Not until 2006: Lawsuit on interpretation of Paxil's suicide risk in drug trials

An inappropriate analysis of clinical trial data by researchers at GlaxoSmithKline obscured suicide risks associated with paroxetine, a profitable antidepressant, for 15 years, according to court documents released last month. Not until 2006 did GSK alert people to raised suicide risks associated with the drug, marketed as Paxil and Seroxat.

An analysis of internal GSK memos and reports, which were released to US lawyers seeking damages, suggests that the company had trial data demonstrating an eight-fold increase in suicide risk as early as 1989. Harvard University psychiatrist Joseph Glenmullen, who studied the papers for the lawyers, says it's "virtually impossible" that GSK simply misunderstood the data - a claim the company describes as "absolutely false."

Glenmullen's report rests on documents obtained by lawyers in Los Angeles, who are bringing around 30 cases against GSK linking suicides and suicide attempts to the use of Paxil. The report was under seal at a district court in Sacramento, California, until 18 January, when the judge agreed to make parts of it public.

The analysis focuses on the "washout" phase preceding a trial, when subjects stop taking most or all medications to avoid confusion with results from the trial itself. Because the washout occurs before patients randomly receive either the drug or the placebo control, adverse events during this time can't be attributable to the trial and so are seldom if ever included in final results.

However, GSK researchers submitting data on Paxil to the US Food and Drug Administration in the late 1980s and early 1990s included suicides and suicide attempts from the washout period in the results for the placebo arms of trials, but not from the Paxil arms. Glenmullen alleges that these extra "placebo" suicides negated suicides attributed to Paxil in the trials, making the drug appear safer than it really was. He says that if the washout results had been excluded, the data would have showed that Paxil increased eight-fold the risk of suicidal behaviour in adults.

GSK spokeswoman Mary Anne Rhyne says inclusion of the washout data "was intended to present the full picture of events that occurred in all phases of the clinical trials - starting from the time patients were enrolled, before they were randomised." She says that even without the washout data, Paxil still came out as safe as the placebo in this trial. She accused Glenmullen of incorrectly analysing the data to reach the opposite conclusion, but didn't respond to a request for numerical proof that Glenmullen's verdict was wrong.

Glenmullen suggests that the FDA would have acted differently had the use of the washout data been made more explicit. Rhyne says that material still under seal shows the FDA to be fully aware of how the washout data was being used. But Glenmullen quotes Martin Brecher, the FDA official who reviewed Paxil's safety, as agreeing during a pre-trial hearing that the use of the washout data was "scientifically illegitimate."

Independent researchers say it was wrong to use washout data as GSK did. "I can't imagine circumstances in which it would be appropriate," says Bruce Psaty of the University of Washington in Seattle.

Advice: Weigh the tradeoffs carefully in deciding whether to take antidepressants.

Browse for similar stories in our index at the very bottom of this page, or read an antidepressant adverse drug reaction story.

Thanks to Helen Haskell for sharing Jim Giles' source story in the Feb. 6 issue of the New Scientist.

It was all about money: Drug company incentive payments

David Olson was suicidal, in a hospital. His psychiatrist tried repeatedly to recruit him into clinical trials of a new drug. Indeed, drug companies paid his doctor thousands of dollars for each patient the doctor recruited. But David refused to be a test subject. His doctor discharged him from the hospital. David committed suicide two weeks later.

The state medical board found the doctor had “failed to appreciate the risks of taking Patient 46 off Clozaril, failed to respond appropriately to the patient’s rapid deterioration and virtually ignored the patient’s suicidality.”

David sister, Susie Olson, said the doctor “had no time for my brother unless David agreed to get into a drug study. He said, ‘You’re wasting my time and the hospital’s.’ It was all about money.”

This doctor was not a marginalized “bad apple.” He was the president of the Minnesota Psychiatric Society. Many other disciplined doctors also received thousands of dollars from drug companies. An analysis reported by Gardiner Harris and Janet Roberts in today’s New York Times found the drug makers gave a total of $1.7 million to 103 Minnesota doctors who had been formally disciplined by the state medical board, over the period from 1997 to 2005.

Advice: Before choosing a new doctor, ask the office manager if the doctor accepts money from drug companies.

Read another of our Minnesota stories on this topic.