Clinical trials for medical devices

Studies involving non-CE marked medical devices carried out in the UK may be regulated as clinical investigations under the Medical Devices Regulations 2002 and require approval from the UK Competent Authority.

This page provides guidance on how to notify the MHRA of proposed clinical investigations involving non-CE marked medical devices. Please see the links at right-hand side of this page to guidance documents contained on this website. Please note that investigations of In Vitro Diagnostic Medical Devices are regulated as performance evaluations and guidance on the requirements for these is included in our Guidance Note 18 which can be found on our registration of medical devices page.

Prior to submitting a notification to the Competent Authority, you are advised to ensure that you have the information necessary to demonstrate compliance with all the relevant essential requirements except for those that are the subject of the investigation. A significant percentage of the grounds for objection that have been raised have resulted from the failure to supply the necessary data within the 60 day time period allowed by the Regulations. Details of the information required are provided in the guidance documents to the right of this page. Please prepare your notification to the MHRA online by using the Integrated Research Application System (IRAS) (external link).  IRAS is a UK-wide system that streamlines the process for applying for permissions and approvals to conduct health and social care research, including clinical investigations of medical devices. It allows users to enter the information for the relevant permissions and approvals once, instead of having to complete several separate application forms for each review body. Filters are used to ensure that data is collected and collated appropriately to the type of study and the approvals and permissions required. IRAS captures the information needed by the MHRA offering the facility for users to print out the completed PCA1 and PCA2 forms and sterilization proforma for signing before making a notification to the MHRA in the usual way.

Notifications will only be accepted by the MHRA once the signed forms, necessary supporting documentation and the appropriate fee have been received by the Agency.

Your notifications should be submitted in the following format:

 

• The documentation should be sent by recorded delivery.
• All information must be in English. If any part of the supporting data consists of material in another language, this must be translated. One copy of the original document in its original language should accompany the application.
• One hardcopy of the full submission and eight rewritable CD-ROM’s are required.
  
• 1. The hardcopy copy of the proposed clinical investigation, must be presented and collated with all pages in their correct numbered sequence, including reprints, diagrams, tables and other data. The method of reproduction used must allow for legible presentation of the text and any relevant drawings with their captions. All papers should be provided in a folder or bound with dividers separating individual documents.
  2. All documents must be arranged on the CDs as separate attachments. Please include a document index on each CD and ensure that all documents are named appropriately ie clinical investigation plan, investigator’s brochure, patient information, patient consent, essential requirements checklist, summary of pre-clinical data, sterilization validation report, risk analysis, instructions for use etc.
  3. Please provide: 
     
     
     • Eight rewritable CD-ROMS, each containing a full set of the supporting documentation
     • One hardcopy of the full set of supporting documentation
     • The hardcopy and all CDs must contain identical information
       
       

• When paying by bank transfer, please provide a copy of the payment transaction receipt, otherwise include the cheque with the submission.
  

The 60-day assessment period will commence from the day the MHRA are in receipt of all of these items.

Blank PCA1 and PCA2 forms and the sterilisation proforma can be viewed on the IRAS website by selecting ‘Help’, ‘Example Application Forms’ and then under the heading MHRA Devices select ‘Clinical investigation of a medical device'.

We are happy to answer any questions that you may have about the UK regulatory process for clinical investigations, prior to making a notification, however, we are not able to perform a full assessment of your proposed clinical investigation protocol at this stage. You are therefore advised to contact us should you have any concerns prior to making a notification. Questions should be directed to Daniella Smolenska at daniella.smolenska@mhra.gsi.gov.uk or by telephone on 020 3080 7363.

In some cases, where specific issues cannot be addressed in writing, it may be considered that a pre-submission meeting or conference call is necessary, and we will be happy to arrange such a meeting if required.

Notifications of clinical investigations should be addressed to:

Daniella Smolenska
Regulatory Affairs Manager (Medical Device Clinical Trials)
5 Magenta
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ

Fees
The following charges apply for the pre-clinical assessment of clinical investigation notifications by the MHRA, with the fees for re-notification in the event of an objection given in brackets:

Class I, IIa, or IIb other than implantable or long-term invasive: £3,020 (£2,120).
Class IIb implantable or long-term invasive, Class III, and active implantable: £4,240 (£2,770).

Details on how to make payments are in our Bank account section.

