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Specificities of the marketing authorisation dossier for biosimilar ATMPs

Introduction

A similar biological medicinal product - hereinafter ‘biosimilar’ - is a biological medicinal product (medicine containing active substances made by or derived from a biological source such as living cells or organisms) highly similar and therapeutically equivalent to an already approved biological medicinal product (the ‘reference medicinal product’) in the European Union, which has lost its patent exclusivity protection. The biological medicinal products include the Advanced Therapy Medicinal Products (ATMPs). 

The biosimilars increase patients’ access to modern and complex treatments at a reduced cost with a level of quality, safety and efficacy equivalent to the authorised reference medicinal products. 

As any other medicinal products, to market a biosimilar within the European Union the applicant needs to hold a marketing authorisation issued by the European Commission. Due to the similarity with an already authorised reference medicine on the basis of a complete dossier in accordance with Article 8 of Directive 2001/83/EC, the marketing authorisation file for a biosimilar will be a simplified one. 

Biosimilar ATMPs shall be authorised at the European Union level. However, we are not aware of any of such product having been authorised in the European Union. This is probably because the technical complexity of the ATMPs manufacturing process as well as the variability of the biological sources is reducing the potentiality for ATMPs’ biosimilarity to be undertaken and demonstrated. 

Consequently, this is a prospective section in case biosimilar ATMPs would be developed. 

Main actors

Biosimilar Marketing Authorisation Applicant: The people, pharmaceutical company applying to the European Medicines Agency for a biosimilar marketing authorisation.  

Biosimilar Marketing Authorisation holder: The people, company benefiting from a biosimilar Marketing Authorisation to distribute and sell a medicinal product highly similar and therapeutically equivalent to an already approved biological medicinal product in the European Union. 

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 evaluating the majority of applications to market biosimilars within the European Union and the European Economic Area, and in any case for biosimilar ATMPs. 

Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency: The Committee for Medicinal Products for Human Use, the EMA's medicines scientific assessment committee, will assess the biosimilar Marketing Authorisation Application and will issue a recommendation on whether the biosimilar should be authorised or not, which is sent to the European Commission. The CHMP is composed by 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. 

Biologics Working Party at the European Medicines Agency: The Committee for Medicinal Products for Human Use will be supported by the Biologics Working Party (BWP) who will provide recommendations and scientific advice on all matters relating directly or indirectly to quality and safety aspects relating to biological and biotechnological medicinal products. 

Biosimilar Medicinal Products Working Party at the European Medicines Agency: The Biosimilar Medicinal Products Working Party (BMWP) provides recommendations to the Committee for Medicinal Products for Human Use on clinical or non-clinical matters relating directly or indirectly to biosimilar medicines, and on the conduct of tests on biosimilars.  

Committee for Advanced Therapies (CAT) at the European Medicines Agency: The Committee for Advanced Therapies (CAT) is responsible for preparing a draft opinion on the quality, safety and efficacy of the biosimilar Advanced Therapy Medicinal Product for final approval by the Committee for Medicinal Products for Human Use as regards as the scientific assessment of a biosimilar marketing authorisation application.  

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 part of the assessment of every biosimilar Advanced Therapy Medicinal Product providing recommendations to the Committee for Advanced Therapies. 

European Commission: The marketing authorisation of biosimilars is granted or not by the European Commission. The European Commission’s legally binding decision is based on the Committee for Medicinal Products for Human Use’s recommendation. 

National competent authority: The national competent authority can assess and approve biosimilars, such as some low-molecular weight heparins derived from porcine intestinal mucosa. 

Definitions

Biosimilar: A biosimilar is a biological medicinal product highly similar and therapeutically equivalent to an already authorised biological medicinal product (the ‘reference medicinal product’) in the European Union for not less than 8 years and for which the data and patent protection are expired. 

Biological medicinal product: A biological medicinal product is a product, the active substance of which is a biological substance (Section 3.2.1.1, Part I, Annex I to Directive 2001/83/EC), a medicinal product containing active substances made by or derived from a biological source such as living cells or organisms. 

Reference medicinal product: A reference medicinal product is a medicinal product already authorised in accordance with European Union law. (Article 10.2(a) of Directive 2001/83/EC) 

Challenges

The applicant for a biosimilar authorisation has to demonstrate in a simplified dossier the high similarity of the biosimilar to the reference medicinal product in terms of quality and clinical aspects, notwithstanding the natural variability of biological medicinal products. Although it is not necessary to demonstrate efficacy and safety per se as this has been established already for the reference medicinal product, the applicant has to provide comprehensive comparability studies supported with pharmaceutical data to evidence and substantiate the similar nature, in terms of quality, safety and efficacy, of the biosimilar and the authorised reference medicinal product. The positive benefit-risk balance of the biosimilar will be based on the high degree of similarity in molecular and biological terms of the active substance to the reference medicinal product. 

