Pre-authorisation procedural guidance is available from the European Medicines Agency (EMA) on initial marketing authorisation procedures for centrally authorised veterinary medicines under the Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6).

The Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) applies from 28 January 2022.

These Q&As provide an overview of EMA's advice on issues that are typically addressed in discussions or meetings with applicants before submitting a marketing authorisation application and throughout the assessment.

They are updated regularly to reflect new developments, to include guidance on further pre-authorisation procedures and to reflect the implementation of new European legislation.

New or revised Q&As are marked as 'New' or 'Rev.' with the relevant date.

Separate guidance is available for marketing authorisation applications submitted on or before 27 January 2022 to be concluded in accordance with Directive 2001/82/EC and Regulation (EU) 726/2004:

Pre-submission meetings

The Agency emphasises the importance of pre-submission meetings, around seven months prior to the anticipated date of submission of the application.

These are a vital opportunity for applicants to obtain procedural, regulatory and legal advice from the Agency.

These questions and answers and successful pre-submission meetings should enable applicants to submit applications that conform with regulatory requirements and can be validated speedily.

Pre-submission meetings also enable applicants to establish contact with the Agency staff who will be involved with the application.

To request a pre-submission meeting:

Veterinary pre-submission meeting request form - in accordance with Regulation (EU) No 2019/6

Reference Number: EMA/340680/2021

English (EN) (328 KB - DOC)

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If an issue is not resolved by the Q&As below, please submit a question via AskEMA.

1. Early considerations and steps prior to submission

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 applicant and the MAH of a centralised marketing authorisation must be established within the European Economic Area (EEA: member states of the European Union, Norway, Iceland and Liechtenstein).

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 shall be treated in the same way as natural persons who are nationals of member states. An applicant should demonstrate that they are 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 registre 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.

It should be emphasised that while the MAH may delegate certain activities to third parties, the MAH remains responsible for ensuring the performance of all obligations imposed on MAHs by the European legislation and by national law, as applicable.

References:

Incentives and assistance available for SMEs focus on reducing financial and administrative entry hurdles for SMEs in pre-marketing authorisation procedures such as scientific advice, the application for marketing authorisation and inspections.

These include:

  • Regulatory, administrative and procedural assistance from the EMA’s SME Office.
  • Fee reductions for pre- and post-authorisation regulatory procedures including scientific advice, scientific services, inspections and maximum residue limits (MRL) applications.
  • Fee exemptions for certain administrative services (excluding parallel distribution).
  • Deferral of the fee payable for an application for marketing authorisation or related inspection (pre-authorisation).
  • Conditional fee exemption where scientific advice provided by CVMP is followed and a marketing authorisation application via the centralised procedure is not successful.
  • Assistance with translations into all EU languages of the product information submitted in a centralised application for marketing authorisation.

In determining which companies are eligible for SME incentives, the EMA applies the EU-definition of micro, small and medium-sized enterprises provided in Commission Recommendation 2003/361/EC.

Companies are classified according to their size (micro, small or medium):

  • Micro-sized enterprises employ less than 10 persons, and have an annual turnover or balance sheet total not exceeding €2 million;
  • Small-sized enterprises have fewer than 50 employees, and an annual turnover or balance sheet total of not more than €10 million;
  • Medium-sized enterprises have less than 250 employees and an annual turnover of not more than €50 million, or an annual balance sheet total of not more than €43 million

and according to their ownership structure (type: autonomous, partner or linked).

Depending on the type of enterprise, some or all of the headcount and financial data from other partner or linked enterprises may need to be taken into account when calculating whether the SME criteria are met.

Further information on the definition of an SME is available in “User guide to the SME definition”, published by the European Commission (see link under References below).

An SME application (declaration form and supporting documentation) should be submitted to the EMA’s SME Office prior to requesting financial or administrative assistance from the Agency. Detailed instructions are available on the dedicated SME webpage under section ‘Applying for SME status’.

SME Office

The SME office was set up by Commission Regulation (EC) No 2049/2005 (‘the SME Regulation’) to provide advice, guidance and assistance to SMEs who want to develop and market medicines in the European Union (EU) and the European Economic Area (EEA). The office facilitates communication with SMEs through dedicated personnel within the Agency, responds to practical or procedural enquiries, monitors applications, and organises training and education events for SMEs.

Fee Reductions/Deferrals

It should be noted that fee reductions and deferrals can only be considered once the applicant has been assigned SME status by the EMA and are subject to the SME status remaining valid at the time that their application or request is validated by the Agency. Fee reductions and fee deferrals will not be granted retrospectively. Further information on fee incentives is available on the SME Office website (Financial advantages of SMEs) and under ‘Fees payable to the European Medicines Agency’.

Translation assistance

Because translating product information into all EU languages represents a considerable financial and administrative burden to SMEs, the EMA provides free-of-charge translations of the product information (summary of product characteristics, conditions of the marketing authorisation, label and package leaflet) required for the granting of an EU marketing authorisation. The applicant remains responsible for providing Norwegian and Icelandic translations according to the timelines and for translations into all languages in the post-authorisation phase.

Due to the timelines required to translate the product information, the Agency will initiate translations through the Centre for Translation (CdT) in Luxembourg prior to the CVMP opinion (normally around day 180 of the procedure) and which will be finalised by CdT by day 215. These translations will then be circulated to member states for quality review in the post-opinion phase (see also Linguistic review process of product information). To be eligible for translation assistance the applicant’s SME status must be valid at the time the translations are initiated.

Companies wishing to benefit from SME incentives should consult the SME Office website (Supporting SMEs). This section provides useful information on how to request SME status, and provides links to information sources (e.g. the User Guide for Micro, Small and Medium-sized Enterprises).

For access to incentives following mergers, acquisitions or product out-licensing, see sections 2.4.1 and 2.5.3 of the User Guide for Micro, Small and Medium-sized Enterprises. If the company does not meet the SME criteria or a product is out-licensed during a procedure to another company which does not meet the SME criteria, there will be no access to the provisions of the SME Regulation or to any other SME specific incentives with effect from the date of change in ownership or the date of signature of the licensing agreement. EMA strongly advises companies to contact the SME office to discuss these specific cases.

For further information or requests please contact:

SME Office helpline

Tel. +31 (0)88 781 8787

E-mail: sme@ema.europa.eu

For further information please see the User guide for micro, small and medium-sized enterprises on the Agency website.

References:

In order to provide support to medicines innovation in the EU, the EMA has established an internal multidisciplinary group including scientific, regulatory and legal competencies, the Innovation Task Force (ITF), creating a forum for early dialogue with applicants. ITF members are scientific and legal administrators appointed from different subject matter areas of the Agency. To fulfil its task the ITF consults, as appropriate, EMA scientific committees and working parties or individual experts.

The scope of the ITF activities encompasses emerging therapies (i.e. gene therapy, cell therapy and engineered tissues), emerging technologies (i.e. new development strategies, new manufacturing approaches) and borderline therapeutics (e.g. combination of pharmaceuticals and devices) for which there is no established EMA scientific, legal and regulatory experience.

Support available to applicants includes:

  • General queries relating to emerging therapies and technologies
  • Briefing meetings, aiming to provide an early guidance and information, in liaison when needed with relevant EMA scientific committees, working parties or experts. Additionally, the briefing meetings complement and reinforce existing formal regulatory procedures, e.g. scientific advice.
  • Regulatory advice in relation to EMA procedures, e.g. marketing authorisation, scientific advice.

As such, ITF provides support to applicants during the early stages of their veterinary medicinal product development. Developers of innovative veterinary medicines can send their enquiries regarding suitability of the ITF support in respect to their product or requests for ITF briefing meetings to ITFvet@ema.europa.eu.

For more information on Innovation Task Force and on how to request a briefing meeting or regulatory advice, refer to the Innovation in medicines webpage. 

 

Reference:

Article 5(5) of Regulation (EU) 2019/6 states that "a marketing authorisation for a veterinary medicinal product intended for one or more food-producing animal species may only be granted if the pharmacologically active substance is allowed in accordance with Regulation (EC) No 470/2009 and any acts adopted on the basis thereof for the animal species concerned".

Pharmacologically active substances for which MRLs have been established are listed in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 in alphabetical order.

Information on the establishment of MRLs can be found on the European Medicines Agency website on Maximum Residue Limits webpage.

Prior to initiating a procedure for a marketing authorisation for a veterinary medicinal product, applicants should establish whether the product in question, if intended for use in food-producing animals, complies with the requirements laid out in Article 5(5) of Regulation (EU) 2019/6, i.e. MRL entries need to be established for the relevant substances in the product.

Many excipients and adjuvants have been included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 with a "No MRL required" status, and others have been entered into the list of Substances considered as not falling within the scope of the Regulation (EC) No 470/2009 with regard to residues of veterinary medicinal products in foodstuffs of animal origin, often referred to as the "out of scope" list.

An excipient for a new product that is not listed in either Table 1 of the Annex to Commission Regulation (EC) No 37/2010 or the "out of scope" list can only be used if it has been demonstrated that the substance is not expected to show pharmacological activity or if, after an evaluation for the establishment of MRLs, it is included in Table 1 of the Annex to Regulation (EU) No 37/2010.

Guidance on the information required for inclusion of an excipient in the "out of scope" list is provided in the Guideline on the data to be provided in support of a request to include a substance in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009.

In accordance with Annex I.6 of Commission Regulation (EU) 2018/782, biological substances other than active principles of biological origin used in immunological veterinary medicinal products may be assessed by CVMP on a case-by-case basis as regards the need for a full MRL evaluation – see the MRL webpage of the EMA website for more information.

References:

Where the product in question is intended for food producing species and relevant MRLs have not been established, the following procedure should be followed:

Applicants should notify the European Medicines Agency of the intention to submit an MRL application. A letter of intent indicating the name of the substance, intended use, target species and intended submission date should be submitted to the Agency at least 6 months before the intended submission of the application for the establishment of MRLs. If the applicant has a valid micro, small and medium-sized enterprise (SME) status or a limited-markets classification, this information should also be included. Applicants are advised to liaise with the Agency in order to agree on an adequate time delay between submission of the MRL application and submission of any related MA application.

Once the applicant has notified his intention to submit an application, the CVMP appoints a rapporteur and, if appropriate, a co-rapporteur. The applicant is notified of the appointment of the rapporteur (and co-rapporteur if appropriate), as well as the preferred submission date (closest to the submission date identified by the applicant). For applications for extensions or modifications of MRLs, usually no co-rapporteur is appointed.

For an MRL application for a new substance a full dossier should be submitted respecting the requirements of Commission Regulation (EU) 2017/12 and following the methodological principles outlined in Commission Regulation 2018/782. Applicants need to submit their application through the eSubmission Gateway / Web Client portal and should follow the Guideline on eSubmissions for a veterinary medicinal product.

For enquiries in respect of a product for which an MRL is required, applicants are invited to seek the advice of the Agency.

Applicants should address their enquiry or request for a pre-submission meeting regarding an intended MRL application via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets.

References:

Regulation (EU) No 2019/6 of the European Parliament and of the Council lays down a centralised Union procedure for the authorisation of veterinary medicinal products for which there is a single application, a single evaluation and a single authorisation allowing direct access to the single market of the Union.

A marketing authorisation granted under the centralised procedure is valid for the entire Union market, which means the veterinary medicinal product may be put on the market in all member states.

Article 42 of Regulation (EU) No 2019/6 defines the scope and eligibility of applications for evaluation under the centralised procedure through which medicinal products must ("mandatory scope") or may ("optional scope") be authorised by the Union.

Mandatory scope - Article 42(2):

For veterinary medicinal products falling within the mandatory scope of the Regulation (EU) No 2019/6, applicants are obliged to use the centralised procedure by submitting their marketing authorisation application to the European Medicines Agency.

Article 42(2) of Regulation (EU) 2019/6 includes the following:

  • Article 42(2)(a) veterinary medicinal products developed by means of one of the following biotechnological processes:

(i) recombinant DNA technology;

(ii) controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells;

(iii) hybridoma and monoclonal antibody methods;

Applications submitted based on Article 19(1)(c) – hybrid biological (including immunological) veterinary medicinal products - which are developed by one of the biotechnological processes above also fall under the mandatory scope of the centralised procedure, and their eligibility request should be based on one of the three options above.

Any veterinary medicinal product which contains a constituent obtained by means of one of the biotechnological processes listed above falls under the mandatory scope, whether the constituent is an active substance of the veterinary medicinal product or not.

  • Article 42(2)(b) veterinary medicinal products intended primarily for use as performance enhancers in order to promote the growth of treated animals or to increase yields from treated animals;
  • Article 42(2)(c) veterinary medicinal products containing an active substance which has not been authorised as a veterinary medicinal product within the Union at the date of the submission of the application;
  • Article 42(2)(d) biological veterinary medicinal products which contain or consist of engineered allogeneic tissues or cells;

This eligibility basis is also applicable to applications submitted based on Article 19(1)(c) – hybrid biological veterinary medicinal products - which contain or consist of engineered allogeneic tissues or cells.

  • Article 42(2)(e) novel therapy veterinary medicinal products.

In accordance with Article 4(43) a novel therapy veterinary medicinal product is:

(a) a veterinary medicinal product specifically designed for gene therapy, regenerative medicine, tissue engineering, blood product therapy, phage therapy;

(b) a veterinary medicinal product issued from nanotechnologies; or

(c) any other therapy which is considered as a nascent field in veterinary medicine;

Optional scope - Article 42(4):

According to Article 42(4) veterinary medicinal products other than those referred to in Article 42(2) may, at the request of the applicant, be accepted for assessment under the centralised procedure if no other marketing authorisation has been granted for the veterinary medicinal product within the Union.

Therefore, a marketing authorisation application for any new veterinary medicinal product can be submitted via the centralised procedure, including generics/hybrids where the reference product is authorised nationally in any member state.

For the purpose of establishing what a new veterinary medicinal product is, the definition of ‘same product’ should be taken into account. As per established principles, ‘same product’ means having the same qualitative and quantitative composition in active substance(s) and the same pharmaceutical form, and being both veterinary medicinal products from applicants belonging to the same mother company or group of companies or which are ‘licensees’.

