Tag Archive for: Back to Basics

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Back to Basics – Mutual recognition procedure (MRP)

With our new logo and new website we expect some new visitors, so, we are continuing our back to basics post for those who may be new to Regulatory Affairs. (If you need help with the jargon visit our A-Z Glossary of Regulatory abbreviations).

MRP

When an Applicant has a single marketing authorisation (MA) in one Member State and wishes to market the same medicinal product in other Member States in EU/EEA, a Mutual Recognition Procedure (MRP) can be used.

The Competent Authority where you hold the single MA acts as the Reference Member State (RMS) and the new Member States you chose are referred to as Concerned Member States (CMSs).

The RMS prepares the Assessment Report on the medicinal product and runs the procedure. The CMSs will raise questions during the procedure.

However, before you submit your MRP application, there are a number of things to consider;

  • You must ensure that the current dossier complies with the current legislation and EU guidelines. If your current dossier is not in line with the current legislation and EU guidelines it must be updated by variation prior to submitting the MRP application.
  • There must be no ongoing variations.
  • You must agree an appropriate time slot and request an updated Assessment Report (AR) from the RMS prior to submitting the application.
  • Each Member State will have a slightly different working procedure, but most require that discussions/requests start at least three months before your preferred starting time.
  • The RMS must allocate procedure number (e.g. IE/H/123/001/MR).
  • You must choose your CMSs carefully. Where applicable, review the approved legal supply status and local requirements (e.g. need for a local representative, local person for pharmacovigilance etc.) and reimbursement procedures etc. of each Member State.

If applicable compare the SmPCs of reference product across the interested territories, identify any differences paying particular attention to the indication(s) and posology.

The MRP follows by a 90-day period followed by a 30-day national phase.

To ensure that your MRP starts on time, it is advised to review the ‘additional data’ requirements of each Member State (e.g. do the cover letters, letter of authorisation need wet/original/notarised signatures etc?) and ensure the correct payment amount has been paid.

The CMSs can raise questions that relate to any aspect of the dossier from Module 1 to Module 5 such as issues with specifications, analytical validation, breakability data on scored tablets, process validation, biostudies including statistics applied to the studies, etc., all have to be addressed as “serious risk to public health”.

The CMSs are not allowed to ask for, and the Applicant is not allowed to supply, new data during an MRP.

Seven calendar days after close/end of procedure the Applicant should send high quality national translations of SmPC, PL and labelling and mock-ups to CMSs.  It is critical that the translation service used is reliable and technically competent to translate medical text.

It is also important that the correct dialect or form of language is used. Due to this tight turnaround time, it is advised that discussions with your translator be performed in well in advance of the predicted Day 90.

The CMS should issue a marketing authorisation within 30 days after closure of the procedure, however in most cases depending on the Member State, this 30-day period is frequently missed.

Day Zero MRPs

A Zero Day MRP is an administrative RUP or MRP with a shortened timetable. A Day zero MRP is used in exceptional cases to mitigate shortages or issues with access to critical medicines in the new Member State.

In most cases the new CMS will not raise any quality or clinical question but will have specific criteria that need to be met prior to accepting a Day Zero MRP. The main prerequisite approval for a Day Zero MRP is that the medicinal product will be marketed in Member State as a result. Even though the procedure is administrative, the applicant should contact the RMS to agree on a submission date.

Countries like Iceland and Malta rely on such procedures due to the small size of the markets there.

Feel free to contact us here at ERA to assist you with all things regulatory in Ireland, UK and across the EU.

We take the pain out of regulatory so that you can take your medicine to the next level.

Written by

Fiona Downey

Fiona Downey 1

Fiona Downey 1

 

 

 

Legal basis

Back to Basics – The Decentralised Procedure (DCP)

We continue our back to basics series for those who may be new to Regulatory Affairs (If you need help with the jargon visit our A-Z Glossary of Regulatory abbreviations).

In the EU, there are two different procedures available to apply for a marketing authorisation application (MAA) for the same medicinal product in more than one Member State at a time:

This Article focuses the Decentralised Procedure (DCP).

