Safety-Related Regulatory Actions and Risk Factors for Anticancer Drugs in Japan

The approval of anticancer drugs in Japan has increased to meet high medical demand. To maximize the benefits of anticancer drugs, adverse drug reactions (ADRs) must be properly managed. However, in some cases, clinically significant safety issues are detected after launch, and safety-related regulatory actions (SRRAs) are implemented.

We aimed to determine the characteristics of SRRAs for anticancer drugs approved in Japan and to identify factors related to the drug development and regulatory approval process associated with the occurrence of an SRRA.

We defined an SRRA as the issuance of a 'Yellow Letter', 'Blue Letter', or an official notification by the Ministry of Health, Labor and Welfare. Anticancer drugs approved in Japan as new active ingredients from April 2004 to July 2016 were analyzed using publicly available information. The Kaplan-Meier survival curve was plotted to estimate the probability of the occurrence of an SRRA, and the Cox proportional hazards model was used to identify risk factors associated with the occurrence of an SRRA. Independent variables were selected using backward/forward stepwise selection according to Akaike's Information Criterion.

An SRRA was implemented for 38 of 63 anticancer drugs. Approximately 70% of SRRAs occurred within 2 years after approval, and the median time between approval and the occurrence of an SRRA was 1.6 years (interquartile range 0.94-2.4). No Yellow Letter was issued during the follow-up period; however, one Blue Letter was issued for 'acute lung injury and interstitial pneumonia' for sorafenib. According to official notifications, 'clinically significant adverse reactions' was the most revised section of package inserts (62%). The probability of an SRRA at the 1-, 2- and 3-year follow-up was 15.9% (95% confidence interval [CI] 6.4-24.4%), 41.3% (95% CI 27.8-52.3%), and 56.8% (95% CI 41.8-68.0%), respectively. Monoclonal antibodies were associated with a low risk of occurrence of an SRRA (hazard ratio [HR] 0.29, p = 0.019), while the large number of patients in pivotal studies (per 100 patients) was associated with a high risk of occurrence (HR 1.07, p = 0.012).

The high-risk period for the occurrence of an SRRA for anticancer drugs in Japan was within 2 years after approval. Among the factors related to the drug development and regulatory approval process, anticancer drugs in the form of non-monoclonal antibodies, and whose pivotal studies included a large number of patients, were more likely to be associated with an SRRA. Postmarketing follow-up should therefore be carefully performed, especially in the first 2 years after approval and for non-monoclonal antibody anticancer drugs. Moreover, postmarketing follow-up is crucial, even if large-scale pivotal studies for regulatory approval have already been performed.