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Medical Device Clinical Investigations

Manufacturers must clinically evaluate a medical device before they can market it in Europe. To do so, the manufacturer has to prove with clinical data whether the medical device is safe and performing. However, if the clinical data are insufficient, he must conduct clinical investigations. These are obligatory for class III and implantable devices with narrow exceptions (Art. 61 (4)). Find out in this article how such clincial investigations are structured.

Clinical Investigations in the MDR

The regulation (EU) 2017/745 (EU MDR) contains requirements for clinical investigations in Art. 62 to 82 and Annex XV covering the following topics:
  • General obligation
  • Patient safety
  • Emergency situations
  • Damage compenzation
  • Eudamed-related provisions
  • Types of clinical investigations
  • Information flows
  • Member state measures
  • Clinical investigation assessment
  • Adverse events

Guidances and Standards

The EU Commission released a couple of guidance documents for clinical investigations with medical devices:
Reference Title Publication
MDCG 2021-28 Substantial modification of clinical investigation under Medical Device Regulation December 2021
MDCG 2021-20 Instructions for generating CIV-ID for MDR Clinical Investigations July 2021
MDCG 2021-8 Clinical investigation application/notification documents May 2021
MDCG 2021-6 Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation April 2021
MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745 May 2020
MDCG 2020-10/2 Clinical Investigation Summary Safety Report Form v1.0 May 2020
Beside that the following helpful MEDDEV guideline are existing that were developed unter the former EU directives:
  • MEDDEV 2.7/2 rev. 2 Clinical investigation, clinical evaluation – Guide for Competent Authorities in making an assessment of clinical investigation notification (2015)
  • MEDDEV 2.7/3 rev. 3 Clinical investigation, clinical evaluation – Clinical investigations: serious adverse event reporting (2015)
  • MEDDEV 2.7/4 Clinical investigation, clinical evaluation – Guidelines on Clinical investigations: a guide for manufacturers and notified bodies (2010)

ISO 14155

The international standardISO 14155:2020 Clinical investigation of medical devices for human subjects – Good clinical practice” currently represents the state of the art, but it is not yet harmonized under MDR. But in recital 64 of the MDR, the previous version of ISO 14155 is explicitly mentioned.
Major changes in ISO 14155:2020 compared to ISO 14155:2012 are:
  • Annex H of ISO 14155:2020 introduces comprehensive risk management requirements across the clinical investigation process. This clinical risk management should be integrated into the overall risk management for the medical device.
  • New requirements on ethical considerations including documents to be submitted, communication with ethics committee, compensation, informed consent, dealing with vulnerable groups, etc.
  • New requirements for auditing clinical trials
  • New informative annexes

Definitions

Art. 2 of EU MDR includes important definitions concerning clinical investigations. We recommend to study the EU MDR definitions in the context of those of ISO 14155. The following table gives an overview about the definition differences:
Term Article EU MDR ISO 14155 definition
clinical benefit 2 (53) no definition
clinical data 2 (48) no definition
clinical evidence 2 (51) no definition
clinical investigation 2 (45) similar definition
clinical investigation plan 2 (47) similar but less detailed
clinical performance 2 (52) similar definition
ethics committee 2 (56) more detailed regarding the responsibilities
informed consent 2 (55) no definition
investigator 2 (54) similar definition, but more detailed
investigational device 2 (46) similar definition
serious adverse event 2 (58) similar definition, but without mentioning chronic disease as consequence
sponsor 2 (49) similar definition but less detailed
subject 2 (50) similar definition
The guideline MDCG 2021-6 provides further explanation of terms. Some ISO 14155 definitions like contract research organization (CRO) and data monitoring committee (OMC) are missing in the EU MDR.

Types of Clinical Investigations

The type of clinical investigations which the manufacturer must select depends essentially on whether the medical device is CE-marked, used within the intended purpose or whether additional invasive or patient burdensome procedures are used. There are three types of clinical investigations that are subject to the requirements of the EU MDR.
  • Clinical investigations for the assessment of conformity (type A) according to Art. 62 are subject to approval. Art. 62 to 81 and the requirements of Annex XV apply.
  • Clinical investigations as PMCF (Post-Market Clinical Follow-Up, type C) are not subject to approval but notification. The requirements of Art. 74 (1) apply.
  • Other clinical investigations (type B) according to Art. 82 are neither subject to approval nor notification. Further requirements may exist in the respective EU member state. The requirements of Art. 62 (2, 3, 4b/c/d/f/h/l and 6) apply.
Note that other types of clinical investigations are used for research purposes and regulated in the respective legislation of the member states (e.g. the German Medizinprodukterecht-Durchführungsgesetz MPDG) . In addition, national legislators set their own practices, such as consulting an ethics committee.
All PMCF studies with and without any additional invasive or burdensome  procedures conducted within the scope of the device’s intended use shall be specified in the PMCF plan (Annex XIV Part B, MDCG 2020-7).

