Miller, Franklin G. PhD; Brody, Howard MD, PhD
Randomized controlled trials (RCTs) are a cornerstone of evidence-based medicine (EBM). Ideally, decisions about patient care are made in light of the balance of available evidence from RCTs concerning the efficacy and safety of particular drug treatments. Physician–investigators play a key role in developing EBM by designing and conducting rigorous and clinically useful trials, analyzing data objectively with respect to statistical and clinical significance, accurately reporting the results in peer-reviewed journals, and conducting systematic reviews and meta-analyses. The integrity of EBM depends critically on the accuracy and the utility of the evidence developed in RCTs. Our aim is therefore to raise consciousness about professional integrity with respect to physician–investigators’ involvement in RCTs, a preliminary step to enacting specific reforms.
Biases that Distort Evidence-Based Medicine
A major threat to EBM derives from the pervasive influence of the pharmaceutical industry on the design and conduct of RCTs and the analysis and publication of results from this research.1,2 Although drug companies fund most RCTs, contributing to EBM is not a primary goal of industry-sponsored research.1,2 The pharmaceutical industry supports RCTs to gain regulatory approval to market drugs and to persuade clinicians to prescribe, and patients to take, them. Profitable drug marketing does not necessarily coincide with promoting EBM. Trials designed to produce evidence needed to secure regulatory approval may have, at best, limited value to clinicians concerned with optimizing patient care.3
Moreover, some industry-sponsored trials are biased in ways that distort the truth about the efficacy or safety of drug treatments. Major biases include
* comparing a new drug with a subtherapeutic dose of a standard drug,4
* failing to publish negative studies with results unfavorable to company products,5,6
* selectively reporting favorable outcomes,6,7
* duplicating publication of positive results,8,9
* omitting adequate statistics for assessing clinical significance (e.g., confidence intervals),10 and
* promoting interpretive spin that exaggerates benefits or minimizes risks of company products.
Two major scandals that emerged during 2004—the suppression of studies showing increased suicide risk in children taking some selective serotonin-reuptake inhibitor (SSRI) antidepressants11 and the delay of up to four years in revealing the cardiovascular risks of rofecoxib (a COX-2 inhibitor)12—highlight the public health implications of allowing clinicians to make treatment decisions for their patients based on distorted or incomplete evidence resulting from commercial influence on RCTs.
The full extent of such publication bias in industry-sponsored trials is unknown. Yet a meta-analysis of 15 studies revealed that industry-sponsored research is more likely to report outcomes favorable to the drugs produced by industry sponsors than is independent research, with a summary odds ratio of 4.05,13 which shows strong bias. Another study showed that more than half of pharmaceutical companies reported requiring investigators to keep information confidential for more than six months after study completion, thus delaying the dissemination of potentially crucial information, and 12–34 % of industry-sponsored academic researchers reported requesting access to research results from their particular sponsors and being denied.14
The various forms of commercial bias in the design and reporting of industry-sponsored trials distort the evidence base for optimal clinical practice.15 The net result is that drugs marketed heavily by pharmaceutical companies may be less efficacious or less safe than the published literature suggests. Such biases in the evidence base guiding medical decisions may interfere markedly with both the quality and cost-effectiveness of medical care. Commercial biases in design and reporting are especially problematic when they occur in leading, peer-reviewed journals. Clinicians may regard the very fact of publication in these journals as an indicator of both the validity and importance of trial results.15 Indeed, pharmaceutical companies purchase and distribute reprints of favorable articles as a marketing tool. For example, the industry sponsor of the Celecoxib Long-term Arthritis Safety Study (CLASS) purchased 30,000 reprints of an article published in the Journal of the American Medical Association concerning the gastrointestinal toxicity of three drugs to treat arthritis.16 This commercially biased article reported a favorable side-effect profile for celecoxib, compared with two older nonsteroidal antiinflammatory drugs, based on only 6 months of follow-up. The data from the full study as originally planned (12–15 months of follow-up), however, failed to show reduced gastrointestinal complications.16,17
