Q&A: 21-37

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This page lists questions 21 to 37 of the European Medicines Agency’s questions and answers on pre-submission guidance for veterinary medicinal products.

The page is 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 topics are marked as “New” or “Rev.” on publication.

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21. How shall I submit an Active Substance Master File (ASMF)? (Rev. January 2017)

Annex I to Directive 2001/82/EC describes the concept of an open and closed Active Substance Master File (ASMF) and specifies that:

“For a well-defined active substance, the active substance manufacturer or the applicant may arrange for the following information to be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File:

(a) a detailed description of the manufacturing process;

(b) a description of the quality control during manufacture;

(c) a description of the process validation.

In this case, the manufacturer shall, however, provide the applicant with all of the data, which may be necessary for the latter to take the responsibility for the medicinal product…”

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 as variations are to be submitted 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 the Notice to Applicants (NtA), 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 including all necessary documents is synchronized to arrive simultaneously with the marketing authorisation application or variation. Therefore, a 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 (e.g. ASMF dossier) are received in a satisfactory form. This also applies to the ASMF-related responses during a procedure (e.g. 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 in the Heads of Medicines Agencies website (Working Group on ASMF Procedures).

Non-applicability of ASMF concept to biological active substances

Further to clarifications from the European Commission on the interpretation of Directive 2001/82/EC, and 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

21.1 What data should be submitted by the ASMF holder? (Rev. January 2017)

In the first submission of an ASMF with an allocated EMEA/ASMF reference number (see below), or for the introduction of an already submitted ASMF to the marketing authorisation of a different medicinal product (e.g. ASMF submitted to the Agency for medicinal product A is now being used for medicinal product B), the ASMF holder is required to submit:

  • ASMF dossier (applicant’s part, restricted part, quality overall Summary (if CTD format) or detailed and critical summary (if NtA format), and expert’s curriculum vitae) only in the case of a first ASMF submission;
  • Letter of access (annex 2 of the ASMF guideline);
  • Submission letter and administrative details (annex 3 of the ASMF guideline) duly filled as detailed in the instructions provided in the additional guidance on documents relating to an active substance master file;
  • A commitment to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter or within the letter of access (annex 2 of the ASMF guideline).

In any later marketing authorisation application or variation submission referencing to an already submitted ASMF with an allocated EMEA/ASMF reference number, 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 previous procedure is valid throughout the product’s lifecycle;
  • Submission letter and administrative details (annex 3 of the ASMF guideline) dully filled 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 reflecting changes to the previously accepted version, as applicable. This includes applicant’s part and/or restricted part, as applicable;
  • A commitment to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter or within the letter of access (annex 2 of the ASMF guideline) only if a letter of access is needed (see above).

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 vet.applications@ema.europa.eu directly for pre‑submission questions regarding classification of changes in the restricted part of the ASMF.

References:

21.2 What data should be submitted by the applicant or MAH? (Rev. January 2017)

Initial marketing authorisation applications

In all cases, the applicant (in the context of an initial marketing authorisation application) 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;
  • a copy of the complete current version of the applicant’s part of the ASMF in the relevant part of the dossier;
  • a copy of the commitment from the ASMF holder to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter in annex 5.11 or within the letter of access (annex 2 of the ASMF guideline) in annex 5.10.

Variations to the terms of the marketing authorisation

In all cases, 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 Type II variation (B.I.a.1.b – Introduction of a manufacturer supported by an ASMF), in addition to the documents mentioned above, the MAH should also submit:

  • a copy of the letter of access (Annex 2 of the ASMF guideline);
  • a copy of the complete current version of the applicant’s part of the ASMF in the relevant part of the dossier;
  • a copy of the commitment from the ASMF holder to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter or within the letter of access (annex 2 of the ASMF guideline).

The MAH or the applicant should ensure that the submission of the ASMF dossier is synchronized to arrive simultaneously with the planned variation or marketing authorisation application. Therefore, a 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 Commission’s variations guideline and for ensuring that the ASMF dossier or the relevant affect sections of the dossier have been submitted.

In the case of type IA and IB variations, the use of the IA and IB pre-notification checklist is recommended prior to the submission of the application. This is intended to help the MAH with the correctness of the submission and to avoid validation comments that may delay the finalisation of the procedure.

