1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ADVISORY COMMITTEE MEETING
Wednesday, September 15,
2004
8:10 a.m.
ACS Conference Room
Room 1066
5630 Fishers Lane
Rockville, Maryland
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P A R T I C I P A N T S
P. Joan
Chesney, M.D. C.M., Chair
Jan N. Johannessen, Ph.D., Executive
Secretary
Deborah L. Dokken, M.P.A.
Steve Ebert, Pharm.D.
Michael E. Fant, M.D., Ph.D.
Samuel Maldonado, M.D.
Robert M. Nelson, M.D., Ph.D.
Thomas B. Newman, M.D., M.P.H.
Judith R. O'Fallon, Ph.D.
FDA
Participants
Solomon Iyasu, M.D.
Dianne Murphy, M.D.
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C O N T E N T S
AGENDA ITEM PAGE
Call to Order and Introductions - P.
Joan Chesney,
M.D., Chair, Pediatric Advisory
Committee 5
Meeting Statement - Jan N. Johannessen,
Ph.D.,
Executive Secretary 5
Statement of Dianne Murphy, M.D. 8
Subpart D Referral Process - Sara F.
Goldkind,
M.D.,
M.A., Bioethicist, Office of Pediatric
Therapeutics 17
Summary
of Deliberations of Pediatric Ethics
Subcommittee held on 9/10/04 - Robert M.
Nelson,
M.D., Ph.D., Chair of the
Subcommittee 26
Overview of Adverse Event Reporting as
Mandated by
BPCA
- Solomon Iyasu, M.D., Medical
Epidemiologist
Office of Pediatric Therapeutics 70
Adverse
Event Reporting
- Ocuflox (ofloxacin) 105
Fosamax (alendronate) 110
Hari Sachs, M.D., Medical Officer,
Division of
Pediatric Drug Development
- Fludara (fludarabine)
Susan McCune, M.D., Medical officer,
Division of
Pediatric Drug Development 125
- Clarinex (desloratadine)
Jane Filie, M.D., Medical officer,
Division of
Pediatric Drug Development 149
Adverse
Event Reporting for Drug Products
Containing Budesonide or
Fluticasone: Pulmicort,
Rhinocort, Flonase, Flovent, Advair, and
Cutivate
- Peter Starke, M.D., Medical Team
Leader,
Division of Pulmonary Drug
Products 172
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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
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P R O C E E D I N G S
DR. CHESNEY: Good morning. I think we're
ready to begin today's deliberations,
and I'd like
to say that we're not going to introduce
the
committee members until Dr. Murphy has
given us an
overview of the previous and current
committees.
And so we
really just, I think, need to start off
the meeting by having Dr. Johannessen
read the
meeting statement.
DR. JOHANNESSEN: Thank you, and good
morning. The following announcement addresses the
issue of conflict of interest with
regard to the
study drug, dextroamphetamine, and
competing
products used for the treatment of ADHD
and to the
adverse event reporting session and is
made part of
the record to preclude even the
appearance of such
at this meeting.
Based on the submitted agenda for the
meeting and all financial interests
reported by the
committee participants, it has been
determined that
all interests in firms regulated by the
Food and
Drug Administration present no potential
for an
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appearance of a conflict of interest at
this
meeting, with the following exceptions:
In accordance with 18 U.S.C. 208(b)(3),
full waivers have been granted to the
following
participants:
Dr. Patricia Joan Chesney for ownership of
stock in a company with a product at
issue valued
at between $25,001 and $50,000, and for
her
spouse's honoraria for speaking on
unrelated topics
at a firm with a product at issue valued
at less
than $5,000;
And Dr. Robert Nelson for an honorarium
for speaking on an unrelated topic at a
firm with a
product at issue valued at less than
$5,000.
A copy of the waiver statements may be
obtained by submitting a written request
to the
agency's Freedom of Information Office,
Room 12A-30
of the Parklawn Building. In the event that the
discussions involve any other firms or
products not
already on the agenda for which an FDA
participant
has a financial interest, the
participants are
aware of the need to exclude themselves
from such
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involvement, and their exclusion will be
noted for
the record.
We would also like to note that Dr. Samuel
Maldonado
has been invited to participate as an
industry representative acting on behalf
of
regulated industry. Dr. Maldonado is employed by
Johnson
& Johnson.
With respect to all other participants, we
ask in the interest of fairness that
they address
any current or previous financial
involvement in
any firm whose product they may wish to
comment
upon.
Thank you, and we'll now turn it
over to
Dr.
Dianne Murphy.
DR. MURPHY: I wanted to just
take a
moment to welcome everybody and to also
tell the
committee that you may not have
realized--or a
number of people on this committee, that
you have
just made a transition. That transition has been
from a subcommittee, which was providing
very
important advice to us, but to now a
full
committee, which advises the
Commissioner directly.
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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.
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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
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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
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she's still going to be very active in
the
pediatric issues, and the Division
Director for
Pediatrics, Shirley Murphy, is now the Deputy
within that office. And we have a new
Division
Director,
just so you'll know these names. Lisa
Mathis I
do not believe is here. She's dealing
with other issues this morning.
For the new members--and I apologize to
the old members because I know you've heard
this.
I
actually took it out of the slide on Monday
because I didn't think that everybody
really wanted
to hear about all the accomplishments of
the
previous committee. But I wanted the new members
to hear a little bit about what the
previous
committee has actually--some of the
issues they
have dealt with. And they have dealt with not only
the ethical issues that have to do with
normal
volunteers, placebo-controlled trials,
the
vulnerable population within
pediatrics. They have
dealt with an enormous array of
scientific issues,
from sleep disorders, hepatitis C, HIV,
antiviral
drug development in neonates, the
current
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epidemiology and therapeutics and
development of
therapies for hyperbilirubinemia,
clinical risk
management for HPA axis suppression in
children
with atopic dermatitis, tracking cancer
risks among
children with atopic dermatitis, and as you all are
aware, last February a discussion of the
FDA
process and review of therapies for
major
depressive disorder.
In addition, this committee has now
reviewed--before today's additional
eight products
that you're going to be hearing about,
has reviewed
over 22 products that were granted
exclusivity, and
you have looked at the one-year
post-adverse event
reporting that has occurred for those
products. I
can tell you that this is an important
process that
we are looking to evolve
constantly. It came up
recently at a congressional hearing as
to how were
we doing this and what were we doing
with it. And
I think
it's important that this committee realize
that it is important what you have to
say to us
about whether we should do anything else
in trying
to follow--gain a better understanding
of what
13
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.
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DR. CHESNEY: Thank you very
much, Dianne.
So I think we would like next to go around
the room and have the new Pediatric
Advisory
Committee
members introduce themselves, and I'd
like to start with the members who are
no longer on
the committee, if they could--that was a
joke. So
let's start with Dr. Maldonado.
DR. MALDONADO: Sam
Maldonado. I work in
pediatric drug development at Johnson
& Johnson,
and as Dr. Murphy said, this is my last
session
with the committee. There will be a new member
from industry.
DR. NEWMAN: I'm Tom Newman. I'm a
professor of epidemiology and
biostatistics in
pediatrics at the University of
California, San
Francisco, and a general pediatrician, and I'm new
to the committee.
MS. DOKKEN: I'm Deborah Dokken,
and I am
also new to the committee, and I am a
patient-family
representative and I really appreciate
having that voice on the committee.
DR. O'FALLON: Judith O'Fallon. I'm a
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professor emeritus of statistics at Mayo
Clinic. I
got called back half-time to cover a
maternity
leave, by the way, going back. But I've been on
the committee since its beginning.
DR. FANT: My name is Michael
Fant. I'm
an associate professor of pediatrics at
the
University of Texas in Houston.
My expertise is in
neonatology and in biochemistry. And I'm new to
the committee.
DR. NELSON: I'm Robert
Nelson. I'm
associate professor of anesthesia and
pediatrics at
Children's Hospital of Philadelphia and University
of Pennsylvania. My clinical area is pediatric
critical care, and I also work in the
area of
ethics, and I was on the previous
subcommittee.
DR. EBERT: Hi, I'm Steve
Ebert. I'm an
infectious diseases pharmacist at
Meriter Hospital
and professor of pharmacy at the
University of
Wisconsin, Madison. I'm an
outgoing member of the
committee.
DR. CHESNEY: And my name is Joan Chesney.
I'm a professor of pediatrics at the
University of
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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
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master's degree in religious studies
with a focus
on comprehensive religious
ethics--comparative
religious ethics, excuse me, and she's
been with
the agency for almost a year, which she
tells me
seems like longer than that.
Dr. Goldkind?
DR. GOLDKIND: It's my pleasure
to be here
today at the inaugural meeting of the
Pediatric
Advisory
Committee and to tell you about the work
of the Pediatric Ethics Subcommittee.
As Dianne mentioned, this is really a
landmark time in pediatric
research. That's the
way we see it because we feel that this
committee
as well as the Pediatric Ethics
Subcommittee can
really make incredibly important
decisions and
consensus statements regarding pediatric
research.
So what I'd like to do now is talk a
little bit about the role of the
Pediatric Ethics
Subcommittee. It is going to be
a subcommittee
that addresses Subpart D referrals and
also ethical
issues that impact on research affecting
the
pediatric population.
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Going back to the part on Subpart D,
there's a mistake in the slide, and
where it says
"Joint 21 CFR 50.54 and 45 CFR 46.407 referrals,"
those are referrals that will come to
both OHRP and
the FDA, and we actually had one of
those to review
on September 10th, which involved the
effects of a
single dose of dextroamphetamine in
attention
deficit hyperactivity disorder, a
functional
magnetic resonance study. And Dr. Nelson, who is
the Chair of the Pediatric Ethics
Subcommittee, is
going to give you a summary of the
deliberations of
the Pediatric Ethics Subcommittee in
that regard.
The subcommittee can also address
referrals that come only to the FDA
under 21 CFR
50.54, and I'm going to talk about these
regulations in a little bit more
detail. But if
there are no referrals and there are
burning
ethical issues that we would like to
address, we
can also take those to the Pediatric
Ethics
Subcommittee for deliberation.
So now to go into a little bit more detail
about the regulations under which we can
have these
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referrals, Subpart D is entitled
"Additional
Safeguards for Children in Clinical Investigations
and Research," and they are
essentially identical
for DHHS and FDA. DHHS regs are Title 45, CFR 46,
also known as "the common
rule" because 17 federal
agencies operate under those
regulations. And the
FDA
regulations are 21 CFR 50.
There is a notable distinction between the
two sets of regulations, and that is the
issue of
waiving parental permission can be done
under Title
45, CFR 46, but not under the FDA
regulations. But
in terms of the Subpart D referral
process and the
general categories of pediatric
research, those are
identical between the two
regulations. And what
I've done
in these slides is include the citations
for both regulations.
So Subpart D has four different categories
under which pediatric research can be
conducted.
The first
category is 50.51/46.404, and that is a
category which states that the research
involves no
more than minimal risk. And it essentially does
not discuss who benefits from the
research, but
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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
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following...
So, in other words, if the IRB feels that
the research has merit for the general
pediatric
population but cannot be classified
under one of
the first three categories, it can make
a referral
to one of the federal agencies--and I'll
discuss
those details in a minute--to have the
protocol
reviewed by an expert panel.
And so what must the research then
satisfy, according to the expert
panel? The
research, in fact, satisfies one of the first three
categories, so the expert panel can make
a
determination that after it reviews the
research,
actually one of the first three
categories does
apply, or the following three conditions
are met:
the research presents a reasonable
opportunity to
further the understanding, prevention,
or
alleviation of a serious problem
affecting the
health or welfare of children; the
research will be
conducted in accordance with sound
ethical
principles; and adequate provisions are
made for
soliciting assent and parental
permission.
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The composition of the Pediatric Ethics
Subcommittee is the following:
Dr. Nelson is the
Chair. According to FACA, we
also need to have two
members of the Pediatric Advisory
Committee
represented on the Pediatric Ethics
Subcommittee.
And in
addition to Dr. Nelson, we included Dr.
Chesney
and Dr. Gorman. And we supplemented the
Pediatric
Ethics Subcommittee with an additional
group of core ethicists: Drs. Fost, Kodish and
Marshall.
The composition of the Pediatric Ethics
Subcommittee under both DHHS regulations and FDA
regulations states that the panel of
experts in
pertinent disciplines, for example,
science,
medicine, education, ethics, and law,
and we
selected from among those groups
according to the
protocol. But most of those groups were
represented on the Pediatric Ethics
Subcommittee
that took place on September 10th. In
addition, we
also had two patient advocates represent
on that
subcommittee.
So once the IRB makes the
determination
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that it wants to refer to a federal
agency, it
refers to the FDA for regulated--if the
products in
the protocol are FDA-regulated, and it refers to
OHRP if
the research is federally funded or
conducted. And we have a very close working
relationship with OHRP, and when a
protocol comes
to us, we also refer it to them for review,
and
they refer a protocol that comes to them
to us.
And in
this case, the protocol was actually
submitted to OHRP, but upon our review
it was noted
that two of the products in the
protocol, both the
MRI
machine and the dextroamphetamine, were FDA-regulated
and so we also had jurisdiction over
that
protocol.
The review would then be conducted by the
Pediatric
Ethics Subcommittee expert panel, and as
I said,
each protocol--we will have a core group of
ethicists, and it will be supplemented
by
appropriate expert panel members and
patient
representatives and/or community
representatives.
The Pediatric Ethics Subcommittee will
bring its recommendations to the
Pediatric Advisory
24
Committee
for endorsement, as Dr. Nelson will do
today, and then those recommendations
will be
submitted to the Commissioner of the FDA
for final
determination. Once that determination is
rendered, it will be forwarded to OHRP,
and OHRP
will send the Commissioner's memorandum
on the
Pediatric
Ethics Subcommittee/Pediatric Advisory
Committee's
recommendations on to the Secretary,
and the Secretary will have his final
determination, particularly in regards
to funding
of the research.
So our goals in this process, clearly the
overarching goal is to advance an
understanding of
pediatric research, and we'd like to do
that
involving additional expert input and
public input.
We also
want to have transparency in the process,
and in that regard we had an open public
comment
period before the Pediatric Ethics Subcommittee.
We also
had an open hearing available at the
Pediatric
Ethics Subcommittee. We also want to
try
and respond to these protocol referrals
in a timely
manner so that they will be helpful to
the IRBs
25
involved. And we want to be able to handle these
referrals in a consistent and clear
manner so that
they can advance the general
understanding of
pediatric research. And we would like to do this
and are doing this in harmony with OHRP
so that we
have a united federal agency response to
pediatric
research.
Thank you.
DR. CHESNEY: Thank you very
much.
Maybe what we could do is introduce and
hear our next speaker and then ask for
questions
from the panel. Dr. Skip Nelson is the Chair of
the Pediatric Ethics Subcommittee, and
he will
discuss with us the deliberations of the
Pediatric
Ethics
Subcommittee with the invited folk that Dr.
Goldkind
just mentioned on last Friday. And the
issue here is that Dr. Nelson has
prepared a
summary of the committee's deliberations,
which you
have in front of you, and I'll let him
highlight
issues that he wants to bring to your
attention.
And what
we're looking for here is an endorsement
by the committee. As we've mentioned, this took a
26
whole day of fairly intense
deliberations last
Friday,
and we don't anticipate that we will have
to repeat that process here. So we're just looking
for the committee's endorsement and any
questions
that you may have, either for the
process as Dr.
Goldkind
just outlined it or for the specific
events of Friday as Dr. Nelson will
present them.
DR. NELSON: Thanks. You have the
document before you. Let me just note, as someone
pointed out, I've got the wrong date in
the
heading. That will be corrected before the final
version goes up. If you see any other typos, feel
free to write them down and share them
with us
after our discussion.
I'd like to walk you through the document.
My intent
here is not to read the document but to
highlight what is in it, since you can
probably
read faster than I can talk. The introduction
simply restates the purpose of the
meeting and then
gives a brief summary of what's in the
summary.
But let me first start with what is the
primary issue that would be raised by
this
27
protocol, which is the particular risk
of the
procedures that are contained within the
protocol.
Now, as a preface to this, one of the
first things that an IRB must determine--and
for
this exercise, the Pediatric Ethics
Subcommittee is
effectively functioning like an
IRB--that the
research design is sound. So after I talk about
risk, I'll then run through a number of
recommendations and
stipulations that the committee made
to assure itself that, in fact, the
research was
sound.
But assuming those are made, the
subcommittee felt that the following
risks would be
appropriate:
The first is the single dose of dextroamphetamine.
Is that
minimal risk? The feeling
was no.
We can a little bit later, if you'd like,
about the definition of minimal risk,
but, in fact,
that was not minimal risk. But the subcommittee
felt that it was no more than what's
called a minor
increase over minimal risk, and it lists
the
reasons there, which I think I'll state
in more
detail for highlight.
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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
29
not medicated when they're not going to
school, and
are often given holidays from the
drug. So it
didn't feel that a 36-hour period of
time was of
any significant risk to those children.
And then the remainder of the procedures,
which are outlined further along, we all
felt were
appropriately considered minimal risk
and,
therefore, were appropriate for either
group within
the protocol.
Now, the one design recommendation that we
made was to consider narrowing the
subject
population that's part of this
protocol. There was
some discussion about the variability in
both
neurodevelopmental stages and then
response to this
dose of the stimulant between the ages of 9 and 18
years of age, with different points
being raised as
to the scientific advantages and
disadvantages of
either the younger age group or the
older age
group.
We didn't feel that we could make this a
stipulation, but felt that the
investigators should
strongly consider narrowing that range
within 9 to
18 to get a more focused population.
30
The other confounder that came up--and
this is also in response to some points
made in the
public discussion--is that trying to
tease apart
the changes that might occur in response
to the
drug over time versus basic underlying
differences
in terms of, if you will, the
neurological
networks, that you need ideally to have
treatment-naive
subjects with ADHD, or at least less
ideally,
if that is a practical difficulty in
doing in this
particular age group, try and get a more uniform
cohort of drug exposure, which is why we
had the
discussion of picking the lower-dose
range.
