cmdh variation cover letter template

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Variation applications  

• Cover letter for Variation Applications in the Mutual Recognition Procedure (December 2022)

Worksharing procedure to RMS according to Article 20 of Commission Regulation (EC) No 1234/2008

• Template of letter of intent for the submission of a worksharing procedure   (June 2019)
• Link to EMA website for Template cover letter for worksharing including CAPs and MRPs

Grouping of type IA variations according to Article 7 of Commission Regulation (EC) No 1234/2008

• Template of letter of intent for the submission of a type IA grouped procedures   ("Supergroup")  (July 2013)

Recommendation on the classification of an unforeseen on variation under Article 5 of Commission Regulation (EC) No 1234/2008

• Template Recommendation form - Article 5 (April 2022)
• Template Request form for recommendation - Article 5 (April 2012 )  

Template for MAHs to provide their responses during type II variations or variation worksharing procedures  

• Template for MAHs response during type II variations   (September 2022)

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• Health and social care
• Medicines, medical devices
• Marketing authorisations, variations and licensing guidance

Medicines: apply for a variation to your marketing authorisation

Apply for changes to your marketing authorisation, including minor variations type IA and IB, major variations type II and extensions.

Variations are either:

• an administrative change such as a change of company name and/or address
• a change to the characteristics of a product that can affect its quality, such as a change to its composition
• a change to the safety, efficacy or pharmacovigilance of the product

Changes are classed as major (type II) or minor. Minor changes are either type 1A or 1B.

You can apply for:

• a single change to one marketing authorisation (MA)
• multiple changes to one or more products and/or MAs

Marketing Authorisation Types

From 1 January 2021, the following Market Authorisation types will be possible in the United Kingdom (UK):

( Guidance relating to application for a licence to market a medicine in the UK )

PL – authorised for use in United Kingdom

• as a purely national UK wide MA
• as part of an MR/DC procedure involving Northern Ireland as CMS, but a UK wide MA

PLGB – authorised for use in Great Britain only (England, Scotland and Wales)

• as a purely Great Britain national
• following conversion of a centrally authorised product (CAP)
• under the unfettered access route (MAH needs to be established in Northern Ireland and any product must access Great Britain, via Northern Ireland as a qualifying Northern Ireland good).

PLNI - authorised for use in Northern Ireland only

• as a purely Northern Ireland national
• as part of an MR/DC procedure including Northern Ireland only

Variations procedures

The variation procedures which will be followed for the different types of Marketing Authorisations from 1 January 2021 are essentially the same as before that date, where relevant, covered by the appropriate European or National legislation. The procedures are dependent on who is responsible for leading the assessment i.e. MHRA for purely national variations, the RMS for MR/DC or Reference Authority for any worksharing variations.

Centralised Marketing Authorisations are authorised for use in Northern Ireland only and any variations to these products will be managed by the EMA.

Until further notice the variations classification guideline , which is a fundamental component of the operation of the variations system, will continue to apply to all types of variations.

Reliance Route

Variations to purely national MAs (PL, PLGB and PLNI) can be presented to the MHRA under the reliance route i.e. following the acceptance of the same change(s) to a related the same product as part of a European procedure e.g. a CAP variation or an MR/DC variation.

If this approach is to be followed, this needs to be made clear in the application and relevant evidence, declarations and supporting information e.g. where relevant, copies of assessment reports should be provided to support the submission. Further guidance will be issued in due course.

Minor variations

These are divided into 2 types: IA and IB.

Type IA change

Type IA changes have little or no impact on the quality, safety or efficacy of the product, for example administrative modifications such as:

• the manufacturer’s name
• a minor change to a control method
• deleting details of where the product is packaged

Type IA procedures are classed ‘do-and-tell’, where you should implement the change before you notify MHRA, ensuring that where relevant (non-immediate notification) you submit the application within 12 months. If the implementation period passes 12 months without a variation being made, a default Type 1B should be submitted. The MHRA will take up to 30 days to process your application.

See the CMDh variations procedure guidance for the details of this type of change.

Type IAIN change (immediate notification)

Type IAIN is a sub-type of type IA and also classed a ‘do-and-tell’ procedure where MHRA requires ‘immediate notification’, within 2 weeks of the change being implemented. A minor change would usually be type IAIN if it interferes with MHRA’s ability to continuously supervise the product.

