Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials

Abstract

Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints.

Figure 1.

(A) A candidate surrogate endpoint is in the pathway through which the disease causally induces risk of the clinically meaningful endpoint, and the intervention's (lightning bolt) effect is on that pathway. (B) An intervention’s effect on candidate surrogate endpoints can provide inaccurate predictions of its effect on clinically meaningful endpoints for several reasons. First, the candidate surrogate may not be directly involved in a causal pathway of the disease. Second, the surrogate may be in a causal pathway of the disease, but there may be other causal pathways of the disease that it does not capture (i.e., there are multiple causal pathways of disease). Third, the surrogate is in the causal pathway of the disease, but there are off-target effects of the intervention. Based on a presentation of data in Reference 20.