Film Analyses/TOQues

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Intentional Infection of Vulnerable Populations in 1946-1948 Another Tragic History Lesson Thomas R. Frieden, MD, MPH Francis S. Collins, MD, PhD

U NETHICAL USES OF HUMANS AS RESEARCH SUBJECTS

represent appalling chapters in the history of medicine.1 To ensure that effective protections against such abuses continue to evolve and im-

prove, it is essential to continue to learn from historical ex- amples. Sadly, a new example has recently come to light.

While conducting research on the Tuskegee study of un- treated syphilis,2 Wellesley College Professor Susan Reverby recently reviewed the archived papers of John Cutler, a US Public Health Service (PHS) medical officer and a Tuskegee investigator. Instead of finding Tuskegee records, however, Reverby found the records of another unethical study. In this study, vulnerable populations in Guatemala—mentally inca- pacitated patients, prison inmates, sex workers, and soldiers— were intentionally exposed to sexually transmitted infec- tions (syphilis, gonorrhea, and chancroid).

The work was directed by Cutler and was done with the knowledge of his superiors, including then Surgeon General Thomas Parran Jr. Funded with a grant from the National In- stitute of Health (NIH) to the Pan American Sanitary Bureau (which became the executive arm of the Pan American Health Organization), the study was conducted in cooperation with Guatemalan investigators by the USPHS Venereal Disease Re- search Laboratory, which 10 years later became a part of the Centers for Disease Control and Prevention (CDC).

As described by Reverby,3 the study’s initial syphilis ex- periments used female sex workers, intentionally infected with Treponema pallidum, as a source of infection to male prison inmates. At that time, sex workers were allowed into Guate- malan prisons. When the rates of female-to-male transmis- sion proved to be low, the research approach changed to the direct inoculation of prison inmates and patients in the Gua- temalan mental hospital. Most inoculation experiments in- volved subcutaneous injection of T pallidum or exposure of the penile foreskin to infectious material. The majority of study subjects were treated with penicillin, although available study records do not document therapy or completion of therapy for all subjects and some received only partial treatment.4

One study subject, a patient with a history of severe epi- lepsy, died of status epilepticus during treatment with peni- cillin. Although additional deaths occurred during the con- duct of the study in the mental hospital, they were most likely

related to the high rates of underlying disease, such as tuber- culosis. The investigators provided some items for institu- tional support, such as anticonvulsant medications and refrig- erators to store vaccines, and offered cigarettes as an incentive to study subjects. The archives provide no indication that indi- viduals understood that they were participating in research.

Most of the gonorrhea and chancroid experiments were conducted with Guatemalan soldiers. While the initial stud- ies involved sexual contact of soldiers with female sex work- ers who had been infected with gonorrhea, subsequent sub- jects were infected through intraurethral inoculations of Neisseria gonorrhoeae and cutaneous inoculations of Hae- mophilus ducreyi, and then treated with penicillin and sul- fathiazole, respectively.

Ethical Violations Ethical violations in this study clearly include the following: (1) study subjects were members of vulnerable populations including institutionalized and mentally disabled persons, prison inmates, and soldiers (who could not give valid informed con- sent); (2) individuals were intentionally infected with patho- gens that could cause serious illness; and (3) deception was used in conducting the experiments. Correspondence between the investigators and their superiors also recognized the un- ethical nature of the work. A letter from Cutler’s supervisor, R. C. Arnold, written in 1948, notes that, “I am a bit, in fact more than a bit, leery of the experiment with the insane people. They can not give consent, do not know what is going on, and if some goody organization got wind of the work, they would raise a lot of smoke.”4 The study was never published.

Unfortunately, such studies were not rare at the time. For example, intentional infection of prison inmates with gon- orrhea and syphilis was conducted in Terre Haute, Indi- ana, and Sing Sing prison, respectively.5,6

Safeguards Over the past 60 years, regulations safeguarding humans par- ticipating in research have been enacted7 (TABLE). The Nurem- berg Code, which articulated the requirement for voluntary consent of research participants, was issued in 1947, in re- sponse to Nazi human experimentation. The Declaration of

Author Affiliations: Director, Centers for Disease Control and Prevention, At- lanta, Georgia (Dr Frieden); and Director, National Institutes of Health, Bethesda, Maryland (Dr Collins). Corresponding Author: Thomas R. Frieden, MD, MPH; Director, Centers for Dis- ease Control and Prevention; 1600 Clifton Rd, NE, MS D-14; Atlanta, GA 30333 ([email protected]).

©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, November 10, 2010—Vol 304, No. 18 2063

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Helsinki, the first international set of ethical principles for medical research involving human research participants, was adopted in 1964 by the World Medical Association. The Na- tional Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, created following the revelation of the Tuskegee study, issued the landmark Bel- mont Report on ethical principles and guidelines for re- search involving humans in 1979.8 In 1981, these guidelines were embodied in Health and Human Services (HHS) regu- lations to protect research participants (45 CFR 46).9 In 1991, Subpart A of these regulations (“The Common Rule”) was adopted by an additional 16 federal agencies.

