History of Research Ethics

Advances in research ethics have primarily been instigated by the exploitation of human subjects. Even though some evidence suggests that ethical issues in human experimentation had been recognized and addressed as early as the late 1800s, the 1947 Nuremberg Code is commonly cited as the first document to govern the conduct of human research. This code arose from the war trials of Nazi physicians accused of conducting “murderous and torturous human experiments” on prisoners in concentration camps in the name of medical science. The Nuremburg Code was the first to formally outline standards for the ethical conduct of research on humans. It declared that voluntary consent is “absolutely essential,” subjects should be protected from “unnecessary physical and mental suffering and injury,” subjects may withdraw at any time from the experiment, researchers should stop the experiment if continuation is likely to be harmful to the subject, and the experiment has a legitimate likelihood of bearing fruit.

The period following World War II was marked by a time of increased medical research activity and the development of new methods. To further define the requirements for human experimentation, the World Medical Association published the “Declaration of Helsinki.” First adopted in 1964 at the meeting of the World Medical Association in Helsinki, Finland, the document has undergone multiple, often contentious revisions, most recently in 2008, to address evolving issues in human experimentation. The document builds on and reinforces many of the principles in the Nuremberg Code but excludes 2 of the 12 items in an effort to address perceived deficiencies in the Nuremberg Code. The requirement for voluntary consent of subjects was replaced by a statement that allows guardians to consent for research in subjects who are “legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor.” In doing so, the Declaration of Helsinki became the first document to address experimentation in children and others with limited decisional capacity. The other substantive changes included indications for cessation of research by the investigator, notification of subjects that they may withdraw at any time, and the distinction between therapeutic and nontherapeutic research.

The Declaration of Helsinki did not halt all questionable research activities in the United States. In 1966, Dr. Henry K. Beecher, a former anesthetist in chief at the Massachusetts General Hospital, published a landmark paper in the New England Journal of Medicine in which he exposed multiple instances of contemporaneous research that were in direct violation of what was declared at Helsinki. Beecher documented studies that withheld known effective treatment, administered known harmful therapy, and exploited incompetent patients and children. In the face of soaring research funding, Beecher placed a necessary and influential pause on the process to re-examine the ethics of the field and remind investigators, the field of medicine, and society about our moral responsibilities to research subjects. He also suggested that journal editors were responsible to reject manuscripts of unethical research in the hope that “failure to obtain publication would discourage unethical experimentation.”

In 1972, the Tuskegee Study of Untreated Syphilis became the impetus for the next page in the history of research ethics. The U.S. Public Health Service conducted the Tuskegee study from 1932 through 1972. The study withheld effective therapy for syphilis from hundreds of African American men to observe the progression of syphilis, presumably for the sake of medical research. In response to the horror generated by the discovery and exposure of this study, the U.S. Congress enacted the National Research Act in 1974. This act created the National Commission for the Protection of Clinical Subjects of Biomedical and Behavioral Research to oversee human experimentation in the United States. In 1979, the commission drafted the Belmont Report. The Belmont Report describes the basic ethical principles underlying the conduct of research—respect for persons, beneficence, and justice—and it applies them to research conduct by addressing the specific issues of informed consent, risk-benefit assessment, and selection of research subjects. In addition to establishing the commission, the National Research Act led to the Common Rule in 1991, a set of federal regulations necessitating oversight of government-funded research in the United States. Elements of the policy center on the presence and procedures of institutional review boards (IRBs) and general requirements for informed consent. Subsequent revisions of the regulations addressed vulnerable research subjects, including children.

Even though there is widespread support for the basic ethical principles addressed in these documents, their practical use is continuously debated and refined. Some researchers think that the regulations are necessary to operationalize these principles, whereas others see them as an excessive obstacle to research. The dilemma between promoting scientific advancement and protecting subjects is real and complex; staying on the narrow road that protects both interests requires thoughtful calibration and imaginative solutions.

