The importance of real-world evidence (RWE) is becoming increasingly recognized in the fields. of medicine and healthcare delivery as a complement to evidence from randomized controlled. trials (RCTs). Incorporating RWE - which informs on a treatment's uptake, effectiveness, risks, and benefits under realistic (vs. carefully controlled) conditions among diverse and heterogeneous populations-can specifically benefit efforts to reduce combustible tobacco use, the primary cause of preventable premature death globally. RCTs have shown a variety of quit methods (e.g., nicotine replacement therapy, varenicline, and electronic nicotine delivery systems (ENDS)) to be effective for smoking cessation, but these treatments have varying uptake and success in real-world settings. A likely reason why RCT evidence does not necessarily generalize to real-world settings is that the populations eligible for RCTs do not represent the majority of adults who smoke (e.g., with respect to motivation to quit), underscoring the need for complementary RWE. Accordingly, non-combustible nicotine products (NCNPs) including ENDS that can serve as alternative consumer products and do not require a priori intentions to quit smoking seem to have higher uptake, and therefore greater reach, than traditional medical or pharmaceutical methods. RWE can also advance our limited current understanding of how consumers use reduced-risk products, which could in turn improve generalizability of RCTs in the future, as well as inform clinical communications and regulatory strategies. Since RWE has limitations such as confounding and selection bias, it should be used as a complement, not a replacement for, traditional RCT evidence.

Iran's national harm reduction program, scaled up during a period of substantial decline in HIV prevalence among people who inject drugs, later faced growing operational challenges as client numbers declined at many service sites. This Comment describes the evidence-based restructuring undertaken by the Ministry of Health and Medical Education (MoHME) after approximately two decades of implementation. National studies on population size estimation, geospatial distribution of injecting drug use, and service quality assessment informed a major reconfiguration of the harm reduction network. Underutilized facilities were consolidated, while outreach teams and mobile clinics were repositioned toward underserved areas and emerging drug-use hotspots. The restructuring aimed to improve resource utilization, maintain national coverage, and better align services with changing patterns of drug use and emerging hotspots. Iran's experience highlights the importance of continuous evaluation and adaptation of mature harm reduction programs in response to epidemiological transitions, evolving substance-use patterns, and emerging evidence. The lessons from this process may be relevant for other countries seeking to optimize publicly funded harm reduction services while preserving access for vulnerable populations.