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

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.

Trial Sponsorship and Time to Reporting for Phase 3 Randomized Cancer Clinical Trials

“…The use of surrogate endpoints such as response rate and progression-free survival has been associated with a reduction in oncologic clinical trial reporting times [15]. Echoing these findings, our results demonstrate an association between surrogate endpoint use and reduced TTR on univariate analysis, although this association was not observed on multivariate analysis.…”

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis

“…Surrogate measures of clinical benefit (eg, progression free survival and disease response) have important feasibility advantages because they can be assessed earlier and with smaller sample sizes (and therefore fewer resources) compared with overall survival. A recent study found that cancer drugs approved on the basis of surrogate measures had on average an 11 month shorter development duration compared with drugs approved on the basis of overall survival 81. However, the feasibility advantages of using surrogate measures should be weighed against their several disadvantages.…”

Generating comparative evidence on new drugs and devices after approval

“…According to a recent evaluation, using progression-free survival and response rate in cancer trials was associated with an average 11-month and 19month, respectively, shorter clinical development period compared with using overall survival. 62 Although certain surrogate measures are well-validated, many of the surrogate measures used for approval decisions are not comprehensively validated, highlighting the need to confirm clinical benefit in the post-marketing period. Surrogate measures are particularly common in cancer trials.…”