Clinical Investigation with Medical Devices in Europe
Pre-CE mark Explanatory or Confirmatory Clinical Investigation,
or Post-market Clinical Investigations
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 [Regulatory changes for clinical trials of medical devices (eclevarmedtech.com)], 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, Including Certain First in Human (FIH) Studies of October 1st, 2013.
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, covered by the early feasibility study (EFS) program, 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 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.
This whitepaper provides an overview on the different types of clinical investigations in the EU per MDR 2017/745, the submission routes and submission documents, and also on reporting requirements during conduct, and after completion of a clinical investigation. This whitepaper is based on current practice, which means in the absence of EUDAMED. Until EUDAMED is functionally, coordinated single submissions, SAE reporting and notifications via EUDAMED will not be possible.
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 divide clinical investigations into pilot stage and pivotal stage.
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.
Identifiers for exploratory clinical investigations are, that they “might not have pre-specified primary hypotheses, and can be conducted to generate hypotheses, to be confirmed in subsequent clinical investigations.”
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).”
On the figure of MDCG 2021-6 Annex I the decision pathway is made very visual:
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)
