There are 3 general rationales for early termination of clinical trials: futility, safety, and efficacy. For each rationale, several ethically relevant considerations may shape decision-making in pragmatic clinical trials. The DSMB and the study sponsor should work together before study initiation to evaluate the potential relevance of these considerations when determining thresholds for early termination.
Early stopping for futility rests upon a determination that the trial is unlikely to attain its scientific objective. Stopping a trial early for futility minimizes unnecessary burden on those involved and prevents needless use of resources.
A thorough discussion of the arguments for and against early termination for futility in pragmatic clinical trials has been published elsewhere (Ellenberg et al 2015). An important consideration is that, when treatments in common use are studied, as is generally the case in pragmatic trials, particularly strong evidence may be needed to persuade clinicians and/or healthcare systems of the reliability of the results. Clinicians accustomed to administering a particular therapy may not be convinced that another therapy is as effective when the trial is small. Relatedly, even small differences in outcomes may be informative in some cases when treatments are widely used, given the potential scope for population-level health impact. Furthermore, if both treatments are in common use, there should be no ethical concern about continuing a study, even when it appears that the effects of the treatments are similar.
Early stopping for safety generally occurs when interim data suggest that the harms of a treatment clearly outweigh the potential benefits. Several aspects of pragmatic clinical trials may raise special considerations related to early stopping for safety. For example, as described in the "Data Issues With Monitoring Pragmatic Trials" section of this chapter, data related to safety events may not be available in real time. Contact with study participants may also vary by study arm, meaning higher rates of safety events may reflect differential reporting rather than a signal of potential harm. Finally, for pragmatic trials involving interventions in widespread use, the safety profiles may be well established as compared to novel interventions being studied in explanatory trials. Consequently, DSMBs should weigh the likelihood that a difference in safety outcomes represents a true new safety signal (Simon et al 2019).
In explanatory trials, early stopping for efficacy occurs when interim data suggest that the experimental treatment is more efficacious than its comparator. As with assessments of futility and safety, the pragmatic trial context may influence decisions about early stopping for efficacy. For example, Simon and colleagues (2019) explained:
Pragmatic trials often focus on implementation or policy questions, and a "policy-meaningful difference" is harder to define than a clinically meaningful difference. Implementation decisions must consider magnitude of benefit, anticipated cost, and competing health system priorities. Consequently, early termination of a pragmatic trial as soon as the benefit of a new program or service exceeds a boundary of statistical significance does not necessarily guarantee that health systems will adopt or implement that new program.
In addition, as noted above, pragmatic trials often compare treatments that are in widespread use. This fact may alter the obligations owed by researchers to trial participants as compared to those owed to trial participants in trials involving novel therapies, which the participants would not receive but for their participation in the trial.