Clinical trials for medicines: apply for approval in the UK
Source: gov.uk (2025-10-01)

How to apply for a clinical trial from 28 April 2026, including eligibility, documentation and registration in a public registry.

This guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004 (“the Clinical Trials Regulations”), as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 (https://www.legislation.gov.uk/uksi/2004/1031/contents).

These amendments come into force on 28 April 2026.

Until this date, this guidance is in draft and should only be used to support sponsors in preparing for the implementation of the new regulations. Please see Clinical trials for medicines: apply for authorisation in the UK (https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk) and Clinical trials for medicines: manage your authorisation, report safety issues (https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisation-report-safety-issues) for the guidance that should be followed prior to 28 April 2026.

Legal status of this guidance

The following guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004 (https://www.legislation.gov.uk/uksi/2004/1031/contents) (“the Clinical Trials Regulations”), as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 (https://www.legislation.gov.uk/uksi/2025/538). These amendments come into force on 28 April 2026. For assistance in determining whether a clinical trial is within the scope of these Regulations, see the Is it a clinical trial of a medicinal product? (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/949145/Algorithm_Clean__1_.pdf) algorithm.

Part 2 of Schedule 1 to the Clinical Trials Regulations requires that the investigator and sponsor (https://www.hra.nhs.uk/planning-and-improving-research/research-planning/roles-and-responsibilities/) (and any individual or organisation that the sponsor delegates trial-related activities to) have regard to all relevant guidance with respect to commencing and conducting a clinical trial. Investigators and sponsors must, therefore, ensure that they are fully aware of the information within this guidance and act accordingly to achieve and maintain regulatory compliance.

Clinical trials of a medicinal product

Per regulation 2 of the Clinical Trials Regulations, a clinical trial is any investigation in human participants, other than a non-interventional trial, that is intended to:
- discover or verify the clinical, pharmacological, or other pharmacodynamic effects of the medicinal products
- identify any adverse reactions to the medicinal products; or
- study absorption, distribution, metabolism, and excretion of the medicinal products
with the object of ascertaining safety or efficacy of medicinal products (as defined in regulation 2 of the Human Medicines Regulations 2012 (https://www.legislation.gov.uk/uksi/2012/1916/contents)).

For detailed guidance on determining whether a study is within the scope of the Clinical Trials Regulations, please refer to the Is it a clinical trial of a medicinal product? (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/949145/Algorithm_Clean__1_.pdf) algorithm.

Applying for approval for a clinical trial

What approval is needed before starting a clinical trial?

Per regulation 12 of the Clinical Trials Regulations, a clinical trial must not start until it has received a joint ‘clinical trial approval’, consisting of both:
- a favourable opinion from an ethics committee
- an authorisation from the licensing authority, i.e. the Medicines and Healthcare products Regulatory Agency (MHRA)
Some clinical trials will require approvals in addition to the combined approval from the ethics committee and licensing authority (e.g. approval from the Administration of Radioactive Substances Advisory Committee is needed for trials using radioactive substances). The sponsor is responsible for ensuring that all applicable approvals are obtained prior to starting the clinical trial.

Submitting an application for clinical trial approval

Applications for approval of a clinical trial must use a combined procedure in which a single application (including the documentation (#documents-required-for-an-application-for-clinical-trial-approval)) is submitted through the Integrated Research Application System (IRAS) and reviewed in parallel by the licensing authority and a suitable research ethics committee. Detailed guidance on using IRAS to submit an application for clinical trial approval can be found in the Step-by-step guide to using IRAS for combined review (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/step-step-guide-using-iras-combined-ways-working-cwow/#making).

In exceptional circumstances, an applicant may submit separate applications to the licensing authority for a clinical trial authorisation and to an ethics committee for a favourable opinion. Written approval must be obtained in advance by contacting the licensing authority at xxx@xxx.xx. Requests to make separate applications will be assessed on a case-by-case basis. Please note that the submission processes outlined in this guidance are for applications for clinical trial approval that are submitted through the combined procedure. Information on the processes for submitting separate applications to the licensing authority and ethics committee will be communicated to the applicant once this approach has been agreed. The stated timelines apply to both submission routes, however.

