Therapeutic Window–Guided Regulatory Extrapolation: A Pharmacokinetic and Pharmacodynamic Framework for Deciding When Local Studies Are Necessary

The global development of medicines increasingly contrasts with predominantly national regulatory requirements, often leading to duplicated studies and delayed access to effective therapies. While pharmacokinetic variability across populations is frequently invoked to justify local confirmatory trials, the clinical relevance of such variability depends on whether exposure differences meaningfully alter benefit–risk balance at approved doses. This review proposes a therapeutic window–guided framework integrating pharmacokinetic and pharmacodynamic principles to inform regulatory extrapolation decisions. Rather than treating ethnic sensitivity as a geographic attribute, variability should be assessed mechanistically: exposure shifts become clinically relevant only when they plausibly move patients outside established therapeutic boundaries. Using case-based analyses relevant to Mexican regulatory contexts—nifedipine, sildenafil, and vonoprazan—we illustrate how similar magnitudes of pharmacokinetic variability can carry different regulatory implications depending on exposure–response relationships and therapeutic window width. For drugs with shallow or plateaued exposure–response curves and broad functional therapeutic ranges, foreign efficacy data may be acceptable with targeted pharmacokinetic evaluation or labeling adjustments. Conversely, when mechanistic plausibility suggests clinically meaningful displacement of exposure, focused local studies may be warranted. This framework aligns with International Council for Harmonisation guidance on bridging and multiregional clinical trials while operationalizing a risk-based approach centered on clinically meaningful uncertainty. By prioritizing local evidence only when pharmacologic and clinical criteria justify it, regulatory systems may reduce unnecessary duplication without compromising patient safety.