Katarzyna Wesołowska, Ilona Korczak-Cegielska
In the first part of the article “Changes in clinical trials of medical devices – new requirements, ways to report and supervise clinical trials. Part I.”, we discussed such aspects as registration, how to report and supervise clinical trials, and the requirements for the necessary clinical trial documentation.
It is worth noting that the MDR regulation introduces new requirements that must be carefully analysed and considered in the design and conduct of a clinical trial. The necessary elements of a clinical trial and the new or clarified requirements are presented below, along with a brief description and analysis of them.
1) Sponsor. The MDR Regulation introduces a definition of ‘Sponsor’ in Article 2, paragraph 49. Under the Regulation, this is an individual, company, institution or organisation that takes responsibility for the initiation, management and setting up of the financing of the clinical investigation. According to MDD and AIMD, only the manufacturer or authorised representative was responsible for conducting the clinical trial. This raised questions in the context of the initiation of a clinical trial by an independent clinical investigator.
As defined in the MDR regulation, for example, clinical investigators initiating a clinical trial are required to comply with the clinical trial requirements of the MDR regulation. However, this does not prevent agreements between trial sponsors and investigators. It is the sponsor’s overall responsibility to conduct the trial in accordance with good clinical practice, the Declaration of Helsinki and applicable regulations. In addition, Annex XV of the MDR Regulation, Chapter III details the sponsor’s responsibilities.
2) Legal representative. According to Article 62 of the MDR Regulation, a legal representative must be appointed when the sponsor of a clinical trial is not resident or established in the European Union (EU). The sponsor shall ensure that its legal representative is a natural or legal person resident or established in the EU. The legal representative will be responsible for fulfilling the sponsor’s obligations under the MDR regulation, and to him or her all information for the sponsor shall be directed.
3) Ethics Committee (EC). A clinical trial undergoes scientific and ethical evaluation. Moreover, each stage of the clinical investigation should meet recognised ethical principles. It is the duty of the ethics committee to evaluate the clinical trial and determine whether ethical considerations have been maintained and met. Requirements for the composition of the ethics committee are not specified in AIMDD, MDD or MDR. However, Article 62 of the MDR Regulation specifies that the ethics review should be conducted in accordance with national law, and that the ethics committee conducting the review should include at least one lay person.
The MDR Regulation also requires member states to ensure that the procedures for conducting the assessment are in accordance with the procedures set forth in the regulation for evaluating an application for a clinical trial permit. The EC approval process for an application is not harmonised. This means that some variability has been introduced, for example related to the timing of the EC’s evaluation of an application in different countries. In some cases, application approval times vary from 30 to 90 days.
According to the Law of 7 April 2022 on medical devices, the ethics committee (=called the bioethics committee in the aforementioned law) shall, at the request of a sponsor who intends to conduct a clinical trial in the territory of the Republic of Poland (RP) or make significant changes to a clinical trial, issue an opinion on the clinical trial or an opinion on significant changes to the clinical trial within no more than 45 days from the date of submission of the request.
As a result of failure to meet application requirements, the EC may ask for clarification or reject the application. When the sponsor is asked for clarification, the deadline for processing the application and its further evaluation is suspended in time. To avoid delays caused by failure to obtain clinical trial opinion, both the sponsor and the investigator should make every effort to ensure that all application requirements are met.
4) Approval of the Competent Authority. It is the duty of the Competent Authority to evaluate the clinical trial application and determine whether the regulatory requirements are met. Article 70 of the MDR Regulation outlines the steps in the clinical trial application process, along with specific deadlines that must be followed. For example, within a week of any change, the sponsor must update any changes to the submitted documentation.
The MDR provides for a simplified procedure, and Polish regulations require obtaining an administrative decision from the President of the Office on the scope of the planned changes. According to Article 70(7) of the MDR, clinical trials with Class I devices or non-invasive Class IIa and Class IIb devices may begin immediately after the application validation date, unless otherwise provided by national law, provided that the relevant ethics committee has not issued a negative opinion valid for the entire member state.
