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Clinical trials of idiopathic pulmonary fibrosis: choosing the (right) primary end point

Paolo Spagnolo,Fabrizio Luppi

Idiopathic pulmonary fibrosis (IPF), the most common and lethal of all idiopathic interstitial pneumonias, is a disease that is both rare and orphan. However, in the last decade more than 3000 patients have been enrolled in high-quality clinical trials of IPF, an impressive achievement for a rare condition. The most challenging obstacle in clinical trials of orphan drugs is the recruitment of an adequate number of patients to obtain sufficient evidence of efficacy and safety, but similarly critical is the choice of the appropriate primary end points. In disorders with a poor prognosis – such as IPF – survival is the most logical outcome to measure the efficacy of a given drug. However, such trial design is feasible only in diseases that are fairly common and have a short survival. When a mortality study is impractical, an alternative approach is the use of predictors of survival. There is general agreement that the ideal primary end point should be reliable, reproducible, clinically meaningful, predictive of outcome, responsive to treatment effect, equally applicable to all patients and easy to measure, but none of the outcomes utilized over the last decade of clinical trials of IPF meets all these criteria. In this article we carefully analyze pros and cons of the outcomes most commonly used in pharmacological studies of IPF, and suggest that the choice of the appropriate primary end point should balance scientific, statistical and clinical rigor as well as clinical trial feasibility