This post is an attempt to provide the requirements for conducting clinical trials in the UK post Brexit i.e. since 1 January 2021. The information provided is by no means exhaustive.. Please refer to the resources at the end of the post for detailed guidance.
Click on the ‘+’ sign next to each heading to access the information under each heading.
The Medicines and Healthcare Regulatory Agency (MHRA) is the competent authority that regulates CTIMPs in the UK.
The requirements and procedures for clinical trials in the UK are set out in the Medicines for Human Use (Clinical Trials) Regulations 2004. These regulations require all interventional clinical trials to be ethically approved and authorised by the MHRA. They also include requirements for the application and assessment of each trial, the supply of investigational medicinal products (IMPs), the conduct of clinical trials in accordance with good clinical practice and safety reporting.
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 2019 amend the Medicines for Human Use (Clinical Trials) Regulations 2004 to enable the MHRA to operate as a regulator outside the EU, post Brexit.
Detailed guidance on the manufacture and import of IMPs are described in Eudralex Volume 4 and Eudralex Volume 10, including guidance for the issuance of the Qualified Person Declaration for the importation of IMPs manufactured in third countries outside the EEA.
The sponsor of a clinical trial is the person who takes responsibility for:
- the initiation
- management
- financing (or arranging the financing) of that trial.
Clinical trials can also be sponsored by two or more persons or organisations. This is referred to as joint or co-sponsorship.
Regulation 3 (2) of The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) provides further information on the responsibilities of the sponsor(s).
A sponsor of a clinical trial should be established in the UK or in a country on an approved country list which initially includes EU/European Economic Area (EEA) countries. If this is not the case, then the sponsor must have a legal representative who is so established.
- The approved country list will be reviewed every 3 years.
- There will be legislation to determine considerations to add/remove countries from the list.
Use the online algorithm Is it a clinical trial of a medicinal product? to find out if your study needs MHRA authorisation.
The algorithm is a set of questions that determine:
- whether the substance you’re testing counts as a medicinal product
- whether your trial counts as a clinical trial within the scope of the relevant legislation.
You can also read the clinical trial mock examples to help you decide if your study needs a CTA.
If you are still unsure, you can request a protocol review with the MHRA in order to obtain an opinion on whether a study involving a medicinal product falls within the scope of the clinical trial regulations and therefore requires a clinical trial authorisation (CTA).
You can do this by completing the form here and emailing it with a copy of the protocol to clintrialhelpline@mhra.gov.uk, with ‘Scope – protocol review’ followed by the study title (shortened)’ as the subject line.
Note that from 1 October 2021 the ‘SCOPE’ advice service will only be available via self-service using the guidance on the MHRA website.
The steps are as follows:
- Obtain a EudraCT number
- Complete the application form in IRAS
- Create XML and PDF versions of the MHRA application form, save and sign them electronically
- Submit via MHRA submissions with the rest of the required document (you need to be registered on the platform in order to this)
- MHRA will validate the application
- MHRA will communicate any Request for Information (RFI)/decision directly with the applicant.
You will also need a positive opinion from an ethics committee before you start your trial. You can get this before, at the same time or after you have made your submission to the MHRA.
From January 2022, all new Clinical Trials of Investigational Medicinal Products (CTIMPs) in the UK will be subject to a combined review from the MHRA and the UK Research Ethics Services, in collaboration with the Health Research Authority (HRA), facilitating rapid start up and benefitting patients sooner.
Applicants need only make a single application for both Clinical Trial Authorisation and Research Ethics Committee (REC) opinion and approval is delivered together. A number of sponsors have already used this new process with some reporting a 30 per cent improvement in overall trial set up times.
Applicants are encouraged to start using the service now so they can ensure their internal processes and systems are aligned for January 2022, when all approvals for CTIMPs will be processed via the combined review. Get started now by visiting https://www.hra.nhs.uk/combined-review.
You can read more about this here.
Yes, it is a requirement.
You should use existing and established international registers such as the ISRCTN registry or ClinicalTrials.gov to register your trial, thereby ensuring that the public is aware of your trial. For trials involving both UK and EU sites, a record in the EU Clinical Trials Register will exist (other than for adult Phase 1 studies).
