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PLOS BLOGS Speaking of Medicine

Outing Wyeth and Their Hired Ghosts

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?

Image Credit: David Merz, Flickr.
Image Credit: David Merz, Flickr.

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:

Fugh-Berman AJ (2010) The Haunting of Medical Journals: How Ghostwriting Sold “HRT”. PLoS Medicine 2010

 

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.

 

Discussion
  1. Dr Margaret Winker, in her blog post of 14 October 2014[1], attempts to represent the Wyeth-DesignWrite case as both representative of current practice and commonplace. As leaders of the Global Alliance of Publication Professionals – GAPP (www.gappteam.org), we have been, and continue to be, strong and vocal critics of ghostwriting and we have published numerous articles, editorials, and letters-to-the Editor to clarify the role of professional medical writers. We certainly agree that undisclosed medical writing assistance is both unethical and misleading. However, fully transparent contributions of professional medical writers in the preparation of manuscripts is both acceptable and desirable.
    Winker cites a 2010 article by A Fugh-Berman[2] as evidence of ghostwriting that is unfettered and ruinous to good science and to the health and well-being of the public-at-large. In doing so, she perpetuates the conflation of legitimate professional medical writing and ghostwriting. In June of 2013 we (GAPP) responded[3] to a Fugh-Berman article in PLOS Biology[4].
    As noted in our response to Fugh-Berman, there is a world of difference between the unethical ghostwriting that Fugh-Berman describes and ethical medical writing assistance. Professional medical writers who adhere to current guidelines[5,6] are emphatically not ghostwriters, as they declare their involvement in the paper and their funding source, and ensure that data are presented honestly. Research has shown that papers written with the assistance of professional medical writers are less likely to be fraudulent[7], more likely to comply with best practice reporting guidelines[8], and are accepted more quickly for publication[9, 10]. Research has also shown that publication professionals and professional medical writers are more likely to know about ethical publication practices and guidelines than authors.[11] The implication that the Wyeth-DesignWrite violations represent current practice is challenged by the fact that these practices occurred primarily between 1997 and 2003, while the letter from Senator Grassley’s office initiating discovery actions was issued in 2008, and a draft report issued in 2010. The first systematic review on the reported prevalence of ghostwriting reveals just how much the estimated prevalence of ghostwriting has varied, changed over time, and been unjustly and incorrectly extrapolated from anecdotal experience. [12] Ghostwriting is not acceptable, but exaggerating its prevalence is not helpful.
    A second implication is that misrepresentation of data by professional medical writers is common practice. There are certainly one-off examples of such unprofessional behavior; however, to assert that this was or is the norm is not supported by any credible empirical evidence.
    Practices and policies are not constant. They experience evolutionary processes, just as laws, community morals, and mores do in the course of environmental change. These changes may be rapid – often in reaction to recrimination, discovery of wrong-doing, or in a moment of self-awareness. In evolutionary terms this process may be likened to Stephen J. Gould’s theory of Punctuated Equilibrium.[13] This is represented by the rapid promulgation and enforcement of the ICMJE[14] authorship standards, with subsequent FDAAA legislation in 2007.[15] In other cases, there is more gradual evolution over time. This may be as a result of a need, once the deficient practice is identified, to educate the professional community, and to articulate the new standards to be followed. These cultural changes are reflected in professional association incorporation of authorship standards into their policies. Examples include policy statements by the American Medical Writers Association (AMWA) [16], the European Medical Writers Association (EMWA) [17], the International Society for Medical Publication Professionals (ISMPP) [18], and others. The authorship standards are clearly articulated and adhere to the commonly accepted standards set forth by the ICMJE. These organizations hold their members accountable for adhering to these principals. The 2010 CONSORT statement[19] strongly emphasizes the need for authorship transparency.
    Both types of evolution have occurred in the use of professional medical writers in the preparation of medical and scientific manuscripts; the practices cited by Winker and Fugh-Berman have no place in reporting data from industry- (or non-industry-) sponsored research. Unfortunately, Winker failed to cite the results from the largest study done to date on publication practices for industry-sponsored research.[20] We recommend Winker and others concerned with industry publication practices take into account the findings from the Global Publication Survey should they choose to comment on industry publication practices. Even better, we encourage them to conduct their own research on the current knowledge and application of ethical publication practices in industry and in academia; we would all be interested in the results!
    A very broad “unified theory” of responsible and ethical authorship has been adopted since the transgressions of the Wyeth-DesignWrite incidents. The best endorsement in terms of our profession is probably from the recommendation in Good Publication Practice (GPP2) [6], which as the Global Publication Survey results showed, is one the most frequently used guidelines [20]. The GPS survey results found that over 90% of industry, agency and CRO respondents routinely refer to GPP2 and the International Committee of Medical Journal Editors’ Uniform Requirements. The GPS specifically states; We recommend that authors and professional medical writers working with authors use a published checklist to discourage ghostwriting.[21] In June of 2010, a Joint Position on the Publication of Clinical Trial Results was issued by IFPMA , EFPIA , PhRMA , JPMA , representing the trade associations of the pharmaceutical industry.
    Even the Declaration of Helsinki[22], addresses responsibilities of authors in Principal 20:
    20. Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research. Authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