Eligibility for duplicate applications:

Depending on the type of duplicate application being requested the applicant should indicate in the pre submission request form and application form as proposed basis for eligibility:

  • Article 42(2) – to be used for duplicate applications when the original VMP was granted eligibility to the centralised procedure under articles 42(2) (a), (b), (d) or (e).
  • Article 42(4) – all other cases.

Please see question ‘What are the requirements if I intend to submit duplicate applications for the same veterinary medicinal product?’

In all cases listed above the eligibility of a veterinary medicinal product for evaluation via the centralised procedure must be requested by the applicant by submitting a Pre-submission request form (selecting the indent “Centralised procedure – Eligibility request”), together with appropriate attachments (draft SPC and justification for eligibility) via Service Now Veterinary Regulatory > Pre-Submission-Vets (see question "How and when should the request for eligibility to the centralised procedure be sent to the European Medicines Agency?").

References:

Regardless of whether the product falls into the mandatory or optional scope, an ‘eligibility request’ should always be submitted using the specific form (Pre-submission request form (selecting indent ‘Centralised procedure - Eligibility request)) and accompanied by a justification of eligibility for evaluation under the centralised procedure and draft SPC. The applicant should clearly address the specific criterion fulfilled by the product to be eligible for the centralised procedure. See: Question "Is my veterinary medicinal product eligible for evaluation under the centralised procedure?"

Please note that:

1. In the case where the product falls under the mandatory scope criteria, i.e. Art. 42(2) of Regulation (EU) 2019/6, the relevant justification should be provided.

  • Art. 42(2)(a)(i) – Biotech VMP developed by recombinant DNA technology; or
  • Art. 42(2)(a)(ii) – Biotech VMP developed by controlled expression of genes coding; or
  • Art. 42(2)(a)(iii) – Biotech VMP developed by hybridoma and monoclonal antibody methods; or
  • Art. 42(2)(b) – Performance enhancers; or
  • Art. 42(2)(c) – New active substance which has not been authorised as a VMP within the Union at the date of the submission of the application; or
  • Art. 42(2)(d) - Biological VMP which contains or consists of engineered allogeneic tissues or cells; or
  • Art. 42(2)(e) - Novel therapy VMP

2. In the case where the product falls under the optional scope criterion, i.e. Art. 42(4) of Regulation (EU) 2019/6, the justification should consist of a concise summary document of preferably two pages stating why the product should qualify for evaluation through the centralised procedure.

  • Art. 42(4) - VMP other than those listed under Article 42(2) for which no other marketing authorisation has been granted within the Union.

NB: Only one criterion can be chosen and must be adequately justified.

The applicant should send the request electronically via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets, using the pre-submission request form (selecting the indent “Centralised procedure – Eligibility request”), together with a separate Annex 1 (draft Summary of Product Characteristics) and Annex 2 (Justification for Eligibility).

The CVMP will discuss the request for eligibility to the centralised procedure at its meeting 4 months prior to the intended submission date. In order to allow this, applicants should submit their request and supporting documentation to the Agency at least 3 weeks before the CVMP meeting at which eligibility is to be discussed (note: submission of the eligibility request should be at the latest on the Tuesday of the relevant week, i.e. 21 calendar days in advance of the meeting where eligibility is to be discussed). This will ensure inclusion of the request on the CVMP agenda. An earlier submission of a request for eligibility may be in particular useful for requests that fall under article 42(2)(c) (new active substance) or article 42(4) (optional scope), or if scientific or other advice is sought early in the pre-submission phase.

Any eligibility request received after the deadline will be considered the following month.

NB: Review of eligibility applications may take place over 2 consecutive CVMP meetings if the CVMP considers it necessary to appoint a CVMP member to assess the request.

The outcome of the CVMP discussions will be forwarded by the Agency to the applicant in the week following the CVMP meeting. If the supporting documentation is considered insufficient, further information and clarification from the applicant will be required. Upon receipt of such additional information the request will be re-discussed at the next CVMP meeting and the applicant will be informed accordingly.

At the same CVMP meeting where eligibility to the centralised procedure is accepted the rapporteur/co-rapporteur will be appointed. (See: Question "What is the procedure for appointment of CVMP rapporteurs/co?rapporteurs and their assessment teams?”).

References:

For any scientific evaluation of a veterinary medicinal product in respect of a procedure, a rapporteur and, if relevant, a co-rapporteur shall be appointed from amongst the members of the Committee for Veterinary Medicinal Products (CVMP) and their alternates. For marketing authorisation applications a rapporteur and a co-rapporteur are appointed.

The appointment of the rapporteur and co-rapporteur is made on the basis of objective criteria which will allow the best use of the available expertise in the European Economic Area (EEA).

The role of the rapporteur is to perform the scientific evaluation and to prepare an assessment report for the CVMP and according to the timetable agreed for the evaluation procedure. The co-rapporteur shall prepare a critique of the rapporteur's report.

The appointment of the rapporteur and co-rapporteur is made at the CVMP meeting 4 months prior to the intended submission date and is triggered by the receipt of the eligibility request to the centralised procedure. For information on how to submit the eligibility request including the required documents and procedural timelines see Question ‘How and when should the request for eligibility for the centralised procedure be sent to the European Medicines Agency?’.

If the intended application is deemed to be eligible to the centralised procedure, rapporteur and co?rapporteur will be appointed.

The outcome of the CVMP discussions will be forwarded by the Agency to the applicant in the week following the CVMP meeting. If the supporting documentation is considered insufficient, further information and clarification from the applicant will be required. Upon receipt of such additional information the request will be re-discussed at the next CVMP meeting and the applicant will be informed accordingly.

Intended submission dates must be as realistic as possible. Such information is crucial to the Agency and to the rapporteur/co-rapporteur and their assessment teams for planning purposes. Any anticipated change to the submission date must be notified as soon as possible to the European Medicines Agency. Applicants should be aware that a re-appointment of the rapporteur or co?rapporteur may become necessary due to other ongoing or planned assessments.

Please note that any applicant’s proposals/preferences are not considered for the appointment of the rapporteur and co-rapporteur.

Withdrawal of requests: Should applicants no longer wish to pursue the submission of their application, they should notify the Agency of their intention to withdraw the request for submission of a marketing authorisation application. The notification should be sent electronically via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets. It is not necessary to enclose any additional forms to the email notifying the withdrawal of request to submit a marketing authorisation application. The procedure will be closed accordingly.

References:

The applicant should clearly indicate the legal basis for the submission of the application in the e-AF (electronic application form), i.e. select one of the following articles of Regulation (EU) 2019/6:

  • Article 8 - Full application
  • Article 18 – Generic application
  • Article 19 – Hybrid application
  • Article 20 - Combination veterinary medicinal product application (of known active substances)
  • Article 21 - Informed consent application
  • Article 22 - Bibliographic application
  • Article 23 – Applications for limited markets
  • Article 25 – Applications in exceptional circumstances

The legal basis for a marketing authorisation application determines the data requirements. At pre?submission meetings, it is strongly recommended to discuss the proposed legal basis in view of the available data with the Agency in order to prevent difficulties at validation.

For all different types of applications, the information set out in Annex I of Regulation (EU) 2019/6 should be provided.

The technical documentation necessary for demonstrating the quality, safety and efficacy of the veterinary medicinal product are set out in Annex II of Regulation (EU) 2019/6, as amended by Commission Delegated Regulation (EU) 2021/805.

Article 8 - Full application:

For full applications according to Article 8 of Regulation (EU) 2019/6, the technical documentation necessary for demonstrating the quality, safety and efficacy of the veterinary medicinal product are set out in Annex II of Regulation (EU) 2019/6, as amended by Commission Delegated Regulation (EU) 2021/805.

Any deviations from these requirements, in particular, absence of a study/test report, require justification as to why the results are not provided and whether the requirements as set out in the Annex II of Regulation (EU) 2019/6, are considered fulfilled.

Where Part 3 and/or 4 consists of a combination of reports made up of limited safety, residues, pre-clinical, clinical and/or environmental studies carried out by the applicant and of published literature this kind of application has also to be submitted according to Article 8 of Regulation 2019/6.

Such literature references, when replacing required study reports, should be included in the relevant sections of Part 3 and/or 4 and should be summarised in Part 1C (critical expert reports) as required for any other study report. “Supportive-only” literature references (i.e. provided in addition to study reports), should be provided in the corresponding Part of the dossier as “references” but do not need to be summarised in Part 1C.

Justifications for absence of study reports in each of the sections can be based, for example, on the following principles:

  • Specific derogations foreseen in Regulation (EU) 2019/6;
  • Specific derogations foreseen in CVMP Guidelines;
  • Animal welfare (Directive 2010/63/EU of the European Parliament and of the Council and the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes);
  • Expert assessment explaining why repetition of certain tests or trials is unlikely to extend scientific knowledge of the subject area (e.g., documented clinical experience with the active substance might override the need for certain non-clinical tests);
  • Scientific argumentation regarding inapplicability of such tests and trials.

Article 18 - Generic application:

According to Article 18 of Regulation (EU) 2019/6, the applicant is not required to provide documentation on safety and efficacy if all the following conditions are fulfilled:

(a) bioavailability studies have demonstrated bioequivalence of a generic veterinary medicinal product with the reference veterinary medicinal product or a justification is provided as to why such studies were not required;

(b) the application satisfies the requirements set out in Annex II of Regulation 2019/6;

(c) the applicant demonstrates that the application concerns a generic veterinary medicinal product of a reference veterinary medicinal product for which the period of protection of the technical documentation laid down in Articles 39 and 40 of Regulation (EU) 2019/6 has elapsed or is due to elapse in less than two years.

A generic veterinary medicinal product is defined as a veterinary medicinal product that has:

  • the same qualitative and quantitative composition in active substances as the reference product,
  • the same pharmaceutical form as the reference medicinal product,
  • and whose bioequivalence with the reference medicinal product has been demonstrated.

The reference veterinary medicinal product should be a veterinary medicinal product authorised on the basis of an application submitted in accordance with Article 8 of Regulation (EU) 2019/6 or equivalent legal basis of previous legislation and in accordance with one of the following articles of Regulation (EU) 2019/6:

  • Article 44 (centralised procedure),
  • Article 47 (national procedure),
  • Article 49 (decentralised procedure),
  • Article 52 (mutual recognition procedure),
  • Article 53 (subsequent recognition procedure) or
  • Article 54 (marketing authorisation granted by the Commission as a result of a review procedure).

Article 19 - Hybrid application:

Hybrid applications under Article 19 of Regulation (EU) 2019/6 differ from generic applications in that the results of appropriate safety and residue tests and pre-clinical studies or clinical trials will be necessary when the veterinary medicinal product does not meet all the characteristics of a generic veterinary medicinal product because of one or more of the following reasons:

  • Article 19(a): there are changes in the active substance or substances, indications for use, strength, pharmaceutical form or route of administration of the generic veterinary medicinal product compared to the reference veterinary medicinal product;
  • Article 19(b): bioavailability studies cannot be used to demonstrate bioequivalence with the reference veterinary medicinal product;
  • Article 19(c): there are differences relating to raw materials or in manufacturing processes of the biological veterinary medicinal product and the reference biological veterinary medicinal product.  Furthermore, in accordance with the Annex to Commission Delegated Regulation (EU) 2021/805, for biological (including immunological) veterinary medicinal products, the standard generic approach is in principle not considered appropriate, and a hybrid approach shall be followed.

In such cases the results of tests and trials must be consistent with the data content standards required in the Annex to Commission Delegated Regulation (EU) 2021/805.

These applications will thus rely in part on the results of safety and residue tests and pre-clinical tests or clinical trials for a reference product and in part on new data.

The pre-clinical studies and/or clinical trials performed in relation to a hybrid application can be conducted with batches of reference veterinary medicinal product authorised in the Union or in a third country. Use of batches a reference medicinal product authorised in a third country is not acceptable for studies performed for demonstration of comparable quality characteristics between the test and reference veterinary medicinal products.

If the reference veterinary medicinal product authorised in a third country is used in pre-clinical and/or clinical trials, the applicant should demonstrate that this VMP has been authorised in accordance with requirements equivalent to those established in the Union for the reference veterinary medicinal product. The reference veterinary medicinal product authorised in a third country and the reference veterinary medicinal product authorised in the Union must be so highly similar that they can substitute each other in the clinical trials.

Article 20 - Combination veterinary medicinal product application:

According to Article 20 of Regulation (EU) 2019/6, in the case of medicinal products containing active substances used in the composition of authorised veterinary medicinal products it shall not be necessary to provide safety and efficacy data relating to each individual active substance.

The combination of active substances within a single pharmaceutical form of administration according to this provision is a so-called ‘fixed combination product’.

Applications for combination veterinary medicinal products can be accepted and validated under Article 20 on the condition that all the individual active substances have been authorised in a veterinary medicinal product in the EEA. A combination veterinary medicinal product containing at least one new active substance which has not yet been authorised in a veterinary medicinal product in the EEA, shall be submitted under Article 8.

For applications under Article 20 of Regulation (EU) 2091/6 a full dossier, comprising parts 1, 2, 3 and 4, has to be provided in relation to the fixed combination. Any absence of specific fixed combination data should be duly justified.

Although there is no requirement for the inclusion of data on the individual active substances, it is possible to include information on the individual substances (literature or actual data), especially in order to justify the absence of certain specific data on the combination.

Article 21 - Informed consent application:

According to Article 21 of Regulation (EU) 2019/6, an applicant shall not be required to provide the technical documentation on quality, safety and efficacy if that applicant demonstrates permission, in the form of a letter of access, to use such documentation submitted in respect of the already authorised veterinary medicinal product.

It is a prerequisite for the use of Article 21 as the legal basis that consent has been obtained from the marketing authorisation holder of the reference product for all parts of the dossier and the applicant of the informed consent application should have access permanently to this documentation or should be in possession of the information.

An application based on Article 21 concern products with identical composition, pharmaceutical form and manufacturing process (including raw and starting materials, process parameters and manufacturing sites) as the already authorised veterinary medicinal product.

For informed consent applications, only Part 1A and Part 1B should be submitted, including the Application Form with relevant Annexes (e.g. the letter of consent from the MAH of the authorised medicinal product allowing access to Parts 1C, 2, 3 and 4 of the initial dossier and any subsequent documentation submitted).

If the dossier of the authorised medicinal product includes an ASMF, a new letter of access from the ASMF holder should be included in Part 1 of the informed consent application.