All relevant conditions and documentation must be met for a Type IA/IAIN and confirmed in a copy of the classification guideline with either a tick or where not relevant, Not Applicable (N/A).

No ‘requests for further information’ (RFI’s) apply to Type IA procedures and there is no fee associated with a National Type IA/IAIN. A full fees list and further information about fees, can be found in the section fees for licence variation applications.

Type IB change

If the change is more significant than a IA change but is not a type II change or an extension, it is considered a type IB change. MHRA must approve type IB changes before they are made to the product.

Once MHRA has all the necessary documents, it takes up to 30 days to process your initial application. You could be given a further 30 days to respond to any requests for information letter, which for Type IB are referred to as Notification with Grounds letters (NWG).

These are seen as a conditional determination of a type IB variation, where the applicant has one opportunity to address any deficiencies or omissions.

There is a 30-day deadline to respond to a NWG otherwise the variation will be withdrawn or refused, this also applies if only a partial response has been received by the 30-day deadline.

Major variations (type II)

These changes are more complex and may have a significant impact on the quality, safety and/or efficacy of the product.

MHRA needs to approve major variations before they are made. One example of a major change is adding a new therapeutic indication to a product or updating the current indication (the medical needs the product is used for).

Once MHRA has all the documents, it will take 30, 90 or 120 days to assess your application depending on how urgent or complex the changes are, excluding time taken to answer questions.

Once MHRA has all the documents, it will take 22-days, (reduced timetable), 60-days (standard timetable) or 90-days (extended complex timetable) to assess your application depending on how urgent or complex the changes are, excluding time taken to answer questions.

With questions (RFIs), assessment timeframes become 30, 90 and 120 days respectively.

The below tabulates the various stages for each type II timetable

A reduced Type II procedure (reduced from 60 days to 30) is for variations concerning safety issues and is agreed between the MHRA and the Marketing Authorisation Holder (MAH) and in general will be changes to the SmPC, requested following the assessment of a Periodic Safety Update Report (PSUR) or at the request of the MHRA Pharmacovigilance Unit.

Requests for a reduced timescale should be made to [email protected]

All other forms of submission will be rejected.

Common invalidation errors and pre-submission checklist

Following analysis of submissions MHRA has developed a pre-submission checklist of submission errors. Applicants are strongly advised to use the pre-submission checklist below which will reduce the likelihood of the submitted application being invalidated or rejected.

See our pre-submission checklist (PDF, 26.9KB, 2 pages

The marketing authorisation holder (MAH) is responsible for ensuring that, where relevant, all relevant conditions and documentation are met and the submission of this information and dossiers are the most recent and up-to-date. Deficient or incorrect documentation can lead to invalidation and/or rejection of the variation.

Although extensions are still considered a type of variation, their impact on a product is so significant that you will need to follow the application process to apply for a new MA . The form for this process has a section on extensions.

Extensions can be:

• changes to the active substance(s), including the salt/ester, isomer or biological active substance
• changes to strength, pharmaceutical form or route of administration

See annex 1 of the regulations for more information on extensions.

Revised labels, leaflets and/or packaging

If your variation (eg change of manufacturer) affects details of the labels, leaflets and or packaging (also known as livery) of the product, you will need to include the updated versions with your submission to be assessed.

However, you don’t need to submit a variation if there hasn’t been change to the product and you only want to make style changes to the labels, leaflets and/or packaging.

For example, if you’re changing the design of the leaflet and it has no relation to a change in the product, a variation application is not needed. See patient information leaflets for guidance on how to submit these types of changes.

Submit grouped changes (grouping)

You can apply multiple changes to a single product using the ‘grouping’ format, as long as the changes are directly related.

For example, you can make a change to the manufacturing site of the finished product, change in batch size and the manufacturing process to 1 product. The type of procedure (type IA, IB, II) depends on the extent of the change. You can see details of this in the annex III of the variations Regulation and Schedule 10A of the Human Medicines Regulations.

You can submit grouped changes to an MA with multiple product licences under the European procedure.

If a type IA variation is included in a group with other types of variations, the type IA change should not be implemented until all changes for that group have been approved.

You can group any type IA and IAIN changes for different marketing authorisations, as long as the group only contains IA and IAIN changes and the changes are the same. All of these changes should be implemented before you notify MHRA.