    Transparency and disclosure have indeed led to significant positives in the context of medical and scientific manuscript authorship standards and practices, we are encouraged that the trend will continue, leading toward a better understanding and appreciation of the ethical underpinnings of the medical writing profession. We invite the medical and scientific community to join GAPP in promoting better publication practices, which can lead to greater confidence in the validity and trustworthiness of data presented by those who adhere to these standards.

    REFERENCES
    1 Winker M, Outing Wyeth and Their Hired Ghosts. PLOS Blogs. Posted: October 14, 2014
    2 Fugh-Berman AJ. The haunting of medical journals: how ghostwriting sold “HRT”. PLoS Med. 2010 Sep;7(9):e1000335.
    3 PLoS Biology, Online comment, Fugh-Berman article on medical writers for basic scientists, http://www.plosbiology.org/annotation/listThread.action?root=75773
    4 Fugh-Berman A. How basic scientists help the pharmaceutical industry market drugs. PLoS Biol 2013;11:e1001716 (doi:10.1371/journal.pbio.1001716)
    5 Jacobs A, Wager E. European Medical Writers Association (EMWA) guidelines on the role of medical writers in developing peer-reviewed publications. Curr Med Res Opin 2005;21:317–21
    6 Graf C, Battisti WP, Bridges D, Bruce-Winkler V, Conaty JM, Ellison JM, et al. Good publication practice for communicating company sponsored medical research: the GPP2 guidelines. BMJ2009;339:b4330
    7 Woolley KL, Lew RA, Stretton S, Ely JA, Bramich NJ, Keys JR, et al. Lack of involvement of medical writers and the pharmaceutical industry in publications retracted for misconduct: a systematic, controlled, retrospective study. Curr Med Res Opin 2011;27:1175–82.
    8 Jacobs A. Adherence to the CONSORT guideline in papers written by professional medical writers. The Write Stuff 2010;19:196-200
    9 Bailey M. Science editing and its effect on manuscript acceptance time. AMWA Journal 2011;26:147-52.
    10 Woolley et al. Declaration of medical writing assistance in international, peer-reviewed publications and ethics of pharmaceutical sponsorship (abstract). Peer Review Congress Chicago 2005
    11 Marušić A, Hren D, Mansi B, et al. Five-step authorship framework to improve transparency in disclosing contributors to industry-sponsored clinical trial publications. BMC Med 2014;12:197
    12 Stretton S. Systematic review on the primary and secondary reporting of the prevalence of ghostwriting in the medical literature. BMJ Open 2014;4:e004777. http://bmjopen.bmj.com/content/4/7/e004777
    13 Gould SJ. Punctuated Equilibrium. Cambridge, Mass: Belknap Press, 2007.
    14 ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals* Updated December 2013. http://www.icmje.org/icmje-recommendations
    15 http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/
    16 http://www.amwa.org
    17 http://www.emwa.org
    18 http://www.ismpp.org
    19 CONSORT 2010 Statement. BMJ 2010;340:c332
    20 Wager E, Woolley K, Adshead V, et al. Awareness and enforcement of guidelines for publishing industry-sponsored medical research among publication professionals: the Global Publication Survey. BMJ Open 2014;4:e004780 doi:10.1136/bmjopen-2013-004780
    21 Gøtzsche PC, Kassirer JP, Woolley KL, Wager E, Jacobs A, Gertel A, et al. What should be done to tackle ghostwriting in the medical literature? PLoS Med 2009;6:e23. doi:10.1371/journal.pmed.1000023
    22 http://www.wma.net/en/30publications/10policies/b3/