Independent review of MHRA assessments
The Committee on Safety of Devices audits a selection of the clinical investigation notifications received by the MHRA every year. They audit the MHRA against our procedures, the statutory requirements and the decisions we have taken. The results of these audits are recorded in the Committee on Safety of Devices meeting minutes once a year. Copies of all meeting minutes can be found in the section of our site on the Committee on Safety of Devices.
 

 
Notification process
The processing of the clinical investigation by the Competent Authority is carried out according to the diagrams on pages 37 and 38 of Guidance Note 1.

Guidance Note 1 - Guidance Notes for manufacturers on clinical investigations to be carried out in the UK (741Kb)

If further information is required during the course of the clinical investigation assessment, a letter will be sent to the manufacturer. Should the nature of the requested information be unclear to you, it is essential that you contact the Competent Authority as soon as possible and request clarification or a meeting, conference call or video conference if preferred. Please bear in mind that the Competent Authority has a maximum of 60 days to reach a decision. The clock does not stop when additional information is requested. The current Agency target is to process clinical investigations in an average time of 54 days.

If the final letter raises grounds for objection, the reason for these objections will be set out in detail as an attachment to the regulatory letter. If you require clarification on any of these reasons, you are advised to discuss them with the Competent Authority prior to making a resubmission. When making a resubmission, manufacturers are advised to detail all changes made between the original and the resubmission, the reasons for these, and their effect on the risk assessment. In addition a statement is required from the manufacturer declaring that the protocol remains unchanged except for those aspects noted in the resubmission application. This will enable MHRA to process the resubmission with the minimum of delay.

Please note that regulation 16 (3) of the Medical Devices Regulations 2002 (No 618) allows notification to the UK Competent Authority at the same time as a submission to the Research Ethics Committee. This can be facilitated by using the Integrated Research Application System (IRAS) (external link). However, a clinical investigation may only begin at a particular centre once the manufacturer has received both a letter of no objection from the Competent Authority and the agreement of the Ethics Committee for the clinical investigation to proceed. Requirements for obtaining Ethics Committee approval and for obtaining approval for an additional participating centre, have recently changed.

The UK Competent Authority does not accept approvals from independent ethics committees. Manufacturers should seek the opinion of a National Research Ethics Service (NRES) (or equivalent services in Scotland, Wales and Northern Ireland) appointed ethics committee in all cases unless they can demonstrate a reason why an NRES (or equivalent) appointed committees would not assess their clinical investigation. In such cases the manufacturer will need to demonstrate that any independent ethics committee appointed was constituted in line with NRES guidelines. However please note that NRES will review all clinical investigations due to be conducted outside of the NHS and therefore situations where an independent ethics committee is required are not foreseen.

Full details and specific guidance for applicants can be obtained from the National Research Ethics Service (NRES):
NRES: Ethical review requirements (external link)

There is also guidance for applicants for medical device research:
NRES: Medical devices guidance (external link)

If you require further advice please email NRES Queries Line on queries@nres.npsa.nhs.uk.

More information is also available on the Integrated Research Application System website (external link).

The Competent Authority will try to do everything it can to make this as smooth a process as possible but this will be helped greatly by the Competent Authority receiving all the required and necessary information at the time of the initial submission.

The National Institute for Health Research Clinical Research Network (NIHR CRN) has developed a Study Start up Route Map (external link) specifically for use by manufacturers of medical technology. The map sets out a suggested order for companies to engage with the relevant bodies to obtain the approvals and permissions needed and provides guidance on each step.

Further information and advice may also be available at the Association of British Healthcare Industries (ABHI) website (external link).

Guidance documents
Further information may be found in the following Guidance Notes:

Guidance Note 1 - Guidance Notes for manufacturers on clinical investigations to be carried out in the UK (741Kb)
Guidance Note 3 - Information for clinical investigators (67Kb)
Guidance Note 5 - Guidance on biocompatibility assessment (92Kb)
Guidance Note 17 - Guidance Notes for manufacturers on statistical considerations for clinical investigations of medical devices (115Kb)

Notifications handled by the MHRA

model Clinical Investigation Agreement (mCIA)
A model Clinical Investigation Agreement (mCIA) designed to be used without modification for company-sponsored commercial research involving medical devices in patients in hospitals throughout the UK Health Service has been developed.

The 2011 version of the agreement for use throughout the UK and guidance notes are all available on the UK Clinical Research Collaboration (UKCRC) website (external link).

