Dear Mr Sinčić,
Further to your phone call with Ms Boone yesterday, she asked me to follow up with you with more information on the following aspects:
1)The requirement for the Marketing Authorisation Holder to be established within the EEA: has been established by Article 2 of Regulation (EC) No 726/2004 (https://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1564391536397&uri=CELEX:02004R0726-20190330) which states that: “The holder of a marketing authorisation for medicinal products covered by this Regulation must be established in the Union. The holder shall be responsible for the placing on the market of those medicinal products, whether he does it himself or via one or more persons designated to that effect.”
This establishment requirement has been further clarified in the European Commission Notice to Applicants Chapter 1 – Marketing Authorisation :
“The marketing authorisation holder must be established within the EEA. Article 54 of the Treaty of the functioning of the European Union (Chapter 2 Right of establishment) reads: ‘Companies or firms formed in accordance with the law of a Member State and having their registered office, central administration or principal place of business within the Union must, for the purposes of this Chapter, be treated in the same way as natural persons who are nationals of Member States. “Companies or firms” means companies or firms constituted under civil or commercial law, including co-operative societies, and other legal persons governed by public or private law, save for those which are non-profit-making’. For the purpose of applying this definition in the context of the pharmaceutical legislation it should be clarified that ‘non profit-making’ organisations can be marketing authorisation holders”.
1.2) How can I tell if I am duly established in the EEA as an applicant? Rev. Oct 2020
The Marketing Authorisation Holder (MAH) is the person who holds the authorisation to place a medicinal product on the market and is legally responsible for marketing the medicinal product. The granting of a marketing authorisation by a competent authority does not discharge the holder from civil and criminal liability as provided for by the Union law. The MAH may be a natural or legal person. The MAH of a centralised marketing authorisation must be established within the EEA (Norway, Iceland, Liechtenstein and the Member States of the European Union). In order to fulfil this requirement, the MAH must have a permanent legal structure which is formed in accordance with the law of an EEA Member State and which allows the concerned holder to assume the duties and responsibilities as well as to perform the tasks laid down by Union law. Companies or firms formed in accordance with the law of a Member State and having their registered office, central administration or principal place of business within the EEA will be treated in the same way as natural persons who are nationals of Member States. An applicant should demonstrate that it is duly established in the EEA. A proof of establishment from the applicant company is required by the Agency in order for an application to be validated (e.g. in France, an extrait du egister du commerce et des sociétés, in Belgium an extract from Crossroad Database of Belgian Enterprises apostilled by the Federal Ministry of Belgium). This proof of establishment should be not older than 6 months. This will enable the Agency to confirm that the information provided is up to date. The proof of establishment should be included in annex 5.3 of the application form (available in the Notice to Applicants (NTA) Volume 2B – Application Form: Module 1.2). It should be emphasised that while the MAH may delegate certain activities to third parties, the MAH remains responsible for assuring all the obligations imposed on MAHs by the European legislation and by national law, as applicable. References: • Regulation (EC) No 726/2004 • The Rules governing Medicinal Products in the European Union, Volume 2A, Notice to Applicants, Chapter 1 • Directive 2001/83/EC
2) Obligations for Marketing Authorisation Holders (MAHs):
Aa list of obligations for MAHs is included in the Annex II to Regulation (EC) No 726/2004, which I hereinafter extract for ease of reference:
-the obligation to submit complete and accurate particulars and documents in an application for marketing authorisation submitted to the Agency or in response to obligations laid down in this Regulation and in Regulation (EC) No 1901/2006 to the extent that the failure to comply with the obligation concerns a material particular;
(2) the obligation to comply with conditions or restrictions included in the marketing authorisation and concerning the supply or use of the medicinal product for human use, as referred to in point (b) of Article 9(4) and in the second subparagraph of Article 10(1);
(3) the obligation to comply with conditions or restrictions included in the marketing authorisation with regard to the safe and effective use of the medicinal product for human use as referred to in points (aa), I, (ca), (cb) and (cc) of Article 9(4) and in Article 10(1);
(4) the obligation to introduce any necessary variation to the terms of the marketing authorisation to take account of technical and scientific progress and enable the medicinal products for human use to be manufactured and checked by means of generally accepted scientific methods, as provided for in Article 16(1);
(5) the obligation to supply any new information which may entail a variation to the terms of the marketing authorisation, to notify any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product for human use is marketed, or to supply any information that may influence the evaluation of the risks and benefits of the product, as provided for in Article 16(2);
(6) the obligation to keep product information up to date with current scientific knowledge, including the conclusions of the assessment and recommendations made public on the European medicines web-portal, as provided for in Article 16(3);
