Exploring variables leading to major postmarketing label changes in leading regulatory authorities: a retrospective cohort study in Israel

OBJECTIVE: The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are leading benchmarks for reliance approval pathways, while many regulatory authorities streamline their review processes by referencing these authorities' evaluations and decisions. Major postmarketing (MPM) modifications, reflecting benefit-risk updates, are often added to approved labels. This study aimed to identify variables associated with significant MPM safety modifications by FDA and EMA to understand their potential impact on regulatory decision-making in the reliance process. DESIGN: Retrospective cohort study of new drug applications and supplemental indications approved by the Israeli Ministry of Health (MOH) between 2014 and 2019. The primary outcome was time to first MPM safety modification by the FDA/EMA. Associated factors, including clinical and regulatory variables, were examined using both univariate and multivariable Cox regression analyses. SETTING: Applications with FDA and/or EMA approval at the time of assessment in Israel were included. RESULTS: 467 applications met the inclusion criteria. Oncology therapeutics (HR 2.19 (95% CI 1.71 to 2.80)), approval based on early phase clinical trials data-phase 1 (HR 3.14 (95% CI 1.29 to 7.63)) and phase 2 (HR 1.97 (95% CI 1.47 to 2.64)), facilitated approval pathways (HR 1.68 (95% CI 1.31 to 2.17)) and approval based on a surrogate endpoint (HR 1.92 (95% CI 1.31 to 2.46)), were associated with higher rates of MPM modifications. MPM modifications were documented in 53.1% of applications that underwent a single Advisory Committee on Drug Registration (ACDR) review cycle, compared with 68.67% of applications that required multiple review cycles (HR 1.6, (95% CI 1.19 to 2.16), p=0.001). In multivariable analysis, oncology indications (HR 1.71 (95% CI 1.31 to 2.25)), facilitated approval pathways (HR 1.46 (95% CI 1.13 to 1.92)) and applications approved following multiple review cycles (HR 1.42 (95% CI 1.14 to 2.58)) were found to be predictive factors correlated with MPM modifications. CONCLUSIONS: By considering these associated factors, regulators can strengthen the reliance pathway assessment process, supporting a balance between streamlined evaluation procedures and maintaining rigorous safety and efficacy standards.