Clinical trials for medicines: apply for authorisation in the UK
Source: gov.uk (2025-11-13)

How to apply for a clinical trial including eligibility, phases, model IMPDs, costs and how to make changes to your application.

New Notification Scheme

We have launched our new Notification Scheme that enables a more streamlined and risk-proportionate approach to processing Clinical Trial Authorisations (CTA) for “initial” applications in Phase 3 and 4 trials.

Read more and register your interest (#new-notification-scheme).

As of 1 January 2022 the combined review service, (formerly known as Combined Ways of Working (CWoW), is the way that all new Clinical Trials of Investigational Medicinal Products (CTIMPs) applications are prepared, submitted and reviewed. Combined review offers a single application route and co-ordinated review leading to a single UK decision for CTIMPs.

Please note: CTIMP applications via combined review should be started and submitted using the new part of Integrated Research Application System (IRAS (http://www.myresearchproject.org.uk/CWOW)) and not in the standard part of IRAS. While the regulatory requirements and fees remain the same, the application submission, processing and assessment steps outlined below refer to non-combined review applications. For Combined review applications please refer to the Health Research Authority website (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/).

Clinical Trials and coronavirus (COVID-19)

We have published guidance on managing clinical trials (https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19) during the COVID-19 outbreak, and on clinical trials applications for COVID-19 (https://www.gov.uk/guidance/clinical-trials-applications-for-coronavirus-covid-19).

When a clinical trial authorisation (CTA) is needed

Use the online algorithm 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) (PDF, 68KB, 2 pages) 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 Mock examples to assist with the question ‘Is it a clinical trial of an investigational medicinal product?’ (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1022203/Mock_examples_to_assist_with_determination_of_a_CTIMP.pdf) to help you decide if your study needs a CTA.

For further advice you may also wish to consult your local regulatory department or research governance team. From October 2021 the ‘SCOPE’ advice service will only be available via self-service using the guidance on this webpage.

Please note

This guidance relates to clinical trials of medicinal products. If your query relates to a clinical investigation of a medical device please contact xxx@xxx.xx (mailto:xxx@xxx.xx).

To get advice on whether a trial is a Type A, B or C based on risk assessment please view our guidance on risk-adapted approaches to the management of clinical trials of investigational medicinal products (https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/xx-xxxx-xxxx/Risk-adapted_approaches_to_the_management_of_clinical_trials_of_investigational_medicinal_products.pdf). Should you have a query regarding any proposed risk adaptations please send an email with your query to xxx@xxx.xx (mailto:xxx@xxx.xx).

If your query relates to whether the study product(s) is/are an Investigational Medicinal Product (IMP) or non-IMP, please consult the document ‘Guidance on investigational medicinal products (IMPs) and ‘non investigational medicinal products’ (NIMPS) (Rev. 1, March 2011)’ (https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-10/imp_03-2011.pdf) .

If you wish to know whether your product could be a medicine, rather than a medical device or other product (such as a food supplement or cosmetic), please refer to the medicines borderline page (https://www.gov.uk/guidance/borderline-products-how-to-tell-if-your-product-is-a-medicine).

Trial Sponsor and legal Representative

The sponsor of a clinical trial is the person who takes responsibility for the initiation, management and 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 needs to be established in the UK or a country on an approved country list (https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries) which would initially include EU/European Economic Area (EEA) countries. If this is not the case, then the sponsor must have a legal representative who is so established.

Registration of your clinical trial

From 1 January 2022 the Health Research Authority (HRA) will automatically register clinical trials with ISRCTN Registry as one of the steps to ensure research transparency. This will start with clinical trials of investigational medicinal products (CTIMPs) that are submitted through combined review in the new part of IRAS. It is still a standard condition of a Research Ethics Committee (REC) favourable opinion for clinical trials to be registered on a publicly accessible database, this requirement has not changed. For any submissions submitted up to 31 December 2021 (either via new IRAS or old IRAS) you should register your clinical trials on an established international register such as ISRCTN Registry or ClinicalTrials.gov. If you wish to defer registration of your trial (for example if it is an adult phase I trial) then contact the HRA at xxx@xxx.xx (mailto:xxx@xxx.xx).

