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
Double Tree Hotel
1750 Rockville Pike
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.
Julia Gorey, J.D.
Dianne Murphy, M.D.
Sara Goldkind, M.D., M.A.
Bernard Schwetz, D.V.M., Ph.D.
C O N T E N T S
Call to Order, Introductions
Robert M. Nelson, M.D., Ph.D. 4
Jan N. Johannessen, Ph.D. 6
Subpart D Expert Panel Process
Sara Goldkind, M.D., M.A. 9
Bernard Schwetz, D.V.M., Ph.D. 13
Overview, Charge to Panel and Final Outcome
Robert M. Nelson, M.D., Ph.D. 18
Background on ADHD/Protocol Overview
Judith L. Rapoport, M.D. 34
Questions and Panel Discussion 46
Summary of Submitted Public Comments
Robert M. Nelson, M.D., Ph.D. 119
Open Public Hearing
Vera Sharav 126
Alan Milstein 131
Questions and Panel Discussion 139
P R O C E E D I N G S
Call to Order, Introductions
DR. NELSON: Good morning. We still have
a couple of people that we waiting for, but I
thought we could start with our introductions and
get the meeting going.
Bern, do you want to start with the
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
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
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
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
DR. FOST: Norm Fost, pediatrician at the
University of Wisconsin, Director of the Bioethics
Program and Chair of the IRB.
DR. GORMAN: Rich Gorman, pediatrician in
private practice in Ellicott City, Maryland, and
Chair of the Committee on Drugs for the American
Academy of Pediatrics.
DR. KODISH: My name is Rick Kodish. I am
a Professor of Pediatrics and Bioethics at Case
Western Reserve University in Cleveland, Ohio.
DR. JACOBS: I am Jan Jacobs. I am a
developmental psychologist and professor at Penn
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
DR. JOHANNESSEN: Thank you and good
The following announcement addresses the
issue of conflict of interest with regard to the
study drug dextroamphetamine and competing products
used for the treatment of ADHD, and is made part of
the record to preclude even the appearance of such
at this meeting.
Based on the submitted agenda for the
meeting and all financial interests reported by the
committee participants, it has been determined that
all interests in firms regulated by the Food and
Drug Administration present no potential for an
appearance of conflict of interest at this meeting
with the following exceptions:
In according with 18 U.S.C. 208(b)(3),
full waivers have been granted to the following
participants: Dr. Patrician Joan Chesney for
ownership of stock in a company with a product at
issue valued between $25,001 and $50,000 and for
her spouse's honoraria for speaking on unrelated
topics at a firm with a product at issue valued at
less than $5,000, and Dr. Laurence Greenhill for
his consulting with companies with products at
issue between $10,001 an $50,000.
A copy of the waiver statements may be
obtained by submitting a written request
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.
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
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.
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
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
The FDA involvement with Subpart D
regulations began in the 1990s when the
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.
The Children's Health Act of 2000 mandated
that HHS funded, supported, or regulated research
comply with these additional protections for
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.
The Pediatric Advisory Committee is
endorsed by the Best Pharmaceuticals for Children
Act in 2001 and the Pediatric Research Equity Act
Now, I am going to talk about Subpart D
referrals specifically, and those come
to us under
45 CFR 46.407 and 21 CFR 50.54. That Subpart D
regulation is entitled, "The Additional Safeguards
for Children in Pediatric Research," and it states
that if an IRB does not believe it can approve the
research under one of the first three categories of
Subpart D, the clinical investigational research
may proceed on if: "The IRB finds that the
research presents a reasonable opportunity to
further the understanding, prevention, or
alleviation of a serious problem affecting the
health or welfare of children," and "The Secretary
and/or Commissioner of the FDA, and the Secretary
of DHHS, after consultation with a panel of
experts, such as yourselves, in pertinent
disciplines, science, medicine, education, ethics,
and law, and following an opportunity for public
review and comment determines either that the
clinical investment in fact satisfies one of the
first three categories of Subpart D, or the
following three conditions are met:
1. The clinical investigation research
presents a reasonable opportunity to
understanding, prevention, or alleviation of a
serious problem affecting the health or welfare of
2. The clinical investigation will be
conducted in accordance with sound ethical
3. Adequate provisions are made for
soliciting assent and parental permission.
So, the possible recommendations open to
the Pediatric Ethics Subcommittee that it can make
to the Pediatric Advisory Committee are the
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
It can recommend allowing the
proceed because it satisfies the three conditions
that I just previously outlines under 46.407 or
Or it can recommend that the protocol not
be allowed to proceed, providing specific reasons
for its rejection.
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,
Of course the overarching goal of this is
to advance pediatric research in an ethically sound
Now, I will turn the podium over to Dr.
Bernard Schwetz, D.V.M.,
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
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
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.