There are fees applicable to submission of an application for clinical trial approval (https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees#clinical-trials-application-fees). To pay these fees, please refer to making a payment to MHRA (https://www.gov.uk/guidance/make-a-payment-to-mhra).

Validation of applications

Once submitted, the application undergoes validation checks to ensure that all documentation required for the application to be reviewed has been included.

The outcome of these checks will be communicated by email and through IRAS within 7 calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the licensing authority may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated and the applicant will need to resubmit the application with the deficiencies corrected.

Before preparing an application, please review the common reasons for an application to be found invalid (https://www.gov.uk/government/publications/common-issues-identified-during-clinical-trial-applications/common-issues-validation) by the licensing authority.

Initial review of applications by the authorities

Valid applications are reviewed by the licensing authority and ethics committee. A combined decision will be issued to the applicant by email and through IRAS within 30 calendar days of validation.

The initial decision will be one of the following:
- the licensing authority and ethics committee (“the authorities”) approve the application for a clinical trial approval
- the authorities approve the application for a clinical trial approval subject to conditions
- the authorities do not approve the application for a clinical trial approval, setting out the grounds for this decision and the further information required for the application to be reconsidered
Approval with conditions

If an application is approved subject to conditions, the notice will specify what actions the sponsor must take to meet those conditions and when these actions must be taken by. The clinical trial is considered approved only if all of the specified conditions are satisfied. In most cases, the sponsor must ensure that the conditions are met before the trial commences. The sponsor should keep records of how the conditions have been met, but it is not necessary to inform the authorities that the conditions have been met before starting the trial, unless otherwise specified in the approval letter.

In some cases, the authorities may allow a condition of approval to be fulfilled at a specific timepoint after the trial begins. In these cases, the trial may begin before meeting the condition, but failure to meet the condition by the specified timepoint will mean that the approval is not valid and the trial must be stopped until the condition is discharged. A substantial modification can then be submitted requesting approval to restart the trial (https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval#applying-for-approval-of-a-substantial-modification).

The licensing authority will assess compliance with any conditions of clinical trial approval during inspection.

Requests for further information

If an application for clinical trial approval is not approved, applicants will have 60 calendar days from the date on which the decision letter was issued to provide the requested further information through IRAS (either as a written response or an amended application for approval) in order for the application to be reconsidered.

The application will be treated as rejected if this deadline is not met. However, extensions to this deadline can be requested by contacting the MHRA at xxx@xxx.xx (mailto:xxx@xxx.xx) (or contacting the ethics committee directly, if the information requested relates only to its opinion), explaining why the extension is needed and proposing an alternative submission date.

A decision will be issued by email and through IRAS within 10 calendar days beginning with the date of the response being submitted, stating that the application is either approved, approved with conditions, or not approved. If the application is still not approved, the reasons will be outlined and the application will be treated as rejected. No further amendments to the application will be considered (although the applicant can appeal this decision, as explained in the next section). If the applicant wishes to continue obtaining approval for the clinical trial, a new application will need to be submitted (including the full application fee).

Appeals

If the licensing authority does not approve an application or the applicant disagrees with the conditions attached to the approval by the licensing authority, they have 28 calendar days from receiving the decision to send written notice to (xxx@xxx.xx) of their intention to appeal the licensing authority decision. Per Schedule 5 of the Clinical Trial Regulations, the licensing authority will then inform the Commission on Human Medicines (CHM), and CHM will give the applicant a period of 6 months in which to provide:
- either written representations concerning the decision or a written summary of the oral representations that they intend to make
- any supporting documents
CHM may agree an extension to this 6-month period if requested by the applicant, up to a maximum of 12 months.

If the applicant has chosen to make oral representations to CHM, this will be arranged following receipt of the written summary and supporting documents.

After reviewing the applicant’s representations, CHM will report its findings and advice to the licensing authority. The licensing authority will consider CHM’s report and make a final decision regarding the application for clinical trial approval.

