MHRA guidance on the International Recognition Procedure (IRP) commencing in 2024 - PART 2
16. Can Access Consortium approvals which have not included the MHRA as part of the work-sharing procedure be eligible for IRP?
Yes, Access Consortium approvals which have not included MHRA as part of the work-sharing procedure can be used for the IRP. The Applicant may choose one of the trusted regulators within the Access Consortium as the Reference Regulator (RR) and submit the relevant documents as approved by that specific regulator.
17. Can the IRP also be used for post-authorisation procedures?
Yes, the IRP may also be used for post-authorisation procedures including:
·???????? line extensions,
·???????? variations (Type IB, Type II).
·???????? renewals (including annual renewal of conditional MAs and annual reassessment of exceptional circumstance MAs)
IRP can be used during the lifecycle of products that have been initially authorised or subsequently varied via standalone national, MRDCRP or ECDRP routes. Conversely, where a product has been authorised via IRP, it is acceptable to submit standalone national post-authorisation procedures including variations.
18. More about variations submitted via the IRP
·???????? Variations submitted via IRP should be classified according to MHRA Guidance on Variations to MAs.
·???????? The MHRA retains the authority to reject a variation application if the evidence provided is considered insufficiently robust.
·???????? Variations which impact on patient safety will be assessed in the context of the UK clinical situation and the MHRA may require assessment through a national route where there are specific UK considerations.
19. Obligation to notify MHRA of any information that might influence the evaluation of the benefits and risks of a product authrorised with the IRP?
·???????? Applicants are reminded of the obligation to notify MHRA as soon as reasonably practicable, of any information that might influence the evaluation of the benefits and risks of an authorised product.
·???????? IRP is not a substitute for MAH’s obligations to submit pharmacovigilance data and information to the MHRA and to keep the MA up to date with current scientific knowledge.
·???????? Where there is new information, that might impact evaluation of the benefits and risks of a product, likely to impact clinical management of patients, and/or require proactive communications, there should be no delay in submitting this information to the MHRA. UK requirements for the submission of pharmacovigilance data will apply to the MA including the submission of Periodic Safety Update Reports (PSURs).
·???????? It may be possible to align the PSUR submission cycle with that of the RR.
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20. Recognition route timetables A and B for initial Marketing Authorisation Applications (MAAs) via the IRP
There are two recognition timetables for?initial MAAs:
·???????? Recognition route A: 60-day timetable
·???????? Recognition route B: 110-day timetable
The timetables are calendar days and start once the IRP submission has been validated by MHRA.
It is important to note the following:
·???????? ATMPs?are eligible for Recognition B only. Due to potential differences between guidelines internationally, some IRP applications may require additional checks by MHRA.
?·???????? IRPs that include GB orphan drug designation applications will not be eligible for Route A
?·???????? If the RR has not assessed the Risk Management Plan (RMP), the product will be eligible for Recognition B only.
?·???????? In the case that the RR has assessed an RMP, but the RMP proposed for UK/GB is not the same or not in the same format as the RMP approved by the RR, the product will be eligible for Recognition B only.
?·???????? If a new site is added specifically for the MHRA, the application is eligible for Recognition B only.
?21. What is the purpose of having two recognition routes (A and B) and which application types are eligible?
The purpose of having two routes is to enable fast approval of those IRP applications which require limited assessment.
Recognition A and B only apply to initial marketing authorisations and line extensions.
22. How will suitability for Recognition route A or B timetable be determined?
The MHRA has made available an online?Eligibility checker.
·???????? The Eligibility Checker should only be completed for Initial MAAs (including line extensions).??
·???????? Suitability for Recognition A or B is determined by means of an online Eligibility Checker to be completed by the Applicant?6 weeks before?the planned date of MAA submission.?
·???????? Before filling in the Eligibility Checker please make sure you have read the guidance on IRP.
·???????? The form will ask a series of questions that enables the MHRA to identify the appropriate IRP Route A or B.? In a small number of cases, it will require triage by the MHRA to reach a conclusion on this route.
·???????? Some points worth noting:
o?? To be eligible for Recognition A, the RR approval must have been granted within the previous 2 years.?
o?? To be eligible for Recognition B, the RR approval should have been granted within the previous 10 years.??
o?? If your application is older than 10 years you may still be eligible, but you will need to check with the MHRA before filling in the Eligibility Checker.??
o?? Once you have completed the form and downloaded it, follow the submission instructions at the top of the form.????
o?? Further guidance on the Eligibility Checker and submitting your Marketing Authorisation application is available?here.
23. What happens to applications that are determined not eligible for Recognition route A or B?
Applications that are determined not eligible for Recognition A or B can be submitted as full national applications if MHRA requirements are met.
