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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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,

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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.

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\[Slide.\]

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

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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.

\[Slide.\]

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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

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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

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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

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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

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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

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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

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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

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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

30

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

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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.

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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

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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

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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

35

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

36

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

37

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.

38

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

39

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

40

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

41

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.

42

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,

43

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,

44

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

45

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

46

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.

47

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

48

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

49

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

50

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

51

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

52

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

53

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

54

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

55

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.

56

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

57

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

58

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,

59

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

60

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,

61

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

62

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?

63

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

64

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.

65

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.

I think this a problem, though, that

remains very important, that there really are

people that are using all sorts of tests and

selling them as diagnostic processes to the general

public. I think you could make an argument that

this is a compelling question.

DR. PINE: I actually, first of all, want

to thank you for your question because I think it

does point out almost a procedural element of the

document that you have, so there are three specific

66

comments I would like to make.

One is that both Dr. Rapoport and myself

are\--I don\'t know if beat is the right word\--but

really taught and forced to write an extremely

focused document that very tersely and very

narrowly identifies a key question, so that people

reviewing the protocol can look at that specific

issue.

As Dr. Rapoport mentioned, there is

actually an incredibly exciting, burgeoning

literature and a number of studies supported by

DHHS-funded studies that are answering just the

kind of questions that you raise, and the

technology that we are going to use, if we are

allowed to do this study, takes advantage of some

of the things that people have learned by doing

just the kind of studies that you have mentioned,

doing large-scale fMRI studies looking at these

types of functions in healthy kids, in kids with

ADHD, in fact, even today, there is a paper that

came out in the American Journal of Psychiatry that

uses a very similar technique that compares brain

67

functioning in children with ADHD and healthy

children, that is consistent with the work that we

are proposing, so that is the first thing.

The second thing is, you know, it is also

very exciting to think about things like dopamine

receptors and wanting to do more basic work using

those types of methods.

The thing that many people don\'t

appreciate is that virtually all of the other

methods for looking at neurochemistry could not be

approvable because the potential risks for children

would be higher than the risks that are in this

protocol as they are described, second of all.

Third of all, one of the things that

really captured my attention when Dr. Rapoport

first approached me about this protocol is I

remembered very vividly where I was when the study

from Dr. Vaidya was first published, and I remember

if for a couple of reasons.

One reason was it gathered a huge amount

of media attention, and I think one of the reasons

it did was it brought to the fore this idea about

68

is there a fundamental distinction in the way in

which the brain of a child with ADHD works relative

to the brain of a child who does not have ADHD.

That has been a question that we have been

grappling with for 30 years, as Dr. Rapoport has

mentioned. There has been virtually no way to get

at that. The finding, as it was reflected in that

1998 paper, by far and away provides the most

compelling hint that that is true, that there is a

fundamental distinction between in which the brains

of healthy children and the way in which the brains

of children with ADHD functions.

If that is, in fact, correct, it could

have monumental impact in terms of how we think

about this condition, and there is just no other

way with the current technology that we have to get

at that question.

DR. RAPOPORT: I totally agree with you,

and I think that is very exciting. I mean this is

a huge problem in pediatrics, but I wonder if it

wouldn\'t be helpful to focus initially on fMRI as a

diagnostic tool. I mean that is the most exciting

69

thing to me, that you could actually distinguish

those who truly have ADHD, not that whole

population that is being treated that probably

doesn\'t need to be treated versus the controls

before we need to get into the stimulant medication

for control issues.

Do you understand?

DR. PINE: That has already been done, and

when that has been done, what we tend to see in

regular fMRI studies is a pattern of findings that

is very similar to many other findings on ADHD in

general, meaning that there are relatively subtle

differences in terms of how the brains of healthy

children relative to children with ADHD work when

they are studied with current fMRI technologies,

but they suggest, much like, you know, a lot of the

literature that has led to the current controversy

that there is not a quantum categorical difference

in terms of the functioning of the healthy child\'s

brain and the brain of the child with ADHD, and

there is considerable overlap in terms of how that

bring appears in a healthy child versus the child

70

with ADHD.

Given that problem, the likelihood that

that technology, as it currently exists, is going

to be used as a diagnostic tool is very limited.

DR. RAPOPORT: Well, this gets to the core

of what has been of interest to me. If there is

that much variability, how will you be sure that

you can interpret the results with the stimulant in

a meaningful way?

DR. PINE: There is variability in the

studies that use current fMRI technology without

the stimulant challenge. When you look at the

results in that one paper that was published in

1998, you see a completely different pattern of

results, to the point where there is virtually no

overlap between the two groups, and that is what

really generated the enthusiasm both in the

scientific community, but also in the lay public

that this was the type of test where theoretically,

potentially, there was not that degree of

variability, but one could only see that difference

if one looked at scans acquired both during a

71

placebo condition and under methylphenidate.

The variability was diminished when you

looked at the change in brain functioning when a

child was taking stimulants, and that is why it is

so important to pursue this particular issue of

what happens to the brain of the child when they

are taking psychostimulants.

Let me rephrase it, that most biological

measures that we have, we see this pattern of

overlapping distributions for virtually every test

that we do and virtually every psychiatric

disorder. Once in a while we come upon real

categorical distinctions where we get two

distributions that are just not overlapping.

Whenever we get those, they are incredibly

important to pursue. In the field of ADHD

research, the one area in the last decade where we

have had this is when we look at this study that

was published in 1998 where there were

fundamentally categorical distinct responses in

these two groups.

Was it a fluke? Maybe, but if it is not a

72

fluke, it fundamentally changes the way we look at

the disorder. That is why it is so important to

pursue. It has not been pursued for the exact

reasons that you guys are assembled here today to

discuss. It has not been pursued because it can

only be pursued by examining the response of a

healthy child\'s brain to psychostimulants, and that

just has not been done since 1998 in that type of a

study.

DR. NELSON: Mary Faith Marshall.

DR. MARSHALL: I am going to focus on

something that is a little different than the

previous question.

I would like to ask, during the consent

process, how you would go about explaining the

testing for the exclusion criteria in a pregnancy,

so the pregnancy testing, how that would work out

in terms of the informed consent process.

DR. RAPOPORT: Right. That is difficult.

There is an absolute requirement that any women,

girls who might be sexually active absolutely have

to have a\-- it is not a popular requirement with

73

the investigators, and we don\'t feel any credible

evidence that there is a good reason for it.

We would explain to them that there is

this requirement and explain this as part of going

through a urine test would be necessary, just to be

in the study, explained that way.

DR. MARSHALL: Is it done in the presence

of their parents? What I am getting at is what

privacy protections do you have during the process,

and also I would ask, there are several consent

documents or versions of consent documents in our

folder. I think three of them are versions of a

parental permission document, and then the child

assent document, and I don\'t see anywhere in the

child assent document mention of pregnancy testing.

DR. RAPOPORT: Right. I am going to ask

Dr. Pine who has had more experience with that. I

think not having it mentioned is probably an

oversight, that\'s for sure.

DR. PINE: I guess I would say two

comments related to the questions about the IRB

process, having put a number of the protocols

74

through the IRB. The first thing to realize is

that the discussion of this protocol was tabled

very early in the process, so I think the IRB got

to a really core question that if they couldn\'t

answer it, you know, they were not going to move on

to the discussions of these other details, and I

think that the key issue was whether or not one

could give a psychostimulant to a healthy child,

and once they decided that they were not going to

approve that, they did not discuss some of these

other issues.

I will tell you that this issue, as well

as some of the other issues in our other fMRI

studies, has been a bit of an evolving process, and

what we do now, having learned from experience, is

in the consent form of the parent and the assent

form of the child, it says to both a pregnancy test

will be done, your mother or your father will be

told if your test comes back positive.

We have kind of learned the hard way in

terms of clinically and ethically, that that is the

most justifiable thing to do in discussions with

75

the IRB, and this way, when people come into the

study and assent for it and consent for it, both

the child and the parent know that if their child

comes back with a positive pregnancy test, which

unfortunately happens more likely than we would

want, everybody knows that going in.

DR. MARSHALL: I guess I would just make

the observation then, that as common as this is, I

would, if I were sitting on your IRB, expect to

see, within the protocol itself, a discussion of

the process and the privacy and confidentiality

protections that are there, and that that should be

upfront in any protocol, and wouldn\'t have to wait

for IRB review.

DR. NELSON: Let me follow up, I think

Joan\'s line of questioning, and ask a question

about sort of data analysis. One way to approach

the issue of the inclusion of the normal controls,

and particularly the intervention group, normal

controls is to ask whether the data analysis truly

needs to be blinded and whether there can be a

sequential process by which, at the end of the day,

76

you can demonstrate that you actually need the

controlled intervention data as opposed to the

controlled placebo data to interpret what you have

then seen in the ADH control and intervention data.

So, I mean this is not a drug trial in a

sense where you need to have, you know, if you take

a look at, you pay a penalty in your statistical

significance, so I am just curious, could you do

some sort of sequential design or at least the

burden of proof that you need the control drug data

as sort of elevated beyond what might be in a sort

of standard prospective randomized, controlled

trial.

DR. RAPOPORT: Well, in order to get good

data because of differences across individuals, of

levels, and so on, you would need any subject to

have both a non-drug and a drug condition, so since

they have to agree to come twice, blinding and

having one placebo, so that the subject is blinded,

you don\'t really lose anything.

I think more to the point of answering

your question, since the point of the study is the

77

change between off-drug and on-drug condition, that

is what the study is doing, what I think we would

probably do would be, with a smaller number than,

say, 14, take a look at the data and say if one

had, say, 8 subjects, did one need 14 and had a

very clear answer, and that says test fewer

patients, healthy subjects, if we needed fewer.

Am I answering your question with that? I

thought that is what the implication of your

question was.

DR. NELSON: I guess the way I would

rephrase that, is there any problem if one delayed.

It needs to be blinded to the individual in the

scanner, I assume, and blinded to the interpreter

of the FMRI, but is there any way that you could

design it in a way that you would gather all of

your ADHD data and then have the control data

blinded in a way that at least you then have

demonstrated the need for the control drug data to

make that interpretation.

DR. RAPOPORT: I think we wouldn\'t be able

to, because each study, each test situation is

78

different enough that I think you would, in order

to know whether they were different from the

control or not, you would simply have to design

standardized tests and standardized applications,

that in any given experimental situation, I don\'t

think you would know enough conceivably from just

ADHD alone to be able to know whether they are

behaving the same or differently from a healthy

child.

DR. NELSON: One of the other key things

is an order effect. You know, that there is a fair

amount of concern in order effects. So, if you

were to do a study where everybody gets placebo

first, including the kids, the healthy kids and the

kids with ADHD, and then they get stimulant second,

you couldn\'t tease apart the specific effect of the

medication, on the one hand, versus the fact that

the medication scan always comes second.

You know, half the kids are going to have

to get the medication first, the other half are

going to get placebo first, otherwise, the study is

not interpretable, or it basically becomes the same

79

type of study that has already been done, that\'s

published this month in the American Journal of

Psychiatry.

You are looking at the change, but if you

always do the placebo first, you can never

interpret the change as due to the medication. It

might be due to the medication or it might be due

to the order effect.

DR. RAPOPORT: We always, though, try to

minimize the number of subjects and the exposure.

If we had clear results with 8 subjects instead of

14, we would stop there. If there were no

differences between the ADHD delta and the control

delta, we would not go on and do the twin studies.

DR. NELSON: Dr. Greenhill.

DR. GREENHILL: Just in response to your

question, and I apologize if I missed this point

that was in the protocol, another aspect of what

you are talking about, the blinding relates to

possible or potential benefit to the individual

subject. If the family might get the results of

the study after all the participants have gone

80

through, in other words, they would learn if there

were differences in the performance of the

subjects, that particular individual subject, when

he or she took the test, is that something that is

built into the protocol at this point, because I

know in our IRB, we insist in industry protocols

that the blind be broken, so that subjects can get

results of their experience in the particular

protocol?

DR. ROSENSTEIN: I think that question may

have more relevance for the children with the ADHD

than the children without, because from our

perspective, from the IRB\'s perspective, there is

no prospect of benefit for those children who don\'t

have ADHD, that they be interested in finding out

the results of the study, and I think every

investigator handles that differently depending on

when the overall blind of the study is broken and

what kind of information can be communicated in

real time.

But looking at how that information was

exchange to the families of the children who don\'t

81

have ADHD was never a consideration with respect to

prospect of benefit.

DR. GREENHILL: I was just talking about

the subjects who had diagnosed ADHD.

DR. ROSENSTEIN: I understand, but again,

I think the reason that this protocol is before you

is principally for the children who don\'t, and I

just wanted to emphasize that.

DR. NELSON: Mary Faith Marshall has

another couple of questions for Don, and then we

are scheduled for a break at that point.

DR. MARSHALL: One is just a clarification

question, Don, and that is relative to the IUs that

were used to derive the compensation scheme for

this study, whether that stands for inconvenience

units.

DR. ROSENSTEIN: Inconvenience unit.

DR. MARSHALL: Are those standard

throughout the NIH?

DR. ROSENSTEIN: Yes, they are guidelines,

but there is also, as Dr. Rapoport suggested

earlier, there is room for variability in how you

82

apply those, so that there are certain procedures

that are thought to carry with them greater levels

of inconvenience than others, even if they take the

same amount of time. So, there is some

interpretation in that, but there are some basic

guidelines that we could make available to this

committee, if you would like, from the NIH.

At the end of the day, the IRB has to look

at the bottom line and whether that is consonant

with the study.

DR. MARSHALL: Thank you. The second

question relates to the discussion that the IRB had

in executive session about the protocol on October

28th, I guess sort of the final ones perhaps, the

final discussion.

I want to commend you on the minutes that

are taken of your meetings. They are excellent,

they really are, very thorough.

This may just be a reflection of how the

minutes themselves were written, but under

Discussion in Executive Session, the minutes say,

\"Discussions supporting designating the study as

83

minimal risk, focused on the compelling scientific

justification for the study and the opinion that

the risk of exposure to this drug In a supervised

setting does not exceed the risk children are

typically exposed to.\"

I was wondering if you could maybe just,

if you remember, can describe for us the component

of the IRB discussion of discussion that supported

designating the study as minimal risk relative to

the compelling scientific justification for the

study. Is that a fair question?

DR. ROSENSTEIN: I understand your

question because they are apples and oranges, but

they go into the same equation. There were some

people on the IRB who felt like this clearly fell

within minimal risk, and other people who felt like

it was a stretch and that it would have to be

called a minor increment over minimal risk.

The reason again that this is here is

because the IRB, in its final deliberations, felt

like this was an important study to do, but there

wasn\'t a majority that felt that they could call it

84

minimal risk, so we are not forwarding it to you to

kind of do our work for us, but because we thought

that it was a study that should be approved.

In the discussion of whether it\'s minimal

risk or not, some people raised questions about how

important is it really, so if it\'s minimal risk,

you know, there may not be the same burden, you

know, on the science in a sense, and other people

felt like, well, yeah, it\'s an interesting question

and this is clearly the next logical step, but how

important is it to demonstrate that the brains of

children with ADHD are different.

That was a minority opinion in the IRB,

but it was expressed, and so I think that is what

the minutes reflect there, that the IRB was

struggling with a risk level that was right on the

border and how compelling the science was to

justify it, you know, whether it was just below

that level or just above that level, if that makes

any sense at all.

DR. MARSHALL: It does, thank you.

DR. NELSON: Ms. Treat.

85

MS. TREAT: I just had a couple of

questions. I bring to the table the perceptions of

the general community and families.

There is the perception in the general

community among both ADHD kids and the parents, and

healthy kids, too, that the stimulants that you are

using, especially the one that you are using, is

highly habit-forming and can cause various other

side effects.

I was wondering, since there is so little

research on healthy children, if the stimulant

might\--I recognize that you might believe that a

single dosage carries very low risk based on your

studies of ADHD subjects\--but there is a concern

among some of the people I serve that even a single

dose might cause or might aggravate predispositions

in healthy children, such things as eating

disorders or later abuse, that kind of thing.

In that regard, I also noted that the

dosage that you are using, the 10-milligram dosage,

is higher than the recommended starting dosage of 5

milligrams for the stimulant you are using. I was

86

wondering if you could address that.

DR. ROSENSTEIN: That last question, I

will defer to Dr. Rapoport and Dr. Pine. With

respect to the first comment, this is the challenge

that all IRBs have in interpreting the regulations

when you have an absence of data. No one can

answer the question of what risk there might or

might not be with a single dose of a medicine like

this.

The data that Dr. Rapoport summarized

earlier suggested even when you are using

stimulants chronically, there is not an increased

risk of substance abuse, but perhaps a decrease in

risk. Whether that applies at all to healthy

children who get one dose, we, quite frankly, don\'t

know. So, I think other people around our table

were wondering about that as a contributor to

whether this ought to be considered slightly more

than minimal risk or not, but we just simply don\'t

know, to answer that question about the dose.

DR. RAPOPORT: Yes, we were torn. People

with hyperactive children often do start with a

87

single 5-milligram dose, that is absolutely true.

Our own experience with numerous behavioral

measures is that that so often doesn\'t give a

recognizable signal. We certainly didn\'t want to

go through all of this and not have anybody

including the hyperactive children have any change.

It was the smallest dose to get any

reliable change, and even though any good

pediatrician or doctor would always try to start

conservatively when people are going to start off

and taking something, you know, every day for

weeks, we thought this was the lowest dose that

would be worth doing, because too many children in

our experience don\'t change in a measurable way in

a single dose of 5, but I am not criticizing the

pediatric approach. Just for a single-dose study,

it didn\'t make sense to us.

MS. TREAT: I did have one other question,

and that concerned the IQ parameter that you have.

In the protocol, it says that your only parameter

is the low one, the low IQ being 80. When I and

some of my friends had taken their kids to take the

88

test, the go/no-go test and the stop test, I was

told by the doctor that IQ did have a bearing on

responses to those tests, the higher the IQ, the

less likely or the more likely the subject was to

be able to perhaps even beat the test.

I was wondering if maybe a smaller

parameter for you would\--

DR. RAPOPORT: You mean to have a higher

cutoff, as well as the lower cutoff?

MS. TREAT: Yes.

DR. RAPOPORT: I think I will ask Dan.

DR. PINE: In general, it is true that

there are some associations between IQ and

performance on these types of tests. There is wide

variability across the different kinds of tests, in

the strength of that association, and when we use

these tests behaviorally, meaning just having kids

do the exact same paradigms that Dr. Rapoport is

going to use, we find extremely small, if any,

correlations between IQ and these specific tests.

DR. NELSON: Dr. Greenhill and then Dr.

Jacobs.

89

DR. GREENHILL: Since we are discussing

the consent and assent forms, there are a couple of

questions or suggestions that came to mind.

The perception of families about these

medications relates to the fact that

dextroamphetamine is a schedule drug, which means

that it is classified as a drug of abuse by the

Drug Enforcement Administration.

Pharmacists often remind families of that

when they get a prescription of the drug, and in

some states, those drugs are delivered on different

prescriptions, and they are tracked and monitored,

and physicians\' prescribing rates are tracked.

So, it is important in all our consent

forms that involve schedule drugs, to tell parents

that this is a schedule drug, and considered to be

a drug of abuse by the Drug Enforcement

Administration.

The other thing is that we tend to be more

explicit about adverse events that are connected to

stimulant medication, and even if they play a small

role, it is important for parents to at least have

90

some of the fears that they might have about these

medications addressed explicitly in the consent

form.

A number of families confused

dextroamphetamine with methamphetamine, and it is

helpful in some of our consent forms to make it

clear that although this is a related product, it

is not speed.

In terms of adverse events, there are

infrequent adverse events, but the ones that we see

that occur, such as stomachaches, headaches, and

particularly involuntary motor movements are a big

concern of families, and they occur in these

patients. It is not clear whether they are

triggered by the medications, but should they

appear, the first response on the part of almost

every family I have worked with is get them of the

medicine.

So, they might have some concerns if their

child took one dose of stimulants and began to

sniff or have a blink, and they might associate it

with taking that medication ever if it weren\'t

91

related.

Finally, there is a section in the assent

form that says, \"Occasionally, the MRI examination

will detect something unexpected, in the child\'s

brain is a mass or any kind of abnormality.\"

This has been a big issue at the

institution where I work because that might lead to

every scan requiring a licensed or a

board-certified radiologist looking at them to make

sure there is no evidence of an abnormality or a

mass.