If the applicant remains dissatisfied with this decision, they may notify the licensing authority via xxx@xxx.xx that they wish to appear before or be heard by a person appointed by the licensing authority, and will then a period of 3 months in which to provide:
- a written summary of the oral representations that they intend to make
- any supporting documents
- confirmation of whether they wish for the hearing to be public
Following the hearing, the appointed person will provide a report to the licensing authority. The licensing authority will then make a final decision regarding the application for approval of a substantial modification.

For guidance on the process for appealing a decision by the ethics committee, please refer to the guidance on the HRA website (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/clinical-trial-regulations-reform/guidance-on-changes-to-the-clinical-trials-regulations/the-approvals-process-for-clinical-trials/the-approvals-process-for-applications/).

Applying for clinical trial approval flowchart

The full process is summarised in Figure 1. Flowchart summarising the process of applying for clinical trial approval (https://assets.publishing.service.gov.uk/media/68dbf80bc487360cc70c9f6d/Fig1._Applying_for_approval_in_the_UK.pdf). Please note that this flowchart shows the maximum possible timelines (including sponsor-driven timelines). The time to a decision will be shorter than this for almost all applications.

Withdrawing an application for clinical trial approval

Applicants can withdraw their application for clinical trial approval at any time before a decision is issued or a request for further information is raised by submitting a withdrawal request via IRAS (guidance on this can be found in the Step-by-step guide to using IRAS for combined review (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/step-step-guide-using-iras-combined-ways-working-cwow/#withdrawing)). The submission should include a brief description of why the withdrawal request is being made.

The applicant will receive an email and a notification in IRAS confirming that the application has been withdrawn.

Depending on the proportion of the review that had been completed at the point of withdrawal, some of the application fee may be refunded.

Exceptions to the standard approvals process

Notifiable trials

Certain trials are categorised as ‘notifiable’, per regulation 11A of the Clinical Trials Regulations, and are eligible for automatic authorisation from the licensing authority.

Further details are available in the guidance on notifiable clinical trials (https://www.gov.uk/guidance/clinical-trials-for-medicines-notifiable-trials).

Pre-booked ethics committee meetings

If the applicant does not choose to have their application discussed at the next available ethics committee meeting, the timelines for a decision to be issued on an initial or amended application will begin from the date 7 days before the chosen meeting date, instead of from the date on which the application was validated. For further guidance on this, refer to the Health Research Authority (HRA) website (https://www.hra.nhs.uk/about-us/committees-and-services/online-booking-service/).

Combined trials of an investigational medicinal product and an investigational medical device

For trials that involve both an investigational medicinal product (IMP) and an investigational medical device (IMD), the timelines for a decision to be issued on an initial or amended application will begin from the date of formal acceptance under regulation 16(4) of the Medical Devices Regulations 2002 (https://www.legislation.gov.uk/uksi/2002/618/contents) (i.e. the date on which the application is accepted as valid). Further information on this process can be found in Combined review applications for a combined trial of an IMP and an IMD (https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk).

Consultation with committees and specialist groups

The licensing authority and ethics committee may consult with a relevant committee or specialist group (as defined in regulation 2(1) of the Clinical Trials Regulations) on an application for clinical trial approval.

If a relevant committee or specialist group is consulted on an initial application for clinical trial approval:
- the 30-day timeline for the authorities to issue a decision on clinical trial approval is extended by 90 calendar days (to 120 calendar days from validation)
If a relevant committee or specialist group is consulted regarding the applicant’s response to a request for further information:
- the 10-day timeline for the authorities to issue a decision on clinical trial approval is usually extended by 30 calendar days (to 40 calendar days from the date that the further information or amended application was received from the applicant)
- and the IMP used in the clinical trial is an advanced therapy medicinal product, the 10-day timeline is extended by 60 calendar days (to 70 calendar days from receipt of the further information or amended application from the applicant).
Additional guidance is available on when and how the authorities seek expert advice on an application for clinical trial approval (https://www.gov.uk/guidance/clinical-trials-for-medicines-expert-advice).

Medicinal products for xenogenic cell therapy

Applications for approval of clinical trials involving a medicinal product for xenogenic cell therapy follow the standard submission process but are not subject to statutory timelines for response from the licensing authority and ethics committee. A decision may be issued on these applications at any time following receipt of a valid application.

