OBJECTIVES: This Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept article offers systematic reviewers, guideline authors, and other users of evidence assistance in addressing randomized trial situations in which interventions or comparators differ from those in the target people, interventions, comparators, and outcomes. To clarify what GRADE considers under indirectness of interventions and comparators, we focus on a particular example: when comparator arm participants receive some or all aspects of the intervention management strategy (treatment switching). STUDY DESIGN AND SETTING: An interdisciplinary panel of the GRADE working group members developed this concept article through an iterative review of examples in multiple teleconferences, small group sessions, and e-mail correspondence. After presentation at a GRADE working group meeting in November 2022, attendees approved the final concept paper, which we support with examples from systematic reviews and individual trials. RESULTS: In the presence of safeguards against risk of bias, trials provide unbiased estimates of the effect of an intervention on the people as enrolled, the interventions as implemented, the comparators as implemented, and the outcomes as measured. Within the GRADE framework, differences in the people, interventions, comparators, and outcomes elements between the review or guideline recommendation targets and the trials as implemented constitute issues of indirectness. The intervention or comparator group management strategy as implemented, when it differs from the target comparator, constitutes one potential source of indirectness: Indirectness of interventions and comparators-comparator group receipt of the intervention constitutes a specific subcategory of said indirectness. The proportion of comparator arm participants that received the intervention and the apparent magnitude of effect bear on whether one should rate down, and if one does, to what extent. CONCLUSION: Treatment switching and other differences between review or guideline recommendation target interventions and comparators vs. interventions and comparators as implemented in otherwise relevant trials are best considered issues of indirectness.

Czech National Centre for Evidence Based Healthcare and Knowledge Translation Faculty of Medicine Masaryk University 625 00 Brno Czech Republic; Institute of Health Information and Statistics of the Czech Republic 100 00 Prague Czech Republic

Department of Cardiovascular Medicine John Radcliffe Hospital University of Oxford UK; Department of Population Health London School of Hygiene and Tropical Medicine London

Department of Clinical Research University Hospital Basel University of Basel Basel Switzerland; Research Center for Clinical Neuroimmunology and Neuroscience Basel Berlin Institute of Health Berlin Germany

Department of Health Research Methods Evidence and Impact Michael G DeGroote Cochrane Canada Centre Cochrane Canada and McMaster GRADE Centre McMaster University Hamilton Ontario Canada; Department of Medicine McMaster University Hamilton Ontario Canada; Department of Biomedical Sciences Humanitas University Milan Italy; Cochrane Canada Hamilton Ontario Canada

Department of Health Research Methods Evidence and Impact Michael G DeGroote Cochrane Canada Centre Cochrane Canada McMaster GRADE Centre and Department of Medicine McMaster University 1280 Main St W Hamilton ON L8S 4K1 Canada

Department of Internal Medicine American University of Beirut Lebanon P O Box 11 0236 and Department of Health Research Methods Evidence and Impact McMaster University 1280 Main St W Hamilton ON L8S 4K1 Canada

Department of Medicine and Population Health University of Kansas Health System 3901 Rainbow Blvd MS3002 Kansas City KS 66160 USA; Department of Health Research Methods Evidence and Impact McMaster University 1280 Main St W Hamilton Ontario L8S 4K1 Canada

Evidence based Medicine Department 1 of Internal Medicine Faculty of Medicine and University Hospital Cologne University of Cologne Kerpener Str 62 50937 Cologne Germany

IRCCS Istituto delle Scienze Neurologiche di Bologna Unit of Epidemiology and Statistics Cochrane Review Group Multiple Sclerosis and Rare Diseases of the CNS Via Altura 3 40139 Bologna Italy

Minneapolis VA Health Care System Urology Section 112D One Veterans Drive Minneapolis Minnesota 55417

Princess Máxima Center for Pediatric Oncology Heidelberglaan 25 3584CS Utrecht the Netherlands