1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ETHICS SUBCOMMITTEE OF THE
PEDIATRIC ADVISORY COMMITTEE
Friday, September 10,
2004
8:35 a.m.
Double Tree Hotel
Regency Room
1750 Rockville Pike
Rockville, Maryland
2
PARTICIPANTS
Robert M. Nelson, M.D., Ph.D., Chair
Jan N. Johannessen, Ph.D., Executive
Secretary
P. Joan Chesney, M.D.
Norman Fost, M.D., M.P.H.
Richard L. Gorman, M.D.
Laurence L. Greenhill, M.D.
Ruth Hughes, Ph.D., CPRP
Janis E. Jacobs, Ph.D.
Eric Kodish, M.D.
Mary Faith Marshall, Ph.D.
Diane Treat, Patient-Family
Representative
Tonya Jo Hanson White, M.D.
FDA
Julia Gorey, J.D.
Dianne Murphy, M.D.
Sara Goldkind, M.D., M.A.
Bernard Schwetz, D.V.M., Ph.D.
3
C O N T E N T S
PAGE
Call to
Order, Introductions
Robert M. Nelson, M.D., Ph.D. 4
Meeting Statement:
Jan N. Johannessen, Ph.D. 6
Subpart D
Expert Panel Process
Sara Goldkind, M.D., M.A. 9
Bernard Schwetz, D.V.M., Ph.D. 13
Overview,
Charge to Panel and Final Outcome
Robert M. Nelson, M.D., Ph.D. 18
Background on ADHD/Protocol Overview
Judith L. Rapoport, M.D. 34
Questions and Panel Discussion 46
Summary
of Submitted Public Comments
Robert M. Nelson, M.D., Ph.D. 119
Open
Public Hearing
Vera Sharav 126
Alan Milstein 131
Questions and Panel Discussion 139
4
P R O C E E D I N G S
Call to Order, Introductions
DR. NELSON: Good morning. We still have
a couple of people that we waiting for,
but I
thought we could start with our
introductions and
get the meeting going.
Bern, do you want to start with the
introductions?
DR. SCHWETZ: I will start and
introduce
myself. Thank you, Skip.
Good morning to all of you. I am
Bernard
Schwetz,
the Director of the Office for Human
Research
Protections in HHS.
DR. GOLDKIND: I am Sara
Goldkind, the
bioethicist at the FDA in the Office of
Pediatric
Therapeutics.
DR. MURPHY: I am Dianne Murphy. I am
the
Director
for the Office of Pediatric Therapeutics,
and I wanted to tell you how delighted I
am that we
are having this combined meeting and
look forward
very much to your deliberations.
MS. GOREY: Julia Gorey, Office for Human
5
Research
Protections.
DR. JOHANNESSEN: Jan
Johannessen. I am
the Executive Secretary for this
meeting.
DR. NELSON: Robert Nelson. I am chairing
the meeting, and I am from Children's
Hospital of
Philadelphia.
DR. CHESNEY: My name is Joan
Chesney. I
am in Infectious Disease, and I am a Professor
Pediatrics at the University of Tennessee in
Memphis
and also direct the Academic Programs
Office at
St. Jude Children's Research Hospital.
DR. MARSHALL: I am Mary Faith
Marshall.
I am a
bioethicist at the University of Kansas
Medical
Center.
DR. FOST: Norm Fost,
pediatrician at the
University of Wisconsin, Director of the Bioethics
Program
and Chair of the IRB.
DR. GORMAN: Rich Gorman,
pediatrician in
private practice in Ellicott City,
Maryland, and
Chair of
the Committee on Drugs for the American
Academy
of Pediatrics.
DR. KODISH: My name is Rick Kodish. I am
6
a Professor of Pediatrics and Bioethics
at Case
Western
Reserve University in Cleveland, Ohio.
DR. JACOBS: I am Jan
Jacobs. I am a
developmental psychologist and professor
at Penn
State University.
DR. GREENHILL: Larry
Greenhill. I am
child psychiatrist and professor at New
York State
Psychiatric Institute, Columbia University.
DR. WHITE: Tonya White. I am a child and
adolescent psychiatrist and a
pediatrician at the
University of Minnesota.
MS. TREAT: I am Diane
Treat. I am a
Patient
and Family Representative.
DR. NELSON: Thank you.
We will have a reading of the Meeting
Statement.
Meeting Statement
DR. JOHANNESSEN: Thank you and
good
morning.
The following announcement addresses the
issue of conflict of interest with
regard to the
study drug dextroamphetamine and competing products
7
used for the treatment of ADHD, and is
made part of
the record to preclude even the
appearance of such
at this meeting.
Based on the submitted agenda for the
meeting and all financial interests
reported by the
committee participants, it has been
determined that
all interests in firms regulated by the
Food and
Drug Administration
present no potential for an
appearance of conflict of interest at
this meeting
with the following exceptions:
In according with 18 U.S.C. 208(b)(3),
full waivers have been granted to the
following
participants: Dr. Patrician Joan Chesney for
ownership of stock in a company with a
product at
issue valued between $25,001 and $50,000
and for
her spouse's honoraria for speaking on
unrelated
topics at a firm with a product at issue
valued at
less than $5,000, and Dr. Laurence
Greenhill for
his consulting with companies with
products at
issue between $10,001 an $50,000.
A copy of the waiver statements may be
obtained by submitting a written request
to the
8
Agency's
Freedom of Information Office, Room 12A-30
of the Parklawn Building.
In the event that the discussions involve
any other products or firms not already
on the
agenda for which an FDA participant has
a financial
interest, the participants are aware of
the need to
exclude themselves from such involvement
and their
exclusion will be noted for the record.
We would also like to note that Dr.
Richard
Gorman is participating as a Pediatric
Health
Organization Representative acting on behalf
of the American Academy of Pediatrics.
With respect to all other participants, we
ask in the interest of fairness that
they address
any current or previous financial
involvement with
any firm whose product they may wish to
comment on.
Thank you.
DR. NELSON: Thank you. Let me introduce
our first speaker, Sara Goldkind, who is
a
bioethicist with the Office of Pediatric
Therapeutics at the FDA.
Subpart D Expert Panel
Process
9
Sara Goldkind, M.D., M.A.
DR. GOLDKIND: As. Dr. Murphy
said, we are
extremely excited to be a part of this
landmark
time in pediatric research and look
forward to the
deliberations of this committee.
[Slide.]
As you all know, this is the inaugural
meeting of the Pediatric Ethics
Subcommittee, which
is a subcommittee of the Pediatric
Advisory
Committee, which will meet for the first time next
week.
The Pediatric Ethics Subcommittee is going
to address, as it will do today, the
Subpart D
referrals and also, in the future, we
look forward
to it addressing ethical issues that
impact on
research affecting the pediatric
population.
Today is the first open meeting with OHRP
regarding a joint referral under 45 CFR
46 and 21
CFR
50.54.
[Slide.]
The FDA involvement with Subpart D
regulations began in the 1990s when the
Advisory
10
Committee
at that time made a recommendation on
November
15, 1999, that Subpart D be adopted.
The recommendation was endorsed by the
American
Academy of Pediatrics and by PhARMA.
[Slide.]
The Children's Health Act of 2000 mandated
that HHS funded, supported, or regulated
research
comply with these additional protections
for
children.
[Slide.]
Finally, in April of 2001, the FDA adopted
Subpart D
regulations which are identical to the
Subpart D
regulations found in 45 CFR 46, which is
considered the common rule for HHS.
[Slide.]
The Pediatric Advisory Committee is
endorsed by the Best Pharmaceuticals for
Children
Act in
2001 and the Pediatric Research Equity Act
in 2003.
[Slide.]
Now, I am going to talk about Subpart D
referrals specifically, and those come
to us under
11
45 CFR
46.407 and 21 CFR 50.54. That Subpart D
regulation is entitled, "The
Additional Safeguards
for Children in Pediatric
Research," and it states
that if an IRB does not believe it can
approve the
research under one of the first three
categories of
Subpart
D, the clinical investigational research
may proceed on if: "The IRB finds that the
research presents a reasonable
opportunity to
further the understanding, prevention,
or
alleviation of a serious problem
affecting the
health or welfare of children," and
"The Secretary
and/or Commissioner of the FDA, and the
Secretary
of DHHS, after consultation with a panel
of
experts, such as yourselves, in
pertinent
disciplines, science, medicine,
education, ethics,
and law, and following an opportunity
for public
review and comment determines either
that the
clinical investment in fact satisfies
one of the
first three categories of Subpart D, or
the
following three conditions are met:
1. The clinical investigation research
presents a reasonable opportunity to
further the
12
understanding, prevention, or
alleviation of a
serious problem affecting the health or
welfare of
children.
2. The clinical investigation will be
conducted in accordance with sound
ethical
principles.
3. Adequate provisions are made for
soliciting assent and parental
permission.
[Slide.]
So, the possible recommendations open to
the Pediatric Ethics Subcommittee that
it can make
to the Pediatric Advisory Committee are
the
following:
It can recommend allowing the
protocol to
proceed because it satisfies on of the
first three
categories of Subpart D.
It can recommend allowing the protocol to
proceed, with modifications, because
those
modifications would then allow the protocol to be
approved under one of the first three
categories of
Subpart
D.
It can recommend allowing the
protocol to
13
proceed because it satisfies the three
conditions
that I just previously outlines under
46.407 or
50.54.
Or it can recommend that the protocol not
be allowed to proceed, providing
specific reasons
for its rejection.
[Slide.]
The goals under Subpart D that we feel
that this process is trying to meet are:
transparency, opportunity for public
input,
opportunity to make the determinations
and
recommendations in an efficient and
timely manner,
with clarify and consistency, the
opportunity for
expert input, and additionally,
harmonization with
OHRP, so
that we have a unified, comprehensive,
federal process.
Of course the overarching goal of this is
to advance pediatric research in an
ethically sound
manner.
Now, I will turn the podium over to Dr.
Schwetz.
Bernard Schwetz, D.V.M.,
Ph.D.
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DR. SCHWETZ: Thank you, Sara.
I just wanted to take a couple of minutes
to comment again about the joint nature
of this
review, because normally, there would be
a
subcommittee that would be reviewing a
question
that dealt with the FDA, and the outcome
of that
deliberation by the expert panel would
go to the
Commissioner of the FDA, or there would be a panel
of experts addressing a question about a
protocol
because it was HHS funded or conducted,
and it was
at the 407 level of discussion, and the
question
doesn't involve an FDA-regulated
product, but it
does involve an HHS-funded study, then,
that panel
would make a recommendation that OHRP
would carry
to the Commissioner.
When there is a situation where it is an
FDA-regulated product, and it is an HHS-funded
study, then, we end up in the situation
where we
have a joint review, and we did not want
to create
a situation where we had two separate
expert panels
review of the protocol, not only because
of the
redundancy involved, but the possibility
that two
15
different groups of people would see the
protocol
differently, and we would have
conflicting reviews
of one protocol. So, that is why we have the joint
review.
[Slide.]
I just want to assure you that the HHS and
the FDA regulations regarding the
protocol reviewed
through .51, 2, and 3, and 404, 5, and 6
are
comparable, so that you needn't worry
today about
whether or not the discussion takes into
account
one set of regulations for the FDA
versus a problem
with the HHS regulations. They are comparable.
The difference comes after the Advisory
Committee
makes its decision, and what I want to
lay out for you next is what happens in
the case of
the outcome of a joint review as opposed
as what I
have already described for the review of
either an
HHS
protocol or an FDA protocol.
[Slide.]
So, after today's meeting, Dr. Nelson
will
make a presentation to the meeting of
the full
Advisory Committee on September 15th,
and in that
16
meeting, he will summarize the
discussion today,
and he will summarize your
recommendations, because
as a subcommittee, you can't bring this
to
completion yourself.
As an Advisory Committee, they have the
responsibility for making the final
decision, so
your outcome will be recommended to the
full
Advisory
Committee, and presumably, they will
either accept your recommendation or
come back to
you with some questions or some
recommendations for
you to consider. It is unlikely they would reject
your recommendation, but they could come
back and
ask for further clarification of
something. But
that would be up to Dr. Nelson to
handle, but
whatever that recommendation is, then,
the
recommendation of the full Advisory
Committee will
go to the Commissioner of the FDA, and
assuming
that the Commissioner of the FDA then
recommends to
go forward with this protocol, with this
study,
then, the process is half done.
At that point, we would take the message,
or OHRP would take the message to the
Secretary's
17
Office
that we have had the expert panel review, we
have had public input, the FDA
Commissioner has
made the determination, whatever it is,
to go
forward or to not go forward, so then we
would
carry that message to the Secretary's
Office for
final decision on funding of the study.
So, if, in fact, at that point, the
process has included a recommendation
for some
revision to the protocol, we would also
negotiate
that revision to the protocol with the
PI and with
the sponsor, but when that would be
taken care of,
then, the decision of the Secretary's
Office would
be either to fund the study or not.
So, if, in fact, the decision from the FDA
Commissioner is to not allow this study, to not
support this study, then, we would
simply carry
that message to the Secretary, but it
would not be
revisited of whether or not the study
would be
funded.
The Secretary's decision would carry the
day, but if, in fact, the Commissioner
says to do
the study, then, the Secretary's Office
does have
18
the opportunity to take into account all
the
considerations and decide whether or not
this study
should be funded.
So, then, that would be the end of the
line when the Secretary advises NIH that
the study
should be funded or not.
That is the process, Skip. I
will turn it
back to you.
DR. NELSON: Thank you, Sara, and
thank
you, Bern.
Overview, Charge to Panel, and Final Outcome
DR. NELSON: On the assumption
that we
were not going to assume that everyone
in the
audience, although I hope everyone on
the panel,
but not everyone in the audience is
familiar with
Subpart
D, and that we would run through a little
bit of what an analysis of a research
protocol
involving children would look like, and
I will
basically be following the algorithms
that you
should have in the handout of this
particular
presentation, and you can either look at
the small
print, page 1, or the large print to
page 1,
19
depending on your age and refraction of
your
glasses.
In effect, this is an unusual occurrence
although depending on your state and
whether your
have sunshine laws, we are pretty much
carrying out
an IRB meeting in public, which is an
auspicious
event, and here is a copy of the overall
protocol,
at least in terms of Section 1 and
Section 3, and
what we will basically be starting with
is looking
at the fact that you need to place
pediatric
research in the context of Subpart A,
which is the
common rule to start with, so I will
give some
initial orienting remarks about that.
[Slide.]
Then, we will look at Subpart D
specifically and the specific
protections there,
and then return back to Subpart A and
look at
issues surrounding assent and
permission, and just
take you through the algorithm.
As you will see, the questions the
committee will need to address reflect
the issues
that those regulatory criteria bring.
20
[Slide.]
So, the general criteria of Subpart A, in
other words, the common rule, basically
say that
risks to subjects are minimized by using
procedures
which are consistent with sound research
design, do
not expose subjects to unnecessary risk,
are
performed for diagnostic or treatment
purposes, and
then selection of subjects is equitable,
and then
there is an evaluation of risks and
benefits with
respect to the research.
[Slide.]
Now, what makes pediatrics a little bit
different is in Subpart A, the common
rule, in
terms of all subjects, you will notice
that the
risks are reasonable in relationship to
anticipated
benefits, if any, to subjects and the
importance of
the knowledge that may reasonably be
expected to
result.
Now, logically, if you look at that, you
can have risk balanced by knowledge,
whereas, in
pediatrics, there is a limit to the
risks that we
can expose children to for the purpose
of
21
generating knowledge, and that is where
we end up
with the specific additional safeguards
for
children that fall into two main
categories.
The first is the restrictions on allowable
risk exposure for research not offering
the
prospect of direct benefit, which are
found in
either minimal risk or minor increase,
and we will
go into that, but the second is the
notion that the
justification for risk exposure, if
there is
benefit, would be constrained, as well,
by the
language in Subpart D.
So, I am going to run through briefly how
that would look with this particular
algorithm.
[Slide.]
The first step, assessing the level of
risk presented by each research
intervention or
procedure, and deciding whether it is
either
minimal risk, and then approving it,
disapproving
it, or considering it under 406, 407, or
50.54,
which is this panel, or that it is more
than
minimal risk.
[Slide.]
22
Now, the definition of minimal risk has
been a point of discussion in the ethics
literature. The current definition of minimal risk
is it means the probability and
magnitude of harm
or discomfort anticipate in the research
are not
greater in and of themselves than those
ordinarily
encountered in daily life or during the
performance
of routine physical or psychological
examinations
or tests. I would anticipate that we would have
some discussion around this particular definition.
What I have added is something that is not
in the regulations, which has been
recommended by a
number of different commissions and
reports, is
that minimum risk should be understood
in terms of
the normal, average, healthy children
living in
safe environments. That language happens to be
taken in the Institute of Medicine
report on
research involving children that came
out in March
of this year. So, that
may be a point of
discussion.
After you have made that determination to
sort of move down in this algorithm,
once you
23
determine that it is more than minimal
risk, you
then have to evaluate whether or not
there is
direct benefit from that particular
intervention or
procedure, and that would move you in
two different
directions.
If you did feel that there was a prospect
of direct benefit, you then have to ask
about the
justification for that risk
exposure. The risk
should be justified by anticipated
benefit and the
relationship of anticipated benefit to
risk needs
to be favorable as available
alternatives. We are
likely not going to engage in this
particular
conversation today given the nature of
the
protocol, but this would be the one
route that you
would move down, and then if you decide
there is no
prospect of direct benefit, you would
then move
further down the algorithm to then
evaluate the
level of risk.
[Slide.]
You end up then deciding is it a minor
increase over minimal risk or is it more
than a
minor increase over minimal risk, and
then asking
24
two different questions with respect to
that.
[Slide.]
Now, here is the minor increase over
minimal risk. The series of questions
that need to
be examined is, first, are the
experiences
reasonably commensurate, Yes or No.
If the answer is No, you either disapprove
it or it may fall into 407 or 50.54
review.
Does it provide an opportunity to
understand or ameliorate the child's
disorder or
condition? Again, Yes or No takes you in a
particular direction. If the answer is Yes, then,
you have to ask the question will there
be, in
fact, generalizable knowledge of vital
importance
achieved through that.
If at the end of the day, you think it
falls through here, you can end up approving
it or
disapproving it.
One of the reasons this says disapprove
here instead of possibly going to 407 or
50.54, is
as Sara and I were talking, the language
is
different, but it is hard to understand
how we
25
might interpret reasonable opportunity
under 407 or
50.54, if, in fact, is it not of vital
importance.
The
language is different, but that is an editorial
interpretation. If anyone wants to
discuss that
interpretation, we certainly could in
the course of
our discussion.
[Slide.]
But then you get back to the 407 or 50.54,
which basically then says if there is
greater than
a minor increase over minimum risk, we
need to
understand that it is a reasonable
opportunity to
understand, prevent, or alleviate a
serious problem
affecting children's health or welfare,
and then
conduct it in accord with sound ethical
principles.
Based on
the judgment there, you can either then
consider it for possible approval under
407 or
50.54, or, in fact, if it doesn't meet
those
criteria, recommend it for disapproval.
[Slide.]
Now, once you have done that, we should
then turn back to the issue of parental
permission
and child assent. All four categories
simply have
26
the language that there need to be
adequate
provisions for child assent and parental
permission.
It doesn't provide any particular advice
about what that adequate provision might
be, but
that is something that we would need to
discuss.
Now, permission of one parent is
sufficient, if consistent with State
law, for
research under 404 or 50.51, 405 or
50.52.
For research approved under either the
minor increase over minimal risk, which
is 50.53 or
46.406, the permission of both parents
is necessary
unless, of course, one parent is
deceased, unknown,
incompetent, or not reasonably
available, or when
only one parent, in fact, has legal
responsibility
for the child, again consistent with
State law.
So, that would be true of both the 406
category and the 407 category of
50.54. So, then,
that needs to be considered by the IRB.
[Slide.]
In terms of child assent, this again is
the regulatory language. Adequate provisions for
27
soliciting assent when, in the judgment
of the IRB,
children are capable of providing
assent, and the
advice about that capability to the IRB
is that
they need to account for the age,
maturity, and
psychological state of either some or
all of the
children. So, an IRB could make a determination
for all of the children in that
particular project
or they can basically make a sort of
case-by-case
or sort of classy-by-class depending
upon the range
of ages.
Now, assent is not a necessary condition
for proceeding with the research if the
IRB
determines that the capability of some
or all of
the children is so limited that they
cannot
reasonably be consulted, or if the
intervention or
procedure involved in the research holds
out a
prospect of direct benefit important to
that child
where we would, in fact, think it is
appropriate
for a parent's permission alone to
suffice for
enrolling that child in the research.
[Slide.]
Again, some of the general
criteria of
28
Subpart A
that need to be satisfied, adequate
provisions for monitoring the data
collected to
ensure the safety of the subjects, and
then, where
appropriate, adequate provisions to
protect subject
privacy and to maintain data
confidentiality.
[Slide.]
So, that basically takes us through sort
of an analysis of a protocol, and what I
am going
to recommend to the panel is that we
consider, as
we go through this, to make sure that we
have
touched on all of those particular
issues, and if
we have, I would hope that we have covered
pretty
much everything that is important in the
discussion
of this particular protocol, and perhaps
some other
things, as well, but we should at least
make sure
we cover all of those basis, because
otherwise we
are not being I think true to what the
regulations
would require us to do.
But the overall charge is to provide
advice and recommendations to the
Pediatric
Advisory
Committee on FDA's and certain HHS
regulatory issues. As Bern went through, as a
29
subcommittee, we actually don't have the
regulatory
authority to advise the Commissioner and
the
Secretary, but we will then, through the Pediatric
Advisory
Committee, have that recommendation.
I certainly hope our discussion here is
sufficient and exhaustive enough and
clear enough
that it will be readily apparent to the
Advisory
Committee
that they should agree with what we
decide, but they certainly have the
authority to
think differently about that.
Now, the outcome is we should develop
recommendations whether the protocol
should proceed
and specifically address whether and
how, so there
may be things that we would recommend
need to be
adjusted for the research to it either
does satisfy
us as currently written, or, in fact,
could satisfy
if we had some additional conditions,
either the
categories that are approvable by local
IRB under
minimal risk, minor increase over
minimal risk, or
prospect of direct benefit.
If not, however, we could then look to
whether or not the research could or
does meet the
30
following conditions: that it is a
reasonable
opportunity to understand, prevent, or
alleviate a
serious problem affecting the health or
welfare of
children; that it can be conducted in
accord with
sound ethical principles, and I think
one challenge
for us will be to try to articulate what
we believe
those sound ethical principles are that
would, in
fact, justify it if we come to the
conclusion that
it should go forward under that
category; and then
adequate provisions for soliciting the
assent of
children and permission of their parents
and
guardians.
So, at the end of the day, I hope we have
a very clear set of recommendations,
concrete,
straightforward. There shouldn't be any
interpretation on my part about what
that is. You
should leave this room feeling that, in
fact, what
I am going
to say Wednesday morning reflects
exactly what you want me to say. So, that will be
the goal.
With that, I think we are actually moving
along quite expeditiously, and we can
move on to
31
Dr.
Rapoport if there is no questions by the panel.
Norm.
DR. FOST: I just wanted to make
a
comment. That suggested modification of the
definition of minimal risk, I think is
welcome and
desirable, but there is another element
of the
definition that is widely disputed, that
I think we
might want to get to today, and those of
you who
are involved in advising, you might want
to think
to think about.
That is, the phrase "routine physical
examination or test," there is wide
variability in
IRBs in
whether they interpret that as a routine
visit to a general pediatrician for a
health
supervision visit or to a nephrologist
who routine
does kidney biopsies in people who come
into his
office.
In fact, IRBs have approved
non-therapeutic kidney biopsies, small
bowel
biopsies on the grounds that the nephrologist
investigator says this is what happens
on a routine
visit.
32
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
33
discussion today.
DR. NELSON: As it comes up
through the
discussion, I think we should talk about
how that
impacts on our decisionmaking, if it
does, and if
it does, I mean I think cases are the
best way to
try and specify principles. I really
don't have any
sage advice on how to interpret that.
In terms of Norm's comment, I think he is
right on target, but another interesting
question
is how to interpret this notion of daily
life, so
that other half of the equation has also
been
subject to a fair amount of discussion,
and I think
may impact on our assessment.
DR. FOST: But doesn't your added phrase
take care of that? I mean it clarifies it by
referring to some normal environments.
DR. NELSON: It helps clarify
that, in
fact, that phrase, but at this point,
you know,
that has not been formally adopted in
any kind of
official guidance other than commissions
and
reports.
Dr. Rapoport. Just to give us an
34
approach, I mean we will start off with
the
investigator, then, have some
comments. I don't
know if Don has organized remarks or is
available
for questions. Dr. Rapoport says she can be here
for a while with us, but won't be here
the whole
day, so I am hoping the panel can be
able to get
whatever questions they feel are
important to ask
kind of out of the table at the start of
the day.
Thank you.
Background on ADHD/Protocol Overview
Judith L. Rapoport, M.D.
DR. RAPOPORT: Thank you, Dr.
Nelson, and
members of the committee. I appreciate the chance
to present this. As far as slides go, I
think they
reflect both slides that were prepared
by Dr.
Rosenstein, as well as myself, so I think the
slides, as you will see, will reflect
both IRB and
my own statements, and I will add some
background.
[Slide.]
My own work has involved several different
disorders with children, but I have been
at NIH for
more than 20 years, and a large part of
our work
35
has had to do with the effect of stimulants,
not
just stimulants used therapeutically in
ADHD, but
the effect of dietary substances that
are
substances, particularly caffeine on
behavior.
Children at least in the Washington area
drink a lot of Cokes, as well as an
amazing amount
of iced tea, and as a result, we do have
extensive
notion of what an ordinary child would
experience
by way of exposure to 50 to 100
milligrams of
caffeine in terms of what you would
expect in an
ordinary day.
[Slide.]
This was a protocol to study a single dose
of dextroamphetamine in ADHD. ADHD is a very
controversial, but extremely widespread
condition.
It is
probably the single most common disorder in
child psychiatry clinics today.
It remains very much a bone of contention.
Like many
psychiatric disorders, there is very
little by way of laboratory definition,
that this
diagnosis is made by interview and
various
checklist ratings and duration criteria,
disruption
36
to life, et cetera, but there is
certainly no
laboratory experience, and the advent of
functionality MRI has been, for pediatrics, quite
remarkable particularly for child
psychiatry as a
possible window into understanding the
physiology
of this disorder.
[Slide.]
I don't think for this group I need to go
into details about the symptoms, but it
is a
question of degree, and part of the
controversy
comes because what is seen by people who
are
skeptical as being very arbitrary. As a cutoff, it
is really a degree and duration and
interference
with life decision since all of the
behaviors are
things that children very commonly and
often
exhibit in certain situations.
[Slide.]
Stimulants remain the treatment of choice.
Unfortunately, other nondrug-related treatments,
while being somewhat helpful, really are
of a
different order of magnitude in their
effect, and
the treatment decisions again based on
clinical
37
opinion.
There is increasing public health concern
on high rate of stimulant use, and there
is
considered a great deal of
neuroscience-based
diagnostic treatment and outcome
measures.
[Slide.]
So, one of the questions, and let me say
that this is a really old question that
goes back
to perhaps an unfortunate statement in
the 1930s
when children on stimulants were seen to
calm down
when they were first used actually to
help them
calm during a procedure, a radiographic
procedure,
that was they were sort of almost
accidentally
found to be useful, and there was an
unfortunate
statement made that this was a
paradoxical effect
with paradoxical calming.
That led to the very unfortunate use of an
observation that children would calm on
stimulants
for many pediatricians for a generation
to tell
parents that their children must have "minimal
brain dysfunction" because they
actually did calm
down on the stimulants.
38
I mention this just because I want to
point out that there was considerable
indirect
benefit to older observations than
studies we did
in the early '80s, that, in fact, all
children calm
down, and that, in fact, is not a
diagnostic
response to the stimulants and had very
great
benefit on practice, immediately became
a board
question both for child psychiatry and
pediatrics,
because they thought the point was so
important to
get home.
[Slide.]
Our question was do children with ADHD
have a different brain response to
stimulants, and
this was provoked by a very small study
that had
been approved at Stanford earlier, but
let me just
say that we thought it was very important
to see
whether this is an opportunity to see,
with the
functional MRI, whether there could be
actual
difference in brain response in spite of
an
exhaustive earlier study that showed
that by almost
any measure, whether it's motor
activity, verbal
fluency, ability to retain material, but
by every
39
measure that the children's behavior was
the same,
and we thought we had actually laid this
to rest
that a stimulant had no difference in
effect
between ADHD and healthy children
except, as I say,
a couple of studies came along, which
are reviewed
in detail in the protocol, which raised
the
possibility that, in fact, there might
be a
"paradoxical response."
There were major problems with these
studies, not just their small size, but
the nature
of the tasks, the lack of data in one
case, and the
choice of task in the other, where you
couldn't
unconfound task performance with central
nervous
system response.
These studies, however, because of the
importance, because the conservative
definitions
place ADHD at perhaps 3 to 4 percent of
the
population, and because of the
continuing debate, I
think it's notable how important and the
great
interest in the study, that even that
small study
of Vaidya's, which was approved I think
without
much comment at the Stanford Review
Board, but that
40
was published in PNAS, and I think that
attests
more to the considered importance and
interest in
the issue than that particular study, as
our
excellent colleague would be the first
to say
herself, I think.
At any rate, we felt this could provide
some fundamental information about the
pathophysiology of ADHD and effects of
treatment.
[Slide.]
So, the proposed study was 14 children
with ADHD, and 14 healthy controls. I am
deliberately reading out of order
because only if
there was a difference between. If there was no
difference between their response in the
fMRI,
between the controls and ADHD, we were
not then
going to go on and do the twin part of
the study.
But it then involved recruiting.
I say
"recruiting" because we have
some twin studies
ongoing, but over time some children, of
course, go
out of the age range, so you need to
recruit more
mono and dizygotic twins, concordant and
discordant
for ADHD as an approach for
understanding whether
41
the differences are related to just the
state of
having the disorder or represent an
underlying
trait.
[Slide.]
There is history and physical examination,
blood work, neuropsychological testing,
single
functional MRI session, but there was
also
several--in fact, I am sorry, I believe
that is an
error--I think it involves two MRI
sessions, and
subjects to be paid what is an amount
which we
calculate just by how many hours. This is a
payment that is arrived at simply by
going through
a checklist of procedures and can be
modified one
way or the other by IRB.
[Slide.]
The IRB concerns, and as I say,
these are
slides because when these were prepared,
it wasn't
clear that Dr. Rosenstein was going to
be
presenting, but the primary IRB concern
was about
the risk level of the study for healthy
children
and whether the administration of a
stimulant was
approvable under federal regulations.
42
Questions were raised about the value of
the study in the IRB, although the three outside
scientific reviews were the strongest
reviews that
I have
ever gotten for outside reviews of many
protocols. They were concerned about the level of
payment, and I think wanted to adjust
that downward
if the study were approved.
[Slide.]
I think this has already been covered.
[Slide.]
I think this has also already been
covered, and so I don't think I will go
into this.
[Slide.]
What I would like to say is that in terms
of the risks, we have had years of
research with a
single dose of stimulants in hyperactive
children,
as well as a very well known study that
I alluded
to, in the '80s, with healthy children,
and the
single dose was likely to cause, if
administered in
the morning, some loss of appetite at
lunchtime,
possibly someone might feel a little bit
nervous or
have some trouble sleeping at night, but, for many,
43
because of the duration of effect, if
given early
in the morning, even these would not
occur.
The IRB request to this committee was for
waiver of more than minimal risk. That will have
to be represented by Dr. Rosenstein,
because my own
feeling was that this represented
minimal risk, so
therefore, I am not a good advocate for
that
question.
A bit of history might be of interest.
As
always, we always with all of our
pediatric
studies, consult both formally and
informally with
the hospital ethicists.
A very excellent ethicist was present when
I did the
study in the 1980s, John Fletcher, and I
asked John, as I always did with all my
studies,
did he have any special recommendations,
and he had
two recommendations, one which would be
illegal
now, but made intuitive sense to me at the time,
was that if one or two of the
investigators had
children in the right age, it would make
sense if
their own children took part.
At the moment, this would not
be legal,
44
both because you are not allowed to use
your own
family members, and because NIH
employees and their
families are not supposed to take part,
and so on,
but I must confess that when I review
and I am on
panels, such as this, which I have been
regularly,
in my own heart I often ask myself would
I allow a
child of mine to be in the study. So, both with
his recommendation at the time, we not
only would,
but a couple of us did.
He made another recommendation, which was
that we should pay a lot of attention in
this
protocol to informed consent, and
suggested that
both parents consent and that they both
be highly
educated. So, this is the only study I have ever
done in which all of the parents of all
of the
children had graduate degrees.
That was an interesting process because
the parents were all extremely
interested. We were
not concerned that the children
particularly liked
the experience, although they did enjoy
getting out
of school for a couple of mornings, but
the
parents' interest in the child's
improvement on
45
test performance was considerable.
I think the major thing that I was left
with from that experience, I knew many
of these
children, and so I knew a lot of formal
and
informal follow-up over years, and they
considered
it an interesting experience, but
otherwise totally
benign, and what most of them remembered
later was
just that they did something different
that week
rather than the usual routine.
[Slide.]
There have been studies that showed that
even with long-term use of stimulants,
three or
four showed no long-term use of
subsequent
substance abuse. There is certainly no data
relevant to a single dose, and even the
one study
that suggested that children, after
years of
stimulant, who had ADHD, might have a
slight
increase in risk. Those were children that
included some conduct disorder children
who would
be at predicted higher risk relative to
the general
population.
So, I interpret the long-term
data as
46
being negative, and these are for ADHD
children
with multiple problems who have had
stimulant drugs
for years, and it is on that basis that
I don't
consider a single dose as a risk in
healthy
children in this regard.
I think that is all, and I stayed well
within the timeline. I would be happy to answer to
any questions.
DR. NELSON: Before we get to
questions,
Don, do
you have prepared remarks or not?
DR. ROSENSTEIN: I do not. I was asked to
come just to answer questions about the
IRB
process.
DR. NELSON: Why don't we then go
to
questions, but if there is a question
asked that
you want to defer to the IRB Chair, feel
free.
Questions and Panel Discussion
DR. RAPOPORT: Right. I should also
mention that Dr. Daniel Pine is sitting
here, and
if there are very specific questions
about the
cognitive neuroscience part, I rely on
him for some
of that.
47
DR. NELSON: Okay. Norm and then Rick.
DR. FOST: Dr. Rapoport, I have
three
questions.
First, dose. It is stated in
three
different ways in the protocol that we
got. In
some cases, it is per kilo, some as a
single flat
dose for everybody.
Could you clarify how the dose is
determined?
DR. RAPOPORT: Yes. That reflects that in
addition to whatever personal
inconsistencies, the
differences occurred because we had used
a fixed
per kilogram dose earlier.
The general thinking about
psychopharmacologists with a wide range
of ages was
that it made better sense to give a low,
fixed
dose.
I consulted with several experts in the
field.
However, the way it should have read is
that we would give 10 milligrams per
kilogram,
10-milligram dose, period.
In any cases where it would end up being
more than a per-kilogram dose, we would
adjust it
48
downward, would not include that subject.
DR. FOST: So, 10 is the most
that anybody
would get?
DR. RAPOPORT: That's right.
DR. FOST: Second, on the
compensation or
the payment, you said you something
about toning
that down, and I had a couple of
questions about
it.
The total in the protocol we got was it
might go as high as $570. Number one, was that
intended to go to the parents or the
children, or
divided in some way?
Number two, there is three reasons
for
giving money. One is to compensate people for
expenses, which should be the parents,
not the
children. Two, as an honorarium to thank them.
Three, as
an inducement because of the feeling that
you would have trouble recruiting if you
didn't.
Could you clarify which of those you had
in mind with this money, and if it's the
last, if
it's an inducement, do you think it is
necessary,
or whatever your current thinking is
about
49
modifying it?
DR. RAPOPORT: Right. I might add that in
the 1980 study, nobody was paid anything
because
that was the policy at the time. I think I would
rather defer the question to Dr.
Rosenstein on
this.
Frankly, from an investigator's point of
view, you see what everyone else is
doing, and you
look it up in a list, so he is the one
who can give
the informed answer.
DR. ROSENSTEIN: It is a tough
question,
because it gets at the motivation, and I
am not
sure.
I think what you just heard from Dr.
Rapoport
was that there wasn't any specific
decision that we wouldn't be able to do
the study
unless we paid this amount of money for
an
inducement. I mean there was no evidence of that
whatsoever.
This is a moving target, as you know, and
I think
that at the NIH, what we have seen over the
last several years is that for studies
that did not
offer a prospect of direct medical
benefit, that
involved time, inconvenience, and a
variety
50
of--well, I will just leave it an
inconvenience--that payment has now
become the
norm.
How much to pay is a complicated question
that I don't anybody has got the answer
to, but I
think the notion is that payment should be for some
combination of the time lost and the
inconvenience
to the subjects.
I also don't think that there is agreement
upon whether all the money should go to
the parents
or the money should go to the children in the form
of a gift certificate to a book store or
somewhere
else and how you work that out.
So, quite frankly, we didn't get that far
because at the IRB, where we got, we decided
it
wasn't approvable at our level.
DR. FOST: So, if understand you,
and I
just want to make sure Dr. Rapoport
agrees, you
don't think it is necessary to recruit
to this
study?
That is, if you had no compensation, you
think you could still get sufficient
enrollment.
DR. RAPOPORT: I don't know the answer to
51
that.
I just don't know. It is much
more
complicated now.
Everybody's parent works, has to
take off time, et cetera, so things have
change a
lot in terms of these are children, they
need a
family member to be there for the whole
time, and
things have changed a lot.
Certainly, it wasn't necessary when we did
the study the first time, and that had
no part of
it.
I can't tell you the answer to that.
DR. FOST: The third question is
a
question about risk and assent, not
about the
possible medical risk, but the anxiety
of being in
a scanner.
There is some comment in the protocol
about your previous experience with
functionality
MRIs and
MRIs, and it sort of implies that there
has been almost no adverse
reactions. Is that
case?
What is the incidence of children in your
setting who had sufficient anxiety in
the scanner
that they want to come out or that they
report
afterwards?
DR. RAPOPORT: It is
extremely low, but
52
you understand that we have a very
different
process from the medical world in which
this is not
the case, where children typically have
MRIs when
there is other stressful
circumstances. They are
not interviewed ahead of time to be in
the study
based on their sense of whether they
would mind.
We have the luxury of having a whole
practice session and pretend MRI, a mock
MRI.
Children
also have less claustrophobia because just
literally, they are physically much less
closed in
than adults are, so they are much less
bothered by
that.
As a result, because we prescreen children
for all of our children, describing the
MRI, et
cetera, et cetera, it is almost zero,
but I don't
think that our experience would
generalize to the
real world, of course.
DR. FOST: Right, and you say
almost zero
in the practice MRI session?
DR. RAPOPORT: Even that, because
we tell
the child about it, I mean as part of
even the
informed consent process, we go into
this in
53
detail.
DR. FOST: So, by the time you
get to the
"real one," have you had any
experiences of bad
reactions?
DR. RAPOPORT: Not with any
volunteer
subjects, of which we have now more than 3,000 MRI
scans, but with patients occasionally.
DR. NELSON: Rick Kodish.
DR. KODISH: Thank you for
clarifying
which Rick.
Two questions. The first has to
do with
age and assent or consent. I was struck by the
fairly broad age range in the protocol,
I think 9
to 18.
There was some text that suggested that
there was a significant brain change in
adolescents
that makes the investigators think
differently
about post-adolescent subjects.
I am wondering if it is the case that from
an ethics perspective, an age range of
14 to 18
might be preferable for better assent,
close to
true consent, but from a scientific perspective,
and this is not my area, that, in fact,
the 9 to
54
12, 9 to 14 age.
Is that accurate, and is there a
scientific preference?
DR. RAPOPORT: Right. You are asking a
very good question. We would prefer to have
children that are between the ages of 8
and 12.
Eight is
the lower level age largely because of the
nature of the tests and the ability for
performance.
We had very clear reasons why we didn't
feel a study would be useful in adults,
which I
think are described in the protocol.
Do you want to comment on that?
I think I
would like to ask them because this had
to do with
the neuroscience issue.
DR. PINE: I would just like to
add to Dr.
Fost's
comment, that we also routinely do many
studies in children who have very high
levels of
anxiety disorders, and really would just
second the
comments that Dr. Rapoport made, that
any child who
is going to have a significant problem
with an MRI
scan, really never gets very far along
in the
55
process of doing the study, because it
becomes
pretty obvious both to parents and to
clinicians,
as well as the child, that this isn't
for them.
So,
that's the first thing.
The second thing is I think some of the
major questions at a neuroscientific,
neurochemical
basis, related to stimulants, relate to
changes in
the dopamine system in the brain, and
some of the
most pressing questions focus on the
precise age
range that Dr. Rapoport was just
discussing, the 8
to 12 range.
Many neuroscientists feel that after even
early adolescence, the changes in the
dopamine
system are so profound that even among
15- or
16-year-olds the relevance of the data
that you
would acquire for younger children, who
are
definitely prepubertal or perhaps even
in the early
stages of puberty would not be
comparable and would
not really be sufficiently compelling.
DR. NELSON: Would you mind on
tape just
introducing yourself for the purpose of
our
documentation, please.
56
DR. PINE: Sure. I am Dr. Daniel Pine. I
am a child psychiatrist in the NIMH
Intramural
Research
Program.
DR. KODISH: So, to follow up,
the
eligibility criteria for the study
strike me as
ambiguous. I mean one can say clearly that it is 9
to 18, but am I hearing correctly that
from a
scientific perspective, you would prefer
9 to 14, 9
to 12--
DR. PINE: Yes.
DR. KODISH: --and in some sense,
the
upward expansion of that is to make it
ethically
more reasonable. I mean certainly from the ethics
perspective, my thinking is that older
kids would
be more able to participate in a
decision to do
this.
I do have one more pharmacology question.
DR. ROSENSTEIN: Let me just add
one
comment about that, and this was not a
position
that the entire IRB shared, but there
were some
people on the IRB who also thought it would
make
more sense to study younger children
because those
57
people who were worried about the
potential message
of it being okay to take a single close
of a
medication might be more of an issue for
older
children than for younger children. So, the ethics
argument cuts both ways with respect to
the age
range.
Again, that wasn't an unanimous opinion,
but that was one that was articulated at
the IRB.
DR. RAPOPORT: I certainly think
that from
the point of view of both things, that
is more
compelling to use it in younger
children, both
because of the science of it and that
those people
who were "ADHD," older, may
not be representative,
in fact, of the child population.
But I think from a mood response, the
younger children are very unlikely to
get any
positive mood response to it.
DR. KODISH: And then the last
one, which
will be shorter, has to do with this
particular
drug.
I was struck by your introductory comments
about the incidence of caffeine use in
children,
and I am wondering if there is, the way
that one
has narcotic pharmacoequivalency, is
there data you
58
can give us about 10 milligrams of
amphetamine, how
much caffeine?
DR. RAPOPORT: Our own data is
the most
extensive on that. We had several schools that
participated in this, so we knew about
children's
habitual diet, their habitual behaviors,
and then
they took part in various low and high
does
caffeine versus placebo, and these were
actually
more extensive than single dose
studies. These
were for two weeks at a time.
The lower dose, which was about 50
milligrams, 75 milligrams, as I recall,
of
caffeine, seemed to be about equivalent
to what a
single dose of ADHD, there wasn't a
sense of any
change in appetite or problem sleeping.
DR. KODISH: So, what is normal?
DR. RAPOPORT: The trick was we
did a
survey of households at several
parochial and
public schools, and so on, and
households seemed to
be quite dichotomous. About half of the school
children had very generous exposure to
both
caffeinated soft drinks, as well as iced
tea,
59
sometimes, to me, astonishing amounts,
that the
kids would have several hundred
milligrams a day,
because iced tea is always
"okay."
DR. KODISH: But several hundred
milligrams exceeds the equivalent of 10
milligrams
of amphetamine?
DR. RAPOPORT: By far, by
far. On the
other hand, you know, there were plenty
of
households that didn't, too.
DR. KODISH: Thanks.
DR. NELSON: Dr. Gorman.
DR. GORMAN: I have a couple of
questions
related to the actual protocol. You have already,
in response to Dr. Fost's question,
mentioned that
there are several discrepancies in the
protocol in
terms of dosing.
Could you walk us through, as a committee,
how NIH deals with revising protocols,
so these
discrepancies are eliminated in what I
assume would
be a final protocol, which we are not
reviewing?
DR. RAPOPORT: Right. I think I can only
apologize, and I will take whatever
responsibility
60
for inaccuracies or inconsistencies, but
there is
multiple review, typically with
protocols, it is
read at several levels by the IRB, and
usually
meticulously, and at the meeting, not
only are the
broader issues described, but we are
presented with
very detailed list of typos,
inconsistencies, and
so on, and I would say most of the time,
the review
proceeding is extremely detailed and
careful.
DR. GORMAN: I appreciate
that. I am more
concerned or more interested actually in
what
happens in the future. In the protocol, there is a
typo about the dose, which would need to
be
corrected, so that you wouldn't be in
protocol
violation every time you dosed a child.
DR. RAPOPORT: Right.
DR. GORMAN: How does that
procedure take
place?
DR. RAPOPORT: I think I would
have to ask
Don to
speak to that.
DR. ROSENSTEIN: This is a human
process.
We do the
best we can. It is reviewed by outside
scientific reviewers, inside scientific
reviewers,
61
a pre-review before the IRB. There are 14 members
of the IRB that all review it. At the time of the
continuing review, hopefully, that would
be, you
know, an error like that would be picked
up.
So, the answer is the process is people
read the protocol as carefully as
possible. If
there are discrepancies that are missed,
they are
missed, and hopefully, we pick them up
at the next
pass.
DR. GORMAN: In the IRB world
that I live
in, which I deal mostly with
industry-sponsored
surveys, this would require a protocol
amendment
that would clarify the errors, and that
would be
incorporated into the protocol.
DR. ROSENSTEIN: Of course, once
it's
identified. I thought you were asking
how were we
going to identify--
DR. GORMAN: No, how are you
going to
correct it, so that when we--
DR. ROSENSTEIN: With an
amendment to the
protocol, sure.
DR. GORMAN: There will be an amendment to
62
the protocol that will deal with the
dosing issues?
DR. ROSENSTEIN: It will clarify
whatever
the error was.
DR. GORMAN: Okay.
DR. RAPOPORT: Absolutely.
DR. GORMAN: The second question
comes to
deal with the MRI itself. In the protocol, it
describes that this is a 3-Tesla
coil. Is the
3-Tesla coil experimental or in common
clinical use
at this point?
DR. PINE: I think it is fairly
well
articulated in terms of the view of
3-Tesla magnet,
but it is used regularly for clinical
studies
including at the NIH.
DR. GORMAN: I am sorry, not for
clinical
studies. Is it a clinically approved
device?
DR. PINE: Yes, it is a
clinically
approved device.
DR. GORMAN: Thank you.
Do you plan on getting two parental
signatures on this informed consent if
this study
is found to be approvable?
63
DR. RAPOPORT: I hadn't been, but
I
believe I have learned this morning that
I should.
DR. GORMAN:
Thank you.
DR. NELSON: Dr. Chesney.
DR. CHESNEY: I have questions
about the
need for using stimulant in normal
children at this
point in time, and I have read the
protocol, I have
gone back and looked at a number of the
original
articles, and as a neophyte, tried to
understand
the neuroscience, but I obviously have
many holes.
Since fMRI is so new, I wonder if we
should or potentially should focus efforts
on
learning more about the fMRI findings in
normal
children without stimulant, and in newly
diagnosed
ADHD
children, and in ADHD children on chronic
medications before we need to look at
the issue of
stimulant use in children.
Again, in looking at what has been
published, which looks to me fairly
minimal in
terms of fMRI findings, I, in looking at
dopamine
receptors and transporters, and so on,
and trying
to understand all of that, and I may not
be
64
understanding it, but it seemed to me
like we still
have a lot to learn just by looking at
normal
children again without stimulant, and newly
diagnosed, and chronically treated ADHD
children
before we may need to look at the issue
of giving
stimulant to children, which would make
the issue
temporarily a little more
straightforward.
So, I wondered if you could comment on
that concept of whether we really need
to learn
more about what the activation in normal
children
is.
Thank you.
DR. RAPOPORT: Well, I think Dr.
Pine will
also like to comment, but I would like
to say that
at the NIH, there is always a tension
between the
very strong interest in the basic kinds
of
observations that you describe and when
you apply
them as a clinical problem.
But at least at the NIH, there has been a
great deal of very active work already
in children,
in healthy children with some of these
tests, and,
in fact, Dr. Pine's collaboration and
co-PI on this
protocol reflects that.
65
So, there is a great deal more, the change
from PET scan to a test that doesn't
involve
exposure to ionizing radiation really
revolutionized pediatric studies, so in
a limited
field of research where there isn't much
research
all together, relatively speaking, there
has been
quite a considerable amount already,
several from
people who trained at the NIH and have
gone out to
other leading centers.
So, I don't think it is quite so minimal
given that pediatric research is minimal
in its own
way anyway.
I think this a problem, though, that
remains very important, that there
really are
people that are using all sorts of tests
and
selling them as diagnostic processes to
the general
public.
I think you could make an argument that
this is a compelling question.
DR. PINE: I actually, first of
all, want
to thank you for your question because I
think it
does point out almost a procedural
element of the
document that you have, so there are
three specific
66
comments I would like to make.
One is that both Dr. Rapoport and myself
are--I don't know if beat is the right
word--but
really taught and forced to write an
extremely
focused document that very tersely and
very
narrowly identifies a key question, so
that people
reviewing the protocol can look at that
specific
issue.
As Dr. Rapoport mentioned, there is
actually an incredibly exciting,
burgeoning
literature and a number of studies
supported by
DHHS-funded studies that are answering just the
kind of questions that you raise, and
the
technology that we are going to use, if
we are
allowed to do this study, takes
advantage of some
of the things that people have learned
by doing
just the kind of studies that you have
mentioned,
doing large-scale fMRI studies looking
at these
types of functions in healthy kids, in
kids with
ADHD, in
fact, even today, there is a paper that
came out in the American Journal of
Psychiatry that
uses a very similar technique that
compares brain
67
functioning in children with ADHD and
healthy
children, that is consistent with the
work that we
are proposing, so that is the first
thing.
The second thing is, you know, it is also
very exciting to think about things like
dopamine
receptors and wanting to do more basic
work using
those types of methods.
The thing that many people don't
appreciate is that virtually all of the
other
methods for looking at neurochemistry
could not be
approvable because the potential risks
for children
would be higher than the risks that are
in this
protocol as they are described, second
of all.
Third of all, one of the things that
really captured my attention when Dr.
Rapoport
first approached me about this protocol
is I
remembered very vividly where I was when
the study
from Dr. Vaidya was first published, and
I remember
if for a couple of reasons.
One reason was it gathered a huge amount
of media attention, and I think one of
the reasons
it did was it brought to the fore this
idea about
68
is there a fundamental distinction in
the way in
which the brain of a child with ADHD
works relative
to the brain of a child who does not
have ADHD.
That has been a question that we have been
grappling with for 30 years, as Dr.
Rapoport has
mentioned. There has been virtually no
way to get
at that. The finding, as it was reflected in that
1998 paper, by far and away provides the
most
compelling hint that that is true, that
there is a
fundamental distinction between in which
the brains
of healthy children and the way in which
the brains
of children with ADHD functions.
If that is, in fact, correct, it could
have monumental impact in terms of how
we think
about this condition, and there is just
no other
way with the current technology that we
have to get
at that question.
DR. RAPOPORT: I totally agree
with you,
and I think that is very exciting. I mean this is
a huge problem in pediatrics, but I
wonder if it
wouldn't be helpful to focus initially
on fMRI as a
diagnostic tool. I mean that is the most exciting
69
thing to me, that you could actually
distinguish
those who truly have ADHD, not that
whole
population that is being treated that
probably
doesn't need to be treated versus the
controls
before we need to get into the stimulant
medication
for control issues.
Do you understand?
DR. PINE: That has already been
done, and
when that has been done, what we tend to
see in
regular fMRI studies is a pattern of
findings that
is very similar to many other findings
on ADHD in
general, meaning that there are
relatively subtle
differences in terms of how the brains
of healthy
children relative to children with ADHD
work when
they are studied with current fMRI
technologies,
but they suggest, much like, you know, a
lot of the
literature that has led to the current
controversy
that there is not a quantum categorical
difference
in terms of the functioning of the
healthy child's
brain and the brain of the child with
ADHD, and
there is considerable overlap in terms
of how that
bring appears in a healthy child versus
the child
70
with ADHD.
Given that problem, the likelihood that
that technology, as it currently exists,
is going
to be used as a diagnostic tool is very
limited.
DR. RAPOPORT: Well, this gets to
the core
of what has been of interest to me. If there is
that much variability, how will you be
sure that
you can interpret the results with the
stimulant in
a meaningful way?
DR. PINE: There is variability
in the
studies that use current fMRI technology
without
the stimulant challenge. When you look at the
results in that one paper that was
published in
1998, you see a completely different
pattern of
results, to the point where there is
virtually no
overlap between the two groups, and that
is what
really generated the enthusiasm both in
the
scientific community, but also in the lay public
that this was the type of test where
theoretically,
potentially, there was not that degree
of
variability, but one could only see that
difference
if one looked at scans acquired both
during a
71
placebo condition and under
methylphenidate.
The variability was diminished when you
looked at the change in brain
functioning when a
child was taking stimulants, and that is
why it is
so important to pursue this particular
issue of
what happens to the brain of the child
when they
are taking psychostimulants.
Let me rephrase it, that most biological
measures that we have, we see this
pattern of
overlapping distributions for virtually
every test
that we do and virtually every
psychiatric
disorder. Once in a while we come upon real
categorical distinctions where we get
two
distributions that are just not
overlapping.
