«Clinical investigations of medical devices – guidance for pre-clinical assessors November 2013 MHRA Guidance on legislation Contents 1 The purpose ...»
Guidance on legislation
Clinical investigations of medical devices –
guidance for pre-clinical assessors
MHRA Guidance on legislation
1 The purpose of clinical investigations under the provisions of the directives
2 Role of the competent authority in relation to clinical investigations
3 Role of the expert assessor
4 Required documentation
5 Submission to assessor and timetable for assessment
6 Confidentiality and conflicts of interest
9 Further information
10 Glossary of terms
Appendix 1 – Documentation required for all clinical investigation submissions
Appendix 2 – Documentation to be kept available for the MHRA
This document replaces Guidance Note 4 ‘Pre-clinical assessment guidance for assessors’ Revision history This version Date published Changes V1.0 November 2013 n/a © Crown copyright. Published by the Medicines and Healthcare Products Regulatory Agency Clinical investigations of medical devices – guidance for pre-clinical assessors November 2013 2/10 MHRA Guidance on legislation The purpose of this document is to explain to expert assessors the background to and the system for the pre-clinical assessment of clinical investigations of medical devices, under the provisions of the UK Medical Devices Regulations implementing the Active Implantable Medical Devices Directive and the Medical Devices Directive.
1 The purpose of clinical investigations under the provisions of the directives In order for a medical device to become freely available on the market within the EU, a CE-marking for the device must be obtained. In order to obtain this marking, a manufacturer must go through one or more conformity assessment procedures to confirm that the design and production of the device ensure compliance with all relevant essential requirements of the relevant directive.
In essence the essential requirements are intended to ensure that:
• devices do not compromise the clinical condition or safety of patients, users or, if appropriate, any third party
• devices achieve their intended purposes as designated by their manufacturers; and
• any risks associated with the use of a device are judged by informed clinical opinion to be acceptable when weighed against the benefits to the patient and compatible with a high level of protection of health and safety.
Ensuring compliance with these essential requirements, particularly for those devices associated with a higher risk, may require a review of clinical data. In many cases these data will be available from scientific literature or will be based on previous experience of the use of a device for a
particular designated purpose. However, in certain circumstances involving, for example:
• the introduction of a completely new concept or type of device into clinical practice
• where an existing device is modified in such a way that it contains an entirely novel feature, or where the modification has an important physiological effect
• the use of a device, either CE-marked or non-CE-marked, is proposed for a new purpose or function
• the use of new materials previously untested in humans, coming into contact with the human body, where biocompatibility and biological safety will need to be considered clinical data may only be available from a specifically designed clinical investigation and in these cases the manufacturer should carry out a clinical investigation before CE marking their device.
2 Role of the competent authority in relation to clinical investigations In the UK, the competent authority for the purposes of the Medical Devices Directives is the Medicines & Healthcare Products Regulatory Agency (MHRA), an executive agency of the Department of Health.
Manufacturers are required by the Regulations to notify 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 and to submit the required documentation as set out in the Medical Devices Regulations.
At the end of the 60 day period following notification, the proposed clinical investigation may proceed unless the MHRA has notified the manufacturer within that period that, on grounds relating to health or safety, the device should not be made available for the purposes of that investigation (Medical Devices Regulations: Section 16(4)). However, provided the MHRA is satisfied that there are no grounds for objection, it may notify the manufacturer that the report on the proposed clinical investigation is favourable, before the 60 day time period has elapsed.
Circumstances in which the MHRA may object to an investigation proceeding include:
• where there are reasonable grounds to suspect that a device does not satisfy relevant essential requirements; or
• where there are reasonable grounds to suspect that the clinical investigation is not subject to controls equivalent to the requirements of the relevant European Standard (ISO14155); or
• where there exists professional opinion on the proposed clinical investigation which states that the risk benefit analysis given is inaccurate and that, were the investigation to take place, there would be a significant probability of serious illness, injury or death to the patient or user; or
• where insufficient information has been submitted to enable a proper assessment of the safety aspects of the proposed clinical investigation to be made; or
• where, because the manufacturer has delivered the documentation necessary for the assessment so late that insufficient time remains within the 60 day notification period for an assessment to be made which is adequate to determine whether the proposed clinical investigation involves any risk to health or safety.
The MHRA believes that the way to ensure that it can carry out its functions properly in relation to
clinical investigation is:
• by setting out for manufacturers full details of the information which they must submit to or keep available for the MHRA under the provisions of the Medical Devices Regulations (a Guidance Document for Manufacturers covering both Directives has been prepared);
• by setting up a group of assessors who are experts in a number of areas relevant to a clinical investigation, and to whom the MHRA can apply for an opinion in relation to those aspects of the investigation; and
• by setting up an information handling timetable which is such as to enable the MHRA to carry out a satisfactory assessment within the 60 days allowed.
3 Role of the expert assessor The expert assessor is requested by the MHRA to make an assessment of the relevant features of the proposed clinical investigation in the area of expertise in which he/she has been asked to give an opinion. This is in order that the MHRA can make an informed judgement as to whether there are grounds for objection to a clinical investigation proceeding on the basis of potential risk to the subject or user, or whether it is reasonable, based on the submitted information, to proceed to a clinical investigation in human subjects.
4 Required documentation
Two categories of documentation are required, namely:
• initial information which the manufacturer is required to submit as part of the application for assessment of a clinical investigation of a medical device (Medical Devices Regulations: 16(3) which incorporates Annex VIII, paragraph 2.2); and
• additional information which the manufacturer is required to hold and which may be requested by the assessor through the MHRA (Medical Devices Regulations 16(1)(b) which incorporates Annex VIII, paragraph 3.2).
Assessors are advised that the documentation coming within the second category should only be requested if essential in order to make a reasoned and adequate assessment.
The information falling within these two categories is set out in appendix 1 and appendix 2 of this document.
5 Submission to assessor and timetable for assessment A timetable has been devised in order to provide the necessary time for adequate assessment of the submitted documentation within the time constraints laid down.
• The MHRA will, immediately following the submission of required documentation by the manufacturer, contact the relevant expert assessors to check availability for the purposes of making an assessment of the proposed clinical investigation. In exceptional circumstances, a review meeting of all assessors may be required to discuss an individual clinical investigation.
Under these circumstances, suitable arrangements will be made, as necessary. The documentation will be sent to the agreed experts, and will specify the subject area in which each assessor is requested to carry out the assessment, e.g. clinical research, toxicology, sterilization, etc. Each expert is asked to consider only this area/these areas in making an assessment of the submission.
• Each expert is required to undertake the assessment of the information provided within the designated area of expertise, within two weeks of receipt of the documentation. It is envisaged that the assessment will take between 4-6 hours for each individual assessor in the majority of submissions. If no additional information is required, a report as to whether there are grounds for the MHRA to object to the commencement of the clinical investigation, should be provided.
• Any additional information required by the assessor must be requested through the MHRA within two weeks of receipt of the original documentation. The request will be assessed by the
MHRA to ensure that it is valid under the Directives (see Appendix 2 of this document). At no stage may an assessor contact the manufacturer directly. On receipt of the additional information the assessor is required to complete the assessment as quickly as possible and in any case within two weeks.
• Relevant forms for requesting additional information will be sent to each assessor with each submission.
• A timetable showing the date by which each significant phase of the assessment process should be completed will be sent to each assessor with each submission.
• Once the assessment has been completed, each assessor is required:
(a) to complete and return the final report form which will have been sent with the original submission; and (b) to return all the documentation received from the MHRA.
• The names/addresses/phone numbers/fax numbers of other assessors involved with an individual submission may be obtained from the MHRA on request, in order to allow discussion between assessors if necessary. Such discussions should not involve any third party as all information supplied is classed as ‘Restricted - Commercial’. The MHRA should be informed that such discussions have taken place by the assessor noting this in the final report form.
6 Confidentiality and conflicts of interest All information submitted to an assessor must be treated as ‘Restricted - Commercial’.
Accordingly, assessors will be required to enter into a written agreement to protect the confidentiality of the information supplied to them in the course of an assessment. They will also be required to disclose in the agreement any potential or actual conflicts of interest which may have a bearing on any assessments.
The names of all assessors will be kept confidential and will not be revealed to the manufacturer.
7 Payment A fixed fee will be paid to each external assessor for review of each submission. The fee will include payment to cover costs of returning documentation to the MHRA. An additional fee will be paid to cover travel costs if an expert assessor is required to attend a review meeting.
8 Documents All documentation will be sent to each assessor by courier or registered mail.
On completion of the assessment, each expert assessor must return all the documentation by registered mail or courier.
Requests for further information should be sent by email to the designated MHRA contact for the given notification (contact details will be provided with the documentation).
9 Further information