One reason for that was that the expert
scientists felt that often the dose over
time that
you may need goes up, and if they
unified the dose,
then probably you would end up with a
more uniform
distribution of the length of exposure
to
treatment. But we didn't feel that that reached
the level of a stipulation, but
certainly felt that
that was a strong recommendation to
consider
improving the scientific value of the
study.
Now, there are a number of
required
31
modifications to the protocol. Point A, which I'm
not going to read, is basically my
summary of all
of the procedures in the protocol. And one of the
recommendations is--it was very hard to
find all of
these things, and it would be nice if
they just put
them in one place so no one had to go
reading
through it in all detail. One, for example, that
came up--and I'll just highlight
this--is that
every child will receive a diagnostic
MRI scan,
which is, in fact, part of NIH
policy. You could
find that nowhere in any of the
documentation, and
that came out during discussion. Things like that
need to be in the protocol.
I might add, what we will be doing is
depending upon both the Office of
Pediatric
Therapeutics and the OHRP to make sure this
happens, so it's not something that we
need to then
worry about.
The second point, sequence of subject
testing. They're not planning to
do the kids that
are twins. There are discordant twins, either both
homozygous and dizygotic. They're not going to do
32
those twins unless they see differences
between the
kids with ADHD and the kids without
ADHD. That
sequence of testing, which came out in
testimony,
was very hard to find anywhere in the
protocol, and
that needs to be included. They won't do the twins
if, in fact, they don't find a
difference in the
non-twins.
It was very hard to find the right dose
since there were these dosing
discrepancies, and so
that needs to be clarified. But I've stated what
the committee's understanding is, and,
of course,
if this is different--and this is based
on the
investigators' testimony--that will have
to be
dealt with. And, again, I mentioned the morning.
A functional MRI. The protocol
lacks a
discussion of what came out in the
testimony of the
training that goes on to make sure these
kids are
comfortable inside the machine, make
sure they can
actually do the tasks that they're being
requested
to do, et cetera, exclude kids from
claustrophobia.
Not much
in the protocol about that. I already
mentioned the diagnostic MRI scan, which
needs to
33
be in there.
Pregnancy exclusion. You only
found that
in the parent permission form. The feeling was
that that needs to be discussed in the
protocol and
the child assent documents, and in
particular,
mechanisms for protecting the
confidentiality of
the adolescent that she may or may not
want to go
into the protocol knowing that there's a
pregnancy
test depending upon activities. That needs to be
spelled out. We weren't making a judgment about
how that should be handled other than
the
importance of the confidentiality in
soliciting
that information.
There was a significance discussion of
neuropsychological--I would like to have
questions
at the end, because what will happen is
I bet you
some will be answered, but write them
down.
Neuropsychological testing.
There was a lot of
discussion about this testing. It's not being
performed for diagnostic or treatment
purposes, and
we felt it would be a cleaner study if,
in fact,
this information was not provided back
to the
34
parents. Part of that discussion was based on it
not being done in that kind of a
therapeutic
context.
And then genetic testing. There
is
testing being done only for zygosity,
and we felt
since there was a whole slew of markers
being done
and no discussion about the risk of
those markers
relative to, say, late onset adult
diseases, that
the cleanest way to do that would be to
destroy the
data and the samples after you've
determined the
zygosity of the twins, maintaining only
that piece
of information.
Modifications to the parent permission and
child assent process in documents
follow, of
course, those that need to be included
from the
discussion of the procedures. There were a couple
of specific issues. One is payment. They were
proposing a lot of money--I didn't put
it in here,
but a lot of money. We felt it was too much and
that basically the parents should get
reimbursed
for expenses, and that for young
children, a token--although
we didn't have a discussion of what that
35
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
36
dextroamphetamine to be able to stay up
for your
exams in college, but that doesn't lead
to
addiction because generally you don't
then want to
take it when you plan to fall asleep
during
vacation. And, of course, both permissions.
Now, there were some specific questions
that we were asked to respond to, and I
think for
these questions, perhaps I'll just read
our answers
so that you get it clear.
What are the benefits, if any, to the
subjects and to children in
general? There is no
direct health benefit to the children
included in
the research. The protocol addresses the question
of a unique central response to
stimulants in ADHD,
utilizing a better research design than
previously
published studies and controlling for
performance
differences. As such, the protocol may be able to
untangle clinical state and
trait--meaning genetic
relatedness--differences through the use
of
monozygotic and dizygotic twins who are
discordant
for ADHD. Now, more speculatively--and this was
part of the discussion--the results may
improve our
37
understanding of ADHD in order to
enhance
diagnostic precision and avoid
misclassification
and overtreatment.
Now, the types and degrees of risk that
this presents to subject, I've discussed
a fair
amount of that above, and, again, we
thought that
all of the procedures other than
withholding of the
medications and the blind administration
of study
drugs were minimal risk, and those two
were a minor
increase over minimal risk.
In terms of whether the risks are
reasonable in relation to anticipated
benefits,
this is a key point. For all subjects enrolled in
the research, the risks to subjects are
reasonable
in relationship to the importance of the
knowledge--i.e.,
the benefit to children in general--that
may
reasonably be expected to result.
However, it is
only for the children with ADHD that the
research
is likely to yield generalizable
knowledge which is
of vital importance for the
understanding of the
subjects' disorder.
For you regulatory junkies, you'll know
38
that I'm reading language that is
contained within
the regulations as well, but the
important thing is
then that children without ADHD do not
have a
disorder or condition, which is why this
then could
not be approved by the local IRB,
although the
brain response of children without ADHD
to a single
dose of dextroamphetamine is an important
part of
the generalizable knowledge to be gained
in this
research based on the first step of the
comparison.
So we thought it did present a reasonable
opportunity to further the
understanding,
prevention, or alleviation of a serious
problem
affecting the health or welfare of
children.
So, with that said, the determination of
approval categories that the
subcommittee felt was
appropriate was that the interventions
and
procedures included in the research can be approved
for the children with ADHD under 45 CFR
46.406 and
21 CFR
50.53. That's the category that says no
more than a minor increase over minimal
risk; that
basically the experiences are reasonably
commensurate with those inherent in
their
39
condition; the intervention is likely to
yield
generalizable knowledge about the
subjects'
disorder or condition, which is true for
the ADHD;
and then that there are adequate
provisions for
assent.
Now, because of the lack of a condition in
the kids without ADHD, we felt that it
could not be
approved under those three categories
consistent
with what the IRB found. But we did feel that it
presented a reasonable opportunity to
further the
understanding of a serious problem; that
it would
be conducted in accord with sound
ethical
principles; and that there are adequate provisions
for soliciting assent and
permission. And as such,
we recommend that the involvement in the
research
of children without ADHD is approvable,
assuming
all of the required modifications are
made, under
46.407 or 50.54.
Then one final point. It had
been brought
up in some of the public testimony, the
applicability of a
particular case known as Grimes v.
Kennedy Krieger Institute. Whereas, normally or
40
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,"
41
which means basically the judge
expressed opinion
on other matters, but, in fact, those
other matters
are not binding as law. So for those two reasons,
it was felt that we did not need to get
into the
issue of the applicability of this
particular case
as a subcommittee.
So, with that summary, I guess how about
questions about the document, the protocol
and the
like, and then after that, I certainly
would be
interested in any more general questions
about the
process, if that's a reasonable
approach.
T1B DR. CHESNEY:
We actually have a visitor
this morning. Dr. Bern Schwetz is the Director of
the Office of Human Research
Protections, and I
wondered if we could call on him to come
and make a
few statements before we invite
questions.
DR. NELSON: Sure.
DR. SCHWETZ: Thank you very much, Dr.
Chesney. I just wanted to
express my thanks for
FDA and
this Advisory Committee creating the
opportunity to do this joint review in
one process
rather than have the FDA and OHRP going
in separate
42
ways to review a protocol of this kind
where
there's joint jurisdiction. So particular thanks
to Dr. Nelson for chairing this review
and this
subcommittee. In our opinion,
the process went as
we had hoped it would, with a very
smooth review,
but probably more importantly, a
thorough review
and a recommendation that we feel is a
good
recommendation coming to this Advisory
Committee
for your final review and hopefully
approval.
The review was done in a timely manner,
and that was a challenge considering
that this is a
new committee, a new subcommittee, but
it was done
in a timely way. And I think it was done with an
appropriate cast of experts. So we're very pleased
with this process and, Dr. Chesney, with
your
permission, we're hoping that in those
cases where
we have joint jurisdiction over a
protocol in the
future that we'll be able to bring it
back and
handle it this way.
So thank you very much.
DR. CHESNEY: Thank you for your
comments,
and maybe you could stay here just for a
moment,
43
and we'll ask now for any questions of
the new
committee members for either Dr.
Goldkind, Dr.
Nelson,
or Dr. Schwetz.
Dr. Maldonado?
DR. MALDONADO: I just have a quick
question. Dr Nelson, I see that on page 1 you made
the statement--and I basically also
agree that you
did a great job with this review. You listed the
minor increase over minimal risk, which
I agree are
just a minor increase. But then on page 2, you
gave a--maybe I am just overreading
this, but the
subcommittee strongly encourages the
investigators
to narrow the age. I know you focused on that, and
I may
have missed it. My understanding is
this is
a single-dose study. I don't know what the
concerns will be with single-dose for
neurodevelopmental
stages with a single dose, low dose.
DR. NELSON: The issue is not the
impact
of that dose. There might be a response difference
that you could see, but the question is
teasing
apart--there is a debate on previous
studies that
have been done of structural MRI scans,
and there
44
are actually two previous studies of
functional MRI
scans where the question is whether or
not some of
the differences that may be seen are not
related to
any underlying biological differences,
neurodevelopmental
differences, but, in fact, the kids
with ADHD had been chronically exposed
to a
medication which--I'm not a
neuroscientist. I
guess I would characterize it as whether
it's
created some element of remodeling of
those
systems. And so try and eliminate that confounder,
the feeling was if they would narrow the
age range
and then try to either get
treatment-naive, which
may be difficult, or at least
treatment-uniform at
lower doses which would give you
hopefully a lower
duration of exposure, that you might be
able to
begin to tease apart those two
issues. That was
the scientific discussion among the
experts.
DR. CHESNEY: Yes, Dr. Fant?
DR. FANT: Yes, this question may
be a bit
naive, but it quickly comes to mind,
especially
from the standpoint of taking the kids
off the meds
for a couple of days and trying to
ensure treatment
45
naivete and the question that that may
have on
their response.
And so the question is: Are
there any
over-the-counter stimulants or food
additives that
could potentially interact with their
response and
somehow muddy the data? And if so, is that being
controlled for or addressed in the
protocol?
DR. NELSON: The answer is
yes. I mean,
one of the discussions, of course, by
the IRB was
whether caffeine and the element of
caffeine
consumption could be used as a
judgment. So there
are some confounders and the need to
collect that
data, and it would be sort of
self-defeating if
over the weekend you take the kid off of
his
medication and then he drinks, you know,
a couple
of cases of Jolt Cola--which I don't
even know if
it's still made or not. I have no stock in that
company. No conflict of interest on that
recommendation. Or Mountain Dew. I think Mountain
Dew has a
lot of caffeine in it. So, yes, they
need to pay attention to that.
DR. FANT: And even with adolescents who
46
may be concerned about weight and
appearance and
that sort of thing, some of the
additives that are
contained in supplements in GNC at the
mall, you
know.
DR. NELSON: Right.
DR. MURPHY: So, Dr. Fant, was that a
question or just a recommendation, I
guess is what
I--
DR. FANT: Well, it's a concern
because if
we're talking about giving a drug to,
quote, normal
kids, you really want to ensure that the
data is as
clean, as interpretable as
possible. You wouldn't
want to muddy the waters on something
that could
have easily been avoided.
DR. MURPHY: I think that, you
know, if
there are recommendations that this
committee would
like to make, that's appropriate. And we wanted to
make sure that that was--
DR. NELSON: I see that as just a
refinement of the recommendation to make
sure your
subject populations are as uniform as
possible. So
it's certainly consistent with our
direction.
47
DR. CHESNEY: But we maybe should
add a
sentence or two, Skip, just to--I
thought that was
an excellent point if somebody does--I
don't know
how long those stay in the bloodstream,
but if
that's their breakfast and then they
show up for
the fMRI, there may be a confounding
variable.
Yes, Dr. O'Fallon?
DR. O'FALLON: Did you recommend
that they
collect that information?
DR. NELSON: No, but we can add a
sentence
to that.
DR. O'FALLON: Okay. I think it would be
helpful to make sure that they elicit
that
information.
DR. CHESNEY: Deborah, you were
next.
MS. DOKKEN: I first want to
compliment
Dr.
Nelson's subcommittee. I mean, not only
did
you do a thorough job, but I could fully
understand
what you were talking about, and I was
glad that
you included the issue of compensation
and the
potential pressure on the twins in the
assent
process.
48
I was also glad that at least in some way
you directed attention to the permission
and assent
forms and talking about the chronology
of the
procedures. But I had a further question about
those forms, which, frankly, I don't
know what
their rating is in terms of reading
level, et
cetera.
But they certainly to me were not easy to
read and, in fact, were mixed. Sometimes they used
almost simplistic language; then you
know, the next
sentence--did you talk at all about just
the forms
themselves and the language beyond the
chronology
issue?
DR. NELSON: Yes, we did. But that's just
captured on page 5 under age where we
just say
there's technical language would is not
explained
in lay terminology.
I think two points on the process:
A,
this still then needs to go back through
the NIMH
IRB, plus
it has two offices, not just one now,
that will recognize that for this to be
finally
approved would require that kind of
changes in the
documents. And I'm absolutely confident that with
49
OHRP and
FDA's involvement in making sure that
these requirements happen is that they
will be in
more understandable language.
My own philosophy is there's no reason for
us to sort of nickel-and-dime the actual
text, but
that was discussed.
DR. CHESNEY: Could I just add,
there was
a great deal of discussion about the
protocol and
about the consent form, and, in fact,
one of the
committee members asked if this was a
draft of the
consent form. And the folk from the NIMH
apologized and they said that they got
so busy
addressing the issue of whether this
would have to
come to a subcommittee that they hadn't
really paid
that much attention to the consent form,
but that
they would do that.
Dr. Newman?
DR. NEWMAN: I also want to
compliment the
committee on a really very impressive,
thorough
review.
And I have three points. One is
just a
clarification.
Looking on page 7, comparing
Parts a) and
50
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
51
of vital importance is fundamentally
subjective.
And from
that standpoint, there was a recognition--and
that's why I put earlier on the notion
that
more speculatively. I mean, this is what--I would
characterize this as sort of a basic
science
question about the response and the
neurodevelopmental sort
of receptor physiology.
If, in fact, there is no difference, it
would have an impact significantly on
the
understanding of ADHD, and if there is a
difference, it would impact
significantly, and then
might, not in this protocol but down the
line,
potentially drive diagnostic and
therapeutic
differences. One thing I learned is there are
individuals who are touting different
structural
scanning tools for diagnosis of kids
with ADHD, et
cetera, that many felt, in fact, were not evidence-based.
And so
after hearing that discussion, the
subcommittee members felt that it did
meet the
regulatory standard both for vital
importance and
reasonable opportunity.
There was no, if you will, easily defined
52
paradigm for that.
DR. NEWMAN: Okay. Well, that sort of
leaves me uncertain. Let me go to my next
question, which was in the consent form
they
specifically addressed the issue of
potential
adverse effects of the MRI in terms of
identifying
some little something which then people
go, oh, we
wonder what this is, maybe you should go
have that
checked out, but that not being covered
by the
research study and the family may or may
not have
medical insurance to cover that. And I believe
that's more than minimal risk. That's something
well beyond the range of what people
experience
every day, the possibility of having
some brain
abnormality uncovered, which then you
have to
figure out how to deal with. So I wonder why that
wasn't considered, you know--
DR. NELSON: It was.
I didn't include it
in here because the data actually is
that out of
3,000 scans, they've only found four
abnormalities.
And of
those four, two were benign cysts and two
were actually early diagnosis of tumors
where the
53
child benefited from that. So there was a
discussion in the subcommittee about the
implications of using a screening test
in a
population that--you know, being a
statistician,
you can understand the sensitivity and
specificity
issues.
But after that discussion and the fact
that it's being conducted--it's not a
diagnostic
reading of the functional MRI. It's a separate
diagnostic MRI scan that, after hearing
the
discussion, we felt that it was
appropriate to
consider that under that category.
So they have enough data, I think, to sort
of--at least reassure me that they're
not going to
be turning up a lot of things that end
up with
unnecessary testing.
DR. NEWMAN: If I were a parent
trying to
make an informed decision about
participating in
the study, those data would be very
helpful to me
to know what--to say this may happen,
but they
don't give any numbers on how likely it
is to
happen and what might be found. And so, you know,
I just think it's hard to ask someone to
consent to
54
something, you tell them that risk, but
you don't
tell them how big it is. So I think that would be
helpful for them.
And my last question was just about the
financial compensation.
For the controls, you
know, it sounds like this may take
several hours
out of the parent's day, and so, you
know, having
tried to get people to enroll in studies
before,
you know, I don't know whether there
have been
pretests or what it would take. But if you're
going to ask someone to bring their
normal child in
and get a lot of stuff done, you know,
to me I
think maybe $100 or $110 split between
parent and
child might not be enough to get people
to want to
enroll.
DR. NELSON: No, it was not split
between
parent and child. That would be wages for the
child, and the investigator actually
said--and this
did influence the committee--that she
did not
anticipate any problem with enrollment
even if the
compensation and stipend was zero. I'm just
telling you, that's what she said.
55
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.
56
Any other questions or comments?
Dr.
O'Fallon?
DR. O'FALLON: I was just
wondering about
the pregnancy exclusion. I didn't look at the
consent form closely enough to see. Presumably
they are excluding on the basis of pregnancy. Is
that it?
