Endpoints and Evidence of Efficacy

What do the regulators look for? Safety and efficacy. Developers most often attempt to show efficacy with randomized controlled trials that indicate a statistically significant improvement in a clinically meaningful endpoint.

Pharmaceutical clinical trials use either a clinical endpoint or a surrogate endpoint. Clinical endpoints are things like increased survival rate and less patient pain – signs that the doctors and patients can easily measure or report. Surrogate endpoints are ones for which the doctor must use some technology to evaluate, and they are not a direct clinical benefit. A surrogate endpoint is identified as a biological state likely to predict a clinical benefit. The decrease in biomarker levels and shrinkage of tumors are surrogate endpoints. Clinical endpoints are better, but sometimes surrogate endpoints are more practical for experimenters to get a handle on.  It is often easier and faster for researchers to identify surrogate endpoint; a change in blood chemistry might show up in weeks after treatment commences while waiting to develop survival data can take years.

Disease Free Survival (DFS) is an endpoint often employed in cancer therapy research.  It is the average length of time (or distribution of times) that patients experience from the end of treatment until the cancer relapses.  This metric is more common when discussing treatment by surgery than by chemotherapy. Progression Free Survival (PFS) is more often seen in chemotherapy studies.  It is the length of time from the end of treatment until the disease becomes measurably worse. Overall Survival is a clinical endpoint that is the length of time between the end of treatment and death of the patient (from any cause).  Although overall survival is probably the best metric for a new treatment, it is difficult to measure, especially in cases with slow-growing cancer.  For this reason disease-free survival is often used when applications are made for new medicine approval.

New Approaches to Endpoints in Trials to Show Efficacy

Traditional endpoints used to prove a medicine worked included (1) whether the tumors shrank, (2) how long the patients survive after starting the medicine, and (3) whether symptoms improve and whether quality of life improves.  Where the drug is in development affects endpoint choice.  Early phase clinical trials typically look at safety while later ones look at patient survival.  That’s the way it has been done.

infusionA new paradigm is arising in the industry.  New endpoints look at one or more biomarkers for proving efficacy before FDA approval.  In the past several years, a number of oncology drugs have been approved with evidence from clinical trials that are not traditional.  These endpoints include “minimal residual disease rate and metastasis-free survival”.  That change allows the new medicines to get onto the market. This is especially beneficial in approval of orphan drugs (not many potential patients for trials) and tumor-agnostic therapies.

Under pressure from many fronts to shorten development times, the drug industry has moved toward using new clinical trial endpoints.  As targeted therapies were developed to be used against cancers with specific genetic signatures, it made sense to test effectiveness on how those therapies affected specific biomarkers.

To provide some clarity and help the drug companies, the FDA in 2019 issued guidance on what types of endpoints they would accept for approval of new cancer therapies.   https://www.fda.gov/regulatory-information/search-fda-guidance-documents/master-protocols-efficient-clinical-trial-design-strategies-expedite-development-oncology-drugs-and These standards are for cancer therapeutics, not for medicines used to prevent cancer.

The FDA website lists some endpoints the agency will consider when looking at evidence as to drug efficacy.  For hematological cancers, these include level of asparaginase in the blood, durable complete remission rate, minimal residual disease response rate, progression free survival (PFS), and event-free survival.  For prostate cancer, they include plasma testosterone levels and durable objective overall response rate (ORR).  Pathologic complete response has been used for breast cancer.  Many other solid cancers have surrogate endpoints that include disease-free survival (DFS), progression free survival, and durable objective overall response rate.

There is concern that people don’t understand surrogate endpoint use.  The website Undark opined that “thanks to surrogate endpoints, FDA approval of a cancer drug doesn’t quite mean that it is proven “effective” in the way that patients naturally think it is.”  Doctors at the Mayo Clinic have expressed concerns about how good surrogate endpoints are.

See also: Response Evaluation Criteria in Solid Tumors