This guidance is for manufacturers undertaking a clinical investigation for a medical device. All of the information applies in Great Britain, but different rules apply in Northern Ireland for parts of this process.

The Northern Ireland Protocol requires Northern Ireland to continue to align with EU rules for devices as set out in the the Medical Device Regulation (EU) 2017/745 (EU MDR)(EU MDR) and the the In Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (EU IVDR).(EU IVDR).

Clinical investigations being conducted in Northern Ireland must be submitted for approval in accordance with these regulations. Manufacturers in Northern Ireland should also read our guidance on on where different rules apply when making a submission to the MHRA to to understand where there are additional requirements for their submission.

Clinical investigations being conducted in Great Britain need to meet the requirements of the the Medical Devices Regulations 2002 (SI 2002 No 618, as amended) (UK MDR). (UK MDR).

Where a clinical investigation includes sites in both Great Britain and Northern Ireland, submission to the MHRA must be made in line with the requirements of the EUthe MDR.EU MDR. By meeting the EUthe MDR,EU MDR, requirements of the UKthe MDR forUK MDR for clinical investigations are deemed to be satisfied. Therefore, a single application made to MHRA under the EUthe MDR willEU MDR will cover any sites proposed in both Great Britain and Northern Ireland for the same clinical investigation.

Similarly, if your clinical investigation is being conducted in Great Britain only (no sites in Northern Ireland), your submission may demonstrate meeting the EUthe MDR insteadEU of UKMDR MDR ifinstead of UK MDR if this is the applicant’s preference. You can find out more about how to make a submission under the EUthe MDR inEU MDR in our guidance for for manufacturers in Northern Ireland.

Finally, where a clinical investigation does not currently include Northern Ireland sites, but may wish to include Northern Ireland sites in future, it is recommended that the initial application be made in conformity with EU MDR.

When a clinical investigation is required

Unless:

• anYou exemption applies, or
• they are being used as part of a clinical investigation designed to investigate the performance and safety of the medical device or accessory,

all medical devices to be used on humans must benotify UKCA/CE marked for the purposeMHRA that they are being used for.

In order to be able to UKCA/CE mark any device, a manufacturer must demonstrate that the stated device (referred to in these paragraphs as the “new” device) complies with the relevant essential requirements as listed in Part II and Part III of theyour UKplanned Medical Devices Regulations 2002 (UK MDR 2002), Annex I (as modified by Schedule 2A to the UK MDR 2002) or the general safety and performance requirements (GSPRs) in Annex I of the EU MDR.

To demonstrate such compliance, it will usually be necessary to provide clinical data,investigation, whichif canyou consistplan of:

• aon criticalusing evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the new device, where there is demonstration of equivalence from the new device to the device(s) which the literature refers to, and the data adequately demonstrates compliance with the relevant essential requirements/general safety and performance requirements (GSPRs), or
• a criticalnon-UKCA evaluation of the results of all the clinical investigations conducted with the new device, or
• a criticalnon-CE evaluationmarked ofmedical the combined data provided from the two points above.

Critical analysis and evaluation of scientific literature are broad concepts which can take account of the experience of the new device or of an established device which is already on thehuman marketparticipants and usedan inexemption clinicaldoes practicenot and with which equivalence can be demonstrated in terms of technology, critical performance, design, principles of operation, biological safety, population involved, conditions of use and clinical purpose.apply.

WhenFor seekingstudies to UKCA or CE mark a new device, unless safety and performance can be adequately demonstrated by other means, data generated from a specifically designed clinical investigation of a medical device is likely to be required, in particularGreat withBritain, implantableplease anduse classour IIIguidance to devices.

Indetermine makingif ayou decisionneed as to whethersubmit aan clinicalapplication investigation is required, a manufacturer needs to work through a series of decisions in order to reach a conclusion:to MHRA. 

• What are the essential requirements/general safety and performance requirements relevant to the device in question with which compliance must be demonstrated?
• What data is required in order to demonstrate this compliance?
• What testing is necessary to produce these data e.g. bench testing, animal testing?
• Are clinical data required to demonstrate compliance? If so, do the clinical data already exist on the device in question (published or unpublished) or by analogy with published data generated in respect of an equivalent device (see 2 above).

