Guidance

eCTD guidance for marketing authorisation and post-authorisation applications

Updated 9 July 2024

New IRP marketing authorisation applications (MAAs)

You should submit an International Recognition Procedure (IRP) application to the MHRA as one electronic Common Technical Document (eCTD) sequence through the MHRA Submissions Platform from the Human Medicines tab. This is the only acceptable route for submission of an IRP.  

See information on how to register to use this portal.  

Where applications are amended during the agency’s evaluation, such as following assessment of responses to questions, you should provide a new or consolidated eCTD sequence to maintain the eCTD lifecycle. Replacement sequences of a previously submitted eCTD application (for example, following corrections) are not acceptable. Any modification of an eCTD application must be reflected in a new eCTD sequence. All subsequent sequences should be submitted via the MHRA Submissions Platform.  

All modules of the eCTD should be in EU format (Modules 1-5), with UK-specific information included in Module 1. You must include certain information in the cover letter and the sub-folder in the cover letter area.

Furthermore, you must include certain information in m1-additional-data, to facilitate processing of the application and supporting data, . 

Supporting data relevant to the application should not be placed in m1-additional-data. Wherever possible, place this in the relevant eCTD section. There may be instances where data supplied to the Reference Regulator (RR) are not required by MHRA. This is covered in the Other Reference Regulator documents section below. 

eCTD M2-M5 should include all relevant information required for the MHRA application and will form the baseline of the required information as approved by RR at the MHRA submission date. This will need to comply with any EU regional requirements of the ICH eCTD standards. 

Terminology  

You must use the following terminology / naming conventions: 

cc – EU country code (generally, this will be the UK). 

RR – Reference Regulator, use the ISO Alpha 2 code. 

VAR – Use variable text to provide greater detail of the content of file name.  Note the imitations to naming of files in eCTD. 

EXT – The file extension.  

Document locations 

The following sections indicate where you should provide the data for M1 and the suggested naming convention for that data in the relevant section. 

Cover letter 

Unless otherwise indicated, you should provide the information directly in the text of the cover letter. 

1. State that the route is International Recognition, and whether it is Recognition A or Recognition B, and the RR. 
2. Provide a declaration that all iterations of the RR assessment reports have been submitted. Assessment reports should be listed in a table at the end of the cover letter. 
3. For new IRP MAAs, state the type of RR approval, such as full approval or conditional/provisional/accelerated approval (or international equivalent). 
4. Inform us of any conditions associated with the RR approval, including where the RR has approved a conditional or exceptional use MA (or international equivalent). Include details of these in a separate document called m1/eu/10-cover/cc/RR-conditions-VAR.EXT. 
5. State any proposed conditions for UK/GB approval. Provide details of these in the same document as item 4. 
6. For new IRP MAAs and extension of indication applications, state if there are differences in the wording of the proposed therapeutic indications for UK/GB and the therapeutic indications approved by the RR. A justification for these changes should be provided: m1/eu/10-cover/cc/RR-justification-UK-GB-indications-VAR.EXT. 
7. Provide a justification for the adverse drug reactions (preferred terms and frequencies) listed in section 4.8 of the SmPC (or indicate where in the eCTD module 2 this information is provided): M1/eu/additional-data/cc/RR-justification- Adverse-Drug-Reaction-VAR.EXT. 
8. If the procedure includes an active substance master file (ASMF), include a declaration that the ASMF holder has submitted the applicant’s and restricted parts of the ASMF, including approved variations and all iterations of the assessment reports on the applicant’s and restricted parts. A letter of authorisation to refer to the ASMF should be included as usual. 
9. State whether or not there are any differences in the proposed UK RMP compared to the RMP that was approved by the RR (where relevant). Where there are differences in the proposed safety concerns, additional pharmacovigilance activities or additional risk minimisation measures these should be briefly described in the cover letter. In the case that the GB/UK specific annex (Guidance on pharmacovigilance procedures is used and included with the RMP in 1.8.2, this should be stated. 
10. Provide the following information (in a tabular format) in M1/eu/additional-data/cc/RR-global-history-VAR.EXT:

• a summary of the global regulatory history of the medicinal product
• a statement whether an application for the same product has been approved, withdrawn, refused, or rejected by another RR (provide reasons for any withdrawal, refusal or rejection)
• a statement whether a marketing authorisation for the same product has been withdrawn, revoked, suspended or not renewed by another RR (provide reasons for any withdrawal, revocation, suspension, or non-renewal)

If any do not apply, indicate this in the cover letter. 

