Barton, Greenwood Seek Info From FDA On Antidepressants
March 24, 2004
The Honorable Mark B. McClellan, M.D., Ph.D.
Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Commissioner McClellan:
As part of its continuing oversight of the public health and the safety of
prescription drugs, the Committee is examining issues surrounding the safety and
efficacy of anti-depressants in the pediatric/adolescent population. We
understand that the Food and Drug Administration ("FDA") has had a
longstanding concern about the possibility of increased risk of suicidality in
the adult population taking anti-depressants, specifically Prozac, and convened
an advisory committee meeting in 1991 to discuss this matter. At that time, the
FDA concluded that the available data did not appear to support a finding that
Prozac caused an increased risk of suicide in adults and did not require any
labeling changes on the products. We also understand that over the next 12
years, the FDA continued to monitor and study this issue amid conflicting
scientific reports, some suggesting there may be an increased risk for suicidal
behavior from the use of anti-depressants. Further, during this time period,
several companies were conducting clinical trials of their anti-depressants,
approved by the FDA to treat adults, in the pediatric population with the goal
of gaining FDA approval for use in children.
Two important factual questions of interest to the Committee are the
following: (1) What did the FDA know about issues of safety and efficacy of
anti-depressants in children after these companies submitted their data from
these clinical trials? and (2) When was the FDA provided a complete set of
pediatric clinical data from the respective companies. The answer to these
questions will assist the Committee in assessing: the risks and benefits of
anti-depressants used in children; whether the FDA informed the public in a
timely and thorough manner about the risks for the pediatric population; whether
the FDA adequately evaluated the data relating to both the efficacy and
potential risks of suicide in children taking anti-depressants; and whether
additional legislative or regulatory action will be, or should be, taken with
respect to the labeling of these products.
According to a January 5, 2004 written memorandum by Dr. Thomas Laughren of
the FDA, 12 of 15 studies involving children with major depressive disorder
("MDD"), that were done in accordance with the FDA's written protocol,
showed no efficacy when comparing the drug to a placebo. Dr. Laughren stated,
"[t]he overall success rate for positive studies of 20% (3/15) is clearly a
concern." We note that, in addition to the seeming lack of demonstrated
efficacy in this data set, Dr. Laughren in his comments also indicated a
potential signal for increased risk in suicide attempts and/or suicide-related
behavior in five out of seven anti-depressants tested in pediatric clinical
trials.
We note that while there were issues of safety and efficacy before the FDA,
the off-label prescription of anti-depressants for children with MDD is
significant. To date, we understand that the FDA has approved only Prozac for
use in children with MDD. In addition, Prozac, Zoloft and Luvox also have been
approved by the FDA for use in children diagnosed with Obsessive Compulsive
Disorder ("ODC"). Despite the limited number of FDA approved
anti-depressants for use in children, and the narrow class of disorders for
which they have been approved, prescriptions for anti-depressants in children
continues to be on the rise. According to data presented by the FDA at the
February 2, 2004 Advisory Committee meeting, in 2002, there were over 10 million
anti-depressant prescriptions for children ages 1-17 years of age in the United
States. Of these 10 million prescriptions, approximately 2.2 million (20%) were
written for Paxil, an anti-depressant with no approval for any indication in
children. According to the FDA, Paxil was the second most prescribed
anti-depressant in the United States pediatric population in 2002, despite the
lack of any FDA approval for use in children.
Given the widespread use of Paxil in the U.S. pediatric/adolescent
population, on June 19, 2003, the FDA issued an advisory concerning the use of
Paxil in adolescents and children with MDD due to possible increased risks of
suicide-related behavior. It is our understanding that the FDA's action was
based on newly analyzed pediatric data that had been recently provided by
GlaxoSmithKline, the manufacturer of Paxil, to the FDA and other foreign medical
regulatory authorities, indicating there appears to be a signal for
suicide-related behavior in children and adolescents using Paxil. The FDA
followed up this product-specific advisory warning with another general warning
about the use of anti-depressants in children and adolescents on October 27,
2003.
On March 22, 2004, the FDA issued a public health advisory on the use of
anti-depressants in adults and children cautioning that there should be close
monitoring of potentially suicide-related behavior particularly during the
beginning of treatment or when a dosage change in made. In this most recent
advisory, the FDA also requested that the manufacturers of ten anti-depressants
include a stronger cautionary warning about the emergence of suicide ideation in
all individuals taking anti-depressants. We do not know whether the
manufacturers are required to comply with the FDA's "request" for a
labeling change, and if they do, whether FDA has set up a time frame in which
this labeling change must be made. To date, the FDA has not contraindicated any
anti-depressants for use in children and adolescents, nor has the FDA required
or requested an additional warning on the products' labels that concern the
suicide-related risks that may be heightened in the pediatric population
exclusively.
