3004 — Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

Richey EA (Feinberg School of Medicine, Northwestern University), Shankaran V (Feinberg School of Medicine, Northwestern University), Hirschfeld S (National Insitutes of Health), Trifilio SM (Northwestern Memorial Hospital), McKoy JM (Feinberg School of Medicine, Northwestern University), Carson KR (Washington University School of Medicine), Edwards BJ (Feinberg School of Medicine, Northwestern University), Luu TH (Feinberg School of Medicine, Northwestern University), Sartor AO (Tulane University, Tulane Cancer Center), Bennett CL (VA Center for the Management of Complex Chronic Conditions, Jesse Brown VAMC, Feinberg School of Medicine, Northwestern University )

Objectives:
The accelerated approval (AA) regulation is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA allows sponsors to begin marketing based on improvements in surrogate outcomes. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). We evaluate concerns that the AA approval bar has been raised too high; many drugs that received AA have not completed subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective.

Methods:
Using publicly available databases, we reviewed information on safety, efficacy, clinical development times, and subpart H completion for FDA-approved new molecular entities (NMEs) receiving AA (19 drugs) or regular approval (32 drugs) between 1995 and 2008.

Results:
AA accounted for 78% of FDA approvals for oncology NMEs between 2000 and 2003 versus 38% more recently. Median development times for AA and regular-approved oncology NMEs were 7.3 and 7.8 years, respectively. Phase III trials supported FDA approval for 45% of drugs receiving AA for orphan drug indications and 73% receiving AA for non-orphan drug indications; efficacy was confirmed via Subpart H completion for 42% and 86% of these drugs, respectively. In survival analysis, orphan drugs were 10 times less likely to convert to regular approval than other AA oncology NMEs. Black-box warnings were added to package inserts of two regular approval and four AA oncology NMEs. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials.

Implications:
AA oncology NMEs are safe and effective, although development times are not accelerated. The FDA’s emphasis on interim analyses of phase III trial results has adversely impacted development of oncology NMEs, particularly those targeted for orphan drug indications.

Impacts:
Access to novel, safe, and effective therapeutic options is necessary, particularly for veterans who suffer from rare malignancies. AA for rare cancer indications should be based on results from phase II trials. Safety and efficacy studies among veterans could provide important post-approval data.