In this piece in the British Medical Journal, Peter Doshi summarizes a history that already fills volumes in a short article with supplementary documents. I’ve snipped out some highlights, but I’d suggest reading it in toto. One rarely gets such a full story in such a small place. I’ll jump straight to the punch line. If you want things to be done above board – you have to model that same behavior. In working on republishing the infamous Paxil Study 329, the RIAT team doesn’t want any secrets of its own. There’s really nothing about the Clinical Trials of drugs that justifies secrecy in the first place. Of course, subject confidentiality is an an issue, but it’s easily managed. The stakes in terms of how many people might end up taking the medication studied justify as complete a body of information as possible. That’s what AllTrials is aiming for. That’s what RIAT proposes to insure. That’s what our patients deserve. No secrets. No loopholes. And that’s true for the group trying to vet Paxil Study 329:
by Peter DoshiBritish Medical Journal 2013 347:f6754.
When the Journal of the American Academy of Child and Adolescent Psychiatry [JAACAP] published study 329 in 2001, its editors could have had no idea that the paper would spark a controversy, not only about the use of the antidepressant paroxetine in children but also about secrecy in clinical trials. It is a controversy that rages to this day and that goes to the heart of recent campaigns to gain access to drug companies’ trial data. But one group’s request for data is testing the limits of GSK’s commitment to full transparency. Jon Jureidini, clinical professor of psychiatry at the University of Adelaide, is leading a team to reanalyse and republish the results of GSK’s study 329 — a randomised, double blind, placebo controlled trial of paroxetine for the treatment of depression in adolescents. For over a decade, Jureidini has been critical of how the study was reported in JAACAP in 2001. In 2003, Jureidini and Tonkin wrote to JAACAP: “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.” They noted that “on neither of [the study’s two primary outcome] measures did paroxetine differ significantly from placebo” — yet the Keller et al paper concluded that “paroxetine is generally well tolerated and effective for major depression in adolescents”…
If you’re reading this blog, you know this story – a paper published in a major journal that took trivial, nonsignificant differences from a trial and presented them as clinically meaningful. The GSK/SKB product managers took the article’s already unsupportable claims ["paroxetine is generally well tolerated and effective for major depression in adolescents"] and magnified them further:
Jureidini and colleagues have led a long campaign to compel the journal to correct or retract the article, which was authored by both academics and GSK employees. Earlier this year, Jureidini presented GSK’s chief executive, Andrew Witty, with a final plea to help correct the scientific record. “Your corporation has so far failed to take responsibility for a published report that has harmed young patients who were prescribed paroxetine on the basis of this misleading article. As the CEO of GSK, you have the opportunity to correct the scientific record. I respectfully urge you to do so,” Jureidini wrote [see data supplement on bmj.com]. But GSK defended the integrity of the 2001 publication. “GSK does not agree that the article is false, fraudulent or misleading,” John E Kraus, head of medical governance, wrote to Jureidini…
This was after a decade long attempt to get someone to retract the article by appealing to the journal, authors, sponsoring universities, the pharmaceutical company, the NIMH, etc. When the RIAT process was announced, Paxil Study 329 was an obvious choice. The court had ordered the data posted. It finally fully appeared in August 2012 after the $3 B settlement which featured this article against GSK:
Jureidini has responded by assembling a team to reanalyse and republish study 329. In July they publicly declared their intention to produce a new journal report of study 329, written in accordance with the BMJ endorsed restoring invisible and abandoned trials [RIAT] initiative, which calls for third party authors to publish or republish unpublished and misreported clinical trials. The team’s starting place is a trove of over 6000 pages from a previously internal clinical study report written by SmithKline Beecham in 1998 that was forced into the public domain as a condition of a consent order GlaxoSmithKline agreed to in the settlement of a 2004 lawsuit with the New York State Attorney General. The pages include a report of the trial, the study protocol, statistical analysis plan, blank case report forms, and numerous data tables, which Jureidini’s team will use for its analysis. But GSK’s public posting of its internal report on study 329 is incomplete, lacking an unknown number of pages containing original case report forms from Appendix H. Jureidini and colleagues have therefore asked GSK for access to the deidentified case report forms and the corresponding deidentified electronic participant level data, “so that we can restore the publication of trial 329 in a fair, complete and publicly transparent way”…
This is not a rhetorical point – some power struggle over how transparent is transparent. There’s a big controversy over the adverse effects of SSRIs in kids – hostility, agitation, suicidal thoughts, etc. These things are neither in numbers on a questionnaire nor in one liners on a print-out, they’re sentences and paragraphs written by the clinicians who saw the kids and saw what happened – they’re in case studies. What does Paxil Study 329 tell us about these questions? The answers are in the those Case Report Forms, and they’re redacted in full. So this exchange of letters documents the quest to see those notes in person. It’s the research in this enterprise:
[see letters]
And Peter Doshi has published the primary documents involved. If the RIAT team wants full disclosure of primary documents, the negotiations need to show too:
There is a certain irony in the story of study 329 and its 2001 publication in JAACAP. In a letter to Jureidini, GSK explained that the JAACAP publication “was subjected to peer review on three occasions” and “accurately reflects the honestly-held views of the clinical investigator authors.” But a more pertinent question is whether the published article accurately reflects the trial. In their most recent letter to GSK, Jureidini and his colleagues reiterate their need for the study 329 case report forms and their intention to analyse study 329 “following the original analytic plan.” As such, Jureidini’s team’s efforts to independently analyse and publish the results of study 329 can be viewed as perhaps the most “responsible” of all analyses—and one that it seems may yet overturn the JAACAP publication that GSK continues to defend.
From my perspective, the AllTrials campaign and the general cry for data transparency aim to head off the secrecy that has allowed this kind of thing to happen – "All Trials Registered | All Results Reported." The RIAT Project aims to independently publish trials that have gone unpublished, and to republish discredited studies that have not been retracted, re-examined, or corrected "Restoring invisible and abandoned trials." Together, these are ways the scientific medical community can insist that our academic literature remains truly scientific going in both directions in time. Medicine, Science, and academic enterprises have traditionally been self-policing, part of holding a higher standard than in most other areas. That process also needs to be self-correcting when things have gotten off-track. These efforts are the essence of how that should work…
All I can say is thank God for people like Jureidini.