24. What are the key features of the Recognition route A timetable?
?·???????? To be eligible for Recognition A, the Reference Regulator (approval) must have been granted within the previous 2 years. A CHMP positive opinion or an MRDC positive end of procedure outcome is an RR approval for the purposes of IRP.
·???????? The manufacturing process must be the same as that approved by the RR, with evidence of compliance with Good Manufacturing Practice (GMP) at the time of IRP submission.
·???????? The Recognition A route will be open to applications that meet the criteria for IRP and do not meet any of the Recognition B criteria.
·???????? Recognition A procedures will run to a 60-day timetable from validation, with no clock stop. However, if Major Objections are identified which cannot be resolved within 60 days, the timetable may revert to Recognition B.
?25.?? What are the key features of and which criteria will determine whether an application will follow the Recognition route B timetable?
·???????? To be eligible for Recognition B, the RR approval should have been granted within the previous 10 years. A CHMP positive opinion or an MRDC positive end of procedure outcome is an RR approval for the purposes of IRP.
·???????? IRP applications will follow Recognition B if any one of the following criteria applies:
o?? RR has granted a conditional or exceptional circumstances MA (or international equivalent).
o?? A conditional or exceptional circumstances MA is sought in UK/GB.
o?? Additional manufacturing sites are cited that have not been assessed by the RR (except for secondary packaging, labelling and QP release sites).
o?? There are substantial changes in the manufacturing process or analytical methods compared to what was assessed by the RR.
o?? At least one manufacturing site is not yet GMP certified.
o?? The Environmental Risk Assessment (ERA) has not been assessed by the RR.
o?? The Risk Management Plan (RMP) has not been assessed by the RR.
o?? There are UK-specific risk management activities (e.g., which may be reflected as additional pharmacovigilance or additional risk minimisation activities).
o?? The RR has mandated one or more post-authorisation safety studies (PASS).
o?? The product contains a first-in-class new active substance.
o?? The product incorporates novel or cutting-edge technologies.
o?? Clinical efficacy or safety data are available for a later cutoff than those assessed by the RR.
o?? The pivotal clinical data are from single arm studies.
o?? The pivotal clinical data include real world data.
o?? Advanced therapy medicinal product (ATMP) as classified by the HMRs 2012.
o?? Fractionated plasma product.
o?? Application for orphan drug designation.
o?? Comparator product used in bioequivalence or therapeutic equivalence study was sourced outside the UK/EU/EEA (generic/hybrid applications).
o?? Product is not subject to medical prescription.
o?? Co-packaged medical device components are not CE or UKCA marked.
o?? Where an IVD is required for correct use, the IVD is not CE or UKCA marked.
o?? An approved body or notified body report is not available for integral medical device components.
o?? The RR assessment cites guideline(s) that are not adopted by the MHRA.
o?? Proposed container closure system, shelf-life or storage conditions differ compared to those accepted by the RR and/or additional stability studies have been provided to MHRA.
·???????? Recognition B procedures will run to a 110-day timetable from validation to allow for consultation with the Commission on Human Medicines (CHM). Submission dates for Recognition B to align with CHM dates for New Active Substances (NAS) will be published in due course.
·???????? Recognition B includes one clock stop at day 70, allowing the Applicant up to 60 days to respond to any issues identified. If there are outstanding Major Objections at Day 110, formal advice on approvability will be sought from CHM, and the timetable will revert to the national 210-day timetable.
?26.?? Basic requirements for IRP applications
All IRP applications must meet the following basic application criteria:
?·???????? The product in question is classified as a medicinal product under current legislation and MHRA guidance. How other regulators define a medicinal product in their jurisdiction is of no consequence for IRP applications.
·???????? The Reference Regulator’s (RR’s) assessment package is to be complete, in English and unredacted except for personal information
·???????? The company or authorised representative must be established in the UK, i.e. Great Britain or Northern Ireland, or in the EU/EEA.
·???????? The RR’s assessment relates to a de novo standalone evaluation for a full marketing authorisation, conditional marketing authorisation, or a marketing authorisation under exceptional circumstances (or international equivalents). It cannot be based on a reliance approval. Emergency approvals are not included in IRP.
?27.?? How to apply for the IRP?
About the applicant
The application must satisfy the following conditions:
·???????? The Applicant/MAH must be established in the UK (Great Britain or Northern Ireland) or in the EU/EEA.
·???????? It is anticipated that the Applicant for an IRP application is the same company or belongs to the same (legal) group of companies as the MAH of the RR procedure. This is to ensure that the Applicant/MAH can fulfil the submission requirements as well as all their legal obligations as holder of an MA, such as the obligations stated in Regulations 74 and 75 of the Human Medicines Regulations 2012 (HMRs).
