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

whatever that recommendation is, then, the

recommendation of the full Advisory Committee will

go to the Commissioner of the FDA, and assuming

that the Commissioner of the FDA then recommends to

go forward with this protocol, with this study,

then, the process is half done.

At that point, we would take the message,

or OHRP would take the message to the Secretary's

Office that we have had the expert panel review, we

have had public input, the FDA Commissioner has

made the determination, whatever it is, to go

forward or to not go forward, so then we would

carry that message to the Secretary's Office for

final decision on funding of the study.

So, if, in fact, at that point, the

process has included a recommendation for some

revision to the protocol, we would also negotiate

that revision to the protocol with the PI and with

the sponsor, but when that would be taken care of,

then, the decision of the Secretary's Office would

be either to fund the study or not.

So, if, in fact, the decision from the FDA

Commissioner is to not allow this study, to not

support this study, then, we would simply carry

that message to the Secretary, but it would not be

revisited of whether or not the study would be

funded.

The Secretary's decision would carry the

day, but if, in fact, the Commissioner says to do

the study, then, the Secretary's Office does have

the opportunity to take into account all the

considerations and decide whether or not this study

should be funded.

So, then, that would be the end of the

line when the Secretary advises NIH that the study

should be funded or not.

That is the process, Skip. I will turn it

back to you.

DR. NELSON: Thank you, Sara, and thank

you, Bern.

Overview, Charge to Panel, and Final Outcome

DR. NELSON: On the assumption that we

were not going to assume that everyone in the

audience, although I hope everyone on the panel,

but not everyone in the audience is familiar with

Subpart D, and that we would run through a little

bit of what an analysis of a research protocol

involving children would look like, and I will

basically be following the algorithms that you

should have in the handout of this particular

presentation, and you can either look at the small

print, page 1, or the large print to page 1,

depending on your age and refraction of your

glasses.

In effect, this is an unusual occurrence

although depending on your state and whether your

have sunshine laws, we are pretty much carrying out

an IRB meeting in public, which is an auspicious

event, and here is a copy of the overall protocol,

at least in terms of Section 1 and Section 3, and

what we will basically be starting with is looking

at the fact that you need to place pediatric

research in the context of Subpart A, which is the

common rule to start with, so I will give some

initial orienting remarks about that.

[Slide.]

Then, we will look at Subpart D

specifically and the specific protections there,

and then return back to Subpart A and look at

issues surrounding assent and permission, and just

take you through the algorithm.

As you will see, the questions the

committee will need to address reflect the issues

that those regulatory criteria bring.

[Slide.]

So, the general criteria of Subpart A, in

other words, the common rule, basically say that

risks to subjects are minimized by using procedures

which are consistent with sound research design, do

not expose subjects to unnecessary risk, are

performed for diagnostic or treatment purposes, and

then selection of subjects is equitable, and then

there is an evaluation of risks and benefits with

respect to the research.

[Slide.]

Now, what makes pediatrics a little bit

different is in Subpart A, the common rule, in

terms of all subjects, you will notice that the

risks are reasonable in relationship to anticipated

benefits, if any, to subjects and the importance of

the knowledge that may reasonably be expected to

result.

Now, logically, if you look at that, you

can have risk balanced by knowledge, whereas, in

pediatrics, there is a limit to the risks that we

can expose children to for the purpose of

generating knowledge, and that is where we end up

with the specific additional safeguards for

children that fall into two main categories.

The first is the restrictions on allowable

risk exposure for research not offering the

prospect of direct benefit, which are found in

either minimal risk or minor increase, and we will

go into that, but the second is the notion that the

justification for risk exposure, if there is

benefit, would be constrained, as well, by the

language in Subpart D.

So, I am going to run through briefly how

that would look with this particular algorithm.

[Slide.]

The first step, assessing the level of

risk presented by each research intervention or

procedure, and deciding whether it is either

minimal risk, and then approving it, disapproving

it, or considering it under 406, 407, or 50.54,

which is this panel, or that it is more than

minimal risk.

[Slide.]

Now, the definition of minimal risk has

been a point of discussion in the ethics

literature. The current definition of minimal risk

is it means the probability and magnitude of harm

or discomfort anticipate in the research are not

greater in and of themselves than those ordinarily

encountered in daily life or during the performance

of routine physical or psychological examinations

or tests. I would anticipate that we would have

some discussion around this particular definition.

What I have added is something that is not

in the regulations, which has been recommended by a

number of different commissions and reports, is

that minimum risk should be understood in terms of

the normal, average, healthy children living in

safe environments. That language happens to be

taken in the Institute of Medicine report on

research involving children that came out in March

of this year. So, that may be a point of

discussion.

