Post-Brexit Transition Period Changes. UK’s New Regulatory Landscape.
by Iheoma Anosike
Introduction
Following the end of the United Kingdom’s Brexit transition period on 31 December 2020, the Medicines and Healthcare Products Regulatory Agency (MHRA) will implement a number of changes as the UK forges its new, independent regulatory system. With the end of the year only weeks away, it is paramount that Sponsors are aware of the new regulatory requirements and procedures which will start from next year, in order to launch and/or maintain successful drug development programs in the UK. This article focusses on the key changes which will be made from 1 January 2021, and highlights modifications Sponsors will have to make to existing practices to remain compliant with new MHRA requirements.
From 1 January 2021, the MHRA will be the UK’s standalone medicines and medical devices regulator. Transition from the EU allows the UK to offer fully independent regulatory decisions for both devices and pharmaceuticals, both nationally and in collaboration with other international regulators. From the start of 2021, Great Britain (GB) will be regulated as a sovereign territory under national law, and new IT portals for the exchange of information with stakeholders will be launched. Under the Northern Ireland Protocol, marketing authorisation holders for medicines authorised to be placed on the market in Northern Ireland must follow EU medicines legislation; the MHRA will act in the capacity of the EU national competent authority in respect of Northern Ireland, and there will be unrestricted access to the Great Britain market for companies based in Northern Ireland.
In the following sections, Scendea has provided an overview of the key changes for companies pre-approval, during marketing authorisation application (MAA) assessment, and post-approval. Sponsors should be aware that the MHRA is continually updating its Brexit-related guidance, and the information presented in this paper is correct at the time of publishing.
Pre-Approval Regulatory Interactions/Procedures
Clinical Trials.
The main changes relating to clinical trials post-Brexit relate to registry listings, Sponsor/legal representative oversight of the planned or ongoing study, and investigational medicinal product (IMP) import and/or release.
Sponsors intending to file a clinical trial application (CTA) are required to continue registering clinical studies on international publicly available registries, such as the ISRCTN Registry or Clinical Trials.gov. If a trial involves sites both in the UK and EU, the trial details must be available on the EU Clinical Trials Register. Trials must be registered before the first participant is recruited or no later than 6 weeks after recruitment of the first participant.
For a trial to be approved in the UK, the Sponsor or the legal representative of the trial must be established in the UK or in a country which is on the approved country list which will initially include countries in the EU/European Economic Area (EEA). However, for a trial which is to be conducted in both the UK and EU, a legal representative will need to be established in the EU/EEA to account for the EU sites. This will be the case even if the Sponsor has a legal representative established in the UK. The EU/EEA legal representative should be assigned via a substantial amendment submitted to the relevant EU/EEA competent authorities. It is important to note that in this situation, an amendment will not need to be submitted in the UK to account for the addition of the EU/EEA based legal representative, as long as the Sponsor retains the same UK legal representative for the UK study.
A substantial amendment is warranted when a change in Sponsor or legal representative is made. This will need to be submitted to both the MHRA and Research Ethics Committee (REC). To change any investigational medicinal product (IMP) manufacturing, importation or certification site which is relevant to the supply of the IMP to an ongoing UK trial, a substantial amendment will also need to be submitted to the MHRA.
Presently, IMPs can be supplied from EU/EEA countries directly to UK clinical investigator sites, as these countries are currently included on the approved country list for IMP certification and importation. Furthermore, as is the case with the addition of an EU/EEA legal representative to cover EU/EEA clinical trial sites, if a Sponsor chooses to retain an existing UK IMP release site for the ongoing UK trial but includes an additional EU/EEA site for trials in the EU/EEA only, then no substantial amendment to the MHRA will be required.
Sponsors of a UK clinical trial using IMPs imported into GB from countries on the ‘approved country for import’ list (which for now includes all EU and EEA countries) will require a UK Manufacturing and Import Authorisation (MIA(IMP)) holder to verify that these IMPs have been certified by a Qualified Person (QP) in a listed country, before release to the trial.
This verification process must be overseen by a QP. Tasks relating to the verification of QP certification may be delegated by the QP named on the UK MIA(IMP), to appropriate personnel operating within their MIA(IMP) quality system. Alternatively, a Sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Sponsors also have the option of outsourcing this verification to a third party who holds a UK MIA(IMP).
