Over the course of the last two decades, the clinical research paradigm has shifted dramatically, creating different brands of ethical issues than were typically encountered in the past. Whereas clinical studies were primarily conducted by researchers in academic centers, largely funded by federal sources, the majority of clinical trials are now sponsored by the pharmaceutical industry, and occur in community practice settings. [1] This new investigational structure does not tend to encourage ethical misconduct related to scientific enthusiasm trumping patient safety, as was seen in early documented abuses such as the Tuskegee Syphilis Study; [2] rather, conflicts of interest threatening patient safety and scientific integrity are generated by attractive financial incentives and lack of attention to the challenges inherent in superimposing the role of investigator onto that of clinician. [3] Unfortunately, in spite of several high-profile cases resulting in the concrete identification of many of the pertinent ethical issues, many of the causative behaviors persist, and adoption of preventative measures has been dismayingly unenthusiastic. Here, we revisit these ethical controversies in clinical research, and ask once again what approaches might be taken to remedy the most concerning of these practices.

The majority of private-sector studies are designed by pharmaceutical companies, and then coordinated by contract research organizations (CROs). CROs are hired by pharmaceutical firms to provide institutional review board (IRB) services, recruit clinical investigators with access to an appropriate study population, enroll patients, and assist in data collection. [4] The pharmaceutical sponsors then complete their own data analysis and decide whether to submit the studies for publication. [5] Although this approach has succeeded at being a cost-efficient method for bringing new drugs from the human trial phase to market on a shorter timeline than those conducted in traditional academic settings,[6] these kinds of studies are clearly rife with potentially questionable ethical practices.

To clearly understand what is at stake, let us review the proven varieties of unethical research tactics employed by pharmaceutical companies in the last decade: 1) seeding (marketing) trials (clinical trials designed to look like scientific inquiry, but with the actual intent of increasing the use of branded pharmacotherapies by encouraging physician-investigators to become familiar with the product and therefore prescribe it more often, and unwittingly “market” it to colleagues and patients), 2) ghostwriting and guest authorship (crediting publications to prominent authors with little involvement in the actual execution or planning of the study in order to bolster the legitimacy of the article), and 3) selective publication and reporting (publishing only positive results and suppressing publication of negative results, and distorting trial results to imply better outcomes).[7] Most of these schemes require the participation of physician-investigators, whether they are aware of deception or not. In many cases, however, the deception was apparent, and physicians still participated.

In addition to the above, other no less important ethical concerns with industry contract research are those relating to financial incentives creating conflicts of interest with investigators involved in patient recruitment and retention in studies; financial motives influencing data collection and interpretation; the potential partiality of industry-sponsored IRBs; and investigators tasked with leadership possessing little to no scientific knowledge about the study design or drugs involved and with little to no education or experience in clinical research or principles of research ethics, leading to breaches in the fiduciary nature of the physician-patient relationship and to violations of patient autonomy.

A clear pattern emerges of favoring stockholder interests over those of patients and public health. It is paramount to recognize that although industry money may further clinical research, it has also done much to sully it. Professionals and professional organizations have not adequately fulfilled their roles as patient advocates in this regard, allowing industry to sow distrust in the public mind towards medicine and scientific inquiry. This has undoubtedly contributed to the damaging anti-science rhetoric that has increasingly saturated public opinion of late.

Much of the literature addressing conflicts of interest in industry-sponsored research focuses on the financial conflicts—according to Lemmens, this is an appropriate emphasis because “financial interests are objective, fungible, and quantifiable,” [8] and that “financial interests have an impact on the behavior of many physicians and researchers….such interests ought to be regulated more efficiently.” [9] While it appears that some of the most egregious financial inducements to dubious research practices have begun to be addressed by professional and legal policies (particularly regarding disclosure), [10,11] other potential serious lapses in ethical research behavior continue with surprisingly little attention. And although solutions to biased or unethical research are being pursued, compliance with proposed remedies remains embarrassingly low considering the gravity and number of research conflict scandals in recent years, [12] and how long subversive industry research practices have been known by the scientific and medical community. A major report on conflicts of interest in biomedical research and education was released by the Institute of Medicine in 2009, [13] somewhat accelerating the attention given to improving clinical research practices. [14] For example, the Pharmaceutical Research and Manufacturers of America (PhRMA) drafted their Principles on Conduct of Clinical Trials, [15] voluntary codes of research conduct were enacted regionally, the Association of American Medical Colleges issued conduct recommendations, and the Physician Payments Sunshine Act was enacted under the Patient Protection and Affordable Care Act. But as long as the majority of solutions remain essentially voluntary, adherence to ethical policies will likely continue to be inconsistent.

