As part of the introduction of the MDR (Medical Device Regulation), the Medical Device Coordination Group (MDCG) regularly publishes recommendations which, based on the MEDDEV documents used to date, represent recommendations for action in dealing with the implementation of the requirements of the MDR.

In particular, the area of clinical trials for medical devices places high demands on sponsors within the framework of the MDR Regulation. The recently published guidance document MDCG 2021-6 “Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation” attempts to provide answers to the most pressing and important questions surrounding the planning and conduct of clinical investigations.

The objective of clinical investigations prior to obtaining CE approval is to demonstrate the safety and, in particular, the performance of a medical device. In this context, it is important to clearly distinguish between the terms used in the MDR in order not to get into trouble when setting up the study design of a clinical trial:

Performance:
Defined as the ability of a medical device to fulfill its intended purpose as stated by the manufacturer.

Clinical performance:
Refers to the ability of a device, based on its technical or functional-including diagnostic-characteristics from any direct or indirect medical effects, to fulfill its intended purpose as stated by the manufacturer, such that when used as intended, as stated by the manufacturer, a clinical benefit to patients is achieved.

Clinical Benefit:
Refers to the positive impact of a device on a person’s health as indicated by meaningful, measurable, and patient-relevant clinical outcomes, including diagnostic results, or a positive impact on patient management or public health.

Even more important than these conceptualizations is the distinction between specific types of clinical trials, including those related to the timing of implementation. In the context of generating clinical data by means of clinical trials for highly innovative products, a multi-stage approach is appropriate, and this must also be recorded and described in the corresponding clinical development plan. A reference to the clinical development plan can then be found in the clinical evaluation plan, which forms the basis for the clinical evaluation report. At this point, therefore, the circle closes between the area of clinical testing and clinical evaluation prior to CE approval.

The multi-step approach may be as follows:

1. start with an animal study/cadaver study/experimental study to elicit fundamental basic information on the planned application of the planned medical device and to clarify the scientific question.

2. conduct a pilot study; here a distinction is typically made between

“First in man” studies,
early feasibility studies and
traditional feasibility studies
The primary objective of a pilot study is to test the planned study design for the subsequent pivotal study with a limited number of test subjects and to determine the initial clinical safety and performance of the medical device at an early stage of development. In this context, modifications in the design of the medical device may or may not occur; accordingly, clinical data obtained from pilot studies are not suitable for the purposes of CE approval. However, they represent an important building block in this process and have gained further importance with the introduction of the MDR.

3. conduct the pivotal study/actual pivotal study: after completion of the pilot study(s) and the final design freeze of the planned medical device, the actual pivotal study follows; here, the wise choice of the primary and secondary endpoints as well as the central study hypothesis is crucial. The clinical data collected there then form the basis for the preparation of the clinical evaluation and the ultimate demonstration of compliance with the Essential Safety and Performance Requirements under the MDR.

The responsibility for determining the applicable regulatory basis for conducting a clinical trial (Article 62 MDR versus Article 82 MDR, for example) rests solely with the sponsor of the clinical trial. This should be considered in advance during the planning process. The MDR also specifies in Article 15 that the manufacturer/sponsor must appoint a responsible person in the organization who can deal with these issues and also provide the necessary proof of qualification.

A primarily important aspect of conducting a clinical trial with a medical device without CE approval is the handling of safety-relevant events during the conduct of the clinical trial. Article 80 of the MDR regulates the procedure for these cases. Here, too, the sponsor is responsible for the reports; he must maintain corresponding procedural instructions with the deadlines to be observed, the responsible persons, the procedure in detail, from the occurrence of the adverse event to the conclusion of the reporting case. Further information and assistance on this topic is provided in MDCG document 2020-10/1 “Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745”.

Incidentally, the requirements for conducting clinical investigations also apply to the area of “custom-made devices” as defined in Article 2(3) of the MDR, as well as to devices manufactured and used exclusively within healthcare facilities located in the European Union (Article 5[5]). Accordingly, Articles 62 and 82 of the MDR then also apply here as a consequence.

In connection with the actual execution of the clinical trial, questions about modifications of the original study setting may also arise in the course. A distinction is made between substantial and non-substantial modifications. The first question on this set of issues will be: As a sponsor, how do I know what is a substantial adjustment? Ultimately, any adjustment that can foreseeably have a substantial impact on the safety or health or rights of the test subject or can affect the data quality or reliability of the clinical data collected by the clinical trial. Once agreement is reached on this essential issue, Article 75 of the MDR provides further information on the process for documenting the substantial modification and the corresponding approval process. Here, it is recommended not to submit multiple applications for substantial modifications in parallel, but to wait until the processing of the one application is completed. As a rule, modifications to the test product itself always constitute a substantial modification. In some cases, this may then lead to a new clinical trial application. The decision on this matter is made by the responsible regulatory authority on a case-by-case basis.

