Identification of Adjustment Variables in Indirect Comparisons: A Rapid Review of CAR-T Therapies for Diffuse Large...

Background: Chimeric antigen receptor T-cell (CAR-T) therapies have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of diffuse large B-cell lymphoma (DLBCL), primarily based on single-arm trials or indirect comparisons with stem cell transplantation. However, no direct head-to-head comparisons of CAR-T therapies have been conducted, largely due to their high cost. To assess their true value, indirect treatment comparisons (ITCs) are essential. These comparisons, however, are prone to confounding biases, which necessitate careful adjustments through the identification and measurement of relevant variables. Materials and Methods: This study aims to identify the variables used for adjustment in ITCs of CAR-T therapies for DLBCL and examine the methodologies employed to select them. A rapid literature review was conducted in PubMed in September 2023, focusing on ITCs involving CAR-T therapies for DLBCL. The search was based on keywords categorized into three groups: techniques (ITCs and related terms), drugs (CAR-T therapies), and indication (DLBCL). Results: The rapid literature review identified 21 articles, of which 11 were selected for analysis. Exclusions were made for articles that did not identify confounders, were letters to editors, or addressed conditions other than DLBCL. Among the 11 selected publications, 10 did not clearly specify the methodology used to identify adjustment variables. A total of 25 potential confounders were identified across the studies, with substantial variability in the set of variables used, reflecting a lack of standardization in confounder selection. Commonly identified confounders included the number of prior treatment lines and Eastern Cooperative Oncology Group Performance Status (ECOG PS), although their inclusion as adjustment variables in ITCs was inconsistent, often due to missing data. Conclusions: While the identified confounders are clinically relevant, the methodologies for selecting them remain unclear, resulting in significant variability across studies. Additionally, key variables commonly considered in health technology assessments (HTAs), such as age, sex, and disease severity, were inconsistently incorporated into ITCs. To improve the reliability and consistency of ITC outcomes, there is a pressing need for standardized methodologies for identifying and adjusting for confounders.