

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certainly new procedures for many of the member states. 1

Okay. Now, this is -- The CPMP has a number of 2

permanent expert groups and, again, these are important 3

because they've all been involved in the thimerosal. 4

There is a Biotechnology Working Party looking at the 5

pharmaceutical aspects of biotech products, a Efficacy 6

Working Party looking at the effectiveness of drugs, a 7

Quality Working Party looking at the chemistry and 8

pharmacy of chemicals, a Pharmacovigilance Working 9

Party that's clinical safety of medicine, a Safety 10

Working Party, pre-clinical issues are discussed there, 11

and we can also have ad hoc expert groups as 12

appropriate. But the other working parties are 13

permanent working parties and they work very closely 14

with the CPMP. 15

And my final introduction slide, if you like, this puts 16

very much into context what we are discussing. Before 17

1995, life did exist in the European Union, before the 18

implementation of the European agency, and prior to 19

that we had purely national authorizations. The 20

further you go back, the more national the 21

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authorizations were. And it is very likely that for 1

the older medicines, particularly vaccines, in Europe, 2

that you would have 15 different licenses for the same 3

vaccine. I know that sounds crazy, but that's the way 4

it worked. So you are setting -- The playing field is 5

not a level one when you're looking at these issues, 6

particularly for products prior to 1995. 7

And, of course, in the same vein, although the CPMP is 8

not involved with the National Immunization Programs, 9

it is important to note that the National Immunization 10

Programs vary between the member states. I'm not even 11

sure that you would have two identical immunization 12

programs in the 15 member states. So you are dealing 13

with a very uneven surface to start off with. 14

Many of these issues have been covered already and 15

that's very good, because, you see, we're all thinking 16

the same way. I mean, thimerosal is a widely used 17

preservative and it has been used in biologicals and 18

multi-dose preparations for chemicals, as well as 19

biologicals. Of course, this big issue and the reason 20

why we're all here is that it's a mercury-containing 21

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compound. 1

Now, how we actually got involved with this at the 2

European level was that in January of 1998, the 3

biotechnology working party, who has ongoing dialog 4

with the vaccine manufacturers and reviews vaccines on 5

a regular basis brought up a possible -- the 6

possibility of a safety hazard using thimerosal and, in 7

fact, other organomercurial compounds, although to my 8

knowledge there are very few of those left and only in 9

the very old products. 10

This was referred to the Safety Working Party to look 11

at the preclinical evidence associated with use of such 12

compounds in products in general, in medicines in 13

general, and they reported to the CPMP. 14

Now, the CPMP decided to set up a multi-disciplinary 15

group, and this was to view the benefits versus the 16

risk of thimerosal in medicinal products. And many of 17

the speakers --Even this morning, many of the 18

discussions from the audience are bringing this issue 19

of benefits versus risk of using this. And this was 20

very much in our mind when we undertook this. 21

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Now, the most multi-disciplinary group posed three 1

questions on behalf of the CPMP to the various working 2

parties: that was the rationale for inclusion of 3

thimerosal; Are there suitable alternatives available; 4

And the implications of removal of thimerosal from 5

medicinal products. So they were the three issues that 6

the individual working parties had the review from 7

their perspective. 8

The other points that came up was a questionnaire on 9

the immunization schedules in the first two years of 10

life for all member states was also undertaken. 11

Now, what we asked the member states to do was not only 12

to tell us what vaccines were recommended, but the 13

actual vaccine types if that was possible. It's 14

certainly possible in Ireland because of the 3 1/2 15

million population. The Department of Health in 16

Ireland buys all of the vaccines for any particular 17

year. So although we may have licensed seven or eight 18

DPTs and two or three DTaPs, it is likely that one, or 19

at most two, of those only will be in use in the 20

country at any particular time. And so it's quite 21

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similar in the other member states, so it was possible 1

to actually get actual usage information from this 2

particular immunization questionnaire. 3

Now, the safety issues have been extensively discussed 4

yesterday by people far more appropriate to discuss 5

this than me, but, of course, the issues that we did 6

focus on were the neurotoxicity. Again, we're talking 7

about a potential here, a potential neurotoxicity. 8

Hard data are certainly absent with regards to use in 9

vaccines or, indeed, other medicinal products, but it's 10

the potential because of the mercury content. 11

And we especially focused on certain at-risk groups, 12

pregnant women, to the risk for the fetus, and also 13

infants and -- infants and toddlers. 14

Sensitization was also looked at. Here we do have some 15

pharmacovigilance data. And as you know, the type of 16

sensitization is delayed hypersensitivity. I think it 17

was particularly important because, remember, we were 18

looking at all medicinal products and not just vaccines 19

and we had information on the eye preparations. We 20

also had some very minor information from the 21

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intramuscular immunoglobulin multi-doses which require 1

a preservative, and some of which contain thimerosal. 2

And I think with regards to the vaccinations, we looked 3

at the issue of the type of injection that was to be 4

used, and basically the deeper you go, the less likely 5

you are to get the reaction, and I think that's 6

something that is generally accepted. 7

Yesterday many people discussed nephrotoxicity and, in 8

fact, nephrotoxicity was pursued, particularly by the 9

Pharmacovigilance Working Party, but we really didn't 10

have -- I mean, ever how little data we have with the 11

other two, we certainly had no firm data to draw any 12

conclusions with regards to nephrotoxicity with use of 13

thimerosal in medicines. 14

Now, again, all of these were discussed yesterday. I 15

think with regard to the distribution, we were very 16

much aware of the fact that the -- this crosses the 17

blood/brain barrier. Again, I think -- I have to draw 18

your attention to the fact that we're talking about 19

methylmercury data here, so we're extrapolating. And 20

the brain and placental transfer was obviously 21

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something that was very important for the possibility 1

of neurotoxicity. 2

And we also, based on WHO data and their technical 3

reports, noted that the hair concentration was a very 4

good indicator because a very high concentration of 5

mercury occurred in hair after administration, and so 6

that hair levels could be used as perhaps as a 7

reasonably valid marker and, of course, a non-invasive 8

marker. 9

Metabolism, we did look into the issue of organic 10

versus inorganic. I think we used a working half-life 11

of 50 days, sort of a range 39 to 70. And of course 12

this issue of accumulation, and this was very 13

important, because I think what you're hearing is, it's 14

probably not the single stab, it's the many sources and 15

the multiple administrations. In fact, we did look at 16

this issue of the sources of organic mercury. And, of 17

course, food, especially fish, is a big source. Now, 18

this is oral intake, obviously. And we did look at the 19

possibility that the medicinal intake would also 20

increase your level, your critical level. 21

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Now, the allowable levels that we worked 1

on -- So I was interested to hear the speakers yesterday. 2

We worked on 200 micrograms per week in adults. This 3

is the total permissible weekly intake from WHO figures 4

of, I think, 1989-1990. And, again, these figures are 5

based on methylmercury. All of this information is 6

based on methylmercury. 7

So this is a very rough calculation of how and why we 8

took that, and I think we were looking at the initial - 9

- the initial symptoms of mercury poisoning, and these 10

would -- paresthesia would be very much the early 11

symptom that something was wrong. This was seen in the 12

Iraqi outbreak after a certain number of weeks. It was 13

estimated by the WHO that 50 micrograms per day would 14

give an 0.3 risk of developing paresthesia, which is a 15

fairly low risk. I think if you take a higher level of 16

200 micrograms per week, based on a 70 kilogram man, 17

that's 0.4 micrograms per kilogram per day. That gives 18

you a safety margin of 1.7 against developing an 0.3 19

percent risk of paresthesia. So, again, you're 20

widening your safety margins all the time. So we 21

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accepted the WHO level of 200 micrograms per week as 1

the working level for adults for oral intake of 2

methylmercury. 3

Now, when we came to pregnant women and infants -- And 4

remember, we're looking at all medicinal products in 5

Europe, and this is why we included both categories, 6

pregnant women and infants. The pregnant women, we 7

calculated that the level of 200 micrograms per week 8

for adults should be cut by -- to one-fifth, and this 9

is based on hair concentrations reported in the WHO for 10

the Iraqi women where they had the children and the 11

mother pairs. So our working level for women would be 12

one-fifth the adult dose, above which we would have 13

safety concerns for the fetus. 14

Infants was even more difficult. And as you can see 15

yesterday, there is -- this issue is, is the newborn as 16

sensitive as the unborn? We did a calculation based on 17

the fact that if you take the worst possible case 18

scenario, we came up with a working figure of 200 19

micrograms in the first year of life. However, and I 20

must say the issue of the spiking or the episodic 21

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versus the chronic administration was something that we 1

couldn't actually come to grips with, because I don't 2

think anybody can give advice on that because we 3

actually don't know. 4

So very much, it's very much a part of the version of 5

our safety aspects. All of the safety data that were 6

presented yesterday were reviewed by us and nobody can 7

argue with the facts. It's basically how you deal with 8

the facts and how you interpret them and bring them 9

forward. 10

So if we go back to the three questions that the group 11

posed to the experts working on behalf of the CPMP, the 12

first is the rationale for inclusion of thimerosal, and 13

you've heard all of this before, particularly from this 14

morning's speakers. Vaccines consisting of protein and 15

polysaccharide in a solution or a suspension may 16

potentially support bacterial or fungal growth. Fact. 17

18

So if you add a preservative, this will hopefully 19

prevent contamination, and this can be done either 20

during the manufacture or in the end product, in the 21

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case of multi-dose preparations, and this prevents 1

contamination which could be harmful for the recipient. 2

We heard of the fatal contamination cases yesterday. 3

So if you add a preservative, is it just to prevent 4

contamination? I think we also looked at this idea of 5

maintaining the integrity of the vaccine and to 6

maintain the desired biochemical properties or 7

functions of the active component. Obviously, if you 8

look at -- the whole cell pertussis is an example here. 9

10

Also, we did look at this issue of its use in single- 11

dose vials, and we felt that it could even have a role 12

in single-dose in certain cases. For example, in the 13

influenza vaccine, where you're using the eggs as 14

starting materials. 15

So we felt there is a rationale for including a 16

preservative in some circumstances. Okay. So does it 17

have to be thimerosal. Well, what are the alternatives 18

to thimerosal? And we have some listed here. 19

Phenol, we heard yesterday that that's no longer 20

acceptable by the WHO. Cresol, I'm not sure that I'm 21

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too impressed with cresol. 2-phenoxyethanol, I -- 1

Perhaps I'm getting old and a bit cynical, but I'm 2

really not sure that we have the full safety picture on 3

2-phenoxyethanol. It certainly does look to be a safe 4

and efficacious vaccine -- preservative, but we're 5

actually not 100 percent sure about either of these at 6

this point in time. Formaldehyde has also been used. 7

Now, there are other preservatives that have been used 8

in other medicinal products, like benzochromium 9

chloride. I think the important thing is that for a 10

preservative to be used, they must fulfill the European 11

Pharmacopeia specifications. That's a requirement in 12

order to get a license either nationally or at 13

community level in the European Union. So they do have 14

-- So they will, more or less, fulfill the PH Euro 15

requirements. 16

But we're not really -- Ever how much information we 17

have on thimerosal, I think we have less on the others. 18

So you're into a situation, or are you -- You know the 19

phrase, "The devil you know is better than the devil 20

you don't know." And I think that's a very important 21

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aspect of this whole review. 1

So, well, of course, the real alternative is to get rid 2

of the need for preservatives, and that's why using a 3

good manufacturing practice and get a preservative-free 4

product. 5

Now, again, I think we've heard that that's not always 6

possible. So from that point of view, it's something 7

that has to be debated, but it is an alternative that 8

should be looked at. 9

Right. The final question that the group posed to the 10

experts was the implication of the removal of 11

thimerosal from medicinal products. Well, the group 12

still maintained its position that GMP adherence should 13

reduce the need for preservatives, certainly reduce the 14

need for preservatives. And there will be a need in 15

certain cases, and this is particularly in the multi- 16

dose preparations where the seal is repeatedly 17

breached. I think we did hear some examples of where 18

the multi-dose preparations might be used from Dr. 19

Clements yesterday, and I think we in the European 20

Union are certainly very much aware of the WHO need in 21

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this regard. 1

One particular issue regarding vaccines is the turbid 2

vaccines. So if there's microbial contamination, the 3

turbidity may actually mask this contamination. That 4

was felt to be a particular specific issue that we 5

needed to address. 6

But, finally and most importantly, the implications of 7

the removal of thimerosal from medicinal products, 8

really the group was very concerned that this would 9

pose risks to the continuity of the immunization 10

programs. 11

So the group recommended that we would have adequate 12

labeling for the sensitization on all thimerosal- 13

containing medicines. Now, this is not something that 14

was universally applied in the European Union. There 15

is a requirement that thimerosal or other preservatives 16

are included routinely on the label, but a warning 17

statement has not been mandatory. So it was agreed 18

that this should be drawn up in the interest of 19

informing patients and health care professionals. 20

For vaccination in infants and toddlers, the use of 21

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vaccines without thimerosal or other mercurial- 1

containing preservatives was to be encouraged. 2

However, we were very concerned that the continuing 3

supplies and vaccination programs would be jeopardized, 4

and so it was agreed that we would have a workshop with 5

interested parties. That took place in April of this 6

year with representatives from the WHO. We had Norman 7

Baylor from the FDA. We had representatives from the 8

European Pharmacopeia because, as you can see, the 9

European Pharmacopeia requirements are mandatory to get 10

a license in the European Union, either at -- 11

nationally or community level, and so we need to have 12

the European Pharmacopeia on board if we're 13

recommending changes. 14

We also had the vaccine manufacturers and the other 15

manufacturers, the eye manufacturers, the plasma 16

protein fractionaters (sic), and we also had the 17

representatives from the CPMP and our experts. 18

In the working party, this interested parties meeting, 19

we did reach agreement in principle to labeling, 20

obviously a standardized wording, and we addressed this 21

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issue of whether it's used as a preservative so it's 1

added in a known amount at the end of the procedure or 2

whether it's used in the manufacturing procedure where 3

it's still present in trace amounts, but this, of 4

course, may be important for sensitization purposes. 5

And we also had an agreement in principle to work 6

towards reducing or eliminating thimerosal and, indeed, 7

other mercurial-containing preservatives in the 8

production of vaccines. So we've now moved forward, 9

and we are in the process working to achieve those 10

issues. 11

Now, I would like to draw your attention to the public 12

statement that we issued in July regarding this. As I 13

say, we're very much -- this is very much a working 14

procedure. We haven't come to the end -- We have a lot 15

more work to do -- but it's ongoing. 16

Now, the background points to our public statement 17

were, again, thimerosal has been used for many years. 18

The level of ethylmercury in any single medicinal 19

product is not considered a risk. I think that's 20

something that Norman Baylor said, that the last 21

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speaker said, and I think we would agree. However, 1

it's the cumulative exposure from a range of sources, 2

not just from medicines, but from food, and, indeed, if 3

you read the WHO reports, intake from the air and from 4

water. So there are many sources of mercury. So, 5

therefore, we could -- we could have a situation where 6

this would lead to a potential cause for concern. 7

I don't have the bullet point that Dr. Klein so rightly 8

mentioned yesterday, and I think it is an important 9

one, and I'll actually read it out to you because I 10

have the document here. 11

"Data on methylmercury has been used in the assessment 12

of risks associated with ethylmercury as the toxicity 13

profile of the two compounds would appear to be 14

similar." 15

I think that's a great use of the English language, but 16

I think it's as far as we can go because we don't have 17

the information on ethylmercury and we're doing the 18

best we can with the information that we have, and I 19

think it's probably the same for all of the workers who 20

are doing this at the moment. 21

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Now, the remainder of this, I'm actually going to read 1

for you what we said because each line is very 2

important. 3

"For vaccination in infants and toddlers, the CPMP 4

concluded that although there is no evidence of harm 5

caused by the level of exposure from vaccines, it would 6

be prudent to promote the general use of vaccines 7

without thimerosal and other mercurial-containing 8

preservatives, particularly for single-dose vaccines. 9

This should be done within the shortest possible time 10

frame." 11

Next point. "In the interests of public health and in 12

order not to jeopardize vaccine supplies and 13

immunization programs, the EMEA will continue to work 14

with the WHO, the European Pharmacopeia, the Food and 15

Drug Administration, and vaccine manufacturers with the 16

objective to eliminate organomercurial preservatives in 17

vaccines in the follow-up to the joint workshop which 18

was held in April 1999." 19

Now, this is, I think, very important. "The CPMP would 20

like to stress that this is only a precautionary 21

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measure. There is no evidence of harm from the use of 1

such thimerosal-containing medicinal products. While 2

reformulation work on vaccines proceeds, it is 3

imperative that vaccination continues in accordance 4

with national vaccination schedules to prevent disease 5

outbreaks." That was a very important message that we 6

wish to get across. 7

And finally, just for the sake of completeness, we did 8

look at immunoglobulins and eye and nasal preparations, 9

and basically, apart from the labeling issues, no 10

further action was deemed necessary. I think that's an 11

important issue. 12

Where are we now -- Okay? -- August, 1999? Well, our 13

Pharmacovigilance Working Party has drawn up standard 14

warnings on sensitization for all thimerosal-containing 15

medicines. Now, we need an agreed implementation 16

procedure here, and remember the vast majority of these 17

medicines are licensed at national level, and we all 18

have different time limits and time levels, and that's 19

what makes the European Union so wonderful. It's so 20

varied. But the problem is, we have to agree an agreed 21

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time frame for implementation here. 1

The second is that the Biotechnology Working Party is 2

working on a guidance document relating to the 3

reduction or elimination of thimerosal and, indeed, 4

other preservatives in vaccines. And I would love if 5

Dr. Baylor would come and work with us because many of 6

the issues that he raised are issues that we are 7

raising in our discussion document. Because it's very 8

difficult, each individual case will be a case-by-case 9

basis. 10

I think the other most important -- and I would like to 11

give you this commitment, that we will continue to work 12

with all relevant parties to ensure the continuity of 13

supply of safe and efficacious vaccines. 14

Thank you very much for your attention. 15

(APPLAUSE) 16

just one or two questions. Yes, Rob? 18

Office. 20

Now, I'm impressed with how oftentimes we tend to be 21

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very vertical and look at and consider issues that are 1

only related to our area, and I'm not thinking about 2

what happens in Europe. I'm thinking about what we 3

might do here in the U.S. 4

But when you were considering the issue of cumulative 5

exposure, was there any discussion about issuing any 6

sort of strict guidelines or information to pregnant 7

women regarding ingestion of, let's say, you know, 8

mercury-containing fish? Is that something that is -- 9

for us, obviously, because we're not a food and drug 11

administration. We are primarily -- and I think that's 12

-- we're not -- The agency is not a European FDA. I 13

think we deal specifically with medicines. From a 14

public health point of view, that is important. I 15

think we didn't want to add to the burden. And the 16

reason why pregnant women were particularly 17

investigated was not just from the point of view of the 18

vaccines and any vaccinations that they may get, but 19

because of the possibility that they could be getting 20

anti-D immunoglobulin prior to delivery, which would 21

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affect the fetus. So we specifically honed in on 1

those. 2

I think with regard to your general point, we did not 3

make any recommendations for people to go back and view 4

their national programs. In fact, we said that, you 5

know, in accordance with national decisions. However, 6

some of the national agencies could have gone back to 7

their departments of health who are responsible for the 8

vaccination programs and taken on -- or, indeed, taken 9

on anything with regards to the foods levels as well. 10

It's not something that we would get involved in, but 11

it might be a knock-on effect from the CPMP. 12

Society. 15

You read many quotes from your group, and I wonder 16

whether these are ready available, if there's a website 17

where some of this information may be -- 18

website for you. I am computer illiterate, as you may 20

have gathered. It's a disease, I can't help it, but I 21

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actually have the website. I have a copy here, if 1

anybody would like a copy from the photocopy machine, 2

but it is available on the EMEA website. Interestingly 3

enough, we got very few comments, in fact, from this. 4

We have a website. We have a publication every month 5

from the CPMP. So everything that we do is put on. 6

This was a specific -- a specific public statement that 7

was put out. We actually got very little requests. In 8

fact, we got more requests from the MMWR statement than 9

we did from European statement, which I don't know what 10

that says about European doctors. Certainly, you can - 11

- I'll give you this later on. 12

I notice that you have gone a little further than our 15

Public Health Service and the Academy of Pediatrics 16

have and that you have encouraged the use of 17

thimerosal-free products in the use of infants and 18

toddlers. Was there any discussion about those 19

particular populations in Europe which do have a fairly 20

high background of fish consumption and a presumed 21

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higher background of mercury exposure with regard to 1

even going beyond that? 2

I think the issue was identified for the national 4

agencies to do it as they wish with it. But I think -- 5

The one issue that I didn't raise, because it wasn't a 6

part of the final deliberation, is that we did the 7

immunization schedule, the questionnaire. In fact, two 8

member states had greater than 200 micrograms in the 9

first year of life. Now, one of those, in fact, has 10

since introduced a thimerosal-free version of the 11

vaccine, but I think -- and so they have come down. I 12

think what it did show us is that the vaccination 13

programs are greatly different. Hepatitis B is not 14

mandatory in all member states. It's nearly all DTaP, 15

and the vast majority of DTaP supplied appears to be 16

thimerosal-free. So the two main problems that you 17

might have here in the U.S. don't appear necessarily in 18

our vaccination program for infants, but there was no 19

specific discussion on the additive nature of fish, 20

other than it was highlighted as a point as part of the 21

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accumulation. 1

We'll break for coffee and other things, and start 3

precisely at 10:30. Thanks. 4

(RECESS FROM 10:10 A.M. TO 10:35 A.M.) 5

phase, which is entitled "Immunization Issues During 7

Transition to Thimerosal-free Vaccines." Our first 8

speaker will be Dr. Roger Bernier. Roger is at the 9

CDC, has been the point person for the CDC for 10

thimerosal issues the past couple of months, and he is 11

going to present to us the public health service 12

immunization options. 13

Roger? 14

topic or title would still be appropriate this late in 16

the workshop because I thought that this might be 17

fairly clear by now. But I think that it's still 18

valuable. I think Bob Daum's question during the last 19

session, and as well, the last presentation by Mary 20

Teeling, I think indicates that it would still be 21

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helpful to have a presentation about -- from the public 1

health service point of view, or in the U.S. what is 2

the position that we have evolved to on this thimerosal 3

question. 4

Well, I think it can be expressed by the goals that we 5

have articulated. The first is to reduce or eliminate 6

thimerosal from vaccines as soon as possible. And 7

second, to reduce exposure to thimerosal from vaccines 8

during the transition period to thimerosal-free 9

vaccines. 10

And I think one of the points I want to make is that in 11

some ways something is different, that there is not a 12

business-as-usual view of this matter, and I think that 13

that's one of the things that we're trying to hold 14

together in our minds, the idea that somehow it's not 15

business as usual, yet, in another way, we are trying 16

to do our usual business during the transition period. 17

And how can we keep together these two difficult 18

concepts, if you will, or, the concepts are not 19

difficult, but holding them together is difficult, that 20

we're in a non-business-as-usual mode and we are trying 21

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to do some of our business as usual? 1

