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Original Investigation
April 1, 2019

Estimation of Study Time Reduction Using Surrogate End Points Rather Than Overall Survival in Oncology Clinical Trials

Author Affiliations
  • 1Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland
  • 2School of Medicine, Oregon Health & Science University, Portland
  • 3Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland
  • 4Center for Health Care Ethics, Oregon Health & Science University, Portland
JAMA Intern Med. 2019;179(5):642-647. doi:10.1001/jamainternmed.2018.8351
Key Points

Question  How much time is saved in the 6 to 15 years of drug development by using surrogate end points rather than overall survival as the basis for US Food and Drug Administration approval in contemporary cancer drug trials?

Findings  In this retrospective study of 107 oncology drugs with 188 indications, compared with the duration of studies using overall survival as the basis for approval, progression-free survival was associated with a savings of 11 months, and response rate with a savings of 19 months.

Meaning  Using surrogate end points for oncology drug approval was associated with reduced drug development time by approximately 11 months compared with an overall survival end point.

Abstract

Importance  Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life.

Objective  To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS).

Design, Setting, and Participants  This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018.

Main Outcomes and Measures  The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS.

Results  In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months).

Conclusions and Relevance  From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study’s findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.

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