A clinical investigation of a non-UKCA or CE marked medical device should beat stronglyleast be considered in the following circumstances:

• the device is an implantable or Class III medical device
• youthe areintroduction introducingof a completely new concept of device into clinical practice where components, features and methods of action, are previously unknown
• where an existing device is modified in such a way that it contains a novel feature particularly if such a feature has an important physiological effect, or where the modification might significantly affect the clinical performance or safety of the existing device
• where a device incorporates materials previously untested in humans, coming into contact with the human body or where existing materials are applied to a new location in the human body or where the materials are to be used for a significantly longer time than previously, in which case compatibility and biological safety will need to be considered
• where a device, either UKCA or CE marked, or non-UKCA or CE marked, is proposed for a new purpose or function
• where in vitro or animal testing of the device cannot mimic the clinical situation
• where there is a new manufacturer,manufacturer especially of a high-risk device.

Having established that clinical data collected in a clinical investigation is required for your device, you must notify MHRA of planned investigations in the UK.

For studies in Great Britain, please use our flow chart and guidance to determine if you need to submit an application to MHRA. 

Notifying the MHRA of your planned investigation

You can also find out more about about how to notify us of a planned clinical investigation.

Before devices intended for clinical investigation in Great Britain are made available to a medical practitioner for the purposes of clinical investigation, the manufacturer or UK Responsible Person (UKRP)(UKRP) of the device must give 60 days of prior notice to the Secretary of State for Health by writing to the MHRA.

All notifications should be submitted using the application process on the the Integrated Research Application System (IRAS) (IRAS) portal.

The clinical investigation application form and submission checklist on IRAS helpon IRAS help the MHRA record the applications and accompanying documentation, and applicants ensure that all required information is available and referenced appropriately.

You can find out more about how to compile your application and the process in our our guidance on making a submission. This includes information on what you need to include.

If, within 60 days of formal acceptance of the Notice, the MHRA has not given written notice of objection, the clinical investigation may proceed.

You can find out more about about how we process applications.

The MHRA may give such notice of objection on grounds relating to public health or public policy and the UKthe MDR RegulationsUK MDR Regulations 16(4) and 29(3).

For studies in Great Britain only, there is presently no requirement for manufacturers to appoint a UKRP. a However,UKRP but you may appoint one if you wishwould prefer to.

You can find out more in our guidance on on regulating medical devices.

For studies with sites in Northern Ireland, a representative may need to be appointed in Northern Ireland or the EU. 

You can find out more in our guidance on on regulating medical devices in Northern Ireland.

Complying with clinical investigation requirements

Unless an exemption applies, all medical devices to be used on humans must be UKCA or CE marked for the purpose that they are being used for, unless they are being used as part of a clinical investigation designed to investigate the performance and safety of the medical device or accessory.

In order to be able to UKCA or CE mark any device, a manufacturer must demonstrate that the stated device complies with the relevant essential requirements as listed in Part II and Part III of the UK MDR, Annex I (as modified by Schedule 2A to the UK MDR) or the general safety and performance requirements (GSPRs) in Annex I of the EU MDR.

To demonstrate such compliance, it will usually be necessary to provide clinical data, which can consist of:

• a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where there is demonstration of equivalence of the device to the device to which the data relates and the data adequately demonstrates compliance with the relevant essential requirements and general safety and performance requirements (GSPRs)

• a critical evaluation of the results of all the clinical investigations made

• a critical evaluation of the combined data of the relevant scientific literature and results of the clinical investigation

Critical analysis and evaluation of scientific literature are broad concepts which can take account of the experience of the device in question or of an established device which is already on the market and used in clinical practice and with which equivalence can be demonstrated in terms of technology, critical performance, design, principles of operation, biological safety, population involved, conditions of use and clinical purpose.

When UKCA or CE marking a device, unless safety and performance can be adequately demonstrated by other means, data generated from a specifically designed clinical investigation of a medical device are likely to be required, in particular with implantable and class III devices.

