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Barton, Greenwood Seek Info From FDA On Antidepressants

March 24, 2004


The Honorable Mark B. McClellan, M.D., Ph.D.
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:

  1. 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.

  2. 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.

  3. 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:

    1. Eli Lilly & Co.;

    2. Pfizer Inc.;

    3. Wyeth Pharmaceuticals;

    4. GlaxoSmithKline;

    5. Bristol-Myers Squibb Co.;

    6. Akzo Nobel Inc.; and

    7. Forest Laboratories, Inc.

  4. 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.

  5. All records relating to FDA's decision to issue the June 19, 2003 advisory on Paxil and possible effects in the pediatric/adolescent population.

  6. 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.

  7. 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.

  8. 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.

  9. 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:

    1. Eli Lilly & Co.;

    2. Pfizer Inc.;

    3. Wyeth Pharmaceuticals;

    4. GlaxoSmithKline;

    5. Bristol-Myers Squibb Co.;

    6. Akzo Nobel Inc.;

    7. Forest Laboratories, Inc.;

    8. United Kingdom's Medicines and Healthcare Products Regulatory Agency; or

    9. A U.S. state or federal governmental agency.

  10. 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.

  11. 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:

    1. Name of the company;

    2. Name of the anti-depressant;

    3. Date when pediatric clinical trial data was submitted to FDA;

    4. Date when pediatric clinical trial was completed by company;

    5. 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.

  12. 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.




Joe Barton


James C. Greenwood

Subcommittee on Oversight and Investigations


cc: The Honorable John D. Dingell, Ranking Member

The Honorable Peter Deutsch, Ranking Member

Subcommittee on Oversight and Investigations



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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