Grouping applications for national MAs

For groupings where MAs were granted in the UK through a national procedure only, you will need to apply for grouped changes through the MHRA.

Check the acceptable grouping guidance and the examples of groupings ( PDF , 2.5 MB , 12 pages ) to see if your grouping is acceptable.

If your desired group of changes isn’t included in the guidance or the examples, you need to complete the grouping template , copy and paste it into the main body of an email and send it to [email protected] before you submit your application. We aim to confirm if your grouping is acceptable within 7 working days.

Variations to multiple products (worksharing)

In some circumstances, you can use the worksharing format if you’re submitting the same type IB or type II change or group of changes to multiple MAs. As far as any product which is authorised in the UK is concerned only products which are authorised in Northern Ireland either centrally, purely nationally in Northern Ireland only, or as part of an MR/DC procedure can be the subject of worksharing. Proposals for worksharing applications should be sent to:

• the European Medicines Agency (EMA) if any of the MAs you want to change were granted under the centralised procedure
• the Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) if the MAs were granted under the mutual recognition and/or decentralised procedures and the reference member states were different *the reference member state if the authorisations were granted under the mutual recognition and/or decentralised procedure and the reference member state is was the same for each MA
• the competent authorities for the relevant countries if the MAs were granted under purely national procedures, email [email protected] for the UK.

Once MHRA have all the necessary documents, it will usually take 60 days to assess applications although it could take up to 120 days if the variation(s) are more complex or up to 30 days if urgent.

See the best practice guide on worksharing for details on how to submit an application this way.

Composite coordination collection (CCC)

If you want to apply for changes to one or more product licences (licence for each product under a marketing authorisation) that would affect the product information you can submit a composite coordination collection (CCC). Product information includes the summary of product characteristics, leaflets and labels.

With a CCC you can:

• submit only one consolidated mock-up of the leaflets and labels with all the changes proposed.
• submit a mixture of variations applications and Article 61(3) applications
• apply for single or grouped changes, such as a type IB and/or type II variations (see groupings )

You shouldn’t use this scheme for:

• urgent variations relating to the safety of your product(s)
• standalone type IA notifications
• changes that don’t affect product information (summary of product characteristics, leaflets, labels)
• changes to a product with a centralised licence

You would pay for this scheme as though you were paying for individual variations. See the list of fees

To get your CCC proposal approved and to see how to apply, follow the guidance for CCC application ( PDF , 538 KB , 32 pages ) .

Fees for variations .

Use the Fees Calculator to work out what the fee for your submission will be.

How to apply (all variation types except extensions)

Specific variations are given unique change codes to include in the application form.

Match the right change code to your specific variation by checking the annex in the [European Commission’s guidelines](https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:52013XC0802(04). You will need to include this in your application form.

Submit the variation application form ( MS Word Document , 970 KB ) along with the supporting documents via the MHRA Portal

You can now submit your application via the Central European System Platform (CESP) .

Since January 2016 it has become mandatory for new marketing authorisation, renewal and variation application submissions to be made using electronic application forms (eAFs) . This will apply to all procedure types, including national procedures. If you are making a submission using the portal, you will have to submit using the portal forms as well as submitting the eAF. If you are submitting your application through CESP or MHRA Submissions you will only need to submit the eAF.

You must submit your variation using the electronic Common Technical Document (eCTD) .

We check that eCTD submissions are technically valid using the Extedo Eurs is Yours (EiY) validation tool. We recommend that you use a validation tool to check your submission.

If you have any questions about submitting your variation, email <[email protected]]>.

For submissions via MHRA Submissions please register .

You should use our eAF and cover letter tool to determine what information you need to include in your application. If you do not include the correct information your application will not be validated.

Submissions through the Common European Submission Portal (CESP)

This system is available from the Heads of Medicines Agencies (HMA) and provides a simple and secure mechanism for exchange of information between applicants and regulatory agencies.

The purpose of the system is to:

• provide a secure method of communicating with regulatory agencies via one platform
• allow submission of an application once to reach all required agencies
• reduce the burden for both industry and regulators of submitting/handling applications on CD-ROM and DVD

If you are a first time CESP user and wish to setup up an organisation/university or trust to manage multiple users on the system, register with CESP here .

If you are a standalone user and wish to upload for Non Commercial Use on your own behalf, register with CESP here .

Once registered you will receive credentials to access the portal to your registered email address.