1. Details of substantial changes since the initial approval that impact on the benefit risk.

Other Reference Regulator documents (where applicable)

Please note this is not exhaustive but gives an indication where most types of documents should be placed. 

1. Eligibility form and, where applicable, the outcome of MHRA triage: m1/eu/12-form/cc/cc-form-eligibility.EXT 
2. RR final product information (or international equivalent approved by the RR): M1/eu/additional-data/cc/RR-final-product-information-VAR.EXT  
3. Reports of Good Clinical Practice inspections, by any jurisdiction, of the clinical trials submitted: M1/eu/19clinical-trials/clinicaltrials-VAR.EXT 
4. All RR Approval/Grant letters, MR-DC end of procedure letters or CHMP opinion letters: M1/eu/additional-data/cc/RR-Approval-letter-VAR.EXT 
5. All assessment reports: M1/eu/additional-data/cc/RR-VAR assessment-report.EXT. Variable text in this case should also indicate the type of assessment report e.g. Day-94-PRAC-assessment-report.EXT 
6. Summaries of meetings, other correspondence between the reference regulator and the MAH/Applicant: M1/eu/additional-data/cc/RR-miscellaneous-VAR.EXT 
7. Post-market reviews since the initial RR approval (for example, periodic safety update reports, safety signals): M1/eu/additional-data/cc/RR-Post-Market-Reviews-VAR.EXT. 
8. Individual patient data listings (CSR Appendices 16.4) typically submitted to the FDA in Module 5 are not required in the MHRA submission. Do not include this data in the eCTD to MHRA. 

There are areas where it’s useful to provide documents in Word format. Where these are appropriate and possible, you should provide them in ‘Working Documents’ outside of the eCTD structure. They should follow the same or similar nomenclature to any PDF documents provided in the relevant section of the eCTD. 

For example, Word versions of the following documents: 

• RR assessment reports 
• risk management plan 

Word versions of UK/GB proposed SmPC, label and leaflet are required. 

IRP post-authorisation applications: variations and renewals

You should submit an International Recognition Procedure (IRP) post-authorisation application to MHRA as a new sequence to the existing electronic Common Technical Document (eCTD).

All IRP post-authorisation applications should be submitted through the MHRA Submissions Platform from the Human Medicines tab. This is the only acceptable route for submission of an IRP.  

Where applications are amended during the agency’s evaluation, such as following assessment of responses to questions, you should provide a new or consolidated eCTD sequence to maintain the eCTD lifecycle. Replacement sequences of a previously submitted eCTD application (for example, following corrections) are not acceptable. Any modification of an eCTD application must be reflected in a new eCTD sequence. All subsequent sequences should be submitted via the MHRA Submissions Platform.  

All modules of the eCTD should be in EU format (Modules 1-5), with UK-specific information included in Module 1. You must include certain information in the cover letter, validation checklist form and the subfolder in the cover letter area for post-authorisation applications. This should include the RR that you are using for the application and indicate that this is an IRP procedure.

Furthermore, certain information, to facilitate processing of the application and supporting data, must be included in m1-additional-data. 

Supporting data relevant to the application should not be placed in m1-additional-data. Wherever possible, place this in the relevant eCTD section. There may be instances where data supplied to the Reference Regulator (RR) are not required by MHRA. This is covered in the Other Reference Regulator documents section below. 

eCTD M2-M5 should include all relevant information required for the MHRA application and should be a consolidated sequence of the required information approved by RR at the submission date to the MHRA. This will need to comply with any EU regional requirements of the ICH eCTD standards. 

Terminology  

You must use the following terminology / naming conventions: 

cc – EU country code (generally, this will be the UK). 

RR – Refence Regulator, use the ISO Alpha 2 code. 

VAR – Use variable text to provide greater detail of the content of file name. Note the imitations to naming of files in eCTD. 