Bias in industry-sponsored research and its implications for EBM have received considerable attention in the medical literature.4,6,13,14 Typically, as with the scandals involving the SSRI and COX-2 inhibitor drugs, the primary thrust of published commentaries has been to call for more effective regulation of clinical research. Appropriate regulatory reform is vitally needed, but will in the final analysis prove inadequate unless at least some attention is paid to another factor, much less addressed—the ethical implications when physician–investigators contribute to the distortion of EBM in service of the business mission of pharmaceutical companies, the income of academic medical centers, and personal financial rewards.18,19
To mention just one example, it was somewhat unusual to hear the following question asked during the early months of 2004: just where were the leaders of U.S. child psychiatry during the period of time that studies were being suppressed about SSRIs that they themselves had conducted?20 It later was revealed that these leaders attempted to assess the true situation but were prevented by having effectively signed away their rights to access the total body of data from their own research. In the end, rather than sounding a warning, they issued a statement reassuring clinicians about the safety of prescribing SSRIs to children—a statement based in hindsight on incomplete data, and arguably influenced by their own financial ties to the industry.21 It is quite appropriate to ask what sort of regulatory reforms might prevent such a debacle in the future; but it is equally important to ask what ethical responsibility these academic leaders ought to assume for their behavior.
Professional Integrity and Clinical Research
The privilege, authority, and prestige enjoyed by professions depend ethically on the trustworthiness of professionals. EBM and clinical research are both necessarily practiced within a climate of trust. Patients trust that physicians are competent and that they prescribe drug treatments based on sound evidence demonstrating their effectiveness and safety. Research participants trust that clinical trials have promise of producing clinically valuable knowledge and that their participation in these trials will not expose them to avoidable harm. Professional integrity assures that clinicians and investigators are trustworthy.
Every profession is devoted to serving goals that define that profession’s ethical orientation. In addition, professionals recognize ethical norms that constrain and guide their conduct in pursuit of professional goals. Accordingly, we understand “professional integrity” as loyalty to proper professional goals and faithful compliance with professional norms.22 Traditionally, professions have distinguished themselves from profit-oriented business by dedication to ethical goals of service to persons in need and to society and by commitment to ethical standards of conduct that are more stringent than the mores of the marketplace.23
The primary goal of clinical research is to develop generalizable scientific knowledge with the aim of promoting health and improving medical care. A set of ethical norms constrains and guides physician–investigators in the conduct of clinical research. These norms include seeking to answer clinically valuable research questions, using valid research methods, protecting the rights and well-being of research participants, and reporting the results of clinical research accurately and honestly.24 Physician–investigators violate or compromise their professional integrity when they engage in conduct that fails to serve the primary goal of clinical research or contravenes the ethical norms governing the conduct of such research. Perhaps most important, established investigators who engage in such ethically deficient conduct serve as negative role models to junior physician–investigators seeking guidance in the direction of their own careers in research.
Because the financial goals of pharmaceutical and biotechnology companies are not inherently aligned with the primary goal of clinical research, the involvement of physician–investigators within or outside of academic medicine in industry-sponsored clinical trials poses challenges to their professional integrity. If physician–investigators were to refuse any financial ties to industry, these challenges would be obviated, but this would severely hamper the conduct of clinical research and the development of EBM. Moreover, professional contacts between academic investigators and industry provide an exchange of expertise and sound advice that can promote good science in service of patient care as well as ethical conduct by the pharmaceutical industry. The professional integrity of academic medicine, however, calls for ties between physician–investigators and industry that serve the goals of clinical research and observe appropriate ethical constraints. Questions have been raised in recent years concerning whether academic medicine is “for sale.”25 Financial ties between academic investigators and industry are not inherently ethically suspect; yet the terms on which professional services are sold must be consistent with professional integrity in order to be above suspicion.