A clinical investigation of a medical device must be designed to establish that the performance claimed by the manufacturer can be adequately demonstrated, and that the device is judged to be safe to use on patients taking into account any risks associated with the use of the device when weighed against the expected benefits.

Such an investigation must:

• verify that under normal conditions of use the performance characteristics of the device are those intended by the manufacturer

• determine any undesirable side effects under normal conditions of use and assess whether these constitute risks when weighed against the intended performance of the device

The legal requirements as to methodology and ethical considerations relating to clinical investigations conducted in Great Britain are set out in regulations 16 and 29 of the UKthe MDR andUK MDR and Part II, Annexes VIII and X (general(medical medical devices) and Part III, Annexes 6 and 7 (active implantable devices) of the UKthe MDR (asUK MDR (as modified by Part II of Schedule 2A to the UKthe MDR).UK MDR).

In particular, the clinical investigation must:

• be performed on a basis of an appropriate plan with well-defined aims and objectives

• make use of procedures appropriate to the device under examination

• be performed in circumstances similar to the intended conditions of use

• include sufficient devices to reflect the aims of the investigation taking into account the risk of the device

• examine appropriate features involving safety and performance and their effects on patients so that the benefit risk balance can be satisfactorily addressed

• fully record all adverse events and report serious adverse events to the MHRA

• be performed under the responsibility of medical practitioners, and include the making of a final written report, signed by the medical investigators responsible, which must contain a critical evaluation of all the data collected during the clinical investigation, with appropriate conclusions

The principles of clinical investigations of medical devices are set out in the standard BS EN ISO 14155:202614155:2020 Clinical investigation of medical devices for human participants - Good clinical practice.

Special circumstances requiring particular data

Change in the intended use or performance claims of a device

Clinical data may be required in the case of a device already authorised to carry the UKCA or CE marking where that device is to be used for a new purpose and eventually UKCA or CE marked for that new purpose. The clinical data may need to be generated by a specifically designed clinical investigation, in which case a notification should be made to the MHRA.

Comparative studies

You are not usually required to notify the MHRA if a device is UKCA or CE marked for the purpose intended or, in the case of a comparative study of two devices, where each has obtained prior UKCA or CE marking, and each is used for their original purpose.

However, relevant ethics committee approval would still be required in both cases.

Where at least one of the devices under study is not UKCA or CE marked, the manufacturers of the non-UKCA or non-CE marked devices must notify the clinical investigation to the MHRA.

Prototype devices

We recognise that a manufacturer may wish to submit a small number of ‘prototype models’ of a device to clinical investigation to assess safety or performance and that such prototypes may need to undergo changes prior to large-scale production.

These changes will be regarded as variations included within one application unless, in the view of the MHRA, the risk to patients or users is increased by the proposed changes. Under these circumstances, we reserve the right to request a new submission in order that the safety aspects of the altered device can be given due consideration with regard to patient health and safety.

Clinical investigations also submitted to the FDA or other regulatory authorities

Manufacturers should clearly indicate whether the UK and non-UK protocols are the same. If not, the areas of difference should be referenced and an explanation of the reasons for the differences provided. It is recognised that the objectives of a clinical investigation which is also being carried out in a country or countries outside the UK, may be wider than those required by the UKthe MDR or EUUK MDR.MDR or EU MDR.

Changes to protocol requested by other regulatory authorities should be copied to the MHRA for information. Manufacturers should indicate whether the changes instigated by the non-UK regulatory authority will also be made to the UK protocol.

HealthIn-house Institutionmanufactured exempted medical devices

Products manufactured in-house in a healthcare establishment and undergoing testing for proof of concept are not subject to the provisions of the UKthe MDR providedUK MDR provided that the device compliesis withbeing themanufactured scope and requirementsused ofon patients within the exemption.sole legal entity. In circumstances where the healthin-house institutionmanufacturer sees and intends a commercial medical application in the results generated (irrespective of whether the healthmanufacturer institution and participants are part of the same legal entity) the healthmanufacturer institution will need to notify the MHRA of a proposed clinical investigation.

You can find further information on the the health institution exemption.

Off-label use

If a clinician uses a UKCA or CE marked device for a new, off-label purpose that is unsupported by the manufacturer, then the clinician and the relevant healthcare establishment may take on the responsibilities of ‘the manufacturer’ if they see and intend a commercial application, and must therefore fulfil all the requirements of a manufacturer as set out in the UKthe MDR,UK MDR, including notification of a clinical investigation to the MHRA. They may also take on liability with reference to the device being used off-label.

You can find out more about the regulation of the the off-label use of medical devices.

Research tools

It is the MHRA’s general opinion that a device being used on humans for research purposes, where there is no intended medical purpose for the device, could be a research tool. However, if a manufacturer sees and intends a medical application in the results generated from testing a device, then the device is no longer a research tool, but falls within the definition of a medical device.

ForWhether morethe information,regulations pleaseapply seeto a device will depend on the sectionsintended purpose foreseen by the device manufacturer. If a proposed clinical study includes investigating use of thisa guidancedevice Medicalfor Purposea medical purpose, then such a study is likely to fall within the remit of the UK MDR or EU MDR and Researchrequire tools.notification to the MHRA as a clinical investigation.

We strongly recommend that manufacturers contact us for guidance on whether the regulations will apply before undertaking a study of this nature.

You should tell us:

• who has manufactured the device

• who is conducting the proposed study

• what the intended purpose of the device is

• what the intended purpose of the proposed study is

• whether any medical application is foreseen for the device

• a copy of the study protocol, where possible

Humanitarian use of non-UKCA or non-CE marked devices

The use of individual non-UKCA or non-CE marked devices may be authorised by the MHRA on humanitarian grounds, provided that the MHRA is satisfied that this would be in the interests of the patient and the protection of health. In such cases, the device may not be used until an application requesting such use has been made by the manufacturer and due authorisation has been given by the MHRA. Our authorisation applies only to the use of the individual device for a named individual within the UK. Failure to comply with these requirements is a criminal offence.

You must must apply for humanitarian use of a non-UKCA or non-CE marked device.

Other factors to consider when planning a clinical investigation

Number of devices and participants

In assessing risks to health or safety, one of the areas that will be particularly considered by the MHRA is the proposed number of devices and participants to be included within a clinical investigation. The number must be sufficient to demonstrate performance satisfactorily and to reveal significant risks to patients’ health and safety. At the same time the number should not be so great as to place at risk more participantspatients than necessary at a time when third party assessment of device-related risks has not been carried out.out

The number should:

• reflect the aims of the investigation

• take into account the perceived risk of the device

• comply with relevant medical devices standards where appropriate

You can find out more about about statistical considerations for clinical investigations of medical devices.

Duration

The duration of a clinical investigation of a medical device should allow the demonstration of performance over a period of time sufficient to represent a realistic test of the device. It should allow time for the identification and risk assessment of any associated unacceptable adverse incidents over that period, allowing conclusions to be drawn as to the likely performance in the longer term.

It is not feasible or desirable to perform a clinical investigation lasting the projected lifespan of many devices. Indeed, it is recognised that for a number of devices (for example, orthopaedic implants and vascular stents) the majority of associated adverse incidents may not become clinically obvious for a number of years and that the clinical investigation in question will only demonstrate major short term safety problems.

The duration of a clinical investigation and follow-up period must be in line with relevant medical device standards where appropriate.

Post-market clinical follow-up

ThePart MHRAII isof consideringthe howUK newMDR, approachAnnexes methodologiesVIII suchand asX in(medical silicodevices) modellingand mayPart beIII, usedAnnexes 6 and 7 (active implantable devices) (as modified by Schedule 2A to supplementthe UK MDR) and Article 61 of the EU MDR require manufacturers to actively update their clinical evaluation with data suchobtained from post-market surveillance.

It is intended that followlong-term upsafety timesproblems maybe identified either under Medical Devices Vigilance or through a means of specifically designed post-market clinical studies, either extending the pre-market clinical investigation, by studying a relevant and identified cohort of patients over a defined period of time or through means of a specifically designed registry.

Where post-market clinical follow-up is not deemed necessary, this must be reducedduly withoutjustified undueand documented.

