Clinical Pharmacology Review of Plasma-derived and Recombinant Protein Products: CBER Experience and Perspectives on Model-Informed Drug Development

Abstract

Introduction: Clinical pharmacology studies are one of the major types of regulatory data submitted for review of therapeutic proteins regulated by the Center for Biologics Evaluation and Research (CBER).

Aim: The primary objective of the current study is to provide an overview of the role of clinical pharmacology including pharmacokinetics (PK), pharmacodynamics (PD) and exposure-response analysis at CBER. Furthermore, we aim to provide a baseline estimate for the use of quantitative clinical pharmacology studies prior to implementation of FDA's model-informed drug development (MIDD) pilot programme.

Methods: We survey original Biologics License Applications (BLAs) for plasma-derived and related recombinant therapeutic protein products approved by CBER/FDA (2008-2017).

Results: There were 37 original BLAs that met our inclusion criteria, and 34 of these products (92%) contained human PK data as part of the biological licensing. The products were broadly classified as coagulation factors (54%), IgG and related proteins (24%), and other therapeutic proteins (22%). Coagulation factor VIII and IX products constitute 32% of the BLAs and indicated for treatment of haemophilia A and B, respectively. Twelve products (35%) used model-based approaches (population PK/PD and exposure-response). Over the past 5 years (2013 to 2017), there is a trend for increased application of MIDD approaches as compared to the previous cohort years (2008 to 2012).

Conclusion: In conclusion, clinical pharmacology has played a major role in regulatory review of plasma-derived products, and we expect that the application of quantitative methods will further evolve for these products under the FDA MIDD programme.

Keywords: Clearance; Dosing; MIDD; PDUFA VI; Rare diseases.