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Marketing Authorisation Application file for ATMPs

Introduction

Any company wishing to market Advanced Therapy Medicinal Products (ATMPs) within the European Union (EU) must hold a marketing authorisation issued by the European Commission under the “centralised procedure” following the scientific assessment of the application file by the European Medicines Agency (EMA).

The companies have to submit a single marketing authorisation application file, a dossier containing documentation and data related to the medicinal product, to the European Medicines Agency. This file is based on the Common Technical Document (CTD) including five parts: Module 1 for regional administrative information, 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). While Module 1 is region specific, Modules 2 to 5 are common for all regions and correspond to the mandatory format for marketing authorisation applications in the EU and Japan (this format is also strongly recommended for new drug applications in the USA).

Main actors

Marketing Authorisation Applicant: The people or company applying for a marketing authorisation for a medicinal product.

Marketing Authorisation holder: The people or company benefiting from a marketing authorisation (here for ATMPs, submitted through the “Centralised procedure") to distribute and sell a medicinal product in the European Union.

European Medicines Agency: Under the centralised procedure, companies submit to the European Medicines Agency a single marketing authorisation application file to be assessed by the Committee for Medicinal Products for Human Use (CHMP), the European Medicines Agency's medicines scientific assessment committee.

The European Medicines Agency is also responsible for the scientific assessment of Advanced Therapy Medicinal Products (ATMPs) manufactured at the industrial scale and intended to be placed on the European Union market. In this case, the Committee for Advanced Therapies (CAT) prepares a draft opinion on the quality, safety and efficacy of ATMPs for final approval by the CHMP. The CHMP will then issue and send to the European Commission a final recommendation on whether the medicinal product should be authorised or not.

European Commission: Once the EMA’s Committee for Medicinal Products for Human Use has provided its recommendation, the marketing authorisation of an Advanced Therapy Medicinal Product is granted or not by the European Commission.

Definitions

Marketing Authorisation Application file: Marketing authorisation application requires from the applicant the submission of a file containing documentation and data related to the medicinal product to be authorised. The file must comply with the Common Technical Document (CTD), a set of specifications for the marketing authorisation application dossier. Under the centralised procedure the application is submitted under a standardised electronic format, the electronic Common Technical Document (eCTD), through an online portal (eSubmission managed by EMA). 

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 high quality, and safety and efficacy regarding the benefit/risk balance that shall be positive for the medicinal products.

For Advanced Therapy Medicinal products, a single application is submitted to the European Medicines Agency under the centralised procedure. It 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 within the European Union Member States, Iceland, Norway and Liechtenstein for a five-years period.

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 the scientific assessment of the European Medicines Agency (EMA).

Common Technical Document: A common format for submitting scientific information when applying for marketing authorisations in the European Union, Japan and the United States. (Source: EMA Glossary of regulatory terms)

Electronic common technical document: A common technical document in electronic format. Abbreviated as eCTD. (Source: EMA Glossary of regulatory terms)

Challenges

The marketing authorisation applicants have to provide to the European Medicines Agency a complex, complete and widely-documented dossier (up to 1000 pages) in the required timetable, and which complies with the five modules of the Common Technical Document.

Opportunities and incentives

The marketing authorisation file must comply with the Common Technical Document (CTD), a set of specifications in an internationally agreed format for the preparation of the marketing authorisation application dossier. The CTD is organised into five modules to which all documents and data have to be assigned. Module 1 is region specific and modules 2, 3, 4, and 5 are common for all regions. The majority of the documentation and data relating to the quality, safety, and efficacy of the medicinal products are located in modules 3 to 5.

The submission process of a marketing authorisation under the centralised procedure is organised via the electronic Common Technical Document (eCTD), a standardised electronic format. The full compliance with the Common Technical Document requirements allows the scientific assessment of the application to be carried out by the relevant committees of the European Medicines Agency, and prevents the application dossier from being rejected or re-examined for being incomplete. To facilitate the submission of applications, electronic submissions have been developed via the EMA online portal: eSubmission.

In order to support marketing authorisation applicants in the submission process, the European Medicines Agency provides numerous recommendations and guidance on the presentation and content of the marketing authorisation dossier, the organisation of the Common Technical Document and Electronic Common Technical Document on its website.

Practical steps

The general practical steps are described under the ‘centralised procedure’ entry, and the practical process has to be followed on eSubmission.

Complementary information on what is required in accordance with the European Union legislation is provided below.

  1. Presentation and content of the marketing authorisation file for ATMPs as for other medicinal products for human use

The format requirements (Modules 1, 2, 3, 4 and 5) described in Part I of the Annex to Directive 2001/83/EC shall be followed for marketing authorisation applications for advanced therapy medicinal products.

The technical requirements for Modules 3, 4 and 5 for biological medicinal products, as described in Part I of this Annex, shall apply to advanced therapy medicinal products.

(Annex 1, Part IV, ‘Introduction and general principles’, to Directive 2001/83/EC of the European Parliament and of the Council)

  1. Specific requirements concerning the Common Technical Document for advanced therapy medicinal products

Part IV of the Annex to Directive 2001/83/EC (current version with amendments from Commission Directive 2009/120/EC) deals specifically with ‘Advanced therapy medicinal products’. It contains specific requirements for all advanced therapy medicinal products, as well as for gene therapy medicinal products (using human autologous or allogeneic system, or xenogeneic system), cell therapy medicinal products and tissue engineered products both of human or animal origin, and combined advanced therapy medicinal products separately.

