posted here with the permission of the authors…
Forest Laboratories’ study CIT-MD-18 of citalopram was conducted between 1999-2002. It was a 9-week, 20 site, randomised double-blind comparison of the safety and efficacy of citalopram to placebo in children (aged 7-11) and adolescents (aged 12-17) with major depressive disorder. A report of the study was published as ‘A randomised, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents’ in the American Journal of Psychiatry, as part of Forest’s marketing strategy to promote the use of citalopram [A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents]. In 2009 Forest Laboratories received FDA approval for escitalopram in the treatment of adolescent depression on the basis of the SCT-MD-32 trial of escitalopram and the allegedly positive CIT-MD-18 trial of citalopram.
The American Journal of Psychiatry paper was published with a by-line of three academics (Wagner KD, Robb AS, Findling RL) and three Forest employees (Jin J, Gutierrez MM, and Heydorn WE), but none of the named ‘authors’ on this paper including Dr Wagner (current President-Elect of the American Academy of Child and Adolescent Psychiatry) played a role in drafting the manuscript, which was written by ‘medical writers’ working for the medical communication companies, Weber Shandwick and Prescott Medical Communications, under the direction Forest’s Product Manager Mr. Jeffrey Lawrence. There is no evidence that Dr Wagner or the other academic ‘authors’ contributed substantially to study design or data analysis.
The paper attributed to Wagner et al. concluded that citalopram was significantly more efficacious than placebo for both children and adolescents, and that no serious adverse events were reported. However, marginal statistical significance was only achieved by including eight of nine unblinded subjects, who should have been excluded according to standard practice and the explicit requirements of the study protocol. Also, they withheld information about another trial of citalopram (Study 94404) that had been carried out by the Danish manufacturer of citalopram, Lundbeck, and had already concluded that citalopram was non-efficacious in adolescents, and also increased suicidality in both children and adolescents.
Furthermore, they made claims of comparable rates of tolerability when more citalopram patients developed dangerous states of over-arousal such as hypomania, agitation and akathisia, which led to the patients discontinuing the drug.
Here we provide a review of our difficulties in publishing our paper.
Contrary to the commonly-held belief that medical journals are trusted repositories for reliable medical information, it is extremely difficult to publish criticism of misleading, false and fraudulent reports of pharmaceutical industry-sponsored research. Even the most well respected medical journals have serious conflicts of interest when considering articles that attempt to set straight the scientific record. (See for example, Healy ‘Our Censored Journals‘, Mens Sana Monographs, 2008;6:244-256; Jureidini & McHenry ‘Conflicted Medical Journals and the Failure of Trust‘, Accountability in Research, 2011;18:45-54.) Medical journals are reliant on substantial income derived from reprint orders, pharmaceutical advertisements, grants for continuing medical education as well as other forms of financial support when they the publish industry trials. This influences editorial decisions and conflicts with the journals’ primary mission to publish information that can be relied upon by healthcare practitioners and healthcare policy makers.
As with the case of our attempts to publish criticism of another case of serious misreporting the results of a pediatric depression trial, the now-infamous study 329, we spent over a year with five submissions and rejections before we published this paper. The Journal of Affective Disorders declined to review our paper. Our paper was then rejected by the editorial staff of JAMA Psychiatry without peer review.
| Response from Stephan Heckers [Editor, JAMA Psychiatry
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RE: The Citalopram CIT-MD-18 Pediatric Depression Trial: A Deconstruction of Medical Ghostwriting, Data Misrepresentation and Academic Malfeasance
Dear Dr. Amsterdam: Your article on the publication of the CIT-MD-18 pediatric depression trial is of considerable interest, but is not a good fit for JAMA Psychiatry. The results are primarily descriptive/investigative and do not lend themselves to the inferences we usually draw from scientific studies. Furthermore, much of the material is in the public domain and can be found, without further data analysis, by the educated reader… Stephan Heckers, MD
Editor
JAMA Psychiatry
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Our next two submissions received positive peer reviews that were trumped by editors and publishers with ties to the financial interests of pharmaceutical companies.
First the editor of the Journal of Clinical Psychopharmacology, David Greenblatt, who has significant entanglements with Forest among other pharmaceutical companies, offered us the superficially attractive possibility of a guest editorial. But the devil was in the detail as he requested changes not asked for in the positive peer reviews:
| Initial response from Dr. Greenblatt [Editor of the Journal of Clinical Psychopharmacology]
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We would like to reconsider a revised version of your manuscript in the form of a "Guest Editorial". However quite a bit of work will be needed — to be described below.
