1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ETHICS SUBCOMMITTEE OF THE

PEDIATRIC ADVISORY COMMITTEE

Friday, September 10, 2004

8:35 a.m.

Double Tree Hotel

Regency Room

1750 Rockville Pike

Rockville, Maryland

PARTICIPANTS

Robert M. Nelson, M.D., Ph.D., Chair

Jan N. Johannessen, Ph.D., Executive Secretary

P. Joan Chesney, M.D.

Norman Fost, M.D., M.P.H.

Richard L. Gorman, M.D.

Laurence L. Greenhill, M.D.

Ruth Hughes, Ph.D., CPRP

Janis E. Jacobs, Ph.D.

Eric Kodish, M.D.

Mary Faith Marshall, Ph.D.

Diane Treat, Patient-Family Representative

Tonya Jo Hanson White, M.D.

FDA

Julia Gorey, J.D.

Dianne Murphy, M.D.

Sara Goldkind, M.D., M.A.

Bernard Schwetz, D.V.M., Ph.D.

C O N T E N T S

PAGE

Call to Order, Introductions

Robert M. Nelson, M.D., Ph.D. 4

Meeting Statement:

Jan N. Johannessen, Ph.D. 6

Subpart D Expert Panel Process

Sara Goldkind, M.D., M.A. 9

Bernard Schwetz, D.V.M., Ph.D. 13

Overview, Charge to Panel and Final Outcome

Robert M. Nelson, M.D., Ph.D. 18

Background on ADHD/Protocol Overview

Judith L. Rapoport, M.D. 34

Questions and Panel Discussion 46

Summary of Submitted Public Comments

Robert M. Nelson, M.D., Ph.D. 119

Open Public Hearing

Vera Sharav 126

Alan Milstein 131

Questions and Panel Discussion 139

P R O C E E D I N G S

Call to Order, Introductions

DR. NELSON: Good morning. We still have

a couple of people that we waiting for, but I

thought we could start with our introductions and

get the meeting going.

Bern, do you want to start with the

introductions?

DR. SCHWETZ: I will start and introduce

myself. Thank you, Skip.

Good morning to all of you. I am Bernard

Schwetz, the Director of the Office for Human

Research Protections in HHS.

DR. GOLDKIND: I am Sara Goldkind, the

bioethicist at the FDA in the Office of Pediatric

Therapeutics.

DR. MURPHY: I am Dianne Murphy. I am the

Director for the Office of Pediatric Therapeutics,

and I wanted to tell you how delighted I am that we

are having this combined meeting and look forward

very much to your deliberations.

MS. GOREY: Julia Gorey, Office for Human

Research Protections.

DR. JOHANNESSEN: Jan Johannessen. I am

the Executive Secretary for this meeting.

DR. NELSON: Robert Nelson. I am chairing

the meeting, and I am from Children's Hospital of

Philadelphia.

DR. CHESNEY: My name is Joan Chesney. I

am in Infectious Disease, and I am a Professor

Pediatrics at the University of Tennessee in

Memphis and also direct the Academic Programs

Office at St. Jude Children's Research Hospital.

DR. MARSHALL: I am Mary Faith Marshall.

I am a bioethicist at the University of Kansas

Medical Center.

DR. FOST: Norm Fost, pediatrician at the

University of Wisconsin, Director of the Bioethics

Program and Chair of the IRB.

DR. GORMAN: Rich Gorman, pediatrician in

private practice in Ellicott City, Maryland, and

Chair of the Committee on Drugs for the American

Academy of Pediatrics.

DR. KODISH: My name is Rick Kodish. I am

a Professor of Pediatrics and Bioethics at Case

Western Reserve University in Cleveland, Ohio.

DR. JACOBS: I am Jan Jacobs. I am a

developmental psychologist and professor at Penn

State University.

DR. GREENHILL: Larry Greenhill. I am

child psychiatrist and professor at New York State

Psychiatric Institute, Columbia University.

