GSK needs to Respond re Paxil Suicide Data: The Glenmullen Report

The New Scientist reports (below) that unsealed court documents--including an expert report by Harvard psychiatrist, Joseph Glenmullen, MD--reveal that GlaxoSmithKline knew as early as 1989 that there was an 8-fold increased risk of suicide for patients taking Paxil. Yet, the company did not acknowledge the risk to the public until 2006.

Dr. Glenmullen's analysis focuses on GSK's attributing suicides and suicide attempts during the "washout" phase preceding a trial, to the placebo--thereby misstating the findings.

The "washout" phase of a trial is 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.

But, Dr. Glenmullen found that the Paxil data submitted 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.

"GlaxoSmithKline's Paxil data in its earliest reports to the FDA in 1989 show a statistically significant, greater than eight-fold increased risk of suicidal behaviour - suicide and suicide attempts - for patients put on Paxil when compared to patients put on placebo (dummy) pills," he wrote. "Unfortunately, this demonstration of a causal link between Paxil and suicidal behaviour was obscured by GlaxoSmithKline's improperly reporting the data to the FDA, doctors, patients, and the public for over fifteen years."

His expert report was submitted by plaintiffs' attorney, Karen Barth Menzes, litigating on behalf of parents whose 13-year old son committed suicide in February 1997 after taking Paxil. In his report, Dr. Glenmullen concluded: "It is my opinion to a reasonable degree of medical probability that if GlaxoSmithKline had provided a warning all these years, Benjamin Bratt would still be alive today.". See, Dr. Glenmullen's report at: [Link]

Dr. Glenmullen's report confirms the opinion reached by psychiatrist Peter Breggin, MD, who submitted an expert report in another case in 2001. [Link]

These data manipulation revelations are in line with GSK's fraudulent concealment of Paxil's lack of efficacy in pediatric trials which led NYS Attorney General to sue GSK for fraudulent marketing. [Link]

On Feb. 6, Sen. Chuck Grassley sent a letter GlaxoSmithKline requesting, among other things, when the firm first knew of the drug's suicidality risk. He asked the company to state when it first reported Paxil's risk of suicide to FDA and when it first notified patients and physicians of the risk.

When informed that several pages from the Glenmullen report were withheld by the judge, Sen. Grassely requested the full report, noting that: "The public has a right to know what there is to know about this and other drugs."

THE NEW SCIENTIST
Did GSK trial data mask Paxil suicide risk?
8 February 2008

An inappropriate analysis of clinical trial data by researchers at GlaxoSmithKline obscured suicide risks associated with paroxetine, a profitable antidepressant, for 15 years, suggest court documents (897kb, requires Acrobat Reader) 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 eightfold 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.

Several pages from the report were withheld by the judge, but Chuck Grassely, a Republican senator for Iowa, wrote to GSK on 6 February asking that the missing sections be made public.

"With new questions about when GlaxoSmithKline knew about risks for suicidal behavior compared to when it let the public know about those risks, it seems like it'd be in the drug maker's best interest to provide every bit of information about this issue," said Grassely. "At this point, any sense that more information is being withheld only leads to more suspicion about what went on and what still might be going on. The public has a right to know what there is to know about this and other drugs." "Not until 2006 did GlaxoSmithKline alert people to raised suicide risks associated with Paxil/Seroxat"

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 eightfold 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.

See the "criminal" self investigation of GSK in the UK: 1463 days to Nothing
Also from It's quite an experience: Did GSK trial data mask Paxil suicide risk?
From seroxat secrets...: GlaxoSmithKline hid suicide risks in clinical trial data… what do you think?


From issue 2642 of New Scientist magazine, 06 February 2008, page 12

February 07 2008 Number 004
Paxil Product Liability Suit Gets Second Look From Sen. Grassley

Sen. Charles Grassley sent a letter Feb. 6 to GlaxoSmithKline asking the firm to answer several questions about Paxil and the risk of suicide, including when the firm first knew of the drug's suicidality risk.

Grassley, ranking member of the Senate Finance Committee, sent the letter to GSK President Christopher Viehbacher. It cited a Feb. 6 article in the New Scientist that discussed a report unsealed by the Judge in O'Neal v. SmithKline Beecham. The report claimed that GSK hid data that showed the drug increased the risk of suicide.

The author of the report, Joseph Glenmullen, a clinical instructor in psychiatry at Harvard Medical School, submitted the 74-page document to the plaintiffs' attorney in the case, Karen Barth Menzies.

"GlaxoSmithKline's Paxil data in its earliest reports to the FDA in 1989 show a statistically significant, greater than eight-fold increased risk of suicidal behaviour - suicide and suicide attempts - for patients put on Paxil when compared to patients put on placebo (dummy) pills," he wrote. "Unfortunately, this demonstration of a causal link between Paxil and suicidal behaviour was obscured by GlaxoSmithKline's improperly reporting the data to the FDA, doctors, patients, and the public for over fifteen years."

The plaintiffs in the case brought the suit after their 13-year old son committed suicide in February 1997. "It is my opinion to a reasonable degree of medical probability that if GlaxoSmithKline had provided a warning all these years, Benjamin Bratt would still be alive today," Glenmullen concluded in his report.

U.S. District Judge Frank Damrell Jr., of the Eastern District of California, disagreed. "Prior to February 1997, it is undisputed that the FDA had considered the issue of an increased risk of suicidality and SSRIs, including Paxil, and found that no causal relationship existed to merit a specific suicidality warning for adults or pediatric patients," Damrell said in a Jan. 30 order dismissing the case.

"It was not until 2004, seven years after Benjamin's death that the FDA required such a warning for pediatric patients; to date, no such warning is required for adults over the age of 24," Damrell continued. "Importantly, GSK had no obligation to include a warning for pediatric patients prior to February 1997 because there was no reasonable evidence of an association between the drug and suicidality in children and adolescents."

GSK dismissed Glenmullen's report as unscientific and misleading. "Dr. Glenmullen has carefully selected excerpts from GSK documents and made his own interpretations, without looking at the totality of the data," the company said in a statement. "Indeed, no medical or scientific association or regulatory body has adopted Dr. Glenmullen's methodology to look at the issue of suicidality and antidepressants."

Grassley, R-Iowa, told GSK to respond to his request by Feb. 14. He also asked the company to state when it first reported Paxil's risk of suicide to FDA and when it first notified patients and physicians of the risk. In addition, he requested Glenmullen's full report.

Approximately 100 lawsuits have been filed against GSK claiming Paxil caused homicidal or suicidal behaviour. In addition to the O'Neal suit, three other cases have been dismissed in district courts in California, Indiana and Kansas. In 2001 a Wyoming jury found that Paxil was responsible for a murder-suicide and awarded a family member $6.4 million.

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