The UK’s Regulatory Landscape: A year and a half on from the end of the Brexit Transition Period

Aug 2

by Iheoma Anosike

The United Kingdom’s (UK) post-Brexit transition period ended on 31 December 2020. The Medicines and Healthcare products Regulatory Agency (MHRA) became the UK’s independent regulatory Agency for medicines, medical devices and blood components for transfusion, with different requirements for products placed on the market in the UK with respect to Great Britain (England, Wales and Scotland) and Northern Ireland. The MHRA now makes decisions and carries out all functions which were performed at EU-level except for decisions on marketing authorisation applications (MAA) made through the European procedures to market products in Northern Ireland.

In the run up to 1 January 2021, the MHRA announced numerous new requirements and features associated with the UK’s emerging regulatory framework. Sponsors were encouraged to maintain a flexible approach towards their development programs in anticipation of further updates and guidance from the MHRA. This article summarises the latest guidance released by the MHRA, relating to medicines, since it became the UK’s standalone regulator.

Introduction

On 1 January 2021, EU pharmaceutical law ceased to be effective in Great Britain (GB), i.e., England, Wales and Scotland. Medicines and medical devices have since been regulated in GB under national law by the MHRA, with equivalent products in Northern Ireland falling under the jurisdiction of the EMA and EU legislation, in accordance with the Northern Ireland protocol, which came into effect on 1 January 2021. As the MHRA defines and develops its regulatory framework, updated guidance continues to be published by the Agency.

The following sections provide an overview of key changes which have been implemented by the MHRA since 1 January 2021. It follows on from a previous paper, published in December 2020, in which Scendea summarised the information available just prior to the end of the transition period. This article follows a similar structure in that it discusses updates for Sponsors at the early phase/pre-approval stage, marketing authorisation application (MAA) assessment stage and post-approval stage.

Where updates have not been outlined in relation to a topic discussed in the December 2020 article, it can be assumed that no changes have been announced by the MHRA to date. Considering the continuous developments to the guidance and information, readers should be aware that the information presented in this paper is correct at the time of publishing.

A summary of important updates to the regulatory requirements since 1 January 2021, is provided below, and discussed in more detail in subsequent sections of this article.

Key Updates

Key Updates to Regulatory Requirements since 1 January 2021 for Sponsors at the Pre-approval, Marketing Authorisation Application and Post-Approval Stages of Development.

Pre-Approval

Introduction of the Innovative Licensing and Access Pathway (ILAP) for innovative medicines.
Implementation of a new procedure for the submission and review of clinical trial applications for investigational medicinal products.

Marketing Authorisation Application

Additional details released on the UK orphan drug designation procedure.
Establishment of new assessment routes for MAAs

Post-Approval

Updates provided on pharmacovigilance data requirements for approved products.
Launch of new SUSAR reporting system.

Pre-approval Regulatory Interactions/Procedures

ILAP

The Innovative Licensing and Access Pathway (ILAP) is a regulatory pathway aimed at reducing the time to market for innovative medicines. It provides Sponsors with the opportunity to access multi-stakeholder input from the MHRA, health technology assessment bodies such as the National Institute for Health and Care Excellence (NICE) and patients. Medicines which fall within the scope of the ILAP include new chemical entities (NCE), biological medicines, and repurposed medicines.

To be eligible for the ILAP, Sponsors must apply for an innovation passport. The innovation passport, also referred to as the innovative medicine designation, is open to commercial and noncommercial developers of medicines at the preclinical through to mid-development stage. However, to gain maximum benefit from the designation, sponsors are encouraged to apply for the passport as early on in the development program, as possible. The passport has a broad definition of innovation and both new and repurposed medicines are within scope (Medicines and Healthcare products Regulatory Agency, 2022a).

Sponsors should note that despite being referred to as the innovative medicine designation, the innovation passport does not replace the pre-existing promising innovative medicine (PIM) designation of the Early Access to Medicines Scheme (EAMS), and Sponsors can apply to both. Whilst both designations are specifically applicable to innovative medicines, to be eligible for the PIM designation, products must also be intended for the treatment, diagnosis or prevention of life-threatening or seriously debilitating conditions, with the potential to address an unmet medical need. The designation is issued based on nonclinical and clinical (Phase I/II) data and therefore Sponsors must have early clinical data available. Furthermore, the PIM designation is a prerequisite to enter the EAMS scientific opinion assessment step. Upon completion of the scientific opinion assessment step, an opinion on the benefit/risk balance of the medicine is issued, which supports prescribers and patients in deciding on whether to use the medicine before its license is approved (Medicines and Healthcare products Regulatory Agency, 2022b).

