While negotiations are still ongoing, the structure of the post-Brexit medicine testing and approval process is still unclear, and the UK government has so far ruled out an extension to the transition period which is due to come to an end at the end of this year. What is clear is that the Medicines and Healthcare products Regulatory Agency (MHRA) is becoming independent to the EMA’s drug approval and oversight process. It might result in the testing and release of products being completed under two separate regulatory frameworks.
Due to these uncertainties, the best way to be ready is not to wait for a potential agreement but prepare for the worst and assume a “no-deal” scenario. The focus of this article is implementing clinical trials in the post Brexit Europe.
The EU rules for clinical trials, which are set out in EU Directives including 2001/20/EC , may be no longer be applicable to the UK and this is concerning for the many European companies that run clinical trials and have study sites in the UK or rely on the UK for the supply of their investigational medicines. Because of Brexit, and in the absence of any special agreement for continued cooperation under a European medicines regulatory network, the UK would no longer participate in the free movement of goods within the EU – there is no clear pathway of how the trade of pharmaceutical products will work. The active substance and finished products coming from a UK-based manufacturing site may therefore be considered a third country importation of medicinal products into the EU. Similarly, for companies that have study sites in the UK, careful consideration must be given to how investigational medicines entering the UK from the EU must be handled after the end of the transition period. As such, there are some points to consider when conducting clinical trials:
- The sponsor or legal representative must specify an authorized importer established in the EU.
- The products must be released by a QP who is based within the European Economic Area (EEA) to ensure that the clinical trial product is manufactured in accordance with EU GMP and that the batches produced are verified in accordance with the EU Clinical Trial Authorization. With short shelf life products such as Advanced Therapy Medicinal Products (ATMPs), this brings an additional challenge to the release and distribution process.
As the currently approved labeled product has to be modified in accordance to the change of manufacturing site or QP release site. This change has also to be notified with the relevant authorities.
- When it concerns an authorized product, the pharmacovigilance system master file must be located in the EEA for all companies intending to conduct clinical trials in the EU.
The company must establish a legal representative in the EU and adapt their distribution channels to take importation requirements into account. To change the legal representative from a UK based to an EU based company, it requires a substantial amendment and notification to the Ethics Committee of the relevant competent authority. The Committee responds within a maximum of 60 days from the date of receipt of the notification. However, for certain investigational medical products (IMPs) such as gene therapies and somatic cell therapies, an additional extension of 30 days applies, which means a further 90 days in total for approval in some cases. As an example; if the notification is received on the 15th of August it can take up to the 14th of October before the approval is received. In case of a 90-day approval period the date would be the 13th of November, which is very close to the withdrawal date. For xenogenic cell therapies, there is no time limit to the authorization period. This could have a major impact on ongoing and planned clinical trials as some regulatory authorities have indicated that clinical trials may be suspended if submissions and approvals are not in place by the end of the transition period on the 31st of December 2020. Hence, preparation and timely submission becomes critical.
- Results from clinical trials conducted in the UK completed before the 31st of December 2020 must be submitted to the European Central Database for Clinical Trials – EudraCT.
- Sponsors with study sites in the UK should check that their supply chain and regulatory operations are similarly reviewed to ensure that their study remains compliant with regulatory requirements in the UK in the increasingly likely event of divergence.
In conclusion, as long as there is no longer term Brexit agreement in place, one must plan for the worst-case scenario which means preparing for a ”no deal” scenario whereby the EU and the UK fully diverge with respect to medicines regulation and the healthcare sector no longer benefits from concerted approaches under a European medicines regulatory network. As such, it is incumbent on all clinical trial sponsors to evaluate their current regulatory status and supply chains vis à vis Brexit impact, whether they have study sites in the EU and/or the UK.
Having regulatory subject matter experts and Qualified Persons available with in-depth experience of the requirements for conducting clinical trials throughout Europe, with expertise surrounding both EU and UK requirements, PharmaLex is highly equipped to support your organisation to deal with the upcoming impact. If you would like our team to examine your Brexit Strategy and work with you to prepare for the future, please connect with us to discuss – firstname.lastname@example.org.
Directive 2001/20/EC of the European Parliament and of the Council [INTERNET] available from https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf