In cancer treatment, there’s more than one way to measure patient benefit

By: Richard Pazdur, M.D.

We all want a cure for cancer. But the reality is that advances in cancer treatment rarely come in one big discovery, but rather with the continued step-by-step progress in developing new therapies. Currently, a few cancers—such as childhood leukemia and testicular cancer—can be cured. There are many ways of evaluating cancer therapies, including an improvement in overall survival, stabilizing the disease, and reducing tumor burden and tumor-related symptoms. Over the years, we have discussed with many patients facing serious and life-threatening diseases how to evaluate cancer treatments. The patients have told us there is a need for flexibility in our evaluation process.

Dr. Richard PazdurBefore a new drug is approved, FDA evaluates clinical trials in which the drug is tested in patients. We hope that the study will show a result, or endpoint, that helps us understand if the drug is safe and effective. When evaluating drugs that treat life-threatening illnesses like cancer, the risk-benefit analysis may involve weighing relatively higher risks against relatively smaller benefits.

The gold standard for determining benefit from a new cancer drug traditionally has been a randomized controlled study that demonstrates an improvement in overall survival, or OS. This is a measure of how much longer patients live who take the drug compared with patients who take another drug. An overall survival endpoint clearly demonstrates the drug’s value in extending a patient’s life.

But achieving an improvement in overall survival may not always be possible. Some cancers grow very slowly, so it might take many years for a trial to evaluate whether a potential new drug helps people live longer. Many oncology drugs target specific mutations in the tumor and there may be a limited number of patients with the mutation. Because of the small number of patients, randomized studies evaluating OS may not be possible. Also, many patients in the trial may be taking additional therapies at the time their disease progresses. This may make it difficult to accurately assess the new drug’s effect on overall survival.

When emerging data shows that a new drug demonstrates substantial benefit compared to available drugs, it may not be possible to conduct a randomized trial with certain endpoints comparing the new drug to a standard therapy with modest benefit. This is known as loss of equipoise.

Endpoints other than overall survival can shorten the duration of clinical trials so that drugs can be available sooner to patients. These alternative endpoints include progression-free survival—a measurement of how long a drug may have prevented the cancer from getting worse—and overall response rate—an evaluation of the portion of patients in the trial whose tumor size was reduced by a treatment.

Thousands of patients who previously had few therapeutic options available have already benefited from cancer therapies that were approved based on alternative endpoints, including those with renal cell carcinoma, Merkel cell carcinoma, medullary thyroid cancer, gastrointestinal stromal tumor, metastatic basal cell carcinoma, pancreatic neuroendocrine tumor, multiple myeloma, chronic myelogenous leukemia, chronic lymphocytic leukemia, and certain types of lung cancer.

We’ve held many advisory committee meetings and have heard directly from patients who believe that delaying the growth of cancer or reducing the cancer’s size are of benefit to them, since these endpoints may relate to reduced symptoms and the ability to carry on with many daily activities.

Patients have benefited, too, from the Breakthrough Therapy Designation, which was established in the FDA Safety & Innovation Act of 2012 to expedite the development and review of transformative therapies that show great promise in early clinical trials, compared to available therapy. Drugs that are designated as breakthrough therapies receive more intensive FDA consultation throughout their development period and may also qualify for other expedited development programs such as fast track and priority review. Many oncology drugs have breakthrough therapy designations, and this designation enables FDA to expedite the review of therapies that may meet patient’s needs.

There is still much more to learn about what patients need and expect from their cancer drugs. Our patient-focused drug development program has sponsored daylong meetings with patients and caregivers to discuss their views on a specific disease. A patient at our breast cancer meeting said: “As long as I can live my life and continue to work full-time, that is my goal.”

Based on these and other patient interactions, we are actively investigating ways to incorporate the patient’s experience and quality of life in benefit-risk assessments of new cancer treatments.

It’s also important to recognize that the drug approval process does not end with the drug’s approval. This is just the beginning. By looking at real-world use of the drug in the broader patient population, we may learn more about new uses for the drug, previously unknown side effects, and how different subsets of patients may respond. This information may be added to the drug labeling and can help inform our future regulatory decisions.

Our ultimate goal is to approve products that make a meaningful difference for patients and their loved ones living with the devastating effects of their disease.

Richard Pazdur, M.D., is FDA’s Director, Oncology Center of Excellence

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