This is just a question I would have for

Dr. Pine. We have been told on the IRB that the

protocol for the MRI scans are not designed to

optimally look for masses or other clinical

abnormalities, but to focus on functional, bold

kind of results for registration, and a clinical

wouldn\'t turn to that protocol if he were

clinically evaluating a symptom complex in

patients, looking for a brain tumor.

It may be misleading to tell parents that

this test will give you a bill of health, and I am

92

not clear it does, so I need to ask Dr. Pine.

DR. PINE: It is funny that Dr. Greenhill

says this, because I began my MRI studies at Dr.

Greenhill\'s institution and was taught to think

about MRI studies the exact same way, and I was

shocked when I came to the NIMH four years ago to

learn that we take an additional 20 minutes to put

every child through a far more rigorous

comprehensive clinical assessment of brain anatomy,

both normal and pathological, and that is a rule of

the NIH Clinical Center, that every single child

who will go into the MRI scanner once a year will

have a comprehensive bona-fide clinical assessment

that will be read by a trained neuroradiologist, so

that we can say exactly what is written in the

consent form, and it is very different relative to

any other MR center that I have ever seen.

DR. GREENHILL: That is a benefit.

DR. PINE: It is a benefit.

DR. RAPOPORT: It is not a choice for us,

it\'s an absolute clinical center rule.

DR. NELSON: Dr. Jacobs.

93

DR. JACOBS: I would like to return to the

age question that we were talking about a little

earlier. I am a developmental psychologist, so in

all the research that I look at and do, age is very

big issue.

It seems to me that what we are doing here

is weighing the science and the value it will have

for future treatment an future diagnoses against

the risk to some individual children.

So, the science matters a lot, and it

seems to me that the range that you have proposed,

from 9 to 18, is really too broad, and we have

already talked about that. It appears to me that

particularly the upper ranges, you may have brains

that have changed, and it will be difficult for you

to actually lump that data in with the data from

the younger children, and you don\'t have that many

subjects, so it will be difficult to really tease

it out in a different way.

So, I wonder if you have considered really

narrowing the range especially to the younger

group.

94

DR. RAPOPORT: Yes. I think that it would

make a good deal of sense to narrow it from 8 to

13, for example.

DR. JACOBS: Thank you.

DR. NELSON: I know there is other

questions, but before doing that, let me just ask.

I know, Dr. Rapoport, you said that you have some

commitments, you may need to leave. My question is

whether we should\--I mean we do have plenty of time

for discussion\--whether people want to continue

this conversation or have a break and then continue

the conversation.

I see panelists nodding continue, which is

fine. If anyone needs some natural stimulant, get

it on your own.

Mary Faith had her hand up, then Norm, and

then Dr. Greenhill. So, Mary Faith.

DR. MARSHALL: Mine was really a follow-on

to the informed consent document itself, and these

are just observations, not questions really, and

they may be more appropriately directed at the

Chair of the IRB.

95

One is in the consent documents, the word

\"placebo\" is used early on, and I don\'t see it sort

of spelled out for those who may not understand it,

and that is an obvious thing. It is just an

observation, I am not asking for any defense.

The second one is the use of the word

\"treatment.\" I understand that the substance that

is under investigation is approved in certain uses,

but this is research, and others may not agree with

me, but I have a big allergy to the use of the word

\"treatment\" rather than study drug or something

along those lines.

To me, treatment implies something that

has been empirically derived and is standard

practice. Again, I sit on several DS&Bs for the

NIH, and I bring it up every single time, so I just

have to do it and go on record as saying that.

I do want to reiterate to both of you, I

would see a young girl who tests positive for the

pregnancy test, and it\'s a surprise for everyone,

and us knowing some of the sequela that could come

about because of that, as potentially being greater

96

than any of the other risks we are talking about

here today.

One thing that I see that is common among

protocols and IRB review of protocols is what I

would consider to be a really cavalier approach to

that whole issue and the whole process of consent

and privacy and confidentiality.

So, I really just would like to say that

again, and again I am not asking for any sort of

defense or whatever. I just want to get it out

there on the table.

DR. ROSENSTEIN: Can I respond just to

that one? We do take it very seriously, and we

have modified our approach over the years at the

IRB. I think that whether you agree with this

approach or not, where we are at right now is that

we don\'t test anyone unless they know they are

going to be tested obviously.

The investigators have a great deal of

sensitivity to asking in private are you sexually

active, is there any chance that this might be

positive. I mean all of that isn\'t necessarily

97

laid out in this consent form in front of you, but

we take it seriously, and the other part of it is

that if the terms of the study are unacceptable,

either to the child or to the parent because of

that eventuality, they don\'t have to be in the

study.

DR. MARSHALL: Right, and I appreciate the

fact that they do it seriously, but as a reviewer,

I don\'t see a reflection of that here, and thus, I

have no way of knowing that that is the case.

DR. ROSENSTEIN: Fair enough.

DR. NELSON: Norm.

DR. FOST: I just wanted to make sure I

understood the previous exchange about MRIs. Did I

understand you to say that every child, not just in

this study, but at NIH in general, will get a

standard clinical MRI also?

DR. PINE: Every child and every adult,

every person gets a standard, and it takes 20

minutes.

DR. FOST: It opens a whole can of worms

that we probably don\'t have time to discuss at this

98

minute, but I will have to discuss later, so I just

want to identify it before you leave, so you can

comment on it.

There is a possible benefit, but it is

much more likely to be a risk than a benefit. That

is, when you do screening procedures in a healthy

population, a population that is not expected to

have brain pathology, you are much more likely to

pick up false positives, adventitious findings,

then, someone has to explain to the parent there is

a little something in your child\'s brain, we don\'t

know what it means, but he ought to be followed or

it ought to be repeated.

I am astonished that you (a) would do

that, and I am confused as to why you would do it.

Why being in a study should lead you to have a

clinical MRI. Of course, the whole same set of

questions are raised by the fMRI, which can raise

adventitious findings.

DR. PINE: I would disagree with the fMRI

finding.

DR. RAPOPORT: They are less considered

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diagnostic. We have the largest series of normal

child, healthy child MRIs, I think in the world,

and I can echo though while, of course, it almost

never happens, we have had 4 instances out of 3,000

MRI on about 500 children, who come back every few

years, and 2 of them were benign cysts that the

parents got further consultation and did nothing

about, but in 2 cases they turned out to be brain

tumors that were operated on and had a good outcome

before we found it, so we are 50-50 in our

experience out of these 3,000.

DR. FOST: That is interesting. I hope

you publish that or plan to.

Again, I didn\'t see anything. This is the

first I learned of it from this interchange. I

didn\'t see anything in the protocol or the consent

form.

DR. PINE: I can also tell you, much like

the issue of pregnancy, that working with IRB, we

have adapted the language in the consent form, and

the process for discussing that for the very reason

that you mentioned. I am sure, as Dr. Rosenstein

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would say, the final consent form, should it be

approved, would reflect the current language, which

goes into far more detail about what it means to

have a clinical MRI, what are the range of findings

that we can get, what you will be told, and when

you will be told.

DR. FOST: Like Mary Faith, I am confused

as to what this consent form is. Is this just sort

of a draft consent form? Why is not all this in

the\--especially when it gets to this level, I would

think you would want\--

DR. ROSENSTEIN: It is not a draft. I

will try to answer this the best way I can. This

protocol has been through many, many, many

iterations, and at some point, the fundamental

question about whether it\'s permissible to

administer a single dose of a stimulant to

children, to anyone under 18 has to be asked and

answered.

You have got competing demands of kind of

getting some read on that versus having a document.

I am more than happy\--Dr. Rapoport said she would

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take responsibility\--I will be responsible for any

typos, any omissions, any misleading statement in

the consent form.

We are more than happy\--if you want to

send it back to us with an answer, we will kind of

work on that.

DR. NELSON: If I may, we will stipulate

that the IRB recognizes their process was

short-circuited by the question of whether they

could do this from a regulatory perspective. I

think it needs clean-up.

DR. ROSENSTEIN: Thank you, Dr. Nelson.

DR. NELSON: I think we have beaten them

up enough on that point.

Dr. Greenhill.

DR. GREENHILL: I just have a question for

the head of the IRB. Where do you draw the line

for listing adverse events of a particular

intervention? Our IRB tends to go down the list,

knowing that some families will go the Physicians

Desk Reference and find disturbing adverse events,

and not realize they are under the rare section.

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So, for example, we would put in the

frequent adverse events, headaches, stomachaches,

decreased appetite and decreased weight. We would

put in the infrequent adverse events, such as tics,

and then the rare, such as hallucinosis,

formication.

And then we would address one that is of

great concern to the public, which is growth

slowdown and delay, and to try to put it in the

context this is a single dose.

That is one of the questions I have. Do

you have kind of a guideline that you use at the

NIH?

DR. ROSENSTEIN: We follow a very similar

approach, and whenever there are numbers available,

we include those numbers to try to make it more

understandable. Again, I think everyone here who

has served on an IRB knows that it is as much art

as science about exactly how many things that you

list.

When there are no data relevant to the

side effects for a single dose, it makes it more

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difficult to know how much information is then

misleading, you know, to report the side effects

that are associated with higher doses for chronic

duration may not be doing anyone a service. It\'s a

tough question. We try to be as thoughtful about

it as we can.

DR. GREENHILL: The other question I have

is whether the consent form has to be quite so

conservative in terms of the benefits. Now,

clearly, there is no medical benefit, but there is

a benefit from coming to the NIH and having an

evaluation by an expert team, and there is the

potential benefit of taking the results of the

tests and preparing some kind of report.

I want to just expand this a little bit.

If you don\'t indicate, if you give a WISC, and then

the child six months later goes to school and has

to get a test in order to enter a special program,

for example, get special education, which a lot of

children with ADHD do, they can\'t be tested at that

point because there is as practice effect.

So, we generally put in our consent forms

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something to let the parents know that by taking

the WISC, they will not be eligible to take the

test again for a year to have it interpretable.

For that reason, we try to give the

parents some kind of a form and a report. Now,

initially, when we did a big outpatient study with

the NIMH, called the MTA study, we had a licensed

psychologist sign off on it, so that that piece of

paper that came from the evaluation served as an

official statement of the results of the WISC,

which can play a big role in special ed.,

accommodations of getting special provisions and

getting classification.

Is that something that you might consider?

DR. ROSENSTEIN: Sure, and I think that

over the years, some investigators have shared the

results of some neuropsychological testing, but not

all of the neuropsychological tests are

administered in the same way that they would be in

a clinical setting.

It is analogous to the discussion we were

just having about the MRI. On one level you would

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think of this as a benefit, on another level you

could think of it as a risk. There are some

parents who bring their children into a study as a

child without any problems, but because they have

got suspicions that there may be some difficulties,

and then sure enough, in the course of the

evaluation, some psychiatric problems are

identified. Is that a risk or a benefit?

In the past, we have left the sharing of

information about the evaluation, what is

clinically relevant and what is not, up to the

discretion of the investigator.

DR. GREENHILL: I just want to indicate

that this is a unique situation because getting an

MRI at the NIH doesn\'t preclude you getting one

next week, but it does preclude you getting an IQ

test.

DR. ROSENSTEIN: I understand that, and I

wasn\'t aware.

DR. GREENHILL: The last thing I wanted to

mention is there are a number of issues that I

think have been addressed, and I am trying not to

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beat a dead horse with this issue of the age, but

the older an individual is who has ADHD, the more

likely he has had chronic exposure to stimulants.

Is there any way\--I don\'t think there is

any answer I can come up with off the top of my

head\--but some investigators have required them to

be stimulant-free before coming in and getting an

evaluation. That really impacts the feasibility of

a study because if you are looking even at a

13-year-old who had ADHD, they are very likely in

this country to have been exposed.

Is there any way you can factor in the

exposure, prior exposure in terms of interpreting

the results of the functional MRI, or do you think

that is a problem?

DR. RAPOPORT: I think ideally, one might

be having ADHD children who had never had

stimulants before, but that is not likely to be

true. Our own experience of over 20 years of doing

these studies, where we did have many children that

we were taking total care of, was that the 100th

response to a dose of stimulant tended to be

107

identical with the first, so for this study, I am

not really concerned.

DR. NELSON: Dr. Gorman.

DR. GORMAN: I am not through beating up

the age question. Has this question been answered

in adults? Have adults with ADHD been tested with

single doses, and have normal adults taken single

doses of stimulants to look at their brain

responses?

I ask that question because I have three

children in college, and I can tell you that their

friends\' most common request of me is can I write

them a short prescription for a stimulant medicine

during exam period. So, I suspect there is a lot of

people undergoing this clinical experiment on a

regular basis.

DR. RAPOPORT: The problem is that as Dr.

Pine and other people have shown that different

parts of the brain change, that are active, in

response to these drugs with age. Furthermore,

when you look at who are adults, you need to test

adult ADHD with adults, they turn out to be a

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puzzlingly very different population, the

attributes of adults who identify themselves as

ADHD, there are more females than males, there is

very heavy comorbidity with alcoholism. They don\'t

resemble the long-term follow-up prospectively of

children with ADHD, who, when you follow to that

age, they don\'t seem to have the same profile.

So, we don\'t believe that we would

necessarily be studying the same disorder in the

adult patient controlled, so to speak, as well as

the same brain regions.

DR. GORMAN: Leaving out the different

adult population, you seen to be in a unique

position with your 20 years of experience following

these children, that you would be able to find a

more select population as young adults that have

been diagnosed as ADHD as children.

Is that not true?

DR. PINE: You are still not going to

know, if you were to do that study, and you were to

find a difference, you are still not going to know

if that is a sequelae of having a disease for 20

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years with all the concomitant things that can go

on in the brain as opposed to what that means for a

child who presents to your office as a 10-year-old,

and you are trying to make the decision about, you

know, does this child have a normal or abnormal

functioning brain.

Data in an adult, even an adult who you

know what has happened to them definitively, over

40 years, you can never answer the question about

is the brain function that you are seeing in that

adult really just a downstream reflection of what

has gone on in the past 20 years, and what we

really need is date that speaks to the 10-year-old

child.

DR. RAPOPORT: Moreover, we are looking

for long-term follow-ups with continued subjects

right now, and they are a very small fraction, I

mean vanishingly small, that we couldn\'t do this

study. We are trying to follow up from 15 to 20

years, the 300 patients we have characterized, and

no, we are not able to find a sufficient number

that don\'t have other major disorders that still

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would meet criteria above the age of 18. I have

that data.

DR. GORMAN: The paradigm that the

American Academy of Pediatrics recommends is that

if you believe the pathophysiology is the same, is

to test, before you test in children, to test in

adults, and that is why I am asking that question.

So, I will ask once again very simply.

Has this experiment been done in adults, and does

it show that normals and adult-diagnosed patients

with ADHD have different responses?

DR. PINE: There has not been an exact

replication of the Vaidya study that was published

in 1998, doing the exact same study in adults with

and without ADHD, on the one hand. On the other

hand, there has been an extensive series of fMRI

studies in healthy adults and adults with other

forms of psychopathology looking at the fMRI

response to psychostimulants.

The feeling is that due to some of the

questions that Dr. Rapoport had raised, about how

do you make the diagnosis of ADHD in adulthood and

111

how does it relate that many people have been very

hesitant about embarking on everything that would

be involved in doing that type of a study in

adults. I would add that we share those scientific

concerns.

I think for that reason, the study has not

been done because no matter what you found, many

would question the implications of the findings.

DR. RAPOPORT: There has been one study by

Dr. Volkow, which used PET, which is using a

technique not accessible to children, that did

suggest there might be some difference with respect

to dopamine receptors, but that wouldn\'t be

appropriate, and again, she had all the

peculiarities of her adult sample that I mentioned.

DR. NELSON: Dr. White.

DR. WHITE: I had a question regarding

since fMRI measures, change in hemodynamic

response, and dopamine is involved in the

hemodynamic response, does your design take that

into account, and also, is that a rationale for

using controls?

112

DR. PINE: One of the unique things about

the study is that a particularly sophisticated

group of fMRI methodologists have been assembled at

the National Institute of Mental Health, and, in

particular, Peter Bandatini, who heads the

Methodology Group there, and in his earlier work at

the University of Wisconsin, he actually looked in

adults, the effects of various agents including

psychostimulants on bold perfusion effects in

adults.

So, Peter is a collaborator on the

protocol and ensures Dr. Rapoport and myself that

we will be able to disambiguate hemodynamic effects

due to vascular effects versus neurocognitive

effects.

DR. NELSON: Dr. Chesney.

DR. CHESNEY: I don\'t mean this to be

simplistic, but I guess where will the results of

the study take you? I didn\'t really see any

hypotheses, I sort of wrote out three or four on my

own, but other than simply learning more about,

which is absolutely important in and of itself, and

113

I know research doesn\'t necessarily have a

pragmatic outcome, but you mentioned that clinical

severity would be taken into consideration

depending on where the results came from and went

to.

But I guess in the bigger picture and in

terms of helping us assess the importance of the

stimulant in normal children, what are your

hypotheses, where do you think will take you and

what will be the next step?

That would certainly help me sort out the

overall importance other than just saying what

activates and what doesn\'t activate, which is very

interesting of itself.

DR. RAPOPORT: One, on a scientific level,

it would provide the strongest evidence to date

that there is something different in the way the

brains of ADHD children functioned, which would be

a more abstract scientific level.

i think our hypothesis at the moment would

be that with the appropriate tests where you

disengage performance from brain activity and

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response to the drug, my hypothesis is that there

would not be a difference, and this would help and

counteract a great deal of fraudulent behavior on a

clinical level that is going on, because there are

a great many people out there selling diagnostic

tests that people pay for in spite of the fact that

they have no legitimacy.

I think there is another answer here also.

DR. PINE: I will say again two things. I

think this is a great question that cuts to the

core really of the protocol, and hopefully, it is

reflected in the IRB minute notes, but the IRB

really held both Dr. Rapoport and myself, and the

entire team, to a very precise answer to that

question, and constantly asked us to reframe that.

I would say that Dr. Rapoport and myself,

while we agree on the importance of the question,

and it really is fundamental, on the one hand, and

on the other hand, maybe we have slightly different

visions about where it might go.

Where I really come from is this idea that

I think has been implicit in many of the questions

115

that people have asked about how do you tell the

difference between a child who really had ADHD and

a child who doesn\'t.

As reflected in Dr. Rapoport\'s answer, I

am not sure that we would totally agree on how

close we are to doing that. If this study were to

find similar results that Dr. Vaidya\'s study found,

that would tell us that we are getting reasonably

close to doing that, and that would tell us that in

the not so distant future, when a parent comes to

see us with a child who is basically high

functioning, who is having mild problems in school

that are very common, and the parent says to us

isn\'t there a test that you could do that would

tell me definitively whether or not my child really

has ADHD or not, this study would be a very

important first step towards developing that type

of technology and developing that type of finding.

On the other hand, if the results of the

study were negative, it would say that this

approach is not a good way to go, and that this way

of trying to develop the test as specified in that

116

protocol might not be the best way or perhaps we

might be a long way away from developing that kind

of test.

But that is really the importance of the

work. It is trying to develop a better

physiological based measure that can tell us, yes

or no, does this child have a problem in the way in

which their brain is functioning or not.

MS. TREAT: You know, it seems that there

are a lot of diagnoses of children, young children,

with ADHD. I believe Dr. Jacobs\' comments sort of

support this. As they get older, their brains

change, and many of the people that I know of who

are diagnosed with ADHD as children, got to a point

as they grew older, in the later teen years, where

they no longer needed to be on the medications,

they were better able to concentrate, and that kind

of thing.

I am not a professional, so I am not sure,

but it seems that it would indicate that they may

have been misdiagnosed when they were younger.

In that regard, to me, it seems to make

117

more sense to restrict\--is you were going to

restrict your age range, to restrict it to the

upper age range rather than the lower.

You had mentioned that you would restrict

it to the lower age range, 8 to 13.

DR. RAPOPORT: Yes, for several reasons.

The natural history of ADHD is that as children get

older, they tend to, particularly in adolescence,

many of them no longer meet criteria. It is a

disorder that for many children, when they get

older, they no longer have the problems, and when

they do, it is expressed somewhat differently,

often with more inattention and less motor

restlessness, for example

I think, in general, that there is a wide

degree of misdiagnosis of ADHD, but I think that

when it is done carefully, and when you require

that you have a sustained period of more than six

months, starting before the age of 7, and going on

with the considerable interference with functioning

in at least two settings, not just the home or not

just the classroom, that, in fact, the misdiagnosis

118

at a certain level of severity, of the sort that we

do in our studies, I think the prediction from year

to year of continuation up until adolescence is

very high.

