Did GSK trial data mask Paxil suicide risk?

From:

http://www.newscientist.com/channel/health/mental-health/mg19726424.600-did-gsk-trial-data-mask-paxil-suicide-risk.html

Did GSK trial data mask Paxil suicide risk?

by Jim Giles

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.”

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.

Lawmakers Catch Glaxo Hiding Paxil Suicide Risks – Again (Part II)

From:

http://www.lawyersandsettlements.com/articles/01961/paxil-suicide-risk2.html

February 13, 2008. 

By Evelyn Pringle

Washington, DC: Apparently, GlaxoSmithKline is still trying to hide damaging information about Paxil, because 9 pages of a report released from under a court order last month, are not available to the public. 

However, Senator Charles Grassley has instructed Glaxo to provide him with the full report by February 14, 2008. 

  Evelyn Pringle

In the report, which is dated roughly 6 months ago on June 29, 2007, Harvard Professor, Dr Joseph Glenmullen reveals that Glaxo had clinical trial data since 1989 which showed that Paxil increases the risk of suicide by more than 8-fold compared to patients who received a placebo. 

The report was submitted in O’Neal v Glaxo, a lawsuit filed in a California federal court by the surviving family members of Benjamin Bratt who committed suicide at age 13 while on Paxil. The family is represented by the California law firm of Baum, Hedlund, Aristei & Goldman. 

On January 30, 2008, the judge dismissed the case on the basis of the new preemption policy of the Bush Administration, but the family intends to ask the court to reconsider the ruling, according to Baum Hedlund. 

In his report, Dr Glenmullen also makes a plea for public disclosure of all information that remains sealed under court orders on the basis of Glaxo’s claim that the documents contain trade secrets and states: 

“Given the importance of GlaxoSmithKline’s internal documents, it is unfortunate that so many of the documents cited in this report and the attached Appendix are still confidential.” 

“Given the stakes for public health and safety, GlaxoSmithKline should not be permitted to claim the documents are proprietary trade secrets.” 

“All the documents should be made part of the public record so the full story of Paxil-induced suicidality can be told and the additional necessary steps can be taken to fully protect patients and the public.” 

Dr Glenmullen also mentions a companion report related to children and adolescents and a “Specific Causation Report” in the case of Benjamin Bratt, and Senator Grassley has instructed Glaxo to provide him with a copy of that report as well. 

In what can only be viewed as an eerily prophetic comment, in a letter back on September 16, 2004, to the Secretary of Health and Human Services, and the acting FDA Commissioner at the time, Senator Grassley warned: “I intend to keep the FDA’s feet to the fire to insure that the American public is knowledgeable about the risks of SSRI’s.” 

SSRI’s refer to antidepressants known as selective serotonin reuptake inhibitors that include Paxil, Eli Lilly’s Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs, along with their generic counterparts. Lilly’s Cymbalta, Wyeth’s Effexor and Glaxo’s Wellbutrin are often referred to as SSRI’s but they are slightly different chemically. However, the new antidepressants all carry the same warnings about the suicide risks. 

Senator Grassley’s letter followed the vote by an FDA advisory committee for a black box warning about the increased risk of suicide with kids to be added to the drugs’ labels. 

His angry tone, and not so subtle threat, was due to the fact that, during the advisory committee meeting, it became apparent that not only Glaxo, but all the SSRI makers, had concealed and misrepresented clinical trial data for years in the published medical literature which clearly indicated that there was an increased risk of suicidality with SSRI use. 

In fact, as soon as Glaxo’s was asked about the hidden studies by regulators in the UK, Glaxo issued a “Dear Doctor” letter to physicians in England saying Paxil should not be prescribed to children because it “failed” to work any better than a placebo and frequently caused “hostility, agitation, emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts, and attempted suicides.)” 

Glaxo did not issue any such warning to doctors in the US. 

The paper that garnered the most wrath from pharmacology experts all over the world was published in the July 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry on Paxil study 329, which was conducted from 1993 through to late 1995 or early 1996, according to a leading pharmacology expert, Dr David Healy. 

Twenty academics, considered to be the tops in their field, signed off on the study. The main authors of paper on the study were later found to be in constant contact with Glaxo when the media began reporting that the data published was fraudulent, and include Dr Martin Keller, Dr Neil Ryan and Dr Karen Wagner.

 

In the paper, the authors write: “Of the 11 patients only headache (one patient) was considered to be related to the treatment,” and Paxil is “generally well tolerated and effective.”

 

However, when the actual study was analyzed in 2003, it showed suicidal acts by 5 out of 93 children on Paxil compared to no suicidal acts in the 89 children who received placebo. 

On January 29, 2007, the BBC’s Panorama broadcast, “Secrets of the Drug Trials.” Attorney Karen Barth Menzies obtained many of the secret Paxil documents that were quoted during litigation, and she explained how Glaxo found ways “to blow up out of proportion the supposed benefits in Study 329 and downplayed the negative findings.” 

