Pbio.1001716 1.5

How Basic Scientists Help the Pharmaceutical IndustryMarket Drugs Georgetown University Medical Center, Washington, D.C., United States of America clinical epidemiologists (40%), but less than who do not receive industry funding.
clinical researchers (67%) translational re- searchers (61%), or ‘‘multimodal’’ research- of having a conflict of interest, Joseph J.
ers (71%) [7]. At the 50 universities that Staszak, responded, ‘‘What conflict of analyses that compared results from stud- reported receiving a research-related gift in the late 1990s [8]. Gifts included biomate- sponsorship. This systematic review found a conflict of interest is ‘‘a set of circum- rials (24% of respondents), discretionary that industry-sponsored studies, compared stances that creates a risk that professional funds (15%), equipment (11%), travel funds results for drugs or medical devices; less secondary influence’’ [2]. More simply, conflicts of interest may be seen as cir- was expected in return for the gift.
conclude that a therapy was beneficial [9].
cumstances in which ‘‘individuals’ profes- Sponsor expectations that the gift be used sional responsibilities diverge from their cause they utilize a scientifically reliable personal interests (or when different pro- fessional responsibilities clash)’’ [3].
edged in publications, are certainly rea- synthesizes evidence that meets pre-spec- ified criteria and use explicit methods to of interest (also called competing interests) third (32%) of gift recipients reported that avoid bias in selecting studies for review.
industry and physicians or clinical resear- the use of the gift. This expectation was and publications, and may be important to respondents reported that the firm wanted industry in the production and dissemina- to receive prepublication review of articles effects of industry funding on basic science research. What information exists, howev- to be used for applications that competed of biomedical research, paying for nearly twice as much research (58%) as the federal Positive results for therapeutics in ani- government (33%) [4]. Most of this funding clinical studies. Species differences certain- to publish results that favor a sponsor’s design, reporting bias, analytic bias, and creased from about half (55%) in 1998 to a publication bias also may be important.
quarter (25%) in 2010 [5]. A 2007 survey of3,080 academic life science researchers Citation: Fugh-Berman A (2013) How Basic Scientists Help the Pharmaceutical Industry Market Drugs. PLoS Biol 11(11): e1001716. doi:10.1371/journal.pbio.1001716 relationship with industry [6]. Among the 1,663 research faculty at academic medical Copyright: ß 2013 Adriane Fugh-Berman. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original author and source are credited.
relationship with industry. This numberwas similar to health services researchers/ Funding: The author received no specific funding for this work.
Competing Interests: I have read the journal’s policy and have the following conflicts: I direct PharmedOut, aGeorgetown University Medical Center research and education project that advances evidence-based The Perspective section provides experts with a prescribing and educates healthcare professionals about pharmaceutical marketing practices. I am a paid forum to comment on topical or controversial issues expert witness on behalf of plaintiffs in litigation regarding pharmaceutical marketing practices, including litigation against Pfizer (which owns Wyeth), GlaxoSmithKline, and Takeda Pharmaceuticals.
November 2013 | Volume 11 | Issue 11 | e1001716 ‘‘It is to industry’s advantage to selectively studies in 160 meta-analyses of neurolog- support particular researchers whose point researchers actually concluded that eryth- many studies (1,719) had a ‘‘positive’’ ropoietin had potential antitumor effects encourage selective publication of articles.’’ (919 studies) would have been expected to biases are the most likely explanation.
friendly results. Although the question of analyses found a statistically significant summary effect; of these, the vast majority of industry-funded researchers to reassur- – 108 of 112 studies –favored the thera- ing clinicians and policymakers regarding studies. Writing up studies requires time found significant positive effects of treat- motivated to publish negative data, espe- cially when it is perceived that negative are important tactics for industry. Industry relies on abstracts and posters to convey graduated to testing in humans [10].
marketing messages at scientific meetings, because abstracts and posters are usually journals won’t publish negative studies, from design or reporting bias. Let’s take altered up to the time of presentation.
submitted. A study of papers presented at agents (ESAs), which were licensed in the early 1990s for treating anemia in cancer preclinical studies, case reports, or prelim- inary results of clinical trials. Promising published clinical studies and meta-analy- preliminary results might be presented as ses appeared to show a benefit of ESAs on mortality [11]. It is now known, however, cized, but if the final results of the study do not support commercial goals, the full from industry-funded studies are less likely to be submitted for publication, industry- overall mortality in cancer patients [12]; buried in an obscure, low-impact journal.
