Guidance
Variations to Marketing Authorisations (MAs) from 1 January 2021
How the MHRA will process variations to Marketing Authorisations (MAs) from 1 January 2021.
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For current information, read: Medicines: apply for a variation to your marketing authorisation
The guidance describes the approach the MHRA intends to take to the processing of variations to marketing authorisations from 1 January 2021.
1. Variations Procedure
The procedures detailed under Chapter IIa of Variations Regulation (EC) No 1234/2008, which specifically applied to variations to purely national Marketing Authorisations, will be incorporated into UK law from 11pm on 31 December 2020, and as such continue to apply to both pending and new variations to purely national UK Marketing Authorisations, from 1 January 2021 and can be found in new regulation 65C and Schedule 10A to the Human Medicines Regulations 2012 (“HMRs”).
In addition, unless specifically highlighted under section 3, the current variations classification guidelines, which explains the type of variation (Type IA, Type IAIN, Type IB, Type II or Extension) to submit and, where relevant, the conditions to be met and any required supporting documentation, will continue to apply.
Any extension application should be submitted in accordance with the procedures for new Marketing Authorisations. The variations classification guidelines will continue to apply until the MHRA issues any revised guidance in the future.
The UK will recognise any Article 5 recommendation published by the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh) before 1 January 2021. Any specific request from a Marketing Authorisation Holder (MAH), concerning the classification of a variation, which is still pending (no recommendation) on 1 January 2021 or is submitted after 1 January 2021 will need to be submitted directly to the MHRA, who will issue its own recommendation.
2. Variation of a UK marketing authorisation
Marketing Authorisations authorised in the UK by the MHRA before 1 January 2021 will continue to have effect across the UK (Northern Ireland, in line with applicable EU rules; and Great Britain which means England, Scotland and Wales). This includes those which are currently and will continue to be part of any MR/DC procedure.
For purely national Marketing Authorisations, any pending and new variations will be processed to conclusion after 1 January 2021 as national variations, where the relevant national procedures will be followed.
For Marketing Authorisations which are already authorised as part of MR/DC procedures before 1 January 2021, any pending and new variations will be processed to conclusion after 1 January 2021 as MR/DC variations using the relevant MR/DC procedures led by the RMS. This includes relevant worksharing variations.
Northern Ireland protocol
Under the provisions of the Northern Ireland protocol, medicinal products authorised for Northern Ireland will continue to follow EU rules. The requirements of unfettered access will be respected for those products where the Marketing Authorisation Holder is established in Northern Ireland and the Great Britain marketing authorisation has been obtained as a qualifying Northern Ireland Good.
Community Marketing Authorisations
Medicinal Products authorised via the centralised route will be directly authorised for use in Northern Ireland. Any variations to these Marketing Authorisations will be centrally managed by the EMA in accordance with relevant procedures. A separate MA will not need to be issued by the MHRA for Northern Ireland.
If the same product is separately authorised in Great Britain a separate variation application will need to be submitted to vary that authorisation. Type IA notifications can only be processed on the basis of what is actually submitted to the MHRA for Great Britain.
However, for Type IB and Type II variations, if such a variation is submitted for the corresponding Great Britain authorisation, after approval of the identical changes by the EMA, and evidence of this is included with the submission, this will be taken into consideration according to the reliance route for variations. A lower fee will be charged. Further guidance will be issued in due course.
Products authorised under EU Decentralised or Mutual Recognition Procedures
See guidance concerning the handling of Decentralised and Mutual recognition procedures approved or pending on 1 January 2021.
Under the Northern Ireland Protocol, Medicinal Products authorised via the MR/DC procedure from 1 January 2021, where Northern Ireland is specifically included as a CMS may be authorised for use in Northern Ireland only, where a UK MA in respect of Northern Ireland (PL(NI)) will be issued by the MHRA, or as a UK wide MA (PL) with Northern Ireland as a CMS, and Great Britain aligned with the decisions taken by the RMS , but not part of the DCP/MRP.
Any variations to these Marketing Authorisations will be managed as part of the specific MR/DC procedure, according to the relevant procedures laid down in the Variations Regulation (EC/1234/2008 as amended), where worksharing will also be possible.