Academic researchers’ ties to industry differ in their propensity to conflict with professional integrity. Grant support to academic medical centers to conduct industry-sponsored trials does not compromise professional integrity per se, as long as the research is directed toward the primary goal of EBM, the design is unbiased, and investigators avoid commercial bias in reporting study findings. On the other hand, consulting and speaking fees paid to academic physicians that essentially amount to helping drug companies market their products to physicians are hard to square with their professional integrity as investigators or as physicians.
In any case, there is moral peril in extensive financial relationships between physician–investigators and the pharmaceutical industry. The danger is that investigators will come to identify with corporate goals, thus subordinating the pursuit of sound research by participating in clinical trials that are biased to favor company products or by reporting and interpreting clinical trial results in ways that are favorable to corporate sponsors. The acquiescence or active involvement of physician–investigators in commercially biased research violates their professional integrity in a number of ways. Flawed study design and failing to report the truth about medical treatments depart from the primary goal of clinical research, while compromising the protection of research participants. Risks to patient–participants of research interventions are justified in part, or entirely, by the value of the knowledge to be gained from research.24 Bias in trial design or reporting reduces the social value of clinical trials. Accordingly, it diminishes the risk–benefit ratio of trial participation and is unfair to participants who volunteer to undergo risks for the benefit of future patients.
Not to mince words, Chalmers has characterized publication bias as “scientific misconduct”: “Failure to publish an adequate account of a well-designed clinical trial is a form of scientific misconduct that can lead those caring for patients to make inappropriate treatment decisions.”26, p. 1,405 Insofar as industry-sponsored trials likely distort EBM, physicians who contribute to this research, and benefit financially and professionally from it, share in the responsibility for the deleterious consequences to the quality of scientific evidence and therefore to the quality of optimal patient care.
A culture of entrepreneurialism has penetrated academic medicine, encouraging physician–investigators to collaborate with the pharmaceutical and biotechnology industry.27 Academic physicians typically must raise funds for salary and research support from industry grants and contracts. Moreover, the clinical trials enterprise has become more competitive in recent years, with a growing proportion of trials conducted by contract research organizations and site management organizations that recruit community physicians to enroll patients, thus bypassing academic medical centers.1–2 In response, academic medical centers have retooled their research enterprises with an eye to expanding market share in the clinical trials business. Consulting arrangements and speaking engagements with industry offer lucrative opportunities for academic physicians to enhance their personal incomes.
The language most commonly used in the literature to call attention to this set of problems is that of “conflicts of interest.” The current academic medicine environment is rife with conflicts of interest that involve individual physicians, professional organizations, medical journals, and academic medical centers—not to mention the government agencies and legislatures to which many now turn with calls for regulatory reform. Conflicts of interest, however, do not by themselves span all the issues of ethical importance. At worst, the “conflict of interest” language might perpetuate the problem by suggesting that such conflicts are inevitable, appearing to justify even the most flagrant breaches of professional ethics, or easily manageable, suggesting that mere disclosure is sufficient to neutralize ethical concern regarding compromises to professional integrity.
It is time for the medical profession to stand back and examine ethically its role in contributing to biased industry-sponsored research. While it is a commonplace that he who pays the piper calls the tune, many in the profession appear to have evaded a sense of responsibility for playing the industry tune in designing, conducting, and reporting clinical research. Just as practitioners appear to be in a state of denial that accepting gifts from drug sales representatives influences their prescribing,28 physician–investigators appear seduced by the comforting illusion that they can profit financially from research and consulting relationships with the pharmaceutical industry while continuing to pursue the scientific truth in service of patient care with no strings attached and with full academic freedom. The reassuring language of “managing conflicts of interest” helps to reinforce this self-deception.
Many physician–investigators also appear to have uncritically accepted the commercialization of their work. For example, in a recent article in the Washington Post on publication bias in studies of antidepressants taken by children, a psychiatric investigator involved in several industry-sponsored trials in this area noted that “he would like to see all the data published but he said the research had been paid for—and belongs to—the companies. ‘They have a legitimate right to do what they want with the data,’ he said.”29, p. A1 It is debatable whether or not pharmaceutical companies have a legitimate right to control publication; nevertheless, physician–investigators who conduct studies knowing that negative findings are unlikely to be published compromise their professional integrity. Whereas commercial secrecy is a common business practice, concealment of research findings is antithetical to the ethos of science and EBM.30 Accepting such concealment as merely conforming to usual practice provides unfortunate evidence that some have jettisoned a professional ethic and replaced it with a commercial one.
