Notify the MHRA about a clinical investigation for a medical device

You may need to carry out a clinical investigation as part of the process to obtain a UKCA / CE / CE UKNI marking for your medical device. You must inform the MHRA if you are planning to do this at least 60 days before starting your investigation.

To enable you to decide if you are required to submit a formal clinical investigation please use this flow chart

Medical devices clinical investigations during the coronavirus (COVID-19) outbreak

How to notify the MHRA of your clinical investigation

A notification to the MHRA will not be required for medical devices that are UKCA / CE / CE UKNI marked for the purpose that is under investigation.

Validation Checklist

When MHRA receive your application for a clinical investigation of a medical device our regulatory handers will validate your application against this checklist Validation Checklist- GB New Submissions (MS Word Document, 113 KB) we hope that in providing this checklist it will support you in submitting a valid application.

MHRA guidance

Follow the guidance on compiling a submission (PDF, 211 KB, 16 pages) and guidance for manufacturers when preparing your notification application.

Applications are submitted electronically using the Integrated Research Application System (IRAS)

See information for clinical investigators (PDF, 144 KB, 10 pages) for what is required by clinicians involved in the investigation.

Check the information on the biological safety assessment (PDF, 150 KB, 8 pages) for the scientific data you must submit.

Check statistical considerations (PDF, 163 KB, 14 pages) for presenting statistical information for your clinical investigation.

Check guidance on applying human factors and usability engineering to medical devices including drug-device combination products.

See the guidance on UKCA markings.

Fees

The Medical Devices (Fees Amendment) Regulations 2017 came into force on 1 April 2017. These regulations include the introduction of new fees for amendments to clinical investigations.

You do not need to attach proof of payment to applications. You will receive an invoice to allow you to make payment for the correct amount once your application has been validated.

Information on how to notify the MHRA about an amendment for a clinical investigation can be found below under Amendments. Information on the applicable fees are available using the link below.

Please note: The fee rate is based on a single investigational device being used in a study. Where two or more investigational devices are being used and there is no functional relationship between them, the fee will be increased to reflect the additional workload to the MHRA. For further clarification, contact info@mhra.gov.uk

Assessment

This section concerns clinical investigations being conducted in Great Britain only. Please see the separate section below for studies involving Northern Ireland.

When the MHRA has received your documents and validated them, we will write to you within 5 working days to confirm that the 60-day assessment has started or we will let you know if there are any issues. If there are any issues raised, the 60-day assessment will start when we receive a valid response.

Day 1 of the 60 days is taken as being the first day that follows the date of acceptance of a valid Notification. For example, If an application is received on 24th August and the assessor validates the submission on 28th August, the clock starts on 29th August.

During the assessment, experts will assess the safety and performance of your device as well as the design of the clinical investigation to be carried out. The MHRA will write to you if we require further information. It is essential that you contact the MHRA as soon as possible if you require clarification. Where possible we will arrange a teleconference for a better understanding and to find a resolution within the 60-day assessment time, if there are possible grounds for objection.

A letter will be sent to you by the 60th day with a decision (‘objection’ or ‘no objection’) as to whether or not you can carry out the proposed clinical investigation.

Serious adverse event (SAE) reporting

This section concerns clinical investigations being conducted in Great Britain only. Please see the separate section below for studies involving Northern Ireland.

All serious adverse events, whether initially considered to be device/procedure related or not, involving a device under clinical investigation within Great Britain should be reported to the MHRA.

These can be provided using either the MEDDEV 2.7/3 SAE reporting table, or the MDCG 2020-10/2 SAE reporting table, as long as all SAEs are included.

Please submit an SAE reporting form in the new MORE portal with your completed table attached. If you have not yet registered for the MORE portal, details on how to do so can be found here: MORE Registrations - user reference guide - GOV.UK (www.gov.uk)

Quarterly Summary Reports

In addition to the reporting of individual serious adverse events as detailed above, please provide quarterly summary reports of all serious adverse events.
When providing these summaries please include in tabular format the following information broken down by event type:

• number of serious adverse events
• number of participants affected by those events
• percentage of the total number of enrolled participants affected by those events

When providing this table, please ensure it contains information on SAEs for the entire duration of the trial, not just those which have occurred during this quarter.

Event type	Number of events	Number of participants affected	% of participants affected	Expected % rate of SAE - (based upon literature of similar devices or alternative treatments)
e.g. Stroke
e.g. Heart Failure

Please also include a summary analysis of the serious events together with the manufacturer’s conclusions.

Please submit an SAE reporting form in the new MORE portal with your completed table attached. If you have not yet registered for the MORE portal, details on how to do so can be found here: MORE Registrations - user reference guide - GOV.UK (www.gov.uk)

Study Deviations

Manufacturers must notify the MHRA of all deviations relating to UK study sites only as soon as they have been made aware of them. Details about the nature of the deviation, when it occurred, where it occurred, and any proposed corrective and preventative actions should be provided.

