Other post-authorisation activities: questions and answers

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This page lists questions that marketing-authorisation holders (MAHs) may have on other post-authorisation activities. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.

A PDF version of the entire post-authorisation guidance is available:

These questions and answers have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, volume 2, notice to applicants.

MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.

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1. Which EMA inspection-related activities may occur during the post-authorisation phase?

The following inspection-related activities can occur during the post-authorisation phase:

  • verification of compliance with the principles of good manufacturing practice (GMP), good clinical practice (GCP) and good laboratory practice (GLP);
  • verification of compliance with pharmacovigilance obligations;
  • inspections of blood establishments under the plasma-master-file (PMF) certification system.

The Agency’s Inspections Sector activities that may occur during the post-authorisation phase include the following: verification of compliance with the principles of Good Manufacturing Practice (GMP), Good Clinical Practice (GCP), Good Laboratory Practice (GLP), verification of compliance with pharmacovigilance obligations and inspections of blood establishments under the Plasma Master File (PMF) certification system.

The Sector is responsible for co-ordinating any GMP, GCP, GLP, pharmacovigilance and blood establishment inspections requested by the CHMP in connection with the assessment of marketing authorisation applications, post-authorisation applications, PMF certificate applications and/or the assessment of matters referred to these committees in accordance with the EU legislation. These inspections may be necessary to verify specific aspects of the clinical or laboratory testing or manufacture and control of the product and/or to ensure compliance with GMP, GCP, GLP, pharmacovigilance obligations and quality assurance systems.

When the MAH anticipates the need for EMA inspections in the context of post-authorisation activities (e.g. addition of manufacturing site, submission of pivotal clinical data supporting new indications…), it is advised to contact the EMA in advance of submission in order to clarify the requirements and the timeframe applying to such inspections.

MAH is liable to pay a fee for each inspection specifically requested by CHMP or CVMP in the framework of post-authorisation activities. The basis for charging fees for inspections is provided by Council Regulation (EC) No 297/95, as amended, Article 3(4) refers in broad terms to the fee that may be charged for “any inspection”.

In addition, as part of the Agency’s responsibility for the coordination of the supervision of authorised medicinal products under practical conditions of use, the Agency, in cooperation with the European Directorate for the Quality of Medicines and Healthcare (EDQM), operates a sampling and testing programme.

Communication and action by Member States in response to suspected product defects relating to centrally authorised medicines are also coordinated by the Agency.

Apart from inspection and supervision related activities, the Agency has been given responsibility for issuing certificates of medicinal products in accordance with World Health Organization requirements. Certificates confirm the status of centrally authorised medicinal products and GMP compliance of the sites manufacturing the pharmaceutical forms.

The Agency also coordinates activities in connection with the GMP annexes of the various mutual recognition agreements that have been negotiated between the European Union and non-European countries.

References

  • Relevant references are available on the EMA inspection website

 

2. Can I request scientific advice or protocol assistance during the post-authorisation phase?

Scientific advice or protocol assistance can be requested during the initial development of the medicinal product (i.e. before submission of the marketing-authorisation application) and also during the post-authorisation phase.

Scientific advice or protocol assistance requested during the post-authorisation phase is generally related to, but is not restricted to the following cases:

  • The MAH may seek scientific advice or protocol assistance in the framework of:
    • a new formulation or dosage form;
    • an extension of indication;
    • a paediatric development plan;
    • a new or a change of manufacturing process.
  • The CHMP may request a 'protocol consultation from the Scientific Advice Working Party in the framework of specific obligations or follow-up measures in case of any outstanding issues identified by the (co-)rapporteurs after assessment of protocols proposed by the MAH for the fulfillment of such post-approval commitments. However, this procedure does not prevent the MAH requesting, on its own initiative, scientific advice or protocol assistance in the framework of specific obligations or follow-up measures when it wishes to get feedback from the CHMP on particular issues. In this case, the MAH should follow the usual procedure described above.
3. Could my medicinal product be subject of parallel distribution?

