Life sciences analysis: Rachel Bradley, partner, and Shaan Mehra and Clemency Pleming, trainee solicitors, explain the key provisions of the new EU Clinical Trials Regulation and considers how these compare with the main proposals in the MHRA’s consultation on the UK clinical trials regime.
The new EU Clinical Trials Regulation (EU) 536/2014 (EUCTR), which took effect on 31 January 2022, is the biggest change to the legal framework surrounding clinical trials in Europe since 2001. It will have a global impact, affecting all interventional trials which are even partially conducted anywhere in the EU, at every stage of the trial life cycle. The new EUCTR replaces the EU Clinical Trials Directive (2001/20/EC) governing clinical trials with a more harmonised scheme across the EU.
Since the UK left the EU, the EU regulatory regime no longer applies in Great Britain (ie England, Wales and Scotland) and so neither will the new EUCTR. Due to the Northern Ireland Protocol, parts of the EUCTR will apply in Northern Ireland, although its national competent authority will continue to be the Medicines and Healthcare Products Regulatory Agency (MHRA). Post Brexit the MHRA operates as the clinical trials regulator in the UK and, together with the UK Research Ethics Service, grants permission for clinical trials to take place in the UK, under the amended Medicines for Human Use (Clinical Trials) Regulations 2004, SI 2004/1031.
The new UK Medicines and Medical Devices Act 2021 provides powers to update the current legislation governing clinical trials. Since the passage of that act, the MHRA has recently opened (on 17 January 2022) an eight-week consultation on a set of proposals to improve and strengthen the clinical trials regime in the UK, currently regulated by the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended).
This news analysis looks at some of the key MHRA proposals in the consultation, and how they compare with the new EU regulation.
The new EUCTR is directly effective in all EU member states and the EEA, meaning that any clinical trial which takes place even partially in an EU member state or the EEA will need to comply with its regulatory regime. While the new EUCTR does not affect clinical trials that take place solely in the UK, any UK organisation wishing to carry out an interventional trial even partially in the EU/EEA will need to follow its processes. Meanwhile, institutions in the EU/EEA wishing to carry out clinical trials in the UK will have to go through the UK’s own regulatory process in addition to the EUCTR process.
The EUCTR has the overall objective of making the EU an attractive destination for drug R&D. It aims to achieve this by facilitating multinational co-operation and reducing the regulatory burden on trial sponsors. Practical steps include:
There is also a clear focus on transparency and accessibility of trial data.
The UK’s underlying rationale for its proposals to reform current legislation in the UK is to capitalise on the opportunities presented by Brexit and create a world-class sovereign regulatory environment for clinical trials that will support the development of innovative medicines and ensure that the UK retains and grows its reputation as world leading base for life sciences. The government aims to achieve these through proposals in a number of key areas.
The EUCTR came into force on 31 January 2022. There will be a transition period of three years. Initially the new and old regulatory frameworks will co-exist. From 31 January 2023, existing trials can continue as before, but new trials will need to conform to the new EUCTR. Finally, from 31 January 2025, all trials will be regulated by the new EUCTR. All ongoing trials at that time that were approved under the EU Clinical Trials Directive will need to transition to the new EUCTR.
The MHRA consultation on updates to the UK law will end on 14 March 2022. Any changes to the law would draw from the consultation but might take several years to come into force.
The EUCTR covers all interventional trials involving drugs. Trials of medical devices and other types of treatment such as surgical techniques are not within its scope. The EUCTR also contains a definition of ‘auxiliary medicinal products’—medicinal products which are used in a trial, but which are not the investigational product (eg a rescue medication). The EUCTR provides that only authorised auxiliary medicinal products may be used in clinical trials save that, where there are issues with the availability of authorised products, unauthorised auxiliary medicinal products may be used in justified cases provided they have been manufactured in compliance with good manufacturing practice or equivalent standard.
Non-interventional trials fall outside the scope of the regulation. A non-interventional trial is defined in the EUCTR as one which does not involve the use of treatment strategies or products which go beyond normal clinical practice—so, trials which are purely observational would not require authorisation under the EUCTRs.
