Promoting openness and full disclosure

FYI: Dr. Graham Emslie's (Lilly's) "Prozac Study" in 2004

FDA's Review of Safety & Efficacy Concerns in Anti-Depressant Use by
Children is the subject of a second Congressional hearing by the House
Energy & Commerce Subcommittee on Oversight / Investigations on September
23, 2004 at: Rayburn House Office Building, room 2123, at 11:00 AM.

Ten days earlier, TADS (Treatment for Adolescents with Depression Study)
was showcased at the FDA advisory committee meeting about drug-induced
suicide risks for children and adolescents. TADS is a $17 million dollar
study funded by the National Institute of Mental Health (NIMH) that compared
Fluoxetine (Prozac) with and without cognitive behavior therapy (CBT) to
placebo. The authors claim that the study demonstrated "evidence-based"
superior efficacy for Prozac with or without CBT, compared with placebo. 

However, the study's flawed methodology for obtaining that "evidence"
undermines the validity of those efficacy claims. [1] The flaws include:
(1) Randomization errors--17% of the placebo group had been diagnosed with
ADHD and 9% were taking psychostimulant drugs during the trial; in the
Prozac group 12% were diagnosed with ADHD and 2.8% took psychostimulants.
[1, Table 1] Stimulant drug side-effects may have been misinterpreted as
symptoms of depression--they would have exerted a negative bias on outcome
scales that were used to determine efficacy. 
(2) Failure to compare Prozac/CBT to placebo/CBT.
(3) Unblinded control. When asked by a science reporter whether the
adolescents (aged 12 to 17) knew if they were on Prozac or placebo, the TADS
investigator declined to say. 

Despite its flawed methodology, the rates of harm and suicide-related events
are consistent with-indeed in excess of-harm related events reported by
independent trial analysts. [2, 3] The suicide attempt ratio in adolescents
prescribed Prozac compared to those on placebo
was 6 to 1.
Dr. Graham Emslie, a leading TADS co-investigator acknowledged: "Seven of
the 439 patients attempted suicide during the trial, six of which were in
either the fluoxetine-plus-CBT or the fluoxetine-alone group, while one was
in the placebo group." [4]

This finding exceeds the adult FDA clinical trial data cited by Harvard
psychiatrist, Dr. John Abramson, in an Op Ed, The New York Times, (below):
"more than twice as many depressed adults on new antidepressants kill
themselves than those taking placeboes. The difference was 8.4 versus 3.6
suicides per 1,000 patients a year."

Overarching all other considerations in this debate about the safety and
efficacy of antidepressants in children / adolescents is indisputable
evidence of drug-induced harm. [5, 6] Based on separate analyses of the
evidence by FDA medical officers, an advisory panel concluded (Sept. 14)
that all antidepressants require a black box label warning. In the TADS
study, when prescribed alone, Prozac induced significantly greater
suicide-related events than any other treatment group.

The rate for harm-related and suicide-related events in the Prozac group was
12% and 8.26% respectively. In the placebo group: the rate was 5.36% and
3.57% respectively. [1, Table 3]  Dr. Emslie acknowledged:  "Patients
receiving fluoxetine alone had the highest risk (calculated as an
odds-ratio) of experiencing a harm-related event, compared with those
receiving placebo. Patients in the CBT/fluoxetine group were less likely
than those taking fluoxetine alone, but more likely than those receiving
placebo to experience a harm-related event."  [4]

Dr. Emslie pointed out: "CBT appeared to be exerting some sort of protective
effect, whereas fluoxetine appeared to be associated with harm-related and
suicide-related events." [4] In light of the evidence the TADS study
produced-i.e., significantly greater levels of harm and suicide-related
events than other studies-the authors' recommendations for mass screening
and wide use of Prozac in adolescents are self-contradictory. [1, p.819] 

The British Medical Journal reports  that critics are concerned about the
[TADS] authors' optimistic interpretation of the data. Professor David
Antonuccio of the department of psychiatry and behavioral sciences at the
University of Nevada School of Medicine, objects to "the authors' value
judgment" which "is that the benefit of a few extra improved patients is
worth the cost of a few extra harmed patients. My own risk-benefit analysis
leads me to a different conclusion.." He suggests that CBT alone, or
exercise, should be offered as the first line treatment because of the lower
risk of side effects. [7]

Because TADS was sponsored by the government, the recommendation for
MANDATORY screening and treatment--presumably by government decree-takes on
major significance.
TADS recommends: "the identification of depressed adolescents and provision
of evidence-based treatment should be mandatory in health care systems." [1,
p. 819] Responsible parents are not about to relinquish their freedom and
parental rights to a mental illness industry whose interventions (by decree)
have almost always done more harm than good. [8, 9]

Dr. John March, the principal TADS investigator, and Dr. Graham Emslie, a
senior co-investigator who was principal investigator in two previous Prozac
trials, have extensive, on-going financial ties to Eli Lilly and the other
antidepressant drug manufacturers, [10] and have each served on
industry-sponsored consensus guideline panels whose recommendations have
consistently encouraged the use of antidepressant drugs.[11]

Inasmuch as the TADS treatment recommendations are suspiciously similar to
industry-funded Expert Consensus Guideline Series, such as the Texas
Medication Algorithm Program (TMAP) [11], The Alliance for Human Research
Protection (AHRP) calls upon Congress to investigate collaborative
NIMH-pharmaceutical industry initiatives and treatment recommendations.

