Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?

Abstract

Purpose: Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials.

Methods: We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995.

Results: Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval.

Conclusion: AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Fig 1.

Time line of US Food and Drug Administration (FDA) regulatory events related to accelerated approval (AA). NME, new molecular entity.

Fig 2.

New molecular entities (NMEs) that received regular approval and accelerated approval (AA) from 1995 through 2008. Overall, 37% of oncology NMEs received AA. From 1995 to 2000, 26% received AA; from 2001 to 2003, 78% received AA; since 2004, 32% have received AA.

Fig 3.

Kaplan-Meier curves for subpart H fulfillment for conversion from accelerated US Food and Drug Administration (FDA) approval to regular FDA approval for orphan drug versus non–orphan drug oncology indication. The numbers under each curve are the number of applications awaiting approval at the beginning of each time period for each type of indication.