Article 22 - Bibliographic application:

According to Article 22 of Regulation (EU) 2019/6 the applicant is not required to provide the documentation on safety and efficacy if that applicant demonstrates that the active substances of the veterinary medicinal product have been in well-established veterinary use within the Union for at least 10 years, that their efficacy is documented and that they provide an acceptable level of safety.

The provisions of Section IV.5 of the Annex to Commission Delegated Regulation (EU) 2021/805 shall apply.

It should be noted that, if well-known substances are used for entirely new therapeutic indications, it is not possible to solely refer to a well-established veterinary use and additional data on the new therapeutic indication together with appropriate safety and residues tests and pre-clinical and clinical data should be provided. In such case, an application based on Article 22 is not possible. Article 8 should be used as legal basis.

Article 23 – Applications for limited markets

Article 4(29) of Regulation (EU) 2019/6 defines ‘limited market’ as a market for one of the following medicinal product types:

(a) veterinary medicinal products for the treatment or prevention of diseases that occur infrequently or in limited geographical areas;

(b) veterinary medicinal products for animal species other than cattle, sheep for meat production, pigs, chickens, dogs and cats;

According to Article 23 of Regulation (EU) 2019/6, the applicant is not required to provide the comprehensive safety and/or efficacy data if it is demonstrated that the product is intended for use in a limited market and that the benefit of availability of the new product outweighs the risk associated with the omission of some of the safety and/or efficacy data.

Article 25 – Applications in exceptional circumstances

In exceptional circumstances related to animal or public health, an applicant may submit an application which does not meet all the requirements in terms of submission of all the data on quality, safety and efficacy detailed in Sections II and III of the Annex to Commission Delegated Regulation (EU) 2021/805.

The applicant should demonstrate that for objective and verifiable reasons certain quality, safety or efficacy documentation normally required cannot be provided and the benefit of the immediate availability on the market of the veterinary medicinal product concerned to the animal or public health outweighs the risk inherent in the fact that certain data not being provided.

A marketing authorisation may be granted under Article 25 for a veterinary medicinal product, subject to certain specific obligations, conditions and/or restrictions.

Post-authorisation studies may be requested as part of the conditions for marketing authorisation, and shall be designed, conducted, analysed and presented according to the general principles for quality, safety and efficacy tests set out in the Annex mentioned above.

Duplicate applications:

The same legal basis as the original veterinary medicinal product should be chosen unless the application is an informed consent application for which article 21 should be selected as the legal basis.

Please see question ‘What are the requirements if I intend to submit duplicate applications for the same veterinary medicinal product?’

References:

Please note that during the COVID-19 pandemic pre-submission meetings will be held remotely (teleconference or virtual meeting facility).

General principle

The pre-submission meeting represents an important point in the product development and regulatory approval process and relates to the preparatory steps in advance of submitting a marketing authorisation application. A successful pre-submission meeting should enable the applicant to submit an application which is in conformity with the regulatory requirements and which can be smoothly evaluated. A pre-submission meeting will also enable applicants to establish contact with the EMA staff who will be closely involved in the centralised evaluation procedure of their veterinary medicinal product. Pre-submission meetings are arranged upon request by the applicant.

Purpose/scope of meeting

Pre-submission meetings are aimed at providing applicants with information that will assist them in the finalisation of their planned marketing authorisation application. Such meetings typically address product-specific legal and regulatory issues in order to facilitate later validation and assessment of the application. Pre-submission meetings can be especially helpful to SMEs / other companies that may have limited experience of interaction with the EMA or are unfamiliar with the centralised procedure. However, experience has shown the usefulness of pre-submission meetings even for applicants that already have experience with the centralised procedure, to address issues specific to their upcoming application in view of the constantly evolving regulatory framework and its application.

The pre-submission request form provides an overview of the most relevant topics (checklist) that applicants are advised to consider when preparing their intended application. The topics which the applicant identified for discussion will be addressed at the pre-submission meeting. Applicants are advised to clearly describe the issues in the ‘comments’ box under the topic concerned, and to provide relevant background information. Other topics not listed in the form which the applicant wishes to discuss may be added.

The pre-submission guidance addresses a number of questions which users of the centralised procedure may have, together with hyperlinks to relevant legislative documents and procedural guidelines which further complement the advice given in the pre-submission guidance.

Timing of pre-submission meetings 

A pre-submission meeting is usually requested by the applicant, either after the confirmation by the CVMP of the eligibility of the intended product for the centralised procedure or after the appointment of rapporteurs and co-rapporteur for the evaluation, i.e. 4 months before submission of the application, or it can also be earlier when the future applicant wishes to receive earlier advice, e.g. information regarding the legal basis or eligibility.

The pre-submission meeting request form should be sent at least 6 weeks before the proposed meeting date, so that the meeting can be set up at a mutually agreed date taking into account availability of EMA participants and meeting rooms. The total meeting duration should not exceed 2 hours.

Currently pre-submission meetings will only be held remotely. Applicants may indicate their preference for a date in the pre-submission request form, which will be taken into account by EMA when allocating the exact date and time for the meeting.

Who is involved in a pre-submission meeting?

EMA participants at pre-submission meetings are normally the scientific lead and procedure coordinator for the application, if already appointed, and other staff members relevant for the product under consideration and issues to be discussed. Exceptionally, if scientific issues are to be discussed, the (co-)rapporteurs, if already appointed, can be included, normally via video/teleconference.

Please note that while the scientific lead will usually chair the meeting, the procedure coordinator will be the primary contact point for the applicant.

Documents to be prepared for a pre-submission meeting

  • The pre-submission meeting request form needs to be filled in electronically and sent via platform ServiceNow (detailed instructions are included within the form). This form includes topics and questions to be addressed at the pre-submission meeting and provides a list of attachments most often needed for the discussion.
  • It is advised to provide a draft application form, in particular for pre-submission meetings closer to the submission date, which should be completed as far and as accurately as possible. The form will provide important information on the product and the type of application (e.g. legal basis, reference product details, manufacturing sites) in relation to the topics to be discussed at the meeting. It will also allow EMA to identify topics, other than those requested by the applicant, for discussion/clarification at the meeting, thereby preventing issues to be raised at validation. In order to avoid duplication of information, detailed information to be provided in the application form (e.g. tick-boxes for legal basis, eligibility for centralised procedure) is not required to be repeated in the pre-submission meeting request form.
  • The applicant should indicate any other topic they wish to raise, and, as appropriate, list all topics intended to be discussed in a separate agenda. 

Note: Applicants must in all cases comply with all requirements of Community legislation. Provisions which extend to EEA countries (i.e. the EU member states, plus Norway, Iceland and Liechtenstein) by virtue of the EEA agreement, are outlined in the relevant sections of the text.

How are pre-submission meetings conducted?

Dependent on the topics the applicant wishes to address, it is often appropriate that at the start of the meeting the applicant gives a brief 10-20 minutes presentation on the product development. The applicant’s presentation would normally include, as appropriate:

  • Company’s participants and contact point during the evaluation
  • Brief description of the product
  • Brief summary of the dossier content
  • Particular EU guideline deviations
  • List of questions/issues raised by the applicant

On the basis of the information provided, the participants will discuss with the applicant the issues raised or relevant for the product under consideration, e.g. the appropriateness of the chosen legal basis in view of the available data, highlight elements to be specifically addressed (e.g. missing data, deviations from scientific advice), provide an EMA view on the possibility for requesting approval under exceptional circumstances if applicable, etc. EMA may also draw attention to relevant scientific and regulatory guidelines, recommend (further) scientific advice and suggest improvements to the product information.

Note: Applicants wishing to meet with their appointed rapporteur or co-rapporteur and assessment teams at national level should also inform the EMA scientific lead who will participate to such a meeting via teleconference, where possible. In any case, minutes of such meetings should be provided to the EMA procedure co-ordinator.

Follow-up of pre-submission meetings

Detailed meeting minutes should be prepared by the applicant and provided to the EMA after the meeting. EMA will subsequently review the minutes and agree the final (amended) minutes with the applicant.

References:

According to Articles 44(2) and 31 of Regulation (EU) 2019/6, the maximum timeframe for the evaluation of a marketing authorisation application under the centralised procedure is normally 210 active days, which excludes clock stops during which additional information is to be provided by the applicant in response to questions asked by the CVMP. Exceptionally, where a particular expertise is required, the timeframe for the evaluation may be extended by a maximum of 90 days.

In accordance with Article 44(3) of Regulation (EU) 2019/6, when an application is submitted for a marketing authorisation in respect of a veterinary medicinal product of major interest, particularly from the point of view of animal health and therapeutic innovation, the applicant may request an accelerated assessment procedure.

Any request for accelerated review needs to be sent to the European Medicines Agency accompanied by appropriate justification. Further guidance on the requirements and process is available and is in the process of being updated to bring it into alignment with Regulation (EU) 2019/6. Such a request should be sent at the latest one month before the anticipated date of submission of the application, and preferably at the time of notification of the intention to submit an application.

Applicants shall submit their accelerated assessment request by sending a completed Pre-submission request form (selecting the indent “Request for accelerated assessment of marketing authorisation application” in the field “Scope of Request”) and applicant’s justification via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets.

The request for an accelerated assessment must be duly substantiated. Based on the request, the justifications presented by the applicant, and the recommendations of the rapporteurs, the CVMP will formulate a decision at its next meeting. Such a decision will be taken without prejudice to the (future) CVMP opinion (positive or negative) on the granting of a marketing authorisation. The applicant will be informed of the decision after the CVMP meeting.

If the CVMP accepts the request, the time limit of 210 days to give an opinion will be reduced to 150 days. This time frame will be split into 3 phases of 90+30+30 days of assessment.

After a request has been granted, at any time during the marketing authorisation application evaluation, if the CVMP considers that it is no longer appropriate to conduct an accelerated assessment, the CVMP may decide to continue the assessment under the standard centralised procedure timelines according to Article 44(2) of Regulation (EU) 2019/6.

References:

Duplicate applications (also referred to as multiple applications) for a specific medicinal product already under assessment or authorised via the centralised procedure have automatic access to the centralised procedure. Nevertheless, in all cases the eligibility of a medicinal product for evaluation via the centralised procedure needs to be requested by the applicant by submitting an eligibility request to the European Medicines Agency. Depending on the type of duplicate application being requested the applicant should indicate in the pre?submission request form and application form as proposed basis for eligibility:

  • Article 42(2) – to be used for duplicate applications when the original VMP was granted eligibility to the centralised procedure under articles 42(2) (a), (b), (d) or (e).
  • Article 42(4) – all other cases.

Regarding the legal basis of the duplicate application, the same legal basis as the original VMP should be chosen unless the application is an informed consent application for which article 21 should be selected as the legal basis.

Duplicate applications can be submitted while the original marketing authorisation application is under assessment or after the Commission Decision on the initial application has been issued.

Duplicate applications submitted while the original marketing authorisation application is under assessment:

The objective is to ensure the adoption of a CVMP opinion for a duplicate application at the same time as the CVMP opinion for the initial application. Therefore, for practical reasons, the Agency strongly recommends the following time points for submission:

  • in parallel with the initial application submission (day 0);
  • before the adoption of the list of questions (before day 120) for the initial application;
  • at the time of submission of responses to the list of questions (day 121) for the initial application.

Later submission of the dossier is not recommended due to difficulties with its alignment with the original application.

It should be noted that duplicate applications are subject to a full validation as they are stand-alone applications. Therefore, the validation outcome may differ from that for the original application. If the above timeframes have been duly observed by the applicant, following the positive outcome of the validation, the evaluation of the duplicate applications will be aligned with that of the ongoing initial application. The submission of any duplicate application should therefore be made in advance, to allow sufficient time for their validation to be completed by day 120 or day 121 of the ongoing initial application.

Duplicate applications submitted after Commission Decision has been issued:

An abridged timetable for their assessment will be adopted in line with a 60-day procedure. Submission of such application(s) should therefore be made in advance to allow the completion of their validation before the intended start date of the procedure.

Applicants are reminded that duplicate applications of the same marketing authorisation holder will be covered by the notion of the “global marketing authorisation”.

In accordance with Article 77(2) of Regulation (EU) 2019/6 ‘For each veterinary medicinal product, the marketing authorisation holder shall not have more than one pharmacovigilance system master file’. Therefore, the same PSMF should be used for the original application and any duplicate belonging to the same marketing authorisation holder.

Applicants are not required to notify the Commission of their intention to submit a duplicate application via the centralised procedure.

References:

2. Preparing the dossier

2.1 Product name, product information and prescription status

As part of the Agency’s role in evaluating the safety of medicinal products in the authorisation procedure, it is obliged to consider whether the (invented) name proposed for a veterinary medicinal product could create an animal health concern or potential safety risks.

The EMA operates a procedure to ensure that objections raised by National Competent Authorities (NCAs) against the (invented) name of a medicinal product, due to potential safety risks or other criteria as defined in the CVMP guideline on acceptability of invented names, are identified at an early stage.

Provided that the medicinal product is eligible for evaluation under the centralised procedure, the applicant should inform the Agency of the proposed invented name(s) for their medicinal product as soon as eligibility to the centralised procedure has been granted and prior to the planned submission date of the marketing authorisation application. (See: Question "How and when should the request for eligibility to the centralised procedure be sent to the European Medicines Agency?").

To allow for review of proposed invented names, the applicant(s)/marketing authorisation holder(s) are requested to send to the Agency (VMPname@ema.europa.eu) their proposed invented name(s) and the draft summary of product characteristics (SPC) or product profile and any information justifying the acceptability of the name(s). Up to two invented names per marketing authorisation application can be proposed for consideration.The ‘Proposed Invented Name Request form’ and further details of timing and content of an invented name application are available on the Agency website. In case neither invented name is accepted by the CVMP, the applicant may submit a new request with up to two further proposed invented names. The number of finally accepted invented names cannot exceed two per marketing authorisation application.

Further details on the criteria and the procedure are available in the Guideline on acceptability of names of veterinary medicinal products processed through the centralised procedure.

References:

Proposed invented name(s) justification form for veterinary medicinal products

English (EN) (26.87 KB - DOCX)

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In accordance with Article 43(2) of Regulation (EU) 2019/6, “the application for a centralised marketing authorisation of a veterinary medicinal product shall state a single name for the veterinary medicinal product to be used throughout the Union.” The centralised procedure therefore requires the same single product name in all EU Member States.

