Margaret A. Winker, MD, Senior Research Editor for PLOS Medicine, reflects on the 2010 Policy Forum by Adriane Fugh-Berman that explored the medical literature manipulation behind hormone “replacement” therapy.
The results of the Heart Estrogen/progestin Replacement Study (HERS) and Women’s Health Initiative (WHI) randomized trials stand out as two of the most important and surprising findings in the recent medical literature. The trials showed that hormone “replacement” therapy (HT), which was touted to treat estrogen “deficiency” in menopausal women just as thyroxine is used to treat hypothyroidism, not only did not reduce risk of cardiovascular disease but even increased risk of coronary heart disease, breast cancer, stroke, and pulmonary embolism. These remarkable results were both public and personal: an obstetrics-gynecologist friend on vacation when the news broke was flooded with phone calls from patients who feared their increased risk and wanted to stop HT immediately. My mother, who I had strongly encouraged to take HT given its apparent benefits, had just stopped it after developing endometrial hyperplasia. Of course, until the trials were published the evidence was observational with the known likelihood of confounding, but researchers had tried to control for those issues as best they could and had still found an association. The huge popularity of HT appeared to result from the available evidence, and the steady stream of papers supporting HT for a multitude of diseases including cardiovascular disease, Alzheimer’s disease, and stroke had seemed to indicate consensus around the importance of HT. Or did they?
The use of medical ghost writers by pharmaceutical companies was well established when Adriane Fugh-Berman’s paper was published in PLOS Medicine and the documents on which it was based posted (here and here). However, her revelations of Wyeth’s promotion of HT, culled from a collection of documents obtained from litigation brought by more than 14,000 plaintiffs who developed breast cancer while taking Prempro and made public when PLOS Medicine and the New York Times intervened in the litigation, were remarkable for their breadth and impact, shocking even the most cynical reader. Wyeth used several medical writing firms, but one in particular, DesignWrite, developed and implemented a publication plan on behalf of Wyeth to promote “HRT… a drug in search of a disease” for a number of conditions, ultimately publishing four trial reports and 20 review articles, a total of “over 50 peer-reviewed publications, more than 50 scientific abstracts and posters, journal supplements, internal white papers, slide kits, and symposia.”
Fugh-Berman outlines in excruciating detail the lengths to which DesignWrite went to promote Wyeth’s product. Not only were “authors” enlisted to put their names on the ghostwritten pieces but the ghosts were careful to ensure the “authors’” hesitation about the lack of evidence or misleading messages did not undermine the underlying marketing messages. Responses to peer reviewers who challenged the flawed studies being cited implied that such criticisms were inappropriate: “The review of the current paper is not the appropriate place to criticize the methodologic flaws of published papers”, DesignWrite wrote for the authors.
Even the publication of the HERS and WHI studies were not enough to stop the torrent. Papers were developed to attack the HERS study, minimize the breast cancer risk of HT, and promote other potential unproven and unapproved uses. Wyeth and DesignWrite went so far as to develop material for a seminar, “Expert Forum on Breast Cancer Health,” subsequently published as a supplement complete with the opportunity to earn continuing medical education credit, all funded through an “unrestricted educational grant” from Wyeth. Far from being unrestricted, DesignWrite managed the drafts and responded to reviewer comments along with a member of the Wyeth marketing department.
While HT prescribing declined after publication of the WHI study, it is impossible to know how many women were adversely affected by prescribing influenced by these publications designed to please shareholders. As Fugh-Berman says, “Marketing messages in credible journals have almost certainly contributed to widespread use of HT among millions of women who had no medical indication for the drug.” In response to such actions by the pharmaceutical industry, some medical journals have developed policies such as PLOS Medicine‘s wherein “The involvement of any professional medical writer in the manuscript must be declared” and authors must adhere to the ICMJE authorship guidelines and disclose conflicts of interest, all of which are published with the paper. The PLOS Medicine Ghostwriting Collection includes a number of articles addressing all aspects of ghostwriting, from a “ghost’s” personal experience to several views on what to do about it, all open access of course. Ghostwriting and message manipulation regarding medical evidence will undoubtedly continue, but one can only hope that transparency and exposure may eventually reveal and dissuade the ghosts.
You can read the full Policy Forum here:
This is post 3 of 8 in PLOS Medicine’s 10th Anniversary blog series on the most interesting and influential articles of the last ten years. You can find links to all the posts in the series as they are published here.