The article highlights the key points related to the current regulatory framework for clinical investigations conducted in Ireland.
Table of content
The Health Products Regulatory Authority (HPRA), the country’s regulating agency in the sphere of medical devices, has published a guidance document dedicated to clinical investigations carried out in Ireland. The document provides a general overview of the regulatory requirements set forth under the existing legal framework, as well as provides additional clarifications and recommendations to be taken into consideration by medical device manufacturers, study sponsors, and other parties involved in order to ensure compliance thereto.
At the same time, the authority reserves the right to make changes to the guidance and recommendations provided therein, should such changes be reasonably necessary to reflect corresponding amendments to the underlying legislation.
Regulatory Background
The present guidance document issued by the HPRA provides an overview of the legislative framework governing clinical investigations (CIs) involving medical devices in Ireland. It also offers guidance on submitting applications to the authority for the conduct of CIs.
Recommendations provided in the document are addressed to CI sponsors such as manufacturers, academic groups, and clinical research organizations. However, the information may also be beneficial to ethics committees and other relevant stakeholders.
The authority additionally emphasizes that this guide serves only as a supplementary resource and is not a definitive interpretation of the law or regulations, so the interested parties are encouraged to consult the relevant legislation concerning medical devices in addition to this guide.
Furthermore, the Medical Devices Coordination Group (MDCG), an EU body focused on the improvement of the regulatory framework for medical devices, has published several important documents, including a Q&A for CI sponsors (MDCG 2021-6), and guidance on clinical investigation plans (MDCG 2024-3) and investigator brochures (MDCG 2024-5), which should be reviewed before conducting a CI in Ireland.
What is a Clinical Investigation?
According to the guidance, a clinical investigation (CI) is a systematic study involving one or more human subjects to assess the safety or performance of a medical device. The Medical Devices Regulation (MDR) specifies the requirements for CIs carried out within the EU, while S.I. 261 of 2021 outlines the national requirements for CIs conducted in Ireland.
In particular, there are three main types of CIs:
- Article 62 Studies: These studies generally involve non-CE-marked devices or CE-marked devices used outside their intended purpose. They include early feasibility studies, pilot studies, and pivotal studies of non-CE-marked devices.
- Article 74 Studies: These CIs involve CE-marked devices where the study subjects participants to additional invasive or burdensome procedures.
- Article 82 Studies: This category encompasses all other CIs and must comply with specific national requirements outlined in Part 3, Article 14 of S.I. 261 of 2021.
The document further refers to the relevant articles in the MDR for detailed descriptions of each study type.
Conducting a Clinical Investigation in Ireland
As explained by the authority, in order to commence a CI in Ireland, sponsors must:
- Submit an application or notification to the HPRA.
- Apply to the National Research Ethics Committee for Medical Devices (NREC-MD).
- Fulfill other requirements, such as adverse event reporting.
Submitting a Clinical Investigation Application to the HPRA
The process for submitting a CI application to the HPRA involves several steps.
In particular, an interested party should:
- Step 1: Complete the Relevant Form depending on the study type.
- Step 2: Pay the Relevant Fees. Refer to the Guide to Fees for Human Products to find the correct category for the submission. Include a completed fee application form with your submission. Payment details, including methods for credit transfer or EFT, can be found in the Payment of Fee Instructions.
- Step 3: Submit Documentation and Contact the HPRA – the application or notification form along with the required documents should be submitted through the Common European Submission Portal (CESP).
- Step 4: Notify the HPRA of the CESP Submission. At this stage, the applicant should confirm the submission by emailing the HPRA at devices@hpra.ie with your CESP reference number. The authority also mentions that the application will not be considered complete until all steps are finalized.
HPRA Submission Review Process
According to the guidance, the review process would also differ depending on the application type.
- Article 62 Applications: Within 10 to 15 calendar days of receiving the application and proof of fee payment, the HPRA will validate the application, verify the required documents, and confirm the CI falls within the scope of the MDR. This may take longer if additional information is needed. Upon validation, a unique ID number (CIV-ID) will be provided. If a CIV-ID has already been assigned in another Member State, this information should be included in the application form. The outcome of the review will be issued within 45 calendar days, extendable by 20 days if external expert assistance is required. Additional information requests may prolong the process.
- Article 74 and 82 Notifications: Upon receiving a notification, the HPRA will conduct a high-level review to confirm it falls within the scope of MDR Article 74 or 82. At this stage, the authority reserves the right to request additional information, should this be reasonably needed to complete the review. Following the review, a letter acknowledging the notification will be sent. The CI can commence 30 days after submission, provided ethical approval from NREC-MD is obtained.
Modifications to a Clinical Investigation
In accordance with the applicable regulatory requirements, substantial modifications to a CI require notification and assessment by the HPRA. A party responsible for a CI should submit a Notification of Substantial Modification form and relevant documentation as outlined in section 4.
Research Ethics Committees and Clinical Investigations
In Ireland, all CIs must receive ethics approval from the National Research Ethics Committee – Medical Devices (NREC-MD) before commencement. The NREC-MD review is independent of the HPRA review.
Applications to both entities can be submitted concurrently or separately, but the CI cannot begin until both approvals are secured. Detailed application procedures are available on the NREC website.
Serious Adverse Events (SAE) and Device Deficiency Reporting
The authority additionally emphasizes that SAEs or device deficiencies occurring during a study must be reported to the HPRA via email at devices@hpra.ie.
In particular, the parties involved are encouraged to follow the MDCG Guidance document for safety reporting in CIs (MDCG 2020-10/1) and use the MDCG’s safety report form (MDCG 2020-10/2).
CIs that began before 26 May 2021 are exempt from re-application for authorization but must comply with updated SAE reporting procedures as per MDR.
Ending a Clinical Investigation in Ireland
Notification to the HPRA is required within 24 hours if a CI is terminated or temporarily halted on safety grounds. For other reasons, notification must occur within 15 days.
A CI report must be submitted within one year of the CI ending, or within three months if the CI is halted or terminated early. Reports should be sent to devices@hpra.ie, including the CIV-ID number.
Support for Device Developers
According to the guidance, the HPRA offers various supports to device developers, including:
- Innovation Office: Providing regulatory support and advice, details of which are available on the innovation office webpage.
- Preliminary Meetings: Targeted at early-stage start-up companies, these meetings introduce the HPRA’s role and regulatory requirements for pre-market device development.
- Pre-submission Meetings: Aimed at sponsors planning to submit a CI application, these meetings address any pre-submission queries. Sponsors are encouraged to schedule a pre-submission meeting before submitting an application.
These support options are provided free of charge. To request a preliminary or pre-submission meeting, an interested party should complete the Request for Clinical Investigation Pre-submission meeting form and send it to devices@hpra.ie.
Conclusion
In summary, the present guidance provides an in-depth overview of the regulatory requirements related to clinical trials to be conducted in Ireland as set forth under the existing legal framework. The document outlines the key points to be taken into consideration and also clarifies certain specific aspects associated thereto.
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