TABLE 1.

A comparison of important clinical approval endpoints

Endpoint	Regulatory evidence	Study design	Advantages	Disadvantages
Overall survival	Clinical benefit for regular approval	Randomized studies essential Blinding not essential	Universally accepted direct measure of benefit Easily measured Precisely measured	May involve larger studies May be affected by crossover therapy and sequential therapy Includes noncancer deaths
Symptom endpoints (patient- reported outcomes)	Clinical benefit for regular approval	Randomized, blinded studies	Patient perspective of direct clinical benefit	Blinding is often difficult Data are frequently missing or incomplete Clinical significance of small changes is unknown Multiple analyses Lack of validated instruments
Disease-free survival	Surrogate for accelerated approval or regular approval*	Randomized studies essential Blinding preferred Blinded review recommended	Smaller sample size and shorter follow-up necessary compared with survival studies	Not statistically validated as surrogate for overall survival in all settings Not precisely measured; subject to assessment bias, particularly in open-label studies Definitions vary among studies
Objective response rate	Surrogate for accelerated approval or regular approval*	Single-arm or randomized studies can be used Blinding preferred in comparative studies Blinded review recommended	Can be assessed in single-arm studies Assessed earlier and in smaller studies compared with survival studies Effect attributable to drug, not natural history	Not a direct measure of benefit Not a comprehensive measure of drug activity Measures only a subset of patients who benefit
Complete response	Surrogate for accelerated approval or regular approval*	Single-arm or randomized studies can be used Blinding preferred in comparative studies Blinded review recommended	Can be assessed in single-arm studies Durable complete responses can represent clinical benefit Assessed earlier and in smaller studies compared with survival studies	Not a direct measure of benefit Not a comprehensive measure of drug activity Measures only a subset of patients who benefit
Progression- free survival (includes all deaths) or time to progression (deaths before progression censored)	Surrogate for accelerated approval or regular approval*	Randomized studies essential Blinding preferred Blinded review recommended	Smaller sample size and shorter follow-up necessary compared with survival studies Measurement of stable disease included Not affected by crossover or subsequent therapies Generally based on objective and quantitative assessment	Not statistically validated as surrogate for survival in all settings Not precisely measured; subject to assessment bias, particularly in open-label studies Definitions vary among studies Frequent radiological or other assessments Involves balanced timing of assessment among treatment arms

^*Adequacy as a surrogate endpoint for accelerated approval or regular approval is highly dependent upon other factors, such as effect size, effect duration, and benefits of other available therapy. Source: FDA 2007