According to the current Law on Medical Devices, the President of the Office shall, by administrative decision, within no more than 45 days from the date of validation of the application referred to in Article 70(5) of Regulation 2017/745, either issue a permit or refuse to issue a permit to conduct a clinical trial. In addition, the President of the Office may extend the deadline, referred to above by another 20 days in order to consult with experts. Annex XV to the MDR Regulation, Chapter II, contains a list of documentation that must be attached to the application for a clinical trial. These documents are mentioned in this article in Part I.
5) Inspection of clinical sites. Article 72(5) of the MDR Regulation requires Member States to inspect at an appropriate level the trial site(s) to verify that the clinical trial is being conducted in accordance with the requirements of the MDR Regulation and the clinical investigation plan (CIP). This means that the sponsor should ensure that the clinical site involved in conducting a clinical trial of a medical device is adequately prepared for such inspection.
6) Immediate identification or recall procedures. Article 72(6) of the MDR stipulates that the sponsor establishes a procedure to deal with urgent, emergency situations. The procedure established is to allow for immediate identification and, if necessary, immediate recall of devices used in the clinical trial. This procedure is expected to be incorporated into the manufacturer’s quality management system (QMS) or standard operating procedures (SOP) of the contract organisation conducting the clinical trial on behalf of the sponsor.
7) Coordinated evaluation procedure for clinical trials. Regulation 2017/745, in Article 78, outlines the process for submitting an application for a clinical trial when the trial is to be conducted in more than one member state. The sponsor may submit a single application, sent via the electronic system referred to in Article 73 of the MDR Regulation (the EUDAMED database, described at the beginning of the article) to all member states where the clinical trial is to be conducted. The sponsor should propose that one of the countries act as the coordinating member state. Initially, this procedure will involve only member states that voluntarily agree to the procedure. However, it will become mandatory as of 27 May 2027, unless this date changes as a result of a review that must be conducted by the European Commission by 26 May 2026.
8) Recording and reporting of adverse events occurring during a clinical trial. An important aspect of conducting a clinical trial of a medical device without a CE mark is the handling of events relevant to patient safety during the conduct of the trial. Article 80 of the MDR regulates the procedure for handling such events. Again, the sponsor is responsible for reporting these events, and is also obliged to maintain appropriate operating procedures and timelines that have to be observed from the time of the adverse event until its completion.
In accordance with the MDR Regulation, the sponsor shall record all of the following circumstances in full and immediately report all of the following events to all member states where the clinical trial is conducted. We are talking about serious adverse events where there is a causal relationship with the investigational device, comparator or test procedure, or where such a causal relationship is reasonably possible. In addition, the sponsor is obliged to report device defects that could have led to a serious adverse event had the appropriate action or intervention not been taken or had the circumstances been less favourable.
The need to report only serious adverse events that have a causal relationship to the investigational device, comparator or investigational procedure is a significant difference from AIMDD and MDD. These directives required that all serious adverse events should be immediately reported to all Competent Authorities of the Member States where the clinical investigation is being conducted. It is worth mentioning that based on Article 120(11) of the MDR Regulation, clinical trials initiated in accordance with Article 10 of Directive 90/385/EEC or Article 15 of Directive 93/42/EEC before 26 May 2020 may continue. However, as of 26 May 2020, reports of serious adverse events and device defects shall be made in accordance with MDR Regulation 2017/745.
9) Monitoring. According to Article 72(2) of the MDR, the sponsor shall ensure adequate monitoring of the clinical trial. The scope and nature of the monitoring shall be determined by an assessment that takes into account the characteristics of the clinical trial, including the purpose and methodology of the trial and the degree of deviation of the intervention from standard clinical practice. This means that under the MDR, adequate monitoring is a requirement, not just an option.