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.

21.3 What is the EMEA/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 EMEA/ASMF/XXXXX 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 EMEA/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.

21.4 Who should request an EMEA/ASMF reference number? (Rev. January 2017)

The EMEA/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 EMEA/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 variations. The request for the EMEA/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 EMEA/ASMF reference number, when applicable*. The allocated EMEA/ASMF reference number should be communicated to the applicant or MAH, so that reference to the EMEA/ASMF/XXXXX number is made in all future submissions.


*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. 

21.5 When and how to request an EMEA/ASMF reference number? (Rev. January 2017)

Up to two weeks before submitting a complete ASMF, or an update to an already submitted ASMF, the ASMF holder should request and EMEA/ASMF reference number. The request should be sent to PA-BUS@ema.europa.eu.

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

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

  • Marketing authorisation application (in the field ‘National ASMF number’ of the application form) 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 EMEA/ASMF reference number. Failure to state a valid EMEA/ASMF reference number on the application form will trigger validation questions and may delay the start of procedure.

References:

21.6 Should I have an Agency or an EU ASMF reference number? (Rev. January 2017)

The EU/ASMF reference number allows for the identification by all Competent Authorities (National Competent Authorities and EMA) of ASMFs used in centralised and national (decentralised and mutual recognition) marketing authorisation applications or variations, and therefore enable the ASMF Assessment Report Work Sharing (ASMF AR WS) procedure.

For more information on the ASMF AR WS and the request template forms please consult the Heads of Medicines Agencies website (Working Group on ASMF Procedures).

ASMF holders should either have an EMEA/ASMF reference number or an EU/ASMF reference number before submitting an ASMF. Both numbering systems run in parallel. 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.

References:

21.7 Which format and submission channel should be used for submitting ASMFs? (Rev. January 2017)

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

  • Notice to Applicants: paper or electronic (VNeeS).
  • Common Technical Document (CTD): paper or electronic (NeeS).

Electronic submission is strongly encouraged. ASMF holders, applicants and MAHs are reminded that eCTD format is not accepted for veterinary submissions.

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

References:

Submission to the EMA

As indicated above, ASMF holders should request the EMEA/ASMF reference number to PA-BUS@ema.europa.eu 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

ASMF holders must submit the application to the rapporteur and co-rapporteur, otherwise there may be a delay in the start of the procedure due to the time lapse between the validation by the Agency and the confirmation from the rapporteur/co-rapporteur that they have received the dossier. The submission to the rapporteur and co-rapporteur should be sent at the same time as the submission is sent to the Agency.

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

References:

21.8 How to proceed if there is an existing life-cycle for the ASMF? (Rev. January 2017)

ASMF holders need to request the EMEA/ASMF reference number by filling 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 life-cycle 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 life-cycle of the selected ‘product’ only. This, selected life-cycle will, then receive a new EMEA/ASMF/01xxx number covering all listed CAPs.

Once the ASMF holder is submitting 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:

22. What shall I submit if my veterinary medicinal product contains or consists of genetically modified organisms (GMOs)? (Rev. January 2014)

With the letter of intention to submit an application for a marketing authorisation under 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(1) and 2(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 A to Directive 2001/18/EC and the environmental risk assessment resulting from this information.
  • the results of any investigations performed for the purposes of research or development.

These particulars should be presented as follows:

  • as an attachment to the relevant parts of the application dossier (Parts 1 and 3.E), and
  • in a separate volume or electronic copy, which could stand alone and which could be handled separately from the remainder of the dossier.

Regulation (EC) No 726/2004 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 secretariat will send a copy of the timetable to the CVMP chairman and members, the applicant and the competent authorities under Directive 2001/18/EC. These competent authorities will be given the opportunity to request Part 3.E of the application dossier from the applicant. This request will be channelled via the EMA secretariat 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 I to Directive 2001/82/EC, as amended, 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 secretariat.

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 risk versus the benefit of the use of the product and shall recommend or not the granting of a European Union marketing authorisation.

