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Objectives: Bootstrapping is often used to assess uncertainty in outcomes of randomized controlled trials (RCTs) due to sampling variation and limited sample sizes. Although guidance is available on two-stage bootstrapping for cluster-RCTs, specific guidance is lacking on sampling clusters within bootstrap samples to address the uncertainty in variation across clusters. This study assesses the impact of using different selection approaches to sample clusters in two-stage bootstrapping in a case study on procalcitonin-based antibiotic treatment in IC patients with sepsis. MethOds: The case study was a cluster-RCT including 16 hospitals (4 academic, 12 non-academic) with on average 48 patients per hospital (range n: 1-185). Five cluster sampling approaches were investigated, based on random sampling of: 1) the intended number of patients, 2) 16 hospitals, 3) 16 hospitals maintaining the original ratio academic/non-academic hospitals, 4) as method 2 while maintaining the total number of patients, 5) as method 3 while maintaining the total number of patients. Additionally, a scenario analysis using half of the data was performed. Incremental cost differences and corresponding 95%CIs were determined based on 10,000 bootstrap samples. Results: Different approaches of bootstrapping resulted in variation in the incremental costs per patient (data mean: € 16, bootstrap range: € -24 -€ 183), with approach 5 deviating most from the observed mean incremental cost. 95%CIs also varied in size (smallest 95%CI: € -5,123 -€ 5,986 [method 5], largest 95%CI: € -5,699 -€ 6,566 [method 2]). Differences in outcomes were more pronounced when using half of the data. cOnclusiOns: Using different approaches for sampling clusters in two-stage bootstrapping may influence the mean outcomes and 95%CIs. Determining the most appropriate sampling method based on outcomes and 95%CIs is dependent on the approach for selection used in the real-world trial. When the inclusion strategy is unknown, sensitivity analysis is recommended to assess uncertainty arising from this unknown cluster inclusion process.

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OBJECTIVES: Surrogate endpoints can support early access to novel therapies. In trial-level endpoint validation studies, the association between treatment effect e.g., the hazard ratio (HR) on both the surrogate and hard endpoint can be estimated. We aimed to review studies reporting an association between HRs of surrogate time-to-event endpoints and overall survival (OS) in advanced/metastatic cancers. METHODS: A systematic review was conducted using Medline and Embase. We included full reports assessing the association between HRs of surrogate time-to-event endpoints and OS in advanced/metastatic cancer indications. The following information was extracted: study characteristics, association measure, use of weighted analyses, logarithmic transformation of HRs, use of multivariate analysis, evaluation of crossover impact, use of IQWiG framework, estimating surrogate threshold effect (STE), and reported results and/or regression equations. RESULTS: Forty-five studies were included. Retrieved studies were conducted in 16 different cancer indications. Different methods were used to assess associations, including Spearman's/Pearson's correlation coefficient and linear regression analysis. Weighted analyses, logarithmic transformation of HRs and multivariate analysis were implemented in 35, 26 and 10 studies, respectively. Few studies assessed the crossover impact on the association (8 studies) and implemented IQWiG framework and STE assessment (11 studies and 3 studies, respectively). Detailed results are extracted, summarized and will be presented. CONCLUSIONS: There is inconsistency in conducting/reporting of trial-level endpoint validation studies in advanced/metastatic cancers. Future studies would benefit from building a structured data analysis checklist. Also, trial-level surrogacy was not assessed in all advanced/metastatic cancers and the strength of association varied across indications. The generalizability of results from one indication to another is limited.