A systematic review of noninferiority margins in oncology clinical trials.

Aim: A systematic literature review was conducted to identify and characterize noninferiority margins for relevant end points in oncology clinical trials. Materials & methods: Randomized, controlled, noninferiority trials of patients with cancer were identified in PubMed and Embase. Results: Of 2284 publications identified, 285 oncology noninferiority clinical trials were analyzed. The median noninferiority margin was a hazard ratio of 1.29 (mean: 1.32; range: 1.05-2.05) for studies that reported time-to-event end points (n = 192). The median noninferiority margin was 13.0% (mean: 12.7%; range: 5.0-20.0%) for studies that reported response end points as absolute rate differences (n = 31). Conclusion: Although there was consistency in the noninferiority margins' scale, variability was evident in noninferiority margins across trials. Increased transparency may improve consistency in noninferiority margin application in oncology clinical trials.

Are Published Health Economic Models for Chronic Hepatitis B Appropriately Capturing the Benefits of HBsAg Loss? A Systematic Literature Review.

OBJECTIVES: Sustained hepatitis B surface antigen (HBsAg) loss or 'functional cure' (FC) is considered an optimal treatment endpoint by international clinical guidelines for chronic hepatitis B (CHB), yet rarely is this achieved with current standard of care (SoC). This leads to an under-reporting of FC in clinical trials, observational studies and health economic (HE) models. This paper systematically identifies and assesses how FC is incorporated in published HE models of CHB. METHODS: A systematic literature review was conducted in PubMed and Embase (conducted February 2019) to review how HBsAg loss is captured in HE models. The following items were extracted: rate of (and transition probabilities to) HBsAg loss, HBsAg loss health state costs, and HBsAg loss health state utilities. RESULTS: Sixty-five economics evaluations were identified, and < 50% of these (27/65) incorporated HBsAg loss in their models. Only 15/27 stated HBsAg loss health state costs, 15/27 stated HBsAg loss health state utilities, and 11/27 mentioned treatment-specific transition probabilities to HBsAg loss. The majority of sources these inputs were derived from are not transparent. CONCLUSIONS: The benefits of FC in current HE models are not well captured, as FC is often not reported or not directly related to modelled treatments. This has the potential for novel agents with higher efficacy compared with SoC to be overlooked and undervalued if their worth is not appropriately communicated. In order to ensure optimal access for patients to new and effective therapies, it is important that the benefits of FC are better assessed and captured within HE models.

A comparative network meta-analysis of standard of care treatments in treatment-naïve chronic hepatitis B patients.

Objective: Published network meta-analyses of chronic hepatitis B (CHB) treatments are either out-of-date or excluded key treatments. Therefore, we aimed to comprehensively update the efficacy evidence for the following end points: Hepatitis B surface antigen (HBsAg) loss, hepatitis B early antigen (HBeAg) seroconversion and hepatitis B virus DNA (HBV DNA) suppression. Materials & methods: Approved treatments in CHB and their combinations were evaluated. A systematic literature review was conducted to identify all randomized controlled trials in treatment-naïve CHB patients. Included studies reported at least one of the end points of interest. A frequentist probability network meta-analysis was performed for each end point. The choice of fixed effect or random-effect model was based on the I-square statistic, a measure of variation in study outcomes between studies. The analyses were performed separately for HBeAg-positive and HBeAg-negative patients. For the primary analyses, end points measured 48 ± 4 weeks after treatment initiation were considered. Results: A total of 47 randomized controlled trials (13,826 patients), covering 23 unique treatment regimens, were included: a total of 29 reported HBsAg loss, 36 reported HBeAg seroconversion and 37 reported HBV DNA suppression. For both HBsAg loss and HBeAg seroconversion, pegylated interferon-based regimens were the most effective strategy in both HBeAg-positive and HBeAg-negative patients. On the other hand, for HBV DNA suppression, nucleosides-based regimens were the most effective strategy in both HBeAg-positive and HBeAg-negative patients. Conclusion: Our findings confirm available evidence around the comparative efficacy of available CHB treatments. Therefore, they can be used to update relevant cost-effectiveness analyses and clinical guidelines.

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.

Background: The combination of bortezomib, thalidomide, and dexamethasone (VTd) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Although approved labeling for VTd includes an escalating thalidomide dose up to 200 mg daily (VTd-label), a lower fixed dose of thalidomide (100 mg daily; VTd-mod) has become commonplace in clinical practice. To date, no clinical trials comparing VTd-mod with VTd-label have been performed. Here, we compared outcomes for VTd-mod with VTd-label using a matching-adjusted indirect comparison. Methods: VTd-mod data were from NCT02541383 (CASSIOPEIA; phase III) and NCT00531453 (phase II); VTd-label data were from NCT00461747 (PETHEMA/GEM; phase III). To adjust for heterogeneity, baseline characteristics from VTd-label were weighted to match VTd-mod. Outcomes included overall survival (OS), progression-free survival (PFS), postinduction and posttransplant responses, and safety. Results: VTd-mod was noninferior to VTd-label for OS, postinduction overall response rate (ORR), and very good partial response or better (≥VGPR). VTd-mod was significantly better than VTd-label for PFS, posttransplant ORR, and ≥VGPR. VTd-mod was noninferior to VTd-label for safety outcomes, and inferior to VTd-label for postinduction and posttransplant complete response or better. Conclusions: Our analysis supports the continued use of VTd-mod in clinical practice in transplant-eligible NDMM patients.