Release date: May 2007
Status: Final
Target audience: Pharmaceutical and biotechnology companies planning to submit clinical trials of products to treat cancer to support the claim of effectiveness in a marketing application to the FDA.
Laws and regulations referenced:
- The Federal Food, Drug, and Cosmetic Act: requires a drug to demonstrate substantial evidence of effectiveness as seen from important clinical outcomes or established surrogate endpoints in adequate and well-controlled clinical trials
- The Public Health Service Act: requires a biological product to be potent, safe, and pure as seen from important clinical outcomes or established surrogate endpoints
- Code of Federal Regulations 21 part 314(H) and part 601(E): allows investigational drugs and biologics to show effectiveness in benefiting less-established surrogate endpoints in order to gain fast-track marketing approval (see my third blog entry for more details)
- The Food and Drug Administration Modernization Act of 1997: describes the evidence essential for supporting marketing approval
- International Conference on Harmonisation guidance for industry "E9 Statistical Principles for Clinical Trials": describes issues related to the proper analysis of efficacy endpoints
Rationale: Drugs and biologics are required to demonstrate benefit in efficacy outcomes in adequate and well-controlled trials in order to gain the FDA's approval for marketing. See my fourth blog entry for more details about this requirement. There are various advantages and disadvantages to the endpoints that cancer clinical trials have used in the past to support a claim for clinical benefit.
Summary: This guidance gives the applicants of New Drug Applications and Biologic License Applications recommendations on the efficacy endpoints an oncology clinical trial should have to support marketing approval or labeling claims. These recommended endpoints are presented with their advantages and disadvantages.
Resulting recommendations:
Recommended efficacy endpoints:
1. Overall survival: time from randomization until death from any cause in the intent-to-treat population in randomized controlled trials. This is the conventional efficacy endpoint for cancer trials.
2. Tumor assessments:
a. Disease-free survival: time from randomization until recurrence of tumor or death from any cause. This is an important endpoint in cancers with a high rate of survival, making a survival endpoint impractical.
b. Objective response rate: the proportion of patients with a predefined amount of reduction in tumor size for a predefined minimum time period, typically from time of initial complete or partial tumor response to documented tumor progression. This can be evaluated in a single-arm trial.
c. Progression-free survival: time from randomization until tumor progression or death. This can be a primary endpoint for marketing approval.
d. Time to progression: time from randomization until tumor progression. This is considered inferior to progression-free survival because it does not include deaths, but as been used as a primary endpoint for marketing approval.
3. Symptom Assessments
a. Time to progression: time from randomization until symptomatic progression. These assessments, e.g., weight gain, decreased effusion, have been used as primary efficacy endpoints for marketing approval.
4. Biomarkers: changes in the levels of tumor biomarker. Improvement in biomarker levels can be part of a composite efficacy endpoint for marketing approval.
Impact: This guidance clarifies many issues regarding clinical trial endpoint design that traditionally would have had to be communicated individually to each trial sponsor and may have led to non-approval for applicants who did not discuss these issues with the FDA before initiating their clinical trials. This clarification will allow sponsors of drugs and biologics targeted for cancer treatment to design better clinical trials to support an application for FDA marketing approval, which may increase the likelihood of the success for clinical development programs in general.
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