FOOD AND DRUG ADMINISTRATION
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PEDIATRIC ADVISORY COMMITTEE
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WEDNESDAY,
MARCH 22, 2006
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The
conference convened in Salons A, B, C, D of the Hilton Washington D.C. North,
620 Perry Parkway, Gaithersburg, Maryland, 20877, at 7:30 a.m., pursuant to
notice, Robert M. Nelson, M.D., Ph.D., Chair, presiding.
COMMITTEE MEMBERS PRESENT:
ROBERT M. NELSON, M.D., Ph.D., Chair
JAN. N. JOHANNESSEN, Ph.D, Executive Secretary
DENNIS M. BIER, M.D., Member
ROBERT S. DAUM, M.D., Member
ANGELA DIAZ, M.D., M.P.H., Member
DEBORAH L. DOKKEN, MPA, Member
ELIZABETH GAROFALO, M.D., Industry Representative
RICHARD L. GORMAN, M.D., Member
MELISSA M. HUDSON, M.D., Member
JOHN W. M. MOORE, M.D., M.P.H., Member
THOMAS B. NEWMAN, M.D., M.P.H., Member
JUDITH R. O'FALLON, Ph.D., Member
MARSHA D. RAPPLEY, M.D., Member
VOTING CONSULTANTS:
JORGE ARMENTEROS, M.D.
PAULA KNUDSON
LAUREL K. LESLIE, M.D., M.P.H.
CYNTHIA PFEFFER, M.D.
DANIEL S. PINE, M.D.
BENEDETTO VITIELLO, M.D.
ROBERT WARD, M.D.
FDA STAFF PRESENT:
PAUL ANDREASON, M.D.
GERALD DAL PAN, M.D., M.H.S.
SOLOMON IYASU, M.D., M.P.H.
ROSEMARY JOHANN-LIANG, M.D.
TOM LAUGHREN, M.D.
DIANE MURPHY, M.D.
ROSEMARY ROBERTS, M.D.
ROBERT TEMPLE, M.D.
PRESENTERS:
A.J. ALLEN, M.D., PH.D.
ERIC COLEMAN, M.D.
SUSAN MCCUNE, M.D.
DAVID GRAHAM, M.D., M.P.H.
KATHERINE GELPERIN, M.D., M.P.H.
LARRY GRYLACK, M.D.
ANDREW MOSHOLDER, M.D., M.P.H.
HARI SACHS, M.D.
ALSO PRESENT:
FREDER BAUGHMAN, JR., M.D.
JACQUELINE BESSNER
SEN. CURTIS BRAMBLE
PETER BREGGIN, M.D.
LAWRENCE DILLER, M.D.
MOIRA DOLAN, M.D.
GLEN ELLIOT, PH.D., M.D.
DAVID FASSLER, M.D.
SAM GOLDSTEIN, PH.D
LAWRENCE GREENHILL, M.D.
TODD GRUBER, M.D., M.P.H.
BARBARA HAWKINS
GRACE JACKSON, M.D.
WINNI JOHNSON
SHARON KEINTZ
THOMAS KOBYLSKI
CLINTON LIBBY
CHRISTINE LIMBERS
ELLEN LIVERSIDGE
KENDRICK MOXON
ALSO PRESENT: (CONT.)
TAMAR OSTERMAN
JIM PAICOPOLOS
JUDITH RAPPOPORT, M.D.
DUBOSE RAVENEL, M.D.
DARREL REGIER, M.D., M.P.H.
ALDELAIDE ROBB, M.D.
GAYLE RUZICKA
VERA SHARAV
LEE SPILLER
DAVID STEIN, PH.D
L. READ SULIK, M.D., FAAP
THOMAS SULLIVAN, M.D.
JAMES SWANSON
W. DOUGLAS TYNAN, PH.D.
CYNTHIA WAINSCOTT
KATY WARREN
CAROL WATKINS, M.D.