DR. NELSON: They are. It wasn't very
well described in the consent form,
which was our
point.
DR. O'FALLON: Okay. Well, but that's the
point.
So they have to--so they do have to take
this--they have to have a pregnancy
test. Now, I'm
just curious. How do they think they're going to--I mean,
how do they plan to deal with exclusion
basically on pregnancy alone when they
don't--they
can't tell it to the parent?
DR. NELSON: They didn't outline
that,
but, I mean, I'm confident that they can
come up
with a procedure. We're just asking them to do
that, and I'm sure OHRP will make sure
it's a good
one.
57
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
58
whatever they find, the question is
really whether
this child would benefit from treatment
or not.
And, you
know, the way you determine that is
whether--either trying the treatment and
seeing if
it helps, or if you were going to do a study to see
whether imaging helps, you would see
whether
imaging predicts response to treatment,
not whether
imaging predicts or is associated with
someone
having received this clinical diagnosis.
So I am a little bit worried if it does
show a difference that this will spawn a
whole
imaging industry of people wanting to
get their
children's heads scanned to see whether
they really
have it or not, which I think would just
be going
in the wrong direction.
DR. NELSON: I guess two
comments. This
has nothing to do with the clinical
response of the
children. There is no benefit. It
has nothing to
do with that. Whether or not it--if it does show a
difference, appropriately designed, it
would spawn
a functional MRI industry I think is
speculative
and, in fact, is explicitly, if you at
Subpart A,
59
excluded from what an IRB ought to
consider. The
long-term policy implications of
research is not
something that IRBs are supposed to
consider, and I
wouldn't necessarily import it under
vital
importance.
The question is whether or not there are
structural or functional differences,
and
presumably based on receptor density, et
cetera--it's not my
area so I'm just saying things that you
could have read in the protocol and
listening to
the scientists. And as a basic science question, I
think that's an important one. And how it might
then impact down the road in terms of
understanding
whether there's a differential or similar
response
to stimulants, I mean, the literature is
quite
mixed in terms of reading some of the
background
material in the protocol.
So there is no connection in doing this
with determining why they might respond
clinically.
There is
no--and, in fact, many of our recommendations were
meant to prevent that confusion
from being in the minds of the
participants by
60
removing any semblance of benefit from
the sort of
surrounding aspects of the science. But, you know,
I think
ADHD is a controversial area, and it's
partly why we felt this needed to be
looked at
carefully and then done well, because I
think the
positive or negative results could have
an impact
in different directions.
DR. CHESNEY: I think Skip
expressed it
very well. The purpose of the study was not to
have any clinical diagnostic value or
clinical
implications. The purpose of the study is really
to understand, as Skip said, the
neurophysiology
and neurochemistry--to try to understand
the
neurophysiology and neurochemistry of
ADHD better,
and because of the twin aspect, to see
if there are
any genetic aspects.
Dr. Maldonado?
DR. MALDONADO: A quick question
that goes
beyond this study, but it's in the
context of ADHD.
One of
the premises that I think a lot of
researchers' work is under that if the
studies can
be done in adults, don't do it in
children. And
61
now adults are being diagnosed with
ADHD. Has
something similar been done in adults or can be
done in adults, you know, consenting
adults, so you
don't use this area of consent of
children?
DR. NELSON: Two points. That specific
question was raised by the subcommittee. There
have been similar but not identical
studies, but
it's clear that the adults are different
in this
regard and that the information that you
would get
would be of no use to this issue. And that
discussion actually is why you may
even--in the
discussion it was clear that the
scientific
arguments might push you in the
direction of using
actually the 9 to 12 age group as
opposed to the
older age group because there may even
be those
kinds of adult changes when you get into
sort of
late adolescence. But we felt that that was not
clear enough that we would make a
stipulation as
opposed to recommendation.
So I think that is an important principle,
and it was asked and answered in the
negative, that
adult information here would be of no
use to
62
answering this question.
DR. CHESNEY: Dr. Schwetz, did
you have
any additional comments about the
questions from
the committee?
DR. SCHWETZ: No, I don't have
anything
else to add. Thank you.
DR. CHESNEY: Dr. O'Fallon, you
look like
you were--
DR. O'FALLON: I hesitated simply
because--but I'm
a mother and not an M.D. I've had an MRI.
I don't
know what--for my neck. I was wondering
what a functional MRI for the brain
involves for
the child.
DR. NELSON: Nothing different
than an MRI
scan.
DR. O'FALLON: But the question
is they
are enclosed, so there is the issue of
claustrophobia?
DR. NELSON: Correct, but they
have
screening procedures for that.
There's no issue in
that.
The kids are actually less claustrophobic
than the adults.
63
DR. MURPHY: Skip, why don't you
describe
the screening procedure--
DR. NELSON: They have a training
MRI scan
which is--and they make--you know, first
they've
got to make sure the kids can do these
tasks, so
they use the stop task and a training
MRI scan.
They have
a whole sort of session. I mean,
everybody--if a kid doesn't want to do
it, then
that's the end of it. You know, their procedures
are excellent with respect to that. The issue is
not that they're not doing it. The issue is they
just didn't describe it in the
protocol. They
described it quite completely in the
discussion on
Friday.
DR. MURPHY: I think as a risk
what you're
trying to get at is that those kids that
are going
to have that impact of anxiety,
psychological fear,
will be--will not be enrolled. In other words,
that's where the screening procedure
would help
select those children out.
DR. O'FALLON: Yes, but, of
course, the
screening itself could cause this--I
mean, they
64
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
claustrophobia.
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,
they're excluded.
65
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.
[No response.]
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?
66
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
question?
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
parents
67
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
68
want to consider for the future.
Skip?
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
should say.
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
69
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.
Thank you.
DR. CHESNEY: Thank you.
We don't know
70
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
pediatric exclusivity.
The Best Pharmaceuticals Act for Children,
which was enacted in 2002, does have a
provision
71
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
of the
72
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.
73
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
what the
74
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
adults. So
75
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
inpatient population.
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
and/or any
76
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
longitudinal data.
Other databases that may be
tapped also
77
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
evaluation.
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
Control
Centers.
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
78
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
the MedWatch
79
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
dietary supplements.
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
product.
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
80
reported. This may include accidental or
intentional overdose or occurring from
abuse or
drug withdrawal or failure of expected
pharmacological action.
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
pathophysiologically
81
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
adverse events.
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.
82
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
surveillance programs.
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
83
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
population.
Another source for outpatient
drug use is
84
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
level.
Premier is another database which comes
from approximately 450 acute,
short-stay, non-federal
hospitals. The projection methodology is
85
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
86
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
of focusing
87
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
88
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
these products.
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
helpful.
Any questions from the committee?
Yes,
Dr.
Nelson?
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
that came
89
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
trials themselves.
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
studies.
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
like
90
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
question.
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
System.
So I would say that the AERS
system cannot
91
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
trials and
92
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
process, even
93
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.
94
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
example.
But it seems that there's obviously been
an increasing public outcry for making
sure that
our medical practices are also safe in
addition to
95
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
issue.
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
children, maybe
96
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
children?
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
to that?
DR. IYASU: Are you talking about
the
question?
97
DR. MALDONADO: Pardon me?
DR. IYASU: Are you talking about
the
question?
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
that.
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.
You don't
98
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
99
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
for you.
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
establish
100
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
information.
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
you really
101
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
102
where, I think, the problem is in trying
to assess
it.
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
reports.
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.
Thank you.
DR. CHESNEY: I think it also
doesn't
address the issue of the drugs that didn't
go
103
through exclusivity. But I think in your spare
time, if you could develop a national
database that
would capture this inform for us.
[Laughter.]
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
104
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
105
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.
Dr. Sachs?
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
with me.
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
intervals.
106
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
that which
107
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
108
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
topical form.
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.
109
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.
110
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
osteogenesis imperfecta.
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
pediatric
111
indications.
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
these.
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
safety and
112
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
this trial.
Once again, I'd like to highlight the
relevant safety labeling for pediatric
patients.
113
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
skeleton.
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
approval,
114
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
methotrexate.
115
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
started.
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
with alendronate.
So, in conclusion, only a handful of
adverse events were noted. Most did have
confounders or insufficient information
to ascribe
116
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.
Nelson.
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
product.
DR. SACHS: Correct.
DR. MALDONADO: And in Fosamax,
also the
four reports were ex-U.S.
DR. SACHS: That's correct. They were
foreign reports.
DR. MALDONADO: Do you know if it's the
117
same drug product, or is there a
possibility that
it is a different drug product?
DR. SACHS: I believe that it's
the same
drug product.
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
118
we don't think safety and efficacy has
been
established?
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
big global
119
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
market it.
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
personal device-based
120
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
considered.
121
So we do
want to hear these comments.
DR. CHESNEY: Dr. Maldonado, then
Dr.
Fant.
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
122
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
incorrectly.
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
that data.
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,
123
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
prematurity.
DR. SACHS:
Yes, I mentioned that.
DR. FANT: Oh, okay.
124
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.
125
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
questions that
126
you've been asking about because
oncology drugs are
a little bit different from some of the
other
drugs.
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
patients with
127
cancer.
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
pediatric drug development that could be
improved
to facilitate access to new agents.
Now I'm going to focus a little bit on the
trials that were done for exclusivity
for
fludarabine.
Exclusivity was based on data that was
submitted from two previously published
COG trials:
CCG-097
and CCG-0895. CCG-097 was a Phase I
dose-finding
and PK study of a loading bolus followed
by
a
continuous infusion of fludarabine in patients
with acute non-lymphocytic leukemia,
acute
lymphocytic leukemia, and solid
tumors. CCG-0895
was a Phase I/II dose-finding, PK, and
pharmacodynamic study of a loading bolus
followed
by continuous infusion of fludarabine,
then
followed by a loading bolus and
continuous infusion
of Ara-C in children with previously
treated acute
128
leukemias.
I'm going to talk a little bit in detail
about the first trial, which was
CCG-097. There
were two groups of patients, first those
with solid
tumors and those with the acute
leukemias. The
patients with the solid tumors reached a
maximum
tolerated dose because of dose-limiting
toxicities
that were hematologic--in other words,
myelosuppression. The patients with the acute
leukemia, the goal was marrow ablation,
so their
maximum tolerate dose was not reached
based on this
toxicity--toxicity associated with the
solid
tumors, but their dose was limited by
the concern
for potential CNS toxicity that had been
seen with
adults.
Of note in this trial, there was one
complete and three partial remissions in
26
evaluable children with ALL.
The pediatric adverse events that were
noted in this trial and are included in
the label
are marrow suppression, especially of
platelets,
fever, chills, asthenia, rash, nausea,
vomiting,
diarrhea, and infection. No peripheral neuropathy
129
or pulmonary hypersensitivity was seen
in these
trials.
The second trial, CCG-0895, which I had
previously told you was a sequential
administration
of fludarabine followed by Ara-C, was
undertaken in
31 patients either with ALL or AML. Of note, in
the patients with ALL there was a
33-percent
complete or partial response, and in
those patients
with AML, there was a 50-percent
complete or
partial response. This study was not able to
provide data on the efficacy of
fludarabine alone,
but did provide efficacy and safety data
for the
combination.
I'd like to just point out--let me see if
I can do
it here--that this information from the
first trial, CCG-097, has been included
in the
label as of October 2003.
There are two parts of
the label that have been changed. The first is the
clinical pharmacology in special
populations
pediatric patients, which highlights
that steady-state
conditions were reached early. And then in
the precautions section, pediatric use,
this is a
130
description of that trial that I just
told you
about, followed by the treatment
toxicity that I
also pointed out to you.
In terms of drug use trends in the
outpatient setting or sales of
fludarabine, this is
considerably different from what Dr.
Sachs
presented to you with her millions of
prescriptions. Approximately 280,000 vials only of
fludarabine were sold in the U.S.
annually from May
2001 through April 2004, with no
significant
increase seen after exclusivity. And as Dr. Iyasu
pointed out to you, this particular database
is one
that does not divide it up in terms of
pediatric
and adult use. Just as you would expect,
fludarabine was primarily sold to
clinics and non-federal
hospitals during the 12-month
post-exclusivity period.
In terms of drug use trends in the
inpatient setting, where we do have some
pediatric
data, Premier data showed us that
pediatric use
accounted for 3 percent of discharges
between 2002
and 2003 in which fludarabine was billed. And CHCA
131
data demonstrated that from October 2002
through
September
2003, there were 95 discharges associated
with fludarabine, which were essentially
unchanged
from the previous year.
Now I'm going to switch gears and talk to
you about the adverse event reports for
fludarabine
in the one-year post-exclusivity period
from April
2003 to May 2004.
The total number of reports for all ages
were 300, with approximately a third of
them
occurring in the United States. As expected,
almost all of them were serious, and
over a third
of them involved deaths.
In terms of the pediatric reports, all of
them were serious. There were ten unduplicated
pediatric reports, only one of which was
in the
United
States, and the outcomes for three were
death, and seven were hospitalized, one
which
suffered continuing sequelae.
Of those ten pediatric patients, the
recorded use was for six preconditioning
for bone
marrow or stem cell transplant; for
three, AML
132
relapse; and for one, JMML with
splenectomy prior
to bone marrow transplant. The age for these
reports was predominantly in the 2 to 5
age range
with six reports, one each in the one
month to less
than 2 years, and the 6 to 11 year age
ranges, and
two in the adolescent population.
Dr. Maldonado, this may get to your
question earlier. These are all the adverse event
reports for fludarabine in the one-year
post-exclusivity
period, both adults and pediatric
patients. As you can see, there are a significant
number of adverse events. Those that are
underlined are actually unlabeled
events, including
increased bilirubin, abdominal pain, and
then three
related to either drug ineffective or
disease
recurrence. In the pediatric population, the only
unlabeled event was abdominal pain.
I'm now going to give you a brief
discussion of each of the ten pediatric
patients
followed by a summary of their
categories and a
comparison with the adult information in
the label.
There were three deaths. The first was a
133
four-year-old with ALL who received
fludarabine for
preconditioning for stem cell
transplant. The day
after transplant, she developed fever,
shock, and
multi-organ failure. This was one of the cases
that also reported abdominal pain.
An eight-year-old with ALL who received
irradiation, fludarabine, and
cyclosporine followed
by stem cell transplant, who six days
after
transplant became febrile with a rash,
generalized
edema, tachycardia, abdominal pain, and
cardiac
arrest.
Of note, one of the later cases is a
cardiac tamponade patient. We don't have
additional information, but the
tachycardia to over
200 along with the edema could be
possibly
concerning for that as well. But there is no
additional information.
And the third and final death is a 13-year-old
with bone sarcoma of the rib who
received
fludarabine as preconditioning for stem
cell
transplant and then developed
carcinomatous
pleurisy and died of disease
progression.
134
In terms of the seven hospitalizations,
there was an 18-month-old with hepatic
veno-occlusive
disease after bone marrow transplant for
beta-thalassemia. There was a two-year-old with
relapsed AML who developed photophobia
on the FLAG
study, which is fludarabine, cytarabine,
and
granulocyte colony stimulating
factor. There was
no photophobia noted on rechallenge.
And then I want to highlight an additional
visual disturbance in a three-year-old
with
relapsed AML also on the FLAG study that
developed
bilateral blindness, which resolved
leaving some
degree of blindness, and that's the
sequelae that I
spoke of.
There was a four-year-old with AML relapse
who developed encephalopathy and
recovered.
The only United States case is a
four-year-old
with JMML with splenectomy in
preparation
for bone marrow transplant, who
developed fever and
pneumonia.
There was a five-year-old with AML after
bone marrow transplant who developed
aphasia,
135
vigilance disturbance, and non-specific
encephalopathy. This is a foreign report. It's
not clear whether vigilance disturbance
is a
disturbance of state associated with
encephalopathy
or could potentially also be visual
disturbance,
although most likely just a disturbance
associated
with the encephalopathy.
And then, as I previously mentioned, a 13-year-old
with bone marrow transplant for aplastic
anemia who developed cardiac tamponade
and cardiac
failure four days after transplant, who
recovered
with diuretics and pressors.
So, in summary, there were ten clinically
significant pediatric adverse events,
and if you
break them down into four categories,
there was
cardiac failure in two, cardiac
tamponade in one,
and cardiac arrest in two. This is labeled for
adults for edema and pericardial effusion. The
abdominal pain that I pointed out to you
before
that was not labeled in adults, it is
labeled for
nausea, vomiting, anorexia, diarrhea,
stomatitis,
and GI bleeding in adults. And as I pointed out,
136
the two patients that had abdominal pain
in the
pediatric age range were those with
multi-organ
failure and death.
There were two pediatric patients with
blindness and optic nerve disorder, and
this label,
as I will show you in a moment, is
labeled for
visual disturbance and blindness in
adults. And
encephalopathy is also labeled in
adults.
Just to give you an idea in terms of
whether this is a different signal from
what's seen
in adults, I showed you the most common
adverse
events in terms of those that were more
than 20.
In this
same period of time, all of these events
were reported in adults in the range of
three to
five adult reports.
And I just wanted to show you, this is the
boxed warning for Fludara, and this gets
at a
couple of issues that were discussed
actually
yesterday. This drug should be administered under
the supervision of a qualified physician
experienced in the use of antineoplastic
therapy.
In addition, it is labeled in the boxed
warning
137
that it is associated with severe
neurologic
effects, including blindness, coma, and
death.
Also
labeled here are fatal autoimmune hemolytic
anemia, and down here a warning about
the
combination of use with pentostatin and
fatal
pulmonary toxicity.
So, in summary, there are labeled and
unlabeled adverse events for fludarabine
that have
been reported. There are a number of pediatric
adverse events that were reported in the
post-exclusivity
period that were not recognized in the
clinical trials that were done for
exclusivity.
These
adverse events, however, have been labeled
for adults. These serious adverse events include
encephalopathy, blindness and other
visual
disturbances, and cardiac tamponade and
failure.
These patients tend to be on very
complicated, pre-
transplant regimens that involve
multiple
medications and immunosuppression. I just want to
note that this completes the one-year
post-exclusive adverse
event monitoring as mandated by
BPCA.
But the FDA will continue its routine
138
monitoring of these adverse events for this drug.
Any questions?
DR. CHESNEY: Thank you very
much.
Comments, questions? We need Dr.
Santana,
who is in Oslo.
Any other comments? Dr. Murphy,
are there
any--
DR. MURPHY: I think, you know,
this is
just one of the things we'll be looking
at in the
future when we review these and we don't
think we
see anything going on. How much information do you
want?
Do you want us to present it? Do
you want
us to send it to you beforehand? When we say we
are going to no longer do--when we say
this
completes the exclusivity reporting, it
means that
this process will no longer occur, and
that we are
basically telling you that we think that
that
appears to be an appropriate outcome,
unless you
tell us something differently than
that. We'll now
go back to the usual process of just the
Office of
Drug
Safety doing their reviews and we won't be
reporting this to you.
139
So I did want to make that clear to the
new committee members. That's what that means when
we say that. We don't have any specific questions
for this product.
DR. CHESNEY: Dr. Fant?
DR. FANT: Yes, just a
question. Out of
curiosity, how did the signals that
emerged from
the use of this drug, given the complex
nature of
the disease and the drug regimens that
these kids
are on, compare with the signals that
emerged in
previous reports for some of the other
drugs?
DR. McCUNE: For the other
oncologic
agents or other drugs in general?
DR. FANT: Well, the other
oncologic
agents in these types of patients. Any way to sort
of get a sense of whether there's
something unique
about these signals versus the others?
DR. McCUNE: I actually reviewed
two
oncologic drugs the last time we
presented for this
committee, and I think the process that
we're
really looking for is what you all have
pointed
out:
Are there substantial differences from the
140
adult population? Are there substantial
differences from what's in the label
that should be
potentially added to the label? Although that's
very difficult given all the
confound--the small
numbers of patients and the
confounding. And I
think that it becomes very difficult
because most
of these drugs are not used except in
patients who
have recurrent disease, so they have
disease
progression. They're also on multiple other drugs
and multiple other regimens.
So it can be difficult to pull out a
signal.
That's why we very carefully look at each
one of these adverse event reports to try to see if
maybe there's something more there or if
there's a
relationship that does not show up in
the label for
the adults. And so far, with the three drugs that
we've reviewed in the last year, I
haven't seen a
substantial difference. They're very low numbers
of usage for the drugs in general in the
population, 200,000 versus millions of
prescriptions. And then the pediatric use in that
is very low. Because of that low number, that's
141
why there's been this initiative to try
to get drug
labeling for oncologic drugs because,
otherwise, we
wouldn't have the data to be able to do
labeling or
to be able to get these drugs to the
population
quickly.
DR. CHESNEY: Dr. Ebert, and then
Dr.
Nelson.
DR. EBERT: When you identify
adverse
events that have not been seen
previously in
pediatrics but have been seen in adults
and are in
the labeling, is the implication that
the labeling
does not need to be modified or that it
does need
to be modified?
DR. McCUNE: In general, when
it's been
stated in the label for adults, that's
considered
labeling. If there were something where there was
a substantial signal without the
confounding
variables, that would be something that
could be
discussed. But, in general, unless there's a very
strong signal that is different from
what's seen in
the adults, the label is considered to
be adequate.
DR. CHESNEY: Thank you.
I had that same
142
question, so thank you.
Dr. Nelson?
DR. NELSON: Just a comment
before leading
up to a question. I noticed the significant amount
of pharmacological information in the
label, as you
pointed out, in terms of
pharmacokinetics, and I
speculate I know part of my comfort
level with the
use of these drugs is the fact that in
the United
States 90
percent of the children are treated on
protocol, and the chances of this being
used off-label are
exceedingly low. Is that different in
Europe? Is this either labeled
or do they have--I
mean, I'm just wondering why this seems
to be used
more frequently. Maybe, you know, in that case, I
assume it's not labeled for a pediatric
indication
in Europe, but they must not have as
much of a
control over what happens to where
someone's
obviously using it for bone marrow
transplant
protocols.
DR. McCUNE: I don't know the answer about
labeling in Europe.
DR. MURPHY: That's one place we haven't
143
looked.
But I do think that you're making a good
point.
There has been a concerted effort within
the FDA, working with both NCI and the
American
Academy
of Pediatrics, to address the issue that
was being brought up here. But the fact is that
you won't have these products in Phase
III trials
for children. I mean, that just is not the process
that happens for oncology drugs, though
they're
almost all--most of the children are in
trials. It
has to do with the paucity of, you know,
the
population and the ability to actually
conduct
Phase III
trials.
I know this seems schizophrenic, so I
just--so dealing with that issue, the
quandary was
we would never have products labeled for
kids who
have cancer which--yet we would have a tremendous
amount of information. So there was an entire
process and a number of meetings to look
at how can
we make the information available that
is developed
for this population. That's why there's a guidance
on how to do that and how you can--and
encourage
the development of these products and
research into
144
these products for children. And that's why the
statement was that you don't actually
have to have
the product approved for children for
certain
indications to get this information into
the label.
But it
is, you know, a product, a disease-specific
process, and it's appropriate that
information will
go into the label for the oncology
drugs.
DR. NELSON: But I guess if the
comfort
level in doing that is because there
won't be the
opportunity given the professional organization
for
extensive off-label use, then I guess as
a group at
some point in the future we should
tackle about how
one could discourage off-label use while
at the
same time providing information.
DR. McCUNE: That's one of the
reasons why
I wanted
to point out in the boxed warning that it
does state that a qualified physician
using anti-neoplastic
therapy be the one to administer the
drug.
DR. CHESNEY: Dr. O'Fallon?
DR. O'FALLON: Well, you know,
this is a
real quandary because you're absolutely
right that
145
the vast majority of children are on
these studies,
which is wonderful because they are
being monitored
very carefully. The ones that don't make it on to
the protocols are usually, in my
opinion, ones with
comorbidities or some--or there's such
an advanced
disease. So they're starting to treat them with
these things.
I'm wondering if given the fact that a
year doesn't--given the fact that there
isn't a
huge population of off-label use out
there, a
year's data doesn't give us very much of
a chance
to see off-label problems. Do you see what I mean?
If
they're treating--a million kids were treated
with something in that year, then you've
got a
pretty good idea--a pretty good chance
to pick up
anything that was somehow missed in the
clinical
trial.
But if it's a very small number of kids
that were treated in that year, then we
really
don't have very much of a chance of
picking up
anything either.
DR. McCUNE: The division
continues to
follow reports associated with the use
of this
146
drug, so it's not like we don't have any
follow-up.
But we
just wouldn't come back to present it
necessarily to you unless there was
something that
would be--
DR. O'FALLON: You don't diminish
your
surveillance. You just diminish your reporting to
us.
Is that what we're talking about?
DR. McCUNE: That's correct.
DR. MURPHY: Well, we diminish
going back
and reporting to you. We don't go back and look at
the, you know, trials that you've
already seen. I
mean, since that process has
occurred. If
additional studies had come in, you know, there
might be an opportunity. But I think the only
thing I would say is that if there's
something that
concerns you in the report and it was
combined with
the issue of either a small population
or, as some
of you know from the prior committee,
the
exclusivity is granted before the
approval
sometimes. That's changing because of the timing
on the approvals, but there may not
actually be
much postmarketing in some certain
situations. If
147
those situations--if you are concerned
about
something and either of those two
situations
exists, you could recommend that we come
back and
report to you relevant to whatever, you
wanted more
time to see what was happening. I mean, that is an
option I think this committee has
actually utilized
earlier on when we had a very short
postmarketing
period.
But, again, I think just having a short
postmarketing period wouldn't be the
only reason to
do it.
It would be because there was a question or
some concern that you would like us to
come back
and report to you about.
DR. O'FALLON: Isn't the purpose
of
postmarketing to pick up something that
probably--that could
have slipped through the cracks on the
studies? That's all. If we don't
give ourselves a
very good chance at doing that, we're
not going to
have a chance to pick it up as
much. That's all.
DR. MURPHY: Yes, I mean, and for
the
things you mentioned, I mean, the
studies often--of
course, the cancer studies--but, still,
148
particularly in other studies, they're
much more
exclusionary, and when it gets out
there, it's used
in the broader population. And as has been pointed
out before, AERS is good over time
picking up the
rare, serious events that occur. So if those are
concerns that you have, then you could
recommend
that we continue to report to you.
DR. CHESNEY: Thank you very
much. Could
I suggest
that maybe we take a ten-minute break
before the next speaker? I did want to ask if
there was anybody here for the open
public hearing.
Nobody
has registered yet, but we just wanted to
check.
[No response.]
DR. CHESNEY: No. So I think if we could
come back in ten minutes at 10 after
11:00, and
we'll continue on with all the
subsequent
presentations. Thank you.
[Recess.]
DR. CHESNEY: I think we're ready to get
started. It looked like we should be able to
finish pretty close to our allotted time
for those
149
with appointments with planes, trains
and
automobiles at the end of the
meeting. So we'll
move on to the next presentation.
DR. McCUNE: Thank you. It gives me great
pleasure to introduce Dr. Jane
Filie. Dr. Filie is
a general pediatrician and pediatric
rheumatologist. After years of doing basic
research on connective tissue disorders
and
genetics at the NIH, Dr. Filie was a
pediatrician
in private practice prior to joining the
FDA.
Today Dr. Filie is going to talk to you
about desloratadine.
x DR. FILIE:
Thank you, Dr. McCune.
Good morning, everyone. I would
like to
present the adverse event review for
desloratadine
during the one year post exclusivity.
Desloratadine is an antihistamine by
Schering
Corporation. It was originally approved
in December 2001, and pediatric
exclusivity was
granted in February 2003. It is indicated for the
treatment of seasonal allergic rhinitis
in patients
2 years and older, and for the treatment
or
150
perennial allergic rhinitis and chronic
idiopathic
urticaria in patients six months and
older. The
recommended doses are listed on the
slide.
I would point some facts regarding
loratadine, which is the predecessor of
desloratadine. Loratadine is approved for children
2 years and older, whereas desloratadine
is
approved for children 6 months and
older.
Desloratadine is the major metabolite of loratadine
and possesses similar pharmacodynamic
activity. It
also has less extensive first-pass metabolism
and a
longer half life than loratadine.
Now, the drug use trends for
desloratadine. It accounted for 15 percent of the
prescription non-sedating antihistamine
market from
March
2003 to February 2004. The total number
of
prescriptions increased slightly from
9.8 million
to 10.2 million during the same
period. Pediatric
prescriptions accounted for 1.3 million
prescriptions.
For pediatric exclusivity 246 children, 6
months to 11 years of age were exposed
to
151
desloratadine in three two-week,
double-blind,
placebo-controlled safety studies. The efficacy of
the drug was extrapolated from the adult
efficacy
data.
The safety studies identified a subset of
pediatric patients who are slow
metabolizers of
desloratadine, approximately 6 percent
of all
pediatric and adult patients, and 17
percent of the
African-American patients. There
was no difference
in the prevalence of poor metabolizers
across age
groups, and there was no significant
difference in
adverse events, laboratory tests or
vital signs
between the pediatric poor metabolizers
and normal
metabolizers who received desloratadine
or placebo.
The adverse events that occurred more than
2 percent during the clinical trials,
which
included adults and children over 12
years of age
are listed on this slide.
In the pediatric clinical trials there
were no adverse events reported that
occurred more
than 2 percent of patients in the age
group of 6 to
11 years of age. The adverse events that occurred
more than 2 percent in frequency greater
than
152
placebo are listed on the slide
according to
different age groups as well.
During the one-year post exclusivity,
there were 185 reports for all
ages. Among the 185
reports there were 20 pediatric reports,
6 of them
in the United States. Among the 20 pediatric
reports, there were five serious
pediatric event
reports and there were no deaths.
The pediatric adverse events reported are
listed on this slide. Even though there were 20
reports, these events do not add to 20
because some
reports contained more than one event. The
underlying events are unlabeled events.
I now proceed with a synopsis of the
serious adverse event reports. 12 year old on
desloratadine and nasal beclomethasone
for
unspecified allergy had bronchospasm and
shortness
of breath, hospitalized for an unknown
period of
time.
An 11-year-old on 5 milligram
desloratadine, unknown indication,
developed two
asthma attacks within one month
requiring
153
hospitalization. The patient had five doses of the
drug between the asthma attacks without
difficulty.
And a 6-year-old on desloratadine, 2-1/2
milligrams daily for urticaria,
presented with
Kawasaki
disease three months after the initiation
of treatment.
A 5-year-old on 1.25 milligrams
desloratadine daily for cough and nasal
secretion
experienced somnolence, bradycardia,
diplopia,
dizziness and motor uncoordination, and
this
patient was hospitalized for 12 hours.
Last: a 2-year-old with a
history of
bronchiolitis and wheezing on
desloratadine, 1.25
milligrams, for coughing and rhinitis,
who
experienced status asthmatic as
requiring
hospitalization on two successive days.
Notice that these were all non-U.S. cases.
Although not reported as serious adverse
events, there are a few adverse event
reports that
were clinically significant. For example, a 5-year-old on
desloratadine, 125 milligrams daily for
rhinitis, experienced two days later
somnolence,
154
disorientation, and an unspecified
extrapyramidal
disorder, one week later became
unconscious, and
recovered one day after the drug was
discontinued.
Another relevant case was a 4-year-old
girl on 2-1/2 milligrams of
desloratadine daily,
had been on the drug for a week from
mosquito bites
and no other medications, experienced
spasms of the
upper body which resolved weeks later
after
discontinuation of the drug.
Lastly, a 3-year-old on desloratadine for
8 days of a known dose and specified
medication, no
concomitant medications, experienced
torticollis,
and no other data was available.
Also notice that these are all cases that
occurred abroad.
In summary, there were a few pediatric
adverse event reports during the
pediatric
exclusivity period. There are no new safety
concerns regarding the use of
desloratadine in the
pediatric population. This completes the one-year
post exclusivity adverse event
monitoring, as
mandated by BPCA, and the FDA will
continue its
155
routine monitoring of adverse events for
this drug.
DR. CHESNEY: Any questions? Yes, Dr.
Newman.
DR. NEWMAN: I have two
questions. You
listed a whole of kind of common
pediatric things
that were listed as more commonly occurring
with
medication than placebo. Were any of those
statistically significant?
DR. FILIE: Which--
DR. NEWMAN: This was in the
exclusivity
trial, the fever, diarrhea, upper
respiratory tract
infections, coughing, all of those things. It's
your ninth slide. Greater than 2 percent in
frequency, greater than placebo.
DR. FILIE: No. These were really not so
much different, and the range, the
incidence of
these side effects, adverse events, was
around not
more than 4 percent each, and they were
not really
clinically significant.
DR. NEWMAN: But all of these
were more
frequent with drug than with placebo?
DR. FILIE:
Exactly. Which slide are you
156
talking about?
DR. NEWMAN: It's Slide 9.
DR. FILIE: Yes. These did occur more
than 2 percent, and more frequently than
placebo.
DR. NEWMAN: And were there some
sort of
equal number of adverse effects that
happened less
often with medication than placebo? I mean, I
don't know how--if you look at 100
different
things, and your standard is just more
rather than
statistically significant more, you'll
find a
bunch.
DR. FILIE: You're asking if
there were
some adverse events that occurred more
frequently
in placebo than with the drug?
DR. NEWMAN: Right.
DR. FILIE: Probably so, but I do
not have
the numbers. I cannot tell you that, but this is
what is expressed in the label. Usually what they
will have on the label is what occurs
more
frequently on the drug.
DR. NEWMAN: Unless you can tell
how often
it occurred with both and whether any of
them are
157
significant, this kind of labeling just
doesn't
really help at all. It's not informative.
DR. FILIE: Yeah. Would anyone like to
add?
I would like to invite the Review Division if
they would like to chime in and give any
additional
information. But as far as I can tell without
looking at the reviews, the clinical
reviews right
now, I don't have the numbers.
DR. MURPHY: I think what you're
getting
at is how we do adverse event reporting
in our
labels.
Is that the issue?
DR. NEWMAN: I'm just saying, you
know, if
you look for 100 different things and
your only
standard for reporting it is that it
occurred more
often with--I mean they're not going to
occur at
exactly the same rate with drug and
placebo.
They're
not going to occur at exactly the same
rate, so the fact that it occurs a
little more with
drug than placebo doesn't really
indicate anything,
you know. The question is does it occur either any
one outcome statistically significantly
more, or a
lot more, or if you add them all
together and say,
158
okay, any adverse event, was any adverse event, if
you pool all these together, are one or
more
adverse events more likely with drug
than placebo?
As a clinician who sees a lot of kids who
get antihistamines and sees all of these
things on
the list every day, I mean a lot, I
suspect that
this is not a real association, but then
why put it
on the label? It just doesn't help me at all.
DR. MURPHY: What is done is if
there are
statistically significant differences in the
trials, clearly that is put into the
label, okay?
But what
is also then done--and one could argue the
usefulness of that--but because trials
are very,
you know, as we've discussed, limited in
number,
limited in duration, limited in the
population,
what is also provided is additional
information
about adverse events that occurred more
frequently
in the treatment group than in the
placebo group.
I mean
you're right from a mathematical point of
view, but it is felt that because we
know we're
only looking at a limited amount of data
that it is
appropriate to define that which we
think is
159
clearly statistically significantly
different and
that which we think is just reported
that was seen
in the clinical trials.
And actually there's been discussion of
should we even be including those things
that are 1
percent--what percentage should we have
a cutoff
and how useful it is? But that is some of the
thinking behind why doing it, is that
you don't
really know what the entire context--I
mean the
entire spectrum might be, and this is the
controlled clinical trial against
placebo, and you
know that in a population you're going
to have
background noise, so at least you can
report
against placebo what was seen.