funded clinical trials overall are less likely In either case, scientists may have a posi- tive impression of a therapy from a poster, trials listed in ClinicalTrials.gov found and never learn that the therapy failed to that within two years of study completion, about a third of studies that received full questions about potential adverse effects and abstracts with positive results are far half (54%) of trials funded by government, more likely to be published than negative and 56% of trials funded entirely through atic review of 79 reports found that less basic science research found that research- Less information is available about basic presented at scientific meeting were sub- science studies, but there is reason to be sequently published as full studies [14].
concerned. A key analysis of 16 systematic investigators to report that ESAs promot- reviews of experimental animal studies of publication rates; 42% of posters at three acute ischemic stroke found that 98% (515 significant effects of treatment on infarct volume [20]. It’s impossible to say exactly and posters at a neurosurgery meeting was events. None of the ten researchers funded trim-and-fill to account for missing data, ported EPO-induced signaling events.
ing on drug addiction were published [15].
It should be noted that these studies may were conducted but not reported; the non- not have picked up data from posters that publication rate was estimated to be 14%.
was incorporated into other articles rather bias may have accounted for about a third reviews [20]. In other words, the absence favor a sponsor’s drug has obvious com- of negative studies may result in systematic mercial benefits. According to the former therapy is more beneficial than it actually November 2013 | Volume 11 | Issue 11 | e1001716 for publication for many valid reasons.
speakers, consultants, and researchers to In contrast to clinical research, in which to expand the market for the anti-seizure a specific drug is safe or effective in a ‘‘The work of basic scientists is used for indirect and sometimes direct marketing to basic science is to define mechanisms and ‘‘expand the speaker base—identify and highlight a therapy’s mechanism of action, to suggest surrogate markers of safety and cesses. Full publication of negative results users to speak locally for Neurontin.’’ efficacy, and to differentiate a product from competitors’ based on these findings.
grants to ‘‘key influencers’’ and organized a named lecture series featuring neurology clinical messages in academic presentations information and recognition of a student’s with a more ‘scholarly’ understanding of directors to improve ‘‘public relations efforts, but without the expectation that a rontin new prescriptions.’’ To promote off-label prescribing for neuropathic pain and bipolar disorder, Parke-Davis directly years before it is submitted for regulatory approval [21], when it is still in animal educational programs and used a so-called studies, so preclinical studies may be used publication strategy ‘‘to disseminate the little incentive to preserve the integrity of to create ‘‘buzz’’ about a new drug years information as widely as possible through before it arrives on the market. Bias in the the world’s medical literature’’ [25].
threat of funding withdrawal hangs over a researcher who insists on publishing neg- clinical studies has been found in certain manufacturer of the bestselling menopaus- proved for treating obesity in 2006, then practical standpoint, there is little justifi- cation for the belief that journals will only meetings, promoting hormones off-label to be prescribed ‘‘off-label’’ – that is, for endpoints supported this use, so speakers invoked observational studies, studies with the drug was approved. Although it is legal surrogate endpoints (i.e. cholesterol-lower- prescribe a drug off-label, it is illegal about adverse effects, preclinical studies drugs off-label. Off-label use is common, are used to promote a marketed drug for a accounting for about one in five prescrip- condition for which efficacy in humans has not yet been shown or has been disproven.
Table 1. Examples of journals that publish negative results.
http://www.plosone.org/static/publication.action Journal of Negative Results in Biomedicine Journal of Negative Results in Ecology and Evolutionary Biology Journal of Pharmaceutical Negative Results Journal of Interesting Negative Results in Natural Language Processing and Machine Learning November 2013 | Volume 11 | Issue 11 | e1001716 nize as advertisements. Marketing messag- articles to imply clinical benefits in the es may not mention the targeted drug; for absence of clinical trials (or the presence of that a targeted disease is underdiagnosed, imposed for suppressing risks or mislead- that a mechanism of action is particularly ing clinicians about risks [34]. For exam- exciting, that a class of drugs has unique agreed to pay a record-breaking $3 billion significant drawbacks. Marketing messages to the US government to settle allegations are disseminated in research studies, case related to Avandia (rosiglitazone, a diabe- ters, as well as in presentations and posters and Paxil (paroxetine) off-label [35]. The contractors to ghostwrite ‘‘false and mis- leading’’ articles that claimed, for exam- ple, that the safety and efficacy of Paxil for statistical or editorial ‘‘assistance’’ creates interest were not disclosed [27,28].
an opportunity for results to be suppressed strated despite the fact that the study cited disadvantage competing therapies. Partic- publication also minimized adverse effects.