Clinical investigations and healthcare establishments
The MHRA have received a number of enquiries relating to the implications of the requirements for the clinical investigation provisions under the Medical Devices Regulations 2002 ('the Regulations') for healthcare and related institutions. We are therefore setting out some guidance in relation to this area. This guidance is of a general nature only and cannot be taken to be a definitive statement of the law. Where there is any doubt, you should always seek your own legal advice.

With regard to the obligations of healthcare establishments and related organisations generally under the Regulations, Bulletin 18: Implications on healthcare and other related establishments (61Kb) sets out further information. Guidance Note 1 - Guidance for Manufacturers on Clinical Investigations to be Carried out in the UK (741Kb) sets out detailed guidance in relation to clinical investigations. Both of those publications should now be read in conjunction with this note.

A manufacturer may carry out a clinical investigation as part of the process of obtaining a CE marking for a medical device, ie to demonstrate that the device complies with the essential requirements. Where a medical device is made available for the purposes of a clinical investigation, the manufacturer or his authorised representative must comply with the notification provisions and the clinical investigation must be carried out in accordance with the relevant Directive (see Regulation 16 for general devices and Regulation 29 for active implantable devices).

The MHRA have identified a number of scenarios, which are arising in practice for healthcare and related establishments. We have set out our view of the obligations arising in each of those scenarios below.

1. A healthcare establishment manufactures a medical device and sees the possibility of placing that device on the market either themselves or by selling it to another legal entity for commercial purposes.
Because the device is to be commercialised ie placed on the market, it will need to comply with the provisions of the Regulations. In order to demonstrate conformity with the relevant essential requirements, it may be necessary for the healthcare establishment to carry out a clinical investigation. Any clinical investigation must be notified in accordance with the Regulations, even if it is carried out on patients within the same legal entity.

Where an NHS Innovation Hub is involved, it is the MHRA’s opinion that a commercial application has been identified and therefore a notification to the MHRA will need to be made if a clinical investigation is necessary. The notification will need to be made prior to the clinical investigation commencing.

2. A healthcare establishment manufactures a medical device solely for use on its own patients and does not see the possibility of placing that device on the market.
Because the device is being used in-house and will not be commercialised, a notification to the MHRA will not be required.

3. A healthcare establishment uses a device for a purpose not intended by the manufacturer (as stated in the data supplied by the manufacturer, on the labelling, instructions for use and/or the promotional material), without the knowledge of the manufacturer.
Generally, a healthcare establishment will not be treated as a manufacturer of a device for the purposes of the Regulations because it uses that device for a purpose not intended by the manufacturer. This is because the Regulations do not cover the user. Similarly, where a healthcare establishment uses a device for a purpose other than that stated by the manufacturer on a trial basis on their own patients, the MHRA would not treat that as a clinical investigation unless the intention of the healthcare establishment was to seek commercialisation of the device for the new intended use. However, there might be other legal consequences following from such action such as liability for using a device for a purpose not intended by the manufacturer. Legal advice on this should be obtained. Also, if the action taken by the healthcare establishment involved modification of the device, it is possible that the healthcare establishment might become the manufacturer of what is now a 'new device' if their intention is to seek commercialisation of the modified device. On that basis it would be expected to notify the MHRA of any clinical investigation carried out with a view to commercialisation of that device (see scenario 1 above).

4. A healthcare establishment trials a device already on the market with regard to a new purpose (ie not intended by the manufacturer as stated in the data supplied by the manufacturer, on the labelling, instructions for use and/or the promotional material) and the manufacturer is involved in that process.
Where a manufacturer is seeking to investigate a new use for a device already on the market with a view to CE marking the device for the new purpose, the MHRA consider that the clinical investigation provisions are likely to be engaged. Whether or not that is the case will depend upon the circumstances, including the nature of the trial. In general, if the manufacturer is supplying the device specifically for use in the trial or if they are funding part or whole of the trial, it is the MHRA’s opinion that the clinical investigation provisions will be engaged. The manufacturer will then be responsible for making a notification to the MHRA.

5. A healthcare establishment is asked by a manufacturer to trial a medical device which is not yet on the market and not CE marked.
Where a manufacturer is seeking to investigate the clinical potential of a new device that has not yet come onto the market and is not CE marked, we consider that the clinical investigation provisions will always need to be engaged.

Any queries regarding this document or the clinical investigation procedure should be addressed to:

Daniella Smolenska
Regulatory Affairs Manager (Medical Device Clinical Trials)
5 Magenta
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