Well, I want to try to explain how we got here, and 2

that means, I think, trying to answer the question 3

about why it's worthwhile to try to reduce or eliminate 4

thimerosal. I think one of the important concepts is 5

one that Leslie Ball presented, I think perhaps 6

borrowing from the work of the European Union in trying 7

to calculate what might be the exposure from the 8

vaccines. As you may recall from her presentation 9

yesterday, when you look at DPT, HIB an hepatitis B 10

using three doses, the potential exposure to mercury 11

from vaccines in the United States over approximately 12

the first six months is this 187.5 micrograms, assuming 13

there's not flu. 14

Now, in the U.S. there are -- Again, people caution me 15

not to use the word "standards," and half the time I 16

remember and half the time I forget. These guidelines, 17

I think is the best term that people seem to feel is 18

the best term to describe them. 19

In the U.S. we have three different sets of guidelines. 20

Again these were mentioned yesterday, as well, from 21

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EPA, ATSDR, and FDA, and there are also some from WHO. 1

They are different, from .1 in the U.S. for the EPA, 2

which is the lowest, to .4 with the FDA. 3

Now, one of the concepts that -- And, again, I knew 4

very little about this before and I still am learning 5

about this every week, but this represents my 6

understanding of what we mean by safety margin in 7

relation to these guidelines. 8

This represents the level of zero exposure. And I'm 9

using here as an example the ATSDR guideline, but, 10

apparently, there are safety margins, large safety 11

margins, associated with all of the three guidelines in 12

the U.S. If you take this level as the zero exposure 13

level, the current ATSDR guideline is .3 micrograms. 14

In fact, in the data that the ATSDR relied in the 15

Seychelles, the average exposure in the high-risk 16

group, where no effect was observed in the moms, where 17

I believe it was 15 parts per million, approximately. 18

That translates to 1.3 micrograms, which is four times 19

above the ATSDR guideline level. So this much safety 20

margin exists on this ATSDR guideline. 21

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In addition, if you'll at the highest exposure group in 1

the Seychelle, again, this is the highest exposure in 2

the high-risk group, where again no effect was 3

observed, that equals to approximately 2.5 micrograms, 4

which is eight times over the base line ATSDR 5

guideline. 6

In terms of total exposure that might be permissible 7

under that, if this translates to approximately 250 8

micrograms over the first seven months of life, this is 9

about 1000 and this would be about 2000. 10

After the highest exposure group with a no- effect 11

level, then you get into this grey area because, 12

presumably, between this exposure level where there's 13

no effect and the first level where you begin to see a 14

mild effect, that is a grey zone. We don't know how 15

wide that grey zone is. It might be very narrow or it 16

might be very wide, but there is a grey zone when you 17

begin to see a mild effect. Then at an exposure level 18

that produces very serious effects, obviously, that's 19

represented by this black area in the bar, but this 20

represents the safety margin that we've heard so much 21

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about and that why we've heard that these guidelines, 1

.3 in the case of ATSDR, or .1 or .4, why interpreting 2

them as bright-line types of thresholds is probably not 3

an appropriate way to interpret them, but rather to 4

think more about them as starting points -- starting 5

points or screening levels or whatever most appropriate 6

adjective, but not as a threshold, a bright-line-type 7

of value. 8

Now, again, if 187.5 represents the potential exposure, 9

what are the potential limits that might be allowable? 10

And if you use the different standards, the different 11

guidelines from EPA, ATSDR, and FDA, the -- Dr. Ball's 12

group has calculated -- And we have somewhat slightly 13

different assumptions, so I'm going to show the results 14

that Dr. Ball's group did as well as the one at CDC. 15

They're very similar, but they are slightly different. 16

These are the results from Dr. Ball's calculations. 17

From the calculations that we did at CDC, they are just 18

a little bit higher. The major difference is that we 19

calculated out to 30 weeks, again, thinking that what 20

you wanted in coming up with your suggested limits was 21

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the limits during the period of time that children are 1

most likely to be exposed. For most children, they're 2

not going to be vaccinated exactly at six months. I 3

think this is the question that Stan Plotkin raised 4

yesterday: Why don't you calculate it at seven months? 5

I told Dr. Ball I didn't really plant that question. 6

But if, in fact, you do that, you'd come up with 7

slightly different limits. 8

Now, comparing these two, then, here's the potential 9

exposure as calculated by Dr. Ball from the vaccines on 10

the routine schedule. And if you look at the three 11

guidelines that we have in the U.S., you can see that 12

the total exposure that some children might receive 13

would be in excess of the guidelines suggested by the 14

EPA but would be within the limits of the guidelines 15

suggested by ATSDR and FDA. This is for children at 16

the fifth percentile. 17

Well, that's the potential exposure for some children. 18

What do we know about what children are actually being 19

exposed to? Well, we don't have a lot of information 20

on that at this time, but what we did do is look at the 21

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potential number of combinations of vaccines in the 1

United States for DPT, HIB, and hepatitis B, and look 2

at, of all the possible combinations of ways that 3

infants could be vaccinated, what are all the potential 4

total endpoints in terms mercury exposure that these 5

combinations might lead to. And what it shows is that 6

there's approximately -- I think it's 100 different 7

ways that infants can be vaccinated, but about, say, 15 8

or 20 total mercury exposure endpoints that they can 9

end up with. 10

If you'll look at the vaccine combinations, most of the 11

vaccine combinations that are available in the United 12

States, about a quarter of the combinations produced 13

would produce mercury exposures of about 100 micrograms 14

over the first seven months, or 112. And I've put on 15

here the guidelines where you can see that for some of 16

the combinations, if children got these, they would 17

exceed this EPA guideline but would for all the 18

combinations available in the U.S., children, if they 19

got any of these, would still be below the guidelines. 20

Well, we do have one set of data from the California 21

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Kaiser that is part of our vaccine safety data link, 1

and, basically, what this shows is what mercury 2

exposures 85,000 children received at this HMO, and 3

what you can see is very similar to what you would have 4

predicted based on the existing number of combinations, 5

namely that approximately 90 percent of the children 6

got 112 micrograms or less, 91 percent, 125. Again, 7

for some of these, they were in excess of the EPA 8

guideline, but below the ATSDR and the FDA. 9

And to summarize, I guess, what I've just said for 10

these guidelines, as far as potential exposure, the 11

values were below FDA and ATSDR, above EPA, and on 12

actual, they were well below, if you look at 100 as the 13

actual -- or approximately 100 micrograms as close to 14

an average exposure, this is well below the ATSDR but 15

still above EPA. 16

So it was based on those kinds of considerations that 17

public health service groups and others deliberating 18

about these matters recently basically came to the 19

conclusion that it would be worthwhile to reduce or 20

eliminate thimerosal in vaccines. While we did not 21

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exceed the guidelines from ATSDR and FDA, there was 1

some excess relative to the EPA guidelines, and given 2

that uncertainty and the possibility of a potential 3

risk, I think there was this agreement that it would be 4

prudent to reduce or eliminate thimerosal in vaccines. 5

6

We then would face a transition period where, again, we 7

had now made a commitment to change, but we would still 8

have a supply situation that was similar to the one we 9

had -- There hadn't been any change in supply -- and, 10

therefore, we would have to manage the transition. And 11

one of the major principles guiding this transition was 12

that the benefits of vaccination were believed to far 13

outweigh the risk, if any, of exposure to thimerosal, 14

and this guided many of the choices and decisions that 15

were made. 16

And here, then, captures in policy terms -- Because we 17

can talk all about this, and bottom line is, at some 18

point we have to make a recommendation that makes 19

everything very 20

specific -- you capture -- You have to deal with the 21

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uncertainty and make it specific. And what it boiled 1

down to was the following. 2

That the U.S. has recommended that there be no change 3

during this transition period in the use of DTaP, HIB, 4

or hepatitis B for antigen positive mothers, or for 5

hepatitis -- no change in hepatitis for mothers whose 6

antigen status is unknown, or for infants who come from 7

high-risk populations. However, again, in light of 8

this potential risk and concerns raised by that, there 9

was a feeling that some action need -- should be taken 10

at this time, and the decision was made, or 11

recommendation made, to postpone the initiation of 12

hepatitis B in mothers whose antigen status is negative 13

and for whom that status is proven or documented to be 14

negative. In those mothers, the infant vaccination 15

could be postponed until two to six months. 16

This statement was issued jointly by the American 17

Academy of Pediatrics and the Public Health Service. 18

In subsequent guidance, the Public Health Service 19

expressed a preference for initiating this postponed 20

immunization at the lower end of this agreed-upon 21

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range, and the American Academy of Pediatrics expressed 1

a preference for starting at the upper end of this 2

range. The Academy did recommend that if you had a 3

thimerosal-free vaccine available, then you could begin 4

at the lower end of the range with that product. 5

Now, in the remaining time, I'd like to talk a little 6

bit about what are some of the issues that were raised 7

in reaching these conclusions about where we are, and 8

I'd like to allude to a couple of problems or issues 9

that have arisen in the implementation of these. One 10

of the things that we hope to get out of this workshop 11

is a discussion of the issues around these decisions 12

and help us to evaluate whether or not there are any 13

refinements or adjustments that we need to make to the 14

decisions that were taken. 15

So I'd like to just point out some of the issues that 16

I'm aware of. I think the speakers in the rest of this 17

session will really focus on some of these other 18

issues, and maybe new ones will arrive, but if the 19

workshop could be helpful in getting people's views 20

about these matters as to where we are now and whether 21

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we need to modify in any way, that would be very 1

helpful. 2

Some of the issues that I think were germane to the 3

discussions that we had you've heard a lot about, and 4

that is the assumption abut ethylmercury being treated 5

as methylmercury. I think that that's still the 6

appropriate thing to do. I haven't heard anything at 7

this workshop that suggests that we don't need to do 8

that. 9

Another assumption was that the fetal risk, which is 10

what guidelines are based -- are trying to address, was 11

equal to infant risk, I think we are hearing that 12

perhaps infant risk is lower than fetal risk. So 13

that's a reassuring thing. It's not that we have a lot 14

more data on this, but it's tending to go in the 15

direction from what I'm hearing that infant risk post- 16

natally may be lower than fetal risk. No one is quite 17

ready to make a new guideline I don't think, but it's 18

reassuring rather than being more -- becoming more 19

worrisome. 20

On the issue of the background level of exposure to 21

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mercury, the assumption was made that it's negligible, 1

and I haven't heard anything that makes us believe that 2

we ought to be more concerned about background levels 3

of exposure. 4

Another important issue that has permeated these 5

discussions is that the guidelines are based on chronic 6

exposures. What we are dealing with is an acute 7

exposure and the guidelines may not be applicable. I 8

think, on that score, it still remains unknown. I've 9

heard data on both sides, or observations, I should 10

say, or speculation on both sides, and in my mind this 11

still remains an unknown. 12

In the Department of Health and Human Services, there 13

were three guidelines. I think it's fair to say that 14

because of a two-year process that has been going on in 15

the Department of Health and Human Services, while 16

there were three existing guidelines in the U.S. more 17

weight or preference was given to the ATSDR guideline 18

as the primary guideline to be -- to be guided by, if 19

you will, than the other two. That was a decision that 20

was made, as I say, in the Department of Health and 21

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Human Services because of a two-year process. I've 1

heard nothing to make us believe that we ought to have 2

done that any differently. 3

Also, another point that arose during the whole 4

discussion was how do you apply these guidelines in 5

decision-making. I've tried to allude to that by the 6

schematic that I showed on the safety margins, but this 7

was a big issue. Again, depending on how you interpret 8

those guidelines, as either bright lines or as starting 9

points, can make a big difference in how you react to 10

all this, and I think -- I haven't heard anything to 11

change our view, which was to look at these guidelines 12

as a starting point. 13

In fact, the more I've heard about this, the more I've 14

become convinced that -- at least in Dr. Raub's session 15

yesterday, there was a lot of focus on the guidelines 16

as screening points or screening levels. 17

And, finally, I don't have a slide for this, but I'd 18

like to talk about some of the issues that have arisen 19

that I'm aware of in the implementation of the existing 20

policies. 21

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One of them obviously has to do with hepatitis B. I 1

mean, that's the only vaccine where we expressed a 2

change in the current status. You heard Dr. Mast's 3

presentation yesterday, concerns being raised about the 4

number of infections that may be arising as a result of 5

the new policy change. Perhaps that's something that 6

we were not as fully aware of and didn't have all those 7

calculations at the time the policy was made. The 8

question is, do we need to revisit that in some way? 9

The workability of having an age range, we said that 10

the AAP and the PHS recommend from age two to six 11

months. What is the workability of this? How much 12

difficulty is this causing in the field in terms of 13

confusion among different groups. 14

I think we thought when we issued the recommendation 15

that it would be workable. My impression is that it is 16

working, not without bumps in the road, but that it is 17

a workable recommendation. 18

One other area has to do with communication, and 19

perhaps we need to look at improving communication with 20

providers and parents about this change. We heard from 21

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a speaker in the audience from Philadelphia about 1

confusion that is being caused, and even some mothers 2

of infants of antigen-positive mothers may not be 3

getting vaccine. That clearly is not a change. There 4

has been no change for antigen-positive mothers, and 5

maybe in the communication arena something needs to be 6

revisited. 7

Vaccine supply issues. Issues have arisen about how to 8

manage the stocks of thimerosal-containing and non- 9

thimerosal-containing vaccines. There are issues about 10

what's in the pipeline and what's going to happen to 11

the stocks of vaccine. This may be an issue that we 12

need to visit that we haven't fully addressed. 13

Another one has to do with the supply of vaccines. We 14

may, in the near future, have greater availability of 15

thimerosal-free vaccines. If that happens, will we 16

want to express any preference for thimerosal-free 17

vaccines as they become available? If they're only 18

available from one or some manufacturers but not 19

others, this has implications for the long-term supply 20

of vaccines. Do we want to address that in any way? 21

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And, fourthly, there are issues around flu vaccination. 1

You've heard there have been no recommendations yet. 2

I think that's in the works and, perhaps, not something 3

that we need to be overly concerned with. That will 4

take place. 5

And finally, there are issues around research and a lot 6

of unmet needs in the information area, and that will 7

be the subject of Dr. Rabinovich's panel following 8

later in the morning. 9

So I hope my presentation does provoke some additional 10

discussion about both the issues that were behind the 11

policy discussions, as well as some of the issues that 12

have arisen in implementation. 13

Thank you very much. 14

(APPLAUSE) 15

In the interest of time, I'm going to ask we not take 17

questions, and then I'll -- but I'm certainly going to 18

ask Roger to join the panel up here at the end, and I'm 19

almost certain that we will have a fair amount of time 20

for discussion and questions at that time. So we'll 21

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ask some of our other -- the other presenters to go 1

next. 2

And the first presentation will be by Dr. Jon Abramson. 3

Dr. Abramson is Professor and Chair of the Department 4

of Pediatrics at Bowman Gray School of Medicine. He is 5

the new -- the brand-new Chair of the Committee on 6

Infectious Diseases of the American Academy of 7

Pediatrics, which, of course, has been out front, if 8

not protagonistic (sic), on this issue. 9

So we're happy to have Jon here. Thanks. 10

I think I have to tell a story. It's actually a joke, 12

but you'll understand the moral at the end. 13

There was a millionaire in Florida who put an ad in the 14

paper and said, "I'll give a million dollars, a yacht, 15

or my daughter's hand in marriage to anybody who can 16

swim one lap in my pool." 17

The next morning there were 50 people out by the pool. 18

Everybody was standing around. The millionaire comes 19

out, thanks them for coming, and then he says, "The 20

only thing I haven't told you is there are 12 21

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alligators in the pool." And everybody's standing 1

around buzzing and saying, you know, "This isn't worth 2

it. It's not worth dying over." 3

All of a sudden there's a splash in the pool, and the 4

alligators converge, and guy dives down, comes up about 5

halfway, the alligators converge, he dives down and 6

comes up. And he's pulling himself out of the pool, 7

the alligator bites him on the leg, and he's lying on 8

the pool bleeding, and the millionaire comes up to him 9

and says, "That's the bravest thing I've ever seen." 10

He said, "I assume you want the million dollars." 11

"No." 12

He says, "I assume you want my yacht." 13

"No." 14

He says, "Then you want my daughter's hand in 15

marriage?" 16

He says, "No, I don't even know your daughter." 17

So he says, "What do you want?" 18

He says, "I want the person who pushed me in the pool." 19

(LAUGHTER) 20

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over to -- taking over -- from sitting on the committee 1

to actually being the Chair. 2

(LAUGHTER) 3

issues. I think there was major areas of agreement. 5

In fact, I think for the Public Health Service and the 6

American Academy of Pediatrics the vast majority of 7

issues were agreed upon. 8

Number one, we all agreed that the risk of not 9

vaccinating children for every one of the 11 diseases 10

that we try to prevent with vaccines far outweighed any 11

potential risk of giving the vaccine containing 12

mercury. 13

Two, that we should eliminate or reduce as quickly as 14

possible the amount of mercury in vaccines. 15

And three, which hasn't really been pointed out this 16

morning, is that we agreed that we should delay the use 17

of the vaccine in the baby who is born at term and not 18

use it at term. And why is that? And the reason is 19

that even if you take a full-term baby who weighs 3 20

kilograms and you take any of the standards, from the 21

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EPA standards to the FDA standards, you are exceeding 1

on that day the amount of mercury that is -- that 2

guidelines recommend you give, by greater than tenfold. 3

And we don't know what the safety margin is. This was 4

pointed out today, and I'm sure it was pointed out 5

yesterday, we don't really know whether it's cumulative 6

dose or what that really matters. So we both -- Both 7

the Public Health Service and the American Academy of 8

Pediatrics agreed that the hepatitis B vaccine should 9

be delayed in a mom who is hepatitis B surface antigen 10

negative. 11

So what were the two areas of divergence? And I must 12

state up front that some of the confusion that has 13

occurred has been because of the areas of divergence. 14

We certainly get letters at the Academy asking us why 15

we diverged, and at some point, we probably need to 16

write an editorial just talking about the whole process 17

that went on. Because one of the issues that I'm going 18

to raise later on is: How do you deal with emergencies 19

when the approval process for recommendations varies 20

substantially between the American Academy of 21

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Pediatrics? How do we go through the process of 1

getting our recommendations approved? We, as a 2

technical committee, the Committee on Infection Disease 3

goes through the process of getting our recommendations 4

approves, versus the ACIP or any part of the Public 5

Health System which has to go through a very different 6

process. 7

So where did we diverge? We diverged a little bit at 8

when should you start the hepatitis B vaccine, and it 9

simply was over a matter of how safe do you want to be. 10

Everything we did with hepatitis B and the hepatitis B 11

surface-antigen-negative mom related to how safe do you 12

want to be, what kind of factor do you want to -- 13

safety factor do you want to add? I don't think 14

there's a right answer to it. I think the issue is the 15

safety issue. 16

And the second is, the Academy did not comment about a 17

hepatitis B surface-antigen-negative mom who is in a 18

high-risk group or the family is in a high-risk group. 19

In other words, someone from Africa, for instance. 20

And the Public Health Service said vaccinate them, 21

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vaccinate them at term. We did not comment on it and 1

we specifically didn't comment on it. There's really 2

two things that go into the equation about that. 3

One is that the risk of horizontal transmission during 4

the first two years of life is very, very small. And 5

we are both, both the Public Health System and the 6

American Academy of Pediatrics, strongly recommending 7

that you finish out your immunization, your three-dose 8

hepatitis B immunization by 18 months of age. 9

But the Public Health Service had data 10

that -- at least when we were making the decisions we were 11

not aware of, that said that if you do not start the 12

vaccination at birth, that the completion of the three- 13

dose series goes down from 96 percent to 81 percent. 14

So if you're talking as the American Academy of 15

Pediatrics does to its pediatricians, and you're saying 16

you can make that individual decision based on your 17

family, what's the chance that they're going to come 18

back versus not come back, versus you're dealing with 19

it from a public health perspective and you know that 20

number, you could understand where the difference comes 21

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from. 1

I do think there are remaining issues, and I think 2

Roger highlighted a number of them very well, but one 3

that I'll want to get back to is, when you have 4

emergent situations -- And remember, this was not the 5

only emergent situation. Rotavirus was happening at 6

the same time. I'm not kidding you when I tell you I 7

hung by phone booths for hours at a time, sitting on a 8

phone in Canada, going around Canada and hanging by the 9

phone, and we're trying to deal with this on as fast as 10

possible basis as we can as we're getting the 11

information. 12

So how do you go through the approval process when the 13

approval process is very different? The ACIP cannot 14

come together as a committee without publishing it in 15

Federal Registry. We need to deal with that because 16

this may not be the last emergency that we have to deal 17

with. 18

What is the mercury exposure from other sources? We 19

still haven't dealt with that. And, I mean, we put the 20

data in. I might as well say it. A six-ounce can of 21

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tuna has 17 micrograms of mercury in it, on average. 1