Please use the following Excel template when reporting deviations and keep this as a ‘live’ document so that new deviations can be added. This enables both the sponsor and MHRA to have a complete overview each time it is submitted.

Please send the completed spreadsheet to the MHRA via email at info@mhra.gov.uk.

Coordinated assessment pathway process

The MHRA is working with the Health Research Authority (HRA) to develop a new coordinated assessment pathway which will streamline the review of clinical investigations involving medical devices.

During this phase of testing the MHRA Medical Devices review and the Research Ethics Committee (REC) review are being completed in parallel and information will be shared. If you would like more information on the pathway please read the guidance.

Amendments

This section concerns clinical investigations being conducted in Great Britain only. Please see the separate section below for studies involving Northern Ireland.

Once you’ve received a letter of no objection from us, you must notify the MHRA of all proposed amendments to the investigation. You must wait until we send you another letter of no objection before you implement the changes.

You must tell us about any changes made to:

• the device under investigation
• study documentation, including the clinical investigation plan
• investigators or investigating institutions
• changes requested by an ethics committee

If you don’t tell us about proposed amendments you could be liable to prosecution.

When you notify us of amendments, we need the following information:

• covering letter with:
  • the MHRA reference number for the clinical investigation
  • a table with a summary of each proposed change with the reason for each change

• red lined (showing changes being made) and clean copies of all amended study documentation

• a signed statement by, or on behalf of, the manufacturer that the proposed change(s) do not predictably increase the risk to the patient, user or third party

• details of who to invoice (full company name, address and registered tax/VAT number)

You can send us the amendments by email using the following email address CI-amendments@mhra.gov.uk unless the files are too big, in which case contact us at the same email address to request a link for uploading the documents. Only amendments submitted to this mailbox will be processed and you should not submit amendments to individuals or any other mailbox.

You will need to pay a fee for amendments to clinical investigations (see Fees above).

Northern Ireland

The Northern Ireland Protocol requires Northern Ireland to continue to align with EU rules for devices after 1 January 2021. Therefore, the Medical Device Regulation (EU) 2017/745 (MDR) and the in vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR) will apply in Northern Ireland from 26 May 2021, and 26 May 2022 respectively, in line with the EU’s implementation timeline.

All clinical investigations involving a site in Northern Ireland must be submitted to the MHRA in line with the requirements of EU MDR 2017/745. This single application will also cover any sites proposed in Great Britain in addition to site(s) in Northern Ireland for the same clinical investigation.

The following sections provide guidance for these applications and the requirements for amendments and post market studies involving sites in Northern Ireland.

Assessment of CI Notifications

When the MHRA has received your documents and validated them, we will write to you within 10 calendar days to confirm that the application is valid and the assessment has started or we will let you know if there are any issues. If there are any issues raised we will confirm these in writing and provide a 10 calendar day deadline for a response. The assessment will not start until we have received a valid response. If, after receipt of the response, the application is still considered to be invalid, or the 10 day deadline has expired, we will write to confirm this within 5 calendar days.

Day 1 of the MHRA assessment is taken as being the date that we confirm that we have received a valid application. During the assessment experts will assess the safety and performance of your device as well as the design of the clinical investigation to be carried out. The MHRA will write to you if we require further information. It is essential that you contact the MHRA as soon as possible if you require clarification. If there are possible grounds for refusing authorisation, where possible, we will arrange a teleconference for a better understanding and to find a resolution within the assessment period.

Depending on whether we consult experts, the MHRA will inform you of our decision within 45 or 65 calendar days as per the EU MDR. This period will be suspended in the event that we request additional information for a maximum of 7 calendar days for each request, up to a maximum of 3 requests. Any further requests will not result in a clock stop.

A letter will be sent to you by the final day or before with a decision as to whether or not you can carry out the proposed clinical investigation.

Serious adverse event (SAE) reporting

The following serious adverse events involving a device under clinical investigation within Northern Ireland should be reported to the MHRA:

(a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible;

(b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate;

(c) any new findings in relation to any event referred to in points (a) and (b).

These should be provided using the MDCG 2020-10/2 SAE reporting table.

Please submit an SAE reporting form in the new MORE portal with your completed table attached. If you have not yet registered for the MORE portal, details on how to do so can be found here: MORE Registrations - user reference guide - GOV.UK (www.gov.uk)

Amendments/modifications

Once you’ve received authorisation from us to conduct the clinical investigation within Northern Ireland, you must notify the MHRA of all proposed modifications to the investigation before they are implemented. You must wait until we send you another letter of authorisation before you implement substantial modifications. Depending on whether we consult experts, we will issue our decision within 38 or 45 calendar days.

You must tell us about all modifications, however only those considered to be substantial will require authorisation by the MHRA.

