For the background, let me take the easy way out, and quote Ed Silverman from PharmaLot:
We did cover this issue in the past (here) on Health Care Renewal.
Back in 2001, an infamous study was published in the Journal of the American Academy of Child and Adolescent Psychiatry that declared Glaxo’s [GlaxoSmithKline, GSK] Paxil antidepressant - called Seroxat in the UK - [paroxetine] was “generally well tolerated and effective for major depression in adolescents.” Known as study 329, the findings were used to widely promote the drug, which became a huge seller.
Of course, the study was later held in disrepute after it was learned the results didn’t tell the whole story. In fact, 329 was one of three studies cited by former New York Attorney General Eliot Spitzer, who filed a suit charging Glaxo with “repeated and persistent fraud,” alleging the drugmaker had promoted positive findings, but hadn’t publicized unfavorable data (back story).
As it turns out, study 329, ... already had a sordid history that included ghostwriting charges (here’s some background)....
Furthermore, we can now turn to the Clinical Psychology and Psychiatry Blog for an analysis of what is new about the study by Jureidini et al. The main points were -
The study report (in the Journal of the American Academy of Child and Adolescent Psychiatry) featured results of manipulation of the measures used to assess efficacy to make the drug appear more efficacious:
- Study 329 was designed to employ 8 measures of drug efficacy. It turned out that paroxetine was not statistically significantly superior to the comparator using any of these 8 measures.
- After the study was underway, the authors added a bunch of new measures, including new instruments, and modifications of instruments used in the original 8 measures. Only when using some of these new measures did the drug exhibit any efficacy.
To summarize how the Clinical Psychology and Psychiatry blog put it:
Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.
Worse, the study report simply omitted mention of the data that serious adverse events were more common in patients treated with paroxetine than with placebo, making the drug appear safer than it really may be. Jureidini et al noted that the following phrase,
worsening depression, emotional lability, headache, and hostility were considered related or possibly related to treatment
was omitted from the published report. Furthermore, per Jureidine et al,
Suicidal thoughts and behavior were grouped under the euphemism of 'emotional lability'
Yet the final JAACAP paper only stated,
Only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment
Jureidini et al concluded,
The published conclusions of study 329 and information provided by GSK to health professionals understated adverse effect rates and emphasized post-hoc measures that were not consistent with the unpublished, protocol-defined primary and secondary outcomes.
The article by Jureidini et al adds to our understanding of the various devious ways commercial sponsors of clinical research and the supposedly independent academic investigators who collaborate with them may manipulate the design, implementation, analysis and reporting of clinical studies to make the sponsors' products look better.
As we have said again and again, patients and physicians require the best possible information about benefits and harms of treatments to make the best decisions about such treatments. When those with vested interests in supporting a particular treatment distort the information available to make such decisions, they risk harming patients. In addition, manipulation of clinical studies violates the trust of study participants who thought they were taking part to advance science or health care.
The ongoing revelations about study 329 unfortunately remind doctors and patients who skeptical they must be about how well drugs and devices really are supported by clinical research. Combined with numerous other reports of manipulation and suppression of research, they suggest that:
- medicine, and particularly academic medicine ought to do a far better job of policing itself to ensure the integrity of clinical research
- pharmaceutical, biotechnology and device companies lead by businesspeople and lacking strong corporate cultures and explicit codes of conduct supporting ethical conduct may not deserve our trust
- government regulation of drug and device companies need to be far more stringent
- consideration ought to be given to require that all clinical research be conducted at true arm's length from organizations and people with vested interests in promoting particular products or services assessed by such research
As PharmaLot reported, "The latest study prompted a complaint concerning possible scientific misconduct to be leveled against study 329’s lead author, Martin Keller, a psychiatry professor at Brown University, by David Egilman, a clinical associate professor in community health at Brown. We are awaiting a reply from Keller and Brown provost David Kertzer, who was sent the complaint by Egilman. UPDATE: A Brown spokesman declines to comment."
As I noted in my previous blog post, I am currently on the voluntary faculty of Alpert Medical School of Brown University. I am a former full-time faculty member, and an undergraduate and medical school alumnus of Brown. I am saddened to see the ongoing damage to the reputation of the institution from this case. I do believe that Dr Egilman's complaint warrants full, open, and transparent investigation.