There's obviously a range to it. What does that mean 2

for a pregnant woman? What does it mean to the fetus? 3

I sit on the ACIP Influenza Working Group, and we 4

discussed the issue, what are we going to do with the 5

pregnant mom? Well, the pregnant mom in the second and 6

third trimester has a substantially higher risk for flu 7

than does a non-pregnant mom. So based on our 8

principles, we would recommend giving the flu vaccine, 9

and that's what the working group is going to advise. 10

Now, that doesn't mean the Public Health Service has to 11

agree to it, but that raises the question of "Is that 12

the right decision?" -- I think so -- but do we need to 13

put other things in the consent form to inform a parent 14

or an expectant mom about that. 15

The education of the public. I will tell you that we 16

received a number of letters from angry pediatricians 17

because they don't use computers and the public -- some 18

of the public does, and the public learned about it 19

before the pediatrician did. 20

And I don't know a way of solving it. We actually put 21

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out something that's called the Peds Com, which takes 1

several days to get out and put out, but it is 2

expensive and it's much better and much faster to do it 3

by computer, and it's much cheaper to do it by 4

computer. Those are all issues that come about when 5

you're dealing with an emergent situation. 6

I personally think that the AAP and the Public Health 7

System worked well together during these two emergent 8

situations, and I've actually learned a lot from the 9

process and enjoyed working with them. 10

That's all. 11

Our next speaker is Peggy Webster, who is Director of 13

the National Coalition on Adult Immunization, and she 14

will give us the perspective of that group. 15

Good morning. I just came to represent the National 17

Coalition for Adult Immunizations this morning and give 18

you a statement of where we stand on these issues of 19

thimerosal in vaccines. What I have here is nothing 20

earth-shattering -- I'll give you that -- but let me 21

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just read to you what we put together here, and I 1

appreciate any comments that you might have afterward. 2

While thimerosal has been used as a preservative in 3

many vaccines for many decades without apparent ill 4

effect, it is nonetheless imperative that science and 5

medicine continually seek safer and more effective 6

medicines and procedures. With this in mind, we must 7

make reasoned progress in the area of vaccines and 8

vaccine research. On the one hand, each of us no doubt 9

feels some level of concern in knowing that a small 10

amount of a mercurial compound is present in the 11

vaccines that we give to children, pregnant women, 12

nursing women, and adults. On the other hand, it is 13

also the case that it is difficult to find any 14

definitive data suggesting that the use of such 15

compounds has resulted in any direct harm to humans. 16

We must also recognize that changing from one 17

preservative to another is not without some level of 18

risk itself, no matter how small, and may lead to other 19

potentially unknown side effects. 20

With this understanding, our organization would like to 21

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emphasize concerns about the use of thimerosal in two 1

settings. 2

First, the Advisory Committee on Immunization Practices 3

has rightly made the national recommendation that women 4

who will be beyond their first trimester of pregnancy 5

during the influenza season receive the influenza 6

vaccination. Those who have medical conditions that 7

increase their risk for complications from influenza 8

should be vaccinated before the beginning of the 9

influenza season regardless of the stage of pregnancy. 10

It is important to note that all of the licensed 11

influenza vaccines in the U.S. do contain thimerosal. 12

There has been no reason to believe that there may be 13

adverse fetal effects associated with using thimerosal- 14

containing vaccinations. The NCAI agrees with the ACIP 15

that more data are needed in this special circumstance. 16

Second, there is a small population of vaccine 17

recipients who have an allergic sensitivity to 18

thimerosal. Even when allergy testing does indicate 19

hypersensitivity to thimerosal, most patients do not 20

develop reactions when given thimerosal-containing 21

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vaccines. If reactions do develop, they almost always 1

manifest as local reactions, but, nonetheless, can 2

discourage both patient and provider from further 3

immunization. 4

In effect, the use of thimerosal-containing vaccines 5

means that a small proportion of the population cannot 6

or will not receive vaccines which protect them against 7

the morbidity and mortality of many otherwise vaccine- 8

preventable diseases. 9

The National Coalition for Adult Immunization is an 10

advocacy group that is committed to decreasing the rate 11

of vaccine-preventable diseases in adolescents and 12

adults, and is therefore in support of the 13

recommendation to continue utilizing vaccines until 14

further guidelines are established. 15

In the meantime, NCAI calls for and supports the 16

following steps: 17

First we support the recommendation from the Public 18

Health Service and FDA that all vaccine manufacturers 19

submit a plan for the elimination of all mercury- 20

containing compounds from human vaccines as soon as 21

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possible. 1

Second, we support and call for further research into 2

the benefits and risks of these compounds in 3

individuals and their potential impact on public 4

health, particularly in regards to the possibility of 5

neurodevelopmental effects on the developing fetus. 6

Third, we support and call for the development of 7

communication materials for health care providers and 8

patients that clearly and fairly articulate the current 9

controversy while maintaining public confidence in the 10

enormous individual and societal benefits of 11

immunization. 12

Finally, we support the Public Health Service and the 13

American Association of Pediatrics call for expedited 14

FDA review of manufacturers' supplements to their 15

product license applications which eliminate or reduce 16

the mercury content of their vaccines. 17

Thank you for the opportunity to participate. 18

Our next speaker will be Dr. Neal Halsey. Neal is 20

representing the Institute for Vaccine Safety at Johns 21

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Hopkins University School of Public Health and Hygiene. 1

I didn't come prepared with a rebuttal for Jon 3

Abramson. I should have thought more about it, but I 4

can't come up with jokes quite that quickly, but I 5

agree entirely with what Jon said. I also agree with 6

almost everything that Roger Bernier presented -- I 7

can't find him in the audience right now -- and we can 8

talk about areas where we do disagree, but I do think 9

that the business of providing guidelines to physicians 10

and parents is unfinished during this transition 11

period. I'm asked to comment on what the perspective 12

is of the Institute for Vaccine Safety during the 13

transition period. 14

Well, the position is fairly simple, and that is that 15

all children should be protected against vaccine- 16

preventable diseases using the safest possible 17

vaccines. Actually, I think that everybody in the room 18

would agree with that. 19

The objective in the transition period is to minimize 20

any potential risks that might be there, but, also, as 21

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many people have stated, to maintain public confidence 1

in vaccines, the agencies, the federal agencies 2

responsible for both vaccine safety and for delivery of 3

vaccines, but also to the physicians who not only are 4

responsible for providing those vaccines, but also for 5

advice and guidance to parents of children who are 6

going to be receiving these vaccines. 7

We do need to pay attention to what's happened in the 8

public in recent years over the increased concern about 9

product safety in general, and I won't spend the time 10

to go through all of these examples, but we do need to 11

be aware that there's been concern about environmental 12

exposures of a variety of types, food contamination, 13

automobile safety, toys, as well as drugs and vaccines. 14

Where these have been handled well, it increases the 15

confidence of the Public Health Service and government 16

in general, but there are several examples of where 17

they have not been handled as well as they could have 18

been, especially in Europe, with loss of public 19

confidence in our government agencies that are 20

responsible for protection of safety, and we don't want 21

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that to happen in this situation or any similar 1

situation. 2

My personal belief is that we should follow the 3

examples of what some of the producers of food, 4

particularly children's food, baby food, in this case, 5

from the representative of Gerber Foods, the CEO of 6

Novartis, the parent company, in removing some 7

chemicals, which, personally, I don't think carry any 8

risk for those children. But their philosophy is that 9

"We want a mother to buy our product and have no 10

concern about this issue." We should adopt similar 11

philosophies with regard to vaccines. 12

I'm going to make seven points, and I will come back to 13

each of these in detail and only mention them at the 14

beginning. 15

First, that I think the mercury content of vaccines 16

should be in the package label. 17

Second, that all children are not created equal with 18

regard to their risk of exposure to mercury. 19

Third, that I think hepatitis B has been unfairly 20

targeted and assumed to be in some situations the only 21

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problem that occurs with regard to thimerosal. 1

I think we need to do better -- a better job of 2

informing both physicians and parents about the 3

uncertainties that we've talked about and the options 4

that are available to them to help deal with the 5

potential or perceived possible risk. Everyone has 6

said, and we fully agree, that there should be an 7

expedited review of products with -- by the FDA with 8

reduced or no thimerosal, and FDA has committed to 9

that. So they don't really need us to tell them that. 10

11

I think manufacturers should look very hard at 12

providing unit dosing of vaccines whenever possible. 13

I think there is a problem at the FDA that does need to 14

be addressed and that we need additional resources and 15

scientists to address vaccine safety. 16

To go back over some of these issues, now, the first is 17

the product labeling. I had to ask myself why someone 18

who -- I felt I knew a fair amount about vaccines over 19

the past 25 years and knew something about 20

environmental exposures, why I didn't put it together. 21

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Why I didn't realize how much mercury was actually in 1

vaccines. And I think it's because the product label 2

indicates a concentration of thimerosal of 1 to 10,000, 3

or a .01 percent. 4

And as Leslie Ball walked us through, you have to go 5

through a two- or three- or four-step calculation, and 6

you have to know the molecular weight of thimerosal to 7

come up with the 25 micrograms for mercury. 8

Since mercury is the biological agent, the biological 9

product that's there, and we have guidelines for the 10

amounts of mercury that people should be exposed to, 11

that should be in the product label. 12

There are many factors that are associated with mercury 13

toxicity, and that's what I mean by not all children 14

are created equal with regard to their susceptibility. 15

Many of these were discussed yesterday, so I won't go 16

back over all of them, but there are differences in 17

terms of the age of exposure, the weight of children, 18

other mercury exposures, differences potentially in 19

metabolism and excretion rates on an individual basis, 20

not for the products. No one has really addressed the 21

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very well the genetic predisposition to increased risk 1

of potential toxicity. 2

We can look most clearly at the weights of children, 3

and I've picked girls here. Boys weigh slightly more 4

than girls, but if we're looking at who may be the 5

highest-risk population, the children who are the 6

smallest, are the three standard deviations below the 7

norm, their birth weight of 1.8 kilos, there's a 8

difference, a more than two-fold difference, in the 9

weights of these children, and if exposure to mercury 10

is a weight-based phenomenon when you get a fixed dose, 11

then that two-fold -- that is an important concern. 12

That two-fold difference persists all the way out to 13

almost six months of age. And we need to realize that 14

it's the smallest children that I think that we have to 15

be preparing our guidelines and decisions as to what we 16

do with them. 17

If we take those weights of children and then apply the 18

fixed doses and look at the worst-case scenario of 19

children who may be getting all thimerosal products, or 20

prior to the most recent change in the recommendations, 21

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it plots out like this. And since sending Dr. Clarkson 1

and Dr. Raub the data on the actual weights, I did 2

adjust so that these children were getting hepatitis B 3

when they weighed two kilograms. 4

We have, through the recent guidelines, addressed this 5

exposure here, but, in fact, the exposure that's 6

occurring at two months of age is several-fold higher 7

than that exposure that's occurring at birth. And, 8

yes, the infant is slightly older and therefore may be 9

somewhat less, if there is a risk per dose delivered at 10

that time, then this is something that I think we still 11

have to be concerned about and decide whether or not 12

anything further with regard to advice needs to be 13

given. 14

I do differ with what Roger said and what I think the 15

Public Health Service has concluded, that we can take 16

the exposures and cumulate them over a year or over a 17

six-month period of time. The evidence available about 18

mercury toxicity doesn't support that. Yes, that's one 19

aspect, the cumulative exposure, but there is the 20

problem of an individual exposure at an individual time 21

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from the acute toxicity data that exists. 1

An exposure with a fixed dose, 62.5 micrograms at two 2

months of age, is different than an exposure at six 3

months of age, or if that was at nine months or twelve 4

months. 5

So I really question the philosophy that it doesn't 6

matter when you got it or if you got a significant 7

portion of that, one-third of it all in one day, that 8

you really can take and look at that exposure over a 9

six-month or a twelve-month period. So that's where I 10

do differ. 11

I do not know that any of the guidelines that have been 12

written by any of the agencies say that it's okay. Can 13

you really get all 200 micrograms in the same day? I 14

don't see that written any place, and I don't hear that 15

from the people who have been responsible for 16

developing those guidelines. 17

Which guidelines should be applied? We've been through 18

this too many times. You've seen this similar slide. 19

The Public Health Service has chosen the ATSDR, which 20

is a little more liberal with regard to the allowable 21

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exposures in the EPA. The WHO is quite similar to the 1

EPA, as we have seen, with regard to those exposures. 2

But over how much time can you take a single exposure 3

and then say it's okay to get this over a day, a week, 4

a month, or a year? We don't know. That's an unknown. 5

The choice of the ATSDR guideline, which is based upon 6

the Seychelle data, made sense at the time that it was 7

done. The process was a good process that they used. 8

But does it mean that we should ignore data that have 9

been generated since then, and especially the follow-up 10

in the Faroes Islands? And does it mean that it isn't 11

going to change? The Faroe Island data were generated 12

when these children were 5.5 years, and they were 13

generated looking mostly at global I.Q. And as we 14

heard from Dr. Lucier, there will be additional follow- 15

up and there will be harmonization of the methods to 16

evaluate these children. So they'll do some of the 17

more domain-specific analyses that were done in the 18

Faroe Islands that revealed those very subtle defects 19

that were picked up. So it's an older age in the Faroe 20

Islands and a more specific analyses that were done. 21

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And equally, or, in fact, far more important, as Dr. 1

Lucier mentioned and as Dr. Clarkson mentioned, there 2

is the intermittent exposure that took place in the 3

Faroe Island where it was coming a lot at one time or 4

at monthly doses. And is that the explanation for 5

finding problems in children at seven years of age that 6

were not detected in the Seychelles at 5.5 years? 7

Nobody knows that, but it certainly is one of the 8

hypotheses that might explain the differences in the 9

exposures and we must take it into account. 10

So I don't think that the Public Health Service means 11

we should ignore all of these data, but we do need to 12

be aware that they're there and take them into account 13

and realize that more data will be forthcoming. And 14

what will happen in two years' time if all of the 15

experts review it and say, you know, we really should 16

be using the Faroe Island data as the exposure, how 17

will we be perceived? 18

And again, these defects that are being detected are 19

very subtle defects, and they're not going to be 20

detected without these very sophisticated testings that 21

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was done. 1

Some interesting observations is that the males are 2

more susceptible than females. I think that's a whole 3

area of research that these groups will potentially 4

look at, and finding. This is the finger-tapping test 5

that was done, cumulative amount, both hands, easier to 6

measure differences than one hand. In other words, 7

again, you won't find these with less sophisticated 8

testing. 9

If we accept or use the ATSDR guidelines and we 10

superimpose those on these exposures and we put the 11

daily, the weekly, or the monthly exposure here, we can 12

see that at two months of age we're giving at a single 13

day more than the total monthly allowable exposure for 14

the ATSDR guidelines. And, in fact, the smallest of 15

infants represented in the green bars are receiving 16

almost three times, almost three months' worth of 17

exposure on a single day. Is that really -- I haven't 18

heard ATSDR say that that's really okay to do. I'm not 19

convinced that it really is. And if we were to apply 20

the EPA guidelines or the WHO more recent guidelines, 21

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they are one-third of this. We're giving eight times 1

the maximum exposure that they would give you for a 2

month. Can you get six or eight months exposure in a 3

single day? I don't think that exposure at two months 4

of age can -- You can't take all of these over six 5

months or a year and average them. 6

We haven't told physicians more precisely what they can 7

do to help reduce that exposure. And if we simply 8

limited it to one thimerosal-containing product that 9

was given at 2, 4, and 6 months of age, it would be 10

DTaP or HIB, then you can reduce this to less than -- 11

you can get less than the total monthly exposure for 12

all but the very smallest of infants. 13

If we actually just gave the hepatitis B vaccine and 14

said not use the other two products, then you can get 15

it down below the weekly exposure for almost all 16

infants. 17

And we do have the option that, in many situations, 18

where you don't have to give any thimerosal. And 19

everybody understands that goal, but it actually is an 20

option that's available today. We really haven't told 21

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everybody that that's something that you can do. 1

We've talked about all of the uncertainties. There are 2

many. And again, there's not time to go through all of 3

them, but we do need to focus on the other mercury 4

exposures and which this exposure is added on top of. 5

We haven't really touched on any of the data on the 6

potential effect on mild subtle things with regard to 7

the immune system. Those data are going to be 8

forthcoming in the next two years from various groups. 9

With regard to other mercury exposures, this comes 10

directly from the EPA report to Congress, the key point 11

is that the majority of the population is getting 12

relatively low-to-moderate exposures. But in this 13

country we have some populations that have very high 14

levels of fish intake on a regular basis. And as we 15

heard yesterday, FDA estimates that about 7 percent of 16

women of childbearing age are already consuming fish 17

enough that it would give them more than their 18

guidelines, .1 microgram per kilogram per day. So any 19

additional exposure we give them from vaccines is on 20

top of that baseline that they have set with a safety 21

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factor included. 1

But they also note in the report that 1 percent are 2

receiving more than .37 micrograms per kilo per day. 3

So there's 1 percent of pregnant women out there who 4

are already getting more than what the ATSDR guideline 5

is. And again, what we give them is added on top of 6

that, and these children are being born with that 7

exposure and some are getting this continued exposure 8

through breast milk. 9

After all of the flurry of activity took place in late 10

June and early July, I did take a vacation, went off to 11

Maine to try to do a little canoeing and a little 12

fishing and having some fun, only to come across these 13

signs that says you can't forget about mercury. And, 14

in fact, for the inland waters in much of the east 15

coast of Maine, you're advised not to eat the fish at 16

all if you're a pregnant woman, a nursing woman, or a 17

child who's less than eight years of age. So there are 18

advisories out there from the health departments 19

indicating "limit your exposure to mercury," but 20

they're not being followed. The general consensus in 21

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the local population is that these are largely ignored 1

by many of the local populations. 2

To change to one of the other topics about thimerosal, 3

it's not the perfect preservative. It doesn't totally 4

solve the problem. There are numerous clusters of 5

cases of group A strep disease and presumably other -- 6

one, I think, of other bacteria that have occurred. So 7

it doesn't solve the problem. 8

I personally believe that the manufacturers need to 9

move more toward unit dosing in this country whenever 10

possible. And not only is the benefit from 11

preservatives being not needed in most situations, but 12

there are the reduced errors due to reconstitution that 13

we heard a bit about earlier today. And again, we 14

don't need to go through all of those. There will be 15

another session this fall on some of those issues. 16

There are drawbacks, and these are major limitations 17

that -- and that's increased space requirements in the 18

refrigerator, but I don't think they're quite as bad as 19

what John Clements was telling us. There are some 20

technologies that can reduce the amount of space that's 21

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going to be required to store unit dosing. There will 1

be increased costs, and I recognize that as a major 2

problem for developing countries, but I think that we 3

do need to help in terms of addressing that issue. We 4

need to look at it from this country. 5

So to maintain public confidence in vaccines and people 6

giving advice about vaccines, I think we should put the 7

mercury content in the label. I think we need to 8

modify the vaccine information statements. That is our 9

primary means of communication with families about any 10

potential or perceived risks. We don't have it in 11

there now. I realize the process is long to put it in, 12

but I think that has to be done as soon as possible. 13

I also think physicians should be given more precise 14

guidelines over maximum allowable exposures at each 15

age. Can we really have recommendations for the 16

highest risk and have physicians looking at fish 17

consumption and other things? The Academy of 18

Pediatrics is developing additional guidelines on 19

reduction of mercury exposure from all sources. Those 20

won't be available for six to nine months. I don't 21

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know what the time will be there, but do we need to 1

have separate guidelines for immunization for those 2

children versus others? In general we have said, no, 3

we can't do that. We must make guidelines for 4

everybody that will be applicable to all of the 5

populations. 6

So my personal belief is that we should do what was 7

done in Europe, that we should give a preference for 8

thimerosal-free vaccines for immunization of infants in 9

this country. 10

The last point I'll make is that we need good science 11

to be used in making these decisions, and that good 12

science has to come from all of our federal agencies. 13

As I looked into what was going on at FDA and research 14

into alternative preservatives, research into other 15

ways to approach this and who is going to be reviewing 16

these applications that were all asking for or 17

demanding rapid review, what is the research budget at 18

CBER? The research budget has been cut in the last 19

five years to one-third of what it was before. Instead 20

of being 20 percent more just to keep up with inflation 21

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in that period of time, it's been cut to one-third. I 1

don't know why. I don't know who's responsible, but I 2

hope somebody goes to Congress and says that this is 3

wrong. 4

Thank you very much. 5

(APPLAUSE) 6

The next presentation will actually be by Dr. Bruce 8

Gellen, who is representing the Infectious Disease 9

Society. 10

Infectious Disease Society because, as many of you 12

know, about a year ago we began a project in 13

conjunction with the Pediatric Infectious Disease 14

Society and now joined by the American Academy of 15

Pediatrics that's really trying to look at this issue 16

in a broader way of trying to gauge what the current 17

level of confidence is in our vaccines and immunization 18

program, and by that, to try to see what we can do to 19

maintain or build the confidence in those programs. 20

So, with that, the area of communication and education 21

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has really been a focal point. 1

