Life Sciences Brexit Feed

The VMD have in place continued recognition for the sites of certain regulatory functions carried out in the EU for batches placed on to the market until January 2023. Many of the requirements beyond this will be included in the new VMRs, which are planned to come into effect in 2022.

The VMD’s main objective is to continue to seek future agreements with other countries, including the EU, that benefit veterinary medicine industries in our respective countries. Such reciprocal agreements may be via free trade agreements (FTAs) or mutual recognition agreements (MRAs).

See the guidance here.

The guidance covers the following matters:

• Converting PDNs to UK PILs from January 1, 2021
  • Great Britain: PDNs will no longer be valid in Great Britain and will be replaced by PILs which will allow the products to be marketed in Great Britain only
  • Northern Ireland: PDNs remain valid; no regulatory action is required to continue to market products directly imported from the EU into Northern Ireland only
  • Outline of the process for converting PDNs to PILs
• PDN holders have the option to opt in to the conversion process for all or some of their PDNs: Notify the MHRA in writing (as described below); this process requires minimal information from PDN holders
  • PDN holders have the option not to opt in: Following the end of the transition period, your product(s) will no longer be licensed in Great Britain; you will no longer be able to place your product(s) on the market in Great Britain
  • Product Licence (PL) numbers: Allocated by the MHRA to PDNs based on the existing practice for determining how many separate national licences are needed across a product range; all pack sizes will be covered by a single PL number
  • PILs will be valid for a single source country: A separate PIL will be issued for each source country you request
  • Fee for conversion from a PDN to a Great Britain PIL: None
  • Periodic fee will be due on April 1, 2021 for each PIL requested unless a request to cancel the PIL on March 31, 2021 has been notified to the MHRA (plpi@mhra.gov.uk) no later than December 31, 2020: £307
• Detailed description of the process for converting PDNs to PILs
  • Actions to take if you are a PIL holder: PILs will be issued to the holder of the PDN
    • Have a company number allocated by the MHRA: If you do not already have an MHRA-allocated company number, please contact plpi@mhra.gov.uk ASAP for instructions on how to apply for a number
    • Need to be established in the UK:
      • Not established in the UK but have an associated company established in the UK which you would like to be the holder of the PILs: Contact plpi@mhra.gov.uk ASAP to make this arrangement
      • Do not have an associated, UK-based company: Notify the MHRA before the end of a period of four weeks from the end of the transition period of the name, address, telephone number, and email address of an individual who resides and operates in the UK and who may be contacted in respect of any matter relating to the PIL; you will also need to establish a company in the UK before the end of a period of 24 months from the end of the transition period
        • Contact plpi@mhra.gov.uk as soon as this company has been allocated a number by the MHRA; the MHRA will transfer your PILs to the new company for no fee
  • How to opt in:
    • PDN holders have been provided with a list of PDNs understood to be valid on December 31, 2018; this list will be updated before the end of the transition period:
      • PDN holders should check this list very carefully and notify plpi@mhra.gov.uk of any discrepancy: Some PDNs refer to EU licence numbers which are not listed in the current product information available on the European Medicines Agency (EMA) website; these presentations may no longer be valid and PILs will not be issued for them unless you specifically request one
      • Column for the source countries you want to use for each product: A separate PIL will be issued for each source country you request; if you do not want your PDN for any product converted to a PIL, please enter “none” in this column
      • Return the completed list as soon as possible to plpi@mhra.gov.uk: Return the list no later than 21 days after the end of the transition period if you wish to take part in the conversion process; after this three-week period, it will not be possible to convert further PDNs and a fresh application for a PIL would be necessary, with the associated fee payable
  • How to request further information for companies involved in repacking: PILs require some additional information about the companies involved in the repacking process, including the supplier from whom the product is obtained and the companies involved in importing, repacking, batch release, storing, and distributing the product
    • Supplier information: Complete a “supplier commitment,” signed by a director of the parallel importing company; a commitment by the importing company to confirm validity of authorisations (e.g., WDA) and to record details of the source of each batch of products repacked
    • Deadline for returning this commitment: No later than four weeks after the end of the transition period; this commitment must be returned before any PIL numbers can be issued
    • Companies involved in repacking: Best managed using a “Company Functions List”
      • This can be updated at any time by submitting an updated list to plpi.admin@mhra.gov.uk
      • The latest list will be applied when a new PIL is granted
      • Contact plpi.admin@mhra.gov.uk for a template and example document
      • Deadline for returning this information: No later than four weeks after the end of the transition period; this information must be returned before any PIL numbers can be issued
  • Issue of PL numbers: ASAP after receipt of the list of PILs you require, the MHRA will return an updated list which includes a PL number allocated to each product/source country requested
  • After the end of the transition period:
    • Products for which you have requested a PIL using labels and leaflets consistent with the latest annex on the EMA/EC website and carrying the EU licence number: Immediately after the end of the transition period you may continue to repack and release those products
    • Products for which you have not requested a PIL: May not be released after the end of the transition period
    • Once you have received your list of PIL numbers: You should update the labels and leaflet to use these numbers as soon as practicable
      • Continue to monitor the EMA/EC website and update the labels and leaflet used in your released product to remain consistent with the latest annex on the EMA/EC website
  • Receipt of PILs: The MHRA expects that it will take some months to issue all of the PILs required; they are likely to be produced on a “by product” rather than a “by importer” basis
    • Before the relevant UK marketing authorisation (MA) for the reference product has been issued: The PILs produced may use a substitute UK reference MA to allow cases to be created in the MHRA’s licence management system
      • A change of UK reference product variation will be applied to each PIL by the MHRA at no fee at a later date
    • The PILs produced as part of this process will use the EMA/EC annexes for the label and leaflet documents; no “user test” of the patient leaflet will be required
  • PIL maintenance: Once a PIL for a converted product is issued, the established parallel import variation process applies
    • Variations: Should be submitted and approved before an affected product is released, unless the change falls within the Tell-and-Do scheme; scans of samples should be submitted when required
    • First variation affecting labels and/or leaflets: Must be accompanied by a mock-up of the respective documents
      • Labels: This must begin with the label summary sheet; contact plpi@mhra.gov.uk for a template

The guidance covers the following matters:

• Traditional herbal medicines: From January 1, 2021, the MHRA may expand the list of countries from which it will accept evidence for traditional herbal medicines
  • Currently: For traditional herbal registration, evidence has to be provided that the product or a corresponding product has been used for a period of 15 years within the EU/European Economic Area (EEA)
  • From January 1, 2021: The MHRA may be able to accept the 15 years of traditional evidence from a wider range of countries in addition to EEA countries
    • Suitable countries: Level of pharmacovigilance equivalent to that of the UK; the MHRA will publish a list of suitable countries which will be updated as new entries arise
• Traditional herbal medicines intended to be marketed in Northern Ireland: Traditional use evidence will need to be provided that the product or a corresponding product has been used for a period of 15 years within the EU/EEA
• The MHRA may publish its own list of herbal substances, preparations, and combinations for use in traditional herbal medicines; this will include the entries in the existing EU list and the MHRA list will be updated as new entries arise
  • Only the EU list will be relevant for applicants wanting to apply to market a traditional herbal medicine in Northern Ireland
• Homeopathic medicines: From January 1, 2021, the definition of a homeopathic medicinal product will be expanded
  • The definition will cover products prepared from homoeopathic stocks made in accordance with a homoeopathic manufacturing procedure described in the European Pharmacopoeia or, in the absence of a description there, in accordance with a procedure described in the British pharmacopoeia or in a pharmacopoeia used officially in a country that is included in a list published by the MHRA
  • It is anticipated that the list will include the:
    • British Pharmacopoeia
    • European Pharmacopoeia
    • Pharmacopoeia used officially in an EEA country
      • This list will be updated as new entries arise
• Homeopathic medicines to be marketed in Northern Ireland: The current EU definition of a homeopathic medicinal product will remain 
• Issues relating to place of establishment, variations, and other regulatory issues which would previously have been regulated at the EU-level: Refer to the guidance on marketing authorisations (MAs)

The guidance covers the following matters:

• Preparation of ASMF: Should be prepared in accordance with the Committee for Medicinal Products for Human Use (CHMP) guideline on active substance master file procedure (CHMP/QWP/227/02 Rev 4)
  • Templates (letter of access; submission letter, and administrative details form) included in the annexes to that guideline should continue to be used
  • Submit the Applicant’s Part (AP) of the ASMF as part of the marketing authorisation (MA) dossier, together with a letter of access issued by the ASMF holder
• When an ASMF procedure is to be used which relates to an ASMF that has not previously been submitted to the MHRA: The ASMF holder should submit a copy of the AP and Restricted Part (RP) to the MHRA
  • This should be accompanied by:
    • a completed submission letter and administrative details form;
    • any relevant letter of access;
    • the Quality Overall Summary for the AP and for the RP; and
    • a curriculum vitae for the expert
• Submission of the complete ASMF: The complete ASMF only needs to be submitted once to register the ASMF with the MHRA
  • Timing for the relevant documentation: Should be timed to arrive not more than one month before and not after the intended MAA/MAV submission data
• Changes to an ASMF: Should be handled in accordance with the CHMP guideline (CHMP/QWP/227/02 Rev 4)
  • Responsibilities of the ASMF holder: Notify each applicant/MA holder and the MHRA that changes are being proposed to the ASMF
  • Submission of a new ASMF and any update to the ASMF: Should be made by the ASMF holder using the MHRA
• Submissions portal: The UK will no longer participate in ASMF worksharing procedures with EU Member States
  • Where an assessment of a new ASMF or an update to an ASMF has been conducted by an EU Member State before January 1, 2021: Such an assessment may be taken into consideration in subsequent MAA or MAV applications that are under assessment after January 1, 2021
• Certificates of Suitability (CEPs) are not affected by the UK leaving the EU: They are issued by the European Directorate for the Quality of Medicines and Healthcare (EDQM) which is a Directorate of the Council of Europe and independent of the EU; on leaving the EU, the UK will remain a member of the Council of Europe
  • No change to procedures relating to the use of a CEP to support an MAA or MAV
• Action for MA applicants: Include appropriate information in the MAA or MAV application form
  • Applications where there is: (i) a CEP for a chemical substance that is an active substance or excipient; (ii) a CEP for a herbal drug preparation; and (iii) a CEP for materials of animal or human origin that have been subject to an evaluation of the risk related to transmissible spongiform encephalopathies (TSE): Include a copy of the current version of the relevant CEP in Modules 1 and 3

The guidance covers the following matters:

• Submission of a cover letter of the concerned paediatric study(ies) to the MHRA: The MAH must do this within six months of completion (i.e., date of last visit of last subject undergoing the trial, unless otherwise justified in the protocol) in electronic Common Technical Document (eCTD) format via email to paediatricstudies@mhra.gov.uk
  • The MAH should indicate in the cover letter whether the study(ies):
    • are linked to other paediatric studies which have been or will be the subject of other submissions under Regulation 78A of the Human Medicines Regulations 2012, as inserted by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019: The MAH should provide the study title(s) with approximate date of completion; if the study(ies) relate to a UK-PIP, the MAH should provide the PIP number
    • have been or will be submitted in the UK as part of a variation/extension or any other application including this paediatric study: The MAH should (i) specify the UK procedure number, if available, or the type of application this will be submitted under; (ii) confirm that the application will be submitted within the next six months; and (iii) confirm that, based on the results of the study, no urgent safety update of the product information is required
  • The MAH should provide any relevant information about any related Article 46 of Regulation (EC) No 1901/2006 procedure(s) or EU agreed PIP(s)
  • The MAHs should also state whether as a result of the paediatric study there is a need to update the product information
• Initial appraisal of whether an assessment procedure is required at this stage: Carried out by the MHRA on receipt of the cover letter; one of the following may apply:
  • Assessment of the data is not required at this stage and the MHRA will maintain records including justification for the decision
• Limited evaluation of the study data may be undertaken if the MAH provides robust justification that the study data are unlikely to warrant PI changes
  • The MAH will need to state in the cover letter that one or more of the following criteria are met:
    • the same data have been reviewed in another regulatory procedure by the MHRA or another competent authority and the review has not led to PI changes;
    • the study was conducted mainly in adult patients with limited paediatric patients included;
    • the drug is already licensed in the paediatric population and the study does not provide new pharmacokinetic (PK), efficacy, or safety data;
    • the study, due to its design, limited number of paediatric patients, discontinuation, or other reason does not allow drawing conclusions on efficacy or safety that would impact the drug’s benefit:risk ratio or be useful to prescribers and patients;
    • only interim results from an ongoing study are available which will be assessed later in their totality;
    • the study has been conducted in populations and/or diseases that are not applicable to the UK; and/or
    • other justification as to why a detailed assessment is not required at this stage
      • One or more of the above criteria apply: The MAH should submit the study report and a short clinical overview including justification why PI changes are not necessary; a variation application will not be requested if the MHRA agrees with the MAH’s justification not to update the PI
        • Short clinical overview to clarify the context of the data: Should include information on the pharmaceutical formulation used in the study, the existence of a suitable paediatric formulation, and, if relevant, conditions for an extemporaneous formulation
• If review of the data is required (when the MAH proposes a PI update or when the MHRA concludes after the initial appraisal, that a full assessment is needed to robustly conclude on prospective PI updates): The MHRA will notify the MAH to submit the paediatric data within 60 days as a type II variation application (change code C.I.13 — complex type II variations fees will be applicable)
  • The MAH should submit the following:
    • Final clinical study report;
    • A short clinical overview clarifying the context of the data;
    • A summary of Product Characteristics/Patient Leaflet (SmPC/PL) proposal to update the paediatric information, or when none is considered required, justification that changes are not necessary;
    • For a paediatric study that is part of a development program including a PIP, a line listing of all relevant studies; and
    • If the MAH holds other paediatric studies for the same active substance falling under the scope of EU Article 45 of Regulation (EC) No 1901/2006 which have not yet been assessed by a competent authority, these should be submitted along with a clinical overview clarifying the context of the data
  • If the MAH is unable to submit the type II variation within the 60-day timeframe: The MAH must justify the delay and propose a new submission date
• Results of a paediatric study submitted to the European Medicines Agency (EMA) or CMDh under Article 46 of Regulation (EC) 1901/2006 prior to January 1, 2021: The process will remain within the EU assessment framework and no UK equivalent procedure will be initiated unless the MAH indicates that an urgent safety update of the PI is required
  • Upon finalisation of the EU procedure and availability of the final assessment report: The MAH should submit this to paediatricstudies@mhra.gov.uk
    • The MHRA will check the applicability of the outcome of the EU procedure for UK products
    • If there are proposed changes to the PI which can be directly implemented to relevant UK products, if not already submitted: The MHRA will request MAHs to submit a type IB variation to update the PI within 60 days
• Workflow steps for submission and assessment of MAH-sponsored paediatric studies:
  • Step 1; Day 0: Receipt of letter notifying the MHRA of completed study from MAH via paediatricstudies@mhra.gov.uk
  • Step 2; Day 7: Allocate procedure to medical assessor
  • Step 3; Day 14: Inform MAH whether assessment of the data is required
    • If required: A variation is requested within 60 days, go to step 4
    • If an EMA P46 or CMDh PdWS under Article 46 of Reg.1901/2006 has been completed prior to January 1, 2021 and PI changes is a direct implementation to relevant UK products: Go to step 11
    • If not required: MAH will be informed that no further action is needed
  • Step 4; Day -14: MAH submits data as variation type II, followed by validation process (up to 14 calendar days)
  • Step 5; Day 0 (clock starts): Provide MAH with the start date of the procedure
  • Step 6; Day 59/60 (standard) (in exceptional circumstances (extended) day 89/90): Preliminary AR followed by clock-stop period if there is a need for Request for Information (RFI) or Preliminary/Final AR, where changes to the PI could be implemented at the end of the procedure if applicable
  • Step 7; clock-stop: Should not be longer than 60 days for responses + 60 days for assessment of the responses (extension of clock-stop period could be considered upon request)
  • Step 8; Day 60 (standard) (Day 90 (extended)): Final AR sent to MAH, where changes to the PI could be implemented at the end of the procedure, if applicable
  • Step 9; Day 75 (standard) (Day 105 (extended)): Draft Public paediatric AR sent to MAH to comment on any confidential/commercial sensitive information within 15 days
  • Step 10; Day 90 (standard) (Day 120 (extended)): Publish public paediatric AR on the MHRA website
  • Step 11; Day 60 (only applicable if an EMA P46 or CMDh PdWS under Article 46 of Reg.1901/2006 has been completed prior to January 1, 2021 and PI changes is a direct implementation to relevant UK products): Request will be sent to MAHs for type IB variations submission, to update the PI within 60 days
• Processing and assessment of outcome of EU Article 45 worksharing procedures:
  • MAHs are not required to submit to the MHRA information on paediatric studies completed by January 26, 2007 and which fall under the remit of Article 45 of Regulation (EC) No 1901/2006 worksharing procedure
  • The MHRA will monitor the published Public Assessment Reports (PAR) of Article 45 PdWS procedures
    • If a new PAR is identified: Any proposed (PI) changes and their applicability for UK products with the same active substance will be reviewed
      • If products with the same active substance are not available in the UK or the PI changes proposed are not applicable to UK products: No further action will be taken 
      • If the proposed PI changes are directly applicable to UK products, if not already submitted: The MHRA will send a request to the UK MAHs to submit a type IB variation within 60 days
      • If proposed PI changes are not directly applicable to the UK products: The MHRA may adapt the recommendations and subsequently send requests to UK MAHs for type IB variation, where the UK adapted recommendations will be provided, within 60 days
      • If the MHRA considers that the MAHs should provide supplementary data in order to conclude on potential PI changes for the UK products and a further UK assessment is deemed necessary: A type II variation could be requested within 60 days