In general, devices should follow a post-market clinical follow-up when one or more of the following criteria are identified:

• innovation, where the design of the device, the material, the principles of operation, the technology or the medical indication is new

• severity of the disease

• sensitive target population

• risky anatomical location

• well-known risks associated with a similar marketed device

• well-known risks identified from the literature

• identification of an acceptable risk induring pre-market clinical investigations.evaluation, which should be monitored in a longer term or through a larger population

• identification of emerging risks in similar products

• obvious discrepancy between the pre-market follow-up windows and the expected life of the product

There are additional rules for manufacturers in Northern Ireland.

Type of investigation

The majority of clinical investigations of medical devices will not include a control group. The decision as to whether a control group is necessary however, will depend on the aims of the investigation. For some devices it would only be possible to demonstrate claims adequately by comparison with a separate or untreated group.

If control groups are necessary these should be randomised and prospective, except in exceptional and justifiable circumstances. Pivotal or confirmatory studies should have a control where clinically relevant and appropriate to do so. For all studies, lack of a control group should be justified.

End points

Care should be taken in choosing endpoints to ensure that this will support the stated aims and objectives of the clinical investigation under normal conditions of use. Methods of supporting the demonstration of these endpoints should, as far as possible, be objective. For example, derived from the results of diagnostic or in vitro diagnostic tests, rather than be a subjective factor, such as the severity of symptoms.

You can find out more about about statistical considerations for clinical investigations of medical devices.

Labelling

All devices intended for clinical investigation must bear the wording ‘exclusively for clinical investigation’ as stated in in Part II of the UKthe UK MDR, Annex I (13.3(H)) (medical devices) and Part III, Annex 1 (14.1) (active implantable devices) (as modified by Schedule 2A to the UKthe MDR),UK MDR), and Annex I, chapter III, GSPR 23.2(q) of of the EUthe EU MDR.

This wording may cause confusion to clinical staff as it may be understood, mistakenly, that the clinical investigation being referred to is of a patient rather than the device. The MHRA recommended that manufacturers draw this requirement to the attention of all clinical investigators, ensuring that the meaning of this wording is clearly understood by all staff using or coming into contact with the device being investigated and that the device under investigation is segregated, whereverwhere possible, from any similar devices in routine use.

If a device under clinical investigation has been UKCA or CE marked for another purpose, explanatory labelling to this effect should be attached to the device under investigation.  UKCA or CE marks should be covered when used for the investigation.

Research ethics committee opinions

For all clinical investigations of devices falling within the scope of the UKthe MDR and EUUK MDR,MDR and EU MDR, a relevant research ethics committee (REC)(REC) opinion is required as set out in UKin MDR RegulationsUK MDR Regulations 16(3) and 29(2) and EUand MDR ArticleEU MDR Article 62.3.

This opinion may be obtained in parallel with the MHRA notification. If the REC opinionthe REC opinion is not provided at the time the application is made, it should be forwarded to us as soon as it becomes available.

No clinical investigation of an unmarked device should be started until both the relevant REC opinionrelevant REC opinion and the MHRA have raised no grounds for objection. The MHRA does not accept approvals from independent ethics committees. ApplicantsManufacturers must seek the opinion of a REC withina REC within the UK Health Departments’ Research Ethics Service. REC approvalService. REC approval is required from just one REC,one REC, irrespective of the number of centres participating in the clinical investigation.

The The Research Ethics Service can can advise you on how to apply for a REC opinion.a REC opinion. You can email the Health Research Authority (HRA)(HRA) at at queries@hra.nhs.uk. You should make it clear in your email if the investigation involves a non-UKCA or non-CE marked medical device.

If the MHRA raises no grounds for objection to the investigation in question proceeding, the investigation may only start once REC approvalonce REC approval has been granted and a copy of the REC approvalthe REC approval letter is sent by the applicantmanufacturer to the MHRA.

It may be helpful for us to liaise with the relevant ethics committee concerning notifications. It can also be helpful for the MHRA to send the committee a copy of the final decision for information purposes. For clinical investigations in Great Britain, you will need to complete a clinical investigation application form to grant authorisation for us to contact the committee.

