Katarzyna Wesołowska, Ilona Korczak-Cegielska
Innovation in the medical device market and its real impact on the market and the economy are strongly linked to meeting the relevant regulations at the national and European levels. Therefore, with such a significant change as the introduction of new requirements for clinical trials of medical devices across the European Union (EU) in May 2021, it is important for the medical device industry to familiarise itself with the differences, potential impacts and necessary actions in this regard. This is in order to adequately prepare for the introduction of innovative products or the adaptation of products currently on the market and prevent shortages in the availability of lifesaving and health-saving technologies.
The first significant difference concerns the type of law. In force until 26 May 2021, Directives 93/42/EEC (MDD) and 90/385/EEC (AIMDD) were pieces of legislation that set a goal that all EU countries must achieve. However, it is up to individual countries to determine how to achieve these goals through the implementation of national legislation. Regulation 2017/745 (MDR), unlike the above directives, is a binding piece of legislation that must be applied in its entirety in the EU on the day it becomes effective. This means that EU countries, when authorising and supervising clinical trials, are required to base their assessments and decisions on the same principles.
Another difference is the standardisation of requirements for clinical trials. The MDR contains more detail than the directives, due to the implementation of aspects related to good clinical practice (GCP) many of which previously existed only in the form of recommendations.
In addition, the MDR regulation is expected to foster cooperation between member states in decision-making related to clinical trials and increase the transparency of such trials on the EU market, through the implementation of relevant provisions and tools such as the electronic EUDAMED system.
It is worth mentioning that a major change is the treatment of non-interventional trials of CE-marked devices much more restrictively than before – the new regulations require several clinical trial provisions to be applied to such activities.
It should also be emphasised that in the event the MDR regulation does not establish additional requirements, the trial sponsor should transfer the detailed national requirements, which, in the case of Poland, have been published in the new Law of 7 April 2022 on Medical Devices. An example is the procedure for notifying the Competent Authority of changes. The MDR provides for a simplified procedure, while Polish regulations require obtaining an administrative decision from the President of the Authority on the scope of the planned changes.
All the above changes may seem difficult to implement. To support sponsors in the design and implementation of clinical trials, we will discuss the most important aspects in clinical trials in two parts of the publication. 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.” aspects such as registration, how to report and supervise clinical trials and the requirements for clinical trial documentation will be discussed. Part II of the article will discuss the new requirements with a brief description and analysis of them.
The tool for electronic registration and information exchange in accordance with the MDR is the EUDAMED database (as of the date of the article, it is not yet fully functional and therefore not mandatory for use). The EUDAMED database will be extremely important in implementing the provisions of the MDR regulation and is expected to perform a number of functions, including the registration of devices and operators and reporting of serious incidents and external safety corrective actions. It will also serve an important function in meeting the requirements for clinical trials.
The most important function of the EUDAMED database is to inform the public about ongoing or completed clinical trials of medical devices by requiring sponsors to register each trial that begins. According to Article 73 of the MDR Regulation, in addition to submitting an application for permission to conduct a clinical trial, the sponsor should submit the clinical trial report and its summary to the system, as well as use the system to report serious adverse events and other important device safety information.
It should be considered that the obligations and requirements related to the EUDAMED database will apply six months after the date of publication of the relevant notice in the Official Journal of the European Union indicating that the database is fully operational. Until then, the relevant provisions of the MDD and AIMDD directives, as well as national regulations, must be applied to meet the requirements of the MDR regulation.
As mentioned above, the MDR Regulation, compared to the MDD and AIMDD, contains much more detail in the context of requirements for clinical trials of medical devices. According to Articles 62-80 of the MDR Regulation, among other things, the following are defined: general requirements for clinical trials conducted to demonstrate device compliance, requirements for the informed consent form and its acquisition, the conduct of clinical trials involving subjects incapable of giving consent, and clinical trials involving minors and pregnant women or so-called vulnerable populations. In addition, requirements for clinical trials conducted in emergency situations were developed and described. The MDR Regulation defines the clinical trial trajectory for a CE-marked medical device and specifies the information that should be provided by the sponsor upon completion of a clinical trial or in the event of its temporary halt or early termination. The MDR Regulation clearly defines the clinical trial track, the coordinated evaluation procedure and the requirements for the application submitted for human clinical trial authorisation.
The sponsor is required to prepare an application with the relevant documents when wishing to apply for permission to conduct a clinical trial conducted to demonstrate the compliance of the device with the requirements. The application is submitted to the ethics committee competent for the site where the clinical trial is conducted and to the Competent Authority of the country where the clinical trial takes place. Annex XV of the MDR Regulation, Chapter II contains a list of documentation that must be prepared or attached to the application for permission to conduct a clinical trial. It is also possible that national Competent Authorities may request additional documentation to be considered during the planning of the clinical trial, to avoid unnecessary delays in the application and approval process.