Therefore, whilst both designations serve as a means to an end for their respective pathways, in contrast to the PIM designation, Sponsors who are at an earlier stage of development with little to no clinical data available, can avail of the innovative medicine designation and ILAP. In addition, the innovation passport is associated with broader eligibility criteria and is open to all innovative products. Furthermore, through ILAP, the innovation passport aims to reduce time to market by providing a platform for multi-stakeholder input to achieve expedited approval, whereas the PIM designation through EAMS leads to earlier patient access of a medicine but is not a replacement for normal licensing procedures.

Following submission of the innovation passport application, Sponsors are usually invited within 4 to 6 weeks to discuss with the MHRA how the product fulfils the designation criteria (see below). The supporting evidence to demonstrate that the criteria have been met are dependent on the product’s development stage. An assessment is made to determine the fulfillment of the criteria by MHRA, NICE and the Scottish Medicines Consortium (SMC) within 4 weeks of the MHRA meeting. A single positive innovation passport can cover multiple indications for the same active substance (Medicines and Healthcare products Regulatory Agency, 2022a).

Innovation Passport Criteria

CRITERION 1

Details of the condition, patient or public health area.

Either of the following characteristics need to be met:

The condition is life threatening or seriously debilitating
There is a significant patient or public health need.

If applying under the first characteristic, Sponsors will be expected to provide a summary of the condition and the life threatening or seriously debilitating nature including symptoms, life span and quality of life aspects and current treatment landscape.

Submissions for significant patient or public health need are required to provide clearly defined evidence of a specific need (for example, a need for paediatric formulation, anti-microbial resistance), putting the need into the context of the current patient or public health setting. This evidence is likely to be generated from information in the public domain and or patient engagement activities. For a justification of ‘significant’, the magnitude of the issue(s) should be discussed in a problem statement along with the identified gaps that remain in the current treatment landscape.

CRITERION 2

The medicinal product fulfils one or more of a specific area.

The areas are:

innovative medicine such as an advanced therapy medicinal product (ATMP) or new chemical or biological entity or novel drug device combination
medicines being developed in a clinically significant new indication for an approved medicine
medicines for rare disease and/or other special populations such as neonates and children, elderly and pregnant women
development aligning with the objectives for UK public health priorities such as the Chief Medical Officer, Department of Health and Social Care (DHSC) or Life Sciences Sector Deal (including those in Devolved Administrations, where appropriate).

Depending on the area, the following evidence should be provided:

a full regulatory description of the product is expected so that the product status can be determined (e.g. name of drug substance, pharmaceutical form, route of administration, mechanism of action)
a description of the new indication should be provided in the context of the patient group, including the novelty of the proposal
a description of the use of the medicine in a particular special population should be provided
a description of where and how the product will fulfil public health priorities should be provided.

CRITERION 3

The medicinal product has the potential to offer benefits to patients.

A summary of how patients are likely to benefit from the product or indication coming to market, including proposed improved efficacy or safety, contribution to patient care or quality of life, as compared to alternative therapeutic options should be provided.

The claims can be supported either by data from valid non-clinical models of the condition or if justified extrapolated from another relevant model. Depending on the stage of development of the product any available clinical data in a relevant population of patients can be provided.

Once an innovation passport has been obtained, Sponsors are eligible to work with the stakeholders of the ILAP to develop a target development profile (TDP). The TDP is a product specific roadmap for delivering early patient access and is considered a dynamic document which is updated as new data are generated over the course of development. To build the TDP, tools such as adaptative inspections, novel methodology and innovative clinical trial design, patient recruitment assisted with the Clinical Practice Research Datalink and flexible/expedited licensing routes such as accelerated assessment and rolling review can be leveraged. The TDP defines key regulatory and development features, identifies potential pitfalls and includes a strategy for efficient evidence generation and evaluation.