The Sponsor as a Central Player in Clinical Trials

The term “sponsor” originates from pharmaceutical clinical investigations. Art. 2 (49) EU MDR defines it as “any individual, company, institution or organisation which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation”. If the sponsor resides outside the EU, he requires a natural or legal person as legal representative (Art. 62 (2)).

Tasks of the Sponsor

The following table provides an overview of sponsors tasks:
Sponsor Tasks Article EU MDR
Address new ethical requirements and install the appropriate processes. 62 (4b); 64
Verify if your product requires technical and biosafety testing and pre-clinical evaluation, as well as specific occupational safety and accident prevention measures to ensure the protection of subjects. 62 (4l)
Take into account the stricter qualification requirements for the investigator compared to ISO 14155. 62 (6)
Install a system for compensation for any damage for the subjects. 69
Become familiar with the procedure for applying for the clinical investigation including the submission to member state(s) as well as preparation and update of the respective documentation. 70 (1)
Take into account the requirements of EUDAMED and in particular the use of unique single identification number for all communication concerning the clinical investigation. 70 (1); 73 (2)
Install the appropriate processes for monitoring the clinical investigation in terms of protection of the subjects, reliability and robustness of the data, and compliance with the EU MDR provisions. Determine the extent and nature of the monitoring. 72 (2)
Install appropriate processes to store, analyze and use clinical data, considering appropriate technical and organizational measures to protect the data. 72 (3-4)
Establish a procedure for emergency situations. 72 (6)
Establish procedures for notifying Member State(s) concerning
  • PCMF studies,
  • clinical investigations modifications with substantial impact, and
  • early termination or temporary halt of clinical investigations.
74 (1); 75 (1)* / 78 (12); 77 (1-3)
Install an appropriate process for submissions of clinical investigation report and summary of report to Member State(s). 77 (4-7)
Consider the procedure for a coordinated assessment of the clinical investigation if more than one Member State is concerned. 78 (1-2)
Install appropriate processes for recording and reporting of adverse events. 80
*Cf. gudance MDCG 2021-28 for more details. Except the first obligation given in the table all others depend on the unique device identification (UDI) system and the EUDAMED functionality. Currently, is unclear when the EUDAMED database will be fully  operational.

Data Protection

The EU Commission has published an Q/A document on the interplay between the clinical investigation regulation (EU) 536/2014 and the general data protection regulation 2016/679. The EU Commission states that “[…] 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”.

Clincial Investigation Application

Compared to the previous regulation, there is an important change with regard to clinical investigations for the assessment of conformity (type A). In the case of an investigation carried out by a sponsor in several EU member states, individual applications had to be submitted so far. Now, the sponsor can also submit the application to only one authority for all participating member states (Art. 78). In a transitional period until 25 May 2027, this coordinated procedure is only mandatory in EU Member States which have agreed to apply it (Art. 78 (14)). The sponsor must submit the application using the EUDAMED system and receives a unique single identification number (CIV-ID) for the clinical investigation (Art. 70 (1), MDCG 2021-28). In the further course of the clinical investigation the entire information flow also takes place via EUDAMED. First, the Member State concerned verifies whether the clinical investigation falls within the scope of the EU MDR. For non-invasive Class I-IIb devices, the clinical investigation can then begin immediately. However, the responsible ethics committee must give its approval (Art. 70 (7a)). Clinical investigation of all other devices must be approved by the competent authority before starting (Art. 70 (7b)). In the case of PCMF studies, the sponsor must inform the Member States concerned and submit the documentation referred to in Chapter II of Annex XV. Again, the EUDAMED system must be used (Art. 74 (1)).

Application Documents

The Chapter II of Annex XV summarizes in detail the documents that are needed for the application according to Art. 70:
  • the application form,
  • the investigator’s brochure (IB) and
  • the clinical investigation plan (CIP).
The European Commission can adopt amending delegated acts or implementing acts to ensure an uniform application and state of the art of the requirements according to Chapter II of Annex XV (Art. 70 (8,9)). The following table gives an overview of the application documents for clinical investigations:
Application Form Investigatior‘s Brochure Clinical Investigation Plan (CIP)
  • sponsors details
  • title
  • dates und duration
  • status
  • details clinical evaluation plan (CEP)
  • details multicenter study (if applicable)
  • summary clinical investigation plan (CIP)
  • details investigational device
  • details notified body
  • (…)
  • clinical and non-clinical information on the investigational device
  • rationale
  • objectives
  • design
  • methodology
  • monitoring
  • statistical considerations
  • organization
  • conducting
In the absence of the EUDAMED, the guidance MDCG 2021-28 contains a series of clinical investigation application/notification documents that have been created to support clinical investigations according to EU MDR.

Ethics Committee

The ethics committee of the respective member state is an independent body and issues an opinion regarding the planned clinical investigation based on national legislation (Art. 62 (3)). Furthermore, the ethics committee should take into account “the views of laypersons, in particular patients or patient organisations” (Art. 2 (56)). The ethics committees are subject to national requirements and therefore work differently. However, the EU MDR requires that the procedures of the Ethics Committee be compatible with the regulation. This is challenging for sponsors, especially when they are planning multicentre investigations in different Member States.

