Support specific to ATMPs’ development at EMA level
Introduction
Early interactions procedures with regulators are implemented to support medicines’ (mainly innovative medicines') development, and the specific challenges they face. Some procedures are exclusively for Advanced Therapy Medicinal Products (ATMPs) at the EMA level. They offer incentives or an easier access to the procedures for developers of ATMPs, especially sponsors. The support given by EMA to this type of medicines aims to provide a better and quicker access to therapies for patients.
The procedures are generally dependent on the type of product produced, here ATMPs, but also the status of the stakeholder trying to contact the regulator early. For instance, every sponsor developing an ATMP can interact with EMA through the procedure called ‘scientific recommendation on ATMP classification’. It is a way to know if the product developed falls under the ATMPs legal category, and if so in which type of ATMP. In parallel, sponsors categorised as SMEs can benefit from the ‘ATMP Certification procedure’, while only academia and non-profit organisations can enter into early interaction with the EMA through the ‘ATMP Pilot for academia and non-profit organisations’.
Stakeholders
European Medicines Agency: The European Medicines Agency (EMA) is an agency of the European Union whose goal is to protect and promote human and animal health. The agency is responsible for the scientific assessment of Advanced Therapy Medicinal Products to be marketed within the European Union and the European Economic Area, including in the context of expediting marketing authorisations pathways. The Agency provides a number of incentives and procedures for medicines’ developers to support market access of quality medicines with a positive benefit/risk balance as regards as their safety and efficacy criteria for the final safety and health protection of patients.
Committee for Advanced Therapies (CAT) at theEuropean Medicines Agency: The Committee for Advanced Therapies can be consulted by the European Medicines Agency or the European Commission on any matter related to ATMPs. Within the EMA, its main responsibility is to provide opinions regarding ATMP marketing authorisation applications. It also contributes to scientific advice, in cooperation with the SAWP, where Advanced Therapy Medicinal Products are concerned. The CAT is also responsible for every other procedure that has been developed to support ATMP’ development: scientific recommendation on ATMP classification, ATMP certification procedure, ATMP Pilot Academia. More on CAT on EMA website here.
Medicines’ developers: Medicine developers are the target of early interaction with regulators such as the European Medicines Agency (EMA). Medicines’ developers can be academia, industry, or non-profit organisations although they are generally from the industry sector (mainly big pharma but also SMEs) given the resources necessary for the commercialisation of medicines.
Academia: The EMA’s use of the word refers to ‘public or private higher education establishments awarding academic degrees, public or private non-profit research organisations whose primary mission is to pursue research, and international European interest organisations;’ (Decision of the Executive Director on fee reductions for scientific advice requests on PRIME products for SMEs and applicants from the academic sector, 27 May 2016 EMA/63484/2016 Executive Director, PDF_EN.) Find out more information on Academia and the links between EMA and the Academic community (especially in the context of the framework for collaboration that has been developed by the EMA since 2017) here.
Seeker of interaction: A medicines’ developer interested in a specific procedure or service established within the European Medicines Agency to foster early interaction between regulators and stakeholders with the purpose to facilitate the development of marketable medicines.
Definitions
Early interaction: Possible contact with regulators early on in the development process of a medicinal product by a stakeholder, mostly at the research and development phase. For instance, different types of early interaction exist to establish a contact with the EMA. These vary depending on the type of product, the seeker of interaction, the need for interaction, and the steps in ATMPs’ development.
Advanced Therapy Medicinal Products: Biological medicines for human use that are based on genes, cells or tissue engineering (abbreviated as ATMPs). (Completed and adapted from EMA Glossary of regulatory terms)
ATMP certification: The ATMP certification is a specific procedure established by the EU regulation on ATMP for micro-small- and medium sized enterprises (SMEs) in order to get an assessment from the CAT on the quality and, if available, non-clinical data of ATMPs under development, to identify and address any potential issues early on, and prior to the submission of a marketing-authorisation application. Thus, it is a procedure for early interaction with the CAT. It is dedicated to the holders of the micro-small- and medium sized enterprises (SMEs) status. (Art. 18 Regulation (EC) No 1394/2007)
Scientific recommendation on ATMP classification: A specific procedure established by the EU regulation on ATMP for ATMPs’ developers to consult the EMA to know if a product they are developing is an Advanced therapy Medicinal Product (ATMP) or not, and if so, which type, in accordance with EU legal definitions. At the EMA, CAT is delivering these recommendations after consultation with the European Commission and within 60 days after receipt of the request. (Article 17 of Regulation (EC) N° 1394/2007)
ATMP pilot for Academia and non-profit organisations: This new procedure for early interaction between ATMPs’ developers and EMA has been launched by the EMA to facilitate the translation of ATMPs’ development into authorised medicines for patients by providing enhanced support to selected applicants from the academic and non-profit organisations sector and by identifying and addressing potential gaps in the existing regulatory tools and guidance.