The DCP is only applicable if no marketing authorisation has previously existed in the EU/EEA, as per Directive 2004/27/EC and if an identical dossier is submitted simultaneously in all selected Member States.

To prepare for a DCP submission:

  1. Establish a Reference Member State (RMS).
    • One Member State called the RMS will be selected by the Applicant to lead the assessment of the MAA.
    • To do this, complete a “Request for RMS in a Decentralised Procedure” Form and send it to your preferred RMS at least 2 months before the planned date of submission of the marketing authorisation application.
    • Only one RMS request can be submitted at a time. It is advisable to establish an RMS as soon as possible as DCP slots get booked up very quickly.
    • The guidance, Decentralised Procedure – Requests to act as RMS, provides an overview of the booking system & links to the various National Competent Authorities who act as RMS
  2. Prepare a dossier in accordance with the current legislation and EU guidelines.
  3. Check that the requirements for submissions for new Marketing Authorisations are met for the various Member States to avoid validation comments (at Day -14) and also for any additional requirements to determine if any wet/original/notarised signatures are required
  4. Ensure the correct fee amount has been paid.
  5. Check the dossier for common validation issues raised by the RMS and the CMSs in DCP procedures to prevent them being requested during the validation of your application.
  6. The applicant then simultaneously submits an identical dossier to the RMS and all CMS by the agreed submission date booked with RMS.
  7. The application will be submitted via CESP portal, according to eCTD Guidelines, & then applicant will send any hard copies/original documents required by various Member States as per national requirements.
  • Assessment Reports (Day 70, D120, Day160, D210):
    • The RMS is responsible for preparing an Assessment Report (AR) which summarises the dossier presented by the applicant. The AR characterises and critically evaluates the medicinal product concerned with regard to its quality, safety and efficacy.
    • This AR will be made available to all Concerned Member States (CMS) together with SmPC, PL and labelling by the RMS and forms the basis for the evaluation by CMS.
    • In the case a Member State concerned by the procedure is unable to accept the AR or draft AR on the basis of a “potential serious risk to public health”, the application will be sent to the CHMP for arbitration.
  • End of Procedure can be in 90-210 days after validation phase is closed.
  • It is advisable to plan the national translations in time. It is critical that the translation service used is reliable and technically competent to translate medical text.
  • Seven calendar days after end of procedure the Applicant should send high quality national translations of SmPC, PL and labelling and mock-ups to individual CMSs.
  • There is usually a 30-day National assessment before of the granting of the MA, however the timelines differ in each MS.
  • If consensus is not reached at the end of the procedure, a pre-arbitration (CMDH) and arbitration (CHMP) phase may take place.

We can help you to do all of the above or even better we can do it for you – to save you time and money let our experienced team take the pain out of it for you.

Written by

Marian Winder

Marian Winder 1

Help Support Advise Guidance 21 11 19

Back to Basics – Variations – Types & Timelines

Here is the second installment of our Back to Basics series: VARIATIONS

So, let’s start with a summary of the different types of variations & their timelines.

 Variations are

  • changes made to the dossier of an authorised medicinal product after its initial registration
  • They may concern administrative changes, Quality changes, Safety/Efficacy changes or Vigilance changes
  • Variations can be categorised as Type IAIN, Type IA, Type IB (seen or foreseen) or Type II whether they are within a Centralised, Decentralised (DCP) or National Procedure (NP)
  • Variations can either be a single or grouped together.
  • There is also a mechanism to submit variations by a work sharing procedure.

Procedures around variations are currently governed and harmonised throughout the EU by Commission Regulation (EC) No 1234/2008 of 24 of November 2008 (“the Variations Regulation”) which has subsequently been amended by Regulation (EU) 712/2012.

Variation Types Definition Timelines
Human Medicines Regulations
Type IAIN

 

 A minor variation which has only minimal/or no impact on the quality, safety or efficacy of the medicinal product. The competent authority should be notified immediately after implementation.

