Ein Modell zur Validierung des „prozentualen Anteils der vorausgesagten forcierten Einsekundenkapazität“ (ppFEV1) als Surrogatendpunkt in klinischen Studien zu zystischer Fibrose

Cystic fibrosis is a rare genetic disease in which there is an increase in the viscosity of the secretion of excretory cells due to a defect in a chloride ion channel, the cystic fibrosis transmembrane conductance regulator channel (CFTR channel). The disease manifests itself already in childhood and progresses especially in the respiratory tract and the pancreas. Typical symptoms include progressive poor performance of the patients, chronic cough and chronic pancreatitis. The final course of the disease is via pulmonary fibrosis and respiratory insufficiency until the death of the patients, whereby the mean life expectancy increased to 49 years due to optimised therapy. In addition to symptomatic therapy, a new causal therapy has been established through the development of CFTR modulators. CFTR modulators can increase the opening probability of the CFTR channels or correct the malformation of the CFTR channel. Ivacaftor was the first CFTR modulator to be approved by the US Food and Drug Administration (FDA) in 2012 and later also by the European Medicines Agency (EMA). Lumacaftor, tezacaftor and elexacaftor were other CFTR modulators to follow. As is common with many current drug approvals, ivacaftor and the following CFTR modulators were approved through an accelerated procedure. These procedures are based on the results of clinical trials whose endpoints are not clinical endpoints but surrogate endpoints. While surrogate endpoints offer, among other things, the advantage of a simplified study design, their use carries the risk that the clinical effect may be misinterpreted despite a positive effect of the drug on the surrogate endpoint. For cystic fibrosis, the "percentage of predicted forced expiratory volume in one second" (ppFEV1) determined by spirometry is an important surrogate endpoint that was also used in the pivotal studies for the CFTR modulators named above. Various groups and authors, such as the "International Conference on harmonisation of technical requirements for registration of pharmaceuticals for human use " (ICH), therefore call for the validation of surrogate endpoints for use in clinical trials. One model for this is the information-theoretical model of Alonso and Molenberghs. The research objectives of this paper are firstly to present the information-theoretic model, secondly to provide a review of randomised controlled trials of CFTR modulators suitable for the application of the model, and thirdly to apply the information-theoretic model to the data from the studies found to validate ppFEV1. In the literature search, 16 suitable studies could be found. Due to the lack of study data at the patient level, data for individual patients had to be calculated from the mean values of their therapy groups. On the basis of this data, ppFEV1 could be validated with the information-theoretical model. A high correlation between ppFEV1 and the score of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a clinical endpoint, could be shown. The ppFEV1 thus appears to be a valid surrogate endpoint with a causal relationship with the clinical condition of the patients. The information-theoretical model turned out to be suitable for surrogate parameter validation in practical implementation. Sufficient suitable studies for the model could be found and presented. The ppFEV1 seemed to be a valid surrogate parameter in the calculations. However, due to the lack of data for individual patients in the studies found, this statement cannot be transferred to everyday clinical practice. This represents the greatest limitation of this work. Under the premise of the availability of such data, a validation of ppFEV1 with higher clinical relevance could be repeated with the information-theoretical model.