Guideline for Clinical Trial Application Submissions in the United Kingdom

If you need support for a clinical trial application submission in the UK, please contact us at [email protected]

The United Kingdom is one of the world’s most important countries where clinical trials are conducted. Thousands of biotech and pharma companies around the globe select the UK as destination to carry out their clinical studies.

If you are a biopharmaceutical company planning to run a clinical trial in the United Kingdom, you may be wondering how clinical studies are authorized by British authorities and local ethics committees.

The purpose of this article is to provide you with useful guidance on how clinical trial application submissions work in the UK, including what documents are needed and what evaluation timelines should be expected.

Understanding the Combined Review Through IRAS

Biotech and pharma companies planning clinical trials with drugs and/or medical devices in the UK will have to go through a so called “combined review” process.

The “combined review” means that one single trial application is submitted to both the Medicines and Healthcare products Regulatory Agency (MHRA) and the research ethics committee (REC) at the same time.

This simultaneous application to the MHRA and the ethics committee is performed by using the Integrated Research Application System (IRAS).

In addition, the application is also assessed by the Health Research Authority (HRA), if the trial is to be executed in the National Health Service (NHS).

What Is IRAS?

The?Integrated Research Application System (IRAS)?is a unified electronic platform used to submit clinical trial applications for regulatory and ethics approval in the United Kingdom. Since 1 January 2022, clinical trial sponsors must use IRAS to submit study applications for combined review.

The MHRA, REC, and HRA Evaluation Process

The regulatory (MHRA) and ethics (REC) evaluations take place in parallel, and any clarification requests or queries are raised together. One reply from the study sponsor to these questions is followed by a single decision from both parties. The HRA assessment is normally made simultaneously during the MHRA and REC review process, but it may be delayed on some occasions.

In summary, the MHRA, REC, and HRA reviews have these timelines:

• The applicant (trial sponsor or delegated representative) submits the study application via IRAS for MHRA, REC, and HRA evaluation, and then gets a reply or request from them for additional information within 30 days
• The applicant answers the questions within a period of 14 days (the applicant may request an extension from the MHRA if needed, which will extend the overall timeline)
• The MHRA and REC provide final responses within 16 days
• The maximum time frame from initial submission until the final result from MHRA and REC is 60 days
• The HRA evaluation (study wide review) usually takes place at the same time as that of the MHRA and REC, but it might take longer

Main Documents Required for MHRA Submission

The IRAS platform includes a list of documents to be submitted for the combined review.

The following list mentions the main documents to be included in the MHRA submission package (among others):

• Cover letter
• Clinical trial protocol
• Investigator’s Brochure (IB)
• Investigational medicinal product dossier (IMPD)
• Manufacturer’s authorization, including the importer’s authorization and Qualified Person (QP) declaration on?good manufacturing practice (GMP)?for each manufacturing site if the product is manufactured outside the EU
• Content of the labelling of the investigational medicinal product (IMP)
• Patient information sheet and informed consent form
• Suitability of the investigator document
• Clinical trial insurance certificate

Common Issues Found in MHRA Applications

The MHRA has published a number of?frequent issues identified during clinical trial applications.

We provide below a summary of these issues that can be helpful for clinical trial sponsors.

Validation issues related to:

• Failure to complete section C1 of the CTA application form or section D1 of the notification of amendment form
• Failure to provide PDF documents that have undergone optical character recognition (OCR)
• Failure to provide the correct product name in section D.3.1 of the application form
• Inconsistencies across the application form
• Absence of mandatory documentation

Non-clinical issues related to:

• Statement of compliance with OECD GLP for studies
• GLP compliance and Advanced Therapy Medicinal Products
• Details of analytical methods
• Availability of data for review
• Justification of dose selection for first in human trials
• Contraception recommendations

Clinical issues related to:

• Risk mitigation strategies for all IMPs
• Contraceptive requirements
• Eligibility criteria
• Unblinding in case of clinical emergency
• Duration of treatment or objective/endpoint ‘Until commercially available/marketing authorization’
• Dose stopping criteria
• Adverse event (AE) and Serious adverse event (SAE) recording
• Serious adverse event (SAE) reporting
• Communication plan
• Extensive amendments to a trial protocol
• Reference Safety Information

Pharmaceutical issues related to:

• Characterization Data
• Method Validation Data
• Batch analysis data
• Justification of Specifications
• Retest Period
• Shelf Life
• TSE/BSE certification
• Manufacturer’s Authorization
• QP Declaration
• Labelling

All Documents in Place Before Starting the Trial

A clinical trial in the UK cannot begin until all the relevant authorizations have been obtained from the regulatory authorities and ethics committees.

Evidence of the documents submitted to regulators and review boards and the documents that were approved must be stored in the Trial Master File (TMF).

This will permit auditors and inspectors to confirm that all legal and good practice requirements have been met.

How to Ensure a Smooth and Successful Clinical Trial Submission in the UK

More than 50% of all clinical trial authorization applications received by the MHRA require extra information to be provided before they can be approved.

Many of the issues identified are common and avoidable if available guidance is followed or if a satisfactory justification for not following the applicable guidance is explained in the application.

Clinical trial sponsors wishing to submit a clinical trial application in the UK —particularly those not located in Great Britain— may decide using a clinical research organization (CRO) with proven experience in dealing with IRAS, MHRA, REC, and HRA. This can be a wise decision to save time and ensure a solid and smooth approval process.

Sofpromed is a CRO with solid expertise in submitting clinical trial applications in the United Kingdom. We help small biotech and large pharma clients prepare and submit clinical study applications to MHRA and British ethics committees, giving expert advice to increase the chances of fast approval.

If you need support for a clinical trial application submission in the UK, please contact us at [email protected]