Standard Marketing Authorisation Pathway: Centralised Procedure for ATMPs
Introduction
Any company wishing to commercialise an Advanced Therapy Medicinal Product (ATMP) manufactured at the industrial scale and intended to be placed on the market within the European Union must hold a marketing authorisation issued by the European Commission following the scientific assessment of the application by the European Medicines Agency (the “centralised procedure” of marketing authorisation), with the involvement of the Committee for Advanced Therapies.
The centralised procedure allows the marketing-authorisation holder to commercialise the medicinal product and make it available to patients and healthcare professionals throughout the entire European Union on the basis of a single marketing authorisation delivered at the European level.
Stakeholders
Marketing Authorisation Applicant: The people or company applying for a marketing authorisation.
Marketing Authorisation holder: The people or company benefiting from a Marketing Authorisation submitted through the "Centralised procedure" to distribute and sell a medicinal product in the European Union.
European Medicines Agency (EMA): Under the centralised procedure, companies submit to the EMA a single marketing authorisation application. The EMA is in charge of the scientific assessment of Advanced Therapy Medicinal Products marketing authorisation application. It includes several scientific Committees as well as working parties and scientific advisory groups.
Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency: The Committee for Medicinal Products for Human Use, the EMA's main scientific assessment committee for medicinal products for human use, will assess the Marketing Authorisation Application andwill issue an opinion on whether the medicinal product should be authorised or not. Such opinion is sent to the European Commission, which will decide on granting the marketing authorisation or not. The CHMP is composed of one member appointed by each of the European Union Member States and European Economic Area countries plus Iceland and Norway, and up to five scientific experts.
Committee for Advanced Therapies (CAT) at the European Medicines Agency: The Committee for Advanced Therapies (CAT) is mainly responsible for preparing a draft opinion on the quality, safety and efficacy of each Advanced Therapy Medicinal Product marketing authorisation application, before final opinion by the Committee for Medicinal Products for Human Use as regards to the scientific assessment of a marketing authorisation application. The CAT also participates in the procedure of certification of quality and non-clinical data for small and medium-sized enterprises developing ATMPs, the provision of scientific recommendations on the classification of ATMPs, as well as any other activity requiring expertise on ATMPs. The CAT is composed of 5 members (and alternates) of the CHMP coming from five Member States, one member and one alternate appointed by each other EU Member State, one member and one alternate appointed by their respective Member States from the EEA/EFTA, two members and two alternates representing clinicians and appointed by the European Commission, and two members and two alternates representing patients’ associations and appointed by the European Commission.
Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicines Agency: The PRAC is the European Medicines Agency's committee responsible for assessing and monitoring the safety of human medicines. The PRAC is responsible for all aspects of the risk management of medicinal products and for the assessment of the risk management plan provided by the applicant. The PRAC is notably involved in the assessment of Advanced Medicinal Therapy Products’ marketing authorisation applications though providing advice to the Committee for Medicinal Products for Human Use. The PRAC is composed of a chair, one member and one alternate member appointed by each of the EU Member States, one member and one alternate member appointed by each of the EEA/EFTA States, six members appointed by the European Commission to ensure the availability of the relevant expertise, one member and one alternate representing healthcare professionals and appointed by the European Commission, and one member and one alternate representing patients’ organisations and appointed by the European Commission.
European Commission: In the European Union, the marketing authorisation of Advanced Therapy Medicinal Products is granted or not by the European Commission. The European Commission’s legally binding decision takes into account the scientific assessment conducted by the European Medicines Agency. Notifications of marketing authorisation from the European Commission are published in the Official Journal of the European Union. All information concerning current or active marketing authorisations, refused, withdrawn, suspended, expired or not renewed for medicinal products subject to the centralised procedure is available on the European Union Register of Medicinal Products.
Definitions
Centralised procedure: The centralised procedure allows the marketing-authorisation holder to market the medicinal product and make it available to patients and healthcare professionals throughout the European Union on the basis of a single marketing authorisation delivered by the European Commission after a single scientific assessment and a single application to the European Medicines Agency (EMA).
