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To: Thomas Insel MD; Tommy Thompson
Re: Published NIMH Prozac Trial Report Concealed Suicide Attempts by
Teens
ALLIANCE FOR HUMAN RESEARCH PROTECTION
(AHRP)
Tel. 212-595-8974 Fax: 212-595-9086
Board of Directors:
Vera Hassner Sharav, President
John H. Noble, Jr., Ph.D, Treasurer
David Cohen, Ph.D, Secretary
Loren Mosher, MD
Meryl Nass, MD
Sally Rogow, Ed.D.
June 22, 2004
Thomas Insel, MD
Director
National Institute of Mental Health
Re: Published NIMH Prozac Trial Report Concealed Suicide Attempts
by Teens
Recent revelations indicate that pharmaceutical companies have selectively
reported partial (favorable) clinical trial results from pediatric antidepressant
trials and concealed evidence of harm from physicians, other health
care professionals, and the public. It is universally agreed in the
literature that failure to disclose all trial results compromises physicians'
ability to provide professional care - thereby increasing the likelihood
of causing preventable harm. More generally, failure to disclose trial
results in scientific publications taints the scientific literature
(by rendering it not credible) and, as New York State Attorney General
Elliot Spitzer charged recently, constitutes plain and simple fraud.
The Alliance for Human Research Protection (AHRP), a non-profit, tax-exempt
educational organization that promotes openness and full disclosure
in research, is concerned that clinical trial data about the potential
hazards of Prozac (fluoxetine) for children and adolescents may have
been concealed from physicians, other health care professionals, and
the public. We are writing to you on this matter because we are concerned
that taxpayer funds to the National Institute of Mental Health (NIMH)
may have been used to conceal some of this data.
As you know, one of two clinical trials submitted by Eli Lilly to
gain Food and Drug Administration (FDA) approval for Prozac to treat
depression in children was funded by the NIMH. A report of this trial
was published in 1997 in Archives of General Psychiatry (Emslie et al.,
1997). Data from this same NIMH-funded trial was used by Eli Lilly to
gain an additional 6-month patent exclusivity for Prozac (FDA, 2001).
The second clinical trial was funded entirely by Eli Lilly, and a report
from this trial was published in 2002 (Emslie et al., 2002). The principal
investigator and lead author in both trials was Dr. Graham Emslie.
According to FDA documents posted on the FDA website on September
25, 2003, at least 2 of 48 children treated with Prozac in the NIMH-sponsored
trial attempted suicide:
Two subjects who attempted suicide may have had their blinded treatment
revealed to a non-study physician who was not an investigator (Fluoxetine
patients 2051 and 2163). (FDA, 2001a, p. 19, italics added)
In the single published report of this trial, however, there is no
mention of any children attempting suicide. Instead, the published report
states:
Side effects, as a reason for discontinuation, were minimal, affecting
only 4 patients who were receiving fluoxetine. (Emslie et al., 1997,
p. 1033)
Furthermore, on April 23, 2004, the NIMH posted an announcement on
its website, entitled "Antidepressant Medications for Children: Information
for Parents and Caregivers." This announcement discusses both Emslie
trials specifically, indicates that one was funded by the NIMH, but
makes no mention of suicide attempts among Prozac-treated children.
Instead, parents were merely told: "The studies found that [Prozac]
reduced depression for many children better than a placebo (a fake pill)
and it did not increase suicide or suicidal thinking."
As part of their evaluation of Eli Lilly's submission for approval
of Prozac for the treatment of depression in children, FDA reviewers
examined Lilly's integrated safety data summaries (ISS) from 3 pooled
Prozac pediatric trials: the NIMH-funded trial (Emslie, 1997), the Lilly-funded
trial with depressed children (Emslie, 2002), and a trial with children
diagnosed with obsessive-compulsive disorder (Geller, 2001) The ISS
includes only solicited reports of adverse drug reactions (ADRs) on
228 children treated with Prozac and 190 given a placebo in these 3
clinical trials.
