Lessons Learned from Confounder Identification: Insights from German HTA Procedures

OBJECTIVES: In the absence of randomized controlled trial (RCT) data, the identification of confounders is crucial for assessing the efficacy of medicinal products. Confounder incorporation as covariates facilitates adjustments for baseline parameters when comparing populations across different studies or utilizing real-world data. Although health technology assessment (HTA) bodies acknowledge the importance of systematic literature reviews and expert judgment in confounder identification, there is currently a lack of clear guidance on how to effectively conduct confounder identification within their frameworks.

METHODS: Methodological requirements for confounder identification were derived from official documents of German HTA authorities. These requirements were systematically compared with methods of confounder identification employed in German HTA (AMNOG) submissions, as well as subsequent assessments by authorities, to evaluate the methods and identify potential pitfalls.

RESULTS: As of December 31, 2023, confounder identification was described in 18 German HTA submissions; however, in most cases it faced substantial criticism from the authorities. The main concerns included insufficient detail in describing confounder identification, thereby impeding the comprehensibility of the manufacturer's decisions; shortcomings of the literature reviews lacking sensitivity due to regional or temporal constraints; and exclusion of relevant confounders either due to their absence in analysis datasets or due to missing data in more than 30% of cases. These issues cast doubt on achieving structural equality between treatment and control arms, potentially compromising the validity of the results. Consequently, the statistical analyses were often not considered for HTA.

CONCLUSIONS: Identifying confounders to be used as covariates for HTA analyses of non-randomized study data demands substantial effort in literature reviews and expert judgments, incurring high costs. The lack of detailed methodological requirements from HTA authorities raises uncertainty about the appropriateness of implemented methods. Establishing a pragmatic and transparent approach for confounder identification in HTA is crucial.