You should continue to include the registry number(s), if available, in section A.5. of the application form in the Integrated Research Application System (IRAS) when you prepare your application. If this is not available at the time of application, you should email this to the MHRA at xxx@xxx.xx (mailto:xxx@xxx.xx) with subject line “Clinical Trial Registration” within six weeks of recruiting the first research participant. You should also let the REC (https://www.hra.nhs.uk/about-us/committees-and-services/res-and-recs/search-research-ethics-committees/) know your registration number as soon as possible.

Combined review of clinical trials of investigational medicinal products

From 1 January 2022, all new Clinical Trials of Investigational Medicinal Products (CTIMPs) applications will be prepared, submitted and reviewed via the combined review service. This offers CTIMP applicants and sponsors a single application route and co-ordinated review by MHRA and the research ethics committee, leading to a single UK decision.

Applications for combined review are prepared and submitted in a new part of the Integrated Research Application System (https://www.myresearchproject.org.uk/CWOW) (IRAS). Further information on the process is available via the Health research Authority website (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/#contents).

Combined review of a CTIMP and Medical Device

Combined review is the way research teams seek approval for new Clinical Trials of Investigational Medicinal Products (CTIMPs) and combined medicine and device trials.

Research teams make a single application using a new part of IRAS, which goes to both the Medicines and Healthcare products Regulatory Agency (MHRA) and a research ethics committee (REC) at the same time. The application also goes for study wide review, such as HRA and HCRW approval, if the study is to take place in the NHS or Northern Ireland HSC.

The regulatory and ethics reviews are done in parallel and any requests for further information (RFIs) are raised jointly. A single response to these requests leads to a single decision from both reviews. Study wide review is usually issued at the same time as MHRA and REC, but may come later if there are still issues to discuss with the applicant.

IRAS is used for the initial application and supports the trial through amendments right up to the end of the trial. Research teams can allocate different roles in the system for colleagues working on the project. Further information is available in our Combined IMP Device guidance (https://assets.publishing.service.gov.uk/media/66167bd16ad004cd0fac0580/Combined_IMP_Device_guidance_10.04.2024.docx)

In Vitro Diagnostic (IVD) Devices including Companion Diagnostic Devices

Please identify in the covering letter of your Clinical Trial Authorisation (CTA) application that your clinical trial includes the use of an IVD device including companion diagnostic devices (https://www.gov.uk/government/publications/in-vitro-diagnostic-medical-devices-guidance-on-legislation). Submit this information via the Integrated Research Application System (IRAS) under the combined review process.

An in vitro diagnostic device is a medical device which —

(a) is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination; and

(b) is intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:

i. concerning a physiological or pathological state,

ii. concerning a congenital abnormality,

iii. to determine the safety and compatibility of donations, including blood and tissue donations, with potential recipients, or

iv. to monitor therapeutic measures,

and includes a specimen receptacle but not a product for general laboratory use, unless that product, in view of its characteristics, is specifically intended by its manufacturer to be used for in vitro diagnostic examination.

A companion diagnostic device is an IVD device, which is essential for the safe and effective use of a corresponding medicinal product to:

(a) identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or

(b) identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product.

IVD devices including companion diagnostic devices may be used in clinical trials of medicinal products (Clinical Trials of Investigational Medicinal Products (CTIMPs)) to stratify patients for inclusion/exclusion in the trial or stratified to a cohort within a trial.

For CTIMPs involving an IVD device with sites in Great Britain:

IVD devices including companion diagnostic devices must bear a UKCA or CE mark for use as intended by the manufacturer in a clinical trial.

A health institution exempted device may be used if the IVD device including companion diagnostic devices will be manufactured and used within the same health institution and either on the premises of their manufacture or on premises in the immediate vicinity without having been transferred to another legal entity.

Where no device that bears the UKCA or CE marking is available for the clinical trial or a health institution exemption does not apply, an analytical performance study should have been conducted prior to the start of the use of the IVD device including companion diagnostic devices with the clinical trial. However, where no analytical performance study has yet been conducted, the characteristics of the IVD device including companion diagnostic devices must be studied. The Tabular Summary that describes the intended performance characteristics of the IVD device or companion diagnostic devices, will be accepted by the MHRA.

