Regulatory Requirements For A Clinical Investigation For Medical Devices According To MDR Annex XIV

By Matthias Fink, M.D., TÜV SÜD America

On May 26, 2021, the Regulation EU 745/2017 (MDR) entered into force after the Date of Application was postponed by one year due to the global COVID-19 pandemic.

Per MDR Article 61.4, a clinical investigation shall be performed for novel implantable and Class III medical devices to demonstrate that the device is compliant with the general safety and performance requirements set out in Annex I of the MDR.

Article 61 defines the following exemptions from the requirement to conduct a clinical investigation:

• When a manufacturer can demonstrate that the device in question is a modification of a device it already markets and the three equivalence characteristics (technical, biological, clinical) are fulfilled.
• If equivalence to a competitor device is claimed, the manufacturer needs to provide to the notified body involved in the conformity assessment procedure a contract between the two manufacturers that demonstrates that the second manufacturer has continuous full access to the technical documentation of the proposed equivalent device. This outlines a much more stringent demonstration of equivalence compared to the Medical Device Directive (MDD). To provide more clarification on the interpretation of the equivalence demonstration in Article 61.4 and 61.5, the MDCG 2020-5 Guidance Document was published.
• Lastly, devices listed in Article 61.6 (b) are also exempted from the requirement to conduct a clinical investigation as long as the clinical evaluation is based on sufficient clinical data.

The requirement to conduct a clinical investigation for implantable and Class III devices has not changed compared to the requirements in the MDD in Annex I, Section 1.1a. But the MDD’s less stringent requirement to demonstrate equivalence to a competitor device was a widely used pathway, and it is expected that there will be an increase in the number of pre-market clinical investigations in the EU under the MDR.

The MDD included only minimal requirements regarding a clinical investigation in Article 15 and Section 2 of Annex X, whereas the MDR provides very detailed requirements for a clinical investigation. Chapter VII defines the legal requirements to conduct a clinical evaluation and clinical investigation in Articles 61 to 82. The detailed requirements for a clinical investigation are provided in Annex XV, which is aligned with the EN ISO 14155, Clinical investigation of medical devices for human subjects.

Medical Device Coordination Group (MDCG) Guidance Provides Clarity

Despite the much more detailed legal requirements for a clinical investigation, in April 2021 the MDCG working group published MDCG 2021-6, Questions & Answers regarding clinical investigation.  This guidance document is mainly intended for sponsors of clinical investigations and includes 28 questions, grouped into various categories, and two annexes. Despite not being legally binding, the national competent authorities of the different EU member states expect that notified bodies are following these guidance documents.

The initial questions are general and provide some definitions and clarifications on the legal framework and requirements of the MDR compared to the MDD and the Active Implantable Medical Devices Directive (AIMDD). Question No. 3 clarifies the very close relationship between the terms “performance,” “clinical performance,” and “clinical benefit” based on their definitions in Article 2 of the MDR. The clinical performance (2(52)) is a more detailed definition of the performance (2(22)) relating to the ability of the device to achieve its intended purpose, thereby leading to a clinical benefit (2(53)) when used as intended.

Question 4 in combination with Annex I of the guidance document addresses clinical investigations for Class I and non-invasive Class IIa and Class Iib devices since they are not included in the requirements for a clinical investigation in Chapter VII of the MDR. For Class I and non-invasive Class IIa and IIb devices, the sponsor of a clinical investigation shall consider the national regulations of the EU member state in which the clinical investigation is conducted. Annex I provides a graphic overview of the different regulatory pathways depending on the regulatory status of a medical device.

Additional questions in the first section of the MDCG guidance provide some clarification on initial pilot studies for medical devices.

Questions 7 to 9 provide clarification on Article 74 concerning clinical investigations regarding CE marked devices. This is relevant to determine which articles of Chapter VII of the MDR are applicable for a post-market clinical follow-up (PMCF) study. A PMCF study would need to follow certain parts of Chapter VII and Annex XV in cases where the study would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome.

The MDCG document provides detailed information on what should be considered invasive and/or burdensome. There is guidance on how to determine if the planned use of the device in a clinical investigation is covered by the intended purpose. The sponsor of the PMCF study needs to assess if the device is only used in alignment with the labeling and the EU declaration of conformity or CE conformity certificate.