Centrally authorised medicinal products placed on the market of one Member State can be marketed in any other part of the European Union (EU) by a distributor ('parallel distributor') independently of the MAH.

The European Commission has given the Agency the responsibility to check compliance of parallelly distributed products with the conditions laid down in EU legislation on medicinal products and with the marketing authorisations. This includes the checking of mock-ups of outer and inner labelling, package leaflets, coloured copies of the repackaged presentations, and wholesale distribution and manufacturing authorisations.

Therefore, prior to initiating parallel distribution of a specific product, parallel distributors must notify the Agency in accordance with the frequently asked questions about parallel distribution.

The Agency will check the conformity of the proposed labelling and package leaflet with the text of the latest annexes to the marketing authorisation for the product concerned centrally authorised medicinal product within 30 working days following validation of the notification and will notify the parallel distributor of any objections or comments. If there are no objections or when objections have been completely addressed by the parallel distributor, the Agency will issue a notice and send it to the parallel distributor, the national competent authority of the Member State of destination, the national competent authority of the Member State where the parallel distributor is located (if different from the Member State of destination) and the MAH of the medicinal product, informing them that the regulatory check has been completed and indicating that the product proposed for parallel distribution complies with the terms of the marketing authorisation of the centrally authorised medicine concerned.

More details on parallel distribution are available in the frequently asked questions on parallel distribution, which parallel distributors, marketing authorisation holders and national competent authorities may have on the parallel distribution notification procedure. 

References

4. How do I notify the European Medicines Agency of changes to my Contact Persons specified in the application form? Rev. January 2016

Applicants and MAHs are required to notify the Agency of any upcoming changes to the following contact people as specified in the application form for initial marketing authorisation (sections 2.4.1-2.4.5 and 2.5.1.1), so that the EMA databases can be updated accordingly:

  • contact person at the MAH address (referred to in section 2.4.1 of the application form). As this contact person is used by the European Commission for notification of Commission decisions to the MAH, this information should be kept up to date and any changes (including during the post-authorisation phase) notified to the Agency promptly;
  • person or company authorised for communication between the MAH and the competent authorities (referred to in sections 2.4.2 and 2.4.3 of the application form). Section 2.4.2 refers to changes to the contact person during the initial application for marketing authorisation. After authorisation of the medicinal product, changes to the person or company authorised for communication with the Agency (referred to in section 2.4.3 of the application form) should be notified to the Agency promptly;
  • qualified person in the European Economic Area (EEA) for pharmacovigilance (referred to in section 2.4.4 of the application form).

With regard to the qualified person in the EEA for pharmacovigilance (QPPV), please refer to question “How to inform the authorities of a change in the summary of the pharmacovigilance system?” in the Pharmacovigilance system section of the post-authorisation guidance.

  • Scientific service of the MAH in the EEA as referred to in Article 98 of Directive 2001/83/EC (referred to in section 2.4.5 of the application form)
  • Contact person in the EEA for product defects and recalls, as defined in Article 79 of Directive 2001/83/EC (referred to in section 2.5.1.1 of the application form)

Any of the above changes should be notified exclusively in writing on company headed paper by fax or letter (which can also be sent electronically) and should be addressed to Product and Application Business Support (PA-BUS) only.

Applicants and MAHs are advised to use this template for these notifications.

Reference

5. How and to whom shall I submit my application?

5.1. Submission to the EMA

From 1 March 2014, the use of the eSubmission Gateway or Web Client is mandatory for all electronic Common Technical Document (eCTD) submissions through the centralised procedure. The European Medicines Agency (EMA) no longer accepts submissions on CD or DVD. This applies to all applications for human medicines.

