Clinical trials with medical devices

The MDR defines a clinical investigation in Art. 2 (45) as “a systematic investigation involving one or more human subjects and conducted for the purpose of evaluating the safety or performance of a device”. The regulatory framework for clinical trials with medical devices in Europe is summarized below.

When are clinical trials required? 

Clinical trials must generally be conducted by the manufacturer if one or more of the following conditions are met: 

• there are gaps in the clinical data that cannot be filled by other sources, 
• it is a class III medical device or implant (exception: modification of an existing medical device and the manufacturer fulfills the associated further requirements (Art. 61 (4) MDR)), 
• a completely new medical device with new features and functions is to be placed on the market, 
• changes to an existing medical device have an impact on clinical safety and performance and/or 
• the medical purpose of an existing medical device is extended. 

Clinical trials in the MDR 

The European Medical Devices Regulation (EU) 2017/745 (MDR) contains requirements for clinical trials in Articles 62 to 82 and Annex XV, which include the following aspects: 

• General obligation 
• Patient safety 
• Emergency situations 
• Indemnification 
• EUDAMED-related provisions 
• Types of clinical trials 
• Information flows 
• Measures taken by member states 
• Evaluation of clinical trials 
• Adverse events 

Guidance documents and standards

The Medical Device Coordination Group (MDCG) of the EU Commission has published a series of guidance documents for clinical trials with medical devices: 

In addition, there are the following helpful MEDDEV guidelines, which were created under the previous EU directives:  

• MEDDEV 2.7/2 rev. 2 Clinical investigation, clinical evaluation - Guidance for competent authorities on the assessment of the notification of a clinical investigation (2015)  
• MEDDEV 2.7/3 rev. 3 Clinical investigation, clinical evaluation - Clinical trials: Reporting of serious adverse events (2015)  
• MEDDEV 2.7/4 Clinical investigation, clinical evaluation - Clinical investigation guidelines: a guide for manufacturers and notified bodies (2010) 

ISO 14155

The international standard “ISO 14155:2020 Clinical investigation of medical devices for human subjects - Good clinical practice” currently represents the state of the art. Although the standard has not yet been harmonized under the MDR, the previous version of ISO 14155 is explicitly mentioned in recital 64 of the MDR.

Definitions

Article 2 of the MDR contains important definitions for clinical trials. We recommend that the definitions of the MDR be considered in conjunction with those of ISO 14155.

The MDCG 2021-6 guideline contains further explanations of terms. Some definitions of ISO 14155 such as contract research organization (CRO) and data monitoring committee (DMC) are missing in the MDR. 

Note that other types of clinical trials may be conducted for research purposes, which are regulated by the respective laws of the Member States (e.g., the German Medizinprodukterecht-Durchführungsgesetz MPDG). In addition, national legislators establish their own procedures, such as consultation with an ethics committee. 

All PMCF studies, with and without additional invasive or burdensome procedures, conducted as part of the intended use of the device shall be reported in the PMCF plan (Annex XIV Part B, MDCG 2020-7). 

The sponsor as a key player in clinical trials. 

The term "sponsor" originates from the field of pharmaceutical clinical trials. Art. 2 (49) MDR defines it as "any person, company, institution, or organization that assumes responsibility for initiating, managing, and establishing funding for the clinical trial." If the sponsor is located outside the EU, it requires a natural or legal person as legal representative (Art. 62 (2)). 

Tasks of the sponsor 

The following table provides an overview of the sponsor's tasks: 

Data protection 

The EU Commission has published a Q/A document on the interplay between Regulation (EU) 536/2014 on clinical trials and the European Data Protection Regulation 2016/679. The EU Commission states: "[...] it is the obligation of the data controller (sponsor/clinic-institution of the investigator) to implement the appropriate technical and organisational measures to ensure and be able to demonstrate that the personal data are processed in accordance with the data protection rules". 

Application for clinical trials 

There is an important change compared to the previous regulation for clinical trials for conformity assessment. In the case of a trial conducted by a sponsor in several EU member states, individual applications previously had to be submitted. Now, the sponsor can also submit the application to only one authority for all participating member states together (Art. 78). In a transitional period until May 25, 2027, this coordinated procedure is only mandatory in those EU Member States that have implemented its use (Art. 78 (14)). 

The sponsor must submit the application via EUDAMED and receives a unique single identification number (CIV-ID, cf. MDCG 2021-20) for the clinical trial (Art. 70 (1), cf. MDCG 2021-28). In the further course of the clinical trial, the entire flow of information also takes place via EUDAMED. First, the Member State concerned checks whether the clinical trial falls within the scope of the MDR. For non-invasive class I-IIb devices, the clinical trial can then start immediately. However, the competent ethics committee must give its approval (Art. 70 (7a)). For all other devices, the clinical trial must be approved by the competent authority prior to commencement (Art. 70 (7b)). 

For PCMF studies, the sponsor must inform the Member States concerned and submit the documents referred to in Annex XV, Chapter II. Here, too, the EUDAMED must be used (Art. 74 (1)). 

Application documents 

Chapter II of Annex XV summarizes in detail the documents required for the application under Article 70 MDR: 

• the application form, 
• the investigator's brochure (IB, see MDCG 2024-5), and 
• the clinical investigation plan (CIP, see MDCG 2024-3). 

The European Commission may adopt delegated acts amending or implementing acts to ensure uniform application and state of the art of the requirements under Annex XV, Chapter II (Art. 70 (8,9)). 

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). Guideline MDCG 2024-3 describes the necessary contents of the CIP in detail.

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.