Prior to the development of the TDP, a TDP form must be completed by the Sponsor which summarises information gathered from the product development, evidence generation plans and scientific advice. The form is submitted to MHRA and the innovation passport holder meets with MHRA and partners of the ILAP to discuss the design and development of the TDP. The TDP is issued to the Sponsor within 4 to 6 weeks of the meeting. As development progresses, the Innovation Passport Holder or the partners may decide that the TDP has progressed as far as possible and at this point the ILAP will close for the product.

Since the introduction of the ILAP, a total of 120 applications for the innovation passport have been received by the MHRA, of which 71 passports have been awarded to date. Applications received have included new and established medicinal products in both common and rare diseases in a variety of therapeutic areas, most commonly oncology, neurology and respiratory (Medicines and Healthcare products Regulatory Agency, 2022a).

Clinical Trials

CLINICAL TRIAL APPLICATIONS

Since 1 January 2022, all new applications for clinical trials of investigational medicinal products (CTIMPs) are prepared, submitted and reviewed by the combined review service (formerly known as the Combined Ways of Working (CWoW)). Combined review offers a single application route for clinical trial authorisation and Research Ethics Committee (REC) opinion, and co-ordinated review leading to a single UK decision for CTIMPs. CTIMP applications via combined review should be prepared and submitted using the new part of the Integrated Research Application System (IRAS) and not in the standard part of IRAS. The regulatory requirements and fees for CTIMPs under the combined review service remain the same as that for non-combined review applications (Medicines and Healthcare products Regulatory Agency, 2022c).

A Sponsor of a clinical trial is the individual(s) or organisation(s) who initiates, manages and finances (or arranges the financing) of a trial. The Sponsor must either be established in the UK or a country on the approved country list which for now includes EU/EEA countries. Alternatively, a Sponsor must have a legal representative who is so established.

In order to qualify for a positive opinion from the REC, a Sponsor must have registered the clinical trial on a publicly accessible database such as the ISRCTN Registry or ClinicalTrials.gov. Since 1 January 2022, the Health Research Authority (HRA) automatically registers clinical trials on the ISRCTN Registry to aid with research transparency. However, Sponsors should note that whilst the HRA recognises that research transparency is a global issue, the Authority also notes that for some early phase trials there may be concerns that registration requirements may make the UK a less attractive place for research. The HRA policy therefore provides for requests to defer registration to be made; the HRA will consider and accept these requests, where there is currently no requirement in legislation to register, and record them against the published REC opinion (HRA Improvement & Liaison Manager, 2017).

The registry number should be included in section A.5. of the application form in the IRAS. If this is not available at the time of application, Sponsors should email this to the MHRA at clintrialhelpline@mhra.gov.uk with the subject line “Clinical Trial Registration” within six weeks of recruiting the first research participant, and inform the REC of the registration number as soon as possible.

A full list of the documents required for the CTIMP application is outlined on the IRAS. Additional guidance on some of these documents is provided below:

Covering letter: when applicable, the subject line should state whether the submission is for a Phase I healthy volunteer trial and is eligible for a shortened assessment time, or if risk proportionate approaches are being used for the conduct of the study.
Investigational medical product dossier (IMPD): please note that an active substance master file (ASMF) is not acceptable as a substitute for an IMPD.
Manufacturer’s authorisation, including the importer’s authorisation and Qualified Person declaration on Good Manufacturing Practice for each manufacturing site if the product is manufactured outside the EU/EEA.
Content of the labelling of the investigational medicinal product (IMP): where this has not been provided, a justification for its absence should be presented.

The combined review assessment will be completed within 30 days of a valid application being submitted. Applications for healthy volunteer trials and sponsor-determined phase I trials in non-oncology patients may qualify for a shortened assessment time and MHRA will work with the REC to expedite these applications.

The MHRA issues the outcome of the submission along with that of the REC, which could be:

acceptance of the request for a clinical trial authorisation;
acceptance of the request for a clinical trial authorisation subject to conditions;
grounds for non-acceptance of the request for a clinical trial authorisation.

