Study: Most oncology drugs approved in Japan based on surrogate endpoints do not undergo confirmatory trials

Oncology drugs approved in Japan over the last 20 years are increasingly using surrogate endpoints as the basis for their approval, but those drugs are also unlikely to undergo confirmatory trials, according to recent research published in JAMA Network Open.

Between 2001 and 2020, international clinical trial guidelines were established, and regulators in Japan revised the country’s anticancer drug guidelines. But over the same timeframe, a problem emerged where drugs were approved quicker in some countries than others, Hideki Maeda, PhD, of the department of regulatory science at Meiji Pharmaceutical University in Kiyose, Japan, and colleagues said.

“These 3 events have substantially changed the methods used for the clinical development of anticancer drugs and the design of clinical trials, and they have also had a substantial impact on end points,” they wrote.

Maeda and colleagues conducted a cross-sectional study of anticancer drugs approved in Japan that used surrogate endpoints (SEPs) in clinical trials as well as which drugs went on to have confirmatory trials where overall survival (OS) was used as an endpoint. They identified 299 anticancer drugs approved in the country between January 2001 and December 2021, which included 142 (47.5%) molecular-targeted drugs.

Concerning tumor type, 87 approvals (29.1%) were major cancers such as non-small cell lung cancer (11.4%), breast cancer (9.0%), colorectal cancer (5.7%), and gastric cancer (3.0%) and 70.9% were not major cancers. Overall, 111 approved drugs (37.1%) had orphan designation and 30 drug approvals (10.0%) were public knowledge-based applications that did not require clinical trials to submit an application for approval. International data were used in 246 drug approvals (82.3%), and 218 drugs (72.9%) had been previously approved by the US Food and Drug Administration (FDA).

While OS was an endpoint in pivotal clinical trials for 1 drug approval (3.6%) between 2001 and 2005, it was an endpoint in 86 approvals (31.7%) between 2006 and 2020. However, 37 of 212 anticancer drugs (17.5%) that used SEPs had confirmatory trials with OS as an endpoint. Researchers found that 75 of 212 anticancer drugs (35.4%) approved on the basis of pivotal trials with SEPs received waivers for confirmatory studies containing OS as an endpoint, 65 approvals (30.7%) had not yet conducted confirmatory trials, and 35 approvals (16.5%) had ongoing confirmatory trials with OS as an endpoint.

Confirmatory trials for 20 drug approvals (9.4%) led to a negative result but were approved after a re-examination with other evidence. “We investigated the reasons for approval, which could not be determined from the re-examination report, and, in many cases, the logical background for the approval was unclear,” Maeda and colleagues said. “However, no considerable safety issues were noted. We believe it will be necessary to assess further judgments on the basis of the results of the confirmatory studies in re-examinations.”

The researchers acknowledged the increasing use of SEPs in pivotal trials for anticancer drugs but noted that “it is becoming clear that the FDA has limited data on the clinical benefits of novel cancer drugs at the time of approval and that the number of randomized clinical trials at the time of approval is decreasing.”

“To that end, it is necessary to consider a mechanism by which regulatory authorities can specify SEPs that can be used in Japan,” Maeda and colleagues said. “Promoting early approval through SEPs and ensuring the implementation of postmarketing commitment studies are considered useful. Complete follow-up of the true end points in postmarketing studies is required when using SEPs.”

JAMA Netw Open Maeda et al

Study: Most oncology drugs approved in Japan based on surrogate endpoints do not undergo confirmatory trials

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