SME status: The SME status gives small and medium companies access to a number of incentives to enhance the development of innovative medicines and ATMPs. To acquire this status, a company has to meet several legal criteria. More information on how to apply for a SME status on the EMA’s website here.
SME office: The SME office was set up by Article 11 of the Commission Regulation (EC) No 2049/2005. The office is dedicated to helping small and medium companies to develop medicines and meet the European Union necessary administrative and legal requirements regarding medicines. The office provides support to companies registered as SME’s.
Challenges
The services and procedures put in place by EMA are designed to help developers to enter into early contact with the agency and overcome the challenges a developer may encounter when trying to bring an ATMP medicine on the European Union market.
The main challenge here is the complexity of implementing legislative and regulatory requirements as well as to develop appropriate guidance for ATMPs’ development in accordance with their scientific and technical specificities. It implies first to know whether a medicine will fall or not within the legal category of ATMPs, and if so, what type of ATMPs it is. Despite the legislative definitions and the EMA’s guidance, such classification remains difficult to anticipate due to the specificities of each ATMP. Thus, it is established on a case-by-case basis and the recommendation of CAT on ATMP classification is of paramount importance.
Another challenge to consider is the status of the medicines’ developer as the various schemes are not always available for all types of stakeholders, given that they sometimes depend on different legislative requirements or incentives, and they are not necessarily involved in the same stage of the medicines’ development life cycle. EMA needs to adapt the support to the different actors involved with the goal of fostering research and the development of new medicines to enable patient’s access to ATMPs, in accordance with the applicable legislative provisions. In such context and contrary to big pharma, SMEs have less resources to be dedicated to regulatory issues in particular, while academia has often considered to be far from the EMA given its main focus on proof of concept, pre-clinical and clinical studies in the early part of medicines’ life cycle.
Apart from finding new ways to allow dialogue between EMA and developers which is one of the main challenges faced by EMA considering its limited human resources, communicating on the existing procedures and services available to support the development of medicine is also fundamental. Despite the organisation of events by EMA, such as stakeholders’ meetings, its very complete website, and its participation in congresses, many stakeholders have no full knowledge of the available tools for early interactions with EMA.
Opportunities and incentives
EMA created several early interaction procedures to accompany medicine developers into navigating the legal requirements at any stage of a medicinal product life cycle, especially in order to obtain and maintain marketing authorisation. The available procedures for early interactions between stakeholders and regulators are meant to foster early patient’s access to medicines.
In addition to the services and procedures available for all medicines or for innovative medicines, procedures specific to ATMPs have been established to support their development in accordance with their scientific and technical specificities. These procedures help to navigate the complex legislative landscape as well as the numerous scientific and regulatory guidance adopted at the European Union level.
Some procedures and incentives have been established in accordance with the legislative requirements, here the EU Regulation on ATMPs (Regulation (EU) 1394/2007): Scientific recommendation on ATMP classification and ATMP certification procedure, as well as fee reductions or waivers.
Another pilot procedure has been developed by EMA on its own initiative to identify and provide support specifically to academia and and non-profit organisations: the ATMP pilot for Academia and non-profit organisations. The ATMP pilot has been launched in September 2022, and first-results are expected in 3 to 4 years. This new opportunity for interaction between academia and the EMA will help the EMA to identify how to better support academic developers in translating basic research developments into medicines. (See: Translational science)
Practical steps
Procedure for all ATMPs’ developers: Scientific recommendation on ATMP classification
This procedure aims to know if a medicine does fall or not within the legal category of ATMPs, and if so, what type of ATMPs it is, in accordance with EU legal definitions. The submission is made to the EMA, and the CAT is delivering these recommendations after consultation with the European Commission and within 60 days after receipt of the request. (Article 17 of Regulation (EC) N° 1394/2007).
This procedure is voluntary and free of charge.
The application includes two forms (one on administrative information and one on classification request and briefing information) that shall be sent via email to the EMA at specific submission dates. Forms, dates of submission and further information including guidance documents on classification, are available on the EMA’s dedicated webpage here.
Moreover, in order to anticipate on the potential classification of a medicine as an ATMP, it may be useful to consult the previous CAT’s summaries of scientific recommendations on ATMPs classification that are available on the EMA’s dedicated webpage here.