BRUCE WISEMAN
JULIE ZITO, PH.D
A G E N D A
CALL TO ORDER, INTRODUCTIONS ................... 7
Robert
Nelson, M.D., Ph.D. (Chair)
CONFLICT OF INTEREST STATEMENTS ............... 10
Jan
Johannessen, Ph.D.
COMMITTEE ROLE IN BPCA SAFETY REVIEWS ......... 12
Solomon
Iyasu, M.D., M.P.H.
CLOFARABINE (Clolar), IRBESARTAN (Avapro),
SIBUTRAMINE
(Meridia) ..................................... 21
Larry
Grylack, M.D.
Alan
Shapiro, M.D.
Eric
Colman, M.D.
Hari
Sachs, M.D.
OPPORTUNITY FOR SPONSOR COMMENTS AND RESPONSE TO
COMMITTEE QUESTIONS ........................... 43
Sponsors
OVERVIEW OF ADHD PORTION OF THE MEETING
INTRODUCTION OF QUESTIONS FOR THE COMMITTEE ... 52
Dianne
Murphy, M.D.
NEW PHYSICIAN LABELING: Where is the Safety
Information? 59
Rosemary
Roberts, M.D.
SUMMARY OF JUNE 2005 PAC
INTERIM ACTIONS AND LANDMARK EVENTS ........... 71
Paul
Andreason, M.D.
A G E N D A
GENERAL OVERVIEW OF RECENT DsaRM MEETING ...... 83
Marsha
Rappley, M.D.
BREAK.......................................... 86
EFFICACY OF PHARMACOLOGICAL TREATMENT OF ADHD 86
Benedetto
Vitiello, M.D.
ADDERALL XR - BPCA REVIEW .................... 101
Susan
McCune, M.D.
USE OF DRUGS FOR ADHD IN THE U.S. ............ 121
Andrew
Mosholder, M.D., M.P.H.
CARDIOVASCULAR RISK WITH DRUG TREATMENTS OF ADHD:
OVERVIEW OF AVAILABLE SAFETY DATA IN CHILDREN 130
Kate
Gelperin, M.D., M.P.H.
ADHD DRUGS AND CARDIOVASCULAR OUTCOMES:
PRELIMINARY FEASIBILITY RESULTS AND POTENTIAL
OBSERVATIONAL STUDIES ........................ 144
David
Graham, M.D., M.P.H.
PSYCHIATRIC ADVERSE EVENTS IN ADHD
CLINICAL TRIALS .............................. 157
Andrew
Mosholder, M.D., M.P.H.
PSYCHIATRIC ADVERSE EVENTS WITH DRUG TREATMENTS
OF ADHD:
REVIEW OF POSTMARKETING SAFETY DATA IN THE
PEDIATRIC POPULATION ......................... 171
Kate
Gelperin, M.D., M.P.H.
CLARIFICATION QUESTIONS ...................... 190
A G E N D A
LUNCH ........................................ 211
OPEN PUBLIC HEARING .......................... 211
SPONSOR PRESENTATIONS ........................ 328
BREAK ........................................ 362
REVIEW OF COMMITTEE QUESTIONS
COMMITTEE QUESTIONS AND DISCUSSION ........... 362
Robert
Nelson, M.D., Ph.D. (Chair)
ADJOURN
P-R-O-C-E-E-D-I-N-G-S
(7:34
a.m.)
DR.
NELSON: Good morning. Welcome to
the meeting of the Pediatric Advisory Committee. I'm Dr. Nelson, the Chair, and I'll turn it
over to Jan to start our business. We'll
do introductions first.
As
a quick reminder, you have to push the mic on and off. Let's start with
introductions. We can start down at this
end, and keep them brief.
DR.
GAROFALO: Yes. I'm Dr. Elizabeth
Garofalo. I'm the Industry
Representative, and I am an independent consultant.
DR.
GORMAN: Dr. Richard Gorman, pediatrician in private practice, and the
representative of Professional Healthcare Organizations.
DR.
LESLIE: Laurel Leslie, Behavior and Developmental Pediatrician at
Children's Hospital, and a Health Services Researcher.
DR.