Moreover, additional data on appropriate pre-clinical tests or clinical trials (relating to Modules 4 and 5) must be provided in case of differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product. It reduces the financial benefits of submitting a simplified dossier even though the results of other tests and trials from the reference medicinal product's dossier shall not be provided. Indeed, if required, the biosimilar ATMPs clinical studies may be as challenging and costly as for the reference ATMP, and they may have to address the same issues in enrolling a sufficient number of clinical trials participants. 

Thus, the comparability process is a tailored-made one especially for biosimilars for which the type and quantity of supplementary data to be provided is variable and depends on each biosimilar. The ability to characterise the product and to demonstrate the similar nature of the concerned products is therefore essential to benefit from the EU support for biosimilars development, while this is highly challenging for biosimilar ATMPs. 

The manufacturing of biosimilars is submitted to the European Union Good Manufacturing Practice (GMP) and European pharmacopeia in the same way as all biological medicinal products placed in the European Economic Area, and their compliance will be verified during regular GMP inspections carried out by the European Medicines Agency and national competent authority. 

Opportunities and incentives

The “biosimilar pathway” developed by the European Union increases patients’ access to safe and effective Advanced Therapy Medicinal Products at a lower cost compared to the existing reference medicinal products which have lost their exclusivity rights. These reduced cost and faster access for patients are mainly due to the simplified dossier the applicant has to submit to the European Medicines Agency’s assessment committees compared with medicinal products with full application.  

The applicant for a biosimilar authorisation has to demonstrate with comprehensive comparability studies the biosimilarity to the reference medicinal product in terms of quality and clinical aspects, notwithstanding the natural variability inherent to biological products. Due to the diversity of biosimilars, the content of the simplified file is determined on a case-by-case basis by the European Medicines Agency for biosimilar ATMPs. 

The European Medicines Agency has issued guideline on similar biological medicinal products and procedural advice on the biosimilar medicinal products marketing authorisation. 

The dossier requirements for similar biological medicinal products are laid down in Part II, Section 4 of the Annex I to Directive 2001/83/EC. 

To go further, the European Commission has published an information guide on biosimilars for healthcare professionals, and published with the European Medicines Agency an information guide for patients on biosimilars medicinal products. 

Practical steps

- Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided. 

(Article 10(4) of Directive 2001/83 EC to the European Parliament and of the Council, current version with amendments) 

Biosimilars CTD’s content 

- Similar biological medicinal products  

The provisions of Article 10(1)(a) (iii) may not be sufficient in the case of biological medicinal products. If the information required in the case of essentially similar products (generics) does not permit the demonstration of the similar nature of two biological medicinal products, additional data, in particular, the toxicological and clinical profile shall be provided. 

When a biological medicinal product as defined in Part I, paragraph 3.2 of this Annex, which refers to an original medicinal product having been granted a marketing authorisation in the Community, is submitted for a marketing authorisation by an independent applicant after the expiry of data protection period, the following approach shall be applied. 

  • Information to be supplied shall not be limited to Modules 1, 2 and 3 (pharmaceutical, chemical and biological data), supplemented with bio-equivalence and bio-availability data. The type and amount of additional data (i.e. toxicological and other non-clinical and appropriate clinical data) shall be determined on a case by case basis in accordance with relevant scientific guidelines. 
  • Due to the diversity of biological medicinal products, the need for identified studies foreseen in Modules 4 and 5, shall be required by the competent authority, taking into account the specific characteristic of each individual medicinal product. 

The general principles to be applied are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency. In case the originally authorised medicinal product has more than one indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications. 

(Annex 1, Part II, Section 4 to Directive 2001/83 EC to the European Parliament and of the Council, current version with amendments) 

1. Eligibility to the marketing authorisation procedure for biosimilars 

- To meet the legal definitions of biosimilar medicinal product and biological medicinal product as a reference medicinal product. 

  • ATMPs are considered to be biological medicinal products: Any authorised ATMP on the basis of a complete dossier (in practice, ATMP authorised under conditional marketing authorisation or marketing authorisation under exceptional circumstances should be excluded) could potentially be a reference medicinal product for a biosimilar. 
  • The biosimilar ATMP and the reference ATMP have the same safety and efficacy profile and are (generally) used to treat the same conditions. 

- At the time of submission of the biosimilar application, the protection period of the reference ATMP should have expired.  

