Joel Lexchin, the author of the translated article, indicates that the pharmaceutical industry is in a situation of conflict. The economic fate of pharmaceutical companies depends on the favourable outcomes of the trials they sponsor, which may make it tempting for them to try and influence studies they are involved in. This situation exists not only in the pharmaceutical industry, but also in the tobacco industry, the banking community, the food and drinks industry and even, as has recently emerged, in the automotive industry.
Lexchin mentions several interventions that the pharmaceutical industry can use to influence the results of the scientific research they sponsor. When these positively biased results are published in journals as research papers, readers who are unaware of this bias can be misled. Below we discuss a number of points that could help readers evaluate papers that present overly optimistic messages. In fact, most of these aspects have already been discussed in previous issues of Geneesmiddelenbulletin. In Gebu 2012; 46: 138-145, Lexchin discussed several aspects of the way the pharmaceutical industry is influencing the results of clinical drug trials. The present article can be regarded as a further clarification of these matters.
Information about new drugs should not be provided by persons who might stand to gain financially from the information provided, even more so when gifts or presents are involved. When doctors of pharmacists read or discuss articles, it might be useful if they do so together with an expert on evidence-based medicine (EBM). They should always check who sponsored the trial.
In selecting articles, readers should limit themselves to the scientific literature, and take several key points into account. For instance, the conclusions presented by authors in the abstracts of their articles often do not follow logically from the research findings. They tend to be too optimistic, and there is usually little reason to attach great value to them. The titles of articles are intended to draw the readers’ attention, but lack subtlety and rarely represent the content correctly. When Geneesmiddelenbulletin discusses articles in the section on New Research, it first presents the conclusions drawn by the authors, and then evaluates this conclusion using criteria to assess the internal and external validity of the study. Occasionally, the authors’ conclusion is judged to be fairly correct; in most cases, however, the validity proves to be highly doubtful. Nor should one attach great value to interviews with the authors presented on the journal’s website, especially if they are in the employment of the industry and depend on external sponsors. Similarly, the press releases published by the manufacturers will not offer a critical assessment of the internal and external validity of the research, as they are intended to convince people of the value of the new drug or the new treatment. Newspaper and magazine journalists are often insufficiently or not at all able to evaluate the problems of the validity of study findings, and tend to take the authors’ conclusions for granted. The value of newspaper headlines has frequently been discussed.
Supplements of medical journals are usually paid for by the manufacturers, and the articles published in them are not subject to the usual process of peer review. Geneesmiddelenbulletin does not regard articles published in such supplements as evidence and does not include them in reference lists. Proceedings of symposia and articles from journals not included in the electronic PubMed database are not regarded as scientific evidence either. Nor does Geneesmiddelenbulletin waste any time on video conferences or abstract services.
Reading and evaluating ‘Papers to change practice’ takes a lot of time and effort, and readers would do better to wait for the new version of the guidelines published by their professional associations. Readers who nevertheless want to evaluate article themselves, can find recommendations for this in sources like Geneesmiddelenbulletin. A recent issue of the Nederlands Tijdschrift voor Geneeskunde (Ned Tijdschr Geneeskd 2015; 159: 1044-1052) elegantly presented advice on the way in which articles should be read.
In addition to the abovementioned criteria for the evaluation of articles and other publications, which can be relatively easily applied, some more general criteria could be added. The larger the number of patients included in a trial, the higher the chances that a statistically significant effect will be found, and the lower the clinical relevance of the effect for individual patients. If an effect can only be found using various highly complicated statistical procedures, such as non-protocol subgroup analyses, the scientific significance of the evidence is doubtful. In evaluating an articles, one should take the sponsoring and the conflicts of interest reported by the authors into account. Weaknesses in an article or study are often revealed in letters to the editor, but such letters usually only appear in the journal several months after the original article was published. In addition, the European registration authorities have to authorise a new drug if it has been proven not be inferior to the drugs that are already on the market.
Geneesmiddelenbulletin has previously discussed some other methodological aspects of evaluating drug research. Gebu 2015; 49: 27-34 explained the pitfalls of interpreting non-inferiority studies. This type of study is usually not the best option to assess the efficacy of a new drug; the best option for this purpose are superiority trials. Furthermore, there are major problems with the use of compound outcome measures (Gebu 2009; 43: 33-34), and with the use of the types of analysis that offer the greatest chance of a positive outcome (per-protocol analysis, last-observation-carried-forward (LOCF) analysis (Gebu 2000; 34: 17-22)). And readers should also consider the relevance of the outcome measures used.
Lexchin recommends erecting ‘a firewall between the money and the people doing the research.’ This would indeed eliminate a large part of the problem, viz. the influence of financial conflicts of interests on the results of research, and hence deserves recommendation.
The abovementioned aspects should be part of the curriculum of medical and pharmaceutical students, and be included in their exams. This will however become ever more difficult to realise, as the researchers are often affiliated to universities and are subject to these undesirable conflicts of interest. University-based researchers who cooperate with the industry should sign a contract stating that they will have to carry out their research completely independently, and obliging them to disclose all their study protocols, including all rough data and findings.