Could such unethical studies happen today? For research funded or conducted by the US government, the answer is no. All federally funded research projects in which human partici- pants are exposed to more than minimal risk must be reviewed by an institutional review board (IRB) before proceeding, and, as described in the Common Rule, must involve written, signed informed consent of research participants or their legally au- thorized representative (except in rare cases). Federal regula- tions instruct IRBs to be “ . . . particularly cognizant of the spe- cial problems of research involving vulnerable populations such as children, prisoners, pregnant women, mentally disabled per- sons, or economically or educationally disadvantaged persons.”9

For institutions violating these regulations, sanctions are imposed by the HHS Office for Human Research Protections. Furthermore, the HHS Office of Research Integrity takes ad- ministrative action against individual investigators for whom a determination of research misconduct has been made.

As clinical research increases in volume and complexity and more frequently crosses country borders—often to reach the most affected populations—continued scrutiny of guidelines governing research involving human subjects remains critical. As technologies evolve, it is essential to continuously consider what new risks—physical, psychological, or informational— might be raised by research, and how investigators can best in- form, engage, and protect research participants.

While effective protections against unethical research con- tinue to evolve across the world, the past exploitations of vul- nerable populations, including the subjects of the study in Gua- temala in the 1940s, are regrettable and deeply saddening. For them, the basic ethical principle of respect for persons was fla- grantly violated. The NIH and CDC are committed to ensur- ing that lessons drawn from the past help shape actions to pro- tect all future research participants, no matter where studies are conducted. The 1946-1948 inoculation study should never have happened, and nothing like it should ever happen again.

Published Online: October 11, 2010. doi:10.1001/jama.2010.1554 This article was corrected on November 9, 2010. Financial Disclosures: None reported.

REFERENCES

1. Lederer SE. Subjected to Science: Human Experimentation in America Before the Second World War. Baltimore, MD: The Johns Hopkins University Press; 1995. 2. Reverby SM. Examining Tuskegee: The Infamous Syphilis Study and Its Legacy. Chapel Hill: University of North Carolina Press; 2009. 3. Susan M. Reverby faculty page. http://www.wellesley.edu/WomenSt/fac_reverby .html. Accessed October 6, 2010. 4. Information on the 1946-1948 United States Public Health Service STD Inocula- tion Study. US Department of Health & Human Services Web site. http://www.hhs .gov/1946inoculationstudy. Accessed October 5, 2010. 5. Mahoney JF, Van Slyke CJ, Cutler JC, Blum HL. Experimental gonococcic urethri- tis in human volunteers. Am J Syph Gonorrhea Vener Dis. 1946;30:1-39. 6. Magnuson HJ, Thomas EW, Olansky S, Kaplan BI, De Mello L, Cutler JC. Inocu- lation syphilis in human volunteers. Medicine (Baltimore). 1956;35(1):33-82. 7. National Institutes of Health, Office of Human Subjects Research. Regulations and ethical guidelines. http://ohsr.od.nih.gov/guidelines/index.html. Accessed August 15, 2010. 8. The Belmont Report: Ethical Principles and Guidelines for the Protection of Hu- man Subjects of Research. 1979. http://ohsr.od.nih.gov/guidelines/belmont.html. Accessed October 6, 2010. 9. Code of Federal Regulations, Title 45 Public Welfare: Part 46, Protection of Hu- man Subjects. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Ac- cessed October 6, 2010.

Table. Evolution of Human Subjects Research and Guidelines Year Event

1932-1972 Tuskegee Syphilis Study

1939-1945 Experiments on concentration camp prisoners by Nazi scientists

1946-1974 Secret human radiation experiments

1946-1948 Guatemalan STD inoculation studies

1947 Nuremburg Code

1953 NIH Clinical Center requires informed consent and independent review

1953-1954 Sing Sing Prison syphilis inoculation study

1956-1971 Hepatitis studies at Willowbrook State School for the Retarded

1962 Kefauver-Harris drug amendments

1963 Jewish Hospital cancer study

1964 World Medical Association Declaration of Helsinki

1966 US Surgeon General policy statement on human subjects re- search (IRB origin)

1971 NIH Office for Protection from Research Risks established

1974-1978 National Commission for the Protection of Human Subjects

1974 HHS regulations for human subjects research

1975 CDC Office of Human Research Protections established

1978-1983 President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research

1979 Belmont Report released

1981 HHS 45 CFR 46 and Food and Drug Administration 21 CFR 50, 56 regulations published

1985 NIH Clinical Center Bioethics Program founded

1991 45 CFR 46 (Common Rule) adopted

1993 CIOMS guidelines released

1994 Presidential apology for secret radiation experiments

1995 World Health Organization Guidelines for Good Clinical Practice

1996- 2001 National Bioethics Advisory Commission

1997 Presidential apology for Tuskegee

1998 NIH support for bioethics training and research expanded

1999 NIH support for international research and ethics training

2000 World Health Organization operational guidelines for ethics com- mittees

2001-2009 President’s Council on Bioethics

2002 Secretary’s Advisory Committee on Human Research Protec- tions

2005 UNESCO Universal Declaration on Bioethics and Human Rights

2009 Executive order to create Presidential Commission for the Study of Bioethical Issues

Abbreviations: CDC, Centers for Disease Control and Prevention; CFR, Code of Federal Regulations; CIOMS, Council for International Organizations of Medical Sciences; HHS, Department of Health & Human Services; IRB, institutional review board; NIH, National Institutes of Health; STD, sexually transmitted disease; UNESCO, United Nations Edu- cational, Scientific and Cultural Organization.

COMMENTARY

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