The natural history of the disorder,

though, is different, and I think the points that

were made by several committee members is that I

think it does get more complicated in the older age

range, and that anything we found out earlier would

be much more generalizable to the vast majority,

the great majority of ADHD children and the ones

for whom these questions were initially addressed.

DR. NELSON: Thank you. I think at this

point, I would like to transition to some material

we need to get on the table before we do our public

discussion period at 11:00 and then perhaps give

people a chance to stretch their legs before that.

I would like to thank Dr. Rapoport for her

patience and clarity in answering our questions,

and Don, as well, and your colleague.

DR. RAPOPORT: Thank you. Dr. Pine had to

make a plane, and that is why he left early.

119

DR. NELSON: Thank you.

At 11:00, we will be having a time of open

public hearing, but before that, there were some

comments that were submitted in response to the

request for public comments that I was going to

summarize.

Basically, we can then take a short break

before we have the open public hearing at 11:00.

Summary of Submitted Public Comments

Robert N. Nelson, M.D., Ph.D.

DR. NELSON: The full text of the public

comments should be in the packets that people have

for this meeting. I have summarized them by

basically dividing them into issues, so we can see

what each person said or didn\'t say about given

issues.

The backgrounds of the three responses

that we received, one was the parent of a child

with ADHD, also who had chaired an IRB in the past.

One was a health professional, and the other was a

lay person who also happens to be a grants and

contracts administrator at a university level

120

institution.

In terms of scientific merit, parent of

the child with ADHD, and these are quotes taken

from those comments, thought that there was a

possibility of great scientific benefit with

respect to the causes, diagnosis, and treatment of

ADHD, which poses significant challenges to many

children and their families, and may also help

distinguish between appropriate medical uses of

dextroamphetamine and more questionable uses.

The health professional simply commented

that the studies needed to generate important

information, and the lay person felt that being

able to comment on the scientific validity or

utility of doing the study, particularly in normal

children, was beyond, in this case, her particular

expertise.

In terms of risks to subjects, two

commented on this. The parent of the child with

ADHD felt that a single dose of dextroamphetamine

is unlikely to be harmful, further, there are

safeguards in place, and the child and/or parent

121

and guardian may discontinue participation at

anytime.

The lay person expressed concerns regard

the drug abuse potential that might be suggested by

having one dose, which might lead to curiosity

about additional doses.

In terms of parental permission, the

parent of the child with ADHD thought the consent

documents are clear. The health professional

thought they were clear. The lay person had a lot

to say about the consent forms, and I have not

quoted it all, I have simply summarized her points.

I didn\'t feel that the documents fully

explained the procedures involved in the study, and

particularly she mentioned the screening, physical

exam, the teacher contact for rating scales,

genetic testing for twins, the decision to test

twins with respect to zygotic status could have

emotional implications for parent and twins, the

MRI in terms of full description, and she felt that

the technical language, it was a bit too technical

as opposed to lay terms, and that they didn\'t

122

really provide much discussion to the alternative

to participation.

In terms of child assent, the health

professional said that the assent documents need to

be written at age appropriate reading level, but

did not say, although you could infer, that they

didn\'t feel that this was the case with these

forms.

The lay person felt the inclusion criteria

in the protocol states that it should have consent,

but she pointed out they should have talked about

assent, and also commented on the fact that the

pregnancy testing was not mentioned in the assent

form, nor whether the results will be shared with

the parent.

In terms of financial incentives, the

parent of the child with ADHD felt that the

payments were not too high, but did feel that the

payments ought to be directed to the child in some

fashion.

The lay person felt, you know, maximum 570

being paid, but it doesn\'t describe who will be

123

compensated. To this person, it seemed like a

large amount for the child, and it seems

inappropriate to compensate the parent. \"It

appears coercive\" is a direct quote. With no

direct benefit to the child, it appears that the

parent is benefiting financially while putting the

child at some risk and certainly an inconvenience.

The benefit section refers to the compensation as a

benefit. Again, this becomes coercive.

Assessment of risk category. This was the

parent of the child with ADHD who you may recall

also chaired an IRB. For children with ADHD, I

would consider the study a minor increase over

minimal risk within the range usually borne by

children with the disease with an offsetting

societal benefit that could not otherwise be

gained.

For the normal controls, the risk is

greater than minimal in that they would not receive

the medication or the functional MRI in normal

life, however, it is unlikely that a single dose of

dextroamphetamine would cause harm, and again

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safeguards are in place.

The bottom line. The parent of the child

with ADHD felt that I would encourage approval of

this study, and the lay person said I do not feel

comfortable about approving this study in its

current form.

So, that is a summary of the three

responses that we received as a request for the

public comment period, and you have the full text

of those comments that are being handed out now,

and I think were available to people that are here

for the public session.

In order to give us at least a little bit

of a transition between our discussion and the

public comment period, I would suggest we take a

break, which by my watch will be about 12 minutes.

We will take a short break. Thank you.

For the panel members, I was asked to read

this before the break. The discussion of the

protocol is a public one, therefore, we should not

discuss the protocol amongst ourselves during the

break.

125

\[Break.\]

Open Public Hearing

DR. NELSON: We will now be moving into

our open public hearing. Before introducing the

people who have requested time to speak, I have a

statement to read.

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decisionmaking. To

ensure such transparency at the open public hearing

session of the Advisory Committee meeting, FDA

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, FDA encourages you, the

open public hearing speaker, at the beginning of

your written or oral statement to advise the

committee of any financial relationship that you

may have with a sponsor, its product, or, if known,

its direct competitors. For example, this

financial information may include the sponsor\'s

payment of your travel, lodging, or other expenses

in connection with your attendance at the meeting.

126

Likewise, FDA encourages you at the

beginning of your statement to advise the committee

if you do not have any such financial

relationships. If you choose not to address this

issue of financial relationships at the beginning

of your statement, it will not preclude you from

speaking.

At this point, there are two individuals

that have requested time to speak, and since Vera

Sharav had requested it officially prior to the

meeting, I think we will allow her the first

position.

You can speak from the podium, so you can

see us, and we can see you.

Vera Sharav

MS. SHARAV: I am Vera Sharav and I am

President of the Alliance for Human Research

Protection, an organization that focuses precisely

on ethical research issues and recently, in

particular, on ethics of using children in

non-therapeutic experiments.

Having listened to some of the

127

presentations as far as the scientific issues, I

think part of what I was going to comment is right

flat-out there.

There is a fundamental flaw with these

neuroimaging experiments including this one, and

that is, that the children diagnosed with ADHD for

the most part have already been exposed to drug.

Those drugs, dextroamphetamine, Ritalin, whichever

one they use, does, in fact, alter the brain, and

there is no quarrel with that, there is no

argument.

How can you then do a scientifically valid

experiment in which you are comparing the brains of

children who have never been exposed to drug and

those who have and then claim to find some

differences that you could be sure of are not drug

related?

I think the fact that this hasn\'t been

done, or if it has been done, it hasn\'t been

published, we ask why. Wouldn\'t it be simple to,

first of all, establish, in fact, what the brains

of normal children are like and do the ADHD differ?

128

Now, as far as this experiment, this

experiment would expose healthy, primarily

disadvantaged children, let\'s face it, with the

amount of payment, to a brain-altering substance

for no benefit to that child.

Now, this is a clear-cut affront to the

moral standards of the Nuremberg Code, the

Declaration of Helsinki, and the 1983 Federal

Protections that were established precisely to

protect children from experiments such as this.

Dextroamphetamine, I want to remind you,

is a DEA Schedule II drug. It is a controlled

substance, which means it is addictive. Now, Dean

Nadler of UCLA has done extensive work to show

that, indeed, Ritalin is addictive and leads to

addiction.

The proposed experiment fails to meet the

fundamental principles of the Belmont Report -

respect for persons, beneficence, and justice,

which are the very basis for 45 CFR 46.

Why are we even considering using children

as human guinea pigs in such an experiment? But we

129

are.

The Advisory Panel would be derelict in

its responsibility if it did not study carefully

the landmark 2001 Maryland Court of Appeals

Decision, Higgins v. Kennedy Kreiger, which

resolutely affirmed the Nuremberg Code and

prohibited using children in non-therapeutic

experiments if there is any but a minimal risk.

The Court stated: \"It is not in the best

interest of any healthy child to be placed in a

non-therapeutic research environment which might

possibly be, or which proves to be, hazardous to

the health of the child in order to test methods

that may ultimately benefit all children.\"

The proposed experiment is a giant step

backward. It was immoral when Dr. Rapoport

conducted it in 1978, and it is immoral today.

Changing the scanning equipment does not change the

immorality of the experiment.

By what ethical standard is it acceptable

for anyone to entice a child and parents with a

\$570 stipend to become an experimental human guinea

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pig? But then whose children are we considering

here?

If this experiment goes forth, the lessons

to disadvantaged children will be to earn money,

sign up for drug experiments, amphetamine today,

cocaine tomorrow, Ecstasy next month. There are

always researchers looking for subjects in

experiments, such as this.

Should children be the first on whom this

is done? Again, I refer to the Maryland Court,

which is the highest court in Maryland. It

declared: \"To turn over human and legal ethical

concerns solely to the scientific community is to

risk embarking on slippery slopes that all too

often in the past, here and elsewhere, have

resulted in practices we or any community should be

ever unwilling to accept.\"

In effect, the Court declared quite

clearly that American society does not consider

children the equivalent of rats, hamsters, monkeys,

and the like.

The Alliance for Human Research Protection

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urges that the research involving children should

apply the Maryland Court standard, and not what we

have been hearing today. It is very easy to find

excuses to use children, but how will you feel

should something go awry, as in research it very

well might. There are not guarantees.

Thank you.

DR. NELSON: Thank you.

The next speaker is Alan Milstein.

Alan.

Alan Milstein

MR. MILSTEIN: Good morning. As to a

conflict of interest, I am an attorney. I

represent victims of clinical trials. I also

represent a number of mothers of kids with ADHD,

alleged ADHD. So, if you see it as a conflict, so

be it I guess.

Let\'s look at the three principles of the

Belmont Report. The first is justice, which has to

do with the selection criteria. Now, when you are

offering \$570, you know that is an admission that

you are, in essence, going to pay people, in

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essence, to rent their children. You are going to

induce those who need the money to volunteer their

children for this experiment.

It\'s just you can\'t use money as the

inducement. Now, I know that Dr. Rapoport seemed to

imply that somehow that was just added in, and we

don\'t need the money, so let\'s assume for the

moment that you eliminate the money at all, because

really, the only reason to participate in the

experiment is altruism.

The second principle of the Belmont Report

is beneficence. This has to do with weighing the

risks against the benefits, and there are no

benefits at all to the subjects.

What are the risks? Now, it was unclear

to me exactly how she was analogizing the single

dose. I mean she was saying, well, gee, these kids

in these schools drink a lot of sodas. I asked one

of the individuals involved about how many cups of

coffee would the single dose be. I think he said

four to five, is that right?

I mean would you do the experiment, would

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you do an experiment where you give healthy child

five cups of coffee? Would you do an experiment

where you give a healthy child a single dose of

cocaine?

What about the other risks? The only

risks that were talked about by the principal

investigator was the risk of a single dose of this

amphetamine. Now, she is saying it is minimal

risk. I personally don\'t buy that, but there are

other risks, there are the emotional trauma that

the children will go through, both from going

through the MRI and also let\'s look at what is this

study really saying to the kid with alleged ADHD.

We are going to put you through this MRI.

Why? Because you have a brain disorder. Is that

an emotional scar that the child, who is the

subject in the experiment is going to bear,

particularly an 8-year-old? Here, come into our

lab, 8-year-old, you have ADHD. You have a brain

disorder, and now we are going to put you through

this big MRI to see if we can find it.

This is not an experiment with minimal

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risks, and when you weigh the risks against the

benefits, the benefits are zero. There is no way

you can come up with any kind of equivalency. I

mean do you think you could do this experiment with

no informed consent?

Because, you know, you can do an

experiment with no risk at all without informed

consent and get away without informed consent

because there is no risk. Do you think in any way

in the world you could do this experiment without

informed consent? Of course not. There is risk to

the experiment, both to single dosing these kids\--I

mean you could have a very rare anomalous response

to the single dose by one kid.

What is going to happen if one of the

children, whether you are talking about the ADHD

kids alleged, the ADHD kids, or the healthy kids,

what will happen if one of these subjects has an

extreme reaction to the single dose?

I mean there are extreme reactions to

single doses of Paxil and Wellbutrin, and certainly

cocaine. What will happen if you have that kind of

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extreme reaction?

The third principle of the Belmont Report

is respect for persons. This has to do with the

informed consent process. Now, I disagree with the

way Skip was showing the CFR with respect to what

the requirements are for informed consent when you

are talking about children, because there is a

difference between a therapeutic study and a

non-therapeutic study when you are talking about

can you allow a parent to give surrogate consent

for a child.

That is the issue here - can a parent give

surrogate consent for a child in a non-therapeutic

study where the child is going to receive no

benefit, which is different than asking the parent

whether he or she will give consent for the child

in a therapeutic study, such as a cancer study or

some child disease study where there could be a

perceived benefit for the child.

It is my view that there can be no

surrogate consent in that situation. Why not?

Because the only reason to agree to be in a

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non-therapeutic study is altruism. That is the

only reason to do it. That is a moral choice that

an individual will make for the benefit of society.

No parent can make that moral choice for the child.

It is not the parents\' choice. It\'s the

individual\'s choice.

That is what respect for persons means, it

is individual autonomy, whether you are talking

about a child at the age of 8, or you are talking

about somebody with Alzheimer\'s who can\'t make that

kind of choice for him or herself. Nobody can make

that moral choice for another person that you

should do this altruistic deed for the good of

society.

So, it is my view that this study offends

all three principles of the Belmont Report.

Let me talk just briefly about this,

because the assumption, and if you read through

that whole protocol and the informed consent

document, the assumption is that there is\--because

there is nothing in there about the controversy

about ADHD\--the assumption in all those documents

137

is that this is a real disease, it\'s a disorder.

What is this ADHD? It\'s 3 to 5 million

kids in this country are diagnosed as having ADHD.

That is about 5 percent of the children in this

country. That compares to 0.03 percent in England.

Is this a disease that only American have? It is a

disease diagnosed 80 percent in boys in this

country. Is it a disease that only boys have?

I mean anybody who has taken these, you

know, the Conners test, or the DSM-IV test, I mean

I have taken it, I fail every time. I had what my

grandmother used to call Sphilkes when I was a

child, I still have it. That doesn\'t mean I am

ADHD. Why? Because anybody who sat through the

morning session, if I were to quiz everyone when

you sat through the morning session, did you lose

your focus occasionally? Did you mind wander

occasionally? Of course. Does it mean you are

ADHD?

It is also a white, suburban,

upper-middle-class or middle-class disease, because

those are the individuals diagnosed with ADHD.

138

I was struck by another line in the

materials under Conflicts of Interest, which is a

subject that it means a great deal to me, because I

was involved in the Gelsinger case, which really

brought to light this problem of conflicts of

interest, and the researcher said none.

Now, just because it\'s government

researchers does not mean there are no conflicts of

interest.

The study of ADHD is rife with conflicts

of interest. I mean this is a disorder that many

people believe was manufactured by the

psychiatrists or the drug companies, or at least if

not manufactured, mythologized to the point that so

many individuals in this country, so many kids are

diagnosed with ADHD and prescribed these drugs.

So, to just blindly say there are no

conflicts of interest, I think reflects a

misunderstanding of what we mean by conflicts of

interest.

So, in short, I would strongly advise that

this study not be approved.

139

Thank you.

DR. NELSON: Thank you, Alan.

Let me ask if there is anyone who is

attending this session who has not expressed so far

a desire to speak publicly, if there is anyone who

would want to at this point provided you have lost

your focus?

\[No response.\]

DR. NELSON: Okay. What I would suggest

we do right now is perhaps present the questions

and get that done at this point, and then we can

start with our continued discussion of the issues.

Questions and Panel Discussion

DR. NELSON: The questions for the panel

are four. Let me just read them and then provide a

couple of overall comments.

First, what are the potential benefits of

the research, if any, to the subjects and to

children in general?

Second, what are the types and degrees of

risk that this research presents to the subjects?

Third, are the risks to the subjects

140

reasonable in relation to the anticipated benefits,

and is the research likely to result in

generalizable knowledge about the subject\'s

disorder or condition?

Fourth, does the research present a

reasonable opportunity to further the

understanding, prevention, or alleviation of a

serious problem affecting the health or welfare of

children?

Now, those are the questions, and there

may be other questions by the end of the day that

we need to come to a decision on as far as the

regulatory burden of deciding can this go forward

and under what conditions, under what category, if

it may.

Procedurally, I would just suggest that we

sort of focus in three separate steps. One is what

I would call protocol related scientific issues and

continued discussion of those issues that have been

raised.

After we get some clarity on that, moving

into discussions of risks and benefits, and those

141

sorts of issues, and then at the end, then consider

issues of assent and permission, and the like.

All of our various recommendations, as I

think about trying to sort of chair an IRB meeting,

and some of you have already done this, and do it,

so there may be different styles, but I generally

assume if someone brings up a recommendation, that

if I don\'t hear anyone object, that that is

something that can go forward.

So, I think it is important if someone

says I think this should happen, if someone

disagrees, to make that clear, so we can then have

that as an explicit discussion, because if all of

us just simply start saying, well, we agree with

this, we agree with that, we agree with this, we

are going to be here a long time.

The other thing that I generally encourage

us to do is we are also, we are actually not an IRB

although the issues we are addressing are. I know

there is a fair amount of criticism that has

already been labeled about the consent documents

and the like.

142

I don\'t think we need to wordsmith. I

think if we provide guidance in terms of what needs

to be in those documents, that we can rely I am

sure on the offices of both the FDA and the OHRP to

make pretty well sure that they are wordsmithed

independently of the IRB and the like, so listing

what we think need to be in there is one thing. I

don\'t think we need to get into the specific

language per se unless there is something such as

adverse events that need to be listed particularly.

But I would encourage us to try and minimize that

over time.

At the end of the day, hopefully, I will

be able to sort of summarize in a complete fashion

exactly what we have decided and what our terms

are.

So, with that, we basically, and we will

eat lunch at some point in this, as well, let\'s

just open it up.

There has been some important scientific

questions that have been asked, and I often like to

start in IRB meeting at least by turning to the

143

people on the committee that are not involved in

the protocol, and so are not at least directly

conflicted as investigators to get their sort of

independent assessment of some of those issues.

I think, Dr. Greenhill, you had raised the

issue of chronicity of treatment and the issue of

cause and effect, and how one can tease apart, if

you see a change at age of 12, they have been on

drugs since the age of 6, what is drug, what is

brain.

It may be helpful to me to sort of hear

the scientific experts sort of first give their

overall assessment and picture of this, and then we

can see what direction we head at that point.

Do you want to comment first, Dr.

Greenhill?

DR. GREENHILL: Yes. I had raised the

question about exposure, different levels of

exposure. It doesn\'t preclude recruiting a wide

range of individuals as long as one has a way, some

form or another, to be able to use it as part of

the analysis of the results, and to get some

144

documentation, if possible, of exposure.

I just wanted to raise the question to the

investigators to see if they had thought of that as

covariate in the analyses. I think it is probably

going to be difficult to find stimulant-naive

individuals in the ADHD groups.

Clearly, they will be able to find them in

the groups that they believe with no mental

disorder. So, it is important to be able to

determine whether the effects they see have to do,

not in terms of performance, have to do with

exposure.

I didn\'t have anything more to comment

other than that. It would be helpful in the

protocol summary form to be able to address that

fact.

DR. NELSON: Do you think that effect

would be a duration of exposure or just the

presence or absence of exposure, and if it\'s

duration, how would you be able to tease that apart

with an N of 14 in either arm?

DR. GREENHILL: It is very hard to know.

145

We found that one of the primary covariates when we

did the MTA study in terms of the dose, that the

child ended up on, as his or her optimal dose, in

terms of clinical response, and about a third of

the subjects were 7-year-olds, 7- to 9-year-olds,

had had previous exposure to psychostimulants.

Those are the individuals that ended up on

the highest doses in order to get a response. So,

it appeared to affect in the sample about 288

children. The dose that I have heard Dr. Rapoport

looking for, she would hate to put someone in the

study and have them be outside of their response

range, then, as a Type 2 error, conclude there were

no differences between the groups, because they had

used the wrong dose.

