DIF: Concepts, Measurement, and Impact in Patient-Focused Drug Development and Regulatory Decision-Making

Differential Item Functioning (DIF) is critical for Patient-Focused Drug Development (PFDD), particularly in validating Patient-Reported Outcome (PRO) tools. This study links DIF analysis to regulatory decision-making. DIF directly impacts the reliability of drug approval evidence, trial result interpretation, and subgroup consistency evaluation. However, it is not a primary driver of regulatory approval decisions, which prioritize substantial evidence of efficacy and safety. As a “regulatory-impacting measurement bias”, DIF detection ensures measurement fairness (a prerequisite for valid cross-group comparisons) and supports the pursuit of validity by identifying tool flaws for optimization, reveals group-specific response differences, and safeguards the accuracy/comparability of PRO data, thereby supporting precise drug development and reliable efficacy assessments. Methodologically, DIF analysis relies on Classical Test Theory (CTT), Item Response Theory (IRT), and methods such as Mantel-Haenszel, logistic regression, and hybrid approaches, but faces caveats including strict sample size requirements (eg, large calibration samples for IRT models) and challenges in detecting multidimensional DIF. With the growing application of PROs in clinical trials, DIF detection has become an indispensable step to mitigate biases that could mislead drug development decisions. This article systematically reviews DIF’s definition, classification, detection methods, application in drug development, and existing challenges. Integrating the latest global research and regulatory evidence, it discusses DIF’s practical implications for clinical trial design (eg, subgroup analysis, cross-cultural trial adaptation) and regulatory decision-making in PFDD. The work aims to provide theoretical reference and practical guidance for relevant research and practice, highlighting the need to address methodological limitations to strengthen DIF’s role in PFDD.