MDR Clinical Evaluation Requirements including clinical investigation are defined on Chapter VI, Annex XIV and Annex XV respectively. As you know, to CE Mark a medical device under MDR, the importance of obtaining clinical data and evaluation is extremely important. Especially for implantable and Class III devices manufacturers shall implement a very carefully designed PMCF plan during the transitional period. Otherwise during MDR transition, they might face new clinical investigation for their current devices, due to the lack of effective clinical data. To decide if you will need a clinical investigation or an updated clinical evaluation report under MDR, just check the below requirements.
MDR Clinical Evaluation Requirements are not new for most of the medical device manufacturers. To some extend they were already defined in the medical device directives. However, Chapter VI of MDR contains additional requirements for certain type of devices and clarification of the rules regarding clinical data can be seen nearly in all MDR articles. Let’s have a deeper look to these requirements.
As you may already read, Article 2 (44) defines clinical evaluation as a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer. This definition refers to clinical data which has an outmost importance for a medical device. Parallel to this, Article 2 (48) defines the clinical data as information concerning safety or performance that is generated from the use of a device and is sourced from the following:
- clinical investigation(s) of the device concerned,
- clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,
- reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,
- clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up;
These two definitions are combined on Article 2 (55) to explain the clinical evidence and give a clear target to the medical device manufacturers. So, the goal of a clinical evaluation or clinical investigation process shall be to generate sufficient clinical evidence about the safety of a medical device. You might easily recall that although it includes some gaps with MDR, Meddev 2.7.1 Rev 4, which has been issued just before the MDR, aims the same target.
You can easily check the definitions given on Article 2 (45) to (57) to have a better understanding of MDR Clinical Evaluation Requirements.
MDR Clinical Evaluation Requirements
After reviewing the basic terms and definitions, let’s have a look to the details of MDR Clinical Evaluation Requirements. As stated on the above paragraph, Chapter VI lists the requirements for clinical evaluation and investigation. The main task of the manufacturer for CE Marking is to give answers for the applicable general safety and performance requirements (GSPR) listed on Annex I. According to Article 61, these answers shall be based on clinical data providing sufficient clinical evidence, regardless of risk class of the medical device. In other words, the manufacturer shall justify the level of necessary clinical evidence to demonstrate the compliance with the applicable GSPR. The process shall be managed with a structured plan (CEP) parallel to Part A of Annex XIV. Naturally, the output of the process will be clinical evaluation report (CER).
The enhanced requirements for certain type Class IIb, implantable and Class III devices bring some complexity to the clinical evaluation process. The main issue is that for those devices a clinical investigation is needed expect if;
- the device has been designed by modifications of a device already marketed by the same manufacturer,
- the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and
- the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements.
In addition to this a manufacturer may perform a clinical evaluation without conducting a clinical investigation if clinical data of a similar device can be presented. The requirement having a “contract” in place with the manufacturer of the similar device seems to be impracticable unless both are sister companies. Therefore we highly recommend to the manufacturers to create their own data during the transitional period using effective PMCF tools.
Manufacturers of implantable and Class III devices, who can present a sufficient clinical evaluation report under their 93/42/EEC or 90/385/EEC certification are excluded from clinical investigation requirements listed on Article 61. For more details about the relevancy of this type of clinical data please refer to the MDCG guidance document 2020-6.
On the other hand, sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors are also excluded from the clinical investigation requirements. Please bear in mind that the commission reserves the right to modify this list.
Paragraph 9 of Article 61 defines the requirements for devices which do not have medical purpose but covered under Annex XVI of MDR. For those devices, demonstration of clinical benefit shall be understood as demonstrating the performance of the device. Clinical evaluations for these medical devices shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation.
Manufacturers shall bear also in mind, that clinical evaluation under MDR is an ongoing process. For all devices clinical evaluation shall be updated throughout the life cycle of the device. Especially for implantable and Class III devices the related reports shall be updated at least annually.
Clinical Evaluation Plan (CEP)
Manufacturers shall prepare a solid CEP to comply with the MDR Clinical Evaluation Requirements. The plan shall comply with requirements listed on Part A of Annex XIV.
The CEP shall include at least;
- an identification of the general safety and performance requirements that require support from relevant clinical data;
- a specification of the intended purpose of the device;
- a clear specification of intended target groups with clear indications and contra-indications;
- a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters;
- a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects;
- an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device;
- an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non-viable animal or human tissues, are to be addressed; and
- a clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF as referred to in Part B of Annex XIV with an indication of milestones and a description of potential acceptance criteria.
Like any other stage of your clinical evaluation, during the planning phase you may benefit a lot from the MDCG guidance document MDCG 2020 -13. Although this guidance is intended for notified bodies (NB), as manufacturer you may structure your process parallel to the samples given in this document. This might save you long discussions during your certification process with the NB.
Literature Search and Literature Review Protocol
During the clinical evaluation process manufacturers shall identify available clinical data relevant to their medical device. For an effective literature search you may consult Annex A.5 of Meddev 2.7.1 Rev 4. A literature review protocol which is based on a search of scientific literature databases like MEDLINE or PubMed would be a good starting point. The databases shall be searched for equivalent devices (Technical, Biological, Clinical) with similar intended purpose using the right keywords. The gaps in clinical evidence shall be identified through a systematic scientific literature review and reported as an input for the clinical evaluation report.
Clinical Evaluation Report (CER)
As mentioned above use of the MDCG 2020-13 as a template could be a very good solution for ensuring a smooth certification process. Manufacturers may also benefit from parts of Meddev 2.7.1 Rev 4, which do not contradict with the MDR Clinical Evaluation Requirements.
The key point for a successful CER is evaluation of the clinical data generated via the implementation of the literature review protocol according to an appraisal plan. The IMDRF guidance document WG/N56FINAL:2019 includes very good sample methods of appraisal on Annex F.
If you need further clarifications on specific topics related to clinical evaluation or require assistance on clinical investigation requirements of your high-risk medical devices, do not hesitate to contact us. Our experts with notified body experience would be happy to help.