Sponsors will have one-year from 1 January 2021, to implement this assurance system for verifying QP certification of IMPs in listed countries. A substantial amendment should be submitted to the MHRA to include the details of the MIA(IMP) holder performing the ‘supply chain oversight’ role within 1 year of 1 January 2021.
This means that for up until 1 January 2022, IMPs may be supplied direct from the EU/EEA MIA(IMP) holder to the ongoing Great Britain trial site without the GB MIA (IMP) oversight process. From 1 January 2022, until the QP named on the UK MIA(IMP) confirms that the batch of IMP has been appropriately certified by the listed country QP, the IMP should not be made available for use by the GB trial sites. This is in addition to the two-step release procedure described in EU GMP Annex 13.
IMPs coming to Great Britain from Northern Ireland do not require this additional oversight.
However, IMPs coming directly to Great Britain from third countries that are not on the approved country for import list will continue to require QP certification in the UK by the MIA(IMP) holder as per the existing requirements.
Consistent with current EU requirements, summary results from all completed clinical trials must be submitted to the public register(s) where the trial was registered, within 6 months of the end of the trial for paediatric clinical trials, or within one year of the end of the trial for non-paediatric clinical studies. The MHRA will not require a separate submission of the summary results, however a short confirmatory email together with the relevant link must be sent to the Agency once the trial results have been uploaded to the public register. The REC on the other hand will require the submission of a final report outlining the trial results. The timeframe for submission is the same as that for reporting the summary results.
Paediatric Investigation Plans (PIPs).
The assessment of UK PIPs will remain in line with EMA guidance documents and the current EMA class waivers list will be adopted by the UK from 1 January 2021. However, applicants will be required to submit information relevant specifically to the UK. Northern Ireland will remain under the European system for paediatric medicine development; and the agreement of EU PIPs or waivers will continue to apply.
EU PIPs or modifications submitted to the EMA before 1 January 2021, which have been agreed or had a positive opinion issued by the EMA paediatric committee (PDCO), will be adopted as UK PIPs on or after this date, and will not require resubmission to the MHRA. In situations where the PDCO has issued a negative opinion, the MHRA will treat the application as refused, however, Sponsors are able to submit an updated PIP to the MHRA which addresses reasons for refusal.
For new UK PIP submissions made after 1 January 2021, the MHRA will need to be notified of the following:
If there is an agreed EU PIP and the opinion.
If there is an ongoing EU PIP assessment, its timeline in the PDCO assessment cycle.
Any scientific divergence between the submitted UK PIP and EU PIP.
The assessment pathways for UK PIP submissions will vary depending on the status of the EU PIP. Generally the MHRA will accept UK PIP applications which have an agreed EU PIP. Similarly the MHRA will also aim to accept a positive EMA opinion on PIP modifications or a class waiver request . Furthermore, a positive PDCO compliance check (CC) or interim CC will be adopted as the UK CC outcome unless subsequent modifications have led to divergence between the UK and EU PIPs. Sponsors should note that paediatric study plans agreed by the US Food and Drug Administration (FDA) should be provided as part of a UK PIP submission.
A summary of the key action items for Sponsors which are related to the procedures discussed in this section, is provided in Table 1. The associated dates for implementation have also been summarised.
Table 1: Key action items for pre-approval Sponsors
1 - This is on the basis that the Sponsor does not change and retains the same legal representative for the UK study.
2 - PIPs will not require resubmission to the MHRA and will become UK PIPs. However, if the PDCO has issued a negative opinion, the MHRA will treat the application as refused, and applicants can submit an updated PIP to the MHRA which addresses the reasons for refusal. Similarly, a resubmission can also be made to the MHRA if the PDCO has not yet given an opinion, or where the UK disagreed with the PDCO opinion. Abbreviations: LR - Legal Representative;
SA - Substantial amendment.
Assessment Phase Regulatory Interactions/Procedures
Orphan Drug Designation.
Sponsors who wish to request orphan designation status for their medicinal product should note that the MHRA will review applications for orphan designation at the time of a marketing authorisation application (MAA) or variation application. There is no pre-MAA orphan designation. The request is submitted with the MAA in module 1.2 of the eCTD, and a cover letter specifically indicating the intention to seek orphan drug designation should be included. There are no additional fees associated with applying for the designation. Applications are assessed in parallel with the MAA, by the Commission on Human Medicines (CHM). An appeal process is available before the MA is granted, for unsuccessful orphan requests.
