In April 2014, I was interviewed for the Outsourcing Pharma article “CROs Debate: Can Surrogate Endpoints Speed Oncology Drugs to Market?” I appreciated the opportunity to discuss this evolving topic and would like to expand the conversation with some additional commentary.
The gold standard for marketing approval of any cancer treatment has been—and continues to be—improved overall survival. However, FDA has defined a number of clinical measurements that are potential “surrogates” for that gold standard. FDA’s definition of a surrogate endpoint is “a laboratory measure orphysical sign that is intended to be used as a substitute for a clinically meaningful endpoint.”
While we use many lab tests to diagnose, monitor, and choose appropriate treatment for our patients with cancer, I know of no lab tests that have, as yet, been used as primary endpoints in pivotal trials for oncology drugs. That day may come, but only after the lab test has been conclusively linked to an important clinical outcome.
In oncology, the most commonly used physical sign is tumor size, including overall objective response rate (complete and partial) as well as disease control rate. In the FDA document titled “Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics,” the agency states that response endpoints may be suitable for accelerated or regular approval. However, the guidance also states that “drug applications using studies that rely on tumor measurement-based endpoints as sole evidence of efficacy may need confirmatory evidence from a second trial.” Such physical signs may also require review by a third party blinded to treatment, which adds time and expense to the trial. In my experience, response endpoints can be sufficient for accelerated approval, but more a concrete clinical endpoint (e.g., survival) is usually necessary for regular approval.
In the guidance document, FDA also defines any endpoint based on tumor assessment to be a surrogate endpoint. Examples include disease-free survival, progression-free survival, and time to progression. Whether or not these endpoints are sufficient for regular approval depends on host of factors, such as setting (primary or adjuvant treatment), effect size, effect duration, and benefits of other available therapies. Disease-free survival is best suited to the adjuvant setting (where delayed recurrence is a real clinical benefit), while progression-free survival can be used when patients typically survive for many years and have multiple lines of therapy (as in many forms of breast cancer). While either progression-free survival or time to progression can serve as primary endpoints for regular drug approval, the FDA document states a clear preference for progression-free survival because it includes all deaths regardless of cause.
The FDA document also discusses two non-surrogate endpoints (those conferring direct clinical benefits): overall survival and symptom endpoints (patient-reported outcomes). Overall survival is probably the most commonly used endpoint for regular approval, and, to my knowledge, patient-reported symptoms have never been used as the sole basis for FDA approval in oncology. However, symptom improvement, along with pharmacoeconomics, is important to the European Medicines Agency and may become increasingly important in the US as cost management becomes more critical.
Taken together, this information leads me to the conclusion that the classification of a particular endpoint as “surrogate” or “clinical” is not particularly relevant when discussing whether or not the endpoint will support marketing approval by FDA. The most commonly used endpoints for regular approval in oncology are overall survival (classified by FDA as a clinical endpoint) and progression-free survival (classified as a surrogate endpoint, although many oncologists would argue that it is a clinical endpoint). These differences underscore the need to discuss appropriate endpoints with FDA (and/or other regulatory agencies) early in the drug development process.
Lee Schacter, PhD, MD, FACP, is the Executive Medical Director, Oncology, at Clinipace.