According to Article 4(21) of Regulation (EU) 2019/6, the name of the veterinary medicinal product may be “either an invented name not liable to confusion with the common name, or a common name or scientific name accompanied by a trademark or the name of the marketing authorisation holder.” According to Article 4(20) of the same Regulation “The common name is the international non-proprietary name recommended by the World Health Organisation for a substance, or, if one does not exist, the name generally used.”

Although it is not mandatory under Union legislation, in practice many companies submitting marketing authorisation applications under the centralised procedure wish to use invented names for their medicinal products.

As part of the EMA’s role in evaluating the safety of veterinary medicinal products in the centralised procedure, it is considered whether the (invented) name proposed for a veterinary medicinal product could create an animal or public-health concern or potential safety risk.

In particular, the (invented) name of a veterinary medicinal product:

  • should not convey misleading therapeutic or pharmaceutical connotations;
  • should not be misleading with respect to the composition of the product.

For further guidance, applicants should refer to the respective Guideline on the acceptability of names for veterinary medicinal products processed through the centralised procedure.

In the QRD template for product information v.9, each section where the name of the veterinary medicinal product is stated clearly specifies the qualifiers (e.g. strength, pharmaceutical form) that should follow the name of the product because, under the requirements of Regulation (EU) 2019/6, these are different between the SPC, package leaflet, outer packaging and small immediate packaging.

References:

In accordance with Article 33 of Regulation (EU) 2019/6, in the case of a favourable assessment of an application examined in accordance with Article 28, the Agency shall prepare an opinion which shall include, amongst others, details of any conditions or restrictions to be imposed as regards the supply or safe and effective use of the veterinary medicinal product concerned, including the classification of a veterinary medicinal product in accordance with Article 34.

The classification for the supply of the veterinary medicinal product to the user is also referred to as ‘legal status’.

The expression of the legal status in the summary of product characteristics and package leaflet (Annexes I and IIIB of the CVMP opinion) is limited to the main classification, which is common to all member states:

  • veterinary medicinal product subject to prescription, or
  • veterinary medicinal product not subject to prescription.

It is also possible that, for the same veterinary medicinal product, some pack sizes may be classified as subject to prescription, whilst others may be classified as not subject to prescription: <Veterinary medicinal product subject to prescription except for some pack sizes>.

In addition, any national subcategories concerning distribution may be included in a separate boxed area at the end of the package leaflet, in accordance with the provisions of Article 14(2) of Regulation (EU) 2019/6 and the applicable QRD veterinary product information annotated template.

Article 34(1) of Regulation (EU) 2019/6 provides the ‘prescription conditions’, i.e. it lists the types of products which shall be classified as subject to veterinary prescription by the Commission when granting a marketing authorisation:

  • (a) veterinary medicinal products which contain narcotic drugs or psychotropic substances, or substances frequently used in the illicit manufacture of those drugs or substances, including those covered by the United Nations Single Convention on Narcotic Drugs of 1961 as amended by the 1972 Protocol, the United Nations Convention on Psychotropic Substances of 1971, the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 or by Union legislation on drug precursors;
  • (b) veterinary medicinal products for food-producing animals;
  • (c) antimicrobial veterinary medicinal products;
  • (d) veterinary medicinal products intended for treatments of pathological processes which require a precise prior diagnosis or the use of which may have effects which impede or interfere with subsequent diagnostic or therapeutic measures;
  • (e) veterinary medicinal products used for euthanasia of animals;
  • (f) veterinary medicinal products containing an active substance that has been authorised for less than five years in the Union;
  • (g) immunological veterinary medicinal products;
  • (h) without prejudice to Council Directive 96/22/EC, veterinary medicinal products containing active substances having a hormonal or thyrostatic action or beta-agonists.

Notwithstanding the prescription conditions mentioned above, the Commission may also classify a veterinary medicinal product as subject to prescription if it is classified as a narcotic drug in accordance with national law or where special precautions are contained in the summary of product characteristics, as per the provisions of Article 34(2) of Regulation (EU) 2019/6.

However, by way of derogation from the prescription conditions (a)-(h) listed above, the Commission may, except as regards veterinary medicinal products referred to in points (a), (c), (e) and (h), classify a veterinary medicinal product as not subject to prescription if all the conditions listed in Article 34(3) of Regulation (EU) 2019/6 are fulfilled (‘exemption criteria’):

  • (a) the administration of the veterinary medicinal product is restricted to pharmaceutical forms requiring no particular knowledge or skill in using the products;
  • (b) the veterinary medicinal product does not present a direct or indirect risk, even if administered incorrectly, to the animal or animals treated or to other animals, to the person administering it or to the environment;
  • (c) the summary of the product characteristics of the veterinary medicinal product does not contain any warnings of potential serious adverse events deriving from its correct use;
  • (d) neither the veterinary medicinal product nor any other product containing the same active substance has previously been the subject of frequent adverse event reporting;
  • (e) the summary of the product characteristics does not refer to contra-indications related to the use of the product concerned in combination with other veterinary medicinal products commonly used without prescription;
  • (f) there is no risk for public health as regards residues in food obtained from treated animals even where the veterinary medicinal product is used incorrectly;
  • (g) there is no risk to public or animal health as regards the development of resistance to substances even where the veterinary medicinal product containing those substances is used incorrectly.

Once the veterinary medicinal product has received a marketing authorisation, it is possible for the MAH to apply to change the legal status by means of a variation, subject to the necessary data being presented.

References:

‘Local representative’ shall be taken to mean: any private or legal person established in the European Union charged, through a civil contract with the marketing authorisation holder (MAH), with representing him in a defined (geographical) area; this contract excluding any transfer of any responsibility imposed on the MAH by Union law and by national law, regulation and administrative action implementing such Union law.

It must be recalled that EEA countries may not require that a local representative of the MAH be appointed for their territory. Therefore, the arrangements outlined above are purely optional for holders of Union marketing authorisations. Nevertheless, when the holder of a Union marketing authorisation wishes to identify a local representative in the package leaflet, all of the Union must be covered so that users in each Member State and EEA country have equivalent access to a local representative. A local representative may be designated for more than one Member State or EEA country and may also be the MAH when no other local representatives are indicated. In principle, only one local representative should be indicated per Member State or EEA country. Local representatives should be able to address queries in the local official EEA language of the country for which they are designated, in particular for the purpose of receiving reports of suspected adverse events1.

In accordance with Article 14(1)(a) of Regulation (EU) 2019/6, information about the local representative of the MAH may be included:

  • in the package leaflet, section 16 ‘Contact details’ under sub-heading ‘Local representatives’ and it should be indicated whether the local representative is the designated contact point for the reporting of adverse reactions2 by either keeping or deleting the second part of the sub-heading ‘and contact details to report suspected adverse reactions’;
  • by name, telephone number, e-mail address (optional) and postal address, space permitting. References to website addresses or email addresses linking to websites are not allowed, neither for the MAH nor the local representative.

For full guidance on how local representatives should be presented within the product information, applicants should refer to the respective section of the annotated QRD template for product information v.9.

References:

1 In accordance with Article 77(3) of Regulation (EU) 2019/6.

2 In accordance with Article 14(1)(l) of Regulation (EU) 2019/6.

 

A "mock-up" is a copy of the flat artwork design in full colour, presented so that, following cutting and folding where necessary, it provides a replica of both the outer and immediate packaging so that the three dimensional presentation of the label text is clear. It is generally referred to as a "paper copy" or "computer generated version". When provided, mock-ups should be submitted in full size in colour, electronically.

A "specimen" is a sample of the actual printed outer and inner packaging materials without any contents (“empty immediate packaging”) and the package leaflet.

At submission of the initial marketing authorisation application:

  • For validation purposes, the Agency requests that all applications for a Marketing Authorisation should include the labelling texts in English. In addition, applicants are recommended to submit one English mock-up and one multi-lingual mock-up ('worst case') of the outer and small immediate packaging for each pharmaceutical form in the smallest pack size.
  • Mock-ups if submitted will be included in Part 1 of the application dossier.
  • The proposed outer and immediate labelling and package leaflet should be in compliance with the requirements outlined in Articles 10, 11, 12 and 14 of Regulation (EU) 2019/6. Detailed reviews of the content of the labelling and package leaflet proposals and their translations, i.e. Annexes IIIA and IIIB, will take place during the scientific assessment and linguistic review of the application. 
  • Marketing authorisation holders (MAHs[FB1] [LA2] ) are responsible for the correct implementation of the agreed product information texts in their printed packaging materials, in line with the Commission Decision and relevant EU legislation.
  • The Agency can, at any time, request specific specimens from the applicant/MAH for review (e.g. further to a safety-related or product defect issue).
  • When required by the Agency, mock-ups or specimens should be submitted together with the “Mock-Ups/Specimens Submission Form” (Annex 2 of the checking process of mock-ups and specimens of outer/immediate labelling and package leaflets in the centralised procedure for veterinary medicinal products).
  • In some cases, the rapporteurs or the agency may ask for a sample to be submitted as an aid in better understanding (e.g. the shape of a novel type of container or applicator), or in order to get a clearer understanding of space limitations in regard to labelling issues.

 

References:

2.2 Quality

The Agency requires the applicant to provide background information in support of the application relating to the manufacture (including packaging), batch testing and final batch release by the qualified person in the EEA. This should be sent to the Agency along with the application dossier. The EEA includes European Union (EU) member states plus Iceland, Liechtenstein and Norway. Switzerland is not part of the EEA.

Once validated, it is normally not permitted to add a new site or to change the steps of manufacture/ batch release described under Part 1A of the application during the 210-day review period. Any additional site or change in the manufacturing or batch release arrangements should be submitted as a variation after the granting of the marketing authorisation.

Manufacturing sites:

All sites involved in the production of both the active substance(s) and the finished medicinal product must be described (name and detailed address, including building reference) in Part 1A of the application for a marketing authorisation together with a description of the steps performed. This should include:

  • active substance manufacture and packaging
  • any contract laboratories used for testing the active substance (incl. ongoing stability monitoring)
  • bulk medicinal product manufacture
  • diluent/solvent manufacture (if any)
  • manufacture of any other associated medicinal product (if any)
  • finished product manufacture and packaging
  • batch release
  • any contract manufacturing sites
  • any contract laboratories used for testing the finished product
  • Official Medicines Control Laboratory (OMCL) for vaccines if ‘official batch release’ is a requirement for the product in question.

For third country manufacturers, information about any previous EU/EEA inspection in the last 2-3 years (with, if possible, a copy of the inspection report) and any planned EU/EEA inspections should be provided. This should include details of the inspection dates, product categories inspected and the name of the inspecting competent authority.

Documents to be attached to Part 1A of the application:

The following documents should be attached to Part 1A of the application:

  • Copies of the manufacturing authorisation authorising the sites involved in the manufacture, importation, control and testing and qualified-person release of batches of the medicinal product for all sites in the EEA, other than active substance manufacturers. Alternatively, a reference can be made to the appropriate entry in the EudraGMDP database.
  • For sites in the EEA, good-manufacturing-practice (GMP) certificates are not an acceptable alternative to a manufacturing authorisation. However, GMP certificates can be useful additional information. Also, particular attention should be paid that the scope of the manufacturing authorisation for a given manufacturer covers the activities proposed as part of the marketing authorisation application.
  • Reference to the appropriate entry in the EudraGMDP database that the importers, manufacturers and distributors of active substances used as starting materials in the medicinal product, that are established in the Union, are registered with the competent authority of the Member State in which they are established and comply with good manufacturing practice or good distribution practice, applicable.
  • For all sites other than active substance manufacturers located in third countries where a mutual-recognition-agreement (MRA) or other relevant agreement is in place, a document for GMP compliance should be provided. This document must not be older than three years, and must come from the local competent authority that carried out the inspection. Alternatively, a GMP certificate from the EEA inspecting competent authority should be provided if the site has been inspected by an EEA competent authority in the last two or three years. Where the MRA partner has placed the certificate in EudraGMDP, a reference to the entry will suffice. For a list of the countries which have operational MRAs with the EU, please consult the website on MRAs.
  • For all sites other than active substance manufacturers located in third countries with no MRA with the EU, a GMP certificate from the EEA inspecting competent authority if the site has been inspected by an EEA competent authority in the last two or three years. Alternatively, a reference can be made to the appropriate entry in the EudraGMDP database.
  • In addition to the above, a copy of the registration or other document analogous to a manufacturing authorisation from the local competent authority demonstrating that the site is authorised for manufacture of the product or pharmaceutical form and details of any inspections performed other than by EEA authorities (e.g. GMP certificates or similar statements from the competent authority that carried out the inspection).
  • A flowchart describing all the main steps involved in the manufacture of the active substance and finished product.
  • For each active substance, a declaration from the qualified persons of the batch release sites in the EEA stating that the active substance manufacturers listed in Part 1A operate in compliance with the detailed guidelines on GMP and that the active substance have been distributed in accordance with Good Distribution Practice for Active Substances.

Contact person in the EU/EEA for product defects/recalls:

A proposed contact point/person in the EEA for quality problems and defective batches of product must also be provided in Part 1A of the application (name, full address, 24 hours emergency phone and fax numbers, e-mail address and mobile phone number, if available).

References:

For each application the applicant must fulfil the requirements laid down in the Commission Delegated Regulation (EU) 2021/805 amending Annex II to Regulation (EU) 2019/6, where demonstration of compliance is required with the Note for Guidance for minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 rev.3 or any future update) as well as with the corresponding monograph of the European Pharmacopoeia.

Demonstration of compliance with the note for guidance can be done by submitting Certificates of Suitability from the European Directorate for the Quality of Medicines and HealthCare (EDQM) in Annex 5.12 of the application form, or by inclusion in the dossier (Part 2.C) of scientific data to substantiate this compliance.

For all applications, the table A on 'materials of animal origin covered by the Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products' should be completed.

For materials from animals not covered by the Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products, applicants are requested to complete the table B on 'other materials of animal origin'.

Materials of human origin

If an application relates to medicinal product which contains or uses in the manufacture materials of human origin, applicants are requested to complete the table C on ‘albumin and other human tissue derived products’.

