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).

Some pragmatic trials use cluster randomization, in which groups (such as clinics, hospitals, or health systems) are randomly assigned rather than individual patients. Because of these differences, the application of ethical principles and regulations to pragmatic trials can be complex (Anderson et al 2015; Sugarman and Califf 2014; Sugarman 2016). Some assert that for many pragmatic trials, altered consent, such as a short oral presentation of options, might better match the potential subjects’ needs and level of 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); however, attitudes regarding the acceptability of alternative approaches vary (Cho et al 2015; Nayak et al 2015; Weinfurt et al 2017).

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.