Work package 3: Non-Clinical Safety
Description of the work package
This Work package 3 involves review of relevant literature, an investigation of the local buccal tolerability of the mini-tablets, if needed, and a summary of all available non-clinical safety evidence documentation which finally needs to be implemented into various regulatory and marketing documents.
For this work, Ethicare is liaising with Dr. Elizabeth Horsley as a consultant to Ethicare and will ensure that the different tasks in this work package are carried out on time.
This work package will ensure that all necessary preliminary investigations have been completed to perform the healthy volunteer trial and the clinical trials, and will include a careful analysis of the existing evidence in order to provide the basis for the Paediatric Investigation Plan (PIP), the clinical Investigator Brochure (IB) and the Investigational Medicinal Product Dossier (IMPD). The need for a local tolerability study is to be evaluated from literature data. If toxicology studies are needed, this WP will include the outsourcing of these studies with the appropriate supervision and data interpretation.
The tasks included in our work package are as follows:
- Literature Review: The use of enalapril and captopril in neonates and in premature neonates has been described in case studies and case series demonstrating the renal effects of ACE inhibitors. The authors typically concluded that utilizing low doses and carefully monitoring renal function during ACE-inhibitor treatment in neonates was beneficial. A careful analysis of all available data will be performed as the basis for the work in this work package.
- Local tolerability study in hamsters or dogs: A local tolerability study may be required due to the increased time that the formulation is present in the mouth, ideally with PK assessment and comparing the older formulation with the minitablet. Furthermore, if needed, a formal preclinical toxicology study in juvenile animals will be performed. In addition, during the first 6 months, the sensitive and specific mass spectrometry (MS) assay for enalapril and enalaprilat in children performed under Good Laboratory Practice (GLP) conditions will be adapted to fulfil all requirements for drug approval in the EU. The assay will be compared to a HPLC-MSMS assay regularly used in healthy volunteer studies.
- Preparation of regulatory documentation: The clinical investigation of a new formulation of an existing drug by a new manufacturer requires supporting documents, such as the IMPD and clinical IB. These documents include a toxicology section which should be written and supported by an expert. This role will be performed by Dr. Elizabeth Horsely.
When developing a new formulation of enalapril for use in paediatric patients, it is crucial to determine whether any potential risks can be reduced by first conducting juvenile toxicology studies. This topic will have to be carefully outlined in the PIP as a basis for a discussion with the Paediatric Committee of the EMA (PDCO).