Ethics of Clinical Trials





Nuremberg Code

Nuremberg Military Tribunal United States v. Brandt et al.


Declaration of Helsinki

World Medical Association


Belmont Report

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research


45 CFR 46 (Common Rule)

US Department of Health and Human Services


Good Clinical Practice: Consolidated Guidance

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use


International Ethical Guidelines for Biomedical Research Involving Human Subjects

Council for International Organizations of Medical Sciences and the World Health Organization


13.1.1 Early Codes of Research Ethics

Albert Neisser, a professor of dermatology and venereology at the University of Breslau and the person who first identified gonococcus, published clinical trials on serum therapy in patients with syphilis in 1898. In an attempt to find a way to prevent the spread of syphilis, he injected serum from syphilis patients into patients who were admitted for other medical conditions. Most of his subjects were prostitutes who were neither informed about the experiment nor asked for consent. After an ensuing outbreak of syphilis, he claimed that it was not due to the serum, but because the patients worked as prostitutes.

In 1900, the Prussian Ministry of Religion, Education and Medical Affairs set forth the Berlin Code of Ethics as a direct response to Neisser’s syphilis study. It stated that all research interventions in a medical institution could only be performed by the medical director or with his or her authorization. All medical interventions other than for diagnosis, healing, and immunization were prohibited under all circumstances if “the human subject was a minor or not competent for other reasons” or if the subject had not given his or her “unambiguous consent” after a “proper explanation of the possible negative consequences” of the intervention. These requirements, in addition to the other aspects of the case, had to be “documented in the medical history” [1].

13.1.2 Nuremberg Code

After World War II, Nazi war criminals were tried before the International Military Tribunal for crimes against humanity. The subsequent Doctors’ Trial which took place on December 9, 1946, charged 23 Nazi physicians and scientists with murder and torture under the guise of scientific research. The Nazi regime labeled all Jews, gypsies, Slavs, homosexuals, and disabled persons as subhuman which did not entitle them to basic human rights. Various experiments in the concentration camps included the dissection of live infants, castration of boys and men without the use of anesthesia, and sterilization of women with an X-ray machine, as well as the effects of high-voltage electric shocks, hypothermia, pressure chambers, and euthanasia [2].

The international outrage from these heinous crimes gave birth to the Nuremberg Code, which was drafted in 1947 as a means to prevent the future abuse of human subjects. Above all, the Nuremberg Code states that participation in research must be voluntary, and research subjects must have the ability to withdraw from the study at any time. The benefits of the research to the individual or to society must outweigh the risks, and any unnecessary suffering must be avoided. Investigators must be qualified to conduct the study and prepared to stop the study should the risks become unacceptable for the participants (e.g., the possibility of death or disabling injury as a foreseeable consequence) [3].

13.1.3 Declaration of Helsinki

The World Medical Association, in response to the atrocities of the Nuremberg Trials, issued the Ethical Principles for Medical Research Involving Human Subjects in 1964 and since then has undergone multiple revisions (most recently in 2008). Taking its name from the city in which it was adopted, these principles became known as the Declaration of Helsinki.

This document stresses the importance of participant health and close monitoring of subjects, especially populations that include the “economically and medically disadvantaged,” those who cannot give informed consent (or who may be doing so “under duress”), those who will not benefit personally from the research, and those for whom “research is combined with [medical] care.” All research subjects must have access to the “best” standard of care treatment as identified in the study, especially pertaining to placebo-controlled trials, which is an attempt to address the potential conflict in the goals of the clinician (to care for the patient) and the researcher (to obtain generalizable knowledge). It also states that voluntary, fully informed consent for all research participants is imperative [4].

13.1.4 The Jewish Chronic Disease Hospital

In 1963, Chester Southam, the chief of virology at the Sloan-Kettering Cancer Institute, injected live, cultured cancer cells into 22 debilitated patients at the Jewish Chronic Disease Hospital in Brooklyn, New York. He believed that despite the patients’ old age and debilitated state, their immune systems would reject the cancer cells. The patients were never fully informed of the experiment because Southam stated that they would be of “no consequence” to them and did not want to unduly upset them by the word “cancer.” Although all of the patients eventually did reject the cancer cells as Southam predicted, the lack of informed consent and disclosure of risks, although minimal, illustrates the prevailing paternalistic attitudes in medical research at that time [5].

13.1.5 Willowbrook Hepatitis Study

Willowbrook was an institution for mentally retarded children in Staten Island, New York. Saul Krugman, an infectious disease specialist, was consulted to study immunity against hepatitis which was endemic to the institution from 1956 to 1967. The study involved feeding controlled amounts of the virus, which is shed in the feces, to healthy children. Although the parents who brought their children to Willowbrook consented to the study, they were coerced into believing that there were no beds available except for research subjects. It was also explained to them that the contraction of hepatitis was “inevitable” when in fact only 30–53 % of children acquired the disease at the institution [6]. In 1966, Henry Beecher, a professor of anesthesiology at Harvard Medical School, criticized numerous clinical trials including the Willowbrook study in his landmark article Ethics and Clinical Research and questioned why Krugman did not place more emphasis on promoting hygiene and sanitation to decrease the risk of infection [7].