According to the FDA medical review, the ISS summaries indicate that
22 children dropped out because of ADRs in the Prozac-treated group
compared to 5 in the placebo groups. The FDA review also states that
there were 3 suicide attempts among the Prozac-treated group versus
one such attempt among the placebo group. FDA's review refers to additional
children being hospitalized for suicidal events: "In addition, one fluoxetine
patient was hospitalized because of suicidality" (p. 26). This leads
one to wonder how many children required hospitalization for suicidal
ideation?
Furthermore, the ISS summaries indicate that 6 of the Prozac-treated
children, but none on placebo, developed mania or hypomania. FDA's medical
reviewer noted: "Mania and hypomania appear to be much more common with
fluoxetine treatment in these trials than has been the case in adult
clinical studies." (FDA, 2001a, p. 27).
The FDA review also reveals that an additional, though unreported
study exists (the identity of which is blanked out in the FDA documents),
it involved 42 depressed adolescents, 21 of whom were treated with Prozac.
This study included a 6-week double blind, placebo-controlled phase,
to be continued for 52 weeks as an open label study. This study, however,
was terminated "due to slow patient recruitment." The ADR data from
the terminated study were not included in Lilly's ISS summaries. However,
according to the FDA's review, there were 5 serious ADRs in the terminated
trial, including 2 cases of "overdose" and 2 adolescents hospitalized
for "suicidality."
When asked by a New York Times reporter about the issue of concealment
of negative findings in pediatric trials of antidepressant drugs, Dr.
Emslie declined to disclose what he knew, invoking secrecy contracts
with pharmaceutical companies (Harris, 2003).
According to Lilly's Clintrace Safety Database for post-marketing,
spontaneously reported ADRs, by August, 2001 - before FDA's approval of
Prozac for children--there were 3,815 ADR reports for 6 to 17 year-old
youths. The following represent more than 1% of reported ADRs and are
more common among this age group than others: dermatitis, overdose,
agitation, aggression, suicide attempts, convulsions, vomiting, and
6 reports of QT interval prolongation, 1 report of QTc prolongation,
3 reports of cardiac arrest, one sudden unexplained death. (FDA, 2002,
p. 4-5)
In light of the above information, AHRP kindly requests that the NIMH
answer the following questions underlying our concerns:
1. How many children receiving Prozac in the NIMH-sponsored study
attempted suicide?
2. Was the NIMH informed about suicide attempts and other adverse
events in the NIMH-sponsored study?
3. How does the NIMH explain that suicide attempts by children treated
with a psychotropic drug in an NIMH-sponsored study were not duly reported
in a publication resulting from that study?
4. How do NIMH officials explain that in the announcement posted by
the NIMH on its website on April 23, 2004, specifically addressing parental
concern about the possible link between antidepressants and suicidality,
suicide attempts by children treated with Prozac in an NIMH-sponsored
study are not disclosed?
AHRP is also concerned about the NIMH's role in funding a study with
taxpayer money that was subsequently used by Eli Lilly to extend its
Prozac patent exclusivity and to obtain FDA approval for treating depression
in children - while apparently failing to ensure that all relevant data
from that study be fully disclosed. AHRP is also concerned that conflicts
of interest may undermine the credibility of taxpayer funded research
findings and support. The following is the basis for our concerns.
In the FDA review of Eli Lilly's submission for the approval of Prozac
for pediatric depression, Dr. Russell Katz, Director of Neuropsychopharmacological
Drug Products, refers to "Study X-658" as "the Emslie study," noting:
Eli Lilly was not involved with the conduct of this study, but obtained
the primary data and performed their own analysis. (FDA, 2001b)
Dr. Andrew Mosholder, FDA expert reviewer, notes:
Lilly arranged to acquire the data from Dr. Emslie and colleagues
in 1997, as part of their pediatric development program for fluoxetineŠ
(FDA, 2001a, p. 16)
In light of the above information, AHRP kindly requests that the NIMH
answer the following questions:
5. How much did NIMH pay for this study?
6. If the study was "part of [Eli Lilly's] pediatric development program
for fluoxetine," did Eli Lilly pay for the data, and did Lilly reimburse
the NIMH for the funds disbursed to Dr. Emslie, his colleagues, and
their institution to conduct the study?
