Vaccine Testing and Vulnerable Human Subjects
A crowd of people receives inactivated poliovirus vaccine in Protection, Kansas
March of Dimes Foundation
In 1966, Henry K. Beecher, MD, published a study describing 22 instances of mainstream medical research that he claimed were unethical. In his article in the New England Journal of Medicine, Beecher described medical studies in which
- medical treatment was withheld from subjects for research purposes
- institutionalized children and adults were involved
- surgeons performed experimental techniques with unknown effects
- infectious or otherwise harmful substances were deliberately introduced into a subject’s body.
Only one of the studies Beecher cited related to vaccine research. As he noted,
This study was directed toward determining the period of infectivity of infectious hepatitis. Artificial induction of hepatitis was carried out in an institution of mentally defective children in which a mild form of hepatitis was endemic. The parents gave consent for the intramuscular injection or oral administration of the virus, but nothing is said regarding what was told them concerning the appreciable hazards involved.
A resolution adopted by the World Medical Association states explicitly: "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 in the interest of the patient." There is not right to risk an injury to 1 person for the benefit of others. —Henry K. Beecher, MD (1966)
The study Beecher summarized was conducted by Saul Krugman, MD, at the Willowbrook State School in Staten Island, New York. Krugman’s work established that hepatitis A and B were different diseases and showed the benefit, before vaccination was available, of gamma globulin as a preventive for hepatitis. Krugman had previously stated his position for infecting the Willowbrook children:
1) Infectious hepatitis, a mild disease in children, was particularly benign in Willowbrook; 2) it was inevitable that most of the newly admitted, retarded children would acquire the disease; 3) only the Willowbrook strain of virus would be employed in these studies; and 4) facilities were available to provide isolation quarters and special medical and nursing care. —Saul Krugman, MD (1958)
Krugman was not the only researcher who experimented on institutionalized but otherwise healthy people; other notable figures in vaccine research and development used similar practices. Werner Henle, MD, at the University of Pennsylvania, conducted a test of influenza vaccine in a prison population and in a state home for the mentally retarded. His study design required administering vaccine to his experimental group and then deliberately exposing them to influenza (he deliberately infected the placebo group with the virus as well). Jonas Salk, MD, conducted similar influenza studies in Michigan.
Later, other researchers would test a variety of vaccines, including vaccines for polio and measles, in institutionalized subjects. These tests, conducted by Salk, Hilary Koprowski, MD, and others, usually did not deliberately infect subjects with the disease agent.
The Nature of Consent
Beecher noted that only a very few of the studies he cited mentioned whether consent had been given. In fact, Beecher questioned the nature of consent in a physician-patient relationship, noting that “patients will accede, on the basis of trust, to about any request their physician may make.” Moreover, he noted, “statements regarding consent are meaningless unless one knows how fully the patient was informed of all risks.”
Beecher’s paper, along with other publications and reform efforts, contributed importantly to changes that increased the scrutiny and regulation of medical research in human subjects. Around this time, the National Institutes of Health began to produce guidelines for federally funded research with human subjects. Significantly, they began to differentiate between the doctor-patient relationship and the researcher-subject relationship by acknowledging that what is in the researcher’s best interest may not be in the subject’s best interest. Their guidelines would attempt to protect the subject by mandating that research institutions pay a high level of attention to the well-being of participants. The guidelines led to the establishment of Institutional Review Boards, which are institutional committees that review and approve research designs involving human subjects.
The 1972 revelations of the denial of syphilis treatment to African American men in the Tuskegee Syphilis Study further focused attention on bioethical aspects of medical research. This environment led to the formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (U.S. Department of Health, Education, and Welfare) in 1974 to study and develop guidelines for the use of humans in medical research.
Today, the NIH’s Office of Human Subjects Research and other federal groups outline detailed guidelines regarding human subjects in medical studies. Many of these guidelines focus specifically on protecting vulnerable populations. For example, children who are wards of the state or other institutions may be included in research only
(1) Related to their status as wards; or
(2) Conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards
Moreover, the guidelines specify that an advocate be assigned to all wards. The advocate must be familiar with the best interests of the particular child.
Other aspects of NIH policy relate specifically to regulation of research in pregnant women, fetuses, infants, children, and prisoners.
Beecher’s landmark article remains an important milestone in the continuing discussion about the nature of informed consent and the participation of vulnerable populations in vaccine and general medical research.
Beecher, H.K. Ethics and clinical research. The New England Journal of Medicine, 1966, 274: 1354–1360. Available in: Harkness J, Lederer SE, Wikler D. Laying ethical foundations for clinical research. (168 KB). Bulletin of the World Health Organization, 2001, 79 (4). Accessed 01/17/2018.
U.S. Department of Health and Human Services, Public Health Services, National Institutes of Health. Guidelines for the Conduct of Research Involving Human Studies at the National Institutes of Health. (55 KB). 5th printing. August 2004. Accessed 01/17/2018.
Krugman, S., Ward, R. Clinical conference: Clinical and experimental studies of infectious hepatitis. Pediatrics 1958:22:1016-1022. Accessed 01/17/2018.
Office of Human Subjects Research. Protection of human subjects, regulations and ethical guidelines, Title 45, Part 46. Public Welfare, Department of Health and Human Services. (536 KB). Revised January 15, 2009. Accessed 01/17/2018.
Rothman, R. Strangers at the bedside: a history of how law and bioethics transformed medical decision making. New York: Basic Books, 1991.
Last update 17 January 2018