Contract research in the community setting creates a perfect storm of circumstances to breed an environment of research ethics violations. Competition for patient subjects results in large financial incentives for enrolling and retaining patients in studies. [16] Physician investigators do not design the trials, and are not necessarily knowledgeable about science behind the drugs being studied. Private sector clinicians do not work in an academic research environment, and are generally poorly educated about good research practices and ethics. They rely on the IRB process to establish the safety and ethics of the study, but have little ability to evaluate it themselves, abdicating any ethical responsibility beyond fulfilling the terms of the contract, collecting good data, and deciding whether the study is a good fit for their patients.[17] Meanwhile, IRBs are often contracted and paid for by the pharmaceutical companies, and thereby mired in financial and loyalty conflicts of their own.

Jill Fisher’s 2008 study indicated that many private practice physician investigators essentially create their own system of ethics around clinical research, but that their ethics are developed more in relation to the pharmaceutical sponsor, not in relation to their patients.[18] All of these factors contribute to a high probability of poor informed consent process, potential for poor patient selection and affected judgment regarding best treatments, and weak understanding of potential ethical pitfalls leading to abuses of patient safety and autonomy. To be sure, simply because there is the possibility of wrongdoing in the face of conflicts of interest does not imply the occurrence of wrongdoing—conflicts of interest indicate a tendency that appropriate policies and regulations are designed to minimize or avoid.[19] Strides toward avoiding the worst conflicts of interest have been made in recent years in academia, but much less has been done to address concerns in the private sector—the arena that pharmaceutical companies specifically sought out to bypass costly and less efficient regulations (regulations that protect patient subjects).

In academia, there certainly are issues of financial conflicts of interest, but investigators more often than not design their own studies, understand the science behind them, and are required by the Department of Health and Human Services (DHHS) to receive education and training in research ethics if federal money is supporting any of their trials.[20] There is more oversight, and IRBs are not hired by the study sponsors. Publishing study results has many motivations, including career advancement, prestige, and scientific interest, none of which are directly opposed to professionalism if prioritized correctly against primary commitments to patient care and scientific integrity. It is not as though these motivations do not exist in contract research, but investigators who are enticed with huge financial rewards and who have little personal stake in a study they didn’t design and possibly don’t fully understand are much more likely to stumble into problematic conflict situations (especially when they may not even be aware of what constitutes unethical conflicts of interest), since financial inducements are set up to far outweigh other more legitimate motivations.

Even when protective policies are adhered to in contract clinical research, it is unclear whether these measures are sufficient to protect patient interests in the intimate setting of the private doctor’s office. For example, disclosure of financial interests in a clinical trial by a private physician (for example, revealing that she is being paid by the pharmaceutical company to recruit patients and collect data for a study) might have unintended paradoxical effects. Simply revealing a conflict does not prevent inappropriate behavior, but can falsely increase a patient’s trust in his physician because disclosure might allay any fears of problems with conflicts. The patient is not necessarily in a position to accurately assess whether his physician’s conflicts will create a problem for him if he chooses to participate in the study. His level of trust for his personal physician may outweigh his ability to examine issues of conflict. On the other hand, revealing conflicts of interest to patients might create distrust or suspicion, even if the physician has only pure motives.

What would it take, then, for a private practice physician, who is recruiting her own personal patients with whom she has built an established relationship of trust, to be in a reasonably safe ethical position to pursue contract research? Various suggestions have been made to attenuate some of the ethical challenges inherent in these kinds of studies,[21] but few have been implemented, and none seem to seriously address the issue that doctors should probably not be recruiting their own patients into studies primarily for financial gain at all. Especially when many of these physicians do not have the expertise to protect their patients if there were ethical or safety issues with the studies, this practice clearly jabs at the heart of beneficent medical professionalism and at the very nature of the physician-patient relationship.