The drug industry's influence on public health policies is threatening the
lives of America's children: children are being targeted for screening,
labeling as mentally abnormal and for exposure to mind-altering drugs that
have been proven to cause suicide-related behavior. The FDA, the NIMH, the
psychiatric establishment--its opinion leaders and publications--are all
under the influence of the drug industry. Unless congress acts, children are

FDA officials have demonstrated bad faith since 1990-referring to "the
relationship between fluoxetine and violence-ideation and "a public relations problem." [12] Today, close to a
million children are prescribed antidepressants without adequate warnings
about the dangers. AHRP calls for Congressional action to protect children
from hazardous drugs-inasmuch as FDA officials have shown little
determination to put children's lives first.

Dr. Abramson does not believe that black box warnings are enough. We agree.
To ensure that drug safety issues take precedence over profit margins, and
to ensure that full disclosure of drug hazards are enforced, he recommends:
"nothing short of an oversight board. [sic, to] make a real difference."
Whereas Dr. Abramson recommends that such a board be modeled after the
Federal Reserve Board, AHRP suggests another alternative--the Securities and
Exchange Commission (SEC)--which acts as a watchdog over the securities
industry and public companies.

1. Fluoxetine, Cognitive-Behavioral Therapy,  and Their Combination for
Adolescents With Depression Treatment for Adolescents With Depression Study
(TADS) Randomized Controlled Trial, JAMA, August 18, 2004-Vol 292, 807-820
2. Jon N Jureidini, Christopher J Doecke, Peter R Mansfield, Michelle M
Haby, David B Menkes, Anne L Tonkin. Efficacy and safety of antidepressants
for children and Adolescents BMJ, online at:
3. Craig J Whittington, Tim Kendall, Peter Fonagy, David Cottrell, Andrew
Cotgrove, Ellen Boddington. Selective serotonin reuptake inhibitors in
childhood depression: systematic review of published versus unpublished data
by THE LANCET, Vol 363, April 24, 2004 
4. Jim Rosack. Drug/CBT Combo Effective In Treating Depressed Youth,
Psychiatric News September 3, 2004, Volume 39 Number 17 C 2004 American
Psychiatric Association. Online at:
5.Andrew Mosholder. Analysis of Original Pediatric Suicidality Data,
Comparison of Initial Analysis, Results and Classified Cases Analysis,
Andrew Mosholder, MD, Center for Drug Evaluation and Research, FDA. February
18, 2004.
6.Tarek Hammad. Review and Evaluation of Clinical Data, Tarek A Hammad, MD,
PhD, MSc, MS, Center for Drug Evaluation and Research, FDA. August 16, 2004.
7. by Jeanne Lenzer Specialists Challenge Claim that Fluoxetine Plus Talk
Therapy Works Best for Depressed Adolescents. British Medical Journal (4
September), 329:529
8. Mandatory Mental Health Screening Threatens Privacy, Parental Rights by
Wendy McElroy. MensNews Daily. September 16, 2004. Online at:
9. Federal amendment would cut funding for mental health screening
initiatives By Rhonda Robinson. Illinois Leader. Wednesday, September 08,
2004. Online at:
10. See: Integrity in Research database. Center for Science for the Public
11. See: Expert Consensus Guideline Series in psychiatry with a list of
pharmaceutical sponsors, a list of the experts, and list of "advocacy"
groups at:
12. SmithKlineBeecham. FDA Conversation Record with Dr. Martin Becher,
Medical Officer, FDA Div. Neuropharmacological Drug Products, October 3,
13. See also: Antidepressants: An Avoidable and Solvable Controversy
Jay S Cohen, MD The Annals of Pharmacotherapy, , 31 August 2004,  Vol. 38,
No. 10, pp. 1743-1746.

Contact: Vera Hassner Sharav
Tel: 212-595-8974
September 18, 2004
Information Is the Best Medicine

Measures to make the results of drug trials more accessible to doctors and
the public, as well as the federal government's probable stiffer warnings on
the use of antidepressants for children, are definitely steps in the right
direction. But my experience as a family doctor on the front lines of
medicine leads me to believe that these moves won't be enough to curb the
influence of the drug companies on our health care.

