A doctor draws blood from a participant in the Tuskegee syphilis study. A federal government advisory panel subsequently would conclude the project was “ethically unjustified.” (Credit: National Archives)
The 20th century witnessed remarkable scientific progress, as well as terrible abuses of people in the name of that progress. In the 1970s, Congress resolved to put an end to that abuse, passed the National Research Act and charged a commission with protecting persons enrolled in biomedical and behavioral research. That National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research put ethical treatment of all people first, even before science. Among its efforts, the commission recognized that injustice would plague any clinical trial that unfairly denied benefits to or disproportionately imposed burdens on any person or group.
Thus, the commission acknowledged that justice in clinical trials, as elsewhere, demands equitable distribution. To that end, the commission set forth an analytical framework, explaining that a choice in favor of justice would reject exploitation of people in clinical trials simply because they could be easily manipulated, convinced to participate or are otherwise compromised. A choice for justice also would reject exclusion of people from clinical trials simply because they were not easily available or would be more difficult to sign up for those trials.
This ethical principle of justice became one of the promises of the commission’s work. Ultimately, the principle was incorporated into federal regulations governing clinical trials, including drug and device trials involving persons.
Despite the purported institutionalization of justice, the benefits and burdens of clinical trials have not been equally distributed across society. Women and minorities have shouldered the burden of that inequitable distribution.
For a drug or treatment likely to be prescribed across the adult population, justice and science seemingly would require testing of that drug or treatment on men and women. Unfortunately, however, medical tragedies overwhelmed the logical conclusion that women should participate in all clinical trials.
Thalidomide struck the first blow. From the late 1950s through the early 1960s, the drug was marketed and used to treat nausea in pregnant women. However, in the 1960s, the medical community determined that thalidomide use resulted in severe birth defects in children.
In the 1970s, politicians and federal regulators reacted to the damaging effects of thalidomide and other drugs in pregnant women. To ensure that pregnant women would be exposed to the least possible risk, federal regulators divided women into two categories for clinical trial purposes: women of childbearing potential, and women not of childbearing potential. The regulations defined a “woman of childbearing potential” as including premenopausal women capable of becoming pregnant, even if, for example, they were taking birth control. Using that definition, regulators excluded those “women of childbearing potential,” who comprised a significant portion of the female population, from most Phase I and early Phase II clinical trials.
This regulatory approach failed to acknowledge the fundamental right of women to be treated as autonomous agents. Moreover, it mandated a knowledge gap regarding the risks and benefits of drugs that ultimately would be used by pregnant women. Thus, information regarding the way pregnant women metabolize drugs, how drugs affect fetal development, and how drugs affect mother and child postpregnancy was under­developed or conspicuously absent from scientific studies and literature. Because the regulations prohibited study of effects on women of childbearing potential, the U.S. Food and Drug Administration (FDA) possessed insignificant or, even, no data to assess the effect of study drugs or treatments on women and their offspring.
Even without those important data, the FDA moved forward and approved drugs and treatments for use by women of childbearing potential. Consequently, the original unjust exclusion ultimately exposed more women and their offspring to a greater risk of harm than if women initially had been allowed to participate in the clinical trials. Thus, one injustice begat more injustices.
The treatment of minorities in ­clinical trials has been even more fraught. In 1932, the Public Health Service joined with the Tuskegee Institute to commence the “Tuskegee Study of Untreated Syphilis in the Negro Male.” The study, which lasted 40 years, violated fundamental ethical principles that guide modern clinical studies.
To illustrate, the researchers failed to provide the participants with a clear and meaningful explanation of the subject or purpose of the study. Additionally, when penicillin became the standard of care for treating syphilis, the researchers did not offer it to the participants. Furthermore, the researchers did not inform the participants that an effective treatment was available outside the study or that the participants were free to leave the study at any time.
In 1972, The Associated Press published a story that exposed the Tuskegee study and led to a public outcry. In reaction, the assistant secretary for health and scientific affairs appointed an ad hoc advisory panel that determined the study was “ethically unjustified.” One month later, the Tuskegee study was ended.
Shortly thereafter, study participants and their families filed a class action. The lawsuit resulted in a settlement, including lifetime health and medical benefits and burial services for all living participants, their wives, widows and offspring.
Today, the deep mistrust of clinical trials in at least some segments of minority populations has grown into a harmful legacy of the Tuskegee study and another injustice: low minority participation in the very clinical trials that could help to cure or treat diseases that plague minority populations. When minority populations are not represented in sufficient numbers in clinical trials, then researchers may not be able to effectively examine risks, benefits and responses to drugs that may differ among demographic subgroups. Additionally, by opting out of participation, those subgroups fail to access potentially promising new treatments.
Recognizing that excluding women and minorities from clinical trials harms all areas of research, therapy and treatment, the National Institutes of Health (NIH) have taken significant steps toward including women and minorities in research.
Beginning in 1994, the NIH have required women and minorities to be included in clinical research it pays for, unless a “clear and compelling rationale and justification” establishes that inclusion would not be appropriate because of the purpose of the research or the health of the participants.
In contrast, the FDA has not taken steps that mirror those of the NIH; instead, the FDA has taken a more incremental approach.
For example, in 1993, the FDA withdrew the prohibition against including women of childbearing potential in clinical trials. Thereafter, in 1998, the FDA mandated that sponsors must document safety and effectiveness of new drugs for demographic subgroups. The FDA further warned that it might withhold final approval of a new drug if the approval application did not analyze the clinical data according to the subgroup data.
In August 2013, the FDA published a report finding that there is a framework within FDA statutes, regulations and policies for product sponsors to provide data on inclusion and assessment of demographic subgroups. Although not a significant step forward, the report reflects continuing FDA and federal focus on including women and minorities in clinical trials.
WHAT LAWYERS CAN DO
Even so, clinical trials may still exclude women and minorities. Nonetheless, lawyers representing individuals and the health care industry can facilitate access by women and minorities to the early and long-term benefits of research.
Among other ways, lawyers can assist by reviewing informed-consent and other documents related to an individual’s participation in clinical trials, and by encouraging individuals to engage their doctors and health care professionals in discussions regarding potential clinical trials related to their health conditions. Those representing health care facilities, pharmaceutical companies or medical device companies can encourage their clients to seek out NIH-funded clinical studies, as appropriate, and negotiate with contract research organizations to ensure that they have plans and/or track records for recruiting and retaining women and minority participants.
Once women and minorities participate in clinical trials in statistically meaningful ways, those groups will have equal access to new treatments. Moreover, their participation may lead to progress in science and advances in personalized medicine, as differences in responses, toxicity and survival may become known and tested. Finally, the commission’s promise of justice will no longer remain elusive for women and minorities.
Jennifer L. Mallory is a partner of Nelson Mullins Riley & Scarborough in Columbia, S.C., where she practices in the pharmaceutical, medical device and health law fields.