Posted on Thursday 17 September 2015
[Note: the Press coverage of our article is on study329.org, but I wanted to mention the article on Retraction Watch because it has Dr. Martin Keller’s response to our paper with an argument similar to the one below…]
14 OCT 1998
Please find attached to this memo a position piece, prepared by Julie Wilson of CMAT, summarising the results of the clinical studies in Adolescent Depression.
As you will know, the results of the studies were disappointing in that we did not reach statistical significance on the primary end points and thus the data do not support a label claim for the treatment of Adolescent Depression. The possibility of obtaining a safety statement from this data was considered but rejected. The best which could have been achieved was a statement that, although safety data, was reassuring, efficacy had not been demonstrated. Consultation of the Marketing Teams via Regulatory confirmed that this would be unacceptable commercially and the decision to take no regulatory action was recently endorsed by the TAT.
As you will see from the position piece the positive trends In efficacy which were seen in Study 329 are being published as a poster at ECNP this year and a full manuscript is in development. Published references will therefore be available for the study. There are no plans to publish data from Study 377.
This report has been prepared for internal use only. Data on File summaries will be prepared and issued once the final reports from the studies have been approved. This position piece will also be available on the Seroxat/Paxil resource database.TARGET [from the Wilson position piece mentioned above]
To effectively manage the dissemination of these data in order to minimize any potential negative commercial impact…
Paroxetine is generally well tolerated and effective for major depression in adolescents.
This study was designed at a time when there were no randomized controlled trials showing antidepressant [tricyclic antidepressant or SSRI] superiority to placebo, so we had no prior data from which to astutely pick our outcome measures. The field has moved strongly away from using the Hamilton Rating Scale for Depression [HAM-D] in adolescent treatment studies and has gone virtually uniformly to using the Children’s Depression Rating Scale-Revised because the latter better and more reliably captures aspects of depression in youth. Surely a national regulatory body charged with approving or not approving a medication for a particular use might well simply say that if a study does not show efficacy on the primary endpoint[s[, it is a failed study and secondary outcome measures cannot then be used for approval. However, as scientists and clinicians we must adjudge whether or not the study overall found evidence of efficacy, and we do not have the convenience of falling back on such a simple rule. If we choose wrongly [in whichever direction], we don’t treat depressed children as well as the data would permit. Because we found a clear pattern of significant p values across multiple secondary analyses [recovery as assessed by HAM-D < 8, HAM-D depressed mood item, the Schedule for Affective Disorders and Schizophrenia for School-Age Children depression item, and Clinical Global Impression score at endpoint], we thought and still think this provides significant evidence of efficacy of paroxetine compared with placebo in adolescent depression. Without established reliable measures that distinguish medication responders from nonresponders at the time the study was designed, it is not surprising that the primary measures did not reach significance while other measures did. It still provides a strong “signal” for efficacy…
An International, Multicenter, Placebo-Controlled Trial of Paroxetine in Adolescents with Major Depressive Disorderby Ray Berard, Regan Fong, David J. Carpenter, Christine Thomason, and Christel WilkinsonJournal of Child and Adolescent Psychopharmacology. 2006 16[1-2]:59–75.…Conclusions: No statistically significant differences were observed for paroxetine compared with placebo on the two prospectively defined primary efficacy variables. Paroxetine at 20–40 mg/day administered over a period of up to 12 weeks was generally well tolerated.
Paroxetine Treatment in Children and Adolescents With Major Depressive Disorder: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Trialby GRAHAM J. EMSLIE, KAREN DINEEN WAGNER, STAN KUTCHER, STAN KRULEWICZ, REGAN FONG, DAVID J. CARPENTER, ALAN LIPSCHITZ, ANDREA MACHIN, AND CHRISTEL WILKINSONJournal of the American Academy of Child and Adolescent Psychiatry. 2006 45:709-719.…Conclusions: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.
The article by Keller et al.  is one of only two to date to show a positive response to selective serotonin reuptake inhibitors [SSRIs] in child or adolescent depression. We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process. The study authors designated two primary outcome measures: change from baseline in the Hamilton Rating Scale for Depression [HAM-D] and response [set as fall in HAM-D below 8 or by 50%]. On neither of these measures did paroxetine differ significantly from placebo. Table 2 of the Keller article demonstrates that all three groups had similar changes in HAM-D total score and that the clinical significance of any differences between them would be questionable. Nowhere is this acknowledged. Instead:
- The definition of response is changed. As defined in the “Method” section, it has a nonsignificant p value of .11. In the “Results” section [without any explanation], the criterion for response is changed to reduction of HAM-D to below 8 [with a p value of .02]. By altering the criterion for the categorical measure of outcome, the authors are able to claim significance on a primary outcome measure.
- In reporting efficacy results, only “response” is indicated as a primary outcome measure, and it could be misunderstood that response was the primary outcome measure. Only in the discussion is it revealed that “Paroxetine did not separate statistically from placebo for…HAM-D total score,” without any acknowledgment that total score was one of the two primary outcome measures. The next sentence is a claim to have demonstrated efficacy for paroxetine.Thus a study that did not show significant improvement on either of two primary outcome measures is reported as demonstrating efficacy. Given that the research was paid for by Glaxo-Smith-Klein, the makers of paroxetine, it is tempting to explain the mode of reporting as an attempt to show the drug in the most favorable light. Given the frequency with which it is cited in other scientific papers, at conferences and educational functions, and in advertising, this article may have contributed to the increased prescribing of SSRI medication to children and adolescents. We believe it is a matter of importance to public health that you acknowledge the failings of this article, so that its findings can be more realistically appraised in decision-making about the use of SSRIs in children.