RESEARCH INITIATIVES REQUIRING INSTITUTIONAL AND/OR FEDERAL REVIEW & APPROVAL: HUMAN SUBJECTS

Nuremberg Code (1947)  The United States Holocaust Memorial Museum documents the atrocities of the second world war in Europe.  Following the war, an American military tribunal opened criminal proceedings against 23 leading German physicians and administrator for their willing participation in war crimes and crimes against humanity on December 9, 1946.   On August 19, 1947, the judges of the American military tribunal delivered their verdict in the case of the USA vs. Karl Brandt et. al.. Before announcing the guilt or innocence of each defendant, they confronted the difficult question of medical experimentation on human beings. Several German doctors had argued in their own defense that their experiments differed little from previous American or German ones. Furthermore they showed that no international law or informal statement differentiated between legal and illegal human experimentation. This argument worried Drs. Andrew Ivy and Leo Alexander, American doctors who had worked with the prosecution during the trial. Previously on April 17, 1947, Dr. Alexander submitted a memorandum to the United States Counsel for War Crimes which outlined six points defining legitimate research. The verdict of August 19 reiterated almost all of these points in a section entitled "Permissible Medical Experiments" and revised the original six points into ten. Subsequently, the ten points became known as the "Nuremberg Code".

The following is a summary of the defining principles:

  1. voluntary consent of the human subject;
  2. the experiment should yield fruitful results for the good of society, unprocurable by other methods or means;
  3. the experiment should be based on animal experimentation and a knowledge of the disease or other problems so that anticipated results will justify the experiment;
  4. the experiment should avoid all unnecessary physical and mental suffering and injury;
  5. no experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur;
  6. the degree of risk should never exceed that determined by the humanitarian importance of the problem to be solved;
  7. proper preparations and adequate facilities should protect the subject against even remote possibilities of injury, disability, or death;
  8. the experiment should be conducted only by scientifically qualified persons with the highest degree of skill and care;
  9. the human subject should be at liberty to bring the experiment to an end at any time; and
  10. the scientist in charge must be prepared to terminate the experiment at any stage, if there is probable cause to believe that a continuation of the experiment is likely to result in injury, disability, or death to the subject.

Universal Declaration of Human Rights (1948)  On December 10, 1948 the General Assembly of the United Nations adopted and proclaimed the Universal Declaration of Human Rights.  It outlines and presents a "universal declaration of human rights as a common standard of achievement for all peoples and all nations, to the end that every individual and every organ of society, keeping this Declaration constantly in mind, shall strive by teaching and education to promote respect for these rights and freedoms and by progressive measures, national and international, to secure their universal and effective recognition and observance, both among the peoples of Member States themselves and among the peoples of territories under their jurisdiction."

The United Nations High Commissioner for Human Rights presents the  history and explanation of the Declaration which is comprised of 30 Articles and was the first major achievement of the United Nations.

Several of the Articles are listed for illustrative purposes.

World Medical Association Declaration of Geneva: Physician's Oath (1948 & as revised)  The Ethics Policies of the World Medical Association binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient."

World Medical Association Declaration of Helsinki - Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects (1964 & as revised):  The Purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis of disease.  In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research.  Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the Declaration of Helsinki (alternate source: The Wits Bioethics Division) recommendations as a guide to every physician in biomedical research involving human subjects.