References:

Annex II to Regulation (EU) 2019/6 as amended by Commission Delegated Regulation (EU) 2021/815 describes the concept of an Active Substance Master File (ASMF) and specifies that:

“For a non-biological active substance, the applicant may arrange for the information on active substance to be supplied directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File. In this case, the manufacturer of the active substance shall provide the applicant with all the data (applicant’s part of the Active Substance Master File) which may be necessary for the latter to take responsibility for the veterinary medicinal product. A copy of the data provided by the active substance manufacturer to the applicant shall be included in the medicinal product dossier. The manufacturer of the active substance shall confirm in writing to the applicant that he shall ensure batch-to-batch consistency and not modify the manufacturing process or specifications without informing the applicant.”

It should be emphasised that the concept of the ASMF shall only apply to a well-defined active substance and cannot be used for excipients, finished products and biological active substances. The information related to excipients, finished products and biological active substances shall be provided within the marketing authorisation application by the applicant and any post-authorisation changes will be submitted as variations by the Marketing Authorisation Holder (MAH).

In case an application under the centralised procedure includes the submission of an Active Substance Master File (previously referred to as European Drug Master File (EDMF)), applicants should be aware of the fact that, as mentioned in the guideline on the Active Substance Master File Procedure (EMEA/CVMP/134/02), an ASMF consists of 2 parts:

  • An ASMF applicant’s part, also referred to as open part, which shall be at the disposal of the applicant.
  • An ASMF restricted part, also referred to as closed part, which is a confidential document closed to the applicant.

Both parts need to be separated and follow the structure of Part 2 of VNeeS, or module 3.2.S of the common technical document (CTD), as applicable.

The content requirements as described in the above mentioned guideline should be followed.

Applicants should note that the ASMF constitutes an integral part of the dossier and therefore should always be made available to the EMA and CVMP Members. The applicant is responsible for the submission of all necessary documents.

The applicant or MAH should ensure that the ASMF dossier submitted by the ASMF holder is synchronized to arrive simultaneously with the marketing authorisation application or variation. Therefore, close communication between the MAH or applicant and the ASMF holder is highly recommended.

Marketing authorisation applications or variations cannot be validated until all the necessary documents (medicinal product dossier and ASMF dossier) are received in a satisfactory form. This also applies to the ASMF-related responses during a procedure (e.g. responses to day 120 lists of questions and day 180 lists of outstanding issues). Applicants should be aware that a procedure cannot restart until the responses from the ASMF holder are received by the Agency.

The ASMF is developed to keep intellectual property (IP) confidential. However, it should be noted that the introduction of an ASMF is also possible in cases where the applicant is also the IP holder of the active substance.

ASMF holders are reminded of their responsibility to inform the MAHs of any changes to their ASMFs. Similarly, MAHs are reminded of their legal obligation to submit the applicable variation to their marketing authorisations when changes are proposed to the ASMF, i.e. when an updated version of the ASMF is submitted, the marketing authorisations linked to that ASMF will only integrate the ASMF update once the applicable variation is submitted and positively concluded.

Additional information on the ASMF procedure can be found in the on the Heads of Medicines Agencies website (Working Group on ASMF Procedures) and the Agency’s website (Guideline on Active substance Master File procedure).

Non-applicability of ASMF concept to biological active substances

As explained in the guideline on ASMF, the ASMF concept is not acceptable for biological medicinal products.

The characterisation and determination of biological active substances requires not only a combination of physicochemical and biological testing, but also extensive knowledge of the production process and its control.

The MAH/applicant for a biological medicinal product could therefore not comply with the requirement to ‘take responsibility for the medicinal product’ without having full and transparent access to these quality-related data. The use of an ASMF would prevent such access and should therefore not be allowed for biological active substances.

In addition, active substances, which are present in certain medicinal products such as vaccines, do not fit with the concept of a ‘well-defined’ active substance.

References

What data should be submitted by the ASMF holder?

In the first submission of an ASMF to EMA, the ASMF holder is required to submit:

  • ASMF dossier (applicant’s part, restricted part, quality overall Summary (if CTD format) or critical expert report (if VNeeS format), and expert’s curriculum vitae);
  • Letter of access (annex 2 of the ASMF guideline). The letter of access template published already contains the commitment from the ASMF holder to inform the applicant and the EMA of any change to the ASMF. By submitting the letter of access completed using the template provided (annex 2 of the ASMF guideline) the requirement to submit such a commitment is considered fulfilled;
  • Submission letter and administrative details (annex 3 of the ASMF guideline) duly filled in as detailed in the instructions provided in the additional guidance on documents relating to an active substance master file;

In any later marketing authorisation application or variation submission referring to an ASMF already submitted to EMA, the ASMF holder is only required to submit:

  • Letter of access (annex 2 of the ASMF guideline) if the ASMF is used in a new marketing authorisation application or variation for a veterinary medicinal product not supported by the ASMF. For variations for a veterinary medicinal product already supported by the ASMF, there is no need to re-submit the letter of access as the one already provided within the previous procedure is valid throughout the product’s lifecycle;
  • Submission letter and administrative details (annex 3 of the ASMF guideline) duly filled in as detailed in the instructions provided in the Additional guidance on documents relating to an active substance master file;
  • The relevant revised sections of the ASMF dossier (applicant’s part and/or restricted part, as applicable) reflecting changes to the previously accepted version;

The contact details of the ASMF holder contact person must be the same in the cover letter of the ASMF, in the letter of access and the application form submitted by the applicant or MAH.

The ASMF dossier and any subsequent updates should only be submitted once.

The ASMF holder may, at its discretion, contact the Agency via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets directly for pre-submission questions regarding classification of changes in the restricted part of the ASMF.

References:

What data should be submitted by the applicant or MAH?

Marketing authorisation applications

In the context of a marketing authorisation application the applicant should submit:

  • application form stating, in section 2.5 “Manufacturers”, the correct EMEA/ASMF or EU/ASMF reference number;
  • a copy of the letter of access (annex 2 of the ASMF guideline) in annex 5.10 of the dossier. The letter of access template already contains the commitment from the ASMF holder to inform the applicant and the EMA of any change to the ASMF. By submitting the letter of access completed using the template provided (annex 2 of the ASMF guideline) the requirement to submit such commitment is considered fulfilled;
  • a copy of the complete current version of the applicant’s part of the ASMF in the relevant part of the dossier;

Variations to the terms of the marketing authorisation

In cases where the veterinary medicinal product is already supported by the ASMF in question, the MAH should submit:

  • variation application form stating the correct EMEA/ASMF or EU/ASMF reference number in section 3 “Types of change(s)”;
  • if applicable, copy of the revised sections of the applicant’s part of the ASMF which should be identical to the ones submitted by the ASMF holder.

In cases where a new ASMF is being introduced as part of a variation requiring assessment (F.I.a.1.a – Introduction of a manufacturer of the active substance supported by an ASMF), the MAH should submit:

  • variation application form stating the correct EMEA/ASMF or EU/ASMF reference number in section 3 “Types of change(s)”;
  • a copy of the letter of access (Annex 2 of the ASMF guideline) which already contains the commitment from the ASMF holder to inform the applicant and the EMA of any change to the ASMF;
  • a copy of the complete current version of the applicant’s part of the ASMF in the relevant part of the dossier.

The MAH or the applicant should ensure that the submission of the ASMF dossier by the ASMF holder is synchronized to arrive simultaneously with the planned variation or marketing authorisation application. Therefore, close communication between the MAH or applicant and the ASMF holder is highly recommended.

Effective liaison between the MAH and the ASMF holder will promote the appropriate classification of the changes in accordance with the EMA/CMDv Guidance on the details of the classification of variations requiring assessment and ensure that the ASMF dossier or the relevant affected sections of the dossier have been submitted.

The latest version of the ASMF submitted in the context of a previous centralised procedure will be considered the current version of that ASMF. The current version of the ASMF should correspond to the version of the ASMF applicant’s part declared in a new marketing authorisation application or variation application form and included in the relevant part of the dossier. This will be subject to compliance checks during validation of the MAA and variation.

Example:

The version of EMEA/ASMF/12345 (EMEA/ASMF reference number) currently held at the Agency is: AP January 2012/RP April 2013.

If the version of the ASMF included in the dossier of the marketing authorisation application and referenced in the application form is AP November 2011, the applicant will be requested to update the dossier and the application form according to the current version of the EMEA/ASMF/12345.

Equally, if the version of the ASMF included in the dossier of the marketing authorisation application and referenced in the application form is AP December 2012, the ASMF holder will be requested to submit the latest version of the ASMF together with annex 3 of the ASMF guideline.

References:

What is the ASMF reference number?

From 1 September 2013, ASMF holders submitting their ASMF dossiers relating to a centrally authorised product (CAP) are asked to send it to the Agency and Committee members only once.

According to the new ASMF submission rules the Agency will assign a reference number on request prior to submission of the ASMF that can cover multiple CAPs.

The ASMF reference number is an internal reference number sequentially assigned by the EMA to enable an appropriate data lifecycle management of ASMFs used in one or more centralised marketing authorisations.

The ASMF reference number does not replace the responsibility of the ASMF holders to version control their ASMF (in accordance with good manufacturing practice) nor replaces their own ASMF numbering system.

The ASMF reference number will follow one of these structures:

  • EMEA/ASMF/XXXXX: this structure of ASMF reference number will be allocated when the ASMF is used in a marketing authorisation application in the centralised procedure and or in a variation for a centrally authorised product. The ASMF in this instance is not following the ASMF assessment worksharing procedure.
  • EU/ASMF/XXXXX: this structure of ASMF reference number will be allocated when the ASMF follows the ASMF assessment worksharing procedure. This ASMF reference number can be allocated either by EMA (if the first submission of the ASMF is within a centralised marketing authorisation application or variation) or by the corresponding NCA (if the first submission of the ASMF is within a marketing authorisation application or variation in the decentralised procedure (DCP)).

References:

Who should request an ASMF reference number?

The ASMF reference number should be requested by the ASMF holder for:

  • new ASMFs submitted for marketing authorisation applications and variations as of 1 September 2013. From this date, reference to an ASMF reference number will be checked at validation,
  • ASMFs submitted to the EMA before 1 September 2013 in cases where the ASMF is referenced in a new marketing authorisation application or variation. The request for the ASMF reference number should be made before submission of a new marketing authorisation application or variation to update the ASMF.

For previously submitted ASMFs, in cases where the ASMF is used in more than one marketing authorisation the ASMF holder should only request one ASMF reference number, when applicable[1]. The allocated ASMF reference number should be communicated to the applicant or MAH, as they need to include the ASMF reference number in all future submissions.

When and how to request an ASMF reference number?

Up to two weeks before submitting a complete new ASMF, or an update to an already submitted ASMF that has not been allocated yet an EMEA/ASMF or EU/ASMF reference number, the ASMF holder should request an ASMF reference number. To submit your request, raise a ticket via EMA Service Desk, using the Question option. The type of question to be selected is “Request for high-level procedure or ASMF number” followed by sub-option “ASMF number” and attaching the ASMF number request form. To raise a ticket via EMA Service Desk you need an EMA account. Should you not have one, you may create one via the EMA Account Management portal.

ASMF reference numbers are sequentially allocated. A request form is available.

The ASMF reference number allocated should be referenced in all subsequent communications (e.g. in response to validation issues, list of questions, list of outstanding issues, upcoming variation) and should always be included in the following documents:

  • Marketing authorisation application (application form: in the field ‘National ASMF number’ if it is an EMEA/ASMF reference number or in the field ‘EU ASMF reference Number if available’ if it is an EU/ASMF reference number) or variation application form (in the field ‘Present and Proposed’);
  • Letter of access (annex 2 of the ASMF guideline);
  • Submission letter and administrative details (annex 3 of the ASMF guideline).

It is the responsibility of the ASMF holder to inform the applicant of the marketing authorisation application or the MAH in case of variations of the allocated ASMF reference number. Failure to state a valid ASMF reference number on the application form will trigger validation questions and may delay the start of procedure.

References:

Should I have an EMEA/ASMF or an EU/ASMF reference number?

ASMF holders should either have an EMEA/ASMF reference number or an EU/ASMF reference number before submitting an ASMF to EMA, but never both.

If an ASMF that is going to be submitted for the first time to EMA already has an EU/ASMF reference number previously allocated by an EU Competent Authority, the ASMF holder should not request to EMA either an EMEA/ASMF reference number or an EU/ASMF reference number. The EU/ASMF reference number allocated previously to that ASMF is the one to be used for the submission to EMA.

The EU/ASMF reference number allows for the identification by all Competent Authorities (National Competent Authorities and EMA) of ASMFs used in the ASMF assessment worksharing procedure. This procedure can be used for ASMFs that support marketing authorisations or variations in the centralised, decentralised and mutual recognition procedures.

ASMF holders are encouraged to request an EU/ASMF reference number if the ASMF is expected to be used in centralised and national applications (decentralised and mutual recognition procedures) and have not been used in any of these procedures previously.

For more information on the ASMF assessment worksharing procedure and the EU/ASMF reference number request template form please consult the Heads of Medicines Agencies website (Working Group on ASMF Procedures).

References:

Which format and submission channel should be used for submitting ASMFs? (Rev. October 2020)

Currently the following formats are accepted for ASMF submissions for veterinary applications:

  • Electronic VNeeS.
  • Common Technical Document (CTD): electronic (NeeS and eCTD).

Submissions of veterinary medicinal product dossiers in eCTD format cannot be accepted by regulatory authorities. However, a specific provision applies for ASMF dossiers. Please consult the document Exceptions to the VNeeS format for further details.

Guidance on the electronic formats can be found on the eSubmission website (VNeeS and NeeS).

References:

Submission to the EMA

As indicated above (see: When and how to request an ASMF reference number?), ASMF holders should request the ASMF reference number via EMA Service Desk using the request form available. However, it is reminded that ASMFs submitted in support of marketing authorisation applications or variations for veterinary medicinal products should be submitted for the attention of Veterinary Applications (vet.applications@ema.europa.eu).

From 1 January 2017 all ASMF submissions to the Agency in respect of veterinary medicinal products must be made using the eSubmission Gateway / Web Client Portal. Further guidance is available on the Veterinary eSubmission website. 