General CESP training is available to all registered users via CESP’s training menu once logged into the system. Training on demand videos are available and you can also sign up to our free online weekly live demonstrations. CESP encourage all users to attend training before using the system. View FAQs .

Supporting documents

For CMS submissions send a dispatch date list (detailing when you intend to dispatch the products) to all member states before submitting your application if your MA was granted through the mutual recognition or decentralised procedures. The list should be emailed to [email protected] for type IB and II changes and include a copy in the ‘additional data’ section of the eCTD format.

Type IA and IB

For type IA and IB variation applications you need to include:

• a cover letter with your MA number, type of variation and reason for the variation
• an explanation of your grouped variations if applicable, making specific reference to the Heads of Medicines Agencies (HMA) acceptable groupings guidance and examples of groupings ( PDF , 2.5 MB , 12 pages ) or the confirmation email from MHRA agreeing you can submit grouped variations
• the supporting information required for specific variations as set out in the annex of the European Commission’s guidelines
• present and proposed details of your product presented as a separate document if necessary
• a contents page listing all documents included in your submission

For type II applications, you must include all of the above and:

• relevant information to support your application such as publications and any cited references
• a new or updated addendum to the ‘quality overall summary’, clinical and non-clinical overviews

Summary of product characteristics (SPC)

If relevant, the summary of product characteristic fragments (SPC) should be submitted to MHRA in the correct format using the templates below. If you do not use these templates your submission will be rejected.

These templates should not be altered in any way, other than inserting the relevant information. They should be saved using the following naming conventions in the ‘workingdocuments’ folder of your eCTD:

m1 -3-1-01: SPC section 1 – product name ( MS Word Document , 22 KB )

m1 -3-1-02: SPC section 2 – Qualitative and quantitative composition ( MS Word Document , 21.5 KB )

m1 -3-1-03: SPC section 3 - pharmaceutical form ( MS Word Document , 19.5 KB )

m1-3-1-4.1: SPC section 4.1 - therapeutic indications ( MS Word Document , 19.5 KB )

m1 -3-1-4.2: SPC section 4.2 - posology and administration ( MS Word Document , 19.5 KB )

m1 -3-1-4.3: SPC section 4.3 - contra-indications ( MS Word Document , 19.5 KB )

m1 -3-1-4.4: SPC section 4.4 - special warnings and precautions ( MS Word Document , 19.5 KB )

m1 3-1-4.5: SPC section 4.5 – interaction ( MS Word Document , 19.5 KB )

m1 3-1-4.6: SPC section 4.6 - fertility, pregnancy and lactation ( MS Word Document , 23.5 KB )

m1 3-1-4.7: SPC section 4.7 - driving and use machines ( MS Word Document , 19.5 KB )

m1 3-1-4.8: SPC section 4.8 - undesirable effects ( MS Word Document , 19.5 KB )

m1 3-1-4.9: SPC section 4.9 - overdose, emergency and antidotes ( MS Word Document , 19.5 KB )

m1 3-1-5.1: SPC section 5.1 – pharmacodynamics ( MS Word Document , 19.5 KB )

m1 3-1-5.2: SPC section 5.2 – pharmacokinetics ( MS Word Document , 19.5 KB )

m1 3-1-5.3: SPC section 5.3 - preclinical safety ( MS Word Document , 19.5 KB )

m1 3-1-6.1: SPC section 6.1 – excipients ( MS Word Document , 19.5 KB )

m1 3-1-6.2: SPC section 6.2 – incompatibilities ( MS Word Document , 19.5 KB )

m1 3-1-6.3: SPC section 6.3 - shelf life ( MS Word Document , 19.5 KB )

m1 3-1-6.4: SPC section 6.4 - special precautions ( MS Word Document , 19.5 KB )

m1 3-1-6.5: SPC section 6.5 – container ( MS Word Document , 19.5 KB )

m1 3-1-6.6: SPC section 6.6 – disposal ( MS Word Document , 19.5 KB )

m1 3-1-07: SPC section 7 - marketing authorisation holder ( MS Word Document , 19.5 KB )

m1 3-1-08: SPC section 8 - marketing authorisation number ( MS Word Document , 19.5 KB )

m1 3-1-09: SPC section 9 - date of the first authorisation or renewal ( MS Word Document , 19.5 KB )

m1 3-1-10: SPC section 10 - date of revision of the text ( MS Word Document , 19.5 KB )

m1 3-1-11: SPC section 11 – dosimetry ( MS Word Document , 19.5 KB )

m1 3-1-12: SPC section 12 – radiopharmaceuticals ( MS Word Document , 19.5 KB )

More information

The European Commission has published guidelines for submitting variation applications including the change codes needed. You may also find the common scenarios for submitting variations ( PDF , 171 KB , 7 pages ) useful.

