Govt Prozac study Recommends MANDATORY Screening & Drugs – “Overdosed America”_OpEd NYT
Sun, 19 Sep 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.  The flaws include:
- 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.
- Failure to compare Prozac/CBT to placebo/CBT.
- 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. ,  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.” 
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. ,  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.” 
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.”  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. 
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. , 
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,  and have each served on industry-sponsored consensus guideline panels whose recommendations have consistently encouraged the use of antidepressant drugs.
Inasmuch as the TADS treatment recommendations are suspiciously similar to industry-funded Expert Consensus Guideline Series, such as the Texas Medication Algorithm Program (TMAP) , 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 doomed.
FDA officials have demonstrated bad faith since 1990-referring to “the relationship between fluoxetine and violence-ideation and suicide-ideation.as “a public relations problem.”  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.
 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
 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: http://bmj.bmjjournals.com/cgi/content/full/328/7444/879?
 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
 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: http://pn.psychiatryonline.org/cgi/content/full/39/17/1
 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. http://www.ahrp.org/risks/SSRImosholder/index.php
 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.
 by Jeanne Lenzer Specialists Challenge Claim that Fluoxetine Plus Talk Therapy Works Best for Depressed Adolescents. British Medical Journal (4 September), 329:529 http://bmj.bmjjournals.com/cgi/content/full/329/7465/529?
 Mandatory Mental Health Screening Threatens Privacy, Parental Rights by Wendy McElroy. MensNews Daily. September 16, 2004. Online at: http://www.mensnewsdaily.com/archive/m-n/mcelroy/2004/mcelroy091604.htm
 Federal amendment would cut funding for mental health screening initiatives By Rhonda Robinson. Illinois Leader. Wednesday, September 08, 2004. Online at: http://www.illinoisleader.com/news/newsview.asp?c=19335
 SmithKlineBeecham. FDA Conversation Record with Dr. Martin Becher, Medical Officer, FDA Div. Neuropharmacological Drug Products, October 3, 1990. http://www.ahrp.org/risks/SSRI0904/BrecherAppendix.pdf
 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. http://www.theannals.com/cgi/content/full/38/10/1743
Contact: Vera Hassner Sharav
September 18, 2004
Information Is the Best Medicine
By JOHN ABRAMSON
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 demonstrate.
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 Medicine.”
Copyright 2004 The New York Times Company
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