However, based on the requirements of the MDR regulation, the trial sponsor fills out an application form, which should include information on the entity responsible for the trial (the sponsor), the status of the application (first submission, resubmission of an application for clinical trial eligibility or an application describing significant changes to the clinical trial) and the title of the clinical trial. A resubmission of an application or an application for approval to conduct an amendment to a clinical trial, requires the sponsor to provide details for the device for which an application has already been submitted, including the date and reference number of the earlier application and highlighting any changes from the earlier application. In addition, the sponsor should submit data or a reference to the clinical evaluation plan and a list of the member states and third countries where the clinical trial is planned (if a multinational trial is involved) along with a presentation of the trial sites (if a multicentre trial is involved) and the required competence of the principal investigator confirming the ability to conduct the clinical trial according to the trial plan. When applying for permission to start a clinical trial, a brief description of the investigational medical device must also be submitted, along with information on whether the device intended for the clinical trial contains a therapeutic substance, including a derivative of human blood or human plasma, or whether it is manufactured using non-viable tissues or cells of human or animal origin or their derivatives. The clinical investigation plan (CIP) and the summary of the clinical investigation plan are also evaluated.
Where appropriate, when the clinical trial is conducted with a comparator device, all information needed to identify such a device should be provided. The application should also include a statement that the investigational device complies with the general safety and performance requirements (Annex I of the MDR), except for those issues for which the clinical trial is being conducted, and regarding those issues that every precaution has been taken to protect the health and safety of the patient.
When reporting a clinical trial and applying for licensure, the sponsor attaches to the clinical trial dossier a prepared investigator’s brochure and documents to be used to obtain informed consent, including a copy of the patient information and informed consent (IC) document. According to good clinical practice (GCP), it is required that the process of obtaining informed consent is done in a manner that does not pressure the patient to decide to participate in the clinical trial, with sufficient time for the patient to become familiar with all available documents and make a free decision. Information should be provided to the patient in a form that the patient understands, without complex wording and expressions, in the patient’s native language. The investigator’s brochure (IB) should include, among other things, clinical and non-clinical information about the investigational device that is relevant to the study and available at the time of application. All investigators involved in the study should be informed in a timely manner about any updates to the investigator’s brochure or other relevant information that has become available. The investigator’s booklet (IB) should be fully traceable. The investigator’s brochure shall also include a characterisation and description of the investigational device, a summary of the benefit-risk analysis and risk management, including information on known or foreseeable risks associated with the use of the investigational device and any adverse reactions, contraindications and warnings. The IB shall also include information and instructions on the use of the device, a description, and results of tests, in particular, where applicable, in vitro and ex vivo tests, mechanical and electronic tests, biocompatibility tests, and any verification and validation regarding the performance and use of the investigational device. If possible, the investigator’s brochure should include existing clinical data available in the scientific literature, clinical data on the safety and performance of equivalent devices or similar devices from the same manufacturer. It is also necessary to have a detailed description of the clinical procedures and diagnostic tests used during the clinical trial and included in the brochure, particularly information on any deviations from normal clinical practice.
The most important document that must be submitted to the relevant authorities when applying for approval to conduct a clinical trial is the clinical investigation plan (CIP). This is the document that provides the guideposts and guidelines that we will follow when conducting a clinical trial. The clinical trial plan justifies the purpose of the clinical trial and outlines the research hypothesis. The study plan also describes the type and type of clinical trial and the study’s endpoints, i.e. the primary and secondary endpoints of the clinical trial. The description also includes the methodology for conducting the study and its documentation (data management) along with the method of analysis (selected statistical issues, as appropriate) of the clinical trial. The plan argues for the size of the study population on which the clinical trial is being conducted, along with information on the study group and any criteria for patient inclusion and exclusion in / from the trial. The clinical trial plan includes, among other things, information on the investigational device and research and clinical procedures, liability information with respect to the device (in particular, about control of access to the device), further actions with respect to the device used in the clinical trial, and the return of unused, expired, or defective devices. The CIP also strictly defines issues in safety, including the identification of adverse events and serious adverse events, device defects, procedures and deadlines for their reporting. The clinical trial plan includes and describes a plan for monitoring the entire trial. If required, the study plan should include criteria and procedures for follow-up of participants after the study is completed, stopped or terminated early, follow-up of participants who have withdrawn their informed consent and procedures for participants excluded from observation.
When applying for the initiation of a clinical trial to the Competent Authority where national law so provides, a copy of the opinion of the relevant ethics committee or copies of the opinions of the relevant ethics committees (in the case of a multi-centre trial) must be submitted. In the case where, in accordance with national law, the opinion(s) of the ethics committee is not required at the time of application, the opinion(s) should be forwarded to the Competent Authority as soon as it is available. It is mandatory to submit proof of insurance coverage or other mechanism to compensate study participants for injury, in accordance with Article 69 of the MDR Regulation and relevant national law.
The MDR Regulation introduces new requirements that must be carefully considered and considered in the design and conduct of a clinical trial. The new requirements will be analysed in the next part of the article in the series ” Changes in clinical trials of medical devices -new requirements, ways to report and supervise clinical trials. Part II.”
Bibliography
1: 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.
2: PN-EN ISO 14155:2021-02 Clinical testing of medical devices on humans — Good clinical practice.
3: Polish Act on Medical Devices of 7.04. 2022.
4: MDCG 2021-6 Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation April 2021.
Abbreviations
1: MDD – Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, Medical Device Directive.
2: AIMDD – Council Directive of 20 June 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 5 April 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.