In Pursuit of Greater Reproducibility and Credibility of Early Clinical Biomarker Research

Biomarkers underlie many clinical tests that are integral to the practice of personalized medicine. Reproducibility and scientific credibility of clinical biomarker early development studies are critical to avoid advancing worthless or potentially harmful biomarker-based tests into late-phase clinical studies and clinical practice. This commentary discusses key aspects to consider when conducting and evaluating early clinical biomarker research. Greater attention to these aspects would enhance research reproducibility and better prioritize biomarkers for further clinical development. Recognition of the problem of irreproducibility of preclinical drug development research led to a call for transparent reporting standards and recommendations for improved study designs.1 Similar principles apply to early research aiming to develop clinical biomarker tests (henceforth termed “early clinical biomarker research”), but there are important differences too. A major difference between preclinical drug development studies and early clinical biomarker development studies is that the latter are often conducted retrospectively using stored specimens collected in routine clinical care settings or in the context of research studies originally addressing different questions. Thus, early clinical biomarker research has features of retrospective observational studies that extend beyond the experimentally controlled settings typical for preclinical drug development research. The development process for biomarker-based tests usually begins with a study aiming to establish whether a biomarker is associated with some clinical outcome or other phenotype. The test may be based on a single biomarker or a panel of biomarkers combined via a statistical prediction model; for example, using “omics” assay technologies that measure “related sets of biological molecules in a comprehensive fashion.”2 Further development requires a series of studies to gather more evidence and eventually incorporate the biomarker into a clinical test that is validated for a specific clinical use. The clinical role for a biomarker-based test typically falls into one or more of the following categories (see US Food and Drug Administration / National Institutes of Health glossary at https://www.ncbi.nlm.nih.gov/books/NBK326791/): diagnostic, monitoring, pharmacodynamics/response, predictive, prognostic, safety, and susceptibility/risk. This commentary focuses on overarching principles to consider in