Centrally authorised product: Referred as CAP for “Centrally Authorised medicinal Products” in EMA documents) A medicine with a single marketing authorisation issued by the European Commission and valid across the European Union. [Source: EMA Glossary of regulatory terms]
Clock stop: A period of time during which the evaluation of a medicine is officially stopped, while the applicant prepares responses to questions from the regulatory authority. The clock resumes when the applicant has sent its responses. [Source: Adapted from EMA Glossary of regulatory terms]
(Co-) rapporteur: One of the two members of EMA’s committee leading the assessment of an application. [Source: EMA Glossary of regulatory terms]
List of outstanding issues: A set of questions addressed to an applicant (generally a company) during a procedure, such as during the evaluation of a marketing authorisation application. [Source: Adapted from EMA Glossary of regulatory terms]
List of questions: A set of questions addressed to a company during a procedure, such as a marketing authorisation application. [Source: Adapted from EMA Glossary of regulatory terms]
Marketing authorisation: The approval to market a medicine in one, several or all European Union Member States. (Source: EMA Glossary of regulatory terms)
All medicinal products must have been granted a marketing authorisation prior to be placed legally on the market within the European Economic Area. The purpose of the marketing authorisation is to ensure safety, efficacy and high quality of authorised medicinal products. For Advanced Therapy Medicinal Products, a single application is submitted at the European Medicines Agency under the centralised procedure, and will be scientifically assessed by the Committee for Medicinal Products for Human Use (CHMP) as well as other relevant Committees, especially the Committee for Advanced Therapies (CAT). The marketing authorisation issued by the European Commission is valid in the European Union Member States, Iceland, Norway and Liechtenstein for a five-years period.
Marketing Authorisation Application: A Marketing Authorisation Application is an application submitted by a marketing authorisation applicant to the competent authority, i.e. the European Medicines Agency for the marketing authorisation of advanced therapy medicinal products within the European Union.
Marketing Authorisation Applicant: The people, company applying for a marketing authorisation for a medicinal product.
Marketing Authorisation holder: The company or the legal entity which has been granted a marketing authorisation to distribute and sell its medicinal product on a given market (for ATMPs, the market of European Union).
Marketing authorisation file: The file requested for marketing authorisation applications. The marketing authorisation file is based on the Common Technical Document (CTD), a document including five parts: Module 1 for regional administrative information (specific to each Member State), Module 2 for the CTD summary, Module 3 on quality (chemical, pharmaceutical, biological and biotechnological data), Module 4 on safety (toxico-pharmacological data) and Module 5 on efficacy (clinical data).
Oral explanation: A presentation and discussion in person between representatives of an applicant and an EMA committee. [Source: EMA Glossary of regulatory terms]
Risk-benefit balance: An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks, i.e. any risk relating to the quality, safety or efficacy of the medicinal product as regards patients' health or public health. (Articles 28a and 28 of Directive 2001/83/EC)
Variation (or ‘Variation to the terms of a marketing authorisation’): A change to the terms of a marketing authorisation. (Article 2.1 of Regulation (EC) n°1234/2008)
Extension of a marketing authorisation (or ‘extension’): a variation which is listed in Annex I of Regulation (EC) n°1234/2008 and fulfils the conditions laid down therein. (Article 2.4 of Regulation (EC) n°1234/2008) They are generally changes to the active substance or changes to strength, pharmaceutical form and route of administration.
Type IA variation (or ‘Minor variation of type IA’): a variation which has only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned. (Article 2.2 of Regulation (EC) n°1234/2008)
Type II variation (or ‘Major variation of type II’): a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned. (Article 2.3 of Regulation (EC) n°1234/2008)
Type IB variation (or ‘Minor variation of type IB’): a variation which is neither a minor variation of type IA nor a major variation of type II nor an extension.(Article 2.5 of Regulation (EC) n°1234/2008)
Challenges
Obtaining a marketing authorisation under the centralised procedure is an expensive and time-consuming process which can delay patients’ access to Advanced Therapy Medicinal Products, especially as it is difficult for ATMP’s to provide consistent long-term efficacy data in particular. To provide more flexibility, several expediting pathways are available for ATMPs as for other medicinal products: conditional marketing authorisation, marketing authorisation granted under exceptional circumstances and/or following an accelerated assessment. The European Medicines Agency (EMA) has also developed and promoted regulatory schemes to allow an earlier access to innovative medicinal products in fostering their development while meeting regulatory requirements. It includes ATMPs in particular through the following tools: early contact with regulators, PRIority Medicines (PRIME), adaptive pathways approach to medicinal products development and data generation, and ATMP pilot for academia and non- profit organisations.
The final and legally binding decision issued by the European Commission is based on the scientific assessment conducted by EMA. It is valid in all EU Member States, as well as in Iceland, Norway and Liechtenstein. Although the European Commission is not bound by the EMA’s scientific assessment, it is quite rare that it does not follow its recommendations.
The marketing authorisation shall be refused if the risk-benefit balance is not considered to be favourable, the therapeutic efficacy is insufficiently substantiated by the applicant and the qualitative and quantitative composition is not as declared. The marketing authorisation will also be refused if any particulars or documents submitted with the application do not comply with the legislation. (Article 26 of Directive 2001/83/EC).
A marketing authorisation may also be maintained, suspended, withdrawn, not renewed, or modified (variations). It may also have expired.
Opportunities and incentives
In accordance with the centralised procedure, the marketing authorisation applicant is responsible to submit a marketing authorisation application dossier including required documentation and data related to the medicinal product concerned. It is based on the Common Technical Document (CTD), a set of specifications for the marketing authorisation application dossier. The application is submitted under a standardised electronic format, the electronic Common Technical Document (eCTD), through an online portal to facilitate the submission process under the centralised procedure.
In order to support marketing authorisation applicants, the European Medicines Agency provides numerous procedural guidance documents and advices on its website.
The EMA has also established and developed regulatory support schemes to allow an earlier access to innovative medicinal products:early contact with regulators, PRIority Medicines (PRIME), and ATMP pilot for academia and non-profit organisations.
Early contacts with the European Medicines Agency before marketing authorization application
Any issues or questions related to the marketing authorisation application dossier can be discussed with the European Medicines Agency during the pre-submission phase as part of early contacts with regulators. Pre-submission meetings can be arranged to provide assistance and guidance to the applicant before finalising the application file.
Contacts with the European Medicines Agency during the assessment of the application
During the whole evaluation process the marketing authorisation applicant will maintain regular contacts and interactions with the European Medicines Agency, particularly with the 'Product Team' set up for each Advanced Therapy Medicinal Product.
Practical steps
An Advanced Therapy Medicinal Product has to be authorised to be placed on the market within the European Union. The centralised procedure is compulsory for its evaluation and authorisation and the single application is made to the European Medicines Agency. The single application is made to the European Medicines Agency (EMA).
The refusal of a Union marketing authorisation constitutes a prohibition on the placing on the market of the medicinal product concerned throughout the European Union.
1/ The evaluation procedure is explained in EMA procedural guidance
EMA procedural advice on the evaluation of ATMPs provides information on the composition of the assessment teams and appointments of Rapporteurs, the roles and responsibilities of all interested parties involved in the evaluation procedure for ATMPs, the timetable of the assessment, the withdrawal of Marketing Authorisation Application, and Re-examination of the opinion.
It has been updated in 2017 to clarify the evaluation procedure, and the changes have been highlighted in an EMA presentation on Adoption of the revised guidance concerning Procedural Advice on the Evaluation of Advanced Therapy Medicinal Products.