2. Procedure for the marketing authorisation of a biosimilar 

2.1 Early dialogue prior to submission 

Early dialogue with the European Medicines Agency as early as possible is strongly recommended by the EMA.  

Aim: To discuss with the EMA, especially rapporteurs of the CHMP, PRAC and CAT about the comparability between the similar biological medicinal product and the reference medicinal product at the levels of quality, safety and efficacy, as well as the type and quantity of supplementary data to be provided.  

How:  

  • Through CHMP scientific advice or protocol assistance for orphan medicines. (More information on EMA website here on Requesting scientific advice or protocol assistance from EMA). 
  • Through a pre-submission meeting: after having created an EMA account via the EMA Account Management portal; the MAA pre-submission interactions form (available here, at the bottom of section 2.9 under “references”) shall be filled in electronically and sent to the EMA, by raising a ticket via EMA Service Desk, using the Question option “Pre-Submission Phase Request”, followed by the sub-option “Pre-Submission Interactions”. (More information on the EMA website can be found here in section 2.9.). 

2.2 Submission of an application 

When? 

  • Seven months before submission: to notify the EMA of the intention to submit a similar biological medicinal product application to allow Rapporteur /Co-Rapporteur appointment and PRAC (Co-) Rapporteurs’ identification six months prior to the marketing authorisation application intended submission date.  

How?  

  • A similar ATMP application follows the same procedure as for any other ATMP marketing authorisation application: Please see Centralised procedure and MAA file.
  • The only specificity relies on the content of the MAA file, the detailed content of each module for biosimilar application being described on EMA website (here, see in particular  2.4).  

3. Assessment of an application, granting of a marketing authorisation, and other aspects of the procedure 

  • A similar ATMP application follows the same procedure as for any other ATMP marketing authorisation application: Please see Centralised procedure and MAA file. 
  • For more details, on marketing authorisations of biosimilars, please refer to the EMA website here. 

Interactions with regulators

Interactions between the European Medicines Agency (EMA) and the biosimilar marketing authorisation applicant

The agency and its different committees are the entry point for a biosimilar Advanced Therapy Medicinal Product’ application, providing scientific support, advices and guideline to the applicant to secure the access of the biosimilar to patients.  

  • Early contacts with the EMA before the submission of the biosimilar marketing authorisation application: the applicant is encouraged to have early discussions and contacts with the European Medicines Agency, six to seven months before the submission of its request, to prepare the assessment. Pre-submission meetings give the applicant the opportunity to meet the rapporteurs from different European Medicines Agency’s scientific committees, to present the content of the biosimilar dossier.  
  • Contacts with the European Medicines Agency during the assessment of the biosimilar marketing authorisation: during the whole assessment process, the applicant for a biosimilar marketing authorisation will maintain regular contacts and interactions with the European Medicines Agency’s scientific committees, in particular to provide any explanations, documentation and data needed on the biosimilarity of the proposed biosimilar and the authorised reference medicinal product. 

Interactions between biosimilar marketing authorisation holder and the European Medicines Agency and national competent authority

The manufacturing of biosimilar Advanced Therapy medicinal Products requires tighter monitoring to ensure the safety and efficacy of the biosimilar on an ongoing basis in accordance with the European Union Good Manufacturing Practice. 

The European Medicines Agency and the national competent authority will regularly evaluate and inspect (on-site and samples analysis) the marketing authorisation holder during the five-years duration of the authorisation, to monitor the benefit-risk balance of the biosimilar, and if necessary to take regulatory actions to protect public health. 

European Union Legislation

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. 

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 

European Union Guidance

European Medicines Agency procedural advice for users of the centralised procedure for similar biological medicinal products applications, 19 August 2019, EMA/940451/2011 

The document addresses a number of questions which users of the centralised procedure may have. It provides an overview of the EMA position on issues, which are typically addressed during the course of Pre-Submission Meetings. 

Scientific guidelines: The EMA’s scientific guidelines on biosimilar help medicine developers to prepare marketing authorisation application for human medicines. 

EMA - Biosimilar medicinal products marketing authorisation 

Biosimilar Medicinal Products Working Party: Whenever work of a temporary or an ad-hoc nature is required, the Committee for Medicinal Products for Human Use (CHMP) may establish a temporary working party to conduct it. The BMWP is one of the current CHMP temporary working parties. 