HRA approval HRA approval and confirmed management permission

Each individual site in the clinical investigation must have confirmed management permission.

NHS organisations in England provide this by confirming that they have the capacity and capability to take part in the study.

In Northern Ireland, Scotland and Wales NHS organisations provide a letter of NHS Permission.

Non-NHS organisations should confirm their management permission and receive a favourable Site-Specific Assessment from the REC.the REC.

The clinical investigation must not begin in the UK until you have received the relevant confirmation for that individual site. In addition, clinical investigations must not commence in any NHS site in England until they have also received HRA Approval.received HRA Approval.

You can get more detailed guidance from from the HRAthe HRA. You can also email the HRA at the HRA at queries@hra.nhs.uk, making it clear that the investigation involves a non-UKCA or CE marked medical device.

After you have made your submission

When the MHRA has received your submission, we will follow our assessment process to decide whether to approve your clinical investigation. We aim to make our decision within 60-days.

You can find out more about what we do, and when, in our guidance on on approving clinical investigations.

When you need to communicate with the MHRA

Making amendments or modifications to the investigation

OnceAll you have received your MHRA approval letter, all proposed changes to the clinical investigation must be notified to the MHRA and not implemented until a further letter of no objection tohas been received.

You must tell us about changes to:

• the amendment/modificationdevice hasunder beeninvestigation

• study received.documentation, including the clinical investigation plan

• investigators or investigating institutions

• changes requested by an ethics committee

FurtherAll guidancerequests for amendments should include the following information:

• a covering letter with the MHRA reference number for the clinical investigation (for example CI/2026/XXXX/GB)

• a table with a summary of each proposed change to the clinical investigation and the justification for each change

• a copy of all the amended study documents with the changes tracked

• clean copies of all the amended study documentation

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

• a signed statement by or on submittingbehalf amendmentsof the manufacturer that the proposed changes do not predictably increase the risk to MHRAthe maypatient, beuser foundor herethird party

There are different rules for manufacturers in Northern Ireland.

MHRAWe retainsretain the right to request a new clinical investigation notification if we believe the amendments or modifications:

• increase the risk to either the patient or the user

• negatively impact the reliability and robustness of the data generated

• constitute a new investigation in accordance with Regulation 56(3) of the UKthe UK MDR

Where being undertaken, feasibility or pilot studies should be complete before conducting a pivotal study. Increases to the sample size or number of centres participating in the study will only be considered with appropriate justification.

Final clinical investigation report

Manufacturers are required to notify the MHRA when a clinical investigation comes to an end as stated in Regulations 16(11) and 29(10) of the UKthe MDR andUK MDR and Article 77 of EUof MDR.EU MDR.

You should provide us with a copy of the final clinical investigation report within 1 year of the end of the clinical investigation.

Early termination or temporary halt of clinical investigation

Manufacturers are required to notify the 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 UKthe MDR.UK MDR.

YouWe shouldmay providerequest us with a copy of the final written report withinof 1a yearclinical investigation of a device falling within the endscope of the clinicalUK investigation.MDR (Regulations 16(10) and 29(9)).

There are are different rules for manufacturers in Northern Ireland.

Adverse events involving devices undergoing clinical investigation

Regulation 16(10)(a) and Part II, Annex X of the UKthe MDR (asUK MDR (as modified by Part II of Schedule 2A to the UKthe MDR)UK MDR) require manufacturers to record fully all adverse events and report all serious adverse events occurring in all participating centres to the MHRA.

A ‘serious adverse event’ is one which:

a) led to death or

b) led to serious deterioration in the health of the participant, that either resulted in:

• a life-threatening illness or injury or
• a permanent impairment of a body structure or a body function or

• in-patient or prolonged hospitalisation or

• medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function

c) led to foetal distress, foetal death or a congenital abnormality or birth defect

Planned hospitalisation for a pre-existing condition, or a procedure required by the clinical investigation plan, without serious deterioration in health, is not considered a serious adverse event.