The guidance covers the following matters:

General approach to UK-PIPs

• The PIP application process: The MHRA will simplify this by offering an expedited assessment (where possible) and by mirroring the submission format and terminology of the EU-PIP system 
  • Scientific content and assessment required: Kept in line with EMA guidance documents
• Northern Ireland: Remains part of the EU’s system for paediatric medicines development including agreement of EU-PIPs or waivers
• Paediatric obligations in line with the unfettered access Great Britain Marketing Applications: Will be met by the agreed EU-PIP or waiver as required
• Format and submission procedure for UK-PIP applications: Will be published separately
  • Applicants should include information relevant specifically to the UK, particularly with respect to any areas of unmet therapeutic need that this product intends to cover in the UK
• For any UK paediatric submissions that do not fall into any of the prespecified criteria listed above: A case-by-case discussion should always be considered
• Further step-by-step information on the process of submitting PIPs via the new MHRA submissions portal will be available in a user reference guide which will be published separately

PIP submissions

EU-PIP or modifications to PIPs submitted before January 1, 2021:

• EU-PIPs and modifications agreed by the EMA before January 1, 2021: Adopted as UK-PIPs on or after that date; will not require resubmission to the MHRA
• Valid request for an EU-PIP or modification or waiver made to the EMA but no decision given before January 1, 2021, and EMA Paediatric Committee (PDCO) has given a positive opinion with which the UK has concurred: Adopted as a UK-PIP; will not require resubmission to the MHRA
• Valid request for an EU-PIP or modification or waiver made to the EMA, but no decision given before January 1, 2021 and PDCO has issued a negative opinion: The MHRA will treat the application as refused; applicants can submit an updated PIP to the MHRA which addresses the reasons for refusal
• Valid request for an EU-PIP or modification or waiver made to the EMA but no decision given before January 1, 2021 and PDCO has not yet given any opinion, or the UK disagreed with the PDCO opinion: Submit the PIP to the MHRA, unless the applicant notifies the MHRA that they do not wish the application to proceed
  • EU-PIPs which become UK-PIPs under these transitional provisions will be referred to as adopted UK-PIPs in this guidance
  • New UK-PIP submissions after January 1, 2021 that have been assessed and agreed by the MHRA, will be referred to as agreed UK-PIPs

UK-PIP submissions after January 1, 2021:

• Information should be provided on whether there is:
  • an agreed EU-PIP and the opinion and supporting documentation is included;
  • an ongoing EU-PIP assessment, its timeline in the PDCO assessment cycle (i.e., day 30, 60, clock stop, day 90, or 120);
  • any scientific divergence between the submitted UK-PIP and the EU-PIP
• Assessment pathways for UK-PIP submissions from January 1, 2021: Annexes I and II

UK-PIP with agreed EMA opinion from January 1, 2021 or ongoing assessment at EMA from January 1, 2021:

• Positive PDCO opinion: The MHRA will aim to accept this
  • A focused assessment may be needed considering (but not restricted to) the following:
    • unmet UK paediatric needs;
    • paediatric-only development particularly for an innovative product;
    • the incidence of the disease in the UK population;
    • the relevance of the scientific arguments by EMA/PDCO in the summary report (SR) to the UK paediatric population;
    • any additional safety or efficacy concerns for the UK population;
    • the nature and number of licensed products already available for the intended paediatric indication;
    • the feasibility of performing the proposed paediatric studies in the UK only;
    • PIP is to support a UK Paediatric Use Marketing Authorisation (PUMA)
      • The applicant may request a full assessment
• PDCO opinion is negative: Applicant has the option to withdraw the UK-PIP or continue with the MHRA assessment
  • If the applicant chooses to continue with the MHRA assessment: Consider incorporating changes to the UK-PIP during clock-stop, for the elements that received a negative PDCO assessment
    • If the applicant chooses to withdraw the UK-PIP and a new UK-PIP is submitted: The new PIP should be updated to address the reasons for refusal

UK-PIP with no EU-PIP from January 1, 2021: Full assessment of the UK-PIP is required

• Additionally, the applicant should clarify if:
  • there has been a previous negative EMA/PDCO PIP opinion;
  • there was a withdrawn EU-PIP prior to the adoption of an EMA/PDCO opinion;
  • the current UK submission has been updated since the previous negative or withdrawn EU-PIP;
  • the applicant has included the previously withdrawn or negative EMA/PDCO PIP SR as part of the supporting documents in the MHRA submission; or
  • during assessment, consideration will be given to the scientific discussions of the EMA/PDCO which led to the negative opinion or the withdrawal of the EU-PIP

PIP modifications

Modifications of an adopted or agreed UK-PIP: 

• When a PIP modification is submitted, it should confirm if there is:
  • an agreed EU-PIP modification;
  • an EU-PIP modification assessment ongoing;
  • the modification submitted is for an adopted or agreed UK-PIP; or
  • a significant scientific divergence between the current agreed EU-PIP and the agreed UK-PIP
• Modifications submitted for UK-PIPs where there is an EU-PIP: Include the most recent PDCO opinion and PIP SR
• Modifications submitted for agreed UK-PIPs: 
  • Where the EU opinion for the initial UK-PIP was accepted by the MHRA: Focused assessment
  • Where the initial UK-PIP underwent full assessment: Full assessment
    • The applicant may request a full assessment

UK-PIP modification of an agreed EMA opinion or ongoing assessment at EMA:

• Positive PDCO opinion: The MHRA will aim to accept this in cases where the initial UK-PIP was agreed on the basis of an agreed EU-PIP
  • A focused assessment may be needed considering (but not restricted to) the following:
    • unmet UK paediatric needs;
    • paediatric-only development particularly for an innovative product;
    • the incidence of the disease in the UK population;
    • the relevance of the scientific arguments by EMA/PDCO in the SR to the UK paediatric population;
    • any additional safety or efficacy concerns for the UK population;
    • the nature and number of licensed products already available for the intended paediatric indication;
    • the feasibility of performing the proposed paediatric studies in the UK only; or
    • PIP is to support a PUMA
  • Negative PDCO opinion whilst the UK assessment is ongoing:
    • Applicant has the option to withdraw the UK-PIP modification request or continue with the MHRA assessment
      • If the applicant chooses to withdraw the UK-PIP modification request and a new UK-PIP modification is submitted: The new UK-PIP modification request should be updated to address the reasons for refusal
      • If the applicant chooses to continue with the MHRA assessment: The applicant can discuss amendments to the proposals before the final MHRA opinion on the proposed modification is agreed

UK-PIP modification with no agreed EU-PIP modification: A full assessment of modification will be required if there is no agreed EMA modification opinion

Submission of Paediatric Class Waivers

• From January 1, 2021 the current EMA class waivers list will be adopted by the UK
• Positive EMA opinion on a class waiver request: The MHRA will aim to accept this
• No EMA opinion: An MHRA assessment will be undertaken
• Negative EMA opinion on whether a class waiver applies:
  • applicant should submit a full product-specific waiver request for an MHRA assessment which should include an EMA opinion on the class waiver;
  • if there is an EMA opinion on the applicant’s subsequent product-specific waiver request, then this should be made available to determine if a focused or full assessment is required

Compliance Check (CC)

Adopted UK-PIP CC:

• Positive PDCO CC or interim CC: Adopted as the UK CC outcome unless subsequent modifications have led to divergence between the UK-PIP and the EU-PIP
  • The applicant must pay particular attention to the agreed timelines of those measures which would need to be completed after the PDCO CC to ensure compliance on the date of the UK marketing authorisation (MA) submission
    • PDCO compliance outcome documents: Should be submitted ahead of, or at the time of, the MA application

Agreed UK-PIP CC:

• No PDCO CC or any scientific divergence between the agreed UK-PIP and the EU-PIP: UK assessment required for full or interim CC
• Positive PDCO CC or the UK-PIP is equivalent to the EU-PIP: The MHRA will adopt the PDCO CC outcome
  • Applicants are encouraged to request a CC ahead of submission of an MA application where one is required for validation
  • At completion of the CC procedure, the MHRA will issue compliance outcome documents

Noncompliance:

• Due to (minor) administrative issues, or discrepancies that do not affect the scientific conduct of the study: A streamlined assessment will be proposed at the time the applicant is informed of the noncompliance outcome
  • This will combine a shortened modification procedure with a rapid CC
• If the above is not applicable: The applicant will be required to submit a modification for a full assessment to align the noncompliant key elements of the opinion with those of the completed study report
  • A rapid CC will be offered at the end of a positive modification agreement

Statements of compliance:

• When all of the agreed PIP measures have been completed, will be issued, if appropriate, when an MA application (initial, extension, or variation) is granted
• The Summary of Product Characteristics and, where applicable, the package leaflet will include the results of the studies referred to in the UK-PIP

Paediatric Study Plans (PSP)

• PSP agreed by the U.S. Food and Drug Administration: Applicants should provide the agreed PSP as part of their UK-PIP submission

Unmet needs in the UK paediatric population

• Defined by:
  • therapeutic areas identified by UK health bodies as high-priority public health concerns;
  • product development in conditions identified after consultations with UK experts and patient groups, including those for rare diseases identified under the auspices of the Department of Health and Social Care (DHSC) policy paper — UK strategy for rare diseases;
  • product development in conditions (or paediatric groups) identified as critically important in the Paediatric Regulation 10-year report; and
  • products which are intended to be authorised as orphan medicines

The guidance covers the following matters:

• Actions to take once you have been issued a new Marketing Authorisation (MA) to convert a previously EU-wide to an MA for Great Britain:
  • Establish and register a Great Britain presence for your MA: No later than 24 months from January 1, 2021
    • Submit amended artwork for approval to accommodate the following new administrative information:
      • Name and address of Marketing Authorisation Holder (MAH) or representative
      • Great Britain MA number 
      • Name and address of product manufacturer for batch release
  • Ensure all stock released to market is in compliant packaging: No later than 36 months from January 1, 2021
  • Variation application submitted between the grant of the new MA and 24 months from January 1, 2021: You may need to amend the labelling and/or the patient information leaflet (PIL) to take account of new information; the changed artwork which accompanies that variation application should include the new administrative information at that earlier time
    • Making changes to the labelling and/or the PIL: Submit full colour mock-ups as part of the variation submission
    • Only changing the name and address of the MAH and/or the manufacturer for batch release (stated in PIL): You may do this as part of a Better Regulation of Medicines Initiative (BROMI) notification
    • Making other changes to the statutory information or the pack design (which are not consequential to a change to the Summary of Product Characteristics (SmPC): Submit the artwork for full assessment to the Product Information Quality Unit under change code P2
      • Normal fee arrangements apply to the above
    • Packs containing the Falsified Medicines Directive (FMD) safety features: Will still be accepted in the UK, provided they are in line with other UK packaging requirements
• Multicountry packs, including packs with more than one language on the pack and/or in the PIL: The MHRA will continue to allow these, provided that the entirety of the information is compliant with the UK requirements
• National MAs previously the subject of a mutual recognition or decentralised submission: Will be considered as purely national licenses
  • Changes to packaging components which previously may have been suitable for submission via an MR 61(3) submission: Will now be considered under the national rules
    • In many cases, these changes will be suitable for self-certification under the BROMI scheme; some changes will need to be submitted for full assessment 
• See full details on how to submit applications for assessment, national best practice guidance, and the fees

The Guidance covers the following matters:

• Purpose of the written confirmation: confirms that, for a third country exporting active substances to the European Economic Area (EEA), (i) the standards of Good Manufacturing Practice (GMP) are equivalent to those in the EU/EEA; (ii) the manufacturing plant is subject to regular inspections; and (iii) significant noncompliance events would be communicated to the EEA without delay
• From January 1, 2021, Great Britain will be recognised as a Third Country for the export of Active Substances for human use to the EEA: For each shipment of Active Substance manufactured in Great Britain that is exported to the EEA and Northern Ireland, a Written Confirmation will be required
  • A template for the Written Confirmation can be found on the European Commission website
• Active Substance manufacturers in Northern Ireland: Will continue to be recognised by the EEA
• Generation of Written Confirmations for Active Substances manufacturers in the UK: You will not need to provide any information to the MHRA to allow the Written Confirmation to be generated; Written Confirmations will be generated for Active Substance manufacturers in Great Britain whether they intend to export Active Substances or not
  • Manufacture of a biological active substance: Considered to be a partial manufacture of the biological medicinal product; these activities are recorded in section 1.3 of the UK Manufacturing Authorisation (MA) and the associated GMP certificate issued following a satisfactory inspection
    • If you hold an MIA that includes manufacture of a biological active substance: Separate registration of an active substance manufacturer is not required; no written confirmation will be issued (already confirmed by the MHRA GMP certificate)
• Obtaining Written Confirmations for importation of Active Substances manufactured in other third countries: You will still need to obtain the Written Confirmations from the issuing authority in that country
  • Supply of Active Substances manufactured in Northern Ireland to Great Britain: A Written Confirmation will not be required
• Requirements for distributors of Active Substances that you did not manufacture: Written Confirmations will not be generated for your activities
  • If a Written Confirmation is required for export activities: It can be obtained from the appropriate issuing authority, or directly from the manufacturer
• Validity period of a Written Confirmation: Valid for the same period as the corresponding GMP certificate; where required the MHRA will offer an assessment to reissue GMP certificates of Active Substance manufacturing sites in Great Britain, prior to January 1, 2021 to allow the generation of Written Confirmations with an appropriate validity period
• Companies with confidential GMP certificates: The Written Confirmation will not be published on the MHRA website; it will be sent to the contact named on your Active Substance registration
• Requirement for both a GMP certificate and a Written Confirmation if you export Active Substances manufactured in Great Britain to the EEA or Northern Ireland:
  • GMP certificate: Required by UK law to be issued after an inspection
  • Written Confirmation: Required by EU regulations for any import of Active Substances into the EEA by a third country
    • A “Questions and Answers” document on the EU expectations relating to Written Confirmations is available on the European Commission website which details how the Written Confirmation should be provided to the customer within the EEA
• The need for Written Confirmations is expected to be an interim position: At a suitable point after January 1, 2021, an application will be made to recognise Great Britain’s GMP standards for the manufacture of Active Substances in Great Britain as equivalent to those in the EU
  • Written Confirmations will no longer be required once a country has been accepted as having equivalent GMP standards

The Guidance covers the following matters:

• Variations procedure for both pending and new variations to purely national UK Marketing Authorisations: From 11 p.m. on December 31, 2020, the procedures detailed under Chapter IIa of Variations Regulation (EC) No 1234/2008 will be incorporated into UK law; can be found in new regulation 65C and Schedule 10A to the Human Medicines Regulations 2012 (HMRs)
  • The current variations classification guidelines, which explain the type of variation (Type IA, Type IAIN, Type IB, Type II, or Extension) to submit and, where relevant, the conditions to be met and any required supporting documentation: will continue to apply (unless specifically highlighted below)
  • Submission of any extension application: submit in accordance with the procedures for new Marketing Authorisations; the variations classification guidelines will continue to apply until the MHRA issues any revised Guidance in the future
  • Any Article 5 recommendation published by the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) before January 1, 2021: the UK will recognise
  • Any specific request from a Marketing Authorisation Holder (MAH) concerning the classification of a variation which is still pending (no recommendation) on January 1, 2021 or is submitted after January, 1 2021: will need to be submitted directly to the MHRA; the MHRA will issue its own recommendation
• Variations of a UK marketing authorisation:
  • All MAs authorised in the UK by the MHRA before January 1, 2021: will be national (UK)
  • Any pending and new variations: will only be processed to conclusion after January 1, 2021 as national variations, where the relevant national procedures will be followed
  • Northern Ireland: Under the Northern Ireland protocol, medicinal products authorised via the centralised route will be directly authorised for use in Northern Ireland; a separate MA will not need to be issued by the MHRA for Northern Ireland
    • Variations to those MAs: will be centrally managed by the EMA in accordance with relevant procedures
    • If the same product is separately authorised in Great Britain: a separate variation application will need to be submitted to vary that authorisation
    • Products authorised under EU mutual recognition or decentralised (MR/DC) procedures: Under the Northern Ireland protocol, medicinal products authorised via the MR/DC procedure, where Northern Ireland is specifically included, will be authorised for use in Northern Ireland; a UK MA in respect of Northern Ireland will be issued by the MHRA
      • Variations to these MAs: will be managed as part of the specific MR/DC procedure, according to the relevant procedures laid down in the Variations Regulation (EC/1234/2008 as amended), where worksharing will also be possible
      • If the same product is separately authorised in Great Britain: a separate variation application will need to be submitted to vary that authorisation
  • How pending variations (no decision) on January 1, 2021 will be finalised:
    • Purely national Marketing Authorisations (not part of any worksharing procedure): will be processed to conclusion under the transitional provisions, using the same purely national procedures that were in place prior to January 1, 2021
    • UK Marketing Authorisation covered under Chapter II of Regulation (EC) No 1234/2008 (variations to marketing authorisations granted in accordance with Chapter 4 of the 2001 Directive, i.e., MR/DC variations (Type IA, Type IB, or Type II) and purely national Marketing Authorisations before 1 January 2021, but part of a worksharing procedure under Article 20 of Regulation (EC) No. 1234/2008 (Type IB or Type II): the variation will be processed to its conclusion as a purely national variation
      • Every effort will be made to ensure that relevant procedural time periods are observed
      • The ongoing assessment will take into account where in the overall procedure the application has gotten to on January 1, 2021
        • Any information previously obtained, and any assessment reported on before January 1, 2021, will be taken into consideration as part of the UK assessment process
      • Action to take if the applicant does not wish to continue with the relevant variation as a national (UK) application: notify the licensing authority in writing to say you no longer want the application to proceed; a partial fee refund may be applicable
  • Final decision for a variation procedure has been taken by the lead authority but not finally processed in the UK before January 1, 2021 where the UK is not the Reference Member State or Reference Authority: the MHRA will implement the agreed outcome of the procedure
  • New variations submitted from January 1, 2021: will be processed as purely national variations according to the same transposed procedures as were in place prior to January 1, 2021; there will be no provision for worksharing
  • New variations submitted from January 1, 2021 to MAs issued as a result of Northern Ireland’s involvement in European procedures: will be managed in line with the base procedures
    • All other new variations: will be processed as purely national variations according to the same transposed procedures as were in place prior to January 1, 2021; there will be no provision for worksharing
• Points to note for specific changes submitted from January 1, 2021:
  • Change to finished product manufacturing site (including, as appropriate, primary and/or secondary packaging site): should be submitted under the relevant sub-change code under B.II.b.1 and be suitably supported; this includes the submission of a copy of the relevant manufacturing authorisation or, as appropriate, a valid good manufacturing practice (GMP) certificate issued by the UK, or a GMP certificate (or equivalent document) from the competent authority of a country on the approved country for batch testing list (currently EEA Member States, Australia, Canada, Israel, Japan, New Zealand, Switzerland, and the United States); where relevant, reference to the EudraGMP database will suffice
  • Change to importer/batch release site/quality control site: should be submitted under the relevant change code under B.II.b.2 and be suitably supported
    • Importer/batch release: change should be supported by including a copy of the relevant manufacturing authorisation or a valid GMP certificate issued within the last three years (as issued by the UK or a country included on the approved country for import list (currently EU/EEA Member States)); where relevant, reference to the EudraGMP database will suffice
    • Quality control site: change should be supported by including a copy of the relevant manufacturing authorisation or a valid GMP certificate (as issued by the UK or a country included on the approved country for batch testing list (currently EEA Member States, Australia, Canada, Israel, Japan, New Zealand, Switzerland, and the United States); see separate Guidance considering any specific exclusions; where relevant, reference to the EudraGMP database will suffice
  • Change of marketing authorisation holder (MAH) e.g., from a company outside the UK to one established in the UK: cannot be done as a variation
    • Requires submission of a change of ownership application
    • From January 1, 2021 the MAH will have 24 months to comply with rules on establishment in the UK
    • In the interim: the MHRA will require a contact in the UK; the MHRA will contact EU or EEA MAHs to ask for details of a UK contact
  • Change to the name/address of the MAH: can be submitted as a Type IA IN under change code A.1, provided that it is not a change to the legal entity
  • Change to the location of the Pharmacovigilance Systems Master File (PSMF) or the Qualified Person for Pharmacovigilance (QPPV): should be submitted under change code C.I.8.a (Type IA IN), provided the conditions and documentation requirements can be fully met
    • The QPPV for UK authorised products: must be authorised
    • The PSMF for UK authorised products: must be accessible electronically from the UK at the same site at which reports of suspected adverse reactions may be accessed
      • Further Guidance on the submission of pharmacovigilance system details will be published in due course
  • Implementation of the outcome of referrals and procedures concerning the Periodic Safety Update Report (PSUR) or post-authorisation safety studies (PASS):
    • Where the procedure has been finalised before January 1, 2021: The outcomes in relation to any required variations will be processed based on the decision already taken; depending on the nature of the required changes, the variations should be submitted under the relevant main change codes of C.I.3 or B.V.b (usually type IA); the actual submission category will depend on the specific nature of the required changes, taking into consideration if further assessment is required and its level
    • From January 1, 2021: The MHRA will be carrying out its own assessments; the outcomes of these assessments will be published together with advice on implementation
      • Where a variation is required it will usually be a Type IA
  • Submission of protocols and final study reports for post authorisation safety studies (PASS) (although not actually variations), whether or not carried out in relation to a condition of the MA or voluntarily: should be submitted to the MHRA within 12 months of the data collection; these will be processed according to the Type II variations procedure; they should be submitted under change code C.I.13
    • The submission should be accompanied by the appropriate fee, which is the same as that of a Type II or Type II complex variation
  • Submission of paediatric study reports for assessment: From January 1, 2021 holders of a UK marketing authorisation who sponsor a paediatric study (which involves the use in the paediatric population of a medicinal product to which that authorisation relates) must submit the results of this study to the MHRA within the period of six months from the end of the study
    • Where an initial appraisal indicates that an assessment is required: the MAH will be asked to submit the paediatric data as a Type II complex variation to MHRA under change code C.I.13
    • If the results of a paediatric study have been submitted for assessment to EMA or CMDh under Article 46 of Reg. 1901/2006/EC prior to January 1, 2021: The MHRA will request MAHs to submit a Type IB variation to update the product information (PI) if there are proposed changes to the PI that can be directly implemented to relevant UK products following the completion of the EU procedure

The guidance covers the following matters:

• Continued circulation of veterinary medicines placed on the market before January 1, 2021: Medicine lawfully placed on the UK or EU markets before January 1, 2021 can continue to be made available on these markets and to circulate between the two markets until it reaches the end user (Article 41 of the EU Withdrawal Agreement); this includes medicines moving from GB to NI, NI to EU, and GB to/from EU
  • “Placed on the market”: Available for sale or supply and there has been a written or verbal agreement (or offer of an agreement) to transfer ownership of the medicine to another legal entity; the placing of a manufacturing order is insufficient to qualify for continued circulation as the medicine must have been manufactured and Qualified Person (QP) certified and released
  • Medicines with an MA in the country of destination that meet these criteria, which include those already in the supply chain and stored by a wholesaler in the UK or EU (who has been sold or supplied the medicines): Can continue to move between the UK and EU markets without the need for repeating batch (QC) testing and QP certification/release to meet import or export requirements
• Medicines placed on the market by 11 p.m. on December 31, 2020: To qualify for continued circulation between the GB, NI, and EU markets, batches of medicines must be placed on the market which means (i) manufactured; (ii) certified and released by a QP; (iii) made available for sale or supply in the manufacturer’s stock management system
  • Additionally, before 11 p.m. on December 31, 2020: The medicine must have transferred ownership by sale or supply to another legal entity; or, an offer to either purchase or take ownership of the medicine must have been made to the manufacturer by another legal entity. Where there is an offer, the actual transfer of ownership may take place after 11 p.m. on December 31, 2020
    • This may include transfer of stock for sale or supply to different legal entities in the same company group
• Evidence for confirming that the veterinary medicine has been “placed on the market” before 11 p.m. on December 31, 2020 before selling or supplying a veterinary medicine from GB to NI or the EU: Evidence can include providing to the supply chain a written statement to confirm that ownership has transferred by sale or supply to another legal entity, or an offer to take ownership had been made, before 11 p.m. on December 31, 2020; wholesale dealers who hold stock, have (or have offered to) purchase or take ownership of veterinary medicines before 11 p.m. on December 31, 2020, may need to obtain evidence of this from the manufacturer; in some cases, the wholesale dealers’ own records may also be acceptable evidence
  • No need to provide evidence for products moving from the EU to GB: The Veterinary Medicines Directorate will continue recognise EU batch (QC) testing and QP certification/release until January 2023
• Product movement between the EU and NI, or from NI to GB: No import or export requirements
• Potential scenarios for the GB manufacturer: For all the scenarios below by 11 p.m. on December 31, 2020 a batch has been QP certified and released and is in the EU, GB or NI manufacturer’s warehouse
  • Scenarios where the medicine has not been placed on the market:
    • A batch is ‘on hold’ in the warehouse inventory system: The qualifying criteria have not been met because the medicine is not available for sale or supply in the stock management system; EU importation rules will apply for products moving from GB
    • A batch is marked as available for sale or supply in the warehouse system and no offer has been made by another legal entity to the manufacturer to take ownership of the medicine: The qualifying criteria have not been met because there is no offer of purchase or ownership transfer
  • Scenarios where the qualifying criteria have been met:
    • A batch is marked as available for sale or supply in the warehouse system, and the ownership of that medicine has been transferred to the affiliate in the EU, GB or NI which is a separate legal entity from the original owner; the medicine is still physically located in the EU, GB or NI manufactures’ warehouse: This medicine has been transferred to a different legal entity and qualifies for provisions under Article 41
    • A batch is marked as available for sale or supply in the warehouse system, and a separate legal entity to the manufacturer has offered to either purchase or take ownership of the medicine, and the sale or transfer of ownership is not complete: This medicine has an offer to purchase or take ownership and qualifies for provisions under Article 41
    • A batch is pre-allocated to supply the NI market; ownership of the medicine is transferred to a different legal entity in the EU: This medicine has been transferred to a different legal entity and qualifies for provisions under Article 41
    • A batch is marked as available for sale or supply in the warehouse system, and ownership of the medicine was transferred to a different legal entity before the end of the transition period then ownership is then transferred back to the manufacturer (this second transfer of ownership can take place at any time); the medicine remains in the same physical location throughout: This medicine had been transferred to a different legal entity and qualifies for provisions under Article 41
      • The medicines in the above scenarios can be supplied from January 1, 2021 without the need to meet EU importation rules for products moving from GB

The guidance covers the following matters:

• Renewals for Centrally Authorised Products (CAPS) converted from EU to UK Marketing Authorisations (MAs): Treated as if they were granted on the date the corresponding EU MA was granted; the renewal date will stay the same 
  • Your MAs will remain in force until a decision has been made on your renewal applications
• Renewals submitted for MAs granted through mutual recognition or decentralised procedures:
  • If you do not get a decision before January 1, 2021: You do not need to resubmit the renewal
  • If a final decision has been made on your renewal, but it has not been processed in the UK before January 1, 2021: The MHRA will implement the agreed outcome
  • Where a final decision has not been made: The MHRA will ensure that the renewal process is concluded and processed by the appropriate route
• Renewals for MAs submitted from January 1, 2021: Continue to submit your renewal applications nine months before they expire 
  • Requirements for renewal submissions: Remain the same for products authorised in the UK; should include the documents currently required in the EU as detailed in the following guidance: (i) CAP renewals and annual reassessments; (ii) Renewals for products authorised through MRP or DCP procedures
    • Reduced submission requirements: The MHRA will continue to accept the reduced submission requirements for renewals of MAs for products authorised under Article 10.1 as set out in the CMDh Best Practice Guide on processing renewals in the MRP/DCP
• Renewals for conditional MAs submitted from January 1, 2021: Continue to submit your renewal applications six months before they expire 
  • Great Britain MAs and converted EU MAs that were granted as conditional MAs: Submit the application to the MHRA
• Renewals for MAs granted via the Unfettered Access route:
  • Great Britain-only MA: Submit an application to renew the MA in line with the above guidance
  • MA remained in line with the EU or Northern Ireland MA: The MHRA will accept the same renewal application as submitted to the EU; a reduced fee will apply
• Changes to fees:
  • First renewal of a product containing a new active ingredient at the time of authorisation: £9,682
  • Related applications made at the same time as the first renewal: £747
• No fees:
  • Subsequent MA renewal applications
  • Renewing conditional MAs

The Guidance covers the following matters:

• Great Britain conditional Marketing Authorisations (MAs): From 1 January 2021, the MHRA will introduce a new Conditional Marketing Authorisation (CMA) scheme for new medicinal products in Great Britain; CMAs will be valid for one year and will be renewable annually
  • Eligibility criteria of the new scheme: the same as the EU scheme; intended for medicinal products that fulfil an unmet medical need
    • When is eligibility determined: at the time of the Marketing Authorisation Application (MAA) assessment
  • Actions for those submitting a conditional MAA:
    • MAA must contain: adequate evidence of safety and efficacy to enable the MHRA to conclude that the risk-benefit balance of the medicinal product is positive
    • Applicants should:
      • (i) state their justification for a CMA and clearly indicate what clinical studies are under way and when comprehensive clinical data will become available
        • The MHRA may grant a CMA where comprehensive clinical data is not yet complete but it is judged that such data will become available soon
      • (ii) submit their MAA dossier as for a full MA
  • Assessment of a conditional MAA dossier: The MHRA will determine whether to approve the application and grant a CMA or whether the risk-benefit ratio is negative and reject the application
    • The MHRA may take into account the designation of a product as being eligible for a CMA by the EMA or another jurisdiction; the final decision on eligibility for the Great Britain scheme rests with the MHRA
  • Northern Ireland MA applications for products falling within the mandatory scope of the Centrally Authorised Procedure: submit to the EMA
• Great Britain MAs under exceptional circumstances: The MHRA’s existing scheme will continue to be available for medicines where a comprehensive data package cannot be provided because (i) the condition to be treated is rare, or (ii) because collection of full information is not possible or is unethical
  • Eligibility criteria: The scheme has the same eligibility criteria as the EU; approvals will only be granted where there are exceptional circumstances and where the applicant can demonstrate that it is not possible to provide comprehensive data on the efficacy and safety under normal conditions of use
    • The MHRA may take into account the designation of a product as being eligible for an exceptional circumstances scheme by the EMA or another jurisdiction; the final decision on eligibility for the Great Britain scheme rests with the MHRA
  • Actions for those applying for UK MAs under exceptional circumstances:
    • Applicants are required to discuss their submissions with the MHRA before submitting their MAA
    • The MHRA is likely to impose specific obligations on the holder of an MA that is approved under exceptional circumstances; these will be communicated to the applicant during the review and will be aimed at the provision of information on the safe and effective use of the product
  • Applications for MAs under Exceptional Circumstances in Northern Ireland: submit to the EMA
• National scientific advice: The MHRA will continue to offer its national scientific advice service, available for developers of medicinal products, and can be requested at any stage of the product’s development, after 1 January 2021
  • Fees payable for scientific advice:
    • Exempt from the fee: Applications for scientific advice submitted by UK-based small and medium-sized enterprises (SMEs); applicants are required to submit evidence of their SME status together with the scientific advice form
    • No fee: requests for advice that is purely regulatory in nature

The guidance covers the following matters:

• Change to the trial sponsor/legal representative: This is a substantial amendment requiring submission to both the MHRA and the Research Ethics Committee (REC); the UK requires the sponsor or legal representative of a clinical trial to be in the UK or country on an approved-country list which would initially include EU/EEA countries
  • Where the sponsor is from the rest of the world and the legal representative is established in the UK and there are sites elsewhere in the EU/EEA: From January 1, 2021 the sponsor will need to assign an EU/EEA legal representative for these sites via a substantial amendment to the relevant EU/EEA competent authorities
  • No amendment will need to be submitted to the MHRA in the following circumstances:
    • Where the sponsor or legal representative for an ongoing trial is established in the EU/EEA
    • If the sponsor retains the UK legal representative for the UK study 
    • If a sponsor remains in the UK and a legal representative is added to cover EU/EEA sites
• To change (add/replace) any investigational medicinal product (IMP) manufacturing, certification or importation site relevant for supply of IMP to an ongoing UK trial: A substantial amendment will be required to be submitted to the MHRA
  • No amendment will need to be submitted to the MHRA if: The sponsor chooses to retain an existing IMP release site for the ongoing UK trial but includes an additional EU/EEA site for trials in the EU/EEA only
    • The IMP supply chain from a country on the approved country list, which would initially include EU/EEA countries, will allow direct supply to clinical investigator sites
  • Action to take from January 1, 2021:
    • If the holder is required to be included for importation to an ongoing trial: 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 one year of January 1, 2021
      • For up to one year after January 1, 2021 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
• Amendments to the Research Ethics Committee: The Health Research Authority (HRA) has produced guidance on when amendments are required to be submitted for REC review

The guidance covers the following matters:

• From January 1, 2021 the following legal obligations will apply to holders of UK marketing authorisations (MA) (including those that over the whole of the UK, or are specific to Northern Ireland or to Great Britain, including Great Britain MAs granted to allow unfettered access from Northern Ireland):
  • To operate a pharmacovigilance system for UK-authorised products
  • To have permanently and continually at its disposal an appropriately qualified person responsible for pharmacovigilance (QPPV) that resides and operates in the EU or the UK and is responsible for the establishment and maintenance of the pharmacovigilance system for UK-authorised products
    • QPPV is not in the UK: You must nominate a national contact person for pharmacovigilance who resides and operates in the UK and reports to the QPPV
      • This individual should have access to the reports of suspected adverse reactions
      • The individual should be able to facilitate responses to pharmacovigilance queries raised by the MHRA, including via inspections
    • Time period for appointing a national contact person for pharmacovigilance: 12 months from January 1, 2021
      • Once appointed: Notify their details to the MHRA via the MHRA Submissions Portal
  • To maintain and make available upon request a pharmacovigilance system master file (PSMF) that describes the pharmacovigilance system for UK-authorised products
    • Location and accessibility of PSMF:
      • MAs that cover the whole of the UK or are specific to Northern Ireland: At the site in the EU where the main pharmacovigilance activities are performed or at the site where the QPPV operates; the PSMF must be accessible electronically from the UK at the same site at which reports of suspected adverse reaction may be accessed
      • MAs that are specific to Great Britain: The PSMF must be accessible electronically at the same point in the UK from which the reports of suspected adverse reactions may be accessed
      • The PSMF needs to be permanently and immediately available for inspection at the stated location in the UK
    • PSMF format, content and representation of pharmacovigilance systems:
      • A single PSMF can be used for all UK-authorised products (assuming that the pharmacovigilance system applied to all products is the same)
      • The PSMF must describe the global pharmacovigilance system and reflect the global availability of safety information for UK-authorised products
      • There are different approaches to establishing a pharmacovigilance system, e.g., (i) MAHs can establish more than one pharmacovigilance system; (ii) a pharmacovigilance system can be shared by several MAHs
      • The PSMF should be an accurate representation of the pharmacovigilance system that has been established and you must make sure that every pharmacovigilance system covering UK-authorised products has been assigned a unique PSMF number by the MHRA
    • How to request a UK PSMF number: All PSMFs that cover UK-authorised products should be registered with the MHRA; you should request a unique UK PSMF number from the MHRA for each pharmacovigilance system that you are operating for UK-authorised products; where the pharmacovigilance system is shared by several MAHs, a single request for a UK PSMF number should be submitted to the MHRA
      • A UK PSMF number can be requested via the MHRA Submissions Portal from January 1, 2021
      • When to request the UK PSMF number? Not until you are either applying for a new UK MA, or notifying the MHRA of a change in the details of the QPPV for UK-authorised products from the QPPV details that were registered in the eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) on December 31, 2020
• Notification of QPPV and PSMF details to the MHRA by existing holders of UK MAs: Submit Type IAIN variations related to the SPS to the MHRA and these submissions should cover all UK product licences (PL) under a unique pharmacovigilance system
  • How to make your submission to update the summary of the applicant’s pharmacovigilance system (SPS)? Via the MHRA Submissions Portal as a Type IAIN – C.I.8 variation via the MHRA Submissions Portal; use Agency Activity Reference ID: G0098 – Variation Type IA – Establishing UK QPPV-PSMF and Subactivity Text: H002 – “Original Submission”
    • Submit your SPS updates as single changes
    • Submit in collections of no more than 25 PLs
    • Submit no more than two collections in a single package or within a single week without prior notification
  • Documentation you must supply:
    • proof that the applicant has at their disposal a qualified person responsible for pharmacovigilance and a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Part 11;
    • the country (which must be either the UK or a Member State) in which the appropriately qualified person resides and carries out their tasks;
    • contact details of the appropriately qualified person who resides and operates in the EU or the UK;
    • a reference to the location where the PSMF for the medicinal product can be accessed, which must be in the UK;
    • the UK PSMF number
      • Failure to supply all of the above may lead to the rejection of the submission
  • Submission time frames from January 1, 2021: Please refer to the Submission timeframe overview which has an overview of the timeframes for submitting SPS details to the MHRA
    • From January 1, 2021 you must notify the MHRA of the details in the SPS following any changes to the QPPV responsible for UK-authorised products from the baseline information held by the MHRA (i.e. the QPPV details that were registered in eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) at the end of December 13, 2020)
      • QPPV updates submitted prior to December 13, 2020: You should have received a successful acknowledgement message (coded as ‘01’) indicating that the information in the XEVPRM has been processed successfully
      • Changes to the QPPV submitted after December 13, 2020: Will not be included in the baseline dataset
      • The submission of SPS details for licences that were authorised via the EU centralised procedure should be handled differently to UK national licences
  • Guidance relating to UK national licences (including those authorised via mutual recognition or decentralised procedures): From January 1, 2021 if the identity, location and contact details of the QPPV responsible for UK-authorised products are identical to that of the EU/EEA QPPV immediately prior to 1 January 2021 (as entered in XEVMPD), no immediate action is required to notify the MHRA
    • Within two weeks of a change of identity, location or contact details of the QPPV responsible for UK-authorised products: Submit single change Type IAIN - C.I.8 variation; this should cover all UK PLs under a unique pharmacovigilance system (in collections of no more than 25 PLs)
    • If you anticipate no changes to the QPPV details from those entered in XEVMPD by June 30, 2022: Submit these details for the QPPV, together with the UK location that the PSMF can be accessed from and UK PSMF number as a single change Type IAIN – C.I.8 variation by this deadline
  • Licences authorised via the EU centralised procedure: All existing MAs authorised through the centrally authorised procedure will automatically be converted into UK MAs; these MAs will be issued with a UK MA number before the end of the transition period
    • Period to submit the baseline initiating sequence data and related information in eCTD format: One year, starting on January 1, 2021
    • Follow the following guidance at the point of submission of the baseline initiating eCTD sequence:
      • Identity, location or contact details of the QPPV responsible for UK-authorised products are different to that of the EU/EEA QPPV immediately prior to January 1, 2021 (as entered in XEVMPD): Simultaneously submit a Type IAIN – C.I.8 variation as a separate sequence in the same submission package; this variation will be processed once the baseline sequence is processed
      • Identity, location or contact details of the QPPV responsible for UK-authorised products are identical to that of the EU/EEA QPPV immediately prior to January 1, 2021 (as entered in XEVMPD): No immediate action is required to notify the MHRA; take the following actions following receipt of the baseline sequence approval letter from the MHRA:
        • Within two weeks of a change of identity, location or contact details of the QPPV responsible for UK-authorised products: Submit a single change Type IAIN – C.I.8 variation; this should cover all UK (ex-EU) PLs under a unique pharmacovigilance system (in collections of no more than 25 PLs)
        • If you anticipate no changes to the QPPV details from those entered on XEVMPD by June 30, 2022: The details of the QPPV and PSMF should be submitted by this deadline
• Guidance for applicants for UK MAs from January 1, 2021
• The material to accompany an application for a UK MA must include a summary of the applicant’s pharmacovigilance system which must include the following elements:
  • proof that the applicant has at their disposal an appropriately qualified person responsible for pharmacovigilance who resides and operates in the EU or the UK;
  • the country (which must be either the UK or a Member State) in which the appropriately qualified person resides and carries out his or her tasks;
  • the contact details of the appropriately qualified person;
  • a statement signed by the applicant which says that they have the necessary means to fulfil the tasks and responsibilities listed in Part 11;
  • a reference to the location where the pharmacovigilance system master file for the medicinal product can be accessed electronically, which must be in the UK;
  • the UK PSMF number
• MHRA Submissions Portal: Use Agency Activity Reference ID: G0001 – Initial Marketing Authorisation Application and Subactivity Text: H002 – “Original Submission”
  • Information on the QPPV and PSMF for UK-authorised products should be entered in section 2.4.4 of the electronic application form (eAF)
    • QPPV resides and operates in the UK: The checkbox entitled “The above-mentioned qualified person resides and operates in the EEA” can remain unchecked
    • The UK location where the PSMF can be accessed from does not need to be registered in the Article 57 database, therefore the associated checkbox can remain unchecked
• Notification of QPPV and PSMF details to XEVMPD:
  • Prior to January 1, 2021: Continue to submit QPPV and PSMF details for all UK-authorised products to XEVMPD, including any changes to these details
  • From January 1, 2021 for products in respect of Northern Ireland (UK-wide and Northern Ireland-only MAs: In addition to notifying the QPPV and PSMF details to the MHRA, you must also continue to submit this information to XEVMPD

The guidance covers the following matters:

• MHRA actions to facilitate the grandfathering process: Will assign a Great Britain Product Licence (PLGB) number to CAPs based on the existing practice for national licences
• Actions for marketing authorisation holders of a CAP:
  • Review list of currently authorised CAPs; advise the MHRA ASAP of any errors or omissions in that list
  • Advise the MHRA of any CAPs you do not want converted into Great Britain MAs; if you are planning to opt out of having a GB licence for a product, advise the MHRA of this ASAP, ideally as part of your full return, or, if not, via a separate communication to the MHRA
    • Marketing authorisation holders can opt out of the conversion process for all or some of their CAPs by notifying us in writing by January 21, 2020
      • After January 21, 2020, the product(s) will no longer be licensed in Great Britain and can no longer be placed on the market in Great Britain
  • Advise the MHRA of the Great Britain marketing status of each of the products
  • Advise the MHRA of any products/presentations that have been withdrawn or cancelled
  • Advise the MHRA of the MAH company number
  • If possible, provide the MHRA with a single point of contact for all your products; in the case of a company group, the MHRA needs a contact for each marketing authorisation holder affiliate within that group
  • Reply with the number of PLGB numbers you require, if you are intending to do a Change of Ownership (COA) when you submit your baseline submission
  • Inform the MHRA of which company number prefix to use; the MHRA will allocate the PL number(s) and send you an updated list to use when submitting the baseline submission
    • Advise by writing to the MHRA at capconversion@mhra.gov.uk
• Fees: There is no fee associated with the conversion from a CAP to a Great Britain MA; the annual periodic fee will be payable for converted CAPs from April 1, 2021
• Operation of the Sunset Clause for CAPs converted to UK MAs: The period of three years will be restarted from the date of conversion to a Great Britain MA

