EMA Guidance: The EU Submission, Timelines and Review Talk (EUSTART)

Preparing a marketing authorisation application (MAA) requires a sufficiently complete and mature dossier before submission. The European Medicines Agency (EMA) has developed the EU Submission, Timelines and Review Talk (EUSTART) to help applicants, rapporteurs, national competent authority (NCA) assessment teams, and EMA identify important issues before an application is submitted.

EUSTART supports preparation for the joint pre-submission meeting (PSM), with the aim of facilitating a smooth assessment, reducing the need for clock-stop extensions, avoiding premature dossiers, and supporting agreement between the applicant and rapporteurs on the planned submission date.

Purpose of EUSTART

The EUSTART meeting provides an opportunity for the applicant, rapporteur(s), NCA assessment teams, and EMA to discuss relevant aspects of the planned application.

Applicants should inform the EMA Product Lead about the EUSTART request and provide the briefing package to the NCA(s) and EMA Product Lead at least 3 weeks before the meeting. They should also be prepared to discuss dossier-related issues and provide meeting minutes within 2 weeks after the EUSTART, including conclusions on dossier maturity and the anticipated submission date.

Regulatory, administrative, and procedural matters should be raised in writing with the EMA team during pre-submission interactions before the EUSTART.

Supporting a Mature Application

An important objective of EUSTART is to help determine whether an application is sufficiently mature for submission.

Applicants should ensure that the key information required for assessment is available at the time of MAA submission. The guidance reminds applicants that substantial data from new studies should generally not be introduced in responses to the List of Questions (LoQs) or List of Outstanding Issues (LoOIs) unless specifically requested by CHMP.

This is particularly important because assessment time is limited and clock-stops granted by CHMP have a fixed standard duration.

General Regulatory Topics

EUSTART may cover the choice of legal basis for the MAA and, where applicable, the reference and comparator products used in bridging studies.

Discussions may also address the proposed bridging strategy, scientific advice or protocol assistance, applicable CHMP or ICH guidelines, and any deviations from these during development.

Other topics include the proposed indication, orphan designation, paediatric requirements and PIP compliance, accelerated assessment, conditional marketing authorisation, marketing authorisation under exceptional circumstances, new active substance status, additional market protection, and the comprehensiveness of the data package at filing.

Proposed post-authorisation commitments or obligations may also be discussed.

Quality and GMP Topics

Quality and GMP discussions focus on important manufacturing and quality information expected to be available at submission.

Topics may include starting materials, commercial batches used in confirmatory clinical trials, comparability exercises, quality specifications, and investigations concerning the potential presence of nitrosamines.

Where a medical device is co-packaged or integrated with the medicinal product, relevant information such as the notified body opinion and applicable MDR requirements should be considered.

Applicants should also consider manufacturing and testing arrangements, including sites involved in manufacturing, testing, and batch release.

Important submission information includes manufacturing process validation, analytical procedure validation, final stability data, manufacturing authorisations, and valid GMP certificates for relevant third-country sites. The possible need for inspections of third-country sites may also be discussed.

Non-Clinical Topics

EUSTART may cover the non-clinical development programme and compliance with applicable guidance, including ICH S9 where relevant.

Applicants may discuss literature data relating to genotoxicity, carcinogenicity, and other toxicity areas, including the reliability and comprehensiveness of the available information.

Other topics include Environmental Risk Assessment development, major concerns from preclinical studies, potential SmPC or RMP wording, and planned non-clinical post-authorisation measures.

Clinical and GCP Topics

Clinical discussions may cover the development and completeness of pharmacokinetic information, including special patient populations, drug-drug interactions, age, and gender.

Applicants may also address PK/PD modelling, Model-Informed Drug Development (MIDD), and the pivotal clinical data package.

The proposed target population should be considered in relation to the population studied in the pivotal trials, while the proposed posology should be consistent with the pivotal study.

Other areas include population biomarkers, availability of final clinical study reports, GCP inspections and audits, planned future inspections, estimands, non-inferiority or equivalence studies, clinical relevance margins, major safety concerns, additional risk minimisation measures, and post-authorisation monitoring or development plans.

The availability of mature product information at the time of submission should also be considered.

Reviewing the Submission Date

EUSTART also supports discussion of the planned MAA submission date.

Applicants should identify foreseeable issues that could affect the accuracy of the proposed submission date and provide up-to-date information on ongoing or planned developments, including quality-related activities.

They should also indicate when important data or results are expected to become available. This information helps the participants assess whether the proposed submission timeline is realistic and whether the application is sufficiently mature for submission.

References

• EMA – The EU Submission, Timelines and Review Talk (EUSTART)