The US Food and Drug Administration’s (FDA’s) requirements for the regulatory approval of drugs has evolved greatly during the last few decades. One of the biggest changes occurred in 1992 with the Accelerated Approval program, which aimed to expedite marketing of new therapies by allowing the use of surrogate measures.
In oncology, these surrogate markers might include endpoints like pathological complete response, objective response rate, event-free survival, disease-free survival, or progression-free survival1 — measures “thought to predict clinical benefit” but not measures of clinical benefit by themselves.2
Between 1992 and 2017, more than 90 cancer drugs were granted accelerated approval by the FDA, but only 1 in 5 had confirmatory trials reporting improvement in overall survival.3 The increased reliance on surrogate endpoints may be “reducing the amount of evidence available at the time of approval and increasing uncertainty about the existence or amount of clinical benefit.”4
A recent study by Bishal Gyawali, MD, PhD, of the Program on Regulation, Therapeutics and Regulation (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, and departments of oncology and public health sciences at Queen’s University, Kingston, Canada, and colleagues reviewed the FDA’s Table of Surrogate Endpoints released in 2018. The researchers aimed to evaluate the strength of correlation of the surrogate endpoints listed with overall survival.5
“This table is very useful, but is limited because all the tumors are grouped together and there is no evidence given for any of the surrogate endpoints listed on the table,” Dr Gyawali told Cancer Therapy Advisor.
Using breast cancer as an example, Dr Gyawali and colleagues used trial-level data from systematic reviews, meta-analyses, and correlation studies to determine if each surrogate endpoint correlated with overall survival.
They found that none of the correlation studies in their analysis evaluated correlation of event-free survival with overall survival. Additionally, treatment effects of pathologic complete response, disease-free survival, objective response rate, and progression-free survival were not strongly correlated with treatment effects on overall survival. The only exception was for disease-free survival in HER2-positive early breast cancer.
“The biggest way to improve the table is to provide evidence and scientific validity for including each endpoint and justification for [its use] for accelerated or regular approval,” Dr Gyawali said. “A comprehensive database of the validity of each surrogate endpoint for each tumor type would be useful for regulators around the world.”