1	Recent Approaches to Surrogate Endpoint Validation Stuart G. Baker, Sc.D. National Cancer Institute sb16i@nih.gov
2	What do we mean by validation of a marker or endpoint? A marker or endpoint is validated if there is confidence in proceeding to the next stage of evaluation Methodology depends on the application Biomarkers for the early detection of cancer Biomarkers for predicting cancer recurrence Biomarkers for targeting intervention in treatment trials Surrogate endpoints
3	Examples of validation Biomarkers for early detection of cancer Next stage: further study as a trigger for early intervention with cancer-mortality endpoint Validation: high sensitivity and specificity in an independent test sample Biomarkers for predicting cancer recurrence Next stage: randomized trial of standard versus new treatment for those with poor prognosis Validation: high predictive value positive and negative in an independent test sample
4	Examples of validation (continued) Biomarkers for targeting intervention in a treatment trial Next stage: recommendation for population with the biomarker Validation: randomized trial of intervention in subjects with the biomarker Surrogate endpoints Next stage: recommendation for population (although sometimes further study) Validation: correct conclusions about effect of intervention on true endpoint (in trial with both surrogate and true endpoints)
5	Surrogate endpoint: definition Measure or indicator of a biological process that is (a) used to make conclusions about the effect of intervention on a true endpoint that is a health outcome (b) obtained sooner, at less cost, or less invasively than a true endpoint
6	Validating a surrogate endpoint NEXT STAGE: Application trial: surrogate but not true endpoint is observed What is the effect of intervention on true endpoint? VALIDATION: Validation trial in which both surrogate and true endpoints are observed Are the conclusions about the effect of intervention on true endpoint the same when based on (i) only surrogate endpoint (ii) only the true endpoint ?
7	Issues in validating a surrogate endpoint Hypothesis testing framework Estimation framework Caveats Recommendations
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11	Drawbacks of hypothesis testing framework: If Prentice Criterion is not rejected, it is not clear how “close” is good enough. With estimation, it is easier to include data from previous trials of surrogate and true endpoint Generally estimation is preferred to hypothesis testing (e.g for weighing harms and benefits)
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14	“Meta-analytic” methods for combining data from previous trials Method 1 Regression on trial-level statistics e.g. fraction with surrogate and true endpoint in each previous trial Gail et al 2000; Buyse et al 2000 Combine predicted intervention effects effect of intervention on true endpoint based on data from each previous trial Baker 2005 Simpler computations
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19	Comparison using hypothetical data:
20	Be aware of caveats even if surrogate is validated Extrapolation to a new intervention Surrogate endpoint for benefit does not predict harms that might arise after surrogate is observed
21	Caveats are less critical if Preliminary drug development when next stage is further testing Evaluating a different dose or timing of an intervention previously shown effective (using a true endpoint) at another dose or timing
22	Recommendations Use meta-analytic estimation approach for validation of surrogate endpoint Check if same conclusion about effect of intervention on true endpoint using (i) surrogate endpoint and (ii) true endpoint But hard to get data from previous trials! Even if validated, remember caveats extrapolation to a new intervention unknown effect of intervention on harms