The impetus for these changes comes largely from revelations in the Food and
Drug Administration's review of the new class of antidepressants, known as
selective serotonin reuptake inhibitors, in the treatment of depression in
children and adolescents. Many studies, the review found, show that the
drugs are no more effective than placebos, but significantly increase the
risk of suicidal tendencies. So why are doctors writing millions of
prescriptions each year to treat depressed children with these drugs?

Much of the problem stems from drug companies' unequal treatment of the
clinical trials they sponsor. Findings that support drug sales tend to get
published in medical journals, and become accepted as fact. Unfavorable
findings often don't see the light of day. This leaves even the most
dedicated doctors and best informed patients (and parents) unaware of
important evidence about the drugs they're prescribing and using.

In response, the editors of 11 of the world's leading medical journals have
agreed to publish only studies that are registered at the outset.
Registration creates a trail, making it more difficult to suppress
unfavorable results. Legislative efforts are also under way to make
completed studies available to the public.

There are many examples, however, of drug sales skyrocketing despite the
availability of research showing negative results or serious side effects.
An article published in the Archives of General Psychiatry in April 2000
provides a preview of the limited effect that we can expect from registering
and posting results of all studies. In this case, researchers obtained the
results of all clinical trials of new antidepressants like Prozac, Paxil and
Zoloft done from 1987 to 1997, published and unpublished, from the F.D.A.
under the federal Freedom of Information Act.

The pooled results showed that an older class of antidepressants, known as
tricyclics, was actually more effective, belying all the hype about the
"revolutionary'' new antidepressants. The researchers reported that among
the longer-term studies (which better reflect actual use), the new
antidepressants were 8 percent more effective than placebos, while
tricyclics like Elavil were 12 percent more effective. The most disturbing
finding was that more than twice as many depressed adults on new
antidepressants kill themselves than those taking placeboes. The difference
was 8.4 versus 3.6 suicides per 1,000 patients a year, respectively.

How much impact did the availability of these results have on doctors'
prescribing patterns? Evidently not much: the new antidepressants remained
the best-selling class of drugs in the United States in 2000 and 2001.
The medical journal editors understand that just registering studies isn't
enough. Their real goal is full transparency in clinical trials, meaning
that research plans and complete data from studies should be available for
independent review. But even this is not sufficient to counteract commercial
influence, as the cases of the blockbuster drugs Celebrex and Vioxx

The results of large manufacturer-sponsored studies of these two arthritis
drugs were published in The Journal of the American Medical Association and
The New England Journal of Medicine, respectively, in 2000. The original
data upon which both articles are based have been posted on the F.D.A. Web
site since February 2001.
Both drug-company sponsored articles led doctors to believe that their
patients would be better served by prescribing the new drugs. But the data
posted on the F.D.A. Web site tell a very different story. Patients on
Celebrex did not have significantly fewer serious gastrointestinal problems
than those who took the older types of arthritis medicine.

In fact, during the second six months of treatment (data not even mentioned
in the article), users of Celebrex developed serious gastrointestinal
problems more often than users of the older drugs. The bottom line is that
Celebrex is much more expensive, provides no better relief of arthritis
symptoms, and overall causes 11 percent more serious complications than the
other drugs.
The data about Vioxx offer an answer to the supposedly unresolved question -
whether it increases the risk of heart attacks, strokes and blood clots.
Even among people without elevated risk, those taking Vioxx suffered twice
as many serious cardiovascular complications as those who took naproxen
(sold as Naprosyn or Aleve). Most important, the data on the F.D.A. Web site
show that patients taking Vioxx developed 21 percent more serious
complications than those who took naproxen.

Since that data was posted more than three years ago, American doctors have
prescribed more than $15 billion worth of Celebrex and Vioxx. Full
transparency, it appears, doesn't solve the problem of commercial influence
either.  Given the drug industry's domination of our medical knowledge,
nothing short of an oversight board - modeled after the Federal Reserve
Board, will make a real difference. The board's members must serve lengthy
terms to avoid political influence and have no commercial ties. This body
would make use of the excellent work already being done by the reviewers
within the F.D.A. (though too often their analyses remain invisible to the
public) as well as the commercial, nonprofit, and government-sponsored
research that is already being done.

Like the National Institute of Clinical Excellence in Britain (which has a
budget of less than $30 million a year), this board would independently
evaluate scientific evidence relevant to selected diseases and treatments to
determine optimal medical care including lifestyle changes. The board's
recommendations would define the standards of medical care based on what is
best for Americans' health, not what will generate the most profit.

If the latest round of reforms relating to drug research stops with
registering and posting the results of clinical studies, it will stand only
as window-dressing on a method of producing and disseminating medical
knowledge that is better designed to serve drug makers' interests than to
improve Americans' health.

John Abramson, a clinical instructor at Harvard Medical School, is the
author of the forthcoming "Overdosed America: The Broken Promise of American
Copyright 2004 The New York Times Company

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