A review of clinical pharmacology deficiencies of European centralised drug marketing authorisation applications.

ABSTRACT

The aim of this observational review was to review trends in deficiencies in clinical pharmacology dossiers by analysing the frequency and characteristics of major objections (MOs) related to clinical pharmacokinetics and dose-exposure-response (DER) relationships in assessment reports for medicinal products submitted in centralised procedures to the European Medicines Agency (EMA). Initial Assessor (Day 120) assessment reports between 2013 and 2018 were reviewed MOs and characterised with regards to ATC code, orphan status, legal basis and type of molecule, major objection topic and if scientific advice had been sought during development. 23% of the 551 identified Day 120 assessments contained at least one major objection related to clinical pharmacology. Most common topics identified were related to the pharmacokinetics in the target populations, analytical methods, dose-exposure-response relationships, absorption, distribution, metabolism, excretion, comparative bioavailability, and bioequivalence issues. The importance of a robust clinical PK dossier in the assessment of marketing authorisation applications was highlighted by the high frequency of major objections. This review should provide valuable insights to ensure that aspects of bioanalytical methods, comparative bioavailability, PK in the target population and DER relationships are thoroughly addressed in future marketing authorisation applications.