Ethical and regulatory requirements for subject enrollment in clinical research are critical considerations in the design of a research study. One critical determination is whether individual permission with informed consent and authorization must be obtained, or if the research can proceed with a waiver or alteration of these requirements. In contrast to traditional clinical trials, which commonly study new therapies in highly controlled settings, pragmatic clinical trials rely on streamlined processes to measure outcomes in heterogeneous populations in real-world clinical settings (Califf and Sugarman 2015).

There are a number of reasons why the application of ethical principles and regulations regarding informed consent can be complex for PCTs.  These include, for example, an increase in the use of novel study designs, such as cluster randomization in which the unit of randomization may be a clinic, hospital or health system as opposed to an individual, or a step-wedge design in which the intervention is introduced to sites at different times (Anderson et al 2015; Sugarman and Califf 2014; Sugarman 2016). Some assert that for many pragmatic trials, altered consent, such as a streamlined presentation of key elements integrated into the flow of care (Kim and Miller 2014), might better match the potential subjects’ needs and the level of study risk while enabling important research (McKinney 2016; Faden et al 2014; McKinney et al 2015; Dickert et al 2018; Morain and Largent 2021; Zhang et al 2021).  Others propose waiver of informed consent altogether, which is allowable for clinical investigations, including PCTs, that pose no more than minimal risk to a human participant and meet the other regulatory criteria. However, attitudes regarding the acceptability of alternative approaches to full research consent vary, and this remains a topic of debate in the research community (Cho et al 2015; Nayak et al 2015; Weinfurt et al 2017). While the focus of this chapter is on initial consent, for some research, there may be a requirement for ongoing consent, for example, if new procedures or new risks are added.

In this chapter, we review regulatory requirements for informed consent, discuss waivers and alterations of consent, examine mechanisms for notification, and share data on stakeholder responses to different approaches to consent and notification—all with a focus on special considerations for pragmatic trials. We also briefly comment on Health Insurance Portability and Accountability Act (HIPAA) authorization.