So, after today's meeting, Dr. Nelson will
make a presentation to the meeting of the full
Advisory Committee on September 15th,
and in that
meeting, he will summarize the discussion today,
and he will summarize your recommendations, because
as a subcommittee, you can't bring this to
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
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
The Secretary's decision would carry the
day, but if, in fact, the Commissioner says to do
the study, then, the Secretary's Office
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
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
depending on your age and refraction of your
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.
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.
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.
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
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
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.
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
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
After you have made that determination to
sort of move down in this algorithm,
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
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.
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
two different questions with respect to that.
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
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
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
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.
Now, once you have done that, we should
then turn back to the issue of parental permission
and child assent. All four categories
the language that there need to be adequate
provisions for child assent and parental
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.
In terms of child assent, this again is
the regulatory language. Adequate provisions for
soliciting assent when, in the judgment of the IRB,
children are capable of providing assent, and the
advice about that capability to the IRB is that
they need to account for the age, maturity, and
psychological state of either some or all of the
children. So, an IRB could make a determination
for all of the children in that particular project
or they can basically make a sort of case-by-case
or sort of classy-by-class depending upon the range
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.
Again, some of the general
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.
So, that basically takes us through sort
of an analysis of a protocol, and what I am going
to recommend to the panel is that we consider, as
we go through this, to make sure that we have
touched on all of those particular issues, and if
we have, I would hope that we have covered pretty
much everything that is important in the discussion
of this particular protocol, and perhaps some other
things, as well, but we should at least make sure
we cover all of those basis, because otherwise we
are not being I think true to what the regulations
would require us to do.
But the overall charge is to provide
advice and recommendations to the Pediatric
Advisory Committee on FDA's and certain HHS
regulatory issues. As Bern went through, as a
subcommittee, we actually don't have the regulatory
authority to advise the Commissioner and the
Secretary, but we will then, through the Pediatric
Advisory Committee, have that recommendation.
I certainly hope our discussion here is
sufficient and exhaustive enough and clear enough
that it will be readily apparent to the Advisory
Committee that they should agree with what we
decide, but they certainly have the authority to
think differently about that.
Now, the outcome is we should develop
recommendations whether the protocol should proceed
and specifically address whether and how, so there
may be things that we would recommend need to be
adjusted for the research to it either does satisfy
us as currently written, or, in fact, could satisfy
if we had some additional conditions, either the
categories that are approvable by local IRB under
minimal risk, minor increase over minimal risk, or
prospect of direct benefit.
If not, however, we could then look to
whether or not the research could or
does meet the
following conditions: that it is a reasonable
opportunity to understand, prevent, or alleviate a
serious problem affecting the health or welfare of
children; that it can be conducted in accord with
sound ethical principles, and I think one challenge
for us will be to try to articulate what we believe
those sound ethical principles are that would, in
fact, justify it if we come to the conclusion that
it should go forward under that category; and then
adequate provisions for soliciting the assent of
children and permission of their parents and
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
With that, I think we are actually moving
along quite expeditiously, and we can
move on to
Dr. Rapoport if there is no questions by the panel.
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
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
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
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
Dr. Rapoport. Just to give us an
approach, I mean we will start off with the
investigator, then, have some comments. I don't
know if Don has organized remarks or is available
for questions. Dr. Rapoport says she can be here
for a while with us, but won't be here the whole
day, so I am hoping the panel can be able to get
whatever questions they feel are important to ask
kind of out of the table at the start of the day.
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.
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
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
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,
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.
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.
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
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.
So, one of the questions, and let me say
that this is a really old question that goes back
to perhaps an unfortunate statement in the 1930s
when children on stimulants were seen to calm down
when they were first used actually to help them
calm during a procedure, a radiographic procedure,
that was they were sort of almost accidentally
found to be useful, and there was an unfortunate
statement made that this was a paradoxical effect
with paradoxical calming.
That led to the very unfortunate use of an
observation that children would calm on stimulants
for many pediatricians for a generation to tell
parents that their children must have "minimal
brain dysfunction" because they actually did calm
down on the stimulants.
I mention this just because I want to
point out that there was considerable indirect
benefit to older observations than studies we did
in the early '80s, that, in fact, all children calm
down, and that, in fact, is not a diagnostic
response to the stimulants and had very great
benefit on practice, immediately became a board
question both for child psychiatry and pediatrics,
because they thought the point was so important to
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
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
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
These studies, however, because of the
importance, because the conservative definitions
place ADHD at perhaps 3 to 4 percent of the
population, and because of the continuing debate, I
think it's notable how important and the great
interest in the study, that even that small study
of Vaidya's, which was approved I think without
much comment at the Stanford Review
Board, but that
was published in PNAS, and I think that attests
more to the considered importance and interest in
the issue than that particular study, as our
excellent colleague would be the first to say
herself, I think.
