Post-market Clinical Investigation with Medical Devices in Europe as per ISO 14155:2020 and MDR 2017/745

Post-market Clinical Investigation with Medical Devices in Europe as per ISO 14155:2020 and MDR 2017/745 

Introduction

This blog summarizes the different post-market Clinical Investigation types as given in the ISO 14155:2020 and MDR 2017/745.

Post-market Clinical Investigations as per ISO 14155:2020

As per ISO 14155:2020 Annex I, section I.2.3, a post-market clinical investigation is:

• “A clinical investigation carried out following market approval of a medical device, intended to answer specific questions relating to clinical performance, effectiveness or safety of a medical device when used in accordance with its approved labelling.”
• “If marketed medical devices are being investigated for new indications, other than described in the approved labelling, requirements for pre-market clinical investigations apply.”

Clinical investigations at the post-market stage can be confirmatory and interventional or observational and non-interventional. Observational clinical investigations may collect prospective or retrospective data. An example of the confirmatory, interventional post-market clinical investigation is the PMCF clinical investigation as per Art. 74 (1) MDR 2017/745.

With post-market clinical investigations, data of a broader subject population, the real-world use, long-term outcomes, or rare adverse events can be investigated.

What needs to be considered for non-interventional clinical investigations, like registries, observational studies, or survey studies, is the non-interventional assignment process to a device.

While for interventional studies, often the gold standard is a randomized controlled trial (RCT), the decision on the treatment is already done by the physician, and the patient will only be asked to participate in the clinical investigation based on the treatment.

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).”

Link to MDR 2017/745 Articles

The principle of ISO 14155:2020 Annex I post-market stage applies to clinical investigations as per MDR 2017/745 Article 74.1 PMCF clinical investigations and the Art. 82 other clinical investigations

• Article 74.1 PMCF clinical investigations fall under the post-market stage, although the confirmatory design and interventional aspects need to be taken into account for planning these studies also
• Article 82: Requirements regarding other clinical investigations, if:
• It is an interventional clinical investigation with a CE-marked or non-CE marked device, but not for purposes of Art. 62.1 (example: CE marked Stent, investigation to explore the impact on blood flow; non-CE marked smart monitoring device, investigation to explore changes in the behavior of subjects when using the device)
• 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)
• clinical investigations with CE-marked devices, within the scope of intended use, without any additional burden to the subject, but not for safety and performance would be post-market stage (observational), but are out of scope of the MDR 2017/745. This does not imply that they are out of scope of the national regulations of a Member State as well.

Submission of the notification or application of the Clinical Investigation

Since the MDR 2017/745 focuses on submissions to the Competent Authority of the EU Member States, the requirements for the submissions to the Ethics Committees are regulated via the Member States’ national laws, and it is recommended to check the respective EC website for advice.

With a rough categorization, it would be two types of post-market clinical investigations: CIs per Art. 74(1) and per Art. 82. These would lay down the criteria for the route of submission:

While it is a clear notification process For PMCF clinical investigations as per Art. 74 (1), for Art. 82 studies, it depends not only on national requirements but also on the objectives of a clinical investigation. In some countries, the submission of a notification is required, while in other countries, for Art. 82 other clinical investigations, a submission of an application is mandatory. This is summarized in the figure below: