MHRA ramps up detail on no-deal plans
Blog BREXIT

Along with other agencies, the Medicines and Healthcare products Regulatory Agency, the MHRA, has removed the word “unlikely” from its references to the possibility of “no deal”, and is accelerating its planning for this eventuality, though it is “not [its] policy or … preferred approach”.

Further to the consultation launched in October, the MHRA published a response to that consultation by updating its no deal guidance on 3 January and 4 January.

In this guidance, which covers medicines, clinical trials and medical devices, the MHRA states that if there’s no deal, then from the point of Brexit:

Medicines

• the UK’s participation in the EMRN will cease
• the UK will no longer be a part of the EU centralised, mutual recognition and decentralised procedures
• the MHRA will take on the functions currently undertaken by the EU (via EMA) for the UK market, requiring changes to UK law, via the Human Medicines Regulations 2012
• the MHRA proposes to continue using, until further notice, the EU GMP and GDP guidelines
• transitional legislation will ensure that all currently granted CAPs, or Centrally Authorised Products, automatically become UK MAs (“grandfathering”), giving MAHs:
  • a short period (later clarified as up to 22 April) within which to opt out of having a UK MA
  • a year to provide the MHRA with baseline data for the CAPs that are converted (and the MHRA will accept a ‘basic’ baseline data set initially to enable variations and other post-authorisation submissions to be processed, even when the full baseline data is still pending)
• for CAP applications that are pending at the point of Brexit:
  • the application submitted to EMA must also be submitted to the MHRA
  • if the CHMP has issued an opinion already, the MHRA will make its decision taking into account that opinion
  • if no CHMP opinion has yet been issued, the MHRA will continue to assess the application as a national procedure, taking into account any CHMP assessment that has already taken place

• for mutual recognition or decentralised procedure applications that are pending at the point of Brexit, a transitional provision will be made and the MHRA will complete the assessment and if successful, they will be approved as UK MAs

• UK MAs based on EU reference products that have been granted (or are pending) prior to Brexit will remain valid in the UK
• UK MAs already approved in decentralised and mutual recognition procedures will remain valid in the UK
• for generic MAs, the MHRA will not have access to the data provided in support of EU approved products and therefore new generic applications would need to be based on reference products that have been authorised in the UK
• MA applications for ATMPs to be marketed in the UK, whether for an initial, variation or in progress application, or a conversion from a CAP, would be treated in line with other MAs
• abridged procedures for obtaining an MA in the UK would remain but would be amended as it will not be possible to rely on a European reference product for any new applications submitted after Brexit
• sharing of common systems, and formal exchange and recognition of data submitted between the UK and EU would cease; the MHRA will have oversight of all pharmacovigilance activities in the UK (this includes risk management plans, reports of suspected adverse drug reactions from the industry, UK and non UK ICSRs, PSURs and PASS)
• the MHRA will offer new assessment procedures for applications for products that would until now have been made to the European Medicines Agency for CAPs, alongside its existing 210 day national licensing route, with a 67 day timeframe for products containing new active substances or biosimilars submitted to the EMA and received a CHMP positive opinion
• the MHRA plans to work to reduce the 210 day timetable to 180 days and to offer a ‘rolling review’ for new active substances and biosimilars to allow companies to make an application in stages throughout the product’s development, and a full accelerated assessment as a choice for new active substances, in 150 days (it will publish further guidance regarding these proposals in due course)
• the EU criteria for orphan medicines will be adopted by the MHRA, though some UK specifics will be incorporated in due course
• decisions on paediatric investigation plans (PIPs) will be made by the MHRA (it has expressed an intent to ensure incentives remain to encourage such medicines onto the UK market)
• data and market exclusivity periods will not change in the UK, and will start on the date of authorisation in the UK or EU, whichever comes first
• rules on legal presence in the UK for MAHs will be in place:
  • an MAH should be established in the UK by the end of 2020 (and a change of ownership will need to be submitted to MHRA to change from an EU MAH to a UK MAH for UK MAs)
  • a QPPV should be established in the UK on day one, but until the end of 2020, an EU QPPV may assume responsibility for UK MAs until a QPPV who resides and operates in the UK can be established (a variation must be submitted to the MHRA to change QPPV)
  • a QP for products manufactured in the UK or directly imported into the UK from a country not on an approved country list (which will include the EU and EEA) must reside and operate in the UK
  • where the MAH is not established in the UK on exit day, companies must put in a place a UK-based contact person within four weeks of Brexit

• the UK will continue to recognise QP certification from EU / EEA countries but UK holders of Wholesale Authorisations must notify the MHRA within six months to continue to import medicines QP certified in the EU / EEA to revise their WDA and put in place an assurance system to ensure any medicines they import have been QP certified
• packaging and leaflets for UK products will have to be amended by end of 2021 to comply with UK requirements, including UK administrative information such as the UK MAH’s name and address, etc., with more urgent updates required earlier
• the MHRA will continue to accept proposals for packaging and leaflets in the English language that include information on other jurisdictions (e.g. Ireland), providing UK requirements are met
• it is expected that UK stakeholders will not be able to comply with the requirement under the Falsified Medicines Directive to verify and authenticate and therefore the legal obligations related to this would be removed for all players in the UK supply chain
• the UK will unilaterally align to the EU/EEA exhaustion regime from Brexit to provide continuity in the immediate term for businesses and consumers so that parallel imports of goods including medicines can continue from the EU/EEA
• medicines that hold an MA in another Member State or are CAPs, and are “essentially similar” to a product granted a UK MA, may still be imported under a parallel import licence
• parallel import licence holders must in future be established in the UK; those currently holding licences have until 31 December 2020 to effect this change if currently established elsewhere in the EU/EEA but only four weeks from Brexit to put in place a UK-based contact person (who will no longer be required once a UK licence holder is established)
• holders of parallel distribution notices, issued by the EMA, in respect of CAPs will, where the UK is listed in that notice as a destination country, be automatically, and with no fee, issued with a parallel import licence, providing specified information is given to the MHRA by 21 April 2019
• for batches of immunological medicinal products or a medicinal product derived from human blood or plasma, the UK is unlikely to still be part of the OMCL but would work to put in place mutual recognition of Official Control Authority Batch Release (OCABR) batch testing with other countries, such as Switzerland and Israel. For countries where there is no mutual recognition agreement, the MHRA will require UK certification of batches by the UK’s NIBSC before the medicine can be placed onto the market. There will be a risk-based approach regime taking into account an approved country list, which will include all EU/EEA countries upon the point of Brexit
• UK-based online sellers would no longer be required to display the EU common logo to sell into the UK; the MHRA proposes to explore requiring a new ‘UK logo’ for UK-based online sellers from 2021
• the MHRA will charge fees for the tasks taken on from the EMA, such as GBP 62,421 for a major application for an MA for a new active substance

Clinical Trials

• the UK’s participation in the European regulatory network for clinical trials will end
• the MHRA will take on the responsibilities for the UK that are currently undertaken through the EU system
• the UK will continue to recognise existing approvals – both for regulatory and ethics
• the UK would require the sponsor or legal representative of a clinical trial to be in the UK or country on an approved country list, which will initially include EU/EEA countries
• the MHRA’s contact point idea has been dropped following stakeholder feedback during the consultation, therefore, note that the EU’s current position is that where trials are pan-EU, sponsors or legal representatives must be based in the EU
• the UK’s current regulatory framework, as per the 2004 Regulations, will remain in force but will be modified under the EU Withdrawal Act to ensure it still works post Brexit
• the new EU Clinical Trials Regulation 536/2014 will not be in force in the EU at the time of Brexit and so will not be incorporated into UK law at that point. The UK has issued an update on the Regulation, with a clear commitment to align with it where possible without delay when it does come into force in the EU, subject to UK parliamentary approvals
• for IMPs coming into the UK, the UK will recognise QP certification done in an approved country (which will initially include all EU/EEA countries) but note that the EU’s current position is that QP certification of IMP must be undertaken within the EU/EEA
• all importers of IMPs into the UK will require a Manufacturers Licence (MIA), and clinical trial sponsors will have 12 months from Brexit to comply with the following rules:
  • IMPs being supplied directly from EU/EEA states permitted
  • IMPs coming from countries on the approved list, the MIA (IMP) holder must put in place an assurance system overseen by a QP to check these IMPs have been QP certified in the EU/EEA
  • IMPs coming from other countries would, as today, require QP certification in the UK by the MIA (IMP) holder
• as now, the MHRA will require sponsors to submit all UK relevant SUSAR reports but they must be submitted via UK based IT systems, as they will no longer be able to report via EMA systems
• as now, the MHRA will require sponsors to submit annual safety reports for all UK trials
• the ability for UK patients to participate in multinational trials will not change
• as now, UK clinical trial applications will continue to be authorised by the MHRA and ethics committees
• as now, clinical trial applications require the contact details of the principal investigator(s) at UK sites
• post-Brexit, the MHRA will be improving processes for clinical trials to enable closer working with ethics bodies and allowing a single application and a single national decision in the UK
• the UK intends to align transparency provisions with those currently operating in the EU, to avoid duplication by companies; in the short term, the MHRA advises continued registration with EudraCT, ISRCTN, ClinicalTrials.gov and in the longer term, the UK will have its own specific hub that will give both UK patients and researchers a single reference point for all UK trials by the time the EU’s new portal goes live as part of the CTR

