Understanding the challenge of comparative effectiveness research in focal epilepsy: A review of network meta‐analyses and real‐world evidence on antiepileptic drugs

Abstract

Objective: Head-to-head randomized controlled trials (RCTs) are the gold standard for assessing comparative treatment effects. In the absence of direct comparisons between all possible antiepileptic drugs (AEDs), however, clinical decision-making in focal (partial onset) epilepsy relies on alternative evidence borne from indirect comparisons including network meta-analyses (NMAs) and from real-world evidence (RWE) studies. We review NMAs and observational RWE studies comparing AEDs in the adjunctive setting to compare the robustness of these methods and to formulate recommendations for future evidence development. Methods: A literature review identified NMAs and RWE studies comparing AEDs for the adjunctive treatment of focal seizures published between January 2008 and October 2018. NMAs were evaluated for robustness using a framework based on guidelines from the National Institute for Health and Care Excellence Decision Support Unit and the International Society for Pharmacoeconomics and OutcomesResearch. RWE studies were evaluated using the GRACE checklist. Results: From a total of 1993 records, 11 NMAs and six RWE studies were eligible. Key limitations identified in the NMAs include nonsystematic selection of RCTs, unexplored heterogeneity between included RCTs in terms of study and patient characteristics, and selection of AEDs and AED doses or dosing strategies that are not reflective of clinical practice. The main limitations of RWE studies concern sample size, design, and analysis methods. Approximately 90% of comparisons between individual AEDs were nonsignificant in the NMAs. None of the RWE studies adjusted for baseline differences between comparator groups; therefore, they lack the validity to make comparative conclusions. Significance: Current NMAs and RWE studies provide only nominal comparative evidence for AED treatments in focal epilepsy, and should be used with caution for decision-making due to their methodological limitations. To overcome these hurdles, adherence to methodological guidelines and concerted efforts to collect relevant outcome data in the real world are needed. |

Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures

“…Direct head-to-head comparative efficacy and safety studies of ASMs are rarely conducted [6]. While head-to-head studies are preferred to guide clinical decision-making, these studies are costly and not required for ASM regulatory approval [6,7]. In the absence of direct comparison studies, an indirect treatment comparison (ITC), by means of a meta-analysis based on a network of clinical trials, can identify how ASMs measure up to each other, thereby providing valuable information to guide appropriate prescribing in clinical practice [6][7][8].…”

“…While head-to-head studies are preferred to guide clinical decision-making, these studies are costly and not required for ASM regulatory approval [6,7]. In the absence of direct comparison studies, an indirect treatment comparison (ITC), by means of a meta-analysis based on a network of clinical trials, can identify how ASMs measure up to each other, thereby providing valuable information to guide appropriate prescribing in clinical practice [6][7][8]. This is accomplished by combining data from studies that have at least one treatment arm in common, usually the placebo arm [9].…”

Clinical Management of Drug Resistant Epilepsy: A Review on Current Strategies

“… 43 Another methodological approach is to compare data of the same randomized studies using network meta-analyses. 45 However, results were similar and mostly showed no statistically significant differences between ASDs for adjunctive therapy. 45 However, all these systematic reviews suffered from similar limitations.…”

“… 45 However, results were similar and mostly showed no statistically significant differences between ASDs for adjunctive therapy. 45 However, all these systematic reviews suffered from similar limitations. 44 , 45 Because all ASDs are compared to placebo, a key issue is to assume that response to placebo is similar across studies.…”

“… 45 However, all these systematic reviews suffered from similar limitations. 44 , 45 Because all ASDs are compared to placebo, a key issue is to assume that response to placebo is similar across studies. However, as demonstrated in other diseases, this proved to be wrong.…”