In January 2017, the Office of Human Research Protections (OHRP) of the Federal Department of Health and Human Services (HHS) released a major update to the Common Rule, the federal regulations that govern the protections of human research participation in federally funded research. The explicit goal of this update is to increase participant protection while removing unnecessary burdens on the conduct of research that do not serve such protection. Changes include broadening the kinds of research that are exempt from regulation under the rule or could be reviewed through streamlined procedures, and decreasing ongoing oversight when no individuals are at risk of harm. The changes that may have the biggest impact on the research oversight community are those that redefine the requirements for informed consent. Additional disclosures are added to the list of elements required to be present in the informed consent document to address the increasingly complex research environment, the different roles played by investigators, and the regulations also adopt a new model for informed consent in general. That model moves beyond a list of required disclosures by putting greater obligation on researchers to be attentive to participants’ understanding and decision-making. The old model of disclosure was relatively simple to implement, although there was a general awareness that a focus on disclosure allowed the consent process to shift from an ethical requirement to a legal exercise. The new model is more complicated, and will require both guidance from the federal agencies involved and experience with consent in practice to implement well. To address the requirement for experience, the updated regulations also require that consent forms for higher risk biomedical research be shared and be publicly available, providing a resource for ongoing learning and research.

The ability for each of us to make our own decisions about important events and commitments is fundamental to our sense of well-being and control over our lives. We live in a complex society of competing social and individual interests, and protecting this ability is similarly complex. It is all too easy for our decisions to appear free but actually to be the result of misinformation, manipulation, or paternalism. Respecting the individual’s right to make decisions is particularly challenging in the context of research. This is due to the fact that while benefits of participation accrue to society, the individual participant bears the burden. The discrepancy in knowledge, authority, and power between investigator and participant may stand in the way of a shared understanding of the goals of research. [1]

The difficulty of insuring free decision-making in the research context has led to the development of frameworks, or principles, to help us talk about competing interests. Similarly, these principles have been realized in regulation. Heavily influenced by the 1979 Belmont Report, the Federal Policy for the Protection of Human Subjects, or “Common Rule” was first published in 1991. In the Federal Register under Public Welfare (Title 45) and specified for the Protection of Human Subjects (Part 46), the Common Rule is denoted as 45 CFR § 46. [2] Part 46 is comprised of four principal subparts: basic policy (Subpart A), additional protections for pregnant women, human fetuses, and neonates involved in research (Subpart B), additional protections pertaining to the biomedical and behavioral research involving prisoners as subjects (Subpart C), and additional protections for children involved as subjects of research (Subpart D). [3] As this article relates solely to the contents of 45 CFR § 46, further references will begin with §46.

While the development of a framework for discussion and establishment of clear regulatory requirements may be necessary to support the practical conduct of research, both principles and regulations risk distracting us from the fundamental value of voluntary participation. The requirement for free decision-making has been formalized as the principle of respect for persons, and in the regulatory requirements of informed consent.  We must resist the temptation to argue these as terms-of-art, and remember their common-sense meaning and visceral truth. Free and voluntary consent (which is not free if it is given without understanding, or as a result of misleading or incomplete information) should be one of the defining characteristics of a free society.

Research (particularly biomedical research, which drove research regulation) has structural elements that need to be systematically addressed to ensure that each decision to participate is made freely, in the sense that each decision is made with full consideration of the relevant facts, presented in a way this is not misleading, manipulative, or exploitive. These elements originate in the separation between the researcher and participant, both in role and background. Accordingly, the dimensions of consent and its regulation can be considered along the two primary dimensions of the researcher and the participant.

The researcher may have several roles in the context of the research. In many cases, a biomedical researcher is also a doctor, and often provides medical care to patients who are also participants. The roles of doctor and investigator have different primary duties; the former’s duty is to the best interests of the individual patient, while the latter’s duty is to the integrity of the study. In cases where a single individual is acting in both these roles, and the roles are in conflict, it is the norm in practice to defer to the doctor’s role. [4]

In the present research environment, researchers may have a third role—that of a businessman. This role has fewer explicit ethical duties and is implicitly more self-serving. The role may also serve as a stand-in for other self-serving motives for researchers, including career advancement and recognition, both of which are more difficult to articulate than commercial gain.

For practical reasons, the pre-2019 research regulations did not directly address the conflicted roles of the researcher, although some institutions and IRBs routinely did this in practice. While §46.111(a)(1) of the Common Rule requires disclosure that the study involves research, [5] the regulation does not require an explanation of what this means, or how it differs from other interactions a participant could reasonably expect to have with an investigator. The updated Common Rule3 does not require such an explanation, [6] but it does make several other changes to the requirements for consent that recognize and require disclosure of certain aspects of the investigator’s role that may otherwise be unknown to the participant. In particular, §46.116(b)(9) requires participants be told their specimens and information, if no longer clearly associated with them, may be used for other research without their permission. §46.116(c)(7) requires disclosure of whether the research has commercial intent. §46.116(c)(8) requires that investigators explicitly discuss whether participants’ results will be returned to them and under what circumstances. The first disclosure speaks to a practice of the researcher as investigator of which the participant may not have been aware; the second addresses the role of the investigator as entrepreneur or businessman, and the third requires an explicit differentiation between the role of investigator and doctor.

The second major dimension of consent is the characteristics of the participant themselves. While a person acting in the role of “researcher” has clear duties consequent to that role, and is generally expected or required to have certain expertise, much less commonality can be assumed between individuals acting in the participant role. Participants vary widely in their level of education and medical/scientific knowledge, may be sick or well, and may have other characteristics that make them susceptible to manipulation or exploitation. In addition, research must sometimes be done with individuals who are not legally competent to make decisions for themselves, such as patients with dementia or children.