Applicants must submit the following:

(a) If using a UKCA or CE marked device as intended by the manufacturer, the clinical trial applicant should submit, on a company letterhead, a confirmation that identifies the device manufacturer, their UK responsible person (if applicable) and MHRA device registration on the Public Access Registrations Database (PARD) (https://pard.mhra.gov.uk). This must be submitted with the clinical trial application through IRAS.

(b) If the clinical trial site in GB is using a health institution exempted device, the clinical trial applicant should submit, on a company letterhead, a confirmation that includes the UKAS accreditation schedule (https://www.ukas.com/find-an-organisation/) to ISO 15189 and identifying the device(s) on the schedule. This must be submitted with the clinical trial application through IRAS.

(c) If no UKCA or CE marked device is available or the health institution exemption does not apply, the MHRA requests the following items.

Please submit the information for i. AND iii., OR ii. AND iii.

i. If the analytical performance study has been conducted, submit the analytical performance summary report(s) for the IVD device including companion diagnostic devices, demonstrating evidence of device performance. The MHRA will assess the analytical performance to ensure the device is suitable for the clinical trial. The MHRA will issue a decision letter with the outcome.

AND

iii. The completed checklist (https://assets.publishing.service.gov.uk/media/68a72c4b969253904d155765/Checklist_template_for_clinical_performance_IVD_devices_20-8-25.docx) (MS Word Document, 49.3 KB).

OR

ii. If no analytical performance study has yet been conducted at time of application, a Tabular Summary (https://assets.publishing.service.gov.uk/media/68a7290d2f18566482155760/Tabular_Summary_input__template__for_non_marked_IVD_devices_20-8-25.docx) (MS Word Document, 35.5 KB) should be submitted. This document is a description of the analytical methods including acceptance limits and parameters for performing validation. The MHRA will assess the tabular summary and will issue a decision letter with the outcome. Please supply the contents requested without modifying the structure of the template.

AND

iii. The completed checklist (https://assets.publishing.service.gov.uk/media/68a72c4b969253904d155765/Checklist_template_for_clinical_performance_IVD_devices_20-8-25.docx) (MS Word Document, 49.3 KB).

Analytical performance means the ability of the device to correctly detect and/or measure a particular analyte. Analytical performance study refers to technical test performance, which may include data to demonstrate accuracy (derived from trueness and precision), analytical sensitivity (e.g. limit of detection, limit of quantitation), analytical specificity, linearity, cut-off, measuring interval (range), carry-over, as well as determination of appropriate specimen collection and handling, and endogenous and exogenous interference on the results.

Please see the IVD process flow diagram (https://assets.publishing.service.gov.uk/media/691600c4493305b49ce6e797/IVD_process.pdf) to help with your submission.

The MHRA will review the application provided and may request additional information.

The clinical trial applicant should respond fully to one round of question(s) issued in a Grounds for Non-Acceptance letter, within 14 calendar days from receiving the request for information. The MHRA will assess the information and provide a final outcome. If no response is received within 14 calendar days, the clinical trial application will be rejected.

This guidance applies to clinical trial sites in Great Britain and includes trials where patient samples are tested outside the United Kingdom, but where the results are used in patient management decisions in Great Britain. This guidance does not apply to clinical trials where the results are not used to make patient management decisions in Great Britain. Patient management decisions will include but are not limited to stratification, selection of participants and randomisations into arms of a clinical trial study.

Clinical trials which subsequently determine the clinical performance of the IVD device including companion diagnostic devices should be registered (https://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.gov.uk%2Fguidance%2Fregister-medical-devices-to-place-on-the-market&data=05%7C02%7Cwebupdates%40mhra.gov.uk%7Ceeeb44bee763490cc48308dcc3584368%7Ce527ea5c62584cd2a27f8bd237ec4c26%7C0%7C0%7C638600031197073129%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=hZO30wReQISzJTMWW3tITmNBX%2Bfw%2FX%2FW%2FjJZadbT%2FJ8%3D&reserved=0).