So, it is helpful to have at least some

indication of whether the individual was on

medication before and what the dose level was. You

can make some adjustments in terms of if they

weren\'t on dextroamphetamine, what the equivalent

dose would be.

That said, I just want to mention that in

146

terms of this protocol, this is an extension of a

protocol that was done 25 years ago almost, and was

one of the most important protocols to come along

in the field of children\'s mental disorders for a

variety of reasons.

I think it was kind of a classic study

took a bold step and included individuals with no

mental disorder, when this field had really

struggled with that. A number of surrogates had

been used, and the studies gave no meaningful

results. One study used kids with reading

disability versus those with ADHD, and was really

unable to draw any conclusions about whether there

was a paradoxical response or not.

When Dr. Rapoport carried out this study,

it helped the field immensely because doctors are

no longer able to give the medication as a

diagnostic test because clearly, the responses were

the same in individuals with no mental disorder,

and that was very, very helpful.

I see this as another step in the advance

of science to be able to use the model of comparing

147

individuals without the disorder to those with the

disorder using the most advanced kind of techniques

that among the techniques available to study brain

function has actually low rates of risk and

techniques that are used across the age range

routinely in medical situations, such as the MRI.

I think it has very high scientific merit,

and in terms of single dose of dextroamphetamine,

among the doses that are prescribed by physicians

in the community, although I agree it is classified

as a Schedule II, it is safer than many of the

other medications that are used in practice.

Just if you talk about toxicity and

lethality, common drugs like aspirin are far more

lethal, and you can give a single dose of aspirin

that will remove someone\'s hearing or cause massive

hemorrhage. You can\'t do that with

dextroamphetamine, and aspirin is

across-the-counter medication.

I am not saying that dextroamphetamine is

benign. It is just that we are talking about a

small single dose, and it is not comparable to

148

cocaine, it is not comparable to Ecstasy, it is not

comparable to heroin, it is not comparable to

giving someone cyanide.

I mean the terms that we are throwing

around and drugs that were being compared are so

different that it is hard to know how to even talk

about them in the same sentence.

Dextroamphetamine is the medication used

in the treatment of ADHD that has the longest track

record. It goes back to 1937. There is far more

data on its safety and efficacy in terms of

duration, across time, and in terms of long-term

side effects than we have with just about any other

medication used in the treatment of mental

disorders for children.

Dr. Rapoport is using a dose that is a

lower end, not the bottom dose, but the lower end

of the efficacy scale. The approved FDA range for

that drug, for it full, total-day dosing, is 40

milligrams. That is the top dose. The lowest dose

is 5 milligrams. It is approved down to age 3. It

is one of the only psychoactive drugs, it is the

149

only psychostimulant that is approved below age 6.

So, the range of safety is greater than

that of psychostimulants or other medications used

for ADHD, and so comparatively, within the range of

treatments, it is a safe treatment, a single dose,

and there are lots protections offered in the

protocol.

My only urging on the part of the consent

and assent forms is I feel a lot more descriptive

material needs to be provided to families, so they

can get their worries and concerns addressed

upfront about growth, addiction sensitization,

weight loss, need for special diets, difficulties

with sleep, impact on academic performance, all

that can be put in.

Secondly, I really urge the consent form

and the investigators to think of possible

benefits. I agree with everything that has been

said. This study offers no specific benefit to the

children who have no mental disorder. It will be

really stretching a point to say a single dose

would offer any benefit to someone with ADHD,

150

however, there are assessment procedures which

could be beneficial to any of the children in the

study, that are being done already.

It requires some work on the part of the

investigator to put them in the form of a report.

DR. NELSON: Let me keep this on the

protocol for a second and let me ask you a

follow-up on that dosing question, and then go to

Norm, who I think had some questions.

This issue of the dose and the chronicity.

Your comment about the longer they were on the

stimulant, the higher the dose, they needed to get

a dose response clinically, could one perhaps try

and get some uniformity among the ADHD group by

making, as an entrance criteria, the dose that they

may be one, for example, that they would only

enroll subjects that were on, for clinical

purposes, 10, 15, 20 milligrams, whatever would be

appropriate, instead of across the whole range of

stimulant use.

Would you, by doing that, (a) could you do

that, or would the older ones always be on the

151

higher dose, and (b), would that result in a more

uniform sort of population that you could begin to

at least make comparisons across groups instead of

having a wide variability within group?

DR. FOST: Why not limit it to

treatment-naive patients? I mean it is a common

diagnosis. How hard would it be to recruit the

study to treatment-naive patients if you think this

is a serious design issue?

DR. GREENHILL: Maybe I can address that.

Going back to a study that was designed a long time

ago, 12 years ago, the MTA study, the decision was

made\--this was a study that was supposed to answer

a lot of questions about the comparative efficacy

of psychological versus medical treatments\--the

conscious decision was made to pick a young age

group, not an older age group, because the

presentation of the symptoms of this disorder

changes with age.

Younger children have more motor

disruptive kinds of problems, older children have

more academic performance and judgment kinds of

152

problems. We found also that we had a higher rate

of children who had not been treated with

stimulants if we picked a younger age group.

The younger the age group, the more the

dopamine system is in development, and the narrower

and younger the age range, the more the

developmental issues are not confounding the

responses.

So, if I were designing this, and I had

carte blanche, I would go for a group of children

who were 7 to 9 years old, and I could take just

stimulant-naive kids in that case, because there

would be a number of them that wouldn\'t.

If I were going for an older age range, on

our IRB, we would look for individuals who had some

difficulty with treatments, and therefore, had not

been exposed to a lot of stimulant treatment, but

then again you run to the confound that if you take

that group and give them stimulants, then, you may

get all kinds of unpredictable responses.

So, I think it is best to go with a group

that is relatively stimulant-naive and younger, in

153

a narrow age range, deal with all the developmental

issues, not only in terms of the performance on

measures, but actually the state of the dopamine

system.

Now, I have, as a conflict of interest,

this is not a financial one, it is a scientific

one, my area of interest is in preschoolers,

because that is where the maximum amount of

development in the dopamine system is occurring,

and I have had to deal with a lot of ethical issues

and studying children ages 3 1/2 to 5, who have

attention deficit hyperactivity disorder.

We have a mountain of developmental and

scientific issues, but that particular group is an

early onset, so therefore, shows more extreme,

severe kinds of problems with ADHD.

I am not recommending it for this study at

all, I am just saying that it led me to study a

younger age group in order to deal with these

problems of finding stimulant-naive, because all

our children have to be stimulant-naive to get into

our protocol.

154

But there is another reason that I think

an age range just at the start of primary school is

important. That is the peak time for

identification of the disorder, between second and

fourth grade. That is the time when the impairment

is the most, when the individuals are showing the

most difficulties with their academics and they are

getting the highest rate of peer rejection for the

disorder.

Peer rejection is one of the most

predictive factors in the younger child for later

disability. It is far more predictive, for

example, than IQ, for low self-esteem and problems

in adolescence, you know, as a test, and that has

been found in the fast track study and a number of

other studies that have looked at kids with

disabilities.

So, because peer rejection is the greatest

because academic difficulties are the greatest,

that is actually the modal age of referral over the

past 10 years for kids with ADHD. That is the

prime time to focus one\'s efforts if you are going

155

to compare performance differences and other

differences between kids with no mental disorder

and kids with ADHD, and it is also a time when the

dopamine system is in its most rapid form of change

and development.

So, for that reason, I think they would

have the best yield in terms of brain differences

on functional MRI, and those would be the kids most

in need.

Now, of course, you have got to balance

against that, this feeling that an assent really

can\'t be done. At our IRB, it is 8 years of age

kind of roughly as a working rule. Below 7 or 8,

you can\'t really get an assent form.

But we have had to work out assent

procedures for 3- and 4-year-olds, and that is a

requirement we put in our forms that have to do

with a child\'s ability to be able to say no during

a research protocol, and we don\'t take kids in of 3

or 4, or 5 or 6 who the parents and we don\'t

believe can really object if they are in a

procedure and say no, I don\'t want to do this.

156

So, that is another form of assent. It is

not written. So, for all of those reasons, I think

the protocol, some of the issues scientifically, we

are only talking about the science, some of the

confounds could be avoided if they picked a narrow

range toward the younger end, not below the age

that most pediatricians start treatment, and if you

start at age 7, you have got good data meeting all

the DSM-IV requirements.

One of them is duration of 6 months and

onset of impairment before age 7. In that way, you

could get more stimulant-naive kids. You wouldn\'t

have such a difficulty with feasibility, and I

think it might address some of these other

questions.

DR. NELSON: Let me see if I can keep us

focused on that point, but just to make a comment

in case people think we are off our mark. I mean

the first thing we need to decide if this is sound

research design, and if it\'s not, then, issues of

vital importance and reasonable opportunities sort

of fall by the wayside. So, let\'s stay on this

157

question.

What I hear you saying is that, yes,

focusing in the younger age group, because that

came up in the discussion earlier with the

investigators, and then perhaps trying to narrow

that range either to treatment-naive or at least

early treatment or treatment predictable sort of

uniformity within that population would help the

science.

Are there other people who want to comment

on that particular point?

DR. WHITE: The longitudinal studies of

ADHD have been in structural imaging studies, and

the functional imagine studies look a little bit

different in the sense that you are looking at

change.

So, what would be helpful to see is when

the ADHD subjects are off medications, what are

their symptom patterns at that time, and then how

do they change when they are on medication.

So, the chronicity of I guess being on

medication with the functional study is different

158

than with the structural imaging study. We are

looking at changes in gray matter, white matter,

CSF, and that.

DR. NELSON: The protocol has them off for

36 hours before they get, is that a sufficient time

to be off, or are you talking about off for a

longer period of time in terms of effect of being

off?

DR. WHITE: It should be long enough, it

would be helpful to get rating scales, and which I

think they are doing when they are off medication.

It would be nice to know how they were doing in a

setting, such as a school setting, so ratings at

that period.

DR. NELSON: Dr. Hughes.

DR. HUGHES: As we talk about the

scientific merit of the study, I think it is

important that we differentiate, well, as we have

had this discussion, one of the thoughts I have had

is that hopefully, over time, there will be a

series of studies that begin to look at this issue,

that this is not the end-all and be-all study that

159

needs to answer all questions.

I am a bit concerned at some of our

comments that that is where we may be going. In

some ways, it makes sense to me that if, indeed,

this study moves forward and a finding is that

there is difference between those normal healthy

children and children with ADHD, then, you begin to

ask, okay, what is that difference about.

Is it because they have been on medication

for a period of time, is it important, then, as a

next step, to look at naive children. I am not

saying necessarily that that is what we should talk

about, but I think it is so important that we not

think of this study as the only shot at examining

this or moving forward.

These are issues that I think a number of

the things brought up today, that it may well take

a series of studies to really fine-tune and move

forward. And that is different than the scientific

merit of what is proposed today, and I just would

like us to be careful about differentiating those

two.

160

DR. NELSON: A quick follow-up and then

Norm. With that approach, what would be the first

study that you would do, and is this it?

DR. WHITE: Well, given that we are not

yet sure that there is a difference between healthy

kids and kids with ADHD in this area, I think the

more we restrict the subject population, while it

makes for a cleaner and tighter research protocol,

it also\--it is the difference between, well, it

services research, the difference in my mind

between efficacy and effectiveness, that while the

research protocol gets tighter and tighter, its

actual meaning in the real world gets narrower and

narrower.

Does that make sense to people?

DR. NELSON: In other words, even if they

needed a more narrow range to be able to see some

significant differences, that it would still be

useful as a pilot maybe to see differences in the

broader range is what I hear you saying. That

would help you then interpret and design subsequent

studies.

161

DR. WHITE: Yes, that\'s right. Thank you.

DR. NELSON: Let me go to Norm.

DR. FOST: I just want to sure I

understood Dr. White\'s comments. I thought I

understood Dr. Greenhill to say that prior dosing

could be a confounding variable, and did I

understand you to say that you disagree with that,

that you think that being off 36 hours erases that?

I am just trying to understand if that is a

critical design issue or not.

DR. WHITE: Actually, what I was saying

was that the changes in the brain that have been

reported have been structural brain changes, and

there is I think a lot of questions that we don\'t

know, and that I would say as far as when you are

looking at functional brain changes, the most

important thing is what is the change from their

baseline off and on medication, and if those

changes occur, significant changes, if they are

symptomatic with ADHD off medication, they have all

the symptoms, and you treat them with medication,

and you are looking at changes in essentially blood

162

flow within specific regions of the brain, that is

the question that you are addressing.

DR. FOST: So you are not terribly

concerned about the confounding of prior doses?

DR. WHITE: I am not. It would be very

nice to have naive subjects, but the again you are

asking a question that might be a little bit

different and less generalizable.

DR. NELSON: Dr. Gorman.

DR. GORMAN: Again, this is a procedural

issue that I will defer to the Chair, but at an IRB

I sit on, we generally don\'t discuss potential

protocol changes until we discuss whether we feel

the present protocol is acceptable.

So, while I have found a lot of this

information learned and has certainly increased my

appreciation for some of the difficulties in

performing this science, it still hasn\'t addressed

for me the question of whether the present protocol

will be able to get over the hurdles that we have

assigned for it.

So, the question to me is that we are not

163

in the position to suggest changes or seems

procedurally, we should discuss the protocol as

presented and then discuss ways we would try to

improve it if we find it unacceptable in its

present form.

DR. NELSON: Why don\'t you speak directly

to that point, then, if you want to?

DR. GORMAN: With the permission of the

Chair.

DR. NELSON: You don\'t have to be quite so

formal.

DR. GORMAN: In this group sometimes that

is an advantage.

I have appreciated that there was a

short-circuiting of the discussion at the IRB level

in terms of their discussion in detail of the

informed consent, and that has sort of placated my

concerns about the deficiencies in some required

elements that were not in the informed consent.

However, that did not placate my concern

about the protocol as written, which had

discrepancies and errors present in it. It has

164

been over one year since that IRB review. I would

have assumed that those difficulties that were

exposed or discussed or illuminated during that

discussion would have resulted in a protocol

amendment, which would have been included in the

protocol, so that when we reviewed the protocol, it

would have been in a form that was close to what we

are actually going to approve if this was an IRB.

I found the plasticity of this protocol at

this late state somewhat disturbing. The fact that

the dose could change, the age range of patients to

be included in the study could change, the allowed

dosing would change, the inclusion/exclusion

criteria would change, all of which was discussed

by the principal investigator at the podium, which

makes me look at the protocol that I am looking as

still a work-in-progress rather than something that

is ready for review.

DR. NELSON: Norm.

DR. FOST: But, Rich, I mean I agree with

much of what you said, but suppose these areas were

cleaned up, that is, the consent form were adequate

165

by your measure or anybody else\'s, do you think the

basic issue of doing the study as designed, giving

the healthy and affected kid this dose, with these

MRIs, and so on, is approvable given a coherent

protocol with all the ambiguities about dose, and

so on, clarified, and an adequate\--

DR. GORMAN: Norm, that is exactly the

question that I am asking, which is if I had the

clarified protocol, I would be then willing to

answer that question, but not knowing at this point

what the cutoff dosage for the dosing will be, what

the age range of the subjects will be, I am not

ready to answer that question.

DR. NELSON: Let me hop in here, Norm. My

sense is given that your comments\--and I have heard

a lot of similar comments\--is that there is no

question that we would say whether it is under any

one of these four categories, that this could be

approved with no modifications.

So, I think that is fairly easy to

probably get off the table at this point. So,

then, the question becomes is it possible for us,

166

as this group here, to make recommendations about

what modifications we think would be necessary in

order for it to be approvable under any one of

those four categories.

Now, if this was an IRB, which we are not,

there would be a discussion as to whether we should

to the investigators\' work for them or just send it

back for more work, and wait to do that later.

Now, I wouldn\'t recommend we do that here

precisely because we are a different body, but we

need to provide the guidance that would allow that

to happen, and partly because, you know, we don\'t

have another meeting next week or next month

scheduled as you would on an IRB.

So, my sense is we are in a position where

we need to say what is it that we think would need

to happen with this, whether it\'s protocol

differences, whether it\'s consent differences,

whatever differences those are, once we get to a

discussion of the categories and the risks, may or

may not approve it under those four categories.

Then, we need to specifically address what

167

got it here, which is the dextroamphetamine for the

healthy children absent a condition and what the

risk classification ought to be for that.

But I am assuming for the sake of

discussion that we are going to have to specify all

the modifications that we think would be required

for us to even engage in that conversation.

Is that fair? Norm.

DR. FOST: First, I agree with what you

say, I just want to add to it. This is not an IRB.

If it were an IRB, we would defer this, but send

the investigator a message that we think this\--if

we are rejecting it, then, it is not deferred\--but

what we would probably do is say we think the basic

idea here is approvable, if there were agreement

about that, but there is a lot of problems you need

to clarify, A, B, C, through X. Send it back and

then we will reconsider it, but it is approvable is

the word we would use if it were tidied up, but the

core substantive ethical issue that we are raising

here, of exposing these children to this drug, in

this dose, and this MRI, we think it is basically

168

okay.

So, I will just state my view, I think

that core thing is okay, I actually think it is

okay under 406. I think it\'s a minor increment

over minimal. We may not get agreement, unanimity

about that, we may not get any other votes on that,

but under 407, with the criteria that you outlined

earlier, I think that\'s approvable.

That said, I think it\'s regrettable that

there is so much ambiguity and sloppiness, if you

will, about some of it, but that is correctable,

and I think if those things were corrected and came

back to the IRB, I don\'t think this committee is in

a position to re-meet, and I don\'t think it needs

to.

It is a little troubling because the IRB

didn\'t seem to pick up on any of these things

either, and that is what some of us are concerned

about, but if this group specified that on the core

substantive issue, which I think is what we are

really here for, and not to micromanage the consent

process, with side comments that we think A through

169

M really need to be tidied up, my position is that

it is approvable under either 406 or 407.

I just want to say that is a shortcut of a

lot of complicated, controversial discussion. I

think Alan Milstein raised a lot of really profound

points that all of us have been worried\--

DR. NELSON: I am anticipating that we

will come back to that.

DR. FOST: \--have been worried about for

25 years, but this isn\'t a seminar either, and we

don\'t have all day to talk about all those and to

say what the responses are to the very serious and

important issues.

DR. NELSON: I will ask you about whether

healthy children have a condition under 406, but we

will go to Rick.

DR. KODISH: As Skip knows, I am not fond

of thinking as categorically maybe as he is in

terms of 406 versus 407, but would like to try to

step back and take a bigger ethical look at things.

My sense is that I would agree with Norm

that this is approvable. I think that is a good

170

word to use, and we can maybe defer the

categorization later.

The thing that I want to bring to the

table is the issue of money, and I think that is a

significant ethical issue here, and I guess it

strikes me as more approvable if it was possible to

eliminate the money completely.

DR. FOST: That is my A through M.

DR. KODISH: i would put it at A, to

follow up.

DR. NELSON: I think it important to get

out some sort of basic starting point.

Dr. Hughes.

DR. HUGHES: I need some clarification

about the process of approval, so that I can think

through this. My assumption is that when this

study went to the IRB, and there was a focus on the

level of risk involved and a discomfort with

approving it at that level, that all other sort of

discussion got short-circuited, so there was not an

opportunity then for an amendment. Is that not

true?

171

DR. FOST: No, I don\'t agree with that.

DR. NELSON: Well, that is the answer,

whether that should have been the answer.

DR. FOST: I don\'t think that is a valid

response.

DR. HUGHES: Okay. That is what I need to

understand.

DR. FOST: Let me say with all respect for

the IRB, I wouldn\'t want our IRB\'s minutes to be

subject to this public hearing, because the same

sort of criticisms could and would be found, so I

am not being holier than thou. I am sure anybody

here could find similar problems with ours.

But since we are here, and we are asked to

comment on it, and we want to be thorough, I think

we are sort of obliged to comment.

The investigator should never have

submitted a protocol that didn\'t mention that an

MRI is going to be done, that doesn\'t mention to

these young girls the pregnancy testing. Those are

just\--I am no talking about style or corrections\--

those are gross omissions of substantive issues.

172

Secondly, the IRB, in its initial review,

should have said\--they wrote lengthy, detailed

minutes, as Mary Faith said, they are wonderful

minutes. They just don\'t even seem to notice that

these sort of major factors are left out. They had

10 months to do that. There was no distraction by

a 407 process that would have precluded them from

sending a letter back we have a major 407 problem

here, but in addition, there is about nine other

things that you need to get back to us. It has

been a year.