Medical Devices

• the UK’s participation in the European regulatory network for medical devices will cease
• the MHRA will take on the functions currently undertaken through the EU system for the UK market
• during a time limited period, the MHRA will continue to allow devices to be placed on the UK market that are in conformity with the applicable EU Directive
• relevant labelling requirements will continue to apply regarding CE marks and CE certificates
• the UK will comply with all key elements of the MDR and IVDR
• UK-based Notified Bodies will no longer be recognised by the EU after Brexit, meaning the devices they have certified will no longer be in conformity with the applicable EU Directive and as such those products will not be able to be placed on the EU market
• the MHRA will give UK-based Notified Bodies an ongoing legal status and continue to recognise the validity of certificates that they issued prior to Brexit, allowing those products to be placed on the UK market
• the MHRA will continue to accept labelling in the English language that include information from other jurisdictions (e.g. Ireland), providing UK requirements are met
• the UK will continue to recognise existing clinical investigation approvals – both for regulatory and ethics approvals – and there will be no need to re-apply
• the MHRA will continue to perform market surveillance of medical devices on the UK market and be able to take a decision over the marketing of a device in the UK, regardless of the position of the EU regulatory network, or any decision of the CJEU
• all medical devices, active implantable medical devices, IVDs and custom-made devices will need to be registered with the MHRA prior to being placed on the UK market, and grace periods of 4-12 months depending upon the product will apply to allow time for compliance. The registration requirements will require:
  • the GMDN code, meaning that groups of similar products can come under a single registration
  • once the MDR and IVDR fully apply (from May 2020 and May 2022 respectively), the UK will then mirror the new requirements within the legislation, which will mean individual registration of all products
• medical device manufacturers not established in the UK must have a UK Responsible Person established in the UK with a UK registered address to take responsibility for the product in the UK (but no labelling changes will be required to reflect this)

Julia Gillert is a Senior Associate in the Corporate Department of Baker & McKenzie's London office and is a key member of the Healthcare industry group within the London office and European and Global networks. Julia advises both domestic and international companies in the med-tech, pharma and healthcare sectors on a wide range of regulatory and general compliance matters. Julia has contributed to a variety of regulatory healthcare related publications and practice handbooks and co-edits the firm's European Healthcare Newsletter. Julia sits on the ABHI's Legal Issues Committee.

Els Janssens is a senior associate in our Abu Dhabi office and provides knowledge management support to Baker & McKenzie’s global and MENA Pharmaceutical and Healthcare industry group. Els started her career in 2000 at Baker and McKenzie in Brussels focusing her practice on pharmaceutical law and commercial litigation. She has worked six years in London as a legal adviser with the European Medicines Agency (EMA). During this period she has supported the EMA’s activities in medicines oversight and regulation and interacted with the European Commission on legal matters relating to medicinal products. She also worked one year as senior legal counsel in Johnson & Johnson’s European legal department providing regulatory advice regarding various medicinal products and supporting the public affairs function on new legislation.