In contrast to the FDA's actions on this issue, the British government's
medical regulatory authorities contraindicated all anti-depressants, except
Prozac, for use in children and adolescents. Further, both Canada and Britain
have required additional labeling on anti-depressants, such as Paxil, warning of
the potential suicide-related behavioral risks in the pediatric population
associated with use of the products. It is our understanding that the FDA and
the British government's medical regulatory authority were provided the same
data analysis from GlaxoSmithKline concerning the increased risk in
suicide-related behavior in children taking Paxil. It is unclear, at this point,
whether the British authorities and the FDA have the same pediatric data sets
from all of the various companies marketing anti-depressants. Given the serious
implications that certain anti-depressants may have for children, the Committee
is interested in learning the rationale for FDA's decision not to require
stronger warnings on the labeling for pediatric use of an anti-depressant
product when, for example, a company's own analysis of their data indicates an
increased risk of suicide-related behavior in children.
Finally, it is our understanding that beginning in the summer of 2003, and
prompted by GlaxoSmithKline's disclosure of their "new" Paxil
pediatric analysis, the FDA requested that the other companies that performed
pediatric clinical trials on anti-depressants re-analyze their data concerning
suicide-related behavior and provide these data sets to the FDA so that the FDA
may undertake a more comprehensive review of the data. According to testimony
given at the February 2, 2004 Advisory Committee meeting, after several
follow-up requests from FDA to the various companies, the FDA was able to get
the specific types of data sets and patient level data they requested and
undertook an analysis of the data. The Committee is interested in learning who
at FDA undertook this analysis and the results thereof, because at this February
2, 2004 meeting, the FDA indicated they had requested a second analysis of the
data by Columbia University researchers. The Columbia University analysis is
expected to be completed by this summer.
A recent press report raises a question about whether an FDA official, tasked
with evaluating the pediatric clinical trial data relating to potential suicidal
risks, was prevented from presenting a report with his conclusions at the
February 2 Advisory Committee meeting. On February 1, 2004 the San Francisco
Chronicle reported that Andrew Mosholder, an FDA Medical Officer, was
"barred from publicly presenting his finding that several leading
antidepressants may increase the risk of suicidal behaviors among
children." The article states that Dr. Mosholder, with the FDA's Office of
Drug Safety, was charged with reviewing data from 20 clinical trials involving
over 4,100 children. An anonymous FDA official was quoted as stating that Dr.
Mosholder was told by Russell Katz, director of FDA's Division of
Neuropharmacological Drug Products, that he would not be able to present his
report because he had reached a conclusion and, therefore, was biased. Another
FDA official, Anne Trontell, indicated that Dr. Mosholder's analysis would not
be presented at the February 2 meeting because it was not a finalized document.
We note that the transcript of the February 2 meeting reflects that Dr.
Mosholder did not present a report on his evaluation of the anti-depressant
pediatric clinical trial data concerning suicide-related behavior.
The Committee is interested in learning what Dr. Mosholder's role was in the
review of the pediatric clinical trial data for anti-depressants, whether Dr.
Mosholder was prevented from presenting his findings a month prior to the
scheduled meeting (and if so, why), and whether FDA institutional processes
prevented Dr. Mosholder's report from being finalized in time for the February 2
Advisory Committee meeting (and if so, why). Further, given that the Advisory
Committee agreed with FDA's recommendation that Columbia University reanalyze
the pediatric anti-depressant data, the Committee is interested in learning who
at FDA was knowledgeable about Dr. Mosholder's conclusions and whether his
conclusions were a factor in the decision to involve an outside group, such as
Columbia University, in conducting another data analysis before the FDA decides
whether to take further regulatory action in this matter.
In light of the Committee's concern over the public health of children and/or
the need to expedite public and physician confidence in the use of
anti-depressants for children, the Committee seeks written analyses, data,
correspondence and background information of clinical trials involving depressed
children. To assist this investigation, we are requesting that, pursuant to
Rules X and XI of the U.S. House of Representatives, you provide the Committee
with the information requested below by Monday, April 5, 2004:
-
All records provided by or to the FDA in
connection with the February 2, 2004 FDA Advisory Committee meeting
involving the Psychopharmacological Drugs Advisory Committee (PDAC) and the
Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (Peds
AC), including, but not limited to, records relating to the planning of this
meeting and its agenda.
-
All records of Dr. Andrew Mosholder, Dr. Mary
Willy, Dr. Russell Katz, Ms. Anne Trontell and Dr. Thomas Laughren, relating
to efficacy and safety of anti-depressants in the pediatric and/or
adolescent population, including, but not limited to, all draft or final
reports, internal correspondence, e-mails and notes concerning pediatric or
adolescent anti-depressant clinical trials and any records relating to
spontaneous reports (AERS system) on the same issue.
-
All records of communication relating to
anti-depressants and suicide-related risks or efficacy in the pediatric
and/or adolescent population between the FDA and the following companies:
-
Eli Lilly & Co.;
-
Pfizer Inc.;
-
Wyeth Pharmaceuticals;
-
GlaxoSmithKline;
-
Bristol-Myers Squibb Co.;
-
Akzo Nobel Inc.; and
-
Forest Laboratories, Inc.
