Generalizability of pharmaceutical randomized controlled trial eligibility criteria for progressive pulmonary fibrosis.

Abstract

Background: Progressive pulmonary fibrosis (PFF) is of substantial interest for novel pharmacotherapy discovery, but little is known about clinical trial eligibility criteria. We evaluated eligibility criteria of PPF randomized controlled trials (RCTs), their representativeness in registry patients, and forced vital capacity (FVC) changes and mortality according to trial eligibility.

Methods: A systematic search was used to identify completed and in-progress phase II and III PPF RCTs. Common clinical trial eligibility criteria used in ≥60% of previous PPF RCTs were identified. The most common criteria for PPF used in RCTs ("trial-PPF criteria") and the clinical practice guideline definition of PPF ("guideline-PPF criteria") were both applied to patients enrolled in a prospective multicenter Canadian registry. Common trial eligibility criteria were tested for their frequency and association with health outcomes in registry patients who met trial-PPF and guideline-PPF criteria.

Results: Ten different definitions of PPF were used in 16 RCTs. At the time of meeting PPF definitions, 50% of 864 patients with trial-PPF and 44% of 408 patients with guideline-PPF met the common trial eligibility criteria. For both definitions, trial-eligible patients had more rapid 1-year FVC decline but better transplant-free survival than trial-ineligible patients. Patients with unclassifiable interstitial lung disease (ILD) had higher proportion of trial exclusion compared to those with connective tissue disease-associated ILD and fibrotic hypersensitivity pneumonitis. Annual FVC decline (trial-PPF: -67 to -21 mL; guideline-PPF: -116 to -41 mL) and 1-year transplant-free survival (trial-PPF: 90.5 to 97.5%; guideline-PPF: 87 to 96.2%) varied in trial-eligible patients across ILD subtypes.

Conclusions: Existing RCTs use a variety of definitions for PPF with eligibility criteria that have limited representativeness. FVC decline and transplant-free survival vary according to trial eligibility and ILD subtypes.