Substantial modification includes:

• changes to the medical device under investigation
• changes to the design or methodology of the clinical investigation, or to background information
• changes to the procedures undertaken by participants
• changes to the risk/benefit assessment for the study
• significant changes to study documentation such as clinical investigation plan, investigator’s brochure, participant information sheets, consent forms, letters to GPs or other clinicians, information sheets for relatives or carers
• appointment of a new chief investigator
• inclusion of a new trial site (not listed in the original application)
• appointment of a new principal investigator at a trial site
• temporary halt of a study to protect participants from harm, and the planned restart of a study following a temporary halt
• a change to the definition of the end of the study
• extension of the study beyond the period specified in the application form
• any other significant change to the protocol
• changes requested by an ethics committee

For non-substantial modifications you are only required to notify us to ensure our records are up-to-date. If upon review of the proposed non-substantial modification, the MHRA consider it to fall within the substantial category, the MHRA will inform the sponsor, and the proposed modification should not be implemented until an MHRA authorisation is received.

Non-substantial modifications are changes that are unlikely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the investigation and include:

• a change of sponsor(s) or sponsor’s legal representative
• a change to the insurance or indemnity arrangements for the study
• minor changes to the protocol or other study documentation, e.g. correcting typographical errors, updating contact points, minor clarifications
• changes to the chief investigator’s research team
• changes to the research team at particular trial sites (other than appointment of a new principal investigator)
• changes in funding arrangements
• minor changes in the documentation used by the research team for recording study data
• changes in the logistical arrangements for storing or transporting samples

Post Market Studies

You must notify the MHRA of all clinical investigations conducted in Northern Ireland involving CE marked devices that also involve procedures additional to the normal conditions of use of the device, that are also invasive or burdensome.

The notification must be made at least 30 days prior to commencing the study.

When you notify us of these clinical investigations, we need the following information:

• Application form
• Investigator’s Brochure
• Clinical Investigation Plan/protocol
• Signed statement
• REC opinion
• Proof of insurance cover or indemnification of subjects
• PIS and IC
• Arrangement to ensure protection and confidentiality of personal data
• Details of the technical documentation (risk analysis, test reports) kept available

Applications are submitted electronically using the Integrated Research Application System (IRAS).

In Vitro Diagnostic Medical Devices (IVDs)

Unless an exemption applies, all IVDs being placed on the market or put into service in the UK are required to have the relevant mark of conformity (UKCA, CE or CE UKNI).

This includes IVDs used in clinical trials of medicines (CTIMP) to stratify patients for inclusion/exclusion in the trial or stratified to a cohort within a trial.

At the time of the clinical trial application, where clinical performance of the IVD is yet to be demonstrated, for CTIMPs taking place in GB the IVDs must have a UK mark of conformity only for the analytical performance of the IVD (e.g. detection of a biomarker). This will include reagents, equipment, calibrators, controls and software. These are likely to be self-certified IVDs under the current medical device regulations. For CTIMP conducted in Northern Ireland separate guidance will be provided.

Alternatively the Sponsor must provide the MHRA with a tabular summary description of the analytical methods including acceptance limits and parameters for performing validation.

Trials which determine the clinical performance of the assay (biomarker validity) will need to be registered as IVD performance evaluation studies.

See guidance on in vitro diagnostic medical devices: guidance on legislation.

Special circumstances for healthcare establishments

You don’t need to notify the MHRA of a clinical investigation if:

• you have manufactured the medical device in-house for your own patients with no objective to place it on the market

You may need to notify the MHRA of a clinical investigation if:

• you want to provide a medical device to another organisation, that up until now has been manufactured in-house for patients, for data to support safety and performance of a commercial product.

See common scenarios for healthcare establishments (PDF, 90.8 KB, 2 pages) which may be relevant to you.

Health Research Authority (HRA) and Health and Care Research Wales (HCRW) Approval

HRA and HCRW approval applies to all project-based research taking place in the NHS in England and Wales. It brings together the assessment of governance and legal compliance, undertaken by dedicated HRA and HCRW staff, with the independent Research Ethics Committee (REC) opinion provided through the UK Research Ethics Service.

It replaces the need for local checks of legal compliance and related matters by each participating organisation in England and Wales. For information on how to prepare and submit an application for HRA and HCRW Approval, refer to the HRA website.

More information

For more details on classifications, see MEDDEV 2.4/1 for guidance on classifications.

If you have any questions before submitting your notification, email info@mhra.gov.uk.

Clinical investigation numbers

The following table provides information on the number of valid clinical investigation applications that have been reviewed by year. Of these, the number withdrawn by the applicant before MHRA issued a decision, and the number objected to along with the most common reasons for objection, are provided.

Year	Completed review	Withdrawn by applicants	Grounds for objection raised	Common reasons for objection
2019	58	6	15	Insufficient evidence provided to demonstrate the appropriate biological safety, clinical or technical effectiveness of the device or poor study design
2020	49	6	9	Insufficient evidence of biological safety, sterilisation and software testing
2021	71	8	12	Insufficient devices validation and sterilisation process qualifications, unclear CE marking status, missing evidence demonstrating the appropriate biological safety, clinical or technical effectiveness of the device or poor study design