ment of publications or posters is ethically suggestions on whether or not to publish, present, bury, or selectively report specific physicians and scientists to ‘‘author’’ publications crafted by industry [4]. Arti- and misrepresentation of reported results distorts the biomedical literature, makes write their own articles may still submit to ‘‘ghost-management’’ [37], allowing a company to provide statistical analysis or ‘‘editorial assistance’’ (often an industry health. It goes without saying that scien- tists should accurately report and analyze studies are crucial to assessing benefits Zyprexa (olanzapine) [39], Paxil (paroxe- and risks of therapies and to determining tine), ‘‘Fen-phen’’ (fenfluramine and phen- whether further research is indicated.
termine, used for weight loss), Neurontin (gabapentin, approved for seizures), Vioxx ment disclosed in litigation from Wyeth’s (rofecoxib, an analgesic), and Zoloft (ser- traline, an antidepressant) [25]. Undoubt- ‘‘Industry is a major funder of basic science a planned article, ‘‘The Atherosclerotic Process and the Impact of Estrogens’’ ships and public/private sector partnerships ‘‘The Impact of Timing of Initiation of participate in ghostwritten articles is un- searchers to do work of value to industry starting to pay attention to the fact that partners and to help demonstrate that value ment Therapy’’ [33]) that would use basic science studies and observational studies to on articles they have not written, but in 2010 only 13 (26%) of the top 50 academic medical centers in the US had policies in place that prohibit participation in medi- cal ghostwriting [40]. While these policies are laudable, no researcher in the US has yet been sanctioned for ghostwriting [41].
sponsor to ghostwrite an article, industry cations of industry influence on clinical review of articles by a sponsor may result dollars in fines for off-label promotion, discussed widely within basic science. It November 2013 | Volume 11 | Issue 11 | e1001716 difficult conversation regarding the ethical former pharmaceutical executive for extremely helpful insights and comments on an earlier I would like to acknowledge Kenneth Dretchen PhD, Richard Gillis PhD, Tony Scialli MD,Elizabeth Jeffery PhD, and an anonymous 1. Rascovar B (31 March 1999) Lawmakers under- abstracts submitted to scientific conferences on martha-rosenberg/hormones-still-pushed-sti_b_ mine court reform. Baltimore Sun. Available: drug addiction predict full publication? BMC http://articles.baltimoresun.com/1999-03-31/ Med Res Methodol 9: 23. doi:10.1186/1471- 29. Writing Group for the Women’s Health Initiative news/9903310338_1_bail-bondsmen-licensed- Investigators (2002) Risks and benefits of estrogen bail-bondsman-bail-bond-business. Accessed 28 16. Harel Z, Wald R, Juda A, Bell CM (2011) plus progestin in healthy postmenopausal women: Frequency and factors influencing publication of Principal results from the Women’s Health 2. IOM (Institute of Medicine) (2009) Conflict of abstracts presented at three major nephrology Initiative randomized controlled trial. JAMA interest in medical research, education, and meetings. Int Arch Med 4: 40. doi:10.1186/1755- practice. Washington, DC: The National Acad- 30. Fugh-Berman AJ (2010) The haunting of medical emies Press. Available: http://www.ncbi.nlm.nih.
17. Patel AJ, Cherian J, Fox BD, Whitehead WE, journals: How ghostwriting sold ‘‘HRT’’. PLOS Curry DJ, et al. (2011) Publication patterns of oral Med 7: e1000335. doi:10.1371/journal.pmed.
and poster presentations at the annual meetings of 3. Cain DM, Loewenstein G, Moore DA (2005) The the Congress of Neurological Surgeons and the 31. Drug Industry Document Archive (DIDA) dirt on coming clean: perverse effects of disclosing American Association of Neurological Surgeons.
(January 18, 2005) The atherosclerotic process conflicts of interest. Journal of Legal Studies 34: and the impact of estrogens - outline. Available: 18. Timmer A, Hilsden RJ, Cole J, Hailey D, http://dida.library.ucsf.edu/pdf/plb37b10. Accessed: 4. Dorsey ER, de Roulet J, Thompson JP, Reminick Sutherland LR (2002) Publication bias in gastro- JI, Thai A, et al. (2012) Funding of US biomedical enterological research - a retrospective cohort 32. DIDA [undated] The atherosclerotic process research, 2003–2008. JAMA 303: 137–43.
study based on abstracts submitted to a scientific and the impact of estrogens – need a new title.
5. Moses H, Dorsey ER (2012) Biomedical research Available: http://dida.library.ucsf.edu/tid/pgc37b10 in an age of austerity. JAMA 308: 2341–2342.