7. How much did the investigators receive in total from Eli Lilly
in the past 10 years?
In sum, you will recognize that our concerns raise important questions
about preventable harm to children who are prescribed antidepressants
without their physician's knowledge about the risks.
Indeed, they also raise questions about the credibility of the most
recent announced findings of an NIMH-funded Prozac trial in adolescents.
New positive findings from this trial were announced on June 2, 2004,
by the NIMH and by the principal investigators, Drs. Emslie and John
March. Though the announcement was reported on the front page of the
New York Times and in numerous other media outlets, no data were released
for independent review, nor was any publication date announced.
We anxiously await your answers to this letter and to our previous
letter of April 30.
Sincerely,
Vera Hassner Sharav, President
David Cohen, Ph.D. Secretary
Loren Mosher, MD
Meryl Nass, MD
John H. Noble, Jr., Ph.D. Treasurer
Sally Rogow, Ed.D
The Alliance for Human Research Protection, AHRP
Jonathan Leo, Ph.D.
Co-Editor in Chief, Ethical Human Psychology and Psychiatry.
cc: Tommy Thompson, Secretary, Department of Health & Human Services
Senator Charles Grassley
Senator Max Baucus
Congressman James Greenwood
Congressman Joe Barton
Congressman Peter Deutch
Related link: NIMH Response
to AHRP Letter, dated Aug 5, 2004
References:
Emslie, G. J., Rush, J., Weinberg, W. A., Kowatch, R. A., Hughes,
C. W., Carmody, T., & Rintelmann, J. (1997). A double-blind, randomized,
placebo-controlled trial of fluoxetine in children and adolescents with
depression. Archives of General Psychiatry, 54, 1031-1037.
Emslie, G. J., Heiligenstein, J. H., Wagner, K. D., Hood, S. L., Ernest,
D. E., Brown, E., Nilsson, M., & Jacobson, J. G. (2002). Fluoxetine
for acute treatment of depression in children and adolescents: A placebo-controlled,
randomized clinical trial. Journal of the American Academy of Child
and Adolescent Psychiatry, 41, 1205-1215.
Food and Drug Administration (FDA). Center for Drug Evaluation and
Research (CDER). (FDA) (2001a, June 25). Application number 18-936/SE5-064,
submitted for application, pediatric exclusivity (September 14, 2000).
Medical Review by Andrew Mosholder, MD. Posted on FDA's website Sept.
25, 2003: http://www.fda.gov/cder/approval/index.htm
FDA CDER. (2001b, July 11). Application #02974. Administrative Correspondence:
Action Memo for NDA 18-936/SE5-064, for the use of Prozac (fluoxetine
HCI) in pediatric patients with Major Depressive disorder (MDD) or Obsessive
Compulsive Disorder (OCD) by [Russell Katz, MD] Director. Division of
Neurophamacological Drug Products / HFD-120. Posted on FDA's website
Sept. 25, 2003:
FDA. CDER. (2002, February 19). Review and evaluation of clinical
data. Memo by Andrew Mosholder, MD. Posted on FDA's website, Sept. 25,
2003:
Geller DA, Hoog SL, Heiligenstein JH, Ricardi RK, Tamura R, Kluszynski
S, Jacobson JG. (2001, July). Fluoxetine Pediatric OCD Study Team. Fluoxetine
treatment for obsessive-compulsive disorder in children and adolescents:
a placebo-controlled clinical trial. American Academy of Child & Adolescent
Psychiatry. 40(7):773-9.
Harris, G. (2003, August 7). Debate Resumes on the Safety of Depression's
Wonder Drugs. The New York Times, p. 1. Available at: http://www.ahrp.org/infomail/03/08/07.php
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