Physicians cannot escape responsibility for contributing to commercial biases in medicine’s evidence base. Physician–investigators often sign contracts acknowledging the proprietary control of industry sponsors over the dissemination of research results, thus acquiescing in publication bias.14 Some write, or merely identify themselves as authors of, articles that selectively report findings and spin the interpretation of results to favor industry products. Other physicians contribute, as peer reviewers or editors, to decisions to publish articles suffering from patent inadequacies in the reporting of data, such as the omission of confidence intervals that permit assessment of the clinical significance of findings,31 thus facilitating interpretive claims that are not supported by the reported results. Perhaps the most extreme case of unprofessional behavior with regard to publication is ghost-writing, where distinguished academic physicians are paid to sign their names to articles that have in fact been prepared by professional writers hired by the company to spin the research in the way judged best for sales promotion.32
Preventing Commercially Biased Research
The enormous attention to conflicts of interest in clinical research has focused predominantly on calls for reporting financial interests in scientific publications.33 Such disclosure may alert critical readers to the need for extra care in interpreting study results but does nothing to prevent the biased omissions and commissions that distort EBM. Moreover, disclosure may work against its intended goals of increasing awareness of conflicts of interest. The senior investigator who discloses consulting relationships with a dozen or more drug firms may impress the audience as being more highly regarded in the field than will the junior investigator who has only one or two conflicts of interest. And the existence of multiple ties to different firms might suggest to the audience that these conflicts effectively cancel each other out, leaving the investigator objective and unbiased. Most important, if a physician–investigator hides or shades the scientific truth in order to produce research results favorable to commercial interests, the mere disclosure of a financial tie will not turn this unethical behavior into ethical behavior.
Preventing or minimizing commercially biased research will require institutional reforms. The registration of clinical trials has figured prominently in public discussion of needed reform.34 Since 1997, registration has been required by the Food and Drug Administration for all trials of drugs for “serious or life-threatening diseases and conditions.”35 However, there is no enforcement process and compliance has been spotty. Recently, the International Committee of Medical Journal Editors (ICMJE) has required prior trial registration as a condition of publishing trial results.36 This provides a strong compliance incentive for pharmaceutical companies seeking publication for the trials they sponsor in medical journals that endorse this policy. Nonetheless, the adequacy of trial registration in preventing biased research depends on what information is mandated for inclusion. The ICMJE statement on clinical trial registration lists a set of minimal informational criteria, including disclosure of the intervention and the comparator, the study hypothesis, and the primary and secondary outcomes under investigation. The statement asserts, “To our knowledge, at present, only http://www.clinicaltrials.gov, sponsored by the United States National Library of Medicine (NLM), meets these requirements.”36
Yet industry-sponsored trials registered on this Web site do not uniformly satisfy these criteria.37 For example, one Pfizer study is described as a 24-week study of a daily oral investigational drug versus placebo in patients with persistent asthma. The drug is not named, there is no mention of the study hypothesis, and neither primary nor secondary outcomes are listed. A Merck study of an unnamed investigational drug in patients with chronic low back pain is described as an active-controlled trial, but the comparator is not named and outcomes are not specified. In contrast, a National Heart, Lung, and Blood Institute placebo-controlled study of acid reflux therapy for asthma patients, also registered at 〈http://www.clinicaltrials.gov〉, identifies the study drug, describes the study rationale and hypothesis, and lists both primary and secondary outcomes.