VITIELLO: Ben Vitiello, National Institutes on Mental Health.
MS.
KNUDSON: Paula Knudson, Community Representative, IRB Administrator,
University of Texas Health Science Center - Houston.
DR.
WARD: Dr. Bob Ward, University of Utah, I'm a Neonatalogist and Pediatric
Clinical Pharmacologist.
DR.
PINE: Danny Pine. I'm a Child
Psychiatrist from the National Center of Mental Health.
DR.
O'FALLON: Judith O'Fallon, retired statistician from the Mayo Clinic.
MS.
DOKKEN: Deborah Dokken, Patient Family Representative.
DR.
DAUM: I'm Robert Daum, Pediatric Infectious Diseases from the University
of Chicago.
DR.
DIAZ: Angela Diaz, Director of Mount Sinai Adolescent Health Center in
New York City.
DR.
MOORE: John Moore, Pediatric Cardiologist, University of California - Los
Angeles.
DR.
NELSON: Robert Nelson, Pediatric Care, Children's Hospital in
Philadelphia.
DR.
JOHANNESSEN: Jan Johannessen, Executive Secretary, Pediatric Advisory
Committee.
DR.
RAPPLEY: Marsha Rappley, Developmental and Behavioral Pediatrics,
Michigan State University.
DR.
HUDSON: Melissa Hudson, Pediatric Hematology Oncology, St. Jude
Children's Research Hospital.
DR.
BIER: Dennis Bier, I'm a Pediatric Endocrinologist and Nutritionist from
Baylor College of Medicine in Houston.
DR.
NEWMAN: Tom Newman, Child Pediatrician and Professor of Epidemiology and
Biostatistics in Pediatrics at UCSF.
DR.
MURPHY: Diane Murphy, Pediatrician, Office of Pediatric Therapeutics,
FDA.
DR.
LAUGHREN: Tom Laughren, Division of Psychiatry Products at FDA.
DR.
ANDREASON: Paul Andreason, Division of Psychiatry Products, FDA.
DR.
DAL PAN: Gerald Dal Pan, Division of Drug Safety, FDA.
DR.
ROBERTS: Rosemary Roberts, Pediatrician, Office of Counter-Terrorism and
Pediatric Drug Development.
DR.
IYASU: Solomon Iyasu, Division of Pediatric Drug Development at FDA.
DR.
NELSON: Thank you, and I'll turn it over to Jan for the Conflict of
Interest Statement and Introductions.
DR.
JOHANNESSEN: Thank you and good morning.
The following announcement addresses the issue of Conflict of Interest
with regard to today's discussion of a report by the Agency on Adverse Event
Reporting as mandated in Section 17 of the Best Pharmaceuticals For Children
Act for Clofarabine, Irbesartan, Sibutramine, and the mixed salts Amphetamine
Product, and two, discussion and reports on Neuropsychiatric and Cardiovascular
adverse events possibly related to other approved ADHD medications. This statement 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 interested firms
regulated by the Food and Drug Administration present no potential for an
appearance of conflict of interest at this meeting. In the event that the discussions involve any
other products or firms not already on the agenda for which an FDA participant
has a financial interest, the participants are aware of the need to exclude
themselves from such involvement, and their exclusion will be noted for the
record.
We
note that Dr. Jorge Armenteros, Dr. Laurel Leslie, Dr. Cynthia Pfeffer, Dr.
Daniel Pine, Dr. Ben Vitiello, Dr. Robert Moore are participating in the
meeting as Voting Consultants, and that Paula Knudson is participating as the
Acting Voting Consumer Representative.
We would also like to note that Dr. Elizabeth Garofalo has been invited
to participate as a Non-Voting Industry Representative, acting on behalf of
regulated industry. Dr. Garofalo is an
Industry Consultant. Dr. Richard Gorman
is participating as the Non-Voting Pediatric Health Organization Representative
acting on behalf of the American Academy of Pediatrics. With respect to all other participants, we
ask in the interest of fairness that they address any current or previous
financial involvement with any firm whose product they may wish to comment
upon. Thank you.
