Comparing cancer drug approval systems in the United States and Japan

Immediate approvals of novel and efficacious drugs are crucial for cancer patients worldwide. However, because there are some discrepancies in the drug evaluation systems among different regulatory agencies on the efficacy of approved drugs, the judgment of regulatory agencies may differ, especially in case of prematurely approved drugs through an expedited drug approval system, such as the accelerated approval (AA) pathway by the US Food and Drug Administration (FDA).¹

In 1992, the US FDA adopted the AA pathway for drugs treating patients with severe and life-threatening diseases. This pathway is intended to provide patients with new treatments as quickly as possible by rapidly approving new drugs based on surrogate endpoints with a reasonable expectation of clinical benefit or intermediate clinical endpoints other than irreversible disease or death. On the other hand, a confirmatory trial to prove the drug's efficacy is mandatory, and if it fails, the approval will be withdrawn. In the past 10 years, AA has been mainly granted for anticancer drugs, accounting for 85% of the total, and around 12% of drugs that received AA were withdrawn afterward.² However, in practice, it is also pointed out that in the case of AA, confirmatory studies are conducted infrequently, showing a gap between the original concept of the system and reality.³

The problem is that AA is unique to the US FDA, but such regulatory decisions often influence the drug regulations of other countries that do not have the same system. For example, although Japan has a conditional and time-limited approval system that resembles the AA, most anticancer drugs are approved through a standard and conventional regulatory pathway and are not quickly withdrawn once approval is granted. A recent example of confusion brought by such differences in the regulatory approval systems is the case of Tecentriq (atezolizumab) in treating patients with advanced triple-negative breast cancer whose tumors express PD-L1. In the United States, the drug received AA for the indication in March 2019 based on the results of the IMpassion130 study.⁴ However, the postapproval confirmatory Impassion131 study did not demonstrate a statistically significant improvement in progression-free survival, resulting in the withdrawal from the manufacturer in August 2021.⁴ Meanwhile, in Japan, this drug was conventionally approved in September 2019 based on the IMpassion130 study. However, even after a year of the decision to withdraw from the US FDA, neither the Japanese regulatory authority nor the company has taken action.

A comparable instance involves Avastin (bevacizumab) in the context of inoperable or recurrent breast cancer. In the United States, the drug received approval in February 2008 as a treatment for breast cancer when used in conjunction with paclitaxel, based on the findings from the E2100 trial.⁵ Nevertheless, in November 2011, the FDA rescinded its approval, citing the outcomes of the AVADO and RIBBON1 studies, which failed to exhibit a definitive life-extending effect.⁵ Contrarily, in Japan, the authorization of bevacizumab combined with paclitaxel for breast cancer treatment, approved in September 2011, remains in effect.

Since the regulatory authorities for drugs in each country make independent decisions, they would not necessarily be required to follow or harmonize the authorities’ decisions in other countries. However, as the most influential regulatory authority in the world, the US FDA's far-reaching influence is not negligible, and countries without the AA pathway, including Japan, must be aware of the problem and should note that, even after approval, it is essential to continuously evaluate the drug's efficacy as a treatment option and ensure that patients benefit from its use.

AUTHOR CONTRIBUTIONS

Yudai Kaneda: Conceptualization; writing—original draft. Hideki Maeda: Writing—review and editing. Akihiko Ozaki: Data curation; writing—review and editing. Yuka Higuchi: Writing—review and editing. Tetsuya Tanimoto: Supervision; Writing—review and editing.

CONFLICT OF INTEREST STATEMENT

Dr Ozaki reported personal fees from Medical Network Systems Inc. and Kyowa Kirin Co. Ltd., outside the submitted work. Dr Tanimoto reported personal fees from Medical Network Systems Inc. and Bionics Co. Ltd., outside the submitted work. All authors have read and approved the final version of the manuscript. Yudai Kaneda has full access to all data in this study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

TRANSPARENCY STATEMENT

Yudai Kaneda affirms that this manuscript is an honest, accurate, and transparent account of the research reported, that no important aspects of the research have been omitted, and that any differences from the planned research (and registration, if relevant) are explained by Yudai Kaneda.