Procalcitonin for triage of patients with respiratory tract symptoms: a case study in the trial design process for approval of a new diagnostic test for lower respiratory tract infections.

Symptoms of cough, fever, chest pain, and shortness of breath are common reasons that patients seek medical care, and they can be due to a variety of medical conditions, including lower respiratory tract infection (LRTI). Only a small proportion of these patients will actually have a bacterial etiology, but many will receive antibiotic treatment because physicians cannot readily determine the etiology at the time of presentation. Current diagnostic methodologies are not sensitive or specific enough to reliably distinguish bacterial from viral or noninfectious etiologies. Procalcitonin (PCT) is a marker of host response. PCT serum levels are elevated in patients with bacterial infection, compared with levels in those with viral infections or other inflammatory pulmonary conditions. Studies have suggested that the determination of PCT levels can identify a subset of patients with LRTI symptoms who can safely avoid antibiotic treatment. As with any new test, clinical trials are necessary to demonstrate the safety and efficacy of the test to obtain U.S. Food and Drug Administration clearance. However, in the absence of standard reference methods for comparison that are reliably sensitive and specific, meeting the regulatory requirements for proof of safety and efficacy is a major challenge. Additional challenges include the choice of study design, the definition and determination of end points, and the justification of statistical analysis.