Current clinical trial application process
The combined review service has been mandatory in the UK since 01 January 2022 for the submission of Clinical Trials of Investigational Medicinal Products (CTIMPs), where a single application is made using a new part of the Integrated Research Application System (IRAS), which provides a coordinated review by both the Medicines and Healthcare products Regulatory Agency (MHRA) and research ethics committee (REC) leading to a single UK decision on the trial. As the review by MHRA and the REC is performed in parallel, requests for further information (RFIs) are raised jointly. The timelines for the review process are reproduced below from the UK NHS Health Research Authority (HRA) website and the overall review process, including responses, should take 60 days but can be extended to 90 days for products containing genetically modified organisms. Extensions to the 14 day timeline for responses to RFIs can be requested, but this will increase the 60 day timeline.
Initial review and application process and timelines
There were no changes to the regulatory requirements associated with a clinical trial application following the introduction of the Combined Review process, however, a public consultation on a set of proposals to improve the clinical trial legislation in the UK was made by the MHRA in association with the HRA and the Northern Ireland Department of Health. This consultation ran from 17 January to 14 March 2022 and the government response was published 21 March 2023.
Public consultation to improve the clinical trial legislation
The findings from this consultation are being used by the government to revise the current UK clinical trial legislation, namely “The Medicines for Human Use (Clinical Trials) Regulations 2004” (SI 2004/1031), as amended, which transposes the EU Clinical Trials Directive 2001/20 EC into UK law. The aim is to provide a more flexible and adaptable regulatory regime that supports different types of trials and ‘ensures patients and their safety are at the focus of all clinical trials’. The following outcomes are taken from the government response to the consultation and will be incorporated into UK clinical trial legislation and/or guidance:
- Embedding the MHRA/REC combined review into legislation with competitive timelines for review of applications (30 days post validation) and issue final decision after RFI response received (10 days), keeping the option for independent submissions available to allow rare exceptions.
- Introducing a nominal maximum of 60 days to respond to RFI with additional flexible extensions available to enable the sponsor to develop robust responses with the aim to avoid multiple rounds of RFIs and allow for consideration of international CTAs for the same trial.
- Introducing an extended timeframe for assessment of an application, where independent expert advice is required should the trial be of high risk.
- Introducing a lapse of trial approval where approval will expire if no recruitment occurs within 2 years, with exceptions for rare diseases and specific circumstances such as during pandemics.
- Amending the process for receiving RFIs so that the sponsor has access to RFIs per discipline on a rolling basis rather than waiting for all requests to be made together.
- Introducing the ability to receive an RFI during the review of a substantial amendment in order to minimise rejections that may cause delays or interruptions to an ongoing trial.
- Streamlining reporting requirements and removing duplication wherever possible, whilst maintaining oversight of participant safety (e.g., removing the requirement for individual SUSARs to be reported to all investigators, removing the requirement to report SUSARs and annual safety reports to RECs in addition to MHRA and extending the written notification for Urgent Safety Measures from no later than 3 days to no later than 7 days).
- Introducing a “notification scheme” for trials where the risk is similar to that of standard medical care, enabling the clinical trial to be approved without the need for a regulatory review and conducted in a risk-proportionate manner.
- Incorporating more elements of risk proportionality for conducting the trial, and updating current GCP principles to include risk proportionality.
- Flexibility on consent provisions where the trial is considered to have low risk.
New notification scheme
The first change to be implemented from the above list was announced 12 October 2023, where a new notification scheme for low-intervention trials (Phase 4 and certain Phase 3 clinical trials) has been introduced by the MHRA. Initial applications for these lower-risk trials, where the risk is similar to that of standard medical care, will be processed by the MHRA within 14 days instead of the statutory 30 days. To qualify for the notification scheme, there must be no ongoing safety issues with the Investigational Medicinal Product (IMP) and the following criteria must be met:
- Phase 4 trials; IMPs must be licensed and used according to the relevant UK, USA, or EU Marketing Authorisation and have no ongoing safety concerns (e.g., other trials on temporary halt / clinical hold or have unresolved urgent safety measures or post-marketing regulatory restrictions).
- Phase 3 trials; at least one of the following applies:
- The trial is already approved in the USA or EU (same protocol, IB version, IMP dossier (EU), same manufacturing process (USA)).
- The MHRA have approved in the last 2 years a previous Phase 3 clinical trial of the IMP(s) at the same dose (or a higher dose), dosing frequency (or a higher frequency) and route of administration, and for the same indication (even if the trial was with a different Sponsor) and utilising the same manufacturing process.
- IMPs are licensed and used according to the relevant UK, USA, or EU marketing authorisation (except for placebo)
Complex trials with innovative design, or those including paediatric, pregnant or breastfeeding participants are not eligible for the notification scheme, as well as IMPs that are first in class or are an advanced therapy medicinal product (ATMP).
Future changes to the regulatory framework for clinical trials will follow once the Statutory Instrument that will update the clinical trials legislation are drafted and implemented. S-cubed will keep you updated with announcements concerning these changes.
If you have any questions on this topic or want to reach out regarding any aspect of your own clinical trials, please don’t hesitate to get in touch. You can contact us through our website (www.s-cubed-global.com), via email (email@example.com), or by telephone (S-cubed Ltd: +44 1235 77 22 60).
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Our Regulatory Affairs team have extensive regulatory expertise in the preparation and co-ordination all the necessary regulatory documentation you may require for a clinical trial in the UK, including IMPDs and IBs. We can support combined review applications, from submission through to determination, and throughout the life-cycle of a clinical trial.