Whenever we get those, they are incredibly
important to pursue. In the field of ADHD
research, the one area in the last
decade where we
have had this is when we look at this
study that
was published in 1998 where there were
fundamentally categorical distinct
responses in
these two groups.
Was it a fluke? Maybe, but if it is not a
72
fluke, it fundamentally changes the way
we look at
the disorder. That is why it is so
important to
pursue.
It has not been pursued for the exact
reasons that you guys are assembled here
today to
discuss. It has not been pursued because it can
only be pursued by examining the
response of a
healthy child's brain to
psychostimulants, and that
just has not been done since 1998 in
that type of a
study.
DR. NELSON: Mary Faith Marshall.
DR. MARSHALL: I am going to
focus on
something that is a little different
than the
previous question.
I would like to ask, during the consent
process, how you would go about
explaining the
testing for the exclusion criteria in a
pregnancy,
so the pregnancy testing, how that would
work out
in terms of the informed consent
process.
DR. RAPOPORT: Right. That is difficult.
There is
an absolute requirement that any women,
girls who might be sexually active
absolutely have
to have a-- it is not a popular
requirement with
73
the investigators, and we don't feel any
credible
evidence that there is a good reason for
it.
We would explain to them that there is
this requirement and explain this as
part of going
through a urine test would be necessary,
just to be
in the study, explained that way.
DR. MARSHALL: Is it done in the
presence
of their parents? What I am getting at is what
privacy protections do you have during
the process,
and also I would ask, there are several consent
documents or versions of consent
documents in our
folder.
I think three of them are versions of a
parental permission document, and then
the child
assent document, and I don't see
anywhere in the
child assent document mention of
pregnancy testing.
DR. RAPOPORT: Right. I am going to ask
Dr. Pine
who has had more experience with that.
I
think not having it mentioned is
probably an
oversight, that's for sure.
DR. PINE: I guess I would say
two
comments related to the questions about
the IRB
process, having put a number of the
protocols
74
through the IRB. The first thing to realize is
that the discussion of this protocol was
tabled
very early in the process, so I think
the IRB got
to a really core question that if they
couldn't
answer it, you know, they were not going
to move on
to the discussions of these other
details, and I
think that the key issue was whether or
not one
could give a psychostimulant to a
healthy child,
and once they decided that they were not
going to
approve that, they did not discuss some
of these
other issues.
I will tell you that this issue, as well
as some of the other issues in our other
fMRI
studies, has been a bit of an evolving
process, and
what we do now, having learned from
experience, is
in the consent form of the parent and the assent
form of the child, it says to both a
pregnancy test
will be done, your mother or your father
will be
told if your test comes back positive.
We have kind of learned the hard way in
terms of clinically and ethically, that
that is the
most justifiable thing to do in
discussions with
75
the IRB, and this way, when people come
into the
study and assent for it and consent for
it, both
the child and the parent know that if
their child
comes back with a positive pregnancy
test, which
unfortunately happens more likely than
we would
want, everybody knows that going in.
DR. MARSHALL: I guess I would
just make
the observation then, that as common as
this is, I
would, if I were sitting on your IRB,
expect to
see, within the protocol itself, a
discussion of
the process and the privacy and
confidentiality
protections that are there, and that
that should be
upfront in any protocol, and wouldn't
have to wait
for IRB review.
DR. NELSON: Let me follow up, I
think
Joan's
line of questioning, and ask a question
about sort of data analysis. One way to approach
the issue of the inclusion of the normal
controls,
and particularly the intervention group,
normal
controls is to ask whether the data
analysis truly
needs to be blinded and whether there
can be a
sequential process by which, at the end
of the day,
76
you can demonstrate that you actually
need the
controlled intervention data as opposed
to the
controlled placebo data to interpret
what you have
then seen in the ADH control and
intervention data.
So, I mean this is not a drug trial in a
sense where you need to have, you know,
if you take
a look at, you pay a penalty in your
statistical
significance, so I am just curious,
could you do
some sort of sequential design or at
least the
burden of proof that you need the
control drug data
as sort of elevated beyond what might be
in a sort
of standard prospective randomized,
controlled
trial.
DR. RAPOPORT: Well, in order to
get good
data because of differences across
individuals, of
levels, and so on, you would need any
subject to
have both a non-drug and a drug
condition, so since
they have to agree to come twice,
blinding and
having one placebo, so that the subject
is blinded,
you don't really lose anything.
I think more to the point of answering
your question, since the point of the
study is the
77
change between off-drug and on-drug
condition, that
is what the study is doing, what I think
we would
probably do would be, with a smaller
number than,
say, 14, take a look at the data and say
if one
had, say, 8 subjects, did one need 14
and had a
very clear answer, and that says test
fewer
patients, healthy subjects, if we needed
fewer.
Am I answering your question with that?
I
thought that is what the implication of
your
question was.
DR. NELSON: I guess the way I
would
rephrase that, is there any problem if
one delayed.
It needs
to be blinded to the individual in the
scanner, I assume, and blinded to the
interpreter
of the FMRI, but is there any way that
you could
design it in a way that you would gather
all of
your ADHD data and then have the control
data
blinded in a way that at least you then
have
demonstrated the need for the control
drug data to
make that interpretation.
DR. RAPOPORT: I think we
wouldn't be able
to, because each study, each test
situation is
78
different enough that I think you would,
in order
to know whether they were different from
the
control or not, you would simply have to
design
standardized tests and standardized
applications,
that in any given experimental
situation, I don't
think you would know enough conceivably
from just
ADHD
alone to be able to know whether they are
behaving the same or differently from a
healthy
child.
DR. NELSON: One of the other key
things
is an order effect. You know, that there is a fair
amount of concern in order effects. So, if you
were to do a study where everybody gets
placebo
first, including the kids, the healthy
kids and the
kids with ADHD, and then they get
stimulant second,
you couldn't tease apart the specific
effect of the
medication, on the one hand, versus the
fact that
the medication scan always comes second.
You know, half the kids are going to have
to get the medication first, the other
half are
going to get placebo first, otherwise,
the study is
not interpretable, or it basically
becomes the same
79
type of study that has already been
done, that's
published this month in the American
Journal of
Psychiatry.
You are looking at the change, but if you
always do the placebo first, you can
never
interpret the change as due to the
medication. It
might be due to the medication or it
might be due
to the order effect.
DR. RAPOPORT: We always, though,
try to
minimize the number of subjects and the
exposure.
If we had
clear results with 8 subjects instead of
14, we would stop there. If there were
no
differences between the ADHD delta and
the control
delta, we would not go on and do the
twin studies.
DR. NELSON: Dr. Greenhill.
DR. GREENHILL: Just in response
to your
question, and I apologize if I missed
this point
that was in the protocol, another aspect
of what
you are talking about, the blinding
relates to
possible or potential benefit to the
individual
subject. If the family might get the results of
the study after all the participants
have gone
80
through, in other words, they would
learn if there
were differences in the performance of
the
subjects, that particular individual
subject, when
he or she took the test, is that
something that is
built into the protocol at this point,
because I
know in our IRB, we insist in industry
protocols
that the blind be broken, so that
subjects can get
results of their experience in the
particular
protocol?
DR. ROSENSTEIN: I think that
question may
have more relevance for the children
with the ADHD
than the children without, because from
our
perspective, from the IRB's perspective,
there is
no prospect of benefit for those
children who don't
have ADHD, that they be interested in
finding out
the results of the study, and I think
every
investigator handles that differently
depending on
when the overall blind of the study is
broken and
what kind of information can be
communicated in
real time.
But looking at how that information was
exchange to the families of the children
who don't
81
have ADHD was never a consideration with
respect to
prospect of benefit.
DR. GREENHILL: I was just
talking about
the subjects who had diagnosed ADHD.
DR. ROSENSTEIN: I understand,
but again,
I think the reason that this protocol is
before you
is principally for the children who
don't, and I
just wanted to emphasize that.
DR. NELSON: Mary Faith Marshall
has
another couple of questions for Don, and
then we
are scheduled for a break at that point.
DR. MARSHALL: One is just a
clarification
question, Don, and that is relative to
the IUs that
were used to derive the compensation
scheme for
this study, whether that stands for
inconvenience
units.
DR. ROSENSTEIN: Inconvenience
unit.
DR. MARSHALL: Are those standard
throughout the NIH?
DR. ROSENSTEIN: Yes, they are
guidelines,
but there is also, as Dr. Rapoport
suggested
earlier, there is room for variability
in how you
82
apply those, so that there are certain
procedures
that are thought to carry with them greater
levels
of inconvenience than others, even if
they take the
same amount of time. So, there is some
interpretation in that, but there are
some basic
guidelines that we could make available
to this
committee, if you would like, from the
NIH.
At the end of the day, the IRB has to look
at the bottom line and whether that is
consonant
with the study.
DR. MARSHALL: Thank you. The second
question relates to the discussion that
the IRB had
in executive session about the protocol
on October
28th, I guess sort of the final ones
perhaps, the
final discussion.
I want to commend you on the minutes that
are taken of your meetings. They are excellent,
they really are, very thorough.
This may just be a reflection of how the
minutes themselves were written, but
under
Discussion in Executive Session, the minutes say,
"Discussions supporting designating
the study as
83
minimal risk, focused on the compelling
scientific
justification for the study and the
opinion that
the risk of exposure to this drug In a
supervised
setting does not exceed the risk
children are
typically exposed to."
I was wondering if you could maybe just,
if you remember, can describe for us the
component
of the IRB discussion of discussion that
supported
designating the study as minimal risk
relative to
the compelling scientific justification
for the
study.
Is that a fair question?
DR. ROSENSTEIN: I understand
your
question because they are apples and
oranges, but
they go into the same equation. There were some
people on the IRB who felt like this
clearly fell
within minimal risk, and other people
who felt like
it was a stretch and that it would have
to be
called a minor increment over minimal
risk.
The reason again that this is here is
because the IRB, in its final
deliberations, felt
like this was an important study to do,
but there
wasn't a majority that felt that they
could call it
84
minimal risk, so we are not forwarding
it to you to
kind of do our work for us, but because
we thought
that it was a study that should be
approved.
In the discussion of whether it's minimal
risk or not, some people raised
questions about how
important is it really, so if it's
minimal risk,
you know, there may not be the same
burden, you
know, on the science in a sense, and
other people
felt like, well, yeah, it's an
interesting question
and this is clearly the next logical
step, but how
important is it to demonstrate that the
brains of
children with ADHD are different.
That was a minority opinion in the IRB,
but it was expressed, and so I think
that is what
the minutes reflect there, that the IRB
was
struggling with a risk level that was
right on the
border and how compelling the science
was to
justify it, you know, whether it was just below
that level or just above that level, if
that makes
any sense at all.
DR. MARSHALL: It does, thank
you.
DR. NELSON: Ms. Treat.
85
MS. TREAT: I just had a couple
of
questions. I bring to the table the perceptions of
the general community and families.
There is the perception in the general
community among both ADHD kids and the parents, and
healthy kids, too, that the stimulants
that you are
using, especially the one that you are
using, is
highly habit-forming and can cause
various other
side effects.
I was wondering, since there is so
little
research on healthy children, if the
stimulant
might--I recognize that you might
believe that a
single dosage carries very low risk
based on your
studies of ADHD subjects--but there is a
concern
among some of the people I serve that
even a single
dose might cause or might aggravate
predispositions
in healthy children, such things as
eating
disorders or later abuse, that kind of
thing.
In that regard, I also noted that the
dosage that you are using, the
10-milligram dosage,
is higher than the recommended starting
dosage of 5
milligrams for the stimulant you are
using. I was
86
wondering if you could address that.
DR. ROSENSTEIN: That last
question, I
will defer to Dr. Rapoport and Dr.
Pine. With
respect to the first comment, this is
the challenge
that all IRBs have in interpreting the
regulations
when you have an absence of data. No one can
answer the question of what risk there
might or
might not be with a single dose of a
medicine like
this.
The data that Dr. Rapoport summarized
earlier suggested even when you are
using
stimulants chronically, there is not an
increased
risk of substance abuse, but perhaps a
decrease in
risk.
Whether that applies at all to healthy
children who get one dose, we, quite
frankly, don't
know.
So, I think other people around our table
were wondering about that as a
contributor to
whether this ought to be considered
slightly more
than minimal risk or not, but we just
simply don't
know, to answer that question about the
dose.
DR. RAPOPORT: Yes, we were
torn. People
with hyperactive children often do start
with a
87
single 5-milligram dose, that is
absolutely true.
Our own
experience with numerous behavioral
measures is that that so often doesn't
give a
recognizable signal. We certainly didn't want to
go through all of this and not have
anybody
including the hyperactive children have any change.
It was the smallest dose to get any
reliable change, and even though any
good
pediatrician or doctor would always try
to start
conservatively when people are going to
start off
and taking something, you know, every
day for
weeks, we thought this was the lowest
dose that
would be worth doing, because too many
children in
our experience don't change in a
measurable way in
a single dose of 5, but I am not
criticizing the
pediatric approach. Just for a single-dose study,
it didn't make sense to us.
MS. TREAT: I did have one other
question,
and that concerned the IQ parameter that
you have.
In the protocol, it says that your only
parameter
is the low one, the low IQ being
80. When I and
some of my friends had taken their kids
to take the
88
test, the go/no-go test and the stop
test, I was
told by the doctor that IQ did have a
bearing on
responses to those tests, the higher the
IQ, the
less likely or the more likely the
subject was to
be able to perhaps even beat the test.
I was wondering if maybe a smaller
parameter for you would--
DR. RAPOPORT: You mean to have a
higher
cutoff, as well as the lower cutoff?
MS. TREAT: Yes.
DR. RAPOPORT: I think I will ask
Dan.
DR. PINE: In general, it is true
that
there are some associations between IQ
and
performance on these types of
tests. There is wide
variability across the different kinds
of tests, in
the strength of that association, and
when we use
these tests behaviorally, meaning just
having kids
do the exact same paradigms that Dr.
Rapoport is
going to use, we find extremely small,
if any,
correlations between IQ and these specific
tests.
DR. NELSON: Dr. Greenhill and
then Dr.
Jacobs.
89
DR. GREENHILL: Since we are
discussing
the consent and assent forms, there are
a couple of
questions or suggestions that came to
mind.
The perception of families about these
medications relates to the fact that
dextroamphetamine is a schedule drug,
which means
that it is classified as a drug of abuse
by the
Drug
Enforcement Administration.
Pharmacists often remind families of that
when they get a prescription of the
drug, and in
some states, those drugs are delivered
on different
prescriptions, and they are tracked and
monitored,
and physicians' prescribing rates are
tracked.
So, it is important in all our consent
forms that involve schedule drugs, to
tell parents
that this is a schedule drug, and
considered to be
a drug of abuse by the Drug Enforcement
Administration.
The other thing is that we tend to be more
explicit about adverse events that are
connected to
stimulant medication, and even if they
play a small
role, it is important for parents to at least have
90
some of the fears that they might have
about these
medications addressed explicitly in the
consent
form.
A number of families confused
dextroamphetamine with methamphetamine,
and it is
helpful in some of our consent forms to
make it
clear that although this is a related
product, it
is not speed.
In terms of adverse events, there are
infrequent adverse events, but the ones
that we see
that occur, such as stomachaches,
headaches, and
particularly involuntary motor movements
are a big
concern of families, and they occur in
these
patients. It is not clear
whether they are
triggered by the medications, but should
they
appear, the first response on the part
of almost
every family I have worked with is get
them of the
medicine.
So, they might have some concerns if their
child took one dose of stimulants and
began to
sniff or have a blink, and they might
associate it
with taking that medication ever if it
weren't
91
related.
Finally, there is a section in the assent
form that says, "Occasionally, the
MRI examination
will detect something unexpected, in the
child's
brain is a mass or any kind of
abnormality."
This has been a big issue at the
institution where I work because that
might lead to
every scan requiring a licensed or a
board-certified radiologist looking at
them to make
sure there is no evidence of an abnormality
or a
mass.
This is just a question I would have for
Dr. Pine.
We have been told on the IRB that the
protocol for the MRI scans are not
designed to
optimally look for masses or other
clinical
abnormalities, but to focus on
functional, bold
kind of results for registration, and a
clinical
wouldn't turn to that protocol if he
were
clinically evaluating a symptom complex
in
patients, looking for a brain tumor.
It may be misleading to tell parents that
this test will give you a bill of
health, and I am
92
not clear it does, so I need to ask Dr.
Pine.
DR. PINE: It is funny that Dr.
Greenhill
says this, because I began my MRI
studies at Dr.
Greenhill's institution and was taught to think
about MRI studies the exact same way,
and I was
shocked when I came to the NIMH four
years ago to
learn that we take an additional 20 minutes to put
every child through a far more rigorous
comprehensive clinical assessment of
brain anatomy,
both normal and pathological, and that
is a rule of
the NIH Clinical Center, that every
single child
who will go into the MRI scanner once a
year will
have a comprehensive bona-fide clinical
assessment
that will be read by a trained
neuroradiologist, so
that we can say exactly what is written
in the
consent form, and it is very different
relative to
any other MR center that I have ever
seen.
DR. GREENHILL: That is a
benefit.
DR. PINE: It is a benefit.
DR. RAPOPORT: It is not a choice
for us,
it's an absolute clinical center rule.
DR. NELSON: Dr. Jacobs.
93
DR. JACOBS: I would like to
return to the
age question that we were talking about
a little
earlier. I am a developmental psychologist, so in
all the research that I look at and do,
age is very
big issue.
It seems to me that what we are doing here
is weighing the science and the value it
will have
for future treatment an future diagnoses
against
the risk to some individual children.
So, the science matters a lot, and it
seems to me that the range that you have
proposed,
from 9 to 18, is really too broad, and
we have
already talked about that. It appears to me that
particularly the upper ranges, you may
have brains
that have changed, and it will be
difficult for you
to actually lump that data in with the
data from
the younger children, and you don't have that many
subjects, so it will be difficult to
really tease
it out in a different way.
So, I wonder if you have considered really
narrowing the range especially to the
younger
group.
94
DR. RAPOPORT: Yes. I think that it would
make a good deal of sense to narrow it
from 8 to
13, for example.
DR. JACOBS: Thank you.
DR. NELSON: I know there is
other
questions, but before doing that, let me
just ask.
I know,
Dr. Rapoport, you said that you have some
commitments, you may need to leave. My question is
whether we should--I mean we do have
plenty of time
for discussion--whether people want to
continue
this conversation or have a break and
then continue
the conversation.
I see panelists nodding continue, which is
fine. If anyone needs some natural
stimulant, get
it on your own.
Mary Faith had her hand up, then Norm, and
then Dr. Greenhill. So, Mary Faith.
DR. MARSHALL: Mine was really a
follow-on
to the informed consent document itself,
and these
are just observations, not questions
really, and
they may be more appropriately directed
at the
Chair of the IRB.
95
One is in the consent documents, the word
"placebo" is used early on,
and I don't see it sort
of spelled out for those who may not
understand it,
and that is an obvious thing. It is just an
observation, I am not asking for any
defense.
The second one is the use of the word
"treatment." I understand that
the substance that
is under investigation is approved in
certain uses,
but this is research, and others may not
agree with
me, but I have a big allergy to the use
of the word
"treatment" rather than study
drug or something
along those lines.
To me, treatment implies something that
has been empirically derived and is
standard
practice. Again, I sit on several DS&Bs for the
NIH, and
I bring it up every single time, so I just
have to do it and go on record as saying
that.
I do want to reiterate to both of you, I
would see a young girl who tests
positive for the
pregnancy test, and it's a surprise for
everyone,
and us knowing some of the sequela that
could come
about because of that, as potentially
being greater
96
than any of the other risks we are
talking about
here today.
One thing that I see that is common among
protocols and IRB review of protocols is
what I
would consider to be a really cavalier
approach to
that whole issue and the whole process
of consent
and privacy and confidentiality.
So, I really just would like to say that
again, and again I am not asking for any
sort of
defense or whatever. I just want to get it out
there on the table.
DR. ROSENSTEIN: Can I respond
just to
that one? We do take it very seriously, and we
have modified our approach over the
years at the
IRB. I think that whether you agree with this
approach or not, where we are at right
now is that
we don't test anyone unless they know
they are
going to be tested obviously.
The investigators have a great deal of
sensitivity to asking in private are you
sexually
active, is there any chance that this
might be
positive. I mean all of that isn't necessarily
97
laid out in this consent form in front
of you, but
we take it seriously, and the other part
of it is
that if the terms of the study are
unacceptable,
either to the child or to the parent
because of
that eventuality, they don't have to be
in the
study.
DR. MARSHALL: Right, and I
appreciate the
fact that they do it seriously, but as a
reviewer,
I don't
see a reflection of that here, and thus, I
have no way of knowing that that is the
case.
DR. ROSENSTEIN: Fair enough.
DR. NELSON: Norm.
DR. FOST: I just wanted to make
sure I
understood the previous exchange about
MRIs. Did I
understand you to say that every child,
not just in
this study, but at NIH in general, will
get a
standard clinical MRI also?
DR. PINE: Every child and every
adult,
every person gets a standard, and it
takes 20
minutes.
DR. FOST: It opens a whole can
of worms
that we probably don't have time to
discuss at this
98
minute, but I will have to discuss
later, so I just
want to identify it before you leave, so
you can
comment on it.
There is a possible benefit, but it is
much more likely to be a risk than a
benefit. That
is, when you do screening procedures in
a healthy
population, a population that is not
expected to
have brain pathology, you are much more
likely to
pick up false positives, adventitious
findings,
then, someone has to explain to the
parent there is
a little something in your child's
brain, we don't
know what it means, but he ought to be
followed or
it ought to be repeated.
I am astonished that you (a) would do
that, and I am confused as to why you
would do it.
Why being
in a study should lead you to have a
clinical MRI. Of course, the whole same set of
questions are raised by the fMRI, which
can raise
adventitious findings.
DR. PINE: I would disagree with
the fMRI
finding.
DR. RAPOPORT: They are less considered
99
diagnostic. We have the largest series of normal
child, healthy child MRIs, I think in
the world,
and I can echo though while, of course,
it almost
never happens, we have had 4 instances
out of 3,000
MRI on
about 500 children, who come back every few
years, and 2 of them were benign cysts
that the
parents got further consultation and did
nothing
about, but in 2 cases they turned out to
be brain
tumors that were operated on and had a
good outcome
before we found it, so we are 50-50 in
our
experience out of these 3,000.
DR. FOST: That is
interesting. I hope
you publish that or plan to.
Again, I didn't see anything.
This is the
first I learned of it from this
interchange. I
didn't see anything in the protocol or
the consent
form.
DR. PINE: I can also tell you,
much like
the issue of pregnancy, that working
with IRB, we
have adapted the language in the consent
form, and
the process for discussing that for the
very reason
that you mentioned. I am sure, as Dr. Rosenstein
100
would say, the final consent form,
should it be
approved, would reflect the current
language, which
goes into far more detail about what it
means to
have a clinical MRI, what are the range
of findings
that we can get, what you will be told,
and when
you will be told.
DR. FOST: Like Mary Faith, I am confused
as to what this consent form is. Is this just sort
of a draft consent form? Why is not all this in
the--especially when it gets to this
level, I would
think you would want--
DR. ROSENSTEIN: It is not a
draft. I
will try to answer this the best way I
can. This
protocol has been through many, many,
many
iterations, and at some point, the
fundamental
question about whether it's permissible
to
administer a single dose of a stimulant
to
children, to anyone under 18 has to be
asked and
answered.
You have got competing demands of kind of
getting some read on that versus having
a document.
I
am more than happy--Dr. Rapoport said she would
101
take responsibility--I will be
responsible for any
typos, any omissions, any misleading
statement in
the consent form.
We are more than happy--if you want to
send it back to us with an answer, we
will kind of
work on that.
DR. NELSON: If I may, we will
stipulate
that the IRB recognizes their process
was
short-circuited by the question of
whether they
could do this from a regulatory
perspective. I
think it needs clean-up.
DR. ROSENSTEIN: Thank you, Dr.
Nelson.
DR. NELSON: I think we have
beaten them
up enough on that point.
Dr. Greenhill.
DR. GREENHILL: I just have a
question for
the head of the IRB. Where do you draw the line
for listing adverse events of a
particular
intervention? Our IRB tends to go down the list,
knowing that some families will go the
Physicians
Desk
Reference and find disturbing adverse events,
and not realize they are under the rare
section.
102
So, for example, we would put in the
frequent adverse events, headaches,
stomachaches,
decreased appetite and decreased
weight. We would
put in the infrequent adverse events,
such as tics,
and then the rare, such as hallucinosis,
formication.
And then we would address one that is of
great concern to the public, which is
growth
slowdown and delay, and to try to put it
in the
context this is a single dose.
That is one of the questions I
have. Do
you have kind of a guideline that you
use at the
NIH?
DR. ROSENSTEIN: We follow a very
similar
approach, and whenever there are numbers
available,
we include those numbers to try to make
it more
understandable. Again, I think everyone
here who
has served on an IRB knows that it is as
much art
as science about exactly how many things
that you
list.
When there are no data relevant to the
side effects for a single dose, it makes
it more
103
difficult to know how much information
is then
misleading, you know, to report the side
effects
that are associated with higher doses
for chronic
duration may not be doing anyone a
service. It's a
tough question. We try to be as thoughtful about
it as we can.
DR. GREENHILL: The other
question I have
is whether the consent form has to be quite so
conservative in terms of the
benefits. Now,
clearly, there is no medical benefit,
but there is
a benefit from coming to the NIH and
having an
evaluation by an expert team, and there
is the
potential benefit of taking the results
of the
tests and preparing some kind of report.
I want to just expand this a little bit.
If you
don't indicate, if you give a WISC, and then
the child six months later goes to
school and has
to get a test in order to enter a
special program,
for example, get special education,
which a lot of
children with ADHD do, they can't be
tested at that
point because there is as practice
effect.
So, we generally put in our
consent forms
104
something to let the parents know that
by taking
the WISC, they will not be eligible to
take the
test again for a year to have it
interpretable.
For that reason, we try to give the
parents some kind of a form and a
report. Now,
initially, when we did a big outpatient
study with
the NIMH, called the MTA study, we had a
licensed
psychologist sign off on it, so that
that piece of
paper that came from the evaluation
served as an
official statement of the results of the
WISC,
which can play a big role in special
ed.,
accommodations of getting special
provisions and
getting classification.
Is that something that you might consider?
DR. ROSENSTEIN: Sure, and I
think that
over the years, some investigators have
shared the
results of some neuropsychological
testing, but not
all of the neuropsychological tests are
administered in the same way that they
would be in
a clinical setting.
It is analogous to the discussion we were
just having about the MRI. On one level you would
105
think of this as a benefit, on another
level you
could think of it as a risk. There are some
parents who bring their children into a
study as a
child without any problems, but because
they have
got suspicions that there may be some
difficulties,
and then sure enough, in the course of
the
evaluation, some psychiatric problems
are
identified. Is that a risk or a benefit?
In the past, we have left the sharing of
information about the evaluation, what
is
clinically relevant and what is not, up
to the
discretion of the investigator.
DR. GREENHILL: I just want to
indicate
that this is a unique situation because
getting an
MRI at
the NIH doesn't preclude you getting one
next week, but it does preclude you
getting an IQ
test.
DR. ROSENSTEIN: I understand
that, and I
wasn't aware.
DR. GREENHILL: The last thing I
wanted to
mention is there are a number of issues
that I
think have been addressed, and I am
trying not to
106
beat a dead horse with this issue of the
age, but
the older an individual is who has ADHD,
the more
likely he has had chronic exposure to
stimulants.
Is there any way--I don't think there is
any answer I can come up with off the
top of my
head--but some investigators have
required them to
be stimulant-free before coming in and
getting an
evaluation. That really impacts the feasibility of
a study because if you are looking even
at a
13-year-old who had ADHD, they are very
likely in
this country to have been exposed.
Is there any way you can factor in the
exposure, prior exposure in terms of
interpreting
the results of the functional MRI, or do
you think
that is a problem?
DR. RAPOPORT: I think ideally,
one might
be having ADHD children who had never
had
stimulants before, but that is not
likely to be
true.
Our own experience of over 20 years of doing
these studies, where we did have many
children that
we were taking total care of, was that
the 100th
response to a dose of stimulant tended
to be
107
identical with the first, so for this
study, I am
not really concerned.
DR. NELSON: Dr. Gorman.
DR. GORMAN: I am not through
beating up
the age question. Has this question been answered
in adults? Have adults with ADHD been tested with
single doses, and have normal adults
taken single
doses of stimulants to look at their
brain
responses?
I ask that question because I have three
children in college, and I can tell you
that their
friends' most common request of me is
can I write
them a short prescription for a
stimulant medicine
during exam period. So, I suspect there
is a lot of
people undergoing this clinical
experiment on a
regular basis.
DR. RAPOPORT: The problem is
that as Dr.
Pine and
other people have shown that different
parts of the brain change, that are
active, in
response to these drugs with age. Furthermore,
when you look at who are adults, you
need to test
adult ADHD with adults, they turn out to
be a
108
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
109
years with all the concomitant things
that can go
on in the brain as opposed to what that
means for a
child who presents to your office as a
10-year-old,
and you are trying to make the decision
about, you
know, does this child have a normal or
abnormal
functioning brain.
Data in an adult, even an adult who you
know what has happened to them
definitively, over
40 years, you can never answer the
question about
is the brain function that you are
seeing in that
adult really just a downstream
reflection of what
has gone on in the past 20 years, and
what we
really need is date that speaks to the
10-year-old
child.
DR. RAPOPORT: Moreover, we are
looking
for long-term follow-ups with continued
subjects
right now, and they are a very small
fraction, I
mean vanishingly small, that we couldn't
do this
study.
We are trying to follow up from 15 to 20
years, the 300 patients we have
characterized, and
no, we are not able to find a sufficient
number
that don't have other major disorders that
still
110
would meet criteria above the age of
18. I have
that data.
DR. GORMAN: The paradigm that
the
American
Academy of Pediatrics recommends is that
if you believe the pathophysiology is
the same, is
to test, before you test in children, to
test in
adults, and that is why I am asking that
question.
So, I will ask once again very simply.
Has this
experiment been done in adults, and does
it show that normals and adult-diagnosed
patients
with ADHD have different responses?
DR. PINE: There has not been an
exact
replication of the Vaidya study that was
published
in 1998, doing the exact same study in adults with
and without ADHD, on the one hand. On the other
hand, there has been an extensive series
of fMRI
studies in healthy adults and adults
with other
forms of psychopathology looking at the
fMRI
response to psychostimulants.
The feeling is that due to some of the
questions that Dr. Rapoport had raised,
about how
do you make the diagnosis of ADHD in
adulthood and
111
how does it relate that many people have
been very
hesitant about embarking on everything
that would
be involved in doing that type of a
study in
adults.
I would add that we share those scientific
concerns.
I think for that reason, the study has not
been done because no matter what you
found, many
would question the implications of the
findings.
DR. RAPOPORT: There has been one
study by
Dr.
Volkow, which used PET, which is using a
technique not accessible to children,
that did
suggest there might be some difference
with respect
to dopamine receptors, but that wouldn't
be
appropriate, and again, she had all the
peculiarities of her adult sample that I
mentioned.
DR. NELSON: Dr. White.
DR. WHITE: I had a question
regarding
since fMRI measures, change in
hemodynamic
response, and dopamine is involved in
the
hemodynamic response, does your design
take that
into account, and also, is that a
rationale for
using controls?
112
DR. PINE: One of the unique things
about
the study is that a particularly
sophisticated
group of fMRI methodologists have been
assembled at
the National Institute of Mental Health,
and, in
particular, Peter Bandatini, who heads
the
Methodology Group there, and in his earlier work at
the University of Wisconsin, he actually
looked in
adults, the effects of various agents
including
psychostimulants on bold perfusion
effects in
adults.
So, Peter is a collaborator on the
protocol and ensures Dr. Rapoport and
myself that
we will be able to disambiguate
hemodynamic effects
due to vascular effects versus
neurocognitive
effects.
DR. NELSON: Dr. Chesney.
DR. CHESNEY: I don't mean this
to be
simplistic, but I guess where will the
results of
the study take you? I didn't really see any
hypotheses, I sort of wrote out three or
four on my
own, but other than simply learning more
about,
which is absolutely important in and of
itself, and
113
I know
research doesn't necessarily have a
pragmatic outcome, but you mentioned
that clinical
severity would be taken into
consideration
depending on where the results came from
and went
to.
But I guess in the bigger picture and in
terms of helping us assess the
importance of the
stimulant in normal children, what are
your
hypotheses, where do you think will take
you and
what will be the next step?
That would certainly help me sort out the
overall importance other than just
saying what
activates and what doesn't activate,
which is very
interesting of itself.
DR. RAPOPORT: One, on a
scientific level,
it would provide the strongest evidence
to date
that there is something different in the
way the
brains of ADHD children functioned,
which would be
a more abstract scientific level.
i think our hypothesis at the
moment would
be that with the appropriate tests where
you
disengage performance from brain
activity and
114
response to the drug, my hypothesis is
that there
would not be a difference, and this
would help and
counteract a great deal of fraudulent
behavior on a
clinical level that is going on, because
there are
a great many people out there selling
diagnostic
tests that people pay for in spite of
the fact that
they have no legitimacy.
I think there is another answer here also.
DR. PINE: I will say again two
things. I
think this is a great question that cuts
to the
core really of the protocol, and
hopefully, it is
reflected in the IRB minute notes, but
the IRB
really held both Dr. Rapoport and
myself, and the
entire team, to a very precise answer to
that
question, and constantly asked us to
reframe that.
I would say that Dr. Rapoport and myself,
while we agree on the importance of the
question,
and it really is fundamental, on the one
hand, and
on the other hand, maybe we have
slightly different
visions about where it might go.
Where I really come from is this idea that
I think has been implicit in many of the
questions
115
that people have asked about how do you
tell the
difference between a child who really
had ADHD and
a child who doesn't.
As reflected in Dr. Rapoport's answer, I
am not sure that we would totally agree on how
close we are to doing that. If this study were to
find similar results that Dr. Vaidya's
study found,
that would tell us that we are getting
reasonably
close to doing that, and that would tell
us that in
the not so distant future, when a parent
comes to
see us with a child who is basically
high
functioning, who is having mild problems
in school
that are very common, and the parent
says to us
isn't there a test that you could do
that would
tell me definitively whether or not my
child really
has ADHD or not, this study would be a
very
important first step towards developing
that type
of technology and developing that type
of finding.
On the other hand, if the results of the
study were negative, it would say that
this
approach is not a good way to go, and
that this way
of trying to develop the test as
specified in that
116
protocol might not be the best way or
perhaps we
might be a long way away from developing
that kind
of test.
But that is really the importance of the
work.
It is trying to develop a better
physiological based measure that can
tell us, yes
or no, does this child have a problem in
the way in
which their brain is functioning or not.
MS. TREAT: You know, it seems
that there
are a lot of diagnoses of children,
young children,
with ADHD. I believe Dr. Jacobs' comments sort of
support this. As they get older, their brains
change, and many of the people that I
know of who
are diagnosed with ADHD as children, got
to a point
as they grew older, in the later teen
years, where
they no longer needed to be on the
medications,
they were better able to concentrate,
and that kind
of thing.
I am not a professional, so I am not sure,
but it seems that it would indicate that
they may
have been misdiagnosed when they were
younger.
In that regard, to me, it
seems to make
117
more sense to restrict--is you were
going to
restrict your age range, to restrict it
to the
upper age range rather than the lower.
You had mentioned that you would restrict
it to the lower age range, 8 to 13.
DR. RAPOPORT: Yes, for several
reasons.
The
natural history of ADHD is that as children get
older, they tend to, particularly in
adolescence,
many of them no longer meet
criteria. It is a
disorder that for many children, when
they get
older, they no longer have the problems,
and when
they do, it is expressed somewhat
differently,
often with more inattention and less
motor
restlessness, for example
I think, in general, that there is a wide
degree of misdiagnosis of ADHD, but I
think that
when it is done carefully, and when you
require
that you have a sustained period of more
than six
months, starting before the age of 7,
and going on
with the considerable interference with functioning
in at least two settings, not just the
home or not
just the classroom, that, in fact, the
misdiagnosis
118
at a certain level of severity, of the
sort that we
do in our studies, I think the
prediction from year
to year of continuation up until
adolescence is
very high.
The natural history of the disorder,
though, is different, and I think the
points that
were made by several committee members
is that I
think it does get more complicated in
the older age
range, and that anything we found out
earlier would
be much more generalizable to the vast
majority,
the great majority of ADHD children and
the ones
for whom these questions were initially
addressed.
DR. NELSON: Thank you. I think at this
point, I would like to transition to
some material
we need to get on the table before we do
our public
discussion period at 11:00 and then
perhaps give
people a chance to stretch their legs
before that.
I would like to thank Dr. Rapoport for her
patience and clarity in answering our questions,
and Don, as well, and your colleague.
DR. RAPOPORT: Thank you. Dr. Pine had to
make a plane, and that is why he left
early.
119
DR. NELSON: Thank you.
At 11:00, we will be having a time of open
public hearing, but before that, there
were some
comments that were submitted in response
to the
request for public comments that I was
going to
summarize.
Basically, we can then take a short break
before we have the open public hearing
at 11:00.
Summary of Submitted Public Comments
Robert N. Nelson, M.D., Ph.D.
DR. NELSON: The full text of the
public
comments should be in the packets that
people have
for this meeting. I have summarized them by
basically dividing them into issues, so
we can see
what each person said or didn't say
about given
issues.
The backgrounds of the three responses
that we received, one was the parent of
a child
with ADHD, also who had chaired an IRB
in the past.
One was a
health professional, and the other was a
lay person who also happens to be a
grants and
contracts administrator at a university
level
120
institution.
In terms of scientific merit, parent of
the child with ADHD, and these are
quotes taken
from those comments, thought that there
was a
possibility of great scientific benefit
with
respect to the causes, diagnosis, and
treatment of
ADHD,
which poses significant challenges to many
children and their families, and may
also help
distinguish between appropriate medical
uses of
dextroamphetamine and more questionable
uses.
The health professional simply commented
that the studies needed to generate
important
information, and the lay person felt
that being
able to comment on the scientific
validity or
utility of doing the study, particularly
in normal
children, was beyond, in this case, her
particular
expertise.
In terms of risks to subjects, two
commented on this. The parent of the child with
ADHD felt
that a single dose of dextroamphetamine
is unlikely to be harmful, further,
there are
safeguards in place, and the child
and/or parent
121
and guardian may discontinue
participation at
anytime.
The lay person expressed concerns regard
the drug abuse potential that might be
suggested by
having one dose, which might lead to
curiosity
about additional doses.
In terms of parental permission, the
parent of the child with ADHD thought
the consent
documents are clear. The health professional
thought they were clear. The lay person had a lot
to say about the consent forms, and I
have not
quoted it all, I have simply summarized
her points.
I didn't feel that the documents fully
explained the procedures involved in the
study, and
particularly she mentioned the
screening, physical
exam, the teacher contact for rating
scales,
genetic testing for twins, the decision
to test
twins with respect to zygotic status could
have
emotional implications for parent and
twins, the
MRI in
terms of full description, and she felt that
the technical language, it was a bit too
technical
as opposed to lay terms, and that they
didn't
122
really provide much discussion to the
alternative
to participation.
In terms of child assent, the health
professional said that the assent
documents need to
be written at age appropriate reading
level, but
did not say, although you could infer,
that they
didn't feel that this was the case with
these
forms.
The lay person felt the inclusion criteria
in the protocol states that it should
have consent,
but she pointed out they should have
talked about
assent, and also commented on the fact
that the
pregnancy testing was not mentioned in
the assent
form, nor whether the results will be
shared with
the parent.
In terms of financial incentives, the
parent of the child with ADHD felt that
the
payments were not too high, but did feel
that the
payments ought to be directed to the
child in some
fashion.
The lay person felt, you know, maximum 570
being paid, but it doesn't describe who
will be
123
compensated. To this person, it seemed like a
large amount for the child, and it seems
inappropriate to compensate the
parent. "It
appears coercive" is a direct
quote. With no
direct benefit to the child, it appears
that the
parent is benefiting financially while
putting the
child at some risk and certainly an inconvenience.
The
benefit section refers to the compensation as a
benefit. Again, this becomes coercive.
Assessment of risk category.
This was the
parent of the child with ADHD who you
may recall
also chaired an IRB. For children with ADHD, I
would consider the study a minor
increase over
minimal risk within the range usually
borne by
children with the disease with an
offsetting
societal benefit that could not
otherwise be
gained.
For the normal controls, the risk is
greater than minimal in that they would
not receive
the medication or the functional MRI in
normal
life, however, it is unlikely that a single
dose of
dextroamphetamine would cause harm, and
again
124
safeguards are in place.
The bottom line. The parent of
the child
with ADHD felt that I would encourage
approval of
this study, and the lay person said I do
not feel
comfortable about approving this study
in its
current form.
So, that is a summary of the three
responses that we received as a request
for the
public comment period, and you have the
full text
of those comments that are being handed
out now,
and I think were available to people
that are here
for the public session.
In order to give us at least a little bit
of a transition between our discussion
and the
public comment period, I would suggest
we take a
break, which by my watch will be about
12 minutes.
We will take a short break.
Thank you.
For the panel members, I was asked to read
this before the break. The discussion of the
protocol is a public one, therefore, we
should not
discuss the protocol amongst ourselves
during the
break.
125
[Break.]
Open Public Hearing
DR. NELSON: We will now be
moving into
our open public hearing. Before introducing the
people who have requested time to speak,
I have a
statement to read.
Both the Food and Drug Administration and
the public believe in a transparent
process for
information gathering and
decisionmaking. To
ensure such transparency at the open
public hearing
session of the Advisory Committee
meeting, FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, FDA encourages you, the
open public hearing speaker, at the
beginning of
your written or oral statement to advise
the
committee of any financial relationship
that you
may have with a sponsor, its product,
or, if known,
its direct competitors. For example, this
financial information may include the sponsor's
payment of your travel, lodging, or
other expenses
in connection with your attendance at
the meeting.
126
Likewise, FDA encourages you at the
beginning of your statement to advise
the committee
if you do not have any such financial
relationships. If you choose not to address this
issue of financial relationships at the
beginning
of your statement, it will not preclude you from
speaking.
At this point, there are two individuals
that have requested time to speak, and
since Vera
Sharav
had requested it officially prior to the
meeting, I think we will allow her the
first
position.
You can speak from the podium, so you can
see us, and we can see you.
Vera Sharav
MS. SHARAV: I am Vera Sharav and
I am
President
of the Alliance for Human Research
Protection, an organization that focuses precisely
on ethical research issues and recently,
in
particular, on ethics of using children
in
non-therapeutic experiments.
Having listened to some of the
127
presentations as far as the scientific
issues, I
think part of what I was going to
comment is right
flat-out there.
There is a fundamental flaw with these
neuroimaging experiments including this
one, and
that is, that the children diagnosed
with ADHD for
the most part have already been exposed
to drug.
Those
drugs, dextroamphetamine, Ritalin, whichever
one they use, does, in fact, alter the
brain, and
there is no quarrel with that, there is
no
argument.
How can you then do a scientifically valid
experiment in which you are comparing
the brains of
children who have never been exposed to drug and
those who have and then claim to find
some
differences that you could be sure of
are not drug
related?
I think the fact that this hasn't been
done, or if it has been done, it hasn't
been
published, we ask why. Wouldn't it be simple to,
first of all, establish, in fact, what
the brains
of normal children are like and do the
ADHD differ?
128
Now, as far as this experiment, this
experiment would expose healthy,
primarily
disadvantaged children, let's face it,
with the
amount of payment, to a brain-altering
substance
for no benefit to that child.
Now, this is a clear-cut affront to the
moral standards of the Nuremberg Code,
the
Declaration of Helsinki, and the 1983 Federal
Protections that were established precisely to
protect children from experiments such
as this.
Dextroamphetamine, I want to remind you,
is a DEA Schedule II drug. It is a controlled
substance, which means it is
addictive. Now, Dean
Nadler of
UCLA has done extensive work to show
that, indeed, Ritalin is addictive and
leads to
addiction.
The proposed experiment fails to meet the
fundamental principles of the Belmont
Report -
respect for persons, beneficence, and
justice,
which are the very basis for 45 CFR 46.
Why are we even considering using children
as human guinea pigs in such an
experiment? But we
129
are.
The Advisory Panel would be derelict in
its responsibility if it did not study
carefully
the landmark 2001 Maryland Court of
Appeals
Decision,
Higgins v. Kennedy Kreiger, which
resolutely affirmed the Nuremberg Code
and
prohibited using children in
non-therapeutic
experiments if there is any but a
minimal risk.
The Court stated: "It is
not in the best
interest of any healthy child to be
placed in a
non-therapeutic research environment
which might
possibly be, or which proves to be, hazardous to
the health of the child in order to test
methods
that may ultimately benefit all
children."
The proposed experiment is a giant step
backward. It was immoral when Dr. Rapoport
conducted it in 1978, and it is immoral
today.
Changing
the scanning equipment does not change the
immorality of the experiment.
By what ethical standard is it acceptable
for anyone to entice a child and parents
with a
$570 stipend to become an experimental
human guinea
130
pig?
But then whose children are we considering
here?
If this experiment goes forth, the lessons
to disadvantaged children will be to
earn money,
sign up for drug experiments,
amphetamine today,
cocaine tomorrow, Ecstasy next
month. There are
always researchers looking for subjects
in
experiments, such as this.
Should children be the first on whom this
is done? Again, I refer to the Maryland
Court,
which is the highest court in
Maryland. It
declared: "To turn over human and legal ethical
concerns solely to the scientific
community is to
risk embarking on slippery slopes that
all too
often in the past, here and elsewhere,
have
resulted in practices we or any
community should be
ever unwilling to accept."
In effect, the Court declared quite
clearly that American society does not
consider
children the equivalent of rats,
hamsters, monkeys,
and the like.
The Alliance for Human
Research Protection
131
urges that the research involving
children should
apply the Maryland Court standard, and
not what we
have been hearing today. It is very easy to find
excuses to use children, but how will
you feel
should something go awry, as in research
it very
well might. There are not guarantees.
Thank you.
DR. NELSON: Thank you.
The next speaker is Alan Milstein.
Alan.
Alan Milstein
MR. MILSTEIN: Good morning. As to a
conflict of interest, I am an
attorney. I
represent victims of clinical
trials. I also
represent a number of mothers of kids
with ADHD,
alleged ADHD. So, if you see it
as a conflict, so
be it I guess.
Let's look at the three principles of the
Belmont
Report. The first is justice, which has
to
do with the selection criteria. Now, when you are
offering $570, you know that is an admission that
you are, in essence, going to pay
people, in
132
essence, to rent their children. You are going to
induce those who need the money to
volunteer their
children for this experiment.
It's just you can't use money as the
inducement. Now, I know that Dr.
Rapoport seemed to
imply that somehow that was just added
in, and we
don't need the money, so let's assume
for the
moment that you eliminate the money at
all, because
really, the only reason to participate
in the
experiment is altruism.
The second principle of the Belmont Report
is beneficence. This has to do with weighing the
risks against the benefits, and there
are no
benefits at all to the subjects.
What are the risks? Now, it was
unclear
to me exactly how she was analogizing
the single
dose. I mean she was
saying, well, gee, these kids
in these schools drink a lot of
sodas. I asked one
of the individuals involved about how
many cups of
coffee would the single dose be. I think he said
four to five, is that right?
I mean would you do the
experiment, would
133
you do an experiment where you give
healthy child
five cups of coffee? Would you do an experiment
where you give a healthy child a single
dose of
cocaine?
What about the other risks? The
only
risks that were talked about by the
principal
investigator was the risk of a single
dose of this
amphetamine. Now, she is saying it is minimal
risk.
I personally don't buy that, but there are
other risks, there are the emotional
trauma that
the children will go through, both from
going
through the MRI and also let's look at
what is this
study really saying to the kid with alleged ADHD.
We are going to put you through this MRI.
Why? Because you have a brain disorder. Is that
an emotional scar that the child, who is
the
subject in the experiment is going to
bear,
particularly an 8-year-old? Here, come into our
lab, 8-year-old, you have ADHD. You have a brain
disorder, and now we are going to put
you through
this big MRI to see if we can find it.
This is not an experiment with
minimal
134
risks, and when you weigh the risks
against the
benefits, the benefits are zero. There is no way
you can come up with any kind of equivalency. I
mean do you think you could do this
experiment with
no informed consent?
Because, you know, you can do an
experiment with no risk at all without
informed
consent and get away without informed
consent
because there is no risk. Do you think in any way
in the world you could do this
experiment without
informed consent? Of course not. There is risk to
the experiment, both to single dosing
these kids--I
mean you could have a very rare
anomalous response
to the single dose by one kid.
What is going to happen if one of the
children, whether you are talking about
the ADHD
kids alleged, the ADHD kids, or the
healthy kids,
what will happen if one of these
subjects has an
extreme reaction to the single dose?
I mean there are extreme reactions to
single doses of Paxil and Wellbutrin,
and certainly
cocaine. What will happen if you have that kind of
135
extreme reaction?
The third principle of the Belmont Report
is respect for persons. This has to do with the
informed consent process. Now, I disagree with the
way Skip was showing the CFR with
respect to what
the requirements are for informed
consent when you
are talking about children, because
there is a
difference between a therapeutic study
and a
non-therapeutic study when you are
talking about
can you allow a parent to give surrogate
consent
for a child.
That is the issue here - can a parent give
surrogate consent for a child in a
non-therapeutic
study where the child is going to
receive no
benefit, which is different than asking
the parent
whether he or she will give consent for
the child
in a therapeutic study, such as a cancer
study or
some child disease study where there
could be a
perceived benefit for the child.
It is my view that there can be no
surrogate consent in that
situation. Why not?
Because the only reason to agree to be
in a
136
non-therapeutic study is altruism. That is the
only reason to do it. That is a moral choice that
an individual will make for the benefit
of society.
No parent
can make that moral choice for the child.
It is not
the parents' choice. It's the
individual's choice.
That is what respect for persons means, it
is individual autonomy, whether you are
talking
about a child at the age of 8, or you
are talking
about somebody with Alzheimer's who
can't make that
kind of choice for him or herself. Nobody can make
that moral choice for another person
that you
should do this altruistic deed for the
good of
society.
So, it is my view that this study offends
all three principles of the Belmont
Report.
Let me talk just briefly about this,
because the assumption, and if you read
through
that whole protocol and the informed
consent
document, the assumption is that there
is--because
there is nothing in there about the
controversy
about ADHD--the assumption in all those
documents
137
is that this is a real disease, it's a
disorder.
What is this ADHD? It's 3 to 5
million
kids in this country are diagnosed as
having ADHD.
That is
about 5 percent of the children in this
country. That compares to 0.03 percent in England.
Is this a
disease that only American have? It is
a
disease diagnosed 80 percent in boys in
this
country. Is it a disease that only boys have?
I mean anybody who has taken these, you
know, the Conners test, or the DSM-IV test,
I mean
I have
taken it, I fail every time. I had what
my
grandmother used to call Sphilkes when I
was a
child, I still have it. That doesn't mean I am
ADHD. Why? Because anybody who sat through the
morning session, if I were to quiz
everyone when
you sat through the morning session, did
you lose
your focus occasionally? Did you mind wander
occasionally? Of course. Does it mean you are
ADHD?
It is also a white, suburban,
upper-middle-class or middle-class
disease, because
those are the individuals diagnosed with
ADHD.
138
I was struck by another line in the
materials under Conflicts of Interest,
which is a
subject that it means a great deal to
me, because I
was involved in the Gelsinger case,
which really
brought to light this problem of
conflicts of
interest, and the researcher said none.
Now, just because it's
government
researchers does not mean there are no
conflicts of
interest.
The study of ADHD is rife with conflicts
of interest. I mean this is a disorder that many
people believe was manufactured by the
psychiatrists or the drug companies, or
at least if
not manufactured, mythologized to the
point that so
many individuals in this country, so
many kids are
diagnosed with ADHD and prescribed these
drugs.
So, to just blindly say there are no
conflicts of interest, I think reflects
a
misunderstanding of what we mean by
conflicts of
interest.
So, in short, I would strongly advise that
this study not be approved.
139
Thank you.
DR. NELSON: Thank you, Alan.
Let me ask if there is anyone who is
attending this session who has not
expressed so far
a desire to speak publicly, if there is
anyone who
would want to at this point provided you
have lost
your focus?
[No response.]
DR. NELSON: Okay. What I would suggest
we do right now is perhaps present the
questions
and get that done at this point, and
then we can
start with our continued discussion of
the issues.
Questions and Panel Discussion
DR. NELSON: The questions for
the panel
are four. Let me just read them and then
provide a
couple of overall comments.
First, what are the potential benefits of
the research, if any, to the subjects
and to
children in general?
Second, what are the types and degrees
of
risk that this research presents to the
subjects?
Third, are the risks to the
subjects
140
reasonable in relation to the
anticipated benefits,
and is the research likely to result in
generalizable knowledge about the
subject's
disorder or condition?
Fourth, does the research present a
reasonable opportunity to further the
understanding, prevention, or
alleviation of a
serious problem affecting the health or
welfare of
children?
Now, those are the questions, and there
may be other questions by the end of the
day that
we need to come to a decision on as far
as the
regulatory burden of deciding can this
go forward
and under what conditions, under what
category, if
it may.
Procedurally, I would just suggest that we
sort of focus in three separate
steps. One is what
I would
call protocol related scientific issues and
continued discussion of those issues
that have been
raised.
After we get some clarity on that, moving
into discussions of risks and benefits,
and those
141
sorts of issues, and then at the end,
then consider
issues of assent and permission, and the
like.
All of our various recommendations, as I
think about trying to sort of chair an
IRB meeting,
and some of you have already done this,
and do it,
so there may be different styles, but I
generally
assume if someone brings up a
recommendation, that
if I don't hear anyone object, that that
is
something that can go forward.
So, I think it is important if someone
says I think this should happen, if
someone
disagrees, to make that clear, so we can
then have
that as an explicit discussion, because
if all of
us just simply start saying, well, we
agree with
this, we agree with that, we agree with
this, we
are going to be here a long time.
The other thing that I generally encourage
us to do is we are also, we are actually
not an IRB
although the issues we are addressing
are. I know
there is a fair amount of criticism that
has
already been labeled about the consent
documents
and the like.
142
I don't think we need to wordsmith.
I
think if we provide guidance in terms of
what needs
to be in those documents, that we can
rely I am
sure on the offices of both the FDA and
the OHRP to
make pretty well sure that they are
wordsmithed
independently of the IRB and the like,
so listing
what we think need to be in there is one
thing. I
don't think we need to get into the
specific
language per se unless there is
something such as
adverse events that need to be listed
particularly.
But I
would encourage us to try and minimize that
over time.
At the end of the day, hopefully, I will
be able to sort of summarize in a
complete fashion
exactly what we have decided and what
our terms
are.
So, with that, we basically, and we will
eat lunch at some point in this, as
well, let's
just open it up.
There has been some important
scientific
questions that have been asked, and I
often like to
start in IRB meeting at least by turning
to the
143
people on the committee that are not
involved in
the protocol, and so are not at least
directly
conflicted as investigators to get their
sort of
independent assessment of some of those
issues.
I think, Dr. Greenhill, you had raised the
issue of chronicity of treatment and the
issue of
cause and effect, and how one can tease
apart, if
you see a change at age of 12, they have
been on
drugs since the age of 6, what is drug,
what is
brain.
It may be helpful to me to sort of
hear
the scientific experts sort of first
give their
overall assessment and picture of this,
and then we
can see what direction we head at that
point.
Do you want to comment first, Dr.
Greenhill?
DR. GREENHILL: Yes. I had raised the
question about exposure, different
levels of
exposure. It doesn't preclude recruiting a wide
range of individuals as long as one has
a way, some
form or another, to be able to use it as part of
the analysis of the results, and to get
some
144
documentation, if possible, of exposure.
I just wanted to raise the question to the
investigators to see if they had thought
of that as
covariate in the analyses. I think it is probably
going to be difficult to find
stimulant-naive
individuals in the ADHD groups.
Clearly, they will be able to find them in
the groups that they believe with no
mental
disorder. So, it is important to be able to
determine whether the effects they see
have to do,
not in terms of performance, have to do
with
exposure.
I didn't have anything more to comment
other than that. It would be helpful in the
protocol summary form to be able to
address that
fact.
DR. NELSON: Do you think that
effect
would be a duration of exposure or just
the
presence or absence of exposure, and if
it's
duration, how would you be able to tease
that apart
with an N of 14 in either arm?
DR. GREENHILL: It is very hard to know.
145
We found
that one of the primary covariates when we
did the MTA study in terms of the dose,
that the
child ended up on, as his or her optimal
dose, in
terms of clinical response, and about a
third of
the subjects were 7-year-olds, 7- to
9-year-olds,
had had previous exposure to
psychostimulants.
Those are the individuals that ended up on
the highest doses in order to get a
response. So,
it appeared to affect in the sample
about 288
children. The dose that I have heard Dr. Rapoport
looking for, she would hate to put
someone in the
study and have them be outside of their
response
range, then, as a Type 2 error, conclude
there were
no differences between the groups,
because they had
used the wrong dose.
So, it is helpful to have at least some
indication of whether the individual was
on
medication before and what the dose
level was. You
can make some adjustments in terms of if
they
weren't on dextroamphetamine, what the
equivalent
dose would be.
That said, I just want to
mention that in
146
terms of this protocol, this is an
extension of a
protocol that was done 25 years ago
almost, and was
one of the most important protocols to
come along
in the field of children's mental
disorders for a
variety of reasons.
I think it was kind of a classic study
took a bold step and included
individuals with no
mental disorder, when this field had
really
struggled with that. A number of surrogates had
been used, and the studies gave no meaningful
results. One study used kids with reading
disability versus those with ADHD, and
was really
unable to draw any conclusions about
whether there
was a paradoxical response or not.
When Dr. Rapoport carried out this study,
it helped the field immensely because
doctors are
no longer able to give the medication as
a
diagnostic test because clearly, the
responses were
the same in individuals with no mental
disorder,
and that was very, very helpful.
I see this as another step in the advance
of science to be able to use the model
of comparing
147
individuals without the disorder to those with the
disorder using the most advanced kind of
techniques
that among the techniques available to
study brain
function has actually low rates of risk
and
techniques that are used across the age
range
routinely in medical situations, such as
the MRI.
I think it has very high scientific merit,
and in terms of single dose of
dextroamphetamine,
among the doses that are prescribed by
physicians
in the community, although I agree it is classified
as a Schedule II, it is safer than many
of the
other medications that are used in
practice.
Just if you talk about toxicity and
lethality, common drugs like aspirin are
far more
lethal, and you can give a single dose
of aspirin
that will remove someone's hearing or
cause massive
hemorrhage. You can't do that with
dextroamphetamine, and aspirin is
across-the-counter medication.
I am not saying that
dextroamphetamine is
benign. It is just that we are talking
about a
small single dose, and it is not
comparable to
148
cocaine, it is not comparable to
Ecstasy, it is not
comparable to heroin, it is not
comparable to
giving someone cyanide.
I mean the terms that we are throwing
around and drugs that were being
compared are so
different that it is hard to know how to
even talk
about them in the same sentence.
Dextroamphetamine is the medication used
in the treatment of ADHD that has the
longest track
record.
It goes back to 1937. There is
far more
data on its safety and efficacy in terms
of
duration, across time, and in terms of
long-term
side effects than we have with just
about any other
medication used in the treatment of
mental
disorders for children.
Dr. Rapoport is using a dose that is a
lower end, not the bottom dose, but the
lower end
of the efficacy scale. The approved FDA range for
that drug, for it full, total-day
dosing, is 40
milligrams. That is the top dose. The lowest dose
is 5 milligrams. It is approved down to age 3. It
is one of the only psychoactive drugs,
it is the
149
only psychostimulant that is approved
below age 6.
So, the range of safety is
greater than
that of psychostimulants or other
medications used
for ADHD, and so comparatively, within
the range of
treatments, it is a safe treatment, a
single dose,
and there are lots protections offered
in the
protocol.
My only urging on the part of the consent
and assent forms is I feel a lot more
descriptive
material needs to be provided to
families, so they
can get their worries and concerns
addressed
upfront about growth, addiction
sensitization,
weight loss, need for special diets,
difficulties
with sleep, impact on academic
performance, all
that can be put in.
Secondly, I really urge the consent form
and the investigators to think of
possible
benefits. I agree with everything that has been
said.
This study offers no specific benefit to the
children who have no mental
disorder. It will be
really stretching a point to say a
single dose
would offer any benefit to someone with
ADHD,
150
however, there are assessment procedures
which
could be beneficial to any of the
children in the
study, that are being done already.
It requires some work on the part of the
investigator to put them in the form of
a report.
DR. NELSON: Let me keep this on
the
protocol for a second and let me ask you
a
follow-up on that dosing question, and
then go to
Norm, who
I think had some questions.
This issue of the dose and the chronicity.
Your
comment about the longer they were on the
stimulant, the higher the dose, they
needed to get
a dose response clinically, could one
perhaps try
and get some uniformity among the ADHD
group by
making, as an entrance criteria, the
dose that they
may be one, for example, that they would
only
enroll subjects that were on, for clinical
purposes, 10, 15, 20 milligrams,
whatever would be
appropriate, instead of across the whole
range of
stimulant use.
Would you, by doing that, (a) could you do
that, or would the older ones always be
on the
151
higher dose, and (b), would that result
in a more
uniform sort of population that you
could begin to
at least make comparisons across groups
instead of
having a wide variability within group?
DR. FOST: Why not limit it to
treatment-naive patients? I mean it is a common
diagnosis. How hard would it be to recruit the
study to treatment-naive patients if you
think this
is a serious design issue?
DR. GREENHILL: Maybe I can
address that.
Going
back to a study that was designed a long time
ago, 12 years ago, the MTA study, the
decision was
made--this was a study that was supposed
to answer
a lot of questions about the comparative
efficacy
of psychological versus medical
treatments--the
conscious decision was made to pick a
young age
group, not an older age group, because
the
presentation of the symptoms of this
disorder
changes with age.
Younger children have more motor
disruptive kinds of problems, older
children have
more academic performance and judgment
kinds of
152
problems. We found also that we had a higher rate
of children who had not been treated
with
stimulants if we picked a younger age
group.
The younger the age group, the more the
dopamine system is in development, and
the narrower
and younger the age range, the more the
developmental issues are not confounding
the
responses.
So, if I were designing this, and I had
carte blanche, I would go for a group of
children
who were 7 to 9 years old, and I could
take just
stimulant-naive kids in that case,
because there
would be a number of them that wouldn't.
If I were going for an older age range, on
our IRB, we would look for individuals
who had some
difficulty with treatments, and
therefore, had not
been exposed to a lot of stimulant
treatment, but
then again you run to the confound that
if you take
that group and give them stimulants, then, you may
get all kinds of unpredictable
responses.
So, I think it is best to go with a group
that is relatively stimulant-naive and
younger, in
153
a narrow age range, deal with all the
developmental
issues, not only in terms of the
performance on
measures, but actually the state of the
dopamine
system.
Now, I have, as a conflict of
interest,
this is not a financial one, it is a
scientific
one, my area of interest is in
preschoolers,
because that is where the maximum amount
of
development in the dopamine system is
occurring,
and I have had to deal with a lot of
ethical issues
and studying children ages 3 1/2 to 5,
who have
attention deficit hyperactivity
disorder.
We have a mountain of developmental and
scientific issues, but that particular
group is an
early onset, so therefore, shows more
extreme,
severe kinds of problems with ADHD.
I am not recommending it for this study at
all, I am just saying that it led me to
study a
younger age group in order to deal with
these
problems of finding stimulant-naive,
because all
our children have to be stimulant-naive
to get into
our protocol.
154
But there is another reason that I think
an age range just at the start of
primary school is
important. That is the peak time for
identification of the disorder, between
second and
fourth grade. That is the time when the impairment
is the most, when the individuals are
showing the
most difficulties with their academics
and they are
getting the highest rate of peer
rejection for the
disorder.
Peer rejection is one of the most
predictive factors in the younger child
for later
disability. It is far more predictive, for
example, than IQ, for low self-esteem
and problems
in adolescence, you know, as a test, and
that has
been found in the fast track study and a
number of
other studies that have looked at kids
with
disabilities.
So, because peer rejection is the greatest
because academic difficulties are the
greatest,
that is actually the modal age of
referral over the
past 10 years for kids with ADHD. That is the
prime time to focus one's efforts if you
are going
155
to compare performance differences and
other
differences between kids with no mental
disorder
and kids with ADHD, and it is also a
time when the
dopamine system is in its most rapid
form of change
and development.
So, for that reason, I think they would
have the best yield in terms of brain
differences
on functional MRI, and those would be
the kids most
in need.
Now, of course, you have got to balance
against that, this feeling that an
assent really
can't be done. At our IRB, it is 8 years of age
kind of roughly as a working rule. Below 7 or 8,
you can't really get an assent form.
But we have had to work out assent
procedures for 3- and 4-year-olds, and
that is a
requirement we put in our forms that have
to do
with a child's ability to be able to say
no during
a research protocol, and we don't take
kids in of 3
or 4, or 5 or 6 who the parents and we
don't
believe can really object if they are in
a
procedure and say no, I don't want to do
this.
156
So, that is another form of assent.
It is
not written. So, for all of those reasons, I think
the protocol, some of the issues scientifically,
we
are only talking about the science, some
of the
confounds could be avoided if they
picked a narrow
range toward the younger end, not below
the age
that most pediatricians start treatment,
and if you
start at age 7, you have got good data
meeting all
the DSM-IV requirements.
One of them is duration of 6 months and
onset of impairment before age 7. In that way, you
could get more stimulant-naive
kids. You wouldn't
have such a difficulty with feasibility, and I
think it might address some of these
other
questions.
DR. NELSON: Let me see if I can
keep us
focused on that point, but just to make
a comment
in case people think we are off our
mark. I mean
the first thing we need to decide if
this is sound
research design, and if it's not, then,
issues of
vital importance and reasonable
opportunities sort
of fall by the wayside. So, let's stay on this
157
question.
What I hear you saying is that, yes,
focusing in the younger age group,
because that
came up in the discussion earlier with
the
investigators, and then perhaps trying to narrow
that range either to treatment-naive or
at least
early treatment or treatment predictable
sort of
uniformity within that population would
help the
science.
Are there other people who want to comment
on that particular point?
DR. WHITE: The longitudinal
studies of
ADHD have
been in structural imaging studies, and
the functional imagine studies look a
little bit
different in the sense that you are
looking at
change.
So, what would be helpful to see is when
the ADHD subjects are off medications,
what are
their symptom patterns at that time, and
then how
do they change when they are on
medication.
So, the chronicity of I guess being on
medication with the functional study is
different
158
than with the structural imaging
study. We are
looking at changes in gray matter, white
matter,
CSF, and
that.
DR. NELSON: The protocol has
them off for
36 hours before they get, is that a
sufficient time
to be off, or are you talking about off
for a
longer period of time in terms of effect of being
off?
DR. WHITE: It should be long
enough, it
would be helpful to get rating scales,
and which I
think they are doing when they are off
medication.
It would be
nice to know how they were doing in a
setting, such as a school setting, so
ratings at
that period.
DR. NELSON: Dr. Hughes.
DR. HUGHES: As we talk about the
scientific merit of the study, I think it
is
important that we differentiate, well,
as we have
had this discussion, one of the thoughts
I have had
is that hopefully, over time, there will
be a
series of studies that begin to look at
this issue,
that this is not the end-all and be-all
study that
159
needs to answer all questions.
I am a bit concerned at some of our
comments that that is where we may be
going. In
some ways, it makes sense to me that if, indeed,
this study moves forward and a finding
is that
there is difference between those normal
healthy
children and children with ADHD, then,
you begin to
ask, okay, what is that difference
about.
Is it because they have been on medication
for a period of time, is it important,
then, as a
next step, to look at naive
children. I am not
saying necessarily that that is what we
should talk
about, but I think it is so important
that we not
think of this study as the only shot at
examining
this or moving forward.
These are issues that I think a number of
the things brought up today, that it may
well take
a
series of studies to really fine-tune and move
forward. And that is different than the scientific
merit of what is proposed today, and I
just would
like us to be careful about
differentiating those
two.
160
DR. NELSON: A quick follow-up
and then
Norm. With that approach, what
would be the first
study that you would do, and is this it?
DR. WHITE: Well, given that we
are not
yet sure that there is a difference
between healthy
kids and kids with ADHD in this area, I
think the
more we restrict the subject population,
while it
makes for a cleaner and tighter research
protocol,
it also--it is the difference between,
well, it
services research, the difference in my
mind
between efficacy and effectiveness, that
while the
research protocol gets tighter and
tighter, its
actual meaning in the real world gets
narrower and
narrower.
Does that make sense to people?
DR. NELSON: In other words, even
if they
needed a more narrow range to be able to
see some
significant differences, that it would
still be
useful as a pilot maybe to see
differences in the
broader range is what I hear you
saying. That
would help you then interpret and design
subsequent
studies.
161
DR. WHITE: Yes, that's right. Thank
you.
DR. NELSON: Let me go to Norm.
DR. FOST: I just want to sure I
understood Dr. White's comments. I thought I
understood Dr. Greenhill to say that
prior dosing
could be a confounding variable, and did
I
understand you to say that you disagree
with that,
that you think that being off 36 hours
erases that?
I am just
trying to understand if that is a
critical design issue or not.
DR. WHITE: Actually, what I was
saying
was that the changes in the brain that
have been
reported have been structural brain
changes, and
there is I think a lot of questions that
we don't
know, and that I would say as far as
when you are
looking at functional brain changes, the
most
important thing is what is the change
from their
baseline off and on medication, and if
those
changes occur, significant changes, if
they are
symptomatic with ADHD off medication,
they have all
the symptoms, and you treat them with
medication,
and you are looking at changes in
essentially blood
162
flow within specific regions of the
brain, that is
the question that you are addressing.
DR. FOST: So you are not
terribly
concerned about the confounding of prior
doses?
DR. WHITE: I am not. It would be very
nice to have naive subjects, but the
again you are
asking a question that might be a little
bit
different and less generalizable.
DR. NELSON: Dr. Gorman.
DR. GORMAN: Again, this is a
procedural
issue that I will defer to the Chair,
but at an IRB
I sit on,
we generally don't discuss potential
protocol changes until we discuss
whether we feel
the present protocol is acceptable.
So, while I have found a lot of this
information learned and has certainly increased my
appreciation for some of the
difficulties in
performing this science, it still hasn't
addressed
for me the question of whether the
present protocol
will be able to get over the hurdles
that we have
assigned for it.
So, the question to me is that
we are not
163
in the position to suggest changes or
seems
procedurally, we should discuss the
protocol as
presented and then discuss ways we would
try to
improve it if we find it unacceptable in
its
present form.
DR. NELSON: Why don't you speak
directly
to that point, then, if you want to?
DR. GORMAN: With the permission
of the
Chair.
DR. NELSON: You don't have to be
quite so
formal.
DR. GORMAN: In this group
sometimes that
is an advantage.
I have appreciated that there was a
short-circuiting of the discussion at
the IRB level
in terms of their discussion in detail
of the
informed consent, and that has sort of
placated my
concerns about the deficiencies in some
required
elements that were not in the informed consent.
However, that did not placate my concern
about the protocol as written, which had
discrepancies and errors present in
it. It has
164
been over one year since that IRB
review. I would
have assumed that those difficulties
that were
exposed or discussed or illuminated
during that
discussion would have resulted in a
protocol
amendment, which would have been
included in the
protocol, so that when we reviewed the
protocol, it
would have been in a form that was close
to what we
are actually going to approve if this
was an IRB.
I found the plasticity of this protocol at
this late state somewhat
disturbing. The fact that
the dose could change, the age range of
patients to
be included in the study could change,
the allowed
dosing would change, the
inclusion/exclusion
criteria would change, all of which was discussed
by the principal investigator at the
podium, which
makes me look at the protocol that I am
looking as
still a work-in-progress rather than
something that
is ready for review.
DR. NELSON: Norm.
DR. FOST: But, Rich, I mean I
agree with
much of what you said, but suppose these
areas were
cleaned up, that is, the consent form
were adequate
165
by your measure or anybody else's, do
you think the
basic issue of doing the study as
designed, giving
the healthy and affected kid this dose,
with these
MRIs, and
so on, is approvable given a coherent
protocol with all the ambiguities about dose, and
so on, clarified, and an adequate--
DR. GORMAN: Norm, that is
exactly the
question that I am asking, which is if I
had the
clarified protocol, I would be then willing
to
answer that question, but not knowing at
this point
what the cutoff dosage for the dosing
will be, what
the age range of the subjects will be, I
am not
ready to answer that question.
DR. NELSON: Let me hop in here,
Norm. My
sense is given that your comments--and I
have heard
a lot of similar comments--is that there
is no
question that we would say whether it is
under any
one of these four categories, that this
could be
approved with no modifications.
So, I think that is fairly easy to
probably get off the table at this
point. So,
then, the question becomes is it
possible for us,
166
as this group here, to make
recommendations about
what modifications we think would be
necessary in
order for it to be approvable under any
one of
those four categories.
Now, if this was an IRB, which we are not,
there would be a discussion as to
whether we should
to the investigators' work for them or
just send it
back for more work, and wait to do that
later.
Now, I wouldn't recommend we do that here
precisely because we are a different
body, but we
need to provide the guidance that would
allow that
to happen, and partly because, you know,
we don't
have another meeting next week or next
month
scheduled as you would on an IRB.
So, my sense is we are in a
position where
we need to say what is it that we think
would need
to happen with this, whether it's
protocol
differences, whether it's consent
differences,
whatever differences those are, once we
get to a
discussion of the categories and the
risks, may or
may not approve it under those four
categories.
Then, we need to specifically
address what
167
got it here, which is the
dextroamphetamine for the
healthy children absent a condition and
what the
risk classification ought to be for
that.
But I am assuming for the sake of
discussion that we are going to have to
specify all
the modifications that we think would be
required
for us to even engage in that
conversation.
Is that fair? Norm.
DR. FOST: First, I agree with
what you
say, I just want to add to it. This is not an IRB.
If it
were an IRB, we would defer this, but send
the investigator a message that we think
this--if
we are rejecting it, then, it is not
deferred--but
what we would probably do is say we
think the basic
idea here is approvable, if there were
agreement
about that, but there is a lot of
problems you need
to clarify, A, B, C, through X. Send it back and
then we will reconsider it, but it is
approvable is
the word we would use if it were tidied
up, but the
core substantive ethical issue that we
are raising
here, of exposing these children to this
drug, in
this dose, and this MRI, we think it is
basically
168
okay.
So, I will just state my view, I think
that core thing is okay, I actually
think it is
okay under 406. I think it's a minor increment
over minimal. We may not get agreement, unanimity
about that, we may not get any other
votes on that,
but under 407, with the criteria that
you outlined
earlier, I think that's approvable.
That said, I think it's regrettable that
there is so much ambiguity and
sloppiness, if you
will, about some of it, but that is
correctable,
and I think if those things were
corrected and came
back to the IRB, I don't think this
committee is in
a position to re-meet, and I don't think
it needs
to.
It is a little troubling because the IRB
didn't seem to pick up on any of these
things
either, and that is what some of us are
concerned
about, but if this group specified that
on the core
substantive issue, which I think is what
we are
really here for, and not to micromanage
the consent
process, with side comments that we
think A through
169
M really
need to be tidied up, my position is that
it is approvable under either 406 or
407.
I just want to say that is a shortcut of a
lot of complicated, controversial
discussion. I
think Alan Milstein raised a lot of
really profound
points that all of us have been
worried--
DR. NELSON: I am anticipating
that we
will come back to that.
DR. FOST: --have been worried
about for
25 years, but this isn't a seminar
either, and we
don't have all day to talk about all
those and to
say what the responses are to the very
serious and
important issues.
DR. NELSON: I will ask you about
whether
healthy children have a condition under
406, but we
will go to Rick.
DR. KODISH: As Skip knows, I am
not fond
of thinking as categorically maybe as he
is in
terms of 406 versus 407, but would like
to try to
step back and take a bigger ethical look
at things.
My sense is that I would agree with Norm
that this is approvable. I think that is a good
170
word to use, and we can maybe defer the
categorization later.
The thing that I want to bring to the
table is the issue of money, and I think
that is a
significant ethical issue here, and I
guess it
strikes me as more approvable if it was
possible to
eliminate the money completely.
DR. FOST: That is my A through M.
DR. KODISH: i would put it at A,
to
follow up.
DR. NELSON: I think it important
to get
out some sort of basic starting point.
Dr. Hughes.
DR. HUGHES: I need some clarification
about the process of approval, so that I
can think
through this. My assumption is that when this
study went to the IRB, and there was a
focus on the
level of risk involved and a discomfort
with
approving it at that level, that all
other sort of
discussion got short-circuited, so there
was not an
opportunity then for an amendment. Is that not
true?
171
DR. FOST: No, I don't agree with
that.
DR. NELSON: Well, that is the
answer,
whether that should have been the
answer.
DR. FOST: I don't think that is
a valid
response.
DR. HUGHES: Okay.
That is what I need to
understand.
DR. FOST: Let me say with all
respect for
the IRB, I wouldn't want our IRB's
minutes to be
subject to this public hearing, because
the same
sort of criticisms could and would be
found, so I
am not being holier than thou. I am sure anybody
here could find similar problems with
ours.
But since we are here, and we are asked to
comment on it, and we want to be
thorough, I think
we are sort of obliged to comment.
The investigator should never have
submitted a protocol that didn't mention
that an
MRI is
going to be done, that doesn't mention to
these young girls the pregnancy
testing. Those are
just--I am no talking about style or
corrections--
those are gross omissions of substantive
issues.
172
Secondly, the IRB, in its initial review,
should have said--they wrote lengthy,
detailed
minutes, as Mary Faith said, they are
wonderful
minutes. They just don't even seem to notice that
these sort of major factors are left
out. They had
10 months to do that. There was no distraction by
a 407 process that would have precluded
them from
sending a letter back we have a major
407 problem
here, but in addition, there is about
nine other
things that you need to get back to us. It has
been a year.
So, I don't think the 407 process has
anything to do with the inadequacies in
the consent
form or the protocol, which has three
different
versions of the dose.
DR. HUGHES: Once the issue of
risk is
decided, then, does it go back to the
IRB for them
to finish work, or what is the next step
after
decisions are made here today?
DR. NELSON: Generally, what has
happened
in the past, since there have been some
of these
reviews conducted by a different process
since this
173
process didn't exist until now, is that
with those
sort of modifications and stipulations
that those
groups have specified as individual
consultants,
then, in this case, the OHRP, since
these were not
FDA
processes, put that all together and worked
with--if there was a recommendation, if
it was
approvable under one of the other
categories--worked with the local IRB
that referred
it and the investigator to clean up all
of these
details, and the same in the case of the
407, but
those, in fact, if you look at the OHRP
web site,
you will see I think five that had been
reviewed,
or four or five under that category.
So, I think it is important for us to say
this is what needs to be done, but I
don't think in
this case, as we would with an IRB who
we have our
own staff to do it, I think we can rely
on both the
OHRP and
the FDA to make sure it gets done. So,
that is why I think we need to deal
categorically.
That would be the process in this case,
but I think we do need to answer the big
question,
which ultimately gets back to whatever
changes, and
174
there may be some of us who say no
matter what they
do to this protocol, I don't think it's
approvable.
So, we need to answer that big question
because absent to that question, working
on the
sort of language of the assent or
consent form is
less important until we answer is it
approvable
under any circumstance, what might that
be, and is
it appropriate, and separating that out
and working
through those categories is what we need
to do.
It sounds like that might be a good time
to sort of break for lunch and then come
back and
actually do it.
DR. HUGHES: Thank you. That was very
helpful.
DR. NELSON: It is noon, or
actually it's
a little after noon.
Dianne Murphy has something to say before
we actually break for lunch.
DR. MURPHY: I just want to
really
re-emphasize what Skip just said, which
is the
first task is what we are calling the
core
question, and it has to do with the
normal aspects,
175
normal volunteers in this protocol.
We really need to do that, and by
referring--because we actually had a
number of
internal discussions about this very
issue--is that
when an IRB refers these protocols,
then, you have
to look at them for all the reasons that
have been
discussed in their entirety, but we
really need to
focus on making sure we, in a way, if we
can, and I
understand there is a very deep, intense
integration of the science and the
overall ethical
issue, but as much as possible, can we
answer that
core question and then address the other
issues
that we have.
Thank you.
DR. NELSON: The meeting is
scheduled to
start at 1:00. I have been told we could start at
1:15 if wanted to, so why don't we do
that. If we
do, we might then just go through break
and see how
much discussion takes place.