DR.
NELSON: So while Solomon is making his way to the podium, let me just
make a quick comment. You'll notice, members of the Committee, that we don't
have a lot of time for questions. I'm
going to ask that as these presentations are being done, you write down your
questions on the assumption that maybe they'll be answered by the next speaker,
rather than taking time after presentations, and then we'll hopefully get done
what we need to get done in an efficient manner. And I'm also going to ask the FDA folks to
try and stay on time, as well, since we'll be expecting that from everybody. Solomon.
DR.
IYASU: Good morning. I'm going to
introduce the Adverse Event reporting under BPCA. This will be the subject of discussions for
the first one hour, and then later, as well.
As you know, we've done several of these presentations in the past. Almost 50 drugs have been reviewed under
BPCA. Of course, this activity is
mandated under Section 17 of the Best Pharmaceuticals for Children Act, which
mandates that for drugs that have been given exclusivity, that during the
one-year period after exclusivity, any reports of postmarketing adverse events
would be reviewed and then presented to this Committee for their review and any
recommendations.
Of
course, most of the reports that we are mandated to discuss here come from the
database of all adverse event reports that were received by the FDA. This has a long history which started in
1969; it has almost more than two million reports. This database contains hundreds of export
drugs and therapeutic biologic products, with the exceptions of vaccines.
As
you know, this is a spontaneous voluntary system. Most of the reports come from manufacturers,
but there are also reports that come from healthcare professionals, consumers,
and patients. More than 90 percent of
all those reports that we have in the AER system come from manufacturers,
because they're required under the law.
Just
to give you some background, the definitions that we use for such reports is
defined under the law. It does not
require that the reporting needs to be -- that the adverse event needs to
be causally related and proven before reporting. Any adverse event, whether or not considered
drug-related, is to be reported to the AER system, so I think accidents,
intentional overdose, any adverse events occurring from abuse or drug withdrawal
calls for action.
Also,
to just update the Committee, and for those who are new to this area,
unexpected adverse drug event is also defined under the law, and it's defined
as an event not listed in the current labeling for the drug product, including
events that may be symptomatically or pathophysiological related to a labeled
event, but differ because of greater severity or specificity.
Again,
there is a regulatory definition, just to give you some background, that a
serious adverse event is any event occurring at any dose that results in any of
the following outcomes, and these outcomes are death or life-threatening
adverse event, hospitalization, or prolonged additional hospitalization,
persistent or significant disability or incapacity, any congenital anomaly or
birth defects, or others that may require some intervention, so there is a
regulatory definition for serious adverse event.
Of
course, one has to assess these reports as they come, and there are many
factors that effect whether there's a causal relationship between a report and the assessment. And key among these factors that we have to
look at FDA are whether there is a temporal relationship between the event and
the drug, that the event occurred after the drug is a strong indicator that
there might be some relationship.
If
we have, of course, information about those events regarding the challenge or
re-challenge, meaning that the AER or the adverse event subsides when a drug is
discontinued, or it reappears when a drug is re-administered, is also
suggestive of a relationship. If we see
a dose response in this report, that's also another suggestive information that
might help us understand whether there's a causal relationship or not.
Again,
we look at the biologic plausibility, looking at prior knowledge about the PK
and the pharmacokinetic actions of these drugs.
We also look at animal clinical studies, and any laboratory evidence
that may be part of the report that we get.
Another
factor that we look at is whether there is a known class effect, that a drug
belongs to a class of drugs that has been proven to have a certain effect that
we're looking at. And very important
consideration has to be given also to underlying disease and concomitant drugs,
because many of these reports that we get are highly confounded by underlying
disease that may be exhibiting the same adverse event that we're looking at.
Now
there are several strengths and also limitations to the AER's database, so when
we look at postmarketing reports, one has to be very careful that it includes all drugs that are marketed
in the United States, and, therefore, it's a very large sweep of what's going
on. A simple, inexpensive system
provides for mostly early detection of safety signals, especially if they are
rare adverse events that are serious.