The new guidance covers the following matters:

• Medicines placed on the market in the European Union or United Kingdom before 11 p.m. on December 31, 2020:
  • Article 41 of the EU Withdrawal Agreement enables these batches to remain available for sale or supply between Great Britain, Northern Ireland, and the European Union after January 1, 2021, without additional regulatory checks if they meet the following requirements:
    • 1. Manufactured;
    • 2. Certified by a Qualified Person (QP);
    • 3. Made available for sale or supply in the manufacturer’s or wholesaler’s stock management system
  • Additionally, before 11 p.m. on December 31, 2020, one of the following requirements must be met:
    • The medicine must have transferred ownership by sale or supply to another legal entity
    • An offer to either purchase or take ownership of the medicine must have been made to the manufacturer or wholesaler by another legal entity (in this case the actual transfer of ownership may take place after 11 p.m. on December 31, 2020)
      • This may include transfer of stock for sale or supply to different legal entities in the same company group
  • A medicine already in the supply chain before 11 p.m. on December 31, 2020: Can continue to be sold under Article 41 without further regulatory checks
    • Such as one stored by a wholesaler in the United Kingdom or the European Union who has been sold or supplied the medicine (thus transferring ownership)
• Placing a manufacturing order for completion after 11 p.m. on December 31, 2020: Insufficient to qualify for continued circulation; the medicine must have been manufactured and QP certified
• Checks required prior to sale or supply to confirm medicines were placed on the market before 11 p.m. on December 31, 2020: Prior to agreeing to supply the products, the wholesale dealer or manufacturer in Great Britain will be responsible for confirming that the person to be supplied in Northern Ireland is authorised to receive the product; medicines placed on the market before 11 p.m. on December 31, 2020, may be supplied to a wholesaler or other authorised person in Northern Ireland; manufacturers are encouraged to ensure that the date of placing on the market is visible to the supply chain
  • Checks should be performed to confirm that a medicine has met the “placed on the market” criteria: Manufacturer or wholesaler in Great Britain may either:
    • Confirm that each batch of medicine has met all of the relevant criteria for being placed on market as listed above; or
    • Confirm that ownership of the medicine has transferred between two UK or EU legal entities before 11 p.m. on December 31, 2020; this alone would suffice, as a medicine cannot legally be sold or supplied unless all the steps above have been met
  • Examples of evidence to confirm that a batch has been placed on the market before 11 p.m. on December 31, 2020: A written statement from the manufacturer or a wholesaler who has sold or supplied the batch or a reference to company internal systems that shows batch certification (e.g., global enterprise resource planning system); other forms of evidence are acceptable 
• Case studies to help clarify when a medicine has been “placed on the market”:
  • Case Study 1:
    • Before the end of the transition period: Medicine has been QP certified and is in manufacturer’s or wholesaler’s warehouse; for stock management reasons, the batch is “on hold” in the warehouse inventory system
      • CONCLUSION: Not been placed on the market
        • Not available for sale or supply
        • If the batch were marked in the warehouse system as available to supply customers when orders are received, this would qualify for the purposes of provisions under Article 41, only once an agreement (or offer of such an agreement) to transfer ownership for sale or supply of the medicine from the manufacturer or wholesaler to another legal entity has taken place
  • Case Study 2:
    • Before the end of the transition period: Medicine has been QP certified and is physically located in manufacturer’s or wholesaler’s warehouse in an EU state; it is marked as available for sale or supply in the warehouse system; the ownership of that medicine then is transferred over to the UK affiliate, which is a separate legal entity from the original owner 
      • CONCLUSION: Placed on the market and would qualify for provisions under Article 41; it could be supplied to Northern Ireland after the end of the transition period
  • Case Study 3:
    • Before the end of the transition period: Medicine has been QP certified and is physically located in manufacturer’s or wholesaler’s warehouse in an EU state; it is marked as available for sale or supply in the warehouse system; a separate legal entity to the manufacturer or wholesaler offers to either purchase or take ownership of the medicine before 11 p.m. on December 31, 2020; the sale or transfer of ownership is not complete before 11 p.m. on December 31, 2020
      • CONCLUSION: Placed on the market and would qualify for provisions under Article 41; it could be supplied to Northern Ireland after the end of the transition period
  • Case Study 4:
    • Before the end of the transition period: Medicine has been QP certified and is physically located in manufacturer’s or wholesaler’s warehouse in an EU state; it is marked as available for sale or supply in the warehouse system; ownership of the medicine has not transferred to another legal entity before the end of the transition period; no offer has been made by another legal entity to the manufacturer or wholesaler to take ownership of the medicine before the end of the transition period
      • CONCLUSION: Not been placed on the market
        • Ownership has not transferred to another legal entity or an offer has not been made to the manufacturer or wholesaler by another legal entity
  • Case Study 5:
    • Before the end of the transition period: Medicine has been QP certified and is physically located in manufacturer or wholesaler’s warehouse in the United Kingdom; it is marked as available for sale or supply in the warehouse system; ownership of the medicine is transferred to a different legal entity, e.g., a company affiliate in the European Union; ownership is then transferred back to the wholesale or manufacturer (the second transfer of ownership could either take place before or after the end of the transition period)
      • CONCLUSION: Placed on the market and would qualify for provisions under Article 41; ownership has transferred to another legal entity before the end of the transition period, and it is available for sale or supply
  • Case Study 6:
    • Before the end of the transition period: Medicine has been QP certified and is physically located in manufacturer or wholesaler’s warehouse in the United Kingdom; ownership of the medicine is transferred to a different legal entity, e.g., a company affiliate in the European Union; the batch is pre-allocated to supply a specific market (e.g., Northern Ireland) 
      • CONCLUSION: Placed on the market and would qualify for provisions under Article 41; ownership has transferred to another legal entity, and it is available for sale or supply 

The guidance covers the following matters:

• Plant variety rights: After January 1, 2021 for new plant varieties you must apply separately in the UK and the EU
  • UK protection: Apply to the Animal and Plant Health Agency
  • EU protection: Apply to the Community Plant Variety Office
    • The EU will continue to recognise EU plant variety rights granted to all breeders before January 1, 2021
• Marketing plant reproductive material in the EU: The EU will not accept UK-certified plant reproductive material
• Fruit propagating material: The EU will not accept UK-certified material
• Seed potatoes: Cannot be exported from the UK to the EU
• Marketing EU plant reproductive material in the UK:
  • Normal international trading rules will be applied to the following:
    • seed, vegetable seed, and other propagating material
    • fruit propagating and planting material
    • ornamental species
    • forest reproductive material
• Marketing UK-certified plant reproductive material in the UK:
  • Comply with the current marketing regulations
  • Maintain identity, labelling, and control assurances
• Distinctiveness, uniformity, and stability (DUS) tests:
  • EU: Will not accept UK DUS tests
  • UK: Will continue to accept EU DUS reports if they are of comparable quality to UK DUS reports (subject to the below exception)
    • The UK will only accept DUS reports from the following approved UK science organisations for agricultural species currently tested by them: Agri-Food and Biosciences Institute; National Institute of Agricultural Botany; Science and Advice for Scottish Agriculture 
• Ornamental species: The EU does not grant equivalence to a third country; however, businesses can trade material freely, subject to plant health, labelling, and country of origin requirements
  • The variety must be on a supplier’s list and accepted in an EU member state

The guidance covers the following matters:

• Legislation: The EU Medical Device Regulation (MDR) and EU In Vitro Diagnostic Regulation (IVDR) will apply in Northern Ireland from May 26, 2021 and May 26, 2022, respectively
• Marking requirements:
  • CE marking required:
    • If you currently CE mark your device on the basis of self-certification: you will be able to continue to do so from January 1, 2021 for the purposes of the Northern Ireland market
  • UK Notified Body undertakes mandatory third-party conformity assessment: UKNI marking required in addition to the CE marking
    • To place a CE marking on your device for circulation in both Northern Ireland and the EU: You must use an EU-recognised Notified Body to undertake any mandatory third-party conformity assessment; the results of conformity assessments carried out by UK Notified Bodies will not be recognised within the EU
  • To place goods on the EU market: Manufacturers must use the CE marking on its own, without the UKNI marking; goods bearing the CE and UKNI marking will not be accepted on the EU market
• Registration requirements: After January 1, 2021, certain medical devices (including in vitro diagnostics (IVDs)) placed on the Northern Ireland market must be registered with the MHRA
  • Class I devices and general IVDs placed on the market by Northern Ireland manufacturers and Authorised Representatives: must be registered from January 1, 2021
  • Grace periods for registering other device classes:
    • Class IIIs and Class IIb implantables, and all active implantable medical devices and IVD List A products: must be registered from May 1, 2021
    • Other Class IIb and all Class IIa devices and IVD List B products and Self-Test IVDs: must be registered from September 1, 2021
• Great Britain-based manufacturers: need to appoint an EU or Northern Ireland-based Authorised Representative to place medical devices on the Northern Ireland market
  • Northern Ireland-based Authorised Representative appointed: The Authorised Representative will need to register all device classes with the MHRA
  • EU-based Authorised Representative appointed: The manufacturer will need to register all device classes other than Class I devices, custom-made devices, and general IVDs with the MHRA
    • It will be possible for a single entity to act as both an Authorised Representative based in Northern Ireland and a UK Responsible Person
• Manufacturers based in the EU or EEA, or a third country manufacturer that has an Authorised Representative based in the EU: You will need to appoint a UK Responsible Person in place from January 1, 2021
  • The UK Responsible Person will act as a regulatory point of contact within the UK from this point and comply with the registration requirements when these begin to apply
• The requirement to appoint a UK Responsible Person will not apply where:
  • you are a manufacturer based in Great Britain;
  • you are a manufacturer based in Northern Ireland;
  • your Authorised Representative is based in Northern Ireland; or
  • you only intend to place a Class I medical device, custom-made medical device, or general IVD on the Northern Ireland market, which has been registered with an EU Competent Authority
• Importer requirements: Where the Northern Ireland importer is not the Northern Ireland-based Authorised Representative or the UK Responsible Person, the importer will be required to inform the relevant Northern Ireland-based Authorised Representative or UK Responsible Person of their intention to import a device
  • In such cases, the Northern Ireland-based Authorised Representative or UK Responsible Person will be required to provide the MHRA with a list of device importers
• Unfettered access provisions: The UK Government will guarantee unfettered access for Northern Ireland’s businesses to the rest of the UK internal market from January 1, 2021
  • Northern Ireland business will be able to continue to place CE- and CE UKNI-marked devices on the Great Britain market after June 30, 2023
  • If you are Northern Ireland-based manufacturer and have already registered your device with the MHRA for the purposes of Northern Ireland, it can then be placed on the Great Britain market and will not need to undergo any further registration in Great Britain
• Post-market surveillance and vigilance: The MHRA will continue to be the Competent Authority for postmarket surveillance activity for devices placed on the Northern Ireland market
  • Incidents occurring in Northern Ireland will need to be reported to the MHRA

The guidance covers the following matters:

• Wholesaler licence: If you import medicine from a country in the European Economic Area (EEA) and then supply it to another country (including the UK), or if you import medicine from a non-EEA country and export it to a non-EEA country
  • Costs: How much you pay depends on the type of application, the number of sites, and your total turnover in licensed human medicines
  • Responsible person: If your company is based in Great Britain, you may need a Responsible Person for Import
• Manufacturer licence: If you import medicine from outside the EEA for use in the UK or to supply it to an EEA country
• Who is responsible for issuing wholesale and manufacturer licences? The MHRA aims to process all applications within 90 working days
• Controlled substance: The Home Office is responsible for imports of human medicine that contains a controlled substance
• Marketing authorisation (MA) licence: This is required before you can sell a human medicine; the process you need to follow depends on the type of MA licence you need
  • Qualified Person: Before a medicine can be released to the market, a Qualified Person (QP) named in the manufacturer/importer licence must certify that it has been manufactured and tested according to (i) the MA; and (ii) good manufacturing practice
  • Inspection: The MHRA will inspect the manufacturing site you use to produce or import the medicine when you are applying for an MA; there is a list of GMP-compliant manufacturers available on the EU’s EudraGMDP website
• You can import an unlicensed medicine if:
  • Introduced product: You import it from a non-EEA country to export it back to a country outside the EEA
    • An introduced medicinal product will not have an MA for the UK or a country on an approved country for import list
  • Special product is available if:
    • Licensed medicines do not work for the special clinical needs of a patient
    • There are no licensed medicines available for the clinical needs of a patient
• Import an introduced product: You must be a licensed wholesale dealer in the UK
  • You may only obtain an introduced medicine from a person authorised in the non-EEA country to supply medicinal products by wholesale distribution
  • You can only export an introduced product to a person authorised in the non-EEA country to receive medicinal products for wholesale distribution or supply to the public
• Import a “special product”: Apply for (i) a manufacturer “specials” licence if you are importing medicine from outside the EEA (and supply supporting documents); or (ii) a wholesaler licence if you’re importing a medicine from a country on an approved country for import list
• Make a notification of intent to import an unlicensed medicine 28 days before you import it:
  • Send a completed notification of intent form to the MHRA (imports@mhra.gov.uk)
  • Each entry must have the unique reference number you have given it, and each unlicensed human medicine must be given a product code
    • This should define:
      • Generic name (of drug substance(s))
      • Brand name, strength, pharmaceutical form, and pack size (for a single pack, as number of items in pack)
      • Manufacturer name and address
      • Exporting country
    • Code must be less than 16 characters in length (including spaces) and must contain only letters and numbers
• The MHRA may object to the import of an unlicensed medicine if:
  • There are concerns about the product’s safety or quality
  • There is an equivalent licensed product available that will meet the special clinical needs of the individual patient
  • There is not a special clinical need for a patient to have the product
    • You can import the product if the MHRA does not object within 28 days of their acknowledgement letter 
• Importers are responsible for ensuring that the products imported comply with the Transmissible Spongiform Encephalopathies (TSE) Regulations
• Urgent import notification: The MHRA may waive the need for the 28-day notice period in cases of a clinical emergency (usually for life-threatening illnesses or where imminent serious injury is likely); urgent import notifications are usually processed within one working day
  • Unacceptable reasons for urgency: Commercial or other non-clinical reasons
• Unlicensed medicines that the MHRA do not licence for import:
  • cisapride
  • melatonin
  • single component measles, mumps, and rubella vaccines
  • subcutaneous immunotherapy (allergy desensitising products)
  • sublingual immunotherapy (SLIT) products
  • supplements from the USA
  • talc preparations for pleurodesis
• Supply of unlicensed medicines between Northern Ireland and Great Britain after January 1, 2021: Once imported into the UK or manufactured in the UK, unlicensed medicines may be supplied between Northern Ireland and Great Britain without making additional notifications to the MHRA
  • The supplier in either territory may supply the unlicensed human medicine to a person authorised to receive a medicine (such as a doctor or a hospital), or to a wholesaler in the receiving territory
    • The supplier will need to confirm that there is a special clinical need for use of the medicine that is unlicensed in the receiving territory
• Fees for safety and quality vetting of unlicensed imported medicines: Charged annually using a banding system based on the number of notifications you submit (see the Guidance for detailed information as to fees)
  • Combination medicines and products, which have two different medicines within one pack, are considered a single notification
  • Separate packs of different products would require separate notifications
  • Customers are provided with an estimate early in the financial year, followed by an invoice once all the information for the year is available
  • A doctor may make the request to a licensed importer, or to a pharmacist who then places the order with the importer; doctors can make the order themselves if they hold their own wholesaler or specials licence

The new guidance covers the following matters:

• Qualified Person certified medicines from the European Economic Area (EEA): From January 1, 2021, these medicines will be accepted in Great Britain if certain checks (explained in guidance on Acting as a Responsible Person for Import) are made; these medicines will not require re-testing or re-certification by a UK Qualified Person if imported and checked by a wholesale dealer in Great Britain. If you hold a wholesale dealer’s licence, it will remain in force from January 1, 2021.
• Actions to take so your wholesaler’s licence can permit the importation of medicinal products from a country that is on an approved country for import list (initially, this will be countries in the EEA) if you undertook this activity before January 1, 2021:
  • Within six months from January 1, 2021: Notify MHRA in writing of your intention to continue to import medicinal products from a country on the list
  • Within two years from January 1, 2021: Nominate and have named on your wholesale dealer’s licence a Responsible Person (import) (RPi)
    • Exemption to the need for an RPi: If the medicine imported from the listed country is not licensed in the UK or the listed country and the medicinal product is either for use as a special medicinal product or is to be exported by the importer as an introduced medicine; in this case you must, within six months from January 1, 2021, notify MHRA in writing of your intention to only import medicinal products from the listed country to which this exemption applies
  • An EEA manufacturer or wholesaler may only supply a licensed medicine to a wholesaler in Great Britain; the sale and supply to an authorised person (hospital, doctor, or retailer) must be from a UK licensed wholesaler
• If you do not hold a wholesale dealer’s licence before January 1, 2021: In order to wholesale deal medicine, you will need to apply for a wholesale dealer’s licence
  • The requirement to name an RPi on the wholesale dealer’s licence will apply immediately to all new licence applications made from January 1, 2021 if you wish to import a licensed medicine from a listed country
• Importing UK or Great Britain authorised human medicines from a country on the list for use in Great Britain: You need a whole sale dealer’s licence that authorises import
  • The licence needs to cover the following activities of handling medicinal products: 1.1 With “an authorisation” (a UK or Great Britain Marketing Authorisation, certificate of registration, or traditional herbal registration)
  • The licence must authorise wholesale distribution operations, including: products imported from countries on a list; products certified under Article 51 of Directive 2001/83/EC
  • You will need an RPi
• Importing human medicines from a country on the list for use as a special medicinal product: You will need a wholesale dealer’s licence that authorises import 
  • Requirements for importing medicines licensed in a listed country: The licence needs to cover the following activities of handling medicinal products: 1.2 Without “an authorisation” (a UK or Great Britain Marketing Authorisation, certificate of registration, or traditional herbal registration) in Great Britain and intended for the Great Britain market
    • The licence must authorise wholesale distribution operations, including: products imported from countries on a list; products certified under Article 51 of Directive 2001/83/EC
    • You will need an RPi
    • The current notification of intent to import an unlicensed medicine remains the same
  • Requirements for importing medicines not licensed in the UK or a listed country:
    • The licence needs to cover the following activities of handling medicinal products: 1.2 Without “an authorisation” (a UK or Great Britain Marketing Authorisation, certificate of registration, or traditional herbal registration) in Great Britain and intended for the Great Britain market
    • The licence must authorise wholesale distribution operations, including: products imported from countries on a list; products not certified under Article 51 of Directive 2001/83/EC
    • You will need an ordinary Responsible Person (not an RPi)
    • The current notification of intent to import an unlicensed medicine remains the same
• Importing human medicines from a country on the list for export as an introduced medicine: You need a wholesale dealer’s licence that authorises import and export
  • Requirements for importing medicines licensed in a listed country as an introduced medicine:
    • The licence needs to cover the following activities of handling medicinal products: 1.1 With “an authorisation” (a UK or Great Britain Marketing Authorisation, certificate of registration, or traditional herbal registration)
    • The licence must authorise wholesale distribution operations, including: products imported from countries on a list; products certified under Article 51 of Directive 2001/83/EC
    • You will need an RPi
  • Requirements for importing medicines not licensed in the listed country or the UK for export as an introduced medicine:
    • The licence needs to cover the following activities of handling medicinal products: 1.3 Without “an authorisation” (a UK or Great Britain Marketing Authorisation, certificate of registration, or traditional herbal registration) in the UK and not intended for the UK market
    • The licence must authorise wholesale distribution operations, including: products imported from countries on a list; products not certified under Article 51 of Directive 2001/83/EC
    • You will need an ordinary Responsible Person (not an RPi)
• Importing medicines from a country on the list for supply to the Great Britain Parallel Import market: You will need a wholesale dealer’s licence that authorises import
  • The imported medicine must have the appropriate marketing authorisation in a country on the list for the designed Great Britain Product Licence Parallel Import (PLPI)
  • The licence needs to cover the following activities of handling medicinal products: 1.4 With a Marketing Authorisation in EEA member state(s) and intended for the GB parallel import market
  • The licence must authorise wholesale distribution operations, including: products imported from countries on a list; products certified under Article 51 of Directive 2001/83/EC
  • You will need an RPi if located in Great Britain
• Sourcing a medicine from Northern Ireland to Great Britain: Rules for importing medicines to Northern Ireland are different because of the Northern Ireland Protocol
  • Sourcing medicinal products from Northern Ireland for wholesale purposes: Permitted under the supervision of an ordinary Responsible Person (not an RPi); an RPi will be required for activities conducted in Great Britain if you hold a WDA with sites in Northern Ireland and Great Britain
  • Products granted an authorisation under the Unfettered Access scheme: Medicines authorised within Northern Ireland will be granted an authorisation in Great Britain; the product licence numbers will be marked with a “(UA)” suffix on the packaging and summary of product characteristics
    • If you source a medicine with a “(UA)” suffix, it may only be purchased from: a Northern Ireland manufacturer or wholesaler (qualifying business); a wholesale dealer in Great Britain
  • Sourcing a medicine with a marketing authorisation from Northern Ireland for supply to the Great Britain Parallel Import market or for export to a third country: You will need a wholesale dealer’s licence; you will also need an ordinary Responsible Person (not an RPi)
  • Sourcing biological medicines: A Northern Ireland manufacturer or wholesaler who supplies biological medicines to Great Britain will need to confirm that a national batch release certificate has been issued by NIBSC for each batch

The new guidance covers the following matters:

• Products that do not require RPi oversight:
  • Products sourced from Northern Ireland for wholesale purposes; permitted under the supervision of a Responsible Person (RP)
  • Products with a UK or Great Britain marketing authorisation that are imported into Great Britain from outside the UK without QP certification from a country on the list will require QP certification under a UK manufacturing and import authorisation before being placed on the market
  • Products without a marketing authorisation in the UK, Northern Ireland, Great Britain, or a listed country; import of such products is permitted under the supervision of a Responsible Person (RP), with notification to the MHRA of each importation that is for supply to the Great Britain market
• Responsibilities of the RPi:
  • To implement a system to confirm for products that have been imported into Great Britain from countries on an approved country for import list (initially, this will be countries in the EEA) (i) that the required QP certification has taken place; and (ii) that the required independent batch release certificate is available for biological products (described on a wholesale dealer’s licence as “immunologicals and blood products”)
    • The RPi may delegate this responsibility but remains responsible for ensuring the effectiveness of these checks
  • To implement a system for confirming QP certification and independent batch release certification (for biological products) has taken place when importing into Great Britain the following products from a listed country:
    • A UK or Great Britain licensed medicine for use in Great Britain
    • A UK or Great Britain licensed medicine for supply to another third country
    • A Northern Ireland or approved country licensed medicine for supply to fulfil special clinical needs
    • A Northern Ireland or approved country licensed medicine imported as an introduced medicine for supply to another third country
    • A Northern Ireland or approved country licensed medicine for use as a parallel import
• What evidence can be used for QP certification? The RPi should ensure that written evidence is available to demonstrate that each batch of product has been QP certified as required in Article 51 of Directive 2001/83/EC
  • Evidence for Great Britain Wholesale Dealer’s Licence (WDA(H)) holders importing a UK, Northern Ireland, Great Britain, or EEA licensed medicine from a listed country to confirm batch certification by a QP:
    • Batch certificate confirming QP certification in accordance with Article 51 of Directive 2001/83/EC
    • A copy of the “control report” (Appendix II to EU Good Manufacturing Practice Annex 16)
    • Statement of certification (ad-hoc, confirming certification in accordance with Article 51 of Directive 2001/83/EC)
    • Reference to company internal systems (e.g., global enterprise resource planning system) that shows batch certification
    • Confirmation that the final manufacturing step (other than batch certification) of an authorised medicine has been performed by a Manufacturing and Import Authorisation holder in a listed country; a copy of the Marketing Authorisation and technical agreement with the manufacturer should be available to place reliance on this supply chain control
    • For medicines authorised in a listed country, batch certification may be verified by confirming that the medicine has been purchased from an authorised wholesaler after it has been “placed on the market” in the listed country
      • Not all of the above options may be suitable for different supply chain relationships
      • Just one of the above pieces of evidence is sufficient to satisfy the requirements of regulation 45AA of the Human Medicines Regulations 2012
    • Other evidence may be acceptable if it confirms that QP certification has taken place for the batch in question
• What evidence can be used for independent batch release certification?
  • A statement from the marketing authorisation holder confirming that a batch certificate has been issued by NIBSC or a Mutual Recognition Agreement partner
  • A copy of the batch certificate issued by NIBSC or a Mutual Recognition Agreement partner
  • Confirmation from NIBSC that a batch certificate has been issued; enquiries should be sent to CPB@nibsc.org
    • Biological products requiring independent batch release certification are listed on the European Directorate for the Quality of Medicines website
• Supply chain security:
  • Checks on products imported from a listed country should also ensure that the product is not the subject of a recall or reported as stolen and is available on the market within the listed country’s licensed supply chain; Good Distribution Practice (GDP) requirements for supplier qualification set out in GDP 5.2 must be maintained
  • Products that have been certified by a QP but have been diverted to countries not within a listed country or Northern Ireland must be imported by the holder of an MIA and recertified by a QP
• Products imported for parallel import or special need: The RPi should implement a process to confirm the status of the unique identifier for prescription-only medicines, if wholesale dealers are importing products (i) for parallel import or (ii) for use for special clinical need or introduction
  • Confirmation of decommissioning may be provided by using evidence such as National Medicines Verification System records from the supplier
  • Products that are supplied as decommissioned must be decommissioned by the final EEA supplier and not at any other point in the supply chain
• Great Britain WDA(H) holders acting as or on behalf of the UK or Great Britain MAH: The expectation is that products have been certified prior to importation; shipment to Great Britain under pre-certification quarantine is not acceptable for the WDA(H) importation model
  • If supply chains require shipment under quarantine prior to QP certification for technical reasons (e.g., products with very short shelf life), the MAH should seek further advice from MHRA by email to GDP.Inspectorate@mhra.gov.uk
• Working as an RPi:
  • Ensure you have training and an understanding of the industry where you have the legal responsibility to ensure that batches of authorised medicines imported from countries on a list have been appropriately certified prior to being placed on the Great Britain market
  • You take responsibility for implementing a system for the WDA(H) as a whole
  • You do not have to be an employee of the licence holder; where you are not an employee, there should be a written contract between the licence holder and the RPi specifying responsibilities, duties, authority, and time on site; if you are a contract RPi, then you are expected to ensure you do not over-extend yourself and apply to act as RPi for too many companies
  • You must be continuously contactable
• Stages to becoming named as an RPi:
  • Stage 1: Eligibility
    • Qualifications: Diploma, certificate, or other evidence of formal qualifications awarded on completion of a university or other higher education course of study in pharmacy, chemistry, medicine, biology, or a related life science; equivalent qualifications for RPi candidates include level 5 qualifications from the Chartered Institute of Logistics and Transport, or a Quality Management System Lead Auditor or Pharmaceutical GMP Lead Auditor qualification awarded by the Chartered Quality Institute; other qualifications may be acceptable
    • Experience: Two years’ experience in performing the functions of a responsible person on a WDA(H); evidence of performing other functions, e.g., a quality assurance role for a pharmaceutical manufacturer, may also be considered equivalent
    • It is expected that you will be a member of a professional body with a published code of conduct
      • Acceptable professional body memberships: The Royal Society of Biology, the Royal Pharmaceutical Society, the Pharmaceutical Society of Northern Ireland, and the Royal Society of Chemistry
      • Additional bodies considered to be equivalent: The Chartered Institute of Logistics and Transport and the Chartered Quality Institute; other professional associations may be acceptable
    • Persons named on the Qualified Persons register will also be eligible to act as an RPi: You must still apply to be named on the RPi register; as an alternative to providing evidence of your qualifications and membership of a professional body, you may provide evidence of your QP registration
  • Once eligibility has been assessed and accepted by MHRA, you can be named on a register; the register will be maintained by MHRA and will include all persons eligible to be named as an RPi
  • Stage 2: Suitability to be named on a specific WDA(H) licence
    • At the time of application, MHRA will confirm whether you are named on the register, and check whether your experience is suitable for the proposed licence activity
      • E.g., an eligible RPi without prior experience in parallel importation might not be considered suitable to be named on WDA(H) where the company are importing licensed products for parallel trade
• Applying to be named as an RPi: RPi applications may be submitted through the MHRA Portal from January 1, 2021
  • The RPi should be a UK resident; provide proof of address and identity when you apply

The guidance covers the following matters:

• Introduction: Requirements for the supply of investigational medicinal products (IMPs) are set out in the Medicines for Human Use (Clinical Trials) Regulations 2004. Detailed guidance on the manufacture and import of IMPs are described in EudraLex Volume 4 and EudraLex Volume 10, including guidance for the issuance of the Qualified Person Declaration for the importation of IMPs manufactured in third countries outside the EEA.
  • These requirements will remain in effect following January 1, 2021
  • There are no changes planned regarding import of IMPs to Great Britain from countries outside the EEA 
• Import of IMPs for use in a clinical trial from countries on an “approved country for import” list (initially, all EU and EEA countries): The Sponsor of a UK clinical trial will require a UK Manufacturing and Import Authorisation (MIA(IMP)) holder to put in place an assurance system to check that these IMPs have been certified by a Qualified Person (QP) in a listed country, before release to the trial
  • The assurance system must be overseen by a QP; however, the IMPs would not require recertification
  • The routine tasks relating to verification of QP certification in a listed country may be delegated by the QP named on the UK MIA(IMP) to appropriate personnel operating within their MIA(IMP) quality system
    • Sponsors may perform verification of QP certification in a listed country themselves if they are the holders of a UK MIA(IMP); alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP)
• Oversight process: There are two routes for IMPs to be received into Great Britain from a listed country for use in UK clinical trials following QP certification by the listed country MIA(IMP) holder: (i) direct to the Great Britain clinical trial site; or (ii) via a Great Britain storage and distribution “hub”
  • Both require the oversight of a UK MIA(IMP) holder and QP, with systems in place to ensure that:
    • IMPs are not made available for use in Great Britain clinical trial sites until appropriate QP certification in a listed country has been verified by the QP named on the UK MIA(IMP)
    • IMPs are only shipped to appropriate Great Britain trial sites detailed within the UK trial application
    • Up-to-date information and documentation relating to the clinical trial and associated Product Specification File are made available by the Sponsor to the QP named on the UK MIA(IMP)
    • The clinical trial is authorised by the MHRA before the IMP is made available to the Investigator
  • There should be written agreements that describe the assigned responsibilities and provision of relevant information between the organisations: These include agreements between:
    • The Sponsor and the UK MIA(IMP) holder responsible for the oversight of import from the listed country
    • The Sponsor and the listed country MIA(IMP) holder
    • The UK MIA(IMP) holder and the Great Britain storage and distribution hub (if applicable)
    • The Sponsor and the Great Britain storage and distribution hub (if applicable)
  • Documentation available to the QP named on the UK MIA(IMP) as part of the oversight process:
    • Details of the manufacturing and distribution supply chain
    • The UK Clinical Trial Application form, plus amendments; this should be used to confirm the site responsible for final certification of the finished IMP
    • The UK Clinical Trial Application and any amendment approval records (including any post-approval commitment requirements)
    • Evidence that the certifying site in the listed country is appropriately licensed and holds a current GMP certificate for the IMP dosage form(s) and associated activities (e.g., manufacture, packaging, testing and/or import from a third country)
    • Details of the approved Great Britain trial sites from the ethics application, plus any updates or amendments
    • Details of each shipment of IMPs to Great Britain, including the addressees’ information; this should be verified against the ethics approvals
    • Details of any excursions from the stated storage conditions during shipment, along with any decisions taken by the Sponsor and certifying QP, and the rationale for those decisions
    • Details of the responsibilities described in the written agreement between the Sponsor and the listed country MIA(IMP) holder
      • The above list is not exclusive or exhaustive; information requirements may vary depending on the responsibilities of each organisation in the supply chain
  • Written evidence should be available to demonstrate that each batch of IMP imported from a listed country has been QP certified for use in the specified UK trial: This should be verified prior to the first shipment of IMP from each batch to the Great Britain trial site(s); batch certification by a QP may be confirmed using evidence such as:
    • Batch certificate confirming QP certification in accordance with Article 13.3 of Directive 2001/20/EC
    • Statement of certification (ad-hoc, confirming certification in accordance with Article 13.3 of Directive 2001/20/EC)
    • Access to the certifying MIA(IMP) holder’s internal systems (e.g., global Enterprise Resource Planning system) that confirms batch certification
      • Not all of the above options may be suitable for different supply chain relationships
      • Just one of the above pieces of evidence is sufficient to satisfy the requirements of the Regulations
      • Other evidence may be acceptable, provided it confirms that QP certification has taken place for the batch in question
• Supply of IMP to a Great Britain clinical trial site: The IMP should not be made available for use by the Great Britain clinical trial sites until the QP named on the UK MIA(IMP) confirms that the batch of IMP has been appropriately certified by the listed country QP
  • This is in addition to the two-step release procedure described in EU GMP Annex 13
  • The Sponsor should ensure that the regulatory release is in place for the UK prior to IMP being made available for use in the trial
• Using a Great Britain storage and distribution “hub”: You may use a distribution facility to store IMPs imported from a listed country before supplying to Great Britain clinical trial sites
  • If IMPs are segregated electronically or physically until certification has been confirmed by the QP named on the UK MIA(IMP), IMPs may be imported to the distribution hub from a listed country before confirming that QP certification has taken place in the listed country
  • Great Britain storage and distribution facilities should be named on the UK MIA(IMP) of the company responsible for oversight of the import
• Reference and retention samples: Additional reference and retention samples are not specifically required to be stored within Great Britain
  • The storage location should be visible to the QP named on the UK MIA(IMP) and defined in the written agreement with the Sponsor
  • The relevant written agreements should include provision for timely access to the samples by the competent UK authority
• IMPs coming to Great Britain from Northern Ireland: Do not require this additional oversight
• IMPs coming directly to Great Britain from third countries that are not on the approved country for import list: Continue to require import and QP certification in the UK by the MIA(IMP) holder per the existing requirements
• Importing non-investigational medicinal products for use in a clinical trial:
  • Importing from a listed country authorised or unauthorised products for use in a UK clinical trial in Great Britain that are (i) non-investigational medicinal products or (ii) unmodified comparators to be labelled in Great Britain prior to QP certification and release to the clinical trial: Use a wholesale dealer’s licence
    • A Responsible Person (import) may be required
  • Importing from a country that is not a listed country: Requires a manufacturer’s licence
  • Importing from Northern Ireland: Will require a wholesale dealer’s licence, unless you are the Sponsor of the clinical trial 

From January 1, 2021, the rules will change as follows:

• British exporters of goods to the EU must complete full export declarations for those goods.  
• British importers of goods from the EU that are on the controlled goods list (available here) must make import declarations. Goods on the controlled list include excise goods, controlled drugs, and precursor chemicals.
• British importers of goods from the EU that are not on the controlled goods list that have a good compliance record may defer declarations for up to six months.
• British importers that choose not to defer their declarations, or are unable to do so, must start making full import declarations from January 1, 2021. The steps for making a full import declaration are available here.  
• From July 1, 2021, all traders will have to complete full export/import declarations.  
• The rules that will apply to Northern Ireland have not yet been decided.

October 16, 2020

From January 1, 2021, it will no longer necessary to submit an Intrastat declaration for goods exported from Great Britain to the EU. The relevant guidance is available here.

• Intrastat declarations are used in the intra-EU movement of goods in place of customs declarations. Subject to limited exceptions (see above), from January 1, 2021, business that import and export goods between the EU and Great Britain will be required to fill out full customs declarations for their goods, and will no longer be required to submit an Intrastat declaration.
• The rules that will apply to Northern Ireland have not yet been decided. 

October 8, 2020

The UK Government has published an updated GB-EU Border Operating Manual, which outlines for businesses and passengers how the British-EU border will operate after the end of the transition period. The UK Government news story is available here.

The UK Government has published a list of customs agents and fast parcel operators that can provide assistance to UK businesses that import and export goods between the EU and Great Britain.

September 10, 2020

The UK Government has published updated rules relating to the rules applicable to excise goods imported into Great Britain from the EU. For excise goods dispatched from an EU Member State from January 1, 2021, importers must complete a customs declaration and follow the relevant customs procedures at the point of entry of those goods into Great Britain.

• Importers of excise goods will not be able to use the Simplified Accompanying Administrative Document or the EU distance-selling arrangements to import excise goods into Great Britain from the EU. Importers must complete a customs declaration and follow the relevant customs procedures at the point of entry of the goods into Great Britain.
• Importers of the excise goods alcohol and tobacco may use the Customs Freight Simplified Procedures (CFSP); this removes the requirement to make a full customs declaration in advance of exportation. To use the CFSP, importers must:
  • Follow the simplified declaration procedure; and
  • Set up a duty deferment account.
• When moving goods suspended from excise duty from their point of entry into the United Kingdom to their final destination, businesses must use the Excise Movement and Control System to move excise duty suspended goods from the place they enter into Great Britain to their final destination.
  • To move excise suspended goods, a business must appoint a registered consignor to move the goods, or become a registered consignor.
• The rules that will apply to Northern Ireland have not yet been decided. 

CHANGES to trading arrangements for each category of drug precursor chemicals

Category 1 substances (the most sensitive substances, such as piperonal, chloroephedrine and ergometrine)

• You’ll need a domestic drug precursor chemical licence if you’re using drug precursors in the UK or trading with any other country.
• You’ll need to apply for an import or export licence.
• The Home Office will issue a PEN.

Category 2A substances (less sensitive substances and pre-precursors, such as acetic anhydride, piperidine, and phenylacetic acid)

• You’ll need to register with the Home Office for a licence if you want to trade with the EU.
• You’ll need to apply for an export licence. You will not need an import licence.
• The Home Office will issue a PEN.

Category 2B substances

• You’ll need to register with the Home Office for a licence if you want to trade with the EU.
• You’ll need to apply for an export licence. You will not need an import licence.
• The Home Office may issue a PEN depending on the requirements of the country you’re exporting to.

Category 3 substances (bulk chemicals that can have different uses, such as toluene, methyl ethyl ketone (MEK), and sulphuric acid)

• You’ll need to register with the Home Office for a licence if you export to the EU in quantities which exceed between 20kg and 100kg per year, depending on the chemical.
• You’ll need to apply for an export authorisation if you’re exporting above certain quantities. You will not need an import licence.
• The Home Office may issue a PEN depending on the requirements of the country you’re exporting to.

Category 4 substances (medicinal products containing ephedrine or pseudoephedrine)

• You’ll need to register with the Home Office for a licence if you want to export to the EU.
• You may need to apply for an export licence depending on the requirements of the country you’re exporting to. You will not need an import licence.
• The Home Office may issue a PEN depending on the requirements of the country you’re exporting to.

The two schemes aim to ensure that patient safety and scientific integrity are upheld to the highest possible standards, while removing red tape and working together to get medicines onto the market quicker:

• Project Orbis: This program reviews and approves promising cancer treatments. It is coordinated by the U.S. Food and Drug Administration, involving Canada, Australia, Switzerland, Singapore, and Brazil.
• Access consortium: This program helps secure improved patient access to high-quality, safe, and effective medicines. It involves Australia, Canada, Switzerland, and Singapore. Previously, the consortium has approved nine innovative prescription medicines (including five new cancer treatments).

The key benefits to sharing the evaluation of medicines across the group are:

• Reducing the duplication of effort, leading to more efficient and effective regulatory review
• Promoting distribution of work to facilitate regulatory decisions
• Joining efforts in learning from each other, adopting a flexible approach to application management, and using the best parts of each evaluation pathway
• Sharing the evaluation of new drug applications, which is cost-effective for the regulators
• Sharing knowledge and expertise, continually improving its regulatory practices, and sharing global regulatory intelligence
• Post-market activities that are helping to identify emerging safety concerns
• Greater access to additional regulatory experts, opportunities for technical discussions, and more informed decision-making
• Partner agencies gaining a greater understanding of areas where their regulatory frameworks diverge, which has increased the potential for better harmonization in the future
• Clear efficiencies in the development of best practice, the sharing of guidance and procedural documents, and international alignment

The MHRA will participate as an observer of both groups before the end of 2020 and will be a full participant from January 1, 2021 after the end of the transition period. The MHRA will have the authority make the final decision to authorize medicines onto the UK market and will have complete autonomy to streamline the approval processes even further if needed outside both schemes.

The new guidance covers the following matters:

• Right to work checks: Until June 30, 2021, employers will need to check a job applicant’s right to work in compliance with current requirements, and applicants can prove their right to work by using (i) their passport or national identity card (EU, EEA, or Swiss citizens); (ii) an immigration status document (non-EU, EEA, or Swiss citizen family members); or (iii) the government’s online right to work checking service (EU, EEA, and Swiss citizens and their family members). Employers have a duty not to discriminate against EU, EEA, or Swiss citizens, and cannot require them to reveal their status under the EU Settlement Scheme until after June 30, 2021. Note that Irish citizens will continue to prove their right to work in the United Kingdom as they do now, under the Common Travel Area.
• EU Settlement Scheme: EU, EEA, or Swiss citizens and their family members who are living in the United Kingdom before January 1, 2021 must apply to the EU Settlement Scheme to continue to live in the United Kingdom after June 30, 2021.
• New immigration system: From January 1, 2021, a new points-based immigration system will apply to people arriving in the United Kingdom. EU, EEA, or Swiss citizens moving to the United Kingdom will need a visa, and employers will require a sponsor license to recruit any worker from outside the United Kingdom. EU, EEA, or Swiss citizens applying for a skilled worker visa will have to show that they have a job offer from an approved employee sponsor.

The press release covers the following details:

• The four contracts with ferry operators will provide capacity equivalent to over 3,000 HGVs per week, mitigating the risk of disruption as the United Kingdom and European Union adjust to new border processes at the end of the transition period
• The contracts have been signed with: Brittany Ferries, DFDS, P&O, and Stena Line
• Collectively, the contracts are worth £77.6 million
• Contract length: Up to six months after the end of the transition period
• The contracts have been awarded through the government’s Freight Capacity Framework

The new guidance covers the following matters:

• Location of the Qualified Person for Pharmacovigilance (QPPV):
  • Centrally authorised Marketing Authorisations (MAs): The QPPV must be located in the EU for these products to be on the Northern Ireland (NI) market. From January 1, 2021, for existing centralised MAs, you will be offered a GB MA for these products.
  • GB MAs: The QPPV can be located anywhere.
  • MAs issued following Mutual Recognition/decentralised procedures: These will continue to be issued by the VMD in respect of NI. The QPPV can be located in the EU, NI, or GB, due to interpretation of the requirements of the Northern Ireland Protocol.
  • UK national MAs (existing) and NI MAs: The QPPV can be located in the EU, NI, or GB for authorisations issued by the UK in respect of NI due to interpretation of the requirements of the Northern Ireland Protocol. The QPPV for GB MAs can be located anywhere.
• Pharmacovigilance inspections: From the January 1, 2021, the VMD will carry out inspections of all Marketing Authorisation Holders (MAHs) for products authorised in the UK; this includes those MAHs located outside of the UK.
  • The VMD will use a risk-based approach to scheduling inspections; risk basis considerations will include last EU inspection date, previous inspection findings, and surveillance intelligence.
  • Inspections will be conducted remotely where possible.
• Detailed Description of Pharmacovigilance system: The UK requirement for the Detailed Description of Pharmacovigilance System is under review; the VMD will provide more information as it becomes available.

The updates to the guidance cover the following matters:

• UK businesses: UK businesses will continue to benefit from the opportunities and rights provided by the GPA, negotiated by the members of the World Trade Organisation (WTO), from 1 January 2021.
• Trade agreements from January 1, 2021: The UK is seeking to reproduce the effects of existing EU agreements (for when they no longer apply to the UK) to ensure continuity of trading arrangements for UK businesses; if the effects of an existing EU agreement are not reproduced, trade with other WTO members will take place on WTO terms when EU trade agreements cease to apply to the UK.
• Procurement opportunities under the GPA: The GPA opens up procurement markets among its parties; as a party to the GPA, UK businesses can bid for certain procurement opportunities in the other parties’ territories and businesses from those parties can bid for certain procurement opportunities in the UK.
• Markets covered by the GPA: The WTO website sets out which markets are covered by the GPA and what types of procurement opportunities are covered in each market; GPA parties use their own online platforms for publishing procurement opportunities; the WTO website provides party specific procurement-related information; the Health and Safety Executive (HSE) will continue to operate as the UK’s regulator.
• Procurement opportunities in addition to GPA coverage: Certain trade agreements between the UK and non-EU countries also include procurement provisions in addition to those covered by the GPA; the terms of these agreements may vary between countries.

A contact form can be used for questions about the GPA or what is covered in the procurement agreements

The new guidance is mainly based on the current CHMP (Committee for Medicinal Products for Human Use) guidelines. Some distinct key features are:

• UK reference products: The Reference Product (RP) should comply with Regulation 48 of the Human Medicines (Amendment, etc.) (EU Exit) Regulations 2019; the UK RP (or an RP representative of the UK product) must be used for the required comparability studies which could include an EU RP with evidence that the RP is licensed in the EU via the centralised procedure; in order to use a non-UK RP in clinical studies, evidence should be provided that the non-UK RP is representative of the UK RP; data and market exclusivity period entitlements for RPs approved before the date of EU exit will continue to apply in the UK. It is interesting to note that all non-UK RPs must be authorised in and sourced from a country with similar scientific and regulatory standards as the UK (examples would be EU/EEA countries, Switzerland, United States, Canada, Australia, and Japan).
  RPs include:
  • products that are, or have been, authorised for at least eight years in the UK (including those authorised by conversion from EU marketing authorisations);
  • products that had an EU marketing authorisation at the end of the transition period, but which did not convert into a UK product licence, as the marketing authorisation holder opted out of the process; and
  • products for which an EU marketing authorisation had ceased to be in force before the end of the transition period, for reasons not relating to quality, safety, or efficacy.

• Biosimilarity principles: A biosimilar should be highly similar to the RP in physicochemical properties, biological activity/potency, and clinical profiles; biosimilar development requires that the impurity profile and the nature of excipients of the biosimilar itself do not give rise to concerns; any observed differences must be duly justified with regard to their potential impact on safety and efficacy; the biosimilar must have the same molecular and biological structure and the same posology and route of administration.
  
  Importantly, there is no regulatory requirement to repeat the demonstration of biosimilarity against the RP (for example, in the context of a change in the manufacturing process) once a UK product licence for the biosimilar has been granted.

• No requirement for in vivo studies in animals: No in vivo studies in animals are requested to be submitted to the MHRA for consideration of a UK licence for a biosimilar product as these are not relevant for showing comparability between a biosimilar candidate and its RP; conduct of in vivo studies in animals does not contribute to resolving the possibility that a biosimilar candidate may not be highly similar to the RP and in vivo studies should not be done with this intent.
• Changes in the requirement for a comparative efficacy trial in most cases: A comparative efficacy trial is not considered necessary in most cases; a well-argued justification for the absence of an efficacy trial, supported by sufficient comparative analytical and functional data, should be included in the submitted application; there may still be cases requiring a comparative efficacy/safety trial, for example, where it is difficult to predict the impact of analytical differences which have not been resolved by adaptations to the manufacturing process; exceptionally, additional clinical safety data may be required where safety uncertainties cannot be resolved without patient exposure pre-licensing.
• No requirement for repeat demonstration of biosimilarity: There is no regulatory requirement to repeat the demonstration of biosimilarity against the RP once a UK product licence for the biosimilar has been granted (for example, in the context of a change in the manufacturing process).
• Relation to other guidelines: The MHRA offers some flexibility in relation to guidelines applicable in other jurisdictions in relation to in vivo studies: the content of Module 4 for the UK can be limited to those studies that are GLP compliant, requirements of other regulators notwithstanding; Module 4 in the UK may not be part of the CTD supporting the product in other regions and the MHRA will accept this deviation.
• Risk management plan (RMP): Where ongoing additional pharmacovigilance activities are required for the RP (for example, participation in ongoing disease registries), these should also apply to the biosimilar candidate, preferably through collaboration or participation in those studies or registries already in place for the RP to enable collection of real-world information to support signal detection of potential safety signals related to the RP and its biosimilars; any additional risk minimisation measures that continue to be required for the RP should also be implemented for the biosimilar candidate, for example educational materials for healthcare professionals and patients or patient alert cards.
• Interchangeability: Once a biosimilar is authorised, it is considered interchangeable with the RP, which means that a prescriber can choose the biosimilar over the RP (or vice versa) and expect to achieve the same therapeutic effect (however, like all biologicals, biosimilars must be prescribed by brand name); substitution at the pharmacy level without consulting the prescriber is not permitted for biological medicines, including biosimilars.
• Clarification about this guidance can be sought by sending an email to MHRA in the first instance: biosimilars@mhra.gov.uk or by seeking MHRA scientific advice.

Thee new guidance covers the following matters:

• The UK’s regulator: The Health and Safety Executive (HSE) will continue to operate as the UK’s regulator. 
• Producing or placing pesticides on the market: On January 1, 2021, Great Britain will establish independent pesticides regulatory rules. To produce or place pesticides on the market, you must be authorised under the new laws; for the time being the new laws will be similar to existing laws. 
• Producing or placing feed on the market: To produce or place food/feed on the market, you must comply with regulations for Maximum Residue Levels (MRLs). Currently, statutory MRLs are set on an EU-wide basis under EC Regulation 396/2005. Previous guidance explains that from January 1, 2021, the HSE will set MRLs based on its own assessments (as well as making its own decisions on active substance approvals and Plant Protection Product (PPP) approval). 
• Existing Plant Protection Product (PPP) authorisations and MRLs: These will continue be valid in Great Britain from January 1, 2021. Previous guidance explains that existing PPP authorisations will remain valid until their current expiry date and existing MRLs will remain valid until they are amended. Authorised PPPs can be placed on the market and used in the same way as before. 
• Northern Ireland: Under the terms of the Northern Ireland Protocol, the EU pesticides legislation will continue to apply after January 1, 2021.

Different steps in the infringements procedure: Article 258 of the Treaty on the Functioning of the European Union (TFEU) gives the Commission, acting as Guardian of the Treaties, the power to take legal action against a Member State that is not respecting its obligations under EU law. The infringement procedure begins with a request for information (a Letter of Formal Notice) to the Member State concerned, which must be answered within a specified period, usually two months. If the Commission is not satisfied with the information and concludes that the Member State in question is failing to fulfill its obligations under EU law, the Commission may then send a formal request to comply with EU law (a Reasoned Opinion), calling on the Member State to inform the Commission of the measures taken to comply within a specified period, usually two months. If a Member State fails to ensure compliance with EU law, the Commission may then decide to refer the Member State to the Court of Justice. However, in almost 95% of infringement cases, Member States comply with their obligations under EU law before they are referred to the Court. If the Court rules against a Member State, the Member State must then take the necessary measures to comply with the judgment. In the specific case of Member States that have failed to implement Directives within the deadline agreed by the EU's Council of Ministers and the European Parliament, the Commission may request the Court to impose a financial penalty on the Member State concerned the first time the Court rules on such a case. This possibility, introduced by the Lisbon Treaty, is laid down in Article 260 (3) of the TFEU.

The new guidance covers the following matters:

• Marketing authorisation application process for orphan designation: The MHRA will be responsible for reviewing applications for orphan designation at the time of a marketing authorisation application. The following conditions must be satisfied: 1. Intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating; 2. Prevalence of the condition in Great Britain (GB) must not be more than 5 in 10,000; and 3. No satisfactory method of diagnosis, prevention, or treatment of the condition concerned exists in GB; satisfactory methods may include authorised medicinal products, medical devices, or other methods of diagnosis, prevention, or treatment which are used in GB
• How to apply: Applicants must send an application form, with their marketing authorisation application, specifically indicating in the cover letter their intention to seek an orphan designation
• Decision on orphan status (as well as a decision of the marketing authorisation): Made by the MHRA’s advisory committee
• Appeal: The applicant has the opportunity to appeal the decision to the CHM before the marketing authorisation is granted; the applicant should inform the MHRA of the intention to appeal as soon as possible 
• Market exclusivity: Up to 10 years from the date of first approval of the product in GB or EU/EEA 
• Paediatric indications: 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 two years of market exclusivity
• Variation applications (section 4.1 of the Summary of Products Characteristics): The orphan criteria will be assessed in parallel to the approval of the new indication; a new period of market exclusivity is only given if the applied for therapeutic indication falls within a new orphan condition 
• Fees: No additional fees for orphan designation application
• SME status: Waiver from scientific advice fees will also be available for UK based SMEs; companies who have, or intend to seek, SME status should ensure that they have the relevant documentation in place if an SME fee refund is to be applied for
• Orphan register: All medicines that gain a GB orphan marketing authorisation will be listed on the GB Orphan Register (active and then withdrawn, suspended or expired)

The updates to the guidance cover the following matters:

• Regulatory Data Protection and Market Exclusivity Periods: Regulatory Data Protection and market exclusivity period entitlements for RMPs approved before January 1, 2021 will continue to apply in the UK

• Great Britain: Any applications of RMPs for new generic medicines or other abridged marketing authorisation submitted after January 1, 2021 will need to fall within the definition in regulation 48 of the Regulations; the Regulations, which will be updated to reflect the change of implementation dates following the transition period, will include: (i) products that are, or have been, authorised for at least eight years in the UK (including those authorised by conversion from EU marketing authorisations); and (ii) products that had an EU marketing authorisation on January 1, 2021 but which did not convert into Great Britain marketing authorisations as the holder opted out of that process

• Northern Ireland: As the EU medicines legislation will remain applicable in Northern Ireland, RMPs included in marketing authorisation applications submitted into Northern Ireland should comply with relevant EU legislation; for Northern Ireland, the definition of a RMP in regulation 48 of the Regulations includes UK-authorised products and products in relation to which: (i) there is an EU-marketing authorisation; or (ii) in relation to which a Competent Authority of an EEA State has granted a marketing authorisation; applicants seeking UK-wide marketing authorisations (Great Britain and Northern Ireland) will be required to comply with requirements applicable in Northern Ireland (namely EU law)

• Authorisation Validity Based on ‘European Reference Medicinal Product’: Authorisations based on a ‘European Reference Medicinal Product’, as described in Article 10.1 of Directive 2001/83 (as amended), that have been granted, and applications that have been submitted to MHRA prior to January 1, 2021, will continue to be valid; however, for applications submitted to MHRA from January 1, 2021, the RMP will need to fall within the definition in regulation 48 as mentioned above

• Non-Great Britain Comparator Products: Where a CP used in bioequivalence and therapeutic equivalence studies is not sourced from Great Britain, the applicant should provide evidence that it is representative of the RMP. The CP should be authorised in and sourced from a country with similar scientific and regulatory standards as the UK (such as the EU/EEA, Switzerland, USA, Canada, Australia, and Japan) and would normally be expected to be:

• part of the same global marketing authorisation (GMA) as the RMP; or
• marketed in the country of origin through a licensing arrangement with the innovator company or corporate entity that currently markets the medicine in Great Britain.

• Identical Applicability of the GMA Concept in Great Britain and the EU: The GMA contains the initial authorisation and all variations and extensions; it includes any additional strengths, pharmaceutical form, administration routes or presentations authorised through separate procedures and under a different name, granted to the Marketing Authorisation Holder (MAH) of the initial authorisation

• Identicality vs. Representativeness: The non-Great Britain CP used is required to be representative of the RMP, but it is not required to be identical to it. Certain minor differences between both products may be accepted, if justified and provided this is supported by bridging data, which could include but are not limited to:

• Colour of tablet coatings (assuming no difference in functionality of coat) or capsule shells;
• Scorelines, embossings, and imprintings on solid dosage forms;
• Flavours in liquid dosage forms; and
• Container closures.

• Demonstration of Identicality of the Non-Great Britain CP to the RMP: In cases where the applicant provides written confirmation from the MAH of the non-Great Britain CP that the CP is identical to the RMP, no further analytical data are required, and the use of this identical non-Great Britain CP is also acceptable for more complex formulations; for the drug substance and finished products specifications, non-significant differences in specifications may be acceptable if fully justified. The written confirmation should confirm the following are identical in both products:

• the route of synthesis of the drug substance(s);
• the drug substance specifications;
• the finished product quantitative composition;
• the manufacturing process including in-process controls;
• the finished product specifications; and
• the stability data.

• Demonstration of Representativeness of the Non-Great Britain CP to the UK RMP: If a CP authorised and sourced from outside Great Britain is used, the applicant should provide adequate data or information to scientifically justify the relevance of these comparative data and establish an acceptable bridge to the RMP. As a scientific matter, the type of bridging data needed should always include data from analytical studies that compare all three products between:

• the RMP and the non-Great Britain CP to establish suitability of the latter as CP in BE/TE studies;
• the proposed medicinal product and the RMP to demonstrate similarity to allow bridging of the RMP data; and
• the proposed medicinal product and the non-Great Britain CP to support the BE/TE studies.

Any observed differences in the data have to be duly justified with regard to their potential impact on safety and efficacy.

• Required Information for the RMP and Non-Great Britain CP: The required Information in Module 1.5.2 of the Common Technical Dossier structure for both the RMP and non-Great Britain CP includes:

• Name and address of the authorisation holder of the non-Great Britain CP used, the product name, the country of authorisation, country of origin, and authorisation number;
• Proof of purchase (batch number, date and place of purchase, and expiry date);
• Samples in their original container closure systems should be available upon request;
• Product information (summary of product caracteristics or equivalent);
• Certificates of analysis (tested according to the proposed specification for the proposed medicinal product);
• The excipients in the formulation of the RMP, when compared to the non-Great Britain CP, should be qualitatively the same. Any differences in excipients would need to be shown to have no effect on safety or efficacy; and
• If quantitative formulation information is available for these two products it should also show the non-Great Britain CP to be representative of the RMP.

The experimental comparison should include the physico-chemical properties and all critical product attributes of the medicinal product; these should include device attributes where appropriate. Where provided, dissolution data should cover the physiological pH range.

• Number of Batches to Be Tested: For the comparison between the RMP and the non-Great Britain CP, data on at least three batches of each product would usually be expected; in cases of products that exhibit a higher inherent batch-to-batch variability or that are complex, a larger number of batches might be required to establish representativeness

• Analytical Methods: The precision and accuracy of the analytical methods and the inter-batch variability are critical to deciding if the formulations of the RMP and non-Great Britain CP are representative of each other; the analytical methods and analytical method validation reports used to generate the physicochemical data should be provided to satisfy this requirement

• Acceptability of Approach: The overall acceptability of such an approach and the type of bridging data needed will be a case-by-case/product-type decision and is recommended to be discussed upfront with MHRA if one or more of the following applies to the product:

• does not exhibit immediate release of the drug substance;
• is not for oral administration;
• is made by complex methods of manufacture;
• exhibits a narrow therapeutic range or safety margin (for example, careful dosage titration or patient monitoring);
• has a steep dose-response relationship;
• a risk of serious undesired effects;
• complicated or variable pharmacokinetics (such as nonlinear pharmacokinetics, variable or incomplete absorption);
• an absorption window (i.e., site-specific absorption); or
• substantial (e.g., greater than 40%) first-pass metabolism.