With the exception of so-called “vulnerable populations,” including those deemed not competent to make their own decisions, the pre-2018 Common Rule was largely silent regarding obligations of the investigator to ensure participant understanding. The old rule required that “the information that is given to the subject or the representative shall be in language understandable to the subject or the representative” (§46.116). “Understandable” is a low bar, and technically can be met through the use of accessible language, but documents that are understandable can require more or less effort to actually understand—and the burden of that effort falls on the participant. The updated rule now places an obligation on the investigator to facilitate such understanding: §46.116(a)(5) states:

Informed consent must begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research. This part of the informed consent must be organized and presented in a way that facilitates comprehension.

And:

Informed consent as a whole must present information in sufficient detail relating to the research, and must be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate.

Requiring that informed consent be written to facilitate understanding forces researchers to consider the consent document and process from the perspective of potential participants.

The problem of how to best address variation among research participants is significant and intimately related to our bias and/or perspective regarding rational decision-making. At one extreme, individuals apprised of the facts are seen as completely autonomous agents, able and responsible for any decisions they make for themselves. At the other extreme, an individual’s personal circumstances must be taken into account so no immediate, transient or particular concerns distort what would otherwise be a rational decision—in this sense, we may all be vulnerable by circumstance. The pre-2018 rule made no assumptions about the participant beyond exclusion of a few well-defined situations like incompetence. Consent forms had to provide the facts, but it was up to the individual to interpret and understand them. This approach implicitly adopts the first extreme described above—the investigator has no responsibility for autonomous and informed decisions made by prospective participants. By adding the requirement that the consent form be written to facilitate comprehension and understanding, the new rule recognizes such an approach is overly simplistic. But as a consequence, it must declare a minimal standard for participant understanding against which a single consent form can be written. The rule does this by embracing the standard of “a reasonable person” (§46.116(a)(4)). The “reasonable person standard” is well established in law, [7] but the updated Common Rule provides no additional guidance as to how this standard should be interpreted in the context of research participation. Absent further definition or intrinsic meaning, the “reasonable person” is a stand-in for a standard to be developed through use, or defined in future guidance.

The new focus on understanding in the consent form is also an acknowledgement of the opacity of the consent process. In general, past failures of the consent form being treated as nothing more than a vehicle for disclosures were addressed by the observation that “consent is a process, not just a form,” [8] and that the consent form was meant to be used as part of an active and ongoing discussion between researcher and participant. The reality of the current research environment, with involvement of for-profit research centers, commercially driven research, the absence of accepted requirements for investigator training, and the fact that the consent is often presented to participants by someone other than the principal investigator, has made any assumptions about the quality of this process suspect. As a process, it is generally inaccessible to systematic compliance monitoring. The incorporation of elements of understanding into the form itself raises practical questions of implementation, particularly in the absence of official guidance, but such an approach may also provide better assurances about the quality of an individual’s decision to participate.

The adoption of intrinsically subjective criteria and undefined standards into the regulatory requirements for consent form in the updated Common Rule is accompanied by a related provision—that consent forms be posted on a publicly available Federal website. (§46.116(h)). This requirement only applies to consent forms for clinical trials, defined in §46.102(b) as:

…a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes.

Yet such a repository will be essential to the development of a common understanding of both the reasonable person standard, key information, proper “organization to facilitate comprehension” and other elements of §46.116(a)(5) that are not explicitly defined. For the first time outside individual (and usually artificial) research contexts, consent documents will be available as objects of research in themselves, allowing us to build an evidence base for effectiveness.

Taken together, the adoption of subjective standards and the provision for a repository of consent forms opens the way for consent to move from a compliance-driven activity to one that more directly serves the ethical purpose of ensuring voluntary and informed participation, one that is calibrated not against absolute principles, but against evolving societal norms. This move is a departure from current practice, and will face significant practical and procedural obstacles. In the present environment, consent forms are generally reviewed by individual institutional review boards (IRBs), each of which assesses compliance with required disclosures and enforces its own particular stylistic interpretation. In the future, the requirement to develop a shared understanding of the various subjective standards in the updated Common Rules, and the availability of a shared repository of forms to serve as the basis for research and discussion, is likely to lead to a more appropriate focus on what really works for participants.

 

[1] A common example is the Therapeutic Misconception. See Henderson GE, Churchill LR, Davis AM, et al. Clinical Trials and Medical Care: Defining the Therapeutic Misconception. PLoS Med. 2007 Nov;4(11):e324. doi: 10.1371/journal.pmed.0040324

[2] U.S. Department of Health and Human Services. Office for Human Research Protections. 45 CFR §46. https://www.hhs.gov/ohrp/regulations-and-policy/regulations. Revised January 19, 2017. Accessed  February 20, 2019.

[3] Electronic Code of Federal Regulations (e-CFR). 45 CFR §46. https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r. Revised January 19, 2017. Accessed  February 20, 2019.

[4] Lidz CW, Appelbaum PS, Joffe S,  Albert K Rosenbaum J, Simon LJ. Competing Commitments in Clinical Trials. IRB. 2009;31(5):1–6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677602/

[5] Protection of Human Subjects, 45 C.F.R. § 46 (2009). https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html. Accessed  February 20, 2019.

[6] Federal Policy for the Protection of Human Subjects, 82 Fed. Reg. 12. January 19, 2017. https://www.govinfo.gov/app/details/FR-2017-01-19/2017-01058

[7] Odwazny LM, Berkman BE. The “Reasonable Person” Standard for Research Informed Consent. The American Journal of Bioethics. 2017;17(7):49–51. http://doi.org/10.1080/15265161.2017.1328540

 

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