Design

The design of the clinical investigation must follow two principles:
  • well-being of subjects (minimal risks and minimal impairments) and
  • generation of scientifically valid, reliable and robust clinical data.
The basis of the clinical investigation is the clinical investigation plan (CIP) including information about type, structure, and parameters. The structure of the CIP is defined in Nr. 3 of Annex XV, Chapter II. The clinical investigation must reflect “latest scientific and technical knowledge” (No. 2.1 of Annex XV, Chapter I). The clinical methods must be appropriate to the investigational device (No. 2.2 of Annex XV, Chapter I) and consider technical and functional features of the investigational device regarding safety and performance (No. 2.5 of Annex XV, Chapter I). Finally, to obtain scientifically valid results, a sufficient number of subjects must be included. Thus, the sponsor has to calculate the sample size based on plausible success criteria. Moreover, the clinical environment must be representative for normal conditions of use (No. 2.1 and 2.4 in Annex XV, Chapter I). Clinical investigation must be in line with the CIP as refered to in No. 1 (a) of Annex XIV, Part A.
The EU Commission will presumably define the criteria for the study design more precisely, e.g. by working out Common Specifications (Art. 9). Check that before starting with the study design.

Interaction with Subjects

The well-being of subjects is of highest interest for the European legislator. Detailed provisions reflect this:
  • protection of vulnerable populations (e. g. pregnant women) and subjects (Art. 64-68),
  • restrictions on the consent of subjects who have a legal representative (e. g. children),
  • subject’s right to physical and mental integrity, privacy and protection of personal data, and
  • prevention of inadmissible recruitment practices.
The sponsor must provide information to subjects being “comprehensive, concise, clear, relevant, and understandable” (Art. 63 (2)) as a part of the informed consent. In order to ensure readability, the informed consent form should not exceed a reasonable length. Moreover, the sponsor has to verify the understanding of the subject by doing an interview (Art. 63 (5)).

Conducting

Overall, conducting clinical investigations is governed by Art. 72 and Annex XV, Chapter III. The sponsor has several important tasks that have already been described above. Essentially, the sponsor must keep the following points in mind:
  • continuous compliance with the clinical investigation plan,
  • continuous monitoring of the conduct (in line with good clinical practice),
  • carefully handling of clinical data (collection, storage, evaluation, protection and security),
  • carefully handling of vigilance data, and of emergencies by means of a specified procedure.

Adverse Events

Definitions in Art. 2 distinguish between “adverse event” and “serious adverse event”. The characteristics for an adverse event are:
  • untoward medical occurrence,
  • unintended disease or injury,
  • any untoward clinical signs (inclusive abnormal laboratory finding), and
  • no compulsory association with the investigational device.
Guideline MDCG 2020-10/1 explains in detail the safety reporting for clinical investigations with medical devices, and Guideline MDCG 2020-10/2 provides a summary safety report form for clinical investigations. In comparison, the serious adverse event leads to serious consequences for patient’s life or health. The sponsor must always record and report serious adverse events (Art. 80 (1-2)). Note the difference between the EU MDR and ISO 14155 regarding adverse events. Only those “identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation” need to be recorded (Art. 80 (1)). Moreover, the sponsor must report device deficiencies with the potential for leading 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 device deficiencies occur in a clinical investigation carried out in several Member States, a coordinated assessment will be started (Art. 80 (4)). The consequences can range from modification over suspension to termination of the clinical investigation.

Reporting

No. 7 of Annex XV Chapter III specifies the structure of the clinical investigation report (CIR) in detail. Check again carefully which differences exist compared to the specifications in Annex D of ISO 14155, such as the indication of the UDI. So far, ISO 14155 has only recommended manufacturers to publish both the positive and negative results of the clinical investigation. However, ISO 14155 (Annex D) does not explicitly require the inclusion of negative results in the CIR. The requirement for a summary in “easily understandable language” is new. The sponsor must submit the summary via EUDAMED (Art. 77 (5)), like the CIR.

Recommendations

  • Be aware of statutory penal provisions of the Member States regarding clinical investigations.
  • With regard to the new regulatory requirements of the EU MDR evaluate the need for clinical evidence concerning your products and develop an appropiate strategy.
  • Monitor the implementing legislation of the EU commission.
  • Establish necessary workflows and efficient structures, e. g. regarding compilation and update of clinical evaluations, risk management and quality management, vigilance and post-market surveillance (PMS) system.
  • Be up-to-date concerning common specifications as well as delegated and implementing acts of the European Commission. They can have relevance for clinical investigations, e. g. publications by the Medical Device Coordination Group (MDCG) on the European Commission’s website.
  • On the website of CONSORT (Consolidated Standards Of Reporting Trials) you will find further information about reporting.  Another valuable resource is the website of STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) hosted by the University of Bern.
  • Finally, we recommend the resources of ICH (International Council for Harmonisation).