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July 23, 2020

What Constitutes a Valid Surrogate End Point in Cancer Clinical Trials?

Author Affiliations
  • 1Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 2Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 3Associate Editor for Statistics, JAMA Oncology
  • 4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
JAMA Oncol. 2020;6(9):1334-1335. doi:10.1001/jamaoncol.2020.1847
JAMAevidence: Users' Guides to the Medical Literature (17:25)
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Historically, novel postneoadjuvant therapies for patients with early breast cancer have been assessed in multiyear trials. In an effort to address the unmet need of postneoadjuvant therapies in high-risk populations, the US Food and Drug Administration established guidelines for expediting the drug approval process by using pathologic complete response (pCR) as the end point. Previous randomized neoadjuvant trials have suggested that this end point may predict long-term outcome in patients with early-stage breast cancer.1

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1 Comment for this article
Surrogate Endpoints in Cancer Treatment
Michael McAleer, PhD(Econometrics),Queen's | Asia University, Taiwan
The important and commendable discussion of using pathologic complete response (pCR)  as the endpoints in scientific oncology clinical trials is analyzed sensitively and clearly in the excellent editorial, with an emphasis on effective treatment of early-stage breast cancer and prostate cancer.

The difficulty in selecting any surrogate measure lies in assessing its accuracy relative to the effect of treatment on the true endpoint, elimination of symptomatic disease, or reduction in the mortality rate for the individual patient.

Important issues regarding the sample size, namely the numbers of patients, drugs, events for treatment, appropriate odds ratios, leading to correlations
(linear or otherwise) of the odds and hazard ratios, need to be tackled rigorously from a scientific perspective, with an emphasis on appropriate quantitative techniques.

Alternative methods of validation based on altering the surrogate endpoints and the sample sizes are essential to be able to determine the robustness of the clinical trials, especially with regard to reducing false positive diagnoses.

If the "disease pathways and mechanism of the treatment affect the true clinical outcome and the surrogate end point", assessing the direction of causality would be problematic and misleading.

This key issue needs to be addressed in determining alternative causal relationships between the surrogate and true endpoints.