How to apply for a clinical trial including eligibility, phases, model IMPDs, costs and how to make changes to your application.
To apply, you must be the sponsor of the trial, or someone authorised by them. If you are not established in the European Community then your legal representative must make the application.
When a clinical trial authorisation (CTA) is needed
Use MHRA’s online algorithmto 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 EU directive
You can also read theto help you decide if your study needs a CTA.
If you are still unsure, email a copy of the protocol (the document describing the objectives, design and methodology) to firstname.lastname@example.org, with ‘Scope - protocol review’ followed by the study title (shortened)’ as the subject line.
This advice relates to clinical trials of medicinal products. If your query relates to a clinical investigation of a medical device please contact email@example.com
You’ll need a EudraCT number.
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 MHRA.
Clinical trial application form
You must create XML and PDF versions, save and sign them electronically, and submit them with the rest of the required documents.
Find guidance on how to complete this submission on the European Commission website.
Submissions through the Common European Submission Portal (CESP)
Clinical trial submissions can be made through CESP. This system is available from the Heads of Medicines Agencies (HMA) and provides a simple and secure mechanism for exchange of information between applicants and regulatory agencies.
The purpose of the system is to:
- provide a secure method of communicating with regulatory agencies via one platform
- allow submission of an application once to reach all required agencies
- reduce the burden for both industry and regulators of submitting/handling applications on CD-ROM and DVD
If you are a first time CESP user and wish to setup up an organisation/university or trust to manage multiple users on the system, register with CESP here.
If you are a standalone user and wish to upload for Non Commercial Use on your own behalf, register with CESP here.
Once registered you will receive credentials to access the portal to your registered email address.
General CESP training is available to all registered users via CESP’s training menu once logged into the system. Training on demand videos are available and you can also sign up to our free online weekly live demonstrations. CESP encourage all users to attend training before using the system. View FAQs here.
Clinical trial applicants can also view the MHRA Clinical Trials Guidelines document.
Clinical trial phases
There are 4 phases of a clinical trial and a product can only go to the next phase if it has passed the safety and effectiveness tests of the previous one. Your application must specify the phase.
Phase I trials, sometimes called first-in-human trials, test a small number of subjects to find out how the treatment works in the body. This type of trial aims to find the lowest dose at which the treatment is effective (the minimum therapeutic dose) and the highest dose at which it can be taken without causing harm.
Phase II trials test the treatment in several hundred people with a given disease or condition. They aim to find out how well the treatment works in larger numbers, identify common side effects, and refine the dose and length of treatment.
Phase III trials typically compare the treatment across several thousand patients to gather more detailed information on how well it works in groups of patients and its safety. The results influence the prescribing and patient information of a medicine once it is marketed.
Trials are carried out after a medicine has been licensed and put on the market. These trials are designed to find out more about the long term harms and benefits of a medicine and to discover new uses for it.
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.
Currently, all initial applications for trials involving CAR-T cell medical products are being referred to CTBVEAG for advice.
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
Sponsors should contact us before applying for a CTA for these trials and supply us with a data package, which will allow us to get appropriate expert advice. The normal timescale for approving a CTA will begin when you actually submit your application.
If you are a sponsor of a FIH trial you should read the CHM guideline on strategies to identify and mitigate risks for first-in-human 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 firstname.lastname@example.org 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’, you should select the date of the CTBVEAG/CHM meeting you want your trial discussed at. You should then prepare a data package containing:
- the IMP dossier
- the investigator’s brochure
- the protocol
- responses to required CHM areas for discussion (see below)
- manufacturer authorisation(s)
- a qualified person (QP) declaration on good manufacturing practice (GMP) (if necessary)
- a summary of scientific advice from any member state or the European Medicines Agency (EMA), if available *a covering letter
You should submit the data package to us by sending an email titled ‘URGENT – FIH SUBMISSION’ to email@example.com or using Eudralink. Fill out the Eudralink account request form to get an account. You should submit it no later than 21 days before the date of the CTBVEAG/CHM meeting it will be discussed at.
The application form/xml file should be sent by email during the week of the CTBVEAG/CHM meetings.
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.
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 be therefore justifiable.
identifies the main points to consider when proposing trials of an IMP administered after previous ATMP use.
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)
- 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 from any Member State or the European Medicines Agency (EMA), 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
- a copy of the 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 password-protected documents. You must provide a file for each section of the submission, even if you don’t have to provide the documents as part of your application. If you do not need to include documents in a section, you must insert a document which gives an explanation for why the document has not been supplied.
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.
You can submit your applications using the Common European Submission Platform (CESP).
We’ve produced guidance on.
Example investigational medical product dossiers (IMPDs)
If you are carrying out a trial using modified established medicines, MHRA has produced some mock examples of completed IMPDs which set out our minimum requirements:
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 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 MHRA within 60 days of us receiving the original valid application.
Notification of 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.
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.
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 a decision on authorisation is reached. It is not possible to withdraw an application once grounds for non-acceptance has 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.
You must also send a signed, formal letter 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, you must state that it is a re-submission in the covering letter and on the application form.
Common issues identified during clinical trial applications
More than half of all applications 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.
This guidance sets out the most common issues and how to avoid them.
The sponsor should carry out a risk assessment based on the potential risks associated with the IMP. View our guidance on,
We provide a notification scheme for certain lower-risk trials, defined as ‘Type A’ trials. In these cases, the risk to the patient from the IMP is considered to be no greater than that of standard medical care.
Trials under the notification scheme also have simplified requirements for conducting the trial. Our guidance documentgives more information about these requirements.
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
- 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
There are different fees based on your type of clinical trial application.
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.
You can contact MHRA Finance Department on 020 3080 6533 or email firstname.lastname@example.org for more information on how to pay fees.
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 email@example.com See Clinical trials named contact for further information.