MDCG 2021-6 Rev. 1 is the Medical Device Coordination Group’s Questions and Answers document on clinical investigations under Regulation (EU) 2017/745 (MDR). Revised in December 2023, it helps sponsors determine which regulatory pathway applies to a planned medical device study.
The guidance addresses pilot and proof-of-concept investigations, studies involving CE-marked devices, Article 82 investigations, combined medicinal product and device studies, usability testing, application documentation, substantial modifications, safety reporting and the responsibilities of a sponsor’s legal representative.
MDCG guidance is not legally binding. The sponsor remains responsible for selecting and documenting the correct regulatory pathway and must also consider the national requirements of every Member State in which the investigation will be conducted.
Introduction to MDCG 2021-6 Rev. 1
MDCG 2021-6 Rev.1 is a cornerstone document for those embarking on clinical investigations of devices within the scope of the Medical Device Regulation (EU) 2017/745 (MDR). Designed for sponsors, this evolving guide may expand with more questions and answers over time. It clarifies the use of the term ‘device’ in line with MDR. This includes medical devices, their accessories, and specific products listed in Annex XVI.
The guide also standardizes the definition of “clinical investigation.” It aligns with Article 2(45) of the MDR, focusing on investigations aimed at assessing a device’s safety or performance. Moreover, it introduces the broader concept of “clinical study.” This encompasses a range of research activities within medical science. It includes clinical trials of medicines, device investigations, and in vitro diagnostic studies. These elements are vital for understanding the full scope of clinical research.
This document touches on key topics crucial for navigating the regulatory landscape:
- Proof of Concept Studies: Offering insights into the initial stages of device development.
- Article 82 Clinical Studies: Clarifying the scope of broader research activities under MDR.
- Pilot Stage Investigations: Defining early feasibility and its regulatory implications.
- Regulatory Pathways: Shedding light on navigating clinical investigations amidst the interplay of MDR, the Clinical Trial Regulation (CTR), and local laws.
- Combined Trials: Addressing the complexities of studies involving both medicinal products and medical devices.
- Invasive or Burdensome Considerations: Guiding sponsors on ethical and participant safety considerations.
- Usability Testing: Outlining when such tests are considered clinical investigations.
- Retrospective Testing: Distinguishing between prospective data collection and the analysis of existing data.
- Submissions and Modifications: Offering guidance on navigating regulatory submissions and changes during the clinical investigation process.
- Legal Representation: Emphasizing the role of legal representatives in ensuring compliance.
MDCG 2021-6 Rev. 1 at a Glance
The applicable regulatory pathway depends on the device’s regulatory status, its intended purpose and the objective of the investigation:
- Non-CE-marked devices or CE-marked devices used outside their intended purpose: Article 62 and Articles 62–81 generally apply when the data will support conformity assessment.
- First-in-human, early feasibility and proof-of-concept investigations: These are considered pilot-stage investigations and should generally follow Article 62. Where there is doubt, MDCG 2021-6 Rev. 1 recommends applying under Article 62.
- CE-marked devices used within their intended purpose: Article 74(1) applies when subjects undergo additional invasive or burdensome procedures. The Member State concerned must be notified at least 30 days before the investigation starts.
- Other investigations involving CE-marked devices: Where Article 74(1) does not apply, Article 82 and the relevant national provisions may apply.
- Other clinical investigations not conducted for an Article 62(1) purpose: Article 82 establishes minimum MDR requirements, but submission requirements are determined nationally.
- Combined medicinal product and medical device studies: The study may need to comply separately with both the MDR and the Clinical Trials Regulation.
The guidance also covers application content, substantial modifications, investigation timelines, safety reporting and the responsibilities of the sponsor’s legal representative. See our guides to MDCG 2020-10/1 safety reporting and the EU clinical investigation legal representative for further operational detail.
Practical Questions Addressed by MDCG 2021-6 Rev. 1
Pilot and Proof-of-Concept Investigations
MDCG 2021-6 Rev. 1 identifies first-in-human, early feasibility and traditional feasibility investigations as pilot-stage clinical investigations. An early feasibility investigation may also be described as a proof-of-concept investigation.