Considerable effort and time will be required to implement an effective and accessible system of clinical trial registration. In the meantime, the appeal of organizations such as the ICMJE to professional integrity, by invoking ethical values and norms that most physician–investigators are apt to endorse, may help curb commercially biased research. However, no regulatory or professionally sanctioned schemes of trial registration and reporting standards, such as the Consolidated Standards for Reporting of Trials, endorsed by leading medical journals, can guarantee compliance.38 Professional integrity and vigilant peer review will continue to be needed to promote ethical conduct in study design and reporting. Public concern with commercially biased research is analogous to the situation of abusive exploitation of patient-participants in clinical research that was revealed in the mid-1960s. The appropriate policy response to that situation was mandating prospective and independent committee oversight of research involving human subjects and written informed consent documents. Effective protection of participants continues to depend, however, on the professional integrity of investigators.39
Educational interventions are needed to promote professional integrity in clinical research. For example, education in EBM, which develops skills in critically appraising the research literature for medical students and physicians in training, should also address commercial biases and professional integrity. Continuing medical education for physician–investigators should include instruction in how to detect practices that promote commercially biased research and the ethical reasons for avoiding these practices. What follows are our observations regarding the general need for heightened consciousness, which is the first step toward formulating concrete solutions.
A change in the culture of academic medicine is needed to restore professionalism. Recognition and respect should be accorded to academic physicians who manifest unstinting dedication to science and patient care and scrupulously avoid integrity-compromising ties to the pharmaceutical and biotechnology industries. However, it is unlikely that anything will change for the better as long as academic physicians who do the bidding of industry in exchange for various forms of payment suffer no deleterious consequences to their careers. As Kassirer has recently observed, “Professional organizations must no longer look away from this issue. If they wish to retain the trust of the public, they must develop far more high-minded policies, indeed ones that would embarrass physicians who collaborate with industry’s marketing goals and would reward doctors who remain free of such conflicts.”27, p. 199
Physician–investigators and academic medical centers must also take a hard look at their own behavior to ask how the no-holds-barred pursuit of research funding has led to practices that, if widely known, might not pass the public-trustworthiness test. In the wake of revelations about concealed risks of medications has come the predictable wave of lawsuits against pharmaceutical manufacturers. The medical profession has always adopted a very dim view of allowing the tort law system to regulate its affairs. One might ask, however, even if only as a thought experiment, what the consequences would be if all of the academic physicians who are listed as authors of papers that downplayed studies’ risks—or who carried out research that revealed risks but that was not published—were named as co-defendants.40 Were it not for the distinguished reputations of these authors, it might be argued, practitioners might have been more reluctant to prescribe the medications those authors tested and implicitly endorsed; hence the authors share some of the responsibility for the ultimate harm that was caused. One might extend the thought experiment to lawsuits aimed at the academic medical centers that allowed their reputations to be used as marketing ammunition by pharmaceutical companies, and that neglected to assure that their individual faculty members adhered to high standards of scientific integrity. If we shrink from the above proposal to use tort lawsuits as the way to police unprofessional behavior among physician–investigators, what equally effective way to improve professionalism can be implemented in its place? The medical profession is made up of both individual practitioners and institutions devoted to health care and medical research. All in the end must display a high level of professional integrity if the profession is to thrive and serve its public-service mission. Today, lack of integrity at all levels feeds on itself. Investigators and academic medical centers equally pursue lucrative research grants without asking whether the end result will promote EBM. Professional organizations and their journals in turn depend for much of their operating funds on pharmaceutical companies and their advertising. It will prove difficult to correct these unprofessional behaviors at all levels simultaneously. The cost of not doing so, however, is nothing less than a massive betrayal of public trust.
Some physician–investigators will only be prevented or deterred from unprofessional conduct by policy reforms and regulatory sanctions. However, in the entrepreneurial climate of contemporary medicine, many investigators may have participated in commercially biased research without reflecting seriously on the ethical implications with respect to the evidence base for medical care, the well-being of patients, and fairness to research participants. Moral education and accountability are served by attention, from the public and within academic medicine, to lapses in professional integrity that have contributed to commercially biased research and thus distorted EBM. Even the best policies governing professional conduct can be maximally effective only if supported by professionals of integrity.
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