After you have made that determination to

sort of move down in this algorithm, once you

determine that it is more than minimal risk, you

then have to evaluate whether or not there is

direct benefit from that particular intervention or

procedure, and that would move you in two different

directions.

If you did feel that there was a prospect

of direct benefit, you then have to ask about the

justification for that risk exposure. The risk

should be justified by anticipated benefit and the

relationship of anticipated benefit to risk needs

to be favorable as available alternatives. We are

likely not going to engage in this particular

conversation today given the nature of the

protocol, but this would be the one route that you

would move down, and then if you decide there is no

prospect of direct benefit, you would then move

further down the algorithm to then evaluate the

level of risk.

[Slide.]

You end up then deciding is it a minor

increase over minimal risk or is it more than a

minor increase over minimal risk, and then asking

two different questions with respect to that.

[Slide.]

Now, here is the minor increase over

minimal risk. The series of questions that need to

be examined is, first, are the experiences

reasonably commensurate, Yes or No.

If the answer is No, you either disapprove

it or it may fall into 407 or 50.54 review.

Does it provide an opportunity to

understand or ameliorate the child's disorder or

condition? Again, Yes or No takes you in a

particular direction. If the answer is Yes, then,

you have to ask the question will there be, in

fact, generalizable knowledge of vital importance

achieved through that.

If at the end of the day, you think it

falls through here, you can end up approving it or

disapproving it.

One of the reasons this says disapprove

here instead of possibly going to 407 or 50.54, is

as Sara and I were talking, the language is

different, but it is hard to understand how we

might interpret reasonable opportunity under 407 or

50.54, if, in fact, is it not of vital importance.

The language is different, but that is an editorial

interpretation. If anyone wants to discuss that

interpretation, we certainly could in the course of

our discussion.

[Slide.]

But then you get back to the 407 or 50.54,

which basically then says if there is greater than

a minor increase over minimum risk, we need to

understand that it is a reasonable opportunity to

understand, prevent, or alleviate a serious problem

affecting children's health or welfare, and then

conduct it in accord with sound ethical principles.

Based on the judgment there, you can either then

consider it for possible approval under 407 or

50.54, or, in fact, if it doesn't meet those

criteria, recommend it for disapproval.

[Slide.]

Now, once you have done that, we should

then turn back to the issue of parental permission

and child assent. All four categories simply have

the language that there need to be adequate

provisions for child assent and parental

permission.

It doesn't provide any particular advice

about what that adequate provision might be, but

that is something that we would need to discuss.

Now, permission of one parent is

sufficient, if consistent with State law, for

research under 404 or 50.51, 405 or 50.52.

For research approved under either the

minor increase over minimal risk, which is 50.53 or

46.406, the permission of both parents is necessary

unless, of course, one parent is deceased, unknown,

incompetent, or not reasonably available, or when

only one parent, in fact, has legal responsibility

for the child, again consistent with State law.

So, that would be true of both the 406

category and the 407 category of 50.54. So, then,

that needs to be considered by the IRB.

[Slide.]

In terms of child assent, this again is

the regulatory language. Adequate provisions for

soliciting assent when, in the judgment of the IRB,

children are capable of providing assent, and the

advice about that capability to the IRB is that

they need to account for the age, maturity, and

psychological state of either some or all of the

children. So, an IRB could make a determination

for all of the children in that particular project

or they can basically make a sort of case-by-case

or sort of classy-by-class depending upon the range

of ages.

Now, assent is not a necessary condition

for proceeding with the research if the IRB

determines that the capability of some or all of

the children is so limited that they cannot

reasonably be consulted, or if the intervention or

procedure involved in the research holds out a

prospect of direct benefit important to that child

where we would, in fact, think it is appropriate

for a parent's permission alone to suffice for

enrolling that child in the research.

[Slide.]

Again, some of the general criteria of

Subpart A that need to be satisfied, adequate

provisions for monitoring the data collected to

ensure the safety of the subjects, and then, where

appropriate, adequate provisions to protect subject

privacy and to maintain data confidentiality.

[Slide.]

So, that basically takes us through sort

of an analysis of a protocol, and what I am going

to recommend to the panel is that we consider, as

we go through this, to make sure that we have

touched on all of those particular issues, and if

we have, I would hope that we have covered pretty

much everything that is important in the discussion

of this particular protocol, and perhaps some other

things, as well, but we should at least make sure

we cover all of those basis, because otherwise we

are not being I think true to what the regulations

would require us to do.

But the overall charge is to provide

advice and recommendations to the Pediatric

Advisory Committee on FDA's and certain HHS

regulatory issues. As Bern went through, as a

subcommittee, we actually don't have the regulatory

authority to advise the Commissioner and the

Secretary, but we will then, through the Pediatric

Advisory Committee, have that recommendation.

I certainly hope our discussion here is

sufficient and exhaustive enough and clear enough

that it will be readily apparent to the Advisory

Committee that they should agree with what we

decide, but they certainly have the authority to

think differently about that.

Now, the outcome is we should develop

recommendations whether the protocol should proceed

and specifically address whether and how, so there

may be things that we would recommend need to be

adjusted for the research to it either does satisfy

us as currently written, or, in fact, could satisfy

if we had some additional conditions, either the

categories that are approvable by local IRB under

minimal risk, minor increase over minimal risk, or

prospect of direct benefit.

If not, however, we could then look to

whether or not the research could or does meet the

following conditions: that it is a reasonable

opportunity to understand, prevent, or alleviate a

serious problem affecting the health or welfare of

children; that it can be conducted in accord with

sound ethical principles, and I think one challenge

for us will be to try to articulate what we believe

those sound ethical principles are that would, in

fact, justify it if we come to the conclusion that

it should go forward under that category; and then

adequate provisions for soliciting the assent of

children and permission of their parents and

guardians.

So, at the end of the day, I hope we have

a very clear set of recommendations, concrete,

straightforward. There shouldn't be any

interpretation on my part about what that is. You

should leave this room feeling that, in fact, what

I am going to say Wednesday morning reflects

exactly what you want me to say. So, that will be

the goal.

With that, I think we are actually moving

along quite expeditiously, and we can move on to

Dr. Rapoport if there is no questions by the panel.

Norm.

DR. FOST: I just wanted to make a

comment. That suggested modification of the

definition of minimal risk, I think is welcome and

desirable, but there is another element of the

definition that is widely disputed, that I think we

might want to get to today, and those of you who

are involved in advising, you might want to think

to think about.

That is, the phrase "routine physical

examination or test," there is wide variability in

IRBs in whether they interpret that as a routine

visit to a general pediatrician for a health

supervision visit or to a nephrologist who routine

does kidney biopsies in people who come into his

office.

In fact, IRBs have approved

non-therapeutic kidney biopsies, small bowel

biopsies on the grounds that the nephrologist

investigator says this is what happens on a routine

visit.

I was at the meetings of the National

Commission when this was discussed, and there was

no question that what was intended was a routine

visit to a pediatrician for a health supervision

visit, but in a drafting error, as commonly occurs,

that didn't get in there.

I think that is what was intended. I

think it would be helpful if there is agreement on

that, for that to be incorporated in the

definition, and if it comes up today, it would be

helpful if we agreed on that.

DR. NELSON: Okay. Mary Faith.

DR. MARSHALL: I just want to ask you to

clarify our understanding of the criteria under 407

and 50.54, a serious problem affecting the health

or welfare of children, that we would interpret

that to mean all children.

DR. NELSON: I guess I am a little

reluctant to provide my interpretation of language

that has no interpretation or guidance provided on

how to interpret it.

DR. MARSHALL: That may come up in the

discussion today.

DR. NELSON: As it comes up through the

discussion, I think we should talk about how that

impacts on our decisionmaking, if it does, and if

it does, I mean I think cases are the best way to

try and specify principles. I really don't have any

sage advice on how to interpret that.

In terms of Norm's comment, I think he is

right on target, but another interesting question

is how to interpret this notion of daily life, so

that other half of the equation has also been

subject to a fair amount of discussion, and I think

may impact on our assessment.

DR. FOST: But doesn't your added phrase

take care of that? I mean it clarifies it by

referring to some normal environments.

DR. NELSON: It helps clarify that, in

fact, that phrase, but at this point, you know,

that has not been formally adopted in any kind of

official guidance other than commissions and

reports.

Dr. Rapoport. Just to give us an

approach, I mean we will start off with the

investigator, then, have some comments. I don't

know if Don has organized remarks or is available

for questions. Dr. Rapoport says she can be here

for a while with us, but won't be here the whole

day, so I am hoping the panel can be able to get

whatever questions they feel are important to ask

kind of out of the table at the start of the day.

Thank you.

Background on ADHD/Protocol Overview

Judith L. Rapoport, M.D.

DR. RAPOPORT: Thank you, Dr. Nelson, and

members of the committee. I appreciate the chance

to present this. As far as slides go, I think they

reflect both slides that were prepared by Dr.

Rosenstein, as well as myself, so I think the

slides, as you will see, will reflect both IRB and

my own statements, and I will add some background.

[Slide.]

My own work has involved several different

disorders with children, but I have been at NIH for

more than 20 years, and a large part of our work

has had to do with the effect of stimulants, not

just stimulants used therapeutically in ADHD, but

the effect of dietary substances that are

substances, particularly caffeine on behavior.