19. Bourgeois FT, Murthy S, Mandl KD (2010) 6. Zinner DE, Bolcic-Jankovic D, Clarridge B, Outcome reporting among drug trials registered 33. DIDA [undated] The impact of timing of Blumenthal D, Campbell EG (2009) Participation in ClinicalTrials.gov. Ann Intern Med 153: 158– initiation of therapy on the cardiovascular effects of academic scientists in relationships with of postmenopausal hormone replacement thera- industry. Health Aff (Millwood) 28: 1814–25.
20. Sena ES, van der Worp HB, Bath PMW, Howells py. Available: http://dida.library.ucsf.edu/pdf/ 7. Zinner DE, Campbell EG (2009) Life-science DW, Macleod MR (2010) Publication bias in research within US academic medical centers.
reports of animal stroke studies leads to major 34. Groeger L (3 July 2012) Big pharma’s big fines.
ProPublica. Available: http://projects.propublica.
8. Campbell EG, Louis KS, Blumenthal D (1998) e1000344. doi:10.1371/journal.pbio.1000344 org/graphics/bigpharma. Accessed: 28 October Looking a gift horse in the mouth: Corporate gifts 21. Coyle L, Benner D (2005) To market, to market: supporting life sciences research. JAMA 279: The seven steps of launch effectiveness. Product 35. U.S Department of Justice. US complaint. United States District Court for the District of Massa- 9. Lundh A, Sismondo S, Lexchin J, Busuioc OA, 22. McPartland JM (2009) Obesity, the endocanna- chusetts. C.A. no 11-10398-RWZ. United States Bero L (2012) Industry sponsorship and research binoid system, and bias arising from pharmaceu- ex rel. Greg Thorpe, et al v. GlaxoSmithKline outcome. Outcome reporting among drug trials tical sponsorship. PLOS ONE 4: e5092.
registered in ClinicalTrials.gov. Cochrane Data- http://www.justice.gov/opa/gsk-docs.html. Ac- 10. Tsilidis KK, Panagiotou OA, Sena ES, Aretouli 23. Radley DC, Finkelstein SN, Stafford RS (2006) E, Evangelou E, et al. (2013) Evaluation of excess Off-label prescribing among office-based physi- 36. Moffatt B, Elliott C (2007) Ghost marketing: significance bias in animal studies of neurological cians. Arch Intern Med 166: 1021–1026.
pharmaceutical companies and ghostwritten jour- diseases. PLOS Biol 11: e1001609. doi:10.1371/ 24. Fugh-Berman A, Melnick D (2008) Off-label promotion, on-target sales. PLOS Med 5: e210.
11. Tonia T, Schwarzer G, Bohlius J (2013) Cancer, 37. Sismondo S (2007) Ghost management: how meta-analysis and reporting biases: The case of 25. Steinman MA, Bero LA, Chren MM, Landefeld much of the medical literature is shaped behind erythropoiesis-stimulating agents. Swiss Med CS (2006) Narrative review: the promotion of the scenes by the pharmaceutical industry? gabapentin: an analysis of internal industry PLOS Med 4: e286. doi:10.1371/journal.pmed.
12. Tonia T, Mettler A, Robert N, Schwarzer G, documents. Ann Intern Med 145: 284–93.
Seidenfeld J, Weingart O, Hyde C, Engert A, 26. Coker LH, Espeland MA, Rapp SR, Legault C, 38. Braun SR (2013) Promoting ‘‘Low T’’: a medical Bohlius J (2012) Erythropoietin or darbepoetin for writer’s perspective. JAMA Intern Med 173: patients with cancer. Cochrane Database Syst hormone therapy and cognitive outcomes: the 1458–60. doi:10.1001/jamainternmed.2013.6892 39. Spielmans GI, Parry PI (2010) From evidence- 13. Bennett CL, Lai SY, Henke M, Barnato SE, based medicine to marketing-based medicine: Evidence from internal industry documents.
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cigarettes next? Op-Ed News. Available: http:// academic medical centers in the United States.
14. Scherer RW, Langenberg P, von Elm E (2007) w w w . o p e d n e w s . c o m / a r t i c l e s / H o r m o n e - Full publication of results initially presented in abstracts. Cochrane Database Syst Rev 18: 100420-14.html. Accessed 28 October 2013.
41. Stern S, Lemmens T (2011) Legal remedies for 28. Rosenberg M (25 January 2010) Hormones medical ghostwriting: Imposing fraud liability on 15. Vecchi S, Belleudi V, Amato L, Davoli M, still pushed, still dangerous. Huffington Post.
guest authors of ghostwritten articles. PLOS Med Perucci CA (2009) Does direction of results of Available: http://www.huffingtonpost.com/ 8: e1001070. doi:10.1371/journal.pmed.1001070 November 2013 | Volume 11 | Issue 11 | e1001716

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