References:

23. What information shall I provide if my veterinary medicinal product contains or uses in the manufacturing process materials of animal and/or human origin? (Rev. January 2014)

For each application the applicant must fulfil the requirements laid down in the Annex I to Directive 2001/82/EC, 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 effected by submitting Certificates of Suitability from the European Directorate for the Quality of Medicines (EDQM), or by inclusion in the dossier (Part 2.D) 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 and the Annex I to Directive 2001/82/EC, 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:

24. Where on my veterinary medicinal product information can I mention a local representative? (Rev. January 2014)

Some holders of European Union marketing authorisations have requested that a local contact point be identified in the package leaflet and on the outer carton. This would normally be the holder of the European Union marketing authorisation. However, where a marketing authorisation holder wishes to add the name of another (local) contact point in some or all EEA countries, the local representative may be indicated:

  • in the package leaflet, under heading 15, by name, address, telephone number and e-mail address (as per the latest QRD template);
  • in the blue box on the outer carton by name and, if space permits, by address, telephone number and e-mail address.

References to addresses on the internet are not allowed, neither for the marketing authorisation holder nor the local representatives.

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, with representing him in a defined (geographical) area; this contract excludes any transfer of any responsibility imposed on the marketing authorisation holder by European Union law and by national law, regulation and administrative action implementing such European Union law.

There has been some confusion with regard to terms such as 'exploitant', 'technical director', 'distributor', etc. Since there is neither a commonly agreed understanding of these terms nor equivalent legal definitions of these terms amongst the EEA countries, and in the absence of any reference or definition in European Union law, reference to such terminology will not be accepted for a medicinal product authorised by the European Union.

It must be recalled that, under the case-law of the EC Court of Justice, EEA countries may not require that a local representative of the marketing authorisation holder be appointed for their territory. Therefore, the arrangements outlined above are purely optional for holders of European Union marketing authorisations.

Attention should be drawn to the fact that in cases where the manufacturer is different from the marketing authorisation holder, only the actual manufacturer responsible for batch release should be mentioned in the package leaflet in addition to the marketing authorisation holder.

References:

The Rules Governing Medicinal Products in the European Union, Volume 6, Notice to Applicants

25. How and to whom should I submit my dossier? (Rev. January 2017)

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:

A dossier, including the application form, product literature (SPC, labelling and package leaflet) and the detailed and critical summaries can be submitted either in hard copy (“paper submission”), or electronically (“e-submission”). While the use of electronic submissions for applications for veterinary medicinal products remains optional the Agency strongly encourages the submission of electronic only applications.

The e-dossier follows the structure of the Notice to Applicants, Volume 6B. 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”. CTD format is generally not appropriate for veterinary dossiers. However, exceptions might be possible for the chemical, pharmaceutical and biological/microbiological information for the finished product (Part 2), but need to be confirmed prior to submission of the dossier.

Guidance has been prepared by the former Telematics Implementation Group on electronic submission (veterinary subgroup) (TIGes-Vet), 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 Agency has published a new formatted table template to be inserted in cover letters, found here.

Active Substance Master File (ASMF):

In cases where anActive 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 and the Web Client are electronic submission channels that can be used for submission of all veterinary applications since 1 April 2014. From 1 January 2017 all procedural submissions to the Agency must be made using the eSubmission Gateway / Web Client Portal.

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 website. Applicants must not send duplicate submissions electronically or via CD-ROM or DVD as this might lead to delays in the handling of applications.

An automated ‘acknowledgement’ email is sent from the system to the applicant. There is no need to send any accompanying hard media or separate paper cover letters for these submissions, as the cover letter will be in add-info folder of the dossier in PDF format.

The use of an electronic submission channel is strongly encouraged.

All applications should be sent to the attention of:

Veterinary Applications
Veterinary Medicines Department
European Medicines Agency
30 Churchill Place
Canary Wharf
London E14 5EU
United Kingdom

Submission to the rapporteur and co-rapporteur:

In parallel to submitting the application to the Agency, applicants must submit the application to both the rapporteur and co-rapporteur. Otherwise there may be a delay in the start of the procedure because of the time lapse between the validation by the Agency and the confirmation from the rapporteur and co-rapporteur that they have received the dossier.

The above method and requirements also apply to the submission of responses to lists of questions and outstanding issues.

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 should also send a copy of this information to the rapporteur and co-rapporteur. In this case, the validation can only be completed after receipt and verification of the information submitted.

If the rapporteur and co-rapporteur have not received their copy of the dossier or validation additional information on the day when the dossier is validated by the Agency, the start of the procedure may be delayed until the procedural starting date of the next month.

