Ethics Committee
The Ethics Committee of the respective Member State is an independent body and provides an opinion on the proposed clinical trial based on national legislation (Art. 62 (3)). In addition, the ethics committee shall consider "points of view of lay persons, in particular patients or patient organizations" (Art. 2 (56)).
Ethics committees are subject to national requirements and therefore operate differently. However, the MDR requires that ethics committee procedures comply with the regulation. This is a challenge for sponsors, especially if they are planning multicenter trials in different member states.
Design
The design of the clinical trial must follow two principles:
The well-being of the subjects (minimal risks and minimal adverse effects), and
Generation of scientifically valid, reliable, and robust clinical data.
The basis of the clinical trial is the CIP, which contains information on the nature, structure, and parameters (No. 3 Annex XV, Chapter II).
The clinical trial must be in accordance with "the latest scientific and technical knowledge" (No. 2.1 Annex XV, Chapter I). The clinical methods must be appropriate for the investigational device (No. 2.2 Annex XV, Chapter I) and take into account the technical and functional characteristics of the investigational device with respect to safety and performance (No. 2.5 Annex XV, Chapter I). Finally, a sufficient number of subjects must be included to obtain scientifically valid results. Therefore, the sponsor must calculate the sample size based on plausible success criteria. In addition, the clinical setting must be representative of normal conditions of use (Nos. 2.1 and 2.4 Annex XV, Chapter I). The clinical trial must be in accordance with the CIP as specified in No. 1 (a) Annex XIV, Part A.
The EU Commission is expected to define the study design criteria in more detail, e.g. by developing common specifications (Art. 9). We recommend to check this before developing the study design.
Interaction with subjects
The welfare of subjects is of paramount interest to European legislators. Detailed provisions reflect this:
- Protection of vulnerable groups (e.g., pregnant women) and subjects (Arts. 64-68),
- Restrictions on consent for subjects who have a legal representative (e.g., children),
- Subjects' right to physical and mental integrity, privacy and protection of personal data, and
- Prevention of improper recruitment practices.
The sponsor must provide subjects with information that is "comprehensive, concise, clear, relevant, and understandable to the subject or his or her legally designated representative" (Art. 63 (2)) and is part of the informed consent. To ensure readability, the informed consent form should not exceed a reasonable length. In addition, the sponsor must verify the subject's understanding through an interview (Art. 63 (5)).
Implementation
Overall, the conduct of clinical trials is governed by Art. 72 and Annex XV, Chapter III. The sponsor has several important responsibilities, which have already been described above. Essentially, the sponsor must adhere to the following:
- Continuous compliance with the CIP,
- continuous monitoring of implementation (in accordance with good clinical practice),
- careful handling of clinical data (collection, storage, evaluation, protection, and security), and
- careful handling of vigilance data and handling of emergencies through an established process.
Where it is intended to make changes to a clinical trial that are likely to have a significant impact on the safety, health or rights of subjects, or on the robustness or reliability of the clinical data generated, the sponsor shall notify the Member State(s) in which a clinical trial is or will be conducted (see explanations in MDCG 2021-28).
Adverse events
The definitions in Art. 2 distinguish between "adverse event" and "serious adverse event". The characteristics for an adverse event are:
- Adverse medical occurrence,
- an unintended illness or injury
- Adverse clinical symptoms (including abnormal laboratory findings), and
- No compelling relationship to the investigational product.
Guideline MDCG 2020-10/1 explains in detail safety reporting for clinical trials involving medical devices. Guideline MDCG 2020-10/2 provides a form for summarizing the safety report of a clinical trial.
Serious adverse events result in serious consequences to the life or health of the patient. The sponsor must always record and report serious adverse events (Art. 80 (1-2)). In contrast to ISO 14155, the MDR requires recording only those adverse events that have been "identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation" (Art. 80 (1)). In addition, the sponsor must report product defects that may lead to serious adverse events (Art. 80 (2)).
In principle, the notification period depends on the severity of the adverse event (Art. 80 (2)). If serious adverse events or product defects occur in a clinical trial conducted in several Member States, a coordinated assessment is initiated (Art. 80 (4)). Consequences may range from amendment to suspension to termination of the clinical trial.
Reporting
No. 7 Annex XV Chapter III details the structure of the clinical investigation report (CIR). Check again carefully what differences there are to the requirements in Annex D of ISO 14155, such as the specification of the UDI. Previously, ISO 14155 only recommended that manufacturers publish both positive and negative clinical trial results. However, ISO 14155 (Annex D) does not explicitly require negative results to be included in the CIR. The requirement for a summary in "easily understandable language" is new (see Commission Guidance on the content and structure of the summary of the clinical investigation report). The sponsor must submit the summary, like the CIR, via EUDAMED (Art. 77 (5)).
Recommendations
- Find out about the criminal law provisions of the member states on clinical trials (e.g., in the German Medical Device Law Implementation Act).
- Find out about the requirements on the part of the competent authorities in the member states (e.g., the Federal Institute for Drugs and Medical Devices).
- Find out about common specifications as well as delegated and implementing acts of the European Commission regarding clinical trials.
- Find out about new or amended publications from the European Commission's Medical Device Coordination Group (MDCG).
- With regard to the new regulatory requirements of the MDR, evaluate the need for clinical evidence for your products and develop an appropriate strategy.
- Establish the necessary workflows and efficient structures, e.g. regarding the creation and update of clinical evaluations, risk management and quality management, vigilance and post-market surveillance (PMS) system.
- The CONSORT (Consolidated Standards Of Reporting Trials) website has more information on reporting. Another valuable resource is the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) website, operated by the University of Bern.