Ethics in Medicine

Research and the role of Institutional Review Boards

The Harvard Medical School Dubai Centre Institute for Postgraduate Education and Research hosted the region’s first ‘Ethics in Research’ on 2 November 008 with the aim of educating the research community about the latest code of ethics in research. Alan Lisbon, MD, Associate Professor of Anaesthesia, Harvard Medical School, looks at past and current ethical implications of research and the role of Institutional Review Boards in developing and implementing ethics in research.

Ethics of Clinical Research Pre-1900

Initiation of experimental science of medicine is attributed to Galen (130-201 AD), a prominent Roman physician and philosopher of Greek origin, and probably the most accomplished medical researcher of the Roman period. Medical research was also practiced in the Middle East – in ancient Persia, individuals condemned to death could at the king’s discretion be used for medical experimentation. There was little regulation of human experimentation up to the early 19th century. Indeed, the English scientist, Dr Edward Jenner (1749-1823), inoculated his own son with swinepox to test his smallpox vaccine.

William Beaumont (1785–1853), a surgeon in the US Army, utilised a fistula tract, left open in a patient after healing from a gunshot wound in the stomach, to study the physiology of the stomach. In an attempt to justify his human experiments, Beaumont set forth a set of principles to guide the researcher, which is now the oldest American document dealing with research and human experimentation. Beaumont’s code of research included, for the first time, that voluntary consent of the subject is necessary; experimental studies in humans are justifiable when information cannot otherwise be obtained; the investigator must be conscientious and responsible; a methodological approach is required to obtain as much information as possible when human subjects are used and no random studies are to be made; experiment is to be discontinued if it causes distress to the subject or the subject objects or becomes dissatisfied.

Claude Bernard (1813– 1878), a French physiologist, An Introduction to the Study of Experimental Medicine, where he outlined that research is permissible to save, cure, or gain personal benefit for the subject. He also declared that human research cannot be harmful to the subject in the name of science, further stating: “Those [experiments] that can only harm are forbidden. Those that are innocent are permissible, and those that may do good are obligatory.” Bernard supported using dying patients in experiments that caused no suffering. However, he also endorsed giving intestinal parasites to a condemned woman to be examined at autopsy.

As recently as just before 1945, there were no regulations concerning the practice of clinical research. Investigators were mainly guided by their conscience and the ethics of immediate peers and mentors while conducting research. The Tuskegee Study of Untreated Syphilis in the Black Man was a clinical study, conducted between 1932 and 1972 in Tuskegee, Alabama by the US Public Health Service, where 399 poor – and mostly illiterate – African Americans, in the late stages of syphilis, were studied to observe the natural progression of the disease if left untreated. The study group was formed as part of the venereal disease section of the US Public Health Service (PHS). The study became controversial, and eventually led to major changes in how patients are protected in clinical studies. Individuals enrolled in the Tuskegee Syphilis Study were not required to give informed consent and were not informed of their diagnosis; instead they were told they had “bad blood” and could receive free medical treatment for minor ailments, rides to the clinic, meals and burial insurance in case of death in return for participating. When penicillin dramatically altered the treatment of syphilis in the 1940s, the PHS withheld it, arguing that never again would they find such a group of untreated individuals and the Tuskegee Study turned into a long term, no-treatment observational study.

There was no formal protocol located to this study, rather the “procedures evolved” as the study progressed, with few of the physicians and none of the subjects really knowing what the study involved. The Tuskegee Syphilis Study is one of the most horrendous examples of research carried out in disregard of basic ethical principles of conduct. The publicity surrounding the study was one of the major influences leading to the codification of protection for human subjects. In fact, a mail and telephone survey carried out from 1998-1999, designed to examine impediments to African-American participation in medical research studies demonstrated that 49% of African-Americans and 17% of whites, who know about the Tuskegee Study would not be willing to participate in future medical research studies. This survey confirms the continuing impact of the study on African-Americans’ trust of medical research studies.

Nuremberg Doctor’s Trial - 1946-47

Another incident of breaching medical ethics was The Medical Case, USA vs. Karl Brandt, et al. (also known as the Doctors’ Trial). The trial was took place in 1946-47 against 23 doctors and administrators accused of organising and participating in war crimes and crimes against humanity in the form of medical experiments and medical procedures inflicted on prisoners and civilians. The Nuremberg Trials were a series of trials most notable for the prosecution of prominent members of the political, military, and economic leadership of Nazi Germany after its defeat in World War II. Guilty verdicts were announced after eight months of testimony. Sixteen of the doctors charged were found guilty, seven were hanged, only four of them physicians.

