Study 329 – Update

Study 329

In 2012 Glaxo Smith Kline was found guilty of illegal marketing of 3 different drugs and fined $3 billion dollars (Google <DOJ vs GSK>). One of the drugs was Paxil (paroxetine), an antidepressant. Glaxo (then Smith Kline Beecham) had conducted three randomized controlled trials (RCT) of Paxil in the mid-1990’s for treating major depression in teenagers. All 3 studies showed that Paxil was no more effective than placebo on both primary and secondary end points and caused significant suicidal ideation in the depressed teens.

Glaxo selected one of the studies, S329, and hired a “ghostwriter” (Sally K. Laden, M.S. of Scientific Therapeutic Communications) to create the first draft of a paper from information supplied to her by Glaxo. Apparently using a reanalysis of the data from a few secondary endpoints, she concluded the paper stating that Paxil was “generally well-tolerated and effective for major depression in adolescents”. Twenty of the most prominent child psychopharmacology researchers signed onto the paper as co-authors, as well as two employees of Glaxo. After being rejected by the Journal of the American Medical Association, the paper was accepted and published by the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP). Reprints of the paper, with cover memos stating “REMARKABLE Efficacy and Safety in the treatment of adolescent depression”, were used by Glaxo sales representatives to convince individual physicians that Paxil was a good medication for adolescent depression. The prescriptions of Paxil for adolescents increased significantly in the years after publication. The Department of Justice, in its 2012 decision, found the paper to be “false and misleading”.

An international outcry from Australia, Europe, and the US followed the publication of S329/Paxil as people became aware that the paper was, in fact, dishonest in its conclusions. Papers were published in other journals condemning it and asking the Editor-in-Chief of JAACAP to retract the paper. Letters critical of the study were sent to the Editor of JAACAP and after publishing them in one issue, no further letters were published. JAACAP is the primary scientific journal that child and adolescent psychiatrists in the US and many other countries use to inform them of the latest research and to assist them in making difficult decisions to help their patients. The Editor who initially accepted and published the article refused to denounce or retract it, as has her successor.

Over the past two years the Executive Committees of the Northern and Central California Regional Organizations of Child and Adolescent Psychiatry unanimously sought to have the “false and misleading” article retracted. Requests to the current and immediate past presidents of AACAP were met, respectively, with a lecture about “editorial independence” and a dismissal: “I have talked with [the Editor] and he assures me [there is no cause for concern].” When we requested that the AACAP Ethics Committee investigate what is clearly a deceptive article and a flawed process, they replied that “Leadership” of AACAP had instructed them not to investigate this matter. Not one of the paper’s authors, including senior academic researchers and prominent members of AACAP, has stepped forward to defend it or to call for its retraction. Finally, when the current Editor-in-Chief of JAACAP spoke to the AACAP Assembly in October 2014 in justification of the article, he mentioned how much he had wrestled with the issue and suggested that there might be “other opinions”, but failed to address the above facts or acknowledge that the article’s conclusions are false.

Finally, the raw data of S329 was made available to and reanalyzed by a team of distinguished scholars and was published in September 2015 in the British Medical Journal with accompanying editorials. The reanalysis demonstrated that paroxetine was no more effective than placebo on all primary and secondary end points and that there was significant suicidal ideation with the medication vs. with placebo. Despite international calls for public retraction of the fallacious article, the leadership of AACAP, citing “a lack of authority” over the editor of JAACAP and simultaneously expressing their commitment to “transparency”, refused to demand its retraction. The editor of JAACAP, citing many agonizing and time-consuming efforts with the Committee On Publishing Ethics (COPE ), refused to retract the article.

What is happening? We cannot speculate and choose not to insinuate. But we can say that factually large amounts of money have been made by Glaxo in their sales of Paxil for adolescent depression. A clinical trials system that depends on pharmaceutical money to fund it is, as currently structured, too easily corrupted. Results of drug trials that show a drug is not effective are rarely published and available only with great effort. “Ghostwriting” of articles has been common. Since complete drug trial data has rarely been available for researchers to evaluate, the integrity of the entire body of scientific information about psychopharmaceuticals for children and adolescents is unknown.

The American Academy of Child and Adolescent Psychiatry has been a splendid advocate for children, a major source of education and information for consumers and practicing child psychiatrists, and the professional home for many of us and for the great majority of child and adolescent psychiatrists in the US and many from abroad. It is therefore very troubling to us that the organization has been unable and unwilling to investigate and transparently address such a profound violation of the treatment of children, of the trust of its 9000+ members, of the search for scientific truth, and of its own Mission Statement.

Allowing the Paxil/S329 article to stand in JAACAP is not “promoting the healthy development of children and adolescents” as stated in the AACAP Mission Statement. It is falsely promoting a pharmaceutical product for use in teens.

In addition, we have discovered that the organizational structure of AACAP does not include an adequate mechanism for holding our leadership accountable.

References: Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial Keller, M. et al JAACAP July 2013.

