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Week 8: Research issues, justice, and conflicts of interest

Introductory Essay

Index

Historical Aspects

Principles of Protection of Human Subjects

The Distinction: Research vs. Treatment

The Animal Subject

Recent Developments

Cross-Cultural and International Dilemmas

The Integrity of Research

The Individual Physician and Research Integrity

There are two general sorts of ethical questions pertinent to medical research. First, we could ask about the ethical duties the investigator owes to the research subject. (This could be asked whether the subject of the experiment is a person, or a non-human animal.) Second, we could ask what duties are incumbent upon all parties in order to maintain the integrity of the research enterprise generally. Some of the same principles pertinent to this second question may shed light upon the ethical relationship between physicians and industry, particularly the pharmaceutical industry.

For the purposes of this course, we situate the debate over research ethics within a larger question, conflicts of interest.  The physician-investigator has a conflict of interest between serving the interests of the patient (getting personalized treatment which will cure the disease), society in general (increasing medical knowledge for tomorrow even if individual patients today do not benefit), and herself (getting more grants, getting promoted, etc.)   We propose that physicians in practice today face two other very common conflicts of interest: 1) working within financial arrangements where reimbursement and rewards sometimes rely upon saving money by denying patients some services that could be helpful to them; and 2) deciding which sorts of gifts to accept from pharmaceutical manufacturers, in the face of ethical arguments that such gifts may undermine the integrity of medicine, and factual arguments that physicians are often unduly influenced by these gifts without being aware of it.  In this way the general ethical issue of how to manage conflicts of interest runs the gamut from highly dramatic cases like the Tuskegee syphilis study, to the most mundane questions of what drug company logo may be on the ball point pen in the physician's pocket.

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Historical Aspects

Research ethics and the protection of the human subject are historically important in medical ethics because the modern "bioethics" movement is said to have begun by grappling with these questions. After World War II, the U.S. was outraged by accounts of experiments conducted by Nazi physicians upon concentration camp inmates, often subjecting the victims to great pain and death. The post-war trials of the Nazi war criminals, including some of the most prominent physicians under the Hitler regime, led to international statements of ethical principles for research, for the first time articulating the duty to obtain the informed consent of the research subject. Thus, recognition of a duty for informed consent in research proceeded by at least a decade the formal recognition of a similar right of patients in medical therapy.

It was at first thought that these ethical problems in the conduct of research were restricted to totalitarian regimes like the Nazis. But this comfortable view was stripped away, first by an expose by prominent investigator Dr. Henry Beecher in the New England Journal of Medicine in 1966, revealing more than 20 research studies conducted by prominent U.S. investigators in which subjects were put at substantial risk without their informed consent. This was followed in 1972 by the revelations of the Tuskegee syphilis study, in which the U.S. Public Health Service had kept black men in Alabama from receiving effective antibiotic treatment for their syphilis for more than 25 years. Later it was revealed that many U.S. servicemen were subjected to experiments during and after World War II without their knowledge or consent. It gradually became clear that one need not be a Nazi in order to fall into the ethical trap of deciding that some presumed greater good overrode the health and well-being of the individual research subject– especially if the subject was poor or a member of a stigmatized minority group.

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Principles of Protection of Human Subjects

Because of these revelations of abuse, research on human subjects was the first area within bioethics to be subjected to government regulation and the imposition of formal ethical guidelines and procedures. These consisted primarily of requirements for informed consent of subjects, and creation of institutional ethics review boards (IRBs) to monitor compliance with the ethical guidelines within all medical institutions conducting research.

The regulations embodied two basic principles of bioethics– respect for autonomy and justice. The principle of beneficence, often invoked in patient care settings, was specifically set to one side in research ethics, because the investigator sets out to do good for humankind generally, especially in the future, through obtaining useful new knowledge– and does not set out specifically to do good for the individual research subject. Thus a conflict of interest is presumed– the individual subject must be protected from possible exploitation in the name of the greater good of the larger society.