10) Independent monitor. Sponsors appoint monitors to check the progress of the clinical trial and to ensure that the clinical trial is being conducted in accordance with the clinical investigation plan (CIP), the principles of good clinical practice (GCP), the Declaration of Helsinki, and applicable regulatory requirements. There is a new restriction on the appointment of monitors, which is set forth in the MDR in Annex XV, Chapter III, paragraph 4, which states that the sponsor shall appoint a monitor independent of the clinical trial site.
This is an important requirement because some clinical trials of medical devices have been monitored by individuals employed by the trial site or where the principal clinical investigator managed the unit responsible for monitoring the clinical trial. This new requirement means that sponsors conducting MDR clinical trials must ensure that the monitor is not part of the research team at the site where the clinical trial is being conducted.
11) Prohibition of deviations. The MDR regulation also specifies certain requirements for the clinical investigation plan (CIP). Namely, according to Annex XV of the MDR, it specifies that the investigation plan should include rules for observing and handling any deviations from the clinical investigation plan at the study site. In addition, the regulation explicitly states that exemptions from the clinical trial plan (CIP) during the conduct of the trial are prohibited. This is also a new requirement and means that the sponsor should take special care in developing a clinical investigation plan, which must meet the relevant regulatory and quality requirements for conducting human clinical trials.
12) Inspections for compliance with good clinical practice. According to Annex XV, Chapter III, paragraph 6 of the MDR regulation, sponsors are required to provide evidence that a clinical trial is being conducted in accordance with good clinical practice (GCP), such as through an internal or external inspection. ISO 14155:2020 Clinical Investigation of Medical Devices for human subjects ‒ Good Clinical Practice includes Annex J, ‘Audits of Clinical Trials’, which is a new annex that provides general guidance on areas that may be covered by the aforementioned inspections.
13) Marking, labelling. If the device is intended for clinical trial only, the manufacturer is required to put the words “for clinical investigation only” on the packaging/label of the device.
14) Record keeping. The clinical trial records referred to in Annex XV of the MDR Regulation shall be retained for at least ten years after termination of the clinical trial of the device. If the device was subsequently placed on the market, for at least ten years after the last device was placed on the market. For implantable devices, the period is at least 15 years.
This article discusses the new requirements under European Regulation 2017/745 (MDR). The most important observations on the applicable changes from the point of view of the clinical trial sponsor as well as the investigator are presented.
Conducting a clinical trial is one of the most time-consuming activities and undoubtedly a very demanding process. The trial sponsor, usually the manufacturer of the medical device, is required to meet a number of regulatory and quality requirements based on national as well as international guidelines and standards. A clinical trial is one of the activities that should be considered already at the device design level, if only because of the time required to conduct it. Hence, medical device manufacturers should make every effort to ensure that the design of the clinical trial is done correctly, its conduct is reliable, and all parties involved in the trial understand their roles and responsibilities.
1: Law of 7 April 2022 on medical devices.
2: MDCG 2021-6 Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation April 2021.
3: Regulation (EU) 2017/745 of the European Parliament and of the Council of April 5, 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC, source: http://data.europa.eu/eli/reg/2017/745/2020-04-24.
4: PN-EN ISO 14155:2021-02 Clinical testing of medical devices on humans ‒ Good clinical practice.
1: MDD -Council Directive 93/42/EEC of June 14, 1993 concerning medical devices, Medical Device Directive.
2: AIMDD – Council Directive of June 20, 1990 on the approximation of the laws of the Member States relating to active implantable medical devices, from the Active Implantable Medical Devices Directive.
3: MDR – Regulation (EU) 2017/745 of the European Parliament and of the Council of April 5, 2017. On medical devices, from the Medical Device Regulation.
4: GCP – Good Clinical Practice, from Good Clinical Practice.
5: CIP – Clinical Investigation Plan, from Clinical Investigation Plan.
5: IC – Informed consent, from Informed consent.
6: IB – Investigator’s brochure, from Investigator’s brochure.
7: EC – Ethics Committee.