Robert J. Levine [The Need to Revise the Declaration of Helsinki.  The New England Journal of Medicine  (Vol. 341, No. 7; 08/12/99)  pp. 531-534] suggested that the Declaration of Helsinki required revision, because it is defective in two important respects: 1) reliance on the distinction between therapeutic and non-therapeutic research, a spurious distinction that leads to unintended errors, and 2) discrepancies with current ethical thinking.  Hence, the declaration is routinely violated by contemporary researchers which "robs the declaration of its credibility."    Troyen A. Brennan [Proposed Revisions to the Declaration of Helsinki — Will They Weaken the Ethical Principles Underlying Human Research?  The New England Journal of Medicine  (Vol. 341, No. 7; 08/12/99)  pp. 527-531] argued the opposite position: "Unfortunately, the proposed revisions of the Declaration of Helsinki allow utilitarianism to overwhelm other values.  These changes would permit investigators to test new pharmaceutical products and devices in placebo-controlled studies in developing countries, as long as proven alternative therapies were not part of the usual care in these countries.  Multinational companies would be able to take advantage of the revisions to shift epidemiologic research to these more efficient venues.  This is not a "dark suggestion," but merely the predictable and logical outcome of the revisions."

Subsequently, the Declaration was revised in October 2000 [McGinn, Paul R. AMNews. 12/18/00] after substantial debate which will undoubtedly continue [see: Povl Riis,  Perspectives on the Fifth Revision of the Declaration of Helsinki and Brian Vastag, Helsinki Discord? A Controversial Declaration.  JAMA (Vol. 284 No. 23; 12/20/00).

Council for International Organizations of Medical Sciences (CIOMS) periodically proposes ethical guidelines in collaboration with The World Health Organization.

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.  The parties include:

The purpose of the ICH is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need for duplicate research and development testing of new medicines. The objective of such harmonization is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.  Please see:

The International Federation of Pharmaceutical Manufacturers Associations represents the research-based pharmaceutical industry and other manufacturers of prescription medicines, worldwide. It is the main channel of communication between this sector of the industry and the World Health Organization as well as other international organizations that are concerned with health-related issues. The Federation also has a central role in the exchange of information within the international industry, and in the development of position statements on matters of policy.  They have provided access to IHC Guideline for Good Clinical Practice recommended for adoption on May 1, 1996 by the ICH Steering Committee.

U.S. Regulations & Laws  Basic regulations governing the protection of human subjects involved in research, development, and related activities supported or conducted by the Department of Health, Education, and Welfare (renamed to the current Department of Health & Human Services; hereafter DHHS) through grants and contracts were published in the Federal Register on May 30, 1974 (39 FR 18914).   Subsequently, regulations were published to provide additional protections for "special groups" containing individuals who may have diminished capacity to consent or who maybe at high risk.

On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.  One of the charges to the Commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider:

The resulting Belmont Report issued in April 1979 attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations.  It is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects.  Unlike most other reports of the Commission, the Belmont Report did not make specific recommendations for administrative action by the Secretary of DHHS.  Rather, the Commission recommended that the Belmont Report be adopted in its entirety, as a statement of the Department's policy.

The Commission was also charged to study the Institutional Review Board mechanism and make recommendations to the Secretary of DHHS as it determined appropriate to assure that biomedical and behavioral research conducted or supported under programs administered by DHHS met the requirements respecting informed consent indentified by the Commission.   This report was approved and published in the Federal Register on November 30, 1978 (43 FR 56173).  Subsequently, regulations were published in the Federal Register on January 26, 1981 (46 FR 8366) which provided a common flexible framework within which Institutional Review Boards (IRBs) could operate to review research funded by DHHS or regulated by the Food & Drug Administration (FDA).   These regulations are codified at Title 45 of the Code of Federal Regulations Part 46 (Protection of Human Subjects) for all projects funded by DHHS and at Title 21 of the Code of Federal Regulations Part 50 (Protection of Human Subjects) and Part 56 (Institutional Review Boards) for research regulated by the FDA for development of new drugs and medical devices.

The Office for Human Research Protections (OHRP) implements these requirements for DHHS by:

Dr. Gary B. Ellis has provided an overview of the process for Protecting the Rights and Welfare of Human Research Subjects in Academic Medicine (Vol. 74, No. 9;  September 1999).

For those wishing to explore in detail the literature of Ethical Issues in Research Involving Human Participants the National Library of Medicine (NLM) has prepared a bibliography of 4,650 citations covering January 1989 through November 1998.

