Understanding New Pharmaceutical Regulation as We Countdown to Brexit
Remember Brexit? While the ongoing pandemic may have distracted focus away from Brexit, there are major regulatory impacts coming soon to which specific attention should be paid. As a refresher – you’ll recall the United Kingdom officially left the European Union on 31 January 2020, and the interim transition period ends on 31 December of this year. In this post, Vera Dinis, senior manager of regulatory affairs, and Leona C. Fitzgerald, senior director of regulatory affairs, explain the implications of that milestone on pharmaceutical regulation and steps you should be taking now to maintain clinical trial business continuity.
Please note: The information provided, while current as of this writing, is subject to change.
Brexit in brief as it relates to the pharma industry
Following a 2016 referendum, the U.K. (comprising England, Scotland, Wales and Northern Ireland) formally left the European Union (EU) at 11 p.m. GMT on 31 January 2020 becoming a “third country” in a process now known as “Brexit.” A transition period became effective immediately and runs to 31 December 2020, to allow both sides to prepare for the change and negotiate their future relationship.
During this transition period. the U.K. remains in the EU customs union and single market with all four freedoms (movement of goods, capital, people and services), and EU pharmaceutical law applies. Essentially, it is “business as usual.”
However, extensive and wide-ranging consequences are expected as of 1 January 2021 (“Day 1”). The future relationship remains unclear despite regular formal negotiations between the U.K. and EU. In summarizing the August 2020 round of negotiations1, the EU’s chief negotiator, Michel Barnier, warned it “seems unlikely” that agreement will now be reached. If no agreement is reached, the U.K. will exit the EU on World Trade Organization (WTO) terms, which we expect to predominantly have financial and logistical impact in terms of clinical trials.
How clinical trial business can be Brexit-ready
Irrespective of the outcome of the negotiations, EU rules governing clinical trials, in particular Directive 2001/20/EC, shall cease to apply to the U.K. (with some exceptions for Northern Ireland outlined below) from Day 1. Therefore, we recommend sponsors of clinical trials review operations to ensure they are Brexit-ready. A helpful tool is the Brexit preparedness checklist2, generated by the Irish Regulatory Authority (HPRA). In addition, various authorities have recently released or updated guidance. Some key regulatory considerations that may need prioritization now to support clinical trial regulatory compliance and continuity to patients involved in trials from Day 1, include:
Import / release of investigational medicinal product (IMP)
Per Article 13 of Directive 2001/20/EC, IMPs can be imported to EU/European Economic Area (EEA) member states (EU countries plus Norway, Iceland and Liechtenstein) only after their batch-release has been certified by a qualified person (QP) in the EU/EEA. Relocation of batch release sites/QPs from U.K. to EU/EEA may be necessary. Such change would impact the Investigational Medicinal Product Dossier (IMPD) and typically require agency submission/approval. Failure to assure this could, in the worst-case, result in discontinuation of trial treatment and thus jeopardize trial participants’ safety3. For U.K. trials, IMPs may be supplied directly from an EU/EEA Manufacturing Import Authorization (MIA) (IMP) holder to an ongoing Great Britain trial site for up to one year post 1 January 2021, but a substantial amendment should be submitted to the MHRA to include the details of a U.K. MIA(IMP) holder within one year of 1 January 20214.
For comparator IMPs authorized in a third country, while EU retesting is not necessary if already conducted in the third country, an EU/EEA-based QP must per Art. 13 of the Directive ensure, subject to exceptions, that each production batch has undergone relevant quality analyses, tests or checks5. The actions as outlined above also apply here.