More information on how to register and connect to the Gateway / Web Client can be found in the eSubmission website and detailed information on the required naming conventions and file formats can be found in European Medicines Agency eSubmission Gateway: Questions and answers relating to practical and technical aspects of the implementation and the eSubmission Gateway web client: Guidance for applicants.  Applicants must follow the CAP Dossier Requirements document and not send duplicate submissions electronically or via CD-ROM or DVD or via CESP as this might lead to delays in the handling of applications. For the submission of non-Centrally Authorised Products or submissions in other than eCTD format, please refer to the “Dossier Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device” document.

An automated acknowledgement email is sent from the system confirming whether the submission has passed the relevant technical validation criteria and whether it has been uploaded to the Agency’s review tool and made available via the Common Repository. There is no need to Applicants must not send any accompanying hard media or separate paper cover letter as the cover letter will be in the relevant part of eCTD module 1 in PDF format.

Where applicable, revised product information Annexes (including Annex A, if applicable) should be included in electronic (Word and PDF) format in the same eSubmission Gateway / or eSubmission Web Client package within a folder called ‘working documents’.Where applicable changes in Word documents should be indicated using ‘Tools-Track Changes’. Clean PDF versions should have all changes ‘accepted’

5.2. Submission to the (Co-) Rapporteurs and other Committee Members

Submissions sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all National Competent Authorities’ representatives and alternates. This will apply to all types of Human Centralised Procedure eCTD submissions, including PMF submissions and ASMF submissions related to centrally authorised products submitted in eCTD format.

For the dossier requirements of the (Co-) Rapporteurs and other Committee members, including delivery addresses where applicable, please refer to the following document: Dossier requirements for Centrally Authorised Products (CAPs).

For the submission of non-Centrally Authorised Products or submissions in other than eCTD format, please refer to the “Dossier Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device” document.

For the particularities concerning applications under Worksharing and PSUR which may include nationally authorised products please check the information in the respective sections of the Post-authorisation Guidance.

Where applications are amended during the agency’s review, such as e.g. responses to a request for supplementary information or a withdrawal, new or consolidated eCTD sequence should be provided in order to maintain the eCTD life-cycle. The same applies in case the outcome of the variation application review is unfavourable for one or more changes applied for (mixed outcome).

Please note that the EMA only accepts submissions made in eCTD format. Any exceptions to this rule can be found from the “Dossier Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device” document.

Please also refer to the TIGes Harmonised Guidance for specific advice on eCTD Submissions.

For practical aspects of eCTD dossier submission under the Variation Regulation (EC) No 1234/2008, please refer to the ‘Q&A - eCTD Variations’ published on the Agency e-submission website.

The use of the electronic Application Forms (eAFs) in the Centralised Procedure is mandatory as of 1 July 2015. Information on the electronic Application Form can be found in the eSubmissions eAF webpage.

When submitting applications the MAH should observe the recommended submission dates published on the agency website (see ‘submission deadlines and full procedural timetables’).

References

6. Must I submit my post-authorisation application in eCTD format?

From 1 January 2010, eCTD is the only acceptable electronic format for all applications and all submission types in the context of the centralised procedure. This applies to all applications (new and existing) and all types of submissions to the European Medicines Agency in the context of the centralised procedure (e.g. new applications, supplementary information, variations, renewals, Follow Up Measures (FUMs), Periodic Safety Update Reports (PSURs) for centralised authorised products, Notifications etc).

When submitting an application in eCTD, any Word document required for Module 1 (e.g. product information Annexes) and Module 2 should be located in the same eSubmission Gateway and eSubmission Web Client package within a folder called “xxxx­_working documents”, where the number (xxxx) equals the sequence number. There is no obligation to submit a full, reformatted eCTD for already authorised products. However, if Marketing Authorisation Holders wish, they may provide the European Medicines Agency with information reformatted as eCTD for their already authorised products. In particular, the European Medicines Agency would encourage the submission of reformatted quality information in eCTD, in order to facilitate the handling of variations and line extensions.

