Implications of Pharmaceutical Industry Funding on ...

OPINION

Implications of Pharmaceutical Industry Funding on Clinical Research Joel R Lexchin

This commentary explores the influence of industry funding and offers suggestions for overcoming some of the problems. First, it is difficult to obtain funding from some sources for research with limited commercial value. Second, lack of communication among researchers can impede scientific progress. Stopping research before meaningful results are available is another area of concern. Next, suppressed or delayed publication of data may bias the results of meta-analyses, resulting in incorrect risk–benefit profiles for drugs. Finally, commercially funded clinical research is more likely to yield positive results than when funding comes from other sources. Possible solutions are explored. Ann Pharmacother 2005;39:194-7. Published Online, 23 Oct 2004, www.theannals.com, DOI 10.1345/aph.1E224

rummond Rennie, west coast editor of JAMA, has preD dicted that the dependence of clinical research on money from the pharmaceutical industry will change only “when commercial ties are linked to deaths (in clinical trials).”1 In the US, the pharmaceutical industry invests just under $15 billion a year in clinical research.2 This commentary explores the influence of industry funding in 5 dimensions: the direction of medical research, sharing of information, stopping clinical trials, publication of research results, and outcome of clinical research. Possible consequences are discussed, and suggestions are offered on how to preserve the integrity of clinical research. Direction of Medical Research In 1985, faculty members with industry support were >4 times as likely as those without (30% vs 7%) to report taking commercial considerations into account in choosing research topics3; the comparable numbers in 1994 –1995 were 35% and 14%, respectively.4 Moynihan5 has documented the extensive commercial investment in research into female sexual dysfunction and how those efforts may end up overemphasizing physiologic criteria at the expense of issues such as the psychological quality of relationships. The research agenda for osteoarthritis of the knee has been shown to reflect the priorities of commercial funders much more than those of the medical and patient communities.6 Author information provided at the end of the text.

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In the 1950s, no trials on acute stroke were funded by pharmaceutical companies compared with >50% in 1991– 1995.7 As the percentage of commercially funded trials continues to expand, it may become more difficult to obtain funding to explore questions that have limited commercial value. Sharing of Information Fifty-six percent of life science companies conducting or sponsoring research in academic institutions reported that they sometimes or often kept the resulting information confidential well beyond the time needed to file a patent.8 Faculty members with industry support were almost twice as likely as those without (11.1% vs 5.8%) to refuse to share research results or biomaterials,4 and the same is true of graduate students and postdoctoral fellows.9 A lack of communication among researchers can impede scientific progress in a number of ways: forcing the unnecessary repetition of research, depleting scarce resources, and causing the discontinuation of projects because of the unavailability of information.10 Stopping Clinical Trials Companies are known to stop trials for purely commercial reasons, such as a change in corporate priorities. Psaty and Rennie11 identified 8 such trials covering a wide range of drugs and diseases, including paclitaxel for ovarian can-

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Implications of Pharmaceutical Industry Funding on Clinical Research

cer and cardiovascular outcomes with verapamil. Patients often enter trials out of a sense of altruism. One of the primary reasons investigators undertake clinical research is to answer questions of scientific importance. Stopping research before it can produce meaningful results breaks trust with both groups and is a betrayal of their dedication to research. Publication of Research Results Receiving money from commercial sources can lead to either a suppression of or delay in the publication of research results.12 One reason for nonpublication may be trade secrets, defined as information kept secret to protect its proprietary value. Faculty members with industrial support are >3 times as likely as those without to generate trade secrets from their research (14.5% vs 4.7%).4 Twenty-seven percent of faculty who participated in relationships with industry delayed publication for >6 months compared with 17% of faculty without such relationships.13 Graduate students and postdoctoral fellows also report that industry funding leads to delays in publication.9 Publication lags can bias the results of meta-analyses, especially if the trials being withheld are negative. A metaanalysis on the use of selective serotonin-reuptake inhibitors (SSRIs) in pediatric depression illustrates the dangers in withholding publication. Published trials suggested a favorable risk–benefit profile for some SSRIs; however, when data from the unpublished trials were added, the conclusion was that, except for fluoxetine, the possibility of harms outweighed that of benefits.14 Almost one-third of academic scientists who received research-related gifts from industry reported that the companies making the donations wanted prepublication review of any articles or reports stemming from their use of the gift.15 Such reviews may have a benign outcome if investigators have full control over data analysis and publication decisions, but where this is not the case, significant changes may result. Bodenheimer16 presented 6 vignettes where publication was stopped or the content of articles was altered by the funding company. In the case of one negative trial, the company did not refuse permission to publish, but stalled so long that the investigator lost interest. Authors with financial relationships with industry are unlikely to report these relationships. Although 26 of 70 researchers studying calcium-channel blockers had received funding from manufacturers of these products, only 2 reported any type of potential conflict of interest.17 Fiftyeight of 100 authors of clinical practice guidelines (CPGs) received research support from pharmaceutical companies, but only 1 of 44 CPGs disclosed these financial interactions.18 Only 8 of 100 industry-sponsored randomized controlled trials in 5 major medical journals reported the role of the sponsor.19 Concern about the lack of disclosure of industry funding is not merely theoretical. Authors’ conclusions in randomized clinical trials published in the BMJ were more likely to favor the experimental treatment if financial competing interests were declared.20 www.theannals.com

Pharmaceutical company–sponsored trials of antidepressants are subject to 3 types of bias, all designed to make the product look safer or more effective: multiple publication of single trials, selectively publishing studies showing positive effects as stand-alone publications, and using analytic techniques that were more likely to produce favorable results.21 Multiple publication of industry-funded trials has been documented in other clinical areas as well.22,23 Redundant and fragmented publications may give an artificially inflated impression of the value of a product.22 Outcome of Clinical Research Five of 6 systematic reviews published since 2002 have concluded that industry-sponsored research is more likely to yield positive results than when funding comes from other sources.12,24-28 Lexchin et al.12 postulated that the favorable results may be a product of publication bias or the use of an inappropriate comparator. Various authors have documented the use of either incorrect comparators or incorrect doses of standard treatments.29-31 Als-Nielsen et al.27 suggested that the cause might be biased interpretation of trial results. Discussion Not all of the studies cited above focused solely on pharmaceutical industry funding. However, even where the authors were looking at companies from a broader range of for-profit industries, a significant number were from the pharmaceutical industry. Therefore, the overall trends are not going to be substantially altered. It is also true that many, if not all, of the problems identified are relevant to studies with noncommercial funding or can arise for nonfinancial reasons. While not to belittle these concerns, the fact is that the large and growing amounts of industry money represent the primary threat to the integrity of clinical research. Funding by pharmaceutical industry sponsors adversely affects research at multiple levels: it redirects the orientation of research toward commercial ends, impedes the sharing of research results, leads to early termination of trials, suppresses or delays publication, produces publication biases that overemphasize the positive aspects of drugs, and systematically yields results that favor the product being tested. Any one of these problems is serious enough, but collectively they represent a major concern that must be addressed. On the other hand, it is obvious that these conclusions do not apply to every company-funded study, and some have added significantly to our knowledge of therapeutics, such as the HOPE (Heart Outcomes Prevention Evaluation) trial.32 Bodenheimer16 stated that many of the investigators he interviewed “confirmed that many collaborations with pharmaceutical companies were conducted on a high professional level.” In 2001, the editors of 13 major medical journals published a statement requiring full disclosure of the sponsor’s


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role in the research and assurances that the investigators were fully accountable for the design and conduct of the trial, had independent access to all data, and controlled all editorial and publication decisions.33 The University of Toronto and its 7 affiliated teaching hospitals reached an agreement stipulating that contract research agreements should not allow sponsors to suppress or censor results or to delay publication >6 months. A review of agreements showed 100% compliance with the first provision and 93% with the second.34 However, in general, the situation in medical schools requires significant improvement. In a 2001 survey of 108 members of the Association of American Medical Colleges, 1% had provisions for ensuring that authors of reports on multicenter trials have access to all trial data, and 10% had provisions around data, collection, and monitoring.35 This is the situation in an academic setting. In the community setting, which accounts for ≥60% of industry money for clinical trials, requirements are likely to be even more lenient.16 More needs to be done at all levels. Individual researchers should refuse to participate in any trials where they do not have a guarantee that the sponsor will not delay publication; they should demand the right to share data as long as no commercial secrets are involved; and they should ensure that completion of the trial, except for ethical reasons, is written into the research contract so that it will be legally enforceable. Companies need to commit to either hard copy or electronic publication of all trials that they fund. The same medical journal editors who put out the 2001 statement are now talking of refusing to publish a trial unless it was publicly registered at its inception.36 Similarly, the Food and Drug Administration should require registration of all postmarketing trials as a condition of maintaining a drug on the market. Finally, there needs to be a dilution of the impact of industry financing through an increased level of sponsorship from public sources. These initiatives alone will not solve the problems associated with company-sponsored clinical research, but they will indicate to the public that the research community takes this problem seriously. Delaying action too long will lead to deterioration in public confidence to the detriment of everyone. Joel R Lexchin MD, Associate Professor, School of Health Policy and Management, York University; Emergency Department, University Health Network; Associate Professor, Department of Family and Community Medicine, University of Toronto, 121 Walmer Rd., Toronto, Ontario M5R 2X8, Canada, fax 416/736-5227, [email protected] Reprints: Dr. Lexchin