The MHRA consultation relates to all clinical trials and the medicinal products used in these trials (referred to as investigational medicinal products or ‘IMPs’).
The MHRA proposals make it clear that the UK will not align with the EUCTR in respect of investigational medicinal product labelling requirements, nor will it the adopt the definition of an ‘auxiliary medicinal product’ introduced by the EUCTR. The MHRA instead proposes the term ‘non-investigational medicinal product’, which would extend the concept to non-medicinal products that may currently be unregulated, such as non-medicinal challenge agents. Risk-proportionate requirements are proposed for labelling of investigational products.
The EUCTR introduces the Clinical Trials Information System (CTIS), a single portal for trial authorisation and management. CTIS went live on 31 January 2022 and is maintained by the EMA. It is intended to make trial approvals more efficient, and to remove the need for sponsors of multinational trials to submit multiple applications in different member states. CTIS will enable the national authorities in each member state to conduct an assessment of the trial proposal jointly and provide a single decision, as follows:
There are also shorter timeframes for approval under the EUCTR. Both the referencing member state (for Part I) and the member states of concern (for Part II) must submit an assessment report within 45 days from the validation date. Validation of the application must take place within ten days from the sponsor’s submission. Extensions of the time limits are possible for certain categories of IMPs or if the referencing member state requires additional information from the sponsor.
While the EUCTR introduces CTIS, the UK proposes the creation of the ‘Integrated Research Application System’ (IRAS). IRAS would enable sponsors to make a combined MHRA/research ethics application submitted through a single UK ’front door’. In order to streamline the appeals process, a single process for a sponsor to appeal the joint decisions has also been proposed.
The requirement for a EudraCT number will also no longer apply under the proposed UK revisions. This will be replaced by a UK specific trial reference number known as an IRAS number. This will be assigned automatically at the time of preparation of an application.
In a broadly similar approach to that taken in the EUCTR, the MHRA proposals set out new maximum standard timeframes for the joint review and decision on a clinical trial application. The maximum timeframe for issuing a study approval would be 30 days from the acknowledgement of a valid application. Sponsor organisations would be allowed up to 60 calendar days to respond to any request for further information, with a final decision being made within ten days from receipt of any responses. These timelines may also be extended by a further 60 calendar days for higher risk investigational products.
The EUCTR introduces a new concept: the ‘low-level’ clinical trial, where the experimental drug has already been authorised for use. Low-level trials are covered by the regulation but have a streamlined process to reflect the reduced risk to the safety of the patients involved.
The UK proposes to introduce a notification scheme for low-intervention trials, similar to the EUCTR. Sponsors can notify the MHRA where the risk is similar to that of standard medical care, and the clinical trial can be approved without the need for a regulatory review. An ethics review will still be required. The MHRA definition of low-intervention trials is broadly similar to the definition provided under the EUCTR.
Under the EUCTR, participation of a subject to a clinical trial is subject to the subject’s written, dated and signed informed consent. The EUCTR provides detailed rules on how sponsors must seek and obtain subjects’ informed consent, which aim at ensuring that each subject is thoroughly informed about the clinical trial, its risk and consequences before expressing consent.
The EUCTR establishes special rules that apply to informed consent in:
For certain cluster trials, a simplified informed consent procedure is permitted, provided certain conditions are met.
The MHRA proposals take a similar approach, seeking to streamline the requirements for informed consent by introducing a simplified/low burden means of seeking agreement from participants for low-intervention clinical trials. The aim is to improve the uptake of these types of low intervention trials.
Under the EUCTR, there are new requirements for trial sponsors while a clinical trial is ongoing, including an increased number of trial milestone notifications, which must be submitted via the CTIS portal in accordance with strict deadlines. These include familiar milestones such as start of recruitment, pauses and restarts, but also some new categories such as a notification of serious breach.
The EUCTR confirms that the sponsor is required to report all suspected serious unexpected adverse reactions to the competent authorities and the ethics committee of the different member states. The sponsor must do so within seven days for those adverse reactions that are fatal or life-threatening, and within 15 days for all other adverse reactions. All reporting of adverse reactions is done through the newly established EU electronic database for safety reporting, ie a module of the EudraVigilance database set up and maintained by the EMA.
