DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ADVISORY COMMITTEE MEETING
Wednesday, September 15, 2004
ACS Conference Room
5630 Fishers Lane
P A R T I C I P A N T S
P. Joan Chesney, M.D. C.M., Chair
Jan N. Johannessen, Ph.D., Executive Secretary
Deborah L. Dokken, M.P.A.
Steve Ebert, Pharm.D.
Michael E. Fant, M.D., Ph.D.
Samuel Maldonado, M.D.
Robert M. Nelson, M.D., Ph.D.
Thomas B. Newman, M.D., M.P.H.
Judith R. O'Fallon, Ph.D.
Solomon Iyasu, M.D.
Dianne Murphy, M.D.
C O N T E N T S
AGENDA ITEM PAGE
Call to Order and Introductions - P. Joan Chesney,
M.D., Chair, Pediatric Advisory Committee 5
Meeting Statement - Jan N. Johannessen, Ph.D.,
Executive Secretary 5
Statement of Dianne Murphy, M.D. 8
Subpart D Referral Process - Sara F. Goldkind,
M.D., M.A., Bioethicist, Office of Pediatric
Summary of Deliberations of Pediatric Ethics
Subcommittee held on 9/10/04 - Robert M. Nelson,
M.D., Ph.D., Chair of the Subcommittee 26
Overview of Adverse Event Reporting as Mandated by
- Solomon Iyasu, M.D., Medical Epidemiologist
Office of Pediatric Therapeutics 70
Adverse Event Reporting
- Ocuflox (ofloxacin) 105
Fosamax (alendronate) 110
Hari Sachs, M.D., Medical Officer, Division of
Pediatric Drug Development
- Fludara (fludarabine)
Susan McCune, M.D., Medical officer, Division of
Pediatric Drug Development 125
- Clarinex (desloratadine)
Jane Filie, M.D., Medical officer, Division of
Pediatric Drug Development 149
Adverse Event Reporting for Drug Products
Containing Budesonide or Fluticasone: Pulmicort,
Rhinocort, Flonase, Flovent, Advair, and Cutivate
- Peter Starke, M.D., Medical Team Leader,
Division of Pulmonary Drug
C O N T E N T S (Continued)
AGENDA ITEM PAGE
- ShaAvhree Buckman, M.D., Ph.D., FAAP, Medical
Officer, Division of Pediatric Drug Development 190
- Joyce Weaver, Pharm.D., Safety Evaluator,
Division of Drug Risk Evaluation 199
- Badrul A. Chowdhury, M.D., Ph.D., Director,
Division of Pulmonary and Allergy Drug Products,
CDER, FDA 211
Open Public Hearing --
Final Comments and Adjourn - P. Joan Chesney, M.D.,
Chair, Pediatric Advisory Committee 239
P R O C E E D I N G S
DR. CHESNEY: Good morning. I think we're
ready to begin today's deliberations, and I'd like
to say that we're not going to introduce the
committee members until Dr. Murphy has given us an
overview of the previous and current committees.
And so we really just, I think, need to start off
the meeting by having Dr. Johannessen read the
DR. JOHANNESSEN: Thank you, and good
morning. The following announcement addresses the
issue of conflict of interest with regard to the
study drug, dextroamphetamine, and competing
products used for the treatment of ADHD and to the
adverse event reporting session and is made part of
the record to preclude even the appearance of such
at this meeting.
Based on the submitted agenda for the
meeting and all financial interests reported by the
committee participants, it has been determined that
all interests in firms regulated by the Food and
Drug Administration present no potential
appearance of a conflict of interest at this
meeting, with the following exceptions:
In accordance with 18 U.S.C. 208(b)(3),
full waivers have been granted to the following
Dr. Patricia Joan Chesney for ownership of
stock in a company with a product at issue valued
at between $25,001 and $50,000, and for her
spouse's honoraria for speaking on unrelated topics
at a firm with a product at issue valued at less
And Dr. Robert Nelson for an honorarium
for speaking on an unrelated topic at a firm with a
product at issue valued at less than $5,000.
A copy of the waiver statements may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building. In the event that the
discussions involve any other firms or products not
already on the agenda for which an FDA participant
has a financial interest, the participants are
aware of the need to exclude themselves
involvement, and their exclusion will be noted for
We would also like to note that Dr. Samuel
Maldonado has been invited to participate as an
industry representative acting on behalf of
regulated industry. Dr. Maldonado is employed by
Johnson & Johnson.
With respect to all other participants, we
ask in the interest of fairness that they address
any current or previous financial involvement in
any firm whose product they may wish to comment
Thank you, and we'll now turn it over to
Dr. Dianne Murphy.
DR. MURPHY: I wanted to just take a
moment to welcome everybody and to also tell the
committee that you may not have realized--or a
number of people on this committee, that you have
just made a transition. That transition has been
from a subcommittee, which was providing very
important advice to us, but to now a full
committee, which advises the
And you have certain responsibilities that are
slightly different, and I'm going to go over those
in a second. And also to the fact that you are not
only just a full committee advising the Commissioner, but
that, as I said, you have certain
responsibilities that you're going to hear some of
them today that are clearly defined.
You have moved from the Center for Drugs
to the Office of the Commissioner, and the office
has been--and this committee is now administered
there the Office of Science. And our new Exec.
SEC. is Jan Johannessen, who has done an
extraordinary making sure that everybody has been
recruited and met all the criteria that we need to
meet and getting you here and assembled and in
helping us charter this new committee.
It is really just a monumental feat
because the agency basically was not allowed to
have any new committees. It actually took Congress
to create you. So I'm spending a little time on
this so you'll understand how important your
deliberations are to the agency.
One of the other activities that has
occurred, as you know, is that there has been the
creation of the Office of Pediatric Therapeutics,
and that office is now responsible for all
pediatric activities across the agency. And,
therefore, this committee may be hearing more--having been
in the Center for Drugs previously, you
may be hearing more about other products such as
devices or formula. So I wanted to make sure that
you are also aware of that.
And I know sometimes that's a bit
overwhelming if you're a cardiologist or an ID doc
or whatever your training. The breadth of what
we're asking you to deliberate upon is quite large.
However, as those of you who have been on the
previous subcommittee are aware, we always bring in
additional experts, that you're here to bring
particularly to those deliberations the pediatric
perspective, because we have lots of technical
committees that have lots of expertise, and we will
always bring that additional expertise as needed to
the deliberations. But it's your particular
pediatric perspective and expertise that we depend
upon at these meetings.
I did want to spend a moment introducing,
so that you can put some faces with names, the
people who are now in the Office of Pediatric
Therapeutics, which is Sara Goldkind, who will be
speaking; Solomon Iyasu, whom you know, who has
been on detail with us for a while; Ann Myers, if
you'd put your hand up, Ann, who is our policy
analyst, so you'll have a face there; and Jean
Harkins, who is not here, but she is the person who
actually runs the Office of Pediatric Therapeutics.
I mention that because it is that office
that is mandated to particularly focus on the
ethical issues and the safety issues, and that this
committee within the Office of the Commissioner has
now also been identified to deal with those issues.
I also wanted to comment on some other
transitions for those of you who have been on the
subcommittee. I'm no longer with the Office of
Counterterrorism, Pediatric Drug Development.
Rosemary Roberts is the new office
director, and so
she's still going to be very active in the
pediatric issues, and the Division Director for
Pediatrics, Shirley Murphy, is now the Deputy
within that office. And we have a new Division
Director, just so you'll know these names. Lisa
Mathis I do not believe is here. She's dealing
with other issues this morning.
For the new members--and I apologize to
the old members because I know you've heard this.
I actually took it out of the slide on Monday
because I didn't think that everybody really wanted
to hear about all the accomplishments of the
previous committee. But I wanted the new members
to hear a little bit about what the previous
committee has actually--some of the issues they
have dealt with. And they have dealt with not only
the ethical issues that have to do with normal
volunteers, placebo-controlled trials, the
vulnerable population within pediatrics. They have
dealt with an enormous array of scientific issues,
from sleep disorders, hepatitis C, HIV, antiviral
drug development in neonates, the
epidemiology and therapeutics and development of
therapies for hyperbilirubinemia, clinical risk
management for HPA axis suppression in children
with atopic dermatitis, tracking cancer risks among
children with atopic dermatitis, and as you all are
aware, last February a discussion of the FDA
process and review of therapies for major
In addition, this committee has now
reviewed--before today's additional eight products
that you're going to be hearing about, has reviewed
over 22 products that were granted exclusivity, and
you have looked at the one-year post-adverse event
reporting that has occurred for those products. I
can tell you that this is an important process that
we are looking to evolve constantly. It came up
recently at a congressional hearing as to how were
we doing this and what were we doing with it. And
I think it's important that this committee realize
that it is important what you have to say to us
about whether we should do anything else in trying
to follow--gain a better understanding
happens to children after these products have been
either approved--or approved and particularly after
they have been studied, because as you heard
yesterday, they don't always get an approval or a
label change, but certainly they have been studied
and they may be granted exclusivity. And that in
itself often results in additional information.
As you go around this morning, it would be
helpful if you would identify if you were on the
previous subcommittee. I'd appreciate that just so
the new members will know. And also, I wanted to
particularly thank Sam--and is Steve here? I don't
see him. Oh, there you are. As Jan said, for
doing double duty. We are still in the process of
identifying the industry and consumer
representatives, a total different process, and
they very kindly agreed to continue to assist us in
these last rigorous days, the last few days.
And, again, thank you for being here, for
your participation, because I know it requires
quite a commitment, and for your thoughtfulness as
we move forward with this new committee.
DR. CHESNEY: Thank you very much, Dianne.
So I think we would like next to go around
the room and have the new Pediatric Advisory
Committee members introduce themselves, and I'd
like to start with the members who are no longer on
the committee, if they could--that was a joke. So
let's start with Dr. Maldonado.
DR. MALDONADO: Sam Maldonado. I work in
pediatric drug development at Johnson & Johnson,
and as Dr. Murphy said, this is my last session
with the committee. There will be a new member
DR. NEWMAN: I'm Tom Newman. I'm a
professor of epidemiology and biostatistics in
pediatrics at the University of California, San
Francisco, and a general pediatrician, and I'm new
to the committee.
MS. DOKKEN: I'm Deborah Dokken, and I am
also new to the committee, and I am a patient-family
representative and I really appreciate
having that voice on the committee.
DR. O'FALLON: Judith O'Fallon. I'm a
professor emeritus of statistics at Mayo Clinic. I
got called back half-time to cover a maternity
leave, by the way, going back. But I've been on
the committee since its beginning.
DR. FANT: My name is Michael Fant. I'm
an associate professor of pediatrics at the
University of Texas in Houston. My expertise is in
neonatology and in biochemistry. And I'm new to
DR. NELSON: I'm Robert Nelson. I'm
associate professor of anesthesia and pediatrics at
Children's Hospital of Philadelphia and University
of Pennsylvania. My clinical area is pediatric
critical care, and I also work in the area of
ethics, and I was on the previous subcommittee.
DR. EBERT: Hi, I'm Steve Ebert. I'm an
infectious diseases pharmacist at Meriter Hospital
and professor of pharmacy at the University of
Wisconsin, Madison. I'm an outgoing member of the
DR. CHESNEY: And my name is Joan Chesney.
I'm a professor of pediatrics at the
Tennessee in Memphis, and my interest is infectious
diseases, and I'm a former subcommittee member.
DR. JOHANNESSEN: My name is Jan
Johannessen, and I'm the Executive Secretary to the
Pediatric Advisory Committee.
DR. MURPHY: Dianne Murphy, Office
Director, Office of Pediatric Therapeutics, FDA.
DR. IYASU: I'm Solomon Iyasu. I'm
medical team leader with the Division of Pediatric
Drug Development and an epidemiologist with the
Office of Pediatric Therapeutics.
DR. CHESNEY: Thank you and welcome to all
the new committee members. You're in for quite a
ride, believe me.
Our first speaker this morning--and,
again, for the new committee members, what you're
going to hear about next was really a historic
process and a historic meeting on Friday. And Dr.
Sara Goldkind is going to introduce the topic for
us. She's a board-certified internist who did a
clinical fellowship in medical ethics at the
University of South Florida. She also has a
master's degree in religious studies with a focus
on comprehensive religious ethics--comparative
religious ethics, excuse me, and she's been with
the agency for almost a year, which she tells me
seems like longer than that.
DR. GOLDKIND: It's my pleasure to be here
today at the inaugural meeting of the Pediatric
Advisory Committee and to tell you about the work
of the Pediatric Ethics Subcommittee.
As Dianne mentioned, this is really a
landmark time in pediatric research. That's the
way we see it because we feel that this committee
as well as the Pediatric Ethics Subcommittee can
really make incredibly important decisions and
consensus statements regarding pediatric research.
So what I'd like to do now is talk a
little bit about the role of the Pediatric Ethics
Subcommittee. It is going to be a subcommittee
that addresses Subpart D referrals and also ethical
issues that impact on research affecting the
Going back to the part on Subpart D,
there's a mistake in the slide, and where it says
"Joint 21 CFR 50.54 and 45 CFR 46.407 referrals,"
those are referrals that will come to both OHRP and
the FDA, and we actually had one of those to review
on September 10th, which involved the effects of a
single dose of dextroamphetamine in attention
deficit hyperactivity disorder, a functional
magnetic resonance study. And Dr. Nelson, who is
the Chair of the Pediatric Ethics Subcommittee, is
going to give you a summary of the deliberations of
the Pediatric Ethics Subcommittee in that regard.
The subcommittee can also address
referrals that come only to the FDA under 21 CFR
50.54, and I'm going to talk about these
regulations in a little bit more detail. But if
there are no referrals and there are burning
ethical issues that we would like to address, we
can also take those to the Pediatric Ethics
Subcommittee for deliberation.
So now to go into a little bit more detail
about the regulations under which we can
referrals, Subpart D is entitled "Additional
Safeguards for Children in Clinical Investigations
and Research," and they are essentially identical
for DHHS and FDA. DHHS regs are Title 45, CFR 46,
also known as "the common rule" because 17 federal
agencies operate under those regulations. And the
FDA regulations are 21 CFR 50.
There is a notable distinction between the
two sets of regulations, and that is the issue of
waiving parental permission can be done under Title
45, CFR 46, but not under the FDA regulations. But
in terms of the Subpart D referral process and the
general categories of pediatric research, those are
identical between the two regulations. And what
I've done in these slides is include the citations
for both regulations.
So Subpart D has four different categories
under which pediatric research can be conducted.
The first category is 50.51/46.404, and that is a
category which states that the research involves no
more than minimal risk. And it essentially does
not discuss who benefits from the
basically describes that there's a ceiling of
minimal risk for exposure for the children.
50.52/46.405 is research that involves
greater than minimal risk but presents the prospect
of direct benefit.
And then 50.53/46.406 involves greater
than minimal risk but presents a prospect of
generalizable knowledge about the disorder or
condition, but there's no prospect of direct
benefit to the participants.
So those are three categories under which
an IRB can classify pediatric research. If the IRB
determines that it cannot classify the research
under those first three categories, however, the
IRB finds that the research presents a reasonable
opportunity to further the understanding,
prevention, or alleviation of a serious problem
affecting the health or welfare of children, and
the FDA Commissioner or Secretary, after
consultation with a panel of experts in pertinent
disciplines, and following an opportunity for
public review and comment determines the
So, in other words, if the IRB feels that
the research has merit for the general pediatric
population but cannot be classified under one of
the first three categories, it can make a referral
to one of the federal agencies--and I'll discuss
those details in a minute--to have the protocol
reviewed by an expert panel.
And so what must the research then
satisfy, according to the expert panel? The
research, in fact, satisfies one of the first three
categories, so the expert panel can make a
determination that after it reviews the research,
actually one of the first three categories does
apply, or the following three conditions are met:
the research presents a reasonable opportunity to
further the understanding, prevention, or
alleviation of a serious problem affecting the
health or welfare of children; the research will be
conducted in accordance with sound ethical
principles; and adequate provisions are made for
soliciting assent and parental
The composition of the Pediatric Ethics
Subcommittee is the following: Dr. Nelson is the
Chair. According to FACA, we also need to have two
members of the Pediatric Advisory Committee
represented on the Pediatric Ethics Subcommittee.
And in addition to Dr. Nelson, we included Dr.
Chesney and Dr. Gorman. And we supplemented the
Pediatric Ethics Subcommittee with an additional
group of core ethicists: Drs. Fost, Kodish and
The composition of the Pediatric Ethics
Subcommittee under both DHHS regulations and FDA
regulations states that the panel of experts in
pertinent disciplines, for example, science,
medicine, education, ethics, and law, and we
selected from among those groups according to the
protocol. But most of those groups were
represented on the Pediatric Ethics Subcommittee
that took place on September 10th. In addition, we
also had two patient advocates represent on that
So once the IRB makes the
that it wants to refer to a federal agency, it
refers to the FDA for regulated--if the products in
the protocol are FDA-regulated, and it refers to
OHRP if the research is federally funded or
conducted. And we have a very close working
relationship with OHRP, and when a protocol comes
to us, we also refer it to them for review, and
they refer a protocol that comes to them to us.
And in this case, the protocol was actually
submitted to OHRP, but upon our review it was noted
that two of the products in the protocol, both the
MRI machine and the dextroamphetamine, were FDA-regulated
and so we also had jurisdiction over that
The review would then be conducted by the
Pediatric Ethics Subcommittee expert panel, and as
I said, each protocol--we will have a core group of
ethicists, and it will be supplemented by
appropriate expert panel members and patient
representatives and/or community representatives.
The Pediatric Ethics Subcommittee will
bring its recommendations to the
Committee for endorsement, as Dr. Nelson will do
today, and then those recommendations will be
submitted to the Commissioner of the FDA for final
determination. Once that determination is
rendered, it will be forwarded to OHRP, and OHRP
will send the Commissioner's memorandum on the
Pediatric Ethics Subcommittee/Pediatric Advisory
Committee's recommendations on to the Secretary,
and the Secretary will have his final
determination, particularly in regards to funding
of the research.
So our goals in this process, clearly the
overarching goal is to advance an understanding of
pediatric research, and we'd like to do that
involving additional expert input and public input.
We also want to have transparency in the process,
and in that regard we had an open public comment
period before the Pediatric Ethics Subcommittee.
We also had an open hearing available at the
Pediatric Ethics Subcommittee. We also want to try
and respond to these protocol referrals in a timely
manner so that they will be helpful to
involved. And we want to be able to handle these
referrals in a consistent and clear manner so that
they can advance the general understanding of
pediatric research. And we would like to do this
and are doing this in harmony with OHRP so that we
have a united federal agency response to pediatric
DR. CHESNEY: Thank you very much.
Maybe what we could do is introduce and
hear our next speaker and then ask for questions
from the panel. Dr. Skip Nelson is the Chair of
the Pediatric Ethics Subcommittee, and he will
discuss with us the deliberations of the Pediatric
Ethics Subcommittee with the invited folk that Dr.
Goldkind just mentioned on last Friday. And the
issue here is that Dr. Nelson has prepared a
summary of the committee's deliberations, which you
have in front of you, and I'll let him highlight
issues that he wants to bring to your attention.
And what we're looking for here is an endorsement
by the committee. As we've mentioned, this took a
whole day of fairly intense deliberations last
Friday, and we don't anticipate that we will have
to repeat that process here. So we're just looking
for the committee's endorsement and any questions
that you may have, either for the process as Dr.
Goldkind just outlined it or for the specific
events of Friday as Dr. Nelson will present them.
DR. NELSON: Thanks. You have the
document before you. Let me just note, as someone
pointed out, I've got the wrong date in the
heading. That will be corrected before the final
version goes up. If you see any other typos, feel
free to write them down and share them with us
after our discussion.
I'd like to walk you through the document.
My intent here is not to read the document but to
highlight what is in it, since you can probably
read faster than I can talk. The introduction
simply restates the purpose of the meeting and then
gives a brief summary of what's in the summary.
But let me first start with what is the
primary issue that would be raised by
protocol, which is the particular risk of the
procedures that are contained within the protocol.
Now, as a preface to this, one of the
first things that an IRB must determine--and for
this exercise, the Pediatric Ethics Subcommittee is
effectively functioning like an IRB--that the
research design is sound. So after I talk about
risk, I'll then run through a number of recommendations and
stipulations that the committee made
to assure itself that, in fact, the research was
sound. But assuming those are made, the
subcommittee felt that the following risks would be
The first is the single dose of dextroamphetamine.
Is that minimal risk? The feeling
was no. We can a little bit later, if you'd like,
about the definition of minimal risk, but, in fact,
that was not minimal risk. But the subcommittee
felt that it was no more than what's called a minor
increase over minimal risk, and it lists the
reasons there, which I think I'll state in more
detail for highlight.
First of all, it has been used since 1937
with a good safety record. It is one of the only
two stimulants that are approved down to age 3, and
the children in this protocol are between 9 and 18.
The greatest side effects are irritability,
restlessness, agitation, and temper outbursts which
generally last only 4 to 5 hours, are infrequent,
and as you'll see later, one of our risk
minimization strategies was to say they should do
this in the morning so you don't have the kid up
all night after you do this. It's used universally
in pediatric practice, and the more common risks
are restlessness, anxiety, loss of appetite,
insomnia--again, why we made that recommendation.
There were two procedures we felt ought
to--well, a second procedure that we felt ought to
be drawn out and highlighted, and that's the
withholding of medication for 36 hours from the
kids with ADHD. The feeling was that also could be
characterized as a minor increase over minimal
risk. The reasoning here is that kids with ADHD
often are not medicated over the
weekend, often are
not medicated when they're not going to school, and
are often given holidays from the drug. So it
didn't feel that a 36-hour period of time was of
any significant risk to those children.
And then the remainder of the procedures,
which are outlined further along, we all felt were
appropriately considered minimal risk and,
therefore, were appropriate for either group within
Now, the one design recommendation that we
made was to consider narrowing the subject
population that's part of this protocol. There was
some discussion about the variability in both
neurodevelopmental stages and then response to this
dose of the stimulant between the ages of 9 and 18
years of age, with different points being raised as
to the scientific advantages and disadvantages of
either the younger age group or the older age
group. We didn't feel that we could make this a
stipulation, but felt that the investigators should
strongly consider narrowing that range within 9 to
18 to get a more focused population.
The other confounder that came up--and
this is also in response to some points made in the
public discussion--is that trying to tease apart
the changes that might occur in response to the
drug over time versus basic underlying differences
in terms of, if you will, the neurological
networks, that you need ideally to have treatment-naive
subjects with ADHD, or at least less ideally,
if that is a practical difficulty in doing in this
particular age group, try and get a more uniform
cohort of drug exposure, which is why we had the
discussion of picking the lower-dose range.
One reason for that was that the expert
scientists felt that often the dose over time that
you may need goes up, and if they unified the dose,
then probably you would end up with a more uniform
distribution of the length of exposure to
treatment. But we didn't feel that that reached
the level of a stipulation, but certainly felt that
that was a strong recommendation to consider
improving the scientific value of the study.
Now, there are a number of
modifications to the protocol. Point A, which I'm
not going to read, is basically my summary of all
of the procedures in the protocol. And one of the
recommendations is--it was very hard to find all of
these things, and it would be nice if they just put
them in one place so no one had to go reading
through it in all detail. One, for example, that
came up--and I'll just highlight this--is that
every child will receive a diagnostic MRI scan,
which is, in fact, part of NIH policy. You could
find that nowhere in any of the documentation, and
that came out during discussion. Things like that
need to be in the protocol.
I might add, what we will be doing is
depending upon both the Office of Pediatric
Therapeutics and the OHRP to make sure this
happens, so it's not something that we need to then
The second point, sequence of subject
testing. They're not planning to do the kids that
are twins. There are discordant twins, either both
homozygous and dizygotic. They're not going to do
those twins unless they see differences between the
kids with ADHD and the kids without ADHD. That
sequence of testing, which came out in testimony,
was very hard to find anywhere in the protocol, and
that needs to be included. They won't do the twins
if, in fact, they don't find a difference in the
It was very hard to find the right dose
since there were these dosing discrepancies, and so
that needs to be clarified. But I've stated what
the committee's understanding is, and, of course,
if this is different--and this is based on the
investigators' testimony--that will have to be
dealt with. And, again, I mentioned the morning.
A functional MRI. The protocol lacks a
discussion of what came out in the testimony of the
training that goes on to make sure these kids are
comfortable inside the machine, make sure they can
actually do the tasks that they're being requested
to do, et cetera, exclude kids from claustrophobia.
Not much in the protocol about that. I already
mentioned the diagnostic MRI scan, which
be in there.
Pregnancy exclusion. You only found that
in the parent permission form. The feeling was
that that needs to be discussed in the protocol and
the child assent documents, and in particular,
mechanisms for protecting the confidentiality of
the adolescent that she may or may not want to go
into the protocol knowing that there's a pregnancy
test depending upon activities. That needs to be
spelled out. We weren't making a judgment about
how that should be handled other than the
importance of the confidentiality in soliciting
There was a significance discussion of
neuropsychological--I would like to have questions
at the end, because what will happen is I bet you
some will be answered, but write them down.
Neuropsychological testing. There was a lot of
discussion about this testing. It's not being
performed for diagnostic or treatment purposes, and
we felt it would be a cleaner study if, in fact,
this information was not provided back
parents. Part of that discussion was based on it
not being done in that kind of a therapeutic
And then genetic testing. There is
testing being done only for zygosity, and we felt
since there was a whole slew of markers being done
and no discussion about the risk of those markers
relative to, say, late onset adult diseases, that
the cleanest way to do that would be to destroy the
data and the samples after you've determined the
zygosity of the twins, maintaining only that piece
Modifications to the parent permission and
child assent process in documents follow, of
course, those that need to be included from the
discussion of the procedures. There were a couple
of specific issues. One is payment. They were
proposing a lot of money--I didn't put it in here,
but a lot of money. We felt it was too much and
that basically the parents should get reimbursed
for expenses, and that for young children, a token--although
we didn't have a discussion of what that
is, but allowing the IRB to have some discretion,
and for older children who would be potentially
capable of working at a wage position such as
minimum wage, the wage model would be appropriate.
And, of course, consistent with FDA policy, this
would be, in fact, divided evenly over the protocol
procedures so that a child who withdraws in the
middle still gets part of the money.
They needed to pay attention to the
opportunity for dissent, particularly in the twin
pairs. We thought that the twin without ADHD could
be under some pressure to be in the study, and they
needed to provide that opportunity. And then some
clarification about the risks of the drug in the
actual consent document, and in many ways we
actually said you should overstate the risks in the
consent document. Although we do not feel that
this drug presents any risk of addiction, the
parents should know that, in fact, it's classified
as a drug of abuse, with an important distinction
being made by our experts between substance abuse
and addiction. It's one thing to say take
dextroamphetamine to be able to stay up for your
exams in college, but that doesn't lead to
addiction because generally you don't then want to
take it when you plan to fall asleep during
vacation. And, of course, both permissions.
Now, there were some specific questions
that we were asked to respond to, and I think for
these questions, perhaps I'll just read our answers
so that you get it clear.
What are the benefits, if any, to the
subjects and to children in general? There is no
direct health benefit to the children included in
the research. The protocol addresses the question
of a unique central response to stimulants in ADHD,
utilizing a better research design than previously
published studies and controlling for performance
differences. As such, the protocol may be able to
untangle clinical state and trait--meaning genetic
relatedness--differences through the use of
monozygotic and dizygotic twins who are discordant
for ADHD. Now, more speculatively--and this was
part of the discussion--the results may
understanding of ADHD in order to enhance
diagnostic precision and avoid misclassification
Now, the types and degrees of risk that
this presents to subject, I've discussed a fair
amount of that above, and, again, we thought that
all of the procedures other than withholding of the
medications and the blind administration of study
drugs were minimal risk, and those two were a minor
increase over minimal risk.
In terms of whether the risks are
reasonable in relation to anticipated benefits,
this is a key point. For all subjects enrolled in
the research, the risks to subjects are reasonable
in relationship to the importance of the knowledge--i.e.,
the benefit to children in general--that may
reasonably be expected to result. However, it is
only for the children with ADHD that the research
is likely to yield generalizable knowledge which is
of vital importance for the understanding of the
For you regulatory junkies, you'll know
that I'm reading language that is contained within
the regulations as well, but the important thing is
then that children without ADHD do not have a
disorder or condition, which is why this then could
not be approved by the local IRB, although the
brain response of children without ADHD to a single
dose of dextroamphetamine is an important part of
the generalizable knowledge to be gained in this
research based on the first step of the comparison.
So we thought it did present a reasonable
opportunity to further the understanding,
prevention, or alleviation of a serious problem
affecting the health or welfare of children.
So, with that said, the determination of
approval categories that the subcommittee felt was
appropriate was that the interventions and
procedures included in the research can be approved
for the children with ADHD under 45 CFR 46.406 and
21 CFR 50.53. That's the category that says no
more than a minor increase over minimal risk; that
basically the experiences are reasonably
commensurate with those inherent in
condition; the intervention is likely to yield
generalizable knowledge about the subjects'
disorder or condition, which is true for the ADHD;
and then that there are adequate provisions for
Now, because of the lack of a condition in
the kids without ADHD, we felt that it could not be
approved under those three categories consistent
with what the IRB found. But we did feel that it
presented a reasonable opportunity to further the
understanding of a serious problem; that it would
be conducted in accord with sound ethical
principles; and that there are adequate provisions
for soliciting assent and permission. And as such,
we recommend that the involvement in the research
of children without ADHD is approvable, assuming
all of the required modifications are made, under
46.407 or 50.54.
Then one final point. It had been brought
up in some of the public testimony, the applicability of a
particular case known as Grimes v.
Kennedy Krieger Institute. Whereas, normally or
often we might anticipate that the kinds of studies
that come before us are going to be multi-institutional,
multi-site, and multi-state and
we're not going to want to get into the business of
commenting on the legal interpretations of all of
those different environments, we have the unique
situation here where this is a single site located
within Maryland, and this is a fairly high profile
court decision. So prior to the meeting, I had
asked for clarification by both FDA and OHRP
attorneys about the applicability, and the feeling,
which I agree with and I think some other
knowledgeable members of the subcommittee that I've
talked with also agree with, is that the holding is
not applicable for two reason: One is NIH is a
federal enclave and not subject to state law; and
second is when this case was considered,
reconsidered, the Maryland Court of Appeals stated
that "the only conclusion that we reached as a
matter of law was that, on the record currently
before us, summary judgment was improperly
granted." So attorneys have a term called "dicta,"
which means basically the judge expressed opinion
on other matters, but, in fact, those other matters
are not binding as law. So for those two reasons,
it was felt that we did not need to get into the
issue of the applicability of this particular case
as a subcommittee.
So, with that summary, I guess how about
questions about the document, the protocol and the
like, and then after that, I certainly would be
interested in any more general questions about the
process, if that's a reasonable approach.
T1B DR. CHESNEY: We actually have a visitor
this morning. Dr. Bern Schwetz is the Director of
the Office of Human Research Protections, and I
wondered if we could call on him to come and make a
few statements before we invite questions.
DR. NELSON: Sure.
DR. SCHWETZ: Thank you very much, Dr.
Chesney. I just wanted to express my thanks for
FDA and this Advisory Committee creating the
opportunity to do this joint review in one process
rather than have the FDA and OHRP going
ways to review a protocol of this kind where
there's joint jurisdiction. So particular thanks
to Dr. Nelson for chairing this review and this
subcommittee. In our opinion, the process went as
we had hoped it would, with a very smooth review,
but probably more importantly, a thorough review
and a recommendation that we feel is a good
recommendation coming to this Advisory Committee
for your final review and hopefully approval.
The review was done in a timely manner,
and that was a challenge considering that this is a
new committee, a new subcommittee, but it was done
in a timely way. And I think it was done with an
appropriate cast of experts. So we're very pleased
with this process and, Dr. Chesney, with your
permission, we're hoping that in those cases where
we have joint jurisdiction over a protocol in the
future that we'll be able to bring it back and
handle it this way.
So thank you very much.
DR. CHESNEY: Thank you for your comments,
and maybe you could stay here just for a
and we'll ask now for any questions of the new
committee members for either Dr. Goldkind, Dr.
Nelson, or Dr. Schwetz.
DR. MALDONADO: I just have a quick
question. Dr Nelson, I see that on page 1 you made
the statement--and I basically also agree that you
did a great job with this review. You listed the
minor increase over minimal risk, which I agree are
just a minor increase. But then on page 2, you
gave a--maybe I am just overreading this, but the
subcommittee strongly encourages the investigators
to narrow the age. I know you focused on that, and
I may have missed it. My understanding is this is
a single-dose study. I don't know what the
concerns will be with single-dose for neurodevelopmental
stages with a single dose, low dose.
DR. NELSON: The issue is not the impact
of that dose. There might be a response difference
that you could see, but the question is teasing
apart--there is a debate on previous studies that
have been done of structural MRI scans,
are actually two previous studies of functional MRI
scans where the question is whether or not some of
the differences that may be seen are not related to
any underlying biological differences, neurodevelopmental
differences, but, in fact, the kids
with ADHD had been chronically exposed to a
medication which--I'm not a neuroscientist. I
guess I would characterize it as whether it's
created some element of remodeling of those
systems. And so try and eliminate that confounder,
the feeling was if they would narrow the age range
and then try to either get treatment-naive, which
may be difficult, or at least treatment-uniform at
lower doses which would give you hopefully a lower
duration of exposure, that you might be able to
begin to tease apart those two issues. That was
the scientific discussion among the experts.
DR. CHESNEY: Yes, Dr. Fant?
DR. FANT: Yes, this question may be a bit
naive, but it quickly comes to mind, especially
from the standpoint of taking the kids off the meds
for a couple of days and trying to
naivete and the question that that may have on
And so the question is: Are there any
over-the-counter stimulants or food additives that
could potentially interact with their response and
somehow muddy the data? And if so, is that being
controlled for or addressed in the protocol?
DR. NELSON: The answer is yes. I mean,
one of the discussions, of course, by the IRB was
whether caffeine and the element of caffeine
consumption could be used as a judgment. So there
are some confounders and the need to collect that
data, and it would be sort of self-defeating if
over the weekend you take the kid off of his
medication and then he drinks, you know, a couple
of cases of Jolt Cola--which I don't even know if
it's still made or not. I have no stock in that
company. No conflict of interest on that
recommendation. Or Mountain Dew. I think Mountain
Dew has a lot of caffeine in it. So, yes, they
need to pay attention to that.
DR. FANT: And even with adolescents who
may be concerned about weight and appearance and
that sort of thing, some of the additives that are
contained in supplements in GNC at the mall, you
DR. NELSON: Right.
DR. MURPHY: So, Dr. Fant, was that a
question or just a recommendation, I guess is what
DR. FANT: Well, it's a concern because if
we're talking about giving a drug to, quote, normal
kids, you really want to ensure that the data is as
clean, as interpretable as possible. You wouldn't
want to muddy the waters on something that could
have easily been avoided.
DR. MURPHY: I think that, you know, if
there are recommendations that this committee would
like to make, that's appropriate. And we wanted to
make sure that that was--
DR. NELSON: I see that as just a
refinement of the recommendation to make sure your
subject populations are as uniform as possible. So
it's certainly consistent with our
DR. CHESNEY: But we maybe should add a
sentence or two, Skip, just to--I thought that was
an excellent point if somebody does--I don't know
how long those stay in the bloodstream, but if
that's their breakfast and then they show up for
the fMRI, there may be a confounding variable.
Yes, Dr. O'Fallon?
DR. O'FALLON: Did you recommend that they
collect that information?
DR. NELSON: No, but we can add a sentence
DR. O'FALLON: Okay. I think it would be
helpful to make sure that they elicit that
DR. CHESNEY: Deborah, you were next.
MS. DOKKEN: I first want to compliment
Dr. Nelson's subcommittee. I mean, not only did
you do a thorough job, but I could fully understand
what you were talking about, and I was glad that
you included the issue of compensation and the
potential pressure on the twins in the assent
I was also glad that at least in some way
you directed attention to the permission and assent
forms and talking about the chronology of the
procedures. But I had a further question about
those forms, which, frankly, I don't know what
their rating is in terms of reading level, et
cetera. But they certainly to me were not easy to
read and, in fact, were mixed. Sometimes they used
almost simplistic language; then you know, the next
sentence--did you talk at all about just the forms
themselves and the language beyond the chronology
DR. NELSON: Yes, we did. But that's just
captured on page 5 under age where we just say
there's technical language would is not explained
in lay terminology.
I think two points on the process: A,
this still then needs to go back through the NIMH
IRB, plus it has two offices, not just one now,
that will recognize that for this to be finally
approved would require that kind of changes in the
documents. And I'm absolutely confident that with
OHRP and FDA's involvement in making sure that
these requirements happen is that they will be in
more understandable language.
My own philosophy is there's no reason for
us to sort of nickel-and-dime the actual text, but
that was discussed.
DR. CHESNEY: Could I just add, there was
a great deal of discussion about the protocol and
about the consent form, and, in fact, one of the
committee members asked if this was a draft of the
consent form. And the folk from the NIMH
apologized and they said that they got so busy
addressing the issue of whether this would have to
come to a subcommittee that they hadn't really paid
that much attention to the consent form, but that
they would do that.
DR. NEWMAN: I also want to compliment the
committee on a really very impressive, thorough
review. And I have three points. One is just a
Looking on page 7, comparing
Parts a) and
b), under--I'm just trying to figure out how--I
have reservations about the value of the research
to kids with ADHD. I really--it's very hard for me
to picture how this research will be useful, but
maybe that's just due to my limited scientific
knowledge. It says under C, the procedure is
likely to yield generalizable knowledge about the
subjects' disorder or condition, which is vital
importance for the understanding or amelioration.
And I really couldn't go along with this being of
vital importance. But then under B it says it
presents a reasonable opportunity to further the
understanding, and I could go along with that. So
I'm not clear on which of these two is the standard
that this research has to pass.
DR. NELSON: You point out an interesting
ambiguity in the regulatory language for which
there is no specific guidance about how one
interprets "vital importance" or "reasonable
opportunity." My own view is that it needs to meet
both, that you would not want reasonable
opportunity to be a lower standard. And the issue
of vital importance is fundamentally subjective.
And from that standpoint, there was a recognition--and
that's why I put earlier on the notion that
more speculatively. I mean, this is what--I would
characterize this as sort of a basic science
question about the response and the neurodevelopmental sort
of receptor physiology.
If, in fact, there is no difference, it
would have an impact significantly on the
understanding of ADHD, and if there is a
difference, it would impact significantly, and then
might, not in this protocol but down the line,
potentially drive diagnostic and therapeutic
differences. One thing I learned is there are
individuals who are touting different structural
scanning tools for diagnosis of kids with ADHD, et
cetera, that many felt, in fact, were not evidence-based.
And so after hearing that discussion, the
subcommittee members felt that it did meet the
regulatory standard both for vital importance and
There was no, if you will, easily defined
paradigm for that.
DR. NEWMAN: Okay. Well, that sort of
leaves me uncertain. Let me go to my next
question, which was in the consent form they
specifically addressed the issue of potential
adverse effects of the MRI in terms of identifying
some little something which then people go, oh, we
wonder what this is, maybe you should go have that
checked out, but that not being covered by the
research study and the family may or may not have
medical insurance to cover that. And I believe
that's more than minimal risk. That's something
well beyond the range of what people experience
every day, the possibility of having some brain
abnormality uncovered, which then you have to
figure out how to deal with. So I wonder why that
wasn't considered, you know--
DR. NELSON: It was. I didn't include it
in here because the data actually is that out of
3,000 scans, they've only found four abnormalities.
And of those four, two were benign cysts and two
were actually early diagnosis of tumors
child benefited from that. So there was a
discussion in the subcommittee about the
implications of using a screening test in a
population that--you know, being a statistician,
you can understand the sensitivity and specificity
issues. But after that discussion and the fact
that it's being conducted--it's not a diagnostic
reading of the functional MRI. It's a separate
diagnostic MRI scan that, after hearing the
discussion, we felt that it was appropriate to
consider that under that category.
So they have enough data, I think, to sort
of--at least reassure me that they're not going to
be turning up a lot of things that end up with
DR. NEWMAN: If I were a parent trying to
make an informed decision about participating in
the study, those data would be very helpful to me
to know what--to say this may happen, but they
don't give any numbers on how likely it is to
happen and what might be found. And so, you know,
I just think it's hard to ask someone to
something, you tell them that risk, but you don't
tell them how big it is. So I think that would be
helpful for them.
And my last question was just about the
financial compensation. For the controls, you
know, it sounds like this may take several hours
out of the parent's day, and so, you know, having
tried to get people to enroll in studies before,
you know, I don't know whether there have been
pretests or what it would take. But if you're
going to ask someone to bring their normal child in
and get a lot of stuff done, you know, to me I
think maybe $100 or $110 split between parent and
child might not be enough to get people to want to
DR. NELSON: No, it was not split between
parent and child. That would be wages for the
child, and the investigator actually said--and this
did influence the committee--that she did not
anticipate any problem with enrollment even if the
compensation and stipend was zero. I'm just
telling you, that's what she said.
DR. CHESNEY: Could I just also comment
for Dr. Newman? It was suggested that they publish
the fact that they had only four abnormal MRIs out
of 3,000, which is certainly not within the realm
of most of our experience where MRIs show you all
kinds of things that you don't want to know. So
that suggestion was made.
We had a lot of discussion about the
science because it's a very--to me it was a very
complex study to understand, and a lot of it was
based on the study by Viga (ph) et all that was
published in '98 or '99. And I thought--it wasn't
until the very--long into the meeting that Dr.
White, who's a child psychiatrist with a lot of
familiarity with functional MRI scanning, pointed
out the importance difference with respect to the
performance task in this study as compared to the
one published in '98 or '99, which had led to
perhaps some erroneous conclusions.
So I think that after a lot of discussion
we finally became convinced that the science was
important, if that's of any help.
Any other questions or comments? Dr.
DR. O'FALLON: I was just wondering about
the pregnancy exclusion. I didn't look at the
consent form closely enough to see. Presumably
they are excluding on the basis of pregnancy. Is
DR. NELSON: They are. It wasn't very
well described in the consent form, which was our
DR. O'FALLON: Okay. Well, but that's the
point. So they have to--so they do have to take
this--they have to have a pregnancy test. Now, I'm
just curious. How do they think they're going to--I mean,
how do they plan to deal with exclusion
basically on pregnancy alone when they don't--they
can't tell it to the parent?
DR. NELSON: They didn't outline that,
but, I mean, I'm confident that they can come up
with a procedure. We're just asking them to do
that, and I'm sure OHRP will make sure it's a good
DR. O'FALLON: Okay. I wonder how they
are going to do it.
DR. CHESNEY: Very important points.
Any other--Dr. Newman?
DR. NEWMAN: Let me just explain what my
reservations are about the value of the research,
and maybe you can reassure me. It seems to me that
ADD is a clinical diagnosis, and in making the
diagnosis, one of the main decisions that you're
trying to guide is whether to begin stimulant
medication. And if you begin stimulant medication,
you want to see whether it helps the child and
monitor that and discontinue it if it's not working
and continue it if it is.
And I just cannot visualize how an MRI
scan would ever sufficiently predict a child's
response to medication to be clinically useful,
because, I mean, they may well find some
statistically significant differences where the
something or other is, you know, a half a standard
deviation different in one group than the other, or
maybe they're quite different. But the fact is
whatever they find, the question is really whether
this child would benefit from treatment or not.
And, you know, the way you determine that is
whether--either trying the treatment and seeing if
it helps, or if you were going to do a study to see
whether imaging helps, you would see whether
imaging predicts response to treatment, not whether
imaging predicts or is associated with someone
having received this clinical diagnosis.
So I am a little bit worried if it does
show a difference that this will spawn a whole
imaging industry of people wanting to get their
children's heads scanned to see whether they really
have it or not, which I think would just be going
in the wrong direction.
DR. NELSON: I guess two comments. This
has nothing to do with the clinical response of the
children. There is no benefit. It has nothing to
do with that. Whether or not it--if it does show a
difference, appropriately designed, it would spawn
a functional MRI industry I think is speculative
and, in fact, is explicitly, if you at
excluded from what an IRB ought to consider. The
long-term policy implications of research is not
something that IRBs are supposed to consider, and I
wouldn't necessarily import it under vital
The question is whether or not there are
structural or functional differences, and
presumably based on receptor density, et cetera--it's not my
area so I'm just saying things that you
could have read in the protocol and listening to
the scientists. And as a basic science question, I
think that's an important one. And how it might
then impact down the road in terms of understanding
whether there's a differential or similar response
to stimulants, I mean, the literature is quite
mixed in terms of reading some of the background
material in the protocol.
So there is no connection in doing this
with determining why they might respond clinically.
There is no--and, in fact, many of our recommendations were
meant to prevent that confusion
from being in the minds of the
removing any semblance of benefit from the sort of
surrounding aspects of the science. But, you know,
I think ADHD is a controversial area, and it's
partly why we felt this needed to be looked at
carefully and then done well, because I think the
positive or negative results could have an impact
in different directions.
DR. CHESNEY: I think Skip expressed it
very well. The purpose of the study was not to
have any clinical diagnostic value or clinical
implications. The purpose of the study is really
to understand, as Skip said, the neurophysiology
and neurochemistry--to try to understand the
neurophysiology and neurochemistry of ADHD better,
and because of the twin aspect, to see if there are
any genetic aspects.
DR. MALDONADO: A quick question that goes
beyond this study, but it's in the context of ADHD.
One of the premises that I think a lot of
researchers' work is under that if the studies can
be done in adults, don't do it in
now adults are being diagnosed with ADHD. Has
something similar been done in adults or can be
done in adults, you know, consenting adults, so you
don't use this area of consent of children?
DR. NELSON: Two points. That specific
question was raised by the subcommittee. There
have been similar but not identical studies, but
it's clear that the adults are different in this
regard and that the information that you would get
would be of no use to this issue. And that
discussion actually is why you may even--in the
discussion it was clear that the scientific
arguments might push you in the direction of using
actually the 9 to 12 age group as opposed to the
older age group because there may even be those
kinds of adult changes when you get into sort of
late adolescence. But we felt that that was not
clear enough that we would make a stipulation as
opposed to recommendation.
So I think that is an important principle,
and it was asked and answered in the negative, that
adult information here would be of no
answering this question.
DR. CHESNEY: Dr. Schwetz, did you have
any additional comments about the questions from
DR. SCHWETZ: No, I don't have anything
else to add. Thank you.
DR. CHESNEY: Dr. O'Fallon, you look like
DR. O'FALLON: I hesitated simply because--but I'm
a mother and not an M.D. I've had an MRI.
I don't know what--for my neck. I was wondering
what a functional MRI for the brain involves for
DR. NELSON: Nothing different than an MRI
DR. O'FALLON: But the question is they
are enclosed, so there is the issue of
DR. NELSON: Correct, but they have
screening procedures for that. There's no issue in
that. The kids are actually less claustrophobic
than the adults.
DR. MURPHY: Skip, why don't you describe
the screening procedure--
DR. NELSON: They have a training MRI scan
which is--and they make--you know, first they've
got to make sure the kids can do these tasks, so
they use the stop task and a training MRI scan.
They have a whole sort of session. I mean,
everybody--if a kid doesn't want to do it, then
that's the end of it. You know, their procedures
are excellent with respect to that. The issue is
not that they're not doing it. The issue is they
just didn't describe it in the protocol. They
described it quite completely in the discussion on
DR. MURPHY: I think as a risk what you're
trying to get at is that those kids that are going
to have that impact of anxiety, psychological fear,
will be--will not be enrolled. In other words,
that's where the screening procedure would help
select those children out.
DR. O'FALLON: Yes, but, of course, the
screening itself could cause this--I
could precipitate this anxiety. I don't know what--at the
time of my MRI, I was told that there's a
fairly high percentage, like 25 percent of adults,
anyway, that experience--well, that's what I was
told, when I was told about it, that experience
DR. GOLDKIND: Could I speak to that?
They actually show the kids a video, and they have
a very well organized approach, even before they do
the screening program that was described to us on
Friday. Additionally, they said that because
children are smaller than adults physically, they
are not as confined. They don't have the feeling
of claustrophobia that adults do based on physical
size and also based on psychological orientation.
Generally speaking, children don't have as high a
claustrophobia rate as adults do.
So for all those reasons, the subcommittee
felt that it was a minimal risk intervention. And
then as Dr. Murphy said, if a children demonstrates
hesitation at any step along the way prior to
getting to the actual enrollment,
DR. NELSON: Twenty-five percent sounds
quite high to me, anyway, even for adults.
DR. O'FALLON: Maybe it's because of the
practice of ours. We have a whole lot.
DR. CHESNEY: Let me ask, not seeing any
further hands being raised, does the committee feel
that they are comfortable endorsing this summary of
the events of Friday? We're not required to take a
vote on this. Unless there is somebody who is not
comfortable endorsing this, we would like to pass
on to Dr. Murphy the committee's endorsement.
DR. CHESNEY: Not seeing any hands being
raised, I think that we can--yes, Dr. Nelson?
DR. NELSON: I just want to ask, you know,
in terms of adding the issue of collecting data and
trying to exclude caffeine and other stimulants
under the design recommendation and the discussion
of the communication of the risk of inadvertent
findings on the diagnostic MRI scan, can that just
be made by office staff? Or do you want me to just
do it myself and give it to you?
DR. JOHANNESSEN: We can do that.
DR. NELSON: Okay.
DR. CHESNEY: Thank you very much, Dr.
Nelson, for chairing this--
DR. MURPHY: We have one more question
over here. Would you like to please identify
yourself for the committee and ask them this
DR. STITH-COLEMAN: My name is Irene
Stith-Coleman from OHRP. What I would suggest is
that if--in terms of the additional statement,
could you clarify if you recommend that it be a
recommendation or stipulation? That would be of
help to OHRP.
DR. NELSON: The first one about caffeine
or other stimulations is going to go under the
design recommendation, not stipulation. And then
the comment about communication of risk, one of our
discussions at the meeting was whether they, you
know, have all the data, but I think the
recommendation that they communicate that
information in a meaningful fashion to
would go under the diagnostic MRI scan, which fits
under a stipulation. The only thing that's a
recommendation to consider, which they could then
come back with arguments for or against, is number
3. Everything else is stipulations.
DR. MURPHY: That was helpful. Thank you.
This is a new process. As Dr. Schwetz said, we're
very enthusiastic about the fact that we aren't
setting up a process that would almost engender or
increase the possibility of having differing
recommendations if you empanel two different groups
and have two different sets of experts. There's
always a probability that you going to get two
different sets of answers. So I think that--however, it's
been very helpful to hear the
comments from this group, and I think that at this
point, Dr. Schwetz, what we need to make a cut on
is where recommendations would just go straight up
forward via both of these mechanisms versus if
there were some major concerns, what we would do in
that situation. I think we're not at that level
right now, but that is certainly
something we would
want to consider for the future.
DR. NELSON: Just one other point that I
think, as word goes out, might be surprising to
many IRBs, although I realize that it's, in fact,
the correct interpretation of the regulations, many
IRBs do not think simply because you're using an
FDA-regulated product in a clinical investigation
or in the research that it's an FDA--that the FDA
has oversight. You know, both of these products
are being used in accord with clinical
recommendations at doses that are being done
clinically. And I think that to many IRBs might be
a surprise. So just to alert you to that as this
word might trickle out. I do know that the FDA
does have jurisdiction, even if it's an approved
drug being used in a clinical investigation. But
many IRBs don't think that--or don't know that, I
DR. MURPHY: And it's new for the agency,
so actually it's something that we are making sure
everyone within the FDA is aware of
also. So I'll
just give you that sort of forewarning.
DR. CHESNEY: Thank you very, very much to
everybody who prepared for Friday's presentations
and for the process, Dr. Nelson for chairing it
all, and Dr. Schwetz and the other members of the
OHRP who were there, but who also took the time to
come today. We very much appreciate your time.
And thank you to the committee for your questions.
They were very, very perceptive given that you
hadn't been at the meeting Friday. You really
raised some very important and additional issues.
I think I will move on to--
DR. MURPHY: I just have one last person I
wanted to thank, and that's Terry Crezenzi (ph) and
Sara Goldkind, working with OHRP, spent many, many,
many weeks and months putting this process
together, and just because she made the terrible
decision to leave us and go on detail elsewhere, I
wanted to make sure we recognize the contributions
that she has made to this process.
DR. CHESNEY: Thank you.
We don't know
about all the behind-the-scenes work, so thank you
very much for clarifying that.
All right. Well, moving on to the next
section of today's meeting, let me introduce Dr.
Solomon Iyasu, who is a pediatrician and medical
epidemiologist. He was with the CDC for 13 years
leading the Infant Health Program there. And here
at the FDA, he's a medical team leader in the
Division of Pediatric Drug Development and a
medical epidemiologist in the Office of Pediatric
Therapeutics. I don't know how you all keep track
of who you are.
Today's talk will provide an overview of
the BPCA mandate for adverse event reporting, the
review process, and FDA's adverse event reporting
system. Dr. Iyasu?
DR. IYASU: Good morning. It's a pleasure
to be here and present to you the adverse event
report for several products that have been given
The Best Pharmaceuticals Act for Children,
which was enacted in 2002, does have a
for mandatory reporting of adverse events for
products that have been given exclusivity. Under
Section 17 of that act, FDA is required to review
adverse event reports during the first one year
after exclusivity is granted to a particular
product. And once that review is done, then the
FDA will report a summary to the Advisory
Subcommittee, which now is a full committee, for
their review and recommendations.
The review process that we have
implemented at FDA for drug products includes a
very close collaboration between the Office of Drug
Safety, which does the primary review of the
adverse events reported for the one-year period,
and then also the Division of Pediatric Drug
Development, who would be participating in this
review, and then finally the Office of Pediatric
Therapeutics, which is the new office which has
overall responsibility over adverse event reporting
for pediatric issues.
Just to outline to you what we've been
doing over the last two years in terms
review process, we have implemented sort of a
process which includes and defines responsibilities
for each of the participating offices. The Office
of Drug Safety has responsibility for reviewing the
adverse events reported during the one year and
also has responsibility for immediately discussing
any serious unexpected events including deaths with
the Office of Pediatric Therapeutics and also the
Office of Counterterrorism. And, finally, it has a
responsibility also for submitting the written
safety review and sharing them with OCTAP, which is
the pediatric group, and the Office of Pediatric
Therapeutics, and, more importantly, with the
review divisions that are responsible for these
particular drug products.
Then OCTAP, which is Office of
Counterterrorism and Pediatric Drug Development,
and OPT have joint responsibilities for also
notifying the Office of Drug Safety once
exclusivity determination is done for any products,
so that the tracking could start then for a period
of one year after that date of determination.
The medical officers within these two
office also have roles in reviewing the ODS reports
that are submitted, and then also looking at the
individual adverse event reports, the MedWatch
reports, and also preparing summaries and
presentations for this committee.
We try as much as possible to focus the
adverse event presentations on issues, safety
issues that may have arisen during the review
process so that the committee's time is better
spent on important issues.
We have also developed, in collaboration
with the Office of Drug Safety, a template for
summarizing the review, and the safety review
includes an executive summary that sort of
highlights what the issues are from the review. We
also include in that template a review of the
adverse event reports for adults and pediatric
patients from the original drug approval date up to
the time that the drug has been reviewed for the
exclusivity process. So it's a longer view, but
it's an overview, really, trying to see
number of reports have been for adults and in
pediatrics, and also trying to get a handle on
whether--how many of them were actually U.S. origin
and how many of them are actually foreign reports.
Then for the more focused pediatric
review, we have a detailed template which I'm
highlighting here were the issues of the specific
reviews that are done by the Office of Drug Safety.
We expect counts and labeling studies of the top 20
most frequently reported adverse events within the
pediatric population as well as adults, but we
focus more on the pediatric issues. We also try to
get from the MedWatch reports the summaries of the
demographics, age, gender, distribution of the
adverse event reports for the one-year period,
including a description of the serious outcomes,
indications, and doses that may have been
associated with these adverse events.
Then there is an evaluation of whether
these adverse events reported during the one-year
period are unexpected events or are they unique to
pediatric patients and not reported in
there's an evaluation that's done sort of comparing
adult and pediatric reports.
Also, an evaluation of whether there is an
increased frequency of non-pediatric adverse events
in this population, but this is done for the one-year
period. And then, finally, sort of developing
adverse event profile for that particular drug
product, which will then sort of highlight what the
issue is, if there is an issue that has developed
during that review process.
We also have for the denominator data,
trying to understand what the exposure us in the
pediatric population, we use various databases that
are available to FDA, which I'll briefly describe
later on, which estimate drug use in the outpatient
setting for this drug product, as well as for the
The role of the Pediatric Advisory
Committee is really to assess and discuss the
presented adverse events. We've been doing this
now for almost two years. And if appropriate,
recommend additional pediatric review
regulatory action if deemed appropriate.
T2A The role is evolving. This is a new
committee, and there may be other responsibilities
or even roles that would be defined as we go into
having more experience with this process.
Now, I want to sort of give you a brief
overview, top-line view of what the adverse event
or the Postmarketing Drug Surveillance Program
includes and the various components that may be
tapped to assess drug safety. The cornerstone
about this is, of course, the passive surveillance
system, which you've heard about so much in
previous presentations, which is the Adverse Event
Reporting System, which includes adverse event
reports, spontaneous reports, and manufacturer
reports that are sent to FDA.
I also mentioned sort of the--on the
denominator side sort of trying to assess exposure,
the drug utilization databases that FDA has access
to, which include outpatient, inpatient, and some
Other databases that may be
for evaluation of adverse events, external health
care databases which may includes claims databases
from special populations or from the general
population, and then there is also information sort
of a repository of background incidence rates on
different adverse events or conditions that may
come from hospital discharge surveys or from the
literature that we may actually tap in our
Then, finally, there are some active
surveillance systems that look into possible drug-associated
adverse events. I'm not going to go
into detail about this, but the DAWN is the Drug
Abuse Warning Network, and then NEISS is the
National Electronic Injury Surveillance System,
which is run by CDC, and TESS is the Toxic Exposure
Surveillance System, which is run out of the Poison
Now, just to give you an overview of the
most pertinent one, which is the AERS database, as
some of you probably know. It originated in 1969
as the Safety Reporting System. It currently
contains more than two million adverse event
reports in the database, contains drug and
"therapeutic" biologic adverse event reports, with
the exception of vaccines which has a separate
reporting surveillance system.
Just to give you some idea of what reports
are, they are mostly voluntary/spontaneous reports
that may come from health care professionals,
consumers, patients, or others. But also a large
majority of them are actually mandatory reports
that come from manufacturers required for
postmarketing reporting purposes by law. All
adverse drug experience information obtained or
otherwise received from any source, foreign or
domestic, will be included in this. And to give
you more detail, there will be more detailed
discussion later on about this.
But in 1993, the whole Adverse Event
Reporting System was redesigned and the MedWatch
form was developed. You probably can't see this
slide, but in your handout you probably can
identify some of the design aspects of
system. But, in short, this is the form that
unifies in terms of reporting for drugs and also
for biologic products and also for devices and
Now, by law there are definitions for
different kinds of reports. What manufacturers
must report is defined under 21 CFR 314 that
includes all adverse event reports from commercial
marketing experience, postmarketing studies, and
scientific literature. And this may include all
domestic spontaneous reports that must be reported
to the FDA. In terms of foreign or literature
reports, all serious, unlabeled events are
mandatory in terms of reporting. And it may
include also study reports which may be serious,
unlabeled, or any adverse event with a reasonable
possibility that the event may be related to a drug
Adverse drug experience is also defined by
the regs. Any adverse event associated with the
use of a drug, whether or not considered drug-related--this
is an important point--has to be
reported. This may include accidental or
intentional overdose or occurring from abuse or
drug withdrawal or failure of expected
Now, I mentioned before the serious
adverse events, and there is a regulatory
definition as well for this: any event occurring
at any dose that results in any of the following
outcomes. And this has been mentioned several
times in yesterday's presentation. Some of you
were not there, but this may include deaths or
life-threatening adverse events or something that
results in hospitalization or prolongation of
hospitalization or persistent/significant
disability or may result in a potential congenital
anomaly or birth defect or requiring intervention
because of an adverse event associated with a drug.
Also, there's a definition also according
to the regs for unexpected adverse drug events or
experience: any event not listed in the current
labeling of the drug product, including events that
may be symptomatically and
related to a labeled event, but differ because of
greater severity or specificity. So examples may
be like hepatic necrosis versus hepatitis. So
there is a regulatory definition as well for those.
Now, just to briefly go over the strengths
of the AERS system, it includes all U.S.-marketed
drug products. It's simple because it's passive
surveillance. It's less expensive than having an
active surveillance system, which may be very
expensive. It provides for early detection of
safety signals, and especially good for rare
There are some very significant
limitations of the AERS system. Underreporting is
a serious problem, but this varies from drug to
drug and also over time. Reporting may be more
during the early phases of the marketing and may
taper off later on. If there is media attention or
public attention on a particular safety issue,
reports may go up. Or it depends on what kind of
drug it is, whether it's OTC or prescription drug.
You may not get as many reports for OTCs
and so on.
So there is a problem with underreporting.
Then there are also issues about quality
and completeness of reports. That also varies, it
often may be poor. You may not get information
maybe that would help you assess temporality of the
drug exposure with the event. You may not get
information on concomitant medications or may not
get very good medical history of the patient from
whom the adverse event is being reported. So that
is an issue which is sort of common to all passive
Another important aspect in terms of
limitations, the limited ability of the system to
really estimate, help estimate true adverse event
risk rate because the numerator is uncertain
because of underreporting, which I mentioned, and
also the denominator must be estimated or it's
projected from sort of drug use databases that we
have, virtually--may be difficult for some
inpatient or OTC drugs.
I'll just briefly go over the outpatient
drug use. I'm doing this for the benefit of the
new members to sort of give you what the sources
are. For outpatient drug use, we mainly tap into
the IMS Health System. One database is National
Prescription AuditPlus, which provides an estimate
of the number of prescriptions from retail
pharmacies. The point on this limitation is that
it does not include information on gender or race
or age. So the information is limited, but it can
give you an estimate of what the outpatient
prescription volume is.
The other database, which is also an IMS
Health product, is the National Disease and
Therapeutic Index, which is a survey of 2,000 to
3,000 office-based physicians and really measures
mentions of drugs during that encounter and
includes a variety of specialties. But one
disadvantage is that the diagnosis cannot be linked
to the drug use. And the projections may be
unstable, especially when use is very limited in
some pediatric--for some drugs in the pediatric
Another source for outpatient
drug use is
the National Sales Perspectives, which is also an
IMS product. This is really a measure of the
volume of drugs that are sold from the
manufacturers to various distribution channels.
This may include retail outlets and non-retail
outlets. This is sort of a surrogate for use if
you see that what is actually moving to the retail
pharmacies or channels is really representing what
is actually being used by patients. But also an
important limitation is that we don't have
information on age and gender in this database, so
we're not able to be more specific.
For inpatient drug use, we have several
databases. One is AdvancePCS, which is based on a
large prescription claims database of the insured
population. That includes about 75 million
patients. But we don't have a projection
methodology to sort of estimate it on a national
Premier is another database which comes
from approximately 450 acute, short-stay, non-federal
hospitals. The projection methodology is
available. It may not be very good for some drugs,
so it is selectively appropriate in terms of making
national projections. Again, the estimates cannot
be linked to diagnosis or any procedure, and
importantly, it misses the drugs that may be
administered at the hospital outpatient clinics,
especially come to mind oncologic drug products.
The last database that we have utilized is
Child Health Corporation of America, which includes
really just pediatric hospitals, and the data come
from about 29 free-standing children's hospitals
distributed around the country. An important
limitation is that this is--we don't have a
projection methodology to estimate at a national
level, so whatever we get in terms of this
database, although it may be specific to the
pediatric population, is not representative of what
the national experience may be.
Now, having gone over this overview, I
just wanted to touch upon the drug products that
we've reported on under the mandated BPCA review
process. We started our first presentation in June
2003, and we covered several products at that time.
The second one was October, the third one was
February, and then June. So we've had four major
adverse event reporting that we've done for over
maybe 22 products, and today's presentations will
be an extension of that.
Just to give you examples of some of the
outcomes of the prior Pediatric Advisory
Subcommittee meetings, we've discussed very
important issues including SSRIs and SNRIs in
relation to suicidal behavior and then class
labeling for neonatal withdrawal, again, with SSRI
products. That was actually a subject of
discussion in the last AC meeting, subcommittee
meeting. And then we have also discussed the
fentanyl transdermal products, which have been
associated with inappropriate use that may have
resulted in some pediatric deaths, and there were
some specific recommendations that were provided by
the subcommittee for FDA regarding these drug
products. So the mandated adverse event reporting
has had important implications in terms
our attention on some of the safety issues.
Despite its limitation of being just for one year,
it's really brought attention to looking at safety
issues in the pediatric population.
Now, just to give you an overview of what
is going to happen today the way it's laid out, we
are going to have presentations on several drug
products, as you can see in the agenda. Dr. Hari
Sachs is going to be presenting the one-year
adverse event reports for ofloxacin, and
alendronate, and Dr. Susan McCune will be presented
on adverse events regarding fludarabine, and Dr.
Jane Filie will be presenting on desloratadine.
And then we'll have a break, and in the next
section we will have several presentations which I
will introduce later in more detail, but we have
adverse event reports for fluticasone- or
budesonide-containing drug products. And there
will be a one-hour slot for this presentation. In
regard to the drug products containing fluticasone,
we'll be addressing that.
There is also a question that
we have for
you to consider, so I wanted you to think about
this while the presentations are going on. We'll
ask you this question, and then we'll be very
looking forward to your recommendations regarding
DR. CHESNEY: Thank you very much. That
was extremely helpful to me, reviewing the
databases. You've probably done that many times
before, and I didn't remember, but it's very, very
Any questions from the committee? Yes,
DR. NELSON: I agree you've taken a system
that doesn't provide a lot of data and tried to
make it as best as possible. I guess this is a
comment that perhaps at some future meeting we may
want to discuss what we could do in the future
perhaps to try and get a better handle on safety.
The reason I'm concerned is if you think about the
expanse of the past two days, all of those drugs
were labeled for suicide as an adverse event, and
most individuals, apart from the signal
out of the requested exclusivity trials, would
think that, in fact, that's potentially unrelated
to the drug and related to the disease. And so
none of that data emerged out of this. What it
emerged out of is a review of the exclusivity
And at some point, I think it would be
worth just discussing as a general topic, apart
from the--you know, as we've done on individual
agent can we do better than this system and what
would that look like. And I'm not sure what the
answer would be in terms of that, but I'm struck--my
impression is that we wouldn't have seen the
signal that we saw that led to the past two-day
meeting using this system. And the only way that
came up was with the request to exclusivity
DR. IYASU: Yes, well, let me make a
comment. As you recall, since you've been involved
in this committee a couple of years, we did a
report on suicidal ideation and also suicidal
behavior associated with drug products
Citalopram and Paxil in the past. Now, we know the
limitations of the system in terms of trying to get
a handle on what the rates are or, you know, the
estimates of the risk on this adverse event.
Nevertheless, I think the AERS system, the best it
can do is that it can sort of identify some adverse
events that may not have been detected during the
clinical trial, but sometimes it's also possible
that if you see it in the clinical trial setting
and you see it also in the one-year post-exclusivity period,
then it sort of raises a
So, actually, I want to go back to what
happened early last year when we were talking about
Paxil. The discussion of the clinical trial data
was done in conjunction with the adverse event
report, so it was supportive in the sense of us--you know,
mandating us to look more carefully at
the clinical trial data because we were also seeing
these reports in the Adverse Event Reporting
So I would say that the AERS
give you an estimate, but it can just focus you or
even help you look more closely at clinical trial
data if you do see these kind of events.
DR. MURPHY: Skip, I think what you're
bringing up is a really important question, and
actually, I was going to say this at the end of the
meeting, but after we do maybe one more meeting
with the new committee with this process, you will
see we have already internally decided--and Dr.
Lumpkin is now my new boss, and we want to
internally review, including, you know, Office of
Drug Safety, New Drugs, and other Centers, have an
internal review of how to enhance the way we go
about the safety reporting, because it's very clear
to us that Congress wants us to be able to make
valid reviews, if you will. We're all telling you
there are problems with this system and we all
know, so how can we enhance it? And I think the
prior committee has seen that we've gone from just
reporting AERS and what's in the label, to going
back to the actual original clinical trials,
looking at signals in those clinical
trying to tell you what was seen then, what's seen
in AERS. So we really do agree that we need to try
to develop the most robust way of doing this.
Now, having sort of laid bare the fact
that we all think this is not the best system and
we want to make this a useful process, I will tell
you that just having the process has an impact that
you don't see. Okay? You know, having been
mandated and going to a division and saying this
product is coming up for review and we need--it
means the divisions, ODS, everybody has to go back
and look at this material. And as Dr. Iyasu was
saying, Paxil was a--I think we mentioned to you,
we delayed actually presenting that because of all
of the activity that was going on. And when we
looked at the AERS system, we saw some actual
concerning things. Now, we couldn't make any
attribution, but compared to the other products--and you
have to do all those--you know, the other
products weren't used as much, et cetera, there
still were some things that were concerning.
So I think we feel that the
as it is right now, has served some useful
purposes, but that clearly we would like to enrich
it and make it more robust and make it more
scientifically useful for the committee to
understand, because, otherwise, what we're always
doing is putting pieces--you know, we're taking
pieces of data and trying to make sense out of
these pieces of data.
So the intent is that we will be coming
back to you, and as I said, we'll see, you know,
how the next meeting or so goes, give the new
committee an opportunity to see this and provide us
additional--and probably come to you as a complete
subject unto itself, a topic for the committee, how
to better do this process.
DR. NELSON: And just to--my comments are
meant to be critical in the positive sense. The
progress since when I remember first hearing some
of this data two years ago has been phenomenal in
terms of what's been able to be accomplished with
all the warts and pimples of the existing data. So
just to say that.
DR. IYASU: Thank you. I appreciate the
comments, and we're always open to suggestions to
make it even better and make it more useful.
DR. CHESNEY: I think Dr. O'Fallon and
then Dr. Ebert. No? Dr. Ebert.
DR. EBERT: This is somewhat related, and
I wonder whether the agency has considered this as
well. But a lot of what you've focused on have
been, of course, adverse events that have happened.
But I'm wondering whether there is also the
opportunity to screen for medication errors that
occur and whether that entire--it may be a slightly
different database, whether that's through IMSP,
for example, and whether there may be systematic
errors that occur in treatment of pediatric
patients as opposed to adult patients, whether it's
product selection or selecting the wrong product
because it looks similar to another substance, for
But it seems that there's obviously been
an increasing public outcry for making sure that
our medical practices are also safe in
these adverse effects that occur.
DR. IYASU: I think that's an important
point. Again, AERS has limitations in that area,
but, nevertheless, I recall in one of the
presentations we had an issue with medication error
involving two products, one was Zoloft and Zyrtec,
and that came out loud and clear, I think, in the
adverse event review, and there may be others also
that may be picked up. Yes, that's an important
DR. CHESNEY: Dr. Maldonado?
DR. MALDONADO: Yes, I have a couple of
questions of process or actually what you said that
one of your list of five items there was unique and
unexpected pediatric AEs, and I just kind of went
through some of the presentations. Is that data
going to be presented in a way that we can actually
see if there is excess pediatric risk in the use of
these drugs, an excess compared to adults?