Submission requirements for the rapporteurs and co-rapporteurs

For Centrally Authorised Products, the ASMF holders submit applications only once to the European Medicines Agency and there should be no further CDs/DVDs or CESP submissions to any individual Member States as distribution will take place electronically between the European Medicines Agency and the National Competent Authorities. Submissions sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all CVMP members, alternates and National Competent Authorities.

The above also apply to the submission of responses to list of questions and list of outstanding issues.

References:

How to proceed if there is an existing life-cycle for the ASMF?

ASMF holders need to request the EMEA/ASMF reference number by filling in the request form. The EMA will provide the requestor with the number within 3 working days. Please note that this number is not equivalent to the EU/ASMF reference number and should never be inter-changed.

If the ASMF holder already has more than one lifecycle filed for the given substance, they will need to select one of these (informing the EMA in the cover letter which one it will be) and follow the lifecycle of the selected ‘product’ only. This selected lifecycle will then receive a new EMEA/ASMF/01xxx number covering all listed CAPs.

When the ASMF holder submits an update or new version to the ASMF, they have to do so with this new number. The ASMF holder will have to prepare a new package where they declare (in the cover letter) that the previously submitted ASMF version has not been modified since it was last submitted.

If there have been modifications (new version) since the last ASMF submission, the relevant parts of the ASMF dossier will have to be updated.

ASMF holders have to inform all MAH(s) about the new EMEA/ASMF/xxxxx number and if an update is submitted to an ASMF related to their centrally authorised product the MAH should then submit the relevant variation application.

References:

[1] Example: substantially different route of synthesis/manufacturing process which results in changes to important quality characteristics of the active substance, e.g. bioavailability of the active substance, may result in the allocation of two different EMEA/ASMF numbers.

Samples (i.e. the finished veterinary medicinal product) for testing the proposed medicinal product are not required to be submitted with an application.

The CVMP may however request the testing of samples of the medicinal product and/or its ingredients during the assessment of the application in accordance with the provisions of Article 29(1)a of Regulation (EU) 2019/6.

In this case the rapporteur and/or co-rapporteur will specify a test protocol (type of samples, number of samples, number of batches, testing to be performed and methods and specifications to be used) and agree with the Agency which Official Medicines Control Laboratory (OMCL) will carry out the required testing.

Sampling and testing will be co-ordinated by the Agency in collaboration with the European Directorate for the Quality of Medicines and Healthcare (EDQM).

The results of the tests are reported to the rapporteur and co-rapporteur and the CVMP for consideration in finalising the CVMP Assessment Report.

References:

2.3 Compliance, environmental risk assessment and pharmacovigilance

Importing site / supervisory authority

According to Article 97(6) of Regulation (EU) 2019/6, each batch of a veterinary medicinal product must be certified by a qualified person prior to release onto the market in the EEA.

In the case of products imported from a third country, and for the purpose of Article 97(7) of Regulation (EU) 2019/6, the site where the certification of batches by the qualified person occurs is considered to be the importing site in the EEA, and not necessarily the site through which the batch first physically enters the EEA. The EEA includes EU member states plus Iceland, Liechtenstein and Norway. Switzerland is not part of the EEA.

The supervisory authority is the competent authority of the member state that granted the manufacturing authorisation provided for in Article 88(1) of Regulation (EU) 2019/6 in respect of the manufacture of the medicinal product concerned. In the case of products imported from third countries, the supervisory authority is the competent authority of the member state that granted the manufacturing authorisation provided in 88(1) of Regulation (EU) 2019/6 to the importer, unless a mutual recognition agreement (MRA) covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured.

In the exceptional circumstances where a valid manufacturing authorisation is not in place at the time of the marketing authorisation submission for any finished product manufacturer, importer or batch-release site located in the EEA, the Agency will consult the supervisory authority and a request for inspection may be triggered. The marketing authorisation procedure will require the inspection outcome before opinion and, in particular, confirmation of the granting of the manufacturing authorisation.

For any finished product manufacturer located in third countries with no MRA that is not in possession of a GMP certificate at the time of the marketing authorisation submission, a request for inspection will normally be triggered. The marketing authorisation procedure will require the inspection outcome before opinion.

Batch testing upon importation:

For medicinal products imported from third countries, retesting of each batch within the EEA upon importation is required unless a mutual recognition agreement (MRA) or other relevant agreement covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured. If such an MRA is in operation, batch controls and tests carried out in the country where the product is manufactured are acceptable.

It should be noted that MRAs cover batch control and testing and do not cover batch release. Batch release must take place in the EEA territory for every production batch released to market in the EEA, regardless of whether an MRA with the exporting country is in place or not.

For the countries that have operational MRAs with the EU, see website on MRAs. Batch release of an imported medicinal product from a third country without retesting is a serious failure of a Qualified Person's legal obligations. It is expected that member states' supervisory authorities launch appropriate administrative measures and may suspend the manufacture of the product concerned or the manufacturing authorisation (Article 133 of Regulation (EU) 2019/6).

Contracting out of certain controls:

Certain of the controls required under the provisions of Article 97 of Regulation (EU) 2019/6 is allowed to be contracted out to third parties, if justified, and provided that the laboratories have been verified by the relevant competent authorities. Laboratories used for contract testing upon importation of medicinal products manufactured in third countries may be located in any EEA country.

The qualified person of the manufacturing authorisation holder named in the application is however responsible for ensuring that any contract laboratory used carries out the controls in accordance with GMP, as applicable and with the requirements of the marketing authorisation, once granted.

References:

With the eligibility request to the centralised procedure for a veterinary medicinal product containing or consisting of genetically modified organisms (GMOs) within the meaning of Article 2(2) of Directive 2001/18/EC, the applicant will be required to provide confirmation that all obligations under the Directive have been complied with.

In cases where there is a lack of clarity about whether the application falls within the meaning of Article 2(2) of Directive 2001/18/EC or whether the animals treated with the veterinary medicinal product would fall within this meaning it is important to contact the Agency as early as possible.

In the case of a medicinal product containing or consisting of GMOs within the meaning of Article 2 of Directive 2001/18/EC, the application must be accompanied by:

  • a copy of any written consent or consents of the competent authorities to the deliberate release into the environment of the GMOs for research and development purposes where provided for by Part B of Directive 2001/18/EC;
  • the complete technical dossier supplying the information requested in Annex III and Annex IV to Directive 2001/18/EC, the environmental risk assessment resulting from this information in accordance with the principles set out in Annex II to Directive 2001/18/EC and the documents required under Part C of Directive 2001/18/EC;
  • the results of any investigations performed for the purposes of research or development.

These particulars should be presented within Part 3.E (in the case of immunological VMPs) or Part 3.A.6 (in the case of biological VMPs that are not immunologicals). This folder should stand-alone and should be able to be handled separately from the remainder of the dossier.

A copy of the written consent(s) of the competent authorities regarding GMO release in the environment should be also included in Annex 5.13 of the application form in Part 1.

Regulation (EU) 2019/6 requires that the rapporteur hold necessary consultations with the competent national authorities under Directive 2001/18/EC, where the medicinal product contains or consists of a GMO.

Once the application has been validated, the EMA will send a copy of the timetable to the competent authorities under Directive 2001/18/EC. These competent authorities will be given the opportunity to request Part 3.E (for immunological VMPs) or Part 3.A.6 (for biological VMPs that are not immunologicals) of the application dossier from the applicant. This request will be channelled via the EMA which will forward the requested information to the competent national authorities under Directive 2001/18/EC.

The risk assessment submitted with the application will be considered in conjunction with the assessment of quality, safety and efficacy according to the requirements laid down in Annex II to Regulation (EU) 2019/6 amended by Commission Delegated Regulation (EU) 2021/805, and will be assessed by the rapporteur, co-rapporteur or their experts.

The competent authorities under 2001/18/EC will be asked to provide any questions they may have on the dossier or assessment to the rapporteur or such person designated by the rapporteur, with a copy of any questions to the EMA.

The final conclusion, however, remains with the Committee, which, having assessed the quality, safety and efficacy data provided by the applicant in support of its product, shall discuss the benefit versus the risk of the use of the product and shall recommend or not the granting of a European Union marketing authorisation.

References:

Under Article 8(1)(c) of Regulation (EU) 2019/6, a summary of the PSMF must be included in the dossier accompanying an application for a new marketing authorisation. This obligation will apply as of 28 January 2022, the date of entry into application of the Regulation.

Applicants or marketing authorisation holders shall have in place one or more pharmacovigilance system master files (PSMF) for their authorised products. A PSMF can cover more than one product, preferably all products authorised to the same marketing authorisation holder, but for each product the marketing authorisation holder can only have one PSMF. The PSMF should describe in detail the pharmacovigilance system with respect to the authorised veterinary medicinal products of the marketing authorisation holder. The PSMF is not part of the marketing authorisation application (MAA) dossier. All PSMFs should be available for inspection or for submission to regulatory authorities upon request. Changes to a PSMF summary can be made through variations not requiring assessment.

The marketing authorisation holder shall designate one or more qualified person responsible for pharmacovigilance (QPPV), but no more than one for each PSMF.  The tasks of the QPPV are described in Article 78 of Regulation (EU) 2019/6. The PSMF and QPPV requirements also apply to products that were authorised under the previous legislative basis.

Transition from DDPS to PSMF

Article 77(2) of the VMP Regulation provides that the marketing authorisation holder must have a PSMF in place for all its authorised veterinary medicinal products. This applies equally to both new and existing products. The PSMF is a key part of the pharmacovigilance system itself. In practice, the PSMF will be the basis for inspections to take place under the VMP Regulation. Therefore, as of 28 January 2022, there must be a PSMF in place for all products on the market.

Details on the process will be added in due course. 

References:

Formerly relevant references:

3. Submission, validation and fees

In order to fulfil EU dossier requirements applicants must submit new marketing authorisation applications as follows:

Languages to be used:

All applications have to be submitted in English.

Format of submissions:

The e-dossier follows the structure of Annex II of Regulation (EU) 2019/6 as amended by Commission Delegated Regulation (EU) 2021/805. Details on the structure are provided in the “Guideline on the specifications for provision of an electronic submission (e-submission) for a veterinary medicinal product” published on the Vet eSubmission webpage. CTD format is also accepted for Part 2: Quality documentation (physicochemical, biological and microbiological information) of veterinary dossiers. The use of CTD is also addressed in the aforementioned guideline.

Guidance has been prepared by the Veterinary Harmonisation Group, made up of representatives from national competent authorities, the Agency and industry, to assist applicants in the preparation of their dossiers. EMA-specific guidance has been published by the Agency.

The use of the electronic Application Forms (eAFs) is mandatory for the Centralised Procedure. The Agency strongly recommends the use of a single electronic application form per submission, even if the submission concerns multiple target species/strengths/pharmaceutical forms.

Information on the electronic application form can be found on the eSubmission eAF webpage.

Active Substance Master File (ASMF):

In cases where an Active Substance Master File (ASMF) exists, the applicant should ensure that the ASMF is submitted by the ASMF holder to the Agency at around the same time as the main application, in order to proceed with the validation of the dossier. See: Question “How shall I submit an Active Substance Master file (ASMF)?” and related questions to ASMF submissions.

Submission to the EMA:

The eSubmission Gateway / Web Client is the mandatory submission channel that should be used for submission of all veterinary applications.

More information on how to register and connect to the Gateway / Web Client as well as training materials on the use of the system can be found on the eSubmission Gateway / Web Client webpage. An automated ‘acknowledgement’ email is sent from the system to the applicant.

Submission to the rapporteur and co-rapporteur:

Since 1 June 2018, the use of the Common Repository is mandatory for all CVMP members to retrieve submissions. Therefore, the applicant should submit their dossier only once, via the EMA eSubmission Gateway / Web Client. For further information, please consult “Dossier requirements for submission of marketing authorisation and maximum residue limit (MRL) applications to the European Medicines Agency (EMA) and to members of the Committee for Medicinal Products for Veterinary use (CVMP)”.

No parallel submissions to rapporteur, co-rapporteur or other committee members is required.

Validation of the application

In the event that the Agency requires additional data, information or clarification in order to complete its validation of the dossier, it will contact the applicant requesting to supply this information within a specific time limit. When supplying the Agency with this information, the applicant is not required to submit any additional copy of this information to the rapporteur and co-rapporteur as they would be able to retrieve this information via the Common Repository. In this case, the validation can only be completed after receipt and verification of the information submitted.

After validation of the application, the Agency will notify the applicant accordingly in writing. The same notification will also be sent to the rapporteur and co-rapporteur and all other CVMP members.

At that stage, the application will be considered to have been delivered to all national competent authorities (NCA), CVMP members, alternates and scientific experts.

A full overview of the submission requirements is available on the Agency webpage.

The Agency also publishes validation checklists for marketing authorisation applications which are used by the Agency and applicants are encouraged to use them as a means to review in advance of their submission that standard requirements are fulfilled.

References:

In the same way as it is important for applicants to plan their application strategies for an efficient use of their resources, it is important for the Agency, CVMP members and experts to be able to plan and allocate their workload efficiently. If the actual submission date is several months after the date originally indicated, the rapporteur and co-rapporteur may find it difficult to provide the necessary expertise and appointment of new rapporteurs could be necessary.

The Agency advises applicants to consider the date of submission very carefully and to notify the Agency, rapporteur and co-rapporteur of a realistic submission date. Furthermore, applicants are requested to notify the Agency, rapporteur and co-rapporteur as soon as possible when the earlier notified submission date cannot be met.

Four months before submission, applicants should request confirmation from the Agency of eligibility to the centralised procedure for their marketing authorisation application (MAA) and provide the intended date of submission. This should be done using the pre-submission request form, selecting 'Centralised procedure - Eligibility request' as the scope of the request. This should be sent via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets. For further details on timelines see Question: "How and when should the request for eligibility to the centralised procedure be sent to the European Medicines Agency?".

The appointment procedure for rapporteurs and co-rapporteurs is triggered by the submission of the eligibility request and will be initiated four months prior to the MAA intended submission date. See:Question "What is the procedure for appointment of CVMP rapporteurs/co-rapporteurs and their assessment teams?”.

Delay in submission: applicants are requested to notify the Agency as soon as possible when the previously notified submission date cannot be met, via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets. For planning purposes applicants are required to provide a new submission date at the time they notify the Agency of the delay in the submission.

