1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ADVISORY COMMITTEE MEETING

Wednesday, September 15, 2004

8:10 a.m.

ACS Conference Room

Room 1066

5630 Fishers Lane

Rockville, Maryland

P A R T I C I P A N T S

P. Joan Chesney, M.D. C.M., Chair

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

Deborah L. Dokken, M.P.A.

Steve Ebert, Pharm.D.

Michael E. Fant, M.D., Ph.D.

Samuel Maldonado, M.D.

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

Thomas B. Newman, M.D., M.P.H.

Judith R. O'Fallon, Ph.D.

FDA Participants

Solomon Iyasu, M.D.

Dianne Murphy, M.D.

C O N T E N T S

AGENDA ITEM PAGE

Call to Order and Introductions - P. Joan Chesney,

M.D., Chair, Pediatric Advisory Committee 5

Meeting Statement - Jan N. Johannessen, Ph.D.,

Executive Secretary 5

Statement of Dianne Murphy, M.D. 8

Subpart D Referral Process - Sara F. Goldkind,

M.D., M.A., Bioethicist, Office of Pediatric

Therapeutics 17

Summary of Deliberations of Pediatric Ethics

Subcommittee held on 9/10/04 - Robert M. Nelson,

M.D., Ph.D., Chair of the Subcommittee 26

Overview of Adverse Event Reporting as Mandated by

BPCA

- Solomon Iyasu, M.D., Medical Epidemiologist

Office of Pediatric Therapeutics 70

Adverse Event Reporting

- Ocuflox (ofloxacin) 105

Fosamax (alendronate) 110

Hari Sachs, M.D., Medical Officer, Division of

Pediatric Drug Development

- Fludara (fludarabine)

Susan McCune, M.D., Medical officer, Division of

Pediatric Drug Development 125

- Clarinex (desloratadine)

Jane Filie, M.D., Medical officer, Division of

Pediatric Drug Development 149

Adverse Event Reporting for Drug Products

Containing Budesonide or Fluticasone: Pulmicort,

Rhinocort, Flonase, Flovent, Advair, and Cutivate

- Peter Starke, M.D., Medical Team Leader,

Division of Pulmonary Drug Products 172

C O N T E N T S (Continued)

AGENDA ITEM PAGE

- ShaAvhree Buckman, M.D., Ph.D., FAAP, Medical

Officer, Division of Pediatric Drug Development 190

- Joyce Weaver, Pharm.D., Safety Evaluator,

Division of Drug Risk Evaluation 199

- Badrul A. Chowdhury, M.D., Ph.D., Director,

Division of Pulmonary and Allergy Drug Products,

CDER, FDA 211

Open Public Hearing --

Final Comments and Adjourn - P. Joan Chesney, M.D.,

Chair, Pediatric Advisory Committee 239

P R O C E E D I N G S

DR. CHESNEY: Good morning. I think we're

ready to begin today's deliberations, and I'd like

to say that we're not going to introduce the

committee members until Dr. Murphy has given us an

overview of the previous and current committees.

And so we really just, I think, need to start off

the meeting by having Dr. Johannessen read the

meeting statement.

DR. JOHANNESSEN: Thank you, and good

morning. The following announcement addresses the

issue of conflict of interest with regard to the

study drug, dextroamphetamine, and competing

products used for the treatment of ADHD and to the

adverse event reporting session 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 a conflict of interest at this

meeting, with the following exceptions:

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

full waivers have been granted to the following

participants:

Dr. Patricia Joan Chesney for ownership of

stock in a company with a product at issue valued

at 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. Robert Nelson for an honorarium

for speaking on an unrelated topic at a firm with a

product at issue valued at less than $5,000.

A copy of the waiver statements may be

obtained by submitting a written request to the

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

of the Parklawn Building. In the event that the

discussions involve any other firms or products 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. Samuel

Maldonado has been invited to participate as an

industry representative acting on behalf of

regulated industry. Dr. Maldonado is employed by

Johnson & Johnson.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement in

any firm whose product they may wish to comment

upon.

Thank you, and we'll now turn it over to

Dr. Dianne Murphy.

DR. MURPHY: I wanted to just take a

moment to welcome everybody and to also tell the

committee that you may not have realized--or a

number of people on this committee, that you have

just made a transition. That transition has been

from a subcommittee, which was providing very

important advice to us, but to now a full

committee, which advises the Commissioner directly.

And you have certain responsibilities that are

slightly different, and I'm going to go over those

in a second. And also to the fact that you are not

only just a full committee advising the Commissioner, but

that, as I said, you have certain

responsibilities that you're going to hear some of

them today that are clearly defined.

You have moved from the Center for Drugs

to the Office of the Commissioner, and the office

has been--and this committee is now administered

there the Office of Science. And our new Exec.

SEC. is Jan Johannessen, who has done an

extraordinary making sure that everybody has been

recruited and met all the criteria that we need to

meet and getting you here and assembled and in

helping us charter this new committee.

It is really just a monumental feat

because the agency basically was not allowed to

have any new committees. It actually took Congress

to create you. So I'm spending a little time on

this so you'll understand how important your

deliberations are to the agency.

One of the other activities that has

occurred, as you know, is that there has been the

creation of the Office of Pediatric Therapeutics,

and that office is now responsible for all

pediatric activities across the agency. And,

therefore, this committee may be hearing more--having been

in the Center for Drugs previously, you

may be hearing more about other products such as

devices or formula. So I wanted to make sure that

you are also aware of that.

And I know sometimes that's a bit

overwhelming if you're a cardiologist or an ID doc

or whatever your training. The breadth of what

we're asking you to deliberate upon is quite large.

However, as those of you who have been on the

previous subcommittee are aware, we always bring in

additional experts, that you're here to bring

particularly to those deliberations the pediatric

perspective, because we have lots of technical

committees that have lots of expertise, and we will

always bring that additional expertise as needed to

the deliberations. But it's your particular

pediatric perspective and expertise that we depend

upon at these meetings.

