October 26

Zolft pediatric study in JAMA challenged by peers – JAMA letters

Zolft pediatric study in JAMA challenged by peers – JAMA letters

Fri, 9 Jan 2004

At the time that two manufacturers publicly acknowledged that their antidepressant drugs (Paxil / Seroxat and Effexor) were unsafe, and ineffective for children, the Journal of the American Medical Association (JAMA) published a clinical trial report by the “Sertraline Pediatric Study Group” (i.e., Pfizer sponsored investigators) caliming: “Sertraline [Zoloft] -treated patients experienced statistically significantly greater improvement than placebo.” See: https://ahrp.org/infomail/03/10/01a.php The press uncritically swallowed those unsubstantiated claims, and proceeded to mislead the public and treating physicians.

The disputed ‘favorable findidngs’ claimed for Zoloft are challenged in letters published in the current issue of JAMA (Jan 1, 2004). Five psychiatrists from the US and UK question the validity of those claims and indeed, question the integrity of the method by which those claims were obtained. In essence, te claimed ‘positive’ findings were made by EXCLUDING noncompleters and nonresponders.

The British authority, once alerted to how the methods by which drug manufacturers have manipulated clinical trials to show ‘positive findings,’ took action to protect children from the hazards of SSRIS. FDA, in sharp contrast, is fiddling while children are needlessly being made to suffer. FDA is tinkering with the clinical trial data, attempting to airbrush the evidence so as to neutralize the negative. Furthrermore, FDA has refused to allow expert scientific testimony that updates the findings of the information received by the British Medicines and Healthcare Regulatory Agency. As a result, American children prescribed SSRIS are at risk of developing drug-induced mania, violence and suicidal behavior.

The JAMA letters: Drs. Maju, Manu, and Joanne Mathews from Dexel University, East Surrey Hospital and West Suffolk Eng (respectively) noted: “[T]he authors excluded some randomized patients from their analysese. According to the principle of mention to treat (ITT), the authors could have assigned the ‘worst-case outcome’ to the excluded patients.”

Dr. David Price from Colorodo Permanente Medical Group questions the rationale for conducting 2 separate trials–that introduce additional variability–rather than 1 large trial. He questions the rationale for lowering the bar on the ‘improvement’ standard–from commonly used 50% response rate to 40% which, as Dr. Price points out, “This seems to create a bias for a favorable result for sertraline. And Dr. Price faults the authors for using a questionable “last observation-carried-over method rather than the more conservative analyssis considering noncopleters and nonresponders.”

Dr. Antal E. Solyom from the University of Virginia questions the scientific and ethical justification of using children in rigid double-blind controlled clinical trials inasmuch as the pitfalls of placebo-controlled trials in antidperssants have been acknowledged even by Dr. David Kupfer, former president of the American College of Neuropsychopharmacologogists. Dr. Solyom points out that “individual case study designs that enroll paptients with severe depression from which suicidal patients are not excluded may be more appropriate.

Finally, Dr. Solyom notes: “Most troubling is the uncritical duplication of all of these trials in the even more heterogeneous and vulnerable child and adolescent psychiatric populations. It would be more constructive to focus on the 40% of depressed adolescents who do not respond to the initial trial and antidepressant treatment.”

Glen Spilmans a statistician from the department of psychiatry, Indiana University, notes that the absence of evidence about the validity of the two scales used to measure an improvement in outcome. “Because of the small magnitutde of difference between groups [on Zoloft compared to those on placebo] and the fairlure to truly assess the degree to which the double blind may have been penetrateed, this trial suggests that sertraline shows little to no perceptible benefit compared with placebo in the treatment of depressed youth.”

An unpublished letter by Dr. Jan Garland, Clinical Professor, Psychiatry University of British Columbia and Clinical Head, Mood and Anxiety Disorders Clinic BC’s Children’s Hospital appears below.

Letter to Editor, JAMA:

As one of the many investigators in various sites who was involved in the Pfizer sertraline pediatric depression trials published in JAMA in August, 2003 (1), I was very concerned for a number of reasons about the data analysis reported in this paper. The most striking feature was the pooling of two trials which is not the orthodox way of handling trial data. The pooled data, a sample size of 376 patients, showed a marginal superiority of medication which is not likely to be clinically meaningful in terms of risk/benefit balance. On selected improvement measures, only 10% more patients improved on sertraline than on placebo, remission rates were not different, and there were more discontinuations in the sertraline group due to adverse effects including suicidality and aggression. Based on this report, it appeared very likely that the individual trials were in fact negative, but this possibility was not discussed by the authors. By pooling the data, what might have been reported as two negative trials was instead converted into one marginally positive trial with the conclusion that “sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD”.

New information about these trials is now available. The recent review of pediatric antidepressant trials by the British regulatory agency includes the appropriate separate analysis of these two trials, and the summary results are now in the public domain (2). >From this analysis, it is clear that the two individual trials each of a good size (almost 190 patients) did not demonstrate the effectiveness of sertraline in treating major depressive disorder in children and adolescents. Hence, the correct conclusion from the data reported by Wagner et al should be that “sertraline is ineffective when compared to placebo and is associated with increased adverse effects”.

E. Jane Garland, M.D.

1. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, et al. Efficacy of Sertraline in the Treatment of Children and Adolescents With Major Depressive Disorder: Two Randomized Controlled Trials JAMA. 2003;290:1033-1041.

2. Committee on Safety of Medicines. Medicines and Health Care Products Regulatory Agency. Selective Serotonin Reuptake Inhibitors (SSRIs): overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents: Summary of clinical trials http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/

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