Sponsors of successfully designated UK orphan products can benefit from incentives such as up to 10 years of market exclusivity from similar products in the approved orphan indication and full or partial refunds for marketing authorisation fees. Requirements for UK orphan designation align with the current requirements in the EU.
Marketing authorisation holders (MAHs) of products with orphan drug designation, who would like to request a new or an extension to an orphan therapeutic indication are required to submit the orphan drug designation application with the variation MA application. A new period of market exclusivity is only given if the applied for therapeutic indication falls within a new orphan condition.
Licensing.
A number of changes have been made to the national licensing procedures available in the UK. New procedures which will be available from next year are summarised in Table 2. Sponsors should note that the MHRA’s existing marketing authorisations under exceptional circumstances procedure and the early access to medicines scheme (EAMS) will continue to be available as before, for medicinal products which meet the relevant requirements.
Sponsors should note that for two years from 1 January 2021, GB will adopt decisions taken by the European Commission on the approval of new MAs in the community MA procedure. Applications should include all information provided to EMA during the licensing procedure and should be accompanied by all iterations of the CHMP assessment report including the final CHMP opinion. The UK will also have the power to take into account marketing authorisation decisions of EU Member States when considering applications for marketing authorisations for products that have been approved via decentralised or mutual recognition procedures. Applications should include all information submitted to the Reference Member State (RMS), accompanied by all iterations of the RMS assessment report, including the RMS end of procedure notification. A declaration of conformity of the UK application with the dossier approved in the RMS should be provided. Applications will be reviewed for compliance with UK specific requirements.
Table 2: Planned UK National Licensing Procedures
Post Approval Regulatory Interactions/Procedures
Centrally Authorised Products.
Marketing authorisation holders of centrally authorised products (CAPs) should note that all CAPs automatically become GB MAs on 1 January 2021 and will be issued with a GB MA. MAHs will have 21 days to opt out of having a GB MA. There is no fee associated with the CAP conversion, but an annual periodic fee will be payable for converted CAPs from 1 April 2021.
Under the Sunset Clause, the period of three years which Sponsors have to place a product on the market, will be restarted from the date of conversion to a GB MA.
To facilitate the conversion process, the MHRA have requested that Sponsors take the following actions:
Review lists of current CAPs and advise the MHRA of any errors or CAPs which are not desired for conversion.
Advise the MHRA of the GB marketing status of each product.
Provide the MAH company number and details of a single point of contact for all products.
Existing CAPs will remain valid for marketing products in Northern Ireland. To support the ongoing regulation of these converted EU MAs, the MHRA needs essential baseline data to be submitted in the form of an initiating electronic Common Technical Document (eCTD) sequence together with certain other related MA-specific information for each converted EU MA. MAHs will have a period of one year starting on 1 January 2021 to submit this data and related information in eCTD format. The MHRA Submissions portal will be ready by 1 January 2021 for these submissions to be made. Until these initiating sequences are submitted and processed, it will not be possible to submit a variation for the converted EU MA unless there are exceptional circumstances. Additional details on how variations will be handled by the MHRA are summarised in Table 3.
Table 3: MHRA Approaches to Variations
Source: MHRA Guidance: Converting Centrally Authorised Products (CAPs) to UK Marketing Authorisations (MAs) from 1 January 2021, ‘grandfathering’ and managing lifecycle changes
Pharmacovigilance.
For medicines authorised in GB, pharmacovigilance data will need to be submitted to the MHRA. Pharmacovigilance requirements for products marketed in Northern Ireland will remain in line with EU legislation and follow EU requirements. Pharmacovigilance data for medicines which are the subject of a UK MA covering both GB and Northern Ireland will need to be submitted in accordance with requirements for both GB and the EU (and to both MHRA and EMA), as appropriate. The Good Pharmacovigilance Practice (GVP) modules will remain in force but the MHRA will publish a guidance note on the exceptions and modifications to the EU guidance in due course.
