Optimizing Clinical Bridging Strategies For Combination Drug Products: A Risk-Based Approach

By Erica Peters, PhD, Senior Scientist, Regulatory Affairs; Izi Bruker, PhD, MPH, Fellow, Clinical and Medical Affairs; Raphael Bilgraer PharmD, PhD, Principal Pharmacometric Consultant, Kymanox Corporation

Clinical bridging studies are essential for ensuring the safety and efficacy of combination drug products when changes occur in formulation, delivery system, or manufacturing. These studies evaluate whether a new presentation (e.g., autoinjector) is bioequivalent (BE) or has comparable bioavailability (BA) to an existing one (e.g., vial-and-syringe), supporting FDA regulatory pathways such as 505(b)(2) and 505(j) ANDAs. The FDA defines key pharmacokinetic (PK) parameters—Cmax, Tmax, AUC₀–ₜ, and AUC₀–∞—used to determine BE, typically requiring the 90% confidence interval of the test/reference ratio to fall within 80–125%.

Bridging studies are influenced by the drug’s characteristics, including its half-life, delivery route, and molecular complexity (e.g., biologics vs. small molecules). Study design must account for variability due to device mechanics, injection depth, and patient characteristics. Tools like population PK (PopPK) modeling allow for simulation of drug behavior across subpopulations and reduce the need for extensive clinical trials.

A four-step risk-based framework is proposed: (1) Assess development stage and identify gaps; (2) Align timelines and integrate quantitative tools; (3) Design tailored studies with interdisciplinary input; and (4) Engage FDA early to refine plans. This method enhances efficiency, reduces regulatory delays, and optimizes resources.

Effective bridging requires collaboration across regulatory, manufacturing, clinical, and pharmacological domains. Strategic planning and early FDA engagement enable sponsors to develop robust bridging strategies, maintain development timelines, and ensure successful transitions between drug-device presentations.