Ethical Principles of Clinical Research

Roy K. Aaron, MD

Jennifer Racine-Avila, MBA

Jerry Menikoff, MD, JD

Dr. Aaron or an immediate family member has received research or institutional support from Orthofix, Inc. and serves as a board member, owner, officer, or committee member of the Orthopaedic Research Society. Ms. Racine-Avila or an immediate family member serves as a board member, owner, officer, or committee member of the Orthopaedic Research Society. Neither Dr. Menikoff nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

The views expressed in this chapter are those of the authors and not necessarily those of the US Department of Health & Human Services, or its division, the Office of the Assistant Secretary for Health.

INTRODUCTION

Medical experimentation on humans is an essential part of the process of translating to the clinic basic discoveries of importance to human health. How human experimentation is accomplished has been the subject of evolving ethical and technical standards. The promulgation of standards for human experimentation has emphasized protection and safety of the research subjects, voluntary, uncoerced consent and opportunity for withdrawal, and competency and responsibilities of the research team. This chapter places contemporary standards for human biomedical experimentation into their evolutionary context and describes the ethical and regulatory environments of clinical research. In this chapter, “clinical research” is used synonymously with “human experimentation” to mean research on human subjects, materials, or data. The chapter is particularly timely since the US federal regulations governing clinical research have just undergone their first major revision since their inception 28 years ago.

HISTORICAL CONTEXT—THE EVOLUTION OF ETHICS OF RESEARCH ON HUMAN SUBJECTS

Prior to the Second World War, there were few standards governing human experimentation and the regulatory environment for clinical research was the province of individual investigators and institutions. Physicians in Nazi concentration camps performed grotesque, abusive, and sadistic medical experiments on unwilling subjects resulting in the death and mutilation of many individuals, primarily Jews, Russians, Poles, prisoners of war, and Gypsies.¹ At the conclusion of the war, the American army conducted a series of military tribunals in Nuremberg for war crimes. Tribunals 1 and 2 have become known as the Doctors’ Trials. Physicians and administrators responsible for forced experimentation on concentration camp prisoners were tried, and some were subjected to capital sentences or imprisonment. The Nuremberg tribunal felt it needed to go further than the trial and sentencing and developed a document describing standards to prevent abusive medical experimentation that became known as the Nuremberg Code (Table 1). This became an influential statement of ethical principles governing experimentation on humans, emphasizing absolute requirements for
voluntary consent and withdrawal by the research subject, the need to protect the subject from harm, and the competency and responsibilities of the researchers.²^,³^,⁴ Subsequently, in 1964, the World Medical Association (WMA) organized the Nuremberg Code into a series of ethical principles known as the Declaration of Helsinki that has influenced the conduct of clinical research for many years.³ Written and revised over many years, it is a substantial document not easily summarized. The current version of the Declaration of Helsinki is found at this website: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. A resolution adopted by the World Medical Association held that, “Under no circumstances is a doctor permitted to do anything which would weaken the physical or mental resistance of a human being except from strictly therapeutic or prophylactic indications imposed by the interest of the patient.”⁵

TABLE 1 The Nuremberg Code: a 10-Point Statement Delimiting Permissible Medical Experimentation on Human Subjects

1. The voluntary consent of the human subject is absolutely eessential.

2. The experiment should be such as to yield fruitful results for the good society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

3. Experiment should be based on animal experimentation…and natural history of the disease…anticipated results will justify the performance of the experiment.

4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

5. No experiment should be conducted where there is a reason to believe that death or disabling injury will occur.

6. The degree of risk to be taken should never exceed…the importance of the problem to be solved by the experiment.

7. Proper preparations should be made…to protect the experimental subject against even remote possibilities of injury, disability, or death.

8. The experiment should be conducted only by scientifically qualified persons.

9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end….

10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe…that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Based on “Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10”. Washington, DC: U.S. Government Printing Office, 1949, vol 2, pp. 181-182.