Typically most of these drugs that are used in
adults tend to advertise more than in children, so
seeing a list of adverse events in
because I'm used to seeing it, without the context
of knowing is this an excess risk? Are children
suffering an excess risk of X adverse event? Or is
this just the background that you see in the use of
the drug? That's one thing. And I haven't seen
that in previous presentations.
And so I come out of the meetings, okay,
yes, I saw several adverse events and some of them
very horrible adverse events, but it doesn't give
me a sense is this something that is a red flag in
pediatrics that needs to be looked at more closely?
That's probably why Dr. Santana asked for the adult
data on SSRIs yesterday, and not so much to look at
the adult data but is an excess risk there in
And the other thing, in your last slide
you said keep in mind the off-label use of
fluticasone. What exactly is it you want us to
focus on when the presentations come so we're alert
DR. IYASU: Are you talking about the
DR. MALDONADO: Pardon me?
DR. IYASU: Are you talking about the
DR. MALDONADO: Yes, the last slide. I
just don't know what you want us to focus on.
DR. IYASU: I think the focus would be for
you to consider the presentations regarding these
drug products, and there will be a series of them,
and then to get your input as to whether there is
any additional labeling concern or information that
you would like to include in the label, concern
about the drugs as--the use of the drugs as labeled
currently. So there is a concern about that. Of
course, you have the label that is included. So
it's as labeled now, they have been used in
different ways, and is there any concern regarding
DR. MURPHY: Sam, they're going to present
what they think the adverse event, if you will, is,
what they've done to deal with it, what's in the
label now, and does the committee think that's
adequate. So it's really--you're right.
have any information to answer that question.
They're just trying to show you where they're going
with the information they're going to present.
DR. IYASU: The context for that question
will be clearer, I guess, once the presentations
are done. But to go back to your first question
about the unexpected--or regarding whether adverse
events are occurring in excess in pediatrics as
opposed to adults, I think that's an important
question, and we haven't really done this for the
products. We do a top-line review for the one-year
period, and then most of the review has focused on
whether the same adverse events have also been
reported in adults. And we do sort of that kind of
comparison based on how frequently the adverse
event terms, as we call them, are reported.
When there is an issue that may be
considered to be critical, then we would like to do
sort of additional cultivations trying to see what
the background rates are, and then also look at
what the reporting rates are. We haven't done that
except, I guess, for SSRIs. But for other
products, that's something that can be done, but,
you know, you must know that there are a lot of
caveats in trying to come up with a reporting rate
or relative reporting rate for these drug products.
But when there is a need to do that, we will
actually do that.
DR. CHESNEY: Dr. Nelson has a question
DR. NELSON: Actually, just a comment on
that. Knowing the deficiencies of the system for
being able to get the denominator, it's not clear
to me that we necessarily need to look at the ADER
system in adults and compare them, and you're sort
of comparing information where you don't know the
denominator in either case.
If you're comparing it to the data that
obtain in clinical trials and look beyond just the
pediatric data in clinical trials to the adult data
in clinical trials and look at it in that context
and see if there's anything, it's different as a
signal for adults, probably that would be useful
data because then you can actually
frequency for adults because we have a hard time
establishing frequency in pediatrics using this
data, which is the main problem with it.
So I wouldn't encourage you to try and do
the thing that we can't do in kids in adults, too,
but if the comparison is made with clinical trials
where you can have that denominator, then that
might--then I think that would probably be useful
DR. MALDONADO: I was referring actually--I've
seen some drugs presented that I'm very
familiar with, and what I've seen here presented,
it's not very dissimilar to what I see outside this
room, meaning that the same adverse events actually
in absolute numbers, much larger in adults. So my
question when I see those presentations here, is
this a signal in pediatrics? Should it be worried
to--and I'm not saying that we should look at the
data. I mean, I think they do a good, a much
better job looking at the data. That's what they
do for life. But it's to identify for us excess
risks, because those are the ones that
have--and I know it's difficult. I know it's
difficult. But just looking at that list without
the context, it leaves me like, yes, I'm not
surprised that this is happening, this is happening
in adults 10 times more or 20 times more.
DR. IYASU: I think you make an important
point there, and we just have to live with the
limitations of the data. What we can do, when it's
an important issue, serious adverse event, we can
go out on a limb and go to other databases like
Claims database, which has its own set of
limitations and caveats. So there are many avenues
that you can go, but reporting rates or relative
reporting rates are the best that we can do with
this limited data set. We have refrained from
doing that because of the limitations in terms of
defining the actual numerator that you use, and
also the denominator, especially for pediatric. So
we may--we're concerned about sending the wrong
signal as to the relative safety of certain drugs
if we don't have--if we're dealing with uncertain
denominators and uncertain
numerators. So that's
where, I think, the problem is in trying to assess
So what we've done is if there is really
an issue, then our best resource is really the
clinical trial data. And what we've done is the
initial sets of presentations that we've done for
adverse events for these drugs did not include a
review of what was actually in the clinical trials
done for exclusivity. Now all our reviews include
summaries of the exclusivity trials and what kind
of safety signal this might have resulted that may
be similar or been supported by the adverse event
So we're trying to strike a balance here
and trying to give you the best information that we
have with all the limitations for interpretation.
So I can't say anything more than that. If there
are other suggestions from the committee, we'll be
very glad to consider them to improve the system.
DR. CHESNEY: I think it also doesn't
address the issue of the drugs that didn't
through exclusivity. But I think in your spare
time, if you could develop a national database that
would capture this inform for us.
DR. CHESNEY: Dr. O'Fallon?
DR. O'FALLON: This brings us back to the
problem--clinical trials provides the very best
data we have, no question about it. You know, I'm
a lover of clinical trials. But there's all those
comorbidities that are excluded that are
encountered, and a good chunk of the patient
population are excluded often from these clinical
trials. And so the question is: If there are a
lot of adverse events being encountered by kids
being treated with these things but they're not in
clinical trials because they keep getting ruled out
due to the exclusion criteria, does the adverse
events--the MedWatch, does that capture those? If
the parents are screaming, do those--like those
people that were the public presenters on Monday,
are their cases ending up in MedWatch?
DR. IYASU: Well, consumers also, you
know, send their reports through the MedWatch
program. Health professionals do. But as I said
before, 80 percent--or more than 80 percent or 90
percent of the reports are actually from
manufacturers. Some of them may actually have been
reported directly to manufacturers from health
professionals, and then they are transferred to us.
The extent of the reports of adverse
events or experiences of adverse events by patients
directly is variable. It's small, actually.
Probably it's very underreported.
DR. O'FALLON: Yes.
DR. IYASU: So we really don't have a way
of capturing that through a passive system such as
AERS, unless you go and do an active surveillance
system, which is a resource issue.
DR. O'FALLON: Yes.
DR. CHESNEY: I think unless there are any
other pressing questions--we're about a half-hour
behind, so maybe we need to move ahead. Dr. Iyasu
is going to introduce our next speaker.
DR. IYASU: Thank you.
Our first speaker
for this section of adverse events is Dr. Hari
Sachs. Hari is a professor of pediatrics with over
15 years of experience in private practice. She
also served on the FDA Non-Prescription Drug
Advisory Committee and is one of the FDA liaisons
to the American Academy of Pediatrics Committee on
Drugs. She will be presenting the adverse events
for ofloxacin and alendronate.
x DR. SACHS: Thanks again for that kind
introduction. Forgive me, I'm a little
mechanically challenged, so if I screw up this
presentation, at least the mechanics of it, bear
I'll be discussing the adverse events for
ofloxacin, trade name Ocuflox, which is an
ophthalmic anti-infective that was approved in July
1993 for the treatment of conjunctivitis and
corneal ulcers due to susceptible bacteria in both
children and adults over one year of age.
Depending on the condition, one to two drops of
ofloxacin applied to the eye at frequent
The exclusivity was granted in March 2003 based on
studies of neonatal conjunctivitis, although
ofloxacin is not approved for that purpose.
As you can see from these statistics,
millions of prescriptions for ofloxacin were
written for both adults and children during the
one-year exclusivity period. Pediatric patients
accounted for almost one-third of these
prescriptions. And, in fact, pediatricians
prescribe almost as much ofloxacin as
ophthalmologists, and not surprisingly, the most
common indication is conjunctivitis.
Now I'll look briefly at the studies
performed for exclusivity, and as you can see, they
are posted on the Web.
The pivotal study was a one-week, active
control trial which compared ofloxacin and
trimethoprim sulfate treatment of conjunctivitis in
infants less than one month of age. The clinical
cure was based both on resolution of discharge and
erythema by (?) lamp exam and microbiology cure.
The safety of ofloxacin is comparable to
is seen in older patients in previous trials. But
although the clinical cure rate for ofloxacin
exceeded the active control, neither of the two
drugs exceeded the historical control, and,
therefore, the study was--it was deemed that this
was not an approvable indication.
Note that the vehicle that's used that's
the historical control does contain benzyl
chromium, which has antibacterial properties.
The submitted data from this trial doesn't
really allow us to figure out why the cure rate was
low, why this study didn't seem to work. But
potentially there are factors related to the design
or conduct of the trial, the bacteriology of
neonatal conjunctivitis, or perhaps the time course
of it, or maybe a combination of all these factors.
In discussing the relevant safety
labeling, I'm going to highlight information that's
either pertinent to pediatrics or the adverse
events. Ofloxacin is a Pregnancy Category C drug
since there are no studies in pregnant women and
there are some effects on animals. It is
potentially excreted in breast milk. Under the
Pediatric Use section in precautions, there's a
statement that although the oral form of ofloxacin
has been associated with arthropathy in juvenile
animals, there is not an association for the
There is a warning about allergic
reactions, including anaphylaxis, which details a
case report of Stevens-Johnson syndrome from the
topical preparation. Most adverse reactions to
ofloxacin, however, are really mild and include
ocular burning or discomfort and, very rarely,
visual changes such as photophobia or blurriness or
systemic symptoms may occur.
Now that you're familiar with the label,
let's look at the adverse events. As you can see,
there really are very few reported adverse events
for ofloxacin in all ages. And during the one-year
post-exclusivity period, there were only three
reports--or three events, actually, all unlabeled,
two of which occurred in one adult and one that
occurred in a pediatric patient.
The pediatric event was a foreign report
that is also found in the literature of corneal
deposits in a 6-year-old who was receiving the
ointment. That's not available in the U.S. And,
in general, these types of corneal deposits
actually resolved by themselves and are thought to
be benign. This patient was actually treated with
scraping fairly early in the course. The natural
history actually is that it should have resolved.
With such few events, we really can't draw
a meaningful conclusion, and while this completes
the one-year post-exclusivity adverse event
monitoring, as mandated, we will continue our
routine monitoring of adverse events for this drug.
Are there any questions?
DR. NELSON: Just to repeat what I think
I--you're unable to tell the ages of the pediatric
use. You can't tell how old the conjunctivitis
prescriptions were? In other words, is it being
used on-label above one year of age, or is there
any off-label use--
DR. SACHS: Most of the use was on-label.
There's one database that captured some of the use
in kids under two, but it didn't separate out which
were under one. So it didn't help. It is
approximately 20 percent of the pediatric use for
that, the lower age group.
DR. CHESNEY: Thank you very much.
x DR. SACHS: Switching gears from one
system to another, I will now discuss the adverse
events that occurred during the post exclusivity
period for alendronate.
Alendronate, or trade name Fosamax, is a
biphosphonate which inhibits bone resorption by
osteoclast, and it was originally approved in
September 1995 for the treatment of osteoporosis in
adult women. Pediatric exclusivity was granted in
April 2003 based on studies of children with
Currently, alendronate is approved only in
adults, and it's for the treatment of osteoporosis
for both men and women, its prevention in women,
and for Paget's disease. The dosage varies from
indication, and there are really no
As you can see from these numbers,
although Fosamax is widely prescribed in the U.S.
for adults, and the use is increasing, the use in
pediatrics is really minimal. There's like 10,000
prescriptions in pediatrics compared to 22 million
for adults. Alendronate is primarily used in the
outpatient setting with the lion's share of
prescriptions from internists, OB-GYNs, and family
practitioners. Pediatricians write very few of
Osteoporosis and osteopenia were the
primary indications for therapy in adults, but in
pediatrics alendronate is used off-label for
treatment of osteoporosis and osteopenia either due
to underlying disease, such as renal or connective
tissue disease, or for its therapy, glucocorticoid
therapy, for example,, fibrous dysplasia, and as
you will see, osteogenesis imperfecta.
