How to Apply for Scientific Advice & Protocol Assistance with EMA

This article provides an overview of the EMA scientific advice and protocol assistance procedure, highlighting the differences between scientific advice and protocol assistance. Protocol assistance is the special form of scientific advice available for developers of designated orphan medicines for rare diseases. The article summarises the key elements of the procedures including pre-submission considerations such as a preparatory meeting, the evaluation phase and post advice actions. We also discuss impact of the EU Pharmaceutical Reform on the scientific advice and protocol assistance procedures.

Introduction

Scientific advice is a very powerful tool for developers of medicinal products. Not only does it guide the developer through the challenges encountered during development, but it also establishes relationships with regulators. The advice will certainly have a positive impact on the development and will enable the developer to streamline their process, ensure a high rate of compliance with regulations and will reduce the risk of Marketing Authorisation Applications being rejected. Whilst the advice is not legally binding, there will be a high expectation that the advice given by EMA will be addressed during development.

Scientific Advice Overview

Scientific advice is a process whereby medicine developers can ask EMA specific questions related to their proposed development plan. Questions typically fall into the development strategy, quality, clinical and non-clinical areas although many questions can fall into more than one area, for example qualification of an impurity. The advice is prospective in nature and EMA do not pre-evaluate results which will be submitted later in development.

Protocol Assistance

Protocol assistance is the term for scientific advice sought for medicines with an orphan drug designation. The same principles and process relating to regular scientific advice apply and additionally, applicants may seek the Agency’s input on topics relating specifically to orphan development such as:

• demonstration of significant benefit within the scope of the designated orphan indication,
• similarity or clinical superiority over other medicines, especially similar products, which have orphan market exclusivity in the same indication.

The fees for scientific advice can be significant and details can be found on the EMA website. Significant fee reductions (up to 100%) are available for  micro, small and medium size enterprises (SMEs) and for protocol assistance. DLRC group can help developers assess whether they may qualify for these fee reductions and are able to apply for SME status for the developer.

Dates for submission of requests for Scientific Advice

Scientific advice is co-ordinated and managed by the EMA’s Scientific Advice Working Party (SAWP) who delivers the advice after adoption at the regular Committee for Medicinal Products for Human Use (CHMP) meetings. There are approximately 11 opportunities per year to obtain scientific advice which is adopted at the monthly meetings of the CHMP. The timings are strict and applicants who miss the allocated submission dates (published on the EMA website) even if late by only one day, will need to wait until the next cycle.

Parallel Scientific Advice

There are programmes in place which allow parallel scientific advice from:

• Regulators and Health Technology Assessment (HTA) bodies
• EMA and FDA

Further details can be found on the EMA Scientific Advice homepage.

Scientific Advice on Clinical Trials

When sponsors require advice relating to clinical trials, it is often sought via scientific advice from individual National Competent Authorities (NCAs) as NCAs are responsible for reviewing and approving clinical trial applications (CTAs) in the EU.  More recently, as part of the initiative ‘Accelerating Clinical Trials in the EU (ACT-EU)’, two consolidated advice pilots are now available for developers requiring advice on clinical trials. The first is the SAWP-Clinical Trial Coordination Group (CTCG) pilot which provides advice on both clinical trials and marketing authorisation application requirements and the second is the Pre-CTA advice pilot.  This pilot aims to provide technical and regulatory support on the dossier of a CTA prior to submission via the CT information system (CTIS).

Key Elements of Scientific Advice Procedure

An overview of the scientific advice procedure is given in the guidance document ‘European Medicines Agency Guidance for Applicants seeking scientific advice and protocol assistance (EMA/4260/2001 Rev. 14).’ The following figure summarises the  two phases of the procedure.

A.      Pre-Submission, Submission and Validation Phase

Preparatory teleconference with EMA

An optional preparatory telecon can be requested at the time of submission of the application for scientific advice. The preparatory meeting offers applicants the opportunity to establish contact with Agency staff and subject matter expert (SME) assessors and to receive feedback on several topics, including the appropriateness of the content and scope of questions and the related applicant’s positions, identification of additional issues to be included in the request, and the opportunity to ask regulatory questions which are outside the scope of scientific advice.  This preparatory meeting may be the only direct communication that the applicant has with the agency and can be extremely useful. Many clients resist having a preparatory meeting due to the additional time required but this should be balanced against the benefit of a meeting which increases the likelihood of a Day 40 outcome, as the EMA has helped to shape the questions and briefing book content.