Ethics of Research on Human Subjects

Applying ethical principles in performing research requires dedication to adherence. Emanuel and colleagues proposed seven requirements for ethical research that comprehensively define and guide evaluations of clinical studies on humans. These requirements provide an inclusive and detailed framework that should ensure performance of ethical research ( Box 81.1 ).

The requirement for social or scientific value requires that to justify potential risks and use of resources, the research should add knowledge to the field, regardless of whether it leads directly to changes in patient care. This requires avoiding unnecessary or needlessly repetitive research. Researchers are obligated to publish their research to benefit society. In pain research, value may include “immediate value,” which may immediately improve health, or “potential value,” which comes from the knowledge of better understanding the science of pain.

Scientific validity requires the research to have adequate methodologic rigor to potentially produce meaningful results regardless of the value of the proposed research. The scientific value of an idea alone does not ensure its validity.

Clinical equipoise is a requirement for interventional research validity and, accordingly, becomes a requirement for ethical research. It describes a state of uncertainty about the superiority of the prospective intervention over existing interventions and must be present for an interventional study to be considered ethical. Although clinical equipoise is the accepted basis for many clinical trials, its practical utility has not been without controversy. Because this stipulation has the potential to present a significant obstacle to initiating clinical trial research, distinctions have been made between individual versus community equipoise by delineating whether the uncertainty must lie with the individual investigator or within the expert medical community.

The requirement for scientific validity is also based on the idea that risks cannot be incurred nor resources used without a functional study design. In pain research, adequate study design may dictate the inclusion of a placebo arm, as often required by the Food and Drug Administration (FDA), a somewhat controversial topic addressed below.

Independent review of research by outside parties is conducted in an attempt to mitigate potential conflicts of interest and address inadequately designed research. In concept, it entails review of all research activity, including project proposal and design, data collection, ongoing monitoring of the research, and final analysis of the results. In practice, it is performed by funding agencies, IRBs, and safety-monitoring boards. Independent review bodies should specifically consider these seven requirements when analyzing the research being reviewed. Independent review is notably concerned about taking advantage of vulnerable patients such as those in chronic pain. Review processes are also pivotal in addressing conflicts of interest.

The requirement for respect for potential and enrolled subjects seeks to ensure privacy and confidentiality, allow subjects to freely withdrawal from research, inform subjects of the results of the study, and maintain the welfare of subjects. Though seemingly simple operationally, the complexity of this requirement lies in including all the principles and many of the requirements mentioned. In short, it demands placing the research subject as the primary center while still conducting useful research.

With reference to pain research, it is worth highlighting the idea of opportunity for withdrawal. People with pain may have unique barriers to accepting their freedom to withdraw from a study because of concerns about obtaining appropriate and effective alternative treatments once they have withdrawn.

Fair subject selection specifies that subject selection and opportunities for participation be based on the goals of the research rather than unrelated factors such as privilege or vulnerability and that those bearing potential risks by participating be able to experience the benefits. An example of research that would violate fair subject selection is testing a new medication primarily on a socioeconomically disadvantaged population for a disease that equally or primarily affects a more advantaged group. This may occur because academic centers are often centered in socioeconomically disadvantaged areas. An example of a different concern is not offering research participation to women when the disease and intervention being studied equally pertain to women. In this case, exclusion of women, perhaps for practical research reasons, may result in subsequent therapeutic recommendations that may not be applicable to the excluded group.

The converse of the requirement for equal opportunity inclusion is exploiting vulnerable populations for research that will not benefit that population or will not result in generalizable knowledge. Nazi experimentations were one such example. Another relevant study is the Willowbrook Hepatitis Study. At the Willowbrook State School for disabled children in Staten Island, New York, numerous disabled children were deliberately infected with infectious hepatitis to study the disease, as well as to test the effects of potential therapies, thus raising concern for exploitation.

For research to be justified, there must be a favorable risk-benefit ratio. Because much of the goal of research is to test untested interventions, the risks and benefits associated with such interventions will in part be unknown or uncertain. To justify research, however, potential risks must be minimized, potential benefits must be enhanced, and the risks and benefits must be commensurate.

