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and then there was one…

Posted on Wednesday 17 August 2016

I’ve gotten email along the way asking me [or chiding me] about my being preoccupied with clinical trials that are more than a decade old, I guess implying that it’s even too boring for the likes of me. I’d like to respond, because I think there’s something very important in the answer. These trials are designed to detect short term efficacy and log adverse effects to determine regulatory approval. They were never intended to direct clinical use of the drugs in practice. And yet they’ve frequently been treated as if they’re the final word, the gold standard in clinical psychiatry. And further, in the published reports, the subjects’ self-rating scales are often insignificant, if they’re even reported, even though the thing that really matters with many of the conditions is the patient’s subjective experience of symptom relief. Then after a drug is approved, further testing is directed towards greener pastures, lucrative approvals for other diagnoses. And as to the continued relevance of these ancient trials, Karen Wagner’s update at the 2016 APA meeting relied on her same old studies [see Child Psychiatrists Look at Specialty From Both Macro, Micro Perspectives]:
Notice my formatting. I think that the 2001 Paxil Study 329 and the 2004 CIT-MD-18 papers have been convincingly debunked by the recent exhaustive second looks: Restoring Study 329… and The citalopram CIT-MD-18 pediatric depression trial…. And as long as we’re in the neighborhood, what about Wagner’s 2003 Pfizer-funded Sertraline trial?
Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials
by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
Journal of the American Medical Association. 2003, 290[8]:1033-41.

CONTEXT: The efficacy, safety, and tolerability of selective serotonin reuptake inhibitors [SSRIs] in the treatment of adults with major depressive disorder [MDD] are well established. Comparatively few data are available on the effects of SSRIs in depressed children and adolescents.
OBJECTIVE: To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD.
DESIGN AND SETTING: Two multicenter randomized, double-blind, placebo-controlled trials were conducted at 53 hospital, general practice, and academic centers in the United States, India, Canada, Costa Rica, and Mexico between December 1999 and May 2001 and were pooled a priori.
PARTICIPANTS: Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD of at least moderate severity.
INTERVENTION: Patients were randomly assigned to receive a flexible dosage [50-200 mg/d] of sertraline [n = 189] or matching placebo tablets [n = 187] for 10 weeks.
MAIN OUTCOME MEASURES: Change from baseline in the Children’s Depression Rating Scale-Revised [CDRS-R] Best Description of Child total score and reported adverse events.
RESULTS: Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score [mean change at week 10, -30.24 vs -25.83, respectively; P=.001; overall mean change, -22.84 vs -20.19, respectively; P=.007]. Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders [P=.05]. Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients [9%] and 5 placebo patients [3%] prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation.
CONCLUSION: The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD.
Figure 2. Weekly and Overall Adjusted Mean CDRS-R Scores
CDRS-R indicates Children’s Depression Rating Scale—Revised Best Description of Child total score. Data are least square means at each visit week, with mean scores averaged to give the overall mean, from a repeated-measures mixed-model analysis with age category, site, treatment, week, and week-by-treatment interaction used as fixed effects, subject as a random effect, and baseline effect as a covariate. Error bars indicate SE of the adjusted means, derived from the repeated-measures mixed-model procedure. P values are as follows: week 1. P=.09; week 2, P=.08; week 3, P =.01; week 4, P=.008; week 6, P=.37; week 8, P=.18; week 10, P=.001; and mean response, P=.007.

Right out of the gate, we have good reason to question these conclusions just by looking at the primary outcome variable graph which only achieved significance at 3, 4, and 10 weeks. But there’s a lot more to give us pause. In all of the depositions, Wagner makes it clear that she neither saw all the data nor checked the analysis in this study either, and that it was written at Pfizer with her coming in as the drafts were revised. Pfizer has gotten off light in the critiques of these clinical trials in that they had a writing firm, Current Medical Directions, that ghost wrote their Zoloft articles faster than they could find KOLs to sign up as guest authors [see zoloft: beyond the approval I… for this part of the story].

But there’s something else that has always bothered me about this paper, and it’s right there in the title – … two randomized controlled trials. What’s that about? Everywhere this trial is reported, they say some version of, "Data from both studies were pooled in a prospectively defined combined analysis." So we are to believe that they had two identical studies that they planned to pool together for analysis, and the obvious question is what makes them two studies? Sounds like one big study to me [and plenty of others reading this paper]. If you were planning two identical studies, it would be likely that you were trying the speed things up to get the two studies needed for FDA Approval. And then we read this from one of the study group investigators in the study:

To the Editor: Dr Wagner and colleagues reported that sertraline was more effective than placebo for treating children with major depressive disorder and that it had few adverse effects. As one of the study group investigators in this trial, I am concerned about the way the authors pooled the data from 2 trials, a concern that was raised by previous letters critiquing this study. The pooled data from these 2 trials found a statistically marginal effect of medication that seems unlikely to be clinically meaningful in terms of risk and benefit balance.

New information about these trials has since become available. The recent review of pediatric antidepressant trials by a British regulatory agency includes the separate analysis of these 2 trials. This analysis found that the 2 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.
    E. Jane Garland, MD, FRCPC
    Department of Psychiatry
    University of British Columbia
    Vancouver
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. Available at: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverviewclintnaldata_101203.htm. Accessibility verified March 12, 2004.
Well, if that’s not enough of a nail in this coffin, there’s even more in Wagner’s response to Dr. Garland’s letter:
Reply: In response to Dr Garland, our combined analysis was defined a priori, well before the last participant was entered into the study and before the study was unblinded. The decision to present the combined analysis as a primary analysis and study report was made based on …
I won’t even finish her explanation because it doesn’t matter, since a priori means before the study starts, not "well before the last participant was entered into the study and before the study was unblinded" [this ploy of redefining the meaning of a priori is familiar to us from a similar bit of sleight of hand in Paxil Study 329]. So looked at from any angle, this is yet another negative clinical trial reported as positive after much jury-rigging – just as worthy of retraction as the other two.
Wagner is scheduled for her usual presentation [Treatment of Depressive Disorders in Children and Adolescents] at the October American Academy of Child and Adolescent Psychiatry annual meeting. I wonder what she’ll find to talk about this year?
  1.  
    Melody
    August 18, 2016 | 8:27 AM
     

    Mickey,

    Thanks for keeping on. I’ve written before about the similarities between psychiatry shenanigans and diabetes shenanigans (how the synthetic ‘insulin’ became the gold standard. Thought you might enjoy the following article, illustrating just how far-reaching jury-rigging goes.

    A popular weight-loss pill was buoyed by studies that understated its harms at
    https://www.statnews.com/2016/08/16/weight-loss-pill-harms/

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