Part IV explains how the requirements in Part I apply to advanced therapy medicinal products, and provides additional requirements where appropriate. After an introduction and updated definitions of gene therapy medicinal product and somatic cell therapy medicinal product, Part IV contains specific requirements regarding Modules 3, 4, and 5 for ATMPs.

Any deviation from the requirements of the Annex to Directive 2001/83/EC shall be scientifically justified in Module 2 of the application dossier. The risk-based approach for advanced therapy medicinal products, when applied, shall also be included and described in Module 2.

For more details, please see Annex 1, Part IV, of Directive 2001/83/EC of the European Parliament and of the Council.

Interactions with regulators

Early contacts with the European Medicines Agency before the submission of the marketing authorisation application file

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 are arranged to provide assistance and guidance to the applicant before finalising the marketing authorisation application file.

See also: Research & Innovation and "Early interactions with regulators" section

Contacts with the European Medicines Agency during the assessment of the marketing authorisation application file

During the entire evaluation process, the marketing authorisation applicant will maintain regular contacts and interactions with the European Medicines Agency, in particular to provide any additional answers or supporting documentation needed.

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

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.

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

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

European Union Guidance

European Union documents

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.

This Notice to Applicants (NTA) has been prepared by the European Commission in consultation with the competent authorities of the Member States, the European Medicines Agency and interested parties in order to fulfil the Commission’s obligations with respect to article 6 of Regulation (EC) No. 726/2004, and with respect to the Annex I to Directive 2001/83/EC as amended.

Electronic Application Forms: The use of the electronic Application Forms (eAF) is mandatory for all procedures from 1 January 2016. The eAFs must be used for all applications: authorisations, variations and renewals.

User guide for the electronic application form: The user guide and regular update for the electronic application form are available on eSubmission website.

Electronic Common technical Document (eCTD)

Content and requirements of application forms

European Medicines Agency

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceuticals and develop ICH guidelines applied by regulatory authorities.

More marketing authorisation guidance documents on EMA website here.

Relevant literature

  1. Marketing Authorisation Applications Submitted to the European Medicines Agency by Small and Medium-Sized Enterprises: An Analysis of Major Objections and Their Impact on Outcomes - Amaouche, Nadia, Hélène Casaert Salomé, Olivier Collignon, Mariana Roldao Santos, and Constantinos Ziogas. Drug Discovery Today 23, no 10 (10/2018): 1801‑1805
  2. The Electronic Common Technical Document - From Design to Submission - Cartwright, Anthony C. International Journal of Pharmaceutical Medicine 20, no 3 (1/06/2006): 149‑158
  3. Hurdles in Gene Therapy Regulatory Approval: A Retrospective Analysis of European Marketing Authorization Applications - Carvalho, Marta, Ana Paula Martins, and Bruno Sepodes.Drug Discovery Today 24, no 3 (03/2019): 823‑828
  4. View of Drug approval process in US, Europe and India and its regulatory requirements: A Review - Chakraborty, Krishnasis, and Kavita Yadav. International Journal of Drug Regulatory Affairs., s. d., (09/2019): 31-39
  5. International Marketing Applications according to the ICH CTD Format:  Comparison of Structure and Document Requirements - Gelman, Rita Segal. The Quality Assurance Journal 10, no 2 (2006): 111‑120
  6. An Overview of the Common Technical Document (CTD) Regulatory Dossier - Jordan, Debbie. Medical Writing 23, no 2 (1/06/ 2014): 101‑105 
  7. Internationalization of Regulatory Requirements - Juillet, Y. Fundamental & Clinical Pharmacology 17, no 1 (2003): 21‑25
  8. The Value and Benefits of the International Conference on Harmonisation to Drug Regulatory Authorities: Advancing Harmonization for Better Public Health  - Molzon, Justina, A Giaquinto, L Lindstrom, T Tominaga, M Ward, P Doerr, L Hunt, et L Rago. Clinical Pharmacology & Therapeutics 89, no 4 (2011): 503‑512
  9. The Common Technical Document: The Changing Face of the New Drug Application -  Molzon, Justina. Nature Reviews Drug Discovery 2, no 1 (01/2003): 71‑74
  10. The International Conference on Harmonization Common Technical Document - Molzon, Justina A. Food and Drug Law Journal 60, no 3 (2005): 447‑452
  11. Preparing the Common Technical Document for Registration of Pharmaceuticals for Human Use (CTD) - Insights and Recommendations - Roth, Robert I.  Drug Information Journal 42, no 2 (03/2008): 149‑159
  12. Dossier for Marketing Authorization in the European Union- Todić, Maida. Bosnian Journal of Basic Medical Sciences 3, no 1 (03/2003): 56‑60

Acknowledgements

Published: 08/11/2022

Last updated: 23/01/2024

Authors:

Luc-Sylvain Gilbert, EuroGCT information officer on Ethical, Legal and Societal Issues

Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence, France

Reviewed by:

Under internal review by EuroGCT Commercialisation Working Group.

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