The European Commission’s regulation1234/2008 as updated by regulation 712/2012 outlines the legislation for processing variations.

Email [email protected] with any queries, or call 020 3080 7400.

Added link to Fees Calculator.

Following the end of the transition period, published new information on marketing authorisation types.

Updated Group Template

Inserted new text/section - Request for Information (RFI)

Updated links to Variations and CCC calculators.

Updated guidance for CCC application.

Links have been updated.

Added a calculator to work out what the fee for your CCC submission will be.

New email address for Area 3 submission queries

Link to variation fees calculator added to the page

Updated pre-submission checklist

New common errors information and pre-submission checklist

First published.

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Variations regulation: regulatory and procedural guidance

Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure - superseded

Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure: document with track changes - superseded

Transitional provisions for implementation of Commission Regulation (EU) No 712/2012 amending Variations Regulation (EC) No 1234/2008

Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products entered into force on 24th August 2012.

Questions and answers on variations to an existing pharmacovigilance system as described in the detailed description of the pharmacovigilance system

Annex B Word template

Annex B PDF template

Template letter of intent work sharing procedure

Letter of intent for the submission of a work sharing procedure to the European Medicines Agency according to article 20 of Commission Regulation (EC) no 1234/2008

Template cover letter for worksharing procedures including centrally authorised products and nationally authorised products

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

• Commission Regulation (EU) No 712/2012 of 3 August 2012 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products
• Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products
• Variations guidelines - Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures
• Electronic variation application form
• Variation application form
• European Medicines Agency/CMDh explanatory notes on Variation Application Form
• eCTD Variation Q&A document
• Regulatory and procedural guidance

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CMDh and other EU updates – March 2024

• 29 March 2024
• CMDh updates

Last updated: 29 March 2024

Report from the CMDh meeting hold on 19 – 20 March 2024

The reports from the CMDh meetings (also called press releases) reflect highlights/important outcomes of each meeting and are usually published in the week following the CMDh meeting. The reports therefore only contain a subsection of the complete CMDh agenda and are used for a more timely communication of the most important outcomes.

The CMDh minutes are a full record of the CMDh meetings (minus redaction of confidential content). They are adopted at the following CMDh meeting and subsequently published.

The  report  from the above meeting includes (but is not restricted to) the following items:

1. Procedural advice on Zero Day MR Procedures

The CMDh agreed on a new procedural advice on Zero Day MR Procedures.

• The Zero Day Procedure is a mutual recognition procedure with a shortened timetable, which can be initiated in exceptional cases to mitigate shortages or issues with access to critical medicines with agreement of the member states concerned.
• The procedural advice document provides information on considerations prior to the initiation of the procedure, dossier requirements and the steps of the procedure.
• The document will be published on the CMDh website under “Procedural Guidance > Application for MA > MRP/RUP”. A link will be provide here once this document is available.

2. Pharmacovigilance Legislation

The CMDh agreed an update of the CMDh Questions and Answers on Pharmacovigilance Legislation.

• The Q&A 2 (“How should I submit a new RMP or an updated RMP to update my dossier?”) has been revised to stress that, for RMP updates, a clean and a tracked version (as a working document in word format) should be submitted to facilitate the assessment.
• The updated Q&A document will be published on the CMDh website under “Questions & Answers”. A link will be provide here once this document is available.

Update on new fee regulation (highlight from the EMA management board meeting, March 2024)

The Board noted that work on preparation for the implementation of the  new fee regulation  has begun.

• This includes the redrafting and updating of various documentation including the cooperation agreement with national competent authorities (NCAs) and the working arrangements that will replace the current implementing rules.
• The working arrangements will further clarify the terminology and requirements of the new regulation, outline conditions for fee incentives and provide a description of payment modalities including remuneration to NCAs.
• provide harmonisation between the fee regulation and pharmacovigilance fee regulation,
• align fees with underlying costs and
• reduce the current complexity of the fee system

Source: EMA

eCTD v4.0 EU M1 Implementation Guide – draft Version 1.1 now available

A new  draft  version of the eCTD v4.0 EU M1 Implementation Guide is now available  here  for consultation. Future versions (together with EU Controlled Vocabularies and other annexes) will be published and announced on the eSubmission website.