For CTIMPs involving an IVD device for performance studies in Northern Ireland, please refer to published guidance on regulation of medical devices in Northern Ireland. (https://www.gov.uk/guidance/medical-devices-eu-regulations-for-mdr-and-ivdr)

Documents to send with your application

The IRAS portal includes a list of documentation to submit for combined review of your application. The following provides some further guidance on the content of some of the specific MHRA documents:
- covering letter: When applicable, the subject line should state that the submission is for a Phase I healthy volunteer trial and is eligible for a shortened assessment time, or if you are using risk proportionate approaches to the conduct of the study. Your covering letter should clearly highlight your Purchase Order (PO) number; this will help us to invoice and allocate your payments promptly and efficiently
- investigational medical product dossier (IMPD): please note that an active substance master file (ASMF) is not acceptable as a substitute for an IMPD
- manufacturer’s authorisation, including the importer’s authorisation and Qualified Person declaration on good manufacturing practice (https://www.gov.uk/guidance/good-manufacturing-practice-and-good-distribution-practice) for each manufacturing site if the product is manufactured outside the EU. Further guidance covering this area (https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries).
- content of the labelling of the investigational medicinal product (IMP): where this has not been provided please provide a justification for its absence
All documents must have copy and paste functionality. We do not currently accept password-protected documents. Other published guidance remains relevant and should be consulted for further information on the submission requirements (with consideration of the MHRA as a sovereign regulator).

If you are using an in vitro diagnostic device in your trial, the covering letter and/or protocol should confirm that any applicable CE marking requirements (https://www.gov.uk/guidance/notify-mhra-about-a-clinical-investigation-for-a-medical-device#in-vitro-diagnostic-medical-devices-ivds) have been complied with (or will be complied with prior to the study start).

Example investigational medical product dossiers (IMPDs)

If you are carrying out a trial using modified established medicines, the MHRA has produced some mock examples of completed IMPDs which set out our minimum requirements:
- 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) (PDF, 4.06MB, 5 pages)
- 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) (PDF, 255KB, 5 pages)
- Mock IMPD for 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) (PDF, 4.14MB, 7 pages)
- Mock IMPD 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) (PDF, 4.2MB, 14 pages)
- 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) (PDF, 54.8KB, 3 pages)
Assessment of your submission

The initial combined review assessment will be completed within 30 days of being submitted. Applications for healthy volunteer trials and sponsor-determined phase I trials in non-oncology patients may qualify for a shortened assessment time and MHRA will work with the research ethics committee to endeavour to expedite these applications. You should state on your covering letter if you think your trial is eligible. Note that trial designs that stretch to investigating the benefit of the treatment to participants may not be eligible for the expedited assessment timeframe.

We will tell you the outcome of your submission along with the outcome of the research ethics committee review, via the combined review process, which could be:
- 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 we raise grounds for non-acceptance you will have the opportunity to respond, usually within 14 days; however this may be extended on request.

Communication informing the applicant of the MHRA and ethics committee decision following receipt of the responses will usually be sent within 60 days of us receiving the original valid application. If an extension to the response date has been agreed this will impact the final decision timeline.

Notification of the decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms (Regulation 19 of SI1031) will be sent within 90 days of us receiving the original application unless otherwise advised.

We have moved from paper to automated electronic communication. To ensure that you receive all our correspondence please ensure that you add xxx@xxx.xx (mailto:xxx@xxx.xx) to your safe sender email list. We will only send official correspondence to the named applicant email address.

Common issues identified during clinical trial applications

More than half of all clinical trial authorisation (CTA) applications for investigational medicinal products (IMPs) received by the Medicines and Healthcare products Regulatory Agency (MHRA) require additional information to be submitted before they are considered approvable. 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 provided in the application.
- Guidance on the most common issues identified during clinical trial applications and how to avoid them (https://www.gov.uk/government/publications/common-issues-identified-during-clinical-trial-applications).
- See our case study: Early breast cancer patients benefit from a study to potentially improve survival outcomes (https://www.gov.uk/government/case-studies/early-breast-cancer-patients-benefit-from-a-study-to-potentially-improve-survival-outcomes)
Withdraw your request before the final decision

You may 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.

To withdraw an application, 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/combined-ways-working-pilot/step-step-guide-using-iras-combined-ways-working-cwow/#withdrawing).

New Notification Scheme

Our new Notification Scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorisation (CTA) for “initial” applications.

The scheme only applies to CTA applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk; it does not include CTA applications for first in human (FIH), Phase 1 or Phase 2, or amendments at this time.