Whilst Sponsors have 14 days to respond to grounds for non-acceptance raised by MHRA, if required, this period can be extended upon request. The MHRA will usually inform the applicant of the decision of the MHRA and REC review following receipt of the responses to the request for further information (RFI), within 60 days of receiving the original valid application. However, these timelines may be impacted if an extension to the response date has been agreed. It is estimated that more than half of all clinical trial authorisation applications for IMPs require additional information before they are considered approvable by the MHRA.

Guidance is available from the Agency on common issues identified during the review of applications and suggested approaches to avoid these problems are provided.

Sponsors should be aware that during the assessment of a clinical trial authorisation application, the MHRA may seek expert advice from the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBVEAG) of the Commission on Human Medicines (CHM). This will depend on the risks associated with the use of the IMP in the trial (i.e. the mode of action of the IMP, the nature of the target and the relevance of the animal models/species) and how the Sponsor plans to mitigate these risks.

Applicants can also decide for themselves whether their trial needs expert advice. Sponsors who are unsure if their product falls into the higher risk category may seek pre-submission advice from the MHRA, who will advise whether expert advice on the trial is needed. Applicants can then select a date for the CTBVEAG meeting where the trial will be discussed. The MHRA encourages applicants to notify the MHRA and the HRA at least 14 days prior to the submission of the clinical trial authorisation application, that an application which requires CHM/CTBVEAG review is planned. The submission should be made no later than 21 days before the date of the CTBVEAG meeting it will be discussed at. Applications that are received later will be assigned to the next available meeting.

IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

Investigational Medicinal Products (IMPs) imported into GB from a country on the ‘approved country for import’ list that have been QP certified in a country on the list will not require recertification in GB. This list includes EEA countries and other countries with whom regulatory equivalence has been confirmed, and is reviewed every three years.

As part of the Oversight Process, a UK Manufacturing and Import Authorisation (MIA(IMP)) holder will be required to verify that these IMPs have been certified by a QP in a listed country.

The authorisation should specify “Importation of QP certified IMPs from a country on the ‘approved country for import list’” as free text within “Other importation activities” in section 2.3 of the licence. In addition, the UK MIA(IMP) holder responsible for the oversight process should be named on the authorisation in addition to the listed country site of final batch certification.

Existing UK MIA(IMP) holders with or without authorisation for the importation and QP certification of IMPs from third countries can submit a variation to the MHRA, requesting for authorisation for the oversight of importation of finished IMPs from approved countries. If no MIA(IMP) is held then an application for a UK MIA(IMP) will need to be submitted. MHRA will assess variations and new MIA(IMP) applications within 90 days of submission.

The license holder should have procedures to manage and document the oversight process and these should be ready for inspection at the time of application. This inspection of the Pharmaceutical Quality System (PQS) requirements for the oversight process may be initially conducted remotely, but this may later require an on-site inspection. Records of all shipments to trial sites in GB using the oversight process should be visible within the PQS and be traceable.

PHARMACOVIGILENCE

Since 1 January 2021, Sponsors or their representatives must report suspected unexpected serious adverse reactions (SUSARs) to the MHRA via one of three routes: the ICSR Submissions portal, the MHRA gateway or the eSUSAR portal. The MHRA gateway route is used to submit bulk SUSAR reports. The eSUSAR route continues to be available and is used for single submissions. If applicable, Sponsors will need to dual report UK-relevant SUSARs to the EMA’s Eudravigilance Clinical Trial Module (EVCTM), as well as to other National Competent Authorities, using the European submission routes (Medicines and Healthcare products Regulatory Agency, 2022d).

Since 1 January 2021, annual development safety update reports (DSURs) that require reporting in the UK need to be submitted via the MHRA submissions portal. The UK no longer has access to the Common European Submission Portal (CESP). At least initially, the EudraCT number will still be the trial reference number (Medicines and Healthcare products Regulatory Agency, 2022d).

MAA Assessment Stage Interactions/Procedures

ORPHAN DRUG DESIGNATION

Orphan drug designation is assessed at the time of a MAA; there is no designation at the premarketing stage. Sponsors should also note that if a medicinal product has designated orphan drug status in the EU under Regulation (EC) 141/2000, a GB orphan MAA can be submitted for assessment. However, products with orphan drug status in the EU cannot be considered for a UK-wide orphan MAA. As a result of this, if a UK-wide orphan marketing authorisation is granted and the medicinal product subsequently receives EU orphan designation, the market authorisation holder (MAH) would need to submit a variation to change this to a GB orphan MA (Medicines and Healthcare products Regulatory Agency, 2021a).

The requirements for UK orphan drug designation align with the current requirements in the EU, with certain criteria repositioned to be specific to GB. The criteria are summarised below:

The medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating
The prevalence of the condition in Great Britain must not be more than 5 in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development
No satisfactory method of diagnosis, prevention or treatment of the condition concerned exists in Great Britain, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition
Satisfactory methods may include authorised medicinal products, medical devices or other methods of diagnosis, prevention or treatment which are used in Great Britain.

Following the validation of the MAA, a decision on orphan status will be made at the time of the decision on approval of the marketing authorisation. Any questions concerning the fulfilment of the orphan designation criteria will be raised with the Sponsor during the evaluation of the MAA.

On grant of a marketing authorisation with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication. Orphan medicines authorised in GB with the results of studies from a paediatric investigation plan (PIP) included in the product information are eligible for an additional 2 years of market exclusivity. The start of the market exclusivity period is set from the date of first approval of the product in GB. If orphan criteria are no longer met for the product, Regulation 58D of the Human Medicines Regulation 2012 (as amended) establishes the possibility for the MHRA to request that the market exclusivity be reduced from 10 to 6 years.

It is not necessary to submit orphan maintenance reports to the MHRA, but they can be provided as additional information. In addition, it should be noted that orphan designation is not awarded separately from the MA and therefore upon submission of a Change of Ownership application for the MA, the orphan designation is automatically transferred.

All orphan products authorised by the MHRA are listed in its Orphan Register. When the period of market exclusivity for an indication ends, the orphan designation for that indication expires and the product is removed from the Orphan Register. However, the product will remain on the Orphan Register if other authorised orphan indications remain within their period of exclusivity.

LICENSING

A number of routes are currently available for the assessment of MAAs by the MHRA: 150-day national assessments, rolling reviews, the European Commission Decision reliance procedure, the decentralised and mutual recognition reliance procedure and the unfettered access procedure. Below, the European Commission Decision reliance procedure, the decentralised and mutual recognition reliance procedure and the unfettered access procedure are discussed.

SUBMISSIONS USING THE EC DECISION RELIANCE PROCEDURE (ECDRP)

Up until 1 January 2023, applicants may seek a Great Britain marketing authorisation that relies on a decision taken by the European Commission relating to a marketing authorisation for the same product in the centralised procedure. This route, known as the EC decision reliance procedure (ECDRP), is available to all authorisations including generics products and variations, approved in the centralised procedure.

For new MA applications, on receipt of the positive CHMP (Committee for Medicinal Products for Human Use) opinion on day 210, or as soon as possible after this date, the ECDRP MAA should be submitted to the MHRA as a single electronic Common Technical Document sequence through MHRA Submissions. The submission should include the entire dossier as reviewed by the CHMP, including the full responses to CHMP questions, each iteration of the rapporteur assessment report and updates throughout the procedure.

When a valid submission is made within 5 days of CHMP positive opinion, the date of CHMP positive opinion will be designated Day 0 of the ECDRP, and the MHRA will aim to determine the Great Britain MA as soon as possible following submission of confirmation of the EC decision. The MHRA’s decision will be shared by Day 67 at the latest, provided that EC decision has been received.

If the application is submitted more than 5 days after the CHMP positive opinion, Day 0 of the ECDRP will be the date of MAA validation, and determination may not align with the date of the EC decision.

The Applicant is responsible for confirming the EC decision to the MHRA; the EC decision letter should be forwarded to the ECDRP mailbox on the day that it is received. Any issues identified during assessment will be communicated to the applicant by Day 46 and should be resolvable within the 67-day timetable without clock-stop. If Major Objections are identified or substantial amendments to the product information are necessary, the timetable will move to the standard National Procedure timetable (Medicines and Healthcare products Regulatory Agency, 2021b, 2022e).

DECENTRALISED AND MUTUAL RECOGNITION RELIANCE PROCEDURE

Sponsors can also request a UK MA or a GB MA based on the decision taken for an EU MA submitted via the decentralised or mutual recognition procedure. This route is referred to as the MRDC Reliance Procedure (MRDCRP), and is not available to products with MAs in EU/EEA Member States granted only through National Procedures.

To request a MA via this route, the entire dossier should be submitted to the MHRA as one electronic Common Technical Document sequence through MHRA Submissions. It must be submitted as approved for marketing in the EU Member States (or Iceland, Liechtenstein, Norway), including the full company responses to Reference Member State (RMS)/Concerned Member States (CMS) questions.

The first round of assessment should be completed by Day 42, at which point the MA will be granted if no concerns are raised. Any points will be sent as a Request for Further Information (RFI) and the clock will be stopped for up to 28 days to give the Applicant the opportunity to respond. If there are no outstanding points at Day 65, the MA will be granted within 67 days of MAA validation (Medicines and Healthcare products Regulatory Agency, 2021c).

THE UNFETTERED ACCESS PROCEDURE (UAP)

The Unfettered Access Procedure (UAP) can be leveraged by Sponsors who are holders of Marketing Authorisations approved in Northern Ireland via European procedures (centralised, mutual recognition or decentralised procedures) and would like to submit a GB MAA. Marketing Authorisation Applications made through the UAP should be recognised by MHRA for GB within 67 days of MAA validation, unless major objections are identified (Medicines and Healthcare products Regulatory Agency, 2021d).

OPTIONS FOR UK-WIDE LICENSES

National applications for UK-wide marketing authorisations are permitted irrespective of whether an application for the same product is approved or has been submitted through the EU decentralised procedures or mutual recognition procedures, as long as the UK in respect to Northern Ireland, is included as a concerned member state (CMS). Depending on whether the application was approved or submitted before or after 1 January 2021, the MHRA has provided Sponsors with a number of options on how to manage the application/authorisation. These are summarised below. It should be noted that for new applications, the UK in respect to Northern Ireland may continue to be included in decentralised and mutual recognition procedures as a CMS.

Any marketing authorisations issued following these procedures will be effective in Northern Ireland only. A separate marketing authorisation application will be needed for GB (Medicines and Healthcare products Regulatory Agency, 2022f).

OPTIONS FOR UK-WIDE LICENSING FOR PRODUCTS APPROVED OR SUBMITTED WITHIN THE DECENTRALISED OR MUTUAL RECOGNITION PROCEDURES

Products approved via the DCP or MRP before 1 January 2021

The MHRA has already issued concerned Sponsors with national UK-wide MAs.

Companies can either:

Maintain a UK-wide MA and retain NI as a CMS. The authorisation in Great Britain will be aligned with, but not part of, the DCP/MRP.
Notify the UK and the RMS (reference member state) in writing that they wish to remove NI as a CMS from the DCP/MRP and maintain a UK wide national MA.
Request that separate MAs are issued for NI as a CMS, and Great Britain.

Applications pending in DCP/MRP where the procedure started before 1 January 2021

Sponsors can choose to:

Retain NI as a CMS, and then, at conclusion of a positive procedure with which the UK agrees, either:
- have a UK-wide MA
- at the end of procedure, request that separate MAs are issued for NI as a CMS and Great Britain.
Notify the UK and RMS in writing that they wish to remove NI as a CMS and continue the application as a UK wide national application.
- The MHRA will determine the application as soon as reasonably practicable and will take all reasonable steps to ensure that it makes a decision to grant or refuse the national application in the time period that would have applied to that application on the date on which the application was submitted in DCP/MRP.
Withdraw the application from the DCP/MRP and apply for a national UK MA on completion of the European procedure using the MRDC

Applications pending in DCP/MRP where the procedure started on or after 1 January 2021

The applicant has the following options:

Retain NI as a CMS to obtain a UK MA valid only in NI. A separate MA is needed for Great Britain. Any subsequent application for a variation to the MA should be submitted through the DCP/MRP.
Notify the UK and RMS in writing that they wish to remove NI as a CMS and continue the application as a UK wide national application.
- MHRA will take all reasonable steps to ensure that it makes a decision to grant or refuse the national application in the time period that would have applied to that application on the date on which the application was submitted in DCP/MRP.
Withdraw the application from the DCP/MRP and apply for a national UK MA on completion of the European procedure using the MRDC Reliance Procedure.