These studies normally enrol a limited number of subjects to generate preliminary information on device safety, performance or functionality. Their results can inform design changes and the planning of subsequent investigations, but the data are generally insufficient on their own to support CE marking.
Because pilot-stage investigations generate preliminary safety or performance data, sponsors should generally follow the Article 62 pathway. If there is uncertainty about the correct route, MDCG 2021-6 Rev. 1 recommends applying under Article 62 and consulting the relevant national competent authority where necessary.
Combined Studies Involving Devices and Medicinal Products
A study that collects data for both a medical device and a medicinal product may need to comply with two separate regulatory frameworks. The device component is governed by the MDR, while the medicinal product component is governed by Regulation (EU) 536/2014, the Clinical Trials Regulation.
There is no single harmonised EU application procedure for these combined studies. Where both frameworks apply, the sponsor must submit the required medical device clinical investigation application or notification and the medicinal product clinical trial application through their respective systems. Each submission must contain sufficient standalone documentation, even where some documents overlap.
MDCG 2022-10 should be consulted separately when a medicinal product clinical trial is conducted in parallel with an IVD clinical performance study. It does not replace the MDR pathway described in MDCG 2021-6 Rev. 1 for medical devices.
When Is a Usability Test a Clinical Investigation?
A usability test is not automatically a clinical investigation. Its classification depends on the purpose and design of the test, how human subjects interact with the device and whether the study assesses the device’s safety or performance.
A usability test may meet the MDR definition of a clinical investigation when subjects are exposed to device-related risks, when poor usability could create safety risks, or when the test evaluates the safety or performance of a prototype or future medical device.
When human subjects are involved but the manufacturer concludes that the usability test is not a clinical investigation, MDCG 2021-6 Rev. 1 recommends documenting that justification in the technical documentation. A usability test that does meet the definition will typically fall under Article 62(1), although Article 82 may apply in some circumstances.
Additional Invasive or Burdensome Procedures
For a PMCF investigation involving a CE-marked device used within its intended purpose, Article 74(1) applies when subjects undergo procedures additional to normal device use that are invasive or burdensome.
Burden should be assessed from the participant’s perspective and can include pain, discomfort, fear, risk, disruption of daily activities or other unpleasant experiences. If the classification is uncertain, the sponsor should seek advice from the competent authority before starting the investigation.
Frequently Asked Questions About MDCG 2021-6 Rev. 1
It is an MDCG Questions and Answers document for sponsors conducting medical device clinical investigations under the EU MDR. Revision 1 was published in December 2023 and contains 50 questions covering regulatory pathways, submissions, modifications, reporting and legal representation.
No. MDCG guidance expresses a common European understanding of how the MDR should be applied, but it is not legally binding. The MDR and applicable national legislation contain the binding requirements.
Proof-of-concept and early feasibility investigations are normally considered pilot-stage investigations. Because they generate preliminary safety or performance data, Article 62 should generally be used. MDCG 2021-6 Rev. 1 recommends applying under Article 62 when there is uncertainty.
Article 62 applies principally to investigations conducted for conformity-assessment purposes. Article 74(1) applies to certain PMCF investigations involving CE-marked devices used within their intended purpose when subjects undergo additional invasive or burdensome procedures. Article 82 applies to other clinical investigations that do not pursue an Article 62(1) purpose, together with applicable national requirements.
No. It depends on the study’s purpose, design, human exposure and whether device safety or performance is being assessed. Manufacturers should document why a usability test involving human subjects does or does not meet the MDR definition of a clinical investigation.
No. Where both the MDR and the Clinical Trials Regulation apply, the relevant device and medicinal product pathways must be followed separately. Each application must be sufficient on its own, even where the supporting documentation overlaps.
Need Support With an EU MDR Clinical Investigation?
Selecting the wrong regulatory pathway can affect the application package, national submissions, study timelines and safety-reporting obligations. MDx CRO supports medical device sponsors with pathway assessment, Clinical Investigation Plan development, competent authority and ethics submissions, monitoring, safety reporting, data management and final clinical investigation reporting.
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