Importance of Idiopathic Pulmonary Fibrosis Staging for Clinical Trial Endpoints

Abstract

We welcome the Pulmonary Perspective on the evaluation of clinically meaningful primary endpoints for idiopathic pulmonary fibrosis (IPF) (1). However, the logic of this discussion is weakened by the failure to acknowledge that the disease progression is influenced by the burden of disease at presentation. The burden of disease is normally described by a staging system, which is currently absent for IPF. One specific endpoint will clearly be insufficient if applied to “all comers with IPF.” Therefore, the definition of endpoints is heavily dependent on the staging of the disease (2). Regrettably, we have not seen a formal staging system emerge from the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline publication (3). We have learned from randomized controlled studies that change in FVC is a very pragmatic endpoint to be applied in patients with “mild to moderate disease,” which equates with a limited burden of disease. In patients with limited disease, defined as a gas transfer of greater than 40% predicted (2), mortality as an endpoint has a very low frequency. In contrast, mortality as an endpoint is more common in patients with advanced disease, defined as a gas transfer less than 40%. Therefore the relative endpoints are dependent on the stage of the disease. This burden/stage of disease can be defined on the basis of simple lung function testing. We would encourage the debate to consider that the appropriate endpoints should be defined on the basis of the burden or stage of disease, and that the discussions highlight the need for a simple reproducible staging system for IPF in a manner comparable to the Global Initiative for Chronic Obstructive Lung Disease classification for chronic obstructive pulmonary disease.