Relevant literature

  1. European Medicines Agency Guideline for Biological Medicinal Products: A Further Step for a Safe Use of Biosimilars - Agostini, Carlo, Canonica, Giorgio Walter, and Maggi, Enrico. Clinical and Molecular Allergy 13, no 1 (15/05/2015): 3.
    1. Scientific abstract
  2. Biosimilars in the EU: a new guide for health professionals - Chaplin, Steve. Prescriber 28, no 10 (23/10/2017): 27‑31.
    1. Scientific abstract
  3. Biosimilars: Hope and concern - Emmanouilides, Christos E, Karampola, Maria I, and Beredima, Maria. Journal of Oncology Pharmacy Practice 22, no 4 (08/2016): 618‑624.
    1. Scientific abstract
  4. Biosimilars: A Regulatory Review - Furlani, Pia. Drug Information Journal 42, no 5 01/09/2008): 477‑485.
    1. Scientific abstract
  5. Biosimilar Naming: A Call for Uniformity in a Complex Field - Genovese, Jacqueline. Brooklyn Journal of International Law 41, no 1 (01/01/2015): 292‑327.
    1. Scientific abstract
  6. The Future of Generic Biologics: Should the United States "Follow-on" the European Pathway? - Kaldre, Ingrid. Duke Law & Technology Review, no 9 (2008): 13.
    1. Scientific abstract
  7. Biosimilars – Science, Status, and Strategic Perspective - Kresse, Georg-Burkhard. European Journal of Pharmaceutics and Biopharmaceutics 72, no 3 (01/08/2009): 479‑486.
    1. Scientific abstract
  8. Biosimilar Regulation in the EU - Kurki, Pekka, and Ekman, Niklas. Expert Review of Clinical Pharmacology 8, no 5 (3/09/2015): 649‑659.
    1. Scientific abstract
  9. Is There Any Regulatory Approval Pathway for Biosimilars? - Manley, Maria Isabel, and Benning-Prince, Sharon. Westlaw UK ». Pharmaceutical Law Insight 3 (2007): 8‑11.
    1. Scientific abstract: Discusses problems that biosimilar biotechnology products face when attempting to obtain simplified access to the EU market. Refers to the EU legal regime and ways of obtaining market authorisation, with particular reference to Art.8 of European Parliament and Council Directive 2004/27. Considers the abridged application favoured by generic manufacturers and the framework relating to biosimilar medicinal products.
  10. Barriers to Biosimilar Approval: Creating Clarity Through the Publication of Product-Class Specific Guidances - McEnrue, Martin. Maryland Journal of International Law 31 (2016): 311‑330. 
  11. Innovation and competition in advanced therapy medicinal products - Enrique Seoane‐Vazquez, Vaishali Shukla, and Rosa Rodriguez‐Monguio. EMBO Molcecular Medicine. (2019) 11: e9992
  12. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework - Prugnaud, Jean-Louis. British Journal of Clinical Pharmacology 65, no 4 (2008): 619‑620.
  13. Economics as a Guide to Developing Public Policies for Biosimilar Pharmaceutical Products - Rozek, Richard P. Queen Mary Journal of Intellectual Property, 2, no 4 (2012): 363‑375.
    1. Scientific abstract
  14. Biosimilar Warfare: The Arrival of Generic Biopharmaceuticals - The Omnitrope Decision - Teare, Isabel. BIO-Science Law Review (BSLR) 8, no 1 (06/005): 9‑13.
  15. Development and Regulation of Biosimilars: Current Status and Future Challenges - Tsiftsoglou, Asterios S., Ruiz, Sol, and Schneider, Christian K. BioDrugs 27, no 3 (01/06/2013): 203-211.
    1. Scientific abstract
  16. Biosimilars in the EU: Nonclinical and Early Clinical Development - Voisin, Emmanuelle, Uguen, David, and Deneux, Marie. Drug Information Journal 44, no 6 (01/11/2010): 741‑743.
    1. Scientific abstract
  17. EMEA: biosimilars: the way forward in Europe - Dipti Dashore and Simon Gohen. BIO-Science Law Review 2005/06, 8(1), 44-47
    1. Scientific abstract: Reviews the development of an EU policy on "biosimilars", similar, generic versions of pre-existing biopharmaceuticals. Includes discussion of: (1) the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP)'s approval of the biosimilars Omnitrope and Valtropin; (2) European Parliament and Council Directive 2001/83 as amended by Directive 2004/27; (3) the CHMP Guideline on Similar Biological Medicinal Products; and (4) related CHMP guidelines. 
  18. Biosimilars approval process - Zuñiga, Leyre, and Calvo, Begoña. Regulatory Toxicology and Pharmacology 56, no 3 (01/04/2010): 374-377.
    1. Scientific abstract