Specific Procedure for SMEs status’ holders developing ATMPs: the ATMP certification procedure
The certification procedure is dedicated to SMEs status’ holders, to know more on the conditions and on how to obtain this status, please see the SMEs’ status section in Practical steps within the entry ‘Support for innovative medicines’ development at the EMA level’and the dedicated EMA’s webpage here.
The certification procedure aims to incentivise SMEs to conduct quality and non-clinical studies on ATMPs, especially for those which would not have the necessary resources to develop such medicines to the end of the commercialisation pathway. Although it is independent from any marketing authorization application, it also aims “at facilitating the evaluation of any future application for clinical trial and marketing authorisation based on the same data. For this reason, the evaluation of an application for certification should be conducted in accordance with the same scientific and technical requirements as those applicable to a marketing authorisation application”. (Recital 3 of Commission Regulation (EC) No 668/2009 of 24 July 2009).
The certification procedure involves a scientific assessment by CAT of quality data and, when available, non-clinical data which have been generated by SMEs at any stage of the ATMP development process. To achieve this assessment, CAT may request supplementary information and/or, upon acceptance from the applicant, a site visit of the premises where the ATMP concerned is being developed.
After this assessment, CAT will issue a recommendation upon which the EMA issues a certification.
The procedure can be divided into two phases:
A pre-submission phase request for ATMP certification:
The sponsor needs to notify the EMA of their intention to submit a request for the procedure by completing the ‘Intent to submit’ pre-submission request form
The developer needs to ask for an ‘ATMP certification’ under the `type of question’ tab to send out a pre-submission request to EMA.
The pre-submission request form for ATMP certification is available here as well as the list of annexes the sponsor needs to complete their submission with.
A phase of submission of the ATMP certification dossier of quality, and if available, non-clinical data
If the request is validated by the EMA through the platform, then the sponsor can submit the same dossier via Eudralink to the CAT members and the EMA service desk as a submission for ATMP certification.
Upon receipt of valid application, the procedure from the evaluation to the certification takes 90 days, excluding potential clock-stops due to the request of supplementary information or site visits.
As of 1 May 2023, one of these two fees is due to the EMA for certification of quality and non-clinical data relating to ATMPs developed by SMEs:
EUR 77,900 for the evaluation of an application relating to quality and non-clinical data;
EUR 51,800 for the evaluation of an application relating to quality data.
Specific Procedure for academia and non-profit organisations developing ATMPs: the ATMP pilot for Academia and non-profit organisations
The ‘ATMP pilot’ aims at providing an increased support for developers of promising ATMPs to meet regulatory requirements regarding quality, safety, and efficacy, and if needed until the submission of marketing authorisation applications. Up to five ATMPs’ developers will be selected by the end of 2024, and will benefit from this specific support from the EMA as well as from the fee incentives applicable to SMEs developers.
The application form includes the applicant details, ATMP product type, Stage of development of the ATMP (Non-Clinical, Exploratory Clinical, Confirmatory Clinical or Other to be specified), as well as information on the product. The latter notably questions whether the developer has already entered into early interaction with the EMA for the ATMP concerned to enter the pilot, and if so, to specify the procedures and schemes used. This can have an impact on the application: for example, the PRIME designation exempts the sponsors from having to give a detailed overview of the development plan for the medicinal product.
Last but not least, for products without PRIME designation, the applicant has to provide justification for an unmet medical need and the overview for development plan.
Interested academia and non-profit organisations can find and download the application form in word format on the section dedicated to the ATMP pilot on the EMA’s website here.
The EMA held multiple webinars on support for academia and non-profit ATMPs’ developers to explain how the pilot will be implemented. The interested developers can watch the latest webinar on the ATMP pilot here, hosted by the EMA on 8 February 2023.
For further information on this pilot, please consult the section dedicated to the ATMP pilot on the EMA’s website here. The EMA can also be contacted via this email address advancedtherapies@ema.europa.eu. This email is also the one for developers to send their application for the ATMP pilot.
European Union Legislation
ATMP certification procedure
Commission Regulation (EC) No 668/2009 of 24 July 2009 implementing Regulation (EC) No 1394/2007 of the European Parliament and of the Council with regard to the evaluation and certification of quality and non-clinical data relating to advanced therapy medicinal products developed by micro, small and medium-sized enterprises (Text with EEA relevance), OJ L 194, 25.7.2009, p. 7–10, CELEX number: 32009R0668
ATMP Certification procedure and Scientific Recommendation on ATMPs Classification
Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), OJ L 324, 10.12.2007, p. 121–137, CELEX number: 32007R1394