In preparation to the Brexit due on 30 March 2019, the Directorate for Health and Food Safety of the European Commission released a Notice to stakeholders to provide guidance in the field of clinical trials as a consequence of UK leaving the European Union to become a third country.

The transformation of UK’s legal status may imply legal repercussions also on the field of how clinical trials are planned, organised, managed and reported. Sponsors (both academic researchers and pharmaceutical companies) – as well as investigators and other persons involved in the preparation and conduct of the studies – need to carefully consider all possible issues raising from the Brexit in order to plan and implement the activities needed to mitigate the impact of the leave.

Considerable uncertainties are expected

The Notice to stakeholders highlights the many uncertainties that might go with the cessation of all Union’s primary and secondary laws from the withdrawal date. No withdrawal agreement has been signed up to now between the UK’s government and the European Union, and it is far to be certain any agreement might be reached in time before the end of March next year. This means that from 30 March 2019 EU’s rules on clinical trials will no longer apply in the UK. In particular, the European regulatory framework still refers to Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, as the more recent EU Regulation 536/2014 on clinical trials on medicinal products for human use is not going to apply before the withdrawal date.

The consequences for clinical studies

Three main consequences impacting on clinical trials are expected by the European Commission following the Brexit, the first of which relates to the supply of investigational medicinal products from the UK, that will become subjected to the holding of an authorisation for import in the EU.

This apply also to manufacturing processes only partially performed in a third country, for example the packaging or repacking which is part of blinding activities. All manufacturing activities and batch release for investigational products, including those based in the third country, have to be checked and validated in accordance with the clinical trial authorisation by a qualified person located in the EU and responding to the authorisation holder. Good manufacturing practices must apply as standards of at least an equivalent quality to those laid down in the EU.

Comparator investigational medicinal products authorised in a third country have also to be verified by the qualified person, called to ensure that each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality. It is worth to note that retesting in the EU is not mandatory if the analytical controls have been already carried out in the third country, according to art. 11(2), second subparagraph, of the Directive 2003/94/EC5.

The second consequence impacts on legal requirements for the sponsor or legal representative of the clinical trial, as from 30 March 2019 they also must be established in the EU. This implies that if the sponsor is currently based in the UK, it should promptly act in order to ensure that after the withdrawal a new sponsor or legal representative will be available within the EU-27. The regulatory procedure is a substantial amendment, thus requiring notification to the competent authority and information of the Ethics Committee.

Finally, it should also be considered the impact of the UK’s leave of the flux of information to be transmitted to EudraCT, the EU clinical trials database. In particular, from the date of the Brexit protocol-related information on UK-specific trials will no longer have to be submitted to the database, except when the trial is part of an agreed Paediatric Investigation Plan and the UK is the only country in which the protocol has been submitted.

Submission to EudraCT have also to be run for the results of studies conducted in UK and completed before the withdrawal date, if the reporting of these results is due before the withdrawal date. Furthermore, the submission to EudraCT continues to be required also after the withdrawal date for results of clinical studies conducted in the UK only, and for multi-country trials where the UK was the only EU/EEA Member State where the clinical trial was conducted, if this is required for non-EU/EEA studies (i.e. if the trial is part of an agreed Paediatric Investigation Plan or falls in the scope of art. 46 of Regulation EC/1901/2006).

The UK as source of medicinal products used in bioequivalence studies

Point 11 of the Q&A documentrelated to the United Kingdom’s withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the Centralised procedure” (released by the EU Commission and EMA on 19 June 2018) discusses the possibility to source from the UK innovator pharmaceutical products to be used in bioequivalence studies of generics outside UK.

This typology of bioequivalence studies can be used in generic/hybrid marketing authorisation applications only if the marketing authorisation for that application will be granted before 30 March 2019, date of the Brexit. The document refers to art. 10(1) of Directive 2001/83/EC or art. 13(1) of Directive 2001/82/EC, stating that the applicant can submit an abridged application if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised in the EU or EEA for not less than eight years.

The Q&As also recall the definition of “generic medicinal product, i.e. a product which has the same qualitative and quantitative composition in active substance and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. As a consequence of the above and without the possibility of a withdrawal agreement, generic dossier holders will have to reinvest an accountable budget and considerable submission time to perform new BE studies for their products using EU innovators to support their ongoing and upcoming submissions.

A consultation on the “no deal” scenario in the UK

On the other side of the Channel, UK’s Medicines and Healthcare products Regulatory Agency (MHRA) launched on 4 October an open consultation on how its legislation and regulatory processes would have to be modified in the event of a “no deal” exit from the European Union. The consultation is open up to 1st November 2018 and it can be accessed online from this link.

MHRA said to be still “committed to reaching agreement on the Withdrawal Agreement and Future Framework in the autumn”; nevertheless, it comes under its responsibility to prepare also for the worst-case scenario, making the needed contingency plans to make sure the UK’s regulatory processes for medicines, clinical trials and medical devices “are legally coherent on exit day”. Under this worst-case hypothesis, the MHRA would become a stand-alone regulator, taking any decisions and carrying out any functions which are currently taken or carried out at EU-level.

The consultation covers four different Statutory Instruments (SIs) currently available in the UK: the Medicines for Human Use (Clinical Trials) Regulations 2004, the Medical Devices Regulations 2002, the Human Medicines Regulations 2012 (HMRs) and the Medicines (Products for Human Use) (Fees) Regulations 2016. Many are the technical changes to such regulations that would be due in order to eliminate references to the EU and insert those to UK, but other suggestions might be considered provided they fulfil a pragmatic and proportionate approach in establishing UK regulatory requirements, allow MHRA to take regulatory action to protect public safety and provide minimum disruption and burden on companies.

Commenting the initiative, the Association of the British Pharmaceutical Industry (ABPI) said that pharmaceutical companies continue to plan for all possible outcomes of negotiations, in close collaboration with the government. “But we have been very clear that the best way to protect patients and public health in the UK and in the EU is to agree future cooperation between the MHRA and the EMA on the regulation of medicines”, said ABPI’s Deputy Chief Scientific Officer, Dr Sheuli Porkess.