Is Badrul here? Would you like to comment
on how your division reports,
particularly I think
for the antihistamines. But it gets to the bigger
labeling issues.
DR. CHOWDHURY: I'm Dr. Badrul
Chowdhury,
the Division Director in Pulmonary and
Allergy
Drugs.
What you're asking is a pretty
broad
160
question I think, is not necessarily
applicable to
this drug as a single entity that
applies across
how an adverse event is reported in the
product
label following clinical trials.
The general practice is--I mean knowing
it's a very limited database for a
clinical trial,
it's usually a few hundred to thousands, and you
cannot really capture everything that
has happened
or could happen. The practice generally is to look
at the numbers that happened with the
drug, look at
the numbers that happened with placebo,
and make
some reasonable cutoff of event that is
more
commonly happening with drug than with
placebo, and
put the numbers then.
Statistical influential statistics on
adverse events is completely useless
because you
cannot really put a p-value against an
adverse
event and conclude it is significant or
not. It
really isn't worth an observation. And it is
really during clinical practice that
more and more
is known, and adverse events, as it is
reported,
gets modified. It is not uncommon for a drug to
161
have an adverse event that you did not
think of as
being a drug-associated adverse event,
but later on
there's cases it bears out to be the
case.
DR. NEWMAN: I would disagree
with that,
that there's no way that in practice
anyone would
pick up any of these adverse events as
being drug
related in the absence of a randomized trial
because the background noise for all of
these
things is a lot.
DR. CHOWDHURY: Nobody's saying
that is
drug-related or drug-causes adverse
events. It is
just that these were observed. And add that to the
interpretation of ultimate use because
if you see
something which is happening more
commonly with the
drug and not happening with placebo, I
mean, it's
not possible to go after each and every
adverse
event and try to make a cause and
association if it
is caused by the drug or not. I mean, just cannot
happen in development in the limited
time period.
We're
just reporting what was seen.
DR. NEWMAN: Okay. My guess is this is
not the time to try to--
162
DR. CHOWDHURY: Oh, it probably
is not,
and this is really I think a more
broader issue of
adverse event reporting in the product label that
comes out of clinical trials across
drugs and
across drug classes done specifically
for
desloratadine.
DR. NEWMAN: So maybe we could
discuss it
more at another time, but just as a
consumer of
this information, I find it pretty
useless.
DR. CHOWDHURY: I mean I would
really not
discount it to that of an extent because
I mean
there are also adverse events that are
here which
actually may even turn out to be
meaningful. I
mean if I just pick an example for here,
appetite
increase. Somebody can say it's completely
useless. But if you really go back and look at all
antihistamines, it is not uncommon for
some older
antihistamines actually to cause persons
to gain
weight.
This was the case with older
antihistamines. Nobody would really link that
association, but it is known that some
older
antihistamine which is not marketed in
the U.S. any
163
more, actually caused increased weight.
And when you see in this report this
appetite increase, I mean you can
discount it being
useless, but who knows? It actually may in the
future might turn out to be useful.
So it's just a pure reporting of the
number that were seen, not necessarily
making a
conclusion if that is associated with
the drug or
not.
DR. MURPHY: Again, it gets back
to what
do you think you're trying to
achieve? I think the
thought here is that, again, this is the
controlled
trial against placebo. You're going to have
problems once it's out with all the
confounders of
background noise, and that it's
appropriate to let
people know in a controlled trial, this
occurred
more frequently than placebo, not making
attribution. But over time you may, as Badrul
pointed out, we will come back and
revisit that
which has been labeled from controlled
trials and
see if it's becoming relevant or more
relevant. I
guess better more relevant.
164
DR. CHESNEY: Thank you. I think this
could be something that was readdressed,
and Dr.
Ebert and
Dr. Nelson have questions. I also.
I've wondered, what stands out to me here
is the movement disorders. What do you make of
that, and is that a common finding in
other
antihistamines. I'm not used to using it to
prevent them.
DR. FILIE: Usually it is not
common to
occur with antihistamines, but these are
newer
generations of antihistamines. It was not
described in the clinical trials either
adults or
children. This was never described.
So this is
why we brought it up as important, and
again, we
need to report the information as it is
and the
numbers as they are, but, yeah, it had
not been
described in the clinical trials for
adults of
children. The earlier generations, like super
heptadine, which was an older
antihistamine, was
known to cause some purposeless
movements in rats
in preclinical studies. So again, this is
something that I think we need to watch.
165
We're looking at an ocean and these
little
signals pop here and there, and probably
only with
time and more numbers, we'll be able to
make a
better interpretation of this.
DR. CHESNEY: Thank you. Dr. Ebert and
then Dr. Nelson.
DR. EBERT: Could you provide a
little
more detail about the two cases of
congenital
abnormalities?
DR. FILIE: Certainly. Let me see if she
can pull this. It's a back-up slide. Can
you find
it?
It's called maternal exposures.
These were two cases, and again, these
reports have very little
information. They are
very vague, and it's very difficult to
make any
attribution of congenital malformation
and link
this to the exposure to the drug. As you can see,
one baby was born with cryptorchidism
and hernia
and was exposed to desloratadine for
five days,
unknown gestational age, and the mother
had
concomitant use of amitriptyline. And the other
case was a baby born with a cleft lip
and palate,
166
and was exposed to multiple medications
for an
unknown length of time and unknown
period of the
pregnancy.
So it's really very vague and difficult to
make any assumption given even the
background rate
of the occurrence of these
malformations.
DR. CHESNEY: Dr. Nelson and then
Dr.
Fant.
DR. NELSON: I think you
correctly
observed that these are isolated events
in an
ocean, but I'd like to comment on the
size of the
ocean.
What strikes me is that these are non-USA
reports that you're reporting, and that
if we want
to try to get some estimate of frequency
that what
we really need--and I guess I would be
making Dr.
Iyasu's
job more difficult--the European Union, if
that's where they're from, is a smaller
market than
United
States, and in fact it may then reflect a
higher frequency than we might think if
we look at
our 10 million prescriptions here. We don't know
then how many prescriptions were
actually written
for the population that's reporting
these events.
167
DR. FILIE: That is correct.
DR. NELSON: And it also raises
an
interesting question whether their
ascertainment
system's better or whether their
physicians are
just more socialized into--I don't use
that term
politically--into reporting, etc. But the data
that is not comparable, we have isolated
events out
of a market that we don't have the
denominator, and
we have a denominator out of a market we
have no
isolated events. So either we're much safer here,
or what? So comment.
DR. FILIE: Exactly, and I think
you're
correct.
DR. IYASU: Could I make a
comment here?
I
wouldn't presume to sort of evaluate how
different our systems are. I won't make a comment
about that.
But in terms of foreign reports, what we
get is probably a very small percentage
of the
actual volume because the requirements
are there
for serious events to be preferentially
reported
from those serious sources. There's no requirement
168
to.
So there is also, you know, many--there's more
focus on the serious events. But in terms of
exposure, I don't know of any database
that we have
access to at FDA that will sort of
estimate what
the exposure that was in Europe,
although they do
have their own databases as well. And IMS has
different streams that also is only
probably making
estimates in drug exposures in Europe.
So I don't think we have the right
databases to try to tease out what the
differences
are, but I think we need to be careful,
wherever
the reports come from, that if there is
an
opportunity to explore them further,
that would be
an important activity which you say you
would make
my job more difficult. But I think this is
something that we can entertain.
DR. CHESNEY: So you can add a
European
database to your American database in
your spare
time.
[Laughter.]
DR. CHESNEY: Dr. Fant?
DR. FANT: Just one comment that stems
169
from one of your case reports, and I
think it just
underscores the importance of these narratives, at
least from what I can glean.
In the 5-year-old, who basically over the
course--two days after starting the
medication,
over the course of a week, developed
somnolence,
disorientation, unspecified
extrapyramidal
disorder, which seemed to progress over
a week to a
state of unconsciousness, and then
recovered one
day after the drug was
discontinued. What you told
us was that one of the features of this
drug was
its relatively long half life. So it's just kind
of perplexing, just from a
pharmacokinetic
standpoint how such severe symptoms--now
they may
be connected; this may be a connection,
but it's
kind of a strange one from the way I interpret
this, and it's worth noting because it
may be real
or it may be something that emerges as
some bizarre
quality related to this particular drug
in terms of
the idiosyncratic reactions it may
elicit in
people.
But I just don't understand how such
severe symptoms can resolve in one day
after being
170
on a drug with a long half life for a
week.
DR. FILIE: Yes.
I agree with you. And
again, these reports are very vague, so
it doesn't
give us much information. And you're right, how
could he just recover in one day how
disoriented
and somnolent this child was. Could be that this
child would have been in that category
if this all
metabolized and really had a more
significant
presentation of the side effects. We just don't
know and can't tell just from the
report.
DR. CHESNEY: Thank you very much.
I think we'll move on to the next topic of
adverse events for budesonide and
fluticasone.
x DR. CHOWDHURY:
Moving on with the next
section of the presentations. In this section
you're going to hear information
regarding adverse
events that have been reported to the
air system
for budesonide and fluticasone
containing products.
These
adverse events may have been reported by
patients, physicians, health
professionals or the
companies themselves, and specifically
they're
reporting of these adverse events to
you, the
171
Pediatric
Advisory Committee, as I mentioned
before, is monitored by the BPCA. It's only for
one year, so you'll hear a lot of
information from
a series of presenters. So we'll have questions
for clarification and also discussions
of the
question that has been posed to the
Committee at
the end of the series of presentations.
So you will hear from four speakers this
morning. The first speaker is Dr. Peter Starke.
Dr. Peter
Starke is a pediatrician and a medical
team leader in the Division of Pulmonary
and
Allergy
Drug Products. He has been with the
Agency
since 2000. Dr. Starke will be summarizing the
regulatory history and the labeling
changes and
will provide a perspective on the safety
of these
drug products which include the orally
inhaled and
intranasal budesonide and fluticasone
propionate
drug products. So this will give you I think a
good background in context for the next
set of
presentations that will focus on the
summaries of
clinical trials as well as the adverse
event
reports.
172
Dr. Peter Starke.
x DR. STARKE:
Good morning. I'm Dr. Peter
Starke. As you've heard, I'm a
pediatrician and a
medical team leader in the Division of
Pulmonary
and Allergy Drug Products. This morning I will
attempt to place the written request
studies and
the adverse event information,
particularly the
adverse event information that you're
about to
hear, into some perspective.
Although you will hear about adverse
events with all the budesonide and
fluticasone drug
products, we're specifically going to
deal with
just the orally-inhaled and intranasal
drug
products, and not the cutaneous drug
products, at
least my talk.
I want to assure you that we've reviewed
this information carefully and are comfortable with
the adverse events that you'll hear
discussed, that
they're appropriately represented in the
label for
both of these drug products. In addition, many of
these types of adverse events occur with
other
orally-inhaled and intranasal
corticosteroids and
173
those two, as appropriate, appear in the
labels for
those drug products.
This is an outline of my talk. I'll set
the stage for the discussion with some
background
on the burden or allergic rhinitis and
asthma in
the United States. I'll then focus on asthma and
review what is considered appropriate
and necessary
treatment for persistent asthma as
defined by the
National
Asthma Education and Prevention Program in
cooperation with the National Heart,
Lung and Blood
Institute.
These guidelines for the diagnosis and
management of asthma were first
published in the
early '90s and then again in 1997, and
again in
2002.
You see the URL for the website listed at
the bottom of the slides.
Then I'll go into some of the regulatory
history and labeling chronology. The labeling for
these drug products has changed
dramatically over
the last 10 years and I'll show you a
lot of what
has happened in that time period. We'll go over
the specific results of growth
suppression studies
174
with both budesonide and fluticasone,
covering the
orally inhaled and then later the
intranasal drug
products, and then I'll touch on the
status of the
current labeling for safety findings for
these
products.
This slide shows you a little bit of the
burden of allergic and non-allergic
rhinitis in the
United
States today. Allergic rhinitis is a very
common disease and it represents
significant
morbidity as you see shown. The figures you see
come from the 1998 Joint Task Force on
Practice
Parameters in Allergy, Asthma and Immunology, and
I'll
touch later on their recommendations for us of
corticosteroids in the treatment of
allergic
rhinitis. I'm not going to talk at all about non-allergic
rhinitis.
However, we'll focus a little bit more on
the burden of asthma. This information and the
information on the next several slides
comes from
the National Information Survey which is
conducted
annually by the National Center for
Health
Statistics at the CDC, and this
information can be
175
found on both the NHLBI and the CDC
websites.
Asthma is a significant public health
concern in the United States. It's associated with
significant morbidity and
mortality. In the United
States
it's estimated that over 20 million persons
are affected including over 6 million
children.
You see
on the slide the associated emergency
department, hospitalization and deaths
during 1999.
This slide represents the burden of asthma
in terms of the prevalence per thousand
population
in the United States today. Again this comes from
the National Health Interview Survey,
and you can
see that the questions on the survey
changed after
a period of time, and these questions
represent
slightly different questions after--I
can't see the
date from here, but something like
1999. Now, what
you see is a rise in prevalence in
asthma over
time, starting in 1980 at about 31 per
thousand,
increasing by 1996 to 54 per thousand,
an increase
of about 74 percent.
Here you see the mortality rates for
asthma in the United States over approximately
the
176
same time period. This again comes from the same
database. You can see that the ICD codes changed
slightly around the year 1999 so they
represent
slightly different coding, but again give you a
good sense of the mortality rates and
what you see
as an increase from 14.4 in 1980--this
is per
million--to a peak of 21.9 million, and
then a
decrease to about 16 million by the year
2000. So
the peak prevalence was in 1995.
What I've shown you is that in the United
States
this represents, asthma represents a huge
burden to individuals as well as to the
health care
system, and while the prevalence of
asthma has
increased and increased quite a bit
since 1980, the
overall increase in mortality has not
reflected the
same rate of rise as the increase in
prevalence.
The
mortality peaked in 1995 and is now declining,
and most practitioners feel that this is
due to a
combination of advances and care that
are
monitoring, patient education and the
use of
controller medications including the use
of
corticosteroids for persistent disease.
177
This slide represents a brief summary of
the medications used in clinical
practice for the
treatment of asthma, and you see quick
relief and
long-term controller medications
listed. I've
highlighted corticosteroids and want to
place their
role into some--as a controller therapy
into some
perspective here. Originally the NAEPP guidelines
recommended the use of controller
medications for
moderate and severe persistent asthma,
but the
latest recommendations now state that
corticosteroids should be used for all
forms of
persistent disease.
Now I'm going to switch topics a little
bit and start to give you a sense of
what's changed
in the labels over the last 10
years. All of these
drugs were approved during the 1980s and
1990s
including budesonide and
fluticasone. There are a
number of years during which some
significant
events occurred. The first was 1994. In that year
the Pediatric Labeling Rule took effect,
and that
labeling rule did a number of things,
but among the
things that it did was that it required
sponsors of
178
approved products to examine the
existing data in
the product label to determine whether
the
pediatric use subsection should be
updated, and
this prompted a number of pediatric
efficacy
supplements and many of these products
were
approved to lower age ranges down to
about 4 to 6,
and subsequently some lower.
In that same year the FDA began to review
the labels for all orally-inhaled and
intranasal
corticosteroids and made a number of
changes over
time.
They started doing it then, but over time
have made a number of changes with the
additions to
the labels of adverse events as reported
to the
companies and to MedWatch.
Now, in 1997 several important events
occurred. First the NAEPP expert panel issued
their second report and I've discussed
the results
of their recommendations already, and
you see them
up here. Second major event was that a growth
suppression study was submitted to the
Agency, and
this study was a one-year study with
intranasal
budesonide. The dose that was used was the highest
179
approved dose of 336 micrograms a day,
and it
showed a statistically significant
growth
suppression effect, but no significant
effect on
hypothalamic-pituitary-adrenal or HPA
access
function.
In addition, other growth studies were
submitted and are published, but
particularly they
were submitted, and for both
orally-inhaled and
intranasal drug products, but
particularly for the
orally inhaled, and with this information several
things occurred.
I'm going to skip over what happened and
just talk briefly first of 1998, come
back to the
allergic rhinitis, and the Joint Task
Force for
Practice
Parameters, in conjunction with the
American
Academy of Allergy, Asthma and Immunology
recognized intranasal corticosteroids as
the most
effective medication for the treatment
of severe
allergic rhinitis.
Going back to asthma, because of the
growth studies that came in a Joint
Advisory
Committee meeting was held. This was a Joint
180
Pulmonary
Allergy and Metabolic and Endocrine
Disease
Advisory Committee meeting, at which time
the results of the growth studies that
had come
into the Agency were discussed. They did recommend
a number of labeling changes, and I'll
show them to
you in the next several slides. That included
putting results of growth studies in the
label, and
adding class labeling for risks for
adverse events
to all labels for orally inhaled and
intranasal
corticosteroid drug products.
In November of that year, in November
of
1998, the FDA implemented these
recommendations,
sent letters to each of the sponsors
requesting
supplements with additional
labeling. Now, this is
the labeling in two of three locations
that was
added to the labels, and as I just
started to say,
there are three locations on the label
where
labeling was added. You see the first two, the
Precautions, general and the Adverse Reactions
sections, and under Precautions,
pediatric use
section, a long paragraph was added.
I haven't shown you the whole
paragraph.
181
I have it
if you want to see it, but this is a
synopsis of what was said, which is
that: Orally
inhaled or intranasal corticosteroids
may cause a
reduction in growth velocity in
pediatric patients.
The
growth effect may occur in the absence of
laboratory evidence of HPA axis
suppression. The
potential for "catch up"
growth following
discontinuation of treatment was not
addressed.
Growth
should be monitored routinely in patients.
To
minimize the systemic effects, each patient
should be titrated to his or her lowest
effective
dose.
Now, through our evaluations of growth
studies, we've come to understand a
number of
important points about these
studies. First, we
feel that growth suppression reflects
systemic
exposure to the corticosteroid. This is likely to
be due to a direct bone effect on
osteoclastic-osteoblastic
activity. That's a presumption that
I'm
saying. We believe it's a very
sensitive
indicator of systemic effects, and
therefore, the
potential to cause systemic
toxicity. And that
182
effect may be generalized to adults as
well as
children. In other words, the growth suppressive
effect, being an indicator of the
potential for
toxicity is not specific to just the
growth
population that's looked at in the
studies.
I'm showing you where a growth defect
study may be positive where an HPA axis
study was
negative. Because of the way we want the
information, we request that these
studies look at,
as accurately as possible, and
characterize the
difference in growth rate in patients
treated with
active and with control. Now, they're quite
technically difficult to perform, and I
do want to
congratulate both drug companies for
having growth
studies with the intranasal and the
orally inhaled
drug products, and I'm going to show the
results
shortly.
I'm not going to go into the details of
the technical difficulties with doing
them and/or
assessing them, but keep in mind that
these require
at least a year on treatment, height
measurements
with stadiometry, and they must be
performed during
183
the relatively level or flat growth
phase,
generally between 3 and 9 or 10 years of
age, after
the infant growth spurt and before the
pubertal
growth spurt.
There are a number of limitations to
interpretation of these studies. They are not
designed to demonstrate reversibility
with
continued use after a year or after
stopping a
medication. They're not designed to evaluate the
effects on final adult height, and you
cannot take
the growth effect and relate it at all
to the
individual patient. For these reasons, they are
very difficult to interpret out of
context of the
study itself.
All the studies were designed prior to
when we published a growth guidance in
2001, and no
two studies had the same design. Therefore, it's
quite difficult to do any kind of cross-study
comparison, and I won't attempt to do
so.
So here's the growth study for inhaled
budesonide. This is the design of the growth
study.
It used Pulmicort Respules. This
is, by
184
the way, not in the label. What's in the label is
the growth results for the 12-week study
that gave
the indication. This information, however, was
discussed at the 1998 Advisory Committee meeting,
and therefore I'm showing it to you now.
This was a 12-month open label extension
of a 12-week double-blind study. The arms you see
with inhaled budesonide and nonsteroidal. There
were several analyses done for different
age
groups, 9 months through 3 years and 4
through 8
years.
Before I show you the results, I just want
to caution you about interpreting
results for the 9
month to 3 year age range, where growth
is not
linear and where one generally has to
measure
length rather than statutory height, and
this
introduces a large variable into these
kinds of
studies.
So here are the results for the orally
inhaled budesonide. You see at the top the 4- to
8-year-olds, and below it the 9 through
3-year-olds. You
see also the budesonide and then the
nonsteroidal groups below it, and the
height
185
changes over the year--I'm sorry, the
growth rate
over a year. The delta is what I would point out
to you.
That's the difference between the active
and control groups. A negative number implies a
growth rate effect, a positive growth
rate effect.
So you
see for the age range of 4 to 8 a growth
suppressive effect of half centimeter,
and for the
lower age range, 1.8 centimeters. So there clearly
is some difference between the two, but
again, it's
hard to interpret what that difference
actually is.
This is the growth study using inhaled
fluticasone propionate, and I believe
this is in
the labeling. This used the Flovent Rotadisk.
It
was randomized, placebo-controlled
one-year study
in prepubertal children. You see that two doses of
fluticasone propionate were used in this
study, 50
and 100 micrograms twice daily.
There are the results. There was
some
indication of a dose response in this
study, and if
you look at the first two lines of the
delta you
see the results compared to placebo for
the 50 and
100 micrograms twice daily.
186
So just to continue and update from 1998
to 2004, the Advisory Committee
recommendations
were implemented, as I've shown
you. I mentioned
already that we published a draft growth
guidance
in 2001. Guidances represent the best thinking of
the Agency, but they do not require
sponsors to
follow that thinking if they can show us
some
alternative methodology.
The labels have been reviewed and updated
with new labeling supplements as they
come in, with
post-marketing adverse events as
reported. You'll
hear the pediatric exclusivity studies
next.
They're
updated with pediatric exclusivity studies
results as appropriate and with the
results of
Phase IV
growth studies as they come in.
Here are the results for the intranasal
budesonide and fluticasone growth
studies, and you
see the moiety on the left, the dose,
the N, the
growth rate over a year, the difference
between
active and placebo and the 95 percent
confidence
intervals when we have them. For convenience I put
on the slide the results of the
beclomethasone
187
study that started this all off in 1997,
and you
see only a very small effect for each of
these two
drug products. But I just want to point out the
budesonide used the lowest approved
dose;
fluticasone used the highest. We do recommend at
this point that sponsors use the highest
approved
dose in these studies.
So the labeling status as of 2004.
All
labels clearly describe the potential
risks for
adverse events; HPA axis studies. We've included
the class labeling. There are some minor
differences between various drug
products in the
wording, but that's probably fine. Growth studies,
as they come in; and all the labels are
being
reviewed and updated as new labeling
supplements
are submitted.
Specific labeling for budesonide and
fluticasone is shown in this slide. Both the
orally inhaled and intranasal drug
products for
both of these drugs have HPA axis growth
and post-marketing
adverse events labeled. In addition--and
this relatively new information, so I've
included
188
it separately--budesonide--and you saw
the results
of the growth study. That study is now in the
label as of the last month or two. In addition, as
of the end of August, budesonide was
relabeled as
Pregnancy
Category B, and this is as the results of
information from three Swedish birth
registries.
You see a
representative of what Category B, one of
the requirements for Category B. It was changed
from Category C to Category B.
So in summary, asthma is a chronic
inflammatory disease of the
airways. It represents
a huge burden to the health care
system. While the
prevalence of asthma has increased since
1980, the
mortality rates increased, and then have
declined,
although the overall mortality rate is
higher now
than it was in 1980. Corticosteroids are
recommended as a primary controller
therapy for
persistent asthma, all forms, and as the
most
effective therapy for severe allergic
rhinitis.
The types of adverse events that may be
expected with this class of compounds,
namely
corticosteroids, have been well
documented over the
189
years, and the FDA is continually
reviewing and
updating the labeling as we get more and
more
information about the individual drug
products.
I've shown you how the labels have changed
dramatically over the last 10 years with
class
labeling. We really haven't gone into HPA axis
information, but you'll hear more about
that in the
written request studies. I've shown you about the
growth studies. You'll hear about the adverse
event data. At this point we believe that the
current labeling for these drugs is
concurrent with
the latest safety data for these
products.
I leave you with this quote from the NAEPP
guidelines, from the 2000 guidelines,
which state
that:
"Inhaled corticosteroids improve health
outcomes for children with mild or
moderate
persistent asthma," and obviously
with severe, "and
the potential but small risk of delayed
growth is
well balanced by their
effectiveness."
Thank you.
Now I'm going to introduce to you Dr.
ShaAvhree Buckman. She is a pediatrician with the
190
Division
of Pediatrics. She has Ph.D. training
in
molecular cell biology and
pharmacology. She's
been a medical officer in the Division
of
Pediatrics for the last two years.
She will be
presenting on the clinical studies for
budesonide
and fluticasone.
x DR. BUCKMAN:
I can now say good
afternoon.
[Laughter.]
DR. BUCKMAN: I will be
presenting a
summary of clinical trial data for
fluticasone and
budesonide. As an overview this table describes
the various fluticasone dosage forms,
the original
dates of approval and current pediatric
approval
information. This table includes topical,
intranasal and orally inhaled products.
The most recent approval, as of May of
2004, was for Flovent HFA Meter Dose
Inhaler. HFA
stands for hydrofluoroalkane, and this
inhaler is
designed with a CFC-free propellant that
is more
environmentally friendly.
This table describes the
various
191
budesonide dosage forms which include
orally
inhaled, intranasal and oral
products. Because the
names of some of these products can become
confusing, the slide just shows some
examples of
some of these products. The Advair Diskus, Flovent
Rotadisk
and Pulmicort Turbuhaler are inhaled
powders. Pulmicort Respules are a solution for
inhalation used in conjunction with
compressed air-driven
jet nebulizers. Also shown here is a
typical Flovent Metered Dose Inhaler
which delivers
aerosolized drug, and Entocort, which is
shown in
the corner, is indicated for oral use
only in adult
patients who have Crohn's disease. We will not be
discussing this product during today's
presentation, but it is a budesonide
containing
product. Also shown here are two nasal
preparations, Flonase as well as
Rhinocort Aqua.
Seven dermatology and pulmonary studies
were requested for pediatric exclusivity
for the
fluticasone moiety. Four studies were requested
for Cutivate, which is the dermatologic
product.
One study was requested for Flonase, two
studies
192
for Flovent, and there was also
requested an in
vitro study report as well as a
population PK
report for Flovent.
First we will discuss the studies for
Cutivate. As background,
Cutivate cream has been
approved for use in children 3 months of
age and
older since June 17th of 1999. A written request
was issued for other fluticasone
containing
formulations on June 25th of 1999. This written
request included three studies for
Cutivate lotion
and one study for Cutivate
ointment. Also as
background, an Advisory Committee was held
in
October
of 2003, which many of you may have
attended, that discussed the clinical
risk
management of HPA axis suppression in
children with
atopic dermatitis who are treated with
topical
corticosteroids. Presently, only Cutivate cream is
indicated for pediatric use, not the
ointment.
The current labeling for Cutivate cream
includes studies which were not
requested for
pediatric exclusivity. 43 pediatric patients were
treated with Cutivate .05 percent cream
for atopic
193
dermatitis covering at least 35 percent
of their
body surface area for four weeks. 2 out of the 43
patients had HPA axis suppression, and
follow-up
testing was available for one of those
two
patients, which demonstrated a normally
responsive
HPA axis
on follow up.
This study using Cutivate ointment was
requested for exclusivity. 35 pediatric patients
were treated with Cutivate ointment for
atopic
dermatitis covering at least 35 percent
of their
body surface area for three to four
weeks.
Subnormal
adrenal function was observed with
cosyntropin stimulation testing in 4 of
the 35
patients. The recovery of adrenal function in
these patients was unknown and follow-up
testing
was not performed. This information was
incorporated into the Pediatric Use
subsection of
the labeling as shown here.
It is important to
note that Cutivate ointment is not
indicated for
pediatric use.
Now we will discuss the clinical studies
for Flonase, the intranasal
product. This study
194
was described to you briefly by Dr.
Starke in the
previous presentation, and it was not
requested for
pediatric exclusivity. This was a one-year multi-center
placebo-controlled trial looking at
longitudinal growth of 150 children,
ages 3 to 9
years with perennial allergic rhinitis.
The mean reduction in growth velocity
after one year of treatment with Flonase
at 200
micrograms per day was estimated at .137
centimeters per year. HPA axis evaluation in these
patients showed no interpretable effects
on urinary
free cortisol. And this study supported safety in
children at the maximum approved dose
and twice the
daily dose typically used in patients at
this age
group.
The recommendation was made for the
results of this one-year growth study to
be
incorporated into labeling, and you can
see where
this was incorporated.
This study for Flonase was requested for
pediatric exclusivity. It was a six-week,
multicenter, placebo controlled HPA axis
study in
195
65 patients between the ages of 2 and 4
years with
allergic rhinitis. 12-hour urinary free cortisol
was used to evaluate the HPA axis. The results of
this study were deemed indeterminate due
to
limitations in urine collection and wide
variations
in baseline urinary free cortisol levels
between
treatments groups. Therefore, no labeling change
resulted.
Now we will discuss clinical studies for
Flovent. We have discussed
studies for Cutivate
and Flonase, and now we'll briefly touch
on an in
vitro study report that was done for
Flovent for
exclusivity.
Prior to starting the clinical program
with Flovent, the sponsor performed a
comparison of
the particle size distribution by
cascade impaction
for Flovent CFC Metered Dose Inhaler
with and
without the use of various spacers as
shown here.
The results appear to indicate that the in
vitro respirable particle content was
similar
whether the metered dose inhaler was
studied alone
or in combination with either of three
different
196
spacers. However, the study was unable to evaluate
factors that would have been important
to the in
vivo clinical setting, and this would
include
variations such as variations in flow
rates, delay
between actuation of a dose and actual
inflow, how
long a mask was held over the nose and
mouth of a
child, and therefore, result of this
study were not
incorporated into labeling.
These studies for Flovent were requested
for pediatric exclusivity as well. Two 12-week
placebo controlled efficacy and safety
studies were
performed in children with symptomatic
asthma, who
were between 6 and 47 months of
age. Detectible
plasma levels of fluticasone were seen
in 13 of the
placebo treated patients. Therefore, it was
impossible to evaluate the actual extent
of patient
exposure and made the interpretation of
the PK/PD
relationship difficult to assess. The
interpretation of this study was that it
was
impossible to determine whether the
studies derived
an accurate estimate of either safety or
efficacy,
and therefore, no labeling change
resulted from
197
these studies.
Now we will discuss the clinical studies
for budesonide. Two studies were requested for
exclusivity. One was a safety study of budesonide
nebulizing solution for the treatment of
asthma in
children 6 months to 1 year of age, and
the second
was an HPA axis safety study of the
budesonide
nasal spray in children between 2 and 6
years of
age.
First we will discuss the studies for
Rhinocort
Aqua, the nasal spray. This was a
6-week
multicenter placebo controlled study to evaluate
the effect of Rhinocort Aqua on HPA axis
in
patients with allergic rhinitis. 78 children were
studied between the ages of 2 and less
than 6 years
of age.
The HPA axis function was evaluated by
low-dose cosyntropin stimulated plasma
cortisol
measurements at baseline and following
six weeks of
treatment. The results of this study were deemed
indeterminate because of difficulties in
determining patient compliance, and no
labeling
change resulted.
198
Now we will discuss a clinical study for
exclusivity using Pulmicort
Respules. This was a
12-week randomized placebo-controlled
study to
evaluate the safety of Pulmicort
Respules at .5 and
1 milligram daily in pediatric patients
with mild
to moderate asthma or recurrent
persistent
wheezing. 141 patients were studied between the
ages of 6 and 12 months. The main safety concerns
that were evaluated were concern for HPA
axis
suppression and suppression of linear
growth.
Of the 141 patients that were randomized,
76 patients had an ACTH stimulation test
at the
beginning and the end of the study. The mean
values of the three treatment groups did
not
indicate any difference in adrenal
responsiveness.
However,
six patients with Pulmicort Respules and
one patient in the placebo group had post-ACTH
plasma cortisol levels that were below
normal.
There was also noted in the bottom study a
dose-dependant decrease in growth
velocity between
the placebo and budesonide treated
groups. Also of
note, pneumonia was observed more
frequently in
199
patients treated with Pulmicort Respules
than
placebo. Three patients were noted in the
budesonide treated group who developed pneumonia
during this study.
These findings were incorporated into the
clinical pharmacology and precautions
subsections
of the label show here. In summary, the studies
for pediatric exclusivity have resulted in labeling
changes for fluticasone and budesonide
containing
products. Pediatric trials for fluticasone and
budesonide have identified important
safety
concerns which have been incorporated
into
labeling.
This concludes my presentation, and I
thank you for your attention.
The next presentation will be given by Dr.
Joyce
Weaver, who is a Safety Evaluator in the
Division
of Drug Risk Evaluation in the Office of
Drug
Safety at the FDA. She will be
presenting the
adverse events for budesonide and
fluticasone.
x DR. WEAVER:
Good afternoon. I'm going to
be presenting both use data and
information about
200
adverse events reported to the FDA's
Adverse Event
Reporting
System for budesonide and fluticasone.
First I'll talk about budesonide. The
total number of prescriptions dispensed
for all
budesonide products increase from
approximately 6
million in 2001 to 7.8 million in 2003
with
pediatric patients accounting for about
29 percent
of the total prescriptions. Rhinocort, the nasal
product, is the most commonly used
budesonide
product, accounting for over half of the
budesonide
prescriptions, and of those, 17 percent
were for
pediatric patients.
The inhalation product, Pulmicort
Respules,
represents most of the rest of the
prescriptions for budesonide. Over half of the
Pulmicort
prescriptions are for pediatric patients.
Entocort
represents a very small portion of
budesonide dispensed.
The FDA's Adverse Event Reporting System,
or AERS, contains about 2,800 adverse
event reports
for all ages covering the lifetime of
the
budesonide products. For the one-year period
201
following approval of pediatric
exclusivity, AERS
contains 157 cases including 38
pediatric cases.
The
pediatric cases did result in some serious
outcomes including one death.
For the pediatric cases reported to us
in
the year after approval of exclusivity,
we received
more reports for boys than for girls,
and most
reports were received for children 2 to
5 years of
age, and most reports were received for
the
inhalation product.
This slide shows the most commonly
reported events in the pediatric cases
in the year
after the granting of exclusivity. Convulsions
were reported most. Additionally, a number of
events were reported that are indicative
of
systemic absorption of budesonide. Seizures are
not an expected reaction with the use of
budesonide. And when we looked at the cases we did
not see a clear relationship between
budesonide use
and the subsequent development of
seizures. One
case was confounded by concomitant use
of
theophylline, and that case did not
include a
202
theophylline level.
Two cases were not confirmed by health
care professionals and the seizures were
not well
described. One patient was receiving CNS
radiotherapy, and that same patient was
receiving
another drug concomitantly that is
labeled for
inducing seizures.
We have 17 cases showing possible systemic
steroid effects including growth
retardation,
decreased blood cortisol, adrenal
suppression and
Cushing's
syndrome.
As I said, we did receive a report of a
death in the year following approval of
exclusivity, and this case was reported
from within
the United States. It was a 3-year-old girl who
had received Pulmicort Respules for 3
months. She
stopped breathing, was transported to an
emergency
room, and she died in the emergency
room. An
autopsy was performed but not establish
a cause of
death.
We conclude from our review of the events
reported to AERS for budesonide in the
year
203
following approval of pediatric
exclusivity that
first, most events, including systemic
steroid
effects, are included in product
labeling; and
second, the convulsions are not labeled,
but we
didn't see a clear relationship to
budesonide.