Annex II of MDCG Guidance 2021-6 contains a non-exhaustive overview of modifications that can in principle be considered substantial in order to better grasp the issue.

With respect to timelines in the clinical trial environment, the start and completion of the actual clinical trial are important aspects that are accompanied by certain reporting obligations. While a declaration or notification at the start of a trial is not explicitly required by the MDR (national regulations may provide different rules in this regard), Article 77(3) of the MDR regulates that the sponsor shall notify the end of the clinical trial no later than fifteen days after its termination. This applies to each individual member state in which the clinical trial is conducted. If there are different times in the different member states where the clinical trial is conducted, this must be done in each individual member state. Article 77(2) of the MDR regulates by definition when a clinical trial is considered “terminated”: “The end of a clinical trial is considered to be the last visit of the last subject, unless another time is specified in the clinical trial protocol.”

Further, the MDR requires the sponsor to provide a clinical trial report no later than or within one year of the defined end of the clinical trial. Again, this requirement applies to each member state in which the clinical trial was conducted. The applicable regulations can be found in Section 2.8, Chapter I and Section 7, Chapter III of Annex XV of the MDR. In the case of a prematurely terminated clinical trial, the above-mentioned period is reduced to three months.

What does such a report look like, what basic requirements does the MDR place on the content, or does the MDR place any requirements at all on the content? This can be answered with a clear “yes”; the current edition of ISO 14155:2020-7 “Clinical investigation of medical devices for human subjects – Good clinical practice” also provides guidance here in Annex D on what should ideally be documented in a report. At this point, we will limit ourselves to the requirements of the MDR: Chapter 3, point 7 of Annex XV of the MDR specifies the minimum requirements for the content, which would be:

 

Cover page/introductory page(s) indicating the title of the trial, the investigational product, the unique identifier number, the clinical trial protocol number, and information on the coordinating investigators and principal investigators of each trial site with signatures.
Author information and date of report
Summary of the trial, which includes the title and purpose of the trial, a description of the trial, the trial design and methods used, the results of the trial, and the conclusion of the trial. Date of completion of the test and, in particular, details of any terminations, temporary suspensions or suspensions of tests.
Description of the investigational device, particularly its well-defined intended use.
Summary of the clinical trial protocol, including objectives, design, ethical aspects, monitoring and quality assurance measures, selection criteria, target patient groups, sample size, treatment plans, duration of follow-up, concomitant treatments, statistics including hypothesis, sample size calculation and methods of analysis, and rationale.
Clinical trial results, which include, with a rationale, subject demographics, outcome analysis related to the selected endpoints, details of the analysis of particular subgroups, and compliance with the clinical trial protocol, as well as cover the approach to missing data and patients who drop out of the clinical trial or become unavailable for follow-up.
Overview of serious adverse events, product adverse effects, and product deficiencies and any corrective actions.
Discussion and overall conclusions that include safety and performance outcomes, assessment of risks and clinical benefits, discussion of clinical relevance according to the state of clinical knowledge, special precautions for specific patient populations, implications with regard to the investigational product, and limitations of the trial.
The MDR basically requires notification of a clinical trial via EUDAMED, but the clinical trial module is still not available. So how to make a proper clinical trial notification?

For the application, all required documents should be sent to the national competent authorities, i.e. in the case of Germany to the Federal Institute for Drugs and Medical Devices (BfArM). In other member states, other transitional regulations may apply, which may need to be taken into account when submitting the application. The EU Commission has compiled an overview of all national competent authorities, which can be downloaded from the following link:

https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_clinical_investigation_contact_points.pdf

Finally, a sentence on how to deal with clinical trials that were started before the MDR came into force under the MDD (93/42/EC) and are currently still ongoing: These can of course be continued and completed. However, the deadlines and procedures for reporting serious incidents must be followed according to Article 80 of the MDR. To facilitate the transition period for the sponsor to adapt their Clinical Investigation Plan (CIP) as well as their procedures for handling serious incident reporting, they may continue to report to their national competent authority until the above mentioned EUDAMED module is available.

Please note that all information and listings do not claim to be complete, are without guarantee and are provided for information purposes only.