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Are Surrogate Endpoints Unbiased Metrics in Clinical Benefit Scores of the ASCO Value Framework?

Sierra Cheng1, Matthew C Cheung1,2, Di Maria Jiang2

  • 1aOdette Cancer Centre, Sunnybrook Health Sciences Centre, and.

Journal of the National Comprehensive Cancer Network : JNCCN
|December 6, 2019
PubMed

Insights

Clinical benefit scores (CBS) calculated using surrogate endpoints like progression-free survival (PFS) or response rate (RR) tend to overestimate actual benefit compared to overall survival (OS) data. These surrogate-derived scores are biased and poorly correlated with OS-derived scores in oncology drug evaluations.

Area of Science:

  • Oncology
  • Clinical Trial Analysis
  • Health Economics

Background:

  • Clinical Benefit Scores (CBS) are integral to the ASCO Value Framework (ASCO-VF).
  • CBS are weighted by efficacy endpoints: hazard ratio for death (HR OS), median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR).
  • When HR OS is unavailable, other endpoints act as surrogates for calculating CBS, used in 39.6% of trials.

Purpose of the Study:

  • To evaluate if surrogate-derived CBS provide unbiased scoring compared to HR OS-derived CBS.
  • To assess the tendency of surrogate-derived CBS to overestimate or underestimate clinical benefit.
  • To examine the correlation between surrogate- and HR OS-derived CBS.

Main Methods:

  • Computed CBS for oncology drugs approved by FDA, EMA, and Health Canada (2006-2017) using the ASCO-VF.
  • Calculated mean differences between surrogate-derived and HR OS-derived CBS.
  • Assessed correlation using Spearman's correlation and average difference using mean absolute error.

Main Results:

  • CBS derived from mOS, HR PFS, mPFS, and RR overestimated HR OS-derived CBS by 5.62, 6.86, 29.81, and 3.58, respectively.
  • Correlation coefficients between surrogate- and HR OS-derived CBS were 0.80 (mOS), 0.38 (HR PFS), 0.20 (mPFS), and 0.01 (RR).
  • Mean absolute errors were 11.32 (mOS), 12.34 (HR PFS), 40.40 (mPFS), and 18.63 (RR).

Conclusions:

  • HR PFS-, mPFS-, and RR-derived CBS are suboptimal surrogates due to bias and poor correlation with HR OS-derived CBS.
  • PFS, despite lower weighting, overestimated CBS within the ASCO-VF.
  • Rescaling surrogate endpoints may not enhance their validity in the ASCO-VF due to poor correlation with HR OS-derived CBS.
Abstract

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