Guidance

International Recognition Procedure - supplementary information

Updated 8 April 2024

This information is designed to address common queries about the International Recognition Procedure guidance

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.

Location of Applicants

The Applicant/marketing authorisation holder (MAH) must be established in the UK (Great Britain or Northern Ireland) or in the EU/EEA. It is anticipated that the MAH for an application via the IRP is the same company or belongs to the same (legal) group of companies as the MAH for the RR procedure. This is to ensure that the MAH can fulfil the submission requirements as well as all their legal obligations, 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.

Recognition routes A and B, timelines and assessment processes

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.

The assessment timeline for Recognition A is 60 calendar days (no clock stop), similar to ECDRP. The Recognition A criteria have been chosen to allow a limited MHRA assessment in most cases.

The assessment timeline for Recognition B is 110 calendar days. Our assessment will be targeted, however, there are aspects of Recognition B applications that are likely to require additional assessment and/or inspection activity. There is the option for us to send a request for further information and stop the clock at Day 70. The clock-stop is up to 60 calendar days to allow the applicant to prepare responses. The applicant can request an extension of the clock-stop.

Both IRP routes are substantially shorter than the 150 to 210 calendar day timetable for a national MA application.

Recognition B conditional/provisional approvals are only eligible from a reference regulator (RR)

While conditional/provisional authorisations from an RR can also qualify for IRP, they will require additional assessment work and are therefore only suitable for Recognition B.

It should be noted that at the time of application, the RR’s list of conditions needs to be provided to us, along with details of RR decisions on the fulfilment of any conditions. Following authorisation in UK/GB, details of subsequent RR decisions on the fulfilment of any conditions should be submitted within a reasonable period.

Advanced Therapy Medicinal Products, ATMPs are only eligible for Recognition B

Due to potential differences between guidelines internationally, some IRP applications may require additional checks by MHRA.

For instance, not all product types are covered by Mutual Recognition Agreements between MHRA and other regulators and some compliance/GMP checks might, therefore, be required by MHRA.

Furthermore, some product classes have different definitions internationally which means that MHRA might have to check that the application in question does indeed fall within MHRA’s remit and within MHRA’s correct classification for such products.

Products that are included or excluded from IRP

IRP can be used for the following types of marketing authorisation applications (MAAs) according to the Human Medicines Regulations 2012 (HMRs):

• Regulation 50: chemical and biological new active substances and known active substances.
• Regulation 51, 51A and 51B: generic applications
• Regulation 52, 52A and 52B: hybrid applications
• Regulation 53, 53A and 53B: biosimilar applications
• Regulation 55: new fixed combination product applications

Traditional Herbal Registrations, Homoeopathic Registrations (Simplified Registration Scheme) and Homeopathic National Rules Authorisations (National Rules Scheme) are excluded from IRP. Bibliographic applications (Regulation 54 of the Human Medicines Regulations) are not eligible.

Data protection for reference products for biosimilars and generics

With regard to biosimilars and generics, Applicants should ensure that there is no infringement of data periods as specified in the HMRs 2012.

Moreover, the Reference Product cited in the application form (i.e. the reference product for purposes of establishing expiry of data exclusivity) has to comply with the definition of a reference product in the HMRs 2012.

Requirements for pre-submission meeting for IRP applications.

A pre-submission meeting (PSM) is not required for IRP applications. We will shortly publish detailed eCTD guidance in addition to the main IRP guidance. Applicants are advised to study these guidelines before requesting a PSM. Specific questions relating to IRP can be sent to the MHRA via RIS.NA@mhra.gov.uk.

For scientific or technical questions, a scientific advice meeting should be requested.

Raising contentious issues, such as differing decisions of other regulatory authorities

Applicants must write to us raising any issues of concern.

In the cover letter, the applicant should state whether an application for the same product has been withdrawn, refused, or rejected by another RR and provide reasons. Significant delays to the assessment of the same product by another RR should be highlighted. The applicant should also state whether a marketing authorisation for the same product has been withdrawn, revoked, suspended or not renewed by another RR and provide reasons.

We must be informed of cases where international regulators have arrived at different assessment outcomes.

This requirement captures complex issues that require further consideration of the data by our specialists at the MHRA. If an in-depth assessment of the data is required, assessment timelines may be extended. The Applicant would be informed accordingly.

Applicants are reminded of the obligation to notify us 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 above address.

Appeals procedure if we reject an IRP application

The appeals procedure for IRP is the same as the current national procedures.

IRP and lifecycle procedures

IRP can be used for line extensions, variations (Type 1B, Type II) and renewal applications (including annual renewal of conditional MAs and annual reassessment of MAs granted under exceptional circumstances).

IRP can be used during the lifecycle of products that have been initially authorised or subsequently varied via standalone national procedures, MRDCRP or ECDRP. Conversely, where a product has been authorised via IRP, submission of standalone national post-authorisation procedures, including variations, is acceptable.

Generally, it is recommended that the same RR is used for IRP applications throughout an individual product lifecycle. MAHs may use more than one RR during an individual product lifecycle, if this can be justified, for example, on patient benefit grounds. Changes of RR during the product lifecycle should be highlighted in the post-authorisation procedure cover letter.

The relevant published MHRA timetables for national post-authorisation procedures will apply to IRP. As Recognition routes A or B only apply to initial MAAs, the eligibility form is not relevant for post-authorisation procedures.

Variations submitted via IRP should be classified according to MHRA Guidance on Variations to MAs.

Line extensions (e.g. new strength, dosage form) are handled as initial applications in the UK, so the considerations for Routes A and B apply. The eligibility form will therefore need to be populated by Companies who wish to apply for a line extension via IRP.

We hold 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 may require assessment through a national route where there are specific UK considerations.

Deadlines for RR approvals

To be eligible for Recognition A, the RR approval must have been granted within the previous 2 years of the submission date. 

To be eligible for Recognition B, the RR approval should have been granted within the previous 10 years of the submission date.

In exceptional cases (e.g. in case of supply shortages for certain products), the cut-off for Recognition B could be extended beyond 10 years. Please contact us in these cases. Additional general guidance on managing potential supply shortages is available at: Medicines shortages: regulatory processes to manage supply disruptions.

Specific GLP/GCP compliance considerations

GLP and GCP requirements for IRP are the same as current national procedures.

Management of supply to Northern Ireland at the time of IRP commencement

Until the Windsor Framework is implemented in Northern Ireland on 1 January 2025, certain products (falling within the scope of the EU Centralised Procedure) can only be authorised for Great Britain.

What happens to ECDRP and MRDCRP procedures if they are still ongoing by the end of the 2023

ECDRP and MRDCRP submissions received before 1 January 2024 will be processed under the existing practices. This applies to initial MAs and variations.

For ECDRP applications, the Committee for Medicinal Products for Human Use (CHMP) positive opinion (but not necessarily the European Commission Decision) should be received before 31 December 2023 and included with the submission.

Exclusion of well established use (WEU) applications from IRP

WEU applications are excluded from IRP because they rely on documentation to demonstrate that the active substances of the product have been in well-established medicinal use within the UK or EU for at least 10 years, with recognised efficacy and an acceptable level of safety. As clinical practice and healthcare systems differ in different jurisdictions, the evidence used to support an authorisation from a RR may not support use in the UK.

Waiting for the RR’s decision to be notified before an IRP application

We must receive documented evidence of the RR’s decision, including final product information, in order to process the application. However, if the RR is the EMA, a CHMP positive opinion letter and final product information is sufficient and it is not necessary to wait for the EC notification. The EC decision date will be used to establish the qualifying periods for Routes A and B.

International compendium requirements in the UK applications

Module 3 will need to refer to BP or Ph.Eur. compendial standards. The drug substance, excipients and finished product must comply with these standards, if tested. However it is not necessary to duplicate testing and test each batch to multiple compendial standards. The test protocols should be made clear in Module 3 and differences from RR highlighted in the cover letter. 

UK MA and the RR MA connections

Once granted the UK and RR MAs are fully independent. This means that they can be varied independently and if the RR MA is withdrawn this will not automatically affect the validity of the UK MA. However, the applicant/MA holder is obliged to notify us as soon as reasonably practicable of any information that might influence the evaluation of the benefits and risks of a pending or authorised product. If cancellation or revocation of the RR MA is related to safety issues the applicant must inform us at the earliest opportunity.