 

‘Immediately’ is not defined in EU guidance but is generally considered to be within 2 or so weeks of implementation* of the change.

 

*For quality changes, ‘implementation’ is when the company makes the change in its own quality system. For product information, it is when the company internally approves the revised product information. The revised product information will then be used in the next packaging run.

e.g. to introduce a PSMF or change company address
  • Do & Tell (close to implementation date)
  • 30 day timetable once validated
  • No clock stop
  • No timetable is issued
  • Rejection is possible if documentation requirements are not met
  • Approval received from the RMS (and maybe from the CMS)

 
Type IA A minor variation which has only minimal/or no impact on the quality, safety or efficacy of the medicinal product.

Where all required data

conditions are met such variations do not require any prior approval, but must be notified by the MAH within 12 months following implementation in so called ‘annual reports’ or may be submitted earlier should this facilitate dossier life-cycle maintenance or when necessary. This is known as the ‘Do and tell’ procedure.

e.g. updated CEP from an already approved manufacturer
  • Do & Tell (Annual basis)
  • 30 day timetable once validated
  • No clock stop
  • Rejection is possible if documentation requirements are not met
  • Approval received from the RMS (and maybe from the CMS)
  • Competent authorities should implement the decision nationally within six months.

 
Type IB Variations which are neither a minor variation of Type IA nor a major variation of Type II nor an extension are classified as Type IB variation by default.

They are further classified as being either foreseen or unforeseen (consult variation guidance documents referenced in section 4, below, for further information) e.g. change of product name for nationally authorised products
  • Tell and Do (await approval before implementation)
  • 30-60 day timetable, once validated
  • clock stop period is possible
  • A timetable is issued
  • Responses to MS comments can be submitted
  • A National Phase is possible

 
Type II Type II variations are classified as major variations. They arise from a change that does not meet the requirements of a Type I variation, but is not so complex as to lead to a new Marketing Authorisation application.  There are two classifications of Type II variations:

(1)    Type II Complex

(2)    Type II Urgent Safety

Type II variations require a formal approval e.g. addition of a new therapeutic indication
  • Tell and Do (await approval before implementation)
  • 30/60/90 day timetable, excluding clock stop
  • A timetable is issued
  • Responses to MS comments can be submitted
  • A National Phase is common

 

Grouping:

Where the same variation(s) affect one or more marketing authorisation(s) from the same holder, the marketing authorisation holder may choose to submit these variations as one application.

In most instances it is possible to group type IA variations regardless of content.

Some competent authorities may not allow grouping for national variations.

In specified cases it is possible to group type IA and type IB/type II variations (consult acceptable and non-acceptable grouping guidance document referenced below, for further information. In these cases the changes will tend to be consequential and the procedure type defaults to the highest recorded procedure.

The website of the relevant competent authority should be referred to, to confirm the possibility of grouping.

For grouping that includes type IB and type II procedures and falls outside the scope of acceptable and non-acceptable grouping guidance documents, consent for the grouping should be sought in advance from the competent authority to avoid rejection.

Worksharing:

Article 20 of the Commission Regulation (EC) No 1234/2008 allows for the possibility for the Marketing Authorisation Holder to submit the same type IB or type II variation or the same group of variations affecting more than one marketing authorisation from the same Marketing Authorisation Holder in one application.

A worksharing procedure allows for one authority to be chosen amongst the competent authorities of the member states to examine the variation on behalf of the other concerned authorities. In case a grouped application is applied this may also contain consequential IA changes.

Line extensions are excluded from worksharing.

 

Further to above, Applicants may wish to pay particular attention to the following CMDh documents:

 

Feel free to contact us here at ERA to assist you with all things regulatory in Ireland, UK and across the EU.

We take the pain out of regulatory so that you can take your medicine to the next level.

Written by

Marian Winder

Marian Winder 1

Marian Winder 1

Need help with all the regulatory jargon?

Check out our updated GLOSSARY OF ABBREVIATIONS AND ACRONYMS.

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