Where a UK wide MA is involved, since the MR/DC variation decision applies UK wide, it can be implemented unless the MHRA notifies the MAH within 30 days of the RMS decision that it cannot be accepted in Great Britain. In this case a separate MA for Great Britain will need to be issued. Where a PL(NI) is issued, if the same product is separately authorised in Great Britain, a separate variation application will need to be submitted to vary that authorisation under domestic legislation. Type IA notifications can only be processed on the basis of what is actually submitted to the MHRA for GB.
However, for Type IB and Type II variations, if such a variation is submitted for the corresponding Great Britain authorisation, after approval of the identical changes by the RMS, and evidence of this is included with the submission, this will be taken into consideration according to the reliance route for variations.
A lower fee will be charged and there will be no fee if the Great Britain authorisation was granted under the unfettered access route, based on a purely national Northern Ireland authorisation(*). Further guidance will be issued in due course.
Where a PL(NI) is issued, if the same product is separately authorised in Great Britain, a separate variation application will need to be submitted to vary that authorisation under domestic legislation. Type IA notifications can only be processed on the basis of what is actually submitted to the MHRA for Great Britain.
However, for Type IB and Type II variations, if such a variation is submitted for the corresponding Great Britain authorisation, after approval of the identical changes by the RMS, and evidence of this is included with the submission, this will be taken into consideration according to the reliance route for variations.
A lower fee will be charged and there will be no fee if the Great Britain authorisation was granted under the unfettered access route, based on a purely national Northern Ireland authorisation. Further guidance will be issued in due course.
2.1. Pending variations (no decision)
How variations that are pending (‘no final decision) on 1 January 2021 would be finalised:
Purely national Marketing Authorisations (not part of any worksharing procedure)
These will be processed to conclusion under the transitional provisions, using the same purely national procedures that were in place prior to 1 January 2021.
UK Marketing Authorisation covered under Chapter II of Regulation (EC) No 1234/2008 (variations to marketing authorisations granted in accordance with Chapter 4 of the 2001 Directive i.e. mutual recognition/decentralised variations (Type IA, Type IB or Type II)
These will be processed to conclusion after 1 January 2021 as MR/DC variations using the relevant MR/DC procedures led by the RMS, where NI will be a CMS.
Purely National Marketing Authorisations before 1 January 2021, but part of a worksharing procedure under Article 20 of Regulation (EC) No. 1234/2008 (Type IB or Type II)
Any worksharing variation involving purely national Marketing Authorisations will be processed to conclusion after 1 January 2021 as part of the existing worksharing procedures led by the relevant Reference Authority.
Action to take if the applicant does not wish to continue with the relevant variation as a national (UK) application
The applicant should notify the licensing authority in writing that they no longer want the application to proceed. A partial fee refund may be applicable in line with the current MHRA fees regulations.
2.2. Pending variations (decision made)
In the event that the UK is not the Reference Member State or Reference Authority for a variation procedure and a final decision has already been taken by the lead authority, but not finally processed in the UK before 1 January 2021, the MHRA will implement the agreed outcome of the procedure.
2.3. New variations submitted from 1 January 2021
All new variations submitted from 1 January 2021 will either be processed as purely national variations, according to the same transposed procedures, as were in place prior to 1 January 2021 or those which were already part of MR/DC procedures prior to then, which will continue to be processed as MR/DC variations.
Northern Ireland protocol
New variations submitted from 1 January 2021 to Marketing Authorisations issued as a result of Northern Ireland’s involvement in European procedures will be managed in line with the base procedures.
All other new variations will be processed as purely national variations, according to the same transposed procedures, as were in place prior to 1 January 2021.
Worksharing will only be possible for purely national Marketing Authorisation authorised for use only in Northern Ireland. However, provided the identical Type IB or Type II variation has already been approved for a related European Marketing Authorisation and evidence of this is included with the submission, this will be taken into consideration during the assessment process according to the reliance route procedure.
A lower fee will be charged and there will be no fee if the Great Britain authorisation was granted under the unfettered access route. Further guidance will be issued in due course.
3. Points to note for specific changes submitted from 1 January 2021
3.1. Change to finished product manufacturer
A change in finished product manufacturing site, including as appropriate primary and/or secondary packaging site should be submitted under the relevant sub-change code under B.II.b.1 and be suitably supported. This includes the submission of a copy of the relevant Manufacturing Authorisation or as appropriate a valid good manufacturing practice (GMP) certificate issued by the UK, or a GMP certificate (or equivalent document) from the competent authority of a country on the approved country for batch testing list (currently EEA Member States, Australia, Canada, Israel, Japan, New Zealand, Switzerland and the USA).
Where relevant reference to the EudraGMP database will suffice.
3.2. Change to importer/batch release site/quality control site
A change in importer/batch release site and/or quality control site should be submitted under the relevant change code under B.II.b.2 and be suitably supported.
3.2.1. Importer/batch release
The change should be supported by including a copy of the relevant Manufacturing Authorisation or a valid GMP certificate issued within the last 3 years (as issued by the UK or a country included on the approved country for import list (currently EU/EEA Member States).
Where relevant reference to the EudraGMP database will suffice.
3.2.2. Quality control site
The change should be supported by including a copy of the relevant Manufacturing Authorisation or a valid GMP certificate (as issued by the UK or a country included on the approved country for batch testing list (currently EEA Member States, Australia, Canada, Israel, Japan, New Zealand, Switzerland and the USA). However, see separate guidance considering any specific exclusions.
Where relevant reference to the EudraGMP database will suffice.
3.3. Change of Marketing Authorisation Holder (MAH)
A change of MAH, such as from a company outside the UK to one established in the UK, cannot be done as a variation. That change requires the submission of a Change of Ownership application.
A change to the name/address of the MAH can be submitted as a Type IA IN under change code A.1, provided that it is not a change to the legal entity.
3.4. Change to the location of the Pharmacovigilance Systems Master File (PSMF) or the Qualified Person for Pharmacovigilance (QPPV)
Any change to the QPPV or location of the PSMF should be submitted under change code C.I.8.a (Type IA IN), provided the conditions and documentation requirements can be fully met.
The QPPV for UK authorised products must be established in the EU/EEA or UK on day one, and the PSMF for UK authorised products must be accessible electronically from the UK at the same site at which reports of suspected adverse reactions may be accessed.
Please see separate guidance on submission of pharmacovigilance details from 1 January 2021.
3.5. Implementation of the outcome of referrals and procedures concerning PSUR or PASS
Where the procedure has been finalised before 1 January 2021, the outcomes in relation to any required variations will be processed according to the EU decision. Depending on the nature of the required changes, the variations should be submitted under the relevant main change codes of C.I.3 or B.V.b (usually type IA). The actual submission category will depend on the specific nature of the required changes, taking into consideration if further assessment is required
Where the procedure is ongoing on 1 January 2021, the outcome of the procedure should be implemented via the appropriate route.
From 1 January 2021, outcomes of these procedures should be implemented as appropriate and where a variation is required it will usually be a Type IA.
3.6. Submission of protocols and study reports for post authorisation safety studies (PASS)
Although not actually variations, whether or not carried out in relation to a condition of the MA or voluntarily, the protocol and final study reports from safety studies should be submitted to the MHRA within 12 months of the end of data collection.
The most effective way of processing these is according to the Type II variations procedure, and they should be submitted under change code C.I.13. The submission should be accompanied by the appropriate fee, which is the same as that of a Type II or Type II complex variation. . See also guidance on our approach to pharmacovigilance procedures from 1 January 2021.
3.7. Submission of paediatric study reports for assessment
From 1 January 2021, holders of a UK marketing authorisation who sponsor a paediatric study (which involves the use in the paediatric population of a medicinal product to which that authorisation relates), must submit the results of this study to the MHRA within the period of six months from the end of the study. MHRA has issued guidance setting out the submission requirements and procedures for assessment of completed paediatric studies.
In cases where an initial appraisal indicates that an assessment is required, the MAH will be asked to submit the paediatric data as a Type II complex variation to the MHRA under change code C.I.13.