Submission requirements for other committee members

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.

Upon receipt of this notification, the applicant should send the application to all other CVMP members forthwith, including any additional data or information supplied during the validation phase as appropriate.

A full overview of the submission requirements for all CVMP members and alternates, their names and contact details is available on the Agency webpage.

References:

26. When shall I submit my application? (Rev. January 2014)

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 their re-appointment 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. Real-time calculation of submission dates will be followed by real-time preparation of the review procedure.

Seven months before submission, applicants should notify the Agency of their intention to submit a marketing authorisation application (MAA) and provide the intended date of submission. This should be done by using the pre-submission request form, selecting 'Centralised procedure - Intent to submit a MAA' as the scope of the request. This should be sent to vet.applications@ema.europa.eu.

The appointment procedure for rapporteurs and co-rapporteurs will be initiated seven 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?”.

Furthermore, applicants are requested to notify the Agency, rapporteur and co-rapporteur as soon as possible when the previously notified submission date cannot be met, by re-sending an updated pre-submission request form, selecting 'notification of change - applicant /contact person details' as the scope of the request.

Applicants are finally requested, if they no longer wish to pursue the submission of their application, to notify the Agency of their intention to withdraw the request for submission of the MAA. This should be done by using the pre-submission request form, selecting 'withdrawal of request' as the scope of the request. This should be sent electronically vet.applications@ema.europa.eu.This will close the case procedure and the whole pre-submission history.

The submission deadlines and full procedural detailed timetables are published as a generic calendar on submission dates. 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.

The date and time of delivery of the dossier to the Agency should be arranged between the applicant and the Agency. The applicant will be informed of recommended submission dates. The recommended dates for applications to be submitted to the Agency are also available on the Agency web site.

In order to accelerate and facilitate the procedure, applicants are invited to submit, in parallel to the Agency, copies of the dossier to both the rapporteur and the co-rapporteur. Otherwise there may be a delay in the start of the procedure because of the time lapse between the validation by the Agency and the confirmation from the rapporteur and the co-rapporteur that they have received the dossiers.

Soon after the notification of a valid application, the Agency will send an invoice to the applicant. The fees should be paid within 30 days of the receipt of this invoice. For more information regarding the applicable fee, see question “What fee do I have to pay and how is the appropriate fee for my application calculated?” .

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

The address for submission of the application is:

Veterinary Applications
Veterinary Medicines Department
European Medicines Agency
30 Churchill Place
Canary Wharf
London E14 5EU
United Kingdom

References:

27. How are initial MAAs validated at the Agency? (Rev. January 2017)

Initial 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 initial MAA has been submitted to the Agency

Once submitted to the Agency in the agreed standard format, the Agency performs in 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 the replacement is not delivered by the intended 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 validation process. This also applies to ASMF submissions.

If any issues are found during 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 in order to resolve any validation issues before the procedure can start.

Validation checklists are used by the Agency to validate initial 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 the relevant fee. A negative outcome means that the applicant will have to submit a new application and will be invoiced a negative validation administrative fee.

References:

28. What timetable applies to the centralised procedure? (Rev. January 2014)

Once the application is validated and provided the rapporteur and co-rapporteur have confirmed that they have received the dossier, the Agency starts the procedure at the monthly starting date published on the EMA website. If, within a month from the start of the procedure, any other member of the CVMP has not received the requested parts of the dossier from the applicant, the Agency will stop the clock until confirmation is received that each member of the CVMP has been delivered the requested documentation. It is therefore important that applicants are able to provide a proof (upon request) of delivery to rapporteur, co-rapporteur and to CVMP members to the Agency.

A timetable is prepared by the Agency in consultation with rapporteur and co-rapporteur. This timetable is then presented to the CVMP for information.

The Agency shall ensure that the opinion of the CVMP is given within 210 days (less any clock-stops for the applicant to provide answers to question from the CVMP) in accordance with the following standard timetable, which can be shortened in exceptional cases. See: Question “Is my veterinary medicinal product eligible for an accelerated review?”