Please note that advanced therapy medicinal products (ATMPs) that are not medicinal products for xenogenic cell therapy are subject to the standard statutory timelines for response from the licensing authority and ethics committee (unless the application requires expert advice, per the previous section).

Documents required for an application for clinical trial approval

Cover letter

A cover letter is mandatory and should include the following:
- all relevant trial identifiers, including the full trial title (and abbreviated title where appropriate), protocol number, IRAS ID, and any global identifiers (such as an EU CT number)
- a statement as to whether or not the applicant considers the trial to be notifiable and the rationale for this decision
- if the trial is notifiable, a statement as to whether there are other practical reasons (as outlined in the guidance on Notifiable trials and automatic authorisation (https://www.gov.uk/guidance/clinical-trials-for-medicines-notifiable-trials)) that mean that the application should go through full assessment
- a short description of any safety concerns that the sponsor is aware of regarding the IMP
- a summary of the trial design, including any novel or adaptive elements
- details of the IMP(s) and any NIMP(s), including name, class, dose and duration of dosing, route and administration
- confirmation that the Investigator’s Brochure (IB) or equivalent has been included for each IMP. For pivotal non-clinical studies referenced, the IB should include the countries in which they were conducted, the Good Laboratory Practice (GLP) study titles and numbers, the name of the sponsor responsible for the study, and confirmation that they are Organisation for Economic Co-operation and Development (OECD) compliant. If a trial is not OECD-compliant, this should be made clear and an explanation should be provided
- confirmation of which section in each IB (or equivalent) contains the reference safety information (RSI) for assessing suspected unexpected serious adverse reactions
- details of the trial population, including whether participants are minors or otherwise not able to give informed consent
- details of the public database the trial will be registered on, including a link if available
- a table of all submitted documents, including version numbers and dates
- a purchase order number for invoicing for the fees applicable to submission of an application for clinical trial approval (https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees#clinical-trials-application-fees)
If relevant, the cover letter should also specify:
- that the application is a resubmission (the changes as compared to the previous submission should be highlighted)
- that the application is being submitted separately to the licensing authority and ethics committee, with evidence of the authorities’ agreement to this approach
- that the applicant believes that the trial is first-in-human or first time the IMP has been used in the UK
- that the IMP is a decentralised manufactured (DM) IMP (https://www.gov.uk/government/collections/decentralised-manufacture-hub). Where this is the case, the cover letter should specify the DM designation number and the DM master file should be included with the full application
- that the trial is likely to require advice from a specialist group or committee and that the necessary information to support the experts’ discussion of the trial (https://www.gov.uk/guidance/clinical-trials-for-medicines-expert-advice) has been included with the application
- that scientific advice related to the trial or IMP has been sought from the licensing authority or a third country
- that the trial is intended to form part of a UK or EU paediatric investigation plan (including the decision, if it has already been issued)
- details of any in vitro diagnostics devices used in the trial (including companion diagnostic devices), specifying their validation status and confirming that any applicable CE marking requirements have been complied with (or will be complied with prior to the study start)
Medicines form

The medicines form is found on IRAS and includes the following sections:
- trial identification information
- sponsor details
- applicant details
- IMP details
- general trial information
- participant population details
- investigator(s) details
Guidance on completing the study information dataset, which is also on IRAS but is reviewed by the ethics committee, can be found in the Step-by-step guide to using IRAS (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/step-step-guide-using-iras-combined-ways-working-cwow/#preparing) for combined review.

Protocol

The clinical trial protocol describes the objectives, design, methodology, statistical considerations, and organisation of a clinical trial.