When considering the potential benefit side of the balance, discussions should pertain to the benefits received by the subject or the subject’s population and, except in unusual circumstances, not those gained by society at large. Potential benefits do not include providing proper medical care. The Tuskegee Study of Untreated Syphilis highlights this point in that the men in this study were thought to be receiving a “benefit” that more properly should have been considered standard health care. Finally, benefits such as money or gifts could conceivably be increased to the point, particularly in certain subjects, that even the most risk-laden endeavors will be outweighed by the non–health-related benefit. In pain research, potential benefits are manifested as the potential to benefit future patients or more immediately benefit the patient or the patient’s population with either access to medications or access to study results that may help the patient choose between medications.

Conceptually, the requirement for assessment and minimization of risk in research is derived from the principle of nonmaleficence. Most would agree that limiting the harm imposed by research activities is appropriate and necessary for the protection of all subjects. U.S. federal regulations governing research on human subjects require that risk to subjects be minimized “(i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.” The regulations also place large responsibility for the oversight of this standard in the hands of review bodies, such as IRBs.

Even though minimizing risk has accepted value, dissension arises in defining risks for any individual subject and study. Delineating risk includes consideration of both the probability and magnitude of the harm. It is meant to include physiologic, psychological, social, economic, and legal risks and to represent aggregate risk for participation, not for any single individual potentially harmful encounter. In light of this, it is difficult to quantify risk, and attempts have been made to create categorical distinctions to guide researchers and review bodies in assessment of the appropriateness of the research activity.

“Minimal risk” is a categorical distinction of risk that is delineated in the federal regulations. The purpose of the category of minimal risk is to set a threshold that triggers closer examination of the risks and benefits of the research. It is defined as follows: “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” As with defining risk itself, the ambiguity inherent in making such a distinction has sparked criticism of the concept. Difficulty in defining minimal risk complicates weighing whether the risks and benefits of a study meet the minimal risk standard. Operationally, the presence of minimal risk can be a reason for altered or “expedited” review processes for research approval.

In pain research, examples of risks include potential medication side effects, persistence of pain symptoms if randomized to the placebo arm without breakthrough dosing available, risks associated with sham procedures, and pain associated with travel and paperwork. It may also include the intentional use of noxious stimuli to test potential pain relief mechanisms.

Those involved in research and oversight should systematically analyze and define the risks and benefits as much as possible to allow the risk-benefit relationship to be elucidated. In the end, potential benefits need to be commensurate with potential risks.

Informed consent is a process that has at its core the principle of respect for autonomy. The purpose of the informed consent process is to ensure that the subject understands the purpose, methods, risks, benefits, and alternatives to the research to the extent that the subject can make a voluntary informed decision about participation. The quality of the informed consent is married to good study design and involves the remaining six requirements.

The initial step in the process of informed consent is the interactive and iterative process of conveying information and discussing all aspects of the research. This interaction also requires the ethereal but essential assessment of sufficient comprehension. Finally, the potential participant may agree to participation.

Consent must be free of coercion. Coercion can take the form of obvious pressure or inducement to participate or may be more subtle in the form of perceived pressure that the potential participant may feel in light of an existing clinical relationship with the investigator on whom the participant depends for medical care. Another form of coercion is offering better medical care not otherwise available. Consider the pressure to participate on a patient in unremitting chronic pain who is desperate for any shot at relief. One way to mitigate this problem is to limit inclusion to patients who have access to excellent pain treatment services before enrollment.

Relevant to this latter point is the seminal concept of therapeutic misconception. The term, coined by Applebaum and colleagues in 1982, refers to the misperception of study participants that their involvement in the study is focused on their individual therapeutic medical care rather than on scientific purposes. It poses a direct threat to informed consent in clinical trials and is particularly relevant to patients in chronic pain, who have vulnerabilities that would particularly predispose them to therapeutic misconception.