An FDA Perspective on the Regulatory Implications of Complex Signatures to Predict Response to Targeted Therapies

Abstract

As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368-72. ©2016 AACR.

Figure 1. Regulatory Options for Complex Signature Development

These options are not mutually exclusive but are separated for pictorial display.

Figure 2. Variability Profile Example with Two Input Combinations

If X has more analytical variability (wider black dashed lines) than Y, the same result (X + Y = 5 solid red line) would have more variability (wider red dashed lines) in some conditions (X = 5, Y = 0) than others (X = 0, Y = 5).