Withdrawal of requests: Should applicants no longer wish to pursue the submission of their application, they should notify the Agency of their intention to withdraw the request for submission of a marketing authorisation application. The notification should be sent via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets. It is not necessary to enclose any additional forms with the email notifying the withdrawal of request to submit a marketing authorisation application. The procedure will be closed accordingly.

The submission deadlines and full procedural detailed timetables are published as a generic calendar on submission dates, available on the Agency website. The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates and milestones that occur during the procedure. Applicants should ensure that a technically valid submission is received by the Agency before the submission deadline. Any technically invalid applications will result in non-acceptance, which may cause a delay in the start of the procedure.

For more information on the requirements for the submission and for the route for submission of the application, see question “How and to whom shall I submit my dossier?”.

References:

Marketing authorisation applications (MAAs) submitted to the Agency as part of the centralised procedure are subject to a validation process. The objective is to make sure all essential regulatory elements required for scientific assessment are included in the MAA prior to the start of the procedure.

There are two elements to validation:

  • technical validation, which takes place once an electronic application has been received by the Agency. This ensures that the structure of the submission is compliant with the EU specification for electronic dossiers for veterinary medicinal products;
  • regulatory and administrative content validation, which can only commence once the application has successfully passed technical validation.

What to expect once an MAA has been submitted to the Agency

Once submitted to the Agency in the agreed standard format, the Agency performs as a first step a technical validation. If the submission is technically invalid the outcome of this technical validation is communicated to the applicant.

If the dossier is technically invalid and a replacement is not delivered by the submission deadline, the start of the procedure is automatically postponed to the next month, as only technically valid and complete applications can be subject to the regulatory and administrative content validation process. This also applies to ASMF submissions.

If any issues are found during the regulatory and administrative content validation, the Agency will issue a request for additional information (validation-supplementary-information (VSI) request) to the applicant. Applicants will have to respond to this request and resolve any validation issues before the scientific evaluation can start.

Validation checklists are used by the Agency to validate marketing authorisation applications. Applicants should use them as a means to review in advance of their submission that standard requirements are fulfilled.

The Agency will communicate the outcome of the validation to the applicant. A positive outcome means that the scientific evaluation will start on the next available start date according to the Agency's timetables and the applicant will be invoiced for the relevant fee. A negative outcome means that the applicant will have to submit a new application and will be invoiced for a negative validation administrative fee.

References:

Fees for obtaining and maintaining a centralised authorisation to market medicinal products for veterinary use in the European Union are levied in accordance with Regulation (EC) No 297/95.

For information on the level of fees applying, including cancellations and fees reductions applicable to certain categories of applicants/marketing authorisation holders or products, please refer to the latest published version of the “Rules for the implementation of Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency and other measures” and the “Explanatory note on fees payable to the European Medicines Agency” available at Fees payable to the European Medicines Agency.

Applicants and marketing authorisation holders being levied a fee by EMA for the first time should contact EMA's accounts team to request a customer account number.

The fee will become due on the date of the notification of the administrative validation and will be payable within 45 calendar days. Approximately 15 days after notification of validation an invoice will be sent to the applicant’s billing address.

The invoice will contain details of the product and type of procedure involved, the fee amount, financial information and the customer purchase order number associated with the procedures invoiced (if provided in the eSubmission delivery file). The Agency does not accept stand-alone notifications of purchase order numbers that are not associated with a dossier.

If the application is found not to be valid an administrative fee will be charged by the Agency.

For queries on fees related to veterinary medicinal products, applicants should use the EMA fees query form available via this link: Contacting the Agency about fees.

References:

The following definitions of strength apply for applications submitted through the centralised procedure or the mutual recognition/decentralised procedures:

  • For single-dose preparations, total use, the strength is defined as the amount of active substance per unit dose.
  • For single-dose preparations, partial use, the strength is defined as the concentration expressed as the amount of active substance per ml, per actuation (puff), per drop, per kg, per m2, or in percentage, as appropriate.
  • For multi-dose preparations, the strength is defined as the concentration expressed as the amount of active substance per ml, per actuation (puff), per drop, per kg, or per m2, as appropriate.
  • For powders for reconstitution (powders for oral solution or suspension, powders for solution for injection, etc.) the strength is defined as the concentration after dissolution or suspension (reconstitution) to the volume specified, with the liquid recommended.
  • For concentrates for solution (for injection or for infusion) the strength is defined as the concentration of the concentrate before dilution.

These definitions will be taken into account for the calculation of fees, as well as for the allocation of EU numbers for presentations used by both the European Medicines Agency and the Commission.

No additional strengths or presentations can be applied for by the applicant after the validation of the application. Such changes can be introduced after the marketing authorisation has been granted through a variation procedure.

References:

Applicants may benefit from fee incentives if at the time of the administrative validation the application or the applicant itself meets the criteria for a fee reduction or deferral. Any changes which may take place after validation would not retrospectively affect the levied fee.

For information on fees, including cancellations and fee reductions applicable to certain categories of applicants/marketing authorisation holders or products, please refer to the latest published version of the “Rules for the implementation of Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency and other measures” and the “Explanatory note on fees payable to the European Medicines Agency” available at  Fees payable to the European Medicines Agency.

SMEs

Applicants which meet the definition of a micro, small or medium-sized enterprise (SME) as set out in Regulation (EC) 2049/2005, are eligible for certain fee reductions from the Agency. This includes fee reductions for scientific advice, pre- and post-authorisation inspections, scientific services, MRL applications, and a full fee waiver for administrative services (with the exception of parallel distribution).

Deferral of the fee payable for the application for marketing authorisation or related inspections may also apply.

It should be noted that fee reductions and deferrals can only be considered once the applicant has been assigned SME status by the Agency. SME applicants wishing to receive written confirmation of a fee reduction and/or deferral should address an email to the Agency’s SME Office.

Further information on the level of fee reductions/deferrals available to SME applicants and how to request them is available on the designated SME website.

Other

Requests for fee reductions may be granted by the Executive Director in exceptional circumstances and for imperative reasons of public or animal health under the terms of paragraph 1 of Article 9 of Regulation (EC) No 297/95 on fees payable to the European Medicines Agency. A formal request for fee reduction addressed to the Executive Director citing Article 9 paragraph 1 is required (see standard operating procedure), providing details of the product, procedure type and applicable fee, and the reason(s) for the request that justify exceptional circumstances and imperative reasons of public or animal health.

References:

On receipt of a submission, details of the product/procedure are entered into a tracking database which attributes product and procedure numbers.

The numbering system aims to allow for a clear identification of any application for the granting, variation, transfer or re-examination of a European Union marketing authorisation for any product and for any of its presentations throughout its life cycle.

The name and the active substance(s) of the product primarily identify applications for the granting of a European Union marketing authorisation for a medicinal product. However for administrative purposes, each application is also given a core number composed of four sections: EMEA/V/C/…, where V stands for veterinary, C for centralised procedure with the remainder corresponding to a sequentially allocated and unique number identifying the whole of the application. This core number, which is provided after the submission of the initial application for marketing authorisation and communicated to the applicant at the start of the procedure, is retained throughout the life cycle of the product.

In every case of an administrative procedure relating to the product, an additional marker denoting the nature of the procedure is appended to this core number, i.e. for the initial application for the granting of the marketing authorisation, any variation, transfer or re-examination of marketing authorisation. A sequential number is added, too. A sequential number is also added for referral procedures affecting centrally authorised products (CAP). The markers currently used are as follows:

Marker

Procedure

Example

/0000

Initial application for marketing authorisation

EMEA/V/C/000789/0000

VRA/xxxx

Variations requiring assessment (regardless of procedural length)

EMEA/V/C/000789/VRA/0001

WSxxxx

Worksharing

EMEA/V/C/WSXXXX

EMEA/V/C/000789/WS/0002

/G

Grouping

EMEA/V/C/000789/VRA/0003/G

S/xxxx

Re-examination of marketing authorisations in exceptional circumstances

EMEA/V/C/000789/S/0004

LM/xxxx

Re-examination of marketing authorisations for limited markets

EMEA/V/C/000789/LM/0005

T/xxxx

Transfer of MA

EMEA/V/C/000789/T/0006

Z/xxxx

(Lifting of) Suspension of MA

EMEA/V/C/000789/Z/0007

A/xxxx

Referral or related procedure

EMEA/V/C/000789/A82/0008

EMEA/V/C/000789/A130/0009

These numbers are used as a reference by the EMA and should be used by the applicant/marketing authorisation holder in all correspondence relating to a certain procedure.

Variations not requiring assessment are processed in UPD and will be assigned automatically a submission identifier. Therefore, they do not follow the numbering system described above.

Presentations

Throughout the first application for the granting of the marketing authorisation, EMEA numbers covering all presentations are assigned. This is mainly relevant during evaluation of the procedure and for the purpose of identifying single presentations. (For correspondence, it is sufficient to indicate the procedural number as above).

A sequential three digit number for each presentation is added to the procedural number (core number plus procedural marker). An example is given below for a product consisting of three different presentations:

Marker

Procedure

New presentations

Initial application for marketing authorisation

EMEA/V/C/000789/0000

EMEA/V/C/000789/0000/001

EMEA/V/C/000789/0000/002

EMEA/V/C/000789/0000/003

For all procedures creating new presentations, this numbering system is superseded after marketing authorisation by the EU numbers, which would from then onwards appear in the CVMP opinions and product information. The EU number is allocated independently of the EMEA number, but retains the principle of identifying each single presentation by ending in a three digit sequential number.

4. Assessment of the application

4.1 Procedure

Once the application is validated, the Agency starts the procedure at the monthly start date published on the EMA website.

The Agency shall ensure that the opinion of the CVMP is given within 210 days not including any clock-stops for the applicant to provide answers to questions from the CVMP. The timetable can be extended by a maximum of 90 days, in accordance with Article 44(2) of Regulation (EU) 2019/6, or shortened to 150 days in exceptional cases, in accordance with Article 44(3) of Regulation (EU) 2019/6. See: Question “Is my veterinary medicinal product eligible for an accelerated review?”.

In general, the following 210-day standard timetable will apply:

ACTION

DAY 1

Start of the procedure

Day 70

Rapporteur's assessment report and comments on the product information sent to the co-rapporteur, CVMP members and the Agency.

Day 85

Co-rapporteur's critique of the rapporteur's assessment report and comments on the product information sent to rapporteur, CVMP members and the Agency. The rapporteur’s assessment report including the co-rapporteur's critique and comments on the product information are sent to the applicant by the Agency (making it clear that the document(s) do not represent the position of the CVMP).

Day 100

Rapporteur, co-rapporteur, other CVMP members and the Agency receive comments from members of the CVMP.

Day 107

Receipt of draft list of questions (including overall conclusions and overview of the scientific data) from rapporteur and co-rapporteur by CVMP members and the Agency.

Day 120

CVMP adopts the list of questions, the overall conclusions and review of the scientific data, and comments on the product information which are sent to the applicant by the Agency.
Clock stop.
At the latest by day 120, adoption by CVMP of request for GMP inspection, if necessary (inspection procedure starts).

Day 121*

Submission of the responses, including revised SPC, labelling and package leaflet text in English and restart of the clock.

* Target dates for the submission of the responses are published on the Agency website (see recommended submission dates)

After receipt of the responses, the procedure is re-started. In general, the following standard timetable will apply:

ACTION

DAY 1

Day 140

Member States provide QRD comments on the product information to the Agency. The Agency sends these comments to rapporteur and co-rapporteur.

Day 160

Joint assessment of responses and comments on product information from rapporteur and co-rapporteur received by CVMP members and the Agency. The Agency sends joint assessment of responses and comments on product information to the applicant (making it clear that it only sets out their preliminary conclusions, that it is sent for information and does not represent the position of the CVMP).

Day 170

Deadline for comments from CVMP members to be sent to rapporteur and co-rapporteur, the Agency and other CVMP members.

Day 180

CVMP discussion and decision on the need for a list of outstanding issues (LoOI) and/or an oral explanation by the applicant. Submission of final inspection report, if applicable, to the Agency, rapporteur and co-rapporteur by the inspections team (at the latest by day 180).
CVMP adopts the LoOI, the overall conclusions and review of the scientific data, and comments on the product information, if applicable, which are sent to the applicant by the Agency.
Clock stop.

Day 181*

Submission of the responses, including revised SPC, labelling and package leaflet text in English and oral explanation (if needed).
Restart of the clock.

* Target dates for the submission of the responses are published on the Agency website (see recommended submission dates).

After receipt of the responses, the procedure is re-started. In general, the following standard timetable will apply:

ACTION

DAY 1

Day 190

Joint assessment of responses and comments on product information from rapporteur and co-rapporteur received by CVMP members and the Agency. The Agency sends joint assessment of responses and comments on product information to the applicant (making it clear that it only sets out the preliminary conclusions of the rapporteurs, that it is sent for information and does not represent the position of the CVMP).
Rapporteur and co-rapporteur circulate Draft CVMP assessment report to CVMP members and the Agency.

Day 197

Deadline for comments from CVMP members to be sent to rapporteur and co?rapporteur, the Agency and other CVMP members.

By day 210

Adoption of CVMP opinion + CVMP assessment report + product information

Within 15 days after adoption of CVMP opinion

Transmission to applicant of CVMP opinion + CVMP assessment report + product information.

Upon adoption of the CVMP opinion, the Agency will inform the applicant within 15 days as to whether the opinion is favourable or unfavourable (including the grounds for the unfavourable outcome, if applicable).

Re-examination

In accordance with Article 44(4) of Regulation (EU) 2019/6, an applicant may give written notice to the Agency that he/she wishes to request a re-examination within 15 days of receipt of the opinion. The detailed grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion. Article 141(4) of Regulation (EU) 2019/6 establishes that the re-examination procedure may deal only with the points of the opinion initially identified by the applicant in the grounds for re-examination and may be based only on the scientific data available when the Committee adopted the initial opinion.

A positive opinion may be subject to re-examination as long as the request for re-examination relates to aspects of the opinion in relation to which there had been objections by the Committee, further to which the applicant opted to amend the application. In such cases, the applicant, when submitting the amended documentation, (e.g. revised product information) prior to the opinion, will need to reserve the right to re-examination in the covering letter.

Applicants should refer to the Agency website for further specific Guidance on re-examination of CVMP opinions.