    Members of GAPP:
    Art Gertel, MS, President, MedSciCom, LLC, Lebanon, New Jersey, USA; Senior Research Fellow, Centre for Innovation in Regulatory Science (CIRS) Cindy W. Hamilton, PharmD, ELS, Assistant Clinical Professor, Virginia Commonwealth University School of Pharmacy, Richmond; Hamilton House Medical and Scientific Communications, Virginia Beach, Virginia, USA Adam Jacobs, PhD, Senior Principal Statistician, Premier Research, Wokingham, UK Jackie Marchington, PhD, CMPP, Director of Operations, Caudex Medical, UK Karen Woolley, PhD, CMPP, Division Lead, Proscribe – Envision Pharma Group, Noosa Heads, Australia; Adjunct Professor, University of the Sunshine Coast, Australia

  2. I thank the members of Global Alliance of Publication Professionals, advocacy group for the International Society for Medical Publication Professionals (1), for their interest in my Speaking of Medicine blog (2) for PLOS Medicine’s 10th anniversary series, highlighting Adriane Fugh-Berman’s article on Wyeth’s efforts to promote off-label indications of Prempro despite research showing patient harm (3). The purpose of the blog was not to discuss the role of medical writers; in fact medical writers are only mentioned once in the article, in a context that supports the idea that medical writers have an appropriate role as long as their contribution is clear: “…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’” (2). Provided medical writers and authors adhere to this policy, I agree that medical writers can help hone an author’s work.

    I did not refer to the prevalence of ghost writing in my blog. However, a study published in 2011 (4) surveyed corresponding authors in Annals of Internal Medicine, JAMA, Lancet, Nature Medicine, New England Journal of Medicine, and PLoS Medicine published in 2008 to estimate prevalence of ghost writing and honorary authorship. A total of 7.9% of authors reported that their articles included a ghost author, defined as an individual who was not listed as an author but who had made contributions that merited authorship, or an unnamed individual who had participated in writing the article. The prevalence of ghost authorship was 11.9% in research articles, 6.0% in reviews, and 5.3% in editorials. The prevalence declined from an overall rate of 11.5% in a similar survey in 1996. Thus, while some progress has been made, more work to ensure that no authors remain ghosts is needed. Undoubtedly the education of medical writers through journal requirements and the efforts of organizations such as GAPP are important steps in addressing this issue.

    Margaret Winker, MD
    Senior Research Editor, PLOS Medicine

    1. http://www.ismpp.org/gapp
    2. Winker MA. Outing Wyeth and Their Hired Ghosts. https://blogs.plos.org/speakingofmedicine/2014/10/14/outing-wyeth-hired-ghosts/#more-18580
    3. Fugh-Berman AJ (2010) The Haunting of Medical Journals: How Ghostwriting Sold “HRT”. PLoS Med 7(9): e1000335. doi:10.1371/journal.pmed.1000335 http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000335
    4. Wislar JS, Flanagin A, Fontanarosa PB, DeAngelis CD. Honorary and ghost authorship in high impact biomedical journals: a cross sectional survey BMJ 2011; 343:d6128. http://www.bmj.com/content/343/bmj.d6128

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