Sitting through here for a couple of days, I'm 2

impressed that you can never stop learning the lessons, 3

and I think I'll talk a little bit about those, but one 4

of the important lessons I learned this morning is that 5

if you chair these AAP committees, you can never go on 6

vacation. Poor Jon was strung out at every phone booth 7

that was in Canada and Neal finds signs in the middle 8

of Maine that tells him he needs to go back and do 9

another PowerPoint presentation. 10

And the final lesson I learned is it sounds like CBER 11

needs to invest in Microsoft to try to help some of 12

their budget requirements. 13

But I think that Sam outlined some of the highlights I 14

want to just underscore, and he did that with his last 15

slide, that the handwriting's on the wall. I think 16

that that really tells us that it's our responsibility 17

to see that it's there, to read it, to interpret it, 18

and then to effectively communicate it to all the 19

people who really need that. As has been outlined by 20

several on the previous panel and at various points 21

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throughout this session, that's the public health 1

community, the clinicians, the parents, the media, and 2

to legislators. 3

I think that we've had an interesting opportunity to 4

interact with colleagues from the environmental 5

toxicology world because, as I've been learning the 6

lessons of risk communications, they're the people who 7

have been doing this for a lot longer than we have, and 8

now we have recognized that that's a part of the 9

business that we need to get into. 10

As the face of the disease has gone away, there is 11

increasing concern about the risks, both real and 12

potential and imagined, of the vaccines, and that we 13

need to address those in the same way the environmental 14

risks come up all the time, and I'll bet you can't open 15

any newspaper in this country where there's some 16

headline about something that you may be exposed to 17

that's causing some ill health. 18

So I think that we've learned some lessons. We've 19

learned some lessons about the development and approach 20

to guidelines and how that can guide not only policy 21

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decisions, but should also guide communication about 1

those decisions. 2

And finally, I think, under the category of lessons 3

learned, from the very beginning of this session 4

yesterday, there were questions about whether or not 5

the decisions that have been made are up for grabs or 6

are reversible, depending on what we heard. 7

I think that we all had the subtle hope that a meeting 8

like this that brings together the world experts would 9

give us the answer to guide us, and I think that if you 10

had heard what I've heard, that we don't have 11

absolutely clear answers and the hopes that a meeting 12

like this would be done in a -- would bring together 13

all those people that would provide that kind of 14

guidance wasn't going to happen because uncertainties 15

remain. And while everybody keeps pointing to Gina to 16

tell us what those uncertainties are, we've heard them 17

and a number of people have highlighted them, but I 18

think that we know that that's what this arena of risk 19

communication is about, which is communicating making 20

good decisions in the absence of complete information. 21

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And I think that we also understand that when faced 1

with an issue, not making a decision or ignoring it or 2

delaying it is, in fact, making a decision. 3

And I think finally what we also need to be more 4

transparent and communicative about is the process that 5

we go -- that we undergo when these things come up. 6

Jon highlighted that, and I think that that's really an 7

issue that we really should be discussing: what do you 8

in these emergency situations? And there will be some 9

that will be far more emergent than this, I imagine, in 10

vaccines and other issues, but I do think that that's 11

something that we really need to address, of how you 12

can, when faced with an emergency, deal with that in a 13

responsible fashion and make moves in a way -- make 14

moves and communicate those moves despite uncertain 15

information. 16

So I think that we've learned that there are health 17

risks of mercury-containing compounds. We have the 18

desire, all of us, to reduce those risks from all 19

sources that we can, and that with a limited data, we 20

are going to be forced to make assumptions and 21

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extrapolations, and there may be differences in how 1

people handle each of those, but that we then need to 2

continue to do our best to be as transparent about all 3

the -- about the process, and to let people know that 4

there actually is a process in place that's looking at 5

these things. I think we have heard that from a number 6

of speakers as well, that it's not as though there are 7

not systems in place that recognize this. And I think 8

that, as Jon highlighted, the fact that this went on, 9

essentially concurrent with the issue of rotavirus, 10

highlighted that to all of us. 11

We have had a number of these, as we've discussed in 12

the past, quote, "case studies," and I think that we 13

really need to take a hard look at the case studies 14

that we've been presented to see what lessons we can 15

learn for the next time and how we can go about making 16

good decisions based on the best available science and 17

communicate those decisions though there's still 18

uncertainty. 19

Thank you. 20

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The final presentation will be from the Association for 1

State and Territorial Health Officials. The 2

presentation will be made by Claire Hannon, who is 3

Director of Immunization Policy for that organization. 4

Territorial Health Officials is the association that 6

represents the state health official or the comparative 7

senior executive in each state health department in the 8

territories, just so you know who we are. 9

John Williamson was scheduled to be here today, but 10

unfortunately he couldn't make it. He's from Alabama, 11

and they had a legislative issue, as we all know. 12

ASTHO doesn't have a specific policy at this time on 13

thimerosal, so I just wanted to give you some 14

background, how we reacted, and a sense of what state 15

health officials feel about the issue. 16

Vaccine policies are decided on a state level, and for 17

that reason, ASTHO still maintains clear support for 18

state flexibility. 19

The ASTHO organization works to make sure that states 20

have the best information available, and we provide an 21

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opportunity for health officials to work with partners 1

and each other to build consensus. We did work quickly 2

on the thimerosal issue and gave state health 3

departments to discuss the issues amongst themselves 4

and with CDC. 5

As I said, we don't have existing policy. And amongst 6

all these discussions with the state health officials, 7

we were not able to reach consensus on specific new 8

policies in such a limited amount of time in reaction 9

to thimerosal. 10

So for that reason, states are using the available 11

science, as well as the CDC and AAP recommendations, to 12

formulate their own policy on a state-by-state basis. 13

At this point, my discussions with state health 14

officials I think would indicate that they don't see a 15

serious cause for concern at the current level of 16

thimerosal but believe it is prudent to reduce or 17

eliminate thimerosal, given that new vaccines with 18

varying manufacturing needs can be expected in the 19

future. 20

We are very concerned with maintaining immunization 21

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coverage, protecting infants from disease, and 1

maintaining public trust. And again, we, as the 2

organization of ASTHO, support consensus building based 3

on science, information sharing, communication among 4

states and all the other parties involved. 5

Just to add a little bit of state perspective, I spoke 6

with Dr. Natalie Smith, who is here today from the 7

California State Health Department. She's a member of 8

the Association of Immunization Managers, and they've 9

also been holding discussions over the last two weeks 10

or so about thimerosal and vaccine safety issues. 11

It does appear that states are taking a variety of 12

approaches in the transition to thimerosal-free 13

vaccine, approaches which are sometimes very different. 14

I think both of our associations are eager to hear the 15

most up-to-date information, including reports from 16

this conference, and share those with the states. The 17

states benefit from clear direction and lead time to 18

implement policy changes. 19

Thanks. 20

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I'm going to ask Roger to come down and join the panel, 1

if you would. And at this point in time, I would like 2

to open this up for questions, for comments. I think 3

members of the audience are certainly welcome to offer 4

their own comments or to direct questions directly to 5

individual members of the panel, and we'll start back 6

here. 7

Bud Anthony? Again, when you do speak, please 8

introduce yourselves prior to your question or comment. 9

Bud? 10

Biologics Consulting Group in Alexandria. 12

turn on the mic there. There's probably a switch right 14

below -- probably up above -- keep going. There you 15

go. It may be easier just to speak from your seat if 16

you have a seat with a microphone. 17

Biologics Consulting Group in Alexandria. And although 19

Neal has cautioned that hepatitis B has been singled 20

out, and it's certainly not the only vaccine that we're 21

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concerned about, but it's my greatest concern, and 1

those concerns were heightened yesterday by the 2

presentation from Dr. Mast, so I have a couple of 3

questions. 4

One has to do with the recommendations for deferring 5

the hepatitis B vaccine in hepatitis B surface-antigen- 6

negative mothers, and that is this: Isn't this policy 7

of selective immunization of infants based upon 8

maternal antibody screening, one that we abandoned 9

almost a decade ago because it did not work? 10

I know the new policy is different. In a perfect 11

world, I'd have no disagreement with it, but it seems 12

to me we're going back to something that did not work 13

very well. 14

My second question is, perhaps, more of a moot 15

question, but as I understand -- as I understood 16

Roger's presentation of the AAP position, it is that 17

when a thimerosal-free hepatitis B vaccine is available 18

that it will be given at two months. Why not give it 19

then to newborns? 20

Thank you. 21

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that we have abandoned. I think it's a policy -- for 2

screening pregnant women. I think it's a policy that 3

we have added to. Maybe I'll let Neal -- and, 4

certainly, Neal has been intimately involved with this 5

in the past. Both let Neal and Roger respond. 6

Well, the Academy policy to give the vaccine at birth 8

was based upon a number of issues, and the Academy 9

policy was published in '92, but the Public Health 10

Service was published in '91, and I don't sense from 11

anybody that I've had any contact with that there's any 12

abandonment of that policy. I believe the Joint 13

Statement still has the language in it, although it was 14

modified, that once the thimerosal-free preparations 15

were available, the preferred age will be at birth. 16

The Academy's policy has been that you can initiate it 17

between birth and two months of age, so there was 18

flexibility within the schedule. That's the 19

terminology that was used. But my belief is it makes 20

sense to go back to birth immunization whenever 21

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possible as soon as we have a thimerosal-free, but Jon 1

is really the chair and should respond. 2

picked on hepatitis B. It is the one disease in the 4

hepatitis B surface-antigen-negative mom that the 5

infant is at very low risk for. The infant is at risk 6

for pertussis. The infant is at risk for HIB disease. 7

So that is why we picked on hepatitis B, not for any 8

other reason. And we've stated clearly in numerous 9

places that once we have thimerosal-free vaccines, we 10

will go back to recommendations for giving it at birth. 11

that babies who we all agree need the vaccine will fall 13

through the cracks, and we heard examples of that 14

yesterday. And the selective policy -- I was not privy 15

to the decision, but it's my strong impression that we 16

got away from selective immunization because it did not 17

work. 18

immunizing. I see us as immunizing at just a delayed 20

period of time. The recommendation is still to get 21

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three doses in by 18 months of age. 1

also been impressed -- I think Bruce made the comment 4

of how much out there there is to learn (inaudible) is 5

that there is a big mercury vacuum in your brain and we 6

don't know much about it and (inaudible) learn a lot in 7

a couple of days. And there's obviously a long way to 8

go in terms of understanding what the effects are on 9

the brain and whether this ethylmercury has any effect 10

at all, much less what the effect of methylmercury is. 11

But I'm wondering how this got so quickly translated 12

into a public and private immunization policy. And I 13

read when the Beatles were doing public performance and 14

they actually gave up performing before they broke up, 15

and the reason they gave up performing is because they 16

were having to perform in larger and larger stadiums. 17

And what they found was they couldn't do anything 18

subtle on stage, because if they tried to, no one would 19

see it and no one would understand it. They were 20

performing in 100,000-seat stadiums. 21

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And in a way we are performing in a similar stadium, 1

because we make very fine and sweet vaccine 2

implementation policy here in rooms like this, or much 3

smaller ones, and expect pediatricians and public 4

health people around the country, and we've heard also 5

around the world, to go forward with these utterances 6

and carry it out in a crisp, precise clinical activity. 7

8

Well, that's not what happens. I've learned from my 9

activities in inner city Chicago that there are -- it's 10

like playing the telephone game, that people whisper 11

and people read these recommendations and then come 12

away with vastly different interpretations of them and 13

vastly different concepts of them and, therefore, the 14

translation of this is going to have errors and 15

consequences along the lines of what Dr. Watson talked 16

about here yesterday. 17

In addition to that, John, I don't know if you were 18

here yesterday, but we know from our inner city 19

population in Chicago that if you look at kids that 20

received their first dose of hepatitis B vaccine at 21

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more than three months of age, only 10.6 percent of 1

those kids have finished the three-dose series by 19 2

months. We also know that if you delayed -- whatever 3

that first intervention is doing, if you delay it and 4

take a (inaudible) in receipt of 4, 3, 1 by two years 5

of age. 6

The bottom line of these two kinds of things is the 7

translation of a sudden change of policy interaction 8

and with, in my view, a relatively minimal amount of 9

information that demands this kind of emergency is that 10

we're going to throw a lot of vaccine programs into 11

confusion. 12

It certainly sounds as if mercury is an issue that we 13

all ought to think about. It certainly sounds as if we 14

all ought to be thinking about how to get a mercury- 15

free vaccine. I'm the first one to stand up and want 16

safer vaccines -- I think that's a crucial part of our 17

program -- but I just don't understand why it was so 18

urgent to shift this immunization policy so quickly. 19

It creates a confusion that you're hearing only distant 20

echoes in this room, because a very few of us are out 21

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on the front line doing vaccine implementation. But, 1

nevertheless, I can tell you, it's beginning to sound 2

like a louder and louder noise among the people that I 3

take phone calls from and interact with every day. 4

So I guess that's my comment, and I'd certainly like to 5

hear anybody's response to that. 6

to answer that question, but I'll probably surprise you 9

by trying to tackle it myself. 10

I think what's happened is that -- I've told this to 11

some people -- we've had a paradigm shift in how we 12

think about this preservative. And when I went to 13

leadership classes, I was told paradigm shifts take 14

years. I think we experienced a paradigm shift in 15

days, or maybe weeks at the most. 16

And it has to do with our consciousness being raised 17

about the potential, potential, effects of mercury. 18

Once we had that realization -- And I think in some way 19

there was a new realization for all of us, and some of 20

us came to it for different reasons in different ways. 21

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1

I think Neal likes to talk about how, you know, the 2

concentration and the dilution were not an easy way to 3

realize this, but all of us in some way have had a sort 4

of heightened awareness now, and we can't do business 5

as usual. I mean, 6

that's -- While there's not a lot of evidence about harm, 7

and it's a potential thing, it does become a matter of 8

choice and goal and direction that you want to go into. 9

That's how I would tackle it. 10

Toxic Substances and Disease Registry. For Dr. Halsey, 13

you brought up some very good and very germane points 14

that's consideration -- 15

on. I'm sorry. Let's try this again. 17

from the Agency for Toxic Substances and Disease 19

Registry. 20

You raised some very good points, and I was just 21

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pointing out that those are things that the government 1

health agencies that are involved in this and involved 2

with the analysis for assessment of health effects of 3

mercury have been concerned about and have considered. 4

And I think this afternoon, in the research needs 5

portion of the program, some of those will be 6

addressed. 7

You also raised some questions or asked questions of 8

ATSDR, and real quickly I'd just like to point out 9

three things. 10

One is that in a series of three injections, three 11

vaccinations, the total dose, as I understand it, is 12

62.5 micrograms per child. While that's to the child 13

in the Seychelles study, we looked at the dose that the 14

mothers received every day on the average throughout 15

pregnancy, and that was 78 micrograms per day. Well, 16

that's to the mother, of course, and on a milligram- 17

per-kilogram basis, that's different. But if you take 18

that 78, then that every week they're receiving almost 19

600 micrograms of mercury, and this goes on throughout 20

pregnancy. Not only that, but the methylmercury is -- 21

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all mercury, or most mercury is accumulated in the 1

fetus at higher levels in the fetal circulation than it 2

is in the maternal circulation. 3

So these were infants or neo -- excuse me, not neonates 4

-- fetuses being exposed throughout critical times in 5

their development, and we're not saying one point of 6

development is more important than the other, or 7

whether it's the beginning of (inaudible) migration 8

early in the third week, or whether it's further into 9

cerebella or cerebral organization, but throughout all 10

those critical points of fetal development, they were 11

exposed to mercury, methylmercury, through high levels 12

of maternal ingestion relative to the levels that we're 13

talking. 14

For what it's worth, methylmercury is believed to be 15

absorbed close to 100 percent, 95 to 100 percent, 16

through the gastrointestinal tract. So those 78 17

micrograms a day is actually an absorbed dose. 18

Two other quick things, then I'd be happy to hear your 19

response, sir. 20

In the Seychelles, by and large, the tests were of 21

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global cognitive function. However, the McCarthy 1

scales tests were conducted, and back in November when 2

the workshop was conducted in Raleigh, one of the 3

panels actually examined the data from the McCarthy 4

subscales and they concluded -- And it's in that report 5

that George Lucier said he had available -- that the 6

data from that on a limited -- not limited, they didn't 7

use the term -- but domain-specific effects indicated 8

no domain-specific change in alteration and function as 9

a result of methylmercury. 10

One thing that I think is a misunderstanding, I think 11

there's the impression that EPA used the Iraqi data and 12

that we used the Seychelles data, and that's, in part, 13

correct. We looked at all the data, but from ASTDR's 14

perspective, we actually used the Faroes -- the results 15

of the Faroes study as the basis as the basis of an 16

additional uncertainty factor. So we did look at that 17

and did consider that in our evaluation. 18

That's all I had to say. 19

the key question that the physician and the parent have 21

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to face on the day of immunization. That is, how much 1

of that exposure can they get on a single day? You 2

haven't given us the answer to that. I would hope that 3

your agency goes back and tries to address that 4

question. Would you really accept getting three months 5

worth of exposure at one time? 6

Mahaffey? 10

First of all, while on average the amount of mercury 12

exposure through food is under the EPA .1 microgram per 13

kilogram per day for adult women, it's certainly not an 14

even distribution and, as Dr. Halsey pointed out, there 15

are groups who are far higher with one percent above 16

the ASTDR level. There are also groups within 17

subpopulations who go a great deal higher, and we have 18

some idea of who these subpopulations are. We know 19

that there are people in this country, probably two or 20

three percent, who eat fish just about every day. So 21

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while, on average, yes, it's true, the exposures are 1

lower, they're certainly equal. 2

As far as the safety factors go, our safety factor of 3

ten really is aimed at dealing with person-to-person 4

variability and kinetics and differences in 5

susceptibility to the effects of mercury. We started 6

with a dose of mercury in maternal hair is about 11 7

parts per million, which is really up there in the 8

range that WHO indicates there are questions about with 9

respect to vulnerability of the fetus. So that safety 10

factor of ten is designed to deal with differences in 11

susceptibility and kinetics. 12

Finally, the question -- I understood from the comment 13

that the American Academy of Pediatrics is planning to 14

look more broadly at mercury exposures and I would 15

certainly be interested in a description of what those 16

plans are. 17

what else we're looking at making recommendations 20

about? It's really outside of the Committee on 21

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Infectious Disease. It's a question of should there be 1

other guidelines as far as fish exposure, other sources 2

of mercury exposure. So I'm really not in a position 3

to comment about it. 4

I would like to address for a second just Bob's 5

comment. For at least many of the people on the 6

Committee on Infectious Disease, the crucial deciding 7

factor for us to make a -- to go forth with a 8

recommendation that differed than saying "Leave 9

everything the same" is, at birth, we were giving many- 10

fold higher than recommended by whoever guidelines you 11

want to use. FDA or EPA or ATSDR, it was more than 12

tenfold. And from everything we could hear, it was 13

unclear that there was that kind of safety factor built 14

into the equation. That's the answer from my 15

standpoint. 16

Institute of Environmental Health Sciences and I'll 19

briefly put my hat on as liaison to the Academy 20

Committee on Environmental Health and say we are 21

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writing a new mercury statement. We think, but we 1

haven't been cleared, the intention for the statement 2

is in and we haven't been cleared to write it yet, but 3

we will write a new mercury statement. All that other 4

mercury stuff that isn't infectious diseases is ours, 5

so we will do that. That's the only thing I have to 6

say about that. So we'll do that. 7

Take that hat off, I wrote the sentence about the 8

McCarthy scale stuff. I think it's a little unfair to 9

take that one sentence out of the context. I think 10

that, broadly speaking, if you use the Faroe data as 11

opposed to the Seychelle data, you would come up with a 12

lower number because the Faroe data are positive and 13

the Seychelle data are negative. So we, in that 14

committee -- I was the Chair of the Psychometric 15

Endpoint Committee for that meeting -- were 16

uncomfortable dismissing the Faroe data on the basis of 17

those objections that had been brought about on 18

confounding domain-specific scores and things like 19

that. So I don't want the impression left that we 20

thought that because of some decomposition of the 21

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McCarthy scales, the Seychelle data were somehow 1

preferable. We ended up saying these are both good 2

studies and you have to take both into account when you 3

look at them. 4

Finally, back to -- It's hard to keep more than two 5

things in my mind at once. Finally, back to risk 6

management and something Dr. Gellen said, I think the - 7

- I think the choice back in June was not between the 8

Public Health Service and the Academy of Pediatrics 9

saying something and, perhaps, producing a change that 10

didn't benefit everybody, but, rather, between -- and 11

saying nothing which would have resulted in everything 12

going along just fine. I think at least the perceived 13

idea was that to say nothing and to have the 14

information that the FDA, during the process of 15

implementing the Modernization Act, had uncovered or 16

analyzed or calculated that these numbers were higher 17

than we had expected would have gone out. There would 18

have been inquiries of physicians, of state health 19

officers, of vaccine programs, of everybody, and that 20

would have gone into a void from -- with no statement 21

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from the Public Health Service or the Academy. So it 1

wasn't a question of this could just sort of go along 2

with nobody saying anything. We won't know what the 3

effect of that kind of uncontrolled and unprepared sort 4

of thing would be because it was circumvented by having 5

something in place, however imperfect and done in 6

whatever haste, but I think that the emergency was not 7

a toxicological emergency. It was the fear that the 8

professional people responsible for answering the 9

questions would be unarmed unless something went out 10

from the Academy of Public Health Services. 11

I'm sorry I took so long. 12

who is partly paranoid by now -- Well, actually, it's a 15

clarification. Neal suggested that the European 16

attitude is to switch to thimerosal-containing vaccines 17

immediately, and I'd like really a clarification from 18

Dr. Teeling because it's my understanding, as I read 19

the CPMP statements, that the ideal is to switch to 20

thimerosal-containing vaccines as soon as possible in 21

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terms of working with manufacturers to eliminate the 1

material from the vaccines. I am not aware, and I'd 2

like Dr. Teeling to clarify, that any national or 3

European authorities have instructed physicians to stop 4

using vaccines containing thimerosal. 5

let Dr. Teeling respond? Okay? 7

What I said is I interpret the wording of that 8

statement is that for infants and children there is a 9

preference -- I didn't say stop -- there is a 10

preference for the use of thimerosal. And I have it 11

written in front of me, but, perhaps, Dr. Teeling could 12

deal with that sentence that I was referring to. I 13

didn't say stop and there isn't any order, it's a 14

preference. 15

that we rule our preferring vaccines without it. The 17

issue is, is it an emergency or not? 18

the issue. There is a black button there. 20

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answer my question. There's no problem. 1