DAYACTION
Day 1Start of the procedure
Day 70Rapporteur's assessment report sent to the co-rapporteur, CVMP members and Agency secretariat
Day 85Co-rapporteur's critique of the rapporteur's assessment report sent to rapporteur, CVMP members and Agency secretariat. The rapporteur's assessment report and the co-rapporteur's critique are sent to the applicant by the Agency secretariat (making it clear that the document(s) do not yet represent the position of the CVMP.)
Day 100Rapporteur, co-rapporteur, other CVMP members and Agency receive comments from members of the CVMP. Between day 70 and day 100, a quality check on the English version of the product information is performed
Day 115Receipt 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 120CVMP adopts the list of questions as well as the overall conclusions and review of the scientific data to be 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 project manager will prepare a revised timetable in consultation with the rapporteur and co-rapporteur for the evaluation of the responses. In general the following standard timetable will apply:

DAYACTION
Day 160Joint response assessment report from rapporteur and co-rapporteur received by CVMP members and the Agency. The Agency sends joint response assessment report to the applicant (making it clear that it only sets out their preliminary conclusions, that it is sent for information and does not yet represent the position of the CVMP). Where applicable, inspection to be carried out
Day 170Deadline for comments from CVMP members to be sent to rapporteur and co-rapporteur, the Agency and other CVMP members
Day 180CVMP discussion of the draft opinion (SPC, labelling and package leaflet) and decision taken on the need for an oral explanation by the applicant. If oral explanation is needed, the clock is stopped to allow the applicant to prepare the oral explanation. Submission of final inspection report to the Agency, rapporteur and co-rapporteur by the inspections team (at the latest by day 180)
Day 181Restart of the clock and oral explanation (if needed). The project manager sends updated SPC and product literature in English to the applicant
By day 210Adoption of CVMP opinion + CVMP assessment report
Day 211Transmission to applicant of CVMP opinion + CVMP assessment report

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

DAYACTION
Day 215 at the latestApplicant provides the Agency with SPC, Annex II, labelling, package leaflet and Annex A in all EU languages, Icelandic and Norwegian
By day 229Member states will send linguistic comments on the product information by e-mail with a copy to the EMA together with QRD Form 1
Day 235Applicant provides the Agency with SPC, Annex II, labelling, package leaflet and Annex A in all EU languages, taking account of comments received from member states (QRD form 2)
By day 237Agency transmission of opinion and Annexes in all EU languages to the applicant, Commission and members of the Standing Committee, Norway and Iceland
239-261Draft Commission Decision
Standing Committee Consultation
By 277Finalisation of EPAR in consultation with rapporteur, co-rapporteur, CVMP and applicant (the latter for confidentiality aspects)
277Final Commission Decision

 Further details on the post-opinion review of translations and forms to be used, are available on the Agency website (product information templates - reference documents).

Once the veterinary medicinal product is authorised and in all cases before the product is placed on the market, mock-ups or specimens of the final outer and immediate packaging and the package leaflet must be submitted to the Agency. See: Question “When shall I submit mock-ups and/or specimens?”

References:

29. What is the CVMP peer review? (New January 2014)

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 new marketing authorisation applications, and also to other procedures: applications for line extensions and major identified type II 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. It consists of the review of the rapporteurs' assessment reports for the purpose of improving the quality of the day 120 list of questions and opinion by the CVMP members that are assigned by the committee as peer reviewers. It is also the particular task of those members assigned as peer reviewers to judge the quality of the assessment reports from the rapporteur and co-rapporteur especially in relation to potential divergences in scientific assessment made by the rapporteur and co-rapporteur.

A strengthened peer review system that can improve the consistency of scientific assessments is one of the objectives set out in the European Medicines Agency road map to 2015.

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 this task.

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 on-going CVMP assessment.

References:

30. How is an EMA application number attributed? (New January 2014)

The numbering system aims to allow for a clear identification of any application for the granting, extension, variation, transfer or renewal 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: EMA/V/C/…, where V stands for veterinary, C for centralised procedure and a unique number code for the product's identification is used.

