Biomarkers in Drug Development: A Useful Tool but Discrepant Results May Have a Major Impact

The high costs incurred when drugs fail during clinical trials has prompted interest in biomarkers as biological indicators for progress of disease, effect of therapeutic interventions, and/or drug-induced toxicity. One of the goals is to reduce attrition of drugs during the clinical, and probably preclinical, phases of drug development, and hence, the overall cost of drug development. The role of biomarkers has been exponentially increasing in guiding decisions in every phase of drug development, from drug discovery and preclinical evaluations through each phase of clinical trials and into post-marketing studies. In early phases of drug development, biomarkers are used to evaluate activity in animal models, prove mechanism of action and concept of an investigational entity, bridge pre-clinical and clinical pharmacology, and evaluate safety in animal models and humans. In late stages of drug development, biomarkers can be used to make decisions in the evaluation of dose-response and optimal regimen for desired pharmacologic effect and safety, and some biomarkers can be used as a surrogate endpoint for efficacy and/or toxicity. Also, biomarkers can predict patients’ response to compound-enabling patient enrichment strategies by identifying certain patient populations that are more likely to respond to the drug therapy or to avoid specific adverse events. This shift toward “personalized medicine,” in which the patient receives a treatment based on his/her genetic makeup as well as medical profile, is helping the drug industry achieve the goal of quick and cost-effective research, especially in poorly served areas such as neurodegenerative disorders and cancer. Biomarker assays range from exploratory type of assays performed on a fit-for-purpose basis to rigorously validated assays when a biomarker is used as a surrogate end point, for patient selection, or for randomization into different arms. Validation of biomarker assays should be considered a continuous and evolving process. It is imperative that biomarker development be accelerated along with therapeutics. Assay validation is essential, but of equal or even greater importance is the monitoring of assay performance and level of quality during production. Despite all of the potential benefits of using biomarkers to advance pharmaceutical research and development, discrepant results can pose a threat to development programs by triggering false decisions.