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References 1. Greenberg DS. Conference deplores corporate influence on academic science. Lancet 2003;362:302-3. 2. Pharmaceutical Research and Manufacturers of America. Industry profile 2003. www.phrma.org/publications/publications/profile02/index.cfm (accessed 2004 Jan 6). 3. Blumenthal D, Gluck M, Louis KS, Stoto MA, Wise D. University–industry research relationships in biotechnology: implications for the university. Science 1986;232:1361-6. 4. Blumenthal D, Campbell EG, Causino N, Louis SK. Participation of life-

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science faculty in research relationships with industry. N Engl J Med 1996;335:1734-9. Moynihan R. The making of a disease: female sexual dysfunction. BMJ 2003;326:45-7. Tallon D, Chard J, Dieppe P. Relation between agendas of the research community and the research consumer. Lancet 2000;355:2037- 40. Dorman PJ, Counsell C, Sandercock P. Reports of randomized trials in acute stroke, 1955 to 1995: what proportions were commercially sponsored. Stroke 1999;30:1995-8. Blumenthal D, Causino N, Campbell E, Louis KS. Relationships between academic institutions and industry in the life sciences—an industry survey. N Engl J Med 1996;334:368-74. Gluck ME, Blumenthal D, Stoto MA. University–industry relationships in the life sciences: implications for students and post-doctoral fellows. Res Policy 1987;16:327-36. Rosenberg SA. Secrecy in medical research. N Engl J Med 1996;334: 392- 4. Psaty B, Rennie D. Stopping medical research to save money: a broken pact with researchers and patients. JAMA 2003;289:2128-31. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326:1167-70. Blumenthal D, Campbell EG, Anderson MS, Causino N, Louis KS. Withholding research results in academic life science: evidence from a national survey of faculty. JAMA 1997;277:1224-8. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-5. Campbell EG, Louis KS, Blumenthal D. Looking a gift horse in the mouth: corporate gifts supporting life sciences research. JAMA 1998;279:995-9. Bodenheimer T. Uneasy alliance: clinical investigators and the pharmaceutical industry. N Engl J Med 2000;342:1539-44. Stelfox HT, Chua G, O’Rourke K, Detsky AS. Conflict of interest in the debate over calcium-channel antagonists. N Engl J Med 1998;338:101-6. Choudhry NK, Stelfox HT, Detsky AS. Relationships between authors of clinical practice guidelines and the pharmaceutical industry. JAMA 2002;287:612-7. Gross DP, Gupta AR, Krumholz HM. Disclosure of financial competing interests in randomised controlled trials: cross sectional review. BMJ 2003;326:526-7. Kjaergard LL, Als-Nielsen B. Association between competing interests and authors’ conclusions: epidemiological study of randomised clinical trials published in the BMJ. BMJ 2002;325:249-52. Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326:1171-3. Huston P, Moher D. Redundancy, disaggregation, and the integrity of medical research. Lancet 1999;347:1024-6. Johansen HK, Gøtzsche PC. Problems in the design and reporting of trials of antifungal agents encountered during meta-analysis. JAMA 1999;282: 1752-9. Clifford TJ, Barrowman NJ, Moher D. Funding source, trial outcome and reporting quality: are they related? Results of a pilot study. BMC Health Services Research 2002;2:18. www.biomedcentral.com/1472-6963/2/18 (accessed 2004 Feb 10). Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003;289: 454-65. Baker CB, Johnsrud MT, Crismon ML, Rosenheck RA, Woods SW. Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry 2003;183:498-506. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 2003;290:921-8. Bhandari M, Busse JW, Jackowski D, Montori VM, Schünemann H, Sprague S, et al. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ 2004;170:477-80. Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, et al. A study of manufacturer-supported trials of nonsteroidal antiinflammatory drugs in the treatment of arthritis. Arch Intern Med 1994; 154:157-63. Safer DJ. Design and reporting modifications in industry-sponsored


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Implications of Pharmaceutical Industry Funding on Clinical Research comparative psychopharmacology trials. J Nerv Ment Dis 2002;190: 583-92. 31. Johansen HK, Gotzsche PC. Problems in the design and reporting of trials of antifungal agents encountered during meta-analysis. JAMA 1999; 282:1752-9. 32. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.

33. Davidoff F, DeAngelis CD, Drazen JM, Nicholls MG, Hoey J, Hojgaard L, et al. Sponsorship, authorship, and accountability. N Engl J Med 2001;345:825-7. 34. Naylor CD. Early Toronto experience with new standards for industrysponsored clinical research: a progress report. CMAJ 2002;166:453-6. 35. Schulman KA, Seils DM, Timbic JW, Sugarman J, Dame LA, Weinfurt KP, et al. A national survey of provisions in clinical-trial agreements between medical schools and industry sponsors. N Engl J Med 2002;347:1335-41. 36. Meier B. Group is said to seek full drug-trial disclosure. New York Times 2004;June 15:A1, C7.

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