Our experience  of preparatory meetings highlights the importance of succinct presentation that highlights the key points of the development and the rationale for the questions posed. We have supported clients in preparing for preparatory meetings in order to maximise their value. It is important to note that the preparatory meeting is about listening to feedback so that the briefing book and questions can be optimised and is NOT about defending the clients positions.

Submission of briefing book

A unique feature of the procedure with the EMA is that the briefing book must be submitted with the initial application. Generally, for scientific advice with individual NCAs, the briefing book is submitted after the initial application and around 2-4 weeks before any advice meeting with the agency. There is a mandatory EMA template for the briefing book. The template provides guidance text, however our experience has helped clients identify the critical information to include,  identifying the most appropriate questions and also develop a succinct stand-alone applicants position for each question.

To avoid unnecessary validation comments, it is important to consider carefully the wording of the proposed questions to be included in the advice request. Questions which are worded in the sense of a pre-assessment of data should be avoided.

The main purpose of this initial phase is to secure a briefing book which has been reviewed by the EMA and is found to be acceptable for the evaluation phase and is hence, validated.

B.      Evaluation Phase

After validation of the application, the evaluation process starts and is classified as Day 0. The reports are discussed at the next months SAWP meeting and then adopted at the next CHMP meeting which will be around Day 40. If the SAWP decides there is the need for a discussion meeting, this will be held after the CHMP meeting but before the next CHMP meeting, hence the advice will be adopted around Day 70 of the procedure.

C.      Post-advice actions

If aspects of the written advice received are unclear or ambiguous, it is possible to request a clarification, with minor clarifications being addressed in writing in an expedited manner, and major clarifications being addressed at the following SAWP meeting.  Any new data, information or a new applicant’s position would usually require a follow-up advice procedure.

Impact of Reforms in EU Pharmaceutical Legislation

The European Commission (EC) is proposing an ambitious revision of the EU pharmaceutical legislation  which includes several points relating to Scientific Advice and proposes to optimise the regulatory support to SME and non-commercial organisations and to provide scientific advice for future MA applicants more generally and in greater depth. Structures allowing the development of advice for companies, in particular SMEs, should also be put in place.

Key points are:

• EMA will continue to provide parallel EMA and HTA scientific advice and advice relating to clinical trials.

• Free scientific advice is retained for sponsors developing medicinal products intended for paediatric use or intended for in utero treatment, prior to submission of the Paediatric Investigation Plan and during its implementation.

• Protocol assistance is retained in the new legislation

• An additional six months data exclusivity will be offered for medicinal products containing a new active substance, where the clinical trials supporting the initial marketing authorisation application use a relevant and evidence-based comparator in accordance with scientific advice provided by the Agency. The proposed wording in the new legislation suggests that it will be a requirement to seek scientific advice in order to claim this additional data exclusivity, however at this stage it is unclear whether this will be a prerequisite.

• As part of the March 2024 European Parliament’s Committee on the Environment, Public Health and Food Safety (ENVI)’s report, which was adopted by the European Parliament in April 2024, additional text was proposed to ensure a separation between those responsible for providing scientific advice to a medicinal product developer and those subsequently responsible for the evaluation of the MAA for the same medicinal product.
  • • The Agency shall ensure that at least one of the two rapporteurs for a marketing authorisation application has not taken part in any pre-submission activities concerning the medicinal product. The reasons for any exceptions shall be documented and published with the European public assessment report (EPAR).

• This last point is an interesting one. One view may be that having consistency of lead NCAs through the process is helpful as they will develop a deeper understanding of the product. Another view is that switching one of the NCAs may enable a more rigorous assessment as it represents the view of a wider number of experts.

• Similarly to the current situation, the key areas of scientific advice shall be included in the EPAR once the corresponding marketing authorisation decision has been taken, after deletion of any information of a commercially confidential nature.

Additional information on the impact of the Pharmaceutical Legislation Reform on Paediatric Development is available in our recent article.

Summary

There is a strong correlation between the success of marketing authorisation applications and applicants following EMA scientific advice, therefore seeking Scientific Advice during drug development is highly recommended. There are several routes to obtaining advice from Regulatory Authorities, such as advice from National Competent Authorities or EMA scientific advice (as summarised in this article.).  In order to provide optimal value from seeking scientific advice, it is important for applicants to understand the nuances of the process, including the value of the preparatory meeting, the most appropriate questions  to ask, how to provide optimal company positions in the briefing book, in addition to navigating the procedure and understanding if any follow-up actions are required.

If you are considering seeking scientific advice on your drug development program, DLRC’s extensive experience in helping clients navigate the scientific advice process will ensure that you obtain optimal input from the Regulators.

Contact DLRC’s team of award-winning regulatory professionals via the link below, or email hello@dlrcgroup.com.