Please, view the following links for more information (EMA website):
3/ Submissions concerning marketing authorisations for ATMPs shall be made on EMA eSubmission gateway
eSubmission gateway should be used for ATMPs regarding:
Full marketing authorisation application
Extension of marketing authorisation (a variation which is listed in Annex I of Commission Regulation 1234/2008 and fulfils the conditions laid down therein)
Renewal of marketing authorisation
Type IA variation
Type IB variation
Type II variation
Periodic Safety Update Report (PSUR)
Post Authorisation Safety Studies (PASS)
Post-Authorisation Measures (PAMs)
Annual Re-Assessment
Article 20 procedures (in case of quality, safety or efficacy issues)
Transfer of marketing authorisation
Art 61(3) Notification (changing the labelling and/or package leaflet text that is not connected to the Summary of Product Characteristics)
Art. 58 (WHO) submissions (An application for a scientific opinion on the use of a human medicine intended exclusively for markets outside of the European Union. Medicines eligible for this procedure are used to prevent or treat diseases of major public health interest. (Source: EMA Glossary of regulatory terms)
Active Substance Master File (ASMF)
Plasma Master File (PMF)
In addition, a copy of eCTD format submission shall be sent to Committee for Advanced Therapies (CAT) members nominated by the European Commission (who are not linked to EMA common repository) except for Type IA or IB variation, Transfer, Art 61(3) Notification, Art. 58 (WHO) submissions, Active Substance Master File (ASMF), Plasma Master File (PMF).
An optional risk-based approach in the development of ATMPs has been established to determine the extent of quality, non-clinical and clinical data to be included in the Marketing Authorisation Application. If applied, it should follow the relevant guideline available on the EMA website here.
Re-examination of Committee for Medicinal Products for Human Use opinion and consultation of notified bodies in the case of a combined ATMPs are also detailed in procedural advices, available on the EMA website here.
7/ Validity and durability of the marketing authorisation
Validity
The authorisation ceases to be valid where the medicinal product has not been placed on the Union market within three years after authorisation or for three consecutive years, or when it has been withdrawn, revoked, suspended or not renewed.
Durability
The marketing authorisation is generally granted for five years, and it can be renewed for an unlimited period.
The Commission shall adopt a decision to vary, suspend or revoke the marketing authorisation, after it has been informed by the European Medicines Agency that a holder of a marketing authorisation failed to comply with the obligations laid down in the marketing authorisation.
European Union Legislation
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
Original text (available in the 24 official languages of the EU)
Document summary (available in the 24 official languages of the EU)
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67-128, CELEX number: 32001L0083, as amended.
Original text (available in the 24 official languages of the EU)
Document summary (available in the 24 official languages of the EU)
Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (Text with EEA relevance), OJ L 242, 15.9.2009, p. 3-12, CELEX number: 32009L0120
Directive 2009/53/EC of the European Parliament and of the Council of 18 June 2009 amending Directive 2001/82/EC and Directive 2001/83/EC, as regards variations to the terms of marketing authorisations for medicinal products (Text with EEA relevance), OJ L 168, 30.6.2009, p. 33-34, CELEX number: 32009L0053
Original text (available in the 24 official languages of the EU)
Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (Text with EEA relevance), OJ L 334, 12.12.2008, p. 7-24, CELEX number: 32008R1234
Original text (available in the 24 official languages of the EU)
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance), OJ L 136, 30.4.2004, p. 1-33, CELEX number: 32004R0726
Original text (available in the 24 official languages of the EU)
Document summary (available in the 24 official languages of the EU)
European Union Guidance
European Union guidelines
Volume 2 of the publications "The rules governing medicinal products in the European Union" contains a list of regulatory guidelines related to procedural and regulatory requirements such as renewal procedures, dossier requirements for Type IA/IB variation notifications, summary of product characteristics (SmPC), package information and classification for the supply, readability of the label and package leaflet requirements.
The Notice to Applicants below has been prepared by the European Commission, in consultation with the competent authorities of the Member States and the European Medicines Agency (EMA).
European Commission, Health and food safety, Directorate-General, Health systems and products Medicinal products, Notice to applicants, Revision 11, July 2019.
The Notice to Applicants has been prepared in accordance with Article 6 of Regulation (EC) No 726/20041 and Annex I of Directive 2001/83/EC2 on the Community code relating to medicinal products for human use. It is intended to facilitate the interpretation and application of the Union pharmaceutical legislation. It is not legally binding and, in case of doubt, reference should be made to the appropriate Union Directives and Regulations.
A new application form for variation to a marketing authorisation for medicinal products (human and veterinary) to be used in the mutual recognition and the centralised procedure has been developed; version September 2021.
European Medicines Agency, Human medicines division, EMA pre-authorisation procedural advice for users of the centralised procedure, 4 February 2022, EMA/821278/2015
This guidance document addresses a number of questions which users of the centralised procedure may have. It provides an overview of the European Medicines Agency’s position on issues, which are typically addressed during the course of pre-submission meetings.
To help developers of gene therapy medicinal products (GTMPs) and cell-based medicinal products (CBMPs) navigate the most important quality-related regulatory requirements
Document describing the procedure for the evaluation of marketing authorisation applications for ATMPs. This procedure is put in place to establish timely and effective interactions between the EMA and the different committees (CAT, CHMP and the Pharmacovigilance Risk Assessment Committee (PRAC)) in conjunction with the Applicant during the centralised evaluation of an ATMP.
Presentation providing an overview of the points raised in response to the following questions: What is the Procedural Advice on the Evaluation of ATMPs, and what is new in the updated version of the Procedural guidance for ATMPs?
Document describing the procedure for interactions between the EMA (particularly the CAT) and Notified Bodies (for medical devices) in relation to the evaluation of combined ATMPs by the CAT. It provides details of possible scenarios and timelines for such interactions within the context of Article 9 of Regulation (EC) No 1394/2007.
Procedure and guidance for the re-examination of different types of CHMP opinions, on the timetable for the applicants/MAHs involvement and for the assessment by CHMP, CAT (in case of ATMPs), rapporteurs, and SAG (Scientific Advisory Group - if deemed necessary), and on the documentation to be supplied.
Submission of applications to the European Medicines Agency, members of the Committee for Medicinal Products for Human use (CHMP), Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Advanced Therapies (CAT)
Guideline on the application of the risk-based approach in the preparation of a marketing authorisation for an ATMP. The concept of a 'Risk-based approach' has been introduced to the legislation for ATMPs with the revision of Annex 1, part IV of Directive 2001/83/EC as amended by Directive 2009/120 EC.
The European Commission services and the European Medicines Agency present wide-ranging actions and target challenges identified by various stakeholders at all stages of development, including manufacturing, early and later phases of development, marketing authorisation process and post-marketing setting.
The review process of the European Medicines Agency
Companies wishing to place an advanced therapy medicinal product on the European Economic Area submit their single marketing authorisation to the European Medicines Agency, which will validate and conduct the scientific evaluation of the application.
Guideline considering issues associated with the processing of renewals in the centralised procedure, with an aim of giving procedural guidance to marketing authorisation holders (MAHs). It has been developed by the CHMP following consultation of the interested parties and the European Commission Services.
Autorisation de mise sur le marché des médicaments - Développement de l'offre et autorisation de mise sur le marché des médicaments dans l'Union européenne - Baumevieille, Marie, et Maurain, Catherine. Propriété industrielle n° 1, Janvier 2009
Produits issus du corps humain, produits de santé et produits alimentaires - Chemtob-Concé, Marie-Catherine. Gazette du Palais, no 321 (17/11/2007): 54
Le droit des biothérapies : entre subsidiarité éthique et harmonisation technique - Peigné, Jérôme. Peigné, Jérôme. RDSS / Dalloz, no 2 (14/03/2008): 292‑306