If the results of a paediatric study have been submitted for assessment to EMA or CMDh under Article 46 of Reg.1901/2006/EC prior to 1 January 2021 MHRA will request MAHs to submit a Type IB variation to update the product information (PI) if there are proposed changes to the PI that can be directly implemented to relevant UK products following the completion of the EU procedure.
This guidance will apply from 1 January 2021 in line with the Human Medicines Regulations (Amendment etc.) (EU Exit) Regulations 2019.
Contact
For further information, please email our Customer Services Centre at info@mhra.gov.uk or call 020 3080 6000. Alternatively, contact your Trade Association by emailing:
- Association of the British Pharmaceutical Industry (ABPI): regulatory@abpi.org.uk
- British Generic Manufacturers Association (BGMA): info@britishgenerics.co.uk
- BioIndustry Association (BIA): regulatory@bioindustry.org
- Clinical & Contract Research Association (CCRA): mail@ccra.org.uk
- Ethical Medicines Industry Group (EMIG): info@emig.org.uk
- Health Food Manufacturers’ Association (HFMA): pennyviner@btconnect.com
- The National Pharmacy Association (NPA): independentsvoice@npa.co.uk
- Proprietary Association of Great Britain (PAGB): regulatory@pagb.co.uk
Last updated 29 December 2020 + show all updates
Guidance
Guidance on 150-day assessment for national applications for medicines from 1 January 2021
How the 150-day assessment timeline for all high-quality marketing authorisation applications works, and how to apply.
Brexit transition: new rules for 2021
The UK has agreed a deal with the EU. This page tells you the new rules from 1 January 2021.
Use the Brexit checker to get a personalised list of actions and sign up for email updates.
For current information, read: Apply for a licence to market a medicine in the UK
The 150-day assessment for national applications
The MHRA offers a 150-day assessment timeline for all high-quality marketing authorisation applications (MAAs), aiming at accelerating the availability of medicines for patients in the UK.
Under this process, the MHRA will evaluate the application for a UK, Great Britain (England, Wales and Scotland) or Northern Ireland marketing authorisation and reach its opinion on approvability within 150 days of submission of a valid application.
Applications eligible for the 150-day Assessment
The 150-day Assessment is available for all high-quality new MA applications submitted to MHRA from 1 January 2021.
Submission of the application
Applications should be submitted via the MHRA Submission Portal.
The fees
The appropriate national fee will apply.
How to apply
New active substances and biosimilar products
Before submission
For medicines containing new active substances or biosimilar products, applicants are recommended to contact MHRA by emailing AcceleratedandRollingReview@mhra.gov.uk in advance of the intended date of submission.
The letter should include the intended date of submission of the dossier advising whether the MAA is to be submitted to UK, Great Britain (England, Scotland and Wales) only, or Northern Ireland only.
If the application includes Northern Ireland, then it must comply with EU requirements.
Prior to the submission, applicants should refer to guidance on Procedures for UK Paediatric Investigation Plans (PIPs) and the UK compliance check (CC) should be completed 60 days before the intended submission.
For medicinal products presented or used with a device component, applicants should refer to guidance on regulating medical devices.
Pre-submission meeting
At the meeting applicants may wish to provide a short summary of the dossier to share their intentions and to verify the new active substance status. They may want to raise any specific issues such as requests for:
- consideration for orphan MA
- conditional MA
- MA under exceptional circumstance
The meeting will also offer opportunity to discuss the arrangements for UK Compliance Check on PIPs. The pre-submission meeting may offer the opportunity to enhance joint discussion with National Institute for Health and Care Excellence (NICE) Health Technology Assessment (HTA) evaluation process.
The MHRA will operate a ‘fixed submission date’ system to facilitate consultation with the Commission on Human Medicines and will publish a set of dates to facilitate planning the submissions to coordinate with appropriate meeting dates of CHM.
Validation of applications
The applicants should submit a valid, full application to the MHRA for evaluation. The accompanying cover letter should detail the intention to seek orphan status or MA under exceptional circumstances as applicable.
A valid application/dossier should include common technical modules (CTD modules 2-5) and a UK specific CTD module 1, consisting of an appropriate Risk Management Plan (RMP), UK PIP CC and/or compliance with UK Orphan Medicines requirements, when applicable.
The SmPC/PIL may be submitted as word documents in the working documents folder. There is an option to put the UK specific SmPC/ PIL/ Labelling text/ mock-ups in the UK specific folder which is available within the eCTD structure.
Applications that refer to an ASMF should ensure that the file (including the restricted part) has already been submitted to MHRA and a suitable letter of access authorising MHRA to make reference to the confidential information in the restricted part of the ASMF should be provided.
The assessment timetable will begin after validation of the application.
Assessment process and expert advice
The assessment process includes consultation with the CHM on fixed dates each month. The submission slots will be linked to the dates of CHM meetings. The MHRA may additionally wish to seek advice/input from therapy area experts (specialty expert groups) during the assessment process.
The assessment process will run in two phases totalling 150 days with an intervening clock-off period between phase I and phase II, if required. Assessment phase I will be completed 80 days after the clock starts. Issues arising or requiring clarification from the initial assessment will be raised with the applicant as a letter requesting further information (RFI) and should be addressed within the clock off period of 60 days.
Requests for extension of the clock off period for up to another 60 days may be granted only for exceptions. Applicants may contact the assessment team for discussing issues raised in the RFI letter. Assessment in phase-I will also address eligibility for grant of orphan status.
Phase II assessment will commence on receipt of the applicant’s responses. Applicants are recommended to contact the MHRA Assessment Team in advance of the intended date of submission of response to align with CHM meetings. Based on the assessment, the MHRA will provide a decision on approvability of the product by day 150.
Appealing a decision to refuse
If the MHRA proposes to refuse to grant the MA based on advice from CHM, there is an opportunity for the applicant to request a review of the decision. The procedure for such review is set out in Schedule 5, and paragraph 11 of Schedule 11, to the Human Medicines Regulations. The MHRA decision letter will detail the appeal process and timelines.
The orphan status will be determined at the time of MA grant. If orphan status is not agreed and the company wishes to appeal this decision, the grant of a marketing authorisation will only be possible when the appeal process is completed.
Publication
Conclusion of the assessment will lead to the publication of a UK Public Assessment Report for the product.
Existing Active Substances Applications
The Applicant should refer to guidance for choosing acceptable reference medicinal products for generic applications and/or bioequivalence (BE) studies for applications made only to Great Britain. The Applicant should also refer to any MHRA product-specific BE guidance for applications made only to Great Britain.
Validation of applications
A valid application/dossier should include common technical modules (CTD modules 2-5, as appropriate), a UK specific CTD module-1, and an appropriate Risk Management Plan. Applications that refer to an ASMF should ensure that the file has already been submitted to MHRA or included in the submission.
The assessment timetable will begin after validation of the application.
Assessment process and expert advice
The assessment process will run in two phases totalling 150 days with an intervening clock-off period between phase I and phase II, if required. Assessment phase I will be completed within 80 days after clock start. Concerns arising from the initial assessment will be raised with the applicant as a letter requesting further information (RFI).
MHRA will seek advice from CHM and/or therapy area experts (specialty expert groups) during the assessment process, as required. All concerns must be fully addressed in the clock off period of 60 days. Requests for extension of the clock off for up to another 60 days may be granted under exceptions only. Applicants may contact the assessment team for discussing issues raised in the RFI letter.
Phase II assessment will begin on receipt of the applicant’s responses. Based on the assessment, the MHRA will provide an opinion on approvability of the product by day 150, and if positive, will grant the MA.
Appealing a decision to refuse
If the MHRA proposes to refuse to grant the MA based on advice from CHM, there is an opportunity for the applicant to request a review of the decision. The procedure for such review is set out in Schedule 5, and paragraph 11 of Schedule 11, to the Human Medicines Regulations. The MHRA decision letter will detail the appeal process and timelines.
Publication
Conclusion of the assessment will lead to the publication of a UK Public Assessment Report for the product.
Guidance
Renewing Marketing Authorisations for medicines from 1 January 2021
The way Marketing Authorisations (MAs) are processed will change from 1 January 2021.
Brexit transition: new rules for 2021
The UK has agreed a deal with the EU. This page tells you the new rules from 1 January 2021.
Use the Brexit checker to get a personalised list of actions and sign up for email updates.
For current information, read: Renew: marketing authorisation for a human medicine
The Medicines and Healthcare products Regulatory Agency (MHRA) will be the UK’s medicines regulator from 1 January 2021. This includes acting as the regulator for products placed on the market in Northern Ireland. There will be some different requirements for products placed on the market in the UK with respect to Great Britain (England, Scotland, Wales) and Northern Ireland.
Renewals for converted Centrally Authorised Products (CAPS)
CAPS converted from EU to UK MAs will be treated as if they were granted on the date the corresponding EU MA was granted. The renewal date will stay the same.
Please refer to Guidance on Converting Centrally Authorised Product (CAPS) to UK MAs.
Your MAs will remain in force until a decision has been made on your renewal applications.
Renewals submitted for MAs granted through mutual recognition (MR) or decentralised (DC) procedures
On 1 January 2021 all holders of existing marketing authorisations (MAs), or applicants for MAs with applications submitted by that date and under review within a decentralised or mutual recognition procedure with UK as a CMS will have a choice on how to manage their marketing authorisations/applications.
Refer to the guidance on handling of decentralised and mutual recognition procedures approved or pending on 1 January 2021.
The default position will be to maintain a UK wide marketing authorisation and retain UK in respect of Northern Ireland (UK(NI) (UK in respect of Northern Ireland) as a CMS. In this case, the authorisation will continue to be a UK wide MA with Northern Ireland as a CMS and Great Britain aligned with, but not part of, the DCP/MRP.
Where this applies any pending applications will be processed to conclusion after 1 January 2021 as MR/DC renewals using the relevant MR/DC procedures led by the RMS.
New applications for a renewal of the MA should be submitted via the DCP/MRP and if approved would apply to the UK wide authorisation with Great Britain implementing the European decision unless the MHRA notifies the MAH within 30 days of the RMS decision that the decision cannot be accepted in Great Britain.
In this case, a separate MA for Great Britain would need to be issued. Other options include having separates MAs for UK(NI) as CMS, and Great Britain. Renewal applications for Great Britain MAs will be processed via the purely national route.
If you’ve submitted renewals for MAs granted through the the DCP/MRP and do not get a decision before 1 January 2021, you will not need to resubmit them.
If a final decision has been made on your renewal but it hasn’t been processed in the UK before 1 January 2021, the MHRA will implement the agreed outcome.
Where a final decision has not been made, the MHRA will ensure that the renewal process is concluded and processed by the appropriate route.
Renewals submitted from 1 January 2021
From 1 January 2021, you should continue to submit your renewal applications 9 months before they expire.
The requirements for renewal submissions will remain the same for products authorised in the UK and should include the same documents currently required in the EU as detailed in the following guidance:
- CAP renewals and annual reassessments
- Renewals for products authorised through MRP or DCP procedures
The MHRA will continue to accept the reduced submission requirements for renewals of MAs for products authorised under Article 10.1 as set out in the CMDh Best Practice Guide on processing renewals in the MRP/DCP.
Conditional Marketing Authorisations
From 1 January 2021, you should continue to submit your renewal applications for conditional MAs 6 months before they expire.
For Great Britain MAs the application should be submitted to the MHRA, who will consider the application in accordance with new regulation 66B of the Human Medicines Regulations 2012.
The same applies to converted EU MAs that were granted as conditional MAs.
Renewals for MAs granted via unfettered access
Where you have a Great Britain-only MA granted via the Unfettered Access route, an application to renew the MA should be submitted in line with the above guidance. Where the MA has remained in line with the EU or Northern Ireland MA we will accept the same renewal application as submitted to the EU and a reduced fee will be applied.