For example, anaphylaxis, liver failure, or plastic anemia, and serious
events like that.
There
are also some important limitations.
Under-reporting is one of the key limitations of the system because they
are spontaneous reports. And the extent
of under-reporting may vary from drug-to-drug and over time. The quality is variable, and because the
numerator, which is events, uncertain in terms of numbers, the denominator also
in terms of exposure is also uncertain, so often it's very difficult to
quantify the risk of these drugs with respect to adverse event.
Now
often the gold standard for looking at causality between an adverse event and a
drug is the randomized control trials.
They are, of course, the best for establishing causality and provide a
non-biased estimate of the risk of a particular drug with respect to a suspect
drug. So especially very important to
have comparative data from these kind of studies to assess when the events
under consideration have a high background rate. But, of course, RCTs also have their own
limitations. They often are short in
duration, and thus have a very small sample size and, therefore, they may not
pick up rare adverse events. And often we
pool safety data across many different randomized trials to improve the precision
and power to detect such events. But, of
course, there are limitations to doing that because the different RCTs that we
pull together may have different methodologies that may limit our ability to
detect some of the events.
And
also, another important feature is that RCT's have this more or less select
population, and are homogenous, and what you would expect to see in daily
clinical practice; therefore, it drives the ability of the risk estimates that
we get from RCTs may not apply to daily patient population. Therefore, there are some limitations even to
RCTs. Of course, not finding an
association from an RCT does not rule out the safety issue when you have a
preponderance of reports, so it's a vicious cycle that you have to --if you
don't get information that is confirmatory, and have you have a preponderance
of reports, then you have to be concerned.
Therefore,
today we'll continue our practice of presenting the adverse events under BPCA,
and we'll provide you a review of the safety events during the year. And as appropriate, we'll also look prior to
the one-year period that's mandated by BPCA to review the adverse events that
are reported to FDA when it's warranted, and that we have some serious adverse
events prior to the one-year.
We
also provide you information on the drug use of the particular drug that we're
looking at, first for out-patient, as well as for in-patient use. We also, for context, provide you a summary
of the clinical, pharmacology, toxicology reviews of the exclusivity
studies. We provided the drug label,
published literature, responsive materials, and presentations, so that you have
a comprehensive set of information to look at.
As
we've done in the past, we'll have -- some drugs are going to be discussed
in an abbreviated fashion when there's no new safety concern, some are going to
be standard presentation when there are unlabeled new safety concerns, and then
we'll have drugs that have in-depth presentation, because there is a safety
concern that we'd like you to look at.
Today
we have four drugs that are scheduled for BPCA safety review. Clofarabine and Irbesartan will have an
abbreviated report, because we don't feel that we have concern regarding safety
for these two drugs, just from the review that we've done. Sibutramine will have a standard
presentation. We'd like to give you a
little more, because there's been extensive reviews of cardiovascular, as well
as fetal toxicity effects of these drugs and, therefore, we'll have two
presentations on this so that we have a comprehensive history of what the state
of knowledge is about Sibutramine regarding these two issues.
And
then the last drug that will be discussed today on the schedule out of BPCA is
Adderall, mixed amphetamine drug. It's
providing an in-depth presentation of this as part of the post exclusivity
-- as part of the session on the entire safety concern of all ADHD
medications later today.
I'd
like to acknowledge the many offices that have helped with all these reviews,
and our first presentation, I'll just get right to it, will be on
Clofarabine. Dr. Larry Grylack from the
Pediatrics Division will present adverse event reviews for Clofarabine. Dr. Grylack has been a medical officer in the
FDA for more than three years. Dr.
Grylack.
DR.
GRYLACK: Thank you, Dr. Iyasu.
It's an honor to be here again this morning presenting to the Advisory
Committee, and apologies to the residents of the Pacific and Mountain time
zones for the early hour. This is an
abbreviated presentation of the Adverse Event Review for Clofarabine. The drug is marketed as Clolar for
intravenous injection. Its therapeutic
category is anti-neoplastic in the sub-category of purine nucleoside anti-metabolite. The sponsor is Genzyme Corporation.
