Editorial: Pharmacogenetics and pharmacogenomics in psychiatry: challenges and opportunities.

Adverse effects (AEs) are untoward medical events that are thought to be causally related to clinical interventions (, ). These events can range from mild, such as headaches and mild nausea, to serious, such as hospitalization or even death. Identifying and monitoring adverse effects are critical for ensuring the safety of patients participating in clinical trials, and help researchers track and mitigate any harms that arise during the course of a study. Research sponsors (e.g., National Institutes of Health, NIH) and regulatory bodies (e.g., US Food and Drug Administration, FDA) have developed and put into place a variety of policies and procedures aimed at protecting patient safety both during clinical trials (e.g., requiring researchers to monitor and report AEs) and after a clinical intervention has been approved for marketing (e.g., through post-market surveillance of AEs). Although the policies and procedures for protecting patient safety are well established for clinical trials, it remains unclear as to whether they are appropriate for ensuring patient safety in implementation science trials. Implementation science is the study of methods and strategies to enhance uptake evidence-based interventions (EBIs) into routine medical care. To this end, implementation trials utilize study designs ranging from clinical effectiveness trials that also assess the context for implementation (e.g., by identifying barriers and facilitators) to trials that directly test how implementation strategies relate to clinical intervention uptake (). This presents challenges from a research sponsor and regulatory perspective because the policies and procedures that were developed for monitoring clinical trials are now being directly applied to implementation trials (e.g., by the National Heart, Lung and Blood Institute) (). However, in implementation trials, the key interventions of interest are implementation strategies to improve the use or uptake of clinical EBIs that typically already have a well-established efficacy and safety profile and thus approximate the risk encountered during routine care. Therefore, directly translating standard patient-safety guidelines from clinical trials to implementation trials may, at best, be of low value in terms of time and resources and, at worst, miss potential harms caused by the implementation strategies being tested. This has called into question the appropriateness of applying clinical trial safety standards to implementation trials (). In this paper, we argue that the standard policies and procedures developed to protect patient safety in clinical trials need to be adapted to better align with the objectives of implementation trials. These standards need to be adapted to: 1) reflect that the clinical interventions used in implementation trials have typically been demonstrated to be safe and effective, and 2) the focal interventions being tested are strategies to enhance uptake of these clinical interventions. As a starting point, we formulate and describe a conceptual model that identifies four distinct pathways leading from implementation strategies to AEs. We propose that these constitute a new class of AEs, Implementation strategy Adverse Effects (IAEs), and provide a definition for such effects. We end by discussing the implications and providing recommendations for advancing our understanding of risks to patient safety in implementation trials.