So, I don\'t think the 407 process has

anything to do with the inadequacies in the consent

form or the protocol, which has three different

versions of the dose.

DR. HUGHES: Once the issue of risk is

decided, then, does it go back to the IRB for them

to finish work, or what is the next step after

decisions are made here today?

DR. NELSON: Generally, what has happened

in the past, since there have been some of these

reviews conducted by a different process since this

173

process didn\'t exist until now, is that with those

sort of modifications and stipulations that those

groups have specified as individual consultants,

then, in this case, the OHRP, since these were not

FDA processes, put that all together and worked

with\--if there was a recommendation, if it was

approvable under one of the other

categories\--worked with the local IRB that referred

it and the investigator to clean up all of these

details, and the same in the case of the 407, but

those, in fact, if you look at the OHRP web site,

you will see I think five that had been reviewed,

or four or five under that category.

So, I think it is important for us to say

this is what needs to be done, but I don\'t think in

this case, as we would with an IRB who we have our

own staff to do it, I think we can rely on both the

OHRP and the FDA to make sure it gets done. So,

that is why I think we need to deal categorically.

That would be the process in this case,

but I think we do need to answer the big question,

which ultimately gets back to whatever changes, and

174

there may be some of us who say no matter what they

do to this protocol, I don\'t think it\'s approvable.

So, we need to answer that big question

because absent to that question, working on the

sort of language of the assent or consent form is

less important until we answer is it approvable

under any circumstance, what might that be, and is

it appropriate, and separating that out and working

through those categories is what we need to do.

It sounds like that might be a good time

to sort of break for lunch and then come back and

actually do it.

DR. HUGHES: Thank you. That was very

helpful.

DR. NELSON: It is noon, or actually it\'s

a little after noon.

Dianne Murphy has something to say before

we actually break for lunch.

DR. MURPHY: I just want to really

re-emphasize what Skip just said, which is the

first task is what we are calling the core

question, and it has to do with the normal aspects,

175

normal volunteers in this protocol.

We really need to do that, and by

referring\--because we actually had a number of

internal discussions about this very issue\--is that

when an IRB refers these protocols, then, you have

to look at them for all the reasons that have been

discussed in their entirety, but we really need to

focus on making sure we, in a way, if we can, and I

understand there is a very deep, intense

integration of the science and the overall ethical

issue, but as much as possible, can we answer that

core question and then address the other issues

that we have.

Thank you.

DR. NELSON: The meeting is scheduled to

start at 1:00. I have been told we could start at

1:15 if wanted to, so why don\'t we do that. If we

do, we might then just go through break and see how

much discussion takes place.

I am told there is no specific room for

the panelists to meet. I think there is as buffet

downstairs, having been here in the past, so moving

176

through that should be fairly expeditious instead

of waiting for something special to be cooked.

Hopefully, we can start right on time at

1:15. Again, to remind people that any substantive

deliberations or discussions of the protocol need

to be carried out publicly, so let\'s not do our

work in private.

Thanks.

\[Luncheon recess taken at 12:05 p.m.\]

177

A F T E R N O O N P R O C E E D I N G S

\[1:15 p.m.\]

DR. NELSON: Begging of the indulgence of

the panel, I would like to suggest a process that I

think will, hopefully, get us to the key questions

as quickly as possible, of course allowing people

to say, if there are constraints around what they

would decide, to state those constraints at the

time.

What I am going to suggest is that we

basically, looking at the algorithm for the risk

association within Subpart D, which is Section Two,

basically run through the procedures that are

within this protocol and, hopefully very quickly,

identify what I anticipate will be the one meriting

the most discussion but there may be a few things

that we need to clean up on the way.

One way of doing that might be, from the

slides that Dr. Rapoport presented, she lists the

protocol procedures that are in there and just for

me to very quickly go through that and get a sense

of where people would put those procedures with

178

respect to the risk of those procedures and then,

ideally, at the end of what I hope would be an

efficient but effective process, identify that key

question that we then want to spend the majority of

our time on which I anticipate is dextroamphetamine

to a healthy child.

But I don\'t want to assume that that is

the case before going through it. So, as you see

on her slide\--I guess it is the middle of Page

3\--there are a number of procedures that are listed

there and there may be others the we want to

highlight. History and physical examination; most

IRBs would be comfortable with that being minimal

risk. There is the issue of pregnancy testing

and, given Mary Faith\'s discussion, I think it

would be\--I guess my question to her would be

presuming that we add stipulations about the

context of that testing and the assent and consent

process and the confidentiality, et cetera, would

that be minimal risk.

DR. MARSHALL: As long as all of the

procedural safeguards were there; yes.

179

DR. NELSON: And I might add\--I have been

taking notes about what people have been saying so

you can assume what you have said before is, in

fact, in my notes.

Then there is the blood work. Then the

specific issue of the genetic testing, although

that genetic testing is primarily for the twins

which wouldn\'t happen unless they found differences

in the two. So, I guess, specifically that issue

may merit some discussion.

Rick?

DR. KODISH: I am comfortable if I hear

that it is only for the twins. I would like a

little more specificity about what the genetic

testing is.

DR. NELSON: Okay. Joan?

DR. CHESNEY: I think it was one of the

folk who wrote in who indicated some concern with

the genetic testing. I don\'t think we got that

page so I don\'t remember the exact details. We got

Bernall and the other one. Do you recall that,

that one of your slides had that\--I think it was a

180

mother of twins.

DR. NELSON: The specific issue of

parentage, I think, was raised but also just

genetic testing. In terms of availability,

comments on that in terms of access to those kinds

of details, the implications of genetic testing.

People are looking at me with blank stares.

Richard?

DR. GORMAN: We would like some insurance

from the investigator and the NIH that this data

will be\--that the samples will be destroyed or the

subjects will be informed that the samples will be

retained if they are, in fact, to be retained.

DR. NELSON: Are there any specific risks

to the populations involved in this study of that

testing, particularly the twins?

DR. FOST: It depends on what the testing

is. We don\'t know what the tests are. If they are

testing them for APO-E; yes.

DR. GORMAN: If they are testing to see if

they are monozygotic or\--if they are just deciding

what type of twin they are\--

181

DR. NELSON: So if it is simply limited to

that.

DR. GORMAN: And the samples are

destroyed, then I think I have little difficulty.

If they are looking for genes that predict ADD and

ADHD and the samples will be stored for future

research, then I think that needs to be explicitly

stated in both the protocol and in the informed

consent.

DR. FOST: And whether results will be

shared with\--they can get it to minimal risk or

even zero risk if they say it is just to confirm

monozygocity or dizygocity and then they will

destroy the samples. Then it would be zero risk.

DR. NELSON: Okay.

DR. FOST: If they are doing more than

that, then one would need to know what the \"more\"

is before deciding what the risk level is.

DR. NELSON: Okay. Joan?

DR. CHESNEY: Can I just ask for

clarification about what this individual wrote in?

\"The genetic testing for the twins is glossed over

182

where a decision to test twins regarding their

zygotic status could have emotional implications

for the parent and/or the twins.\" I am not sure I

understood.

DR. NELSON: Is anyone aware if you are

identical or not, that it makes a difference in

emotional status of twins? It is not my particular

area. Usually, it is pretty obvious.

DR. MARSHALL: Usually, it is pretty

obvious.

DR. NELSON: Boy/girl; that would be an

easy start.

DR. CHESNEY: I just raised it because it

didn\'t make sense\--I didn\'t quite understand it at

the time.

DR. NELSON: But it sounds like, as a

group, that we would be willing, placing this into

minimal risk, if it is limited to zygocity and the

samples are destroyed. They haven\'t specified any

further than that.

DR. JACOBS: They have pretty clearly what

tests they plan to do. On Page 12, at the bottom,

183

they say what alleles will be tested. So I think

that is quite clear. I think what is not there

that people are alluding to is will they do

anything else, in addition to those. But I think

they state pretty clearly what markers they are

going to look at.

DR. FOST: But I don\'t know enough to know

whether any of those alleles are associated with

other disorders that might be stigmatizing and

harmful. If that is all they are doing, and then

they discard the samples, I would call it zero

risk.

DR. JACOBS: That is the problem; yes.

DR. FOST: If they are going to retain

them, or tell parents the results, then it gets

complicated. I see APO-something. I don\'t know

what APO means.

DR. NELSON: APO-B. So, where this

becomes and issue, I guess, is\--I mean, one can

specify it as an \"if-then.\" If there is a concern

about possible stigmatization or predictability of,

say, adult-onset diseases where you are testing an

184

8-year-old on these particular alleles, then that

would be a much different issue than if it is

simply on other grounds determining zygocity or

similarity.

DR. WHITE: They need to disclose that.

Is that something\--

DR. NELSON: That would need to be part of

the consent and assent process.

DR. FOST: It is also part of the

protocol, though, Skip. If they are disclosing

results to parents or children in the way that it

might be stigmatizing or confusing, then it may

become more than minimal risk.

DR. NELSON: Right; it is not minimal

risk.

DR. FOST: It is certainly not something

that happens in a doctor\'s office where you find

suddenly, \"Oh; I\'m APO-B,\" and you don\'t know what

that means. So it is only minimal risk. I mean,

we can only say today, with the information we

have, that it is minimal risk if the samples will

be used solely to determine zygocity and then

185

discarded. That is the only circumstance under

which I could say that I know that it is minimal

risk.

DR. NELSON: And that the information

would not be provided or used in any other way.

DR. FOST: Will not be disclosed. It is

for the sole scientific question of confirming

zygocity.

DR. NELSON: We can set those boundaries

around this testing for the purpose of stating that

because we lack any other information right now.

DR. FOST: That way, the Secretary, if he

wants to send a detailed\--I don\'t know how detailed

the Secretary\'s approval letter is, if it contains

all these \"ifs, ands or buts,\" and conditional

factors. But if it is a detailed letter, it can

say, \"If this panel decides that the thing is

approvable and the Secretary concurs and the

committee concurs,\" then the letter could say that

we concluded that this study is of\--there are

several components to it, that each one, we

determined that risk level was this, minimal, more

186

than minimal, acceptable, if A, B. C. I don\'t know

if this gets to that detail of the letter or not.

DR. NELSON: It will.

DR. FOST: Okay. Then the IRB has the

information on which they can approve the protocol.

They can tell the investigator, \"We approve this

conditional on your destroying the samples.\"

DR. NELSON: With that, how about if we

then move on. I am going to skip the next bullet

point to get back to it. But the risk of a

functional MRI\--Dr. Greenhill?

DR. GREENHILL: I have a question. I

guess I am challenged in consent reading because,

try as I might, I can\'t find any reference to blood

work or genetic testing. Is it in there?

DR. NELSON: No. The assumpution is that

we will get\--there is a lot of work that has to be

done on the consent and assent forms. So I am

assuming, if we get to the end of day and say,

\"These are the conditions under which this could go

forward,\" that the next comment would be, \"And, in

fact, you need to make your documents match this as

187

far as assent and consent.

DR. GREENHILL: Can I a make a suggestion?

DR. NELSON: Sure.

DR. GREENHILL: I think it would helpful

to the parents and to the kids to know that, if

they are twins, they will be tested for whether

they are identical or not. I haven\'t heard this

discussed, but as far as, if they want to know, the

information is available, or not. My inclination

would be to offer it to them.

DR. NELSON: And allow them to say yes or

no up front.

DR. GREENHILL: Yes; if they want the

information or not.

DR. NELSON: Seems reasonable.

DR. GREENHILL: While we are at it, risk

of bruising and infection for blood work and also

how many cc\'s of blood put in tablespoons or

teaspoons needs to be specified because I don\'t

have a sense from the protocol how much this takes.

If you are drawing blood, why get a cheek swab?

You are likely to have\--you could have a lot of

188

samples that you can\'t use. If you are going to do

a blood test, I think it is wasteful\--

DR. NELSON: I think we might be getting a

little bit into micromanagement on that point.

DR. GREENHILL: All right. It\'s just,

without the details, I can\'t tell what they are

doing.

DR. NELSON: Right. It definitely needs

to be in the consent and assent.

DR. GREENHILL: Yes.

DR. NELSON: Joan?

DR. CHESNEY: I think, when you say they

have the option of knowing, of knowing what;

whether they are monozygotic or dizygotic or

whether they are APO-B, QRST?

DR. NELSON: I just heard that as zygocity

alone.

DR. GREENHILL: That\'s all I heard; just

zygocity.

DR. NELSON: The neuropsychological

testing; I guess I would defer to my

neuropsychological colleagues. Often that testing

189

could be seen as minimal risk depending upon the

length of time and the like, appropriate breaks, et

cetera. Is there anything particular that needs to

be said more than that in terms of the

neuropsychological testing, it needs to be

adequately revealed, in terms of the

parent-teaching ratings and those kinds of things?

Is there more to be said than that?

Joan?

DR. CHESNEY: Does that include I.Q.

testing? When they were distinguishing who would

be in the controls and so on, they stipulate the

I.Q.s. So, for a child who has never had I.Q.

testing before, and that information is\--

DR. FOST: Once again, if it is used only

for the scientific purpose and not disclosed, I

would guess it is minimal risk.

DR. CHESNEY: Okay. That was my question.

If that was not disclosed, then I agree.

DR. NELSON: But one could debate that.

If, in fact, they should\--it is not clear to me why

you wouldn\'t want to give that information back to

190

a parent.

DR. FOST: Because this is not a clinical

service they are providing. It is research they

are doing. If they want to embark on doing

neuropsych testing for clinical purposes, then they

should open a separate office and do that.

The purpose of the neuropsych testing is

not to help parents learn whether their kids are

retarded or not or have certain dysfunctions. The

purpose is to standardize the scientific results

and, therefore, it should be restricted to that.

If they want to do more than that, they are

straying from research and they are getting into

complicated issues that we could spend all night

talking about. But they can avoid all that

complexity by just sticking to doing it for the

scientific purpose.

So, once again, I would say it is

approvable. The neuropsych testing is approvable

if it is used only for the

scientific purpose. If it is being used for

something else, then I don\'t know.

191

DR. NELSON: Dr. Hughes?

DR. HUGHES: This is an area I do know

about as a clinical psychologist, and I would

concur that you would never want to give parents

just an I.Q. score, that it really means

interpreting the results and really taking time to

have a fuller assessment, of knowing that child,

what their strengths and weaknesses are and then

making recommendations about where to go forward.

Just an I.Q. number is not useful and

could easily be misinterpreted. So I would agree.

DR. NELSON: Then that just leads to a

follow-up question. One can then go one of two

directions; not use it in this way in terms of

providing information back that is not

appropriately accompanied by counseling and

interpretation or one could, in fact, put in place

those kinds of services if you wanted to provide

that feedback back to the families. So one could

go either direction.

Norm, are you concerned about the middle

ground, you give the score and you don\'t do

192

anything, or if they went into the full\--you get

this testing; here, you can have it back but we are

going to give it to you only if you have it with

appropriate counseling, et cetera?

DR. FOST: I don\'t know what the

competence of these people is to that kind of

counseling. I don\'t know who would do it. It just

raises all these questions. If they want to get

this study done, they want to get it approved by

this panel and by the Secretary and by the IRB, the

simplest way to do that is to limit the results to

the scientific purpose.

DR. NELSON: Dr. Greenhill?

DR. GREENHILL: Just two things. One, to

reiterate that, if you are going to approve the

neuropsychological testing, that the parents should

be alerted that it is being done and how much time

the\--what it will mean for a time period in which

they cannot have testing again and have it

acceptable to school boards. It is usually a year

to avoid practice effects for the I.Q. test. They

should know that because it may or may not be an

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issue.

The second thing gets back to this whole

thing of the consent and SN forms. There is no

description, actually, if what exactly they are

doing, where they are going, how many days it

takes. Is it going to be done during the school

day, after school? I know this is trivial stuff,

but, for parents to schedule, they have to know how

many days of work to take off.

I have no sense of what the procedures

are. Half the procedures are not even listed in

the consent form. So they have to know they are

going to spend so many hours sitting doing pencil

tests and when the blood is drawn. It is the kind

of standard stuff that has almost become boiler

plate or institution, but, without it, it is very

hard for parents to know what they are getting

into, or kids.

DR. NELSON: Let me just get a sense of

people. Norm\'s recommendation is the cleanest way

to do this is to just not provide the data back.

DR. FOST: And to make that clear, that

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it will not be provided.

DR. NELSON: I think we all would agree

that is the cleanest way to do it. Is there at

least a minority view of that to be expressed

because I heard some different views during our

earlier discussion.

MS. TREAT: My question would be what

would you do if the parents want to I.Q. test back?

DR. FOST: You can\'t be in the study.

MS. TREAT: My sense is that, if the

parents know that you are doing I.Q. testing,

several of them will want to know the results of

it.

DR. FOST: Then they shouldn\'t join the

study.

MS. TREAT: My other question is, I guess,

for Dr. Greenhill. If the MRI precludes I.Q.

testing for a year, are there any indications that

the MRI interferes with other tests that are

regularly performed by, like, the school systems,

like the reading tests and the tests that are like

SATs?

195

DR. GREENHILL: It is not the MRI that

precludes. It is just a requirement\--every

psychologist I have talked to, they want to have an

I.Q. test done three months after the first one

because they feel the child is practiced and will

get a higher score. It is not valid. It doesn\'t

harm the subject other than they have to wait and

that may be a problem if a committee on special ed

is meeting to try to place the child and can\'t use

the I.Q. scores, and they want an up-to-date one.

Of course, they won\'t be able to use the

NIMH I.Q. score because I think our panel is going

to recommend that it not be given to the parents.

DR. NELSON: It sounds like that is

emerging as a theme. On this point?

DR. GORMAN: On this point. I think it

also, by adopting Dr. Fost\'s suggestions, we make

this protocol more clear to the parents as we go to

the informed consent that this has no benefit for

them, that this is a study that has benefit for

society but no direct benefit for the subjects.

DR. NELSON: Moving down this list, let me

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skip the administration of the drug and just talk

about the functional MRI. Given the description of

the process that we heard this morning, in terms of

screening and training and the like that goes on,

is it fair to say that this would fall into minimal

risk under those circumstances?

DR. CHESNEY: I don\'t think it was in

their protocol but one of the other protocols where

they used functional MRI screening, they talked

about using a dental plate to keep the child in

place. I didn\'t know if anybody could elaborate on

that. They apparently take an impression of the

child\'s teeth and then put a brace on so they don\'t

move. Is that correct? That seemed a little\--

DR. NELSON: Invasive?

DR. CHESNEY: Pushing the envelope, to me.

Yes; invasive.

DR. WHITE: That is one technique that is

used. Actually, it doesn\'t work as well in

children. It is frequently used in adults and I

know that, at the NIH, what they are using now is a

vacuum-type apparatus that goes around the head and

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it fixates the head, because movement is one of the

major difficulties. Probably with ADHD, it is even

more of an issue. Movement in the scanner will

render the data unusable.

DR. CHESNEY: Would you elaborate on the

vacuum apparatus.

DR. FOST: It is like a cushion. It is a

pillow. You mean an inflatable\--

DR. WHITE: No; it is a pillow that has

small, little beads. They put a vacuum in it and

it just becomes firm but not painful.

DR. FOST: It is a cushion so you can\'t

wiggle your head around.

DR. CHESNEY: So the vacuum is in the

pillow not in the patient.

DR. WHITE: Not in the patient.

DR. NELSON: Rick, you had a comment?

DR. GORMAN: I do. In the protocol, it

mentioned that this is a 3-Tesla coil. 3-Tesla

coils raise body temperatures with prolonged

exposure. I would like to be assured from the

protocol that there is a radiation standard for

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R.F. and temperature raising, so how many

microwaves you can get and how much sonogram energy

you can get for raising body temperature. I would

like to be assured that this protocol meets those

standards.

DR. NELSON: That is easy to do because I

think those standards are posted on the FDA

website, having looked for them before for 3-Tesla

MRI scans, having gone through this. But they are

used clinically.

So, assuming that the mechanisms by which

these kids are trained are not an inappropriate use

of restraints other than a firm pillow, would it be

fair to say that this would be minimal risk.

DR. FOST: I would just want to remind

people what they said both in the protocol and this

morning about the rehearsal session which we use at

our place also which, I think, pretty effectively

screens out kids who might be freaked out by any of

this. And that is why they use it. If a kid turns

out to be anxious, they know about it before they

are in the study, really. They know it in this

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practice session where there is nothing at stake.

So, given that, I think the psychosocial

risk of being in a scanner, given the screening, is

really quite minimal. And they have some data to

support that.