The sponsor must also notify the member states concerned of all serious breaches of the EUCTR or of the clinical trial protocol (the version applicable at the time of the breach). A serious breach is defined as a ‘breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial’.
In contrast, the MHRA’s approach to safety reporting is to take the opportunity to diverge from the EUCTR and seek to remove, amend and/or reduce certain reporting requirements that burden investigators but do not contribute to participant safety.
Under the EUCTR there is a requirement to notify breaches through the EU electronic database. The UK’s proposals would remove the requirement that individual suspected unexpected serious adverse reactions (SUSARs) must be reported to all investigators, and instead be notified via the investigator brochure. They also propose removing the requirement to report SUSARs and annual safety reports to the Research Ethics Committee where justified and approved by the regulatory authority. Further, there is a proposal to remove the requirement to include listings of serious adverse events and serious adverse reactions in annual safety reports and instead include an appropriate discussion of signals/risks associated with the use of the medicinal product, as well as proposed mitigation actions, in those reports. The written notification for urgent safety measures would be extended from no later than three days from when the measure was taken, to no later than seven days.
The EUCTR prioritises transparency and public accessibility to a far greater degree than the existing legislation. This is to address concerns that a lack of openness about trial data results in skewed outcomes, with only successful trials being made public and also that the data available in the existing EU Clinical Trials Register varies between member states.
Under the EUCTR, the default is for all trial data to be publicly accessible via a public area of the EMA portal unless exempted. In particular, data may be exempt from disclosure if their confidentiality can by justified on the basis of: protection of commercially confidential information, protection of personal data, protection of confidential communications between member states, or ensuring effective supervision of the conduct of clinical trials by member states. Information about clinical trial applications not yet approved will also not be publicly accessible. Delaying publication of trial data generated in trials of drugs at an earlier stage in their development will be permitted in some instances, such as during a Phase I trial, where publication of some documents can be deferred for up to seven years after the end of the trial.
There is also a mandatory requirement to provide a summary of the trial results to the public, using appropriate language for a lay audience.
The MHRA takes a similar approach, with an increased focus on transparency of clinical trial data. Under the UK’s proposals there will be a requirement to register a trial in a World Health Organization (WHO) compliant public register prior to its commencement and to publish a summary of the results within 12 months of the end of the trial, unless a deferral is agreed by or on behalf of the Research Ethics Committee. Despite the differing reporting registries, the requirements proposed are generally consistent with those implemented under the EUCTR.
The MHRA consultation proposes plans that include the involvement of people with relevant lived experience in the design, management and conduct of clinical trials, to improve the quality and relevance to participants and ensure as much inclusivity as possible. The new legislation will aim to increase diversity in clinical trials and promote and encourage the inclusion of underserved populations such as pregnant or breast-feeding women. The proposals aim to streamline the make-up of the ethics committee by updating the minimum number of members and updating the definitions of lay and expert members in line with international standards. The current legislation that governs the make-up of trials will be replaced by guidance or policies from the Health Research Authority which will allow for greater agility when making decisions.
The proposed legislation aims to ensure that regulatory oversight in the UK that protects public health is both proportionate and strong. The proposals will allow regulators to refuse a new study request based on ongoing serious non-compliance with the legislation where there is significant harm to participants. Proportionality is also achieved by a proposal to make clear that regulatory action might apply only to a specific part of the trial, rather than causing the whole trial to be stopped.
As the EU and the UK move forward post-Brexit there is a clear intent to streamline and improve the way clinical trials are conducted. However, with the MHRA proposal, there is evidence of a notable divergence in approach between the two legislative frameworks: there is a clear intent in the UK to reduce certain burdens where they may not be necessary to protect patient safety, and at the same time to introduce a level of flexibility. While the EUCTR has been implemented, it remains to be seen what the outcome of the MHRA’s consultation will be, the extent to which their proposals are adopted into law, and what changes we will ultimately see in the clinical trial landscape in the UK.
This analysis was first published on Lexis®PSL on 28 February 2022 and can be found here (subscription required).