1	Surrogate Endpoint Definition and Application: Aspects of the Observational Study and Clinical Trial Interface Ross Prentice Fred Hutchinson Cancer Research Center Surrogate outcome definition and concepts Role of intermediate outcome trials in hypothesis generation and development A lesson from observational studies and clinical trials of postmenopausal hormone therapy and cardiovascular disease
2	Surrogate Endpoint Definition and Concepts T – time to response ‘true’ endpoint {S(t); t > 0} – S(t) is history prior to follow-up time t of surrogate outcome process x – treatment indicator vector When can S replace T for evaluation of effects of x on T? Define S to be a surrogate for T in respect to x if: T independent of x <=> S independent of x (Prentice, 1989, Statist in Med)
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6	Role of ‘Intermediate’ Outcome Trials in Hypothesis Generation and Development Even though intermediate outcomes S may rarely be able to replace a study of T in assessing the effects of a treatment or intervention, trials of well-selected outcomes S in relation to X are fundamental to the development and screening of preventive interventions. Preventive hypotheses mainly arise from observational studies (specificity? bias?); or from therapeutic trials (timing? relevance?) New technologies (e.g., genomics, proteomics) have potential to allow intermediate outcome trials (e.g., human feeding trials, exercise intervention trials) to be increasingly comprehensive and informative. Need for trans-NIH forum to encourage such trials and to identify/prioritize interventions that may be appropriate for full-scale trial evaluations.
7	A Lesson from Combined Postmenopausal Hormone Therapy and Cardiovascular Disease Women’s Health Initiative study of estrogen plus progestin among postmenopausal women in the age range 50-79 at baseline CT OS Age-adj Age-adj Placebo E+P HR Control E+P HR Number of women 8102 8506 35,551 17,503 Number of events: CHD 147 188 1.21 615 158 0.71 Stroke 107 151 1.33 490 123 0.77 VT 76 167 2.10 336 153 1.06
8	Summary Surrogate outcomes rarely available that can provide definitive information about ‘true’ endpoints of interest in respect to treatment effects Intermediate outcome trials becoming practical that can greatly invigorate preventive intervention research agenda Situations where both RCT and observational data are available provide excellent opportunities to identify and address study design and analysis issues, and avoid the promulgation of inaccurate public health information.