1. Difference between the performance, clinical performance and clinical benefit?
Answer: In accordance with the MDR, the performance of a device is its ability to achieve its intended purpose as stated by the manufacturer. By extension, the clinical performance5 of a medical device is the ability of the device to achieve its intended purpose, thereby leading to a clinical benefit when used as intended. Clinical benefit means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health.
2. What are the general differences and improvements related to clinical investigations under EU MDR?
Answer: Regulation (EU) 2017/745 (MDR) will progressively replace both Directives (93/42/EEC and 90/385/EEC) and their transpositions in national law. The first difference is regarding the type of the law. A Directive is a legislative act that sets out a goal that all EU countries must achieve. However, it is up to the individual countries how to reach these goals by the implementation of national laws. A Regulation, as opposed to a Directive, is a binding legislative act that must be applied in its entirety across the EU on the date of application. It means that the rules are applied in an identical manner throughout the EU. Member States, in authorising and supervising the conduct of a clinical investigation, will be required to base their assessments and decisions on the same rules. The MDR contains greater detail than the Directive, which is a result of implementing aspects related to good clinical practice, many of which have previously been present in the form of guidance and standard documents. Further harmonisation at European level will provide greater certainty, which will support an environment that provides greater predictability and is more favourable for conducting clinical investigations, with the highest standards of patient safety, for all EU Member States. It will not only harmonise decisions, but also foster work sharing and collaboration between Member States and enhance the transparency regarding these studies. For certain clinical investigations, the sponsor still needs to check and follow any specific national provisions which may apply.
3. What are the safety reporting requirements for clinical investigations?
Answer: The requirements for safety reporting will depend on whether you are using the investigated medical device within its intended purpose:
If the investigated medical device is CE marked and will be used within its intended purpose, the provisions on vigilance laid down in Article 80(6) and Articles 87 to 90 of the MDR and the acts adopted pursuant to Article 91 of the MDR shall apply for PMCF clinical investigations.
If the investigated medical device is not CE marked, or is CE marked but will be used outside its intended purpose, the provisions on safety reporting laid down in Article 80 of the MDR shall apply.
Please refer to MDCG 2020-10/1 ‘Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745’ for further guidance.
4. How is a substantial modification defined?
Answer: A substantial modification of a clinical investigation is a change to the clinical investigation which is likely to have a substantial impact on the safety or health or rights of the subject, or on the robustness or reliability of clinical data generated by the investigation. Modifications of the clinical investigation plan (CIP), investigators brochure, the subject information sheet and other clinical investigation documentation may or may not be considered as substantial modifications.
Sponsors should also take into consideration the fact that some modifications may seriously impact the design or scientific outcome of the clinical investigation, and may require the initiation of a new clinical investigation. The procedure is further described in Article 75 of the MDR. A non-exhaustive list of modifications that may be interpreted as substantial can be found in Annex II of this document.
5. Does a manufacturer of devices without a medical purpose included have to conduct clinical investigations?
Answer: To ensure the same level of protection of consumers for some products which could be similar to medical devices but without a medical purpose, devices described in Annex XVI to the MDR have to comply with the applicable general safety and performance requirements. Clinical evaluations of those products shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigations. Clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified. Please refer to MDCG 2020-5 Clinical Evaluation – Equivalence, section 4 (f) for further guidance.
6. What is considered as a substantial modification to the clinical investigation or does it lead to the submission of a new clinical investigation?
Answer: In general, a change to the investigational medical device is a substantial modification. Some modifications to the investigational medical device may require a new application for clinical investigation. This will be assessed by Member States on a case-by-case basis with reference to public health, subject and user safety or health, and public policy. Modifications to the device which alter the suitability of the clinical investigation design to provide evidence for the safety, performance or clinical benefit of the device, may result in refusal of the modification and the submission of a new clinical investigation application may be required.
7. If a sponsor intends to introduce modifications to a clinical investigation, when sponsor should notify the Member State?
Answer: The ‘one week’ period starts from the date when the relevant documents (such as clinical investigation plan, investigator brochure, subject information sheet and informed consent form) are issued in an updated version.
It is acknowledged that changes to e.g. a CIP may require subsequent changes to other documents such as patient information, and that these changes may be done on a different date. Such changes can be collected and submitted together when the last affected document is issued, but note that the implementation of the changes to the clinical investigation can not be done until the deadline in Article 75 of the MDR has expired or an authorisation letter is issued by the Competent Authority and/or Ethics Committee if this is required according to national provisions.
8. What notification requirements apply to non-substantial modifications?
Answer: Article 75 of the MDR does not describe how sponsors or authorities shall deal with non substantial modifications. Once EUDAMED is available, sponsors are expected to keep the information in the database up to date in accordance with Article 70(2) of the MDR. However, in the absence of EUDAMED Member States have not yet harmonised their approach, and it is thus necessary to check the national requirements.