Linguistic review

After adoption of a positive CVMP opinion, the preparation of the annexes to the Commission Decision is carried out in accordance with the following timetable:

DAY

ACTION

Day 215 at the latest

Applicant provides the Agency with SPC, Annex II, labelling and package leaflet in all EU languages, Icelandic and Norwegian

By day 229

Member states will send linguistic comments on the product information by e-mail with a copy to the EMA together with QRD Form 1

Day 235

Applicant provides the Agency with SPC, Annex II, labelling and package leaflet in all EU languages, taking account of comments received from member states (QRD form 2)

By day 237

Agency transmission of opinion and Annexes in all EU languages to the applicant, Commission and members of the Standing Committee, Norway and Iceland

239-261

Draft Commission Decision
Standing Committee Consultation

277

Final Commission Decision

 

Further details on the post-opinion review of translations and forms to be used, are available on the Agency website (see guidance on the linguistic review process).

References:

Peer review is a process by which other members of the CVMP review the rapporteur's and co?rapporteur’s scientific evaluation, as well as the validity of the scientific and regulatory conclusions reached. It applies to the assessment of marketing authorisation applications, and also to variations of marketing authorisations, MRL applications and referrals.

Peer review is part of a quality assurance system established at CVMP level to enhance the scientific scrutiny of documents presented to the committee thereby enhancing their scientific quality and consistency. The peer reviewer is expected to review and provide comments on the key document(s) detailing the rapporteurs’ scientific recommendations during the initial assessment phase as well as during any later assessment phase following responses to questions. In this way the peer reviewer plays an important role in ensuring the quality of the assessment reports from the rapporteur and co?rapporteur and provides an important contribution on topics where there are divergences in the scientific assessments performed by the rapporteur and co-rapporteur.

On appointment of the rapporteur and co-rapporteur during a CVMP meeting, the Committee also appoints peer reviewers. The Committee also decides on the number of peer reviewers to be assigned to each specific product/procedure.

Peer reviewers' comments are not made available to applicants. Moreover, it is not intended that applicants directly contact peer reviewers or other CVMP members in the context of an ongoing CVMP assessment.

References:

The Quality Review of Documents (QRD) group operates under the mandate adopted by the EMA Management Board and was initially created on the European Commission's proposal. The group's objective is to facilitate the streamlining of the European decision-making process.

The QRD group is composed of one representative per Member State with experience in regulatory affairs (designated by the national competent authority), and representatives of the Agency (which also provides secretariat facilities). The European Commission is invited to participate.

To date, the group has focussed on the creation of linguistic templates for EMA scientific opinions, and it will continue to work on the controlled upgrade of these. However, the mandate sets out a series of tasks, namely:

  • verification of terminology used in translations of opinions and their consistency with the original version of documents,
  • ensuring linguistic and other formal coherence and consistency between different terminology used in scientific opinions, and promotion of initiatives towards the standardisation of terminology,
  • review and update of opinion templates,
  • promotion of legibility of information and verification of specimens of sales presentations/mock-ups in all EU official languages,
  • consideration of issues which could lead to delays in the Commission's decision-making process and possible development, on request, of advice (particularly with a view to contribute to the development of common understanding on the implementation of legislation and guidelines).

The mandate also provides that "the Group shall develop its own working methods" and will consider "how best it may be associated with the different stages of the evaluation and decision-making process".

A major task of the QRD group is to agree on standard templates for the different types of opinions that the CVMP adopts. This to ensure consistency and accuracy of translations of the product information (summary of product characteristics, labelling, package leaflet) attached to the scientific CVMP opinions and consistency with the legislative requirements in force.

The QRD's product information templates:

  • Set out the standard headings and indicate the most commonly used standard phrases and terms in the official EU languages.
  • Define the format and layout for summary of product characteristics (SPC); labelling and package leaflet (see QRD convention to be followed for the EMA-QRD templates).
  • Provide useful guidance as to the content of the information to be supplied (see QRD veterinary product information annotated template).

The templates are intended to provide applicants with practical advice on how to draw up the product literature, but without prejudice to any final position of the CVMP and European Institutions as to the contents of the document. Similarly, the templates and guidance are without prejudice to the binding nature of the relevant legislation, or as to any legal interpretation to be given by the European Commission or the Court of Justice of the European Union.

QRD reference documents provide more detail guidance on various aspects concerning terminology and style.

Legal requirements: while the template and guidance notes aim to provide practical hints to the applicants, in particular in relation to how to address common problem areas, they are by no means a comprehensive guide to the information required to be included in the product literature. Thus applicants must also refer to the current Union legislation, CVMP guidelines, etc., when drawing up their drafts in order to be able to fully comply with the legal requirements with respect to product literature.

References:

In order to request a change of the applicant, the following documents need to be submitted as part of responses to the Day 120 List of Questions or Day 180 List of Outstanding Issues:

  • A letter requesting the change of applicant and signed by both the previous and the new applicant. Use of this letter facilitates the process to cover required confirmations.
  • A confirmation (within the abovementioned cover letter) that the complete and up-to-date file concerning the veterinary medicinal product, or a copy of this file, has been made available to or has been transferred to the new applicant.
  • An updated application form and its affected annexes (includes proof of establishment of the new applicant within the Union (EEA) issued in accordance with national provisions and which should be no older than 6 months).
  • Updated product information.
  • Any other documents of the marketing authorisation dossier affected by the change of applicant e.g. an updated Letter of Access for an application that includes an Active Substance Master File.

The checkbox ‘contains request for change of applicant’ should be ticked in the eSubmission Gateway & eSubmission Web Client Delivery file user interface, as failure to do so may lead to significant delays in processing the change of applicant request. 

As a consequence of a change of applicant, any fee invoiced following the initial validation (i.e. fee for initial marketing authorisation and pre-authorisation inspection fee) will be credited to the original applicant and re-invoiced to the new applicant. This will include changes, if any, relating to micro, small or medium-sized enterprise.

Applicants are advised to contact the Agency via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets as early as possible if a change of applicant is proposed.

References:

4.2 Inspections

For all inspections requested by the CVMP in respect of an application under the centralised procedure, fees are payable by the applicant in accordance with Regulation (EC) 297/95.

For information on the level of fees applying, including cancellations and fees reductions applicable to certain categories of applicants/marketing authorisation holders or products, please refer to the latest published version of the “Rules for the implementation of Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency and other measures” and the “Explanatory note on fees payable to the European Medicines Agency” available at  Fees payable to the European Medicines Agency.

The fee will become due on the date of the receipt of the inspection report. Approximately 15 days later an invoice will be sent to the applicant’s billing address held on the Agency’s file.

For inspections outside the EEA/European Union the applicant is also required to pay the travel and accommodation expenses of the inspector(s) and any experts or rapporteur involved in carrying out the inspection(s). These expenses are to be paid directly by the applicant to the inspector’s authority.

References:

For the scientific review of centralised applications for marketing authorisations for medicinal products the Agency relies on the expertise located in the Member States.

The same approach exists in the area of GCP inspections that are conducted by the Member States' relevant regulatory authorities. These inspections are conducted on behalf of the European Union and co-ordinated by the Agency if they pertain to centralised applications or referrals.

According to Regulation (EU) 2019/6, Article 9(4), clinical trials shall be carried out taking due account of the international guidelines on good clinical practice of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (‘VICH’), (CVMP/VICH/595/98). Data stemming from clinical trials conducted outside the Union may be taken into consideration for the assessment of an application for a marketing authorisation only if those trials were designed, implemented and reported in accordance with the international guidelines on good clinical practice of the VICH [Regulation (EU) 2019/6, Article 9(6)]. Applicants should follow the application dossier requirements described in Annex I and Annex II of Regulation (EU) 2019/6.

CVMP may request an inspection if concerns arise during the evaluation process that can only be addressed by an inspection. An inspection request would most likely be adopted at day 120 of the evaluation procedure, at the same time as the list of questions. The inspection will be conducted in parallel to the clock stop period.

In the event that an inspection request is adopted, the applicant is notified within 5 working days following the CVMP meeting. This notification includes the sites and study(-ies) to be inspected.

Fees and expenses are charged in accordance with the current regulations and guidelines.

References:

Legislative basis

Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products states that manufacturing authorisation holders are obliged to comply with good manufacturing practice for veterinary medicinal products and use as starting materials only active substances which have been manufactured in accordance with good manufacturing practice for active substances and distributed in accordance with good distribution practice for active substances.

Compliance with the principles and guidelines on good manufacturing practice (GMP) is mandatory within the European Economic Area (EEA). Interpretation of these requirements is provided in part I of the Good Manufacturing Practice (GMP) Guidelines, published in Volume 4 of the rules governing medicinal products in the European Union. Part II of this guide provides for the detailed guidelines on good manufacturing practice for active substances used as starting materials.

The guide to Good Manufacturing Practice consists of detailed guidelines (part I and part II) which are supplemented by a series of annexes specific for certain types of product, or for a particular topic.

Inspections will follow “The Compilation of Community Procedures on Inspections and Exchange of Information” which is published by EMA on behalf of the European Commission on the EMA Inspections page.

Pre-submission notification

In their notification of intention to submit, applicants should mention the name and address of the proposed manufacturer(s) of the active substance(s) and finished product; and the name and address of the proposed site(s) in the EEA responsible for batch release of the medicinal product. If the medicinal product is imported from a third country, it should also include information on GMP inspections of the site(s) concerned carried out in the last 2-3 years by EEA competent authorities or by competent authorities of countries where a Mutual Recognition Agreement (MRA) is in operation, as applicable.

Final manufacturing and batch release arrangements will have to be provided when submitting the application.

A description of the roles of all different sites involved should be included. The manufacturing sites mentioned should be in compliance with Good Manufacturing Practice and hence be "inspection ready" at the time of submission of the application and throughout the assessment. Manufacturing sites in third countries should be aware of European Union GMP requirements as mentioned below.

Once the application is received, it is normally not permitted to add a new site or to change the steps of manufacture/release described in the dossier during the 210 day assessment procedure. Any additional site should be submitted as a variation after the granting of the marketing authorisation.

At receipt of the application, EMA determines if satisfactory inspection information is available. If not, EMA with the rapporteur and co-rapporteur will ask the CVMP to request an inspection of the manufacturer of either the active substance or the medicinal product in order to complete the assessment.

The conduct of these inspections by the EEA competent authorities will be co-ordinated by EMA.

Inspection team

The team will be drawn from the inspection services of the supervisory and other competent authorities of the EEA. On the advice of the rapporteur and/or co-rapporteur the inspection team may include scientific experts and/or a rapporteur for the inspection.

Type of inspection

Inspections may be carried out to verify compliance with Community good manufacturing practice principles and guidelines and/or to cover product or process related issues arising from the assessment of the application. Inspections may cover the following activities:

Manufacture of the Active Substance:

The detailed guidelines on good manufacturing practice adopted by the EEA for the manufacture of the active substance are contained in part II of the EU Guide to Good Manufacturing Practice (Good Manufacturing Practice for Active Pharmaceutical Ingredients) in "The Rules Governing Medicinal Products in the European Union - Volume 4". Inspectors of the competent authorities in the EEA will inspect against the requirements of this guideline.

Manufacture of the Finished Product:

The GMP principles and guidelines applying to the manufacture of medicinal products for veterinary use in the EU are laid down in Commission Directive 91/412/EEC, which are re-stated along with part I of the EU Guide to Good Manufacturing Practice in "The Rules Governing Medicinal Products in the European Union - Volume 4".

Where a manufacturing site is located in the EEA it is normally not necessary to request an inspection to confirm its GMP status as it is required by the above-mentioned Directive to be regularly inspected by the relevant authorities.

An inspection will normally be requested to confirm the GMP compliance status of manufacturing sites in third countries unless satisfactory information is available from an inspection of the same or similar category of product carried out during the last 2-3 years by an EEA competent authority or by the competent authority of a country where a MRA is in operation, as applicable.

In all cases (for sites in the EEA and third countries), an inspection may be requested to cover product or process related issues arising from the assessment of the application. In this case the rapporteur and/or co-rapporteur will provide the inspection team with a list of questions/issues, which should be addressed during the inspection.

Importing Site - Site located in the EEA:

Importing sites in the EEA are required by the provisions of Chapter VI of Regulation (EU) 2019/6, to hold a manufacturing authorisation. Inspections of importing sites to confirm their GMP compliance status are not normally requested in connection with applications for marketing authorisations. Inspections may however be requested to cover product or process related issues arising from the assessment of the application. In this case the rapporteur and/or co-rapporteur will provide the inspection team with a list of questions/issues, which should be addressed during the inspection.

Timetable for inspections

Inspection(s) requested in connection with an application for a marketing authorisation must be carried out and the final report(s) sent to EMA and submitted to the CVMP in accordance with the 210-day time limit for the evaluation of the application by the CVMP.

Once an inspection request is adopted by the CVMP, EMA will write to:

  • the applicant explaining that an inspection(s) will take place, giving details (target date for carrying out the inspection, inspection team, scope of the inspection, contact person in the relevant authority responsible for arranging the inspection);
  • the rapporteur and co-rapporteur for information.

The inspection team will contact the company to determine the inspection dates within the agreed target date. Inspections usually take place in parallel with the "clock stop" period and will approximately be conducted within two months from the adoption of the inspection request.

Inspection reports

Inspectors will send the draft inspection report to the manufacturer within fifteen days of the inspection for comments on major factual errors, any point(s) of disagreement or remedial actions. Where necessary, the manufacturer should respond within a further fifteen days to provide comments and, if necessary, an action plan with a timetable for implementation. This will be considered during the finalisation of the inspection report.

The timing of any discussions, further actions and/or the provision of additional information arising from the inspection will be agreed with the inspectors and communicated by the inspectors to the rapporteur, the co-rapporteur and EMA.

Inspectors will finalise the report and send it to EMA by day 180 at the latest. The report will be circulated to the rapporteur and co-rapporteur. In case of an unsatisfactory inspection report, which cannot lead to a positive opinion on the application for marketing authorisation, discussions between EMA, the rapporteur, the co-rapporteur and the applicant should take place.

Documents for inspection

A site master file for use in preparing and carrying out the inspection will be necessary. The preferred format is given in Part III of the Good Manufacturing Practice (GMP) Guidelines and is the same as that recommended by the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The applicant should supply this document directly to the Inspection Team when requested by it. The site master file is not required to be submitted to EMA.

References:

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