Children at least in the Washington area

drink a lot of Cokes, as well as an amazing amount

of iced tea, and as a result, we do have extensive

notion of what an ordinary child would experience

by way of exposure to 50 to 100 milligrams of

caffeine in terms of what you would expect in an

ordinary day.

[Slide.]

This was a protocol to study a single dose

of dextroamphetamine in ADHD. ADHD is a very

controversial, but extremely widespread condition.

It is probably the single most common disorder in

child psychiatry clinics today.

It remains very much a bone of contention.

Like many psychiatric disorders, there is very

little by way of laboratory definition, that this

diagnosis is made by interview and various

checklist ratings and duration criteria, disruption

to life, et cetera, but there is certainly no

laboratory experience, and the advent of

functionality MRI has been, for pediatrics, quite

remarkable particularly for child psychiatry as a

possible window into understanding the physiology

of this disorder.

[Slide.]

I don't think for this group I need to go

into details about the symptoms, but it is a

question of degree, and part of the controversy

comes because what is seen by people who are

skeptical as being very arbitrary. As a cutoff, it

is really a degree and duration and interference

with life decision since all of the behaviors are

things that children very commonly and often

exhibit in certain situations.

[Slide.]

Stimulants remain the treatment of choice.

Unfortunately, other nondrug-related treatments,

while being somewhat helpful, really are of a

different order of magnitude in their effect, and

the treatment decisions again based on clinical

opinion.

There is increasing public health concern

on high rate of stimulant use, and there is

considered a great deal of neuroscience-based

diagnostic treatment and outcome measures.

[Slide.]

So, one of the questions, and let me say

that this is a really old question that goes back

to perhaps an unfortunate statement in the 1930s

when children on stimulants were seen to calm down

when they were first used actually to help them

calm during a procedure, a radiographic procedure,

that was they were sort of almost accidentally

found to be useful, and there was an unfortunate

statement made that this was a paradoxical effect

with paradoxical calming.

That led to the very unfortunate use of an

observation that children would calm on stimulants

for many pediatricians for a generation to tell

parents that their children must have "minimal

brain dysfunction" because they actually did calm

down on the stimulants.

I mention this just because I want to

point out that there was considerable indirect

benefit to older observations than studies we did

in the early '80s, that, in fact, all children calm

down, and that, in fact, is not a diagnostic

response to the stimulants and had very great

benefit on practice, immediately became a board

question both for child psychiatry and pediatrics,

because they thought the point was so important to

get home.

[Slide.]

Our question was do children with ADHD

have a different brain response to stimulants, and

this was provoked by a very small study that had

been approved at Stanford earlier, but let me just

say that we thought it was very important to see

whether this is an opportunity to see, with the

functional MRI, whether there could be actual

difference in brain response in spite of an

exhaustive earlier study that showed that by almost

any measure, whether it's motor activity, verbal

fluency, ability to retain material, but by every

measure that the children's behavior was the same,

and we thought we had actually laid this to rest

that a stimulant had no difference in effect

between ADHD and healthy children except, as I say,

a couple of studies came along, which are reviewed

in detail in the protocol, which raised the

possibility that, in fact, there might be a

"paradoxical response."

There were major problems with these

studies, not just their small size, but the nature

of the tasks, the lack of data in one case, and the

choice of task in the other, where you couldn't

unconfound task performance with central nervous

system response.

These studies, however, because of the

importance, because the conservative definitions

place ADHD at perhaps 3 to 4 percent of the

population, and because of the continuing debate, I

think it's notable how important and the great

interest in the study, that even that small study

of Vaidya's, which was approved I think without

much comment at the Stanford Review Board, but that

was published in PNAS, and I think that attests

more to the considered importance and interest in

the issue than that particular study, as our

excellent colleague would be the first to say

herself, I think.

At any rate, we felt this could provide

some fundamental information about the

pathophysiology of ADHD and effects of treatment.

[Slide.]

So, the proposed study was 14 children

with ADHD, and 14 healthy controls. I am

deliberately reading out of order because only if

there was a difference between. If there was no

difference between their response in the fMRI,

between the controls and ADHD, we were not then

going to go on and do the twin part of the study.

But it then involved recruiting. I say

"recruiting" because we have some twin studies

ongoing, but over time some children, of course, go

out of the age range, so you need to recruit more

mono and dizygotic twins, concordant and discordant

for ADHD as an approach for understanding whether

the differences are related to just the state of

having the disorder or represent an underlying

trait.

[Slide.]

There is history and physical examination,

blood work, neuropsychological testing, single

functional MRI session, but there was also

several--in fact, I am sorry, I believe that is an

error--I think it involves two MRI sessions, and

subjects to be paid what is an amount which we

calculate just by how many hours. This is a

payment that is arrived at simply by going through

a checklist of procedures and can be modified one

way or the other by IRB.