I am told there is no specific room for
the panelists to meet. I think there is as buffet
downstairs, having been here in the
past, so moving
176
through that should be fairly
expeditious instead
of waiting for something special to be
cooked.
Hopefully, we can start right on time at
1:15.
Again, to remind people that any substantive
deliberations or discussions of the
protocol need
to be carried out publicly, so let's not
do our
work in private.
Thanks.
[Luncheon recess taken at
12:05 p.m.]
177
A F T E R N O O N P R O C E E D I N G S
[1:15 p.m.]
DR. NELSON: Begging of the
indulgence of
the panel, I would like to suggest a
process that I
think will, hopefully, get us to the key
questions
as quickly as possible, of course
allowing people
to say, if there are constraints around
what they
would decide, to state those constraints
at the
time.
What I am going to suggest is that we
basically, looking at the algorithm for
the risk
association within Subpart D, which is
Section Two,
basically run through the procedures
that are
within this protocol and, hopefully very
quickly,
identify what I anticipate will be the
one meriting
the most discussion but there may be a
few things
that we need to clean up on the way.
One way of doing that might be, from the
slides that Dr. Rapoport presented, she lists the
protocol procedures that are in there
and just for
me to very quickly go through that and
get a sense
of where people would put those
procedures with
178
respect to the risk of those procedures
and then,
ideally, at the end of what I hope would
be an
efficient but effective process,
identify that key
question that we then want to spend the
majority of
our time on which I anticipate is
dextroamphetamine
to a healthy child.
But I don't want to assume that that is
the case before going through it. So, as you see
on her slide--I guess it is the middle of
Page
3--there are a number of procedures that
are listed
there and there may be others the we
want to
highlight. History and physical examination; most
IRBs
would be comfortable with that being minimal
risk. There is the issue of pregnancy testing
and, given Mary Faith's discussion, I
think it
would be--I guess my question to her
would be
presuming that we add stipulations about
the
context of that testing and the assent
and consent
process and the confidentiality, et cetera, would
that be minimal risk.
DR. MARSHALL: As long as all of
the
procedural safeguards were there; yes.
179
DR. NELSON: And I might add--I have been
taking notes about what people have been
saying so
you can assume what you have said before
is, in
fact, in my notes.
Then there is the blood work.
Then the
specific issue of the genetic testing, although
that genetic testing is primarily for
the twins
which wouldn't happen unless they found
differences
in the two. So, I guess, specifically that issue
may merit some discussion.
Rick?
DR. KODISH: I am comfortable if
I hear
that it is only for the twins. I would
like a
little more specificity about what the
genetic
testing is.
DR. NELSON: Okay. Joan?
DR. CHESNEY: I think it was one of the
folk who wrote in who indicated some
concern with
the genetic testing. I don't think we got that
page so I don't remember the exact
details. We got
Bernall
and the other one. Do you recall that,
that one of your slides had that--I
think it was a
180
mother of twins.
DR. NELSON: The specific issue
of
parentage, I think, was raised but also
just
genetic testing. In terms of availability,
comments on that in terms of access to
those kinds
of details, the implications of genetic
testing.
People
are looking at me with blank stares.
Richard?
DR. GORMAN: We would like some
insurance
from the investigator and the NIH that
this data
will be--that the samples will be
destroyed or the
subjects will be informed that the
samples will be
retained if they are, in fact, to be
retained.
DR. NELSON: Are there any
specific risks
to the populations involved in this
study of that
testing, particularly the twins?
DR. FOST: It depends on what the
testing
is.
We don't know what the tests are.
If they are
testing them for APO-E; yes.
DR. GORMAN: If they are testing
to see if
they are monozygotic or--if they are
just deciding
what type of twin they are--
181
DR. NELSON: So if it is simply
limited to
that.
DR. GORMAN: And the samples are
destroyed, then I think I have little
difficulty.
If they
are looking for genes that predict ADD and
ADHD and
the samples will be stored for future
research, then I think that needs to be
explicitly
stated in both the protocol and in the
informed
consent.
DR. FOST: And whether results
will be
shared with--they can get it to minimal
risk or
even zero risk if they say it is just to
confirm
monozygocity or dizygocity and then they
will
destroy the samples. Then it would be zero risk.
DR. NELSON: Okay.
DR. FOST: If they are doing more
than
that, then one would need to know what
the "more"
is before deciding what the risk level
is.
DR. NELSON: Okay. Joan?
DR. CHESNEY: Can I just ask for
clarification about what this individual
wrote in?
"The genetic testing for the twins
is glossed over
182
where a decision to test twins regarding
their
zygotic status could have emotional
implications
for the parent and/or the
twins." I am not sure I
understood.
DR. NELSON: Is anyone aware if
you are
identical or not, that it makes a
difference in
emotional status of twins? It is not my particular
area.
Usually, it is pretty obvious.
DR. MARSHALL: Usually, it is
pretty
obvious.
DR. NELSON: Boy/girl; that would
be an
easy start.
DR. CHESNEY: I just raised it because it
didn't make sense--I didn't quite
understand it at
the time.
DR. NELSON: But it sounds like,
as a
group, that we would be willing, placing
this into
minimal risk, if it is limited to
zygocity and the
samples are destroyed. They haven't specified any
further than that.
DR. JACOBS: They have pretty
clearly what
tests they plan to do. On Page 12, at the bottom,
183
they say what alleles will be
tested. So I think
that is quite clear. I think what is not there
that people are alluding to is will they
do
anything else, in addition to those. But I think
they state pretty clearly what markers
they are
going to look at.
DR. FOST: But I don't know
enough to know
whether any of those alleles are
associated with
other disorders that might be stigmatizing
and
harmful. If that is all they are doing, and then
they discard the samples, I would call
it zero
risk.
DR. JACOBS: That is the problem;
yes.
DR. FOST: If they are going to
retain
them, or tell parents the results, then
it gets
complicated. I see APO-something. I
don't know
what APO means.
DR. NELSON: APO-B. So, where this
becomes and issue, I guess, is--I mean,
one can
specify it as an "if-then." If there is a concern
about possible stigmatization or
predictability of,
say, adult-onset diseases where you are
testing an
184
8-year-old on these particular alleles,
then that
would be a much different issue than if
it is
simply on other grounds determining
zygocity or
similarity.
DR. WHITE: They need to disclose
that.
Is that something--
DR. NELSON: That would need to
be part of
the consent and assent process.
DR. FOST: It is also part of the
protocol, though, Skip. If they are disclosing
results to parents or children in the
way that it
might be stigmatizing or confusing, then
it may
become more than minimal risk.
DR. NELSON: Right; it is not
minimal
risk.
DR. FOST: It is certainly not
something
that happens in a doctor's office where
you find
suddenly, "Oh; I'm APO-B," and
you don't know what
that means. So it is only minimal risk.
I mean,
we can only say today, with the
information we
have, that it is minimal risk if the
samples will
be used solely to determine zygocity and
then
185
discarded. That is the only circumstance under
which I could say that I know that it is
minimal
risk.
DR. NELSON: And that the
information
would not be provided or used in any
other way.
DR. FOST: Will not be
disclosed. It is
for the sole scientific question of
confirming
zygocity.
DR. NELSON: We can set those
boundaries
around this testing for the purpose of
stating that
because we lack any other information
right now.
DR. FOST: That way, the
Secretary, if he
wants to send a detailed--I don't know
how detailed
the Secretary's approval letter is, if
it contains
all these "ifs, ands or buts,"
and conditional
factors. But if it is a detailed letter, it can
say, "If this panel decides that
the thing is
approvable and the Secretary concurs and
the
committee concurs," then the letter could say that
we concluded that this study is
of--there are
several components to it, that each one,
we
determined that risk level was this,
minimal, more
186
than minimal, acceptable, if A, B.
C. I don't know
if this gets to that detail of the
letter or not.
DR. NELSON: It will.
DR. FOST: Okay. Then the IRB has the
information on which they can approve
the protocol.
They can
tell the investigator, "We approve this
conditional on your destroying the
samples."
DR. NELSON: With that, how about
if we
then move on. I am going to skip the next bullet
point to get back to it. But the risk of a
functional MRI--Dr. Greenhill?
DR. GREENHILL: I have a
question. I
guess I am challenged in consent reading
because,
try as I might, I can't find any reference
to blood
work or genetic testing. Is it in there?
DR. NELSON: No. The assumpution is that
we will get--there is a lot of work that
has to be
done on the consent and assent
forms. So I am
assuming, if we get to the end of day
and say,
"These are the conditions under which this could go
forward," that the next comment
would be, "And, in
fact, you need to make your documents
match this as
187
far as assent and consent.
DR. GREENHILL: Can I a make a
suggestion?
DR. NELSON: Sure.
DR. GREENHILL: I think it would
helpful
to the parents and to the kids to know
that, if
they are twins, they will be tested for
whether
they are identical or not. I haven't heard this
discussed, but as far as, if they want
to know, the
information is available, or not. My inclination
would be to offer it to them.
DR. NELSON: And allow them to
say yes or
no up front.
DR. GREENHILL: Yes; if they want
the
information or not.
DR. NELSON: Seems reasonable.
DR. GREENHILL: While we are at
it, risk
of bruising and infection for blood work
and also
how many cc's of blood put in
tablespoons or
teaspoons needs to be specified because
I don't
have a sense from the protocol how much
this takes.
If you
are drawing blood, why get a cheek swab?
You are likely to have--you could have a
lot of
188
samples that you can't use. If you are going to do
a blood test, I think it is wasteful--
DR. NELSON: I think we might be
getting a
little bit into micromanagement on that
point.
DR. GREENHILL: All right. It's just,
without the details, I can't tell what
they are
doing.
DR. NELSON: Right. It definitely needs
to be in the consent and assent.
DR. GREENHILL: Yes.
DR. NELSON: Joan?
DR. CHESNEY: I think, when you
say they
have the option of knowing, of knowing
what;
whether they are monozygotic or
dizygotic or
whether they are APO-B, QRST?
DR. NELSON: I just heard that as
zygocity
alone.
DR. GREENHILL: That's all I
heard; just
zygocity.
DR. NELSON: The
neuropsychological
testing; I guess I would defer to my
neuropsychological colleagues. Often that testing
189
could be seen as minimal risk depending
upon the
length of time and the like, appropriate
breaks, et
cetera.
Is there anything particular that needs to
be said more than that in terms of the
neuropsychological testing, it needs to
be
adequately revealed, in terms of the
parent-teaching ratings and those kinds
of things?
Is there
more to be said than that?
Joan?
DR. CHESNEY: Does that include
I.Q.
testing? When they were distinguishing who would
be in the controls and so on, they
stipulate the
I.Q.s. So, for a child who has
never had I.Q.
testing before, and that information
is--
DR. FOST: Once again, if it is
used only
for the scientific purpose and not
disclosed, I
would guess it is minimal risk.
DR. CHESNEY: Okay. That was my question.
If that
was not disclosed, then I agree.
DR. NELSON: But one could debate
that.
If, in
fact, they should--it is not clear to me why
you wouldn't want to give that
information back to
190
a parent.
DR. FOST: Because this is not a
clinical
service they are providing. It is research they
are doing. If they want to embark on doing
neuropsych testing for clinical
purposes, then they
should open a separate office and do
that.
The purpose of the neuropsych testing is
not to help parents learn whether their
kids are
retarded or not or have certain
dysfunctions. The
purpose is to standardize the scientific
results
and, therefore, it should be restricted
to that.
If they
want to do more than that, they are
straying from research and they are
getting into
complicated issues that we could spend
all night
talking about. But they can avoid all that
complexity by just sticking to doing it
for the
scientific purpose.
So, once again, I would say it is
approvable. The neuropsych testing is approvable
if it is used only for the
scientific purpose. If it is being used for
something else, then I don't know.
191
DR. NELSON: Dr. Hughes?
DR. HUGHES: This is an area I do
know
about as a clinical psychologist, and I would
concur that you would never want to give
parents
just an I.Q. score, that it really means
interpreting the results and really
taking time to
have a fuller assessment, of knowing
that child,
what their strengths and weaknesses are
and then
making recommendations about where to go
forward.
Just an I.Q. number is not useful and
could easily be misinterpreted. So I would agree.
DR. NELSON: Then that just leads
to a
follow-up question. One can then go one of two
directions; not use it in this way in
terms of
providing information back that is not
appropriately accompanied by counseling
and
interpretation or one could, in fact,
put in place
those kinds of services if you wanted to
provide
that feedback back to the families. So one could
go either direction.
Norm, are you concerned about the middle
ground, you give the score and you don't
do
192
anything, or if they went into the
full--you get
this testing; here, you can have it back
but we are
going to give it to you only if you have
it with
appropriate counseling, et cetera?
DR. FOST: I don't know what the
competence of these people is to that
kind of
counseling. I don't know who would do it.
It just
raises all these questions. If they want to get
this study done, they want to get it
approved by
this panel and by the Secretary and by the IRB, the
simplest way to do that is to limit the
results to
the scientific purpose.
DR. NELSON: Dr. Greenhill?
DR. GREENHILL: Just two
things. One, to
reiterate that, if you are going to
approve the
neuropsychological testing, that the
parents should
be alerted that it is being done and how
much time
the--what it will mean for a time period
in which
they cannot have testing again and have
it
acceptable to school boards. It is usually a year
to avoid practice effects for the I.Q.
test. They
should know that because it may or may
not be an
193
issue.
The second thing gets back to this whole
thing of the consent and SN forms. There is no
description, actually, if what exactly
they are
doing, where they are going, how many
days it
takes.
Is it going to be done during the school
day, after school? I know this is trivial stuff,
but, for parents to schedule, they have
to know how
many days of work to take off.
I have no sense of what the procedures
are.
Half the procedures are not even listed in
the consent form. So they have to know they are
going to spend so many hours sitting
doing pencil
tests and when the blood is drawn. It is the kind
of standard stuff that has almost become
boiler
plate or institution, but, without it,
it is very
hard for parents to know what they are
getting
into, or kids.
DR. NELSON: Let me just get a
sense of
people.
Norm's recommendation is the cleanest way
to do this is to just not provide the
data back.
DR. FOST: And to make that clear, that
194
it will not be provided.
DR. NELSON: I think we all would
agree
that is the cleanest way to do it. Is there at
least a minority view of that to be
expressed
because I heard some different views
during our
earlier discussion.
MS. TREAT: My question would be
what
would you do if the parents want to I.Q.
test back?
DR. FOST: You can't be in the
study.
MS. TREAT: My sense is that, if
the
parents know that you are doing I.Q.
testing,
several of them will want to know the
results of
it.
DR. FOST: Then they shouldn't
join the
study.
MS. TREAT: My other question is,
I guess,
for Dr. Greenhill. If the MRI precludes I.Q.
testing for a year, are there any
indications that
the MRI interferes with other tests that
are
regularly performed by, like, the school
systems,
like the reading tests and the tests
that are like
SATs?
195
DR. GREENHILL: It is not the MRI
that
precludes. It is just a requirement--every
psychologist I have talked to, they want
to have an
I.Q. test
done three months after the first one
because they feel the child is practiced
and will
get a higher score. It is not valid. It doesn't
harm the subject other than they have to
wait and
that may be a problem if a committee on
special ed
is meeting to try to place the child and
can't use
the I.Q. scores, and they want an
up-to-date one.
Of course, they won't be able to use the
NIMH I.Q.
score because I think our panel is going
to recommend that it not be given to the
parents.
DR. NELSON: It sounds like that is
emerging as a theme. On this point?
DR. GORMAN: On this point. I think it
also, by adopting Dr. Fost's
suggestions, we make
this protocol more clear to the parents
as we go to
the informed consent that this has no
benefit for
them, that this is a study that has
benefit for
society but no direct benefit for the
subjects.
DR. NELSON: Moving down this list, let me
196
skip the administration of the drug and
just talk
about the functional MRI. Given the description of
the process that we heard this morning,
in terms of
screening and training and the like that
goes on,
is it fair to say that this would fall
into minimal
risk under those circumstances?
DR. CHESNEY: I don't think it
was in
their protocol but one of the other
protocols where
they used functional MRI screening, they
talked
about using a dental plate to keep the
child in
place.
I didn't know if anybody could elaborate on
that.
They apparently take an impression of the
child's teeth and then put a brace on so
they don't
move.
Is that correct? That seemed a
little--
DR. NELSON: Invasive?
DR. CHESNEY: Pushing the
envelope, to me.
Yes;
invasive.
DR. WHITE: That is one technique
that is
used. Actually, it doesn't work as well in
children. It is frequently used in adults and I
know that, at the NIH, what they are
using now is a
vacuum-type apparatus that goes around
the head and
197
it fixates the head, because movement is
one of the
major difficulties. Probably with ADHD, it is even
more of an issue. Movement in the scanner will
render the data unusable.
DR. CHESNEY: Would you elaborate
on the
vacuum apparatus.
DR. FOST: It is like a
cushion. It is a
pillow.
You mean an inflatable--
DR. WHITE: No; it is a pillow
that has
small, little beads. They put a vacuum in it and
it just becomes firm but not painful.
DR. FOST: It is a cushion so
you can't
wiggle your head around.
DR. CHESNEY: So the vacuum is in
the
pillow not in the patient.
DR. WHITE:
Not in the patient.
DR. NELSON: Rick, you had a
comment?
DR. GORMAN: I do. In the protocol, it
mentioned that this is a 3-Tesla
coil. 3-Tesla
coils raise body temperatures with
prolonged
exposure. I would like
to be assured from the
protocol that there is a radiation
standard for
198
R.F. and
temperature raising, so how many
microwaves you can get and how much
sonogram energy
you can get for raising body
temperature. I would
like to be assured that this protocol
meets those
standards.
DR. NELSON: That is easy to do
because I
think those standards are posted on the
FDA
website, having looked for them before
for 3-Tesla
MRI
scans, having gone through this. But
they are
used clinically.
So, assuming that the mechanisms by which
these kids are trained are not an inappropriate
use
of restraints other than a firm pillow,
would it be
fair to say that this would be minimal
risk.
DR. FOST: I would just want to
remind
people what they said both in the
protocol and this
morning about the rehearsal session
which we use at
our place also which, I think, pretty
effectively
screens out kids who might be freaked
out by any of
this.
And that is why they use it. If
a kid turns
out to be anxious, they know about it
before they
are in the study, really. They know it in this
199
practice session where there is nothing
at stake.
So, given that, I think the psychosocial
risk of being in a scanner, given the
screening, is
really quite minimal. And they have some data to
support that.
DR. NELSON: What I would like to
do in
looking at this list is to leave the
discussion of
compensation or reimbursement or
inducement of
enticement for its own special
discussion and go
back, I think, directly to the risk of a
single
dose of dextroamphetamine and discuss
the risk. If
you look at the algorithm, discuss the
risk
separate from whether it is being given
to a child
with ADHD or being given to a child
without ADHD,
and then introduce that factor.
So I think that brings us precisely to the
point that brought this before us is the
giving of
that drug to a child without ADHD and,
of course,
in discussing those risks, there may
well be
different risks in the two different
populations
given that these are likely not to be
treatment-naive subjects.
200
So I guess, in looking at this algorithm,
there was a considerable discussion on
the IRB and
the IRB minutes about that being minimal
risk based
on its analogy to excessive caffeine
consumption,
whether that is five cups of coffee, a
six-pack of
Jolt
Cola, three Mountain Dews or other caffeinated
beverages.
So I think we need to sort of tackle
directly whether we think that that is
minimal risk
or more than minimal risk independent
of, then,
after it is more than minimal risk if we
don't
think it is minimal risk, what category
it goes in,
so, specifically, that assignment of
that drug
dose.
DR. GREENHILL: I would argue
that it is
more than minimal risk because it is not
a typical
expected event in a child's life who
isn't ADHD.
The
question is how much more than minimal risk are
we talking about. Is it a minor increment in
minimal risk or more than a minor
increment in
minimal risk?
I just have to disclose that I
have
201
treated many children with
dextroamphetamine. I
regard it as the safest of the
stimulants with the
most predictable effects that occur
within 15
minutes and are gone by about five
hours. There
are things to consider. If this study were, as in
the old days at NIH, only conducted in
the evening
because the MRIs were only available in
the
evening, I would have a very different
estimate of
risk than if it were conducted first
thing in the
morning.
I know that if you bring a child in at
9:00 p.m. and give him 10 milligrams of
dextroamphetamine, he will be up all
night. We
don't know what time these studies are
being done.
I am
assuming they are done in the daytime.
In the
daytime, I think it is a minor increment
over
minimal risk because I would have no
problem giving
any child in this age range that they
state a
starting dose of 10 milligrams.
In fact, more and more that is occurring
as the long duration preparations of the
amphetamines such as Adderall XR are
given. They
202
are given a single dose in the morning
anywhere
between 10 and 30 milligrams. Even though it is
delayed release, they are still getting
quite a
solid dose as their first dose and I
have seen no
problems with that.
So everyone is going to have a different
take on this but I think it is more than
minimal
risk but I think it is a minor increment
over
minimal risk based on many, many
children getting
these medications many of whom I
wouldn't say had
ADHD. The studies that are done
in North Carolina
by Adrian Engle showed that half the
sample of
individuals treated with stimulants in
their rural
community did not meet criteria for
ADHD. Their
main criteria was they were defiant and
they were
male.
They reported no differences in vital signs
or problems across the group.
So that would be my position. We
have to
indicate it is more than minimal risk
but I don't
think it is more than a minor increment
in minimal
risk which, I think, would fit 406.
DR. NELSON: That is the risk category.
203
Then we
have to get to condition. But let's
keep
the risk in play and see other comments
or views on
that risk category.
DR. FOST: Larry, or Dr. White,
what is
the worst thing that you think might
plausibly
happen to either a normal child or a
child with
ADHD from
this dose--not remotely conceivable but
plausibly, that you wouldn't be
surprised if it
happened, the worst thing?
DR. WHITE: The worst thing that
could
happen?
I guess the worst thing is, perhaps, they
become restless and some akasthisia.
DR. FOST: For about how long?
DR. WHITE: Three to four hours.
DR. FOST: Thank you.
DR. GREENHILL: And the worst
things I
have seen happened, particular in the
younger
children, are that they seem to have
more
irritability, restlessness. They get agitated and
they tantrum. That doesn't seem to relate so much
to dose. It is a first-dose effect that you might
see.
But it occurs in under 1-in-100 cases.
It is
204
infrequent to rare.
DR. FOST: Any sequelae from
these? A
week later, does this have any effect on
the child?
DR. GREENHILL: Once the drug
wears off,
which is usually four or five hours, I
don't see
any.
I don't even see troubled sleep that night.
DR. NELSON: Dr. Gorman?
DR. GORMAN: I am going to agree
with that
assessment of a minor increase over
minimal risk
but coming from a totally different
viewpoint. As
a former director of the Maryland Poison
Center, if
someone accidently ingested, a 9 to
18-year-old
accidently ingested, 10 milligrams of
dextroamphetamine, they would be
observed at home
and their parents would be told to call
if there
were symptoms.
So, seeing that this research will take
place in a controlled clinical trial, in
a
controlled setting where they will be
observed for
those symptoms, I would consider this
something
that we would not intervene to correct.
DR. NELSON: Let me specifically ask the
205
question that has been raised by other
comments and
that is, and particularly even in the
IRB minutes,
is the question of potential abuse,
uncovering
abuse, leading to abuse in the
future. Any data on
that?
Any sense that that is a risk?
It was
brought up a number of times in the
documents that
we have.
DR. WHITE: I would say that, in
my
judgment, one dose of 10 milligrams of
dextroamphetamine is less than minimal
risk. But
the fact that there is no research,
really,
long-term research--the only research
that we have
is Dr. Rapoport's follow up of people
who were
involved in the study, some of them she
knew and
she observed. So it is all, I would say,
conjecture.
I think that it is a study that would be
difficult to do for the very reason that
we are
here.
So there is no data. There is
data showing
that those who are on it long term,
those diagnosed
with ADHD, have less risk.
There is also a possibility of
someone who
206
is involved in the study who may, during
a part of
it, if it is included that these are a
substance of
abuse along with some education, may
have a less
risk down the road. So it is not known.
DR. NELSON: Are there any
screening
instruments that could be used
meaningfully to
determine whether any given individual
is at risk
for subsequent addictive behavior?
DR. WHITE: Family history would
be a
possibility, a family history of
abuse. I wondered
about do you exclude people if they have a family
history from the standpoint that what
might be
transmitted genetically is not the abuse
but one's
response to a substance once they
receive it. Some
have more reward mechanisms than others,
different
experiences.
DR. NELSON: That is sort of the
direction
I was
wondering. Even in the absence of data,
could one at least exclude, based on
that
assumption, and still have a reasonable
approach
to--
DR. GREENHILL: It is already an exclusion
207
factor for the subjects. Any history of substance
use or abuse, they can't get in.
DR. NELSON: For the subjects. But we are
talking for the family, family history,
where you
don't have that history and you are
worried about
the propensity of uncovering
something. It is not
my area. I am an ICU doc. So I am
just asking
could we do that and would that address
that
concern.
DR. GREENHILL: I don't know that
there is
any evidence for that. You could argue that
offspring of individuals that had
trouble with
substance abuse might be very negative
about drugs.
There is
some data showing that the context in
which you take drugs for the first time
may have a
big effect on whether you continue
taking the
medication.
If you take it at a party with friends,
the impact is different than if you take
it at the
NIH with
adults standing around you. It is not a
party, I don't think. That is very important for
what goes on.
208
Dr. Rapoport's data showed, interestingly,
because we didn't hear about the whole
study that
she did. She did a study with adults and kids,
normals and individuals, with ADHD. The ADHD
children and the control children were
normal.
They had
mood measures on them and they became
mildly dysphoric on the medication.
Any of the individuals who were older,
like the college students, became
euphoric after
one dose and were taking at a much more
rapid rate.
So she
wondered if there was an age response that
had to do with having euphoric response
to these
drugs.
We see very little evidence of use.
There
is less than a handful of cases in terms
of letters
and anecdotal reports in the literature
of
individuals treated in a treatment
situation with
stimulants who then hoard them and use
them
abnormally.
So the indication has been, particularly
with methylphenidate, not so much with
amphetamine,
that it produces dysphoria. In the making of the
209
Seize the
Future--I think that is what it is
called--reports that come out each year
about
high-school students showed that
experimentation
with the stimulants is usually a
one-time event in
contrast to cocaine and marijuana where
it is
repeated. So they will experiment with them and
they will just stop using.
We are going to be looking at a much
younger group so I think, all in all, we
just don't
have a lot of--no data is not
evidence. The
absence of evidence is not evidence but,
still, we
are waiting for some of the long-term
follow-up
studies like a follow up to the MTA to
see what
happens to the risk of substance use for
those
individuals exposed.
If you believe Tim Willin's data,
he finds
that he cuts the rate of substance use
in those
ADHD kids
who have trouble with a past history of
it but are in active treatment, cuts it
to a third.
So,
apparently, it is found to be among practicing
clinicians anecdotally that it helps
reduce the
rate.
210
But, again, it is a lot to do with
context. You give these medications in a medical
setting. It is not the same as taking it
recreationally. So I just don't get a sense that
giving one dose of this is going to
start a
lifelong career or use or somehow unmask
it.
