PI-008 - USING BIOMARKERS TO PROVIDE EVIDENCE OF EFFECTIVENESS IN DRUG DEVELOPMENT FOR RARE DISEASES: SURVEY RESULTS FOR APPROVED ENZYME REPLACEMENT THERAPIES.

N. Hossain¹, K. Miner², J. Wang³, R. Li³, R. Schuck³, M. Pacanowski³; ¹U.S. Food and Drug Administration, Silver Spring, MD, USA, ²U.S. Food and Drug Administration, Silver Spring, USA, ³U.S. Food and Drug Administration, MD, USA.

Background: Biomarkers are often used in clinical trials for rare diseases to evaluate patient responses to pharmacological interventions. In drug development, biomarkers can contribute to demonstrating substantial evidence of effectiveness to support regulatory approval by (i) providing supportive or confirmatory evidence of drug effect or (ii) use as surrogate endpoints to predict clinical benefit. In the current study we surveyed the biomarkers that were used in the clinical programs for FDA-approved enzyme replacement therapies (ERTs) indicated for inborn errors of metabolism (IEM).

Methods: We systematically reviewed the use of biomarkers in 20 Biologics License Applications for ERTs that were approved for IEM indications by Center for Drug Evaluation and Research at the U.S. FDA from 1994 to 2023. The sources of information included the approved United States prescribing information (USPI) and review documents that are accessible through Drugs@FDA. We then identified the roles of biomarker data in regulatory decision making and conducted further analyses.

Results: Among the 20 ERTs, 19 (95%) products have biomarker information in their approved product labeling and 8 (40%) products reported biomarker information for more than one biomarker. Most programs (16; 80%) used biomarkers to assess substrate reduction. Of the 19 ERTs that reported biomarker data in the product labeling, 7 (37%) ERTs used biomarkers as clinical or surrogate endpoints in efficacy evaluation. Among the 4 most recently approved ERTs, 3 used clinical pharmacodynamic (PD) biomarker data as confirmatory evidence. Overall, 12 (63%) of the ERTs used PD biomarker data providing other supportive evidence.

Conclusion: PD biomarkers have played critical roles in providing pivotal or supportive evidence of effectiveness for approved ERTs and are becoming a key source of confirmatory evidence in recently approved ERTs. Our survey results highlight the importance of a well-planned and executed biomarker assessment strategy in drug development for rare diseases.