Physician and philosopher Edmund Pellegrino beautifully characterized medicine as an endeavor founded on the healing relationship.[22] When this commitment to trust and healing is compromised by secondary interests such as monetary gain, profound damage is done to the institution of medicine by eroding the likelihood of engagement in the authentic and intimate interactions that are required for effective patient care. If a patient comes to distrust her physician, and perhaps by extension the medical establishment in general, she will not be as likely to allow herself to be vulnerable enough to share personal information vital to medical diagnoses, or confident enough in medical advice to act on it. A line in the sand must be drawn that patients can see—it must be unequivocally clear that the physician is committed first to serve the interests of the patient, and that the profession does not tolerate interference with sound medical practice by financial incentives opposed to patient concerns.

At minimum, clinical research in private practice should fulfill several basic requirements to be considered ethical and worth pursuing: The benefits of research would have to outweigh the significant dangers posed to patient safety and autonomy, and to the trust within the physician-patient relationship; education in clinical research and ethics should be mandatory for all investigators and research staff (as it already is for federally-funded research); financial remuneration should be limited to covering the actual costs of research, and should not create incentives for poor patient selection, clouded clinical judgment, or “massaging” data to fit contract requirements; IRBs should be especially robust and unbiased considering their critical role in ensuring patient safety and proper informed consent. None of these requirements should be voluntary—these should be required. Additional concepts, including creating a “firewall” between industry and investigators in the form of regulatory agencies, have also been suggested. [23,24]

It could be argued that these requirements would likely have a limiting effect on the numbers of contract clinical studies done—undoubtedly, this is true. Taking into account the pharmaceutical industry’s poor record of research reliability, [25] these policies would surely also have a positive effect on the quality and clinical usefulness of such regulated studies—I would argue that this seems an acceptable, if not excellent, tradeoff. There is no sufficient reason to allow market forces to erode patient trust and well-being, to damage public confidence in the integrity of science, and to harm public health by allowing inaccurate or misleading studies to drive clinical guidelines (all of which has already occurred).

Considering the widespread complicity of practicing physicians with poor research practices, trusting to the individual to make professionally sound decisions regarding participation in industry-sponsored activities has thus far been proven unrealistic. Those many who would retain professional integrity over accepting easy corporate money have not been the problem—these physicians have likely not been the ones recruited by PhRMA companies, unless out of sheer naïveté. Even if in the minority, there have clearly been enough academic and private-sector doctors willing to succumb to financial inducements that these practices continue somewhat unabated decades after their first exposure. The government has provided stronger guidance for the academic sector, but unless these harmful tactics are made universally illegal (which appears unlikely in the foreseeable future), there is a responsibility for medical professional organizations to take the initiative to clearly delineate the bounds of ethical behavior in the research setting. Licensing bodies regulate medical practice and create enforceable guidelines for professional behavior; it does not seem unreasonable to also oversee allowable criteria for participation in industry-sponsored research in order to protect patient interests and the integrity of the medical profession. Physicians should lead the push to insist on clinical research that is relevant, transparent, safe, and honest, regardless of the source of funding.

In conclusion, as it has often happened in history, the ethics of research are trailing actual practices. Many of the questionable aspects of private contract studies have been known for decades, and yet the system continues to grow in prevalence with little in the way of regulation besides some recent advances in disclosure and trial registration efforts, mostly spearheaded by influential journals.[25] Protecting medical professionalism, and thus the physician-patient relationship, has not received much attention despite being one of the most potent reasons for avoiding the compromising nature of contract clinical investigation. As long as dubious research practices remain technically legal and difficult to police, medical professional organizations should fill this ethical gap and draft clear enforceable guidelines for participation in private clinical studies. Although private-sector pharmaceutical research is an economic behemoth not likely to go away any time soon, it needs to be held to the same standards as academia—the industry “loophole” for cheap, efficient studies should only be allowed to flourish to the degree that it is scientifically, ethically, and clinically sound—and it still has a long way to go.

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