A Comprehensive Approach to Selection of Adverse Drug Reactions for a Drug with Conditional Marketing Authorisation in the European Union.

INTRODUCTION

Delamanid (Deltyba®), a medicinal product with an orphan designation for the treatment of tuberculosis, received a conditional marketing authorisation in the European Union (EU) based on phase 2 data, while phase 3 trial was ongoing. The list of adverse drug reactions (ADRs) in the original Summary of Product Characteristics (SmPC) contained all adverse events (AEs) considered related by the investigator that were reported in at least one of the 321 patients receiving delamanid. The safety profile observed after completion of the phase 3 clinical trial, post-marketing studies and spontaneous reports from post-marketing appeared different from what the initial SmPC was indicating. A comprehensive analysis was undertaken aiming to provide evidence for identification of a well-substantiated and clinically useful delamanid safety profile.

METHODS

In support of the process of ADR identification, a statistical methodology of data from controlled clinical trials was introduced based on the estimation of risk difference and risk ratio for identification of a potential risk from delamanid in high and low incidence situations. Final medical assessment was supported by this statistical analysis of data from controlled clinical trials, any signal from all other Otsuka-sponsored clinical trials, along with data from post-marketing solicited and unsolicited sources.

RESULTS

ADRs were either retained, added to or removed from the ADR list with the same or modified frequency. Thus, the total number of ADRs listed in the original SmPC was significantly reduced.

CONCLUSION

A combination of statistical parameters and medical judgement should be considered for the selection of undesirable effects for the product label and for the safety risk classification.