Now I'll go on to fluticasone.
First,
this is use data for fluticasone cream
and
ointment. Children account for about one third of
the prescriptions for these products.
This is for fluticasone nasal spray.
Prescriptions for nasal spray have remained fairly
consistent over the past two years, with
about 15
million prescriptions in 2003, and
pediatric
patients account for less than 10
percent of all
prescriptions for fluticasone nasal
spray.
This slide shows information for inhaled
fluticasone. For inhaled fluticasone there are
about 7 million prescriptions in 2003,
and there;s
been a downward trend over the past
couple years.
pediatric patients account for about one
quarter of
the prescriptions for the fluticasone
oral
inhalation products.
204
Now, to Advair. We're looking at
this one
separately. Advair's a combination of fluticasone
and a long-acting beta-2 agonist, salmeterol. use
of Advair has increased considerably
over the past
few years. Advair accounted for 17 percent of
orally-inhaled steroid prescriptions in
2001. This
increased to 54 percent in 2003, with
pediatric
patients accounting for 13 percent of
total
prescriptions.
Looking at the adverse events reported for
all fluticasone containing products,
AERS contains
about 4,600 adverse event reports for
all ages
covering the lifetime of the fluticasone
products.
For the
one-year period following approval of
pediatric exclusivity, AERS contains
about 2,100
cases, including 128 pediatric
cases. The
pediatric cases did result in some
serious
outcomes, including 5 deaths.
For the pediatric cases in AERS in the
year after approval of pediatric
exclusivity, we
received most reports for children 6 to
11 years of
age, and most reports were received for
the
205
combination fluticasone and salmeterol
product,
Advair. You can see in the
right-hand column, 82
of the cases that we received, 82 of the
128, were
for reported events for that combination
product.
This slide shows the most commonly
reported events in the pediatric cases
in the year
after the granting of pediatric
exclusivity. We
looked at these cases and we found two
issues.
emerging from this.
The first issue we found was systemic
steroid effects. There were 12 cases showing
systemic steroid effects, and I'll
address this
issue in a couple minutes. The second issue in the
cases was worsening asthma symptoms with
the use of
Advair. We had 22 such cases
reported in the year
following the granting of exclusivity,
including
four cases in which the patient died.
So first we will address the cases
reporting worsening asthma symptoms with
the use of
Advair. And as I said, we
received 22 of these
cases in that one-year period. In 10 cases serious
outcomes were reported, including four
deaths. The
206
patients were 5 to 14 years of age. Race was not
reported in most cases. The time to onset of
symptoms ranged widely from the very
first day the
Advair
was used to after two years of use. And
the
AERS
cases do not show what the relative
contributions of underlying disease and
the use of
Advair
may be in the adverse event.
I'll present the four cases on which the
patients died. The first case is a case
originating from the United States. A 14-year-old
black male was prescribed Advair after
an episode
of respiratory arrest. He had received Advair
Diskus
for 2 years when he experienced an acute
asthma attack. He was transported to an emergency
room.
When he arrived he was in full cardiac
arrest and he died. No autopsy was performed.
The second case also originated from the
United
States. This is a 13-year-old white
male
who had received Advair for about 6
months. He
experienced an asthma attack and he
died. An
autopsy showed chronic bronchitis,
hypertrophy of
bronchial muscle, infiltrate of
eosinophils, mucus
207
plugging of smaller airways, areas of
pneumonia and
air trapping.
The next case originated from outside the
United
States. A 14-year-old asthmatic girl
was
treated with salmeterol for an acute
asthma attack.
When she
did not respond quickly to the treatment
with salmeterol, treatment with a
combined
salmeterol fluticasone product was
started. About
2 hours after her first dose of the
combination
product, the patient's condition
worsened and she
died.
The final case is a case, once again from
the United States. A 13-year-old boy experienced
cardiac arrest and died after receiving
Advair for
an unknown period of time.
The report stated that
while talking to a friend on the phone,
the boy
just stopped talking. An autopsy showed only lung
changes consistent with asthma.
You saw this slide before. I'm
showing
you this slide again to remind you that
most of the
cases we received in the year after the
granting of
exclusivity were received for the
combination of
208
fluticasone and salmeterol product, Advair. And
once again, it was 82 of 128 cases. And while the
use of Advair has been increasing in
children, we
don't think that the increased use
explains the
increased reporting in pediatric
patients for the
product.
This slide shows the pattern of reporting
of pediatric adverse events with Advair,
and the
timing of important regulatory action
and an
important labeling change for
Advair. Going across
the bottom of the slide, each column is
a quarter.
So we
start with a quarter in 2000 and go up to the
first quarter of 2004. In January 2003 the FDA
released a talk paper discussing the
cessation of a
salmeterol safety study, and the interim
analysis
of that study suggested that salmeterol
may result
in worse asthma outcomes. And in August 2003,
Advair
received a boxed warning about the
possibility of worse asthma outcomes
with
salmeterol. And as you can see, the spike in
reporting for Advair occurred around the
time that
Advair received that boxed warning.
209
This slide just shows the boxed warning in
the Advair labeling, and again, the
boxed warning
was incorporated into the labeling
because of the
interim results of the safety study, not
because of
the AERS cases. So that's the first issue with the
fluticasone containing products.
Now I'll address the other issue that we
found in the pediatric cases, and that
second issue
is the systemic steroid effects with the
use of
fluticasone containing products. We had 12 such
cases, including a case in which the
patient died.
Now, to look at these cases a little more
closely, most of the cases occurred with
inhaled
products. In one-half of the cases the patient was
receiving more than one source of
steroids
concomitantly, and we had only one case
that
reported a systemic effect with the use
of a
product within labeled dose and without
an
additional source of steroids on board.
As I said before, we did have a case with
an outcome of death. This case originated from
outside the United States and we don't
have
210
clinical details about the case. An 8-year-old
girl, who used an unknown amount of a
fluticasone
containing product for an unknown dose,
unknown
period of time, developed adrenal crisis
and died.
So what can we conclude from the cases
that we've received for fluticasone
containing
products in the year after the granting
of
exclusivity? Most of the events reported are
included in the labeling, including
systemic
steroid effects and including worsening
asthma with
the use of salmeterol containing products. In the
AERS
cases of asthma exacerbation with Advair, the
relative contribution of underlying
disease and
Advair to
the events is not known.
That concludes my presentation.
You've already met Dr. Chowdhury, but I'll
introduce him again. Dr. Badrul Chowdhury is the
Director
of the Division of Pulmonary and Allergy
Drug
Products. He's been with the Agency
since
1997.
He's an internist, an allergist and an
immunologist, and he'll be summarizing
the
pediatric programs for fluticasone and
budesonide
211
that were presented previously.
x
DR.
CHOWDHURY: Thank you for the
introduction, and I will very briefly
summarize the
programs that were done for fluticasone
and
budesonide containing drug products for
allergic
rhinitis and asthma indications, which
are the
nasal products and oral inhaled
products. I'll go
through them so that you can really put
the
presentations that you heard before,
three of them,
into context of the whole drug
development programs
and where we stand currently with the
labeling
status of these drugs, particularly for
children.
Asthma and allergic rhinitis, as you have
heard before, are common diseases, and
in fact
they're pretty common in children and impose
significant burden on the health care
system and
also on individuals who have these
diseases. And
the prevalence of atopic diseases in
general and
asthma has been studied in depth. The prevalence
of this disease is increasing, but
recently, as yo
have heard before, the trends in death
and
hospitalization are declining. And the various
212
factors which are contributing to this good
outcome
of a serious disease, including
availability and
use of various controller medications.
As you've heard before, corticosteroids
currently are the primary controller
therapy for
all grades of persistent asthma, and
they're being
used, and their use is also being
covered under
various guidelines. For allergic rhinitis, again,
corticosteroid is considered to be the
most
effective therapy.
These drugs, of course as we know now, are
not completely free of adverse
events. The topical
drugs are applied on the surface or the
body, and
historically at one time they were
considered to be
really surface acting and not
systemically active,
but now we know that they are
systemically active,
and has adverse events, which came back
to the
systemic exposures, particularly those
allergic to
suppression of the HPA axis and also
other
metabolic effects. But the benefits of these are
appropriately labeled and overall the
risk/benefit
supports the use of these drugs.
213
Now, I think we may have skipped a slide.
Yes. I will, on the slide, very briefly go
through
the pediatric development of these drugs
so that
you can put the studies that you have
heard in the
context. Usually for asthma and allergic rhinitis
these drugs are developed for adults
first, and
then the efficacy and safety goes down
to the
pediatric patients usually be generating
data and
by extrapolation, because we think the
diseases are
same in adults and children and the
effect of the
drug on the diseases are also the same.
Now, in going down in the age, one
important consideration is to identify
appropriate
dose.
Because this is surface active, therefore PK
is not a good marker for dose selection.
They are
usually done through clinical studies,
and for
these diseases, asthma and allergic
rhinitis, it is
often quite difficult to design
appropriate studies
with efficacy endpoint, but again, they
are being
done to pick the right dose, and the aim
here
being, both for adults and also for
children, to
have a reasonably low effective and safe
dose, and
214
then particularly for the children, show
established safety of that dose.
So safety is a key in going down in the
ages for these drugs, and safety
assessment is done
in a variety of ways and you have heard
some of
them.
To summarize them here in the slide, we look
at clinical trials and monitor them for
adverse
event, laboratory parameters, ECG
findings, et
cetera, and then look at HPA axis in
varieties of
ways, such as ACTH simulation test or
look at
plasma cortisol and urinary cortisols.
And these, which means the clinical
studies and safety assessment of HPA
axis are done
pre-approval. Then the growth study comes in,
process of linear growth, which really
is a
surrogate of systemic effect, and they're usually
long studies, quite difficult to perform
and
interpret, and they're usually done
post-marketing
as a Phase IV. And then of course, after
marketing, we look at post-marketing adverse
events.
So the next three slides I'll
quickly go
215
through these three aspects which is HPA
axis
safety, linear growth and post-marketing
adverse
events, and put some comments of mine on
these
three areas.
You've heard the pediatric studies which
was done for specificity presented, and
typically
for asthma for both of these drugs, they
were
efficacy studies. And the ages that we ask for for
efficacy study at the time we solicited
request was
based on what we already knew and what
we wanted to
know.
For example, for budesonide, it was one year
and below because the drug was already
at that time
approved a study for one year and
above. For
fluticasone it was 4 years and below for
the same
reason again, the drug was studied and
indicated
for 4 years and above.
For allergic rhinitis the study was a 6-week study
primarily designed to look for safety,
which means all kind of safety, adverse
events
reporting, clinical monitoring for
adverse events,
and also HPA axis safety. I will not go through
the results of these.
You've already heard Dr.
216
Buckman
present results. Some of them are
reflected in the label and some of them
are not,
and we made the decisions on a
case-by-case basis,
looking at the study, what we could come
out from
the study in terms of what could go on
the label,
and appropriate labels have been
updated.
For assessment of systemic effects, as I
said before, it is done really by two
ways. One is
assessment of HPA axis directly by
either a
stimulation test or by measuring
cortisols in the
plasma or urine, and these are done
pre-approval,
and for these drugs, generally they're
negative,
but again, not all. If you look across the drug
classes, the product labels are quite
different and
they reflect the studies in the product
labels.
And the growth study which, as you've
heard before, you're studying the
systemic effect
and systemic toxicity perhaps, was also
done for
these drugs, and their effects are quite
numerically small, and they're again
reflected in
the product label.
On the post-marketing side for
adverse
217
events for these drugs, the large number
of adverse
events which is not unexpected, is
systemic
corticosteroid effects or effects related
to
suppression of HPA axis. These are expected and
these are labeled, and these were seen
in the HPA
axis studies and also in the
post-marketing
studies, and the current label reflects
these
potential systemic adverse events.
The worst thing for asthma with Advair is
something which is noted in the product
label quite
prominently, and whether it is coming
from
salmeterol contributing or whether it is
coming
from the fact that Advair is typically
used for
patients who have more severe asthma is
currently
unknown. One can speculate it can be either/or.
Perhaps
the patients with asthma who are more
severe are put on Advair; therefore,
having
worsening of asthma is not necessarily
very
unexpected. And we also know recently that
continued use of beta agonist,
specifically
salmeterol, can worsen asthma. Again, these are
known adverse events that we know of now
and is
218
adequately reflected in the product
label.
To summarize this whole pediatric studies
that we have, the safety concerns would
be use of
oral inhaled and intranasal
corticosteroids,
specifically budesonide and fluticasone
which we
are discussing today, are well
characterized, so we
know what the adverse events of these
drugs are,
and they're adequately described in the
product
label.
The new data that we have obtained under
pediatric initiatives in post-marketing
adverse
events are reassuring because we are not
really
seeing anything new which is totally
unexpected.
What we
are seeing is what we expected to see, and
they're not extremely, extremely common,
and these
are again adequately reflected on the
product
label.
So this risk/benefit assessment, these
drugs of course have some adverse
events, have some
risk, and we think it is adequately
reflected on
the product label, and overall benefit
of the drug
is justified and well balanced with a
safety and
risk assessment of these drugs.
219
Thank you very much, and with this, I'll
stop.
DR. CHESNEY: Thank you very much
to all
the speakers. A very, very comprehensive review of
these two products. Questions from the panel?
Yes,
Deborah first, and then Dr. Fant.
MS. DOKKEN: I want to ask this
question
just because I have to leave in a few
minutes, but
as a lay person I have been scrambling
to keep up
during this discussion. And one of the things that
struck me despite the overall conclusion
that the
results were reassuring, was of course
both the
rise in the use of Advair and the
worsening of
asthma, those adverse events
reports. But then the
fact that the labeling was changed, and
somewhat
for clarification for myself as a
newcomer to this
Committee, but also as I guess a consumer concern,
when the labeling was changed due to the
adverse
events, would that be a trigger for the
MedGuides
that we talked about yesterday? I guess I think in
particular because of the prevalence of
asthma and
the growing numbers, but also I think
those of us
220
who either have children who have asthma
or know
families, there are a number of families
who are
very active if their children have
asthma, and are
good advocates. So they would be cognizant and
would take note of information if it was made
available to them in a way. So that's my question
about the MedGuides. Would those go hand in hand
or subsequently with a change in
labeling?
DR. MURPHY: A Medguide is not
tied any
particular change. It is something that is, the
decision that is arrived at depending on
the
circumstance, so it is an independent
decision.
Badrul, do you want to talk about any
products that have MedGuides?
DR. CHOWDHURY: I don't want to
comment to
the MedGuide here. The issue is that you are
right, that when a box warning or some
significant
labeling or a doctor letter goes out,
which had
happened for salmeterol-containing
products. It is
quite likely that will increase the
adverse event
reporting by physicians or by patients.
And about the use of Advair
and use of
221
Advair in
children, I mean it is somewhat high, and
whether it is a good or a bad thing is
very
difficult to actually conclude and
say. You've
seen for pediatric requests we did not
particularly
request studies for Advair. We requested study for
fluticasone and not for the combination
product,
because we do not think that use of
Advair in very
young children is something which should
be really
routine because there are very difficult
to titrate
the combination products, you actually
have one
product. And we thought in children it's not
really very appropriate drug to
use. But we also
know that Advair is very, very commonly
used, and
is actually quite commonly used in
children and
there are three dose strengths
available. And
often physicians and patients may not go
down on
the dose when their asthma is
controlled.
So I think we have put down enough
information in the label, and also there have been
some dear doctor letters and some of the
public
forums where we have spoken about it,
and we
discourage the use of particularly high
dose Advair
222
if it's not necessary, and also not to
use the
combination products in very young
children where
you want to titrate the dose. So I think it is
adequately recognized.
But again, going too much on the other
side is also a risk because that can
lead to
decreased use of this quite effective
controller
therapy. If you look at the U.S., it's
approximately thought about that about
half of the
patients who should be on controller
therapy
actually are on controller therapy. If you look at
Europe,
it's actually much more high. So even
in
the U.S. with continued education,
continued
awareness, the use of controller therapy
is not
where I think where experts want. So in that
context, putting too much of a
cautionary note may
actually lead the pendulum swinging in
the opposite
directions. This is a tight balance, and I mean
you can give European and they like to
hear that,
but we think that balance is quite well
struck.
MS. DOKKEN: Just one
comment. I mean I
think we talked a lot in the last two
days about
223
that issue of balance. And I guess my own belief
is that there may be a way to inform and
empower
families so that what I talked about
yesterday, so
that they are aware of the risks and can
truly be
part of the risk/benefit analysis. And I
ultimately don't think that that will
lead to
panic, and you know, restricting use of
medications
from patients who need them. But I think it could
lead to more informed decision making.
But also, families are part of the
monitoring system, and if they're not
always aware
of what they're looking for, then they
can't be
very effective monitors.
DR. CHOWDHURY: It is a very good
suggestion, and thank you for the
suggestion, and
we really take the suggestions very
seriously from
the public meetings. Just to let you know that
when there are public advocacy groups
and also
family groups, one of them which is pretty
active
in the family field is Mothers of
Asthmatics. And
they're actually very much aware of what
has been
happening with the FDA. And many of those
224
meetings, they actually come, and they
make
presentations. So they are actually very much in
line, and the persons who head up that
group, we
have lot of discussions with them, and
as far as we
could tell, they're pretty satisfied
where the
balance is right now, but again, your
suggestion is
very well taken, and thank you for that.
DR. CHESNEY: Dr. Fant and then
Dr.
Nelson.
DR. FANT: Just a couple of
questions to
fill in a couple of gaps on background
for me.
One, is
there any data that points to--the decline
in mortality has been commented on a
couple of
times.
Does the data suggest that the use of the
corticosteroids contributes to that, or--I'll
let
you answer that and then I'll just ask
my second
question after that.
DR. STARKE: The data on
mortality comes
from coding, primary coding for hospital
discharge
or death, and that's collected annually
by the CDC.