Definition of “the same product” in IRP

The same product means having the same qualitative and quantitative composition (active substance(s) and excipients), and the same pharmaceutical form, from Applicants belonging to the same company or group of companies or which are ‘licensees’.

Correct routes for approved EU RMP

The existing guidance for the format of the RMP continues to apply. The RMP must follow the EU RMP template. If the reference regulator has assessed the RMP and if it follows the format of the EU RMP template, the application may be suitable for Route A (provided that none of the criteria for Route B are met).

If the RR has not assessed the RMP, the product will be eligible for Recognition B only. In the case that the RR has assessed an RMP, but the RMP approved by the RR is not the same as the proposed UK/GB RMP or not in the required format for UK/GB, the application will be eligible for Recognition B only.

Changes in the pharmacovigilance requirements with introduction of IRP

There are no substantive changes planned to the existing pharmacovigilance guidance which will continue to apply for products authorised through IRP routes. UK requirements for submission of data including individual case safety reports (ICSRs) and Periodic Safety Update Reports (PSURs) continue to apply. Timelines for submission of PSUR reports and the additional monitoring status will be communicated to the applicant at the point of MA grant.

IRP is not a substitute for MA holder’s responsibility for providing us with pharmacovigilance data and keeping the MA up to date with scientific knowledge. If there is new data which could impact upon the evaluation of the benefits and risks, particularly where the clinical management of patients may be affected, we must be informed as soon as reasonably practical.

Variations which impact on patient safety will be assessed in the context of the UK clinical situation and may require assessment via a national route where there are specific UK considerations.

With regards to PSURs, where there is an EU assessment of the PSUR, we will take this into consideration. Where this is not the case, we will assess the PSUR submitted.

Post-authorisation measures required by the reference regulator

All post-authorisation measures and commitments agreed by the reference regulator will also apply to the UK/GB MA unless you are advised otherwise at the time of MA grant.

The MAH should follow the existing guidance for submission of Post-authorisation measures (PAMs) in relation to pharmacovigilance. Submission should be through the appropriate route, either type II variation (e.g. in the case of submission of final study results for a post-authorisation safety study) or via the information update route.

For post-authorisation measures that are mandatory (e.g. a post-authorisation study classified in the Risk Management Plan as category 1 or category 2 or a PAM included as a condition in the product licence) ithat will usually be acceptable to use IRP and to delay the formal submission of these measures until the assessment by the reference regulator has been completed and the decision is available to be included with your submission.  In this instance for pharmacovigilance PAMs the MAH should notify us by email to safetyprojects@mhra.gov.uk at the point the PAM is due for submission, providing a description of the PAM and a summary of the key findings.  If IRP is determined not to be appropriate for formal submission of the PAM we will notify the MAH within 1 calendar month and in which case the appropriate national route should be used for the submission. For conditions relating to Post-Authorisation Efficacy Studies (PAES), advanced notification is not required prior to submission of the PAM via IRP.    For PAES that are Specific Obligations of Conditional Marketing Authorisations, please refer to the guidance on renewals.

Where IRP is used for the submission of a mandatory PAM, there should be no undue delay in the submission following completion of the assessment by the reference regulator.  The appropriate application to MHRA should be made no later than 60 days following the outcome of that assessment being available to the MAH. 

For other types of PAMs, including those submitted using the “information update” route, assessment reports from the reference regulator where available should be submitted and will be taken into consideration.

Where information from a PAM requires an update to the product information this should be submitted via a variation procedure. The variation can be submitted via IRP, and submission delayed until the RR decision is available. Please refer to guidance on variations.

Applicants are also 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 in line with the Human Medicines Regulations Part 11. 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 you intend to use the IRP to vary your MA with 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, you should send the information to us as soon as possible, together with your proposals to:safetyprojects@mhra.gov.uk. We will then inform you if you can submit the variation via IRP once the RR assessment has concluded or whether you need to submit via a national procedure. Failure to inform us may result in you being requested to submit an urgent national variation.

Specific GLP/GCP compliance considerations

GLP and GCP requirements for IRP are the same as current national procedures.

Confirming the GMP status of the manufacturing sites named in the application

GMP certificates issued by the relevant competent authority should be submitted in support of the application. Where a certificate is not available other evidence such as Inspection Reports from MRA partners should be provided. These should clearly identify the scope of the inspection, as relevant to the application, and the outcome of the inspection.