DR. CHESNEY: This is in part for
the IRB
folk, but, given our litigious society,
if one of
these children who was given one dose in
fact
became addicted down the road, is there
a way to
write into the consent form that we
don't know
this, the outcome of this and, if it happens, you
can't blame it on the study?
It concerns me that if we say this is not
more than minimal risk or a minor
increase over
minimal risk and then we get into
trouble 20 years
down the road, I guess there is no way
to obviate
that.
DR. NELSON: You can't waive your
rights
to sue in a consent form. Period.
For any reason.
DR. GREENHILL: But you can
indicate if
there is some concern on some parties
that this
211
is--it gets back to this whole issue of
stating
that it is a medication that is
classified among
abusable drugs and the parents should
know that.
We don't
have strong evidence for one exposure
leading to, even exposing the
vulnerability, but we
can't rule it out. We know that, and they should
be warned that it is a substance that
has been
abused by all age groups in some form or another.
And then they can ask a lot of questions
about it and they will be encouraged to
do so.
DR. HUGHES: From a family point
of view,
I think
that almost every parent of a child with
ADHD will
tell you that there are real issues in
trying to keep your kid taking their
medication.
Rather
than wanting it every day, they would like
to not take it at all.
I think some of that is because of, again,
their environment and their peers and
not wanting
to be labeled ADHD. But certainly, from common
experience for kids with ADHD, we
certainly haven't
seen this.
I also think it is very important
to
212
differentiate between substance abuse
and
addiction. They are not the same. To
my
knowledge, there isn't evidence that it
is an
addictive drug but rather we know that
it gets used
for other than the medically prescribed
purposes
quite commonly. Your comments about the college
students who want it studying for exams,
I think,
is much more common.
I think that differentiation, when it is
talked about in the consent forms, is
very
important, that addiction and substance
abuse are
very different.
DR. NELSON: So, in moving us
along, I
have not heard anyone giving an argument
that the
drug administration should be classified
as minimal
risk.
So that moves us down the right-hand side of
the algorithm into more than minimal
risk. I think
it is fairly clear that I have heard no
one argue
that this offers the prospect of direct
benefit,
although there may be benefits
associated with some
of the informational aspects that have
been talked
about, that that is normally not what
would be
213
considered a direct health benefit.
So that takes us down to no prosect of
direct benefit which then gets us into
the minor
increase over minimal risk or more than
that. So I
guess my question, then, to the group is, in terms
of this drug administration being a
minor increase
over minimal risk, however we choose to
define
that, versus higher than that on the
table is a
couple of opinions that this would be a
minor
increase over minimal risk.
We don't have to all say we agree, if we
agree, bus is there any more to say on
that point
before then going down to the additional
questions
that we need to then address?
Okay. So that takes us down to
the
left-hand side of the bottom part of the
algorithm.
DR. WHITE: One more follow up on
Dr.
Chesney's
comment that there is likelihood that
some of these healthy controls will
experiment with
substances later on.
DR. NELSON: Go ahead.
DR. WHITE: We just know that. And we
214
know that all subjects will be receiving
active
medication. The power of the study--it is much
more powerful to do it in a crossover
design but I
wondered about the possibility of having
either
placebo or a control. You would need two separate
groups in doing it using that approach.
It doesn't give you as much power but it
would be another way in which subjects
wouldn't
know whether they had active drug or
not.
DR. NELSON: In looking at the
other
issues in terms of experience as
reasonably
commensurate, what I would like to do is
focus us
on disorder or condition. Half of the children in
the study will have ADHD either with or
without a
twin.
The other half will be without ADHD, either
with or without a twin who has ADHD.
So I think it is fair to say there is no
disorder or condition or certainly the
children
with ADHD who are unrelated, whether we
want to say
they are at risk but, I think, at this
point, if
they are discordant. So, specifically on that
group.
Norm?
215
DR. FOST: That group?
DR. NELSON: You could say there
are three
groups; that is children without ADHD
that are
unrelated to anyone that has ADHD which
is the
first group. Then there is the twin groups.
Whether
or not the child who does not have--they
are discordant for ADHD--any risk
categories I
think would be a separate question.
DR. FOST: I just want to address
that
question that you are raising. First of all, I
agree with Eric that an overly literal
interpretation in these categories is
probably not
warranted. But, even if we interpret it literally,
if you are asking whether a so-called
normal or
healthy child with no history of ADHD
who gets
enrolled in this study, whether the
study is about
his condition.
I would say yes because part of what the
study is about is how normal children
respond to
amphetamine. That is one of the questions it is
asking is what happens to normal children
when they
get amphetamine. It is about both, what happens to
216
kids with ADHD and what happens to
normal people.
So, one of the conditions that is being
studied is normality. So, if you
want to be
literal and talmudic about whether--I
don't mean
that in an offensive way, but--
DR. NELSON: That is not the way
I was
headed because actually that would view
me as a
rather liberal interpretation of the way
we use
condition or disorder within--
DR. FOST: You added
disorder. I think
the word is condition.
DR. NELSON: Disorder or
condition is in
the regulations.
DR. FOST: This is a study of
healthy
children. That is one of the important questions
they are asking. We have already heard that it has
been important to dispel this ancient
myth that
so-called healthy children respond
differently.
But now
it is at the brain level, at this
functional brain level. And I think we have all
agreed it is an important scientific
question about
whether normal children respond
differently
217
than--because, who knows. There may be
implications for normal people taking
this drug to
perform better in school, to perform
better whether
it is exams or whether it is in grade
school.
DR. NELSON: For the purpose of
focussing
the debate, are you making an argument,
then, that
you would approve this entire study
under the minor
increase over minimal risk since the
children
without ADHD, in fact, have a condition
called
being without ADHD that is part of the
study?
DR. FOST: They have a condition
called
being a normal child.
DR. NELSON: That is the same
thing; yes.
DR. FOST: There is a serious question of
whether amphetamines have an effect on
normal
children. Whether it is clinically useful, they
are not studying that in this study but
I think
that is an important question. So the short answer
is yes, I think it could be.
I don't think we need to go there because
I think
it can be improved under 407 anyway.
But
my opinion would be yes, it needs--
218
DR. NELSON: But that is not an
unimportant--I am not saying people
agree or
disagree with you at this point. Just keeping you
as the person who has put this forward.
DR. FOST: I should say yes.
DR. NELSON: For this panel to
say this
could be approvable under 406 or 50.53
instead of
407 sends a much different message than
to say it
could be approvable under 407 or 50.54.
DR. FOST: Yes; I think it could
be
either.
DR. NELSON: Let's keep it
focused on that
question of disorder or condition and
see where we
are going with it.
DR. JACOBS: I guess I would, for
the last
point that you made, because of the precedent it
would set--now, I see your point and I
think it is
an interesting one. But I don't think that we want
to start defining everyone who is not in
a
condition but is the normal control as
the topic of
interest and say that, well, we could
find out that
normal people have this too, or that
normal people
219
function the same way, or whatever.
I guess I think that is a little
bit
troubling as precedent-setting that this
panel
would be doing. It seems to me that when you talk
about ameliorating, since that is the
word used
here, the disorder or condition, I don't
think we
are trying to ameliorate normalcy here.
So I think that is going too far and I
guess I would prefer not to go down that
branch.
DR. NELSON: Rick?
DR. KODISH: I would just like to
step
back from 100 times magnification maybe
to 10 times
magnification on the microscope and
think about
Subpart A
compared to Subpart D and remember that,
if we are going to call childhood a
condition, it
sort of undermines the whole point of
having a
Subpart
D. So I agree both on the sort of
utilitarian grounds about the precedent
but also on
the bigger picture issue.
DR. NELSON: I am going to
assume, since
no one else has other comments and no
one is coming
to Norm's defense--
220
DR. MURPHY: Can I ask him a
question?
DR. NELSON: You can always ask
Norm a
question.
DR. MURPHY: I am not sure I
understood
your statement because was part of the
basis of
your statement because not just knowing
that there
is a difference in normal, because that
is one part
of the statement, but is part of that
because so
many normal kids are diagnosed with
this? Is that
also informing that opinion?
DR. FOST: No.
DR. MURPHY: Okay; I just wanted to--
DR. FOST: I don't feel a need to
push
this because I think it is going to head
towards
407 anyway and the important question is
whether
the study can go forward. But, to answer your
question, normally we included so-called
normals in
clinical trials as controls; that is, we
assume
nothing will happen to them.
Say, you are using an antidepressant or
something and you are looking
for--anyway. Your
hypothesis is that there will be no
effect on the
221
so-called control population,
antibiotics,
chemotherapy, if you were doing such a
thing. But
there is something different about
ADHD. I don't
want to say unique, but it is very
different in
that we have heard that normal children
do respond
to this pharmacologic agent. Their behavior
changes.
What these investigators are wanting to
know is is there a difference at the brain level.
They
don't know the answer to that. That is
why
they are doing this study and it may be
that there
is no difference at the brain
level. I don't know.
So maybe
there is an effect on normal children
which is, A, an interesting scientific
observation
which is this is, mainly. It is a scientific
question.
It may have therapeutic implications down
the road because I don't think it is a
facetious
question to ask whether normal children
or adults
might benefit from low-dose amphetamine
for
studying, for getting work done, for
improving
performance in a variety of areas. Those are all
222
legitimate clinical and scientific
questions.
So the normals in this study aren't like
normal controls in most studies in which
we are
expecting nothing to happen to
them. I think we
might very well expect something
interesting to
happen to them.
DR. NELSON: I think, in order to
move us
along, the interesting question raised
here is the
definition of disorder or condition and
how it is
interpreted. I am reminded, although I don't
recall--I mean, the Institute of
Medicine report
does have a definition of how to
interpret
condition or disorder in there. I think this would
be an even more liberal interpretation.
So, absent anyone else on the panel
feeling we ought to embrace that
interpretation,
what I would like to do is move us over
into, then,
a discussion of 407 and 50.54
specifically as it
relates to the healthy children because
we
otherwise might run up into some time constraints.
DR. GREENHILL: Just briefly,
what was the
criterion for dismissing 406?
223
DR. NELSON: Well, the question
is--I
mean, you have two groups; those with
ADHD and,
assuming that the diagnostic criteria
are
appropriately applied, assuming they
have a
disorder or condition so that that group
could be
potentially approvable under 406.
The specific question then is what about
the children without ADHD and what
happens to that
group.
Unless you say that, given Norm's argument,
that they have a disorder or condition,
then they
cannot be approved under 406 or 50.53.
Then that brings us into the question of
whether it could be approvable under
50.54/407
which is the final category.
DR. GREENHILL: See, I would
argue that it
is important and would yield
generalizable
knowledge of vital importance for
normals if they
had a different pattern. We don't know. All
science is a gamble. The question is do you make
your decisions about 406, 407 on the
previous
evidence or do you make it on what an
investigator
is hoping to find.
224
Previous evidence showed they were unable
to detect differences between the two
groups. They
hope, by using a different level of
investigation,
by looking at functional responses
because they
have seen in adults different circuitry
used to
deal with the same problem in adults
with ADHD and
adults without.
Wouldn't that yield generalizable
knowledge of vital importance that
normals have a
different pattern of functioning?
DR. NELSON: But all three of
those are
necessary for approval in that category.
DR. GREENHILL: Oh; okay.
DR. NELSON: So, even if it
would, if you
are not willing to grant them a disorder
or
condition until you have that evidence,
then you
can't go into that category.
DR. GREENHILL: Okay; got it.
DR. CHESNEY: Could you say that
one more
time, please?
DR. NELSON: In other words, all
of the
criteria that were found in 45 CFR 406
or 21 CFR
225
50.53 all need to be met in order for
the
intervention or procedure to be approved
under that
category. So, if any one of those is not true,
then you cannot approve it under that
category.
So, for the children with ADHD, they have
a condition or disorder. For the children without
ADHD,
they do not have a condition or disorder.
So
you then would approach the protocol in
two parts
which is, I think, what the NIH IRB
struggled with.
I think
they concluded that the protocol was a
minor increase over minimal risk for
children
with--in both cases but then realized
that they
didn't have a disorder or condition for
the
controls.
DR. KODISH: But it is not
possible by
regulatory thinking, and I am asking
this, to
approve this protocol for the ADHD
subjects under
406 but for the healthy--the protocol is
bundled
together. In other words, my--
DR. NELSON: No, no. If they wanted to
unbundle it. No; you should approve it under two
different categories if you are going to
do that.
226
DR. KODISH: Okay; so it is
permissible to
do that.
DR. NELSON: That is why the
wording is
intervention or procedure and not
research. So the
protocol needs to be unpackaged which is
why I went
through each individual procedure. So, yes; you
can approve the protocol under two
different
categories.
DR. KODISH: So it might be more
proper
for us as a panel, if we are going to go
that way,
to approve the ADHD subjects under 406;
correct?
DR. NELSON: If we wanted to
make--I mean,
that can be part of our
recommendation. That is
what I am hearing people are comfortable
with.
Then the
question is driving on to the 407. One
of
the reasons I want to drive on to that
is I really
do want to hear what sound ethical
principles
people would like to propose be met by
giving a
dose of dextroamphetamine to a child
without ADHD.
DR. FOST: I think it would be an undue
burden on the commission to come
up--there is no
such agreed-on list. But I think there is a widely
227
shared list of other thing that make
research
ethically acceptable; sound scientific
design,
appropriate impartial review,
appropriate standards
for consent and assent, monitoring for
adverse
effects. Maybe I left off a couple but I think
those are key elements of ethically
sound research
and that are met by this proposed study.
DR. GREENHILL: Similar to your
statement
about all three criteria have to be met
under 406,
under 407, there are two criteria. Do they both
have to be met?
DR. NELSON: Yes.
DR. GREENHILL: Okay, because I
am
grappling and struggling with this first
criterion
for normals; reasonable opportunity to
understand,
prevent or alleviate serious problems
affecting
children's health or welfare.
DR. NELSON: If you look at 407,
the
children refer to children as a group
and not to
the children in the research.
DR. GREENHILL: Oh; I see. So the notion
there is that you could have a potential
benefit to
228
children that is not a benefit to the
children in
the research.
DR. MARSHALL: But you beg the
question.
I was
kind of getting at this early on, understand,
prevent or alleviate a serious problem
affecting
children's health or welfare. So I think we have
to talk about what the serious problem
is.
DR. FOST: ADHD.
DR. MARSHALL: But all children;
that is
why 406 works for the children with ADHD
but what
is the argument or what is the rationale
for
normal, healthy children.
DR. FOST: It doesn't say that it
has to
be beneficial to all children. If that were true,
you couldn't study any disease at
all. You can
only study diseases that affect every
single child
which would be an absurd interpretation of
it
because there is no such disease.
DR. NELSON: I think the group of
children
would be the group with ADHD but not the
children
in the research.
DR. KODISH: I'm sorry to interrupt. I
229
think there is another important group
that we
should think about and that is children
who are
misclassified as having ADHD. Without getting into
the political rhetoric on one side or
the other
about it, I think there is an important
scientific
issue here about the diagnostic
classification and
that does pertain to some children who
do not have
ADHD.
DR. NELSON: Dr. Hughes?
DR. HUGHES: If I could just follow up
with that. Are you implying that, for those
children who are misdiagnosed, that this
study has
a potential benefit for them or the
opposite, just
to clarify? I would think it would have a
potential benefit if it later leads down
the road
to having better diagnostic power than
we currently
have.
DR. KODISH: Exactly. I think that the
significance of the study is in its
diagnostic
ability.
DR. NELSON: Dr. Gorman?
DR. GORMAN: I think that the diagnosis
230
and treatment, appropriate treatment, of
appropriate populations for ADHD does
have an
impact on the complete universe of
children. In my
school district, 40 percent of the
educational
dollars associated with the school
system go to
children with special needs. Not all of them have
ADHD, but
a large number do. So making this
diagnosis more appropriate and,
hopefully,
treatment more appropriate might free up
more
educational dollars for the other
students, or
perhaps less, if there were more people
diagnosed.
DR. NELSON: Norm, you mentioned
in your
list of criteria of appropriate
scientific design,
monitoring conduct and the like, the
assent and
permission process. So let me bring us back to the
$570.
DR. FOST: I didn't say monitoring the
process. I said monitoring for adverse events.
DR. NELSON: Right. There was a comma
between them, sorry; the assent and
permission
process, per se. So I would like to bring us back
to the $570. I would also like to raise the
231
question of the relationship between
parental
permission, which is meant to have a
protective
function for the child, and child
assent,
particularly when you get into these
twins. Or I
could imagine on the twin without ADHD
there may be
a considerable amount of pressure to say
yes to be
in this study which is very different
than these
children without a sibling with ADHD.
I am just wondering what people's thoughts
are, first, about the money, and then
how an assent
process would be able to be structured
so that a
child could say no even when you have
got a sibling
with ADHD and a parent who may be very
invested in
this information.
DR. GREENHILL: I just want to
ask one
question of clarification. Doesn't a family with
twins get twice as much money?
DR. NELSON: I am assuming it is
per
subject, too.
DR. GREENHILL: So the pressure
is even
greater.
DR. NELSON: Right.
Process and money.
232
So that
is on the table now.
Norm?
DR. FOST: At first, it was
ambiguous
whether the money was for the parent or
the child
or both or to be divided. I couldn't get any
clarification of that from the comments
this
morning. So that should be clarified.
Second, I think the clarification should
be explicit about some reasonable
estimate of what
they think appropriate compensation to
the parents
is for direct expenses or if they want
time. That
is Point 1. Point 2, be clear about why any money
at all is going to the children. If it is for an
honorarium, then it is just to thank
them and to
teach them something about contributing
to science
and reward them for that.
Then it should come after the fact.
It
should not be in the consent form. When you thank
somebody, you don't say, "If you do
this, I will
thank you." You thank them after they have done it
and it should be quite a token
amount. It should
be $5.00 or $10.00 or a small gift
certificate.
233
I think the money is excessive.
It will
turn somebody's head to be able to get
$500,
somebody who is not well off, in
particular, and
could lead to pressure, as you
described, to get
the kids to do it. It may even be $1,000--we don't
know--which is a substantial amount.
I thought I heard Dr. Rapoport say, but I
wasn't crystal clear, that she doesn't
need it as
an incentive; that is, she had no
trouble
recruiting into a prior study. This is different.
The prior
one--I can't remember if it was an fMRI
study or not.
But if it is the case that she feels she
can recruit without it, then that would
seal the
deal.
There is no reason to offer incentives and
get into this problem of undue pressure
on children
if it is not needed. So these are all things that
the IRB can and should engage in
dialogue with the
investigators about to get clear
answers.
But I would hope that this whole thing
could tilt in the direction of reduced
amounts,
clarification of why the money is
needed, whether
234
it is needed as an inducement and
keeping the
amount for the kids to something in the
honorarium
range which would be post hoc and not in
the
consent form.
DR. NELSON: Let me just ask you
one quick
question on the amount. Some IRBs are sometimes
comfortable with more of a wage model as
opposed to
a token model. If you took that at an eleven
hours, usually people might use anywhere
between
$8.00 and $12.00 an hour depending on
what you get
minimum wage or at Taco Bell and that
sort of
thing.
But if you did 10 times 11, that is only
$110.
Is there a point at which you would say it
shouldn't be any more than X at least to
provide
advice to those who are going to be,
then, working
with the IRB and investigators?
DR. FOST: I think that provides
some
guidance for a tough A, but I think it
would apply
primarily to children who, in fact, earn
wages. In
our IRB, we allow that sort of
discussion for
adolescents who are at an age where they
might be
235
employed--14, 15 or thereabouts--and use
that as a
guidance. But it would not apply to 8, 9 and
10-year-olds who normally don't make
money.
DR. NELSON: Okay. Dr. Jacobs?
DR. JACOBS: I would agree that
the
amounts that are in the protocol now are
excessive,
particularly for doubling them for
people with
twins.
I think it should be clarified if it is
parents or children receiving the money.
I used to do my work 20 years ago, and 25
years ago, without any inducements,
without any
kind of money involved for children or
families and
no other little rewards. It is almost impossible
now to do that and I don't do this kind
of
research. I do research that is attitudinal. Very
few teenagers, particularly, but even
younger
children will be involved in research and very few
parents will be even interested in
talking to you
on the telephone or answering a survey
if there
isn't some sort of money or something
involved.
Sometimes people use lotteries.
They use
other kinds of things. You can put your name in to
236
get a $20 gift certificate for the
bookstore or
that kind of thing. But I wouldn't want us to go
to the place of saying it has to be
zero.
I think this is an excessive amount but I
think that what Dr. Rapoport was saying
that, at
NIH, now,
people are finding that they need to do
these things. I think that is completely accurate.
I see it
in every study that I review and in my own
work.
MS. TREAT: I, too, think that
the amount
of money that is being offered is
excessive. It is
not only enough to turn the heads of the
kids, it
is enough to turn the heads of the
parents. I
think that your proposal, Dr. Nelson, of
going to
something based more on a wage, a
per-hour wage, is
more in line with what would be
appreciated and at
least noticed by the kids, maybe for the 11 hours
that they would spend, maybe $100, $110
or
something like that.
You had mentioned trying to make sure that
the subjects actually agree to be in the
study,
particularly the subjects that might be
a healthy,
237
normal twin of an ADHD twin, and trying
to make
sure that they aren't just being
pressured by a
parent who has particular interests.
It seems to me that asking or having the
examiners ask the child at various
points during
the study, is this okay, do you want to
continue,
would work just as well unless the
parents are
present at every stage. My impression is the
parents won't be present during every
stage of the
testing.
There are three periods for the testing.
There is
the screening test, the MRI with the
placebo, the MRI with the stimulant. Unless the
parents are present at each one of
those, it seems
that the person who is doing the testing
could just
simply ask the subject, are you okay
with
continuing with this and solve the
problem that
way.
DR. NELSON: Are there other
comments on
the actual process, itself?
DR. WHITE: I am involved in
imaging
studies in children and adolescents with
psychotic
238
disorders. I can just tell you our experience. We
do reimburse. We do give for the semi-structured
diagnostic interview, it is about two to
three
hours and we give $20. The neuropsychological
assessment is done over two sessions,
each about
two to two-and-a-half hours. We give $20 for each
of those sessions.
For the imaging session, which is a little
over an hour, we give $30. In our experience, one
of the challenges, if we get a number of
people
from higher socioeconomic status, very
willing to
participate, and a challenge to get individuals
from lower socioeconomic status which,
except for
the patient group--I am talking about
the
controls--the sort of patient groups of
children or
adolescents with schizophrenia, they are
often more
than willing to participate.
We do give them a report afterwards and it
is helpful for them because they have
probably the
most thorough psychiatric evaluation
that they have
had up until that time. They, the
neuropsychological testing is
helpful. So we do
239
make that available for them.
We find that it is difficult to recruit.
We target
areas where there is lower SES and they
will say, "That is not enough
money." So the
amounts that we are giving were not
changing it.
It is nice to offer, and we say "offer
the
families." We don't say we are giving this to the
children or to the parents. It goes to the
families and part of that is for gas to
come in and
time away. They often eat something on the way.
So it is
a small amount and I find it helpful.
DR. NELSON: What I would like to
suggest
now is that we take a 15-minute break
which we are
scheduled for. What that will allow me to do is
try and put together what I see as a
summary of the
points that people have made and I would
like to,
then, present it to you as much to, A,
make sure
that I represent what I have heard you
say but, B,
then, so you have an opportunity to fill
in the
holes with the goal of trying to wrap up
by 3:30.
So let's take a 15-minute break and
reconvene at 2:45.
240
[Break.]
Summary of the Deliberations
DR. NELSON: I will tell you what
I plan
to do and then, hopefully, Dr. Gorman is
here when
I
actually do it. But what I would like
to do is
briefly just summarize what I heard in
terms of
things people would want to have happen
to this
protocol and consent form and assent
forms to make
it better.
I will just run through that list and
then, if there are things that are not
on that
list, then you can fill that in after I have
completed the whole thing. Then I would like to
run through the questions for the panel
and then
specifically try to assign categories
based on our
discussion and do that briefly enough to
where,
then, the rest of you can take your
shots at it and
fill in the holes and tell me where I
have got it
right or where I have got it wrong. Forget about
the right. Just tell me where I have got it wrong
for the sake of efficiency.
The process here will be,
then, what I say
241
now with my notes will then be turned
into a
presentation that will go to the Pediatric
Advisory
Committee
on Wednesday morning, and, depending upon
that discussion, go through the process
that was
presented earlier as far as to the
Commissioner and
to the Secretary.
So, Dr. Gorman is still missing in action.
This is what I have heard and I am going
to divide it into protocol and assent
and
permission, but a lot of things I say
about the
protocol, obviously, if they need to be
disclosed,
I will
try and mention when they should also be in
the assent and permission.
Clearly, there are some discrepancies that
need to be cleaned up in the
protocol. Dosing is
the obvious one. But I also heard a point by Dr.
Greenhill
about minimizing risk in a.m. dosing and
the timing of the studies which I think
needs to be
captured.
In terms of the functional MRI, the
training process and lack of
restraint--I mean, the
kinds of things they are doing ought to
be made
242
more explicit. There is the pregnancy exclusion
and the importance of talking about the
process and
the confidentiality around that process
which needs
to be both in the protocol and in the
assent and
permission. Then explicit discussion of the MRI
study will be done to a diagnostic
specification
needs to be provided both in the
protocol and the
assent and permission form.
One thought I had there is they can easily
provide the data they have about the
positives they
had when they have done normals. I think a parent
who is thinking of putting their child
through an
MRI scan
might want to know that they have seen 4
out of 3,000--
DR. FOST: I wouldn't go down
that road.
I would
like to see the data. It is hard for me
to
believe that only 4 out of 3,000 had
adventitious
findings.
DR. NELSON: Would you agree that
the data
they have should be in there, whether it
is the
correct data or not, Norm?
DR. FOST: I don't know because my guess
243
is they have got all sorts of fuzzy data
in there
and all these blobs that you see in MRIs
that you
don't know what they mean.
DR. NELSON: We will leave that
as a
question. I will soften that.
We had a discussion about the test results
in terms of neuropsychiatric
testing. What I heard
from our discussion was that they should
not be
made available to the parents, given the
problems
in providing that in an appropriate therapeutic
context. But the caveat that the family obviously
needs to know about some of the
limitations in
subsequent testing if there are concerns
about
repeat performance issues such as on the
WISC I.Q.
test.
In terms of genetic testing, we felt the
risk was appropriate there if it was
restricted to
testing with respect to zygocity and
that the
samples would be destroyed. We also felt there
should be an evaluation and we lacked
the
information about the potential stigma
of any of
those other tests and, in particular,
one could
244
refer them to issues in the literature
about
predispositional genetic testing on
children and
the risks of doing that or providing
that data
which would argue against doing that.
As far as the assent and permission
process, there was--
DR. GREENHILL: May I ask a
question just
for clarification.
DR. NELSON: Go ahead.
DR. GREENHILL: When you said the
arguments against--what kind of testing
was that?
I know
the testing for zygocity. Was there
ambiguity about whether they were
testing for other
things?