All serious adverse events, whether initially considered to be device related or not, involving a device under clinical investigation coming within the scope of the UKthe MDR andUK MDR and undergoing clinical investigation, should be reported to the MHRA (Part II, Annexes VIII and X, Para 2.3.5 (medical devices) and Part III, Annex 7, Para 2.3.5 (active implantable devices) (as modified by Schedule 2A to the UKthe MDR)).UK MDR)).

Serious adverse events also include those arising out of the same investigation being carried out in other countries since such events may have a direct influence on the status of the investigation. These reports should initially be made as soon as possible and should not be delayed while the manufacturer attempts to gain access to, or test, the device or make a full investigation. The results of the full investigation should be made available later as appropriate.

MEDDEV 2.7/3 provides provides guidance on the requirements for reporting serious adverse events with with timelines and a template form. You may also use the MDCG 2020-10/2 Rev. 1 SAE reporting table, as long as all required information as defined above is included.

You should submit an serious adverse event reporting form and the completed template form to the MHRA by using the the MORE portal.

You can find out how to do this in the the MORE registration guide.

For blinded control clinical investigations using a UKCA or CE marked device as control, all adverse events should be reported to the MHRA in line with the requirements above.

Where an un-blinded controlled clinical investigation is being carried out using a UKCA or CE marked device as the control, adverse events involving the UKCA or CE marked devices should be reported to the MHRA in line with vigilance guidelines.

The MHRA has the right to withdraw a written notice of no objection if, in its opinion, the serious adverse events give rise to issues of public health (UK(UK MDR RegulationMDR Regulation 16(6) and Regulation 29(5)).

There are are different rules for manufacturers in Northern Ireland.

Quarterly summary reports

As a condition of MHRA approval for a clinical investigation, in addition to reporting individual serious adverse events as detailed above, you must send us quarterly summary reports providing an update on the latest overall safety profile for the investigation.

If the study is UK only, we expect the first QSR to be submitted one quarter after the first participant has been treated.

For studies that also have EU and global sites please provide a QSR one quarter after MHRA approval of the UK study. The report should detail the overall safety profile for ALL study sites.

To provide these summaries, use the the guidance and template. This template is for devices only but you should also use it for device-related reporting on any combined studies. Do not include detail on any investigational medicinal product (IMP) under investigation.

Submit your quarterly summary reports directly through through https://more.mhra.gov.uk/login

Study deviations

Manufactures must notify the MHRA of all deviations to the study 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.

You should use the the MHRA protocol deviation tracker when 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. You should send the completed spreadsheet to the MHRA by emailing emailing info@mhra.gov.uk.

If the MHRA considers the regulations have not been met

Where there are grounds for considering that the requirements of the regulations are not met, the MHRA can:

• withdraw the no objection letter and revoke authorisation

• suspend or terminate the clinical investigation

• require the sponsor to modify any aspect of the clinical investigation

If such action is deemed necessary, we will write to the manufacturer or sponsor to communicate the decision and agree any further actions that may be necessary.

UKCA and CE-marking

Please inform the MHRA in the event that the medical device under investigation is UKCA or CE marked. We request that at the same time MHRA are also provided with a summary report of the clinical data from this clinical investigation that was used to support the UKCA or CE mark.

If the UKCA or CE marking covers the purpose under investigation, further amendments to the study documentation can be made without notification to the MHRA.

Addendum: Post-market clinical follow-up

Part II of the UK MDR, Annexes VIII and X (medical devices) and Part III, Annexes 6 and 7 (active implantable devices) (as modified by Schedule 2A to the UK MDR) and Article 61 of the EU MDR require manufacturers to actively update their clinical evaluation with data obtained from post-market surveillance.

It is intended that long-term safety problems be identified either under Medical Devices Vigilance or through a means of specifically designed post-market clinical studies, either extending the pre-market clinical investigation, by studying a relevant and identified cohort of patients over a defined period of time or through means of a specifically designed registry.

Where post-market clinical follow-up is not deemed necessary, this must be duly justified and documented.

