“This has occurred because physicians have allowed it to happen, and it is time to stop.”—Catherine D. DeAngelis, MD, MPH, and Phil B. Fontanarosa, MD, MBA.
Joseph S. Ross, MD, MHS, of Mount Sinai School of Medicine, NY, and colleagues conclude that many, if not most, rofecoxib clinical trials reports were written by Merck scientists or ghostwritten by Merck-paid contract workers, then disguised with the names of academically affiliated doctors recruited as named authors.1Bruce M. Psaty, MD, PhD, and Richard A. Kronmal, PhD, both from the University of Washington in Seattle, conclude that mortality data from studies of rofecoxib in patients with Alzheimer’s disease or cognitive impairment “were neither provided to the FDA nor made public in a timely fashion.”2
“The profession of medicine, in every aspect—clinical, education, and research—has been inundated with profound influence from the pharmaceutical and medical device industries. This has occurred because physicians have allowed it to happen, and it is time to stop,” thundered JAMA editors Catherine D. DeAngelis, MD, MPH, and Phil B. Fontanarosa, MD, MBA, in an accompanying editorial.3
Catherine D. DeAngelis, MD, MPH, Editor in Chief, JAMA
Ghostwriters on the sly
Dr. Ross defined ghostwriting as the failure to name as an author someone who made a substantial contribution to the research or writing of a manuscript. He defined guest authorship as the designation of someone who does not meet authorship criteria. He and his colleagues conducted a case-study review of court documents, in combination with a review of the relevant medical literature, to describe the practices of ghostwriting and guest authorship related to rofecoxib. The investigators found that Merck scientists publishing clinical trials designed, conducted, and sponsored by Merck often prepared manuscripts and then recruited external, academically affiliated investigators to collaborate on the manuscripts as guest authors.
“Recruited authors were frequently placed in the first and second positions of the authorship list. For the publication of scientific review papers, documents were found describing Merck marketing employees developing plans for manuscripts, contracting with medical publishing companies to ghostwrite manuscripts, and recruiting external, academically affiliated investigators to be authors,” Dr. Ross et al wrote. Documents indicated that medical publishing companies provided to authors near-complete drafts of review manuscripts for editing, in addition to managing submissions and revisions. The paper reproduces a transmittal letter for 1 such draft and a detailed publication plan for 8 clinical articles from Scientific Therapeutics Information, Inc, as well as a contract for Health Science Communications, Inc, to write a 20-page review article for Merck for $23841.00.
One of the manuscripts written by Scientific Therapeutics was submitted to and published in JAMA, for which Dr. DeAngelis said, “[T]here was no disclosure that the manuscript had been written by Scientific Therapeutics Information Inc, a company specializing in the development of scientific literature, ie, writing papers for a price.” To remedy this situation JAMA editors propose, among other things, that individuals who provided writing assistance “must be named in the acknowledgment section of the article, with reporting of their specific affiliations and contributions and whether they were compensated for those contributions.”
The court documents include papers describing Merck compensating investigators with honoraria of $750.00 to $2500.00 for agreeing to serve as authors on review manuscripts ghostwritten on their behalf by medical publishing companies.
“Among 96 relevant published articles, we found that 92% (22 of 24) of clinical trial articles published a disclosure of Merck’s financial support, but only 50% (36 of 72) of review articles published either a disclosure or Merck sponsorship or a disclosure of whether the author had received any financial compensation from the company,” Dr. Ross reported. His team also found that for 15 of 43 review articles (43%) that published disclosures of Merck support, the disclosures were either part of the introduction to a supplement or on a separate “disclosure” page, and they did not turn up at all when articles were accessed electronically.
The investigators concluded, “This case-study review of industry documents related to rofecoxib demonstrates that Merck used a systematic strategy to facilitate the publication of guest authored and ghostwritten medical literature.” They suggested that authors who “sign-off” or “edit” manuscripts written by pharmaceutical industry employees or by medical publishing companies “should offer full authorship disclosure, such as, ‘drafting of the manuscript was done by representatives from XYZ, Inc; the authors were responsible for critical revision of the manuscript for important intellectual content.’”
Managing the mortality data
Drs. Psaty and Kronmal recalculated the numbers on morality in several clinical trials of rofecoxib in patients with Alzheimer’s disease or cognitive impairment. They found that while published articles “did not include analyses or statistical tests of the mortality data, and the 2 articles concluded that regarding safety, rofecoxib is ‘well tolerated,’ the company’s internal intention-to treat (ITT) analyses showed something quite different—a significant increase in total mortality with hazard ration (HR) of 4.43 for one trial and HR 2.55 for the other, with an overall mortality HR of 2.99.
“The data submitted by the sponsor to the FDA in a Safety Update Report in July 2001 used on-treatment analysis methods...This on-treatment approach to reporting minimized the appearance of any mortality risk” Drs. Psaty and Kronmal wrote.
Furthermore, when the FDA started asking about one study (078) after excess mortality was seen in the other, it emerged that 078 had no data safety monitoring board, that safety was being managed by individual study site institutional review boards (IRBs), and that Merck had not provided the IRBs with data about the problems in study 091 “because [Merck Research Laboratories] does not believe that a safety issue has been identified,” according to a letter from Merck to the FDA. Study 078 continued for about 2 more years.
According to Drs. Psaty and Kronmal, “The only human-subjects protections available to the study participants were those provided by the investigators who were blind not only to the treatment allocation but also to the findings for study-wide adverse events, and by the unblinded Merck investigators, who did not discern a safety issue.”
Both these authors and the JAMA editors call for requiring data analysis by an independent academic statistician for clinical trials and for analysis of both ITT and on-treatment safety data.
References
1. Ross JS, Hill KP, Egilman DS, et al. Guest authorship and ghostwriting in publications related to rofecoxib. A case study of industry documents from rofecoxib litigation. JAMA. 2008;299:1800-1812.
2. Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment. A case study based on documents from rofecoxib litigation. JAMA. 2008; 299:1813-1817.
3. DeAngelis CD, Fontanarosa PB. Impugning the integrity of medical science. The adverse effects of industry influence (editorial). JAMA. 2008; 299:1833-1835.
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