Let us first mention some points regarding the overall outlook of the Journal of Clinical Psychopharmacology. We do not share your concerns about what you term "ghostwriting" — more properly described as manuscript preparation assistance. This is just another form of assistance or collaborative effort in the course of research — similar to technical assistance with measurement of plasma drug levels, or statistical consultant input in analysis of data. In the end, the listed authors take responsibility for the content of the manuscript, and that is what matters. We also are not worried about the participation of the pharmaceutical manufacturer in the execution of the study, or the preparation of the manuscript. This is to be expected — they are the sponsors, and they have the most knowledge about the candidate drug and the data. Finally, we are not interested in the litigation. Whatever is going on in the courts will proceed according to that process. [We also note that we ARE concerned that you are serving as a reimbursed expert witness on behalf of the plaintiffs, proposing in the present manuscript what we expect are similar arguments as presented in the context of the litigation. With all of that said, we certainly could reconsider a revised manuscript in which the focus was ONLY on the scientific content of the paper(s) in question. If you disagree with the scientific content or its interpretation, that can be presented, but without the court documents and internal E-mails, and without accusations of malfeasance, misrepresentation, manipulation, whitewashing, complicity, etc. The issue of manuscript preparation assistance is also not in the picture. We hope that you will elect to go this route. Should your revised manuscript be acceptable for publication, we will invite Dr. Wagner and/or Forest Laboratories to submit a response.
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We did not take up Dr Greenblatt’s offer, instead writing to him:
| Response to Dr. Greenblatt [Editor Journal of Clinical Psychopharmacology]
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We are grateful that you have openly articulated an editorial position that we believe is prevalent, but mostly unstated. We disagree strongly with your position, believing that the legal and ethical facts that we presented are essential to understanding the full context of how industry-sponsored clinical trials can misrepresent the data to the medical community. In our view, if medical journals are to achieve scientific status, they cannot censor legitimate criticism for fear of offending the pharmaceutical industry. Any attempt to edit out this content condones scientific misconduct and betrays patients who are damaged by the misreporting of clinical research published in the journals. Therefore we are not inclined to make the changes that you are requesting.
However we do seek your response to a number of points. First, we note that all three reports from peer review were positive and supportive of publication of our paper with only a few minor suggestions for revision. Your decision not to accept our manuscript as a full-length, peer-reviewed research article is certainly at odds with these reviewer’s opinions. Can you explain why you overruled your reviewers? Second, we respectfully disagree with your characterization of ghostwriting as merely being “manuscript preparation assistance.” We agree that if it were, there might be a plausible argument for its use. However the problem of ghostwriting as facilitating the misreporting of data is well documented in the medical and bioethics literature since the late 1990s. We have ourselves contributed numerous articles on the subject. In the present case of Forest and their hired PR firm, Prescott, the spin on the data is well documented and undeniable in the email correspondence that has been de-designated as confidential by the court. If you have another look at our paper, you will find that in Forest’s marketing plan, they explicitly use the term "ghostwritten" to characterize their effort to use thought leaders as academic facades for industry marketing. (p. 6) Do you support a distinction between writing assistance to a legitimate chief investigator and a ghostwriter employed to present the sponsor’s drug’s profile in the most positive light, even if that means lying? Third, we also believe you are mistaken in your view that the authors take responsibility for the content of the manuscript. As you are no doubt aware, the data and the manuscript are the intellectual property of the sponsor company and the latter is only released to the "lead author" by the company’s legal department at the point of submission. In the cases that we have investigated, very few of the academics named on the papers contributed any significant writing or editing of the manuscripts nor did any of them have access to the data. The ghostwriter works from a clinical summary of the data provided by the sponsor company. Can you specify what constitutes adequate oversight by the named authors? Fourth, we stand by our evaluation that this is not only scientific misconduct by the sponsor company, but academic malfeasance. We took on the burden to study the protocol, the study report and the published paper. In our view, the academics named on the paper were negligent in their failure to do the same. The most perfunctory effort on their part would have revealed serious problems with the ghostwriter’s manuscript. Can you say what additional evidence would be required to demonstrate malfeasance? Fifth, you claim that you have no interest in the litigation, but it is only from the discovery process of litigation that the confidential documents and the full clinical data are made available to medical experts for analysis and evaluation. Without litigation, the academic community and the public at large would remain in the dark about the misreporting of the science that guides the prescribing habits of doctors. In the particular case of Citalopram CIT-MD-18, this negative trial was misrepresented as positive to gain a license for escitalopram in adolescent depression. This requires a remedy beyond litigation. Can you explain why you think it is not in the public interest to analyse data only available through litigation? Finally, as you well know, modern science depends in great measure on public disclosure of the studies and the data that support the conclusions. Equally, science advances through the public debate of those studies, including rigorous criticism. The exposure of bad science is at least as important as publication of well-supported science. What is often concealed is the criteria and reasoning behind peer review journals such as yours in making editorial and publication decisions. Those who read medical journals need to know why a manuscript that received favorable peer reviews has been rejected for publication. In light of this, we enlist your participation in the latter aspect of this important public conversation.