·???????? Provided an Applicant can demonstrate and provide written assurance that all the legal obligations can be met at submission, during the assessment process and throughout the life of the MA, it may be possible to accept applications from third parties.
The requirement for a PL number before completion of the eligibility checker
·???????? A product licence (PL) number is required before completion of the eligibility. If you do not have a 5-digit company number, to allow registration on the MHRA Submissions Portal, this should be requested from [email protected].
·???????? A PL number can then be obtained through MHRA Submissions or by emailing [email protected].
The eligibility checker (for inital MAAs only including line extensions)
Suitability for Recognition A or B will be determined by means of an online eligibility checker to be completed by the Applicant 6 weeks before the intended date of MAA submission.
When and how to submit the eligibility checker form:
`???? A table is provided on this?page?indicating when and how to submit the completed eligibility checker form.
· The form should be included in module 1.2 of the eCTD and
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· the cover letter should indicate which recognition route (A or B) and RR you are using.
· The eligibility checked should be emailed to?[email protected] at least 6 weeks before the intended date of IRP submission.
?28. If you are notified that your application is unsuitable for the IRP, do you have other options?
If you are notified that your application is not suitable for IRP, you can submit an MAA via the national route if MHRA requirements are met.
For a national route application, you should request a pre-submission meeting 3 months prior to planned submission if your product contains a new active substance.
Submission of an IRP application (both initial and post authorisation)
Submission of an Initial Marketing Authorisation
You should submit your application through the Human Medicines Portal. No other submission route is acceptable for IRP.
When submitting your initial IRP application, you will be asked to indicate whether your application is:
·???????? Initial Marketing Authorisation NAS – IR Route A?
·???????? Initial Marketing Authorisation NAS – IR Route B?
·???????? Initial Marketing Authorisation – IR Route A?
·???????? Initial Marketing Authorisation – IR Route B?
As per the current functionality, you will need to indicate whether your submission is:
·???????? Original submission
·???????? Validation Correction Request (VCR)
·???????? Response to questions
Submission of an IRP as an electronic Common Technical Document (eCTD)
An IRP application should be submitted 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.??
The necessary guidance is available on this?page?under the following sections:
·???????? Initial applications
·???????? Terminology
·???????? Document locations
·???????? Cover letter
·???????? Other Reference Regulator documents (where applicable)
Submitting your IRP Variation or Renewalnbsp;
You should submit your application through the Human Medicines Portal under MHRA Submission Platform/Hub. No other submission route is acceptable for IRP. You will be asked when submitting to indicate your Application Type. Please choose one of the following options as appropriate for your submission:??
·???????? Variation Type IB – International Recognition
·???????? Variation Type II – International Recognition (New Indication)
·???????? Variation Type II – International Recognition (Excluding New Indication)
·???????? Renewal (yearly or 5 yearly) – International Recognition?
As per the current functionality, you will need to indicate if your submission is one of the following:?
·???????? Original submission?
·???????? Validation Correction Request (VCR)?
·???????? Response?
An IRP variation or renewal application should be submitted to the MHRA as one consolidated sequence of the required information approved by RR at the submission date through the?MHRA Submissions portal. The eCTD should be in EU format. You must include certain information in the cover letter and follow the instruction given in the?eCTD Guidance for IRP.?The latter also gives instructions on where to include the relevant data required to submit for both variations and renewals.?
What documentation should the submission for an initial IRP MAA include?
·???????? For initial MAAs, the IRP submission should include:
o??? documentation of the RR’s approval decision.
o??? all iterations of the RR’s unredacted assessment reports for the initial authorisation and any major post-authorisation procedures (e.g., significant variations, renewals).
o??? the final product information (or international equivalent) approved by the RR.
?What documentation should a submission for a post-authorisation IRP application include?
·???????? For post-authorisation IRP applications (including variations), the submission should include:
o??? documentation of the RR’s approval decision.
o??? all iterations of the RR’s unredacted assessment reports for the relevant post-authorisation procedure.
o??? the final product information (or international equivalent) approved by the RR if applicable.
Some important points to note prior to submitting an IRP application
·???????? Where EMA is the RR, a CHMP positive opinion letter is sufficient documentation of approval. Applicants should not submit their IRP applications until they have received the CHMP positive opinion and agreed final Product Information. For MR-DC recognition, a positive End of Procedure (EoP) letter is sufficient documentation of approval.
·???????? All RR documents submitted in support of an IRP application to MHRA must be in English. A certified translation (verified translation may be acceptable) should be provided for any original documents that are not in English. If a translation is submitted, the Applicant must confirm in writing that it is correct.
