Historically, regulatory agencies have differed in their opinion over both the assessment criteria and timing for the primary endpoint used in community-acquired pneumonia (CAP) trials. The US Food and Drug Administration (FDA) favour an early clinical response (ECR; 3-5 days after randomisation) based on a programmatic definition of improvement in individual symptoms, whereas both the European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) prefer a late endpoint assessed at a test-of-cure (TOC) visit (5-10 days after the end of therapy) and based on the Investigator's judgment of overall condition. However, an analysis of 4,645 patients from six CAP trials, recently published by the US FDA in Clinical Infectious Diseases (CID), showed very high concordance (85.6% of patients) between early and late endpoints. The authors concluded that the early endpoint response was highly predictive of late endpoint success with a positive predictive value of 92.9%. These new data may, therefore, allow a convergence of recommendations for CAP clinical trial design that might be acceptable to all regulatory agencies.
The publication of this paper coincides with the release of the US FDA’s revised guidance to industry for developing drugs to treat CAP. Whilst much of the guidance remains the same as that provided in the 2014 version, there is clarification that, if an intravenous drug is being studied, only patients with a PORT III or higher score should be included, and that the primary efficacy endpoint should now occur at Day 4. The timing of this endpoint is supported by the improvement seen in cough, dyspnoea, chest pain, and sputum production during the first 4 days on therapy that was seen in the CID publication.
References and further reading:
1. Bart, S.M., et al., Concordance of early and late endpoints for community-acquired bacterial pneumonia trials. Clin Infect Dis, 2020.
2. The Division of Anti-Infectives in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration, Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment. Guidance for Industry. 2020.