Efficacy as an Endpoint
Efficacy is defined as “the ability to produce a desired or intended result.” Clinical trials are typically designed to provide evidence of “efficacy” of a new agent, where efficacy is defined as proof that the agent has a therapeutic effect. Efficacy is typically demonstrated in carefully defined patient populations, often using defined endpoints, and in a protocol in which treatment is given standardly, sometimes compared with a placebo. It is becoming widely recognized that such efficacy studies, although providing critical evidence, do not provide adequate information to judge the impact of a new treatment when used in the post marketed setting. In part, this is a result of the fact that, in oncology, the clinical trials have restrictive eligibility criteria, and the sample population experience is extremely limited.
Current measurements for efficacy in Oncology trials include:
Overall survival rates: Survival is considered the most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint. This endpoint is precise and easy to measure, documented by the date of death. Bias is not a factor in endpoint measurement. Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit.
Tumor response, including utitilizing RECIST response criteria. Tumor-assessment endpoints selection should include two judgments. First, a determination of whether the endpoint will support either accelerated approval or regular approval should be ascertained. Second, the endpoint should be evaluated for the potential of bias or uncertainty in tumor endpoint assessments. Drug applications using studies that rely on tumor measurement-based endpoints as sole evidence of efficacy may need confirmatory evidence from a second trial. Accuracy in measuring tumors can differ among tumor settings. Tumor measurements used in response rate determinations can be imprecise in locations where there is a lack of demarcated margins (e.g., malignant mesothelioma, pancreatic cancer, brain tumors). Measurement can include disease-free survival, objective response rate, time to progression and progression-free survival, time to treatment failure.
Symptom Assessment: Symptomatic improvement is considered a clinical benefit. FDA drug approvals have used patient symptom assessments and/or physical signs representing symptomatic improvement (e.g., weight gain, decreased effusion) as the primary efficacy endpoint. However, measures of global health-related quality of life (HRQL) have not served as primary efficacy endpoints in oncology drug approvals.
Biomarkers: Generally, biomarkers assayed from blood or body fluids have not served as primary endpoints for cancer drug approval. Further research is needed to establish the validity of available tests and determine whether improvements in biomarkers predict clinical benefit. The FDA has accepted tumor markers as elements of a composite endpoint.