Replacement sequences of a previously submitted eCTD application (e.g. following corrections) are not acceptable. Instead corrected eCTD applications should always be submitted as a new eCTD sequence. Replacements should always be accompanied by an updated cover letter explaining the reason of the re-submission. Upon validation, the final data package should be submitted to the Committee members only, in accordance with the Dossier requirements for Centrally Authorised Products (CAPs).The submission of reformatted documentation (commonly referred to as a ‘baseline’ submission), should preferably occur simultaneously (but separately) with the submission of a variation, line extension or renewal. A clear distinction between the reformatted (unchanged) information and the documentation supporting the simultaneously submitted variation / line extension or renewal should be made.

An eCTD baseline submission is expected at day 0 of the application procedure, subsequent sequences should then be provided in accordance with the corresponding milestones for that procedure, through to approval. Please note that once the product starts an eCTD lifecycle, all subsequent submissions should follow this mandatory format.

Further details on implementation of the eCTD are provided on the European Medicines Agency e-submission website (http://esubmission.emea.europa.eu/), in particular in the European Medicines Agency Q&A relating to Practical and Technical aspects of eCTD implementation

References

7. What happens to my orphan designation at the end of the market exclusivity period?

Article 5(12)(c) of the Orphan Regulation provides for a designated orphan medicinal product to be removed from the Community register of orphan medicinal products at the end of the period of market exclusivity, as laid down in Article 8.

This means that once the market exclusivity for an authorised orphan medicinal product expires, the medicinal product will be removed from the Community register of orphan medicinal products and, therefore, will no longer be considered as an orphan medicinal product. Consequently, it will not benefit from incentives applicable to orphan medicinal products.

References

8. Who is my contact at the European Medicines Agency during post-authorisation procedures? Rev. June 2016

The Procedure Manager (PM) for your product is the marketing authorisation holder’s (MAH) primary contact point.

The MAH should contact the PM for any questions regarding the evaluation procedure.

Depending on the scope and the complexity of the particular application other members of the product team may be involved during the evaluation, as needed.In such cases the EMA Product Lead (EPL) or other members of the product team may contact the MAH directly to facilitate the discussion on the scientific aspects of the evaluation. Where the applicant is in direct contact with the EPL (or another member of the EMA Product Team) the PM should always be copied on the correspondence.

A number of procedures will be handled by dedicated teams (type IA and IB variations, MA transfers, 61.3 Notifications or referrals) and a different PM will be nominated upon receipt of those applications.

Please see other relevant questions and answers in the EMA pre-authorisation guidance "What is the role of the EMA product team?" and "Who is my contact at the European Medicines Agency during a marketing authorisation application (MAA) evaluation procedure?" and in the EMA post-authorisation guidance "Who is my contact at the European Medicines Agency during an application procedure for extension of indication?" and "Who is my contact at the European Medicines Agency during the post-authorisation phase outside any evaluation procedures?".

9. Who is my contact at the European Medicines Agency during the post-authorisation phase outside any evaluation procedures?

Where any issue in relation to the product arises during the post-authorisation phase, which is not covered by a specific evaluation procedure (i.e. not related to a variation, extension application, renewal, annual-reassessment, PSURs/PSUSA, PASS protocol, referral, post-authorisation measure as well as an administrative procedures), the assigned EMA Product Lead (EPL) is the contact for the marketing authorisation holder (MAH).

Such situations refer to a variety of topics and do include, where applicable, upcoming shortages in supply of the medicinal product, information about emerging safety issues, provision of important late-breaking information that potentially impacts the product profile or the marketing authorisation, as well as withdrawal of the marketing authorisation.

Communication through the EPL is supplementary to, not replacing, the formal reporting requirements and established reporting channels where they exist, e.g. for pharmacovigilance reporting.

Please see other relevant questions and answers in the EMA pre-authorisation guidance "What is the role of the EMA product team?" and "Who is my contact at the European Medicines Agency during a marketing authorisation application (MAA) evaluation procedure?" and in the EMA post-authorisation guidance "Who is my contact at the European Medicines Agency during an application procedure for extension of indication?" and "Who is my contact at the European Medicines Agency during the post-authorisation procedures?".

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