Source: eSubmissions

CTCG Best Practice Guide for sponsors of multinational clinical trials with different Part I document versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014

Version 4 of the above was adopted at the CTCG plenary March 7 2024. You can view it here.

The changes in Version 4 are as follows:

• Sponsor should propose trial category but not apply for low-intervention clinical at time of transition from CTD to CTR.
• Details on CTIS submission for specific situations: i) sponsor is not product owner of an IMP, ii) recommendations for IMPs and AxMPs, iii) when, under CTD, a study was regarded as an interventional clinical trial in some Member States and as a non-interventional clinical study in other Member States.
• Archiving rules and end of trial for CTD trials when some but not all Member States included in transition.

Annex Cover Letter Template vs. 4.0 adopted at CTCG plenary March 6 2024

You can view the Cover letter template here .

Report and minutes from the CMDh meeting hold on 20-22 February 2024

The  report  and  minutes  from the above meeting include (but are not restricted to) the following items:

1. CMDh Best Practice Guide (BPG) on Multilingual packaging

The CMDh agreed an update of the BPG on Multilingual packaging.

The main changes to the updated BPG document are:

• the addition of instruction for the preparation of an ‘EU full/reduced harmonised labelling text’ in the RUP and line extension procedures,
• guidance on changing MS clusters where the “EU reduced harmonised text” is already approved or to change an already approved “EU reduced harmonised text”,
• update of the section on Product names and reformatting of Annex I and II.

The updated document has been published on the CMDh website under “Procedural Guidance > Application for MA”. Here, you can view the track changed (Oct 2021) and clean (Feb 2024) versions of the document.

2. DCP Quality Assessment Report template

The CMDh agreed an update of the DCP Quality AR template. The document has been updated to delete the administrative information table as it was considered to be a duplication of the information already included in the Overview AR template.

The updated document will be published on the CMDh website under “Templates > Assessment Reports > DCP (AR/Comments)”. You can view the updated template here .

3. Meeting of a subgroup of CMDh with Interested Parties dedicated to LoSC and publication of PI updates

The subgroup of the CMDh (including the Safety Outcome Survey (SOS) Working Group) convened a dedicated meeting with representatives of Interested Parties on 22 February 2024.

In the meeting a status update on the new upload system for List of Safety Concerns via web interface was given and the SOS WG initiative on publication of the outcomes of safety variations was discussed.

All presentations have been published on the CMDh website under “About CMDh > Contact with Representative Organisations”. YOu can view them at the links below:

• List of safety concerns: Publication process
• Publishing the outcomes of safety variations

4. Variation worksharing procedures including non-prescription and prescription-only products

Based on a recent example, the CMDh discussed how the agreed OTC wording can be included in section 15 (instructions on use) of the common label wording, when both nonprescription and prescription-only products are included in a variation (worksharing).

Two possible approaches were presented:

• State both OTC and prescription-only options in the common label wording in section 15 of the label of medicinal products with different legal status, with the understanding that only OTC products use this wording in the national label and that this section of the national label would be left blank for a POM.
• Leave the common label wording in section 15 of the label of medicinal products with different legal status blank and OTC instructions would be fully handled in the national phase.

There was no majority in the CMDh for either of the options. The CMDh agreed to refer the question to the OTC Task Force.

5. Guideline on the environmental risk assessment of medicinal products for human use / EMA

The CMDh was informed about the revision of the Guideline on the environmental risk assessment of medicinal products for human use. The revision was adopted by CHMP in February 2024. Publication is planned for early March. The implementation date is 1 September 2024. Assessors training and interested party engagement is planned in advance of the implementation.

• It was highlighted to CMDh that the wording of the current PAR template should be updated to be in line with the guideline.
• The CMDh stressed the need for further guidance and that the CMDh needs to be involved in the preparation of the implementation.
• As the time until the implementation is limited, it was proposed to have a meeting in March between EMA and CMDh representatives to further discuss a harmonised implementation.

