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March 2008 Assessing surrogate endpoints in vaccine trials with case-cohort sampling and the Cox model
Li Qin, Peter B. Gilbert, Dean Follmann, Dongfeng Li
Ann. Appl. Stat. 2(1): 386-407 (March 2008). DOI: 10.1214/07-AOAS132


Assessing immune responses to study vaccines as surrogates of protection plays a central role in vaccine clinical trials. Motivated by three ongoing or pending HIV vaccine efficacy trials, we consider such surrogate endpoint assessment in a randomized placebo-controlled trial with case-cohort sampling of immune responses and a time to event endpoint. Based on the principal surrogate definition under the principal stratification framework proposed by Frangakis and Rubin [Biometrics 58 (2002) 21–29] and adapted by Gilbert and Hudgens (2006), we introduce estimands that measure the value of an immune response as a surrogate of protection in the context of the Cox proportional hazards model. The estimands are not identified because the immune response to vaccine is not measured in placebo recipients. We formulate the problem as a Cox model with missing covariates, and employ novel trial designs for predicting the missing immune responses and thereby identifying the estimands. The first design utilizes information from baseline predictors of the immune response, and bridges their relationship in the vaccine recipients to the placebo recipients. The second design provides a validation set for the unmeasured immune responses of uninfected placebo recipients by immunizing them with the study vaccine after trial closeout. A maximum estimated likelihood approach is proposed for estimation of the parameters. Simulated data examples are given to evaluate the proposed designs and study their properties.


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Li Qin. Peter B. Gilbert. Dean Follmann. Dongfeng Li. "Assessing surrogate endpoints in vaccine trials with case-cohort sampling and the Cox model." Ann. Appl. Stat. 2 (1) 386 - 407, March 2008.


Published: March 2008
First available in Project Euclid: 24 March 2008

zbMATH: 1138.62082
MathSciNet: MR2415608
Digital Object Identifier: 10.1214/07-AOAS132

Keywords: clinical trial , discrete failure time model , missing data , potential outcomes , Principal stratification , surrogate marker

Rights: Copyright © 2008 Institute of Mathematical Statistics


Vol.2 • No. 1 • March 2008
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