Clinical Investigation with Medical Devices in Europe
Pre-CE Mark, Explanatory or Confirmatory Clinical Investigation, and Post-Market Clinical Investigations
This comprehensive guide provides an overview of the different types of clinical investigations in the EU per MDR 2017/745, the submission routes and submission documents, and reporting requirements during conduct and after completion of a clinical investigation. This guide is based on current practice in the absence of EUDAMED.
Introduction
Recently ECLEVAR posted a blog about the response to TGA Consultation of 17th of August 2022 on proposed regulatory changes for clinical trials of medical devices, highlighting the need to clarify TGA's understanding of "novel" medical devices, and linking to ISO 14155:2020 and FDA Guidance for Industry: Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies.
The definitions provided by ISO 14155:2020 in Annex I and the FDA Guidance are almost congruent, whereas the FDA Guidance provides further guidance on the differences between early feasibility and traditional feasibility studies.
While the FDA guidance relates specifically to early feasibility study IDEs only, there is currently no pendant in the EU. If there is a series of early feasibility clinical investigation (CI) for a medical device in the EU, the clinical investigation needs to be submitted per MDR 2017/745 Art. 62 requirements as an own-standing CI, but references to previous CIs, including a summary of changes to the device design, are taken into consideration by the competent Authorities.
Considerations When Planning a Clinical Investigation
Pre-Market Clinical Investigation as per ISO 14155:2020
With the updated ISO 14155:2020, the ISO incorporates a new Annex I on the clinical development stages. Next to the regulatory status of the device at the timepoint of the clinical investigation, pre-market and post-market status, ISO 14155:2020 groups the CIs also depending on the clinical development stage, the type of design, the descriptors of the clinical investigation, and the burden to subjects.
Under the pre-market clinical investigations, ISO 14155:2020 Annex I divides clinical investigations into pilot stage and pivotal stage.
Important Note on Subject Burden
Regarding the burden on subjects, any pre-market clinical investigation is considered to be interventional.
Clinical Development Stage and Type of Design
In the pre-market status, the clinical investigations are either the pilot stage or the pivotal stage. The type of design may be explanatory or confirmatory.
Exploratory Clinical Investigation
Exploratory clinical investigations "might not have pre-specified primary hypotheses, and can be conducted to generate hypotheses, to be confirmed in subsequent clinical investigations."
Confirmatory Clinical Investigation
A confirmatory clinical investigation is "an adequately controlled clinical investigation in which the hypotheses of the primary endpoint(s) are stated before the start of the clinical investigation in the CIP and are analysed by the CIP (i.e. sound confirmative statistical testing is pre-specified, intended, and applied)."
Pilot Stage Clinical Investigations
The pilot stage clinical investigations can be exploratory or confirmatory. These can include:
Types of Pilot Stage Investigations
First in Human Clinical Investigations
"A clinical investigation in which a medical device for a specific indication is evaluated for the first time in human subjects."
Early Feasibility Investigations
"A limited clinical investigation of a device early in development, typically before the device design has been finalized, for a specific indication (e.g. innovative device for a new or established intended use, marketed device for a novel clinical application). It can be used to evaluate the device design concept concerning initial clinical safety and device clinical performance or effectiveness (if appropriate) per intended use in a small number of subjects when this information cannot practically be provided through additional nonclinical assessments or appropriate nonclinical tests are unavailable. Information obtained from an early feasibility clinical investigation can guide device modifications."
Note: Early feasibility clinical investigation can also be called proof of concept clinical investigation.
Traditional Feasibility Investigations
"A clinical investigation that is commonly used to capture preliminary clinical performance, effectiveness, or safety information of a near-final or final device design to adequately plan an appropriate pivotal clinical investigation. Because the clinical investigation of a near-final or final device design takes place later in development than an early feasibility clinical investigation, more non-clinical or prior clinical data are expected than in an early feasibility clinical investigation. A traditional feasibility clinical investigation does not necessarily need to be preceded by an early feasibility clinical investigation."
Pivotal Stage Clinical Investigations
Pivotal stage clinical investigations represent the main confirmatory studies designed to demonstrate safety and effectiveness of the device. These investigations typically involve larger patient populations and are more rigorous in design compared to pilot stage studies.
Link to MDR 2017/745 Articlesfor Invasive and Non-Invasive Clinical Investigations
On the figure of MDCG 2021-6 Annex I the decision pathway is made very visual:
Key Distinction
While Art. 82 clinical investigations with CE-marked devices within the scope of intended use and without any additional burden to the subject fall under the post-market stage (observational), other clinical investigations follow different regulatory pathways.
MDCG 2021-6 Decision Pathway
The MDCG 2021-6 Annex I provides a visual decision pathway that clarifies the regulatory route for different types of clinical investigations based on device status, invasiveness, and subject burden.
Submission Routes and Documentation
Clinical investigations in the EU require submission to competent authorities following MDR 2017/745 requirements. The submission route depends on the type of investigation, device classification, and regulatory status.
Key Submission Requirements
- Clinical Investigation Plan (CIP) with pre-specified hypotheses and endpoints
- Investigator's Brochure with comprehensive device information
- Risk analysis and risk management documentation
- Clinical Evaluation Report (if applicable)
- Informed consent forms and patient information
- Insurance documentation
- Ethics committee approval documentation
Reporting Requirements
During Conduct of Clinical Investigation
Throughout the clinical investigation, sponsors must maintain ongoing reporting to competent authorities and ethics committees. This includes serious adverse event (SAE) reporting, protocol amendments, and safety updates.
Current Practice (Pre-EUDAMED)
Until EUDAMED is fully functional, coordinated single submissions, SAE reporting, and notifications via EUDAMED will not be possible. Current practice requires direct submission to national competent authorities following their specific requirements.
After Completion of Clinical Investigation
Upon completion of the clinical investigation, sponsors must submit a final clinical investigation report to the competent authority and ethics committee. This report must include all data collected, analysis results, and conclusions regarding the safety and performance of the device.
Post-Market Clinical Investigations
Post-market clinical investigations are conducted after the device has received CE marking. These investigations can be observational (Art. 82) or interventional, depending on whether they involve additional burden to subjects or use outside the scope of the intended use.
Regulatory Framework Summary
Key Regulatory Documents
- MDR 2017/745 - Medical Device Regulation
- ISO 14155:2020 - Clinical investigation of medical devices for human subjects
- MDCG 2021-6 - Guidance on sufficient clinical evidence for legacy devices
- MDCG 2020-6 - Regulation of medical device software
- National competent authority guidelines
Need Expert Guidance on Clinical Investigations?
Eclevar Medtech specializes in clinical investigation planning, submission, and management for medical devices under EU MDR. Contact our team to discuss your clinical investigation strategy.
Contact Us