Julia A. Beaver, MD
More than a third of the new indications for oncology drugs that became available for patient care during the past 25 years entered clinical practice as a result of the FDA’s accelerated approval (AA) program, an expedited review process that relies on surrogate endpoints to predict benefit before clinical trials are fully conducted. The use of the program has grown over the years, so much so that more new cancer drugs and indications gained approval through the AA pathway than through the regular review process during the first 6 months of 2017.
That is the picture that emerges from an analysis that FDA officials wrote in March for JAMA Oncology1
after a spate of criticism in academic journals about the agency’s cancer drug approval practices. The report comes at a time when the FDA is seeking to streamline regulatory processes and pick up the pace of new drug approvals.
Supporters of the program, including the FDA itself, deem it a major success. Countless patients have been able to take what confirmation trials usually demonstrate to be life-extending therapies several years before those medications likely could have reached the market via the regular approval process.
However, critics say the benefits of AA in particular and surrogate endpoints in general have come at a high price, with many patients exposed to costly medications that turn out to be inadequate alternatives to drugs with proven efficacy. They say the pace of confirmatory trials to convert AAs into regular approval status has been too slow.
The FDA analysis shows that the AA pathway accounts for 35% of the indications approved for new agents (those classified as new molecular entities) and existing drugs from December 11, 1992, when the program began, through May 31, 2017. Notably, more than half of the monoclonal antibodies approved through the AA program are checkpoint blockade agents targeting the PD-1/PD-L1 pathway that have been credited with ushering in the new era of anticancer immunotherapy (Figure
Endpoints Have Evolved
Much of the controversy about the AA program stems from a broader debate about appropriate endpoints for oncology clinical trials. Since the FDA began requiring clinical trials for new drug approvals in 1962, the gold standard for any new drug approval (not just cancer drugs) has been a randomized clinical trial that demonstrates an improvement in survival or important clinical symptoms. However, surrogate endpoints have been used, such as improvements in blood pressure or serum cholesterol for cardiovascular disease studies.2
For oncology drugs, the FDA usually issued approvals in the 1970s based on the objective response rate (ORR) determined by tumor assessments from radiological tests or physical examinations. In the early 1980s, the agency shifted to what it considered “more direct evidence of clinical benefit,” such as improvement in survival, quality of life (QOL), or tumor-related symptoms.2
In the 1990s, surrogate endpoints were established, including disease-free survival, durable complete response in leukemia, response duration, and relief of tumor-related symptoms.
Drug approval benchmarks came under heavy fire during the AIDS epidemic in the 1980s, when desperate patients and their supporters demanded access to experimental medications as soon as they demonstrated efficacy in any measure that might prove a reasonable proxy for extended survival. The FDA responded in 1992 by writing regulations that created the AA pathway, allowing the FDA to approve drugs based on a surrogate endpoint that is “reasonably likely to predict clinical benefit” for patients with a serious or life-threatening condition who do not have other options or if the experimental therapy demonstrates an improvement over existing treatments.2
(It is 1 of 4 programs the FDA has crafted to expedite drug development; the others are the fast track, breakthrough therapy, and priority review programs.)