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence Jureidini, J. et al BMJ 2015; 351.

Department of Justice Settlement Fact Sheet (Google <DOJ vs. GSK>) 2012

Blog: <1boringoldman> by John “Mickey” Nardo, a child and adolescent psychiatrist, psychoanalyst, and determined and brilliant thinker in our field.

Endorsed by the Executive Committee of NC-ROCAP, 12.3.15

 

 

Ethical issues with s329 and AACAP

 

Dear Members,

 

We, your Executive Committee, want to keep you informed about major issues we’re working on, specifically with the Academy around ethical issues in science and publishing. 

A paper was published in JAACAP (Keller et al., 2001) stating the efficacy of paroxetine for major depression for adolescents. However, the data from the original study (Study 329) was altered by GlaxoSmithKlein. They hired a consultant ghost-writer that did not report serious side effects, nor the real result of paroxetine having no significant benefit. GSK was fined $3 billion by the Department of Justice, though the published papers from this data continue unchanged.
We at NC-ROCAP believe that research is integral to clinical practice and have taken action to ensure ethical standards.  We have:

• Corresponded with the AACAP Ethics Committee which was told by Leadership not to investigate this scandal.

• Corresponded with the Editor-in-Chief, Dr. Andres Martin, asking for his reasons for not retracting the fraudulent article. He did not respond to our inquiry nor one from Central California’s ROCAP

 

• Corresponded with the current AACAP President, who described the issue as one of “Editorial 

Independence” at the recent Assembly meeting. We believe it is one of “Editorial Integrity”.

 

• Passed an Action Statement at the Assembly, requesting that Dr. Martin explain to the October Assembly why he has chosen not to retract what the DoJ calls a “false and misleading article.”

 

• Sent a statement outlining the above to AACAP President Joshi, requesting transparency.

A newly written article is expected to be published soon in the British Medical Journal using the original, unaltered data of Study 329 which will confront us and the media with distinctly different versions of hte paper published in our Journal in 2001.  Although the paper has been challenged a number of times in the literature and severely criticized in court by the Attorney General of New York State and the Federal DOJ, it continues to be cited in the professional literature.

 

We are asking for the highest levels of our organization to take ethical actions to ensure the best care for our patients and to improve the public’s view of our profession.

 

Please contact me (Suzan Song, MD, MPH, PhD(c) at suzan.song@post.harvard.eduif you have questions or wish to be a part of this action.
Sincerely,
The Executive Committee of NC-ROCAP 

For additional information:

 

DEPARTMENT OF JUSTICE
GLAXOSMITHKLINE SETTLEMENT FACT SHEET
  •   GSK has agreed to plead guilty and pay $3 billion as part of this criminal and civil resolution.
  •   Largest combined federal and state health care fraud recovery in a single global resolution in the history of theUnited States.CRIMINAL RESOLUTION

 GSK has agreed to plead guilty to three misdemeanor violations of the Food, Drug and Cosmetic Act:

o Regarding Paxil, GSK will plead guilty to distribution of a misbranded drug due to false and misleading labeling, in violation of 21 U.S.C. §§ 331(a), 333(a)(1)

& 352(a).

o Regarding Wellbutrin, GSK will plead guilty to distribution of a misbranded drug due to inadequate directions for use, in violation of 21 U.S.C. §§ 331(a), 333(a)(1) & 352(f)(1).

o Regarding Avandia, GSK will plead guilty to failure to report data to the FDA, in violation of 21 U.S.C. §§ 331(e), 333(a)(1) & 355(k)(1).

 The information, filed in the District of Massachusetts, alleges that:

o Paxil

  • -  The FDA has never approved Paxil for any purpose for treating patients under age 18.
  • -  From 1999 to 2003, during sales calls, dinner meetings, spa programs, lavish weekend conferences to places such as Puerto Rico and Hawaii, through a false and misleading medical journal article, and through the distribution of free samples for patient use, GSK promoted Paxil to doctors for the treatment of depression and, to a lesser extent, obsessive-compulsive disorder in patients under age 18.

GSK conducted three placebo-controlled clinical studies to study Paxil’s safety and efficacy in treating depression in patients under age 18. In all three studies, GSK failed to demonstrate efficacy on the endpoints identified in the study protocols.

Nevertheless, GSK hired a contractor to write an article on one of the studies that was published in July 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP). The article stated that Paxil “is generally well tolerated and effective for major depression in adolescents.” The article did not explicitly state that the study failed to demonstrate efficacy on either of its two primary endpoints or on any of the secondary endpoints that had been identified in the study protocol.

GSK’s marketing team distributed the JAACAP article to all of the Paxil sales representatives with a cover memo that stated that Paxil had demonstrated “REMARKABLE Efficacy and Safety in the treatment of adolescent depression.” Some GSK sales representatives used the article to urge doctors to prescribe Paxil to treat patients under age 18.

GSK did not write a medical journal article about the other two unfavorable studies nor did it inform its sales representatives about the results of those studies.

 

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