A Regulatory Perspective on Validation of Surrogate Endpoints
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A Regulatory Perspective on Validation of Surrogate Endpoints
Lawrence J. Lesko, PhD, FCP Director of the Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
Key Words Biomarkers; Surrogate endpoints; Drug development; FDA Correspondence Address Lawrence J. Lesko, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002 (e-mail: Lawrence.Lesko@fda .hhs.gov).
The use of biomarkers as surrogate endpoints has had a dramatic and powerful impact on health care and the development and accessibility of drugs. For example, cholesterol is a biomarker used in many clinical trials of cardiovascular drugs such as “statins” where cholesterol reduction is used as a surrogate endpoint for reduced mortality. Although much progress had already been made over the past 20 years—especially in terms of the very real benefits surrogate endpoints have made to efficient medical product development and patient
N E W A D VA N C E S U T I L I Z I N G A C O M B I N AT I O N O F B I O M A R K E R S The challenges of developing a single biomarker as a surrogate endpoint are almost insurmountable for a given pharmaceutical sponsor. However, there is some compelling evidence that combinations of biomarkers can be more predictive of clinical endpoints, and as a result, complementary biomarkers are used in parallel in both early and late drug development and for regulatory decision making. For example, bone fracture rates in osteoporosis clinical trials can be better predicted from bone mineral density when biomarkers of bone formation (eg, serum osteocalcin) and bone resorption (eg, urinary calcium and hydroxyproline) are added to the panel. Biomarkers can arise from many different domains such as the biochemical, pharmacokinetic, pharmacodynamic, imaging, and genomic areas. In addition, more recent advances in imaging have allowed investigators to see quantitative anatomical changes following drug administration. To achieve sufficient predictive value with biomarkers, it is frequently necessary to combine biomarkers from different domains (ie, a “panel of biomarkers”) such that “surrogacy,” in a sense, comes from biomarker data taken together to reflect a combination of disease
care—the industry faces a host of future challenges as the use of biomarkers and surrogate endpoints play a more integral role in the advancement of new medicines along the critical path of drug development. During the 41st DIA Annual Meeting in Washington, DC, Dr. Lawrence Lesko from the Office of Clinical Pharmacology at the Food and Drug Administration presented a discussion on the challenges associated with the validation of surrogate endpoints, highlighting progress to date as well as future objectives.
pathogenesis, change in disease progression, and the beneficial effects of the drug.
FDA SUPPORT OF BIOMARKER DEVELOPMENT Most companies have a biomarker strategy for each new molecule advanced to the develo
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