Finally, the editorial boards of journals should evaluate articles submitted to them more critically, and apply stricter requirements for the statistical analyses, the interpretation of findings and the conclusions drawn from them. Comparisons with the original study protocol ought to be standard practice for editorial boards. Generally speaking, journals should also publish articles with negative results.
Readers who take the above key recommendations into account when evaluating articles will often be disappointed about the scientific merits of most of the articles. This is unfortunate, but nevertheless a reality.
- Pharmaceutical industry profile 2011. Washington DC: PhRMA, 2011.
- National Institutes of Health. The NIH almanac – appropriations. U.S. Department of Health and Human Services, 2011.
- Moses HI, Dorsey ER, Matheson DHM, Thier SO. Financial anatomy of biomedical research. JAMA 2005; 294: 1333-1342.
- Hole OP, Winther FØ, Straume B. Clinical research: the influence of the pharmaceutical industry. Eur J Clin Pharmacol 2001; 56: 851-853.
- Patsopoulos NA, Ioannidis JPA, Analatos AA. Origin and funding of the most frequently cited papers in medicine: database analysis. BMJ 2006; 332: 1061-1064.
- Tallon D, Chard J, Dieppe P. Relation between agendas of the research community and the research consumer. Lancet 2000; 355: 2037-2040.
- Blumenthal D, Campbell EG, Causino N, Louis KS. Participation of life-science faculty in research relationships with industry. N Engl J Med 1996; 335: 1734-1739.
- Blumenthal D, Gluck M, Louis KS, Stoto MA, Wise D. University-industry research relationships in biotechnology: implications for the university. Science 1986; 232: 1361-1366.
- Zinner DE, Bjankovic D, Clarridge B, Blumenthal D, Campbell EG. Participation of academic scientists in relationships with industry. Health Affairs 2009; 28: 1814-1825.
- Krumholz SD, Egilman DS, Ross JS. Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial. Arch Intern Med 2011; 171: 1100-1107.
- Katz KA, Karlawish JH, Chiang DS, Bognet RA, Propert KJ, Margolis DJ. Prevalence and factors associated with use of placebo control groups in randomized controlled trials in psoriasis: a cross-sectional study. J Am Acad Dermatol 2006; 55: 814-822.
- Procyshyn RM, Chau A, Fortin P, Jenkins W. Prevalence and outcomes of pharmaceutical industry-sponsored clinical trials involving clozapine, risperidone, or olanzapine. Can J Psychiatry 2004; 49: 601-606.
- Djulbegovic B, Cantor A, Clarke M. The importance of preservation of the ethical principle of equipoise in the design of clinical trials: relative impact of the methodological quality domains on the treatment effect in randomized controlled trials. Account Res 2003; 10: 301-315.
- Psaty BM, Weiss NS, Furberg CD. Recent trials in hypertension: compelling science or commercial speech? JAMA 2006; 295: 1704-1706.
- Nieto A, Mazon A, Pamies R, Linana JJ, Lanuza A, Jimenez FO, et al. Adverse effects of inhaled corticosteroids in funded and nonfunded studies. Arch Intern Med 2007; 167: 2047-2053.
- Rochon PA, Sekeres M, Hoey J, Lexchin J, Ferris LE, Moher D, et al. Investigator experiences with financial conflicts of interest in clinical trials. Trials 2011; 12: 9.
- Mello MM, Clarridge BR, Studdert DM. Academic medical centers’ standards for clinical-trial agreements with industry. New Engl J Med 2005; 352: 2202-2210.
- Henry DA, Kerridge IH, Hill SR, McNeill PM, Doran E, Newby DA, et al. Medical specialists and pharmaceutical industry-sponsored research: a survey of the Australian experience. Med J Aust 2005; 182: 557-560.
- DiMasi JA. Success rates for new drugs entering clinical testing in the United States. Clin Pharmacol Ther 1995; 58: 1-14.
- Psaty BM, Rennie D. Stopping medical research to save money: a broken pact with researchers and patients. JAMA 2003; 289: 2128-2131.
- Trotta F, Apolone G, Garattini S, Tafuri G. Stopping a trial early in oncology: for patients or for industry? Ann Oncol 2008; 19: 1347-1353.
- Montori VM, Devereaux PJ, Adhikari NKJ, Burns KEA, Eggert CH, Briel M, et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005; 294: 2203-2209.
- 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.
- Lurie P, Wofle SM. Misleading data analyses in salmeterol (SMART) study. Lancet 2005; 366: 1261-1262.
- Psaty BM, Furberg CD, Ray WA, Weiss NS. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. JAMA 2004; 292: 2622-2631.
- Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000; 284: 1247-1255.
- Hrachovec JB, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 2001; 286: 2398.
- Wright JM, Perry TL, Bassett KL, Chambers GK. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 2001; 286: 2398-2399.
- Gøtzsche PC, Hrobjartsson A, Johansen HK, Haahr MT, Altman DG, Chan A-W. Constraints on publication rights in´ industry-initiated clinical trials. JAMA 2006; 295: 1645-1646.