Glaxo recruited the opinion leaders to put their names on the published 329 study, she said, because they were academics whom everybody looked up to, and the company knew that doctors would be far more likely to prescribe Paxil after listening to these doctors than they would be if approached by Glaxo salespersons.

 

One letter that was quoted, revealed that these so-called opinion leaders never even wrote a paper. The letter was from a ghost writer to Dr Keller, informing him that all the necessary materials were enclosed for him to submit the study to a journal for publication. The packet even included a cover letter, with instructions telling Dr Keller to: “please re-type on your letterhead. Revise if you wish.” 

Dr Wagner, along with Dr Graham Emslie, was also responsible for publishing papers on studies that resulted in Prozac’s approval for children, and Dr Wagner and Dr Keller were also investigators on Zoloft studies and several of the unpublished Paxil studies. 

In the October 4, 1999 Boston Globe, Alison Bass reported that in 1998, as a professor at Brown University, Dr Keller was forced to forfeit “hundreds of thousands of dollars” in state grant money and was paid more than $500,000 in consulting fees in 1998, most of it from companies whose drugs he touted in medical journals and at conferences.

In the report, Ms Bass pointed out that Keller was a valuable resource for the University, and had brought in about $14.4 million in research funding from drug companies and federal agencies since 1993. 

According to the report, in 1998, the year Keller published 3 studies with colleagues in the Journal of the American Medical Association and the Journal of Clinical Psychiatry touting the efficacy of Zoloft, he received $218,000 in personal income and more than $3 million in research funding from Zoloft maker Pfizer.

Several ethicists contacted by the Globe said Keller’s unusually large consulting fees, a total of $556,000 in 1998 and $444,000 in 1997, constitute the most serious potential conflict they’ve heard of yet, Ms Bass noted. 

Dr Wagner received an onslaught of criticism from experts all over the world when she misrepresented trial data in a paper on Zoloft, claiming it was safe and effective for use with children. On November 29, 2004, Barry Meier wrote, “Contracts Keep Drug Research Out of Reach,” in the New York Times, and reported that over the past decade, Dr Wagner from the University of Texas Medical Center in Galveston had led or worked on some 20 studies published in medical journals and had also “attracted a large number of industry-financed studies, including those aimed at testing whether antidepressants approved for use in adults were safe and effective in children and adolescents.”

In a financial filing with the university in December 1999, Mr Meier found the same month that a Zoloft trial began recruiting patients, Dr Wagner disclosed that she had received more than $10,000 from Pfizer but she did not provide details. 

She also did not respond to written questions about the payments but a lawyer for the school, told Mr Meier that Dr Wagner had told him that Pfizer had paid her $20,500 during the course of the Zoloft trial. 

Mr Meier also noted that academic researchers routinely receive speaking and consulting fees from companies whose products they test and at Galveston the financial threshold for such a review is $10,000. But the school lawyer, told Mr Meier that the center had been unable to locate records related to Pfizer’s payments to Dr Wagner.

Glaxo’s study 329 was successfully used to promote Paxil for children, and sales to kids skyrocketed to $55 million in 2002 alone. It also served as the smoking gun in a lawsuit filed against Glaxo by New York Attorney Elliot Spitzer, charging Glaxo with fraud for promoting the off-label use of Paxil to children while concealing and misrepresenting the data from 5 studies that showed the increased suicide risks and the fact that Paxil did not work with children. Glaxo settled out of court to shut that lawsuit down within 2 months. 

In 2003, after reviewing the same fraudulent studies, the UK banned the use of Paxil with children, and the FDA scheduled an advisory committee meeting in February 2004 to review the data on all SSRI’s. 

In response to the announcements by the regulatory agencies, the American College of Neuropsychopharmacology (ACNP), which designated a Task Force in the early 1990’s to review the SSRI trial data, and subsequently published an position paper saying SSRI’s were not linked to suicide, appointed a new Task Force in September 2003, to study the matter again.

 

This Task Force was made up of many of the same authors whose published papers were under attack for being fraudulent and included Dr John Mann, Dr Graham Emslie, Dr Karen Wagner, Dr Neal Ryan, Dr Andrew Leon, Dr Fredrick Goodwin, Dr David Shaffer, Dr Beardslee, Dr Jan Fawcett, Dr Herbert Meltzer and Dr Ross Baldessarini. 

Two weeks before the advisory committee meeting, the Task Force issued a report, once again claiming SSRI’s did not cause suicide, and began making what many experts condemned as preemptive statements in the media to influence the advisory committee to vote against adding a warning about the risk of suicide to SSRI labels. 

On January 21, 2007, WebMd’s headline on the internet stated: “Group Finds No Suicide-Antidepressant Link”. 

“Our conclusion is that when you look at the SSRI’s as a group, there is evidence they are effective for treating depression in children and adolescents,” Dr Mann told WebMD. 

“Instead of being a risk for suicidal behavior, they are potentially therapeutic,” he stated.

