Surrogacy Case Study: Prostate Specific Antigen (PSA ... - Isped

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How to demonstrate surrogacy ? • Prentice Criteria: “A test of no treatment effect on the surrogate is equivalent to a test of no treatment effect on the true endpoint” • The treatment has a significant effect on survival • The treatment has a significant effect on PSA • PSA is prognostic for survival • Once PSA is adjusted for, there is no significant treatment effect on survival • Meta-analytic validation: The treatment effect on the Surrogate is used to predict the treatment effect onto the True endpoint. A valid surrogate is one that enables a precise prediction.
Meta-analytic validation First stage: a joint model for individual observations on surrogate and true endpoints (Tij,Sij) Second stage: a linear model for the trial-specific trt effects ⎛αi ⎞ ⎛α ⎞ ⎛a i ⎜ ⎟ = ⎜ ⎟ + ⎜ ⎝ βi ⎠ ⎝ β ⎠ ⎝b i ⎟ ⎞ ⎠ Trial-unit 1 Trial-unit 2 Trial-unit 3 Trial-unit 4 . . Trial-unit k (α PSA , β OS ) (α PSA , β OS ) (α PSA , β OS ) (α PSA , β OS ) . . (α PSA , β OS ) β OS R 2 trial close to 1 Slope = R² trial α PSA To allow precise prediction of the survival treatment effect from the PSA treatment effect Ref: Buyse et al, Biostatistics 2000; Burzykowski et al, Applied Statistics 2001
Page 1 and 2: EORTC Surrogacy Case Study: Prostat
Page 3 and 4: Prostate Specific Antigen (PSA) •
Page 5 and 6: Transition between clinical states
Page 7: Surrogate endpoint • An outcome m
Page 11 and 12: PSA - defined endpoints in prostate
Page 13 and 14: PSA “surrogacy” studies in the
Page 15 and 16: Published PSA surrogacy studies Col
Page 17 and 18: Review • 2 meta-analytic validati
Page 19 and 20: PSA endpoints PSA normalization A P
Page 21 and 22: PSA data (M1) Mean log(PSA) -2 0 2
Page 23 and 24: Treatment effects on OS against tre
Page 25 and 26: Prediction for a new trial - M1 •
Page 27 and 28: PSA doubling-free survival (PSA-D)
Page 29 and 30: Recommendation, M1 hormone sensitiv
Page 31 and 32: 4m vs 24m ADT adjuvant to irradiati
Page 33 and 34: PSA-DT and TTBF surrogate for PCa-s
Page 35 and 36: PSA response or PSA-V surrogate for
Page 37 and 38: Of interest… The search for the g
Page 39 and 40: Conclusions for HRPC on chemotherap
Page 41 and 42: ASCENT trial High dose Calcitriol (
Page 43 and 44: Be aware of your drug’s effect on

Surrogacy Case Study: Prostate Specific Antigen (PSA ... - Isped

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