The Nuremberg Code

In their final judgment, the justices presiding at the trial concluded that the principle of advancement of science bows to a higher principle; protection of individual inviolability. The judgment by the war crimes tribunal at Nuremberg laid down 10 standards to which physicians must conform when carrying out experiments on human subjects in a new code that is now accepted worldwide, the Nuremberg Code. The Nuremberg Code was adopted internationally in 1949, and provides the basic principles of respect for the voluntary nature of human participation in research, true informed consent, and ethical responsibilities of the researcher to ensure human welfare. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. Other provisions require the minimisation of risk and harm, a favourable risk/benefit ratio, qualified researchers using appropriate research designs, freedom for the participant to withdraw at any time and upon observing the likely risk of injury, disability or death, the researcher should terminate the experiment.

Studies of hepatitis in mentally retarded children

Despite introduction of the Nuremberg Code, further issues in ethical research continued in the US as the Willowbrook Study illustrated. Willowbrook State School, built in the late 1930’s, was a state-supported institution for mentally retarded children located in central Staten Island in New York City. Throughout the first decade of its operation, outbreaks of hepatitis were common at the school, and this led to a highly controversial medical study being conducted there between 1963 and 1966, in which healthy children were intentionally injected with the virus that causes the disease. Consent obtained from parents was misleading as it suggested that the children were receiving the vaccine rather than the virus. This example demonstrates that some potential research subjects are more likely to be vulnerable to coercion or undue influence. These include children, prisoners, pregnant women, mentally disabled persons, economically disadvantaged persons, or educationally disadvantaged persons and additional safeguards are instituted to protect them.

The Declaration of Helsinki

The Declaration of Helsinki, developed in 1964, constitutes statements of ethical principles guiding physicians in biomedical research involving human subjects. It requires informed consent of study subjects and describes compliance measures relating to ethical approval and review of research.

In a landmark paper in the New England Journal of Medicine, published in 1966, Dr Henry K. Beecher criticised the lack of sincerity in implementing the basic ethics in clinical research. He described 22 ongoing trials that failed to meet the standards outlined in the Nuremberg Code and the Declaration of Helsinki. He cited 50 episodes of potential “Code” violations which were published in peer-reviewed scientific journals in the US and called for the ethical review of all research results as a requirement for publication and suggested that all data obtained unethically remain unpublished

Following the Declaration, the US National Institutes of Health, under the Directorship of Dr James Shannon, promoted the development of the first Public Health Service Policy on the Protection of Human Subjects, issued in 1966. The Institutional Review Board (IRB) was established as a mechanism through which human subjects would be protected. In 1974, the National Research Act was signed into law in the US, thereby creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, to protect rights and welfare of human research subjects and develop principle for ethical conduct of research.

The Belmont Report

The Belmont Report was created in 1979 by the former United States Department of Health, Education, and Welfare (which was renamed to Health and Human Services) entitled Ethical Principles and Guidelines for the Protection of Human Subjects of Research. This Belmont Report describes the three fundamental principles for conducting research involving human subjects, namely respect for persons, beneficence, and justice, which are now accepted as the requirement for the ethical conduct of such research.

In 1981, the US Department of Health and Human Services (DHHS) and the US Food and Drug Administration (FDA) issued regulations based on the Belmont Report. DHHS issued Code of Federal Regulations (CFR) Title 45 (public welfare), Part 46 (protection of human subjects). The FDA issued CFR Title 21 (food and drugs), Parts 50 (protection of human subjects) and 56 (Institutional Review Boards). The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research. The informed consent process is fundamental in ensuring respect for persons and should serve to educate the subject about the research, the benefits and risks, and the voluntary nature of their participation.

IRBs help provide reassurance to the public that the educational community meets all appropriate ethical standards, and they provide consultation and assistance to investigators to help improve quality of research while protecting participants. An unethical approach can invalidate findings, lead to prosecution, and damage the image of the research community within the public realm as a whole. Regulatory system

In the last several years, a number of widely publicised cases have shown that clinical trial participants’ health, and even their lives, still can be put at risk, and that their rights still can be violated, in spite of IRB oversight. These developments have raised questions about how strong the regulatory system is and whether individual IRBs are performing effectively.

One response to the latter issue has been the creation of new agencies to accredit IRB programmes. The non-profit Association for the Accreditation of Human Research Protection Programs (AAHRPP) has emerged as the central player in the accreditation movement. The mission of AAHRPP is to facilitate research compliance and also to promulgate uniform standards for all IRBs, be responsive to the call for increased public accountability and serve to minimise differences in interpretation and implementation of regulations between institutions across the country.

Clinical research is an important tool to bring basic medical research into practice. However, the safety of the patient needs to be paramount. The purpose of an IRB is to ensure that all work involving human subjects is conducted with internationally accepted ethics and standards.

ate of upload: 25th January 2009

                                               Copyright © 2009 All Rights Reserved.