13.1.6 Tuskegee Syphilis Study

From 1932 to 1972, the Public Health Service conducted a clinical study on the treatment and natural history of syphilis. The subjects were 399 poor and mostly illiterate African American sharecroppers with syphilis in Alabama who neither gave informed consent nor were informed of their diagnosis and the risk to others through sexual contact. They were told that they had “bad blood” and were offered free medical treatment, one free meal per day, and $50 in case of death for the funeral. In 1943, when penicillin was discovered as a cure for syphilis, the subjects in the study were never offered the drug so that the investigators could further study the natural history of the disease. The study resulted in 28 deaths, 100 cases of disability, and 19 cases of congenital syphilis [6]. The story appeared on the front page of the New York Times in July 1972. The study was terminated, and the Public Health Service was forced to settle a $9 million class action lawsuit filed by the NAACP which was divided among the participants.

13.1.7 Belmont Report

The public response to the Tuskegee syphilis study prompted the federal government to establish a National Commission in 1974 for the purpose of drafting guidelines for the ethical conduct of research involving humans. The Belmont Report was published in 1979 and named after the conference center at the Smithsonian Institute in Washington, DC, where the National Commission laid much of the groundwork. The Belmont Report explicitly noted the principles of respect for persons, beneficence, and justice that have become the pillars of the ethical conduct of research.

The principle of respect for persons applies to informed consent and requires that the autonomy of the individual be respected. Those who do not have decisional capacity (e.g., children or persons with intellectual disability) require the consent of an authorized third party who is able to make decisions based on the individual’s best interest.

The principle of beneficence begins with the medical precept primum non nocere—or first do no harm. Potential harm should be avoided if possible, but always minimized, by balancing the risks and the benefits to the research participant. Adhering to this ethical standard is not only the responsibility of the investigator but also of an independent institutional review board (IRB) to determine if the protocol is justifiable.

The principle of justice requires that both the burdens and benefits of research are distributed fairly. Historically, the burdens of research were placed upon the economically disadvantaged and the vulnerable, some of whom never reaped any physical benefits from the research. Because medical research is a public good, all of society should benefit and likewise be called upon to participate equally [8].

13.1.8 Code of Federal Regulations (45 CFR 46 and 21 CFR 50, 56)

As a response to the Belmont Report, the federal government sought to enforce the regulatory requirements of research involving human subjects in the United States. These efforts were incorporated into the Code of Federal Regulations (CFR), Title 45, Part 46 (45 CFR 46) or the Common Rule, which went into effect in 1991. The Common Rule falls under the authority of the Department of Health and Human Services (DHHS) and focuses on the process of review, approval, and oversight of research involving human subjects for all institutions receiving any federal support for research. Subpart A of 45 CFR 46 outlines the responsibilities of the IRB including membership, function, review, and necessary records to approve research protocols. It also delineates the required elements of the informed consent form and the criteria for waiving informed consent. Subparts B, C, and D involve additional protections bestowed upon pregnant women, fetuses, neonates, prisoners, and children [5].

The CFR, Title 21, Parts 50 and 56 (21 CFR 50, 56) protects the rights, safety, and welfare of subjects in clinical investigations involving products regulated by the Food and Drug Administration (FDA) which include food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products [9].

13.1.9 International Guidelines

The Good Clinical Practice (GCP) guidelines (International Conference on Harmonization, 1996) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences and the World Health Organization, 2002), based on the Belmont Report and the Declaration of Helsinki, were adopted as an international standard for designing, conducting, recording, and the reporting of clinical trials. Specifically, they delineate that research must be scientifically sound and must be approved by ethical review committees [10]. In 2008, the FDA published the Final Rule which replaced the requirements of the Declaration of Helsinki with those of the GCP guidelines.

13.2 An Ethical Framework for Research

With the harsh lessons from history, these multiple guidelines and regulations have helped to create a framework with which to minimize the exploitation of humans for research, while still fostering the goals of improving health and health care. Each guideline by itself is not comprehensive in addressing the ethical complexities in research. However, collectively, they uphold eight ethical principles for clinical research: collaborative partnership, social value, scientific validity, fair participant selection, favorable riskbenefit ratio, independent review, informed consent, and respect for participants [11]. Some of these principles will at times conflict, but it is not sound ethical practice to simply ignore one when two or more appear to be at odds. It is the investigator’s responsibility to take all of these principles into consideration and weigh the value of each one for any individual case.

According to the recommendations in the Belmont Report which are now codified in 45 CFR 46, research is “a systematic investigation, including research, development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” And a human subject is aliving individual about whom an investigator obtains data through intervention or interaction with the individual, or identifiable private information” [12]. Surgical innovation is an important topic that does not cleanly fit into the definition of research, yet is not considered standard of care. This topic goes beyond the scope of this chapter, but the ethical issues of informed consent and risk assessment remain paramount as surgical innovation continues to play an important role in the progress and development of surgical care [13].

13.2.1 Collaborative Partnership

Clinical research, in its role to serve a social good, should create a partnership with the community in which the research is being conducted. Although there is no legal requirement to do so, communication between the investigator and the community helps to prevent any exploitation and can maximize the potential benefits to the community. The goals of research can be attained through respect for the community’s values, context, culture, and social practices. This partnership can be formed through community advisory boards, advocacy groups, and town hall meetings. Care should be taken to ensure that both the direct and indirect benefits of the research are fairly distributed between the research team and the community [11].

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Sep 26, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Ethics of Clinical Trials
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