I did want to spend a moment introducing,

so that you can put some faces with names, the

people who are now in the Office of Pediatric

Therapeutics, which is Sara Goldkind, who will be

speaking; Solomon Iyasu, whom you know, who has

been on detail with us for a while; Ann Myers, if

you'd put your hand up, Ann, who is our policy

analyst, so you'll have a face there; and Jean

Harkins, who is not here, but she is the person who

actually runs the Office of Pediatric Therapeutics.

I mention that because it is that office

that is mandated to particularly focus on the

ethical issues and the safety issues, and that this

committee within the Office of the Commissioner has

now also been identified to deal with those issues.

I also wanted to comment on some other

transitions for those of you who have been on the

subcommittee. I'm no longer with the Office of

Counterterrorism, Pediatric Drug Development.

Rosemary Roberts is the new office director, and so

she's still going to be very active in the

pediatric issues, and the Division Director for

Pediatrics, Shirley Murphy, is now the Deputy

within that office. And we have a new Division

Director, just so you'll know these names. Lisa

Mathis I do not believe is here. She's dealing

with other issues this morning.

For the new members--and I apologize to

the old members because I know you've heard this.

I actually took it out of the slide on Monday

because I didn't think that everybody really wanted

to hear about all the accomplishments of the

previous committee. But I wanted the new members

to hear a little bit about what the previous

committee has actually--some of the issues they

have dealt with. And they have dealt with not only

the ethical issues that have to do with normal

volunteers, placebo-controlled trials, the

vulnerable population within pediatrics. They have

dealt with an enormous array of scientific issues,

from sleep disorders, hepatitis C, HIV, antiviral

drug development in neonates, the current

epidemiology and therapeutics and development of

therapies for hyperbilirubinemia, clinical risk

management for HPA axis suppression in children

with atopic dermatitis, tracking cancer risks among

children with atopic dermatitis, and as you all are

aware, last February a discussion of the FDA

process and review of therapies for major

depressive disorder.

In addition, this committee has now

reviewed--before today's additional eight products

that you're going to be hearing about, has reviewed

over 22 products that were granted exclusivity, and

you have looked at the one-year post-adverse event

reporting that has occurred for those products. I

can tell you that this is an important process that

we are looking to evolve constantly. It came up

recently at a congressional hearing as to how were

we doing this and what were we doing with it. And

I think it's important that this committee realize

that it is important what you have to say to us

about whether we should do anything else in trying

to follow--gain a better understanding of what

happens to children after these products have been

either approved--or approved and particularly after

they have been studied, because as you heard

yesterday, they don't always get an approval or a

label change, but certainly they have been studied

and they may be granted exclusivity. And that in

itself often results in additional information.

As you go around this morning, it would be

helpful if you would identify if you were on the

previous subcommittee. I'd appreciate that just so

the new members will know. And also, I wanted to

particularly thank Sam--and is Steve here? I don't

see him. Oh, there you are. As Jan said, for

doing double duty. We are still in the process of

identifying the industry and consumer

representatives, a total different process, and

they very kindly agreed to continue to assist us in

these last rigorous days, the last few days.

And, again, thank you for being here, for

your participation, because I know it requires

quite a commitment, and for your thoughtfulness as

we move forward with this new committee.

DR. CHESNEY: Thank you very much, Dianne.

So I think we would like next to go around

the room and have the new Pediatric Advisory

Committee members introduce themselves, and I'd

like to start with the members who are no longer on

the committee, if they could--that was a joke. So

let's start with Dr. Maldonado.

DR. MALDONADO: Sam Maldonado. I work in

pediatric drug development at Johnson & Johnson,

and as Dr. Murphy said, this is my last session

with the committee. There will be a new member

from industry.

DR. NEWMAN: I'm Tom Newman. I'm a

professor of epidemiology and biostatistics in

pediatrics at the University of California, San

Francisco, and a general pediatrician, and I'm new

to the committee.

MS. DOKKEN: I'm Deborah Dokken, and I am

also new to the committee, and I am a patient-family

representative and I really appreciate

having that voice on the committee.

DR. O'FALLON: Judith O'Fallon. I'm a

professor emeritus of statistics at Mayo Clinic. I

got called back half-time to cover a maternity

leave, by the way, going back. But I've been on

the committee since its beginning.

DR. FANT: My name is Michael Fant. I'm

an associate professor of pediatrics at the

University of Texas in Houston. My expertise is in

neonatology and in biochemistry. And I'm new to

the committee.

DR. NELSON: I'm Robert Nelson. I'm

associate professor of anesthesia and pediatrics at

Children's Hospital of Philadelphia and University

of Pennsylvania. My clinical area is pediatric

critical care, and I also work in the area of

ethics, and I was on the previous subcommittee.

DR. EBERT: Hi, I'm Steve Ebert. I'm an

infectious diseases pharmacist at Meriter Hospital

and professor of pharmacy at the University of

Wisconsin, Madison. I'm an outgoing member of the

committee.

DR. CHESNEY: And my name is Joan Chesney.

I'm a professor of pediatrics at the University of

Tennessee in Memphis, and my interest is infectious

diseases, and I'm a former subcommittee member.

DR. JOHANNESSEN: My name is Jan

Johannessen, and I'm the Executive Secretary to the

Pediatric Advisory Committee.

DR. MURPHY: Dianne Murphy, Office

Director, Office of Pediatric Therapeutics, FDA.

DR. IYASU: I'm Solomon Iyasu. I'm

medical team leader with the Division of Pediatric

Drug Development and an epidemiologist with the

Office of Pediatric Therapeutics.

DR. CHESNEY: Thank you and welcome to all

the new committee members. You're in for quite a

ride, believe me.

Our first speaker this morning--and,

again, for the new committee members, what you're

going to hear about next was really a historic

process and a historic meeting on Friday. And Dr.

Sara Goldkind is going to introduce the topic for

us. She's a board-certified internist who did a

clinical fellowship in medical ethics at the

University of South Florida. She also has a

master's degree in religious studies with a focus

on comprehensive religious ethics--comparative

religious ethics, excuse me, and she's been with

the agency for almost a year, which she tells me

seems like longer than that.

Dr. Goldkind?

DR. GOLDKIND: It's my pleasure to be here

today at the inaugural meeting of the Pediatric

Advisory Committee and to tell you about the work

of the Pediatric Ethics Subcommittee.

