Much of the modern economy is impacted by today's increasing globalization, and clinical research is at the forefront. Cost is a significant factor that may propel clinical research beyond U.S. borders (Shah, 2002). It is estimated that the cost per subject for tracking and other administrative requirements is up to ten times more for an American subject as compared with a subject abroad (O'Reilly, 2009). The number of people enrolled in clinical research worldwide is significant; in 2009, that number was 50 million and growing (Shetty, 2009). In the past decade, the percentage of research conducted overseas has continued to increase, and by 2010, more than 50 percent of clinical trial subjects and sites were located overseas (Levinson, 2010). The volume of studies and sometimes-remote locations give rise to the potential for lack of oversight and little recourse for vulnerable populations that may be affected by participation in clinical research.
As the research community and the world reflect on the legacy of the Tuskegee syphilis experiments, it is appropriate, given the global nature of clinical research, to also remember three additional studies in which appropriate protections were not provided to human subjects. From Tuskegee to Nuremberg, and from Guatemala to Nigeria, the research community and the public are reminded of past failures marked by a lack of respect for the human subjects involved. Remembrance, here, is not intended to vilify or to blame, but rather to ensure that adequate human subject protections are never again forgotten, particularly for vulnerable populations.
USPHS Syphilis Experiments in Tuskegee, 1932-1972
During the 1920s, researchers of the U.S. Public Health Service (USPHS) developed plans to study the response of black males to disease, hypothesizing that the response would differ from that of white males. In Macon County, Alabama, nearly forty percent of black males tested positive for syphilis and researchers believed that this community would be ideal to study disease progression. Although the initial plans included medical treatment, the financial devastation of the Depression in 1929 eliminated project funding. Rather than abandoning all research, USPHS researchers decided to proceed with a limited study. (Thomas & Quinn, 1991)
Under the amended research design, USPHS hired Nurse Eunice Rivers to coordinate the study, officially known as "The Tuskegee Study of Untreated Syphilis in the Negro Male." Nurse Rivers, a black woman, was a graduate of the Tuskegee Institute and had worked on various public health projects in Alabama since the early 1920s. By hiring Nurse Rivers, USPHS researchers believed that they could more efficiently reach community members. (Thomas & Quinn, 1991)
From the beginning, the study was marked by decisions to withhold information. Men involved in the study were told only that they were being tested for "bad blood," a euphemism for a variety of illness including syphilis, anemia, and fatigue. Each of the 600 men initially involved in the study was tested for syphilis; 399 of these men were found to have syphilis and the remaining 201 men tested negative (Jones, 1993). The men were not informed of either the purpose of the study, or whether they had syphilis; further, no information about modes of transmission or treatment was provided. Researchers intended for the study to conclude after six months of observation; however, the study was extended in an effort to examine the men at regular intervals until their death. By tracking the men through their lives and then performing an autopsy after death, researchers aimed to follow the complete progression of untreated syphilis. (Jones, 1993)
Researchers employed several tactics to persuade the men to continue in the study and the families to permit autopsies after the men in the study died. Actions were taken that created an illusion of treatment. For example, the men in the study were given iron, aspirin, and placebo treatments (Jones, 1993). In some cases, this regimen did provide a modest improvement in the men's health and resulted in further study participation. Many of the men involved in the study would have been otherwise unable to afford medical exams and willingly accepted the exams offered in exchange for participation. Researchers also offered free spinal taps, advertising the procedure as a special treatment. While these procedures aided researchers in obtaining information about neuro-syphilis, they were of no therapeutic value to the men involved in the study (Brandt, 1978). In order to encourage families to allow autopsies, family members were approached and offered a small stipend for burial costs in exchange for their permission to conduct an autopsy. As many of the families had limited economic resources for burial expenses, the stipend was a persuasive inducement. (Jones, 1993)
Over the 40-year course of the study, treatments for syphilis advanced. At the beginning of the study, the standard treatment of the disease consisted of a combination of arsenic, mercury, and bismuth given over an extended period. By the early 1940s, physicians began treating patients with an abbreviated course, generally one week, of an arsenic derivative and bismuth. Researchers actively coordinated with local clinics to ensure that the men involved in the study did not receive treatment (Jones, 1993). By the mid-1940s, penicillin became the treatment of choice for syphilis, and Alabama law required that anyone testing positive for venereal diseases be treated with appropriate medication (Jones, 1993). Again, researchers ensured that the men involved in the study were neither tested nor treated as required by law. Researchers also provided the names of men involved in the study to draft boards and physicians treating World War I! draftees, requesting that these men not receive the penicillin treatment that was administered to all other draftees diagnosed with syphilis (Thomas & Quinn, 1991). The men involved in the study remained unaware of their diagnosis and the benefit of treatment.
Although the men involved in the study were not given diagnosis and treatment information, the study itself was not kept from the medical community. Articles were published in medical journals and papers on the study were presented at medical conferences, but few, if any, ethical objections were raised to the study protocol and methodology (White, 2000). Over the 40-year span of the study, significant achievements occurred in the protection of human subjects and yet, the study continued without change. A contemporaneous development, the Nuremberg Code, discussed below, set forth guidelines on human research and clearly articulated the requirement for informed consent. During the 1960s and early 1970s, USPHS began developing guidelines for clinical trials and peer review, although the men involved in the study did not appear to benefit from these protections. (Jones, 1993)
Some of the first objections to the study arose in 1964, after an article was published describing the 30-year history of the study. A physician wrote to the authors and questioned the ethical approach of the study in denying treatment (Jones, 2000). Despite these questions, no change to the study was made. Five years later, a USPHS employee raised additional ethical concerns, and USPHS convened a review panel, which consisted of white physicians, ali but one of whom were already familiar with the study's existence and methods. The only panel member who recommended physical examinations and treatment for the men involved in the study was the physician who was previously unaware of the study (Jones, 1993). Further compounding the panel's disturbing analysis was a determination that the socioeconomic status and education level of the men involved in the study rendered informed consent impossible. The panelists subsequently decided to ask the Macon County Medical Society for consent, substituting the judgment of the medical board members for that of the men involved in the study. Finally, in 1972, a reporter for the Associated Press, Jean Heller, reported the details of the study. The article resulted in outrage and ultimately led to study termination, after 40 years of experiments involving human subjects who neither consented, nor were given appropriate protections. (White...