The Challenges and Concerns Companies Face Pertaining to the US Food and Drug Administration 510(k) Process for Cardiac Biomarkers

Cardiac troponins I (cTnI)8 and T (cTnT) have been internationally recognized as the standard biomarkers for the detection of myocardial injury, the diagnosis of myocardial infarction (MI), and risk stratification of patients presenting with symptoms of acute coronary syndrome (ACS). Laboratory medicine, cardiology, and emergency medicine organizations have endorsed the use of the 99th-percentile troponin value, which is derived from a reference population, as the medical decision-making cutpoint. From the time of the first US Food and Drug Administration (FDA) clearance of cTnT in 1995 through 2010, the FDA-cleared cTnT and CTnI assays were predicated on the ROC curve–derived cutpoint optimized for diagnostic sensitivity and specificity. The PATHFAST cTnI assay introduced by Mitsubishi in 2001 is apparently the first assay cleared by the FDA on the basis of the 99th-percentile value that aids in the diagnosis of MI. With the growing literature describing multiple research high-sensitivity cTnI (hs-cTnI) assays and an hs-cTnT assay (marketed outside the US, not FDA cleared), manufacturers are facing new challenges in bringing to market these new assays that use the 99th percentile as the cutpoint value for medical decisions. Several leaders in the in vitro diagnostics industry have been asked to give their views on important issues that affect laboratory scientists and clinicians.On April 30, 2010, the FDA issued a “Points to Consider” paper providing an overview of both analytical- and clinical-performance expectations for assays that are to be submitted for 510(k) clearance on the basis of the 99th-percentile cutoff. What do you see as the major analytical and clinical challenges presented by this document? David Hickey: We at Siemens realize that the utility of troponin assays has evolved, and we understand that our methods of validating the performance of new troponin assays must also evolve. Some of the analytical and clinical challenges …