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Original Investigation
May 28, 2019

Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval

Author Affiliations
  • 1Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Department of Oncology, Department of Public Health Sciences, and Division of Cancer Care and Epidemiology, Queen’s University, Kingston, Ontario, Canada
JAMA Intern Med. 2019;179(7):906-913. doi:10.1001/jamainternmed.2019.0462
Key Points

Question  When a cancer drug that has received accelerated approval from the US Food and Drug Administration (FDA) is claimed to have verified clinical benefit in a confirmatory trial, what constitutes the verification of benefit?

Findings  In this updated review of 93 cancer drug indications granted accelerated approval by the FDA from December 11, 1992, through May 31, 2017, confirmatory trials reported that 20% (n = 19) had improvement in overall survival, 21% (n = 20) had improvement in a different surrogate measure, and 20% (n = 19) had improvement in the same surrogate measure used in confirmatory trials and preapproval trials.

Meaning  Few cancer drugs approved via the accelerated FDA approval pathway were judged to have verified benefits based on improvement in survival reported in confirmatory trials.


Importance  The US Food and Drug Administration’s (FDA’s) accelerated approval pathway allows investigational cancer drugs to be approved by demonstrating a beneficial effect on a surrogate measure (eg, progression-free survival) that is expected to predict a real clinical benefit (eg, overall survival). However, these drugs must undergo postapproval confirmatory studies to evaluate their actual clinical benefits. In an assessment of the accelerated approval pathway published in 2018, the FDA concluded that this pathway was successful because only 5 (5%) of 93 accelerated drug approvals had been withdrawn or revoked over the last 25 years.

Objective  To compare the end points used in preapproval trials leading to accelerated approval with the end points used in the required confirmatory trials that verified clinical benefit and to update the outcomes of accelerated approvals with confirmatory trials that were ongoing at the time of FDA’s review.

Design, Setting, and Participants  A review of the literature on end points used in preapproval and confirmatory trials of cancer drugs that received accelerated approval and a review of the FDA’s database of postmarketing requirements and commitments focused on the outcomes of confirmatory trials that were ongoing at the time of FDA’s review of cancer drug approvals published in 2018.

Main Outcomes and Measures  End points used as confirmation of clinical benefit in cancer drugs that received accelerated approval, updated status of the confirmatory trials, and regulatory outcomes for cancer drugs that did not meet expectations in the confirmatory trials.

Results  The FDA published a review of 93 cancer drug indications for which accelerated approval was granted from December 11, 1992, through May 31, 2017. Of these approvals, the FDA reported that clinical benefit was adequately confirmed in 51 and confirmatory trials for 15 of these indications (16% of the main sample) accelerated approvals reported improvement in overall survival. For 19 approvals (37%), the confirmatory trials used surrogate measures that were the same as those used in the preapproval trials. In this updated review, confirmatory trials for 19 of 93 (20%) cancer drug approvals reported an improvement in overall survival, 19 (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 (21%) reported improvement in a different surrogate. Five confirmatory trials were delayed, 10 were pending, and 9 were ongoing. For 3 recent approvals, the primary end points were not met in the confirmatory trials; however, 1 cancer drug indication still received full approval.

Conclusions and Relevance  Confirmatory trials for one-fifth (n = 19 of 93) of cancer drug indications approved via the FDA’s accelerated approval pathway demonstrated improvements in overall patient survival. Reassessment of the requirements for confirmatory trials may be necessary to obtain more clinically meaningful information.

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