In the UK, any favourable opinion given by a research ethics committee is subject to the condition that the clinical trial is registered on a publicly accessible database. Registration should occur before the first participant is recruited and no later than six weeks after recruitment of the first participant. This has not changed since Brexit. You should continue to include the registry number, if available, in the Integrated Research Application System (IRAS) when you prepare your application.
The Health Research Authority (HRA) has made a commitment in its Make It Public research transparency strategy, in the long term, to register clinical trials on behalf of sponsors and researchers. Until this system is place you should register your clinical trials on an established international register such as ISRCTN registry, or ClinicalTrials.gov.
Yes it is possible.
If a sponsor wishes to request a deferral of study registration within the required timeframe, in accordance with current transparency rules (e.g. due to commercial sensitivity), they should contact the Health Research Authority (HRA) at study.registration@hra.nhs.uk.
| Step | Time taken |
|---|---|
| Initial assessment of application | Within 30 days of application being submitted |
| Applications for healthy volunteer trials and sponsor-determined phase I trials in non-oncology patients | May qualify for shortened assessment time (average 14 days) |
Yes, you can submit further supporting documentation before assessors begin their assessment of the application. You can’t send additional documents once we have begun assessment.
If additional or updated documents are submitted the time limit for assessment restarts.
The outcome of your submission will be one of the following:
- acceptance of the request for a clinical trial authorisation
- acceptance of the request for a clinical trial authorisation subject to conditions
- grounds for non-acceptance of the request for a clinical trial authorisation
If the MHRA does not accept your submission you will be told why and will usually have to amend your application and resubmit (see timelines provided in the table below).
| Amended request letter from MHRA for specific product types | No of days in which the MHRA will send a letter after receiving the original valid application |
|---|---|
| General medicinal product (Reg 18) or a product with special characteristics (Reg 20) | Within 60 days |
| A gene therapy, somatic cell therapy (including xenogenic cell therapy) product or products containing genetically modified organisms (Reg 19) | Within 90 days unless otherwise stated. |
Yes, you can withdraw your request at any point before an assessment decision on your clinical trial authorisation application is reached. It is not possible to withdraw an application once grounds for non-acceptance have been issued.
A risk proportionate approach to the initiation, management and monitoring of certain clinical trials is possible. The sponsor should carry out a risk assessment based on the potential risks associated with the investigational Medicinal Product (IMP). You can view the MHRA guidance here.
The MHRA provides a notification scheme for certain ‘Type A’ trials in which the risk to the patient from the IMP is considered to be no greater than that of standard medical care. These are trials involving medicinal products licensed in any EU Member State if:
- the trial relates to the licensed range of indications, dosage and form of the product, or;
- the trial involves off-label use (such as in paediatrics and oncology) that is established practice and supported by enough published evidence and/or guidelines
If the MHRA raises an objection to the notification, the submission is treated as a standard request for authorisation and an assessment of the submission is carried out. This may result in either:
- acceptance of the request for a clinical trial authorisation subject to conditions, or;
- grounds for non-acceptance of the request for a clinical trial authorisation.
For certain trials, the MHRA will seek advice from the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBVEAG) of the Commission on Human Medicines (CHM). The CHM will then discuss the trial at their meeting, which will take place later in the same week as the CTBVEAG meeting.
The MHRA will make the decision to refer applications for expert advice based on an assessment of the risks and how the sponsor plans to mitigate them. Areas looked at when considering risk factors include:
- mode of action
- nature of the target
- relevance of animal species and models
Other applications may also be referred for expert advice if issues are identified during the assessment process.
Examples of trials where expert advice may be needed include first-in-human (FIH) trials with novel compounds where the:
- mode of action involves a target that is connected to multiple signalling pathways (target with pleiotropic effects), eg leading to various physiological effects or targets that are ubiquitously expressed
- compound acts (directly or indirectly) via a cascade system where there may be an amplification effect which might not be sufficiently controlled by a physiological feedback mechanism
You can view further examples here.
