Posted on Thursday 16 October 2014
by Carlo Carandang, Rekha Jabbal, Angela MacBride, and Dean ElbeJournal of the Canadian Academy of Child and Adolescent Psychiatry. 2011 20: 315–324.
FDA Approval Process & Legal Action
While only one RCT for escitalopram was statistically superior to placebo on the primary outcome measure, according to Forest Laboratories, Inc. [US manufacturer of Lexapro] the FDA decision to approve escitalopram was based on two RCTs – the escitalopram RCT with positive results and an earlier trial with citalopram. “Escitalopram is the only active enantiomer of the racemic drug citalopram, so we considered it reasonable to [deem] the positive citalopram study along with the positive escitalopram study as sufficient evidence to support the approval,” said Karen Mahoney, an FDA spokesperson. A 2002 application for a pediatric indication for citalopram had previously been rejected by the FDA, and the US patent for citalopram expired in 2003.
The FDA approval decision for escitalopram came shortly after filing of a federal civil suit alleging Forest Laboratories, Inc. had illegally marketed escitalopram and citalopram for off-label use in children and adolescents from 1998 to 2005. The suit also alleged the company suppressed publication of a negative citalopram trial, and reports of increased suicidality in pediatric patients. This lawsuit was joined with another lawsuit regarding another Forest Laboratories, Inc. product levothyroxine, and was eventually settled in September 2010 for the sum of $149 million.The citalopram trial [Wagner et al., 2004] that formed part of the basis for escitalopram FDA approval was alleged to have been written and submitted by a medical “ghost-writer” on behalf of Forest Laboratories, Inc. In April 2009, one month after the FDA approval for escitalopram in adolescents was granted, Forest Laboratories, Inc. admitted that a medical communications company, Prescott Medical Communications Group was not acknowledged as a contributor to the article at the time of publication. This practice is not allowed by the American Journal of Psychiatry, and an editor’s note regarding correction of this matter was published in August 2009…
At this point, I will admit that I had lost interest in my initial quest [FDA Approval of Celexa/Lexapro] because I’d run across something that was far more interesting. So let’s start over. The new topic is the 2009 Editor’s Note in the American Journal of Psychiatry about their earlier 2004 article on Celexa:
The article "A Randomized, Placebo-Controlled Trial of Cilalopram for the Treatment of Major Depression in Children and Adolescents," published in the June 2004 issue of The American Journal of Psychiatry [vol. 161, pp 1079-1083] is alleged by the United States Department of Justice in an ongoing suit to have been written and submitted to the Journal by a commercial medical writer on behalf of Forest Laboratories, Inc.
We requested responses from Drs. Karen Dineen Wagner, Adelaide S. Robb, and Robert L Findling [authors in their role as investigators in the clinical trial at their respective universities], Dr. William E. Heydom [the senior Forest laboratories study director], and Forest laboratories. Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts, This paper was submitted as a Brief Report, which the Journal’s editors requested be resubmitted as a full-length Article. Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.
A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. Hie manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."
We are satisfied that the named contributors of this article satisfy the criteria for authorship as set forth in the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" from the International Committee of Medical Journal Editors. However, the Journal’s Instructions to the Authors in 2004 and our policy today do not allow contributions by unnamed writers to the preparation of a paper. Thus, the editorial contributions of Prescott Medical Communications Croup should have been acknowledged in the published article as required at the time the article was published.
Furthermore, Forest Laboratories failed to disclose to the Journal that it was aware of data from a study by Lundbeck that showed increased suicidality in children and adolescents who were treated with citalopram. Authors and sponsors are expected to disclose the existence of all data that affects the interpretation of their study. This note will appear in Medline and other databases as a Comment on the paper.
The official complaint [United States and Christopher R. Gobble v. Forest Laboratories Inc. and Forest Pharmaceuticals Inc. Civil Action No. 03-10395-NMG] is posted at …
Robert Freedman, M.D.
Michael D. Roy
|American Journal of Psychiatry. 2009 166:942-943.|
I’d never seen this before. It’s like a picture window into how much competition there was for the adolescent depression market, and how corrupt the whole enterprise had become. While we can respect Editor Robert Freedman for publishing this Editor’s Note, his certification of authorship is, of course, a sham – as is Dr. Wagner’s claim that she knew nothing of the ghost authoring. In the first place, the paper was presented to her already drafted. Whether it was written by Forest senior study director Dr. William Heydorn or someone else, it certainly wasn’t Wagner’s or her co-investigator’s work. And since she was in the author role in multiple other ghost-written trial reports at that time, her claim of naïveté about hired professional writers holds no water. She was everywhere in those days – Paxil, Prozac, Zoloft, Celexa – an author on each of these of ghost-written journal articles – all four claiming efficacy and safety in depressed adolescents for their respective drug:
2001: Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial. "Paroxetine is generally well tolerated and effective for major depression in adolescents."by Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, and McCafferty JP
2002: Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial. "Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression."by Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG
2003: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. "…sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD."by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
2004: A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. "…treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated."by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, and Heydorn WE
As for the specific suit that brought this particular bit of ghost-writing into the public eye? The case against Forest Laboratories ultimately settled [see September 15, 2010: Drug Maker Forest Pleads Guilty: Will Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations]. But even in this instance where the ghost-writing was exposed and admitted, the American Journal of Psychiatry, official journal of the American Psychiatric Association, chose to collude with the fiction that the academics on the by-line were genuine authors, and the journal left the study in place.
The American Psychiatric Association seems to be poised to engineer yet another identity shift in psychiatry [the prequel…, anything but over…, the sequel I…], apparently intending to proceed without acknowledging the misadventures of the last makeover, without participating in the reform efforts like Data Transparency or revised Conflict of Interest policies, without correcting or at least flagging the large fiction sections of our journal libraries. The American Academy of Child and Adolescent Psychiatry meeting in San Diego next week appears to be moving along the same silent path. Beside the obvious moral and ethical tangles involved, it seems to me that there’s an enduring liability being assumed by the professional organizations, the academic community, and our peer reviewed journals when they incorporate this attitude of denial and rationalization. The active participants in the deceit and corruption that accompanied the industrial invasion of academic and organized psychiatry actually represented only a segment of psychiatrists, albeit a segment in high places. Many of their names are already on this page, most are cataloged throughout this blog. And while too many in the specialty followed their lead, it was also the only major highway open to traffic, and it’s easy to forget how little many of us knew of this before the last six or seven years. That’s not intended as an excuse, but rather a commentary on the state of play.