Any procedure performed additionally to those under the normal conditions of use of the device and which cause pain and discomfort or put the patient at any risk are considered burdensome. Furthermore examples for procedures which should be considered invasive are provided.

Additionally, there is guidance on devices without a medical purpose included in Annex XVI and custom-made devices or in-house manufactured devices in the context of a clinical investigation.

The next questions clarify when a modification of an ongoing clinical investigation is considered substantial, and the concerned competent authority needs to be informed. It is clarified that the “one week” notification period to the concerned competent authority starts with the date the updated clinical investigation documentation (e.g., clinical investigation plan or informed consent sheet) is issued.

Questions 21 to 24 reiterate the defined timelines and the reporting data of a clinical investigation as required per Article 77.

Both the MDR in Annex XV, Chapter 3 point seven and the ISO 14155:2020 in Annex D provide detailed information on the content of the final clinical investigation report. Question 25 provides some additional information on the content of that report.

The guidance also reiterates that clinical investigations that started under the MDD or AIMDD before the Date of Application of the MDR on May 26, 2021, can be continued under the requirements of the directives as long as the reporting requirements in Article 80 of the MDR are followed. Additional information on these reporting requirements is provided in the MDCG 2020-10/1, Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745, guidance document.

The Role Of Notified Bodies

It is noteworthy that the MDCG 2021-6 does not mention notified bodies, which is an additional confirmation on the position that notified bodies should not be involved during the planning and conducting phases of a clinical investigation before a manufacturer applies for the conformity assessment procedure to obtain the CE mark. In the past, national competent authorities allowed some limited discussion between a manufacturer and a notified body on the regulatory requirements of a clinical investigation in that early stage. Over the past few years this exchange has been limited by the national competent authorities. At this point, any form of assessment of a manufacturer’s documentation outside the conformity assessment procedure is considered consulting and is not allowed. This was just recently reiterated in Revision 3 of the MDCG 2019-6, Questions and answers: Requirements relating to notified bodies, published in October 2021.

National Competent Authority Approval

Any pre-market clinical investigation requires the approval of the national competent authority of the country in which the study is conducted; in case of multinational studies, approval by more than one authority might be necessary. Article 78 provides the requirements for a coordinated assessment procedure for these multinational studies. Currently, this process is in an initial pilot phase involving a few national competent authorities of the bigger EU member states. When a sponsor plans to conduct a multinational clinical investigation, it should contact the authorities of the respective member states to determine whether the coordinated assessment procedure might be feasible. Additionally, the clinical investigations require the approval of an ethics committee (EC) or an institutional review board (IRB).

Both institutions will provide regulatory and ethical feedback but not necessarily any clinical expertise on the study design. Per Article 61 Section 2, manufacturers of implantable Class III and Class IIb active devices intending to administer and/or remove a medicinal product (Annex XII, Rule 12) may contact the expert panel, as defined in Article 106, to obtain feedback on a clinical evaluation strategy or the proposal for a clinical investigation. For devices that do not fall under these classifications, manufacturers can only rely on internal or external clinical expertise during the planning phase of a clinical investigation to define the correct study design and endpoints to demonstrate safety and performance of the device when used as intended. Another relevant topic on which a manufacturer might need some clinical expertise is the planned study duration, especially for a long-term implant.

Conclusion

The MDCG 2021-6 guidance document Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation provides additional clarification on the regulatory requirements of the detailed provisions in Chapter VII and Annex XV of the MDR. To ensure that the sponsor of a pre-market clinical investigation is choosing the correct study design and endpoints, manufacturers might need to involve the proper internal and/or external clinical expertise. For certain medical devices (Class III implantable and Class IIb, per Rule 12), a manufacturer has the possibility to obtain the feedback on a planned clinical investigation from an expert panel. With the equivalence route being more stringent under the MDR, especially if equivalence to a competitor device is claimed, this might lead to an increased number of pre-market clinical investigations in the EU.

About The Author:

Matthias Fink, M.D., is TÜV SÜD America’s global team leader for the Ortho, Trauma and Dentistry Team at the Clinical Centre of Excellence as well as team manager of the Clinical Focus Team North America. A board-certified orthopedic and trauma surgeon, he has 17 years of experience in orthopedic, trauma, and reconstructive surgery and extensive training in cardiovascular and thoracic surgery. Prior to joining TÜV SÜD America, he was a clinical reviewer for the Clinical Centre of Excellence at TÜV SÜD Product Service in Germany.