You may need to carry out a clinical investigation as part of the process to obtain a UKCA, / CE or/ 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.

ForUse studies in Great Britain, use this flow chart to decide if you are required to submit a formal clinical investigation.

ForPlease studiesnote: in Northern Ireland or Great Britain and Northern Ireland, use the flow chart and accompanying guidance in the Northern Ireland section below.

Note: applications under Annex XVI of the Medical Device Regulation (EU) 2017/745 (MDR)(MDR) for devices with no intended medical purpose cannot be accepted in GB.

Clinical investigation enquiries

For any specific enquires relating to applications for clinical investigations,investigations contact please submit your enquiry to info@mhra.gov.uk and ensure you add ‘clinical investigation enquiry’ in the subject line.line so it can be managed appropriately.

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Validation checklistChecklist

When we receive your application for a clinical investigation of a medical device our regulatory handers will validate your application against the Clinical investigation application checklistcheck list. UseWe hope that in providing this checklist toit helpwill support you submitin submitting a valid application.

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Assessment

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

When wethe MHRA has have received your documents and validated them, we will contact to you within 5 working days to confirm that the 60-day assessment period has started, or we will let you know if there are any issues. If wethere raiseare any issues,issues raised, the 60-day assessment period 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 application. For example, if an application is received on 24 August and the assessor validates the submission on 28 August, the clock starts on 29 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. We willThe MHRA will write to you if we require further information. It is essential that you contact us asthe MHRA as soon as possible if you require clarification.

If there are possible grounds for objection, where possible we will arrange a teleconference for a better understanding and to find a resolution within the 60-day assessment time.

WeA letter will sendbe yousent ato letteryou by the 60th day with a decision (‘objection’ or ‘no objection’) as to whether or not you can carry out the proposed clinical investigation.

Payment for a Clinical Investigation

You will need to pay a fee for your clinical investigation (see Fees above).

Please provide the following information when applying for your clinical investigation, this will enable accurate and timely invoicing:

• Company name and full address
• Contact name and email address of the individual responsible for paying the fee
• If applicable a company invoice or transaction number

Once you have received your invoice and made the payment, please provide evidence of payment by email, quoting the MHRA reference (CI/XXXX/XXX).

Please send to: CI-applications@mhra.gov.uk

Serious adverse event (SAE) reporting

This section concerns clinical investigations with sites in Great Britain,Britain only, and clinical investigations with sites in both Great Britain and Northern Ireland. Please see the the separate section below for for studies with Northern Ireland sites only (no sites in Great Britain).only.

In line with UK Regulations and MEDDEV 2.7/3, all reportable events must be fully recorded and notified to the the MHRA. This includes all serious adverse events, irrespective of whether the device has been assessed as having a causal relationship, and reportable events (per MEDDEV 2.7/3) occurring in third countries in which a clinical investigation is performed under the same clinical investigation plan. 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 the required information is included.

Please submit an SAE reporting form in the new MORE portal with your completed table attached.

See details on how to register for the MORE portal.

MEDDEV 2.7/3 also contains further guidance on clinical investigation reporting in Great Britain.

Quarterly summary reports

As aper conditionthe conditions of MHRA approval for a clinical investigation, in addition to the reporting of individual serious adverse events as detailed above, youplease mustprovide sendQuarterly usSummary quarterlyReports summarythat reportsshould providingprovide an update on the latest overall safety profile for the investigation.

ToWhen provideproviding these summaries, use the  QSR Template Guidance V2 (PDF, 140 KB, 5 pages). This template is for devices only but you should also usebe itused for device-related reporting on any combined studies. Do not include detail on any investigationalInvestigational medicinalMedicinal productProduct (IMP)(IMP) under investigation.

Submit yourQuarterly quarterlySummary summary reports should be submitted directly throughvia https://more.mhra.gov.uk/login

End of study reports

EmailPlease email your end of study report to CI-applications@mhra.gov.uk.

Study deviationsDeviations

Sponsors must notify the MHRA of all deviations (relatingrelating to UK study sites only)only as soon as they arehave been made aware of them. IncludeDetails details about the nature of the deviation, when it occurred, where it occurred, and any proposed corrective and preventative actions.actions should be provided.

Use the following MHRA protocol deviation tracker 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 the MHRA to have a complete overview each time it is submitted.

Send the completed spreadsheet byto the MHRA via email to at info@mhra.gov.uk.

Coordinated assessment pathway process

MHRA is collaborating with the Health Research Authority (HRA) on the coordinated assessment pathway which involves our two organisations sharing information during our assessment of medical device clinical investigations. For this process we require the MHRA Devices application to be submitted first and then the REC application to be submitted as soon as MHRA has confirmed the devices application to be valid.