Applications submitted in DCP/MRP where the procedure has not started

Sponsors can either:

Retain NI as a CMS. A separate marketing authorisation application is needed for Great Britain
Withdraw the application from UK(NI) in the EU procedure and apply as a national procedure in the UK to obtain a UK-wide marketing authorisation.
Withdraw the application from the DCP/MRP and apply for a national MA on completion of the European procedure using the MRDC Reliance Procedure.

Post-approval Regulatory Interactions/Procedures

PHARMACOVIGILENCE

Sponsors should note that pharmacovigilance data for medicines which are the subject of a UK MA covering both GB and Northern Ireland will still need to be submitted in accordance with requirements for both GB and the EU (and to both MHRA and EMA), as appropriate. This is due to the fact that for products authorised for sale or supply in Northern Ireland, EU pharmacovigilance requirements will continue to apply in addition to UK requirements. The EU Good Pharmacovigilance Practice (GVP) guidance largely remains in force but the MHRA has published a guidance document on the exceptions and modifications to the EU guidance.

To meet UK requirements, the pharmacovigilance data discussed below are required for submission to the MHRA.

UK and non-UK Individual Case Safety Reports (ICSRs)
Signal Detection
Periodic Safety Update Reports (PSURs)
Risk Management Plans (RMPs)
Post-Authorisation Safety Studies (PASS) protocols and final study reports.

PHARMACOVIGILANCE DATA REQUIREMENTS

*Adapted from Medicines and Healthcare products Regulatory Agency, 2022e.*

For Sponsors who hold a UK MA which covers NI, outcomes from EU decisions regarding PSURs, PASS and signal assessments must be implemented, and the same type of variation procedure as recommended in the EU procedure should be used to implement the change for the UK MA. The same also applies for holders of GB-only MAs for converted centrally authorised products (Medicines and Healthcare products Regulatory Agency, 2021e).

Conclusion

The changes and updates made to the UK’s regulatory framework have largely followed the structures and procedures set up in the EU. To a considerable degree, a level of harmonisation exists between both jurisdictions, which means Sponsors should be able to effectively avail of benefits associated with designations, innovative and approval pathways by procedures and timelines consistent with those in place pre-Brexit. Given the significance of the UK market, it is likely that Sponsors will regard the UK as a key jurisdiction in their regulatory strategic plans and development programs. As such, keeping abreast of the latest regulatory updates which the MHRA continues to share is important. This will aid in ensuring that Sponsors maintain compliance with the Agency’s regulatory requirements, maximise gain from the available incentives, and reduce development costs and time to market.

References

HRA Improvement & Liaison Manager (2017). HRA Clinical Trial Registration Deferral Policy and Procedure.

Medicines and Healthcare products Regulatory Agency (2021a). Orphan medicinal products.

Medicines and Healthcare products Regulatory Agency (2021b). European Commission (EC) Decision Reliance Procedure.

Medicines and Healthcare products Regulatory Agency (2021c). Decentralised and mutual recognition reliance procedure for marketing authorisations.

Medicines and Healthcare products Regulatory Agency (2021d). Unfettered Access Procedure for marketing authorisations approved in Northern Ireland.

Medicines and Healthcare products Regulatory Agency (2021e). Guidance on pharmacovigilance procedures.

Medicines and Healthcare products Regulatory Agency (2022a). Innovative Licensing and Access Pathway.

Medicines and Healthcare products Regulatory Agency (2022b). Apply for the early access to medicines scheme (EAMS).

Medicines and Healthcare products Regulatory Agency (2022c). Clinical trials for medicines: apply for authorisation in the UK.

Medicines and Healthcare products Regulatory Agency (2022d). Clinical trials for medicines: manage your authorisation, report safety issues.

Medicines and Healthcare products Regulatory Agency (2022e). Marketing Authorisation Application submission dates for 150-days national and European Commission decision reliance procedures.

Medicines and Healthcare products Regulatory Agency (2022f). Guidance on handling of Decentralised and Mutual Recognition Procedures which are approved or pending.

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Tom Allport