Exposees of Modern Human Subjects Research

Serious lapses in the ethical conduct of research on humans have occurred in modern history even in the U.S.  Beecher (1966) is regarded by many as being the seminal paper highlighting examples of "troubling practices" from leading medical schools, university hospitals, private hospitals, governmental military departments, governmental institutes, Veterans Administration hospitals, and industry.  He cited 22 examples of "unethical or questionably ethical" studies to call attention to the need for more rigorous attainment of informed consent and the importance of an "intelligent, informed, conscientious, compassionate, responsible investigator."  This courageous paper is even more significant when you consider that it was published before the end of  the Tuskegee study that was allowed to continue until 1972.

The introduction to the NLM's bibliography cited above presents a chilling summary of one of the most significant events with President Clinton's pledge for prevention of future similar acts.

"On May 16, 1997, President Clinton apologized to the survivors and families of hundreds of men used in a research project to study the progression of untreated syphilis. These men were mainly sharecroppers from Macon County, Alabama (the area surrounding Tuskegee). They were poor, African American, and had few resources available to them. In 1932, when they were offered free medical care by physicians and researchers involved with the United States Public Health Service, they believed they had found treatment for what they had been told was "bad blood." Instead, they were enrolled in an observational research study, without their knowledge or consent. In exchange for their participation (which included agreeing to an autopsy at death), the men received free medical examinations (primarily to provide data for the study), transportation and hot meals on the days of their examinations, and $50 for burial expenses. Even though some rudimentary remedies for syphilis were available in the early years of the study, they were not offered to these men, so that the study of the natural history of the untreated disease would not be jeopardized. 1

The study (the Tuskegee Study of Untreated Syphilis in the Male Negro 2) did not end until 1972, forty years after it had begun, and twenty years after penicillin had been identified as an effective treatment for syphilis. The New York Times headline exposing the experiment read, "Syphilis victims in U.S. study went untreated for 40 years." 3 The article revealed the details of the study and called it "the longest nontherapeutic experiment on human beings in medical history." According to the Report of the Tuskegee Syphilis Study Legacy Committee, "In the almost 25 years since its disclosure, the Study has moved from a singular historical event to a powerful metaphor. It has come to symbolize racism in medicine, ethical misconduct in human research, paternalism by physicians, and government abuse of vulnerable people." 4

According to President Clinton, "The legacy of the study at Tuskegee has reached far and deep, in ways that hurt our progress and divide our nation. We cannot be one America when a whole segment of our nation has no trust in America. An apology is the first step, and we take it with a commitment to rebuild that broken trust. We can begin by making sure there is never again another episode like this one. We need to do more to ensure that medical research practices are sound and ethical, and that researchers work more closely with communities." 5

In his remarks, the President promised that several steps would be taken to assure that such research tragedies would not happen again. The plan, laid out by the President, contained five elements and was designed to begin the process of restoring the public trust that had been severely damaged, particularly in the African American community. The first step was to award a planning grant to Tuskegee University so that the University could establish a Center for Bioethics in Research and Health Care. This Center will serve as a museum of the Tuskegee Syphilis Study and support the University's efforts to strengthen bioethics training. The second element was to increase community involvement in research, so that the lost trust of some segments of society could begin to be restored. A third element of the plan was to strengthen researchers' training in bioethics to help increase their understanding of the core ethical principles of respect for individuals, beneficence, and justice, as set forth in the Belmont Report. 6 Fourth, a commitment was made to provide post-graduate fellowships to train more bioethicists, especially among African Americans and other minority groups. Finally, by executive order, the President extended the charter of the National Bioethics Advisory Commission to October of 1999. 7