So this
data, it's difficult to extrapolate any or
interpret what the meaning of that data
is compared
225
to the use of controller therapy. I don't think
you can make any specific comments on
the
relationship.
DR. FANT: We know from studies
that the
use of corticosteroids is the most
effective
controller or one of the most effective
controllers, but we don't know for sure
if it is
the major contributor to the decline in
mortality;
is that correct?
DR. STARKE: That's correct.
DR. CHOWDHURY: Let me make a
comment
here.
I mean usually--I mean you can't really make
a conclusion regarding an intervention
and outcome
which is mortality because in aspect
it's still a
very heavy event, so it's actually very,
very
difficult to make that conclusion. It's probably a
combination of all. But if we take surrogates, for
example, which is exacerbations of
asthma, or
hospitalizations because of asthma,
which usually
are surrogates of even worst outcomes, I
mean
usually with controller therapy all of these
actually goes down, and I would not
really pick out
226
one class of drug over the other as more
contributing than the other.
DR. FANT: No, no. I'm not trying to pick
out any. I'm just trying to get a better sense to
help me sort of understand the
complexity of this
in weighing--
DR. CHOWDHURY: It is, and I
think one can
reasonably say--Dr. Starke mentioned
that the
better outcome that you're seeing is a
combination
of a lot of things, including better
views of
controller therapy. But other factors are also
playing a role.
DR. FANT: My second question
relates to
Advair
specifically and the adverse events that
seem to be associated with that. Is there any data
or information that looks at similar
events that
occurred when similar--the same two
classes of
drugs were used separately but in
combination? Is
it something that seems to be unique to
Advair? Is
it something that clearly seems to be an
interaction between a long-acting beta
agonist and
steroids? Does it seem to be a beta agonist issue
227
only?
Do we have any information that may help
kind of provide hints and what may be
the
underlying problem, if there is one?
DR. CHOWDHURY: That's a very
tricky
question and maybe even a very tricky
study to do,
and the bottom line is the data is not
available.
And there
are no studies long term looking at
outcomes. What we have long term is the use of a
beta agonist alone versus placebo, and
you have
probably heard about that study. But there is
nothing such available comparing an
Advair arm
concomitantly taken, so that data is not
there.
DR. FANT: Or adverse events that
have
been reported and in the narrative
certain things
get blamed, like--
DR. CHOWDHURY: Adverse events
are there
with fluticasone, adverse events are
there with
Advair,
and as you have seen, with Advair the
adverse events are just more, and they're higher,
they're more serious. So that signal is there.
But, I
mean, there is no controlled studies that
can go into the explanation whether it
is from
228
Advair or
whether it's something else confounding
which is contributing to that. Those controlled
studies are not available.
I don't think it really is a very useful
information either because it's quite
well known
that Advair is taken by patients who are
more sick
and, therefore, having an adverse
outcome coming
out of a sicker patient population is
not a big
surprise, and also with the new beta
agonist study
we know that routine use of beta agonist
leads to
worsening asthma and increased
death. And that's
already in the product labeling for
Salmeterol and
also for Advair. So the information already is in
a way known that routine use of beta
agonist--
DR. FANT: But if you have a
sicker
patient who's getting treated with a
drug that puts
him at increased risk, if there's an
interaction
effect, that certainly is a patient I
would really
want to--really would not want to
elevate that risk
anymore.
DR. CHOWDHURY: Again, there is--
DR. FANT: You know, I'm not--
229
DR. CHOWDHURY: No, these are important
discussions to have because it's
actually quite
important for, I think, everybody in the
country to
be aware of this. It is an increased risk of
adverse outcome, but the risk is
actually very,
very small. If you look at the black box language
which was put up very briefly, the
number of deaths
is like in two digits out of a 16,000
patient
population. This is a very small signal.
And I
don't think really for the small signal
one should
not use the drug. The drug is very effective.
There's
no question about that. And it's also
pretty safe. And the signal, which is a serious
signal, is not very common. So I don't think--it
is really, again, a balance. The signal is really
coming out of a very small number of
patients. And
the more studies going through to the
NIH
initiatives trying to identify who those
patients
may be who actually would have the risk,
that has
been partly identified with the
short-acting beta
agonist. The studies which have been published--there's a
large study which shows the biomarkers
230
associated with that. And in the future, there
will be studies coming out trying to
identify
patients who are at risk.
DR. FANT: Thank you.
DR. CHESNEY: Dr. Nelson?
DR. NELSON: I'd just like to
highlight
two issues that are raised by the
Flovent
exclusivity studies, which I realize may
be
impossible to talk about today but might
merit
further conversation in the future.
One is the choice of control group.
Those
particular trials included children who
had been
receiving symptomatic treatment two
times a week
which meets NHLBI criteria for the
provision of
anti-inflammatory; but, nevertheless, a
third of
them were randomized to placebo. So the question
would be: What is the current thinking about
appropriate control groups when you have
actually
treatment guidelines that, in fact, a
third of the
population did not receive?
The second point is this was the study
that also then had misallocation of
study drug, and
231
so you end up with the irony--and they
also were
then granted exclusivity, and I don't know if
that's because the written request was
not ironclad
enough to not give them exclusivity, or
if, in
fact, it was felt that they weren't to
blame for
the misallocation. But either way--and I realize
each of these issues merit debate in
their own
right, but if you sequence them together
in the
most unfavorable light--which is not
necessarily
what I'm going to argue for, but some
might--you
have a study that withheld effective
medication
from a third of the kids in the study
that didn't
get done right, resulted in useless
data, and they
got the money anyway.
DR. CHOWDHURY: Let me take the
questions
very, very briefly, because you told it
very
correctly, these are really larger
discussions.
The first issue is regarding placebo in
these trials. There are two things to consider.
They're
actually placebo-controlled but not really
without any drug treatment arm. These patients can
take rescue medications as necessary and
actually
232
can drop out of the studies if their
asthma becomes
uncontrolled.
The second thing is that in a short-term
study taking off control therapy has not
been shown
to affect asthma in the longer
term. There's
CAM(?)
studies out there going for quite some time,
which does not show that if you do not
use a
control therapy for a short term, then
the lung
function of those children is reversibly
damaged.
So there is some gain to obtained from
some study, and withdrawing control therapy
for a
short time period with the proper rescue
medications available is, again, a
reasonable
risk/benefit for the study.
And the second issue regarding, I would
say, misallocation, whatever the reason
being, of
having drug in the placebo, is not
something that I
would--GSK did not want that to happen,
neither did
we, and the reason it happened is not
really very
clear.
And you are totally right.
Because of
this, drug levels in the plasma, the
studies were
not useful. And whether exclusivity should have
233
been granted or not, I will defer to Dr.
Murphy on
that.
It's a tricky issue.
DR. CHESNEY: Before Dianne
comments, we
may be looking at the same study. I can't tell.
But Dr.
Buckman's Slide 18, which was the--is that
the same study?--where they found levels
in the
placebo and really couldn't come up with
any
conclusions at all, and your first
thought is: Why
was exclusivity granted when this study
really on
paper doesn't look very good?
Dianne?
DR. MURPHY: Between ShaAvhree
and I, our
memories are not clear enough to give
you a factual
answer.
So we think it's because we weren't--you
know, but one of the problems with
exclusivity is
that there's a short-term--we have to
determine the
exclusivity before the complete analysis
is
performed. And we will get back to you.
I think
this is one of the action items we need
to get back
to this committee at the next meeting
about why was
exclusivity granted in this
situation. But our
hazy combined recall--maybe Peter can
help us. We
234
didn't know at this point.
DR. CHOWDHURY: Let me also chime
in on
this.
The studies for pediatric exclusivity comes
into a supplement to the NDA, and we
have a time
clock for reviewing the studies because
it involves
a lot of analysis, often going into the
data and
all, and the time frame is six months
for pediatric
studies. And exclusivity is granted or denied very
early on.
DR. MURPHY: It's within 90 days, so--
DR. CHOWDHURY: So when the
application
comes in, we file the application, and
then the
exclusivity is granted based on whether
the study
was done fulfilling the criteria set
forth in the
written request. And the analysis goes on. So, I
mean, one is happening before the other.
DR. MURPHY: What is determined,
just
again, for what we can tell you,
is: Did they do
the studies that we asked them to
do? And so when
the division comes to the Exclusivity
Board, they
bring the written request and basically
a check
item.
They go through every item. Did
they do 2,
235
randomize? You know, now, you could say it wasn't
well controlled, but the division
answers as best
it can without having completed the
analysis. And,
therefore, the finding of some of these
things,
particularly some of the compliance
issues and the
scientific investigation issues are not
available
frequently until literally towards the
end of the
analysis.
DR. NELSON: Just a quick
comment. I can
appreciate the systems issues in my
approach
working in an ICU, this is all CQI
systems issues.
And if,
in fact, it's the simple existence of a 3-month
difference between one decision versus
another and the data gets analyzed, then
maybe we
need to look at that as an issue. But I think
certainly the intent of the exclusivity
is to have
interpretable data. And maybe there needs to be a
fix.
Whether that's a regulatory fix or a
legislative fix--I realize you can't
advocate for
legislative fixes, but it just seems to
me a gap
that ought to be examined, and this
would, in my
mind, be a sentinel event. If I had something
236
happen in my ICU, we would look at it as
a sentinel
event and say, How do we close that gap?
DR. MURPHY: Actually, it used to
be worse
because we didn't have all of them on
six months.
And so
the system was even more likely to have a
problem, is what I was trying to
say. We were
hoping by having the six months versus
the 90 days
that we would have less events, but
clearly we
still have them.
DR. STARKE: Let me see--I'll try
to
answer the question as best as I
can. I was the
medical officer who reviewed the studies
and
presented to the Pediatric Exclusivity
Board at the
time.
If I'm not mistaken--I'd have to go back and
look, but I believe it was a 10-month
clock for
this that had preceded that. And the Pediatric
Exclusivity Board met early in the analysis
process. It was only later in the process that we
found these events had occurred in the
biopharmaceutical portion of the study.
DR. MURPHY: That's what I was
referring
to.
Until the recent legislation, there were even
237
longer dates. Thanks for clarifying that.
DR. O'FALLON: Well, who is
responsible
for doing those biochemical, whatever,
analyses?
Is that
supposed to be the investigator who put--the company
that gives it to you and you're
supposed to look at it? Or is the FDA supposed to
run it?
DR. CHOWDHURY: You're asking who
is
responsible for analysis of the
results? It is the
company or the company's contractor who
is doing
the study is supposed to do the
analysis. And I'm
pretty sure when the submission of
the (?) was
made, the company knew that there was
some problem
with placebo arms having active drug.
DR. O'FALLON: And they didn't
share that
information, they didn't give that to
you?
DR. CHOWDHURY: It was there in
the whole
submission. That's the reason we know about it,
and we did not approve the
application. But if you
go back to what was discussed earlier,
the
exclusivity determination is made very
early on in
the chronology of events. And in that time, that
238
formulation, that placebo had drug. I mean, it was
not identified, and even if it was
identified, you
actually had to look at the cause of
what happened
and can still the study be salvaged
anyway? And
that takes time. And because of that, we have this
six months versus ten months of clock to
go through
all of these. And by the time exclusivity is
granted, it's basically based on was the
study done
based on what was asked. Analysis just cannot
happen at that time because it requires
time.
It is a system that, Dr. Nelson, as you
pointed out, really as a--noting as a
case.
DR. CHESNEY: The newest
legislation is
for six months, not 90 days anymore?
DR. MURPHY: No, for the
review. All
pediatric applications now are
considered six-month
reviews.
DR. CHESNEY: Any other questions
or
comments from the committee?
[No response.]
DR. CHESNEY: Let's turn to the
question
then which we have been asked
specifically to
239
address. Based on the presentations you have heard
today regarding drugs containing
fluticasone or
budesonide, do you have any concerns
about the use
of these drug products as labeled? If you do have
concerns, could you please raise your
hand?
[A show of hands.]
DR. CHESNEY: I believe with the
members
of the committee who are still here we
have a
consensus that we do not have any
concerns about
the use of these drug products as
labeled based on
the very comprehensive reviews you've
presented to
us.
x All right.
Well, let me then just try to
summarize what we have--the discussions
we
participated in this morning. The first had to do
with the review of the Subpart D
Pediatric Ethics
Subcommittee summary, which was presented by Dr.
Nelson,
with some very good discussion by the
committee. The committee had two additional
recommendations for the summary, the
first of which
was to assure that no stimulants were
provided
within some reasonable period of time
before the
240
study was initiated, and the second was
that a
comment be added to the consent form
regarding the
available NIMH information that only
four of 3,000
patients who have had MRIs had any
significant
findings. Do I have that correct?
Thank you.
Second, the committee understands that
there will be no further reporting
required for the
four drug products presented
mid-morning:
ofloxacin, alendronate, fludarabine, and
desloratadine.
The third point, there was significant
discussion regarding adverse event
reporting for
drugs either approved or not approved
for use in
children, and I think not new to this
particular
committee hearing is the perception that
we need
better databases; particularly we need
better
databases that involve children. We also need
better denominator data that involve
children, and
I don't
think there was a lot of discussion
reviewing the potential need for active
surveillance for better documentation of
adverse
events.
241
And just to emphasize again the importance
of having information from controlled
clinical
trials in order to better assess adverse
events.
Finally, on the last issue with regard to
budesonide and fluticasone, we were
presented with
very comprehensive data regarding the
linear growth
assessments, the HPA axis suppression,
and
regarding postmarketing adverse event
reporting.
And the
committee--first of all, there was a
recommendation that a MedGuide be
provided for
pediatric family caregivers with respect
to the new
labeling for Salmeterol and Advair label
changes.
And,
secondly, a concern which was discussed in
some detail today and yesterday, which I
think
overall we could say has to do with the
quality of
the studies requested for exclusivity,
and I think
we understand the process, but as Dr.
Nelson
pointed out, what we've come up against
may be
totally a process issue. And we understand better
the reasons for why some of--why
exclusivity is
granted when the clinical trials may not
necessarily seem to us to have been
designed as
242
well as they might have and the results
turn out
not to be very helpful.
Any other summary comments that I have
neglected with respect to the committee?
[No response.]
DR. CHESNEY: And, finally, in
response to
the specific question we were asked to
address, we
do not have concerns about the use of
these drug
products with respect to budesonide and
fluticasone
as currently labeled.
And, finally, just to thank particularly
the FDA speakers who spoke this
morning. I just
have this fantasy that you rehearse
these things
for days and days beforehand and that somebody
oversees them and tells you exactly when
were going
to have mental questions because you
address them.
At least
as soon as they come in my mind, you
address the issues. So we're just extremely
grateful for how much you respect our
time and for
how comprehensively and well you review
the topic.
That is
just very much appreciated.
Thank you also to Jan
Johannessen, who has
243
done an incredible job of keeping
everybody on
track for the past week. This has certainly been a
long trek, more so for you than for us
for sure.
To thank all the panel members who are
still here who raised always very
stimulating and
thoughtful questions from my
perspective.
To thank Skip for chairing the first-ever
Pediatric
Ethics Subcommittee.
To thank Dianne, as always, for overseeing
this whole operation; Solomon for his
always
comprehensive presentations.
And, finally, I think this is Dr. Ebert's
last meeting and Dr. Maldonado's last
meeting. Am
I
correct? And anybody else?
[No response.]
DR. CHESNEY: So I think they
both got
recognized at the June meeting of the
old
committee, but in any case, thank you
from my
perspective for coming back and joining
us for this
meeting and for being a part of this
committee.
I'll let Dr. Murphy have a follow-up--oh,
one more thing. Before we finish officially, I
244
wondered if the committee could stay for
just one
minute.
We had suggested potentially at the June
meeting writing up some of the--well,
I'll address
it right now--some of the issues that
have come up
over the years, and I am here to tell
you that Dr.
Laurel
Leslie, who I understand in the pediatric
community is known as a writing machine,
has
already written up a potential
manuscript based on
her review of what happened
yesterday. And she's
very interested in finalizing this and
submitting
it to a journal, and I would appreciate
your
thoughts, which we could do after we
officially
finish the meeting, as to who should be
included in
that, what journal you might consider
that that
should go into. She's thinking about Pediatrics,
but I wonder, as we discussed in June,
if there
might be a more comprehensive audience
if she
thought about something like JAMA. But if you
wouldn't mind at the end in a few
minutes just
giving me your thoughts about that, I
would be very
appreciative.
So, Dr. Murphy, to finalize?
245
DR. MURPHY: How many ways can I
say thank
you?
That really ought to be the question.
I know
you guys have been--ladies and
gentlemen, excuse
me, have been through a grueling four or
five days.
I think
what was interesting to hear this
discussion this afternoon, which very
much
paralleled the questions that came up
yesterday
with the antidepressants where you have,
you know,
an adverse event that's part of the
disease, if you
will, and how you dissect that out and
when do you
not say the labeling is sufficient,
because the
division is certainly--they also do the
labeling.
So I think it's a real compliment to you
and the division that this committee,
which has
been trained, mandated, and working on
labeling,
you guys have done a good job. So I want to really
comment. I wasn't sure what they'd say.
Again, we
look very much forward to the ongoing
activities,
and particularly, Dr. Nelson, to the
immense amount
of work that you put into condensing
that entire
day's ethical discussion and
synthesizing it so
well for this group that they had as few
questions
246
and recommendations that they did, and
the ones
that they had were very thoughtful and
very good.
I just
look forward to working with you guys in the
future.
Thank you.
DR. CHESNEY: And is my understanding
correct that our next meeting is a week
from today?
Is that--
[Laughter.]
DR. MURPHY: I wanted to say one
last
thing.
Jan had no idea he was getting two
committees. He thought he was getting one.
And we
are trying to make it so that you all
don't have to
have residences here in Washington,
though I
understand some universities do
that. But we'll
try to be reasonable in our future
requests on your
time.
Thank you.
[Whereupon, at 1:10 p.m., the
meeting was
adjourned.]
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