As Dianne mentioned, this is really a

landmark time in pediatric research. That's the

way we see it because we feel that this committee

as well as the Pediatric Ethics Subcommittee can

really make incredibly important decisions and

consensus statements regarding pediatric research.

So what I'd like to do now is talk a

little bit about the role of the Pediatric Ethics

Subcommittee. It is going to be a subcommittee

that addresses Subpart D referrals and also ethical

issues that impact on research affecting the

pediatric population.

Going back to the part on Subpart D,

there's a mistake in the slide, and where it says

"Joint 21 CFR 50.54 and 45 CFR 46.407 referrals,"

those are referrals that will come to both OHRP and

the FDA, and we actually had one of those to review

on September 10th, which involved the effects of a

single dose of dextroamphetamine in attention

deficit hyperactivity disorder, a functional

magnetic resonance study. And Dr. Nelson, who is

the Chair of the Pediatric Ethics Subcommittee, is

going to give you a summary of the deliberations of

the Pediatric Ethics Subcommittee in that regard.

The subcommittee can also address

referrals that come only to the FDA under 21 CFR

50.54, and I'm going to talk about these

regulations in a little bit more detail. But if

there are no referrals and there are burning

ethical issues that we would like to address, we

can also take those to the Pediatric Ethics

Subcommittee for deliberation.

So now to go into a little bit more detail

about the regulations under which we can have these

referrals, Subpart D is entitled "Additional

Safeguards for Children in Clinical Investigations

and Research," and they are essentially identical

for DHHS and FDA. DHHS regs are Title 45, CFR 46,

also known as "the common rule" because 17 federal

agencies operate under those regulations. And the

FDA regulations are 21 CFR 50.

There is a notable distinction between the

two sets of regulations, and that is the issue of

waiving parental permission can be done under Title

45, CFR 46, but not under the FDA regulations. But

in terms of the Subpart D referral process and the

general categories of pediatric research, those are

identical between the two regulations. And what

I've done in these slides is include the citations

for both regulations.

So Subpart D has four different categories

under which pediatric research can be conducted.

The first category is 50.51/46.404, and that is a

category which states that the research involves no

more than minimal risk. And it essentially does

not discuss who benefits from the research, but

basically describes that there's a ceiling of

minimal risk for exposure for the children.

50.52/46.405 is research that involves

greater than minimal risk but presents the prospect

of direct benefit.

And then 50.53/46.406 involves greater

than minimal risk but presents a prospect of

generalizable knowledge about the disorder or

condition, but there's no prospect of direct

benefit to the participants.

So those are three categories under which

an IRB can classify pediatric research. If the IRB

determines that it cannot classify the research

under those first three categories, however, 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 FDA Commissioner or Secretary, after

consultation with a panel of experts in pertinent

disciplines, and following an opportunity for

public review and comment determines the

following...

So, in other words, if the IRB feels that

the research has merit for the general pediatric

population but cannot be classified under one of

the first three categories, it can make a referral

to one of the federal agencies--and I'll discuss

those details in a minute--to have the protocol

reviewed by an expert panel.

And so what must the research then

satisfy, according to the expert panel? The

research, in fact, satisfies one of the first three

categories, so the expert panel can make a

determination that after it reviews the research,

actually one of the first three categories does

apply, or the following three conditions are met:

the research presents a reasonable opportunity to

further the understanding, prevention, or

alleviation of a serious problem affecting the

health or welfare of children; the research will be

conducted in accordance with sound ethical

principles; and adequate provisions are made for

soliciting assent and parental permission.

The composition of the Pediatric Ethics

Subcommittee is the following: Dr. Nelson is the

Chair. According to FACA, we also need to have two

members of the Pediatric Advisory Committee

represented on the Pediatric Ethics Subcommittee.

And in addition to Dr. Nelson, we included Dr.

Chesney and Dr. Gorman. And we supplemented the

Pediatric Ethics Subcommittee with an additional

group of core ethicists: Drs. Fost, Kodish and

Marshall.

The composition of the Pediatric Ethics

Subcommittee under both DHHS regulations and FDA

regulations states that the panel of experts in

pertinent disciplines, for example, science,

medicine, education, ethics, and law, and we

selected from among those groups according to the

protocol. But most of those groups were

represented on the Pediatric Ethics Subcommittee

that took place on September 10th. In addition, we

also had two patient advocates represent on that

subcommittee.

So once the IRB makes the determination

that it wants to refer to a federal agency, it

refers to the FDA for regulated--if the products in

the protocol are FDA-regulated, and it refers to

OHRP if the research is federally funded or

conducted. And we have a very close working

relationship with OHRP, and when a protocol comes

to us, we also refer it to them for review, and

they refer a protocol that comes to them to us.

And in this case, the protocol was actually

submitted to OHRP, but upon our review it was noted

that two of the products in the protocol, both the

MRI machine and the dextroamphetamine, were FDA-regulated

and so we also had jurisdiction over that

protocol.

The review would then be conducted by the

Pediatric Ethics Subcommittee expert panel, and as

I said, each protocol--we will have a core group of

ethicists, and it will be supplemented by

appropriate expert panel members and patient

representatives and/or community representatives.

The Pediatric Ethics Subcommittee will

bring its recommendations to the Pediatric Advisory

Committee for endorsement, as Dr. Nelson will do

today, and then those recommendations will be

submitted to the Commissioner of the FDA for final

determination. Once that determination is

rendered, it will be forwarded to OHRP, and OHRP

will send the Commissioner's memorandum on the

Pediatric Ethics Subcommittee/Pediatric Advisory

Committee's recommendations on to the Secretary,

and the Secretary will have his final

determination, particularly in regards to funding

of the research.

So our goals in this process, clearly the

overarching goal is to advance an understanding of

pediatric research, and we'd like to do that

involving additional expert input and public input.

We also want to have transparency in the process,

and in that regard we had an open public comment

period before the Pediatric Ethics Subcommittee.

We also had an open hearing available at the

Pediatric Ethics Subcommittee. We also want to try

and respond to these protocol referrals in a timely

manner so that they will be helpful to the IRBs

involved. And we want to be able to handle these

referrals in a consistent and clear manner so that

they can advance the general understanding of

pediatric research. And we would like to do this

and are doing this in harmony with OHRP so that we

have a united federal agency response to pediatric

research.