-
All records relating to GlaxoSmithKline's
submission of data analyses in pediatric/adolescent clinical trials
involving Paxil, including, but not limited to, all submissions contained as
attachments to their May 22, 2003 letter to the FDA.
-
All records relating to FDA's decision to issue
the June 19, 2003 advisory on Paxil and possible effects in the
pediatric/adolescent population.
-
All records relating to the FDA's decision to
issue the October 27, 2003 advisory on possible effects of anti-depressants
in the pediatric/adolescent population.
-
All records relating to the FDA's decision to
issue the March 22, 2004 advisory on monitoring adults and children taking
anti-depressants for suicidal-ideation and to request a labeling change for
ten anti-depressants.
-
All records relating to communications by FDA
employees that raise questions or concerns about the safety or efficacy of
anti-depressants in the pediatric/adolescent population.
-
All records relating to communications that
raise questions or concerns about the safety or efficacy of anti-depressants
in the pediatric/adolescent population between FDA and any of the following:
-
Eli Lilly & Co.;
-
Pfizer Inc.;
-
Wyeth Pharmaceuticals;
-
GlaxoSmithKline;
-
Bristol-Myers Squibb Co.;
-
Akzo Nobel Inc.;
-
Forest Laboratories, Inc.;
-
United Kingdom's Medicines and Healthcare
Products Regulatory Agency; or
-
A U.S. state or federal governmental
agency.
-
All records relating to communications
concerning proposed or finalized labeling changes with respect to warnings
about the safety or efficacy of anti-depressants in the pediatric/adolescent
population including, but not limited to, Wyeth's independent decision to
change the labeling on Effexor with respect to safety risks in children.
-
A listing of all the pediatric/adolescent
clinical trials involving anti-depressants that the FDA received data for
which there was an obligation for the company to submit the data to the FDA.
For each such trial, include the following information:
-
Name of the company;
-
Name of the anti-depressant;
-
Date when pediatric clinical trial data was
submitted to FDA;
-
Date when pediatric clinical trial was
completed by company;
-
Summary of FDA's "response" to
the clinical trial and what, if any, regulatory action FDA took with
respect to approving the particular drug for an indication in the
pediatric population.
-
State the person(s) at FDA responsible for
evaluating and providing a written analysis of the data that was requested
by FDA, in the summer and fall of 2003, from various manufacturers of
anti-depressants who performed clinical trials in children.
Please note that, for purposes of responding to this request, the terms
"records" and "relating" should be interpreted in accordance
with the attachment to this letter. In addition to the above requested
materials, the Committee staff would also like to set up a mutually convenient
time to interview: Andrew Mosholder, Thomas Laughren, Russell Katz, Ann Trontell,
Mary Willy, Paul Seligman, Syed Ahmad, Katherine Gelperin, Rita
Quellett-Hellstrom, Caroline McCloskey, Parivash Nourjah, Alan Brinker, Mark
Avigan, Diane Wysowski, David Graham, Judy Staffa, Cindy Kornegay, and Lois
LaGrenade.
In order to set up the requested interviews, as well to answer any questions
you may have on this matter, please contact Alan Slobodin at (202) 225-2927 or
Kelli Andrews at (202) 226-2424 of the Committee Staff.
Sincerely,
Joe Barton
Chairman
James C. Greenwood
Chairman
Subcommittee on Oversight and Investigations
cc: The Honorable John D. Dingell, Ranking Member
The Honorable Peter Deutsch, Ranking Member
Subcommittee on Oversight and Investigations
Attachment
1. The term "records" is to be construed in the broadest sense and
shall mean any written or graphic material, however produced or reproduced, of
any kind or description, consisting of the original and any non-identical copy
(whether different from the original because of notes made on or attached to
such copy or otherwise) and drafts and both sides thereof, whether printed or
recorded electronically or magnetically or stored in any type of data bank,
including, but not limited to, the following: correspondence, memoranda,
records, summaries of personal conversations or interviews, minutes or records
of meetings or conferences, opinions or reports of consultants, projections,
statistical statements, drafts, contracts, agreements, purchase orders,
invoices, confirmations, telegraphs, telexes, agendas, books, notes, pamphlets,
periodicals, reports, studies, evaluations, opinions, logs, diaries, desk
calendars, appointment books, tape recordings, video recordings, e-mails, voice
mails, computer tapes, or other computer stored matter, magnetic tapes,
microfilm, microfiche, punch cards, all other records kept by electronic,
photographic, or mechanical means, charts, photographs, notebooks, drawings,
plans, inter-office communications, intra-office and intra-departmental
communications, transcripts, checks and canceled checks, bank statements,
ledgers, books, records or statements of accounts, and papers and things similar
to any of the foregoing, however denominated.
2. The terms "relating," "relate," or
"regarding" as to any given subject means anything that constitutes,
contains, embodies, identifies, deals with, or is in any manner whatsoever
pertinent to that subject, including but not limited to records concerning the
preparation of other records.
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