[Slide.]

The IRB concerns, and as I say, these are

slides because when these were prepared, it wasn't

clear that Dr. Rosenstein was going to be

presenting, but the primary IRB concern was about

the risk level of the study for healthy children

and whether the administration of a stimulant was

approvable under federal regulations.

Questions were raised about the value of

the study in the IRB, although the three outside

scientific reviews were the strongest reviews that

I have ever gotten for outside reviews of many

protocols. They were concerned about the level of

payment, and I think wanted to adjust that downward

if the study were approved.

[Slide.]

I think this has already been covered.

[Slide.]

I think this has also already been

covered, and so I don't think I will go into this.

[Slide.]

What I would like to say is that in terms

of the risks, we have had years of research with a

single dose of stimulants in hyperactive children,

as well as a very well known study that I alluded

to, in the '80s, with healthy children, and the

single dose was likely to cause, if administered in

the morning, some loss of appetite at lunchtime,

possibly someone might feel a little bit nervous or

have some trouble sleeping at night, but, for many,

because of the duration of effect, if given early

in the morning, even these would not occur.

The IRB request to this committee was for

waiver of more than minimal risk. That will have

to be represented by Dr. Rosenstein, because my own

feeling was that this represented minimal risk, so

therefore, I am not a good advocate for that

question.

A bit of history might be of interest. As

always, we always with all of our pediatric

studies, consult both formally and informally with

the hospital ethicists.

A very excellent ethicist was present when

I did the study in the 1980s, John Fletcher, and I

asked John, as I always did with all my studies,

did he have any special recommendations, and he had

two recommendations, one which would be illegal

now, but made intuitive sense to me at the time,

was that if one or two of the investigators had

children in the right age, it would make sense if

their own children took part.

At the moment, this would not be legal,

both because you are not allowed to use your own

family members, and because NIH employees and their

families are not supposed to take part, and so on,

but I must confess that when I review and I am on

panels, such as this, which I have been regularly,

in my own heart I often ask myself would I allow a

child of mine to be in the study. So, both with

his recommendation at the time, we not only would,

but a couple of us did.

He made another recommendation, which was

that we should pay a lot of attention in this

protocol to informed consent, and suggested that

both parents consent and that they both be highly

educated. So, this is the only study I have ever

done in which all of the parents of all of the

children had graduate degrees.

That was an interesting process because

the parents were all extremely interested. We were

not concerned that the children particularly liked

the experience, although they did enjoy getting out

of school for a couple of mornings, but the

parents' interest in the child's improvement on

test performance was considerable.

I think the major thing that I was left

with from that experience, I knew many of these

children, and so I knew a lot of formal and

informal follow-up over years, and they considered

it an interesting experience, but otherwise totally

benign, and what most of them remembered later was

just that they did something different that week

rather than the usual routine.

[Slide.]

There have been studies that showed that

even with long-term use of stimulants, three or

four showed no long-term use of subsequent

substance abuse. There is certainly no data

relevant to a single dose, and even the one study

that suggested that children, after years of

stimulant, who had ADHD, might have a slight

increase in risk. Those were children that

included some conduct disorder children who would

be at predicted higher risk relative to the general

population.

So, I interpret the long-term data as

being negative, and these are for ADHD children

with multiple problems who have had stimulant drugs

for years, and it is on that basis that I don't

consider a single dose as a risk in healthy

children in this regard.

I think that is all, and I stayed well

within the timeline. I would be happy to answer to

any questions.

DR. NELSON: Before we get to questions,

Don, do you have prepared remarks or not?

DR. ROSENSTEIN: I do not. I was asked to

come just to answer questions about the IRB

process.

DR. NELSON: Why don't we then go to

questions, but if there is a question asked that

you want to defer to the IRB Chair, feel free.

Questions and Panel Discussion

DR. RAPOPORT: Right. I should also

mention that Dr. Daniel Pine is sitting here, and

if there are very specific questions about the

cognitive neuroscience part, I rely on him for some

of that.

DR. NELSON: Okay. Norm and then Rick.

DR. FOST: Dr. Rapoport, I have three

questions.

First, dose. It is stated in three

different ways in the protocol that we got. In

some cases, it is per kilo, some as a single flat

dose for everybody.

Could you clarify how the dose is

determined?

DR. RAPOPORT: Yes. That reflects that in

addition to whatever personal inconsistencies, the

differences occurred because we had used a fixed

per kilogram dose earlier.

The general thinking about

psychopharmacologists with a wide range of ages was

that it made better sense to give a low, fixed

dose. I consulted with several experts in the

field. However, the way it should have read is

that we would give 10 milligrams per kilogram,

10-milligram dose, period.