Thank you.

DR. CHESNEY: Thank you very much.

Maybe what we could do is introduce and

hear our next speaker and then ask for questions

from the panel. Dr. Skip Nelson is the Chair of

the Pediatric Ethics Subcommittee, and he will

discuss with us the deliberations of the Pediatric

Ethics Subcommittee with the invited folk that Dr.

Goldkind just mentioned on last Friday. And the

issue here is that Dr. Nelson has prepared a

summary of the committee's deliberations, which you

have in front of you, and I'll let him highlight

issues that he wants to bring to your attention.

And what we're looking for here is an endorsement

by the committee. As we've mentioned, this took a

whole day of fairly intense deliberations last

Friday, and we don't anticipate that we will have

to repeat that process here. So we're just looking

for the committee's endorsement and any questions

that you may have, either for the process as Dr.

Goldkind just outlined it or for the specific

events of Friday as Dr. Nelson will present them.

DR. NELSON: Thanks. You have the

document before you. Let me just note, as someone

pointed out, I've got the wrong date in the

heading. That will be corrected before the final

version goes up. If you see any other typos, feel

free to write them down and share them with us

after our discussion.

I'd like to walk you through the document.

My intent here is not to read the document but to

highlight what is in it, since you can probably

read faster than I can talk. The introduction

simply restates the purpose of the meeting and then

gives a brief summary of what's in the summary.

But let me first start with what is the

primary issue that would be raised by this

protocol, which is the particular risk of the

procedures that are contained within the protocol.

Now, as a preface to this, one of the

first things that an IRB must determine--and for

this exercise, the Pediatric Ethics Subcommittee is

effectively functioning like an IRB--that the

research design is sound. So after I talk about

risk, I'll then run through a number of recommendations and

stipulations that the committee made

to assure itself that, in fact, the research was

sound. But assuming those are made, the

subcommittee felt that the following risks would be

appropriate:

The first is the single dose of dextroamphetamine.

Is that minimal risk? The feeling

was no. We can a little bit later, if you'd like,

about the definition of minimal risk, but, in fact,

that was not minimal risk. But the subcommittee

felt that it was no more than what's called a minor

increase over minimal risk, and it lists the

reasons there, which I think I'll state in more

detail for highlight.

First of all, it has been used since 1937

with a good safety record. It is one of the only

two stimulants that are approved down to age 3, and

the children in this protocol are between 9 and 18.

The greatest side effects are irritability,

restlessness, agitation, and temper outbursts which

generally last only 4 to 5 hours, are infrequent,

and as you'll see later, one of our risk

minimization strategies was to say they should do

this in the morning so you don't have the kid up

all night after you do this. It's used universally

in pediatric practice, and the more common risks

are restlessness, anxiety, loss of appetite,

insomnia--again, why we made that recommendation.

There were two procedures we felt ought

to--well, a second procedure that we felt ought to

be drawn out and highlighted, and that's the

withholding of medication for 36 hours from the

kids with ADHD. The feeling was that also could be

characterized as a minor increase over minimal

risk. The reasoning here is that kids with ADHD

often are not medicated over the weekend, often are

not medicated when they're not going to school, and

are often given holidays from the drug. So it

didn't feel that a 36-hour period of time was of

any significant risk to those children.

And then the remainder of the procedures,

which are outlined further along, we all felt were

appropriately considered minimal risk and,

therefore, were appropriate for either group within

the protocol.

Now, the one design recommendation that we

made was to consider narrowing the subject

population that's part of this protocol. There was

some discussion about the variability in both

neurodevelopmental stages and then response to this

dose of the stimulant between the ages of 9 and 18

years of age, with different points being raised as

to the scientific advantages and disadvantages of

either the younger age group or the older age

group. We didn't feel that we could make this a

stipulation, but felt that the investigators should

strongly consider narrowing that range within 9 to

18 to get a more focused population.

The other confounder that came up--and

this is also in response to some points made in the

public discussion--is that trying to tease apart

the changes that might occur in response to the

drug over time versus basic underlying differences

in terms of, if you will, the neurological

networks, that you need ideally to have treatment-naive

subjects with ADHD, or at least less ideally,

if that is a practical difficulty in doing in this

particular age group, try and get a more uniform

cohort of drug exposure, which is why we had the

discussion of picking the lower-dose range.

One reason for that was that the expert

scientists felt that often the dose over time that

you may need goes up, and if they unified the dose,

then probably you would end up with a more uniform

distribution of the length of exposure to

treatment. But we didn't feel that that reached

the level of a stipulation, but certainly felt that

that was a strong recommendation to consider

improving the scientific value of the study.

Now, there are a number of required

modifications to the protocol. Point A, which I'm

not going to read, is basically my summary of all

of the procedures in the protocol. And one of the

recommendations is--it was very hard to find all of

these things, and it would be nice if they just put

them in one place so no one had to go reading

through it in all detail. One, for example, that

came up--and I'll just highlight this--is that

every child will receive a diagnostic MRI scan,

which is, in fact, part of NIH policy. You could

find that nowhere in any of the documentation, and

that came out during discussion. Things like that

need to be in the protocol.

I might add, what we will be doing is

depending upon both the Office of Pediatric

Therapeutics and the OHRP to make sure this

happens, so it's not something that we need to then

worry about.

The second point, sequence of subject

testing. They're not planning to do the kids that

are twins. There are discordant twins, either both

homozygous and dizygotic. They're not going to do

those twins unless they see differences between the

kids with ADHD and the kids without ADHD. That

sequence of testing, which came out in testimony,

was very hard to find anywhere in the protocol, and

that needs to be included. They won't do the twins

if, in fact, they don't find a difference in the

non-twins.

It was very hard to find the right dose

since there were these dosing discrepancies, and so

that needs to be clarified. But I've stated what

the committee's understanding is, and, of course,

if this is different--and this is based on the

investigators' testimony--that will have to be

dealt with. And, again, I mentioned the morning.

A functional MRI. The protocol lacks a

discussion of what came out in the testimony of the

training that goes on to make sure these kids are

comfortable inside the machine, make sure they can

actually do the tasks that they're being requested

to do, et cetera, exclude kids from claustrophobia.

