Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Keywords: FVC, 6MWT, composite endpoint for IPF trials; idiopathic pulmonary fibrosis; image and circulatory biomarkers for IPF trials; meaningful outcomes as endpoints for IPF trials; patient reported outcomes for IPF trials.

Figure 1.

(A) Natural course of lung function decline in patients with IPF based on data from placebo arms of clinical trials. Reproduced from Raghu et al., 2017 (6) with permission from the European Respiratory Journal. (B) Patients with ascertained diagnosis of IPF generally follow one of three courses: 1) most patients follow the pathway of slow decline over 3–5 years since the diagnosis (“slow progression”); 2) some patients experience a more rapid decline in lung function over several months (“rapid progression”); and 3) others remain stable over several years before progressing. Acute exacerbations (AE) can occur at any time and may lead to accelerated loss of lung function or death. Progression of disease is manifested by decline in forced vital capacity and distortion of the lung by extension of honeycomb cysts from subpleural areas in lower lobes to more proximal areas in all portions of lung as seen macroscopically in HRCT scans of the chest over several years and at autopsy. Adapted from Podolanczuk et al., 2023 (1) with permission from the European Respiratory Journal. HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis.

Figure 2.

Multiple pathways of the disease process and an intervention’s multiple mechanisms of action (10, 13).

Figure 3.

IPF trials with FVC as the primary efficacy endpoint.

Figure 4.

Summary of the features of the 6-minute walk test (6MWT) in IPF patients.

Figure 5.

Factors that may influence the reliability of an imaging biomarker. QIB = quantitative imaging biomarker.

Figure 6.

Process of biomarker qualification driven by specific context-of-use.