New regulatory landscape for biosimilars in the UK and EU post Brexit transition period

FOLLOWING THE UK’s departure from the EU on 31 January 2020 and the expiry of the transition period on 31 December 2020, the UK is now being treated as a ‘third country’ by the EU and new UK legislation has taken effect, crystallising the regulatory legal frameworks applicable to medicines. The recent conclusion of the Trade and Cooperation Agreement (TCA) has also lifted years of uncertainty regarding the future relationship between the UK and the EU. This is therefore a useful juncture for biopharma companies to take stock and assess the regulatory opportunities and challenges that lie ahead.

Background

In October 2019, the UK and the EU concluded the Withdrawal Agreement, which provided an agreed framework for the UK’s departure from the EU. The Withdrawal Agreement included the creation of a ‘transition period’ for the continued application of EU law in the UK while a trade deal was being negotiated. After months of negotiations, the UK and EU finally concluded a TCA, mere days before the expiry of the transition period, narrowly avoiding a ‘no-deal’ scenario under which the UK and EU would have to operate on World Trade Organization terms.

The TCA has limited the immediate disruption to the supply of medicines, particularly by enabling tariff and quota-free trade between the UK and the EU (provided the rules of origin requirements are met). However, while the TCA streamlines some issues – for example, by enabling mutual recognition of good manufacturing practice (GMP) inspections and certificates – it has not avoided the regulatory consequences of the UK becoming a ‘third country’, as described below.

The TCA did not secure agreement on other key issues identified by the industry, such as mutual recognition on batch testing and release. This will lead to duplicative regulatory procedures and costly and time-consuming bureaucracy (with some limited exceptions for countries that have historically been dependent on medicine supplies from Great Britain, namely Ireland, Northern Ireland, Cyprus and Malta provided by a European Commission Notice¹).

Consequences of the UK becoming a ‘third country’ for biopharma companies

At the heart of the regulatory changes for biopharma companies is the fact that the UK has become a ‘third country’ under EU law. This means that in order to commercialise medicinal products in the UK or the EU, companies must now comply with the applicable regulatory legal framework in each jurisdiction. This means that some regulatory activities, such as batch testing and qualified person certification conducted in Great Britain, will no longer be recognised in the EU.

Consequently, biopharma companies had to implement regulatory and, in some cases, structural changes in order to continue to market their products in the EU; for example:

• the transfer of centralised marketing authorisations (MAs) held by UK entities to entities located in the EU
• relocation of the qualified person responsible for pharmacovigilance (QPPV) and backup arrangements, from the UK to the EU, where necessary
• locating the Pharmacovigilance System Master File (PSMF) within the EU
• the requirement to submit reports into EudraVigilance in line with the reporting requirements for non-EU cases
• for EU biosimilar applications where the reference medicinal product (RP) has been authorised after the end of the transition period, the RP is required to be authorised in an EU Member State
• EU biosimilar applications should now refer to pivotal studies that have been conducted with a medicinal product sourced in the EU (although some exceptions for use of a non-EU authorised version of the reference medicinal product may be possible under EMA guidance)²
• medicines imported from Great Britain into the EU will be subject to batch testing and release. Additionally, biosimilars must obtain an Official Control Authority Batch Release (OCABR) Certificate tested by an Official Medicines Control Laboratory (OMCL) within the EU.

The new regulatory framework for biosimilars in the UK

To minimise disruption and prevent the creation of a legal void, the regulatory framework for biosimilars that existed before the end of the transition period has effectively been preserved in UK domestic legislation pursuant to the European Union (Withdrawal) Act 2018 (EUWA) as ‘retained EU law’. By retaining a snapshot of EU legislation at its core, the UK has prevented substantial divergence to the regulation of biosimilars and other medicines – at least for the time being.

However, some changes have been immediately necessary,^3,4 to enable the retained EU law to operate effectively. Among other things, these amendments enable the Medicines and Healthcare products Regulatory Agency (MHRA) to function as the UK’s standalone medicines regulator. Further amendments⁵ include the implementation of the Northern Ireland Protocol (NIP), pursuant to which the EU pharmaceutical acquis will continue to apply in Northern Ireland (subject to periodic consent of the Northern Ireland Legislative Assembly), adding an extra layer of regulatory complexity.

The UK Government has also signalled its intention to use the new Medicines and Medical Devices Bill to position the UK as a world-leader in innovation and life sciences, which could result in future regulatory divergence within the confines of existing international agreements and standards, as agreed in the TCA.