Not much in the protocol about that. I already

mentioned the diagnostic MRI scan, which needs to

be in there.

Pregnancy exclusion. You only found that

in the parent permission form. The feeling was

that that needs to be discussed in the protocol and

the child assent documents, and in particular,

mechanisms for protecting the confidentiality of

the adolescent that she may or may not want to go

into the protocol knowing that there's a pregnancy

test depending upon activities. That needs to be

spelled out. We weren't making a judgment about

how that should be handled other than the

importance of the confidentiality in soliciting

that information.

There was a significance discussion of

neuropsychological--I would like to have questions

at the end, because what will happen is I bet you

some will be answered, but write them down.

Neuropsychological testing. There was a lot of

discussion about this testing. It's not being

performed for diagnostic or treatment purposes, and

we felt it would be a cleaner study if, in fact,

this information was not provided back to the

parents. Part of that discussion was based on it

not being done in that kind of a therapeutic

context.

And then genetic testing. There is

testing being done only for zygosity, and we felt

since there was a whole slew of markers being done

and no discussion about the risk of those markers

relative to, say, late onset adult diseases, that

the cleanest way to do that would be to destroy the

data and the samples after you've determined the

zygosity of the twins, maintaining only that piece

of information.

Modifications to the parent permission and

child assent process in documents follow, of

course, those that need to be included from the

discussion of the procedures. There were a couple

of specific issues. One is payment. They were

proposing a lot of money--I didn't put it in here,

but a lot of money. We felt it was too much and

that basically the parents should get reimbursed

for expenses, and that for young children, a token--although

we didn't have a discussion of what that

is, but allowing the IRB to have some discretion,

and for older children who would be potentially

capable of working at a wage position such as

minimum wage, the wage model would be appropriate.

And, of course, consistent with FDA policy, this

would be, in fact, divided evenly over the protocol

procedures so that a child who withdraws in the

middle still gets part of the money.

They needed to pay attention to the

opportunity for dissent, particularly in the twin

pairs. We thought that the twin without ADHD could

be under some pressure to be in the study, and they

needed to provide that opportunity. And then some

clarification about the risks of the drug in the

actual consent document, and in many ways we

actually said you should overstate the risks in the

consent document. Although we do not feel that

this drug presents any risk of addiction, the

parents should know that, in fact, it's classified

as a drug of abuse, with an important distinction

being made by our experts between substance abuse

and addiction. It's one thing to say take

dextroamphetamine to be able to stay up for your

exams in college, but that doesn't lead to

addiction because generally you don't then want to

take it when you plan to fall asleep during

vacation. And, of course, both permissions.

Now, there were some specific questions

that we were asked to respond to, and I think for

these questions, perhaps I'll just read our answers

so that you get it clear.

What are the benefits, if any, to the

subjects and to children in general? There is no

direct health benefit to the children included in

the research. The protocol addresses the question

of a unique central response to stimulants in ADHD,

utilizing a better research design than previously

published studies and controlling for performance

differences. As such, the protocol may be able to

untangle clinical state and trait--meaning genetic

relatedness--differences through the use of

monozygotic and dizygotic twins who are discordant

for ADHD. Now, more speculatively--and this was

part of the discussion--the results may improve our

understanding of ADHD in order to enhance

diagnostic precision and avoid misclassification

and overtreatment.

Now, the types and degrees of risk that

this presents to subject, I've discussed a fair

amount of that above, and, again, we thought that

all of the procedures other than withholding of the

medications and the blind administration of study

drugs were minimal risk, and those two were a minor

increase over minimal risk.

In terms of whether the risks are

reasonable in relation to anticipated benefits,

this is a key point. For all subjects enrolled in

the research, the risks to subjects are reasonable

in relationship to the importance of the knowledge--i.e.,

the benefit to children in general--that may

reasonably be expected to result. However, it is

only for the children with ADHD that the research

is likely to yield generalizable knowledge which is

of vital importance for the understanding of the

subjects' disorder.

For you regulatory junkies, you'll know

that I'm reading language that is contained within

the regulations as well, but the important thing is

then that children without ADHD do not have a

disorder or condition, which is why this then could

not be approved by the local IRB, although the

brain response of children without ADHD to a single

dose of dextroamphetamine is an important part of

the generalizable knowledge to be gained in this

research based on the first step of the comparison.

So we thought it did present a reasonable

opportunity to further the understanding,

prevention, or alleviation of a serious problem

affecting the health or welfare of children.

So, with that said, the determination of

approval categories that the subcommittee felt was

appropriate was that the interventions and

procedures included in the research can be approved

for the children with ADHD under 45 CFR 46.406 and

21 CFR 50.53. That's the category that says no

more than a minor increase over minimal risk; that

basically the experiences are reasonably

commensurate with those inherent in their

condition; the intervention is likely to yield

generalizable knowledge about the subjects'

disorder or condition, which is true for the ADHD;

and then that there are adequate provisions for

assent.

Now, because of the lack of a condition in

the kids without ADHD, we felt that it could not be

approved under those three categories consistent

with what the IRB found. But we did feel that it

presented a reasonable opportunity to further the

understanding of a serious problem; that it would

be conducted in accord with sound ethical

principles; and that there are adequate provisions

for soliciting assent and permission. And as such,

we recommend that the involvement in the research

of children without ADHD is approvable, assuming

all of the required modifications are made, under

46.407 or 50.54.

Then one final point. It had been brought

up in some of the public testimony, the applicability of a

particular case known as Grimes v.

Kennedy Krieger Institute. Whereas, normally or

often we might anticipate that the kinds of studies

that come before us are going to be multi-institutional,

multi-site, and multi-state and

we're not going to want to get into the business of

commenting on the legal interpretations of all of

those different environments, we have the unique

situation here where this is a single site located

within Maryland, and this is a fairly high profile

court decision. So prior to the meeting, I had

asked for clarification by both FDA and OHRP

attorneys about the applicability, and the feeling,

which I agree with and I think some other

knowledgeable members of the subcommittee that I've

talked with also agree with, is that the holding is

not applicable for two reason: One is NIH is a

federal enclave and not subject to state law; and

second is when this case was considered,

reconsidered, the Maryland Court of Appeals stated

that "the only conclusion that we reached as a

matter of law was that, on the record currently

before us, summary judgment was improperly

granted." So attorneys have a term called "dicta,"

which means basically the judge expressed opinion

on other matters, but, in fact, those other matters

are not binding as law. So for those two reasons,

it was felt that we did not need to get into the

issue of the applicability of this particular case

as a subcommittee.