The protocol should include (where applicable):
- a descriptive title, a sponsor-created identification number, the version number and the date of the last update
- discussion of the trial’s relevance, design, anticipated risks and benefits, and participant recruitment and informed consent procedures (setting out any particular considerations with respect to inclusion of participants unable to provide informed consent or belonging to other special populations). For a multi-part trial where the submission does not include full detail to enable the conduct of all the trial parts, outline any adaptive elements and plans for future substantial modifications
- justification for the use of placebos, standard of care arms, or real-world data comparators
- an unambiguous definition of the end of the trial. This should usually be the date of the last visit of the last participant, and a justification should be given for any exceptions (e.g. for trials involving human tissue, analysis of samples should be undertaken as part of the data collection before the end of trial is declared)
- a description of any additional care for trial participants once their participation has ended
- a description of any sub-studies conducted at any trial locations
- a discussion of safety events and recording and reporting procedures
- procedures for unblinding of the IMP in the case of an adverse reaction
- a synopsis of the protocol
- a signature from the sponsor and the chief investigator (for single-location trials) or overall coordinating investigator (for multi-centre trials) (electronic signatures are acceptable)
For more detailed guidance on the content and format of the protocol, see Appendix B of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (E6(R3)) (https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Step4_FinalGuideline_2025_0106.pdf) and the ICH M11 Technical Specification, once adopted.

Investigational Medicinal Product dossier

Background

Applications for clinical trial approval must include a dossier or equivalent (see section on cross-referencing and simplified investigational medicinal product dossiers (https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-approval-in-the-uk#cross-referencing-and-simplified-investigational-medicinal-product-dossiers)) for each IMP (including placebos and reference products) to be used in the proposed trial that details the product’s quality, manufacturing process, and control measures, and data from non-clinical studies and clinical usage. If an IMP dossier is not provided, the application must include an explanation for this.

In addition to the guidance on structure and content in the following sections, please review Points to consider when preparing the IMP dossier (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/317987/Points_to_consider_when_preparing_the_IMP_dossier.pdf) along with the mock IMP dossiers for modified established medicines.
- Over-encapsulation of a tablet (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/xx-xxxx-xxxx/Over-encapsulation_of_a_tablet.pdf)
- Over-encapsulation of a broken tablet (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/xx-xxxx-xxxx/Over-encapsulation_of_a_broken_tablet.pdf)
- Mock IMP dossier for Positron Emission Tomography (PET) – non-clinical (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/xx-xxxx-xxxx/Mock_IMPD_for_PET___non_clinical.pdf)
- Mock IMP dossier for PET – pharmaceutical (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/xx-xxxx-xxxx/Mock_IMPD_for_PET_-_pharmaceutical.pdf)
Quality data

Quality data should be structured in accordance with Module 3 of the Common Technical Document (https://www.ich.org/page/ctd).

Applicants should also refer to the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-scientific-guideline) and the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials (https://www.ema.europa.eu/en/requirements-quality-documentation-concerning-biological-investigational-medicinal-products-clinical-trials-scientific-guideline).

Good Manufacturing Practice compliance

The IMP dossier should include confirmation that locations of drug product manufacturing (where manufacturing is as defined in regulation 2 of the Clinical Trials Regulations) are compliant with Good Manufacturing Practice (GMP). This is not required if the IMP has a marketing authorisation in the UK or EU and is not modified.

The IMP dossier should include, where applicable:
- a suitably scoped manufacturer’s authorisation for each UK or EEA manufacturing, importation and/or batch certification location involved in the manufacture, packaging, repackaging, labelling, and UK or EEA importation (if relevant) or batch certification of the drug product
- a declaration by a qualified person (QP) at each UK or EEA importation or batch certification location confirming that each location outside the UK or EEA that was involved in the manufacture, packaging, repackaging, and labelling of the drug product complies with GMP at least equivalent to that in the UK or EU
- for batch-certified IMPs imported into Great Britain from an approved country for import (https://www.gov.uk/government/publications/list-of-approved-countries-for-authorised-human-medicines/list-of-approved-countries) which have been certified by a QP at an authorised location in that country, the name of the UK location responsible for the oversight process and a suitably scoped Manufacturing and Import Authorisation (MIA(IMP)) for the site. Re-certification in Great Britain is not required where a UK oversight process is established
Please note that under regulations 37 and 37A of the Clinical Trials Regulations, a manufacturer’s authorisation is not required where:
- an IMP is assembled in a hospital or health centre by a doctor or pharmacist or a person acting under the supervision of a pharmacist, as long as the IMP is being used exclusively in that hospital or health centre or any other that is a trial location for the same clinical trial in which the product is to be used
- a radiopharmaceutical used for diagnostic purposes is manufactured or assembled by the holder of a manufacturer’s licence (defined in regulation 8(1) of the Human Medicines Regulations 2012 (https://www.legislation.gov.uk/uksi/2012/1916/contents)), which does not relate to the manufacture of the IMP, and the radiopharmaceutical is exclusively for use in a hospital or health centre which is a trial location for the clinical trial in which the product is to be used or is taking part in the clinical trial
In addition to this guidance, please also refer to the guidance on importing IMPs into Great Britain (https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries/importing-investigational-medicinal-products-imp-from-countries-on-a-list-to-great-britain#oversight-process) from an approved country.