At any rate, we felt this could provide
some fundamental information about the
pathophysiology of ADHD and effects of treatment.
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
the differences are related to just the state of
having the disorder or represent an underlying
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.
The IRB concerns, and as I say, these are
slides because when these were prepared, it wasn't
clear that Dr. Rosenstein was going to be
presenting, but the primary IRB concern was about
the risk level of the study for healthy children
and whether the administration of a stimulant was
approvable under federal regulations.
Questions were raised about the value of
the study in the IRB, although the three outside
scientific reviews were the strongest reviews that
I have ever gotten for outside reviews of many
protocols. They were concerned about the level of
payment, and I think wanted to adjust that downward
if the study were approved.
I think this has already been covered.
I think this has also already been
covered, and so I don't think I will go into this.
What I would like to say is that in terms
of the risks, we have had years of research with a
single dose of stimulants in hyperactive children,
as well as a very well known study that I alluded
to, in the '80s, with healthy children, and the
single dose was likely to cause, if administered in
the morning, some loss of appetite at lunchtime,
possibly someone might feel a little bit nervous or
have some trouble sleeping at night, but, for many,
because of the duration of effect, if given early
in the morning, even these would not occur.
The IRB request to this committee was for
waiver of more than minimal risk. That will have
to be represented by Dr. Rosenstein, because my own
feeling was that this represented minimal risk, so
therefore, I am not a good advocate for that
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
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
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.
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
So, I interpret the long-term
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
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
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
DR. NELSON: Okay. Norm and then Rick.
DR. FOST: Dr. Rapoport, I have three
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
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
downward, would not include that subject.
DR. FOST: So, 10 is the most that anybody
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
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
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
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
of--well, I will just leave it an
inconvenience--that payment has now become the
How much to pay is a complicated question
that I don't anybody has got the answer to, but I
think the notion is that payment should be for some
combination of the time lost and the inconvenience
to the subjects.
I also don't think that there is agreement
upon whether all the money should go to the parents
or the money should go to the children in the form
of a gift certificate to a book store or somewhere
else and how you work that out.
So, quite frankly, we didn't get that far
because at the IRB, where we got, we decided it
wasn't approvable at our level.
DR. FOST: So, if understand you, and I
just want to make sure Dr. Rapoport agrees, you
don't think it is necessary to recruit to this
study? That is, if you had no compensation, you
think you could still get sufficient enrollment.
DR. RAPOPORT: I don't know the answer to
that. I just don't know. It is much more
complicated now. Everybody's parent works, has to
take off time, et cetera, so things have change a
lot in terms of these are children, they need a
family member to be there for the whole time, and
things have changed a lot.
Certainly, it wasn't necessary when we did
the study the first time, and that had no part of
it. I can't tell you the answer to that.
DR. FOST: The third question is a
question about risk and assent, not about the
possible medical risk, but the anxiety of being in
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
DR. RAPOPORT: It is
extremely low, but
you understand that we have a very different
process from the medical world in which this is not
the case, where children typically have MRIs when
there is other stressful circumstances. They are
not interviewed ahead of time to be in the study
based on their sense of whether they would mind.
We have the luxury of having a whole
practice session and pretend MRI, a mock MRI.
Children also have less claustrophobia because just
literally, they are physically much less closed in
than adults are, so they are much less bothered by
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
DR. FOST: So, by the time you get to the
"real one," have you had any experiences of bad
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
Two questions. The first has to do with
age and assent or consent. I was struck by the
fairly broad age range in the protocol, I think 9
to 18. There was some text that suggested that
there was a significant brain change in adolescents
that makes the investigators think differently
about post-adolescent subjects.
I am wondering if it is the case that from
an ethics perspective, an age range of 14 to 18
might be preferable for better assent, close to
true consent, but from a scientific perspective,
and this is not my area, that, in fact,
the 9 to
12, 9 to 14 age.
Is that accurate, and is there a
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
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
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
DR. PINE: Sure. I am Dr. Daniel Pine. I
am a child psychiatrist in the NIMH Intramural
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
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
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
people who were worried about the potential message
of it being okay to take a single close of a
medication might be more of an issue for older
children than for younger children. So, the ethics
argument cuts both ways with respect to the age
range. Again, that wasn't an unanimous opinion,
but that was one that was articulated at the IRB.
DR. RAPOPORT: I certainly think that from
the point of view of both things, that is more
compelling to use it in younger children, both
because of the science of it and that those people
who were "ADHD," older, may not be representative,
in fact, of the child population.
But I think from a mood response, the
younger children are very unlikely to get any
positive mood response to it.