See MHRA / HRA Coordinated pathway for further information.

Combined review of a CTIMP and medical device

Combined review is the way research teams requestseek approval for clinicalnew trialsClinical Trials of investigationalInvestigational medicinalMedicinal productsProducts (CTIMPs)(CTIMPs) and combined medicine and device trials.

Research teams make a single application using a new part of IRAS, which goes to both the 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.HSC.

The regulatory and ethics reviews takeare placedone 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-wideStudy 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.

Amendments

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

Once you’ve received a letter of no objection from us, you must notify us ofthe MHRA of all proposed amendments to the investigation. You must wait until we send you another letter of no objection before you makeimplement 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 dodon’t not tell us about proposed amendments,amendments you could be liable to prosecution.

BeginPlease begin your amendment submission on HRA IRAS.

ReferYou can refer to the IRAS userUser guideGuide’s section on amendments.

When you notify the MHRA of amendments, includewe require the following:following information:

• a covering letter with the MHRA reference number for the clinical investigation (for(e.g. example,CI/2023/XXXX). CI/2023/XXXX)Please -ensure make sure you include the following details for thewho personis making the amendment payment:
  • payment are included: a. company name and full address
  • b. contact name and email address of the individual responsible for paying the fee
  • if c. If applicable a PO number or transaction number
• a table with a summary of each proposed change with the justification 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
• proof of paymentpayment. (followPlease follow the payment process as outlined in the section below)below.

If

Incomplete youSubmissions. doWhere not follow the above guidance above,is thenot submissionfollowed, it will beresult returnedin tothe you.

submission being returned.

Email the amendments to 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. WeOnly will only process amendments submitted to this mailbox.mailbox will be processed. Do not submit amendments to individuals or any other mailbox.

Payment for an amendmentAmendment

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

Note: wePlease donote: MHRA does not consider an amendment submission valid until we have received all required documents (including proof of payment).payment) Wehave been received. The Agency will not review the amendment or provide a final regulatory decision (approval or objection letter) until this time.

ToPayments makecan be made online via Make a payment:payment to MHRA.

Please note the following updated process:

1. Make a payment via Make a payment to MHRA quoting the MHRA reference ref (CI/ XXXX/XXXX) and the amendment number (for(e.g. example, amendment No1) as the invoice number.
2. Once you have made the payment, please submit your amendment to CI-amendments@mhra.gov.uk including all the documents required as stated above.

Ensure that you provide evidence of payment is provided and quote the MHRA reference number (CI/XXXX/XXX) and amendment number as the email subject.

After you have received the decision letter for your amendment,amendment you will receivebe sent an official invoice. ThisPlease note this is for your records only and no further action is required.

Early termination or temporary halt of a clinical investigation

Sponsors mustare required to notify usthe MHRA of the early termination of a clinical investigation and provide a justification for the early termination as stated in Regulations 16(11) and Section 29(10) of the UK MDR 2002.

SendThe MHRA may request a copy of the final written report of a clinical investigation of a device falling within the scope of the UK MDR 2002 (Regulations 16(10) and 29(9)) to CI-applications@mhra.gov.uk.29(9)).

Sponsors shouldare also requested to notify usthe MHRA of a temporary halt of a clinical investigation.

Send the notifications to to the MHRA via email at info@mhra.gov.uk.

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)(MDR) and the in vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR)(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 requiring application to the MHRA (which involve a site in Northern Ireland) must be submitted to the MHRA in line with the requirements of EU MDR 2017/745.

Note: This 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.

For clinical investigations involving a site in Northern Ireland, please use this flow chart and accompanying guidance to determine if you needare required to submit an application to the MHRA.

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 applicationsApplications

When wethe haveMHRA 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,started or we will let you know if there are any issues. If there are any issues,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, wethe application is still considerconsidered theto applicationbe 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,assessment experts will assess the safety and performance of your device as well as the design of the clinical investigation to be carried out.

We The MHRA will write to you if we needrequire further information. It is essential that you contact usthe MHRA as soon as possible if you needrequire 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, wethe MHRA will inform you of our decision within 45 or 65 calendar days as per the EU MDR.MDR. This period will be suspended ifin 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.

WeA letter will sendbe yousent ato letteryou by the final day (oror before)before with a decision as to whether or not you can carry out the proposed clinical investigation.

Serious Adverseadverse Eventevent (SAE) Reporting under Regulation (EU) 2017/745reporting

This section concerns clinical investigations with sites in Northern Ireland (butonly.  no sites in Great Britain).  For studies with sites in Great Britain,Britain only, or for studies conducted in both Great Britain and Northern Ireland, please see the separate section above.