DR. WHITE: Tonya White. I am a child and

adolescent psychiatrist and a pediatrician at the

University of Minnesota.

MS. TREAT: I am Diane Treat. I am a

Patient and Family Representative.

DR. NELSON: Thank you.

We will have a reading of the Meeting

Statement.

Meeting Statement

DR. JOHANNESSEN: Thank you and good

morning.

The following announcement addresses the

issue of conflict of interest with regard to the

study drug dextroamphetamine and competing products

used for the treatment of ADHD, and is made part of

the record to preclude even the appearance of such

at this meeting.

Based on the submitted agenda for the

meeting and all financial interests reported by the

committee participants, it has been determined that

all interests in firms regulated by the Food and

Drug Administration present no potential for an

appearance of conflict of interest at this meeting

with the following exceptions:

In according with 18 U.S.C. 208(b)(3),

full waivers have been granted to the following

participants: Dr. Patrician Joan Chesney for

ownership of stock in a company with a product at

issue valued between $25,001 and $50,000 and for

her spouse's honoraria for speaking on unrelated

topics at a firm with a product at issue valued at

less than $5,000, and Dr. Laurence Greenhill for

his consulting with companies with products at

issue between $10,001 an $50,000.

A copy of the waiver statements may be

obtained by submitting a written request to the

Agency's Freedom of Information Office, Room 12A-30

of the Parklawn Building.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement and their

exclusion will be noted for the record.

We would also like to note that Dr.

Richard Gorman is participating as a Pediatric

Health Organization Representative acting on behalf

of the American Academy of Pediatrics.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose product they may wish to comment on.

Thank you.

DR. NELSON: Thank you. Let me introduce

our first speaker, Sara Goldkind, who is a

bioethicist with the Office of Pediatric

Therapeutics at the FDA.

Subpart D Expert Panel Process

Sara Goldkind, M.D., M.A.

DR. GOLDKIND: As. Dr. Murphy said, we are

extremely excited to be a part of this landmark

time in pediatric research and look forward to the

deliberations of this committee.

[Slide.]

As you all know, this is the inaugural

meeting of the Pediatric Ethics Subcommittee, which

is a subcommittee of the Pediatric Advisory

Committee, which will meet for the first time next

week.

The Pediatric Ethics Subcommittee is going

to address, as it will do today, the Subpart D

referrals and also, in the future, we look forward

to it addressing ethical issues that impact on

research affecting the pediatric population.

Today is the first open meeting with OHRP

regarding a joint referral under 45 CFR 46 and 21

CFR 50.54.

[Slide.]

The FDA involvement with Subpart D

regulations began in the 1990s when the Advisory

Committee at that time made a recommendation on

November 15, 1999, that Subpart D be adopted.

The recommendation was endorsed by the

American Academy of Pediatrics and by PhARMA.

[Slide.]

The Children's Health Act of 2000 mandated

that HHS funded, supported, or regulated research

comply with these additional protections for

children.

[Slide.]

Finally, in April of 2001, the FDA adopted

Subpart D regulations which are identical to the

Subpart D regulations found in 45 CFR 46, which is

considered the common rule for HHS.

[Slide.]

The Pediatric Advisory Committee is

endorsed by the Best Pharmaceuticals for Children

Act in 2001 and the Pediatric Research Equity Act

in 2003.

[Slide.]

Now, I am going to talk about Subpart D

referrals specifically, and those come to us under

45 CFR 46.407 and 21 CFR 50.54. That Subpart D

regulation is entitled, "The Additional Safeguards

for Children in Pediatric Research," and it states

that if an IRB does not believe it can approve the

research under one of the first three categories of

Subpart D, the clinical investigational research

may proceed on if: "The IRB finds that the

research presents a reasonable opportunity to

further the understanding, prevention, or

alleviation of a serious problem affecting the

health or welfare of children," and "The Secretary

and/or Commissioner of the FDA, and the Secretary

of DHHS, after consultation with a panel of

experts, such as yourselves, in pertinent

disciplines, science, medicine, education, ethics,

and law, and following an opportunity for public

review and comment determines either that the

clinical investment in fact satisfies one of the

first three categories of Subpart D, or the

following three conditions are met:

1. The clinical investigation research

presents a reasonable opportunity to further the

understanding, prevention, or alleviation of a

serious problem affecting the health or welfare of

children.

2. The clinical investigation will be

conducted in accordance with sound ethical

principles.

3. Adequate provisions are made for

soliciting assent and parental permission.

[Slide.]

So, the possible recommendations open to

the Pediatric Ethics Subcommittee that it can make

to the Pediatric Advisory Committee are the

following:

It can recommend allowing the protocol to

proceed because it satisfies on of the first three

categories of Subpart D.

It can recommend allowing the protocol to

proceed, with modifications, because those

modifications would then allow the protocol to be

approved under one of the first three categories of

Subpart D.

It can recommend allowing the protocol to

proceed because it satisfies the three conditions

that I just previously outlines under 46.407 or

50.54.

Or it can recommend that the protocol not

be allowed to proceed, providing specific reasons

for its rejection.

[Slide.]

The goals under Subpart D that we feel

that this process is trying to meet are:

transparency, opportunity for public input,

opportunity to make the determinations and

recommendations in an efficient and timely manner,

with clarify and consistency, the opportunity for

expert input, and additionally, harmonization with

OHRP, so that we have a unified, comprehensive,

federal process.

Of course the overarching goal of this is

to advance pediatric research in an ethically sound

manner.

Now, I will turn the podium over to Dr.

Schwetz.

Bernard Schwetz, D.V.M., Ph.D.

DR. SCHWETZ: Thank you, Sara.

I just wanted to take a couple of minutes

to comment again about the joint nature of this

review, because normally, there would be a

subcommittee that would be reviewing a question

that dealt with the FDA, and the outcome of that

deliberation by the expert panel would go to the

Commissioner of the FDA, or there would be a panel

of experts addressing a question about a protocol

because it was HHS funded or conducted, and it was

at the 407 level of discussion, and the question

doesn't involve an FDA-regulated product, but it

does involve an HHS-funded study, then, that panel

would make a recommendation that OHRP would carry

to the Commissioner.

When there is a situation where it is an

FDA-regulated product, and it is an HHS-funded

study, then, we end up in the situation where we

have a joint review, and we did not want to create

a situation where we had two separate expert panels

review of the protocol, not only because of the

redundancy involved, but the possibility that two

different groups of people would see the protocol

differently, and we would have conflicting reviews

of one protocol. So, that is why we have the joint

review.

[Slide.]

I just want to assure you that the HHS and

the FDA regulations regarding the protocol reviewed

through .51, 2, and 3, and 404, 5, and 6 are

comparable, so that you needn't worry today about

whether or not the discussion takes into account

one set of regulations for the FDA versus a problem

with the HHS regulations. They are comparable.

The difference comes after the Advisory

Committee makes its decision, and what I want to

lay out for you next is what happens in the case of

the outcome of a joint review as opposed as what I

have already described for the review of either an

HHS protocol or an FDA protocol.

[Slide.]

So, after today's meeting, Dr. Nelson will

make a presentation to the meeting of the full

Advisory Committee on September 15th, and in that

meeting, he will summarize the discussion today,

and he will summarize your recommendations, because

as a subcommittee, you can't bring this to

completion yourself.

As an Advisory Committee, they have the

responsibility for making the final decision, so

your outcome will be recommended to the full

Advisory Committee, and presumably, they will

either accept your recommendation or come back to

you with some questions or some recommendations for

you to consider. It is unlikely they would reject

your recommendation, but they could come back and

ask for further clarification of something. But

that would be up to Dr. Nelson to handle, but