CTA applications submitted under this scheme will be processed by the MHRA within 14 days, instead of the statutory 30 days, provided the sponsor can demonstrate the trial meets the inclusion criteria (#new-notification-scheme-criteria). These criteria could change, if the evidence supports the need for this, including the potential to expand the scheme in the future.

Register your interest in our new Notification Scheme

Applications under the new Notification Scheme are submitted via the combined review process using the Integrated Research Application System (IRAS); there are no documentation exemptions. You should prepare your complete submission package and submit it in the new part of IRAS as described above.

All applicants (commercials and non-commercials) whose trials meet these criteria should participate in the scheme by registering their interest.

Complete this form (https://forms.office.com/Pages/ResponsePage.aspx?id=XOon5Vhi0kyif4vSN-xMJsp6Uizarx1OmZz35RhsEuVUMURNSjU4VkQzSExQMFZQUjZSVVdIS0NOMS4u) to register your interest.

MHRA acceptance of an application under the new Notification Scheme will be confirmed within 14 calendar days from the application received effective date and authorisation by the MHRA will be granted unless any criterion is not suitably met . If the MHRA considers the application does not meet the new Notification Scheme criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under full CTA assessment with a decision communicated within the 30-day statutory timeframe.

Applicants are reminded to ensure common issues identified during clinical trial applications (https://www.gov.uk/government/publications/common-issues-identified-during-clinical-trial-applications) are addressed before submitting their application.

The new Notification Scheme is subject to our existing fees. Read more information about fees (#fees).

You can contact us (#contact) if you have any questions about the new Notification Scheme.

New Notification Scheme criteria

Phase 4

Phase 4 trials are post-marketing or surveillance trials of licensed medicines. They gather information on the drug’s effect across a wider population, side effects associated with long-term use and drug-drug interactions.

Phase 4 trials must meet both of the following criteria:
- All investigational medicinal products (IMPs) are licensed and used according to the relevant UK, USA, or EU marketing authorisation (except for placebo)
- There are no ongoing safety concerns with the IMP(s) that the Sponsor is aware of, for example other trials on temporary halt / clinical hold, other trials with unresolved urgent safety measures or post-marketing regulatory restrictions.
Phase 3

Traditional Phase 3 trials are conducted in more than 300 participants, although there may be exception to this (for example in the cases of rare diseases). They are usually multicentre and include pivotal pre-marketing trials and evaluate the efficacy and safety of the drug, usually with a comparison to placebo or standard of care treatment. They do not include proof of concept, dose-finding, dose-response or proof of efficacy trials, which would usually be labelled Phase 2.

Phase 3 trials must meet at least one of the following criteria:
- The trial is already approved in the USA or EU based on the same protocol and IB versions submitted to MHRA, and for EU approvals, the same version of the IMP dossier. For trials approved in the USA only, the IMP dossier submitted to the MHRA must document the same IMP manufacturing process.
- 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), Inclusion of ‘duration (or a longer duration)’ in the criteria for phase 3 trials and route of administration, and for the same indication1 (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).
In addition, to be eligible for the scheme a Phase 3 trial must not include any of the following:
- Complex, innovative trial design (e.g. basket, umbrella and platform) that allows for prospective major adaptations such as the addition of indications or IMPs via future amendments2
- Includes paediatric participants3
- Includes pregnant or breastfeeding participants
- IMP is first in class4
- IMP is an advanced therapy medicinal product (ATMP)5
1: ‘Same indication’ means the same target disease*, of the same severity, in the same age group and (if relevant) in the same drug combination or line of treatment. This should be as per the stated eligibility criteria. *A subset/subtype of the target disease is not considered to be the same. 2: Trials with complex innovative designs: CTFG Recommendation paper on complex clinical trials (12 February 2019) (https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2019_02_CTFG_Recommendation_paper_on_Complex_Clinical_Trials.pdf). Blagden, S.P., Billingham, L., Brown, L.C. et al. Effective delivery of Complex Innovative Design (CID) cancer trials—A consensus statement. Br J Cancer 122, 473–482 (2020) (https://www.nature.com/articles/s41416-019-0653-9). 3: Under 18 years of age 4: A first-in-class IMP uses a new and unique mechanism of action to treat a medical condition or disease. 5: An ATMP is a medicinal product which is either: a gene therapy medicinal product, a somatic cell therapy medicinal product, or a tissue engineered product. A definition of ATMPs is found in Directive 2001/83/EC as amended by the ATMP Regulation 1394/2007 and includes combination ATMPs.

