Guidance

Clinical trials for medicines: apply for authorisation in the UK

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

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) 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.

Clinical Trials and coronavirus (COVID-19)

We have published guidance on managing clinical trials during the COVID-19 outbreak, and on clinical trials applications for COVID-19.

When a clinical trial authorisation (CTA) is needed

Use the online algorithm Is it a clinical trial of a medicinal product? (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?’ 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 devices.regulatory@mhra.gov.uk.

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. Should you have a query regarding any proposed risk adaptations please send an email with your query to clintrialhelpline@mhra.gov.uk.

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)’ .

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.

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 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 study.registration@hra.nhs.uk.

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 clintrialhelpline@mhra.gov.uk with subject line “Clinical Trial Registration” within six weeks of recruiting the first research participant. You should also let the REC 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 (IRAS). Further information on the process is available via the Health research Authority website.

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 for each manufacturing site if the product is manufactured outside the EU. Further guidance covering this area.
  • 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 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:

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 MHRA_CT_Ecomms@mhra.gov.uk 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.

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.

Risk Proportionate Approaches

A risk proportionate approach to the initiation, management and monitoring of certain clinical trials is possible. The sponsor should carry out a risk assessment based on the potential risks associated with the IMP. View our guidance on risk-adapted approaches to the management of clinical trials of investigational medicinal products.

We will perform a risk adapted assessment of certain ‘Type A’ trials in which the risk to the patient from the IMP is considered to be no greater than that of standard medical care. These are trials involving medicinal products licensed in any EU Member State if:

  • the trial relates to the licensed range of indications, dosage and form of the product, or;
  • the trial involves off-label use (such as in paediatrics and oncology) that is established practice and supported by enough published evidence and/or guidelines.

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. 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 clintrialhelpline@mhra.gov.uk 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 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 (clintrialhelpline@mhra.gov.uk; approvals@hra.nhs.uk) that the application is planned and it requires EAG/CHM review to ensure an appropriate REC meeting is scheduled. The submission should be made no later than 21 days before the date of the CTBVEAG meeting it will be discussed at, but ideally much earlier to enable a smooth review process. Applications that are received later will be assigned to the next available meeting.

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 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.

Please see the Make a payment to MHRA section on how to pay relevant 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. Applications under the Notification Scheme do not incur a fee.

Invoices for Clinical Trial Authorisation applications, and Substantial Amendment applications 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. 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 020 3080 6533 or email sales.invoices@mhra.gov.uk 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 020 3080 6456 (Monday to Friday 8:30am to 4.30pm) or email clintrialhelpline@mhra.gov.uk. See Clinical trials named contact for further information.

Published 18 December 2014
Last updated 7 January 2022 + show all updates
  1. Included information about the new combined review service.

  2. Updated the note regarding CTIMP applications

  3. Updated the information regarding the combined review service.

  4. Updated details on 'When a clinical trial authorisation (CTA) is needed'

  5. Update about the 'SCOPE' advice service. From October 2021 the ‘SCOPE’ advice service will only be available via self-service using the guidance on this webpage.

  6. Updated guidance for the registration of clinical trials.

  7. Following the end of the transition period, removed information about using EC systems like CESP, published new information about the notification scheme and submitting a clinical trial authorisation application form.

  8. Change to covering letter requirements and fees section

  9. Added contact information on Clinical Trial Application form section.

  10. New information and 'request form' added to the section 'when a clinical trial authorisation is needed'.

  11. Addition of document covering Points to consider for trials allowing inclusion of patients previously treated with an Advanced Therapy Medicinal Product

  12. Updated common errors PDF.

  13. Additional information added to the section: Documents to send with your application.

  14. Updated clinical trial mock examples.

  15. Information about proof of payment requirements updated.

  16. Updated to include a link to guidance on common issues identified during clinical trial applications and how to avoid them.

  17. Updated contact information for fee section.

  18. Additional information about applications for trials involving CAR-T cell medical products added to the page.

  19. Updated contact information.

  20. Contact information updated.

  21. Updated information under 'Assessment of your submission’.

  22. Physical media submissions (CD/DVD) for medicines licences and clinical trial applications will not be accepted from 1 February 2016.

  23. First published.