- Jureidini J, Clothier R. Elsevier should divest itself of either its medical publishing or pharmaceutical services division. Lancet 2009; 374: 375.
- Bero LA, Galbraith A, Rennie D. The publication of sponsored symposiums in medical journals. N Engl J Med 1992; 327: 1135-1140.
- Cho MK, Bero LA. The quality of drug studies published in symposium proceedings. Ann Intern Med 1996; 124: 485-489.
- Rochon PA, Gurwitz JH, Cheung M, Hayes JA, Chalmers TC. Evaluating the quality of articles published in journal supplements compared with the quality of those published in the parent journal. JAMA 1994; 272: 106-113.
- Citrome L. Citability of original research and reviews in journals and their sponsored supplements. PLoS One 2010; 5: e9876.
- Kauffman M, Julien A. Scientists helped industry to push diet drug medical research: can we trust it? Hartford Courant 2000 April 10.
- Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in health postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333.
- Singer N. Medical papers by ghostwriters pushed therapy. New York Times 2009 August 5.
- Cowley AJ, Skene A, Stainer K, Hampton JR. The effect of lorcainide on arrhythmias and survival in patients with acute myocardial infarction: an example of publication bias. Int J Cardiol 1993; 40: 161-166.
- The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406-412.
- Lexchin J, Bero L, Djubegovic B, Clark O. Pharmaceutical industry sponsored research: evidence for a systematic bias. BMJ 2003; 326: 1167-1170.
- Ramsey S, Scoggins J. Commentary: practicing on the tip of an information iceberg? Evidence of underpublication of registered clinical trials in oncology. Oncologist 2008; 13: 925-929.
- Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Medicine 2008; 5: e217.
- Elm E von, Rollin A, Blümle A, Huwiler K, Witschi M, Egger M. Publication and non-publication of clinical trials: longitudinal study of applications submitted to a research ethics committee. Swiss Med Wkly 2008; 138: 197-203.
- Hole OP, Nitter-Hauge S, Cederkvist HR, Winther FØ. An analysis of the clinical development of drugs in Norway for the year 2000: the completion of research and publication of results. Eur J Clin Pharmacol 2009; 65: 315-318.
- Hall R, de Antueno C, Webber A. Publication bias in the medical literature: a review by a Canadian Research Ethics Board. Can J Anaesth 2007; 54: 380-388.
- Kho ME, Brouwers MC. Conference abstracts of a new oncology drug do not always lead to full publication: proceed with caution. J Clin Epidemiol 2009; 62: 752-758.
- Krzyzanowska MK, Pintilie M, Tannock IF. Factors associated with failure to publish large randomized trials presented at an oncology meeting. JAMA 2003; 290: 495-501.
- 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.
- Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252-260.
- Lee K, Bacchetti P, Sim I. Publication of clinical trials supporting successful new drug applications: a literature analysis. PLoS Medicine 2008; 5: e191.
- Bardy AH. Bias in reporting clinical trials. Brit J Clin Pharmacol 1998; 46: 147-150.
- Eyding D, Lelgemann M, Grouven U, Harter M, Kromp M, Kaiser T, et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 2010; 341: e4737.
- Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA 2008; 299: 2304-2312.
- Doshi P. Neuraminidase inhibitors: the story behind the Cochrane review. BMJ 2009; 339: 1348-1354.
- Huston P, Moher D. Redundancy, disaggregation, and the integrity of medical research. Lancet 1996; 347: 1024-1026.
- Tramer MR, Reynolds DJM, Moore RA, McQuay HJ. Impact of covert duplicate publication on meta-analysis: a case study. BMJ 1997; 315: 635-640.
- Spielmans GI, Biehn TL, Sawrey DL. A case study of salami slicing: pooled analyses of duloxetine for depression. Psychother Psychosom 2010; 79: 97-106.
- Jureidini J, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk & Safety Med 2008; 20: 73-81.
- Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001; 40: 762-772.
- Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med 2009; 361: 1963-1971.
- Chan A-W, Hrobjartsson A, Haahr MT, Gøtzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 2004; 291: 2457-2465.
- Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003; 289: 454-465.
- Sismondo S. Pharmaceutical company funding and its consequences: a qualitative systematic review. Contemp Clin Trials 2008; 29: 109-113.
- Lundh A, Lexchin J, Sismondo S, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Library 2011. Epub September 7, 2011.
- Lewis T, Reichman JH, So AD. The case for public funding and public oversight of clinical trials. Economists’ Voice 2007; 4: 1-4.
- Angell M. The truth about the drug companies. New York: Random House, 2004.
- Baker D. The benefits and savings from publicly funded clinical trials of prescription drugs. Int J Health Serv 2008; 38: 731-750.
- Shibuya K, Ciecierski C, Guindon E, Bettcher DW, Evans DB, Murray CJL. WHO framework convention on tobacco control: development of an evidence based global public health treaty. BMJ 2003; 327: 154-157.
- Røttingen J-A, Chamas C. A new deal for global health R&D? The recommendations of the Consultative Expert Working Group on Research and Development (CEWG). PLoS Medicine 2012; 9: e1001219.
*The literature refers to the Dutch text