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