So, with that summary, I guess how about

questions about the document, the protocol and the

like, and then after that, I certainly would be

interested in any more general questions about the

process, if that's a reasonable approach.

T1B DR. CHESNEY: We actually have a visitor

this morning. Dr. Bern Schwetz is the Director of

the Office of Human Research Protections, and I

wondered if we could call on him to come and make a

few statements before we invite questions.

DR. NELSON: Sure.

DR. SCHWETZ: Thank you very much, Dr.

Chesney. I just wanted to express my thanks for

FDA and this Advisory Committee creating the

opportunity to do this joint review in one process

rather than have the FDA and OHRP going in separate

ways to review a protocol of this kind where

there's joint jurisdiction. So particular thanks

to Dr. Nelson for chairing this review and this

subcommittee. In our opinion, the process went as

we had hoped it would, with a very smooth review,

but probably more importantly, a thorough review

and a recommendation that we feel is a good

recommendation coming to this Advisory Committee

for your final review and hopefully approval.

The review was done in a timely manner,

and that was a challenge considering that this is a

new committee, a new subcommittee, but it was done

in a timely way. And I think it was done with an

appropriate cast of experts. So we're very pleased

with this process and, Dr. Chesney, with your

permission, we're hoping that in those cases where

we have joint jurisdiction over a protocol in the

future that we'll be able to bring it back and

handle it this way.

So thank you very much.

DR. CHESNEY: Thank you for your comments,

and maybe you could stay here just for a moment,

and we'll ask now for any questions of the new

committee members for either Dr. Goldkind, Dr.

Nelson, or Dr. Schwetz.

Dr. Maldonado?

DR. MALDONADO: I just have a quick

question. Dr Nelson, I see that on page 1 you made

the statement--and I basically also agree that you

did a great job with this review. You listed the

minor increase over minimal risk, which I agree are

just a minor increase. But then on page 2, you

gave a--maybe I am just overreading this, but the

subcommittee strongly encourages the investigators

to narrow the age. I know you focused on that, and

I may have missed it. My understanding is this is

a single-dose study. I don't know what the

concerns will be with single-dose for neurodevelopmental

stages with a single dose, low dose.

DR. NELSON: The issue is not the impact

of that dose. There might be a response difference

that you could see, but the question is teasing

apart--there is a debate on previous studies that

have been done of structural MRI scans, and there

are actually two previous studies of functional MRI

scans where the question is whether or not some of

the differences that may be seen are not related to

any underlying biological differences, neurodevelopmental

differences, but, in fact, the kids

with ADHD had been chronically exposed to a

medication which--I'm not a neuroscientist. I

guess I would characterize it as whether it's

created some element of remodeling of those

systems. And so try and eliminate that confounder,

the feeling was if they would narrow the age range

and then try to either get treatment-naive, which

may be difficult, or at least treatment-uniform at

lower doses which would give you hopefully a lower

duration of exposure, that you might be able to

begin to tease apart those two issues. That was

the scientific discussion among the experts.

DR. CHESNEY: Yes, Dr. Fant?

DR. FANT: Yes, this question may be a bit

naive, but it quickly comes to mind, especially

from the standpoint of taking the kids off the meds

for a couple of days and trying to ensure treatment

naivete and the question that that may have on

their response.

And so the question is: Are there any

over-the-counter stimulants or food additives that

could potentially interact with their response and

somehow muddy the data? And if so, is that being

controlled for or addressed in the protocol?

DR. NELSON: The answer is yes. I mean,

one of the discussions, of course, by the IRB was

whether caffeine and the element of caffeine

consumption could be used as a judgment. So there

are some confounders and the need to collect that

data, and it would be sort of self-defeating if

over the weekend you take the kid off of his

medication and then he drinks, you know, a couple

of cases of Jolt Cola--which I don't even know if

it's still made or not. I have no stock in that

company. No conflict of interest on that

recommendation. Or Mountain Dew. I think Mountain

Dew has a lot of caffeine in it. So, yes, they

need to pay attention to that.

DR. FANT: And even with adolescents who

may be concerned about weight and appearance and

that sort of thing, some of the additives that are

contained in supplements in GNC at the mall, you

know.

DR. NELSON: Right.

DR. MURPHY: So, Dr. Fant, was that a

question or just a recommendation, I guess is what

I--

DR. FANT: Well, it's a concern because if

we're talking about giving a drug to, quote, normal

kids, you really want to ensure that the data is as

clean, as interpretable as possible. You wouldn't

want to muddy the waters on something that could

have easily been avoided.

DR. MURPHY: I think that, you know, if

there are recommendations that this committee would

like to make, that's appropriate. And we wanted to

make sure that that was--

DR. NELSON: I see that as just a

refinement of the recommendation to make sure your

subject populations are as uniform as possible. So

it's certainly consistent with our direction.

DR. CHESNEY: But we maybe should add a

sentence or two, Skip, just to--I thought that was

an excellent point if somebody does--I don't know

how long those stay in the bloodstream, but if

that's their breakfast and then they show up for

the fMRI, there may be a confounding variable.

Yes, Dr. O'Fallon?

DR. O'FALLON: Did you recommend that they

collect that information?

DR. NELSON: No, but we can add a sentence

to that.

DR. O'FALLON: Okay. I think it would be

helpful to make sure that they elicit that

information.

DR. CHESNEY: Deborah, you were next.

MS. DOKKEN: I first want to compliment

Dr. Nelson's subcommittee. I mean, not only did

you do a thorough job, but I could fully understand

what you were talking about, and I was glad that

you included the issue of compensation and the

potential pressure on the twins in the assent

process.