The
indication in the Clolar label is the treatment of patients 1-21 years old with
relapsed or refractory acute lymphoblastic leukemia after at least two prior
regimens. Pediatric exclusivity was
granted for Clolar in patients 1-21 years of age on July 14th, 2004,
which was prior to the marketing approval date of December 28th,
2004. Of note is that Clolar did not
have prior marketing approval for any age.
The
in-patient, out-patient, and sales databases used by the FDA document no use of
Clofarabine. Also, the Children's Oncology
Group database reported no usage. The
sponsor estimates 200-300 uses per year.
The
FDA Office of Drug Safety's Adverse Event Search covered the period from the
time of market approval, December 28th, 2004, until August 14th,
2005, which was the one-year post-exclusivity date. There were 12 unduplicated pediatric adverse
event reports, eight of which were domestic reports. Of the 12 reports, four were deaths, and five
were hospitalizations.
Details
of the four deaths that occurred in patients receiving Clofarabine during the
exclusivity review period are presented on this slide. One patient suffered a cardiac arrest after
an episode of aspiration and treatment
with airway suction occurring 48 hours after the fifth dose of
Clofarabine. The patient had a history
of cardiac dysfunction, and post-mortem exam revealed cardiac fiber
hypertrophy.
The
second death was associated with tumor lysis syndrome, resulting in multi-organ
failure one day after the start of Clofarabine treatment. The third death was described as being caused
by progressive disease one month after the diagnosis of capillary leak syndrome
occurring within 24-hours of the first dose of Clofarabine. The fourth death reported was due to a
cardiac arrest associated with an error in medication not being used for the
treatment of the leukemia. This death
occurred seven weeks after treatment with Clofarabine.
This
completes the post-exclusivity adverse event reporting as mandated by the Best
Pharmaceuticals for Children Act. Most
adverse events are currently labeled or would not be unexpected in association
with a disease, or with the concomitant treatments received by the
patients. The Food and Drug
Administration recommends routine monitoring of Clofarabine for adverse events in
all populations. We would like to know
whether the Pediatric Advisory Committee agrees.
Finally,
I'd like to acknowledge all of these individuals from the Office of Drug
Safety, Office of New Drugs, and the Office of Clinical Pharmacology
Biopharmaceutics who provided reports which contributed to my presentation
today. I would also like to acknowledge
Denise Pica-Bronco who has admirably filled Kristin Fucas' role of coordinating
our Advisory Committee presentations within the Division of Pediatric Drug
Development. Thank you for your
attention.
I
would like to next introduce one of my colleagues, Dr. Alan Shapiro. Dr.
Shapiro is a Pediatric Infectious Disease Specialist with a Ph.D. in
Biochemistry. His past research includes
work in immunology, infectious diseases, and molecular pharmacology. He has also had training in Pediatric
Nephrology and Medical Genetics. Dr.
Shapiro has been with the Division of Pediatric Drug Development for over
two-years working as a medical officer.
Really, the FDA should give him more than two-years credit considering
all his many talents, training aspects.
Dr. Shapiro.
DR.
SHAPIRO: Thank you, Larry. Now I'd
like to discuss the adverse events for Irbesartan. Irbesartan, also known as Avapro, is an
anti-hypertensive in the Angiotensive II receptors class. Its sponsor is Sanofi-Synthelab. Its indication is for the treatment of
hypertension alone or with other anti-hypertensive agents, also for the
treatment of diabetic nephropathy in patients with type II diabetes and
hypertension. Its original market
approval was September 30th, 1997, and exclusivity was granted on
September 16th of 2004.
To
summarize, no pediatric adverse events were reported to AERS during the year
following exclusivity. We did find a raw
count of four adverse events, three serious, since market approval. When we did a hands-on review of these
adverse events, we only found one unique adverse event report. That consisted of a patient with urticaria
and erthema multiforme minor in a seven year old clinical trial participant who
had a vial respiratory infection.
Urticaria and hypersensitivity are described in the product label.