As with any type of clinical research, it is important to protect the rights, interests and welfare of human subjects. This is based on the ethical principle of respect for persons (or autonomy). This principle generally requires that a competent person has a right to decide what is or is not done to them. In research, a primary mechanism for achieving this is through the informed consent process.

Who might need to be protected/considered?

The issue of identifying a research subject is fairly straightforward in conventional research, and the overarching regulations governing research were designed with this type of research in mind.

The Federal Policy for the Protection of Human Subjects, also known as the Common Rule, is a set of rules for the protection of human subjects (45 CFR 46 subpart A). The Common Rule defines a human subject as "a living individual about whom an investigator (whether professional or student) conducting research obtains

(1) Data through intervention or interaction with the individual, or
(2) Identifiable private information §46.102."

With pragmatic clinical trials (PCTs), identifying those who need to be considered—and the appropriate methods for respecting their autonomy—becomes more complicated. Smalley et al (2015) define 3 categories of research participants in PCTs: direct participants, indirect participants, and collateral participants. Recognizing the different individuals and manner in which they may be affected by pragmatic research can help to ensure their rights and welfare are protected. For example, because PCTs are conducted in real-world settings, they may affect individuals by way of routine exposure to an environment (eg, a hospital) in which a PCT is being conducted. For example, when PCTs are cluster randomized (ie, the unit of randomization is the facility, provider, community, etc), individuals may be indirectly exposed to an intervention. In other words, they may not be the direct target of the intervention (direct participant), but they may be exposed to it nonetheless (indirect participant). Finally, although this group is not considered to be "research subjects" in US federal regulations, collateral participants exist; these are patients, caregivers, and patient advocacy groups who may be affected by the occurrence or findings of the trial. Consideration of this population and effective communication with them is important (Smalley et al 2015).

What are the risks to participants?

The idea behind informed consent is that people need to be afforded the opportunity to weigh the relative risks, possible benefits, and potential burdens of a research study before deciding whether to participate. The risks involved in some research are largely informational—the risk of harm is not physical at all—but comes from inappropriate disclosure of private information. For other research, the risks involved may be deemed "minimal" by an IRB, especially if the treatments being compared are each considered standard of care and the research interventions do not pose substantial risks or burdens.

With PCTs, there may be several approaches related to the autonomy interests. In this chapter, we review three broad approaches: informed consent, disclosure and authorization, and nondisclosure. We also examine data on people's preferences regarding consent, disclosure and authorization, and nondisclosure.