DR. NELSON: They have that list
on the
bottom of Page 12. What is ambiguous is they
really didn't say how they would use any
of that
information and we didn't have
sufficient detail to
know if one of those particular tests,
for example,
if it was APO protein E or something,
would be
linked to a late-onset disorder that
might place
some risk of that information, if it
came into the
245
family dynamic.
So we felt we wanted to just close that
door by saying don't do it, make sure
you don't do
it.
DR. FOST: They also don't tell
us in the
protocol or the families in the consent
whether
they plan to store the samples against
the
possibility of doing some other specific
ADHD
genetic testing down the road.
DR. GREENHILL: We have a caveat
that
would tell parents to put in the consent
form that
what we are doing is not genetic testing
because,
if they tell their doctor about that and
it goes
into a chart note and an insurance
company checks
it, then that will put those patients in
different
categories.
DR. NELSON: We can make a note
of that
but I think that is a prudent
thing. So genetic
testing is my term for it.
DR. GREENHILL: That term is
not--you tell
the parents specifically, "This is
not genetic
testing." It is twin testing.
246
DR. NELSON: We are micromanaging
on that
point.
DR. FOST: Just because it is
wrong
doesn't mean it is indefensible.
DR. NELSON: In terms of assent
and
permission, I think there is a clear
emphasis that
there needs to be much more procedural
detail, that
there was a lot that was missing in that
process.
But,
specifically, two process points, the payment
is excessive, whether it is a token for
the child
or a limited-wage model based on time,
there were
different points of view. I think my preference
would be to leave that to the IRB to
determine what
is appropriate. Certainly expenses to the parent
and other sorts of out-of-pocket things,
there was
no disagreement with that.
DR. FOST: Just a modification of
that,
Skip. I don't know if it is
excessive. I think it
is.
DR. NELSON: They say 11 hours.
DR. FOST: But, if it is
necessary for
recruitment, if they tell us this
study--if they
247
have plausible evidence that this study
can't be
done in any other way, I might rethink
it. I think
that is unlikely.
DR. NELSON: We don't have that
evidence
before us so I guess--
DR. FOST: It is excessive if it
is
unnecessary.
DR. GREENHILL: The principal
investigator
said it was unnecessary; yes.
DR. FOST: I think she said that;
yes.
DR. NELSON: Yes; she did. So I think we
should leave that rest.
DR. CHESNEY: Actually, $51 an
hour, so I
would volunteer.
DR. NELSON: You are in infectious
disease; right where you don't get paid
for any
consults.
The process of dissent needs to be at
least looked at and appropriate. The other things
in there were the issues of
drug-of-abuse
classification, adverse effects, infrequent-rare.
I am basically short-handing things that
Dr.
248
Greenhill
said and also the distinction between
substance abuse and addiction which I thought was
helpful for me at least to understand
some of the
issues.
Expunging any language about treatment and
making sure any language about no
benefit is there.
Of course,
both parents would be an important part
of that permission process.
That is a shorthand of what I heard in
terms of what people feel would be
necessary
independent of the answer to the
specific
questions. Now, let me run through the questions
and if there are things I have missed on
modifications, then you can be writing
it down and
I will
copy them.
What are the potential benefits of the
research, if any, to the subjects and to
children
in general? I think the way that we have talked
about it, there are no direct health
benefits. To
the extent that we have placed
restrictions in the
provision of the information back to
families, I
think we have even strengthened the
argument that
249
there is no direct benefit and that any
benefit of
this is simply for the knowledge that
may be gained
for the population of children with ADHD
and
potentially children who are normal but
mainly for
children with ADHD or are misclassified
as having
ADHD.
The types and degrees of risk that this
research presents--
DR. FOST: I might have a respectful
dissent on that. I think this is a study about two
groups of people, people diagnosed with
ADHD and
people who are not. They are very interested in
both.
DR. NELSON: Correct. That is what I
said.
There may be benefit to those who don't have
ADHD in
terms of knowledge, not in terms of any
direct benefit.
DR. FOST: Well, there will be
knowledge
gained about norms. Either they respond in the way
ADHD
people do or they don't and that will be news.
DR. NELSON: Okay. I am happy taking my
"may" and making it a
"will," assuming that it
250
turns out that way.
DR. FOST: I just think it is
different
from most controlled trials in that
there is a
serious scientific interest in how
so-called
normals react.
DR. NELSON: Okay. I am not sure it is
necessary for me to list the types and
degrees of
risk.
I think most of that has been discussed and
the like. Are the risks to the subjects reasonable
in relationship to the anticipated
benefits. There
I assume,
if we are looking at the language of
Subpart
A, it would be, "if any," and is the
research likely to result in
generalizable
knowledge about the subject's disorder
or
condition.
Since we have already decided that there
is no direct health benefit to these
children,
whether they have ADHD or not, the
question here is
the reasonableness of the risk with
respect to the
generalizable knowledge to be obtained.
To the extent that I have heard people
are
willing to approve this under 406 or
50.53 for the
251
children with ADHD and recommend that it
could be
approved under 407 or 50.54 for the
children
without ADHD, I will assume that the
answer to
Question
3, even though we haven't asked and
answered it explicitly, would be yes
because, if it
isn't, we shouldn't go there.
Then, likewise, for the reasonable
opportunity.
DR. FOST: I didn't understand
what you
just said.
DR. NELSON: I am assuming the
answer, are
the risks to subjects reasonable in
relationship to
anticipated benefits, if any, and to the
knowledge
would be yes. Otherwise, if it is no, then we
might as well close up and go home. Disapprove
would be the answer. Likewise, No. 4. If it is
not a reasonable opportunity, we should
close up
and go home and say disapprove.
DR. CHESNEY: Can I comment? To me, this
is the crux of the matter. We have been talking
about this, but will the results that
they obtain
make a difference? To me, I can't separate this
252
from is the study design such that the
results will
give us an answer, will be
beneficial. Will this
study provide generalizable knowledge?
I guess I felt better about it
when they
did some explanations this morning but I
still come
back to the question of whether we
wouldn't benefit
more by getting more what I would call
baseline
data on normal children and ADHD
children but
normal children without medication. I am probably
confusing things or maybe not answering
what you
are asking here but--somebody else can
phrase that
better, but will this study provide
knowledge that
will be worth all of this discussion and all of
this work.
Dr. Greenhill, maybe you can answer that.
DR. NELSON: Or Dr. White; either
one.
DR. CHESNEY: Or Dr. White; I'm
sorry.
DR. WHITE:
I was going to comment on
something. One of their goals was to replicate a
study that had some flaws in it, the one
that was
done at Stanford. They didn't bring up--but one of
the primary flaws is controlling for
performance
253
among the subjects. So, if there are differences
in performance among groups, then there
can be
changes in the activation patterns in
the
functional scan based on performance
which would be
different than what they are looking
for.
So they have two design modifications in
this study that make it very well suited
to address
this question. One is that they have a task, the
stop task, which controls for
performance. So they
can look directly at that question. The other is
they use an event-related paradigm
rather than a
block design. An event-related paradigm allows you
to tease apart each answer to the
question that
they make and look specifically.
So I see it as a major improvement over
the other study and I think they said
that this
morning, too, and I agree with that.
DR. MARSHALL: To follow up on
that, do
you feel as though--and maybe reflecting
back on
Norm's
comments about healthy children, do you feel
as though, in a sense, they really are
asking or
sort of doing two studies? They ares doing one
254
with ADHD children and they really are
interested
in normal children? Should this be two separate
studies?
Part of this really does bear on my
determination about how we define a
serious problem
that affects the health or welfare of
children. I
do look at the interests of children
collectively
under that rubric. How do you define a serious
problem? Well, it is something that may not, in
terms of sort of how onerous it is, be
very high on
the scale, but it if it affects a lot of
children,
then it is a serious problem. Or it could affect
less children but be high on the onerous
scale, if
I am
making sense.
I am worried here that we are trying to
put words in the investigators' mouths
and redesign
their study a little bit. So it is important to me
to get at this question of health and welfare
of
children.
DR. WHITE: You had a couple of
questions.
I don't
want to put words in the investigators
mouths, but the way I saw it was they are looking
255
at the difference in response. Therefore, you need
both groups in order to answer that
question. That
is how I view it, although I agree that
there is
very little knowledge about how the chemistry,
neurochemical development of the
brain--and so I am
sure they are also interested in normal
development
and how children respond.
DR. NELSON: Dr. Gorman?
DR. GORMAN: I think this is one
of those
rare cases where either answer brings
into a sharp
focus benefits for children. If children with
ADHD's
brains process and/or react to medicines
differently, we learn one important
factor. If all
brains work the same with
neurostimulation, we
learn another important piece of
information.
I think the hypothesis of the study is
that the response is the same. So I think this is
important information for the entire
universe of
children as opposed to just the ADHD
children. So
I looked
at this as--and that is where, when Norm
said before that--he tried to make
childhood a
condition which we would all agree
luckily most of
256
us outgrow it.
What happens then is that this study,
either way, gives important
information. So I
don't think that the answer of whether
they are
different or the same is as important as
knowing
whether they are different or the same
because it
leads us down totally different pathways
in the
future.
DR. MARSHALL: Right. I just think we
need to be very explicit and careful
about that in
terms of our deliberation.
DR. CHESNEY: I just wanted to
follow up
on your comment which is extremely
helpful to me,
this business of go/no-go, task/no-task,
performance versus something for the
non-informed
was very confusing. Even as hard as I tried, I
couldn't sort it out. So what you have just told
me is, to me, very important, that this
study
design does correct for a flaw in the
other study
and should give us either the same or
different
information because the study design is
better, is
improved on.
257
You also said that it does require the
drug in the normals, and I didn't quite
understand--that you needed both to--if you could
elaborate on that a little bit. You needed both
populations with drug and without drug
for--in
other words, why couldn't you use normal
children
without drug versus ADHD with drug?
DR. WHITE: They are looking at
the
differential response between medication
in
subjects with ADHD versus healthy
controls. There
is one thing actually I am a little
confused about
is that the hypotheses that they are the
same,
which she said this morning, is a little
bit
different than the hypotheses that were
listed.
But the thought is that if the mechanisms,
and I think of the brain as working in
networks,
that it is not one area or another one,
but the
networks of how the brain works and
orchestration
is different between subjects with
ADHD. If you
give a stimulant, it alters that network
back up to
normal.
If you give it to a healthy
control, how
258
does that change it and does it,
then--is it
similar or is it different--really
addresses the
question as to how these neural networks
change. I
don't know if I am doing a good job
answering the
question.
DR. NELSON: No; I think that is
fine. A
quick comment and then a question to the
group. To
say you think things will be the same is,
as a
hypothesis, the same as thinking, for a
sample
size, you have to postulate a
difference. In fact,
you can't calculate a sample size from
something
being totally the same.
So you have to say there is a difference
and then calculate how many you need to
show it
even if you are trying to prove that, in
fact, you
don't reach that difference. So I guess I don't
see a difference in the way that she
stated versus
the way it was stated for the purpose of
the
protocol. But I got the view that they both
actually thought differently about what
they might
find, the two investigators.
But there is one thing that I
left out of
259
my summary and that was the discussion
of age and
of dosing, narrowing out the sort of
prior dosing
in order to sort of do that. I did that because I
didn't get a sense of a clear consensus
coming out
of that, that we should restrict it to
either
teenagers--I mean, there seem to be
arguments on
both sides for doing one or the other.
So I purposely didn't put that in there.
So let me
put that on the table to see if that was
appropriate or not.
DR. KODISH: My take is if, under
broad
strokes, forgetting about
categorization, we are
going to find this ethically appropriate
work to do
because the ethics is obviously
key. As an "after
that" thought, it becomes important
to do the best
science that can be done.
What I heard from the P.I. is that the
best science that can be done is in the
younger age
group.
So, whereas my normal ethics instincts
would say older age group, I think this
is one of
those cases where the science would lead
us to
younger.
260
DR. NELSON:
Meaning 8 to 12.
DR. JACOBS: That is what she
said. Could
I
comment. I think that is definitely
what we
heard this morning. That is what I would suggest,
too.
But I don't think this group needs to say it
should only be done in 8 to 12-year
olds. It seems
to me the best science would be to
restrict the age
range because I think they are going to
have a
little "apples and oranges"
problem if they don't.
So I think that they should restrict the
age range. I think you could make an argument
either way, that they the upper range
first and
then, in the next study, they do the
lower range or
something like that. But I mean, it seems to me, I
would agree that the best science would
be the
lower age range.
But I think we should be recommending that
they restrict the age range and she
seemed willing
to do that this morning.
DR. FOST: I think that these
comments are
just recommendations and not conditions.
DR. JACOBS: Yes; right.
261
DR. NELSON: Everything I have
listed was
something that I would expect to make
sure it
happened. The restricting of the age range, it
sounds like we think it should happen
but how they
do that is a separate question.
DR. FOST: Well, you are saying if
they
don't restrict the age range, the
Secretary
should--
DR. NELSON: That is the one
exception,
Norm. That is the
exception. But everything else
I listed
was not meant to be discretionary.
So let me, I guess, go to the specific
question. It sounds like, from our discussion,
assuming these modifications and that we
would
recommend, that giving a single dose of
dextroamphetamine would constitute a
minor increase
over minimal risk; that, in fact, this
would be
approvable with these stipulations even
for the
ADHD
group under 50.53 or 406 as a minor increase
over minimal risk given the
commensurability
disorder or condition and generalizable
knowledge;
that, for those children that don't have
ADHD,
262
that, nevertheless, it still does
present a
reasonable opportunity to understand,
prevent or
alleviate a serious problem; and that we feel,
again, with these stipulations that it
could be
conducted in accord with sound ethical
principles
paying attention to assent and
permission,
appropriate science, monitoring of adverse
effects,
minimization of risk through a.m. dosing
and the
like.
DR. FOST: I am not sure I
followed you.
You are
separating it out and saying the ADHD
children could be approved under 406 and
the
normals under 407?
DR. NELSON: Yes. So I guess, then,
having said that, I would like to turn
to our FDA
and OHRP colleagues and ask if they
think we have
finished with a clear set of
recommendations, or
are there any ambiguities that need to
be cleared
up with that?
DR. SCHWETZ: The ambiguity that
I was
concerned about is one that you have
clarified just
a couple of minutes ago, make sure that
if there
263
are recommendations, they are
distinguished from
the stipulations because that is what we
will have
to negotiate.
DR. NELSON: Okay.
DR. SCHWETZ: Otherwise, I think
we are--I
am satisfied with that as a clearer
conclusion.
DR. MURPHY: I do think, though,
Skip, in
our presentation and response, we will
need to--and
you have gone through the questions but
we will
need to articulate what this committee
said were
the potential benefits because that is
the question
we posed. So we are going to have to do that. The
discussion has done that but I do think
that we are
going to need to do that. You have gone through
the risks and you have answered the
other
questions. That was the only thing I want to just
point out. I don't know if you want to take a
final comment on that or not; that was
all.
DR. NELSON: Meaning the benefits
of the
research overall on Question 1.
DR. KODISH: I am willing to take
a stab
and throw out on the table the very
practical
264
result that we would improve the
diagnostic
precision around ADHD and that is a
benefit to
children as a class.
DR. MURPHY: And does the rest of
the
committee agree with that?
MS. GOREY: One more thing, Skip,
if you
could maybe please clarify why this is a
minor
increase over minimal risk.
DR. NELSON: Well, there are two
ways to
do that. One is versus minimal risk and the other
is versus more than a minor increase
over minimal
risk.
I would love it, as I said to Dianne at the
break, if we could take the tape and
capture the
statement that Dr. Greenhill gave
specifically
about the risks of a single dose of that
particular
drug because I think he articulated it
well and
everyone else on the committee thought
that that
was a good statement.
I was not transcribing what he had to say
at the time. So I know that Dianne might have
asked you to try and write a little bit
of that
down but, to me, that was the clearest
succinct
265
statement about why this would not be
minimal risk
and why it was not more than a minor
increase. For
me to try to reproduce that now from
memory, I
think, would probably distort what he
had to say.
If we have to, we can try and capture that
little segment off the tape and get that
down more
quickly than when the transcript would
become
available would be my suggestion.
DR. GOLDKIND: If I could just
rephrase
what you said since I transcribed
it. You had said
that it was more than a minimal risk
because it is
not part of routine life but that the
effects are
gone in approximately five hours, and
that you
thought that the first thing in the
morning-- which
Skip has
already defined--in the morning would be
best and would decrease the risks of sleepless
night for children, and that the worst
possible
outcome is restlessness, irritability
and
akasthisias which are gone in
approximately four
hours.
So those were some of the reasons that you
cited for it being a minor increase over
minimal
266
risk.
DR. GREENHILL: I wouldn't say
akasthisia.
I don't think akasthisia is--
DR. GOLDKIND: I think Dr. White
did.
DR. GREENHILL: Oh; okay.
DR. WHITE: Just restlessness
would
probably be better than akasthisia.
DR. GOLDKIND: Does that
adequately
summarize it?
DR. GREENHILL: And that I think
it is not
more than a minor increment over minimal
risk
because the drug, the medication, has
been in use
to treat ADHD for a longest period of
time of any
of the medications we have approved
since 1937 and
it is approved over the widest age range
of the
stimulants. Most stimulants are approved down to
age 6 and this is approved down to age
3.
DR. GOLDKIND: And that you thought
it was
safer than one dose of aspirin.
DR. GREENHILL: No, no; I think
the
toxicity from excessive doses is less
than that of
common over-the-counter drugs, a number
of--Advil;
267
certainly it is safer than Advil if
taken in excess
because you can have destruction of
liver tissue if
a teenager takes a bottle of Advil or
Tylenol.
So, just to try to put it in context.
That is
not going to happen with a bottle full of
amphetamine. What they will get is elevated blood
pressure and high rates of pulse and, if
they take
several bottles, they may get a
seizure. But we
are not talking about irreversible
damage that
happens with a common,
over-the-counter--so, just
to try to put it in context, it is a
drug
universally used in pediatric practice,
in this
country, at least, and, in other
countries, it is
one of the few drugs that was ordered into--for
example, Australia, in terms of their
allowing
medications in for treatment of
children.
So I think that puts it in a framework of
knowledge about its safety limitations.
DR. NELSON: Mary Faith?
DR. MARSHALL: I just would like
a final
process.
DR. FOST: I just want to go back to the
268
exchange between Dianne and Rick about
what the
benefits, the societal benefits, would
be. I am
not sure that I understand, Rick, how
this will
improve diagnostic precision about
ADHD. I mean,
nothing is going to come out of this
that will be a
diagnostic test, for sure. They are not going to
do fMRI testing.
I mean, what I think it will help, it will
improve understanding about what, if
any,
differences exist between children
diagnosed with
ADHD and
those who have not, whether there are
genetic factors in their brain responses
to
amphetamines. Those findings may lead to further
studies which--I mean, if, for example,
this shows
a difference between the response of
kids with ADHD
and those who do not, then you could go
on and
study more practical screening tests and
see if
they correlate with these fMRI findings.
But I don't think anything is going to
come out of this study, itself, that
will help
anybody diagnose somebody with
ADHD. That may be
one down the road.
269
DR. KODISH: I guess I was taken
with the
mention of fraudulent tests that are out there now
and eliminating those. I am interested if either
of you think Norm is closer to the mark
here or I
am.
DR. WHITE: I know that Dr.
Rapoport
mentioned that a couple of times, and it
shows the
interest in the community. In the community where
I am,
people pay a lot of money to find--use
imaging tests to try and determine
whether someone
has ADHD or not. They are used clinically without
much of a research based although my
understanding
is that they might be looking into
researching that
more.
So I was actually wondering if that is a
topic, if the community at large is very
interested
in this question about diagnosis and the use of
imaging, this is certainly a step in
right
direction and I agree, it won't answer
the question
completely but the scientific process
slowly.
DR. FOST: But the studies that
are being
used out there are not these studies.
270
DR. WHITE: No.
DR. FOST: And these studies
aren't being
compared to those studies so these won't
shed any
light on whether those studies correlate
with these
studies or not.
DR. FOST: I just think we should
not
oversell. The cure for cancer is not coming out of
this study.
DR. NELSON: Agreed. Ms. Treat?
MS. TREAT: I am sure that you
will find
an opportunity for this comment and I
must have
lost focus at the time, but I just
wanted to note
that it seemed that there is a
discrepancy between
the minimal weight stated in the consent
form and
the minimal weight identified in the
protocol and
what Dr. Rapoport had responded
with. So she said
the minimal weight was 40 kilograms.
DR. NELSON: I included that
under the
dosing discrepancy because that is where
there is
an impact on the dosing, making sure
they got the
weights correct.
I know Mary Faith wanted to
make a process
271
comment, so if would could transition to
process
comments. I think this is the first time this has
been done. So we won't assume that it is being
done the only way or the best way and
that there
will always be ways we could do it
better.
So I know that the FDA and the OHRP is
very interested in inviting comments
from anyone,
individually as panelists or from anyone
in the
audience, in terms of the process,
itself, not so
much what this protocol or this issue
but the
process and how it could be made
better. I believe
you are the volunteer for whose E-mail
it is going
to go to?
DR. JOHANNESSEN: Yes.
DR. NELSON: Basically, Jan Johannessen
who, if you go to the pediatric page on
the FDA
which is down about two-thirds on the
right-hand
side, hit pediatrics, and, up in the
upper
right-hand corner, you will see the Pediatric
Advisory
Committee. You hit that link and you
will
get his E-mail.
So feel free to send him a
message about
272
process. With that, Mary Faith?
DR. MURPHY: Just before she says
that. I
am very glad you brought this up but we
really--this is not a reaction. We had actually
planned to ask you all to make sure that
you
provide us that input and to others
again, as Skip
said.
This really was a planned part of this
meeting that we want that feedback. So thank you.
DR. MARSHALL: I will try and be
brief.
Skip and
I were both part of at least the OHRP 407
process that was resuscitated back in
December of
2000.
I think the process has evolved rapidly in a
positive way and a lot of the credit for
that, I
think, is to OHRP and to the staff there
and the
real serious way in which they have
considered the
feedback that other panels, the previous
panels,
have given them. You see it changing over time.
Quickly, my sense today, and, again, these
are sort of general for the future sorts
of things,
is that, in striving towards an ideal,
the more we
could do to help Dr. Rosenstein and the
Chairs and
members of every IRB and all the
investigators, Dr.
273
Rapoport
and her colleagues, if and when it looks
as though it is going to move towards a
407 review
process would be that they would, at the
local
level--and Don said this. We didn't just punt this
to the federal government.
But I do feel as though there
are--perhaps, there is a need for maybe
a little
more--perhaps guidance is too strong a
word but
structure in terms of how things are put
forward
and what would be expected of the local
IRB or the
investigator.
I feel as though, both in terms of the
protocol and the IRB review, there were
a lot of
things missing here that, in the future,
we have
learned from today and might bring to
the table.
I am a little worried. I feel as though,
in a sense, we have done some of what we
said we
weren't going to do and that is
micromanaging or
specifying. I have seen things in the protocol
that, had I been the local IRB reviewer,
I would
have sent it right back and said,
"We are not going
to bother with this until you fill in
these holes."
274
So, for it to have gotten this far, I
think maybe speaks to areas where the
process
should be improved. I think it also raises the
question in my mind--I don't know Dr.
Rapoport.
Everyone
speaks very well of her and her science
and the former studies and so forth that
are a
bedrock of things that have followed.
But, from my perspective, if it is not
there and it is not articulated, then I
worry not
only about whether it was thought about
but how
that research is going to be carried out
in the
real world if there hasn't been
attention to detail
and so forth in terms of spelling things
out.
So I would maybe ask that when we go back,
or when the FDA and the OHRP go back and
reconsider
the process as it evolves that we look
at maybe
some more concrete structure of what is
required of
the local folks prior to accepting it
for review or
sending it forward to the panel.
DR. CHESNEY: I would like to
just come
back to the issue that Norm raised
because I think
not only did it trigger many of us to
think
275
differently about giving this drug to
these
children but we are doing research on
the normal
children here because we don't know what
the
outcome of giving this drug will show
us. It may
well be that the investigators will find
something
that will trigger them to move in a
different
direction for the normal children. I think, for
those of you who are gurus in verbiage
and numbers,
I think
maybe that is something we need to think
about for the future, particularly
because of the
whole issue of psychostimulants and
psychiatric
drugs in children is becoming more and
more
important in our country.
So I would just like to reemphasize that I
feel that Norm made an excellent point
in terms of
looking at normal childhood as a
condition
and--enough said.
DR. NELSON: Richard?
DR. GORMAN: I would like to
comment the
Chair on,
I think, if not the original creation,
certainly the wide dissemination of the
algorithm
that we use today. I know it comes from the
276
regulations, but having it in an
algorithm form
helped focus both the thought processes
I,
personally, prepared for this meeting,
as well as
the discussion as we went through the
day's
discussion. I thought it was very helpful and
would hope that that part of the format
would
continue.
I would echo the responses of Dr. Marshall
that I think some preparation on the
part of the
local IRB in terms of stripping away
some of the
areas that we then spent a fair amount
of time
discussing which, in some ways,
distracted from the
central questions that we brought
together to
answer could be remediated by giving
some direction
to local IRBs before these protocols get
to this
place.
I would also recommend that we--I think
Skip
probably has a fair idea of how he is going to
present this to the subcommittee and
then how he is
going to communicate that to the
Secretary and the
Commissioner. But, perhaps,
having a structure in
which we are supposed to put our
responses so that
277
we can sort of see the format of that
letter or the
framework of that letter without the
details, for
future, might help people structure
their remarks
during the discussion.
DR. NELSON: Thank you. That is actually
a good suggestion. I am not sure what that would
look like but we could give some thought
to it.
DR. GORMAN: I am always in favor
of
creating boiler plates so that the wheel doesn't
have to continue to be reinvented each
time and
might make the life of the Secretary
easier because
he gets used to reading all the
letters. Parts at
the beginning, he just skips right over
that.
DR. NELSON: Other comments?
DR. FOST: I am not sure I
understood your
comment, Rick. Maybe this over-reaction to it.
I
would be concerned about taking single
protocol
reviews such as this and translating
them into
generalizable restrictions, rules that
OHRP or FDA
then says, "This is the way you do
it from now on."
DR. NELSON: I didn't hear him
that way.
All I heard was, when I write a letter--let
me
278
speak for you, Richard, if that is all
right.
DR. GORMAN: Thank you, Skip.
DR. NELSON: If we write a
letter, these
are the points that are going to be in
it so we
need to make sure these are the points
that we have
touched on. Basically, in my mind, I had something
like that working and that is why we
went through
this process. So that is all I hear, not that
there is a sort of cookbook approach
that we can
then promulgate so that--I mean, that is
not what I
heard.
So I agree with you, we shouldn't just be
doing this by cookbook.
Any final comments, Bern?
DR. SCHWETZ: Yes.
I would just like to
thank the subcommittee. I think for moving the
first dual process, dual review, through
the chute,
I think
you did a great job. Dr. Nelson, I
think,
is also to be thanked in particular for
providing
the leadership to make this happen. So, thank you
all.
DR. GOLDKIND: I will just ditto
that.
DR. NELSON: Thank you.
With that, I
279
guess the meeting is adjourned.
[Whereupon, at 3:35 p.m., the
meeting was
adjourned.]
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