Non-clinical pharmacology and toxicology data

The dossier must include the available non-clinical pharmacology and toxicology data for the IMP, preferably structured according to the headings of the current version of Module 4 of the ICH Common Technical Document (https://database.ich.org/sites/default/files/M4S_R2_Guideline.pdf) and structured in tables with a brief accompanying narrative.

The dossier should include:
- study titles and numbers
- test facility names and addresses
- study dates and, if applicable, finalisation dates
- a statement of compliance with GLP for all studies or the extent of compliance being claimed, with robust justification for non-GLP compliance
- summaries of the studies from which the data has been derived that are sufficiently detailed to assess the adequacy of each study and adherence to acceptable protocols
- a critical analysis of the data, including justifications for omissions of data, and an assessment of the safety of the product in the context of the proposed clinical trial (rather than a factual summary of the studies conducted)
- confirmation that test materials used in toxicity studies have qualitative and quantitative impurity profiles representative of clinical trial materials
Previous clinical trial and human experience data

The IMP dossier must include summaries of all available data from previous clinical trials and human experience with the IMP, preferably structured according to the headings of the current version of Module 5 of the ICH Common Technical Document (https://www.ich.org/page/ctd) and structured in tables with a brief accompanying narrative.

The IMP dossier should include:
- a statement of compliance with the conditions and principles of Good Clinical Practice (GCP), as described in Schedule 1, Part 2 of the Clinical Trials Regulations, for all clinical trials referenced which accurately reflects the design and performance of the trials, including any issues that may impact the use of the data originating from them
- links to the public registry entry for each trial referenced, which should include the results. If any trials have not been registered or the trial results have not been uploaded, this should be explained and justified (e.g. a phase I trial with a deferral or waiver to the UK requirement to register)
Risk and benefit assessment

The IMP dossier should include a brief critical analysis of the non-clinical and clinical data in relation to the potential risks and benefits of the proposed trial.

The risk and benefit assessment should:
- identify any referenced studies that were terminated prematurely and the reasons for the early termination
- evaluate safety margins in terms of relative systemic exposure to the IMP, preferably using either area under the curve data or peak concentration data, rather than applied dose
- discuss the clinical relevance of findings in the non-clinical and clinical studies and any recommendations for further monitoring of effects and safety in the clinical trials
If the protocol already includes a risk and benefit assessment, the IMP dossier may reference the relevant section to avoid duplication.

Cross-referencing and simplified investigational medicinal product dossiers

The applicant can:
- cross-reference other documents included in the application in the IMP dossier, e.g. the IB, the protocol, and standalone GMP documents such as QP declarations or MIA(IMP) licences
- cross-reference an IMP dossier from a previously approved clinical trial that used the same IMP (if this IMP dossier is from a different organisation or sponsor, a letter of authorisation is also required). Please note that GMP documents and labelling documents are trial-specific and cannot be cross-referenced from a previously approved trial
- replace sections of the IMP dossier with the current Summary of Product Characteristics (SmPC) or equivalent for the IMP (if an application to modify the current SmPC is outstanding, explain the nature of this modification and the reason for it)
- if the IMP is defined in the protocol in terms of active substance or ATC code, replace sections of the IMP dossier with one representative SmPC or equivalent per active substance or ATC group (which is then considered the RSI for the trial)
See the following table which summarises scenarios in which a simplified IMP dossier may be submitted (https://assets.publishing.service.gov.uk/media/68dbf839c487360cc70c9f6f/Tab1._Simplified_IMPD.pdf). Please note that GMP information and labelling is still required in all cases.