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Dr Greenblatt replied:
| Final response from Dr. Greenblatt [Editor of the Journal of Clinical Psychopharmacology]
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Thank you for your thoughtful letter of May 14. We understand your position on this matter. We don’t have anything to add beyond what was expressed in our communication of May 5. We do hope that you will elect to proceed with a revised manuscript based on the content of our May 5 letter.
Best regards and thanks for submitting your work to the Journal.
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We then resubmitted a revised paper to Acta Psychiatrica Scandinavica, attracting constructive advice from peer reviewers that led to an improved manuscript, and ultimately positive reviews, however, the editor, Povl Munk-Jørgensen, wrote to us as follows:
| Response from Povl Munk-Jørgensen [Editor of the Acta Psychiatrica Scandinavica]
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First, please let me apologize for having kept you waiting for a reply. However, we have now received the publishers’ considerations based on the publishers’ legal expert’s recommendations.
The publishers represented by journal publishing manager Lisbeth Cranfield writes 23 September 2015 about your manuscript to me that she in the "current state cannot recommend that the article is published". Further, she writes "the main issue with this article that needs to be addressed is that Wagner et al is contacted and asked for their side of the story. Their side of the story should be included in the article". Further, she writes that if I "wish to follow this route" we should further need to involve the legal expert to determine "the right questions to be asked". It seems that the whole matter is getting a bit out of my hands as an academic psychiatrist editing a clinical psychiatric journal. The matter is further complicated by the fact that I am leaving the chair as editor at the turn of the year. That means that the process could be pretty long (we should ask the publishers’ legal expert "what questions to ask you". You should then revise the manuscript which should then be sent to the legal advisor, who should respond to me, who should pass the matter on to you, and after your response you should properly start all over again with my succeeding editor. I therefore suggest that we stop the process at this point. You may benefit from the reviewers’ second assessment (found at the bottom of this email) and carry on with a journal somewhat more experienced in this kind of legal matters. Maybe you could ask Professor David Healy about where to submit your paper? I am not happy about writing this, but I find it the only realistic decision to make to regrettably thank no to publish your paper in the Acta Psychiatrica Scandinavica. Thank you very for your patience.
Best regards
Professor Povl Munk-Jørgensen
Editor-in-Chief, Acta Psychiatrica Scandinavica
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We then submitted to the International Journal of Risk & Safety in Medicine, who once again had the courage and commitment to publish potentially controversial material, for which we thank them.
We have subsequently called on the editor of the American Journal of Psychiatry to retract the Wagner et al paper.
| Letter to Robert Freedman, M.D [Editor of the American Journal of Psychiatry]
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We write to you as the editor in chief of the American Journal of Psychiatry to request the retraction of Forest Laboratories report of study CIT-MD-18, published as Wagner et al., "A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents", in your journal in June 2004.
The CIT-MD-18 study clearly failed to demonstrate efficacy for citalopram in children and adolescents. However, by way of Forest-sponsored ghostwriting and data manipulation this study was misrepresented as positive, and used to gain a licence for escitalopram for the treatment of adolescent depression. Subsequent to the publication of the Wagner et al. article, you published an editor’s note on its authorship and its failure to report the negative Lundbeck study of citalopram in the treatment of depression in children and adolescents (Freedman R, Roy MD, Am J Psych 2009, 166:942-943). You also published criticism of obvious problems in the reporting of the CIT-MD-18 trial results (Martin A, et al. Am J Psych 2005, 162:817). Your journal took no further corrective action at that time. With the recent publication of our article, ‘The citalopram CIT-MD-18 pediatric depression trial: A deconstruction of medical ghostwriting, data manipulation and academic malfeasance’ , in the International Journal of Risk & Safety in Medicine (2016, 28:33 – 43, attached) we, along with other scientists, have drawn attention to further serious misrepresentations that were published in the Wagner et al. paper. As a result of recently declassified documents from litigation, the extent of Forest Pharmaceutical’s data manipulation is only just becoming clear, and is beyond what was available to the public previously. Some of this declassified information is documented in the enclosed article; however, more will be revealed as more documents are released in the public domain in the near future. We are sure that you agree that the integrity of science depends on disinterest in hypotheses and rigorous adherence to the results of experimental testing. This is particularly important in medicine where significant harm to patients can result from the failure to embrace the ideal of evidence-based medicine. We therefore ask that you retract the Wagner et al. article which otherwise represents a stain of the reputation of the American Journal of Psychiatry.
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We received no reply for over 2 months, until after a second follow up email on 12 July, Dr Freedman sent an email which read in its entirety:
RE: Am J Psychiatry 2004; 161:1079–1083 We are not retracting this article. Robert Freedman MD
We understand that retracting a paper is a major decision, and that an editor will have misgivings about doing so. We do not understand the hostility and disrespect in dealing with a legitimate request.
When the probability of having a ghostwritten, fraudulent, industry-sponsored clinical trial accepted for publication in a high-impact medical journal is substantially higher than the probability of having a critical, deconstruction of the same trial accepted there can be no confidence in the medical literature.