Is There A Consensus Regarding Clinically Relevant Non-Inferiority Margins Used For Key Oncology Endpoints In Non-Inferiority Oncology Trials?

Abstract

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.

Comparative efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) without and with daratumumab (D‐VTd) in CASSIOPEIA versus VTd in PETHEMA/GEM in transplant‐eligible patients with newly diagnosed multiple myeloma, using propensity score matching

“…The efficacy endpoints included in the PSM analysis were overall sur- [15]. Results that did not achieve significance and did not qualify per the noninferiority criteria were treated as inconclusive.…”

“…Response rates and AEs were analyzed based on an odds ratio calculated using a two‐sided 95% CI by fitting a logistic regression model. Results that did not achieve statistical significance (5%) were interpreted with the use of noninferiority margins [ 15 , 16 ]. A targeted literature review identified noninferiority margins for response, safety, PFS, and OS as follows: 13% (rate difference), 13% (rate difference), 1.333 (HR), and 1.298 (HR), respectively [ 15 ].…”

“…Results that did not achieve statistical significance (5%) were interpreted with the use of noninferiority margins [ 15 , 16 ]. A targeted literature review identified noninferiority margins for response, safety, PFS, and OS as follows: 13% (rate difference), 13% (rate difference), 1.333 (HR), and 1.298 (HR), respectively [ 15 ]. Results that did not achieve significance and did not qualify per the noninferiority criteria were treated as inconclusive.…”

Matching‐adjusted indirect comparison of efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) as per label compared with modified VTd dosing schedules in patients with newly diagnosed multiple myeloma who are transplant eligible

“…Absolute rate difference and odds ratios (ORs), calculated with two‐sided 95% CIs, were used to determine treatment response and safety outcomes; P ‐values for ORs were determined using the two‐sided Fisher's exact test. Based on recent oncology studies, results that did not achieve statistical significance (5%) were interpreted with the use of noninferiority margins [ 11 , 12 ]. Noninferiority margins for response, safety, PFS, and OS were identified as 13% (rate difference), 13% (rate difference), 1.333 (HR), and 1.298 (HR), respectively [ 11 ].…”

“…Based on recent oncology studies, results that did not achieve statistical significance (5%) were interpreted with the use of noninferiority margins [ 11 , 12 ]. Noninferiority margins for response, safety, PFS, and OS were identified as 13% (rate difference), 13% (rate difference), 1.333 (HR), and 1.298 (HR), respectively [ 11 ].…”