Changes to fees
The new fees will be:
- £9,682 for the first renewal of a product containing a new active ingredient at the time of authorisation
- £747 for related applications made at the same time as the first renewal
There will be no fees for:
- subsequent MA renewal applications
- renewing conditional MAs
Contact
For further information, please email our Customer Services Centre at info@mhra.gov.uk or call 020 3080 6000. Alternatively, contact your Trade Association by emailing:
- Association of the British Pharmaceutical Industry (ABPI): regulatory@abpi.org.uk
- British Generic Manufacturers Association (BGMA): info@britishgenerics.co.uk
- BioIndustry Association (BIA): regulatory@bioindustry.org
- Clinical & Contract Research Association (CCRA): mail@ccra.org.uk
- Ethical Medicines Industry Group (EMIG): info@emig.org.uk
- Health Food Manufacturers’ Association (HFMA): pennyviner@btconnect.com
- The National Pharmacy Association (NPA): independentsvoice@npa.co.uk
- Proprietary Association of Great Britain (PAGB): regulatory@pagb.co.uk
Last updated 29 December 2020 + show all updates
Guidance
Rolling review for marketing authorisation applications from 1 January 2021
How the rolling review process for marketing authorisation applications will work, and how to apply.
Rolling review
The rolling review is a new route for marketing authorisation applications (MAA), where an applicant for a marketing authorisation submits increments of the eCTD dossier for pre-assessment by the MHRA rather than as part of a consolidated full dossier submission.
The rolling review is intended to streamline the development of novel medicines by offering periodic enhanced regulatory interaction and advice to reduce the risk of failure at the final phase and may be integrated with the Target Development Profile (TDP) to provide a clearer pathway for development of innovative medicines.
It may be used for a new active substance (NAS) in the UK, Great Britain (England, Scotland and Wales), or Northern Ireland. This is in accordance with regulation 50(5) of the Human Medicines Regulations, or for a similar biological medicinal product in Great Britain in accordance with regulations 53A of the Human Medicines Regulations.
Products eligible for the rolling review
MAAs for any NAS based on a ‘full dossier’, including biological products, are eligible for the rolling review. Similar biological applications, i.e., biosimilar products, are also eligible.
Submission of the application
Companies who wish to enter the rolling review should request a pre-submission meeting to discuss the product, its intended target populations and the data in each module to be submitted. Companies may specify future MAA designated for UK, Great Britain (England, Scotland and Wales) only, or Northern Ireland only.
To apply for a pre-submission meeting, a completed application should be forwarded to the AcceleratedandRollingReview@mhra.gov.uk. Following receipt of the request, the MHRA will arrange a mutually acceptable date for the meeting. There is no fee payable for the pre-submission meeting.
Applications, including the first module(s) to be assessed, should be submitted via the MHRA Portal.
The fees
Each phase of assessment (for quality, non-clinical and clinical modules) will attract a fee payable as set out in Regulation 28(A) of Schedule 2 to the Medicines (Products for Human Use) (Fees) Regulations 2016.
Process and sequence
The process is a modular approach to submission and evaluation. The quality, non-clinical and clinical data may be submitted separately or jointly, depending on individual circumstances and/or data availability, in the format of common technical modules (CTD modules 3-5, as appropriate).
Pre-assessment of modules
Following the process by the Information Processing Unit (IPU), the assessment of the first module will start from Day 0. The assessment cycle will be completed within 60 days. Following each assessment cycle, a Module Assessment Summary (MAS) will be issued by Day 60. The MAS will offer the applicant opportunities to update the module which should be included in the final phase. The same timeline above will be applied to other module assessments.
The assessment process may include consultation with the CHM and/or therapy area experts (specialty expert groups) during the pre-assessment process.
Final phase (for marketing authorisation application)
Before submission
Applicants should refer to guidance on Procedures for UK Paediatric Investigation Plans (PIPs) and the UK compliance check (CC) should be completed 60 days before the intended submission.
Pre-submission meeting
A pre-submission meeting with the MHRA around 90 days in advance of the intended submission for the final phase is recommended. At the meeting applicants may wish to provide a short summary of the dossier, as well as to raise any special issues such as requests for consideration for orphan MA, conditional MA or MA under exceptional circumstances. The pre-submission meeting may offer the opportunity to enhance joint discussion with the National Institute for Health and Care Excellence (NICE) Health Technology Assessment (HTA) evaluation process.