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 first application for the granting of the MA, any extension, variation, transfer or renewal of MA. A sequential number is added, too. The markers currently used are as follows:

MarkerProcedureExample
/0000First new applicationEMEA/V/C/000789/0000
IA/xxxxType IA variationEMEA/V/C/000789/IA/0001
IB/xxxxType IB variationEMEA/V/C/000789/IB/0002
II/xxxxType II variation (regardless of procedural length)EMEA/V/C/000789/II/0003
X/xxxxExtension applicationEMEA/V/C/000789/X/0004
S/xxxxAnnual Re-assessmentEMEA/V/C/000789/S/0005
T/xxxxTransfer of MAEMEA/V/C/000789/T/0006
R/xxxxRenewal of MAEMEA/V/C/000789/R/0007
Z/xxxx(Lift of) Suspension of MAEMEA/V/C/000789/Z/0008

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

Presentations
In addition, the numbering system covers all presentations (pharmaceutical forms, strengths and pack sizes) of the product. This is mainly relevant during evaluation of the procedure and for the purpose of identifying single presentations in lists such as the Annex A to the opinion. (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, with two ensuing procedures creating new presentations:

MarkerProcedureNumbers in Annex A
First new applicationEMEA/V/C/000789/0000EU/2/13/123/001
EU/2/13/123/002
EU/2/13/123/003
Type II variation creating three new presentationsEMEA/V/C/000789/II/0004EU/2/13/123/004
EU/2/13/123/005
EU/2/13/123/006
Annex II application creating a further three new presentationsEMEA/V/C/000789/X/0005EU/2/13/123/007
EU/2/13/123/008
EU/2/13/123/009

NB: For all procedures creating new presentations, this numbering system is superseded after MA by the EU numbers, which would from then onwards appear in the Annex A to opinions. The EU number is allocated independently of the EMA number, but retains the principle of identifying each single presentation by ending in a three digit sequential number.

31. When can I expect a pre-approval GMP inspection and how are they conducted? (Rev. January 2014)

Legislative Basis

Directive 2001/82/EC states that manufacturing authorisation holders are obliged to comply with the good manufacturing practice (GMP) for medicinal products and to use as starting materials only active substances that have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials

The principles and guidelines for GMP for medicinal products for veterinary use are stated in Directive 91/412/EEC. Compliance with these principles and guidelines is mandatory within the European Economic Area (EEA), interpretation of these requirements is provided in part I of the Guide to Good Manufacturing Practice, 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.

The ad hoc GMP Inspection Services Group within the Agency is in charge of publishing a "compilation of procedures" on behalf of the European Commission to gather all these guidelines, outlining the quality system requirements for national GMP pharmaceutical inspectorates. The compilation is published on the ‘Inspections page’ of this website.

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 and/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 sequence of all different sites involved should be added. The manufacturing sites mentioned should be in compliance with Good Manufacturing Practice (GMP) 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 Community 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, the Agency determines if satisfactory inspections information is available. If not, the Agency with the rapporteur and co-rapporteur asks the CVMP to make a request for inspection of the manufacturer of either the active substance or the medicinal product in order to complete the assessment.

The performance of these inspections by the EEA competent authorities will be co-ordinated by the Agency taking into account:

  • Inspections carried out of the same manufacturers by the EEA Countries
  • Inspections carried out of the same manufacturers by competent authorities of countries where a MRA is in operation, when applicable
  • The advice of the rapporteur/co-rapporteur
  • Specific issues and questions raised during the assessment of the application

Inspection team

The team required to perform the inspection will be proposed and co-ordinated by the Agency secretariat. 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 as referred to in the provisions of Article 33 of Regulation (EC) No 726/2004.

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 Title III of Directive 2001/82/EC as amended, 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 the Agency 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 the Inspection sector of the Agency will write within 5 working days 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 agree 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.

If the manufacture of the product is carried out infrequently or is not scheduled to take place during the period when the assessment of the application is to take place, the inspection team and the rapporteur/co-rapporteur may agree to inspect the manufacture of a similar product or process.

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 and, if necessary, attached to it.

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 the Agency.

Inspectors finalise the report and send to the EMA inspections sector by day 180 at the latest, whichcirculate it to the rapporteur, co-rapporteur and CVMP. In case of an unsatisfactory inspection report, which cannot lead to a positive opinion, discussions between the Agency, the rapporteur, the co-rapporteur and the applicant should take place.

Documents for inspection

It is helpful to have a site/plant master file for use in preparing and carrying out the inspection. The preferred format is that recommended by the Pharmaceutical Inspection Co-operation Scheme (PIC/PICS). The applicant should supply this document directly to the inspection team as far in advance of the inspection as possible. The site/plant master file is however not required to be submitted to the Agency.

