Delays in New Drug Applications and Associated Factors for Orphan Anticancer Drugs in Japan Compared with the USA

Abstract

The approval of orphan anticancer drugs is encouraged in Japan to meet high social demand. However, approval lag and its main component, submission lag, between the USA and Japan continues to be an issue for these drugs. We aimed to identify the main reasons for submission lags with orphan anticancer drugs, to compare these between orphan and non-orphan anticancer drugs, and to identify factors associated with the main reasons for submission lags for orphan anticancer drugs. We investigated anticancer drugs approved in Japan between April 2004 and December 2017 using publicly available information. We used Pearson’s product moment correlation coefficient to identify correlations between submission lag and initiation lag or development-time lag, and we used the Mann–Whitney U test to compare contributors to submission lags for both orphan and non-orphan anticancer drugs. We used multiple regression analysis to identify potential factors associated with the main reasons for submission lags for orphan anticancer drugs at the indication level. Independent variables were selected using backward/forward stepwise selection according to the Akaike information criterion. In Japan, the number of approved indications for orphan anticancer drugs consistently increased between 2004–2007 and 2016–2017. The median submission lag for orphan anticancer drugs in 2016–2017 was 515.0 days [interquartile range (IQR) 182.0–999.0], and this lag was significantly correlated with the initiation lag (correlation coefficient 0.77, P < 0.001) but not with the development-time lag (correlation coefficient − 0.031; P = 0.82). The initiation lag was significantly longer for orphan than for non-orphan anticancer drugs [median 1428.0 (IQR 890.8–2655.8) vs. 1178.0 days (369.0–1874.0); P = 0.033]. Cytotoxic drugs were significantly associated with a longer initiation lag (coefficient 2011.8; P = 0.0023), whereas designation as a breakthrough therapy in the USA was significantly associated with a shorter initiation lag (coefficient − 1272.3; P = 0.020). The initiation lag for orphan anticancer drugs was the main factor affecting submission lag and was longer than that for non-orphan drugs. Of the factors associated with initiation lags, designation as a breakthrough therapy (or the possibility of such a designation) in the USA may lead to earlier initiation of clinical development of an orphan anticancer drug in Japan. In turn, this may reduce the submission lag.