PRO14 Statistical Solutions for Analytic Challenges in Registries for HTA-Purposes

Abstract

With the GSAV* law, the German Federal Joint Committee (G-BA) has been authorized to mandate the collection of data on routine practice use of orphan drugs, drugs with conditional marketing authorization (MA), and drugs with MA under exceptional circumstances. Our aim is to highlight methodological challenges investigators will face when combining clinical practice data from different registries, using the example of the rare neuromuscular disorder 5q-associated spinal muscular atrophy (SMA). Challenges include missing data, variable data quality, imbalance in treatment groups, confounding, nonparametric distributions, and heterogeneity of patients. We will compare these challenges to the quality criteria highlighted in the IQWiG Rapid Report A19-43 [Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG), 2020]. We present a pre-specified statistical workflow on how to organize a set of prospective observational data, and how statistical challenges in the analysis of registries could be addressed. We describe our utilization of mixed-effects models as the primary analysis [Pinheiro, 2012] to address the statistical challenges of these data in line with European Medicines Agency (EMA) guidelines [European Medicines Agency (EMA), 2010]. We suggest random splitting as an additional technique. We contrast our methods with those provided in the IQWiG Rapid Report, which favors a propensity score matching approach. The method of Conditional Inference Trees [Hothorn et al., 2006], previously employed for the analysis of clinical registries [Evaniew et al., 2019; Martin et al., 2020], has not been specifically addressed in the current IQWiG methods paper, but will also be discussed in the German HTA context. There are a multiplicity of statistical models available to generate balanced comparisons of treatment arms in clinical registry data. These methods might improve analyses conducted with G-BA-mandated registries as part of the German HTA process. * Gesetz für mehr Sicherheit in der Arzneimittelversorgung.