 

In fact, the $30-million Dr Mann, who admitted under oath in a jury trial that it was possible that he got over $30 million in research funding from drug companies over a 10-year period, said the group found strong evidence that SSRI’s help depressed kids and that suicide rates started going down when SSRI’s became available. 

He claimed that a 14-year study showed a decline in suicide rates in kids. “Across 15 countries there has been a 33% decline in suicide rates amongst youths,” he told WebMD. 

“Doctors must go on treating depression, and SSRI’s appear to be a reasonable choice,” he stated. 

The FDA even allowed Task Force members Dr Andrew Leon and Dr Neil Ryan to participate as voting members of the February 2, 2004 advisory panel. 

The day after a September 2004 advisory committee finally voted to add a black box warning to the SSRI labels, on September 14, 2004, Senator Grassley issued a press release stating that the FDA “needs to learn an important lesson from what’s developed this year on the matter of kids and antidepressants.” 

“Transparency in government is the best policy,” he noted. “Parents and doctors should not be left in the dark, and especially when information that’s available could be a matter of life and death.”

 

“Given the scientific findings,” he added, “it’s obvious that the strongest label warning for this class of drugs is critically important for the health and safety of young Americans.” 

“These measures are especially critical,” he said, “since I also understand from previously released studies and from the Advisory Committee’s own deliberations that only one of the nine antidepressant drugs has been proven to provide any benefit to children and adolescents.” 

“In fact,” he pointed out, “in almost all cases, the FDA’s own data demonstrates that these drugs actually perform no better than do placebos.” 

In a September 16, 2004, letter, Senator Grassley asked the FDA to “very quickly and fully consider” the recommendations for the black box and med guides, “before the lives of more children are needlessly lost because parents and others lack adequate, readily understandable information when they most need it.” 

He also brought up the issue of informed consent and said he was curious about the FDA’s rationale for not requiring doctors to provide a clear, informed consent document that parents must read, understand and sign before accepting a prescription, as the FDA had done with the drug Lotronex, due to a 1 in 300 risk of ischemic colitis in patients. 

In the case of antidepressants, Senator Grassley pointed out, “a suicide-related event involving Prozac (fluoxetine) is about 1 in 15 according to the TADS study, and about 1 in 30 for all SSRI’s, according to FDA’s own study.” 

The letter said that the informed consent form should at least include the following points: (1) Only Prozac has been shown to be effective in treating depression in children and adolescents, and is the only drug approved for this; (2) All others have been shown to be no different than a placebo, and their use in the treatment of children and adolescents is not an approved use; (3) All antidepressants increase the risk of suicidality, and (4) The risk of a suicide event (planned or actually attempted) is one for every 15 to 30 children and adolescents taking the antidepressant. 

Senator Grassley also asked what the FDA planned to do about educating doctors and the public about the risk-benefits of antidepressants, especially in children. Obviously, the short answer to that question more than three years later is, not a thing. 

In fact, in the January 17, 2008, Wall Street Journal, David Armstrong and Keith Winstein reported that, “the effectiveness of a dozen popular antidepressants has been exaggerated by selective publication of favorable results, according to a review of unpublished data submitted to the Food and Drug Administration.” 

“As a result,” they wrote, “doctors and patients are getting a distorted view of how well blockbuster antidepressants like Wyeth’s Effexor and Pfizer Inc.’s Zoloft really work,” in discussing research led by Erick Turner, a psychiatrist at Oregon Health & Science University, published in a study in New England Journal of Medicine. 

They also point out that sales of antidepressants total about $21 billion a year. 

In all the studies, old and new, which promote the off-label sale of SSRI’s for children with claims that the drugs work and do not cause suicide, almost without fail, the same names appear as investigators and authors. A complete listing includes Dr John Mann, Dr Martin Keller, Dr Graham Emslie, Dr Frederick Goodwin, Dr Karen Wagner, Dr Neal Ryan, Dr Charles Nemeroff, Dr David Dunner, Dr Andrew Leon, Dr John March, Dr David Shaffer, Dr John Rush, Dr Mark Olfson and Dr Robert Gibbons. 

This time around, in addition to going after Glaxo for concealing and misrepresenting the data that showed an 8-fold increased risk of suicide, somebody needs to take the bull by the horns and see to it that these industry-funded quacks get thrown in the slammer. 

It’s also more than apparent that a few FDA officials belong there as well.

 

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a ‘fair use’ of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit.

The information herein shall not be considered an endorsement of anyone discontinuing psychiatric drugs. If you are stopping taking medication it is advisable to reduce the dose gradually WITH EXTREME CAUTION, as it is difficult to predict who will have problems withdrawing. It is worth getting as much information and support as you can, and involving your doctor wherever possible. You will find withdrawal information here:                                 

One response to this post.

  1. I just wanted to drop in and say that you certainly offer a very interesting look at this. Thanks for your time.

    Reply

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