EXT – The file extension.  

Document locations 

The following sections indicate where you should provide the data for M1 and the suggested naming convention for that data in the relevant section. 

Cover letter 

Unless otherwise indicated, you should provide the information directly in the text of the MAA cover letter. Download and complete a copy of the IRP validation checklist form and submit as an annex to the cover letter.

Provide the information below in the validation checklist form and submit it with all variation and renewal IRP applications and other post-authorisation IRP applications where relevant.

1. State that this is a variation (or renewal) International Recognition application, the Reference Regulator, and the route used to obtain the initial UK/GB application (national UK, MRDC or ECDRP (EMA), IRP Route A, or IRP Route B).
2. Provide a declaration that the UK IRP application is for the same product as that approved by the RR. The same product means the same qualitative and quantitative composition, same dosage form, same MAH (or company group or ‘licensees’). 
3. Provide a declaration that all iterations of the RR assessment reports have been submitted. Assessment reports should be listed in a table at the end of the cover letter or Annex I of the form. 
4. Inform us of any conditions associated with the RR approval. Include details of these in a separate document called m1/eu/10-cover/cc/RR-conditions-VAR.EXT. 
5. State any proposed conditions for UK/GB approval. Provide details of these in the same document as item 3. 
6. For a variation where there is a new indication, state if there are differences in the wording of the proposed therapeutic indications for UK/GB and the therapeutic indications approved by the RR. Provide a justification for these changes: m1/eu/10-cover/cc/RR-justification-UK-GB-indications-VAR.EXT. 
7. If the procedure includes an active substance master file (ASMF), include a declaration that the ASMF holder has submitted the applicant’s and restricted parts of the ASMF, including approved variations and all iterations of the assessment reports on the applicant’s and restricted parts. A letter for permission of access should be provided. 
8. State whether or not there are any differences in the proposed UK RMP compared to the RMP that was approved by the RR (where relevant). Where there are differences in the proposed safety concerns, additional pharmacovigilance activities or additional risk minimisation measures these should be briefly described in the cover letter or Annex II of the form. In the case that the GB/UK specific annex (Guidance on pharmacovigilance procedures) is used and included with the RMP in 1.8.2, this should be stated. 
9. For this variation (or renewal) application state whether the same change has been approved, withdrawn, refused, or rejected by any other RR. Provide reasons for any withdrawal, refusal or rejection in Annex III of the form.  

Other Reference Regulator documents (where applicable) 

Please note: this is not exhaustive but gives an indication where most types of documents should be placed. You should only provide the following information relevant to the variation (or renewal) you are applying for in the UK. 

1. The RR final product information (or international equivalent approved by the RR): M1/eu/additional-data/cc/RR-final-product-information-VAR.EXT  
2. Reports of Good Clinical Practice inspections, by any jurisdiction, of the clinical trials submitted: M1/eu/19clinical-trials/clinicaltrials-VAR.EXT 
3. All RR approval/grant letters, MR-DC end of procedure letters or CHMP opinion letters: M1/eu/additional-data/cc/RR-Approval-letter-VAR.EXT 
4. All assessment reports: M1/eu/additional-data/cc/RR-VAR assessment-report.EXT. Variable text in this case should also indicate the type of assessment report, for example, Day-60-FVAR-.EXT 
5. Summaries of meetings, other correspondence between the reference regulator and the MAH/Applicant: M1/eu/additional-data/cc/RR-miscellaneous-VAR.EXT 
6. Post-market reviews since the initial RR approval (for example, periodic safety update reports, safety signals): M1/eu/additional-data/cc/RR-Post-Market-Reviews-VAR.EXT. 
7. Individual patient data listings (CSR Appendices 16.4) typically submitted to the FDA in Module 5 are not required in the MHRA submission. Do not include this data in the eCTD to MHRA. 

There are areas where it is useful to provide documents in Word. Where these are appropriate and possible, provide them in ‘Working Documents’ outside of the eCTD structure. They should follow the same or similar nomenclature to any PDF documents provided in the appropriate section of the eCTD. 

For example, Word versions of the following documents: 

• RR assessment reports 
• risk management plan 

Word versions of UK/GB proposed SmPC, label and leaflet are required.