Real-World Evaluation of Regulatory Judgments on Anticancer Drug Use During Pregnancy in Japan: A Retrospective Analysis from 2004 to 2024.

BACKGROUND: The administration of antineoplastic agents to pregnant women requires comprehensive evaluation of fetal risks and therapeutic benefits for the mother. In Japan, there has traditionally been a tendency to uniformly classify such cases as 'contraindicated' when reproductive toxicity data are insufficient. However, a shift toward a more flexible policy has occurred since the approvals of daratumumab and pembrolizumab in 2017. OBJECTIVE: This study quantitatively evaluated the changes in regulatory decisions regarding the administration of antineoplastic agents to pregnant women approved by the Ministry of Health, Labour and Welfare (MHLW) following review by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan since October 2004 to identify influencing factors and compare decision trends with those of the US Food and Drug Administration (FDA). METHODS: A total of 129 drugs approved by the PMDA and FDA were analyzed. The evaluation included classification of decisions (contraindicated, warning, benefit-based administration), annual trends (Joinpoint regression), and background factors (logistic regression). RESULTS: Since 2018, the proportion of drugs judged as 'benefit-based administration' increased to 82.5%. Significant positive associations were observed between benefit-based administration and the following predictors:more recent PMDA approval year, monoclonal antibody drug modality (vs small molecules), absence or presence offetal death, and absence or presence of reversible alterations. Fetal growth retardation showed a negative association with benefit-based administration; 'unassessable' classifications tended to act as a barrier to decision making. The concordance rate with the FDA was only 12.4%, suggesting systematic differences in decision-making approaches. CONCLUSION: In recent years, the PMDA has adopted a more flexible approach that prioritizes clinical benefit. Importantly, the presence of assessable information-rather than the absence or presence of risk-was identified as a key factor influencing regulatory decisions. However, this descriptive comparison did not restrict the sample to clinically similar drugs. Therefore, while the observed differences likely reflect regulatory tendencies to some extent, they may also be partially influenced by differences in drug background characteristics.