In general, devices should follow a post-market clinical follow-up when one or more of the following criteria are identified:

• innovation, where the design of the device, the material, the principles of operation, the technology or the medical indication is new
• severity of the disease
• sensitive target population
• risky anatomical location
• well-known risks associated with a similar marketed device
• well-known risks identified from the literature
• identification of an acceptable risk during pre-market clinical evaluation, which should be monitored in a longer term or through a larger population
• identification of emerging risks in similar products
• obvious discrepancy between the pre-market follow-up windows and the expected life of the product

There are additional rules for manufacturers in Northern Ireland.

Further information

We have more more guidance on clinical investigations. 

If you have any questions the clinical investigation procedure you can email email info@mhra.gov.uk.

Glossary

Active implantable medical device: any active medical device which is intended to be totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain after the procedure.

Active medical device: any medical device relying for its functioning on a source of electrical energy or any source of power other than that directly generated by the human body or gravity.

Adverse device event: a device-related adverse incident.

Adverse incident: any undesirable clinical occurrence in a participant whether it is considered to be device-related or not.

Approval letter: shorthand terminology referring to MHRA’s letter of No Objection, issued in response to a clinical investigation notification (application), which allows an applicant to proceed with their clinical investigation.

Clinical benefit: the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcomes, including outcomes related to diagnosis, or a positive impact on patient management or public health.

Clinical evidence: clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefits, when used as intended by the manufacturer.

Clinical investigation: any systematic investigation or study in human participants, undertaken to verify the safety and performance of a device, under normal conditions of use.

Clinical investigation plan: a document that includes detailed information on the rationale, aims and objectives, design and proposed analyses, methodology, and conduct of the clinical investigation.

Clinical performance: the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer.

Clinical investigator means the person responsible for the conduct of a clinical investigation and who takes the responsibility for the health and safety of the participants involved.

Device intended for clinical investigation: within the context of this document, any device intended for use by an appropriately qualified practitioner when conducting clinical investigations in an adequate clinical environment.

Implantable device: any device which is intended to be totally introduced into the human body, or to replace an epithelial surface or the surface of the eye, by surgical intervention and which is intended to remain in place after the procedure. Any device intended to be partially introduced into the human body through surgical intervention and intended to remain in place after the procedure for at least thirty days is also considered an implantable device.

Invasive device: a device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body. A body orifice includes any natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening such as a stoma.

Research ethics committee: an independent and properly constituted body of medical professionals and non-medical members whose responsibility is to ensure that the health, safety and human rights of the patients participating in a particular clinical investigation are protected.

Manufacturer:  The definition of a manufacturer may be found in UK MDR Regulation 2, or EU MDR Article 2(3).  However, for the purposes of this guidance, it may be often used interchangeably with ‘sponsor’.

Medical device: any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:

• diagnosis, prevention, monitoring, treatment or alleviation of disease

• diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,

• investigation, replacement or modification of the anatomy or of a physiological process

• control of conception

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.

(For Great Britain, the applicable definition of a medical device may be found in UKin MDR RegulationUK MDR Regulation 2. For Northern Ireland, the applicable definition may be found in Article 2(1) of the EUthe MDR.)EU MDR.)

Multicentre investigation: a clinical investigation, conducted according to a single clinical investigation plan, which takes place at different investigation sites.

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

• a change of sponsors or sponsors’ legal representative

• a change to the insurance or indemnity arrangements for the study

• minor changes to the protocol or other study documentation, for example, correcting 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

Performance of device: the action of a device with reference to its intended use when correctly applied to the appropriate participants.

Relevant essential requirements: such of the essential requirements, or such aspects of the essential requirements as apply to a device, not including, in the case of a device intended for clinical investigation, such of those requirements, or aspects of them, as are the subject of the investigation.

Relevant General Safety and Performance Requirements: the general safety and performance requirements, or such aspects of the general safety and performance requirements as apply to a specific device.

Subject or participant means a human being, who is either a patient or a non-patient volunteer, participating in a clinical investigation.

Substantial modification: changes that are likely to have a substantial impact on the safety, health or rights of the participants or on the robustness or reliability of the clinical data generated by the investigation and include:

• 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

Surgically invasive: an invasive device which penetrates inside the body, other than through an established body orifice, with the aid or in the context of a surgical operation.