Respect for autonomy is honored by the requirements of informed consent. By being openly told about the nature of the research, and then freely consenting, the subject becomes (in a moral sense) a colleague and collaborator in the research. Trying to create a sense of moral equivalence between investigator and subject is the opposite of what was stated in one research scandal of the 1960's, the Jewish Chronic Disease Hospital case, in which elderly hospitalized men were injected with cancer cells without informed consent. The lead investigator, Dr. Southam, was asked by a reporter if he would agree to be a subject in this experiment himself. He replied that the risk was very low (although one of their subjects developed disseminated cancer as a result of the trial); but since highly trained cancer researchers were so rare, it would be wrong of him to take even this small risk. This claim of being morally superior to the research subject was exactly what the duty of informed consent and respect for the subject’s autonomy was designed to reverse.

The second principle, justice, was invoked in response to the revelations that very often, risky experiments were conducted on subjects who were especially vulnerable and easily exploited. Prisoners and the mentally retarded, for instance, were disproportionately represented among the subjects of such research. The new government regulations specified additional safeguards, effectively raising the bar before research could be done on such populations. The principle of justice requires in particular that if one group of people within society stands to benefit the most from certain research studies, the risks and costs of those studies should be borne primarily by that same group. To subject prisoners or charity patients to risky experiments to develop new drugs or treatments which will benefit predominantly the well-to-do is unfair. Before a study is done on an easily exploited population, the investigators should show that it is for some reason not feasible to do the study on subjects more free to give or to withhold consent– as would be the case, for example, if a genetic disease exists predominantly within one minority racial group.

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The Distinction: Research vs. Treatment

Clinical investigators, used to conducting their research in a largely unregulated environment, chafed at these new rules during the 1970's and 1980's. One argument they raised was that experimentation was hardly confined to research settings. In treating a patient with hypertension, for instance, one might have to try several different medications and dosages before one found the treatment that controlled blood pressure effectively with the least side effects. But it was not demanded that the physician treating the hypertensive patient get approval from an IRB and have the subject sign an 8-page consent form.

This objection led bioethicists to specify the fundamental distinction between research and treatment, or perhaps more properly, between the investigator-subject relationship and the physician-patient relationship. "Experimentation," they admitted, could apply equally well to both realms and so was not the critical moral point. What was critical, rather, was that the research enterprise exists primarily to produce new knowledge while treatment is administered primarily to help the individual patient. True, the lines may sometimes be blurred. A research subject, undergoing a thorough physical exam for enrollment in the study, may be discovered for the first time to have a heart murmur and may get prompt diagnosis and treatment of an important valvular defect. A patient undergoing treatment in the physician’s office may develop a previously unreported adverse drug reaction, leading to publication of an important case report. But the fact that a research subject may gain personal health benefits, or that a patient may generate new knowledge, is a secondary phenomenon which does not negate the fundamental ethical character of the two activities respectively.

The conclusion then drawn from this distinction is that, because the primary goal of medical therapy is the benefit of the individual, the patient can trust the physician in a way that it would not be rational for the research subject to trust the investigator. Regulations for informed consent and patient protection in the therapeutic realm can therefore be somewhat less complex and less strenuous, because they supplement rather than replace this basic individual trust. More stringent regulations and protections are needed in the research arena precisely because the well-being of the individual is not the investigator’s first loyalty.

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The Animal Subject

Some philosophers of the 17th and 18th century argued that animals were mere objects which humans could ethically use for their benefit and convenience however they pleased. Surgical experiments on awake animals (vivisection) were commonly performed during this era. Both philosophical debate and public outcries against vivisection led to a gradual alteration of views, and it is now widely held that some ethical duties are owed to animal subjects as well as to human subjects. Regulations now exist to protect animals from unnecessary pain and suffering in the experimental setting.

In this teaching unit we will deal very little with animal rights, and with arguments that even with these new regulations, exploitation of animals for most experiments to benefit humans is unethical. We will simply note that this area of ethics is a serious debate with thoughtful views on many sides. Unfortunately, many physician-investigators have generalized from the "kooks" at one fringe of the animal-rights movement, and have concluded that any restrictions on the use of animals in experiments to benefit humans are ridiculous on their face. We find it unfortunate that otherwise intelligent scientists have been so quick to dismiss a valid and complex area of ethical discussion.