In any cases where it would end up being

more than a per-kilogram dose, we would adjust it

downward, would not include that subject.

DR. FOST: So, 10 is the most that anybody

would get?

DR. RAPOPORT: That's right.

DR. FOST: Second, on the compensation or

the payment, you said you something about toning

that down, and I had a couple of questions about

it.

The total in the protocol we got was it

might go as high as $570. Number one, was that

intended to go to the parents or the children, or

divided in some way?

Number two, there is three reasons for

giving money. One is to compensate people for

expenses, which should be the parents, not the

children. Two, as an honorarium to thank them.

Three, as an inducement because of the feeling that

you would have trouble recruiting if you didn't.

Could you clarify which of those you had

in mind with this money, and if it's the last, if

it's an inducement, do you think it is necessary,

or whatever your current thinking is about

modifying it?

DR. RAPOPORT: Right. I might add that in

the 1980 study, nobody was paid anything because

that was the policy at the time. I think I would

rather defer the question to Dr. Rosenstein on

this. Frankly, from an investigator's point of

view, you see what everyone else is doing, and you

look it up in a list, so he is the one who can give

the informed answer.

DR. ROSENSTEIN: It is a tough question,

because it gets at the motivation, and I am not

sure. I think what you just heard from Dr.

Rapoport was that there wasn't any specific

decision that we wouldn't be able to do the study

unless we paid this amount of money for an

inducement. I mean there was no evidence of that

whatsoever.

This is a moving target, as you know, and

I think that at the NIH, what we have seen over the

last several years is that for studies that did not

offer a prospect of direct medical benefit, that

involved time, inconvenience, and a variety

of--well, I will just leave it an

inconvenience--that payment has now become the

norm.

How much to pay is a complicated question

that I don't anybody has got the answer to, but I

think the notion is that payment should be for some

combination of the time lost and the inconvenience

to the subjects.

I also don't think that there is agreement

upon whether all the money should go to the parents

or the money should go to the children in the form

of a gift certificate to a book store or somewhere

else and how you work that out.

So, quite frankly, we didn't get that far

because at the IRB, where we got, we decided it

wasn't approvable at our level.

DR. FOST: So, if understand you, and I

just want to make sure Dr. Rapoport agrees, you

don't think it is necessary to recruit to this

study? That is, if you had no compensation, you

think you could still get sufficient enrollment.

DR. RAPOPORT: I don't know the answer to

that. I just don't know. It is much more

complicated now. Everybody's parent works, has to

take off time, et cetera, so things have change a

lot in terms of these are children, they need a

family member to be there for the whole time, and

things have changed a lot.

Certainly, it wasn't necessary when we did

the study the first time, and that had no part of

it. I can't tell you the answer to that.

DR. FOST: The third question is a

question about risk and assent, not about the

possible medical risk, but the anxiety of being in

a scanner.

There is some comment in the protocol

about your previous experience with functionality

MRIs and MRIs, and it sort of implies that there

has been almost no adverse reactions. Is that

case? What is the incidence of children in your

setting who had sufficient anxiety in the scanner

that they want to come out or that they report

afterwards?

DR. RAPOPORT: It is extremely low, but

you understand that we have a very different

process from the medical world in which this is not

the case, where children typically have MRIs when

there is other stressful circumstances. They are

not interviewed ahead of time to be in the study

based on their sense of whether they would mind.

We have the luxury of having a whole

practice session and pretend MRI, a mock MRI.

Children also have less claustrophobia because just

literally, they are physically much less closed in

than adults are, so they are much less bothered by

that.

As a result, because we prescreen children

for all of our children, describing the MRI, et

cetera, et cetera, it is almost zero, but I don't

think that our experience would generalize to the

real world, of course.

DR. FOST: Right, and you say almost zero

in the practice MRI session?

DR. RAPOPORT: Even that, because we tell

the child about it, I mean as part of even the

informed consent process, we go into this in

detail.

DR. FOST: So, by the time you get to the

"real one," have you had any experiences of bad

reactions?

DR. RAPOPORT: Not with any volunteer

subjects, of which we have now more than 3,000 MRI

scans, but with patients occasionally.

DR. NELSON: Rick Kodish.

DR. KODISH: Thank you for clarifying

which Rick.

Two questions. The first has to do with

age and assent or consent. I was struck by the

fairly broad age range in the protocol, I think 9

to 18. There was some text that suggested that

there was a significant brain change in adolescents

that makes the investigators think differently

about post-adolescent subjects.

I am wondering if it is the case that from

an ethics perspective, an age range of 14 to 18

might be preferable for better assent, close to

true consent, but from a scientific perspective,

and this is not my area, that, in fact, the 9 to

12, 9 to 14 age.