DR. NELSON: What I would like to do in

looking at this list is to leave the discussion of

compensation or reimbursement or inducement of

enticement for its own special discussion and go

back, I think, directly to the risk of a single

dose of dextroamphetamine and discuss the risk. If

you look at the algorithm, discuss the risk

separate from whether it is being given to a child

with ADHD or being given to a child without ADHD,

and then introduce that factor.

So I think that brings us precisely to the

point that brought this before us is the giving of

that drug to a child without ADHD and, of course,

in discussing those risks, there may well be

different risks in the two different populations

given that these are likely not to be

treatment-naive subjects.

200

So I guess, in looking at this algorithm,

there was a considerable discussion on the IRB and

the IRB minutes about that being minimal risk based

on its analogy to excessive caffeine consumption,

whether that is five cups of coffee, a six-pack of

Jolt Cola, three Mountain Dews or other caffeinated

beverages.

So I think we need to sort of tackle

directly whether we think that that is minimal risk

or more than minimal risk independent of, then,

after it is more than minimal risk if we don\'t

think it is minimal risk, what category it goes in,

so, specifically, that assignment of that drug

dose.

DR. GREENHILL: I would argue that it is

more than minimal risk because it is not a typical

expected event in a child\'s life who isn\'t ADHD.

The question is how much more than minimal risk are

we talking about. Is it a minor increment in

minimal risk or more than a minor increment in

minimal risk?

I just have to disclose that I have

201

treated many children with dextroamphetamine. I

regard it as the safest of the stimulants with the

most predictable effects that occur within 15

minutes and are gone by about five hours. There

are things to consider. If this study were, as in

the old days at NIH, only conducted in the evening

because the MRIs were only available in the

evening, I would have a very different estimate of

risk than if it were conducted first thing in the

morning.

I know that if you bring a child in at

9:00 p.m. and give him 10 milligrams of

dextroamphetamine, he will be up all night. We

don\'t know what time these studies are being done.

I am assuming they are done in the daytime. In the

daytime, I think it is a minor increment over

minimal risk because I would have no problem giving

any child in this age range that they state a

starting dose of 10 milligrams.

In fact, more and more that is occurring

as the long duration preparations of the

amphetamines such as Adderall XR are given. They

202

are given a single dose in the morning anywhere

between 10 and 30 milligrams. Even though it is

delayed release, they are still getting quite a

solid dose as their first dose and I have seen no

problems with that.

So everyone is going to have a different

take on this but I think it is more than minimal

risk but I think it is a minor increment over

minimal risk based on many, many children getting

these medications many of whom I wouldn\'t say had

ADHD. The studies that are done in North Carolina

by Adrian Engle showed that half the sample of

individuals treated with stimulants in their rural

community did not meet criteria for ADHD. Their

main criteria was they were defiant and they were

male. They reported no differences in vital signs

or problems across the group.

So that would be my position. We have to

indicate it is more than minimal risk but I don\'t

think it is more than a minor increment in minimal

risk which, I think, would fit 406.

DR. NELSON: That is the risk category.

203

Then we have to get to condition. But let\'s keep

the risk in play and see other comments or views on

that risk category.

DR. FOST: Larry, or Dr. White, what is

the worst thing that you think might plausibly

happen to either a normal child or a child with

ADHD from this dose\--not remotely conceivable but

plausibly, that you wouldn\'t be surprised if it

happened, the worst thing?

DR. WHITE: The worst thing that could

happen? I guess the worst thing is, perhaps, they

become restless and some akasthisia.

DR. FOST: For about how long?

DR. WHITE: Three to four hours.

DR. FOST: Thank you.

DR. GREENHILL: And the worst things I

have seen happened, particular in the younger

children, are that they seem to have more

irritability, restlessness. They get agitated and

they tantrum. That doesn\'t seem to relate so much

to dose. It is a first-dose effect that you might

see. But it occurs in under 1-in-100 cases. It is

204

infrequent to rare.

DR. FOST: Any sequelae from these? A

week later, does this have any effect on the child?

DR. GREENHILL: Once the drug wears off,

which is usually four or five hours, I don\'t see

any. I don\'t even see troubled sleep that night.

DR. NELSON: Dr. Gorman?

DR. GORMAN: I am going to agree with that

assessment of a minor increase over minimal risk

but coming from a totally different viewpoint. As

a former director of the Maryland Poison Center, if

someone accidently ingested, a 9 to 18-year-old

accidently ingested, 10 milligrams of

dextroamphetamine, they would be observed at home

and their parents would be told to call if there

were symptoms.

So, seeing that this research will take

place in a controlled clinical trial, in a

controlled setting where they will be observed for

those symptoms, I would consider this something

that we would not intervene to correct.

DR. NELSON: Let me specifically ask the

205

question that has been raised by other comments and

that is, and particularly even in the IRB minutes,

is the question of potential abuse, uncovering

abuse, leading to abuse in the future. Any data on

that? Any sense that that is a risk? It was

brought up a number of times in the documents that

we have.

DR. WHITE: I would say that, in my

judgment, one dose of 10 milligrams of

dextroamphetamine is less than minimal risk. But

the fact that there is no research, really,

long-term research\--the only research that we have

is Dr. Rapoport\'s follow up of people who were

involved in the study, some of them she knew and

she observed. So it is all, I would say,

conjecture.

I think that it is a study that would be

difficult to do for the very reason that we are

here. So there is no data. There is data showing

that those who are on it long term, those diagnosed

with ADHD, have less risk.

There is also a possibility of someone who

206

is involved in the study who may, during a part of

it, if it is included that these are a substance of

abuse along with some education, may have a less

risk down the road. So it is not known.

DR. NELSON: Are there any screening

instruments that could be used meaningfully to

determine whether any given individual is at risk

for subsequent addictive behavior?

DR. WHITE: Family history would be a

possibility, a family history of abuse. I wondered

about do you exclude people if they have a family

history from the standpoint that what might be

transmitted genetically is not the abuse but one\'s

response to a substance once they receive it. Some

have more reward mechanisms than others, different

experiences.

DR. NELSON: That is sort of the direction

I was wondering. Even in the absence of data,

could one at least exclude, based on that

assumption, and still have a reasonable approach

to\--

DR. GREENHILL: It is already an exclusion

207

factor for the subjects. Any history of substance

use or abuse, they can\'t get in.

DR. NELSON: For the subjects. But we are

talking for the family, family history, where you

don\'t have that history and you are worried about

the propensity of uncovering something. It is not

my area. I am an ICU doc. So I am just asking

could we do that and would that address that

concern.

DR. GREENHILL: I don\'t know that there is

any evidence for that. You could argue that

offspring of individuals that had trouble with

substance abuse might be very negative about drugs.

There is some data showing that the context in

which you take drugs for the first time may have a

big effect on whether you continue taking the

medication.

If you take it at a party with friends,

the impact is different than if you take it at the

NIH with adults standing around you. It is not a

party, I don\'t think. That is very important for

what goes on.

208

Dr. Rapoport\'s data showed, interestingly,

because we didn\'t hear about the whole study that

she did. She did a study with adults and kids,

normals and individuals, with ADHD. The ADHD

children and the control children were normal.

They had mood measures on them and they became

mildly dysphoric on the medication.

Any of the individuals who were older,

like the college students, became euphoric after

one dose and were taking at a much more rapid rate.

So she wondered if there was an age response that

had to do with having euphoric response to these

drugs.

We see very little evidence of use. There

is less than a handful of cases in terms of letters

and anecdotal reports in the literature of

individuals treated in a treatment situation with

stimulants who then hoard them and use them

abnormally.

So the indication has been, particularly

with methylphenidate, not so much with amphetamine,

that it produces dysphoria. In the making of the

209

Seize the Future\--I think that is what it is

called\--reports that come out each year about

high-school students showed that experimentation

with the stimulants is usually a one-time event in

contrast to cocaine and marijuana where it is

repeated. So they will experiment with them and

they will just stop using.

We are going to be looking at a much

younger group so I think, all in all, we just don\'t

have a lot of\--no data is not evidence. The

absence of evidence is not evidence but, still, we

are waiting for some of the long-term follow-up

studies like a follow up to the MTA to see what

happens to the risk of substance use for those

individuals exposed.

If you believe Tim Willin\'s data, he finds

that he cuts the rate of substance use in those

ADHD kids who have trouble with a past history of

it but are in active treatment, cuts it to a third.

So, apparently, it is found to be among practicing

clinicians anecdotally that it helps reduce the

rate.

210

But, again, it is a lot to do with

context. You give these medications in a medical

setting. It is not the same as taking it

recreationally. So I just don\'t get a sense that

giving one dose of this is going to start a

lifelong career or use or somehow unmask it.

DR. CHESNEY: This is in part for the IRB

folk, but, given our litigious society, if one of

these children who was given one dose in fact

became addicted down the road, is there a way to

write into the consent form that we don\'t know

this, the outcome of this and, if it happens, you

can\'t blame it on the study?

It concerns me that if we say this is not

more than minimal risk or a minor increase over

minimal risk and then we get into trouble 20 years

down the road, I guess there is no way to obviate

that.

DR. NELSON: You can\'t waive your rights

to sue in a consent form. Period. For any reason.

DR. GREENHILL: But you can indicate if

there is some concern on some parties that this

211

is\--it gets back to this whole issue of stating

that it is a medication that is classified among

abusable drugs and the parents should know that.

We don\'t have strong evidence for one exposure

leading to, even exposing the vulnerability, but we

can\'t rule it out. We know that, and they should

be warned that it is a substance that has been

abused by all age groups in some form or another.

And then they can ask a lot of questions

about it and they will be encouraged to do so.

DR. HUGHES: From a family point of view,

I think that almost every parent of a child with

ADHD will tell you that there are real issues in

trying to keep your kid taking their medication.

Rather than wanting it every day, they would like

to not take it at all.

I think some of that is because of, again,

their environment and their peers and not wanting

to be labeled ADHD. But certainly, from common

experience for kids with ADHD, we certainly haven\'t

seen this.

I also think it is very important to

212

differentiate between substance abuse and

addiction. They are not the same. To my

knowledge, there isn\'t evidence that it is an

addictive drug but rather we know that it gets used

for other than the medically prescribed purposes

quite commonly. Your comments about the college

students who want it studying for exams, I think,

is much more common.

I think that differentiation, when it is

talked about in the consent forms, is very

important, that addiction and substance abuse are

very different.

DR. NELSON: So, in moving us along, I

have not heard anyone giving an argument that the

drug administration should be classified as minimal

risk. So that moves us down the right-hand side of

the algorithm into more than minimal risk. I think

it is fairly clear that I have heard no one argue

that this offers the prospect of direct benefit,

although there may be benefits associated with some

of the informational aspects that have been talked

about, that that is normally not what would be

213

considered a direct health benefit.

So that takes us down to no prosect of

direct benefit which then gets us into the minor

increase over minimal risk or more than that. So I

guess my question, then, to the group is, in terms

of this drug administration being a minor increase

over minimal risk, however we choose to define

that, versus higher than that on the table is a

couple of opinions that this would be a minor

increase over minimal risk.

We don\'t have to all say we agree, if we

agree, bus is there any more to say on that point

before then going down to the additional questions

that we need to then address?

Okay. So that takes us down to the

left-hand side of the bottom part of the algorithm.

DR. WHITE: One more follow up on Dr.

Chesney\'s comment that there is likelihood that

some of these healthy controls will experiment with

substances later on.

DR. NELSON: Go ahead.

DR. WHITE: We just know that. And we

214

know that all subjects will be receiving active

medication. The power of the study\--it is much

more powerful to do it in a crossover design but I

wondered about the possibility of having either

placebo or a control. You would need two separate

groups in doing it using that approach.

It doesn\'t give you as much power but it

would be another way in which subjects wouldn\'t

know whether they had active drug or not.

DR. NELSON: In looking at the other

issues in terms of experience as reasonably

commensurate, what I would like to do is focus us

on disorder or condition. Half of the children in

the study will have ADHD either with or without a

twin. The other half will be without ADHD, either

with or without a twin who has ADHD.

So I think it is fair to say there is no

disorder or condition or certainly the children

with ADHD who are unrelated, whether we want to say

they are at risk but, I think, at this point, if

they are discordant. So, specifically on that

group. Norm?

215

DR. FOST: That group?

DR. NELSON: You could say there are three

groups; that is children without ADHD that are

unrelated to anyone that has ADHD which is the

first group. Then there is the twin groups.

Whether or not the child who does not have\--they

are discordant for ADHD\--any risk categories I

think would be a separate question.

DR. FOST: I just want to address that

question that you are raising. First of all, I

agree with Eric that an overly literal

interpretation in these categories is probably not

warranted. But, even if we interpret it literally,

if you are asking whether a so-called normal or

healthy child with no history of ADHD who gets

enrolled in this study, whether the study is about

his condition.

I would say yes because part of what the

study is about is how normal children respond to

amphetamine. That is one of the questions it is

asking is what happens to normal children when they

get amphetamine. It is about both, what happens to

216

kids with ADHD and what happens to normal people.

So, one of the conditions that is being

studied is normality. So, if you want to be

literal and talmudic about whether\--I don\'t mean

that in an offensive way, but\--

DR. NELSON: That is not the way I was

headed because actually that would view me as a

rather liberal interpretation of the way we use

condition or disorder within\--

DR. FOST: You added disorder. I think

the word is condition.

DR. NELSON: Disorder or condition is in

the regulations.

DR. FOST: This is a study of healthy

children. That is one of the important questions

they are asking. We have already heard that it has

been important to dispel this ancient myth that

so-called healthy children respond differently.

But now it is at the brain level, at this

functional brain level. And I think we have all

agreed it is an important scientific question about

whether normal children respond differently

217

than\--because, who knows. There may be

implications for normal people taking this drug to

perform better in school, to perform better whether

it is exams or whether it is in grade school.

DR. NELSON: For the purpose of focussing

the debate, are you making an argument, then, that

you would approve this entire study under the minor

increase over minimal risk since the children

without ADHD, in fact, have a condition called

being without ADHD that is part of the study?

DR. FOST: They have a condition called

being a normal child.

DR. NELSON: That is the same thing; yes.

DR. FOST: There is a serious question of

whether amphetamines have an effect on normal

children. Whether it is clinically useful, they

are not studying that in this study but I think

that is an important question. So the short answer

is yes, I think it could be.

I don\'t think we need to go there because

I think it can be improved under 407 anyway. But

my opinion would be yes, it needs\--

218

DR. NELSON: But that is not an

unimportant\--I am not saying people agree or

disagree with you at this point. Just keeping you

as the person who has put this forward.

DR. FOST: I should say yes.

DR. NELSON: For this panel to say this

could be approvable under 406 or 50.53 instead of

407 sends a much different message than to say it

could be approvable under 407 or 50.54.

DR. FOST: Yes; I think it could be

either.

DR. NELSON: Let\'s keep it focused on that

question of disorder or condition and see where we

are going with it.

DR. JACOBS: I guess I would, for the last

point that you made, because of the precedent it

would set\--now, I see your point and I think it is

an interesting one. But I don\'t think that we want

to start defining everyone who is not in a

condition but is the normal control as the topic of

interest and say that, well, we could find out that

normal people have this too, or that normal people

219

function the same way, or whatever.

I guess I think that is a little bit

troubling as precedent-setting that this panel

would be doing. It seems to me that when you talk

about ameliorating, since that is the word used

here, the disorder or condition, I don\'t think we

are trying to ameliorate normalcy here.

So I think that is going too far and I

guess I would prefer not to go down that branch.

DR. NELSON: Rick?

DR. KODISH: I would just like to step

back from 100 times magnification maybe to 10 times

magnification on the microscope and think about

Subpart A compared to Subpart D and remember that,

if we are going to call childhood a condition, it

sort of undermines the whole point of having a

Subpart D. So I agree both on the sort of

utilitarian grounds about the precedent but also on

the bigger picture issue.

DR. NELSON: I am going to assume, since

no one else has other comments and no one is coming

to Norm\'s defense\--

220

DR. MURPHY: Can I ask him a question?

DR. NELSON: You can always ask Norm a

question.

DR. MURPHY: I am not sure I understood

your statement because was part of the basis of

your statement because not just knowing that there

is a difference in normal, because that is one part

of the statement, but is part of that because so

many normal kids are diagnosed with this? Is that

also informing that opinion?

DR. FOST: No.

DR. MURPHY: Okay; I just wanted to\--

DR. FOST: I don\'t feel a need to push

this because I think it is going to head towards

407 anyway and the important question is whether

the study can go forward. But, to answer your

question, normally we included so-called normals in

clinical trials as controls; that is, we assume

nothing will happen to them.

Say, you are using an antidepressant or

something and you are looking for\--anyway. Your

hypothesis is that there will be no effect on the

221

so-called control population, antibiotics,

chemotherapy, if you were doing such a thing. But

there is something different about ADHD. I don\'t

want to say unique, but it is very different in

that we have heard that normal children do respond

to this pharmacologic agent. Their behavior

changes.

What these investigators are wanting to

know is is there a difference at the brain level.

They don\'t know the answer to that. That is why

they are doing this study and it may be that there

is no difference at the brain level. I don\'t know.

So maybe there is an effect on normal children

which is, A, an interesting scientific observation

which is this is, mainly. It is a scientific

question.

It may have therapeutic implications down

the road because I don\'t think it is a facetious

question to ask whether normal children or adults

might benefit from low-dose amphetamine for

studying, for getting work done, for improving

performance in a variety of areas. Those are all

222

legitimate clinical and scientific questions.

So the normals in this study aren\'t like

normal controls in most studies in which we are

expecting nothing to happen to them. I think we

might very well expect something interesting to

happen to them.

DR. NELSON: I think, in order to move us

along, the interesting question raised here is the

definition of disorder or condition and how it is

interpreted. I am reminded, although I don\'t

recall\--I mean, the Institute of Medicine report

does have a definition of how to interpret

condition or disorder in there. I think this would

be an even more liberal interpretation.

So, absent anyone else on the panel

feeling we ought to embrace that interpretation,

what I would like to do is move us over into, then,

a discussion of 407 and 50.54 specifically as it

relates to the healthy children because we

otherwise might run up into some time constraints.

DR. GREENHILL: Just briefly, what was the

criterion for dismissing 406?

223

DR. NELSON: Well, the question is\--I

mean, you have two groups; those with ADHD and,

assuming that the diagnostic criteria are

appropriately applied, assuming they have a

disorder or condition so that that group could be

potentially approvable under 406.

The specific question then is what about

the children without ADHD and what happens to that

group. Unless you say that, given Norm\'s argument,

that they have a disorder or condition, then they

cannot be approved under 406 or 50.53.

Then that brings us into the question of

whether it could be approvable under 50.54/407

which is the final category.

DR. GREENHILL: See, I would argue that it

is important and would yield generalizable

knowledge of vital importance for normals if they

had a different pattern. We don\'t know. All

science is a gamble. The question is do you make

your decisions about 406, 407 on the previous

evidence or do you make it on what an investigator

is hoping to find.

224

Previous evidence showed they were unable

to detect differences between the two groups. They

hope, by using a different level of investigation,

by looking at functional responses because they

have seen in adults different circuitry used to

deal with the same problem in adults with ADHD and

adults without.

Wouldn\'t that yield generalizable

knowledge of vital importance that normals have a

different pattern of functioning?

DR. NELSON: But all three of those are

necessary for approval in that category.

DR. GREENHILL: Oh; okay.

DR. NELSON: So, even if it would, if you

are not willing to grant them a disorder or

condition until you have that evidence, then you

can\'t go into that category.

DR. GREENHILL: Okay; got it.

DR. CHESNEY: Could you say that one more

time, please?

DR. NELSON: In other words, all of the

criteria that were found in 45 CFR 406 or 21 CFR

225

50.53 all need to be met in order for the

intervention or procedure to be approved under that

category. So, if any one of those is not true,

then you cannot approve it under that category.

So, for the children with ADHD, they have

a condition or disorder. For the children without

ADHD, they do not have a condition or disorder. So

you then would approach the protocol in two parts

which is, I think, what the NIH IRB struggled with.

I think they concluded that the protocol was a

minor increase over minimal risk for children

with\--in both cases but then realized that they

didn\'t have a disorder or condition for the

controls.

DR. KODISH: But it is not possible by

regulatory thinking, and I am asking this, to

approve this protocol for the ADHD subjects under

406 but for the healthy\--the protocol is bundled

together. In other words, my\--

DR. NELSON: No, no. If they wanted to

unbundle it. No; you should approve it under two

different categories if you are going to do that.