References:

32. Can I expect a pre-approval Good Clinical Practice (GCP) inspection? (Rev. January 2014)

The Agency relies for the scientific review of centralised applications for marketing authorisations for medicinal products on the expertise located in the member states.

The same approach exists in the area of inspections where inspections are conducted by member states' inspectorates on behalf of the European Community. These inspections, including the ones to evaluate compliance with GCP, are co-ordinated by the Agency if they pertain to centralised applications or referrals.

Clinical studies should be conducted in accordance with the Guideline on Good Clinical Practices (CVMP/VICH/595/98) and Annex I to Directive 2001/82/EC, as amended.

CVMP may request an inspection if significant concerns arise during the evaluation process that can only really be addressed by an inspection. It is most likely that an inspection request would be adopted at day 120 at the same time as the list of questions, and the inspection 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 studies to be inspected. Fees and expenses are charged in accordance with the current regulations and guidelines.

References:

33. What role does the EMA QRD group have and where can I find the templates for product information? (Rev. January 2014)

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 mandate states the group's objective as being "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.

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 also convention to be followed for QRD templates in order to ensure absolute consistency between all language versions).
  • Provide useful guidance as to the content of the information to be supplied (see also QRD template with QRD group explanatory notes).

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 Agency, 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 Communities.

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 Community 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:

34. How is a pre-submission meeting conducted at the EMA? (New January 2014)

General principle

The pre-submission meeting represents an important point in the product development and regulatory approval process, and relate 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 the applicant wishes to discuss may be added.

Guidance on the topics is provided in the Questions and Answers of the EMA pre-submission guidance for users of the centralised procedure. 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. 6-7 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.

Who is involved in a pre-submission meeting?

EMA participants at pre-submission meetings are normally the project manager for the application, if already appointed, and other staff members relevant for the product under consideration application and issues to be discussed. If exceptionally scientific issues are to be discussed sometimes also the (co-)rapporteurs, if already appointed, can be included, possibly via video/teleconference.

Please note that the project manager will usually be chairing the meeting and will remain the primary contact point between the applicant and the rapporteurs during the application procedure.

Documents to be prepared for a pre-submission meeting

  • The pre-submission meeting request form needs to be filled in electronically and sent to vet.applications@ema.europa.eu. 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 accurate 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, conditional approval) 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, and 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?

In general face-to-face meetings are held at the EMA but teleconferences are also possible.

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 minute 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 project manager who will participate to such a meeting via teleconference, where possible. In any case, minutes of such meetings should be provided to the EMA project manager.

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:

35. Do I qualify as a small or medium sized enterprise (SME)? (Rev. January 2014)

Incentives and assistance are available from the EMA for SMEs, which 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:

  • Administrative and procedural assistance from the SME Office at the Agency.
  • Fee reductions for scientific advice, scientific services, inspections and MRL applications (90% fee reduction).
  • Fee exemptions for certain administrative services (excluding parallel distribution).
  • Deferral of the fee payable for an application for marketing authorisation or related inspection.
  • Conditional fee exemption where scientific advice is followed and a marketing authorisation application is not successful.
  • Assistance with translations of the product information documents 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 enterprises employ less than 10 persons and have an annual turnover or balance sheet total not exceeding € 2 million;
  • Small enterprises have fewer than 50 employees and an annual turnover or balance sheet total of not more than € 10 million;
  • Medium 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 category (autonomous, partner or linked).

Depending on the category in which the enterprise fits, some or all of the headcount and financial data from other partner or linked enterprises may need to be counted when calculating whether the SME criteria are met.

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

A declaration of SME status (form available on EMA website on SMEs) should be submitted to the SME Office prior to requesting financial or administrative assistance from the Agency.

SME Office

The ‘SME office’ has been set up within the agency to address the particular needs of smaller companies. The office aims to facilitate communication with SMEs through dedicated personnel within the Agency who will respond to practical or procedural enquiries, monitor applications, and organise workshops and training sessions for SMEs.

Fee Reductions/Deferrals

SME applicants wishing to request a fee reduction and/or deferral should address a letter of intent to the SME Office (see below) of the EMA. 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 reductions/deferrals is available in the document “Fee reductions/deferrals for micro, small and medium-sized enterprises (SMEs)”.

