Collateral findings in pragmatic clinical trials are findings that emerge during the course of the trial that are unrelated to the primary research question but may have implications for the individual patients, clinicians, or healthcare systems from whom or within which research data are collected (Morain et al 2020). Several examples of collateral findings can be identified in the NIH Collaboratory Trials.

One example comes from the LIRE trial, which examined the effect of inserting prevalence data for common findings in people without back pain into spine imaging reports. As part of a prespecified secondary analysis, the LIRE research team identified several thousand patients for whom imaging findings indicated osteoporosis, but without any corresponding indication in the electronic health record that those patients had received a diagnosis of osteoporosis or a related treatment (Morain et al 2020; Morain et al 2022).

Another example comes from the STOP CRC trial, which revealed that some screening tests used in a study exploring strategies to increase rates of colorectal cancer screening in underserved populations had positive rates far exceeding those of other tests. This finding suggested that false-positive test results may have driven potentially unnecessary follow-up testing—presenting risks and burdens not only for the individuals who received the screening tests, but also for their healthcare systems (Nielson et al 2018).

What responsibility do researchers, institutions, and sponsors have for managing collateral findings in pragmatic clinical trials? One response might be to consider ethical guidance developed for "incidental findings" and "secondary findings." An incidental finding is a finding that is "discovered in the course of conducting [explanatory] research but is beyond the aims of the study" (Wolf et al 2008). A secondary finding is a finding that is "actively sought by a practitioner that is not the primary target" (President’s Commission for the Study of Bioethical Issues 2013). Yet, while collateral findings in pragmatic trials may share some characteristics of both incidental and secondary findings, guidance for managing incidental and secondary findings has been developed in the contexts of explanatory research, clinical care, and genomics. These contexts differ from pragmatic trials in ethically relevant ways, limiting the applicability of prior guidance to collateral findings from pragmatic trials (Morain et al 2020).

In this chapter, we examine the ethical considerations related to the identification and management of collateral findings from pragmatic trials by describing these findings and how they differ from findings that emerge in other contexts, such as incidental and secondary findings. We also summarize empirical evidence on stakeholder perspectives regarding collateral findings from pragmatic trials and outline several recommendations for policy and practice.