I mean, I think what you're referring to is the 2

sentence, "For vaccination in infants and toddler, the 3

CPMP concluded that although there is no evidence of 4

harm caused by the level of exposure from vaccines, it 5

would be prudent to promote the general use of vaccines 6

without thimerosal and other mercurial-containing 7

preservatives, particularly for single-dose vaccines." 8

So I think you're both right and I think the statement 9

that you're talking about is that this should be done 10

within the shortest possible time frame, but in order 11

to achieve this, we must work in cooperation with the 12

WHO and the European Pharmacopeia as vaccine 13

manufacturers, FDA, et cetera. 14

So I think the prudence is to move to that. We are not 15

recommending stopping vaccinations in the meantime. 16

Now, it does state here that vaccinations should 17

continue according to national legislation. And in 18

reply to the second part of your question, this 19

statement went out on the 8th of July. And certainly, 20

my visit to the CPMP at the end of July, I had not been 21

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informed that any national authorities had made a 1

change. However, we did look at -- And I think this is 2

an issue that has been looked at not particularly in an 3

hurry, but is an ongoing issue at the national level, 4

and there is the instance of one particular country, 5

Austria, which had a tick-borne encephalitis, which is 6

a particular type of disease which is very specific to 7

the Austrian population. They use a vaccine for that. 8

And the addition of the tick-borne encephalitis 9

vaccine added an additional burden of thimerosal to 10

their vaccination programs, and I am aware that they 11

have now withdrawn that vaccine and are using a 12

thimerosal-free vaccine which has recently been 13

authorized. 14

So I think it's an ongoing issue in Europe, much more 15

so than it would appear to be here. I think we've been 16

living with this for the last year and a half or so, 17

with this move, and I think we have had communications. 18

Indeed, we have had some vaccines where the companies 19

have already started to put in variations to reduce or 20

eliminate thimerosal from the vaccines. So it's 21

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probably a more ongoing issue. I think this statement 1

is from the 8th of the July and, as to hard facts as a 2

result of that, we haven't had anything else yet. 3

Roger? 5

to give a sense of deliberations of the Public Health 7

Service and the Academy of Pediatrics. 8

One of the big issues, in a situation where you're 9

trying to take something that you believe is safe to 10

make it safer, you are introducing a change, but for 11

the sake of the credibility of the program, there was a 12

big concern about not creating a perception of good 13

vaccines and bad vaccines. And I think that this issue 14

of preference gets into that category, that as we 15

transition, we're trying to avoid the perception that a 16

label of bad vaccine that would be put on a vaccine 17

that contains thimerosal because it was considered to 18

be a safe product. So there was a lot of discussion 19

about this issue. So I think when we talk about 20

preferences, we have to be careful. We all do prefer, 21

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but I don't think it's a preference in the sense that 1

we're willing to call things good vaccines, bad 2

vaccines. Now, that was a very important driver for a 3

lot of the deliberations. 4

have a question. 7

Yesterday, I was very impressed by the rapidity of the 8

CDC surveying the hepatitis B screening practices, et 9

cetera, in the wake of this change. That was really 10

very impressive to have data like that. I wondered, 11

given Dr. Daum's comments and also anecdotal things 12

that I've heard about physicians misinterpreting the 13

recommendations to assume that thimerosal-free vaccines 14

are indeed evil and they don't use them, whether 15

there's any attempt or plan by CDC to look at the 16

effect of these recommendations on immunization timing 17

or the rates of immunization outside of hepatitis B? 18

Yesterday, Dr. Schwartz presented, I think, a pretty 19

persuasive case, that if you delay DTP or HIB or 20

whatever, you can clearly have a potential problem. I 21

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wonder, is the CDC going to be looking at that? 1

Statement -- I believe there were six of them. One of 3

them is to carry out surveillance activities for these 4

changes, and that is something that I think CDC is 5

thinking about. Dr. Mast had told me yesterday about 6

planned investigations to look specifically at 7

hepatitis B issues, but at the moment, there's not a 8

detailed action plan. In fact, we're stretched pretty 9

thin doing a lot of these rotavirus investigations and 10

doing a case-control study related to rotavirus, but it 11

was foreseen in the Joint Statement, that there would 12

be surveillance to monitor the implementation to see if 13

any adjustments needed to be made. 14

Just to follow up on a couple of the comments, I think 17

one of the things that may have occurred, and I guess 18

luckily I was out of the country when all this 19

happened, but if I was here I could speak more from 20

firsthand knowledge, is that there is this spectrum of 21

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what our public health emergencies are, true public 1

health emergencies, epidemics of pneumococcal disease 2

or exposures to toxic or infectious substances, and 3

then there are potential public health threats. I 4

think this very clearly is a potential public health 5

threat that warrants very careful consideration and, 6

because of the kind of consequences people have talked 7

about, very careful consideration of the response. But 8

under the microscope of the media and public concern 9

and all that, what has tended to happen is that whether 10

something is a potential public health threat or a 11

public health emergency, they're all being handled as 12

public health emergencies. I think although I'm 13

hearing that the agencies all work together well under 14

the circumstances, I would second Bruce's comments, 15

that I think, one, I'd think through carefully if there 16

are any ones we can improve our responses to these 17

kinds of issues, not necessarily critiquing the 18

response to this issue in its particulars, but not 19

falling into that particular trap of everything being a 20

crisis and everything being an emergency. That's 21

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really all I wanted to say. 1

moment. 4

(LAUGHTER) 5

epidemic of disease that I think we're beginning to see 7

as a result of the controversy. When I hear John 8

Abramson talk about a 3 kilogram normal infant and say 9

on that day we exceed the guide by tenfold or when I 10

heard Roger Bernier say "I haven't heard anybody say 11

differently," I mean, I understand that the complexity 12

is enormous and I think that that's an underestimate. 13

I also want to make it clear that I am speaking 14

professionally, as an epidemiologist with thirty-plus 15

years now, and though I work for Merck, I'm not 16

speaking for Merck. This has not been cleared. 17

I spent twenty-eight years at CDC, mostly infectious 18

disease, mostly outbreaks, mostly training 19

epidemiologists, but in '96, I became the Chief of 20

Environmental Epidemiology from North Carolina and I 21

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learned a lot of NOELLs and LOELLs and mercury in fish 1

and I was responsible for wording of the signs on the 2

creeks that gave the warnings and was very unhappy with 3

the way we had to interact with the regulators and the 4

sort of emphasis on regulation without the true public 5

health effectiveness of making those warnings heedable 6

(sic). It's all over the east coast. It's not just up 7

in Maine. It's in Maryland, it's in North Carolina, 8

it's all the way down to the Gulf Coast. 9

When a MRL, a minimum risk level, or other guideline is 10

applied here, it's -- I think it's being misapplied and 11

I think it's being misapplied because of the way we 12

label slides and because of the shorthand way we have 13

to speak, but we have no data for ethylmercury. So in 14

addition to what has been said, and I respect the 15

rights and the integrity of everybody that said it, I 16

think it's also legitimate to say that when a MRL, 17

which is for chronic exposure for ingestion or 18

inhalation and for methylmercury, is applied to what we 19

are injecting with vaccines, will we get it all on the 20

same day and we, at the same time, ignore any excretion 21

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or we assume that it is all totally instantly 1

bioavailable, I think that's an abuse of the MRL and I 2

think we need to make slides say those things and say 3

it the right way so that everybody understands that the 4

shorthand doesn't confuse them. 5

That's the concern, and I want to state it clearly 6

because I am concerned about the epidemic of disease 7

that this controversy is causing. That is, delayed 8

vaccinations are not good. 9

speaker. I think there has been a misuse of these MRLs 12

and guidelines. They are, as the speaker pointed out, 13

intended for chronic long-term exposures. So the 14

number you get for long-term exposure is a daily 15

exposure that goes on continuously, six months, a year, 16

and so on. You can't take that number and apply it to 17

a single day, as apparently has happened by the 18

statement that in a single day they'll get ten times 19

what the guidelines says. The guideline is intended 20

for day after day after day exposures. Let me give you 21

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an example. 1

A comment was made about eating six ounces of tuna fish 2

which contains 17 micrograms of mercury. Now, if you 3

take that once, as a pregnant female weighing 60 4

kilograms, the increase in mercury level in blood or 5

tissues would be so small you couldn't measure it. If 6

you took that six ounces day after day for six months 7

to a year, her blood levels would slow rise until they 8

reach the level consistent with these guidelines, about 9

20 parts per day. 10

So there seems to be a tremendous misunderstanding as 11

to what these guidelines mean, and with the benefit of 12

hindsight, we should write a talk on the kinetics of 13

mercury so that we have some understanding of what the 14

meaning of a day dosage in terms of tissue levels 15

versus the meaning of a six-month dose. And this is -- 16

I mean, in this learned audience, it worries me that 17

there's such a misunderstanding of the guidelines. 18

Lord only knows what the general public views these as. 19

(APPLAUSE) 20

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clinician's perspective and from an educator, both for 2

physicians and nursing staff. 3

This event -- And I just want to emphasis the last two 4

speakers; I agree a hundred percent -- has really 5

stressed the front lines, once again, in ways that are 6

hard to imagine until you sit in a clinic with a rapid 7

rate of health care delivery challenges you where there 8

is no adequate recognition of the complexity of 9

immunization health care delivery and you very rapidly 10

have thirty-minute visits that are not being counted or 11

are not paid for in any of our systems, trying to 12

answer questions that this illustrious group can't 13

answer. I think that the whole issue of how we 14

translate what the questions are and the words we use 15

have a huge impact, and I want to take a lesson from 16

the latex allergy issue. 17

We've moved away from saying we need to create latex- 18

free environments because it's unrealistic. We talk 19

about latex-safe environments which acknowledge that 20

there is some latex exposure. 21

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So just the language of saying thimerosal-free does 1

convict in the layperson's mind and most providers who 2

already don't think much of the vaccines. Some of the 3

worst people who don't want to be immunized are 4

physicians and nurses as a group. 5

Why aren't we talking about thimerosal-safe and 6

recognizing that there is a balancing of issues in that 7

arena? If we're going to make edict, then what about 8

information fact sheets for providers and for the 9

public that are readily available and palatable and 10

let's call them "Draft version 1," so that the edicts 11

that come down are translatable and usable in a quick 12

user-friendly fashion. I think we should enhance the 13

funding for the CDC section that helps write in a 14

language that people understand. 15

If AAP, ACIP, et al. -- And it is very hard to teach 16

people about all these organizations and what they do. 17

I'd love you to give me a teaching slide set on it 18

that's user-friendly for our use. Why not use those 19

people as you're working these rapid-response edicts to 20

create those interim or early VIS version 1 so that as 21

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you're evolving these issues, you take the rest of the 1

world with you? When I've been to the Armed Forces 2

Epidemiologic Board, I've said to them, "Do you all 3

care that almost no one knows you exist or what you do 4

and you're twixes never get to anybody who's doing the 5

work?" And that is not just a problem in the military 6

health care system. That is a problem throughout the 7

health care system. Just speaking for, as I say, the 8

nurses and physicians on the front lines, you know, we 9

want to work with you, but it's awfully hard and also 10

challenging. 11

Dr. Klein? 13

we've learned from this experience is that introducing 15

immunization in the nursery is a very positive feature 16

of vaccine utilization and that that lesson should be 17

carried through with hepatitis returning to the nursery 18

at the earliest possible time, but the opportunity to 19

introduce during that period where there is so much 20

positive educational opportunity, I think, is one of 21

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the most important things we've learned in the last 1

couple of days. 2

positive note, I'll ask that we wind things up and 4

certainly thank our speakers, our panel, and all the 5

participants for their comments. It, indeed, has been 6

a terrific morning and we look forward to a terrific 7

afternoon. 8

We will start back again at 1:30 on the dot. 9

(LUNCH RECESS FROM 12:25 P.M. TO 1:34 P.M.) 10

look even further beyond the issues that we discussed 12

earlier this morning and to begin to develop -- to 13

identify, define, and develop the important issues for 14

research regarding preservatives in vaccines and, 15

specifically, thimerosal. The person that we've asked 16

to lead the discussion this afternoon is Dr. Regina 17

Rabinovich from the National Institutes of Health. 18

Regina actually will take over and moderate the rest of 19

the session for this afternoon. Regina? 20

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wish Sam Katz was here so I could thank him for the big 1

buildup, but you know what he was really trying to do 2

was set the stage so that you were trying to both 3

listen to the meeting, as well as begin deriving your 4

own conclusions as to what the next steps were. And 5

you've all come here awake from lunch ready to work 6

because I'm going to attempt to define the landscape as 7

I understand it right now. I am not going to attempt 8

to devise or force consensus because I don't think it's 9

doable. Then I'm going to define some of the questions 10

that remained in my mind as I listened to the 11

presentations of pre-clinical, clinical, and public 12

health and industry perspectives. 13

The panel members will each -- Dr. Clarkson, if you 14

could join us up front, so that as each panel member 15

speaks, they'll be up at the front. The panel members 16

will each -- have been asked to speak for several 17

minutes, no more than five or I will cut it off. I 18

have Bill Egan's watch, good interagency collaboration 19

here, and then the real work starts and all of you have 20

to make sure that we have covered what it is we should 21

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be considering in terms of research priorities, 1

important questions, what's doable, and what's 2

answerable. 3

I chose to spell "thimerosal" the way I finally learned 4

to spell it, which is the U.S. way, and let me -- Okay. 5

This is just a little part of the vaccine R and D 6

component that I happened to have a slide ready for, 7

but it's to remind me to remind us that when we talk 8

about individual vaccines and when we worry about the 9

vaccine schedule that each of the vaccines has gone 10

through an intensive process of evaluation from Phase I 11

through Phase IV where safety is a consideration as the 12

number of subjects goes up and the questions that 13

you're answering, be it immunogenicity, efficacy, or 14

effectiveness, alter. There's, in reality, a huge 15

oversight process to this part of it, and I think it's 16

true for preclinical and what manufacturers need to do 17

with potency and establishment licensure applications, 18

which you guys don't have to follow anymore, that kind 19

of thing. But it includes people overlooking the 20

trials, people looking at ethics, the safety monitoring 21

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boards, and as you go into Phase IV, which is kind of 1

where we are now with the immunization schedule, the 2

post-licensure period -- This is fifty years or sixty 3

years post-licensure -- including the company, the 4

federal agencies, the parents, interests groups, and we 5

all have some interest or another, as well as those 6

people from the National Vaccine Injury Compensation 7

Program. 8

I have to state some principles which I hope, but don't 9

presume, that everyone will agree with. Although some 10

of them are truisms, I think that it's really important 11

to keep those in the context of: What is the next step 12

and what is it important to do? 13

First of all, vaccines are not perfect. Everyone 14

agrees with that, I would hope. Yet, we understand the 15

enormous value of the role of vaccines in preventing 16

disease. That was beautifully stated yesterday. 17

I think what people don't realize unless they've been 18

involved in some process development or evaluation of 19

that process is that GMP, those standards defined by 20

the field of good manufacturing process, are not 21

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perfect. Actually, I've seen some studies where you 1

can quantify the rate at which you will have 2

contamination of a vial given different GMP practices, 3

but that it's not zero. It's a quantifiable risk. At 4

the same time, there are both regulatory and field 5

requirements for a preservative in multi-dose vials. 6

There are some questions that we'll come up and things 7

that I still haven't learned after two days of 8

discussion regarding use of multi-dose vials in the 9

public sector, both domestically and globally. 10

I have learned that the ideal preservative does not 11

exist. I was trying to elucidate the characteristics 12

of an ideal preservative. I've got that list for 13

vaccines and antimicrobials, and I decided I really 14

didn't know enough to do that, but, perhaps, it would 15

be helpful to have someone help us by doing that. But 16

the ideal preservative probably does not exist. 17

I think another principle that you should all 18

acknowledge as we are attempting to come up with the 19

required research agenda is that the data that you have 20

heard and the data that we're having to deal with and 21

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listen to from the environmental community and the 1

infectious disease community are qualitatively 2

different. As you heard in the afternoon yesterday, 3

you're talking vaccine efficacy. You've got relatively 4

clear endpoints. You've got measurable health effects. 5

And when you're talking to the environmental 6

epidemiologists and environmental health people, 7

they're talking a language which makes sense to them 8

and for us, it's like parts per million and it's 9

modeling with uncertainty factors. Yet, to them, and 10

in the field of environmental epidemiology, many of 11

those approaches, although not driven to consensus, 12

have a validity and a validity that we, in the 13

infectious disease community in evaluating the 14

randomized clinical trials, the gold standard, have 15

difficulty attributing them. It's probably just better 16

to acknowledge that you've got two communities talking 17

across each other. 18

Now, there are some principles that I think I've 19

learned from thimerosal, and if I haven't, please feel 20

free to speak up because this is what I learned and it 21

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should be correct. The first is that we have to look 1

at thimerosal in context, and the context is that 2

children do not grow up in a mercury-free bubble. They 3

don't grow up in a mercury-free bubble prenatally and 4

they certainly don't do it postnatally. This is 5

probably my third day-long or -- Well, I don't know if 6

you can group all the conference calls we had in that 7

two-week period into a two-day period, listening to a 8

number of different people talk about thimerosal and 9

realizing that the efforts to decrease mercury exposure 10

in childhood is not something new, that twenty years 11

ago -- I don't remember the date exactly -- there were 12

diaper powders that had mercury in it, in which it 13

wasn't until people recognized that those were deleted 14

from there. So this is not a -- This is not new. We 15

haven't dealt with it in vaccines. 16

I think the principle is that the health goal is to 17

decrease exposure to mercury overall before you get 18

into the issue ethyl versus methyl or inorganic, et 19

cetera. 20

The other principle is that -- Someone asked me on the 21

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way in, they said, "Is this thing about coffee not in 1

the room, is that a regulation or a guideline?" I 2

went, "It's a regulation. They'll throw you out of 3

here." That's a regulation. This is not. This is a 4

guideline. I think that I want -- Where's Roger? I 5

want that slide that shows the gray zone, the white 6

zone, because we got it from whoever presented that at 7

the influenza meeting, and I think that's the best 8

graphic to really present. It doesn't matter, .1 9

versus .3, until you start talking in smallest children 10

and then I'm not sure how it matters, but the .1 versus 11

.3 versus .4 are built into how the non-methyl people 12

think about guidelines and what kind of question 13

they're trying to answer when they create guidelines. 14

The environmental community, having listened to three 15

different sets of them -- Or maybe at least three 16

different sets of them -- are not unified in their 17

assessment of ethylmercury. They may be a lot more in 18

consensus about methylmercury, but they've done that on 19

the basis of detailed review, and I don't think we have 20

the data to look at that. This is the scientific 21

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issues relevant to have effects from exposure to 1

