A hospital in the background, a patient and a medicin in the foreground and a big datasheet, symbolizing Medical Device Clinical Trials

Medical Device Clinical Trials

Manufacturers must clinically evaluate a medical device before they can market it in Europe. To do so, the manufacturer has to examine clinical data in order to investigate whether the medical device is safe and performing. However, if the clinical data are insufficient, he must conduct medical device clinical trials. These trials are known as “clinical investigations” by the EU MDR. Find out in this article how such studies are structured.

Documents

The clinical evidence level depends on the respective medical device. The manufacturer must determine and justify it in accordance with the requirements of the EU MDR. Medical device clinical trials are obligatory for class III and implantable devices (Art. 61(4)).The EU Commission released a couple of guidance documents under the old EU directives in the recent years. Note that the following guidance documents were largely incorporated in the EU MDR:Now, the requirements for medical device clinical trials are part of Art. 62 through 82 and Annex XV of EU MDR (see the summary in the following figure).Infographics showing topics of EU MDR articles related to medical device clinical trialsThe manufacturer must use data from obligatory Post-Market Surveillance System (PMSS, as integral part of the quality management system) among others for updating summary of safety and clinical performance (Art. 83(3)). Operational details of the Post-Market Clinical Follow-up (PMCF) are given in Annex XIV Part B.

Definitions

Art. 2 of EU MDR includes important definitions concerning medical device clinical trials. In addition, they must meet the requirements of good clinical practice (GCP) according to ISO 14155 (Recital 64). Hence, we recommend to study the EU MDR definitions in the context of those of ISO 14155. The followoing table gives an overview about the context.
TermEU MDR ArticleISO 14155 definition
clinical benefitArt. 2(53)no definition
clinical dataArt. 2(48)no definition
clinical evidenceArt. 2(51)no definition
clinical investigationArt. 2(45)similar definition
clinical investigation planArt. 2(47)similar but less detailed
clinical performanceArt. 2(52)similar definition
ethics committeeArt. 2(56)more detailed regarding the responsibilities
informed consentArt. 2(55)no definition
investigatorArt. 2(54)similar definition, but more detailed
investigational deviceArt. 2(46)similar definition
serious adverse eventArt. 2(58)similar definition, but without mentioning chronic disease as consequence
sponsorArt. 2(49)similar definition but less detailed
subjectArt. 2(50)similar
Other ISO 14155 definitions like contract research organization (CRO) and data monitoring committee (OMC) are missing in the EU MDR.
Should you still miss certain definitions in either the EU MDR or the ISO 14155 have a look at corresponding sources from pharmaceutical legislation.

Types of Medical Device Clinical Trials

There are three types of medical device clinical trials that are subject to the requirements of the EU MDR.
  • Medical device clinical trials 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.
  • Medical device clinical trials as PMCF investigation (type C) according to Art. 74(1) are not subject to approval but notification. The requirements of Art. 74(1) apply.
  • Other medical device clinical trials (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.
The type of clinical trial 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. To find out what type of medical device clinical trial applies, follow this flowchart.Infographics showing types of medical device clinical trials
Note that other types of clinical trials are used for clinical research purposes. 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).

The Sponsor as Central Role in Medical Device Clinical Trials

The term “sponsor” originates from pharmaceutical clinical trials. 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

Find here an overview of sponsors tasks:
ObligationArticle
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 trial 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 trial.70(1); 73(2)
Install the appropriate processes for monitoring the clinical trial 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 investigations,
  • clinical trial modifications with substantial impact, and
  • early termination or temporary halt of clinical trial.
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 trial if more than one Member State is concerned.78(1-2)
Install appropriate processes for recording and reporting of adverse events.80
Except the first obligation given in the table all others depend on the unique device identification (UDI) system and the EUDAMED functionality. It is in particular currently not clear when the EUDAMED database will be operational.
Note as well, that the compensatory arrangements for subjects are made separately in each Member State.

Data Protection and Medical Device Clinical Trials

Recently, the EU Commission has published an Q/A document on the interplay between the Clinical Trials Regulation and the General Data Protection Regulation. 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”.

Application of Medical Device Clinical Trial

Compared to the previous regulation, there is an important change with regard to medical device clinical trials for the assessment of conformity (type A). In the case of a trial 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 27 May 2027, participation in this coordinated procedure is voluntary for the EU Member States.The sponsor must submit the application using the EUDAMED system and receives a unique number for identification (Art. 70 (1)). In the further course of the clinical trial the entire information flow also takes place via EUDAMED.First, the Member State concerned verifies whether the medical device clinical trial falls within the scope of the EU MDR. For non-invasive Class I-IIb devices, the clinical trials can then begin immediately. However, the responsible ethics committee must give its approval (Art. 70 (7a)). Clinical trials of all other devices must be approved by the competent authority before starting (Art. 70 (7b)).In the case of type PCMF investigations, 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. 71 (1)).

Application Documents

The chapter II of Annex XV summarizes in detail the documents that are needed for the application according to Art. 70. These are:
  • 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 Annex XV Chapter 2 (Art. 70 (8,9)).The following figure gives an overview of the application documents for medical device clinical trials.
Infographics showing an overview of application documents for medical device clinical trial
Note that a new edition of the ISO 14155 is expected in 2019. In Annex H comprehensive risk management requirements across the medical device clinical trial process are introduced. This clinical risk management should be integrated into the overall risk management for the medical device. 

Ethics Committee

The ethics committee of the respective member state is an independent body and issues an opinion regarding the planned clinical trial 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 trials in different Member States.

Design

The design of the medical device clinical trial 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 medical device clinical trial is the clinical investigation plan (CIP) including information about type, structure, and parameters. The structure of the CIP is defined in Annex XV Chapter II (3).The clinical trial must reflect “latest scientific and technical knowledge” (Annex XV I 2.1). The clinical methods must be appropriate to the investigational device (Annex XV I 2.2) and consider technical and functional features of the investigational device regarding safety and performance (Annex XV I 2.5).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 (Annex XV Chapter I 2.1 and 2.4). Medical device clinical trials must be in line with the CIP as refered to in 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)).

Conduct

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

Adverse Events

Article 2 distinguishes 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.
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 (6.4.1) 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)).
Infographics showing the scheme of recording and reporting medical device adverse events
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 medical device clinical trial 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 trial.

Report

Annex XV III (7) 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 unique identification number.So far, ISO 14155 (Section 7.3) has only recommended manufacturers to publish both the positive and negative results of the clinical study. 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 para. 5), like the CIR.

Recommendations

  • Be aware of statutory penal provisions of the Member States regarding medical device clinical trials.
  • 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.
  • When the 2019 edition of the ISO 14155 is available perform a gap analysis.
  • 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 system (PMSS).
  • Be up-to-date concerning common specifications as well as delegated and implementing acts of the European Commission. They can have relevance for clinical trials, 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).

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