Following the apology, the Department of Health and Human Services charged several of its agencies with implementing the President's plan. In support of the first two elements, funds have been awarded to Tuskegee University for the establishment of a Center for Bioethics, and several meetings have been held to explore how communities, especially minority communities, can be involved in the planning and implementation of research. In response to the third and fourth elements, interagency Program Announcements soliciting research and training grant applications have been developed, issued, and are ongoing. They are designed to: support research to examine ethical issues surrounding research involving human participants; 8 provide training opportunities in the form of mentored scientist awards in research ethics; 9 and develop short term courses in research ethics. 10

Although regulatory safeguards for protecting research participants have improved significantly in recent years, 11 historical cases such as the Tuskegee Syphilis Study stand as examples of the potential for ethical problems in research involving human participants, and of the need for vigilance in protecting the rights and welfare of these individuals. Contemporary safeguards such as requirements that federally funded research protocols be submitted to an institutional review board (IRB) are important, but by themselves are insufficient. Educating researchers and the public about research ethics is critical for the full protection of research participants."

For persons wishing to read more about  historical perspectives on research ethics, the second section of the NLM's bibliography includes references to some of the most striking lapses in research ethics (e.g. the Tuskegee Syphilis Study, the Willowbrook experiment, the human radiation experiments, etc.). This section also includes a number of citations regarding the egregious Nazi "experiments," the subsequent Nuremberg Trial, the resulting Nuremberg Code, and their role in the development of protections for research participants.

References

  1. Jones JH, Bad Blood: The Tuskegee Syphilis Experiment, new and expanded ed., New York: Free
    Press, 1993.
  2. Vonderlehr RA, Clark T, Wenger OC, Heller JR Jr. Untreated syphilis in male Negro; comparative
    study of treated and untreated cases. Ven Dis Inform 1936 Sep;17(9):260-5. Also J Am Med Assoc
    1936 Sep 12;107:856-60.
  3. Heller J. Syphilis victims in U.S. study went untreated for 40 years. New York Times 1972 Jul 26;1, 8.
  4. Report of the Tuskegee Syphilis Study Legacy Committee Final Report--May 20, 1996 [report on the Internet]. [place unknown]: The Committee; 1996 [cited 1999 April 29]. [8 p.]. Available from: http://www.med.virginia.edu/hs-library/historical/apology/report.html.
  5. Remarks by President Clinton in apology for study done in Tuskegee [speech on the Internet]. Clinton WJ. Washington: The White House; 1997 May 16 [cited 1999 April 29]. [3 p.].
  6. The Belmont report: ethical principles and guidelines for the protections of human subjects. Bethesda
    (MD): U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research; 1978. 8 p. Also available on the Internet from: http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm.
  7. Executive Order 13046. Further Amendment To Executive Order 12975, Extension Of The National Bioethics Advisory Commission. [file on the Internet]. Washington: The White House. Office of the Press Secretary; 1997 May 16 [cited 1999 May 10]. [1 p.]. Available from: http://bioethics.gov/about/further.htm.
  8. Research on ethical issues in human studies. PA [Program Announcement]-99-079 [announcement on the Internet]. Bethesda,(MD): National Institutes of Health; 1999 Mar 31 [cited 1999 April 29]. [15 p.] Available from: http://www.nih.gov/grants/guide/pa-files/PA-99-079.html.
  9. Mentored scientist development award in research ethics. PA-99-050 [announcement on the Internet] Bethesda (MD): National Institutes of Health; 1999 Jan 22 [cited 1999 April 29]. [10 p.]. Available from: http://www.nih.gov/grants/guide/pa-files/PA-99-050.html.
  10. Short-term courses in research ethics. PA-99-051 [announcement on the Internet]. Bethesda (MD): National Institutes of Health; 1999 Jan 22 [cited 1999 April 29]. [6 p.]. Available from: http://www.nih.gov/grants/guide/pa-files/PA-99-051.html.
  11. Protection of Human Subjects-Title 45 Code of Federal Regulations Part 46, Revised June 18, 1991. Available from: http://www.nih.gov:80/grants/oprr/humansubjects/45cfr46.htm.

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