(7) the obligation to provide, at the request of the Agency, any data demonstrating that the risk-benefit balance remains favourable, as provided for in Article 16(3a);
(8) the obligation to place the medicinal product for human use on the market in accordance with the content of the summary of the product characteristics and the labelling and package leaflet as contained in the marketing authorisation;
(9) the obligation to comply with the conditions referred to in Article 14(8)and Article 14-a;
(10) the obligation to notify the Agency of the dates of actual marketing and of the date when the medicinal product for human use ceases to be on the market, and to provide to the Agency data relating to the volume of sales and the volume of prescriptions of the medicinal product for human use, as provided in Article 13(4);
(11) the obligation to operate a comprehensive pharmacovigilance system for the fulfilment of pharmacovigilance tasks, including the operation of a quality system, maintenance of a pharmacovigilance system master file and performance of regular audits, in accordance with Article 21 of this Regulation in conjunction with Article 104 of Directive 2001/83/EC;
(12) the obligation to submit, at the request of the Agency, a copy of the pharmacovigilance system master file, as provided for in Article 16(3a);
(13) the obligation to operate a risk management system as provided for in Article 14a and Article 21(2) of this Regulation in conjunction with Article 104(3) of Directive 2001/83/EC and Article 34(2) of Regulation (EC) No 1901/2006;
(14) the obligation to record and report suspected adverse reactions for medicinal products for human use, in accordance with Article 28(1) of this Regulation in conjunction with Article 107 of Directive 2001/83/EC;
(15) the obligation to submit periodic safety update reports, in accordance with Article 28(2) of this Regulation in conjunction with Article 107b of Directive 2001/83/EC;
(16) the obligation to conduct post-marketing studies, including post-authorisation safety studies and post-authorisation efficacy studies, and to submit them for review, as provided for in Article 10a of this Regulation and Article 34(2) of Regulation (EC) No 1901/2006;
(17) the obligation to ensure that public announcements relating to information on pharmacovigilance concerns are presented objectively and are not misleading and to notify them to the Agency, as provided for in Article 22 of this Regulation and Article 106a(1) of Directive 2001/83/EC;
(18) the obligation to comply with the time limits for initiating or completing measures specified in the Agency’s decision on deferral following the initial marketing authorisation of the medicinal product for human use concerned and in accordance with the definitive opinion referred to in Article 25(5) of Regulation (EC) No 1901/2006;
(19) the obligation to place the medicinal product for human use on the market within two years of the date on which the paediatric indication is authorised, as provided for in Article 33 of Regulation (EC) No 1901/2006;
(20) the obligation to transfer the marketing authorisation or to allow a third party to use documentation contained in the file of the medicinal product, as provided for in the first paragraph of Article 35 of Regulation (EC) No 1901/2006;
(21) the obligation to submit paediatric studies to the Agency, including the obligation to enter information on third country clinical trials into the European database, as provided for in Articles 41(1) and (2), 45(1) and 46(1) of Regulation (EC) No 1901/2006;
(22) the obligation to submit an annual report to the Agency as provided for in Article 34(4) of Regulation (EC) No 1901/2006 and to inform the Agency in accordance with the second paragraph of Article 35 of that Regulation.
3) Information on whether an applicant can submit any clinical trials data that they have not done themselves, e.g. studies from universities, hospitals etc.
As Ms Boone has confirmed to you already, this is indeed possible and an applicant can submit the results of studies which they have not performed themselves. This can take many forms. It may be trials conducted by another developer (e.g. pharma company) with whom the applicant has a co-development or licensing agreement or from whom they have purchased the rights to the medicine concerned. They may also include studies conducted by health bodies/academia either in cooperation or independently. In general these are submitted as part of a dossier which nonetheless does contain clinical trials conducted by the applicant or a licensing partner/early developer.
In each case the clinical trials must meet the scientific and ethical standards that are applicable to clinical trials in the context of a marketing authorisation application, including those of Good Clinical Practice.
There is no specific EMA guidance for the above, as this is clearly explained in the existing legislation, and in particular in Annex I of Directive 2001/83/EC:
Introduction and general principles
“(8) All clinical trials, conducted within the European Community, must comply with the requirements of Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (1). To be taken into account during the assessment of an application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to be used in the European Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the Declaration of Helsinki.”
In addition, for clinical trials conducted outside the EU and included in a marketing authorisation application, according to Article 8(ib) of Directive 2001/83/EC, the application for a marketing authorisation application should contain a statement to the effect that clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC.
I hope this helps, please do not hesitate to let us know if you have further questions.
Institutional Liaison Officer
Institutional and Policy (AF-IP) Department
Dec 10, 2021, 5:47 PM