Sponsor or EU legal representative
The sponsor or its EU legal representative must be established in the EU/EEA per Art. 19, Dir. 2001/20/EC. U.K.-based sponsors of an EU trial must appoint an EU legal representative before Day 1, and sponsors based in a third country utilizing a U.K.-based EU legal representative should relocate to an EU/EEA-based representative prior to Day 1. Failure to meet this requirement will be a breach of Directive 2001/20/EC and could trigger a request for corrective actions by member state authorities3. From Day 1 the sponsor or legal representative of a U.K. trial must be based in the U.K. or a country on an approved country list which shall initially include EU/EEA countries4. Typically, change of EU legal representative requires regulatory authority submission in EU countries. However, amendment submission in the U.K. is not required where the sponsor or legal representative for an ongoing trial is established in the EU/EEA. PPD can act as EU legal representative and support necessary amendment submissions. Please contact us by email if you need support in this regard.
Submission of clinical trial information
Certain trial information must be submitted to the EU clinical trials database, EudraCT, per EU law. However, changes are expected from Day 1, which sponsors should plan for, including potential standard operating procedures updates. For example, submission of U.K.-specific trial protocol-related information is no longer required, except when the trial is part of an agreed Paediatric Investigation Plan and the U.K. is the only country where the protocol has been submitted4.
For U.K. trials, submissions through the U.K. national submission portal is expected from Day 1 and sponsors should gain access to the portal prior to this date (click here to be directed to MHRA website).
Results of U.K. trials that end before 1 January 2021 must only be submitted if the reporting is due by then. Results of trials conducted only in the U.K. and results of multi-country trials where the U.K. was the only EU member state involved must be submitted to EudraCT, also after the end of the transition period, if this is required for non-EU studies (i.e., if the trial is part of an agreed Paediatric Investigation Plan or falls in the scope of Article 46 of Regulation (EC) No 1901/2006)4 .
The clinical trial summary report should not be submitted to the U.K. regulatory authority (MHRA), but a short confirmatory email with link to the register where results have been uploaded should be provided6.
Regardless of whether an agreement is reached during the political negotiations, new border and customs procedures shall apply from Day 1. In July, the U.K. government set out its Border Operating Model7 describing a three-stage implementation to help minimize potential border disruption, with full implementation by 1 July 2021.
In an August letter to medicines suppliers8, the U.K. Department of Health and Social Care described considerations to mitigate potential supply disruption including clinical trial supplies. In this context, we recommend sponsors consider taking mitigating actions for any product that may cross U.K. borders such as all IMPs including comparators, laboratory kits, devices and any ancillary supplies in addition to supply of samples to central labs.
Northern Ireland Exceptions
Article 185 of the Withdrawal Agreement9 makes certain provisions of EU law applicable to Northern Ireland (NI) after the transition period, in particular Art. 13 of Dir. 2001/20/EC. Please note that this is still being fine-tuned and can be subject to further changes. We would advise sponsors to take the following into account:
- NI QP will be made equivalent with U.K. QP, meaning product would need to be rereleased by EU QP before can be shipped into EU territory
- NI will be bound by the EU manufacturing “level playing field” regulations, meaning EU rules for good manufacturing practice of IMPs apply in NI
- IMP manufactured in NI and shipped to the EU might not be considered an imported IMP, however this might change as negotiations on border are not fully finalized yet
On 1 September, the MHRA advised that further guidance in this regard will be provided in due course4.
Additional impacts on clinical trials
In addition to the examples outlined here, Brexit is expected to have wide-ranging impacts on clinical trials. As such, we recommend sponsors conduct cross-functional assessment in the above areas and additional areas such as transfer of data to/from U.K., people (e.g., EU nationals based in the U.K. and vice versa), financial impact (e.g., currency and treasury), as well as make efforts to ensure suppliers are Brexit-ready.
At this moment, it is highly recommended that action is taken now to get ready for new rules that begin in January 2021. At PPD, we have a cross-functional, Brexit-readiness team working to embrace the change and ensure our clients, the clinical trials and marketing authorizations we manage are ready for Day 1. Our regulatory intelligence and Brexit operations teams will continue to monitor the landscape to support this transition. With our patients in mind, all steps will be taken to assure that Brexit implementation will have no impact on patient safety and access to medicines.