I was also glad that at least in some way

you directed attention to the permission and assent

forms and talking about the chronology of the

procedures. But I had a further question about

those forms, which, frankly, I don't know what

their rating is in terms of reading level, et

cetera. But they certainly to me were not easy to

read and, in fact, were mixed. Sometimes they used

almost simplistic language; then you know, the next

sentence--did you talk at all about just the forms

themselves and the language beyond the chronology

issue?

DR. NELSON: Yes, we did. But that's just

captured on page 5 under age where we just say

there's technical language would is not explained

in lay terminology.

I think two points on the process: A,

this still then needs to go back through the NIMH

IRB, plus it has two offices, not just one now,

that will recognize that for this to be finally

approved would require that kind of changes in the

documents. And I'm absolutely confident that with

OHRP and FDA's involvement in making sure that

these requirements happen is that they will be in

more understandable language.

My own philosophy is there's no reason for

us to sort of nickel-and-dime the actual text, but

that was discussed.

DR. CHESNEY: Could I just add, there was

a great deal of discussion about the protocol and

about the consent form, and, in fact, one of the

committee members asked if this was a draft of the

consent form. And the folk from the NIMH

apologized and they said that they got so busy

addressing the issue of whether this would have to

come to a subcommittee that they hadn't really paid

that much attention to the consent form, but that

they would do that.

Dr. Newman?

DR. NEWMAN: I also want to compliment the

committee on a really very impressive, thorough

review. And I have three points. One is just a

clarification.

Looking on page 7, comparing Parts a) and

b), under--I'm just trying to figure out how--I

have reservations about the value of the research

to kids with ADHD. I really--it's very hard for me

to picture how this research will be useful, but

maybe that's just due to my limited scientific

knowledge. It says under C, the procedure is

likely to yield generalizable knowledge about the

subjects' disorder or condition, which is vital

importance for the understanding or amelioration.

And I really couldn't go along with this being of

vital importance. But then under B it says it

presents a reasonable opportunity to further the

understanding, and I could go along with that. So

I'm not clear on which of these two is the standard

that this research has to pass.

DR. NELSON: You point out an interesting

ambiguity in the regulatory language for which

there is no specific guidance about how one

interprets "vital importance" or "reasonable

opportunity." My own view is that it needs to meet

both, that you would not want reasonable

opportunity to be a lower standard. And the issue

of vital importance is fundamentally subjective.

And from that standpoint, there was a recognition--and

that's why I put earlier on the notion that

more speculatively. I mean, this is what--I would

characterize this as sort of a basic science

question about the response and the neurodevelopmental sort

of receptor physiology.

If, in fact, there is no difference, it

would have an impact significantly on the

understanding of ADHD, and if there is a

difference, it would impact significantly, and then

might, not in this protocol but down the line,

potentially drive diagnostic and therapeutic

differences. One thing I learned is there are

individuals who are touting different structural

scanning tools for diagnosis of kids with ADHD, et

cetera, that many felt, in fact, were not evidence-based.

And so after hearing that discussion, the

subcommittee members felt that it did meet the

regulatory standard both for vital importance and

reasonable opportunity.

There was no, if you will, easily defined

paradigm for that.

DR. NEWMAN: Okay. Well, that sort of

leaves me uncertain. Let me go to my next

question, which was in the consent form they

specifically addressed the issue of potential

adverse effects of the MRI in terms of identifying

some little something which then people go, oh, we

wonder what this is, maybe you should go have that

checked out, but that not being covered by the

research study and the family may or may not have

medical insurance to cover that. And I believe

that's more than minimal risk. That's something

well beyond the range of what people experience

every day, the possibility of having some brain

abnormality uncovered, which then you have to

figure out how to deal with. So I wonder why that

wasn't considered, you know--

DR. NELSON: It was. I didn't include it

in here because the data actually is that out of

3,000 scans, they've only found four abnormalities.

And of those four, two were benign cysts and two

were actually early diagnosis of tumors where the

child benefited from that. So there was a

discussion in the subcommittee about the

implications of using a screening test in a

population that--you know, being a statistician,

you can understand the sensitivity and specificity

issues. But after that discussion and the fact

that it's being conducted--it's not a diagnostic

reading of the functional MRI. It's a separate

diagnostic MRI scan that, after hearing the

discussion, we felt that it was appropriate to

consider that under that category.

So they have enough data, I think, to sort

of--at least reassure me that they're not going to

be turning up a lot of things that end up with

unnecessary testing.

DR. NEWMAN: If I were a parent trying to

make an informed decision about participating in

the study, those data would be very helpful to me

to know what--to say this may happen, but they

don't give any numbers on how likely it is to

happen and what might be found. And so, you know,

I just think it's hard to ask someone to consent to

something, you tell them that risk, but you don't

tell them how big it is. So I think that would be

helpful for them.

And my last question was just about the

financial compensation. For the controls, you

know, it sounds like this may take several hours

out of the parent's day, and so, you know, having

tried to get people to enroll in studies before,

you know, I don't know whether there have been

pretests or what it would take. But if you're

going to ask someone to bring their normal child in

and get a lot of stuff done, you know, to me I

think maybe $100 or $110 split between parent and

child might not be enough to get people to want to

enroll.

DR. NELSON: No, it was not split between

parent and child. That would be wages for the

child, and the investigator actually said--and this

did influence the committee--that she did not

anticipate any problem with enrollment even if the

compensation and stipend was zero. I'm just

telling you, that's what she said.

DR. CHESNEY: Could I just also comment

for Dr. Newman? It was suggested that they publish

the fact that they had only four abnormal MRIs out

of 3,000, which is certainly not within the realm

of most of our experience where MRIs show you all

kinds of things that you don't want to know. So

that suggestion was made.

We had a lot of discussion about the

science because it's a very--to me it was a very

complex study to understand, and a lot of it was

based on the study by Viga (ph) et all that was

published in '98 or '99. And I thought--it wasn't

until the very--long into the meeting that Dr.

White, who's a child psychiatrist with a lot of

familiarity with functional MRI scanning, pointed

out the importance difference with respect to the

performance task in this study as compared to the

one published in '98 or '99, which had led to

perhaps some erroneous conclusions.

So I think that after a lot of discussion

we finally became convinced that the science was

important, if that's of any help.

Any other questions or comments? Dr.

O'Fallon?

