PSI Scientific Committee Webinar: Surrogate Endpoints

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14.00 - 16.00 UK TIME

The Statistical Evaluation of Surrogate Endpoints in Clinical Trials
Geert Molenburghs  (I-Biostat)
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 Both humanitarian and commercial considerations have spurred intensive search for methods to reduce the time and cost required to develop new therapies. The identification and use of surrogate endpoints is a general strategy that has stimulated much enthusiasm, but how can one establish the adequacy of a surrogate, in the sense that treatment effectiveness on the surrogate will accurately predict treatment effect on the intended, and more important, true outcome? What kind of evidence is needed, and what statistical methods portray that evidence most appropriately? The definition of validity, as well as formal sets of criteria, have been proposed, including use of the proportion explained, jointly the within-treatment partial association of true and surrogate responses, and the treatment effect on the surrogate relative to that on the true outcome.  In a multi-centre setting, these quantities can be generalized to individual-level and trial-level measures of surrogacy. Consequently, a meta-analytic framework studying surrogacy at both the trial and individual-patient levels has been proposed. The framework commonly used will be sketched, also against the background of alternatives. A perspective will be given on further and ongoing developments.

A Surrogate Endpoint for Chronic Lymphocytic Leukemia 
Natalie Dimier  (Roche)
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 The standard primary endpoint in clinical trials of chronic lymphocytic leukemia (CLL) is progression-free survival (PFS). Patients with CLL who achieve levels of minimal residual disease (MRD) of <1 clonal cell/10,000 leukocytes in peripheral blood (PB) at the end of initial treatment are considered MRD negative, and have been shown to experience significantly improved PFS. This analysis aims to support the evaluation of MRD response at the end of treatment as a surrogate endpoint for PFS in CLL, based on a retrospective analysis of 3 multicenter, randomized, Phase 3 clinical trials containing a total of 1203 patients. The primary endpoint of each study was investigator-assessed PFS and a meta-regression model was developed to predict treatment effect on PFS using treatment effect on MRD.

Overall Response Rate, Progression-Free Survival, and Overall Survival with Targeted and Standard Therapies in Advanced Non–Small-Cell Lung Cancer
Hui Zhang, Shenghui Tang  (FDA)
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 We conducted analyses to explore trial-level and patient-level associations between overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) trials. We identified 14 trials (N = 12,567) submitted to US Food and Drug Administration since 2003 of treatments for advanced NSCLC. Only randomized, active-controlled trials with more than 150 patients were included. Associations between trial-level PFS hazard ratio (HR), OS HR, and ORR odds ratio were analyzed using a weighted linear regression model. Patient-level responder analyses comparing PFS and OS between patients with and without an objective response were performed using pooled data from all studies. On a trial level, there is a strong association between ORR and PFS. An association between ORR and OS and between PFS and OS was not established. The patient-level analysis showed that responders have a better PFS and OS compared with nonresponders.

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