Supplementary materials: Network connectivity, between-study heterogeneity and timepoint challenges in generalized myasthenia gravis: a feasibility assessment of indirect treatment comparisons
These are peer-reviewed supplementary materials for the article 'Network connectivity, between-study heterogeneity and timepoint challenges in generalized myasthenia gravis: a feasibility assessment of indirect treatment comparisons' published in the Journal of Comparative Effectiveness Research.
Appendix A: Additional Figures and Tables
- Figure S1: Generalized network diagram of included RCTs.
- Figure S2: Overview of data sources searched for the SLR.
- Figure S3: PRISMA flow diagram for SLR results.
- Table S1: Summary of subgroup analyses for MG-ADL and QMG outcomes reported for registration phase 3 RCTs in gMG for newer targeted immunotherapies.
- Table S2: Evidence base for the ITC feasibility assessment.
- Table S3: Cross-trial comparison of trial eligibility (i.e., inclusion/exclusion) criteria.
- Table S4: Cross-trial comparison of general trial design characteristics.
- Table S5: Cross-trial comparison of reported placebo data for MG-ADL and QMG outcomes reported for registration phase 3 RCTs in gMG for newer targeted immunotherapies.
- Table S6: Database search strategy on the Ovid platform (searched August 3rd, 2023).
- Table S7: Conference proceedings covered in Embase or requiring a hand search of conference websites.
- Table S8: Search strategy for conference proceedings search of conference websites.
- Table S9: Search strategy for report search of regulatory and HTA agency websites.
- Table S10: PICOS (eligibility) criteria for the SLR.
- Table S11: Risk of bias assessment for RCTs from the SLR considered in the ITC feasibility assessment.
Appendix B: Full Systematic Literature Review Methods and Results
- Methods: Overview and Protocol
- Methods: Database Search
- Methods: Grey Literature and Hand Searches
- Methods: Eligibility Criteria
- Methods: Study Selection
- Methods: Data Extraction
- Methods: Quality Assessment
- Results
Aim: We performed a feasibility assessment to systematically evaluate randomized controlled trials (RCTs) for generalized myasthenia gravis (gMG) treatments. The goal was to identify the advantages and disadvantages of different indirect treatment comparison (ITC) methods. Materials & methods: A systematic literature review was conducted to identify relevant gMG RCTs for ITCs. The feasibility of ITCs was assessed by comparing design (including study duration and dosing schedules), population and outcome characteristics of retrieved trials, investigating network connectivity and considering appropriate IT methods to address identified challenges. Results: The feasibility assessment considered 15 relevant RCTs for gMG treatments. Several barriers to conducting robust ITCs were identified, including within-trial imbalances in patient characteristics, small trial sizes and cross-trial differences in potential treatment effect modifiers (TEMs; e.g., antibody status, disease duration and prior treatment exposure). Further, heterogeneity in placebo administration characteristics and background therapies, and crosstrial variation in placebo response for key outcomes were noted. Additionally, treatment strategies (i.e., cyclical vs continuous), dosing schedules and outcome assessment timepoints were inconsistent across trials, necessitating careful consideration of methods and timepoints when interpreting outcomes. The findings suggest that ITCs anchored on placebo as a common comparator may be prone to bias, and more than one ITC approach may be necessary. Conclusion: ITC analyses in gMG have inherent challenges related to imbalanced treatment effect modifiers, network connectivity, varying dosing strategies and assessment timepoints. Multiple approaches to ITCs, with careful evaluation of underlying assumptions and limitations, are advised to limit bias and ensure robust comparative efficacy estimates are available to decision makers.