  19. The regulatory framework of biosimilars in the European Union - Minghetti, Paola, Rocco, Paolo, Cilurzo, Francesco, Del Vecchio, Lucia, and Locatelli, Francesco. Drug Discovery Today 17, no 1 (01/01/2012): 63-70
    1. Scientific abstract
  20. Drug safe harbour provisions in the USA and Europe: implications for the emerging biosimilars - Kretzschmar, Marcus D. Journal of Intellectual Property Law & Practice 9, no 4 (04/2014): 298-311.
    1. Scientific abstract
  21. Demonstration of Biosimilarity, Extrapolation of Indications and Other Challenges Related to Biosimilars in Europe - Tsiftsoglou, Asterios S., Trouvin, Jean Hugues, Calvo, Gonzalo, and Ruiz, Sol. BioDrugs 28, no 6 (1/12/2014): 479-486.
    1. Scientific abstract
  22. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways - Schiestl, Martin, Zabransky, Markus, and Sörgel, Fritz. Drug Design, Development and Therapy 11 (16/05/2017): 1509-1515.
    1. Scientific abstract
  23. Regulatory Information and Guidance on Biosimilars and Their Use Across Europe: A Call for Strengthened One Voice Messaging - Barbier, Liese, Mbuaki, Allary, Simoens, Steven, Declerck, Paul, Vulto, Arnold G., and Huys, Isabelle. Frontiers in Medicine (9/03/2022): Published online.
    1. Scientific abstract
  24. Guidelines EMA pour le développement de médicaments biosimilaires - Vleminckx, C., et Ehmann, F. Oncologie 13, no 5 (01/05/2011): 191-195.
    1. Scientific abstract
  25. Biosimilaires : le point sur les notions d’interchangeabilité et de substitution - Fontès Le Gal, Cécile, et Chiappin, Mathilde. Revue générale de droit médical 7, no 28 (01/2020): 245‑258.
    1. Scientific abstract  
  26. L’encadrement des médicaments biosimilaires à la croisée des logiques sanitaires et économiques - Juillard-Condat, Blandine, et Taboulet, Florence. Journal international de bioéthique et d’éthique des sciences 29, no 2 (2018): 87‑111.
    1. Scientific abstract
  27. Qu’est-ce qu’un biosimilaire ? Jusqu’où va la similarité ? - Gravel, P., et Le Cotonnec, J.-Y. Oncologie 13, no 5 (01/05/2011): 183‑190.
    1. Scientific abstract
  28. Les biosimilaires, des biomédicaments comme les autres ? - Mrozovski, Jean Michel. Actualités Pharmaceutiques 58, no 586 (01/05/2019): 44‑47.
    1. Scientific abstract
  29. Impact de la réglementation sur l’accès au marché européen des médicaments biosimilaires. Des arbitrages nécessaires entre critères sanitaires et économiques au regard des approches juridiques internationales - Tabutiaux, Agnès, et Pecyna, Joanna. Revue générale de droit médical 5, no 26 (01/2018): 249‑267.
    1. Scientific abstract
  30. Entre difficultés de statuer sur la question de substitution et incitations financières à leur prescription : quelle régulation optimale pour les médicaments biosimilaires ? - Bocquet, François. Revue générale de droit médical 7, no 28 (01/2020): 227‑244.
    1. Scientific abstract
  31. Les aspects juridiques du développement des médicaments biosimilaires - Bocquet, François, et Paubel, Pascal. RDSS Dalloz, no 1 (19/02/2012): 121-133.
    1. Scientific abstract: Les brevets de nombreux médicaments biologiques innovants, couvrant un large éventail de pathologies aiguës et souvent invalidantes, tombent aujourd'hui dans le domaine public. Après les génériques copiant les médicaments d'origine chimique, le marché des biomédicaments s'ouvre désormais à la concurrence de « copies » avec les biosimilaires. Le présent article a pour objet d'analyser, sur le plan juridique et scientifique, ce qui rapproche les biosimilaires et les génériques, mais également ce qui les distingue. 

More

Consensus information paper prepared by the project group Market Access and Uptake of Biosimilars and adopted by the Steering Group of the Process for Corporate responsibility in the field of Pharmaceuticals with the contribution of the European Medicines Agency, 2013 

Biosimilar medicines Multistakeholder Event - 13 December 2022

  • This event was aimed for discussing the potential of biosimilars for health systems sustainability, and educating/raising awareness.

EMA product-specific biosimilar guidelines: 

Acknowledgements

Published: 17/02/2023

Authors: 

Luc-Sylvain Gilbert, EuroGCT ELSI Legal Information Officer,

and Aurélie Mahalatchimy, EuroGCT WP4 Convenor 

Reviewed by:

Under internal review by EuroGCT Commercialisation Working Group.

Parcours de développement

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