·???????? It is your responsibility to provide the requested documentation. It is not the responsibility of the RR to provide any documentation to the MHRA.
·???????? Further information on the location of the RR documents within module 1 of the eCTD will be provided in due course.
·???????? A pre-submission meeting (PSM) is not required for IRP applications. However, you may request a pre-submission meeting to discuss the IRP dossier and requirements, and procedural or regulatory issues. For scientific or technical questions, a scientific advice meeting should be requested.
?Information that must be included in the cover letter accompanying an IRP application
The information that must be included in the cover letter for an initial and post-authorisation application is different and you can find the necessary information on this?page.
29. National Requirements
Information on specific requirements is provided below:
Orphan Drug Designation
IRPs that include GB orphan drug designation applications will not be eligible for Route A. See further information on?orphan drug designation application.
Paediatric requirements
For submissions that will trigger paediatric requirements, applicants should ensure the latest UK Paediatric Investigation Plan (PIP) / waiver opinion / decision or class waiver decision, and the compliance check outcome documents, are included in the IRP application dossier.
If paediatric requirements are triggered in any other jurisdiction, the latest PIP/Paediatric Study Plan (PSP)/waiver opinion/decision or class waiver decision should be submitted to the MHRA Paediatrics Team as part of the UK-PIP submission.
Further information can be found?here.
Risk Management Plan (RMP)
The RMP must meet MHRA requirements and follow the EU RMP template. Where appropriate, the format of GB/UK-specific RMP annex + approved EU RMP is also acceptable. Please read the guidance on this?page?for further information on the required format of the RMP.
If paediatric requirements are triggered in any other jurisdiction, the latest PIP/Paediatric Study Plan (PSP)/waiver opinion/decision or class waiver decision should be submitted to the MHRA Paediatrics Team as part of the UK-PIP submission.
Further information can be found?here.
Advanced therapy medicinal products (ATMPs)
ATMPs?are eligible for Recognition B only.
Environmental Risk Assessment
The ERA needs to have been assessed by the reference regulator for the product to be eligible for Recognition A. If the ERA has not yet been assessed by an RR, the product will be eligible for Recognition B only.
Good manufacturing practice (GMP)
The Applicant will need to confirm that all manufacturing sites have a current GMP certificate that meets MHRA requirements.
If a new site is added specifically for the MHRA, the application is eligible for Recognition B only.
If the site in question has no relevant inspection history, the timelines for the Recognition process may be extended until an inspection has been successfully completed.
Where available, inspection information from Mutual Recognition Agreement (MRA) partners and Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) participating authorities should be submitted to support verification of the GMP status of manufacturing sites based in third countries. This information will be utilised in accordance with the principles of?Inspection Reliance
Nitrosamine risk assessment
Before the Recognition procedure for a new product can be approved, the Applicant must provide a nitrosamine risk assessment in line with MHRA guidance. Please see the following link for more information:?Medicines: Marketing Authorisation Holders’ submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing
Generic and biosimilar applications
The proposed indications and posology must be in line with the UK Reference Product.
Applicants should ensure that there is no infringement of data and market exclusivity (DME).
In the case of generic or hybrid medicines, if the comparator product used in the bioequivalence or therapeutic equivalence study was not sourced from the UK/EU/EEA market, reference should be made to the MHRA guidance on comparator products in bioequivalence and therapeutic equivalence studies:
Until the Windsor Framework is implemented on 1 January 2025, if the comparator product is not sourced from the UK/EU/EEA market, the generic or hybrid medicine can only be authorised in Great Britain.
See MHRA’s?guidance for biosimilars.
Other specific information
Information on the following is provided on this?page:
·???????? Plasma Products
·???????? Compendial requirements
·???????? Active Substance Master Files (ASMFs)
Fees
Fees for submission for international recognition applications have now been included on the MHRA website on this?page.
Reference regulator documents
The Reference regulator document lists on this?page?show the documents that comprise a complete assessment for each Reference Regulator (RR).
The full set of documents must be submitted in your application.
Active Substance Master File (ASMF)
·???????? If an ASMF has been submitted to the reference authority for the application in question, the ASMF holder must submit an identical copy of the complete ASMF (Applicant’s and Restricted Parts) to MHRA.
·???????? Modules 2.3 and 3 must be submitted in consolidated form together with relevant sections of Module 1 according to MHRA requirements that includes the Letter of Access, the Assessment Report from the Restricted Part, the List of Questions and the response of the ASMF holder to the Restricted Part.
·???????? If the ASMF has been subsequently modified (i.e. after first authorisation abroad and before submission to MHRA), the approved variations, with the corresponding assessment reports, must be submitted separately in parallel and noted in the cover letter together with a comparison showing the changes (old / new).
30. Further information