Researchers Jay Amsterdam, MD, Leemon McHenry, PhD, and Jon Jureidini, MD recently published a paper aimed at exposing how the pharmaceutical industry corrupts clinical trials through the manipulation of scientific data. They discuss ghostwriting in medical journals, the use of key opinion leaders as co-conspirators, and the failure of top medical journals to uphold standards of science and peer review.
“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.”
The failure to adhere to regulatory standards and scientific and ethical tenets is a significant threat to evidence-based medicine, the authors contend. It is well known that pharmaceutical industry promotional efforts are laundered. In the case of ghostwriting, this involves employing medical communication companies to write research articles, and then academic consultants are paid to take authorship. The details of these unethical practices have recently become more apparent through litigation.
“Ghostwriting in the hands of the pharmaceutical industry has become a major factor in the ‘crisis of credibility’ in academic medicine,” the authors write, “The integrity of science depends on the trust placed in individual clinicians and researchers and in the peer-review system which is the foundation of a reliable body of knowledge. When, however, academic physicians allow their names to appear on ghostwritten articles, they betray this basic ethical responsibility and are guilty of academic misconduct.”
Data misrepresentation can occur during the stage in which the medical ghostwriter sends a draft of the manuscript to the corporate sponsor. Ghostwriters are often directed to “spin” the data, in other words, to portray it inaccurately in favor of the agenda of the pharmaceutical industry. Once this has been achieved, the manuscript is submitted to an article for peer review and the ghostwriter either disappears from mention or is acknowledged in the fine print for “editorial assistance.”
“Ghostwriting is not limited to drafting a manuscript; rather it is an academic façade for research that has been designed, conducted and analyzed by industry and it is the main vehicle through which the misrepresentation of the data in favor of the study drug is achieved,” explain the researchers.
They elaborate further, noting that given the patterns that ghostwritten publications only come to light when damages result in litigation or when government inquiries or physicians result in their exposure, the vast majority of ghostwritten publications in medicine to date will likely never be revealed.
The second point of corruption in the publication process highlighted by the authors is the use of key opinion leaders and co-conspirators. Physicians with influence over their peers or surrounding medical practices and prescribing behaviors have been identified by the pharmaceutical industry and labeled “key opinion leaders” (KOLs). KOLs are then invited to participate in drug promotion as co-conspirators and, as with ghostwriting, this practice goes concealed as well. Amsterdam and team describe how this is achieved:
“Pharmaceutical companies claim to engage KOLs in the drug development process to gain expert evaluation and feedback on marketing strategy, but in reality, these academic physicians are carefully vetted by the industry on the basis of their malleability to the sponsor’s products. KOLs are highly paid ‘product champions’ who are engaged to ‘defend the molecule.’”
Finally, as KOLs engage in this process and take authorship of ghostwritten publications, medical journals have remained complicit and fail to adhere to scientific standards. Rather than promoting articles that critically deconstruct ghostwritten papers, medical journals, now dependent on pharmaceutical revenue, are pressured to publish articles favorable of industry-sponsored trials.
“Thus the publication of ‘positive’ studies showing drug safety and effectiveness means more pharmaceutical advertising and more orders of reprints for dissemination by the sales force. In contrast, a ‘negative’ study showing poor tolerability or ineffectiveness results in no such revenue,” the authors write.
Even when peer reviewers recommend against publication, medical journals, or their attorneys, override this decision, pressured by threats of libel action from pharmaceutical industries. When confronted with fraudulent papers, journals refuse to retract articles.
In response to this protected concealment of misconduct, researchers Amsterdam, McHenry, and Jureidini deconstructed the corrupt practices of three specific studies.
SmithKline Beecham Paroxetine Study 329:
The first study, known as “SmithKline Beecham Paroxetine Study 329” compared the safety of two antidepressants, paroxetine and imipramine, for the treatment of child and adolescent depression. Deconstructing this case began with obtaining a series of court documents that revealed ghostwriting, and pharmaceutical companies manipulating outcome data in the interest of promoting off-label marketing of SSRI antidepressants to children and adolescents. Authorship was fraudulently credited to Keller et al., but was ghostwritten by Sally K. Laden of Scientific Therapeutics Information, Inc. After its publication by the Journal of the American Academy of Child and Adolescent Psychiatry (JAACP), it became one of the most frequently cited articles to support the safety of SSRIs for adolescents. In actuality, the results of this trial showed negative efficacy for antidepressants and positive signs for harm.
Forest Laboratory Citalopram Study CIT-MD-18:
As with the first study, the second study featured also received media attention for the manipulation of outcome data. “Forest Laboratory Citalopram Study CIT-MD-18” similarly published false conclusions deeming SRRI antidepressants as safe for children and adolescents.
“However,” the authors write, “deconstruction of study data and court documents revealed that the claims of Wagner et al. were predicated upon a combination of misleading analysis of the primary study outcome, an implausible effect size, introduction of post hoc outcomes as if they were primary outcomes, failure to report negative secondary outcomes, inclusion of eight unblinded subjects into efficacy analyses, and misleading analysis and reporting of adverse events.”
The article, also ghostwritten with KOLs claiming authorship, failed to mention the symptoms of citalopram including hypomania, agitation, and akathisia, which lead to the discontinuation by numerous participants.
SmithKline Beecham Paroxetine Study 352:
The third study received less media attention and involved the manipulation and misrepresentation of outcome data in adults diagnosed with bipolar affective disorder. Misconduct of this study was revealed when academics filed complaints of plagiarism and research misconduct against KOLs at medical research universities across the U.S. as well as pharmaceutical company executives.
Amsterdam and fellow researchers deconstruct the details of the published article to demonstrate how the so-called authors had little or no direct involvement in any aspect of the study design, conduct, analysis, or writing process. Furthermore, they delineate specifically how results were misrepresented by conflating concepts of efficacy and safety and cherry-picking data to minimize the rate of manic and hypomanic symptoms of paroxetine. This study was published in the American Journal of Psychiatry. They conclude:
“In summary, the paroxetine 352 study was a non-informative trial with insufficient statistical power and inconclusive results. There was no evidence of any paroxetine efficacy in bipolar disorder, and the suppression of safety data from the YMRS [Young Mania Rating Sclae] outcome measure hid the presence of paroxetine-induced manic induction.”
While the exposure of misconduct in industry-sponsored clinical trials is undoubtedly sobering, and perhaps even shocking, Dr. Amsterdam and researchers make it a point to emphasize that these three cases are not the exception. In fact, they conclude with a warning:
“All industry-sponsored trials are suspect and should be treated as such. Because so few gain public scrutiny and even fewer are ever formally retracted, it is important to make these articles transparent to correct the scientific record and protect patients from potential harm.”
Amsterdam, J. D., McHenry, L. B., and Jureidini, J. N. (2017). Industry-corrupted psychiatric trials. Psychiatr. Pol. 2017; 51(6): 993–1008 (Full Text)