Is that accurate, and is there a

scientific preference?

DR. RAPOPORT: Right. You are asking a

very good question. We would prefer to have

children that are between the ages of 8 and 12.

Eight is the lower level age largely because of the

nature of the tests and the ability for

performance.

We had very clear reasons why we didn't

feel a study would be useful in adults, which I

think are described in the protocol.

Do you want to comment on that? I think I

would like to ask them because this had to do with

the neuroscience issue.

DR. PINE: I would just like to add to Dr.

Fost's comment, that we also routinely do many

studies in children who have very high levels of

anxiety disorders, and really would just second the

comments that Dr. Rapoport made, that any child who

is going to have a significant problem with an MRI

scan, really never gets very far along in the

process of doing the study, because it becomes

pretty obvious both to parents and to clinicians,

as well as the child, that this isn't for them.

So, that's the first thing.

The second thing is I think some of the

major questions at a neuroscientific, neurochemical

basis, related to stimulants, relate to changes in

the dopamine system in the brain, and some of the

most pressing questions focus on the precise age

range that Dr. Rapoport was just discussing, the 8

to 12 range.

Many neuroscientists feel that after even

early adolescence, the changes in the dopamine

system are so profound that even among 15- or

16-year-olds the relevance of the data that you

would acquire for younger children, who are

definitely prepubertal or perhaps even in the early

stages of puberty would not be comparable and would

not really be sufficiently compelling.

DR. NELSON: Would you mind on tape just

introducing yourself for the purpose of our

documentation, please.

DR. PINE: Sure. I am Dr. Daniel Pine. I

am a child psychiatrist in the NIMH Intramural

Research Program.

DR. KODISH: So, to follow up, the

eligibility criteria for the study strike me as

ambiguous. I mean one can say clearly that it is 9

to 18, but am I hearing correctly that from a

scientific perspective, you would prefer 9 to 14, 9

to 12--

DR. PINE: Yes.

DR. KODISH: --and in some sense, the

upward expansion of that is to make it ethically

more reasonable. I mean certainly from the ethics

perspective, my thinking is that older kids would

be more able to participate in a decision to do

this.

I do have one more pharmacology question.

DR. ROSENSTEIN: Let me just add one

comment about that, and this was not a position

that the entire IRB shared, but there were some

people on the IRB who also thought it would make

more sense to study younger children because those

people who were worried about the potential message

of it being okay to take a single close of a

medication might be more of an issue for older

children than for younger children. So, the ethics

argument cuts both ways with respect to the age

range. Again, that wasn't an unanimous opinion,

but that was one that was articulated at the IRB.

DR. RAPOPORT: I certainly think that from

the point of view of both things, that is more

compelling to use it in younger children, both

because of the science of it and that those people

who were "ADHD," older, may not be representative,

in fact, of the child population.

But I think from a mood response, the

younger children are very unlikely to get any

positive mood response to it.

DR. KODISH: And then the last one, which

will be shorter, has to do with this particular

drug. I was struck by your introductory comments

about the incidence of caffeine use in children,

and I am wondering if there is, the way that one

has narcotic pharmacoequivalency, is there data you

can give us about 10 milligrams of amphetamine, how

much caffeine?

DR. RAPOPORT: Our own data is the most

extensive on that. We had several schools that

participated in this, so we knew about children's

habitual diet, their habitual behaviors, and then

they took part in various low and high does

caffeine versus placebo, and these were actually

more extensive than single dose studies. These

were for two weeks at a time.

The lower dose, which was about 50

milligrams, 75 milligrams, as I recall, of

caffeine, seemed to be about equivalent to what a

single dose of ADHD, there wasn't a sense of any

change in appetite or problem sleeping.

DR. KODISH: So, what is normal?

DR. RAPOPORT: The trick was we did a

survey of households at several parochial and

public schools, and so on, and households seemed to

be quite dichotomous. About half of the school

children had very generous exposure to both

caffeinated soft drinks, as well as iced tea,

sometimes, to me, astonishing amounts, that the

kids would have several hundred milligrams a day,

because iced tea is always "okay."

DR. KODISH: But several hundred

milligrams exceeds the equivalent of 10 milligrams

of amphetamine?

DR. RAPOPORT: By far, by far. On the

other hand, you know, there were plenty of

households that didn't, too.

DR. KODISH: Thanks.

DR. NELSON: Dr. Gorman.

DR. GORMAN: I have a couple of questions

related to the actual protocol. You have already,

in response to Dr. Fost's question, mentioned that

there are several discrepancies in the protocol in

terms of dosing.