methylmercury. 2

Two-day meeting full of preclinical primate/human 3

epidemiologic -- we haven't done that for ethylmercury 4

and we won't have the data to do it at this point. I 5

think the last thimerosal principle that the vaccine 6

community -- we're faced to deal with is different from 7

what the environmental folks have to deal with. It's 8

what I call the Caesar's wife principle. And some of 9

those things my dad taught me, but you sort of 10

remember, is that not only did Caesar's wife have to be 11

pure, she had to appear pure. This issue of appearance 12

being everything, that we have to not only be doing 13

what we think we're doing, but to appear and to be able 14

to inform and to be open and transparent about it. I 15

think it's something we need to keep in mind as we go 16

on and define the research. 17

So gaps? Now, gaps are in the context of what I 18

thought were the general principles, and they're not 19

necessarily in the most logical sequence. I sort of 20

started pasting together my thoughts over the past day 21

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and a half and the past two hours. Let me just go 1

through them and I promise to distribute them to anyone 2

who wants something a little bit more logical here. 3

None of the mostly methyl exposure epidemiologic 4

studies took into effect -- into measurement of effect, 5

although they have clinical hair samples, et cetera, an 6

understanding of the potential role of immunization of 7

the child of an additional bolus during the time of 8

infancy. This all relates to mercury, in general, and 9

not just necessarily just thimerosal. I'll try to 10

speak with some more relevance specifically to 11

thimerosal on the next slide. 12

The whole issue of the sensitivity of the human in the 13

postnatal period versus the prenatal period, I think 14

there are still a lot of questions unanswered about 15

that. What was clear in the group that evaluated the 16

effects of methylmercury is you have to look not only 17

at the route of exposure and the method of exposure, 18

but with particular relevance to where in the 19

neurocognitive development you think the sensitivity to 20

exposure exists. 21

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There were questions made and I think the pediatric 1

community has learned a lot about lead. We're used to 2

thinking about that substance and how to decrease 3

exposure and how to deal with the parts-per-million 4

issue there. That's something I think we know probably 5

more about. Apparently, from a statement made 6

yesterday, the effect of lead is a continuous variable 7

over time. Is that a relevant sort of framework for 8

thinking about mercury? The issue which we have to 9

acknowledge I think remains unanswered: Is toxicity 10

related to peak or chronic exposure? Because the 11

guidelines are based on chronic oral and the exposure 12

that we're talking about is different. It leads to 13

bolus and peak and intermittent. 14

Now, we spent several conference calls arguing about 15

ethyl/methyl and, you know, I was going, "Is there a 16

difference of carbon group? Is that organic 17

concentrate ethyl/methyl?" A colleague of mine, Dr. 18

DeBosky, said, "Yes, but think about it. It makes a 19

really big difference. You're talking ethyl alcohol 20

versus methyl alcohol." Okay. I will admit that I 21

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don't know. While it may be perfectly reasonable, in 1

an effort to assure that we're doing is the safest 2

possible, to take the data that we have for 3

methylmercury and to extend the conclusions and the 4

considerations to ethylmercury. I don't know. It's -- 5

In thinking of methylmercury in the kinds of settings 6

that are referenced here, the primate data printed on 7

methylmercury exposure which has been associated with 8

motor and sensory changes, alterations in primates, and 9

much less with cognitive effects, led to their 10

conclusion that they needed data on specific domains. 11

Not being 12

a -- What's it called? -- not environmental, but a 13

development specialist, I'm not quite sure what 14

specific domains are. I just know it means more than 15

global assessment of cognitive or any single parameter 16

of development. 17

We need to evaluate potential health impact of prenatal 18

exposure and, if we're going to do that and figure out 19

ways to answer those kinds of questions, it has to be 20

in the context of timing of exposure as it's related to 21

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those critical windows of susceptibility during 1

development. That was recommended by the methyl group 2

and I think the ethyl group, and ethyl considerations 3

need to include that. 4

Now, when I start talking about ethylmercury and 5

especially ethylmercury presented intramuscularly, the 6

question really is, how different is it from 7

methylmercury? The potential differences, and I've 8

heard everything from "mercury is mercury" to "it may 9

be 20 percent less toxic" or "really, you need to use 10

it as the model" to "we don't know." And the 11

differences could relate to the potential health 12

effects and the pharmacokinetics, the biological 13

activity, the clinical endpoints one must worry about, 14

the effect of a route of administration, and the dose 15

schedule. And even something as relatively simple to 16

answer -- And we hope to have data not too long from 17

now, Dr. Clarkson -- is, is it excreted and how in 18

infancy? We can't answer that today and we should be 19

able to do that if we're doing our jobs very shortly 20

from now. 21

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What levels are reached intramuscular -- after 1

intramuscular doses of childhood vaccines? We can't 2

answer that today. And Dr. Clarkson presented what I'm 3

now calling the Clarkson model, and I think it's 4

something that can be tested and it can be tested with 5

some observational data and we hope to hear more about 6

that. 7

The potential health effects have been learned from 8

either high dose or poisonings. And the one that's 9

acknowledged is the sensitization which is an effect 10

regardless of how ethylmercury is presented, but at low 11

doses, how one can correlate what's known at toxic 12

doses to low doses, to me, is unclear and remains a 13

question. 14

The issue of cumulative levels, it's clear that -- I 15

was worried that after listening to all this, I still 16

don't know what's new to vaccines versus background 17

exposure and what is the most appropriate useful, 18

accurate, truthful time frame for evaluating childhood 19

exposure. You know, in statistics, you can take a dose 20

level and divide it to an average daily dose over six 21

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months or over seven months and -- Let's figure out 1

before we start doing the math what the appropriate 2

window is that we're worried about and do it in 3

consultation with the environmental folks who -- and 4

then compare the different strategies to decrease 5

mercury exposure, regardless of source, to that 6

measure. 7

I guess I did ask some questions yesterday trying to 8

understand the impact of some things that we thought we 9

knew, and when statements were made about as to how 10

ethylmercury and methylmercury came apart a little 11

differently, I asked, is this good or bad? Well, it 12

could be good and it could be bad. So the theoretical 13

concerns of nephrotoxicity and neurotoxicity, the brief 14

review of the literature we did showed nephrotoxicity 15

could be more of a concern, but I haven't heard anyone 16

talking about the potential of nephrotoxicity. So 17

these are both theoretical and I think we need more 18

information. 19

At the same time, there are gaps in our knowledge of 20

vaccines and the vaccine field, and that has to do with 21

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alternative preservatives. I'm glad to hear that some 1

of the manufacturers have a lot more information than 2

we appear to have on specific pharmacokinetics of 3

methylmercury for -- What is it? -- 2-phenoxy, 4

whatever. I'm not sure it's published. If it isn't, 5

it should be published and we should evaluate it 6

because we have a sixty-year track record with these 7

vaccines. And before we go around running to replace 8

them with another preservative, I think we have lots of 9

questions to be answered. Do that very carefully. It 10

doesn't mean that the data can't be collected or at 11

least wait to hear from our colleagues in the industry 12

that the feasible goal and that this data, the safety 13

data that we're interested in, can be collected. 14

Although we heard a lot about the cost of eliminating 15

and the lack of feasibility of eliminating multi-dose 16

vials, I didn't hear any data and I think it would be 17

useful to know -- Maybe we heard a little bit from WHO, 18

but for the U.S. -- what is the real cost of 19

eliminating the multi-dose vials and going to single- 20

dose vials and what's the real cost in terms of space 21

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that's needed to maintain the cold chains for these 1

vaccines? I think you need that for decision-making 2

for the U.S. and I think there's other factors 3

globally. In a country where we 4

are -- I have to quote Dr. Orenstein -- paying three million 5

dollars per dose -- per case of wild-type poliomyelitis 6

to provide -- to avert poliomyelitis due to vaccine, we 7

obviously value vaccine safety and we have the 8

resources to support that kind of approach. So if it's 9

an issue of eliminating multi-dose vials, what are the 10

costs? 11

Can there be novel approaches to limiting mercury 12

content? By this, I meant -- The "novel" word is one 13

that we use at NIH when we want to sort of reach in and 14

have people come up with things that we haven't thought 15

of. By "novel," I mean some suggestions made around 16

how to play with formulation and a way to limit 17

thimerosal, but different kinds of delivery vehicles, 18

total delivery vehicles, which may not need it. Dry 19

powders, DNA vaccines, whatever, vovel formulations and 20

approaches to limiting mercury content. Notice that 21

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say "limiting" without presumption of value to that of 1

absolute elimination. 2

I think it is possible to get a little bit more data on 3

when in the first two years of life are infants exposed 4

to hepatitis B, because we keep having to come back and 5

discuss that when it comes to the hepatitis B issues. 6

There will be -- There will be -- This is not a 7

question. There will be an ongoing need to conduct an 8

assessment of the cumulative effect of the immunization 9

schedule. And Bruce talked about lessons learned, and 10

I think a lesson learned is as we add and recommend 11

vaccines that we need to look not only at individual 12

vaccines but at the schedule that we're recommending 13

from every perspective. I'm sure we'll continue to be 14

surprised, but we won't be caught with this one again. 15

Data, people have raised "Who's going to do this?" and 16

"Are you going to talk about it?" So let me ask: Do 17

we have data -- I don't think we do -- on which to 18

comment upon the long-term effects on vaccine-level 19

exposure to ethylmercury? I think the first place to 20

look, and I'd ask those communities that have -- the 21

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scientific communities that have these databases, can 1

some sort of assessment be made from analysis or 2

evaluation of existing data sources? In other fields 3

like the diabetes issue, we were able to provide, I 4

think, useful analysis from an existing database 5

resulting from a randomized clinical trial in a country 6

in which there was a very detailed and validated 7

diabetes registry to answer a specific question. Are 8

there places we could be looking for information 9

pertaining to this or do we need to go look for novel 10

sources and at what point do we need to go? Do we have 11

enough knowledge about what's going on from animal 12

models or fairly simply measurement of levels in 13

children to have a high enough level of concern that we 14

need to worry about bad health effects as opposed to 15

recognizing the levels that are being administered 16

potentially through vaccines? And I think Roger 17

presented the diversity of the vaccine schedules to say 18

we need to limit exposure. 19

There are different presumptions that lead you to 20

different conclusions. 21

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Finally, how to communicate controversial and 1

inconclusive data and at the same time maintain 2

confidence in vaccines. I think we began to hear today 3

what becomes sort of second-guessing what was a very 4

difficult time of a vaccine group trying to understand 5

data that, as you heard over the past two days, was not 6

conclusive, but what was quite worrisome, and to decide 7

when it's compelling enough for some action and at what 8

point and what timing information is distributed. 9

There are lessons learned about systems we need to put 10

in place and how to access our advisory committees 11

rapidly and how to maintain -- Where's Dr. Plotkin? 12

What's the word? -- sang-froid. 13

The charge to the panel -- And I'll ask each speaker to 14

talk for three to five minutes and I have my FDA watch 15

on -- is, number one: 16

What are priorities for research from your perspective? 17

Number two, even if you don't include that in whatever 18

you had thought you were going to present up to now, 19

can you comment on the feasibility and the urgency to 20

do so? 21

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I ask you to do this in the constant context of a 1

comment that George Kirwan would make if he was here 2

and he would say, "You know, the most expensive words 3

in the English language are, I wonder if." So you have 4

to put some value on if the "if" that you're trying to 5

answer is, indeed, important for science, for public 6

health, or public policy. 7

The first speaker will be Dr. Clarkson. I think you 8

just need lights on. Do you need to turn this off? 9

suggestions that the group might want to consider, 11

first of all, is this calculation that I did which I 12

think it -- the calculations like this have to be done 13

to assess risk from ethyl and methylmercury. You have 14

to base them on blood levels because all of these 15

guidelines from these various government agencies and 16

so forth all start with toxic blood levels and minimum 17

toxic blood levels and so forth, and they work from 18

them. So what I've given here, for example, is the 19

blood levels that might develop in an infant given 20

these schedules of vaccines. For example, the first 21

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shot only raises the blood level to about four parts 1

per billion which is actually about the equivalent of 2

the EPA guideline. 3

So I heard this morning a single dose will be ten times 4

or something the EPA guideline. It's certainly not. 5

It might approach about the EPA guidelines, but as you 6

can see, as it builds up with subsequent doses from the 7

vaccines, it does certainly exceed the EPA guideline by 8

a factor of four or five. 9

But all this is based on all kinds of assumptions. One 10

is that methyl is the same ethyl, which it probably 11

isn't. It's based on the assumption that there's no 12

excretion, and as the Chairperson pointed out, that's 13

something that we should definitely check and I 14

promised to do that, be a good boy. 15

We also should validate hair as a marker for exposure 16

to ethylmercury. That would allow us to do some more 17

population studies to see what hair levels are like in 18

infants, but we have to validate it first. I think 19

that can be done with the infants already available. 20

Hair monitors methylmercury and not inorganic. The 21

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hair then could be very useful. It might just monitor 1

the intact ethylmercury in the infant which is probably 2

responsible for the neurological effects, and we'd have 3

to have some other measure for inorganic mercury like a 4

blood sample. 5

As I say, I learned an important thing -- many things 6

from this meeting, but one was that we didn't take into 7

account vaccines in the Seychelles study. I think it's 8

possible now -- Thank you, Dr. Myers -- that it's 9

possible that we may now be able to go back and look at 10

that. We have an enormous amount of behavioral data, 11

clinical data, development data on these kids who are 12

now nine years of age. So we have a huge database. So 13

we might be able to now take a look and see who got 14

vaccines and how much and whether this has an impact on 15

our data, and we might therefore get some -- I hope 16

some useful human data out of this. Of course, this 17

will be a vaccine on top of a substantial dose of 18

methylmercury. So this could be useful, too. When we 19

heard about all other kinds of mercury exposures that 20

kids are exposed to, here you've got a population that 21

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really is getting an exposure, on the average, ten 1

times higher than the U.S. population. If we 2

superimpose vaccines on top of that, if we're going to 3

get any effect, we'll get it in the Seychelles as I 4

mentioned. If we don't get an effect, I think it will 5

be very reassuring for this situation. 6

As far as animal experiments are concerned, I 7

understand that it's really not going to be practical 8

to do a major Seychelles type study in this country 9

with regard to vaccines, but I think that animal 10

experiments are feasible. I mean, one can do a lot of 11

neurobehavioral tests and kidney function tests on 12

animals. There are three or four papers in the 13

literature on ethylmercury, so we've got good 14

guidelines to start with for ranging effects. So I 15

would suggest we could do that or somebody could do 16

that. We'd be happy to make them an offer. I'm in my 17

elements this afternoon. I'm after research money. 18

The other point is that -- especially with regard to 19

this figure here, the salicylic acid may be playing a 20

role here. I've talked to some of my colleagues here 21

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today and yesterday. We don't know how rapidly it may 1

go from the intramuscular side. I've assumed in this 2

figure here that it's a very rapid, almost 3

instantaneous distribution, but it may not be and 4

that's something we could test in animals, too. All 5

our previous animal work has been done with 6

ethylmercury chloride, which is a very lipid soluble 7

commodity that diffuses readily from tissues. It will 8

be interesting to see if the salicylate compound 9

behaves the same way. For example, if you're looking 10

at the transport of methylmercury into the brain, 11

methylmercury-L sistine gets in the brain rapidly. The 12

disomer, the optical isomer, the only difference is the 13

optical activity. The disomer does not go into the 14

brain. So the chemical compound, not just the mercury 15

itself, but the chemical compound when mercury is 16

present may play a very important role in its 17

distribution and kinetics. This may -- If it was a 18

slower release, for example, these peaks may not be as 19

high as they are in this figure. So I think it's worth 20

considering. 21

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So with that, Madam Chairman, I hope I've earned myself 1

a little grant of some sort. I don't know. 2

(LAUGHTER) 3

presentation that you think all of the -- answering all 5

of these are doable? 6

Gerber. 9

times yesterday, as well as today, we can speculate on 11

what the mercury levels may be in infants who've 12

received immunizations with thimerosal-containing 13

vaccines, but as far as the actual data demonstrating 14

what those levels are, there really is very little. In 15

fact, the only data that we have comes from stages of 16

study at the nursery at Emory. We heard yesterday 17

about the limitations of that study, the fact that it 18

hasn't been published except in abstract form, the fact 19

that there are only five term infants and fifteen 20

premature infants, that the fifteen premature infants 21

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had a mean weight of only 750 milligrams, concerns 1

about the methodology of that study. So, needless to 2

say, with that being the only data that we have, we 3

really have very little. 4

As little as we have about the levels, we have even 5

less about the distribution, about the kinetics, about 6

the metabolism, about the excretion of ethylmercury. 7

In fact, we know essentially nothing about those things 8

in ethylmercury. 9

So what we at the NIH are proposing to do, and we're 10

proposing to do this in conjunction with our 11

colleagues, Dr. Ball and Dr. Pratt at the FDA, and 12

we're proposing to do this through our vaccine and 13

treatment evaluation units at Maryland and at 14

Rochester, working with Dr. Clarkson at that same 15

institution. What we're proposing to do is to attempt 16

to obtain this data and we attempt to do this by 17

getting together a cohort, first of all, of premature 18

infants who have been vaccinated with the hepatitis B 19

vaccine sometime within the last week to several 20

months. These would be infants whose mothers were 21

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hepatitis B surface-antigen positive, infants whose 1

mothers hepatitis surface-antigen status was unknown, 2

or infants who were born at hospitals that were not 3

following the current recommendations of withholding 4

the hepatitis B vaccine until a later time and those 5

infants born to hepatitis B surface-antigen negative 6

mothers. 7

And what we've proposed to do after identifying these 8

premature infants is to obtain blood, stool, and urine 9

specimens from them, as well as maternal hair samples. 10

The maternal hair samples would be to get a baseline 11

idea of what the in utero exposure had been. Maybe as 12

a point of clarification, and we can get it from Dr. 13

Clarkson later, I understood you to say that we could 14

not measure inorganic mercury in hair, only organic, 15

but I was unclear as to whether we could distinguish 16

ethyl from methyl and maybe you could address that 17

later. 18

But, in any case, in addition to the premature infants, 19

we would then want to look at a cohort of term infants 20

and look at term infants coming from three different 21

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kinds of pediatric practices, one practice in which the 1

routine immunization had been providing the patients 2

with vaccines that had a relatively high amount of 3

thimerosal. We would want to look at a second group of 4

practices where the cumulative exposure from 5

vaccination of thimerosal would be relatively low, and 6

then, finally, practices or a group of practices where 7

only thimerosal-free vaccines had been used. Again, we 8

would want to look at these infants within one month to 9

several months following the two-month immunization and 10

at that point determine what the exposure, what the 11

combined exposure had been at that two-month visit, as 12

well as all of the possible previous exposure to 13

thimerosal from earlier immunizations, and collect 14

blood, stool, urine from those patients, as well as 15

maternal hair samples if we could. 16

We would also want to look at a similar group of 17

infants from those same three types of pediatric 18

practices after the sixth-month immunization and, 19

again, make a determination of the total thimerosal 20

exposure at that six-month immunization, as well as any 21

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exposure from previous immunizations and again collect 1

blood, stool, urine specimens from those infants, as 2

well as maternal hair samples if we could. 3

Hopefully, with that information, we would be in a 4

position to make some determinations about what the 5

expected mercury levels would be after immunization 6

with thimerosal-containing vaccines, about what the 7

distribution, what the metabolism, what the excretion 8

of ethylmercury in these infants would be. 9

Is this feasible? I think it is feasible. One 10

limitation of the feasibility is trying to do this as 11

soon as possible while children are still receiving 12

thimerosal-containing vaccines. Why is this important? 13

If we're moving towards -- hopefully moving towards a 14

situation where infants in this country would no longer 15

be receiving thimerosal-containing vaccines, I think 16

there are three reasons. First of all, I think the 17

information that would be obtained would be helpful for 18

those parents whose infants have already or will 19

continue to receive thimerosal-containing vaccines. 20

Number two, as we heard from Dr. Clements, although we 21

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may be approaching thimerosal-free vaccines in the near 1

future, for much of the world, this is something that's 2

not going to happen for several years, at least several 3

years, so this information would be important for those 4

populations. Finally, as one of the charges in the 5

Joint Statement from the American Academy of Pediatrics 6

and the Public Health Service, this type of research 7

was one of the things that we had committed ourselves 8

to performing. 9

Thank you. 10

members, she deliberately did not want us to consult. 13

So if some of the same things came up, you would 14

presumably take it as a reinforcement of the kind of 15

things we should be doing. 16

I think speaking -- I work at CDC. I'm part of the 17

National Centers for Infectious Diseases, and as we 18

have listened over the past two days, but also over the 19

last several weeks, to some of the issues that have 20

been brought up around thimerosal, I have been 21

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repeatedly struck by the fact that we really don't know 1

how this compound breaks down. We heard yesterday from 2

Jeffrey Englhardt that there's very little kinetic data 3

on thimerosal, but the one paper that we have seen in 4

squirrel monkeys suggests that a fair proportion of 5

this breaks down not into ethylmercury but breaks down 6

into inorganic mercury. And we've heard the data on 7

methylmercury. We're now hearing a little bit about 8

how we want to do the studies on ethylmercury. I think 9

it's absolutely critical that we know how this compound 10

breaks down, because if what we're looking at is 11

inorganic mercury, we're looking at a different thing 12

again. We've heard very little at all about inorganic 13

mercury. Dr. Clarkson mentioned that if we want to do 14

studies in hair that we cannot use inorganic mercury as 15

a marker. I have learned more about how you do these 16

studies over the last few weeks than I ever wanted to 17

know and I still feel very ignorant about many of these 18

things, but I do see that -- do feel that that is, in 19

terms of both feasibility and urgency, one of the first 20

things we should be doing. It's, certainly in animals, 21

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a fairly straightforward experiment to do. 1