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Recent Developments

The general content of the research-ethics debate has changed since the 1980's when the informed consent and IRB movement was just becoming established. The current IRB structure is increasingly under attack, not from investigators yearning for the old days of no oversight, but from thoughtful investigators who argue that IRBs have become too bureaucratic and now protect the research subject from non-existent risks while ignoring more serious risks coming from another direction.

Research subjects have also chimed in with their own objections to the subject-protection bureaucracy. The predominant anecdote of the 1970's was the Tuskegee experiment and the Nazi exploitation, so naturally the focus of the rules promulgated in that era was protecting subjects from harm. In the late 1980's the predominant anecdote was how AIDS patients were being kept out of trials of new, promising, antiretroviral drugs because the investigators had decided that they did not quite meet the ideal study criteria. Subjects were now less worried about being saved from harm, and more concerned that a paternalistic bureaucracy would deprive them of the benefit from new treatments. Due to political pressure from AIDS activists, the inclusion criteria for some of these studies was considerably relaxed.

Also more recently, philosophers like Franklin Miller have begun to dispute the traditional distinction between the physician-patient and investigator-subject relationships. Miller has argued that it is psychologically unrealistic to expect that a well-trained physician who then undertakes a career in research will suddenly lose all her instincts to care about the well-being of patients, and search only for the advancement of knowledge. Nor should the blurring of roles be seen as an ethical defect, since it actually constitutes an additional protection for the individual subject. Miller is not proposing that we throw out IRBs and research regulations, but he does propose that we accept that this distinction is muddier than the bioethicists had at first proclaimed.

One way of making Miller’s point is to return to a often-quoted phrase from Henry Beecher’s 1966 expose: "the [most] reliable safeguard [is] provided by the presence of an intelligent, informed, compassionate, responsible investigator."  In the 1970's most bioethicists viewed this statement as a cop-out and demanded more regulations and bureaucracy. In the 21st century we now see that regulations and bureaucracy have created their own problems and have not necessarily provided the wholesale protection for subjects that we fondly imagined. We are now back to exploring how to hone the ethical sensitivities of the investigator, realizing that the ethical investigator is indeed an indispensable element in the ethical conduct of research.

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Cross-Cultural and International Dilemmas

The increasingly international conduct of medical research has also caused a strain on the two ethical principles invoked in the 1970's– respect for autonomy and justice. In the cross-cultural and international setting, it is not always clear what these mean.

The dilemma was well exemplified in 1998 by the debate over trials of antiretroviral drugs in West Africa and Thailand, in which a lower-dose regimen was compared to placebo in preventing transmission of HIV from mother to fetus. The trials were attacked because the lower-dose regimen was compared to placebo and not to the standard dose regimen currently in use in the US. Some commentators even compared these trials to the Tuskegee syphilis study as an exploitation of third-world populations without adequate consent. Opponents of the trials argued that the lower-dose drug regimen was still too expensive for the host nations, and so if it was shown effective, the benefit would accrue to the US by allowing us to save money on anti-HIV drugs in pregnancy. Supporters of the trials pointed out that the present standard of care in the host countries was no care at all, so that the placebo control group was defensible.

What does the principle of respect for autonomy require in this setting? Does it mean that people all over the world need to individually read and sign a Western-style consent form– even if they are illiterate and there is no satisfactory way to translate some complex medical concepts into the local language? Or does it mean that the consent process should mirror the extant cultural practices of the local community, such as consent by the village elder rather than by each individual person– even if some of those cultural decision processes reduce women and others in the community to second-class status?

What does the principle of justice require in this setting? Does it mean that subjects in the experiment must receive a level of care equivalent to patients in the West– even if such care is well beyond the ability of the host nation to pay for, and even if providing that level of care is tantamount to demanding that the agency funding the research single-handedly reform the health care system of the host nation? Or does it mean that the level of care provided and tested should deal with the real-world problems and economic limitations of the host nation– even if that level of care is well below that of the US, and even if US populations may reap substantial benefits from the results of the research?