Investigator’s Brochure

Background

The IB provides a summary of the clinical and non-clinical data about the IMP relevant to the study of the product in human participants.

Its purpose is to:
- support investigators and others involved in the trial in understanding the rationale for, and complying with, key features of the protocol
- serve as the reference safety information for assessing of the expectedness of any adverse reaction that occurs during the clinical trial
The information in the IB must be checked and, if necessary, updated at least once per year.

For detailed guidance on the content and format of the IB, refer to Appendix A of the ICH Guideline for Good Clinical Practice (E6(R3)) (https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Step4_FinalGuideline_2025_0106.pdf).

Reference safety information

The IB should include a specific section for the RSI, which is a list of all expected serious adverse reactions (SARs) related to an IMP and their frequencies.

Detailed guidance on the RSI can be found in Clinical trials for medicines: collection, verification, & reporting safety events (https://www.gov.uk/guidance/clinical-trials-for-medicines-collection-verification-reporting-safety-events).

Equivalents to the Investigator’s Brochure

If the IMP is already authorised in the EU, EEA or an ICH country, the IB may be replaced with the SmPC or equivalent. However:
- if the IMP is not being used according to its authorised conditions of use, this SmPC must be supplemented with relevant non-clinical and clinical data to support its use in the clinical trial
- if the IMP is identified in the protocol only by its active substance, one SmPC that is as representative as possible of use within the trial should be chosen to replace the IB for all medicinal products with that active substance
Where an SmPC or equivalent is used in place of an IB, section 4.8 ‘Undesirable effects’ (or the equivalent section) of the SmPC will be used as the RSI.

Other required documents

In addition to the above, the applicant must submit the following (or an explanation if not provided):
- a description of the content of the label for all IMPs, in accordance with the guidance on clinical trial-specific labelling (https://www.gov.uk/guidance/clinical-trials-for-medicines-labelling) (or a statement that IMPs will be labelled according to Part 13 of the Human Medicines Regulations 2012 (https://www.legislation.gov.uk/uksi/2012/1916/contents/made))
- any documents relevant to applications for trials requiring consultation with a committee or specialist group (https://www.gov.uk/guidance/clinical-trials-for-medicines-expert-advice)
- if received, copies of any scientific advice relevant to the trial (including relevant correspondence with the Commission on Human Medicines or other regulatory authorities) or any paediatric investigation plan opinion
- for trials that include the use of an IVD device (including companion diagnostic devices), additional documentation is required per the guidance on Clinical trials that include an in vitro diagnostic device (https://www.gov.uk/government/publications/clinical-trials-that-include-an-in-vitro-diagnostic-device).
This guidance does not include documents that are reviewed only by the ethics committee. For these documents, and for optional documents that may be submitted alongside the application for clinical trial approval, refer to the HRA guidance on document management for combined review applications (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/document-management-combined-review-applications/).

Please note that all documents must have copy and paste functionality and that password-protected documents are not accepted.

Registration of a clinical trial

Under regulation 25(1) of the Clinical Trials Regulations, a clinical trial must be registered in a public registry either before the date that the first participant signs the consent form or 90 calendar days after approval of the trial is granted, whichever is earlier.

Sponsors may apply to the HRA for a deferral (or waiver) to the registration requirement, explaining why this is needed, at any point before the deadline for registering the clinical trial. Phase I clinicals trials may be eligible for an automatic deferral of up to 30 months from the conclusion of the trial, provided that the required minimum information is registered in a public registry before the aforementioned deadline for registering the clinical trial.

See detailed guidance from the HRA on the requirement to register a clinical trial (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/clinical-trial-regulations-reform/guidance-on-changes-to-the-clinical-trials-regulations/research-transparency-requirements-for-clinical-trials/).

Please note that under regulation 17(2)(b)) of the Clinical Trials Regulations, the licensing authority can take into account any outstanding failures to comply with regulation 25(1) (unless a deferral or waiver has been approved) when assessing future applications by the same sponsor.