Other speakers have talked about looking at where it's 2

compartmentalized, the issue of giving thimerosal 3

intramuscularly versus orally, which is where most of 4

the data we have on methylmercury comes from, what is 5

the half-life, is it excreted in infants -- I was very 6

surprised to discover that it's thought there is no 7

excretion, but we don't know -- the role of the bolus 8

effect. I'm also delighted to hear that you're going 9

to be going back and looking in the Seychelles at the 10

possibly effects of immunizations. I don't know -- 11

the seafood. 14

But I think that that's a real important study to do, 15

clearly from the Faroe Island studies and the 16

Seychelles Island studies. If there are effects of the 17

mercury from the vaccines, they're going to be subtle. 18

It's going to be very hard to do any kind of study in 19

current populations that are being immunized, 20

especially as we have heard from FDA that the 21

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commitment is to move towards mercury-free vaccines if 1

at all possible. I think that -- I've certainly not 2

heard any argument against that. If we need 3

preservatives in certain cases, if we need to keep 4

thimerosal there for a specific reason, FDA will be 5

willing to discuss that, but, clearly, the move is to 6

move -- get rid of mercury if we can. That comes in 7

the context of the environmental mercury load. I think 8

it's very easy for us to focus on our little issue of 9

vaccines, but that's not where this is coming from. 10

This is coming from the fact that we live in a mercury- 11

contaminated environment and seeing the contribution of 12

vaccines within that context I think is critical. 13

From CDC's perspective, I think it's very important and 14

very urgent that we monitor any changes on immunization 15

practices. The data that Eric Mast presented yesterday 16

I found very disturbing, that in such a short time you 17

can already see an effect of this. We heard from -- I 18

don't know if they're going to address this, but we've 19

heard from the manufacturers over the last few weeks 20

that we could not go to a thimerosal-free schedule 21

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right now without introducing dramatic vaccine 1

shortages, which would totally disrupt the current 2

schedule. 3

So we clearly want to keep our current immunization 4

program in place, we want to reassure people, and we 5

also want to -- in some way, come up with a time line 6

for reducing or removing thimerosal. I think that that 7

is something that CDC can contribute to in terms of 8

doing surveillance on what effect is being had on the 9

schedule itself. 10

I don't want to talk much about the manufacturing 11

issue, but I did hear the issue of combination vaccines 12

raised. I think that -- I mean, there were many other 13

compelling reasons for going towards combination 14

vaccines, but I think that that is something that we 15

should be pushing towards, but if we do need to be 16

keeping preservatives in, then, obviously, that's a way 17

of reducing it. Looking at other ways of reducing the 18

thimerosal load, we heard the idea of reducing the 19

amount of vaccine that's actually given. 20

Lastly, I just want to leave you with the idea that we 21

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really, really need to increase our ability to 1

communicate with our constituents. I think that we can 2

certainly be faulted over -- in terms of being 3

complacent about the efficacy and safety of vaccines, 4

and it's become clear over the last two or three years 5

that the public's concern about vaccine safety has 6

risen. We've seen congressional hearings recently on 7

that issue, and I think the way that we communicate, 8

both with the public and also with providers, is 9

critical in terms of maintaining confidence in our 10

program and in giving them information to give to their 11

constituents in order to reassure them, or not, if 12

that's what we need to be doing as we've seen in the 13

case of the rotavirus issue, which has been going along 14

parallel with that. 15

So I hope that's given a few thoughts from our 16

perspective. Thank you. 17

a half-an-hour to talk, so I'll try to go quickly. 20

I have to first apologize for the fact that I was not 21

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here yesterday. I couldn't make it, so I missed a lot 1

of the detailed discussion. I want to tell you that 2

during the course of the several weeks and also during 3

the course of this morning, when thinking about 4

research in this area, particularly as it relates to 5

thimerosal and what we need to know and what we don't 6

know, I have a little trouble getting past the fact -- 7

getting past what we're going to do with any data at 8

this point that we collect with thimerosal. I think 9

that we have made a judgement -- or a judgement has 10

been made on the basis of a desire to eliminate 11

thimerosal because it makes sense not to inject 12

mercury. And there is not, to my knowledge, a specific 13

outcome besides that that we're trying to avoid. So in 14

designing studies to look at thimerosal, it's hard for 15

me to think specifically about outcomes that I would 16

have any confidence in or that I would think about to 17

counterbalance the decisions that have been made so 18

far. I'm not trying to be flip about this, but I think 19

-- I think we have to be a little careful about 20

thinking that data that we collect on thimerosal, while 21

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I think it will be useful in our understanding of 1

thimerosal and its metabolism, it's not clear to me 2

that it's going to tell us too much about potential 3

rare adverse events that may occur as a result of 4

having thimerosal. 5

Now, having said that, at the end of this morning, I 6

heard Dr. Clarkson, who knows far more about thimerosal 7

and mercury than I do and also is from Rochester like I 8

am, so that raises him a little bit higher on the scale 9

-- Rochester, New York, that is -- it seems clear to me 10

that we, infectious disease vaccinologists, perhaps 11

have no idea how to use these numbers that we're using 12

and using as our guidelines. So if I were to back off 13

what I said at first and think about things that I 14

would like to know, it would be: How do we assess 15

cumulative effect when we talk about vaccination? The 16

only data, I guess, that would be convincing to me 17

would be data that actually measured levels in the 18

blood or in an appropriate bodily fluid that could be 19

related to the potential toxic effects that we're 20

worried about. Those are mostly neurological. You 21

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know, I think we need to, however, then think, what if 1

it's undetectable? Would that change what we're 2

thinking? If it wouldn't, then we have to accept that 3

the outcome of these studies is going to be for our 4

understanding and not going to really help us in terms 5

of future use of thimerosal. 6

So I think we, as manufacturers -- or our company is 7

looking more towards potential new formulations or new 8

preservatives that could be used or towards the 9

elimination of the use of preservatives, and that 10

obviously gets us to single-dose vials. I think it's 11

important for us not to underestimate the practices 12

that was just mentioned in the United States. Multi- 13

dose vials are greatly favored. I mean, the reason we 14

use them in the United States is because that's what 15

the physicians' offices prefer. In Europe, that's not 16

the case. They, in fact, prefer single-dose vials. So 17

that is the market there. 18

So this is not an overnight change from a multi-dose 19

dose presentation to single-dose only because of the 20

capacities that have been developed in our 21

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manufacturing around those needs. 1

In thinking about new preservatives, I think we need to 2

think hard about what outcomes we'd be looking for from 3

a safety perspective when we use new preservatives, and 4

it seems clear to me that tests for toxicity that 5

thimerosal passed are obviously not enough for the next 6

preservative. So we need to think about what outcomes 7

we're specifically looking for. Somebody said this 8

morning, for the unknown, the new preservatives are 9

really the unknown and without experience, and we need 10

to think in our research, when we think about research, 11

what those outcomes would be. 12

Lastly, I just want to comment, Norman Baylor talked 13

this morning about the FDA review process and the 14

desire to expedite review. I need to point out that on 15

those two slides, the list of potential requirements 16

for the presentation for a new preservative or the 17

presentation of any new formulation is potentially not 18

a small task, and if you're talking about doing 19

stability studies in real-time, usually that's a two- 20

year real-time stability study. If you're talking 21

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about doing consistency studies and if you're talking 1

about efficacy trials, you're talking about several 2

years and fairly major programs for the presentation of 3

new preservatives. So all of that needs to be put 4

together before the review process can start, 5

obviously. 6

So I just wanted to tell you that when we think about 7

these changes in formulations, we think about the time 8

lines that are required prior to that submission and 9

those are fairly long time lines from a manufacturing 10

perspective. 11

That's all I've got to say. Thanks. 12

for me. I teach biology classes for six hours on 15

Saturday and I always run out of time before I get the 16

information through. So five minutes is really going 17

to be a challenge. 18

Most of what I have to say, and I'm approaching from a 19

toxicology and human health risk assessment 20

perspective, has already been said, but I just wanted 21

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to put a couple of points of clarification that I don't 1

know -- This may help. This is just from a general 2

introductory biology textbook. I don't know how many 3

people really understand when we're talking about the 4

main specific effects versus global effects. An 5

example of the global effect is IQ. The main specific 6

effects -- This is 1999, so we know a lot more about 7

the brain than we did a hundred years ago and we know 8

that specific areas of the brain are associated with 9

specific cognitive or motor functions. I don't have a 10

pointer here -- Oh, great, thanks. 11

If you can just look, where it says "language 12

structure" on the upper left and go down, we know that 13

certain areas of the brain are associated with that. 14

So specific neuropsychological tests are designed to 15

probe specific cognitive functions and the ultimate 16

intent is to find out if -- even although you may not 17

have been exposed to enough of a substance to have an 18

effect on global function cognitively, there still 19

might be enough effect in a particular area of the 20

brain associated with a certain function. So when they 21

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talk about domain-specific effects versus global 1

effects, that's, in general, the difference between the 2

two. 3

Again, the first one on here is just common sense, but 4

what I did is I tried to break down things that I 5

thought might help from a risk assessment perspective. 6

The first is really more of a common sense thing and 7

it could easily be an in vitro study if it has not 8

already been done. This is just to look at the 9

effectiveness as a preservative of reduced amounts of 10

Thimerosal. Again, that would -- if it has not already 11

been done by the manufacturers, it'd be an easy thing 12

to do. 13

Metabolic and biomarker studies are also important. 14

Again, these have pretty much been covered, but we know 15

that Thimerosal is actually water-soluble. So as a 16

water-soluble substance, it's possible that it could be 17

excreted through the kidneys as Thimerosal. So how 18

rapidly is that bond between the group, the sulfur, and 19

the ethylmercury broken? If it's not broken quickly, 20

then there may not be the level of exposure 21

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theoretically that there would be as if it were quickly 1

broken. 2

Then, of course, we've already discussed the 3

measurement of both ethylmercury and mercuric ion in 4

the feces and urine. Having had three kids, I'm glad 5

I'm not going to be a part of having to dip into that 6

one. 7

Ethylmercury in the hair of the Seychelles Island 8

population -- Well, the Faroe I'm not sure about. Dr. 9

Grandjaun is not here, but Dr. Clarkson has already 10

addressed the ethylmercury in the Seychelles 11

population. So they might look into that. 12

Another thing regards one of the differences in looking 13

at this Thimerosal is not only the fact that it's a 14

bolus, we're talking about most of our knowledge 15

relating to either the unborn or to adults, and I just 16

want to really quickly explain something and then 17

suggest that it might be looked into. 18

In adults, the primary source of excretion of organic 19

mercury -- Primarily methylmercury is what most of the 20

information about -- is through an enterohepatic 21

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circulation. That is that the mercury is absorbed from 1

the gut and it goes up through the circulation into the 2

liver where it's conjugated with glutathion and leaves 3

the liver in the bile salts back down to the 4

gallbladder, through the bowel, and then back into the 5

intestine where it continually gets recycled. So it's 6

not always bowel available. Now, in rodents we know 7

that during the suckling period, which is about twenty- 8

one days in rats, that the glutathion, which is needed 9

to conjugate the mercury, is not produced in sufficient 10

quantities to lead to the circulation. There's been 11

some studies in primates that have shown that in real 12

young primates that that might also be the case. In 13

humans, we really don't know, it may be the case or it 14

may not be, but I think it would be interesting to find 15

out when that enterohepatic circulation is to the 16

extent that glutathion is produced and can conjugate 17

the mercury and actually comes into being. That ties 18

into again with excretion. 19

Longer-term things: A lot of classic toxicology-type 20

studies; neurodevelopmental studies of Thimerosal which 21

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would do dose-response studies and research animals and 1

also look at different ages of animals, particularly 2

after the animal is born and how the early stages of 3

development compares to adulthood; the next one, 4

contribution of Thimerosal from vaccines to total and 5

individual tissue burdens. Kate Mchaffey from EPA and 6

others were stressing the importance of looking at the 7

total body burden of mercury. We're not just being 8

exposed to Thimerosal. We're getting some in our food 9

and some from other sources. ATSDR is involved in a 10

Great Lakes research project that it's been sponsoring 11

for years or co-sponsoring, and we may have some of 12

this data and this may -- we may have the mechanism for 13

getting some of this data. 14

The last thing is the immunologic effects of Thimerosal 15

need to be investigated in laboratory animals as well. 16

I'm sure that's five minutes plus. 17

last of a series of speakers who, for the most part, 20

vigorously agree with each other. It's very hard to 21

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say something that's new and unique. On the other 1

hand, I want to offer some thoughts as the Senior 2

Science Advisor to the Commissioner of the FDA and the 3

Director of the FDA National Center for Toxicological 4

Research. 5

As you might expect within an organization of the 6

nature and size of the FDA, there will be different 7

research agendas on almost everything, and that 8

certainly would be true for ethylmercury as well, but a 9

point I want to make is that I think that because of 10

the nature of the exposures, these converge for 11

something like ethylmercury. 12

If Thimerosal or mercury is taken out of vaccines, I 13

think further work on ethylmercury for the Center for 14

Biologics would not be a very high priority, especially 15

in comparison to the need for data on the replacements 16

for Thimerosal. I think this isn't just a question of 17

a research agenda for ethylmercury, it's an even more 18

important question that if we succeed, then the problem 19

starts of knowing how successful the replacements are. 20

That has got to be a high priority, along with 21

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whatever we need to know about ethylmercury. 1

On the other hand, it isn't very likely that Thimerosal 2

is going to be replaced in vaccines completely in a 3

reasonable length of time. So that is still a need to 4

have data on ethylmercury. Then look at the bigger 5

picture of the FDA in total where the concern is for 6

drugs, cosmetics, foods, as well as vaccines. Then 7

it's a given that we need to have more data on 8

ethylmercury to understand that kind of a complex 9

picture. It must include considerations about 10

additivity of ethylmercury from different sources, but 11

a point that hasn't been made in this meeting so far is 12

the need to consider the additivity between 13

ethylmercury and methylmercury. We treat them as if 14

they're not acting in the same cells, and at some times 15

they are. So I don't think we can look at ethylmercury 16

in isolation without considering methylmercury or other 17

sources of ethylmercury other than vaccines. 18

So one of the high priorities that I think is for us to 19

reduce the uncertainties that surround the idea that 20

methylmercury and ethylmercury are the same. We know 21

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they're not, but that's where we are today and we don't 1

have much data on ethylmercury to really confirm 2

whether it's more or less toxic. We know for the 3

kidney it's probably more, but we all seem to assume 4

that methylmercury is the gold standard for concern and 5

ethylmercury may not be as bad. We don't have enough 6

data to say that with a hundred percent confidence. 7

While there are some priorities that I would say maybe 8

just a little bit differently than some of the 9

preceding speakers, I would agree that the sensitivity 10

of the fetus versus the neonate is very important, and 11

for some of you who have forgotten about the sensitive 12

windows during fetal development, the nervous system 13

develops post-natally. So isn't unreasonable to expect 14

there would be particular windows of sensitivity. So 15

it isn't the matter of averaging the dose over the 16

whole neonatal period, it's what's the week or what's 17

the day or what's the series of hours that represent a 18

particular event in the development of the nervous 19

system when this whole thing might be dangerous. It 20

may be weeks surrounding that when there isn't a major 21

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problem. We don't have that information. 1

The idea of sensitive subpopulations, as I reviewed 2

literature on ethylmercury, it appeared as though there 3

were people who were much more sensitive than others -- 4

This is adults, and I don't know why, but the 5

possibility that that would exist with neonates is not 6

impossible -- the question of peak blood levels versus 7

the blood levels -- I distinguish between a single 8

exposure and chronic, because when you're talking about 9

newborns, that's not chronic. That's what happens 10

right then and the following days over which they're 11

not exposed to a vaccine again. 12

So the real question in my mind is the peak -- the 13

effect of the peak blood level versus the blood level 14

during the distribution and elimination phase of the 15

original exposure to ethylmercury. Then you add to it 16

another exposure beyond that with another vaccination 17

or from food or whatever, but it isn't a matter of 18

chronic versus acute exposure for this neonate. We 19

don't know the impact of the area under the curve 20

during the elimination phase versus the impact on the 21

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cells of nervous system during that peak level. Is it 1

just a difference in the exposure? Is that just the 2

dose response curve? Or is time important? That, 3

again, gets into the windows of sensitivity and we 4

don't have the kind of data to address that. 5

In addition, the intermittent versus the continuous 6

exposure, there are examples where intermittent 7

exposure is important because the rate of delivery to 8

the cells is more important. The rate of delivery, the 9

rate of change within cells, could be more important 10

than the average concentration. That could explain the 11

intermittent versus the continuous response. 12

The valid bar markers of exposure, I think we have to 13

have that. That is obviously of considerable 14

importance. The elimination from the neonate, we're 15

using a conservative estimate when we say it's not 16

being removed by anything other than dilution, but we 17

need to get that information. 18

One that I haven't heard discussed, the fact that we 19

know that ethylmercury is a skin sensitizer when it's 20

put on the skin and now we're injecting this IM at a 21

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time when the immune system is just developing, the 1

functionality of the immune system is just being set at 2

this age. So now we're injecting a sensitizer several 3

times. During that period of time, what's the impact 4

of a sensitizer -- of something that is known to be a 5

skin sensitizer, what is the effect on the functional 6

development of the immune system when you give a 7

chemical of that kind repeatedly IM? 8

Now, regarding the question of feasibility and urgency, 9

the kinds of studies that we're talking about, the 10

pharmacokinetic studies, the distribution, the 11

elimination, all these other things that we can do in 12

rodents, we can do them in primates, so those are 13

feasible. It just takes money and expertise and good 14

work. We don't know need shotty work at this stage by 15

people rushing in and doing something that they don't 16

quite know what they're doing. This is a time when the 17

rest of the data that we make new decisions on have got 18

to be better than the quality of information that is 19

normally available when people on a random basis begin 20

to collect information and, in retrospect, it doesn't 21

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fit into a real good picture when you analyze it. 1

That's true of a lot of chemicals. There need to be 2

some definitive studies now that are done very well. 3

The urgency, from the standpoint of -- Now I'm speaking 4

as a toxicologist. I think anytime there's an 5

avoidable source of exposure to mercury, we need to 6

look at it real hard, but, obviously, there are 7

consequences in many cases of taking steps. I don't 8

think this is an emergency, that mercury is being used 9

in this manner, but if it's an avoidable exposure, we 10

should do something about it. I also recognize that if 11

we do something precipitous, we could create an 12

emergency and that has got to be considered as equally 13

important as the concern over mercury itself. 14

Why mercury represents a priority concern for me as a 15

teratologist and a developmental toxicologist who has 16

been doing this kind of work my whole career is the 17

fact that this can cause irreversible damage to the 18

development of the nervous system. That's why, in my 19

mind, it's different than nephrotoxicity. A reversible 20

damage, whether it's in an adult or a neonate, 21

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whatever, that's different than permanent damage to the 1

function of the nervous system, permanent damage to the 2

function of the immune system. So that's why I think, 3

among the issues that we look at with mercury or with 4

other heavy metals, the fact that you would cause 5

irreversible damage to the nervous system, in 6

particular, is something that makes the kind of 7

priority where we shouldn't sit back and say, well, we 8

got through this one and now we'll pay attention to 9

other priorities. I think we've got to stay on 10

mercury. 11

Thank you. 12

all the panel members to come up to the front table and 14

I'd like to open the floor for discussion, and I see 15

that they're lined up already. So you guys better 16

hurry up. 17

Dr. Klein? 18

remarks, particularly in regard to that graph that you 20

showed, the figure, in terms of a potential first dose 21

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of vaccine that has thimerosal in it given at birth. 1