I'll briefly discuss the results of the
studies that were performed for exclusivity.
Both pharmacokinetic and
efficacy and safety studies were performed to
evaluate the treatment of severe osteogenesis
imperfects, or OI, in pediatric patients ages 4 to
18. The PK studies found that the oral
bioavailability of alendronate relative to the IV
dose was really similar in both children and
adults. Exclusivity was granted based on
submission of the 12-month analysis of this trial
in pediatric patients with OI, and both doses that
were used in the trial did significantly increase
lumbar spine bone marrow density, which was the
primary endpoint. But, unfortunately, a key
secondary endpoint was not reached, and that was
actually the occurrence of fractures either by
report or by x-ray.
The adverse events in the one-year
analysis appear comparable to those seen in adults,
and it's hopeful that this trial--there's going to
be more data coming in on a one-year extension of
Once again, I'd like to highlight the
relevant safety labeling for pediatric
Alendronate is considered a Pregnancy Category C
drug, with animal studies that have shown maternal
hypocalcemia that sometimes leads to early
delivery, and although there's no human data,
theoretically there can be an effect on the fetal
Due to significant gastrointestinal
irritation, alendronate is contraindicated in
patients who have a risk of esophageal emptying--excuse me,
have a delay in esophageal emptying or
risk of aspiration or cannot stand upright. And
patients with hypocalcemia or allergy are told not
to take the drug. Esophageal perforation,
including ulcerations or erosions, are also
described in the warning section of the label.
Precautions include the recommendation to
monitor calcium and vitamin D status. And
gastrointestinal symptoms, such as abdominal pain
or nausea, musculoskeletal pain, headache,
dizziness, and taste perversion are the more common
side effects that are seen.
Now, since alendronate
paralleling the relatively small percent of
pediatric use, pediatric adverse events really
represent only a very small percent of adverse
events. There were 17 total reports for pediatrics
out of 18,000 total reports. And this is kind of
indicated in the post exclusivity period as well,
with only four pediatric case reports that were
unduplicated. And there were no deaths.
The four reports include two cases of
hepatocellular injury, one patient that suffered a
drug-drug interaction potentially, and one infant
that had hypocalcemia and prematurity.
Hepatotoxicity was noted in two children
that were treated for steroid-induced osteoporosis,
and the details of their cases are reported on this
slide. But, briefly, liver dysfunction was
temporarily associated with the onset of
alendronate therapy and resolved after its
discontinuation and treatment with pulse steroids
in both patients. One patient did have underlying
liver dysfunction, and the other patient was on
The drug interaction occurred in a 7-year-old with
JRA who was taking cyclosporine, and after
starting alendronate, the cyclosporine levels
decreased, and his disease flared. Once the
alendronate was stopped, the cyclosporine levels
returned to normal. There was some fluctuation in
baseline levels, so the exact interaction is
unclear--I mean baseline levels of the
cyclosporine, that is, before the alendronate was
The last case was the prenatal exposure
which describes hypocalcemia, hypocortisolism, and
prematurity in a male infant that was born to a
woman with multiple medical problems, including
gestational diabetes, and who was on multiple
medicines. Hypocalcemia is known to occur in
premature infants, infants of diabetic mothers, and
several of these therapies, as well as potentially
So, in conclusion, only a handful of
adverse events were noted. Most did have
confounders or insufficient information
causality. We did look at a preliminary analysis
of the adult hepatic events, and that does not seem
to raise any concerns. And this will complete the
mandated reporting for alendronate from BPCA, but
we will continue its routine monitoring.
Are there any questions?
DR. CHESNEY: Dr. Maldonado, and then Dr.
DR. MALDONADO: I observed that in the
ofloxacin you had only one adverse event, and it
was a different drug product, it was not the same
drug product in the United States?
DR. SACHS: Right. Well, it's the
ointment form as opposed to we just have drops.
DR. MALDONADO: So it's a different drug
DR. SACHS: Correct.
DR. MALDONADO: And in Fosamax, also the
four reports were ex-U.S.
DR. SACHS: That's correct. They were
DR. MALDONADO: Do you know if it's the
same drug product, or is there a possibility that
it is a different drug product?
DR. SACHS: I believe that it's the same
DR. MALDONADO: And the reason I ask, for
those who are not familiar, you see internationally
the same names, and sometimes they are different
products actually, because the FDA approves drug
products, not drugs or--and sometimes there are
different components in the drug product. So when
you include them, actually that's good that you
highlighted that, because that may be relevant to
the adverse events.
DR. CHESNEY: Dr. Nelson?
DR. NELSON: Just a question about
labeling, but not in the safety and efficacy
component. I don't understand, if, in fact,
there's been a pharmacokinetic study, why we would
say that the pharmacokinetics have not been
investigated in patients less than 18 years of age.
I mean, that's what the label says. Wouldn't we
normally include some pharmacokinetic
data even if
we don't think safety and efficacy has been
DR. MURPHY: No.
DR. NELSON: Why?
DR. MURPHY: Because you're giving it an
implied approval. You're giving the dosing. Now,
if the--not always.
DR. NELSON: Well, we can--
DR. MURPHY: Let me--you know, that's a
whole big discussion, and you heard we have this
tension between trying to inform and not providing
a marketing freebie at the same time. So if that
pharmacokinetic study was done and found that there
was, you know, something very different going on or
some concern, then we could say on a dosing--I'm
talking about past. I'm talking about prior
practice, okay? So whether that's all going to
change--you know, it's good to provide you feedback
on this. I just wanted to say that in the past one
of the concerns that has been expressed has been
any information you put in the label about
pediatrics--I'm just starting from the
concern--depending on what it is, if it's not a
safety, you know, warning, in essence provides a de
facto approval and/or an ability of the company to
As an example, they could go out and say,
well, look, FDA put this information in the label
about how to use it in kids. So there is that
balance of trying to make sure that it's clear if
we put information in, in what context that
information is put in the label.
Now, I mean, please proceed to say you
think we should have put it in the label; we're
interested in hearing that sort of stuff. But I'm
just trying to provide why we routinely wouldn't
put information that we obtain into the label.
DR. NELSON: Just a quick response. I was
heartened to hear from Bob Temple yesterday that
that position was being readdressed. I previously,
until your comment, wouldn't have applied it to
just basically the pharmacokinetic information.
But I'll also point out that most people, myself
included, get my information from
systems, which do include dosing data. And,
in fact, one of those two systems I have on my Palm
actually included depression as an indication for
an unlabeled use.
So I appreciate the concern about
encouraging it, but I actually think adding more
information might, in fact, discourage it if there
was an emphasis of making sure that information
was, in fact, accurate and then transmitted
accurately to clinicians. I know that's a whole
broader discussion, but--
DR. MURPHY: I think we need to hear that.
I mean, that's what this committee is here for.
You're looking at the pediatric perspective on
this, and there has always been this tension. And
I think I've told this committee before, there are
those of us who think we are mandated in some ways
to put some of this information in the label.
There have been others in the agency who have been
very concerned about doing that.
I think what you heard yesterday was a
very different approach that's being
So we do want to hear these comments.
DR. CHESNEY: Dr. Maldonado, then Dr.
DR. MALDONADO: I'm just going to give you
a perspective, and Dr. Murphy is right, people may
misuse the information. I'm not saying that that
wouldn't happen. But, for example, the drugs that
are being used off-label--and we know--and I'll
just give you the perspective of one that I'm
working--it's a company, and we rarely have the PK
data. And we now found out, although we believe
that the dose being used off-label was the correct
dose, and that's the dose that we use in the PK, we
found out that that's incorrect, that children are
being underdosed. This is an antimicrobial.
The clinical studies are ongoing, and they
may be ready in five years, by the way, because of
the long-term follow-up that we need to do. In the
meantime, people are using off-label this drug
incorrectly. And you're in the bind that you
cannot communicate that because it may be perceived
as, you know, promotion. But you want to
communicate it. It's difficult. I know exactly
the concern that the FDA has because it can be
misused. But at the same time, not conveying it,
it allows people to continue using the drug
DR. NELSON: Can't your solution be--I
assume there's some academic investigators
potentially involved at study sites, letting them
release at least the PK data in a publication? Or
does that also violate--I mean, here it sounds like
you might even have a moral obligation to put out
DR. NELSON: Yes, the data has actually
been published in a poster format so people who are
more sophisticated in the area of infectious
diseases already know that that's incorrect. And
that's as far as we've gone.
DR. MURPHY: But I think that this is a
perfect example of the quandary, because as all of
you know--and you heard yesterday--we have a
history of putting things in the label that nobody
ever finds anything about the
information. I mean,
that's just the way life is. And with our health
care system the way it is right now, it's actually
getting worse, one could say, I think, as far as
physicians having time to access some of this
information in a timely manner.
But I would say, you know, if I were in
the Anti-Infectives Division and the company came
to me and said, oh, we've got this information, we
want you to put it in the label, but we're not
ready to submit our application yet to show you
whether it's safe or efficacious, you can see what
the problem is.
DR. CHESNEY: Dr. Fant?
DR. FANT: One small point for completeness
related to the case of neonatal hypocalcemia.
You highlighted with an asterisk the drugs known to
be associated with hypocalcemia, but it may be
worth also putting an asterisk and highlighting the
condition of diabetes itself in addition to the
DR. SACHS: Yes, I mentioned that.
DR. FANT: Oh, okay.
DR. SACHS: I just put the medications,
but yes, oh, yes.
Behind these presentations, actually, are
a group of folks at ODS and in the divisions that
contributed to the report, and I just want to kind
of publicly acknowledge them as well: Jennie
Change, Renan Bonnel, Mark Avigan, Wiley Chambers,
Gianna Rigoni, Judy Shaffer, and Michael Evans. So
there's actually a lot of people that go into these
presentations that you don't see.
I would now like to introduce Dr. Susan
McCune, who is a neonatologist, whose previous
experience has included academic neonatal practice
at Johns Hopkins and Children's National Medical
Center. She recently received her master's degree
in education and has worked on computer-based
educational models for pediatrics. She will be
presenting the adverse events for fludarabine.
On a personal note, it's a pleasure for me
to be working with her again because she was, I
think, my chief resident when I was a resident at
Children's. Things go full circle.
x DR. McCUNE: Thank you, Hari.
It was an honor to work with Hari as a
resident, and it's an honor and a privilege 20
years later to work with her again at the FDA.
As Dr. Sachs said, I'm going to discuss
the one-year post-exclusivity report for the
adverse events for fludarabine.
In terms of background information,
fludarabine, or trade name Fludara, is a synthetic
adenine nucleoside analog that primarily acts
through inhibition of DNA synthesis. It is
produced by Berlex Laboratories. Its indication in
adults is for the treatment of adult patients with
unresponsive B-cell chronic lymphocytic leukemia.
Of note, there are no pediatric indications that
are approved for this drug. The original marketing
approval date was April 18, 1991, and pediatric
exclusivity was granted on April 3, 2003.
I want to stop for a moment and talk to
you a little bit about the background of oncology
and pediatric drugs at the FDA, and I think this
gets a little bit to some of the
you've been asking about because oncology drugs are
a little bit different from some of the other
There has been a special initiative at the
FDA to increase pediatric drug labeling for
oncology drugs and to prioritize the availability
of new oncologic agents to pediatric patients. To
achieve this goal, three items that I'd like to
point out for your attention:
The first is the draft guidance for
industry that's entitled "Pediatric Oncology
Studies in Response to a Written Request" that was
published in June of 2000. The guidance is part of
this initiative to generate new knowledge to assist
practitioners and to provide early access to
emerging new drugs.
In addition, the Best Pharmaceuticals for
Children Act that was signed into law on January 4,
2002, established the Pediatric Subcommittee of the
Oncologic Drugs Advisory Committee and prioritized
new and emerging therapeutic alternatives that
could be available to treat pediatric
Another report entitled "Patient Access to
New Therapeutic Agents for Pediatric Cancer," which
was published in December 2003 and was a report to
Congress, was a report that identified areas in