For trials ongoing in both the UK and in European member states, dual reporting is needed. You will need to report each SUSAR to both the MHRA and relevant member states, as well as to the European Medicines Agency’s (EMA’s) Eudravigilance Clinical Trial Module (EVCTM).
In order to differentiate SUSAR reports from post-marketing ICSRs, the new reporting systems will enable sponsors and CROs to specify the type of report from a study and assign the study type as a clinical trial.
You must submit SUSARs in Great Britain (GB) and in Northern Ireland (NI) to the MHRA in one of the following ways:
1. Via the eSUSAR website (used to submit single SUSAR reports)
The availability of the eSUSAR website for sponsors and CROs who wish to continue reporting SUSARs using this route has been retained.
If you currently report SUSARs using the eSUSAR website there is no additional need to register to either the ICSR Submissions or the MHRA Gateway to submit SUSARs.
The eSUSAR website route is used to submit single SUSAR reports.
2. Using the ICSR Submissions tool (used to submit single SUSAR reports)
The ICSR Submissions is a web reporting tool that replaces the EudraVigilance website (EVWEB). It mimics the same reporting processes by enabling users to complete the online reporting form with details of the SUSAR. It also has the functionality to allow users to upload files that have been submitted via the Eudravigilance System. This by-passes the need to complete the form.
The ICSR Submissions route is used to submit single SUSAR reports. To submit SUSARs to the MHRA using this route, visit the ICSR Submissions portal to register. Select ‘Request company account’ and follow the step-by-step guide to gain access to ICSR Submissions in the reference guide Registration for ICSR Submissions.
The ICSR Submissions registration video demo also covers the end-to-end process for registering to use the ICSR Submissions to report SUSARs.
3. Using the MHRA gateway (used to submit bulk SUSAR reports)
The MHRA Gateway replaces the Eudravigilance Gateway and offers a direct, secure database-to-database transmission of SUSARs into the MHRA system. The MHRA Gateway route is used to submit bulk SUSAR reports.
In order to gain access to, and submit SUSARs via, the MHRA Gateway, you will first need to access and register with another portal called MHRA Submissions.
The reference guide Gaining Access to MHRA Submissions provides a step-by-step account of how to set up user access. Guidance on managing users of the portal is also available in the reference guide Managing users on MHRA Submissions.
Three video demos provide further information on the user access management process and user permissions for using MHRA Submissions.
The MHRA Gateway registration video demo covers the end-to-end process for registering to use the MHRA Gateway to report SUSARs.
Direct links to the MHRA Gateway and MHRA Submissions are only provided once reporters are registered.
Yes, it is a requirement.
The time frame for publishing the summary of results is within 6 months of the end of trial for paediatric clinical trials or within one year of the end of trial for non-paediatric clinical trials.
You should publish your summary results within these timeframes in the public register (or registers) where you have registered your clinical trial.
No, generally it isn’t necessary to submit a clinical trial summary report to the MHRA. However, you must send a short confirmatory email to CT.Submission@mhra.gov.uk once the result-related information has been uploaded to the public register and provide a link.
From January 2022, all new Clinical Trials of Investigational Medicinal Products (CTIMPs) in the UK will be subject to a combined review from the MHRA and the UK Research Ethics Services, in collaboration with the Health Research Authority (HRA), facilitating rapid start up and benefitting patients sooner.
Applicants need only make a single application for both Clinical Trial Authorisation and Research Ethics Committee (REC) opinion and approval is delivered together. A number of sponsors have already used this new process with some reporting a 30 per cent improvement in overall trial set up times.
Applicants are encouraged to start using the service now so they can ensure their internal processes and systems are aligned for January 2022, when all approvals for CTIMPs will be processed via the combined review. Get started now by visiting https://www.hra.nhs.uk/combined-review.
You can read more about this here.
You can find more information:
- on the MHRA website here and here.
- in this presentation from the MHRA entitled EU Exit and post-transition guidance, clinical trials webinar – October 2020′.
Image by mcmurryjulie from Pixabay