A manufacturer may need to carry out a clinical investigation (clinical trial) 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 of the relevant directive.
It is a legal requirement (the Medical Devices Regulations 2002 No. 618) that a manufacturer notify the UK competent authority (the MHRA) of their intention to undertake a clinical investigation of a non-CE-marked medical device within the UK, at least 60 days before commencement of the proposed investigation.
In this section...
Please read our document ‘Clinical investigations of medical devices – guidance for manufacturers' (463Kb) for detailed information on the process of clinical investigations. A summary is given below.
Note: Investigations of in vitro diagnostic medical devices are regulated as performance evaluations and guidance on the requirements for these is on our in our document on the IVD Directive.
Details of the information that the MHRA needs are given in our guidance document (463Kb). These broadly include:
- Signed statement
- Detailed information on the device
- Clinical investigation plan
- Research ethics committee opinions
How to present the information
You must prepare your notification to the MHRA online by using the Integrated Research Application System (IRAS) (external link). IRAS allows you to print out the completed PCA1 and PCA2 forms and sterilization pro forma for signing before sending them to the MHRA.
Notifications of a clinical investigation will only be accepted by the MHRA once we have received the signed forms, necessary supporting documentation and the appropriate fee.
Before submitting a notification to the MHRA, you are advised to ensure that you have all the information necessary. A very common reason for the MHRA objecting to an investigation is the failure of the manufacturer to supply the necessary data within the 60 day time period allowed by the Regulations.
Your notifications must be submitted in the following format:
- 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.
- You must provide 8 electronic copies of the full submission, each on a separate CD
- All pages must be in their correct, numbered sequence, including reprints, diagrams, tables and other data.
- All text and any relevant drawings and their captions must be clear and legible.
- All documents must be arranged on the CDs as separate attachments.
- 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.
- When paying by bank transfer, please provide a copy of the payment transaction receipt, otherwise include the cheque with the submission.
- Send the documentation by recorded delivery to:
Crina Cacou, Regulatory Affairs Manager (Medical Device Clinical Trials), Floor 4 yellow zone, 151 Buckingham Palace Road, London SW1W 9SZ
The MHRA will do everything it can to make the process as smooth as possible but this will be helped greatly by manufacturers sending us all the required and necessary information at the time of the initial submission.
FeesThese depend on the class of device. The figure in brackets denotes the fees for re-notification in the event of an objection:
- Class I, IIa, or IIb other than implantable or long-term invasive: £3,820 (£2,920).
- Class IIb implantable or long-term invasive, Class III, and active implantable: £5,040 (£3,570).
Details on how to make payments are in our bank account section.
Notifications of intent to carry out a clinical investigation must be sent to the MHRA at least 60 days before commencement of the proposed investigation. The 60 day assessment period will commence from the day the MHRA receives a valid notification.
On receipt of an application, the MHRA will check that it is valid and will write to the company within two working days to either confirm that the 60 day review process has started or identifying any issues making the application invalid. In the latter case, the 60 day clock will start on receipt of a valid response to the issues raised.
On receipt of a valid application, the MHRA will appoint a number of experts to assess the safety of the device and the design of the study. If any additional information or clarification is required, the MHRA will write to the company as and when questions are raised by these experts. This process of written correspondence between the MHRA and the company will continue until all issues have been resolved to MHRA’s satisfaction or the 60th day is reached (whichever happens first).
If issues are identified that are considered potential grounds for objection the MHRA will invite the company to have a teleconference during the 60 days with the expert(s) who raised these issues. The aim is to gain understanding on both sides to enable resolution of these issues quickly and within the 60 days.
The MHRA will issue a decision (Objection or No Objection) in the form of a letter by the 60th day (or before wherever possible).
Additional guidanceWe also have the following documents:
Information for clinical investigators (131Kb)
Biological safety assessment (109Kb)
Guidance for pre-clinical assessors (143Kb)
Statistical considerations (150Kb)
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 as the clock on the 60-day assessment period does not stop when additional information is requested.
Questions should be directed to Crina Cacou by email on email@example.com or by telephone on 020 3080 7338.
In some cases, where specific issues cannot be addressed in writing, a pre-submission meeting or conference call may be necessary, which we can arrange.
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 from the Association of British Healthcare Industries (ABHI) website (external link).
Full details and specific guidance for applications for ethics committee approval 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 firstname.lastname@example.org.
Independent review of MHRA assessments
The Committee on the Safety of Devices (CSD) audits a selection of the clinical investigation notifications received by the MHRA every year. The CSD audits 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 the 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 the Safety of Devices.
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
Guidance on devices which are manufactured by healthcare establishments for use on their own patients is available in the In house manufacture section.
The MHRA has identified a number of scenarios, which are arising in practice for healthcare and related establishments. We set out our view of the obligations 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 (for free or at a reduced cost) 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.
Where the study has been initiated by the healthcare establishment and the manufacturer’s involvement is limited to supply of the device and/or funding, a co-sponsor agreement can be drawn up with the healthcare establishment contracting serious adverse event reporting and management of the study to the investigators. In all cases the manufacturer will remain ultimately responsible for meeting the requirements in the Medical Devices Regulations 2002 for clinical investigations.
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.
Notifications handled by the MHRA
Clinical investigations reviewed
Proportion where grounds for objection were raised
Average review time (days)