When two well-meaning and thoughtful observers can survey an experimental study in a third-world country, and one sees shameless exploitation of the local populace where the other sees a realistic attempt to help the host country with its health problems, this particular debate within research ethics is bound to continue.

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The Integrity of Research

The second large area of research ethics has less to do with the protection of the subject and more to do with the fundamental integrity of the research process itself.

Research as we conceive of it demands commitment to certain basic principles, including truthfulness in gathering and reporting data, and openness in sharing results so that they can be duplicated and criticized by the larger community of scientists.

For many years, it seemed as if the major threat to these principles came from a few individual scientists, motivated by fear of being thwarted in their career advancement, who deliberately falsified research data. More recently we have become more aware of a systematic threat to research integrity from the increasing commercialization of medical research.

When pharmaceutical and biotechnology firms invest millions of dollars in the development of a new treatment– and when rumors of a treatment’s failure in research trials might cause the company’s stock to lose a quarter or a third of its value in the market– then financial incentives within the industry may run directly counter to the integrity of the scientific process as traditionally conceived. Firms have a strong incentive to squelch the publication of experimental data which are unfriendly to its product, and to keep positive experimental findings secret so that competitors cannot gain an advantage. We even see a rush to patent genes, cell lines, and other products of human biology.

In recent years numerous "scandals" related to the commercialization of research have appeared in the public and medical press. Physician-investigators have lost their jobs or been threatened with lawsuits by drug companies for trying to publish data which the company did not want released. Drug companies, frustrated with the slowness of the university research process, have turned to for-profit, non-academic research firms to conduct the drug trials required for approval of new drugs. This has in turn spawned a cottage industry of private physicians, with little research training, contracting with the for-profit firms to conduct clinical trials. At least a few such physicians have been found submitting fraudulent data so as to maximize their own profits. For-profit research firms have turned to for-profit IRBs to provide "ethical" review of the research studies and the use of human subjects.

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The Individual Physician and Research Integrity

The ethical issues in assuring the integrity of the scientific research process may at first seem quite distant from the life of the individual medical practitioner– assuming that the practitioner has not elected to run a for-profit clinical trial business out of his office. But included in this set of ethical issues is the general question of the correct relationship between the medical profession and the various industries that supply essential products needed to treat patients. Hardly anyone wants to stop the development of new drugs or shut down companies which devote themselves to producing high-quality, high-purity products. So how can the medical profession as a whole, and the individual physician as part of the profession, reap the appropriate benefits of the relationship with industry, while avoiding practices which threaten the ethical integrity of medicine?

This issue arises in a microcosm in an everyday ethical problem– how physicians should relate to drug detail people and others who market drugs and other medical products. The marketing of drugs to physicians has become a huge business, with more being spent annually in the U.S. on marketing to physicians than is spent on all medical schools and all residency programs combined. Defenders of these practices– which may include something as innocent as a free ballpoint pen with the name of a popular drug printed on it, all the way up to all-expense-paid vacations at plush resorts (spouse included) for physician "opinion leaders" who agree to listen to a 3-hour "medical education" program organized by the company– argue that this is the most effective way in a capitalist society to disseminate new information to practitioners, and that individual practitioners can properly assess the value of the information provided without undue bias. Opponents point to studies that the information provided by detail people is often slanted or wrong, and that physicians are indeed heavily biased by this information though they often do not recognize this.

The line between medical research ethics and individual practitioner integrity is often crossed in marketing efforts because at least some ethically questionable marketing practices are packaged as research. For instance, physicians may be paid a fee to fill out a short form each time they prescribe a new drug. Ostensibly the physician is being paid to provide research data to the company as part of post-drug-release surveillance. But critics charge that what is often happening is that the scientific value of such forms is nil, and physicians are instead being paid a fee for prescribing the new drug as much as they can.

What counts as a balanced approach to this area of practice, which accepts the positive value of a capitalist, free-market culture and system of supply, while still preserving the integrity of the profession by demanding that the drug prescribed for the patients should represent the physicians' best scientific judgment, and not which company bought them dinner at an expensive restaurant last week?

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