226

DR. KODISH: Okay; so it is permissible to

do that.

DR. NELSON: That is why the wording is

intervention or procedure and not research. So the

protocol needs to be unpackaged which is why I went

through each individual procedure. So, yes; you

can approve the protocol under two different

categories.

DR. KODISH: So it might be more proper

for us as a panel, if we are going to go that way,

to approve the ADHD subjects under 406; correct?

DR. NELSON: If we wanted to make\--I mean,

that can be part of our recommendation. That is

what I am hearing people are comfortable with.

Then the question is driving on to the 407. One of

the reasons I want to drive on to that is I really

do want to hear what sound ethical principles

people would like to propose be met by giving a

dose of dextroamphetamine to a child without ADHD.

DR. FOST: I think it would be an undue

burden on the commission to come up\--there is no

such agreed-on list. But I think there is a widely

227

shared list of other thing that make research

ethically acceptable; sound scientific design,

appropriate impartial review, appropriate standards

for consent and assent, monitoring for adverse

effects. Maybe I left off a couple but I think

those are key elements of ethically sound research

and that are met by this proposed study.

DR. GREENHILL: Similar to your statement

about all three criteria have to be met under 406,

under 407, there are two criteria. Do they both

have to be met?

DR. NELSON: Yes.

DR. GREENHILL: Okay, because I am

grappling and struggling with this first criterion

for normals; reasonable opportunity to understand,

prevent or alleviate serious problems affecting

children\'s health or welfare.

DR. NELSON: If you look at 407, the

children refer to children as a group and not to

the children in the research.

DR. GREENHILL: Oh; I see. So the notion

there is that you could have a potential benefit to

228

children that is not a benefit to the children in

the research.

DR. MARSHALL: But you beg the question.

I was kind of getting at this early on, understand,

prevent or alleviate a serious problem affecting

children\'s health or welfare. So I think we have

to talk about what the serious problem is.

DR. FOST: ADHD.

DR. MARSHALL: But all children; that is

why 406 works for the children with ADHD but what

is the argument or what is the rationale for

normal, healthy children.

DR. FOST: It doesn\'t say that it has to

be beneficial to all children. If that were true,

you couldn\'t study any disease at all. You can

only study diseases that affect every single child

which would be an absurd interpretation of it

because there is no such disease.

DR. NELSON: I think the group of children

would be the group with ADHD but not the children

in the research.

DR. KODISH: I\'m sorry to interrupt. I

229

think there is another important group that we

should think about and that is children who are

misclassified as having ADHD. Without getting into

the political rhetoric on one side or the other

about it, I think there is an important scientific

issue here about the diagnostic classification and

that does pertain to some children who do not have

ADHD.

DR. NELSON: Dr. Hughes?

DR. HUGHES: If I could just follow up

with that. Are you implying that, for those

children who are misdiagnosed, that this study has

a potential benefit for them or the opposite, just

to clarify? I would think it would have a

potential benefit if it later leads down the road

to having better diagnostic power than we currently

have.

DR. KODISH: Exactly. I think that the

significance of the study is in its diagnostic

ability.

DR. NELSON: Dr. Gorman?

DR. GORMAN: I think that the diagnosis

230

and treatment, appropriate treatment, of

appropriate populations for ADHD does have an

impact on the complete universe of children. In my

school district, 40 percent of the educational

dollars associated with the school system go to

children with special needs. Not all of them have

ADHD, but a large number do. So making this

diagnosis more appropriate and, hopefully,

treatment more appropriate might free up more

educational dollars for the other students, or

perhaps less, if there were more people diagnosed.

DR. NELSON: Norm, you mentioned in your

list of criteria of appropriate scientific design,

monitoring conduct and the like, the assent and

permission process. So let me bring us back to the

\$570.

DR. FOST: I didn\'t say monitoring the

process. I said monitoring for adverse events.

DR. NELSON: Right. There was a comma

between them, sorry; the assent and permission

process, per se. So I would like to bring us back

to the \$570. I would also like to raise the

231

question of the relationship between parental

permission, which is meant to have a protective

function for the child, and child assent,

particularly when you get into these twins. Or I

could imagine on the twin without ADHD there may be

a considerable amount of pressure to say yes to be

in this study which is very different than these

children without a sibling with ADHD.

I am just wondering what people\'s thoughts

are, first, about the money, and then how an assent

process would be able to be structured so that a

child could say no even when you have got a sibling

with ADHD and a parent who may be very invested in

this information.

DR. GREENHILL: I just want to ask one

question of clarification. Doesn\'t a family with

twins get twice as much money?

DR. NELSON: I am assuming it is per

subject, too.

DR. GREENHILL: So the pressure is even

greater.

DR. NELSON: Right. Process and money.

232

So that is on the table now.

Norm?

DR. FOST: At first, it was ambiguous

whether the money was for the parent or the child

or both or to be divided. I couldn\'t get any

clarification of that from the comments this

morning. So that should be clarified.

Second, I think the clarification should

be explicit about some reasonable estimate of what

they think appropriate compensation to the parents

is for direct expenses or if they want time. That

is Point 1. Point 2, be clear about why any money

at all is going to the children. If it is for an

honorarium, then it is just to thank them and to

teach them something about contributing to science

and reward them for that.

Then it should come after the fact. It

should not be in the consent form. When you thank

somebody, you don\'t say, \"If you do this, I will

thank you.\" You thank them after they have done it

and it should be quite a token amount. It should

be \$5.00 or \$10.00 or a small gift certificate.

233

I think the money is excessive. It will

turn somebody\'s head to be able to get \$500,

somebody who is not well off, in particular, and

could lead to pressure, as you described, to get

the kids to do it. It may even be \$1,000\--we don\'t

know\--which is a substantial amount.

I thought I heard Dr. Rapoport say, but I

wasn\'t crystal clear, that she doesn\'t need it as

an incentive; that is, she had no trouble

recruiting into a prior study. This is different.

The prior one\--I can\'t remember if it was an fMRI

study or not.

But if it is the case that she feels she

can recruit without it, then that would seal the

deal. There is no reason to offer incentives and

get into this problem of undue pressure on children

if it is not needed. So these are all things that

the IRB can and should engage in dialogue with the

investigators about to get clear answers.

But I would hope that this whole thing

could tilt in the direction of reduced amounts,

clarification of why the money is needed, whether

234

it is needed as an inducement and keeping the

amount for the kids to something in the honorarium

range which would be post hoc and not in the

consent form.

DR. NELSON: Let me just ask you one quick

question on the amount. Some IRBs are sometimes

comfortable with more of a wage model as opposed to

a token model. If you took that at an eleven

hours, usually people might use anywhere between

\$8.00 and \$12.00 an hour depending on what you get

minimum wage or at Taco Bell and that sort of

thing. But if you did 10 times 11, that is only

\$110.

Is there a point at which you would say it

shouldn\'t be any more than X at least to provide

advice to those who are going to be, then, working

with the IRB and investigators?

DR. FOST: I think that provides some

guidance for a tough A, but I think it would apply

primarily to children who, in fact, earn wages. In

our IRB, we allow that sort of discussion for

adolescents who are at an age where they might be

235

employed\--14, 15 or thereabouts\--and use that as a

guidance. But it would not apply to 8, 9 and

10-year-olds who normally don\'t make money.

DR. NELSON: Okay. Dr. Jacobs?

DR. JACOBS: I would agree that the

amounts that are in the protocol now are excessive,

particularly for doubling them for people with

twins. I think it should be clarified if it is

parents or children receiving the money.

I used to do my work 20 years ago, and 25

years ago, without any inducements, without any

kind of money involved for children or families and

no other little rewards. It is almost impossible

now to do that and I don\'t do this kind of

research. I do research that is attitudinal. Very

few teenagers, particularly, but even younger

children will be involved in research and very few

parents will be even interested in talking to you

on the telephone or answering a survey if there

isn\'t some sort of money or something involved.

Sometimes people use lotteries. They use

other kinds of things. You can put your name in to

236

get a \$20 gift certificate for the bookstore or

that kind of thing. But I wouldn\'t want us to go

to the place of saying it has to be zero.

I think this is an excessive amount but I

think that what Dr. Rapoport was saying that, at

NIH, now, people are finding that they need to do

these things. I think that is completely accurate.

I see it in every study that I review and in my own

work.

MS. TREAT: I, too, think that the amount

of money that is being offered is excessive. It is

not only enough to turn the heads of the kids, it

is enough to turn the heads of the parents. I

think that your proposal, Dr. Nelson, of going to

something based more on a wage, a per-hour wage, is

more in line with what would be appreciated and at

least noticed by the kids, maybe for the 11 hours

that they would spend, maybe \$100, \$110 or

something like that.

You had mentioned trying to make sure that

the subjects actually agree to be in the study,

particularly the subjects that might be a healthy,

237

normal twin of an ADHD twin, and trying to make

sure that they aren\'t just being pressured by a

parent who has particular interests.

It seems to me that asking or having the

examiners ask the child at various points during

the study, is this okay, do you want to continue,

would work just as well unless the parents are

present at every stage. My impression is the

parents won\'t be present during every stage of the

testing.

There are three periods for the testing.

There is the screening test, the MRI with the

placebo, the MRI with the stimulant. Unless the

parents are present at each one of those, it seems

that the person who is doing the testing could just

simply ask the subject, are you okay with

continuing with this and solve the problem that

way.

DR. NELSON: Are there other comments on

the actual process, itself?

DR. WHITE: I am involved in imaging

studies in children and adolescents with psychotic

238

disorders. I can just tell you our experience. We

do reimburse. We do give for the semi-structured

diagnostic interview, it is about two to three

hours and we give \$20. The neuropsychological

assessment is done over two sessions, each about

two to two-and-a-half hours. We give \$20 for each

of those sessions.

For the imaging session, which is a little

over an hour, we give \$30. In our experience, one

of the challenges, if we get a number of people

from higher socioeconomic status, very willing to

participate, and a challenge to get individuals

from lower socioeconomic status which, except for

the patient group\--I am talking about the

controls\--the sort of patient groups of children or

adolescents with schizophrenia, they are often more

than willing to participate.

We do give them a report afterwards and it

is helpful for them because they have probably the

most thorough psychiatric evaluation that they have

had up until that time. They, the

neuropsychological testing is helpful. So we do

239

make that available for them.

We find that it is difficult to recruit.

We target areas where there is lower SES and they

will say, \"That is not enough money.\" So the

amounts that we are giving were not changing it.

It is nice to offer, and we say \"offer the

families.\" We don\'t say we are giving this to the

children or to the parents. It goes to the

families and part of that is for gas to come in and

time away. They often eat something on the way.

So it is a small amount and I find it helpful.

DR. NELSON: What I would like to suggest

now is that we take a 15-minute break which we are

scheduled for. What that will allow me to do is

try and put together what I see as a summary of the

points that people have made and I would like to,

then, present it to you as much to, A, make sure

that I represent what I have heard you say but, B,

then, so you have an opportunity to fill in the

holes with the goal of trying to wrap up by 3:30.

So let\'s take a 15-minute break and

reconvene at 2:45.

240

\[Break.\]

Summary of the Deliberations

DR. NELSON: I will tell you what I plan

to do and then, hopefully, Dr. Gorman is here when

I actually do it. But what I would like to do is

briefly just summarize what I heard in terms of

things people would want to have happen to this

protocol and consent form and assent forms to make

it better.

I will just run through that list and

then, if there are things that are not on that

list, then you can fill that in after I have

completed the whole thing. Then I would like to

run through the questions for the panel and then

specifically try to assign categories based on our

discussion and do that briefly enough to where,

then, the rest of you can take your shots at it and

fill in the holes and tell me where I have got it

right or where I have got it wrong. Forget about

the right. Just tell me where I have got it wrong

for the sake of efficiency.

The process here will be, then, what I say

241

now with my notes will then be turned into a

presentation that will go to the Pediatric Advisory

Committee on Wednesday morning, and, depending upon

that discussion, go through the process that was

presented earlier as far as to the Commissioner and

to the Secretary.

So, Dr. Gorman is still missing in action.

This is what I have heard and I am going

to divide it into protocol and assent and

permission, but a lot of things I say about the

protocol, obviously, if they need to be disclosed,

I will try and mention when they should also be in

the assent and permission.

Clearly, there are some discrepancies that

need to be cleaned up in the protocol. Dosing is

the obvious one. But I also heard a point by Dr.

Greenhill about minimizing risk in a.m. dosing and

the timing of the studies which I think needs to be

captured.

In terms of the functional MRI, the

training process and lack of restraint\--I mean, the

kinds of things they are doing ought to be made

242

more explicit. There is the pregnancy exclusion

and the importance of talking about the process and

the confidentiality around that process which needs

to be both in the protocol and in the assent and

permission. Then explicit discussion of the MRI

study will be done to a diagnostic specification

needs to be provided both in the protocol and the

assent and permission form.

One thought I had there is they can easily

provide the data they have about the positives they

had when they have done normals. I think a parent

who is thinking of putting their child through an

MRI scan might want to know that they have seen 4

out of 3,000\--

DR. FOST: I wouldn\'t go down that road.

I would like to see the data. It is hard for me to

believe that only 4 out of 3,000 had adventitious

findings.

DR. NELSON: Would you agree that the data

they have should be in there, whether it is the

correct data or not, Norm?

DR. FOST: I don\'t know because my guess

243

is they have got all sorts of fuzzy data in there

and all these blobs that you see in MRIs that you

don\'t know what they mean.

DR. NELSON: We will leave that as a

question. I will soften that.

We had a discussion about the test results

in terms of neuropsychiatric testing. What I heard

from our discussion was that they should not be

made available to the parents, given the problems

in providing that in an appropriate therapeutic

context. But the caveat that the family obviously

needs to know about some of the limitations in

subsequent testing if there are concerns about

repeat performance issues such as on the WISC I.Q.

test.

In terms of genetic testing, we felt the

risk was appropriate there if it was restricted to

testing with respect to zygocity and that the

samples would be destroyed. We also felt there

should be an evaluation and we lacked the

information about the potential stigma of any of

those other tests and, in particular, one could

244

refer them to issues in the literature about

predispositional genetic testing on children and

the risks of doing that or providing that data

which would argue against doing that.

As far as the assent and permission

process, there was\--

DR. GREENHILL: May I ask a question just

for clarification.

DR. NELSON: Go ahead.

DR. GREENHILL: When you said the

arguments against\--what kind of testing was that?

I know the testing for zygocity. Was there

ambiguity about whether they were testing for other

things?

DR. NELSON: They have that list on the

bottom of Page 12. What is ambiguous is they

really didn\'t say how they would use any of that

information and we didn\'t have sufficient detail to

know if one of those particular tests, for example,

if it was APO protein E or something, would be

linked to a late-onset disorder that might place

some risk of that information, if it came into the

245

family dynamic.

So we felt we wanted to just close that

door by saying don\'t do it, make sure you don\'t do

it.

DR. FOST: They also don\'t tell us in the

protocol or the families in the consent whether

they plan to store the samples against the

possibility of doing some other specific ADHD

genetic testing down the road.

DR. GREENHILL: We have a caveat that

would tell parents to put in the consent form that

what we are doing is not genetic testing because,

if they tell their doctor about that and it goes

into a chart note and an insurance company checks

it, then that will put those patients in different

categories.

DR. NELSON: We can make a note of that

but I think that is a prudent thing. So genetic

testing is my term for it.

DR. GREENHILL: That term is not\--you tell

the parents specifically, \"This is not genetic

testing.\" It is twin testing.

246

DR. NELSON: We are micromanaging on that

point.

DR. FOST: Just because it is wrong

doesn\'t mean it is indefensible.

DR. NELSON: In terms of assent and

permission, I think there is a clear emphasis that

there needs to be much more procedural detail, that

there was a lot that was missing in that process.

But, specifically, two process points, the payment

is excessive, whether it is a token for the child

or a limited-wage model based on time, there were

different points of view. I think my preference

would be to leave that to the IRB to determine what

is appropriate. Certainly expenses to the parent

and other sorts of out-of-pocket things, there was

no disagreement with that.

DR. FOST: Just a modification of that,

Skip. I don\'t know if it is excessive. I think it

is.

DR. NELSON: They say 11 hours.

DR. FOST: But, if it is necessary for

recruitment, if they tell us this study\--if they

247

have plausible evidence that this study can\'t be

done in any other way, I might rethink it. I think

that is unlikely.

DR. NELSON: We don\'t have that evidence

before us so I guess\--

DR. FOST: It is excessive if it is

unnecessary.

DR. GREENHILL: The principal investigator

said it was unnecessary; yes.

DR. FOST: I think she said that; yes.

DR. NELSON: Yes; she did. So I think we

should leave that rest.

DR. CHESNEY: Actually, \$51 an hour, so I

would volunteer.

DR. NELSON: You are in infectious

disease; right where you don\'t get paid for any

consults.

The process of dissent needs to be at

least looked at and appropriate. The other things

in there were the issues of drug-of-abuse

classification, adverse effects, infrequent-rare.

I am basically short-handing things that Dr.

248

Greenhill said and also the distinction between

substance abuse and addiction which I thought was

helpful for me at least to understand some of the

issues.

Expunging any language about treatment and

making sure any language about no benefit is there.

Of course, both parents would be an important part

of that permission process.

That is a shorthand of what I heard in

terms of what people feel would be necessary

independent of the answer to the specific

questions. Now, let me run through the questions

and if there are things I have missed on

modifications, then you can be writing it down and

I will copy them.

What are the potential benefits of the

research, if any, to the subjects and to children

in general? I think the way that we have talked

about it, there are no direct health benefits. To

the extent that we have placed restrictions in the

provision of the information back to families, I

think we have even strengthened the argument that

249

there is no direct benefit and that any benefit of

this is simply for the knowledge that may be gained

for the population of children with ADHD and

potentially children who are normal but mainly for

children with ADHD or are misclassified as having

ADHD.

The types and degrees of risk that this

research presents\--

DR. FOST: I might have a respectful

dissent on that. I think this is a study about two

groups of people, people diagnosed with ADHD and

people who are not. They are very interested in

both.

DR. NELSON: Correct. That is what I

said. There may be benefit to those who don\'t have

ADHD in terms of knowledge, not in terms of any

direct benefit.

DR. FOST: Well, there will be knowledge

gained about norms. Either they respond in the way

ADHD people do or they don\'t and that will be news.

DR. NELSON: Okay. I am happy taking my

\"may\" and making it a \"will,\" assuming that it

250

turns out that way.

DR. FOST: I just think it is different

from most controlled trials in that there is a

serious scientific interest in how so-called

normals react.

DR. NELSON: Okay. I am not sure it is

necessary for me to list the types and degrees of

risk. I think most of that has been discussed and

the like. Are the risks to the subjects reasonable

in relationship to the anticipated benefits. There

I assume, if we are looking at the language of

Subpart A, it would be, \"if any,\" and is the

research likely to result in generalizable

knowledge about the subject\'s disorder or

condition.

Since we have already decided that there

is no direct health benefit to these children,

whether they have ADHD or not, the question here is

the reasonableness of the risk with respect to the

generalizable knowledge to be obtained.

To the extent that I have heard people are

willing to approve this under 406 or 50.53 for the

251

children with ADHD and recommend that it could be

approved under 407 or 50.54 for the children

without ADHD, I will assume that the answer to

Question 3, even though we haven\'t asked and

answered it explicitly, would be yes because, if it

isn\'t, we shouldn\'t go there.

Then, likewise, for the reasonable

opportunity.

DR. FOST: I didn\'t understand what you

just said.

DR. NELSON: I am assuming the answer, are

the risks to subjects reasonable in relationship to

anticipated benefits, if any, and to the knowledge

would be yes. Otherwise, if it is no, then we

might as well close up and go home. Disapprove

would be the answer. Likewise, No. 4. If it is

not a reasonable opportunity, we should close up

and go home and say disapprove.

DR. CHESNEY: Can I comment? To me, this

is the crux of the matter. We have been talking

about this, but will the results that they obtain

make a difference? To me, I can\'t separate this

252

from is the study design such that the results will

give us an answer, will be beneficial. Will this

study provide generalizable knowledge?

I guess I felt better about it when they

did some explanations this morning but I still come

back to the question of whether we wouldn\'t benefit

more by getting more what I would call baseline

data on normal children and ADHD children but

normal children without medication. I am probably

confusing things or maybe not answering what you

are asking here but\--somebody else can phrase that

better, but will this study provide knowledge that

will be worth all of this discussion and all of

this work.

Dr. Greenhill, maybe you can answer that.

