William G. Nelson, MD, PhD Photo by Joe Rubino

THE FOOD AND DRUG ADMINISTRATION (FDA) relies on clinical trial findings to judge whether new drugs are safe and effective cancer treatments. It is possible to obtain reliable data from clinical trials to assess adverse effects. However, evaluating treatment benefits can be more complicated.

Ideally, clinical trial endpoints should feature direct assessments of safety and efficacy. Overall survival—life versus death—may well be the most straightforward assessment of drug benefit. However, indirect assessments, called surrogate endpoints, can speed up evaluation of new drugs for cancers where changes in survival might take too long or be too costly to wait for.

Surrogate endpoints for anti-cancer drugs should be parameters that are easily measured, are evident well in advance of life-threatening disease progression and correlate well with overall survival. Frequently used surrogate endpoints for cancer drugs include tumor shrinkage (response), duration of treatment response (time to progression or progression-free survival) and length of time until cancer reappears after initial surgery or radiation therapy for clinically localized disease (time to recurrence or relapse-free survival).

In recent decades, researchers have identified several biomarkers that sample many of the key properties of cancer cells. Many of these biomarkers are detectable in tumor tissues or in blood and bodily fluids. While biomarkers can help identify the right patients for a treatment, changes in biomarker levels during or after treatment can also serve as surrogate endpoints for clinical benefit.

The evidence connecting surrogate endpoints to more meaningful clinical outcomes like improvement in quality of life or overall survival varies greatly. For validated surrogate endpoints accepted by the FDA, extensive testing in clinical trials or population-scale studies supports the assertion that the endpoint can reliably anticipate true treatment benefit. As an example outside of cancer, the use of blood pressure as a validated surrogate biomarker for stroke has propelled the introduction of anti-hypertensive drugs into clinical practice.

For the FDA’s Accelerated Approval Program, the agency will accept surrogate endpoints reasonably likely to predict a clinical benefit, which allows more rapid evaluation of drugs to treat serious conditions like cancer that have substantial unmet medical needs. For these surrogate endpoints, the scientific rationale may be compelling, but the data corroborating the correlation with clinical benefit are not adequate for traditional FDA approval. For this reason, commercial sponsors for anti-cancer drugs receiving accelerated approval must commit to completing clinical trials that more directly test patient benefit before receiving full FDA approval. If the confirmatory trial does not reveal patient benefit, the FDA can remove the drug from the marketplace.

Do surrogate endpoints really expedite the approval of anti-cancer drugs? Or does their use prompt approval of ineffective treatments? In 2018, the FDA reported its experience with accelerated approval based on surrogate endpoints for anti-cancer drugs from Dec. 11, 1992, to May 31, 2017, in JAMA Oncology. Over that period, the FDA granted accelerated approval for 64 anti-cancer products encompassing 93 new indications; 53 of the products were entirely new agents. Fifty-one of the indications (55%) were verified by subsequent trials; these drugs became available for cancer treatment an average of 3.4 years earlier with accelerated approval. Only five of the indications (5.4%) failed to show direct benefit in confirmatory trials, prompting withdrawal of the products from the market. The remainder have not yet completed confirmatory trials or proven their benefit.

The use of surrogate endpoint biomarkers is increasing, accompanied by a surge in anti-cancer drug approvals by the FDA. Critics of this trend caution that the amount of evidence supporting surrogate endpoint correlations with overall survival may be insufficient, underscoring a need for more vigilance in monitoring clinically meaningful outcomes in controlled clinical trials after either accelerated or traditional FDA approval. 

Of course, the be-all and end-all measurement for cancer treatment will always be improved overall survival for all who confront cancer, and as a consequence, reduced cancer mortality.

William G. Nelson, MD, PhD, is the director of the Johns Hopkins Kimmel Cancer Center in Baltimore.