For UK & EU based sites a copy of the relevant Manufacturers Authorisation is sufficient.

Reference is drawn to Page 63 (Outline of a Procedure for Co-ordinating the Verification of the GMP Status of Manufacturers in Third Countries) and Page 83 (Use of Certificates) of the Compilation of Union Procedures on Inspections and Exchange of Information.

UK(NI) status as a CMS in MR/DC procedures?

Following the implementation of the Windsor Framework on 1 January 2025, Northern Ireland can remain a Concerned Member State (CMS) in the Mutual Recognition/Decentralised Procedures (MRP/DCP). This means that Marketing Authorisation Holders may still use the MRP/DCP to apply for a PLNI. However, it will not be possible for a MAH to simultaneously hold a PLNI and a PL (a UK-wide licence). If the MAH wishes to seek a PL (a UK-wide licence) this will require them to withdraw NI as a CMS as outlined in the guidance on UK-wide licensing of human medicines.

Future Adverse Event reporting and guidance for Northern Ireland

The MHRA is currently reviewing guidance, including guidance related to pharmacovigilance, and updates will be issues in due course.

Products  authorised through MRDC

The MRDC reliance procedure has been incorporated into IRP.  However, for UK-wide Marketing Authorisations post authorisation changes cannot be made through IRP if Northern Ireland remains a CMS in an MRDC procedure.  If a company intends to use IRP for post authorisation changes then Ni should be withdrawn as a CMS from the MRDC procedure. 

Integral drug/device combination products

MHRA will require a Notified Body Opinion report.  This is mandatory for NI.   MHRA does not intend to issue GB MAs through IRP except in cases where NI must be excluded for legal reasons for example due to the mandatory scope of the EU centralised procedure.

Reference Medicinal Product is no longer available

If the UK reference medicinal product is no longer available, then an application under Regulations 51 or Regulation 52 of the Human Medicines Regulations 2012 will not be possible.  In these cases, an alternative legal basis will need to be used.   Applications under Regulation 54 are not eligible for IRP.

No reference product exists in the UK 

If an active substance is not already authorised in the UK then the IRP application will be classed as a new active substance regardless of its legal basis in the RR jurisdiction.  An application under Regulation 50 of the HMRs supported by a full dossier on quality, safety and efficacy will be needed.   If the product was not a new active substance in the RR then the RR approval is unlikely to be adequate for IRP as the supporting dossier would be substantially different.

Reference Regulator bioequivalence requirements and/or study designs are different from UK requirements

The approach to be taken in these circumstances depends on what the difference are.  A Scientific Advice Meeting is advised to discuss situations where the bioequivalence study does not fulfil the requirements of guidance adopted by the UK. [add link to  guidance].  In each case the comparator needs to be representative of the UK reference medicinal product and if not the MHRA guidance on Comparator products (CPs) used in bioequivalence (BE), pharmacokinetic (PK) and therapeutic equivalence (TE) studies supporting abridged applications should be considered.  [add link]

Delay to availability and submission of Reference Regulator Reports

IRP applications submitted without the anticipated Reference Regulator reports will result in a Validation Correction Request.  They will not be allocated for assessment until the omission has been rectified therefore applicants are advised not to submit until the necessary supporting documentation has been assembled.

Reference regulator strengths not marketed in UK

IRP can be used to license strengths of a product approved by the reference regulator but not currently licensed in UK.  For a generic or hybrid application the strength proposed needs to be consistent with the posology and indications of the UK reference product and UK clinical practice, not cause confusion with existing strengths and be supported by appropriate data.  A product specific request for advice on this is recommended.

Changes to Pack Sizes

Pack sizes not already approved by the Reference Regulator can be included in the submission to MHRA provided that the container/closure system is identical to that approved by the RR and the additional pack sizes fall within the sizes approved by the RR.

Application Form

Whilst the UK eAF is UK/EU specific and there are no options in the drop down menus for non- EU Reference Regulator countries, this information is collected in Eligibility checker and also the cover letter.  The MHRA human medicines portal – the only route for IRP applications – is being enhanced to capture this information

Contact

For further information on medicinal products for human use, please email RIS.NA@mhra.gov.uk.