Requesting approval of trials with complex innovative designs

The MHRA supports the conduct of trials with complex innovative designs such as umbrella, basket, platform and master protocol plus submodules.

These trial designs are characterised by the presence of prospective major adaptations.

Examples of major adaptations are addition of new investigational medicinal products or introducing new trial populations.

The Sponsor should choose the best design to address the trial objectives, to ensure that the benefit-risk balance of the trial is positive and to ensure the reliability of results.

When submitting a Clinical Trial Authorisation application for a trial with prospective major adaptations the trial Sponsor needs to justify the choice of a complex trial design, ensure that each adaptation as well as the entire trial are safe and scientifically sound and describe how the integrity of trial results will be maintained throughout the conduct of the trial.

Some points to consider when planning a complex innovative design trial can be found in the article Blagden, S.P., Billingham, L., Brown, L.C. et al. Effective delivery of Complex Innovative Design (CID) cancer trials—A consensus statement. Br J Cancer 122, 473–482 (2020) (https://www.nature.com/articles/s41416-019-0653-9).

Although the paper is written for cancer trials the recommendations can apply to trials in other indications.

Major adaptations introduced via substantial amendments

It may be appropriate to propose major adaptations via submission of a substantial amendment request.

Two scenarios can occur.
- If a trial was approved as a trial with complex innovative design introduction of future major adaptations will be consistent with the original trial objectives. Sponsors need to seek approval from the MHRA before implementing major adaptations if they were not fully described in the protocol approved at the time of the initial application. If the proposed changes are safe and scientifically sound they will be deemed approvable by the MHRA when reviewing the substantial amendment application.
- It is understood that in some cases major adaptations may be necessary for trials with a design that did not envisage future significant adaptations (i.e. not complex innovative designs such as umbrella, basket and platform). In this case when submitting the substantial amendment request the trial Sponsor needs to address in writing the following points:
- a strong rationale must be provided why the major adaptations should be implemented in the current trial and why they do not constitute a new trial;
- an explanation why the adaptations are safe and scientifically sound
- declaration that the introduction of the proposed changes does not jeopardise trial integrity, i.e. the use and analysis of the data generated by the trial up to the time of the proposed adaptations.
If a robust rationale is not provided at the time of submission of a substantial amendment, the request may be refused. Indeed also, if the rationale is not deemed acceptable by the regulator or any of the points above have not been adequately addressed the request may be refused.

Before submitting an application for authorisation of a trial with complex innovative design and/or an amendment requesting approval of major adaptations Sponsors are recommended to establish a dialogue with the MHRA and seek advice.

Sponsors should consult our guidance on How to seek advice from the MHRA (https://www.gov.uk/guidance/medicines-get-scientific-advice-from-mhra).

Applications that need expert advice

For certain trials, we 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. We 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 we look at when considering risk factors include:
- mode of action
- nature of the target
- relevance of animal species and models
We may refer other applications for expert advice if we identify issues 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), e.g. 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
- compound acts (directly or indirectly) via the immune system with a target or mechanism of action which is novel or currently not well characterised
- is novelty in the structure of the active substance e.g. a new type of engineered structural format such as those with enhanced receptor interaction as compared with the parent compound
- level of expression and biological function of the target receptor may differ between healthy individuals and patients with the relevant disease
- is insufficient available knowledge of the structure, tissue distribution, cell specificity, disease specificity, regulation, level of expression and biological function of the human target, including down-stream effects
- compound acts via a possible or likely species specific mechanism or where animal data are unlikely to be predictive of activity in humans
If you are a sponsor of a FIH or early stage clinical trial you should read the Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf). You should use the document to help you identify risk factors and create mitigation strategies.

Sponsors should use the criteria above to decide if their trial needs expert advice. You can get pre-submission advice from us if you are unsure if your compound falls into the ‘higher-risk’ category.

To get advice you should send an email with ‘URGENT – EAG/CHM QUERY’ as the title to xxx@xxx.xx (mailto:xxx@xxx.xx) including:
- a summary of the nature of the compound
- its target/mechanism of action
- the relevance of the animal model(s)
We will send a response to this email within 14 days.