DR. NELSON: Or Dr. White; either one.

DR. CHESNEY: Or Dr. White; I\'m sorry.

DR. WHITE: I was going to comment on

something. One of their goals was to replicate a

study that had some flaws in it, the one that was

done at Stanford. They didn\'t bring up\--but one of

the primary flaws is controlling for performance

253

among the subjects. So, if there are differences

in performance among groups, then there can be

changes in the activation patterns in the

functional scan based on performance which would be

different than what they are looking for.

So they have two design modifications in

this study that make it very well suited to address

this question. One is that they have a task, the

stop task, which controls for performance. So they

can look directly at that question. The other is

they use an event-related paradigm rather than a

block design. An event-related paradigm allows you

to tease apart each answer to the question that

they make and look specifically.

So I see it as a major improvement over

the other study and I think they said that this

morning, too, and I agree with that.

DR. MARSHALL: To follow up on that, do

you feel as though\--and maybe reflecting back on

Norm\'s comments about healthy children, do you feel

as though, in a sense, they really are asking or

sort of doing two studies? They ares doing one

254

with ADHD children and they really are interested

in normal children? Should this be two separate

studies?

Part of this really does bear on my

determination about how we define a serious problem

that affects the health or welfare of children. I

do look at the interests of children collectively

under that rubric. How do you define a serious

problem? Well, it is something that may not, in

terms of sort of how onerous it is, be very high on

the scale, but it if it affects a lot of children,

then it is a serious problem. Or it could affect

less children but be high on the onerous scale, if

I am making sense.

I am worried here that we are trying to

put words in the investigators\' mouths and redesign

their study a little bit. So it is important to me

to get at this question of health and welfare of

children.

DR. WHITE: You had a couple of questions.

I don\'t want to put words in the investigators

mouths, but the way I saw it was they are looking

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at the difference in response. Therefore, you need

both groups in order to answer that question. That

is how I view it, although I agree that there is

very little knowledge about how the chemistry,

neurochemical development of the brain\--and so I am

sure they are also interested in normal development

and how children respond.

DR. NELSON: Dr. Gorman?

DR. GORMAN: I think this is one of those

rare cases where either answer brings into a sharp

focus benefits for children. If children with

ADHD\'s brains process and/or react to medicines

differently, we learn one important factor. If all

brains work the same with neurostimulation, we

learn another important piece of information.

I think the hypothesis of the study is

that the response is the same. So I think this is

important information for the entire universe of

children as opposed to just the ADHD children. So

I looked at this as\--and that is where, when Norm

said before that\--he tried to make childhood a

condition which we would all agree luckily most of

256

us outgrow it.

What happens then is that this study,

either way, gives important information. So I

don\'t think that the answer of whether they are

different or the same is as important as knowing

whether they are different or the same because it

leads us down totally different pathways in the

future.

DR. MARSHALL: Right. I just think we

need to be very explicit and careful about that in

terms of our deliberation.

DR. CHESNEY: I just wanted to follow up

on your comment which is extremely helpful to me,

this business of go/no-go, task/no-task,

performance versus something for the non-informed

was very confusing. Even as hard as I tried, I

couldn\'t sort it out. So what you have just told

me is, to me, very important, that this study

design does correct for a flaw in the other study

and should give us either the same or different

information because the study design is better, is

improved on.

257

You also said that it does require the

drug in the normals, and I didn\'t quite

understand\--that you needed both to\--if you could

elaborate on that a little bit. You needed both

populations with drug and without drug for\--in

other words, why couldn\'t you use normal children

without drug versus ADHD with drug?

DR. WHITE: They are looking at the

differential response between medication in

subjects with ADHD versus healthy controls. There

is one thing actually I am a little confused about

is that the hypotheses that they are the same,

which she said this morning, is a little bit

different than the hypotheses that were listed.

But the thought is that if the mechanisms,

and I think of the brain as working in networks,

that it is not one area or another one, but the

networks of how the brain works and orchestration

is different between subjects with ADHD. If you

give a stimulant, it alters that network back up to

normal.

If you give it to a healthy control, how

258

does that change it and does it, then\--is it

similar or is it different\--really addresses the

question as to how these neural networks change. I

don\'t know if I am doing a good job answering the

question.

DR. NELSON: No; I think that is fine. A

quick comment and then a question to the group. To

say you think things will be the same is, as a

hypothesis, the same as thinking, for a sample

size, you have to postulate a difference. In fact,

you can\'t calculate a sample size from something

being totally the same.

So you have to say there is a difference

and then calculate how many you need to show it

even if you are trying to prove that, in fact, you

don\'t reach that difference. So I guess I don\'t

see a difference in the way that she stated versus

the way it was stated for the purpose of the

protocol. But I got the view that they both

actually thought differently about what they might

find, the two investigators.

But there is one thing that I left out of

259

my summary and that was the discussion of age and

of dosing, narrowing out the sort of prior dosing

in order to sort of do that. I did that because I

didn\'t get a sense of a clear consensus coming out

of that, that we should restrict it to either

teenagers\--I mean, there seem to be arguments on

both sides for doing one or the other.

So I purposely didn\'t put that in there.

So let me put that on the table to see if that was

appropriate or not.

DR. KODISH: My take is if, under broad

strokes, forgetting about categorization, we are

going to find this ethically appropriate work to do

because the ethics is obviously key. As an \"after

that\" thought, it becomes important to do the best

science that can be done.

What I heard from the P.I. is that the

best science that can be done is in the younger age

group. So, whereas my normal ethics instincts

would say older age group, I think this is one of

those cases where the science would lead us to

younger.

260

DR. NELSON: Meaning 8 to 12.

DR. JACOBS: That is what she said. Could

I comment. I think that is definitely what we

heard this morning. That is what I would suggest,

too. But I don\'t think this group needs to say it

should only be done in 8 to 12-year olds. It seems

to me the best science would be to restrict the age

range because I think they are going to have a

little \"apples and oranges\" problem if they don\'t.

So I think that they should restrict the

age range. I think you could make an argument

either way, that they the upper range first and

then, in the next study, they do the lower range or

something like that. But I mean, it seems to me, I

would agree that the best science would be the

lower age range.

But I think we should be recommending that

they restrict the age range and she seemed willing

to do that this morning.

DR. FOST: I think that these comments are

just recommendations and not conditions.

DR. JACOBS: Yes; right.

261

DR. NELSON: Everything I have listed was

something that I would expect to make sure it

happened. The restricting of the age range, it

sounds like we think it should happen but how they

do that is a separate question.

DR. FOST: Well, you are saying if they

don\'t restrict the age range, the Secretary

should\--

DR. NELSON: That is the one exception,

Norm. That is the exception. But everything else

I listed was not meant to be discretionary.

So let me, I guess, go to the specific

question. It sounds like, from our discussion,

assuming these modifications and that we would

recommend, that giving a single dose of

dextroamphetamine would constitute a minor increase

over minimal risk; that, in fact, this would be

approvable with these stipulations even for the

ADHD group under 50.53 or 406 as a minor increase

over minimal risk given the commensurability

disorder or condition and generalizable knowledge;

that, for those children that don\'t have ADHD,

262

that, nevertheless, it still does present a

reasonable opportunity to understand, prevent or

alleviate a serious problem; and that we feel,

again, with these stipulations that it could be

conducted in accord with sound ethical principles

paying attention to assent and permission,

appropriate science, monitoring of adverse effects,

minimization of risk through a.m. dosing and the

like.

DR. FOST: I am not sure I followed you.

You are separating it out and saying the ADHD

children could be approved under 406 and the

normals under 407?

DR. NELSON: Yes. So I guess, then,

having said that, I would like to turn to our FDA

and OHRP colleagues and ask if they think we have

finished with a clear set of recommendations, or

are there any ambiguities that need to be cleared

up with that?

DR. SCHWETZ: The ambiguity that I was

concerned about is one that you have clarified just

a couple of minutes ago, make sure that if there

263

are recommendations, they are distinguished from

the stipulations because that is what we will have

to negotiate.

DR. NELSON: Okay.

DR. SCHWETZ: Otherwise, I think we are\--I

am satisfied with that as a clearer conclusion.

DR. MURPHY: I do think, though, Skip, in

our presentation and response, we will need to\--and

you have gone through the questions but we will

need to articulate what this committee said were

the potential benefits because that is the question

we posed. So we are going to have to do that. The

discussion has done that but I do think that we are

going to need to do that. You have gone through

the risks and you have answered the other

questions. That was the only thing I want to just

point out. I don\'t know if you want to take a

final comment on that or not; that was all.

DR. NELSON: Meaning the benefits of the

research overall on Question 1.

DR. KODISH: I am willing to take a stab

and throw out on the table the very practical

264

result that we would improve the diagnostic

precision around ADHD and that is a benefit to

children as a class.

DR. MURPHY: And does the rest of the

committee agree with that?

MS. GOREY: One more thing, Skip, if you

could maybe please clarify why this is a minor

increase over minimal risk.

DR. NELSON: Well, there are two ways to

do that. One is versus minimal risk and the other

is versus more than a minor increase over minimal

risk. I would love it, as I said to Dianne at the

break, if we could take the tape and capture the

statement that Dr. Greenhill gave specifically

about the risks of a single dose of that particular

drug because I think he articulated it well and

everyone else on the committee thought that that

was a good statement.

I was not transcribing what he had to say

at the time. So I know that Dianne might have

asked you to try and write a little bit of that

down but, to me, that was the clearest succinct

265

statement about why this would not be minimal risk

and why it was not more than a minor increase. For

me to try to reproduce that now from memory, I

think, would probably distort what he had to say.

If we have to, we can try and capture that

little segment off the tape and get that down more

quickly than when the transcript would become

available would be my suggestion.

DR. GOLDKIND: If I could just rephrase

what you said since I transcribed it. You had said

that it was more than a minimal risk because it is

not part of routine life but that the effects are

gone in approximately five hours, and that you

thought that the first thing in the morning\-- which

Skip has already defined\--in the morning would be

best and would decrease the risks of sleepless

night for children, and that the worst possible

outcome is restlessness, irritability and

akasthisias which are gone in approximately four

hours.

So those were some of the reasons that you

cited for it being a minor increase over minimal

266

risk.

DR. GREENHILL: I wouldn\'t say akasthisia.

I don\'t think akasthisia is\--

DR. GOLDKIND: I think Dr. White did.

DR. GREENHILL: Oh; okay.

DR. WHITE: Just restlessness would

probably be better than akasthisia.

DR. GOLDKIND: Does that adequately

summarize it?

DR. GREENHILL: And that I think it is not

more than a minor increment over minimal risk

because the drug, the medication, has been in use

to treat ADHD for a longest period of time of any

of the medications we have approved since 1937 and

it is approved over the widest age range of the

stimulants. Most stimulants are approved down to

age 6 and this is approved down to age 3.

DR. GOLDKIND: And that you thought it was

safer than one dose of aspirin.

DR. GREENHILL: No, no; I think the

toxicity from excessive doses is less than that of

common over-the-counter drugs, a number of\--Advil;

267

certainly it is safer than Advil if taken in excess

because you can have destruction of liver tissue if

a teenager takes a bottle of Advil or Tylenol.

So, just to try to put it in context.

That is not going to happen with a bottle full of

amphetamine. What they will get is elevated blood

pressure and high rates of pulse and, if they take

several bottles, they may get a seizure. But we

are not talking about irreversible damage that

happens with a common, over-the-counter\--so, just

to try to put it in context, it is a drug

universally used in pediatric practice, in this

country, at least, and, in other countries, it is

one of the few drugs that was ordered into\--for

example, Australia, in terms of their allowing

medications in for treatment of children.

So I think that puts it in a framework of

knowledge about its safety limitations.

DR. NELSON: Mary Faith?

DR. MARSHALL: I just would like a final

process.

DR. FOST: I just want to go back to the

268

exchange between Dianne and Rick about what the

benefits, the societal benefits, would be. I am

not sure that I understand, Rick, how this will

improve diagnostic precision about ADHD. I mean,

nothing is going to come out of this that will be a

diagnostic test, for sure. They are not going to

do fMRI testing.

I mean, what I think it will help, it will

improve understanding about what, if any,

differences exist between children diagnosed with

ADHD and those who have not, whether there are

genetic factors in their brain responses to

amphetamines. Those findings may lead to further

studies which\--I mean, if, for example, this shows

a difference between the response of kids with ADHD

and those who do not, then you could go on and

study more practical screening tests and see if

they correlate with these fMRI findings.

But I don\'t think anything is going to

come out of this study, itself, that will help

anybody diagnose somebody with ADHD. That may be

one down the road.

269

DR. KODISH: I guess I was taken with the

mention of fraudulent tests that are out there now

and eliminating those. I am interested if either

of you think Norm is closer to the mark here or I

am.

DR. WHITE: I know that Dr. Rapoport

mentioned that a couple of times, and it shows the

interest in the community. In the community where

I am, people pay a lot of money to find\--use

imaging tests to try and determine whether someone

has ADHD or not. They are used clinically without

much of a research based although my understanding

is that they might be looking into researching that

more.

So I was actually wondering if that is a

topic, if the community at large is very interested

in this question about diagnosis and the use of

imaging, this is certainly a step in right

direction and I agree, it won\'t answer the question

completely but the scientific process slowly.

DR. FOST: But the studies that are being

used out there are not these studies.

270

DR. WHITE: No.

DR. FOST: And these studies aren\'t being

compared to those studies so these won\'t shed any

light on whether those studies correlate with these

studies or not.

DR. FOST: I just think we should not

oversell. The cure for cancer is not coming out of

this study.

DR. NELSON: Agreed. Ms. Treat?

MS. TREAT: I am sure that you will find

an opportunity for this comment and I must have

lost focus at the time, but I just wanted to note

that it seemed that there is a discrepancy between

the minimal weight stated in the consent form and

the minimal weight identified in the protocol and

what Dr. Rapoport had responded with. So she said

the minimal weight was 40 kilograms.

DR. NELSON: I included that under the

dosing discrepancy because that is where there is

an impact on the dosing, making sure they got the

weights correct.

I know Mary Faith wanted to make a process

271

comment, so if would could transition to process

comments. I think this is the first time this has

been done. So we won\'t assume that it is being

done the only way or the best way and that there

will always be ways we could do it better.

So I know that the FDA and the OHRP is

very interested in inviting comments from anyone,

individually as panelists or from anyone in the

audience, in terms of the process, itself, not so

much what this protocol or this issue but the

process and how it could be made better. I believe

you are the volunteer for whose E-mail it is going

to go to?

DR. JOHANNESSEN: Yes.

DR. NELSON: Basically, Jan Johannessen

who, if you go to the pediatric page on the FDA

which is down about two-thirds on the right-hand

side, hit pediatrics, and, up in the upper

right-hand corner, you will see the Pediatric

Advisory Committee. You hit that link and you will

get his E-mail.

So feel free to send him a message about

272

process. With that, Mary Faith?

DR. MURPHY: Just before she says that. I

am very glad you brought this up but we

really\--this is not a reaction. We had actually

planned to ask you all to make sure that you

provide us that input and to others again, as Skip

said. This really was a planned part of this

meeting that we want that feedback. So thank you.

DR. MARSHALL: I will try and be brief.

Skip and I were both part of at least the OHRP 407

process that was resuscitated back in December of

2000\. I think the process has evolved rapidly in a

positive way and a lot of the credit for that, I

think, is to OHRP and to the staff there and the

real serious way in which they have considered the

feedback that other panels, the previous panels,

have given them. You see it changing over time.

Quickly, my sense today, and, again, these

are sort of general for the future sorts of things,

is that, in striving towards an ideal, the more we

could do to help Dr. Rosenstein and the Chairs and

members of every IRB and all the investigators, Dr.

273

Rapoport and her colleagues, if and when it looks

as though it is going to move towards a 407 review

process would be that they would, at the local

level\--and Don said this. We didn\'t just punt this

to the federal government.

But I do feel as though there

are\--perhaps, there is a need for maybe a little

more\--perhaps guidance is too strong a word but

structure in terms of how things are put forward

and what would be expected of the local IRB or the

investigator.

I feel as though, both in terms of the

protocol and the IRB review, there were a lot of

things missing here that, in the future, we have

learned from today and might bring to the table.

I am a little worried. I feel as though,

in a sense, we have done some of what we said we

weren\'t going to do and that is micromanaging or

specifying. I have seen things in the protocol

that, had I been the local IRB reviewer, I would

have sent it right back and said, \"We are not going

to bother with this until you fill in these holes.\"

274

So, for it to have gotten this far, I

think maybe speaks to areas where the process

should be improved. I think it also raises the

question in my mind\--I don\'t know Dr. Rapoport.

Everyone speaks very well of her and her science

and the former studies and so forth that are a

bedrock of things that have followed.

But, from my perspective, if it is not

there and it is not articulated, then I worry not

only about whether it was thought about but how

that research is going to be carried out in the

real world if there hasn\'t been attention to detail

and so forth in terms of spelling things out.

So I would maybe ask that when we go back,

or when the FDA and the OHRP go back and reconsider

the process as it evolves that we look at maybe

some more concrete structure of what is required of

the local folks prior to accepting it for review or

sending it forward to the panel.

DR. CHESNEY: I would like to just come

back to the issue that Norm raised because I think

not only did it trigger many of us to think

275

differently about giving this drug to these

children but we are doing research on the normal

children here because we don\'t know what the

outcome of giving this drug will show us. It may

well be that the investigators will find something

that will trigger them to move in a different

direction for the normal children. I think, for

those of you who are gurus in verbiage and numbers,

I think maybe that is something we need to think

about for the future, particularly because of the

whole issue of psychostimulants and psychiatric

drugs in children is becoming more and more

important in our country.

So I would just like to reemphasize that I

feel that Norm made an excellent point in terms of

looking at normal childhood as a condition

and\--enough said.

DR. NELSON: Richard?

DR. GORMAN: I would like to comment the

Chair on, I think, if not the original creation,

certainly the wide dissemination of the algorithm

that we use today. I know it comes from the

276

regulations, but having it in an algorithm form

helped focus both the thought processes I,

personally, prepared for this meeting, as well as

the discussion as we went through the day\'s

discussion. I thought it was very helpful and

would hope that that part of the format would

continue.

I would echo the responses of Dr. Marshall

that I think some preparation on the part of the

local IRB in terms of stripping away some of the

areas that we then spent a fair amount of time

discussing which, in some ways, distracted from the

central questions that we brought together to

answer could be remediated by giving some direction

to local IRBs before these protocols get to this

place.

I would also recommend that we\--I think

Skip probably has a fair idea of how he is going to

present this to the subcommittee and then how he is

going to communicate that to the Secretary and the

Commissioner. But, perhaps, having a structure in

which we are supposed to put our responses so that

277

we can sort of see the format of that letter or the

framework of that letter without the details, for

future, might help people structure their remarks

during the discussion.

DR. NELSON: Thank you. That is actually

a good suggestion. I am not sure what that would

look like but we could give some thought to it.

DR. GORMAN: I am always in favor of

creating boiler plates so that the wheel doesn\'t

have to continue to be reinvented each time and

might make the life of the Secretary easier because

he gets used to reading all the letters. Parts at

the beginning, he just skips right over that.

DR. NELSON: Other comments?

DR. FOST: I am not sure I understood your

comment, Rick. Maybe this over-reaction to it. I

would be concerned about taking single protocol

reviews such as this and translating them into

generalizable restrictions, rules that OHRP or FDA

then says, \"This is the way you do it from now on.\"

DR. NELSON: I didn\'t hear him that way.

All I heard was, when I write a letter\--let me

278

speak for you, Richard, if that is all right.

DR. GORMAN: Thank you, Skip.

DR. NELSON: If we write a letter, these

are the points that are going to be in it so we

need to make sure these are the points that we have

touched on. Basically, in my mind, I had something

like that working and that is why we went through

this process. So that is all I hear, not that

there is a sort of cookbook approach that we can

then promulgate so that\--I mean, that is not what I

heard. So I agree with you, we shouldn\'t just be

doing this by cookbook.

Any final comments, Bern?

DR. SCHWETZ: Yes. I would just like to

thank the subcommittee. I think for moving the

first dual process, dual review, through the chute,

I think you did a great job. Dr. Nelson, I think,

is also to be thanked in particular for providing

the leadership to make this happen. So, thank you

all.

DR. GOLDKIND: I will just ditto that.

DR. NELSON: Thank you. With that, I

279

guess the meeting is adjourned.

\[Whereupon, at 3:35 p.m., the meeting was

adjourned.\]

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