Translation assistance

Because translating product information into all EU languages represents a considerable financial and administrative burden to SMEs entering the EU market, the EMA will provide for translation of product information documents (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 provision of the Norwegian and Icelandic translations according to the normal timelines and for the maintenance of all translations 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 checked through the national competent authorities in the member states (see also QRD product information - Tools used by the EMA to facilitate the streamlining of the European Decision Making process). 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 visit the SME Office section of the EMA website first. This section provides useful information on how to request SME status, and provides a link to useful information sources (e.g. the User Guide for Micro, Small and Medium-sized Enterprises (SMEs) on the administrative and procedural aspects of the provisions, laid down in Regulation (EC) No 726/2004, that are of particular relevance to SMEs).

For further information or requests please contact:

SME Office

Tel. +44 (0)20 3660 8575

E-mail: smeoffice@ema.europa.eu

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

References:

36. How can I get support from the EMA regarding emerging therapies and technologies? Role of the Innovation Task Force (ITF) (New January 2014)

In order to provide support to medicines innovation in 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 sectors 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 (i.e. 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 or working parties. Additionally, the briefing meetings complement and reinforce existing formal regulatory procedures e.g. scientific advice.
  • Requests for regulatory advice on the eligibility to EMA procedures e.g. marketing authorisation, scientific advice.

The scope of the ITF comprises support to veterinary medicines during the early stages of their development. For enquiries regarding suitability of the ITF in respect to their product or requests for ITF briefing meetings, applicants for innovative veterinary medicines are invited to send all potential applications to: vet.applications@ema.europa.eu.

For more information on Innovation Task Force and on how to request a briefing meeting or regulatory advice refer to the EMA Medicines and Emerging Science webpage. 

References:

37. Where can I find the relevant documents regarding the legislation concerning veterinary medicinal products (New January 2014)

The treaties on which the European Union and the European Communities are founded are available in the EUR-lex repository of European law. To exercise the Union’s competences, the institutions may adopt regulations, directives, decisions, recommendations and opinions.

Information about the hierarchy of the European Union texts can be found in the Annex I to Chapter 1 of Volume 6 of the Notice to applicants and regulatory guidance for medicinal products for veterinary.

The rules governing medicinal products in the European Union concerning medicinal products for veterinary use is published on the European Commission website:

  • Volume 4 – Good manufacturing practices for medicinal products for human and veterinary use;
  • Volume 5 – EU pharmaceutical legislation for medicinal products for veterinary use, contains most of the relevant Directives, Regulations, decisions and communications;
  • Volume 6 – Notice to applicants and regulatory guidance for medicinal products for veterinary use:
  • Volume 6A - Procedures for marketing authorisation:
    • Introduction;
    • Chapter 1 – Marketing authorisation;
    • Chapter 2 – Mutual recognition;
    • Chapter 3 – Community referral;
    • Chapter 4 – Centralised procedure;
    • Chapter 5 – Variations;
    • Chapter 6 – Community marketing authorisation for veterinary medicinal products;
  • Volume 6B - Presentation and content of the dossier: provides guidance for the compilation of dossiers for applications for marketing authorisation, and is applicable for the centralised procedure and national procedures, including mutual-recognition and decentralised procedures;
  • Volume 6C - Regulatory guidelines: related to procedural and regulatory requirements, e.g. renewal procedures, variation procedures, summary of product characteristics (SPC), package information and classification for the supply, environmental risks of veterinary medicinal products, definition of potential serious risk;
  • Volume 7 – Scientific guidelines for medicinal products for veterinary use (thisguidance is prepared by the CVMP, and are available on the EMA website (see below));
  • Volume 8 - Maximum residue limits;
  • Volume 9B – Pharmacovigilance for medicinal products for veterinary use.

The European Commission website offers the possibility to create a CD-ROM with the content of the rules governing medicinal products in the European Union, which can be used off-line with an integrated search engine.

Scientific guidelines related to quality, safety and efficacy are available on the Agency website, together with concept papers, draft guidelines and overviews of comments received during the consultation on draft versions.

The Agency also publishes procedural and technical guidance and document templates, which are intended to provide technical and procedural advice to applicants for marketing authorisations for medicinal products coming within the scope of the centralised procedure.

References

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