DR. O'FALLON: I was just wondering about

the pregnancy exclusion. I didn't look at the

consent form closely enough to see. Presumably

they are excluding on the basis of pregnancy. Is

that it?

DR. NELSON: They are. It wasn't very

well described in the consent form, which was our

point.

DR. O'FALLON: Okay. Well, but that's the

point. So they have to--so they do have to take

this--they have to have a pregnancy test. Now, I'm

just curious. How do they think they're going to--I mean,

how do they plan to deal with exclusion

basically on pregnancy alone when they don't--they

can't tell it to the parent?

DR. NELSON: They didn't outline that,

but, I mean, I'm confident that they can come up

with a procedure. We're just asking them to do

that, and I'm sure OHRP will make sure it's a good

one.

DR. O'FALLON: Okay. I wonder how they

are going to do it.

DR. CHESNEY: Very important points.

Any other--Dr. Newman?

DR. NEWMAN: Let me just explain what my

reservations are about the value of the research,

and maybe you can reassure me. It seems to me that

ADD is a clinical diagnosis, and in making the

diagnosis, one of the main decisions that you're

trying to guide is whether to begin stimulant

medication. And if you begin stimulant medication,

you want to see whether it helps the child and

monitor that and discontinue it if it's not working

and continue it if it is.

And I just cannot visualize how an MRI

scan would ever sufficiently predict a child's

response to medication to be clinically useful,

because, I mean, they may well find some

statistically significant differences where the

something or other is, you know, a half a standard

deviation different in one group than the other, or

maybe they're quite different. But the fact is

whatever they find, the question is really whether

this child would benefit from treatment or not.

And, you know, the way you determine that is

whether--either trying the treatment and seeing if

it helps, or if you were going to do a study to see

whether imaging helps, you would see whether

imaging predicts response to treatment, not whether

imaging predicts or is associated with someone

having received this clinical diagnosis.

So I am a little bit worried if it does

show a difference that this will spawn a whole

imaging industry of people wanting to get their

children's heads scanned to see whether they really

have it or not, which I think would just be going

in the wrong direction.

DR. NELSON: I guess two comments. This

has nothing to do with the clinical response of the

children. There is no benefit. It has nothing to

do with that. Whether or not it--if it does show a

difference, appropriately designed, it would spawn

a functional MRI industry I think is speculative

and, in fact, is explicitly, if you at Subpart A,

excluded from what an IRB ought to consider. The

long-term policy implications of research is not

something that IRBs are supposed to consider, and I

wouldn't necessarily import it under vital

importance.

The question is whether or not there are

structural or functional differences, and

presumably based on receptor density, et cetera--it's not my

area so I'm just saying things that you

could have read in the protocol and listening to

the scientists. And as a basic science question, I

think that's an important one. And how it might

then impact down the road in terms of understanding

whether there's a differential or similar response

to stimulants, I mean, the literature is quite

mixed in terms of reading some of the background

material in the protocol.

So there is no connection in doing this

with determining why they might respond clinically.

There is no--and, in fact, many of our recommendations were

meant to prevent that confusion

from being in the minds of the participants by

removing any semblance of benefit from the sort of

surrounding aspects of the science. But, you know,

I think ADHD is a controversial area, and it's

partly why we felt this needed to be looked at

carefully and then done well, because I think the

positive or negative results could have an impact

in different directions.

DR. CHESNEY: I think Skip expressed it

very well. The purpose of the study was not to

have any clinical diagnostic value or clinical

implications. The purpose of the study is really

to understand, as Skip said, the neurophysiology

and neurochemistry--to try to understand the

neurophysiology and neurochemistry of ADHD better,

and because of the twin aspect, to see if there are

any genetic aspects.

Dr. Maldonado?

DR. MALDONADO: A quick question that goes

beyond this study, but it's in the context of ADHD.

One of the premises that I think a lot of

researchers' work is under that if the studies can

be done in adults, don't do it in children. And

now adults are being diagnosed with ADHD. Has

something similar been done in adults or can be

done in adults, you know, consenting adults, so you

don't use this area of consent of children?

DR. NELSON: Two points. That specific

question was raised by the subcommittee. There

have been similar but not identical studies, but

it's clear that the adults are different in this

regard and that the information that you would get

would be of no use to this issue. And that

discussion actually is why you may even--in the

discussion it was clear that the scientific

arguments might push you in the direction of using

actually the 9 to 12 age group as opposed to the

older age group because there may even be those

kinds of adult changes when you get into sort of

late adolescence. But we felt that that was not

clear enough that we would make a stipulation as

opposed to recommendation.

So I think that is an important principle,

and it was asked and answered in the negative, that

adult information here would be of no use to

answering this question.

DR. CHESNEY: Dr. Schwetz, did you have

any additional comments about the questions from

the committee?

DR. SCHWETZ: No, I don't have anything

else to add. Thank you.

DR. CHESNEY: Dr. O'Fallon, you look like

you were--

DR. O'FALLON: I hesitated simply because--but I'm

a mother and not an M.D. I've had an MRI.

I don't know what--for my neck. I was wondering

what a functional MRI for the brain involves for

the child.

DR. NELSON: Nothing different than an MRI

scan.

DR. O'FALLON: But the question is they

are enclosed, so there is the issue of

claustrophobia?

DR. NELSON: Correct, but they have

screening procedures for that. There's no issue in

that. The kids are actually less claustrophobic

than the adults.

DR. MURPHY: Skip, why don't you describe

the screening procedure--

DR. NELSON: They have a training MRI scan

which is--and they make--you know, first they've

got to make sure the kids can do these tasks, so

they use the stop task and a training MRI scan.

They have a whole sort of session. I mean,

everybody--if a kid doesn't want to do it, then

that's the end of it. You know, their procedures

are excellent with respect to that. The issue is

not that they're not doing it. The issue is they

just didn't describe it in the protocol. They

described it quite completely in the discussion on

Friday.

DR. MURPHY: I think as a risk what you're

trying to get at is that those kids that are going

to have that impact of anxiety, psychological fear,

will be--will not be enrolled. In other words,

that's where the screening procedure would help

select those children out.

DR. O'FALLON: Yes, but, of course, the

screening itself could cause this--I mean, they

could precipitate this anxiety.