This article was first published on Lexis®PSL Life Sciences on 7 March 2019. Click for a free trial of Lexis®PSL.
The draft Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 2019 (draft 2019 Clinical Trials Regulations) will come into place if the UK exits the EU without a deal. The UK is currently scheduled to leave the EU on 29 March 2019 (exit day). Their purpose is to provide clarity, continuity and ensure safety in relation to clinical trials in the event that the UK leaves the EU without a deal in place.
Currently, the regime for clinical trials is harmonised across the EU by Directive 2001/20/EC. The UK has implemented this through the Medicines for Human Use (Clinical Trials) Regulations 2004, SI 2004/1031 meaning that the MHRA authorises all interventional clinical trials of medicines and that ethics approval needs to be sought. The draft 2019 Clinical Trials Regulations amend SI 2004/1031 to address the shortcomings as a result of the withdrawal of the UK from the EU in the event of no deal being in place.
Under SI 2004/1031, a sponsor or their legal representative must be established in the EU. The UK will be a third country following the UK’s exit from the EU without a deal and no longer part of the EEA.
The draft 2019 Clinical Trials Regulations allow a sponsor or legal representative to be established in the UK or in a country on an approved MHRA list (draft 2019 Clinical Trials Regulations, regs 5 and 26) taking into account the country’s ability to contact and liaise with the MHRA. On exit day this list will include all EEA states. As a result, many pharmaceutical companies will not be required to change their country of establishment, even if based in the EEA and not in the UK, as they will still be able to carry out a trial in the UK post-exit day.
Reporting suspected adverse reactions
Where clinical trials are being conducted at trial sites elsewhere in the EEA as well as in the UK, as the UK will no longer have access to the EMA reporting database, any suspected unexpected serious adverse reactions (SUSARs) relating to trials in a country other than the UK need to be reported to the MHRA (draft 2019 Clinical Trials Regulations, reg 15). If any SUSARs occur in such clinical trials taking place outside the UK, the sponsor must ensure that the MHRA is notified within seven days of becoming aware, if the SUSAR is fatal or life-threatening, or within 15 days in any other event (draft 2019 Clinical Trials Regulations, reg 15(2)(b)). Sponsors should also be aware that any SUSAR in an EU member state will also need to be notified to the EMA, resulting in the administrative burden of a double notification.
Otherwise, there are no further changes to the adverse event reporting regime so businesses should still submit annual safety reports to the MHRA.
Import of investigational medicinal products (IMPs)
Sponsors of trials taking place within the UK that import IMPs into the UK for such trials need to ensure that the correct licence and certification has been acquired. The Human Medicines (Amendment etc) (EU Exit) Regulations 2019 provide that, in the case of no deal, a marketing authorisation holder currently in the EEA should be established in the UK by 2020. The table below sets out the requirements for all IMPs being imported into the UK depending upon where the IMPs are being imported from:
|Manufacturing licence (MIA) required.
|Qualified person (QP) certification in the EEA state recognised in the UK.
|An approved country in list.
|Assurance system required to be put in place by MIAholder to check that the IMP has been QP certified in the EU/EEA state. This should be overseen by the QP.
|Another country (excluding EEA and approved country)
|As today, requires QP testing in the UK by the MIA holder.
Therefore, for IMPs coming from an EU/EEA member state, there is no need to QP-certify once the IMPs reach the UK, and a certification from an EU QP will continue to be sufficient initially, thus reducing the administrative burden on importers. Sponsors will have 12 months from exit day to comply with the above requirements so businesses should get processes in place to ensure all IMPs are correctly certified and that an MIA licence is in place within the time period of 12 months (draft 2019 Clinical Trials Regulations, reg 26, para 3 and 4).
The draft 2019 Clinical Trials Regulations, reg 19 inserts a new regulation 43A which sets out the MHRA requirement to publish a list of countries whose regulatory framework satisfies the UK’s in relation to the importing of IMPs (draft 2019 Clinical Trials Regulations, reg 26, para 4). The criteria for inclusion on this list include:
On the other hand, if the IMPs are being exported to the EU/EEA from the UK, then they need to be QP-certified in accordance with EU equivalent good manufacturing practice (see further: European Commission, Notice to Stakeholders - Withdrawal of the United Kingdom and EU Rules in the Field of Clinical Trials, para 1). Prior to exit day, the MHRA will publish further guidance on importing and exporting IMPs.
Transparency of clinical trials
Rather than submitting the information on UK-based clinical trials to the EU clinical trials register, the MHRA has the power under the draft 2019 Clinical Trials Regulations to publish trial information in line with the information currently recorded. This information includes:
Good clinical practice (GCP) guidance
Currently the EMA has the power to govern GCP. In light of the fact that the UK will no longer be able to participate in the EU regulatory framework, the draft 2019 Clinical Trials Regulations put in place new MHRA powers to issue guidance on applications to ethics committees and for requesting authorisation of clinical trials. The MHRA can also determine the content of the trial documents for UK clinical trials. Having the ability to amend conditions and principles of GCP means that standards can be updated and the MHRA can keep in line with the EU landscape.
The draft 2019 Clinical Trials Regulations do not adequately cover the issues in relation to the export of IMPs to the EU or importing from countries not on the approved country list. The MHRA has issued guidance stating that a QP for any IMPs manufactured in the UK or imported from a non-approved country must operate and reside in the UK. According to the European Commission, if a sponsor is running a trial in the EU, the IMPs must be QP-certified in the EU/EEA (see further: Notice to Stakeholders - Withdrawal of the United Kingdom and EU Rules in the Field of Clinical Trials). This poses a potential issue for sponsors who are based in the UK but undertaking pan-European trials.
There may be additional EU requirements following the withdrawal of the UK from the EU if a UK sponsor wishes to run multistate clinical trials in other EU member states. This is not covered by the proposed regulations since they apply to UK trials only. However, it is likely that a UK sponsor would need to have a legal representative established in the EU and sponsors may have to make additional clinical trial applications in the relevant EU member states resulting in increased costs. Also, they must ensure that the IMPs have been appropriately QP-certified and that all SUSARs are reported on the relevant portal. All of this means that conducting trials will be more cumbersome in the EU unless a bespoke agreement is reached to streamline the process. So, sponsors of clinical trials should keep informed of any Government guidance leading up to and post-exit day.
Also, regulation and implementation of clinical trials rests solely with the MHRA and so there are questions over its capacity to execute its new powers to ensure that the transition runs smoothly.
It is expected that the EU will be implementing Regulation (EU) 536/2014, the Clinical Trials Regulation (CTR) in 2020. If the withdrawal agreement, which includes the provision of a transition period ending on 31 December 2020, is approved and ratified, the new CTR is likely to be implemented into UK domestic legislation, ensuring that clinical trial legislation remains harmonised with the EU. The Government has committed to aligning with the CTR even if it comes into application after the transitional period, and even in the event of a ‘no deal’, however, we will not have the right to gain access to the shared central IT portal. The explanatory memorandum to the draft 2019 Clinical Trials Regulation confirms that the Government commitment is not addressed in these Regulations which are limited to correcting deficiencies in retained EU law (ie SI 2004/1031) arising from the UK withdrawal from the EU. The commitment in relation to the CTR will be delivered through a separate legislative vehicle which will be brought forward when the application date of the CTR is known.
The purpose of the draft 2019 Clinical Trials Regulations is to ensure that there is as little impact on the UK regulatory framework as possible in the event that the UK leaves the EU without a deal. Its aim is to consolidate the powers in the MHRA to remove administrative burdens on sponsors of clinical trials taking place in the UK, whether they are based in the UK or an EU/EEA country. As a result, the impact for such sponsors will be minimal. Where the impact will be felt will be for UK sponsors of trials who wish to conduct trials in the EU, as the same type of measures are not currently contemplated for that scenario. For example, unless the position changes, as mentioned above, there will be an additional need to have IMPs QP-certified in the EU for EU-based trials.
The Government has provided an impact assessment alongside the draft 2019 Clinical Trials Regulations setting out the impacts to businesses in the life science sector but there is still uncertainty over how the UK will leave and what legislation and trade arrangements will be put in place, so businesses should not rely on such predictions and keep an eye on further developments and guidance.