In this post, I continue my closer look at a few select areas of the revised Common Rule, which was published January 18, 2017 of this year, and is scheduled to go into effect January 19, 2018. 

One set of changes that has not gotten very much attention is that around the definition and categorization of “vulnerable” research subjects. In this post, I explain what those changes are and reflect a bit on their significance.

The Common Rule (both the pre-2018 version and the revised version) mentions “vulnerable” populations in three contexts—once with respect to IRB membership (§_.107), once in the context of equitable subject selection (at §_.111(a)(3)), and once when invoking the need for additional protections for subjects deemed vulnerable (at §_.111(b)).

However, two types of changes have been made to the rule’s discussions of vulnerable subjects. First are changes to the categories of subjects that are classified as vulnerable. In addition to replacing the “mentally disabled” with the more accurate and sensitive “individuals with impaired decision-making capacity,” the “handicapped” and “pregnant women” have been removed from all lists of vulnerable categories of subjects.

These changes are welcome and long overdue, none more so than the removal of pregnant women from the list. As has been argued repeatedly since the publication of a 1994 Institute of Medicine report on barriers to inclusion of women in clinical research, the categorization of pregnant women as a vulnerable population in need of special protections has resulted in the exclusion of pregnant women from the vast majority of clinical trials. As a result, treatment decisions for pregnant women are often made without an evidence base, despite the fact that pregnant women will and do get sick. If there is any way in which pregnant women are vulnerable, it is to risks associated with getting inadequate or inappropriate treatment, given the scarcity of information about how drugs and other interventions work in the complex environment of the pregnant body. As has been argued by the researchers and ethicists involved in the Second Wave Initiative, pregnant women should be protected by research, not protected from it. In 2013, the NIH Office of Research on Women’s Health recommended that “pregnant women …be reclassified from their current status as a ‘vulnerable’ population to that of a medically complex population, necessitating special scientific and ethical considerations. A corollary is the need to change the presumption of exclusion of pregnant women to one of inclusion.” One can only hope that the removal of pregnant women from the list of vulnerable populations is another important step in that direction.

The second type of change made regarding vulnerability in the revised Common Rule has to do with the definition, or perhaps more accurately, the scope, of vulnerability addressed by the rule. In the pre-2018 rule, two of the three provisions that mention vulnerable subjects (at §_.107 and §_.111(a)(3)) do not further specify any particular type of vulnerability, while the third (at §_.111(b)) makes reference specifically to subjects who may be vulnerable to coercion or undue influence. In the revised rule, all three contexts in which vulnerable subjects are mentioned now limit their scope to vulnerability to coercion and undue influence. The list of categories of subjects that are vulnerable in this way has also been made uniform across all three mentions of vulnerability, and comprises children, prisoners, individuals with impaired decision-making capacity, and economically or educationally disadvantaged persons.

The preamble to the 2015 Notice of Proposed Rulemaking (NPRM) made clear that these revisions to the scope of vulnerability were designed to address the aforementioned inconsistency in the current regulations. But perhaps more surprisingly, the NPRM also suggested that “the only vulnerability that needs to be considered [by an IRB] is vulnerability to coercion or undue influence, and not other types of vulnerability.”

Vulnerability to coercion and undue influence references limitations to a person’s ability to provide informed consent to participate in research. These limitations could be due to a person’s current circumstances (in the case of prisoners or the educationally or economically disadvantaged), or due to a temporary or permanent lack of capacity (in the case of the children and individuals with impaired decision-making capacity).

To be sure, these are important concerns for IRBs. But vulnerability to coercion and undue influence are not the only kinds of vulnerability relevant to research. There is also vulnerability to being specifically targeted to take on the burdens of research, potentially without the promise of proportionate benefits; vulnerability to being exploited or disrespected during the research process, due to inequalities of power or other resources; vulnerability to taking on excessive risks, for instance because of co-morbidities, or environmental or social factors that make research participation particularly risky for some populations; and, importantly, vulnerability to being excluded from the opportunity to participate in research for reasons of convenience. In other words, there are other types of vulnerability that have to do with special or sensitive characteristic of particular populations that entail we should be particularly concerned about their involvement (or not) in research—not just the circumstances under which they enroll in research, but how they may be treated throughout.                 

As Ivor Pritchard, Senior Advisor to the Director of OHRP, recently pointed out in remarks at the meeting of the Canadian Association of Research Ethics Boards (CAREB), some of the concerns about the revised rule’s narrowing of “vulnerability” might be assuaged by recognizing that the language regarding equitable subject selection at §_.111(a)(3) leaves plenty of room for IRBs to take account of the sorts of vulnerability outlined immediately above. That criterion reads as follows:

Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted. The IRB should be particularly cognizant of the special problems of research that involves a category of subjects who are vulnerable to coercion or undue influence, such as children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons.

In other words, when IRBs properly apply this criterion and examine the purposes of the research and the setting in which it takes place, they will determine whether adequate attention has been paid to whether the proposed research population has any characteristics that might make them particularly vulnerable in other ways, for instance, to bearing undue risks and burdens or being at a higher level of risk, or whether, given the purposes of research, some potential group is being arbitrarily and unjustifiably left out. But the worry is that equitable subject selection is already a complex and difficult issue for IRBs, one about which I believe they have inadequate guidance. An explicit call to pay special attention to those who are vulnerable to coercion or undue influence risks the possibility that IRBs will take this as permission to ignore other types of vulnerability.

What do you think? How do you read the narrowing of the scope of vulnerability in the revised rule to just vulnerability to coercion and undue influence? What do you make of the rule’s authors saying (in the NPRM preamble) that only vulnerability to coercion or undue influence, and not other types of vulnerability, needs to be considered by an IRB? I look forward to your thoughts.