Prevailing uncertainties regarding the therapeutic interchangeability of PD-1 and PD-L1 inhibitors affect both clinical decision making and health-care budgeting. This Personal View presents a comprehensive assessment of the fragmented regulatory landscape of PD-1 and PD-L1 inhibitors, highlighting the complex dynamics of market competition, pricing, and the effect on health-care budgets. Our paper explores the current state of clinical trials, uninformative trial designs, and the challenges they pose in evaluating the therapeutic interchangeability of these drugs. To address these challenges, research that will inform us of the extent of interchangeability of PD-1 and PD-L1 inhibitors is needed. We recommend head-to-head randomised controlled trials, standardised study designs for indirect comparisons, trials with monotherapy groups, post-approval trials funded from private or public sources, and adoption of a near-equivalence framework in both conducting and evaluating trials.