The 20-Year Old Study that Shook Medicine

The controversy over clinical trial transparency exploded last week as the BMJ published a reanalysis of previously hidden data on an antidepressant drug called Paroxetine (or Paxil). Paxil was approved for adults in 1992 by the Food and Drug Administration (FDA), but its manufacturer, GlaxoSmithKline (GSK), wanted to expand its market to adolescents, and was able to do so on the basis of results from “Study 329,” a 2001 trial it funded involving 275 adolescents with major depression in which the drug appeared to be effective.

Study 329 compared Paxil, a selective serotonin reuptake inhibitor (SSRI) to imipramine, the first developed tricyclic (TCA) antidepressant, and a placebo. Major endpoints in Study 329 were patients’ reported feeling of depression using the Hamilton Rating Scale for Depression, a succinct questionnaire consisting of 21 questions. Study 329 concluded that Paxil was a safe and effective treatment for adolescents with depression; however, shortly after Paxil became a mainstream treatment for adolescent depression, patients began coming forward with claims of increased suicidal thoughts and tendencies.

Numerous lawsuits have been brought forward against GSK from families with children prescribed the drug, and almost a decade after Study 329 was published, GSK settled a case with the Department of Justice for $3 billion for recurrent incidences of adverse side effects in adolescents. Some speculate that Study 329 was ghostwritten to emphasize positive results and ignore negative results.

In response to the controversy, GSK released Study 329’s raw data in 2013, and it was reanalyzed by the RIAT (Restoring Invisible and Abandoned Trials) Initiative, an independent group of international researchers that strives to have investigators publish any abandoned or misreported trials. In their new analysis of Study 329, the “efficacy of paroxetine and imipramine was not statistically or clinically significantly different from the placebo for any […] efficacy outcome.” Moreover, RIAT researchers uncovered clinically significant increases in adverse effects, especially around suicidal ideation and behavior. The lead author of Study 329, Professor Emeritus Martin Keller of Brown University, along with eight other authors of the original publication have defended the original analysis.

Nevertheless, the controversy over Paxil has produced a cultural change at GSK—and one that has the capacity to transform pharmaceutical research and academic medicine. GSK was the first pharmaceutical company to endorse the AllTrials campaign, which calls for all clinical trials to be registered and all their results reported. The company has built a platform to enable researchers to access the results from previous clinical trials—and other companies such as Johnson & Johnson and Bristol Myers Squibb have developed similar data sharing projects with academic institutions. As Sir Iain Chalmers, coordinator of the James Lind Initiative and co-founder of AllTrials told that “GSK has shown moral and scientific leadership that puts to shame many in the academic community.”

“Among pharmaceutical companies, GSK under its current management has led the way in promoting clinical trial transparency and provides a practical mechanism to make trial re-analyses possible. The reanalysis of Study 329 illustrates the knowledge dividends from the company’s new policies and contrasts strikingly with the scientific misconduct that characterized the company’s behavior under previous management.”

Dr. Lauren Quattrochi, Director of the AllTrials campaign in the USA, acknowledged that “This is a prime example of why clinical trial transparency is a necessary facet when conducting research in patients.” The case of Paxil underlines the importance of impartial research analysis and reporting strategies. Unfortunately however, Study 329 from GSK is likely only one of many clinical trials of all the drugs currently on the market where unflattering or negative data has been left on the cutting room floor.

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