What is a clinical investigation?
A clinical investigation is any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a medical device.
The Medical Device Regulation 2017/745 (MDR) becomes fully applicable on 26 May 2021. This will bring about a number of changes with respect to clinical investigations.
One important change with respect to the MDR is that there are a number of different types of clinical investigations specifically described within the legislation, including:
- Pre-market clinical investigations, i.e. clinical investigations of devices without a CE mark (see Article 62 of the MDR, which may apply).
- Post-market clinical investigations, i.e. post-market clinical follow-up (PMCF) investigations (see Article 74 of the MDR, which may apply).
- Clinical Investigations undertaken for purposes other than those listed in Article 62 of the MDR (see Article 82 of the MDR and the additional requirements laid out in national legislation (S.I. No. 261 of 2021)).
- Clinical investigations of medical devices without an intended medical purpose (see Annex XVI of MDR for further information).
Further information on the types of Clinical Investigations, and the requirements for application or notification to the HPRA, can be found in the HPRA Guide to Clinical Investigations carried out in Ireland. Please also refer to the guidance document "MDCG 2021-6 Regulation (EU) 2017/745 - Questions & Answers regarding clinical investigation", available on the European Commission website, which provides answers to frequently asked questions regarding clinical investigations.
What type of supports does the HPRA provide to device developers?
The HPRA have a key strategic aim of supporting the innovation of medical products. Depending on the stage of development of the device, the HPRA can offer the following supports:
- Queries to the Innovation Office. This is a cross departmental initiative in the HPRA to support any innovative medical product. Further information is available on the Innovation Office webpage.
- Preliminary meetings with device developers. These are typically for early stage ‘spin-out’ or ‘start-up’ organizations. The purpose of these meetings is to provide an introduction to the role of the HPRA and a broad overview of the regulatory requirements in the pre-market phase of medical device development.
- Pre-submission meetings. These are typically for study sponsors who have prepared for a clinical investigation in Ireland, and who may have some outstanding questions prior to the submission of their application to the HPRA.
All of the above services are free of charge. The HPRA encourage preliminary and pre-submission meetings with sponsors of clinical investigations. To apply for a pre-submission meeting, please complete this form and send it to firstname.lastname@example.org
How do I submit an application for, or a notification of, a clinical investigation to the HPRA?
Step 1: Complete the relevant HPRA application form (for clinical investigations falling under Article 62 MDR) or notification form (under Article 74 MDR or Article 82 MDR) for clinical investigation in Ireland.
Step 2: Pay the relevant fees.
Further details are available at the HPRA:
Step 3: Submit the necessary documentation via CESP, the Common European Submission Portal.
Step 4: Send an email to email@example.com to advise that an application to undertake a CI has been submitted via CESP, along with the reference number provided by the CESP system for a successful submission.
If you have not used CESP before, the website has general information, frequently asked questions and regular tutorials for study sponsors.
The MDR provides for a central European electronic system for clinical investigation applications (i.e. the EUDAMED system). This system is subject to delay and in the meantime, applications should be made via CESP.
Please note that from 26 March 2021, the HPRA will not be in a position to accept applications to conduct clinical investigations under the Medical Device Directives. This is to allow for the assessment period necessary for clinical investigations and to allow sponsors to meet the transitional provisions of the MDR. Article 120 (11) of the MDR provides that only clinical investigations which have started to be conducted under the Directives, prior to 26 May 2021 may continue on that basis. Clinical investigations that commence on or after 26 May 2021 will need to have an authorisation issued by the HPRA under the MDR.
Clinical Investigation Modification
For a substantial modification to a clinical investigation, which has previously received a 'Letter of no objection', with respect to the Directive, or a ‘Letter of authorisation’ with respect to the MDR, sponsors must apply to the HPRA prior to implementing the modification. The relevant application form for clinical investigation applications should be used.
Article 75 of the MDR does not describe how sponsors or authorities shall deal with non-substantial modifications. Once EUDAMED is available, sponsors are expected to keep the information in the database up to date in accordance with Article 70(2) of the MDR. In the absence of EUDAMED, non-substantial modifications will require an application to the HPRA prior to implementation. The relevant application form can be found here and the modification should be marked as ‘non-substantial’.
In cases of doubt, as to whether a proposed modification is substantial or non-substantial, please contact the Medical Device Department at firstname.lastname@example.org.
Serious Adverse Event and Device Deficiency Reporting
The European Commission has published guidance on the reporting of serious adverse events (SAE) and device deficiency (MDCG 2020 10/1 Safety Reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745) and the HPRA expects all sponsors to follow this guidance.
The MDR provides transitional provisions for studies that are ongoing with respect to the Directives (i.e. studies that have started to be conducted prior to 26 May 2021). These investigations may continue to be conducted after the date of application of the MDR, but the reporting of SAE and device deficiencies shall be carried out in accordance with the MDR requirements from 26 May 2021. The new reporting requirements apply prospectively to SAE and Device deficiencies that happen after 26 May 2021. Sponsors do not need to retrospectively verify if adverse events that occurred before 26 May 2021 meet the new MDR SAE definition.
Where controlled documents, relating to clinical investigations commenced under the Directives, need to be updated to bring the procedures for SAE reporting into line with the requirements of Article 80 of the MDR, the HPRA does not require an application for modification of the clinical investigation, strictly for these aspects.
As the EUDAMED system is delayed, reporting should take place via email@example.com until such a time as EUDAMED is functional for SAE reporting.
Research Ethics Committees and Clinical Investigations
In general, clinical investigations of investigational medical devices require two types of assessment, from a National Competent Authority for medical devices and from a relevant Research Ethics Committee, prior to beginning the study. For further information on the establishment of a National Research Ethics Committee for Medical Device research in Ireland, related to the MDR, please see the NREC website (www.nrecoffice.ie).
Further guidance on clinical investigation is available:
If you have a query about Clinical Investigations in Ireland please contact the Medical Device Department at firstname.lastname@example.org