DR. KODISH: And then the last one, which
will be shorter, has to do with this particular
drug. I was struck by your introductory comments
about the incidence of caffeine use in children,
and I am wondering if there is, the way that one
has narcotic pharmacoequivalency, is
there data you
can give us about 10 milligrams of amphetamine, how
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
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
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
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
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
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
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
DR. GORMAN: There will be an amendment to
the protocol that will deal with the dosing issues?
DR. ROSENSTEIN: It will clarify whatever
the error was.
DR. GORMAN: Okay.
DR. RAPOPORT: Absolutely.
DR. GORMAN: The second question comes to
deal with the MRI itself. In the protocol, it
describes that this is a 3-Tesla coil. Is the
3-Tesla coil experimental or in common clinical use
at this point?
DR. PINE: I think it is fairly well
articulated in terms of the view of 3-Tesla magnet,
but it is used regularly for clinical studies
including at the NIH.
DR. GORMAN: I am sorry, not for clinical
studies. Is it a clinically approved device?
DR. PINE: Yes, it is a clinically
DR. GORMAN: Thank you.
Do you plan on getting two parental
signatures on this informed consent if this study
is found to be approvable?
DR. RAPOPORT: I hadn't been, but I
believe I have learned this morning that I should.
DR. GORMAN: Thank you.
DR. NELSON: Dr. Chesney.
DR. CHESNEY: I have questions about the
need for using stimulant in normal children at this
point in time, and I have read the protocol, I have
gone back and looked at a number of the original
articles, and as a neophyte, tried to understand
the neuroscience, but I obviously have many holes.
Since fMRI is so new, I wonder if we
should or potentially should focus efforts on
learning more about the fMRI findings in normal
children without stimulant, and in newly diagnosed
ADHD children, and in ADHD children on chronic
medications before we need to look at the issue of
stimulant use in children.
Again, in looking at what has been
published, which looks to me fairly minimal in
terms of fMRI findings, I, in looking at dopamine
receptors and transporters, and so on, and trying
to understand all of that, and I may not
understanding it, but it seemed to me like we still
have a lot to learn just by looking at normal
children again without stimulant, and newly
diagnosed, and chronically treated ADHD children
before we may need to look at the issue of giving
stimulant to children, which would make the issue
temporarily a little more straightforward.
So, I wondered if you could comment on
that concept of whether we really need to learn
more about what the activation in normal children
is. Thank you.
DR. RAPOPORT: Well, I think Dr. Pine will
also like to comment, but I would like to say that
at the NIH, there is always a tension between the
very strong interest in the basic kinds of
observations that you describe and when you apply
them as a clinical problem.
But at least at the NIH, there has been a
great deal of very active work already in children,
in healthy children with some of these tests, and,
in fact, Dr. Pine's collaboration and co-PI on this
protocol reflects that.
So, there is a great deal more, the change
from PET scan to a test that doesn't involve
exposure to ionizing radiation really
revolutionized pediatric studies, so in a limited
field of research where there isn't much research
all together, relatively speaking, there has been
quite a considerable amount already, several from
people who trained at the NIH and have gone out to
other leading centers.
So, I don't think it is quite so minimal
given that pediatric research is minimal in its own
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
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
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
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
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
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
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
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
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
DR. NELSON: Mary Faith Marshall.
DR. MARSHALL: I am going to focus on
something that is a little different than the
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
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
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
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
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,
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
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
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
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
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
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
type of study that has already been done, that's
published this month in the American Journal of
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
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
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
But looking at how that information was
exchange to the families of the children
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
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
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
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
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
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.
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
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
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
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
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
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.
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
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
some of the fears that they might have about these
medications addressed explicitly in the consent
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
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
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
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
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.
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
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
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
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.
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
than any of the other risks we are talking about
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
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
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
DR. FOST: It opens a whole can of worms
that we probably don't have time to
discuss at this
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
DR. PINE: I would disagree with the fMRI
DR. RAPOPORT: They are less considered
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
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
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
You have got competing demands of kind of
getting some read on that versus having a document.
am more than happy--Dr. Rapoport said she would
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: 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
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,
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
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
When there are no data relevant to the
side effects for a single dose, it makes
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
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
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
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
DR. ROSENSTEIN: I understand that, and I
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
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
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
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
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
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
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
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
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
would meet criteria above the age of 18. I have
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
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
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
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
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
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
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
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
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
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
protocol might not be the best way or perhaps we
might be a long way away from developing that kind
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
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
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
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
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
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
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
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
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
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 guardian may discontinue participation at
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
really provide much discussion to the alternative
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
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
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
The lay person felt, you know, maximum 570
being paid, but it doesn't describe who
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
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
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
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
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
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
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
You can speak from the podium, so you can
see us, and we can see you.
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
Having listened to some of the
presentations as far as the scientific issues, I
think part of what I was going to comment is right
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
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
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
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
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
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
pig? But then whose children are we considering
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