Where possible, the UK has taken a pragmatic approach to the post-transition regulation of medicines, to minimise disruption following its change in status to a ‘third country’ while taking advantage of the opportunity to improve existing regulatory pathways and create regulatory flexibilities; for example:

• existing centrally authorised MAs were automatically converted to Great Britain MAs on 1 January 2021 (unless MA holders opted out). Affected companies have a period of one year to submit their essential baseline data to the MHRA and must establish a legal presence in the UK by 1 January 2023. Centrally approved MAs in Northern Ireland remain unaffected in accordance with the EU pharmaceutical acquis.
• MHRA guidance confirms that it will accept batch testing conducted in the EEA for a period of two years until 1 January 2023, avoiding duplication of these tests in the UK
• the QPPV for UK MA holders may be located in the UK or the EU (although if the QPPV is not located in the UK, a ‘national contact person for pharmacovigilance’ located in the UK must be appointed by 1 January 2022)
• some greater flexibility has also been provided in relation to the location of the PSMF for MAs that cover the whole of the UK or Northern Ireland
• mirroring the position taken in the EU, from 1 January 2021, the RP for UK biosimilar applications may include: (i) products authorised in the UK for at least eight years, including products authorised in the UK by conversion from EU MAs; (ii) products that had an EU MA in force on 31 December 2020, but which did not convert to GB MAs; or (iii) products for which an EU MA had ceased to be in force before the end of the transition period, for reasons not relating to quality, safety or efficacy
• the list of possible RPs does not include medicines authorised in the EU after expiry of the transition period, although guidance relating to exceptions for use of a non-EU authorised version of the RP continues to apply
• biosimilars will require national certification by the UK’s stand-alone National Control Laboratory, the NISBC, before they can be placed onto the Great Britain market (with the exception of batches that have an EU OCABR certificate issued before 1 January 2021 and those batches manufactured and certified by a country with whom the UK has a mutual recognition agreement, namely Switzerland and Israel)
• the NISBC will, however, continue to accept EU OCABR certificates in Northern Ireland, with the exception of batches of vaccines and immunologicals whose OCABR certificate was issued in a different EEA State to that in which the batch was manufactured
• The NISBC will apply a risk-based approach to decide when to apply laboratory testing in addition to protocol review.

New opportunities for biosimilars in the UK

As part of its programme to make the UK a world leader in life sciences innovation while reducing the time to patient access for new medicines and technologies, the MHRA has introduced new MA procedures to prioritise access to new medicines and create new routes of evaluation for novel products and biotechnological products in the UK. This may enable expedited regulatory approvals for biosimilars in the UK under a new 150-day ‘accelerated assessment’ procedure or a new ‘rolling review route’ that involves a process of ongoing regulatory input and feedback designed to enable applicants to ‘get it right first time’. Rolling regulatory reviews have already performed an important role in enabling expedited access to COVID-19 vaccinations.

The MHRA has also consulted⁶ on further changes to its guidance that may streamline the licensing of biosimilars in the UK. Significantly, the consultation proposes that in most cases a comparative efficacy trial will not be considered necessary, provided that well-argued justification is provided, in contrast with the EMA’s approach. Additionally, no in vivo studies from animals are requested as the draft guidance states these are not relevant for showing comparability between a biosimilar candidate and its reference product. Furthermore, the MHRA has indicated that it may be willing to accept real-world evidence (RWE) in support of regulatory submissions.

Overall, companies now have greater certainty of the key regulatory foundations for biosimilars and a clearer view of the new normal for operating in the UK and the EU. However, the UK’s desire for nimble, forward-looking regulation may lead to greater divergence in the future. Equally, it remains unclear whether the UK would adopt any changes that follow from the EU’s new Pharmaceutical Strategy,⁷ which is considering targeted policies that support ‘greater biosimilar competition’ and clarification of the conduct of trials on patented products (the so-called ‘Bolar-type’ provision). No doubt, industry stakeholders will be desirous of regulatory alignment where possible and there is still hope that further mutual recognition agreements with the EU can be secured. Biopharma companies will need to continue to horizon-scan for new opportunities and challenges that will emerge from the evolving regulatory landscape.

References

1. [Internet]. Ec.europa.eu. 2021 [cited 21 January 2021]. Available from: https://ec.europa.eu/health/sites/health/files/human-use/docs/c_2020_9264_en.pdf
2. [Internet]. Ema.europa.eu. 2021 [cited 21 January 2021]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf
3. The Human Medicines (Amendment etc.) (EU Exit) Regulations 2019, SI 2019/775
4. The Human Medicines and Medical Devices (Amendment etc.) (EU Exit) Regulations 2019, SI 2019/1385
5. The Human Medicines (Amendment etc.) (EU Exit) Regulations 2020, SI 2020/1488
6. Consultation document: MHRA guidance on the licensing of biosimilar products [Internet]. GOV.UK. 2021 [cited 21 January 2021]. Available from: https://www.gov.uk/government/consultations/mhra-draft-guidance-on-the-licensing-of-biosimilar-products/consultation-document-mhra-guidance-on-the-licensing-of-biosimilar-products
7. [Internet]. Eur-lex.europa.eu. 2021 [cited 21 January 2021]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:52020DC0761&from=EN