Now, you indicated that your -- that it would be about 2

4 micrograms with that first dose. I wonder if you 3

could -- If you eliminate that first dose, the rest of 4

the curve presumably would be approximately the same; 5

is that correct? In other words, what benefit do we 6

gain in your model from eliminating that first dose? 7

before, but this basically -- As we said, all of these 9

guidelines that we've talked about today don't start 10

with the dose. Well, some of our Iraqi stuff did, but, 11

basically, when you're making these risk assessments on 12

human health, epidemiologists -- (inaudible) on 13

ethylmercury, you start with a hair level or blood 14

level, let's say a minimum toxic level or some 15

threshold level, some level associated with toxicity. 16

Then an expert committee may or may not apply safety 17

factors. For example, originally, from the Japanese 18

data, there was a blood level of 200 parts per billion. 19

A committee comes along and applies a safety factor of 20

10, so it's now 20 parts per billion in blood. Then 21

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from that point, the committee will go on and figure 1

out -- calculate what is the long-term daily dose that 2

will give you a toxic level of 20. That's how it's 3

done. There's various calculations. 4

The original data is not a dose. It's a blood level or 5

a hair level. And the best way for us to compare a 6

single dose to the chronic dose is to ask blood level 7

results from that single dose or what blood level 8

results from that chronic dose. The example I 9

mentioned this morning with eating six ounces tuna 10

fish, which has something like 17 micrograms of mercury 11

-- Let's say 20. Well, if you consume one can, the 12

effect on your blood level would be so tiny you can't 13

measure it, but if that's taken day after day after day 14

for six months to a year -- It takes about a year to 15

get into a steady state where intake balances excretion 16

-- that blood level will rise measurably to a level of 17

about 20 parts per billion, which is one of the FDA 18

safe limits. 19

So a single dose is a very different situation than a 20

chronic dose in terms of body burden. 21

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Now, in this case, you go to the top, a single dose of 1

12.5 micrograms here at birth, given the bodyweight -- 2

We took a bodyweight of 1.8 kilograms -- and we assume 3

the blood volume was 8.5 percent bodyweight and you 4

assume that 5

5 -- You do all this arithmetic and you will come out with a 6

blood level of about 4 parts per billion, which is 7

about where the equivalent blood level will be for the 8

EPA guidelines. So you get with this one dose to about 9

the EPA guideline. You certainly do not exceed, as I 10

heard this morning, by a factor of 10. Okay? 11

As you continue with these doses over this six-month 12

period, assuming there's no elimination of ethylmercury 13

from the body and assuming ethyl behaves like methyl, 14

you will -- eventually, you will exceed the EPA 15

guideline. At month number 2, you will get up to a 16

level of about 15. By six months, you may get up to a 17

level in the 20s, which then starts to exceed the other 18

guidelines, the FDA guidelines, the ASTDR, and so on. 19

Let's say there is no vaccine given at birth, but the 21

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same series of immunizations is given beginning at two 1

months of age. Does that affect your curve at all? 2

points by about 4 parts per billion. Essentially, what 4

would happen is you would have a line sort of parallel 5

to this, which would start off -- Usually, background 6

levels in blood are less than 1 part per billion 7

depending on how much fish the mother may have 8

consumed. So you would just draw a line more or less 9

parallel to this with 4 parts per billion below it. So 10

you would still get in six months, you know, close to 11

about 20 parts per billion, close to the other 12

guidelines. 13

Orenstein? 15

Walt Orenstein, CDC. 17

It's interesting that I didn't hear anybody talking 18

about looking at outcome kinds of studies in vaccinated 19

children. Roger Bernier presented data from the 20

Vaccine -- one of the institutions in the Vaccine 21

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Safety data link. Kaiser I think had over 30,000 1

children in a distribution at least of different 2

thimerosal intakes, and I presume most of those kids 3

are now between two and four years of age or somewhere 4

along that line. 5

Is there a reason why none of you considered that? Or 6

is it I didn't hear you? Is it too many confounders, 7

too difficult a study to do, or do you think it would 8

be worthwhile trying to look at some outcome in a 9

population such as that? 10

actually involved in the Seychelles or Faroe studies 13

can comment on this, but my impression is that those 14

studies were extremely difficult to do in those 15

limited, very limited populations compared to the 16

United States, and that to attempt to reproduce 17

something like the Seychelles studies or the Faroe 18

studies in this country with all the potential 19

confounders would be -- the expense would probably be 20

prohibitive and it would be extremely difficult to do 21

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properly. 1

based on the Seychelles experience? 3

that we have to take into account in the Seychelles is 5

really quite large anyway, and I imagine it will be 6

much worse here. You can't do a randomized clinical 7

trial, but that would be the ideal scientific way of 8

dealing with it. 9

to consider is, as a couple of the speakers have said, 12

that the cat is out of the bag, the horse out of the 13

barn, and that thimerosal is going to be out of the 14

vaccines. In addition not only to looking at the 15

replacement for thimerosal, which I think is very 16

important, and the gentleman who spoke earlier from 17

SmithKline didn't specify exactly what has been looked 18

at with 2-phenoxyethanol, and I think we need to make 19

sure that our potential concerns with that substance 20

and with other substances are dealt with. 21

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One of the other things that we haven't looked at is 1

what other additives there are in vaccines or adjuvants 2

that are used with vaccines and what the impact of 3

those may be. I think if we're going to learn 4

anything, it is that thimerosal has been in vaccines 5

for a long time and nobody really thought a whole lot 6

about it until all of a sudden it seemed to spring on 7

everyone's consciousness, and there may very well be 8

other things that are parts of the immunization program 9

that are found in vaccines and we need to do, I think, 10

a much better job thinking about what additional 11

research may be done in order to be ready should any 12

concerns arise in the future or to identify any 13

problems before they're identified by the media or 14

people who may misinterpret what those data mean. 15

I think before I spent any money doing further research 16

on thimerosal, I would be inclined to look very 17

carefully and see what money needs to be spent on 18

things that are going to be important to the 19

vaccination program in the U.S. in the future. 20

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to me, that the thimerosal issue or that the concerns 2

about thimerosal were sprung on anybody. I mean, we -- 3

At least on the vaccine manufacturer side, this is an 4

issue we've been dealing with for quite a number of 5

years. And in Europe, we heard this morning, it's been 6

a fairly major issue for a number of years, and we have 7

been moving in the direction that in new vaccines in 8

the future is actually to move away from the use of 9

thimerosal because of -- because of the concerns and 10

the potential unknowns about it. 11

So I think it's unfair to say that this was a surprise, 12

that we, from a manufacturing perspective anyway, 13

didn't know about the issues with thimerosal. I think 14

the surprise was more the reaction to it and the 15

immediacy in the U.S. particularly. 16

So I want to add to that to say that there is generally 17

very great care taken to what is put into vaccines and 18

the potential toxicity of what is put into vaccines. 19

Perhaps, we can see that the most when we think about 20

adjuvants and new technologies for improving immune 21

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responses. That has been a process that we've been 1

working on for probably the last ten years and it is a 2

slow and careful process guided by toxicology and 3

guided by our desire to make sure that we don't 4

introduce anything that's not safe. So, you know, I 5

think we are doing that. 6

A point I would like to just mention, while I agree 9

that we need to look at the future with respect to 10

other potential preservatives, I do think we're looking 11

at a transition period where even -- a very long 12

transition period where thimerosal will continue to be 13

used in a number of vaccines. So I probably share less 14

-- I feel like the balance needs to be looked at on 15

both ends. What are the risk factors and what is the 16

information we need to know to make good scientific 17

decisions and guidance with respect to the use of 18

thimerosal and really understand that so that we can 19

give good instructions and good advice. But as we 20

heard, if we, if ever, go to zero, we need to still 21

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deal with those issues. 1

So my sense is that we need to achieve a balance here. 2

We need to understand more about thimerosal because in 3

the past two days, I think we have recognized there 4

really is a paucity of data and I think some of the 5

points made about looking at the developing nervous 6

system, looking at the developing immune systems and 7

the effects of these agents on that at critical times 8

of development hasn't been -- hasn't been done, and I 9

think that knowledge is very important. 10

So I would -- While I agree with some of the comments 11

that we need to look to the future, I also think 12

there's a lot of science that need to be done in 13

looking at these organomercurials. 14

question and I would have said it anyway, but I think 17

there is a problem of perception. I personally think 18

it's very unlikely that any harm has been done. I 19

don't think anybody believes -- most people don't 20

believe that it has. I really -- I don't think so. 21

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But I think the public perception will be that it might 1

have, and we know from our experiences that we've been 2

dealing with in the past five years with regard to 3

alleged adverse events of a variety of type, that 4

including things that we have learned some of the 5

subtle neurologic defects that may come from the 6

studies in the Faroe Islands, you can bet there will be 7

many parents who believe their child may be affected. 8

And they do need data to address that issue. I believe 9

the data will be likely to be negative, but if we don't 10

have the data, how can we say that it's not negative? 11

This is one situation where there will have been 12

exposure to something that might have done it. It's 13

not the same as some of the other allegations that we 14

have dealt with. 15

So I do believe that there is a need and probably for 16

much more than the study that Walt was talking about, 17

which is a limited number of small -- a relatively 18

small number, even though it's in the tens of thousands 19

of children, to just take a look at some of the simple 20

outcomes, but there probably is a need for a careful 21

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study. I'm not that type of investigator, but the 1

people who do these neurodevelopmental things very 2

carefully need to determine the feasibility. They need 3

to look at all of the other exposures. This is not a 4

simple study. This would be very complicated and I 5

don't look forward to being responsible for those, but 6

I think if we don't have that, we're just going to have 7

the continued public trust erosion that says you don't 8

care or you don't think so. And what's going to happen 9

to the Vaccine Compensation Program? There will be, 10

undoubtedly, applications for that and who knows what's 11

going to be the outcome of those deliberations by the 12

Special Master. 13

So I think there is a need and probably for more than 14

one study based upon the problems that we've seen 15

elsewhere by the interpretation of different studies 16

and in different populations who have a very different 17

baseline rate of exposure to mercury. You can't just 18

pick those populations that are at the low background 19

of other environmental exposure because you're likely - 20

- you're then -- it'll be stated, perhaps correctly, 21

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that you biased it in your favor in saying that there's 1

no effect from those. 2

anybody in terms of need for such a study? 4

of public trust, it's an important question to ask. I 6

feel quite strongly that we have -- there's a lot of 7

data that we need to know just about what happens to 8

the thimerosal before we can even get into those 9

studies. So I think it's something to bear in mind. 10

I was very happy to hear that Dr. Clarkson will be able 11

to look or possibly be able to look at what happens to 12

vaccines in the Seychelle where there is a huge burden 13

of mercury. If that's possible to do in the Faroe 14

Islands, I would want to do it there, too, where you 15

already have the careful outcome measures looked at. I 16

agree it's not the U.S. population, but it would 17

certainly give you a parameter and a range for where 18

you can start to apply that to this population and to 19

get an idea of whether we really need to do them. The 20

biggest problem I have with that is that if we find a 21

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negative, then there will be so many confounders that 1

people will say "Well, you just didn't do the study 2

right." And for the time and expense, I would say that 3

that was -- that's the kind of study that you want to 4

keep in the back of your mind, and Gina talked about 5

looking for populations, databases that may have been 6

collected for other things that we could possibly get 7

that kind of data from that wouldn't involve setting a 8

study de novo. 9

have sort of similar comment maybe since you said 11

exactly what I was going to say. My question is 12

actually for Neal which is that, since you seem to 13

think there is a clear and present sort of danger here 14

that should be taken out immediately, what data would 15

you need personally to be convinced otherwise? 16

is evidence of a clear and present danger. That was 18

not my intent by anything that I have said, but I have 19

participated in writing in the Academy statement and 20

elsewhere that there is no evidence that harm has been 21

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done. There is a clear problem with regard to the 1

potential or the perceived potential for harm, and I 2

believe that the correct steps have been taken by the 3

FDA at this time of requesting within the realm of what 4

they're capable of in the absence of any data of 5

requesting action to determine what can be done and how 6

fast it can done to remove this. 7

So the corrective step from that standpoint has been 8

taken. What I do believe has not been done adequately 9

to date is a showing of the uncertainties that we have 10

at this time and provision of more specific guidance to 11

physicians with regard to what options are available. 12

I mean, the basic principles that I learned a long time 13

ago about dealing with perceived risks is that you do 14

take an action, but you also have to inform people of 15

what additional steps they may take and this is not too 16

different than some other vaccine safety issues that 17

we've dealt with in the past five years. We have DTP 18

whole cell and DTaP, the acellular pertussis. We have 19

given a preference to that vaccine that we think is 20

safer with regard to some side effects. With regard to 21

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inactivated polio vaccine versus oral polio vaccine, we 1

have moved in a fairly rapid process toward the vaccine 2

that seems to be safer, but one of the first steps we 3

did was to inform people that there were two different 4

vaccines and that there are these benefits and risks of 5

each one. We haven't taken that step yet with this 6

process, but I think we have an obligation to 7

physicians and the public to at least talk about the 8

actions that are there. 9

heard part of the process. The web pages have had for 11

a long time the concern about thimerosal and that we're 12

giving children mercury. Those have been up for a long 13

time. My groups have known that vaccines contained 14

mercury. What was new then and sort of gave rise to 15

the urgency was not knowledge that it was mercury or 16

mercury-derivative, but the content, the volume. And I 17

think it was the assessment of the potential highest 18

exposure given the immunization schedule and the 19

products available. 20

You raised questions about communicating uncertainty 21

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and at what point you send that out further. Bruce, 1

you've been dealing with this for a year. Maybe there 2

are other experts here on risk communication. How do 3

you take something which has been out in the community, 4

it's on the web pages, where we have a little bit more 5

information which give rise to concern and which our 6

vaccine information statements already contain 7

everything from hypersensitivity to death on every 8

single statement -- how do you more appropriately 9

answer concerns? Can you comment upon that? 10

question, they should be speaking and not me. 12

But I will say that one of the things that we've heard, 13

and I think that while this session is designed to sort 14

of sketch out a potential research agenda which people 15

can go back and figure out what's feasible and not, 16

what's fundable and not -- One of the things that we 17

heard at the hearing and that we hear repeatedly and I 18

think Neal echoed in some of his comments just a minute 19

ago was the sense that you need to actually demonstrate 20

that you're taking these concerns seriously and doing 21

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something about them. I think the fact that we have 1

recommendations for vaccines and people have a 2

perception that they've been harmed in some way and 3

nobody cares about harm is really a big part of the 4

problem. So I think that as these various studies get 5

sketched out, I think we all need to know what they 6

are. So that when someone -- when people ask us, they 7

say, "Well, what are you doing about it?" that we can 8

be very clear about all that's going about it. There's 9

a lot going on already. We've highlighted a number of 10

things that are deficit, but I think we also have to be 11

clear that all of this is going on because, though this 12

is the information age, we'll never have complete 13

information. We're always going to live in some sort 14

of uncertainty and I'm sure that nobody would have ever 15

dreamt that this would have been the issue of the day 16

and now we see all the gaps in this. So I think as we 17

begin to move along, there will be other things like 18

that and we always recognize that there are more things 19

to fill in, and I think what we're doing about those is 20

something that we have to communicate quite vigorously. 21

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am -- we're talking about perceptions, perceptions of 3

danger and so on, I must say that I'm reminded of Alice 4

in Wonderland. Now, I don't happen to remember the 5

exact story, but at one stage I think Alice is talking 6

about a situation and she says, "Well, we'll have a 7

trial and then we'll have a sentence." And the Red 8

Queen says, "No, first the sentence and then the 9

trial." 10

So, you know, it strikes me that a perception has 11

certainly been created through the change in the 12

vaccine schedule and so on and that there is a real 13

problem. Now, after these two days, I must say that 14

I'm actually less sure that there is a problem while I 15

was when this meeting started. I do have to repeat my 16

comment that I think this meeting should have been held 17

sometime ago before the announcements. 18

I'd like to thank the panel and turn it back to Dr. 20

Marty Myers. 21

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just a little bit ago and asked me if I would take over 2

at this point and ask Dr. Klein, our rapateur, to give 3

us a summary. We're a little bit ahead, though we seem 4

to be at that point. Dr. Klein? 5

afternoon's discussion. I think it was the best 7

summary of this meeting. It included almost everything 8

that I had noted. So I will touch on only a few 9

points. 10

One, the goals of the meeting were to inform and have 11

dialogue among experts from different disciplines, and 12

I think we've achieved that very successfully. 13

Certainly, for those of us whose knowledge of ethyl, 14

methyl, or other forms of mercury was limited or none, 15

we've learned a lot. I think we'll all be able to find 16

the Seychelles and Faroe Islands on the map and be able 17

to discuss them with authority. 18

(LAUGHTER) 19

will be published in MMWR. We'll have to call on some 21

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of you to clarify and make sure that we don't write 1

something that is either unintelligible or incorrect. 2

So we'll be calling on you for your help. 3

I think we've learned that preservatives are critical 4

in the preparation of vaccines and there will be 5

preservatives, even if they are different from the ones 6

that are currently used, but they are important during 7

the manufacturer process, during administration, and 8

particularly during multi-dose vial usage. Even there, 9

the concerns that the multi-dose vials be used as 10

instructed on the label and that they have a relative 11

limited period of time for their usage and the 12

contamination may overwhelm the preservative if those 13

instructions are not followed. 14

In relationship to the manufacturer processing, I was 15

particularly impressed with Dr. Clements' discussion 16

and presentation that there are a lot of manufacturers 17

in countries with different standards and that perhaps 18

some of the data that will come from these areas of 19

research will be universally available for local 20

manufacturers and perhaps give them an additional 21

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safeguard. 1

The regulation issues, I raise a question of timing in 2

the sense that any new product or change in formulation 3

is substantial in terms of new studies that will be 4

needed and this is a process that will be gradual and 5

take place over a period of years. Dr. Clements gave 6

the timetable. Dr. Paradiso added to that, but, 7

certainly, in terms of finding the preservative, the 8

clinical trials for the products containing that 9

preservative, the regulatory issues in terms of 10

approval and, subsequently, reformulation, we're 11

probably talking about a minimum of five years before 12

new preservative preparations are on the market. And 13

that may be, give or take, two or three years. 14

In terms of thimerosal, by either spelling, it works 15

and has worked for these many years and one can at 16

least have some confidence that disasters have not 17

occurred to our knowledge from such usage, but the 18

toxicity data are limited. And what has been presented 19

to us by our colleagues in toxicology is that the data 20

on methylmercury has been used in the assessment of 21

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risks associated with ethylmercury and the toxicity 1

profile of the two compounds should be considered to be 2

similar so that, even though it may be a stretch that 3

ethyl and methyl are similar, the absence of 4

information dictates what we need to use the data about 5

methyl at least is a starting point and surrogate for 6

our discussions. 7

In terms of thimerosal, again, that it's not the amount 8

of the preservative in each vaccine, but it's now with 9

the burst of new product and the cumulative amount of 10

mercury that is present that has raised the concern. 11

I think most important is the words "eliminate/reduce" 12

and that the perception should be, particularly keeping 13

in mind the timetable of years, that our goal is to 14

achieve elimination but first reduction and that those 15

terms always be used in a paired fashion and that the 16

gradual changes, rather than precipitous changes, is a 17

reality. 18

Finally, we talked a lot about delivering the message 19

and I think that's an increasing part of our decision- 20

making, and at anytime we do come to a change in 21

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current policy, we need to anticipate the reception of 1

that change among caretakers, physicians, health care 2

workers, parents, consumer advocates, legislators, 3

manufacturers, and particularly, I think, our role as a 4

leader in these discussions throughout the world. 5

So every action will have a reaction. I think a lot of 6

the discussion yesterday about the action that was 7

taken in changing the schedule of the hepatitis B 8

vaccine from birth bears on that, making sure that that 9

message and the reason for the change is delivered to 10

those who are actually responsible for the change, the 11

hospitals in altering their policies are cognizant of 12

the reasons for the changes, that the clinics 13

understand that any gaps that would be created -- I 14

think Bob Down's data and the CDC data that suggest 15

that that first immunization in the nursery is very 16

important in subsequent vaccine utilization by selected 17

families leads us to believe that delivering the 18

message and the caretaker's delivering the message to 19

the parents becomes a very critical part in decision- 20

making. 21

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I think Gina said it very well, that the generic issue 1

is to become more capable, more skilled in how to 2

communicate controversial and inconclusive data so that 3

we maintain confidence of our public. And as long as - 4

- the time that I've been on the Red Book and 5

subsequently, this has been and will be a continued 6

challenge, and I think we need all the help we can get 7

in making sure that our decisions not only are 8

appropriate scientifically, but they are communicated 9

to the public in a manner that the constituency 10

understands the reasons for the change and is accepting 11

of those changes. 12

I'd like to congratulate Dr. Myers and staff for 13

putting together a meeting that I find to have been one 14

of the most informative and interesting programs that 15

I've attended in a long time. So thank you very much, 16

Marty. 17

(APPLAUSE) 18

(CONCLUSION OF WORKSHOP AT APPROXIMATELY 3:14 P.M.) 19

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C E R T I F I C A T E

G E O R G I A )

FULTON COUNTY )

I, Pamela T. Lennard, being a Certified Court Reporter

in and for the State of Georgia, do hereby certify that the

foregoing, consisting of pages 1 through 238 (DAY TWO -

VOLUME I) inclusive, was reduced to typewriting by me

personally or under my supervision and is a true, complete,

and correct transcript of the aforesaid proceedings reported

by me.

I further certify that I am not related to, employed

by, or attorney or counsel for any parties, attorneys, or

counsel involved herein; nor am I financially interested in

this matter.

WITNESS MY HAND AND OFFICIAL SEAL, this 5th day of

September, 1999.

_____________________________

Pamela T. Lennard, CCR-CVR

CCR No. B-1797

[SEAL]