If we confirm that the application comes within the category of ‘higher risk’, or you have determined this yourself, you should select the date of the CTBVEAG meeting (https://www.gov.uk/government/organisations/commission-on-human-medicines/about/membership#clinical-trials-biologicals-and-vaccines-eag) where you want your trial discussed.

You should prepare your complete submission package and submit it in the new part of IRAS as described above.

At least 14 days prior to submission you should alert MHRA and HRA (xxx@xxx.xx (mailto:xxx@xxx.xx)); xxx@xxx.xx (mailto:xxx@xxx.xx)) that the application is planned and it requires EAG/CHM review. To ensure an appropriate REC meeting is scheduled, relevant study information such as the IRAS ID (if available) and whether your study involves the use of an Advanced Therapy Medicinal Product (ATMP) is required. It is recommended that an IRAS ID is obtained prior to alerting the MHRA and HRA of this planned submission and included in the email notification. The rest of the application process is as described above for all applications. The combined response letter will be sent to the sponsor as soon as possible after the REC meeting. Please refer to HRA website for further information regarding scheduling of the REC meeting.

CHM areas for discussion

At the CHM meeting the experts will discuss your application, including the responses you provide to the CHM areas for discussion. These are:
- the function of the target in man
- the ability of the subject to maintain a normal physiological response to challenge in the presence of the investigational product
- the transition from preclinical to human testing, particularly with regard to highly species-specific molecules
- the potential for on-target and off-target effects and how this will be handled in the clinic
- the doses used in the relevant animal species (particularly with regard to the use in the animal model of the starting dose to be administered to man)
- a rationale for the starting dose in man (including, for example receptor occupancy)
- a rationale for the study population (particularly for the use of healthy volunteers)
- a rationale for the administration schedule for the initial and subsequent cohorts - this should include the time interval between doses administered to individual subjects
- a rationale for the dose escalation particularly with regard to potential adverse effect
- a rationale for the proposed trial site, including the facilities available
Trials in patients previously treated with an Advanced Therapy Medicinal Product

Previous use of an Advanced Therapy Medicinal Product (ATMP) was a standard exclusion criterion for participation in a clinical trial. Recent data show that despite previous ATMP administration some patients present with disease progression or relapse. Administration of a new Investigational Medicinal Product (IMP) could therefore be justifiable.

Points to consider for trials allowing inclusion of patients previously treated with an Advanced Therapy Medicinal Product (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/735741/Points_to_consider_for_trials_allowing_inclusion_of_patients_previously_treated_with_an_Advanced_Therapy_Medicinal_Product_Web.pdf) identifies the main points to consider when proposing trials of an IMP administered after previous ATMP use.

Fees

There are different fees based on your type of clinical trial application (https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees#clinical-trials-application-fees). The fees applied to the New Notification Scheme are listed under Clinical trials: applications fees (https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees#clinical-trials-application-fees).

For the purposes of fee determination, an application supported by quality data for blinding purposes (for example, placebo comparator or over-encapsulation) remains within the category of applications without an IMPD.

Invoices for Clinical Trial Authorisation applications, Substantial Amendment applications, and Annual Safety Reports are sent directly to the applicant shortly after a valid submission has been established. The covering letter for the application should clearly highlight your Purchase Order (PO) number where available. The applicant is the person listed in section C1 of the Application form, or section D1 of the Amendment form. We are unable to address the invoice to someone other than those listed in the sections above.

It is the responsibility of the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. Penalty fees may be incurred for non-payment, details of the penalties are set out in the Fees Regulations (https://www.legislation.gov.uk/uksi/2016/190/contents). Non-payment may also result in suspension of any licence or authorisation, followed by legal proceedings for unpaid amounts, as a debt due to the Crown.

You can contact MHRA Finance Department on xx-xxxx-xxxx or email xxx@xxx.xx (mailto:xxx@xxx.xx) for more information on how to pay fees.

Contact

For information about your submission, including status and tracking enquiries, contact the clinical trials helpline on xx-xxxx-xxxx (Monday to Friday 8:30am to 4.30pm) or email xxx@xxx.xx (mailto:xxx@xxx.xx). See Clinical trials named contact (https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisation-report-safety-issues#clinical-trials-named-contact) for further information.