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.

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

The service is open now to all CTIMP sponsors and applicants. If you have any new CTIMP applications planned over the coming weeks or months, then they should be submitted via combined review. To register, make a submission, or to get more information, please refer to the Health Research Authority website.

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 about 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 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

Any favourable opinion given by a UK Research Ethics Committee is subject to the clinical trial being registered on a publicly accessible database. The Health Research Authority (HRA) has made a commitment in its Make It Public research transparency strategy, in the long term, to register clinical trials on behalf of sponsors and researchers. Until this system is place 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 Research Ethics Committee (REC) know your registration number as soon as possible.

Ethics committee

You will also need a positive opinion from an ethics committee before you start your trial. You can get this before, at the same time or after you have made your submission to the MHRA.

Clinical trial authorisation application form

You’ll need to complete the form on the Integrated Research Application System (IRAS) and include a EudraCT number.

You must create XML and PDF versions of the MHRA application form, save and sign them electronically, and submit them via MHRA submissions with the rest of the required documents.

Documents to send with your application

Your submission package must include:

  • a covering letter (when applicable, the subject line should state that the submission is for a Phase I trial and is eligible for a shortened assessment time, or if it is submitted as part of the notification scheme). Your covering letter should clearly highlight your Purchase Order (PO) number; this will help us to invoice and allocate your payments promptly and efficiently
  • a clinical trial application form in PDF and XML versions
  • a protocol document
  • an investigator’s brochure (IB) or document replacing the IB
  • an investigational medical product dossier (IMPD) or a simplified IMPD (note an ASMF is not acceptable)
  • a non-investigational medicinal product dossier (if required)
  • a summary of scientific advice obtained from the MHRA or any other regulatory authority, if available
  • 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.
  • a copy of the UK or EMA’s decision on the paediatric investigation plan and the opinion of the paediatric committee, if applicable
  • the content of the labelling of the investigational medicinal product (IMP) (or 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).

The information you provide in the submission package will be used to validate your application. Incomplete applications will be rejected. The naming of your files is important and clearly naming files in your submission will reduce validation issues.

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:

Submitting your application

Clinical trial submissions should be made through MHRA submissions. Further details on how to register and submit via this platform.

Assessment of your submission

The initial 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 (average 14 days). 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 subjects may not be eligible for the expedited assessment timeframe.

We will tell you the outcome of your submission, 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 do not accept your submission you will be told why and will usually have to amend your application and resubmit.

Letters informing the applicant of the MHRA’s decision relating to an amended request for a general medicinal product (Reg 18) or a product with special characteristics (Reg 20) will be sent by the MHRA within 60 days of us receiving the original valid application.

Notification of the MHRA’s decision relating to an amended request for a gene therapy, somatic cell therapy (including xenogenic cell therapy) product or products containing genetically modified organisms (Reg 19) 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.

Change your application before or during assessment

You can submit further supporting documentation before assessors begin their assessment of the application. You can’t send additional documents once we have begun assessment.

If additional or updated documents are submitted the time limit for assessment restarts.

You should submit updated or additional documentation to us by email.

Email: clintrialhelpline@mhra.gov.uk

The email must be sent by the contact person listed in the application form and must be entitled:

‘Changes to submitted documentation/additional documentation to CTA (Number XXXXX/XXXX/XXX-XXXX) - EudraCT Number XXXX-XXXXXX-XX.’

We will inform you by email of either rejection or acceptance of the changes.

If the request is accepted the date of your email will be reflected on your acknowledgement letter.

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, you must send an email entitled ‘Withdrawal of CTA – EudraCT Number XXXX-XXXXXX-XX.’ The email must be sent by the contact person listed in Section C.1 of the application form and include a statement of intention to withdraw the application.

Email: clintrialhelpline@mhra.gov.uk

You must also attach a signed, formal request to withdraw the application on company-headed paper including:

  • the EudraCT number, CTA number (if available) and protocol number of the application to be withdrawn
  • a brief description of the reasons for withdrawing the application

Once we receive the formal letter, it will be processed within 5 days and an acknowledgement email will be sent to you to confirm that the application has been withdrawn.

If you want to resubmit your application after withdrawing it (or if it is rejected), you must state that it is a re-submission in the covering letter and on the application form.

Notification scheme

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 provide a notification scheme for 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 made under the notification scheme must include:

  • covering letter which includes the statement that this is a submission under the notification scheme
  • Clinical Trial Authorisation application form + valid xml
  • protocol
  • Summary of Product Characteristics (SmPC)
  • justification for absence of labelling (or the content of trial-specific labelling if this will be used)
  • justification for the absence of a manufacturer’s authorisation (or a copy of the authorisation for each manufacturing site involved in repackaging of the marketed product, where this site is not a hospital or health centre).

Following submission, the notification will be acknowledged by the MHRA with a letter to say that the trial may go ahead after 14 days from receipt of notification, if the MHRA has not raised any objections. This means that the acknowledgement letter will act as the authorisation.

If no Notification Objection letter is received from the MHRA the clinical trial authorisation becomes valid. The applicant will also receive email confirmation, from the clinical trial helpline, that no objection to the notification has been raised.

If the MHRA raises an objection to the notification, the submission is treated as a standard request for authorisation and an assessment of the submission is carried out. This may result in either:

a) acceptance of the request for a clinical trial authorisation subject to conditions, or;

b) grounds for non-acceptance of the request for a clinical trial authorisation.

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), eg 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 eg 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 – FIH 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 or CHM meeting where you want your trial discussed.

You should then prepare your submission package as described above, with the exception of the application form, but including your responses to the required CHM areas for discussion (see below) and send directly to the Clinical Trials Unit email clintrialhelpline@mhra.gov.uk with ‘URGENT – FIH SUBMISSION’ as the subject line. Alternatively, the documents can be sent via MHRA MOVEit. To request access to MHRA MOVEit, please contact clintrialhelpline@mhra.gov.uk. You should submit it no later than 21 days before the date of the CTBVEAG/CHM 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.

We will assess the information provided and may provide feedback on the content and completeness of the data package. A formal letter with questions to the sponsor will be sent as soon as possible (but no later than 14 days) after the CTBVEAG 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 Annex 1 form, or section D1 of the Annex 2 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 further 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 26 October 2021 + show all updates
  1. Updated the note regarding CTIMP applications

  2. Updated the information regarding the combined review service.

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

  4. 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.

  5. Updated guidance for the registration of clinical trials.

  6. 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.

  7. Change to covering letter requirements and fees section

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

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

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

  11. Updated common errors PDF.

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

  13. Updated clinical trial mock examples.

  14. Information about proof of payment requirements updated.

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

  16. Updated contact information for fee section.

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

  18. Updated contact information.

  19. Contact information updated.

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

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

  22. First published.