Biotechnology Healthcare - June 2008 - (Page 25) TABLE 1 Endpoint Overall survival A comparison of important clinical approval endpoints Regulatory evidence Study design Advantages • Universally accepted direct measure of benefit • Easily measured • Precisely measured • Patient perspective of direct clinical benefit Disadvantages • May involve larger studies • May be affected by crossover therapy and sequential therapy • Includes noncancer deaths • Blinding is often difficult • Data are frequently missing or incomplete • Clinical significance of small changes is unknown • Multiple analyses • Lack of validated instruments Clinical benefit • Randomized for regular apstudies essential proval • Blinding not essential Clinical benefit • Randomized, for regular blinded studies approval Symptom endpoints (patientreported outcomes) Disease-free survival Surrogate for accelerated approval or regular approval* • Randomized studies essential • Blinding preferred • Blinded review recommended • Smaller sample size and • Not statistically validated as shorter follow-up neces- surrogate for overall survival in sary compared with all settings survival studies • Not precisely measured; subject to assessment bias, particularly in open-label studies • Definitions vary among studies • Not a direct measure of benefit • Not a comprehensive measure of drug activity • Measures only a subset of patients who benefit Objective Surrogate for response rate accelerated approval or regular approval* • Single-arm or ran- • Can be assessed in domized studies single-arm studies can be used • Assessed earlier and • Blinding preferred in smaller studies in comparative compared with survival studies studies • Blinded review • Effect attributable to recommended drug, not natural history • Single-arm or randomized studies can be used • Blinding preferred in comparative studies • Blinded review recommended • Randomized studies essential • Blinding preferred • Blinded review recommended Complete response Surrogate for accelerated approval or regular approval* • Can be assessed in • Not a direct measure of benefit single-arm studies • Not a comprehensive measure • Durable complete of drug activity responses can represent • Measures only a subset of paclinical benefit tients who benefit • Assessed earlier and in smaller studies compared with survival studies • 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 Progressionfree survival (includes all deaths) or time to progression (deaths before progression censored) Surrogate for accelerated approval or regular approval* *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 MAY/JUNE 2008 · BIOTECHNOLOGY HEALTHCARE 25
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