Could you walk us through, as a committee,

how NIH deals with revising protocols, so these

discrepancies are eliminated in what I assume would

be a final protocol, which we are not reviewing?

DR. RAPOPORT: Right. I think I can only

apologize, and I will take whatever responsibility

for inaccuracies or inconsistencies, but there is

multiple review, typically with protocols, it is

read at several levels by the IRB, and usually

meticulously, and at the meeting, not only are the

broader issues described, but we are presented with

very detailed list of typos, inconsistencies, and

so on, and I would say most of the time, the review

proceeding is extremely detailed and careful.

DR. GORMAN: I appreciate that. I am more

concerned or more interested actually in what

happens in the future. In the protocol, there is a

typo about the dose, which would need to be

corrected, so that you wouldn't be in protocol

violation every time you dosed a child.

DR. RAPOPORT: Right.

DR. GORMAN: How does that procedure take

place?

DR. RAPOPORT: I think I would have to ask

Don to speak to that.

DR. ROSENSTEIN: This is a human process.

We do the best we can. It is reviewed by outside

scientific reviewers, inside scientific reviewers,

a pre-review before the IRB. There are 14 members

of the IRB that all review it. At the time of the

continuing review, hopefully, that would be, you

know, an error like that would be picked up.

So, the answer is the process is people

read the protocol as carefully as possible. If

there are discrepancies that are missed, they are

missed, and hopefully, we pick them up at the next

pass.

DR. GORMAN: In the IRB world that I live

in, which I deal mostly with industry-sponsored

surveys, this would require a protocol amendment

that would clarify the errors, and that would be

incorporated into the protocol.

DR. ROSENSTEIN: Of course, once it's

identified. I thought you were asking how were we

going to identify--

DR. GORMAN: No, how are you going to

correct it, so that when we--

DR. ROSENSTEIN: With an amendment to the

protocol, sure.

DR. GORMAN: There will be an amendment to

the protocol that will deal with the dosing issues?

DR. ROSENSTEIN: It will clarify whatever

the error was.

DR. GORMAN: Okay.

DR. RAPOPORT: Absolutely.

DR. GORMAN: The second question comes to

deal with the MRI itself. In the protocol, it

describes that this is a 3-Tesla coil. Is the

3-Tesla coil experimental or in common clinical use

at this point?

DR. PINE: I think it is fairly well

articulated in terms of the view of 3-Tesla magnet,

but it is used regularly for clinical studies

including at the NIH.

DR. GORMAN: I am sorry, not for clinical

studies. Is it a clinically approved device?

DR. PINE: Yes, it is a clinically

approved device.

DR. GORMAN: Thank you.

Do you plan on getting two parental

signatures on this informed consent if this study

is found to be approvable?

DR. RAPOPORT: I hadn't been, but I

believe I have learned this morning that I should.

DR. GORMAN: Thank you.

DR. NELSON: Dr. Chesney.

DR. CHESNEY: I have questions about the

need for using stimulant in normal children at this

point in time, and I have read the protocol, I have

gone back and looked at a number of the original

articles, and as a neophyte, tried to understand

the neuroscience, but I obviously have many holes.

Since fMRI is so new, I wonder if we

should or potentially should focus efforts on

learning more about the fMRI findings in normal

children without stimulant, and in newly diagnosed

ADHD children, and in ADHD children on chronic

medications before we need to look at the issue of

stimulant use in children.

Again, in looking at what has been

published, which looks to me fairly minimal in

terms of fMRI findings, I, in looking at dopamine

receptors and transporters, and so on, and trying

to understand all of that, and I may not be

understanding it, but it seemed to me like we still

have a lot to learn just by looking at normal

children again without stimulant, and newly

diagnosed, and chronically treated ADHD children

before we may need to look at the issue of giving

stimulant to children, which would make the issue

temporarily a little more straightforward.

So, I wondered if you could comment on

that concept of whether we really need to learn

more about what the activation in normal children

is. Thank you.

DR. RAPOPORT: Well, I think Dr. Pine will

also like to comment, but I would like to say that

at the NIH, there is always a tension between the

very strong interest in the basic kinds of

observations that you describe and when you apply

them as a clinical problem.

But at least at the NIH, there has been a

great deal of very active work already in children,

in healthy children with some of these tests, and,

in fact, Dr. Pine's collaboration and co-PI on this

protocol reflects that.

So, there is a great deal more, the change

from PET scan to a test that doesn't involve

exposure to ionizing radiation really

revolutionized pediatric studies, so in a limited

field of research where there isn't much research

all together, relatively speaking, there has been

quite a considerable amount already, several from

people who trained at the NIH and have gone out to

other leading centers.

So, I don't think it is quite so minimal

given that pediatric research is minimal in its own

way anyway.