#Patient level meta analysis definition full

We performed a methodological review of studies evaluating the validity of PFS as a surrogate for OS in cancer clinical trials. In this study, we aimed to systematically review all studies evaluating the validity of PFS as a surrogate for OS in cancer clinical trials, with a particular focus on the methods used and whether they were appropriate. Other criteria proposed to assess the validity of surrogate endpoints include IQWIG 10 or the biomarker surrogate evaluation schema (BSES). 9 Both questions are of interest: the first for patient management (the surrogate being a marker of prognosis), and the second for drug development (use of the surrogate potentially gaining months or years of development time). This meta-analysis method has become the recommended approach. This paradigm includes the meta-analytic method, which evaluates the association between the surrogate and the true endpoint across individuals, as well as a correlation of the treatment effect between both endpoints across studies. 8 In this study, we focused on the “causal-association” paradigm in which the effect of treatment on the surrogate is associated, across studies or population subgroups, with its effect on the true endpoint. Four major frameworks have been developed for evaluating surrogate markers in randomised trials.

#Patient level meta analysis definition full

Prentice, in 1989, was the first author to introduce four criteria to be met to support surrogacy: (1) treatment has a significant impact on the surrogate endpoint (2) treatment has a significant impact on the true endpoint (3) the surrogate and true endpoints are correlated (4) the full effect of treatment on the final endpoint is captured by the surrogate. 7 Methods for surrogacy validation have evolved over recent decades. For years, surrogacy and correlation have been confused. Surrogate validation is a demanding procedure that must be performed for each clinical context (localisation, indication and treatment). 5 Approval was withdrawn in 2011 after several trials showed that the PFS improvement was lower than expected, with no OS improvement. Otherwise, approvals may be misleading 4 as underlined by the example of bevacizumab that obtained FDA-accelerated approval in 2008 for metastatic breast cancer based on PFS improvement. More than one-third of trials that received US Food and Drug Administration (FDA) marketing approval between 20 used PFS as a primary endpoint, 3 which is possible in theory only if PFS has been validated as a surrogate endpoint for OS. In oncology, surrogate endpoints, especially progression-free survival (PFS), are frequently used as primary endpoints in place of overall survival (OS), the most clinically meaningful endpoint. They should have a scientifically plausible link to the true endpoint, and ideally, the surrogate should be embedded within the causal pathway of the disease progression to the true endpoint. 1 Surrogate endpoints are used for measuring treatment benefits earlier, and allowing for a lower sample size.

ConclusionsĪlthough most studies used a meta-analytic approach as recommended, our methodological review highlights heterogeneity in methods and reporting, which stresses the importance of developing and applying clear recommendations in this area.Īccording to the Biomarkers Definition Working Group, a surrogate endpoint is a biomarker intended for substituting a clinical endpoint and expected to predict clinical benefit, harm or lack of these. Of the 47 studies concluding that PFS is a good surrogate for OS, for 15 (32%), there was no quantitative argument for surrogacy. Although a meta-analytic approach was used in 83 (91%) studies, the methods used to validate PFS as a surrogate of OS were heterogeneous across studies.

We identified 91 studies evaluating the validity of PFS as a surrogate for OS in 24 cancer localisations. We conducted a systematic review by searching MEDLINE via PubMed and the Cochrane Library with no limitation on time, selected relevant studies and extracted data in duplicate on how surrogacy was evaluated (meta-analytic approach, assessment of correlation and level of evaluation). We aimed to identify all studies evaluating the validity of PFS as a surrogate for OS in oncology, and to describe their methodological characteristics. Validation of PFS as a surrogate must be done for each indication and each intervention. Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology.