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 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 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 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 

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 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 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.

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.