6. MAA Electronic Application Form

Following discussion in the eAF maintenance group, the CMDh discussed if section 2.4.1. of the eAF for new MAAs should be updated to include either a drop-down menu or a free text field to give the possibility to add national specifics regarding the MAH (e.g. local representative and co-distributor).

• The discussion was triggered as in some MSs the MA can only be granted based on the information in the eAF. If certain national information is not available in the eAF, the MAH has to submit a variation to add the information after the MA has been granted.
• MSs expressed different positions. Some mentioned that e.g. the local representative is provided in other sections of the eAF or in the cover letter. It was also noted that this would open the door to requests of a lot of country-specific, additional information via the eAF.
• The CMDh agreed by majority that such national requirements/information should not be included in the eAF.
• On a different issue, the eAF maintenance group was asked to harmonise the information given in the eAF with regard to ASMF and CEP holders (company name vs name and address)

7. Request for variation worksharing procedure including several safety updates

The CMDh discussed a request from a MAH for a complex variation worksharing procedure including several grouped safety updates. The CMDh discussed if the procedure could/should be split into smaller packages.

• It was noted that a general decision on a split cannot be made. A split would depend on the scope of the individual changes and whether all proposed changes are related to each other.
• Generally, the MAH should provide a justification for the proposed grouping. It was also generally considered useful to review all changes together, but this would not be a valid reason to group unrelated changes.
• As it concerns the implementation of safety information, the submission of individual changes should not be delayed.
• In case more than one WS variation would be needed, these could be submitted and assessed in parallel at the same time with the same timetable.
• The CMDh generally promotes the use of variation worksharing.
• The reference authority could discuss with the MAH if some minor unrelated changes could be taken out of the procedure.
• Due to the complexity of the procedure the reference authority was advised to use the longer timetable of 120 days.

EMA Eudravigilance Registration manual and documents

Revision 14 (13 March 2024) of the EMA EudraVigilance Registration Manual has been published. You can view it here .

The Document EudraVigilance registration documents of 13 March 2024 has been published. You can view it here.

Commission proposes new measures for the better lifecycle management of medicine authorisations

The Commission has proposed to amend the  variation legislation for medicines , to make the lifecycle management of medicines more efficient and better adapted to the modern context.

The Regulation, which is part of the EU’s Pharmaceutical Strategy for Europe, adapts the current system for variations to marketing authorisations, to make it more efficient, reduce administrative burdens and better respond to scientific and technological advances.

Since it was last revised, the Variations Regulation has made a marked contribution in harmonising and aligning the life-cycle management of medicines, post-authorisation, across the EU. However, the rules need to be updated in line with recent scientific and technological advancements and a rise in the number of variation requests.

The proposed revisions will facilitate quicker processing of variations, benefiting both marketing authorisation holders and regulatory authorities. They will facilitate more efficient lifecycle management of medicines while awaiting the broader proposed reform of the EU’s pharmaceutical legislation.

Here, you can view the proposed Draft delegated Regulation and its Annex .

Source: European Commission

Useful factsheets

The European Commission has recently published the following useful factsheets:

• Steering innovation to address unmet medical needs
• Access to medicines in all Member States
• Addressing shortages of medicines and ensuring security of supply
• Incentives to steer innovation and achieve public health objectives

CMDh annotated QRD template for MR/DC procedures (Based on version 10.4 of the QRD template for CP)

This template has been updated. Here, you can view the track changed (April 2021) and clean (March 2024) versions of the document.

There are small changers throughout the document.

Source: CMDh

EudraVigilance – EVWEB User Manual

The Manual has been updated to version 1.7 (29 February 2024).

Revision 1.7 contains the following updates:

• Figures 5 and 126 were amended.
• Some hyperlinks were updated (in sections 1-4); − References to the ICH E2B(R2) message format were updated (or removed where applicable, as this message format was superseded by the ICH E2B(R3) format);
• The following section was updated: 3.9.1 “Import Function”;
• The following sections were added: 3.9.1.1 “Import of a single XML file”, 3.9.1.2 “Import of multiple XML files” and 3.11.3.2 “Use of Automation tools (API/RPA) in the ICSR download and Captcha control for Level 2B (L2B) download requests”;
• Some editorial amendments were made to align the format with other EMA documents.

Deadlines for submission of applications for orphan medicinal product designation to the EMA and corresponding COMP timetable for valid applications 2024/2025

You can view the submission deadline table here .