The reporting requirements of Regulation (EU) 2017/745 apply to these studies.
The sponsor shall fully record all of the following:

• any adverse event of a type identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation;
• any serious adverse event;
• 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;
• any new findings in relation to any event referred to in points (a) to (c).

The sponsor shall report, without delay to MHRA, all the following:

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

Reports can be provided using the MDCG 2020-10/2 SAE reporting table.
Please submit an SAE reporting form in the MORE portal with your completed table attached.
See details on how to register for the MORE portal.

MDCG 2020-10 also contains further guidance on clinical investigation reporting for Northern Ireland.

For enquiries please see the above section of this guidance page.

Amendments/modifications

Once you’ve received authorisation from us to conduct the clinical investigation inwithin Northern Ireland, you must notify usthe MHRA of all proposed modifications to the investigation before youthey makeare anyimplemented. changes. You must wait until we send you another letter of authorisation before you makeimplement substantial modifications. Depending on whether we consult experts, we will sendissue you our decision within 38 or 45 calendar days.

You must tell us about all modifications, but 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 only need to notify us to ensure our records are up to date. If upon review of the proposed non-substantial modification, wethe MHRA consider it to befall inwithin the substantial category, wethe MHRA will inform the sponsor, and the proposed modification should not takebe placeimplemented 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 usthe 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.

YouThe notification must makebe themade notification at least 30 days beforeprior startingto commencing the study.

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

• application form
• investigator’s brochure
• clinical investigation plan or 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

SubmitApplications yourare applicationsubmitted electronically using the Integrated Research Application System (IRAS).

Early termination or temporary halt of clinical investigation

Sponsors mustare required to notify the MHRA of the temporary halt or early termination of a clinical investigation and provide a justification within 15 days, or 24 hours if the decision was taken on safety grounds. The clinical investigation report and summary must be provided within 3 months for such studies that are temporarily halted or terminated early.

Medical devices: clinical investigations and performance studies in Northern Ireland

Information about changes to the operation of certain clinical investigations and performance studies in Northern Ireland.

Certain clinical investigations and performance studies that take place in Northern Ireland require the sponsors to be established either in Northern Ireland or the EU or to have a legal representative established in Northern Ireland or the EU.

The rules that apply (Medical Device Regulation (Regulation 2017/745) (MDR)(MDR) and In Vitro Diagnostics Regulation (Regulation 2017/746) (IVDR)(IVDR) allow the UK to disapply these rules.

This requirement applies if the investigation or study is only taking place inwithin its territory and not in the EU. Therefore, the MHRA is disapplying the requirement for the sponsor or their legal representative of a clinical investigation or performance study to be established in Northern Ireland or the EU, provided all of the following conditions are met:

• the investigation or study must also be taking place in both Northern Ireland and Great Britain
• the investigation or study must not be taking place in an EU member state
• the sponsor must be either established in or have a written agreement with a legal representative in Great Britain, who is responsible for ensuring compliance with the sponsor’s obligations in the MDR or IVDR
• the sponsor must establish a contact person in Northern Ireland for the clinical investigation or performance study, who will be the addressee for all communications with the sponsor provided for in MDR or IVDR
• any communication with that contact person is deemed to be communication with the sponsor

All remaining requirements under the MDR and IVDR apply. This guidance will take immediate effect.

For further information, contact the MHRA on info@mhra.gov.uk.

In vitroVitro diagnosticDiagnostic medicalMedical devicesDevices (IVDs)

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

This includes IVD devices used in clinical trials of medicines (CTIMPs)(CTIMPs) to stratify patients for inclusion/exclusion in the trial or stratified to a cohort inwithin a trial.

At the time of the clinical trial application, where clinical performance of the IVD device is yet to be demonstrated, for CTIMPs taking place in GB, the IVD device must have demonstrated evidence supplied to the MHRA for the analytical performance of the IVD (for(e.g. example, detection of a biomarker) as summary reports of each study or protocol. This will include reagents, equipment, calibrators, controls and software. For use of IVD devices in CTIMPs conducted in Northern Ireland, refer to guidance available on Clinical investigations and performance studies in Northern Ireland.

Alternatively, if the analytical performance study has not takenbeen place,conducted, the sponsorSponsor must provide the MHRA with a tabularTabular summarySummary (MS Word Document, 49.7 KB) description of the analytical methods,methods including acceptance limits and parameters for performing validation. YouPlease should supply the contents requested without modifying the template structure.

Trials which determine the clinical performance of the assay mustwill need to be registered as as IVD performance evaluation studies.studies.

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

Special circumstances for healthcare establishments

You do not need to notify usthe 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 productproduct.

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)(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.