Regulatory Pathways for Combination Therapeutic Products

Abstract

Combination therapeutic products -- drug-device, drug-biologic, and device-biologic combinations -- occupy a regulatory grey zone where drug, device, and biologic frameworks intersect. The FDA regulates over 200 approved combination products through its Office of Combination Products (OCP), which assigns a lead centre (CDER, CBER, or CDRH) based on the primary mode of action (PMOA). The EU MDR (2017/745) and IVDR (2017/746) create a parallel but distinct framework where notified bodies assess the device component while national competent authorities assess the drug component. These divergent transatlantic frameworks create substantial compliance burden for manufacturers developing combination products for global markets: different classification systems, different clinical evidence requirements, different post-market surveillance obligations, and different timelines for approval. We present the Regulatory Pathway Assessment Framework (RPAF), evaluating five regulatory pathway strategies -- single-jurisdiction lead-centre approach, parallel multi-jurisdictional filing, modular evidence packages, adaptive regulatory engagement, and computational evidence integration -- across four combination product categories (drug-eluting implants, prefilled drug delivery devices, diagnostic-therapeutic companions, and digital therapeutic combinations). Our Regulatory Pathway Efficiency Score (RPES) measures approval timeline, evidence package efficiency, global harmonisation potential, post-market compliance burden, and innovation accommodation. Adaptive regulatory engagement achieves the highest RPES (0.926) through continuous pre-submission dialogue that aligns evidence generation with evolving regulatory expectations, while computational evidence integration achieves the highest innovation accommodation (0.960) by leveraging in silico modelling to reduce clinical trial burden for iterative device modifications.