From 1 January 2021, Sponsors will have to notify the MHRA of safety signals submitted to the EMA that are relevant to the product, as well as those raised by the EMA. Sponsors are obliged to notify the MHRA of emerging safety issues within 3 working days after establishing that a signal or a safety issue from any source meets the definition of an emerging safety issue.
The MHRA will continue to accept EU versions of the periodic safety update report (PSUR), but where UK specific information has been requested, this should be included in a specific annex. For now, the EU reference date list should be followed, and PSURs should be submitted to the UK at the same time as the EU submission. PSUR submissions should be made via the MHRA Submissions portal, which will be ready for use from 1 January 2021.
For all UK MAs, including those that cover the whole of the UK or are specific to Northern Ireland or to GB, the MAH must have permanently and continuously at their disposal a qualified person for pharmacovigilance (QPPV) who resides and operates in the EU or the UK. If a Sponsor chooses to establish a QPPV who resides and operates in the EU, they must nominate a national contact person (NCP) for PV who resides and operates in the UK and reports to the QPPV. This individual should have access to the reports of suspected adverse reactions. There will be a temporary exemption in place which allows the Sponsor 12 months from 1 January 2021 to appoint a national contact person for pharmacovigilance (PV) that resides and operates in the UK.
For all UK MAs, including those that cover the whole of the UK or are specific to Northern Ireland or to GB, the MAH must maintain, and make available upon request of the MHRA, a pharmacovigilance system master file (PSMF) that describes the pharmacovigilance system for UK authorised products. The same PSMF main body can be used to fulfil both EU and UK requirements however, a set of PSMF annexes covering EU authorised products (and products in respect of Northern Ireland) should be maintained separately from a set of annexes covering products in respect of GB only. Sponsors should request a unique UK PSMF number from the MHRA for each pharmacovigilance system they are operating for UK authorised products. The UK PSMF number can be requested from the MHRA Submissions portal from 1 January 2021.
Existing UK MAHs are also required to submit a summary of the pharmacovigilance system (QPPV and PSMF details), for all UK MAs. This should be submitted as a Type IAIN - C.I.8 variation by 30 June 2022, however, if the MAH changes its UK QPPV from the baseline information held by the MHRA before this date, the variation will need to be submitted within 2 weeks of changing the details of the QPPV. The baseline information is the QPPV details that were registered in eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) at the end of 13 December 2020. The submission should cover all UK product licences (PL) under a unique pharmacovigilance system however collections should consist of no more than 25 PLs.
For converted CAPs, if the UK QPPV details are different to that of the EU/EEA QPPV immediately prior to 1 January 2021 (as entered in XEVMPD), Sponsors should simultaneously submit a Type IAIN - C.I.8 variation as a separate sequence in the same submission package as the baseline initiating eCTD sequence. On the other hand, if the details for the UK QPPV are identical to that in XEVMPD immediately prior to 1 January 2021, no immediate action is required to notify the MHRA of the UK QPPV and UK PSMF details, and the same procedure for UK national licences mentioned previously should be followed (i.e. submit a single change Type IAIN - C.I.8 variation within two weeks of change to QPPV details, or by 30 June 2022 if no change).
From 1 January 2021, for products in respect of Northern Ireland (UK-wide and Northern Ireland-only MAs), in addition to providing the MHRA a summary of the pharmacovigilance system, Sponsors must also continue to submit this information to XEVMPD in accordance with Regulation (EC) No 726/2004 Article 57(2).
A summary of the key action items for Sponsors, which are related to the procedures discussed in this section, is provided in Table 4. The associated dates for implementation have also been summarised.
Table 4: Key action items for post-approval Sponsors
*If the MAH changes its UK QPPV before 30 June 2022, the variation will need to be submitted within 2 weeks of changing the details of the QPPV. For converted EU MAs, if the MAH changes its UK QPPV before 1 January 2021, this will need to be submitted with the baseline initiating CTD sequence (within 1 year of 1 January 2021).
Conclusions & Summary
Many of the features of the proposed new regulatory framework to be implemented in the UK, remain in close alignment with those of the EU. Nonetheless, a number of changes have been announced by the MHRA, and it is important that Sponsors are fully aware of new requirements. Drug developers are also encouraged to maintain a flexible approach towards their pre-existing or new UK product development programs, as further guidance/information is expected to be released.