Regulations of research on human subjects in the United States have been codified by the federal government. In the mid-1950s, the Clinical Center of the National Institutes of Health (NIH) adopted guidelines taken directly from the Nuremberg Code that applied to the use of normal volunteers in research.⁶ Subsequently, the NIH and the FDA developed more extensive regulations of clinical research.⁷ In 1966, the NIH developed a policy of approving funding for research with human subjects only if the grantee institution provided prior review of research methods and an analysis of the risks and benefits of the research proposal.⁶^,⁷

Despite these codifications, abusive clinical research continued, including in the United States.⁵ A partial list of experiments performed without informed consent are plutonium injections by Manhattan Project physicians (1945-1947), radioactive iodine and other isotope administration experiments by the Atomic Energy Commission (1950-1970), radiation experiments in the Marshall Islands (1954), CIA studies of hallucinogens (1953) and pertussis (1955), the Willowbrook Experiments on psychiatric patients (1965), and the exposure of US service personnel to atomic radiation tests (1940-1971).¹^,⁵ The Tuskegee Syphilis Experiment (1972) that observed the progression of untreated syphilis in poor black men despite an available treatment was a particularly notorious example of abusive clinical research.

The series of ethical abuses in human subjects research, particularly the Tuskegee Experiment, led Congress to pass the National Research Act (1974) which created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, whose charge it was to articulate ethical principles, and to develop guidelines, for human subjects research. After four years of discussions, the Commission published, “Ethical Principles and Guidelines for the Protection of Human Subjects of Research” also known as the Belmont Report (1979). The Belmont Report defined research as distinct from clinical practice. Clinical practice was defined as an intervention solely for the purpose of providing diagnosis, preventive treatment, or therapy to an individual whereas research tested hypotheses and was designed to create information generalizable to the population at large. The Report delineated three fundamental ethical principles for human subjects research: respect for persons, beneficence, and justice (Table 2). Respect for persons stipulated that individuals should be considered as autonomous agents and, in general, required informed consent for participation in research. Beneficence
should underlie the assessment of risk/benefit considerations in research. Justice should inform the selection or exclusion of research participants.

TABLE 2 The Belmont Report

Respect for Persons	Protecting the autonomy of all individuals, treating them with courtesy and respect, and requiring informed consent. Individuals with restricted autonomy are entitled to research protections.
Beneficence	Maximizing benefits for the research project while minimizing risks to the research subjects.
Justice	Ensuring that nonexploitative and well-considered procedures are administered fairly. The distribution of costs and benefits to potential research participants should be considered with fairness.

In 1981, the Department of Health and Human Services revised federal regulations to be as consistent as possible with the principles articulated in the Belmont Report. These principles were subsequently codified in the Code of Federal Regulations (45 CFR part 46) (1991) as the “Federal Policy for the Protection of Human Research Subjects,” based largely on the Belmont Report, and issued by 16 federal departments and agencies.⁸ This became known as the Common Rule, and it applied to research that was either funded or conducted by those federal agencies (Table 3). The Common Rule provides the contemporary United States conceptual framework for research on human subjects and has governed the conduct of much of the research on human subjects including clinical trials. Among the concepts embodied by, or underlying, the Common Rule are informed consent and the right to voluntary withdrawal, the need for a well-articulated, testable hypothesis, an appropriate research design with consideration of risks to subjects, adequate predicate information to justify a clinical study, and an appropriately trained and responsible research team.

TABLE 3 Core Principles of the Common Rule

1. Review of research by independent committee (institutional review board)

2. Minimizing risks to subjects

3. Appropriate relationship among benefits to subjects, risks to subjects, and knowledge that might be learned from the research

4. Potential risks to subjects

5. Equitable selection of subjects

6. Obtaining and documenting informed consent of subjects or their representatives

WHERE ARE WE NOW?

Because of the complexity of contemporary clinical research, among other things, the agencies following the Common Rule have over the past several years been involved in a process to update it. Separately, some commentators have felt that the principles of the Belmont Report were also in need of updating.

THE BELMONT REPORT

Five themes for possible revision have been identified: (1) distinctions between clinical research and clinical practice, (2) harms to communities, (3) transparency of research activities, (4) implications of protectionism, and (5) the relationship between Belmont’s ethical principles and their applications (Table 4).⁹ “The Belmont Report was an impressive and inspiring response to the ethical issues of its day. Since its release, the field of research involving human subjects has developed in complex and unexpected ways, challenging the report’s ethical framework to respond to not only the fears related to research abuses that it stemmed from, but also to the increasing commodification of biomedicine, the exclusion of many groups from research, the globalization of research, the desires of many to have access to experimental drugs, the lack of generalizability and reproducibility of many research findings, and the unique harms and histories that communities have experienced as a result of research.”⁹

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