The MHRA will operate a ‘fixed submission date’ system to facilitate consultation with the Commission on Human Medicines and will publish a set of submission dates to facilitate planning the submissions and coordinate with appropriate meeting dates of CHM.
Validation of applications (MAAs)
A valid application/dossier should include submission of any unassessed modules or data, which may include the clinical module, UK specific CTD module 1, consisting of an appropriate Risk Management Plan (RMP), UK CC and/or orphan designation application (if applicable).
The SmPC/PIL may be submitted as word documents in the working documents folder. There is an option to put the UK specific SmPC/ PIL/ Labelling text/ mock-ups in the UK specific folder which is available within the eCTD structure.
The assessment clock will begin after validation of the application.
Final phase assessment
The final phase should be completed within 100 days in two stages as 60 + 40 days with an intervening clock off period. If required, a letter requesting further information (RFI) may be issued by Day 60 with the clock stopped. Applicants will have the opportunity to discuss any issues identified with the MHRA within 30 days.
Once the RFI response is received, the clock will resume on Day 61, and the EAG/CHM will be consulted again with the final decision on approvability reached by Day 100. The orphan status will be determined at the time of grant of the marketing authorisation.
Appealing a decision to refuse
If the MHRA proposes to refuse to grant the MA based on advice from CHM, there is an opportunity for the applicant to request a review of the decision. The procedure for such review is set out in Schedule 5, and paragraph 11 of Schedule 11, to the Human Medicines Regulations.
The MHRA decision letter will detail the appeal process and timelines. If orphan status is not agreed and company may wish to appeal this decision, the grant of a marketing authorisation will only be possible when the appeal process is completed.
Publication
Grant of a Great Britain marketing authorisation will lead to the publication of a Great Britain Public Assessment Report for the product.
EU guidance documents referred to in the Human Medicines Regulations 2012
Links to EU guidance, as it stood immediately before end of transition period.
Brexit transition: new rules for 2021
The UK has agreed a deal with the EU. This page tells you the new rules from 1 January 2021.
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This is EU guidance specifically referred to in the Human Medicines Regulations 2012 (HMRs), as these are due to be amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 and the Human Medicines (Amendment etc.) (EU Exit) Regulations 2020.
Before the end of the transition period, the Government is putting in place legislation to allow the continued sale of and access to medicines as well as to implement the Northern Ireland Protocol in relation to medicines regulation.
This will be done via amendments to the HMRs by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 and the Human Medicines (Amendment etc.) (EU Exit) Regulations 2020. The 2020 Regulations have been approved by Parliament and are now UK law.
The HMRs set out a comprehensive regime for the authorisation of medicinal products for human use; for the manufacture, import, distribution, sale and supply of those products; for their labelling and advertising; and for pharmacovigilance.
They also provide for enforcement powers for the authorisation and supervision of medicinal products for human use.
The amendments to the HMRs address the fact that the UK will no longer be part of the harmonised EU medicines network following the end of transition period.
However in Northern Ireland the EU regulations will continue to apply in accordance with the Northern Ireland Protocol. They replicate the current arrangements so far as possible in Great Britain but also make appropriate changes to reflect the fact that the MHRA will operate outside of the EU network while acknowledging the special provisions that will apply in respect of Norther Ireland.
Part of maintaining the current position involves continued reliance on EU guidance documents. Where existing EU law refers to various pieces of EU guidance, those references are inserted into the 2012 Regulations.
The relevant version of the EU guidance is the version as it stood immediately before the end of the transition period.
Those versions can be accessed below for reference in Great Britain (England, Scotland and Wales).
With regard to Northern Ireland, the relevant version of this guidance can be obtained from the EU websites.
Guidance on applications for marketing authorisations (MAs)
View all the files in this section
Guidance on inspections
View all the files in this section
Guidance on packaging and leaflets
View all the files in this section
Guidance on Good Manufacturing Practice
View all the files in this section
Guideline on similar biological medicinal products
View all the files in this section
Guidelines for generic medicinal products for omitting bioavailability studies from an application
View all the files in this section
Guidance for medical devices
View all the files in this section
Guidelines for variations
Last updated 30 December 2020 + show all updates