The new Regulation (EU) 2017/746 (IVDR) has introduced stricter and more detailed requirements for conducting performance studies of in vitro diagnostic medical devices (IVDs) compared to the previous Directive 98/79/EC (IVDD). The key focus of these changes is on enhancing patient safety.

In the first part of the article, we delve into the design and conduct of performance studies in accordance with the IVDR, Good Clinical Practice, and ISO 20916:2019. This involves introducing the performance evaluation procedure, including the review of scientific validity and analytical and clinical performance, as well as covering study methods and clinical data collection.

This article discusses regulatory issues related to the requirements of the Regulation 2017/746 (IVDR) and ISO 20916:2019 Good study practice for clinical performance studies using specimens from human subjects. These outline the rules for notifying ethics committees and competent authorities in EU member states of the performance studies, supervising these studies and their monitoring. The first section deals with the categorization of in vitro diagnostic medical device performance studies, which impacts the notification process and the level of supervision.

Categorization of Performance Studies

The term “performance study” encompasses various types of projects, from analytical studies conducted in fundamental research laboratories to those involving patients and using prospectively collected clinical samples. Both IVDR and ISO 20916:2019 introduce the categorization of studies based on participant safety.

Moving into the specific types of performance studies, the first type, an interventional study, involves clinical decisions based on diagnostic test results from the investigational IVD. This procedure is conducted when a reference test of a similar design or an approved diagnostic standard is unavailable. Therefore, an interventional trial is planned when dealing with a new, previously unstudied pathogen or introducing an innovative device. Interventional studies are subject to the most rigorous monitoring. It is necessary to collect indirect clinical evidence indicating the patient’s actual condition to determine diagnostic parameters of the investigational device, such as diagnostic sensitivity and specificity. Initiating this type of study requires obtaining a positive opinion from the ethics committee and approval from the member state’s competent authority.

Another type of performance study, as per ISO 20916:2019, is the invasive study. This involves conducting a research project where patients may face additional health risks related to sample-taking. Article 58 of the IVDR outlines situations wherein surgically invasive sample-taking is conducted exclusively for the purpose of a performance study or when additional invasive procedures or other risks are involved. The results of such trials can be confirmed by an established reference method conducted using certified equipment. Healthcare professionals will base their decisions on a result obtained from a certified device rather than the investigational device. In an invasive study, the risks faced by the research team are limited to the sample-taking procedure. This type of trial requires a favorable opinion of an independent ethics committee and, as in the case of an interventional study, approval from the member state’s competent authority.

The third type of study involves the utilization of archived samples obtained from a biobank or other institution with a repository of relevant biological material. This category also includes trials leveraging patients’ historical clinical data or studies where a sample is not explicitly collected for the study. In the latter scenario, the research team will utilize residual biological material left over from a standard diagnostic cycle. This type of study will involve a limited set of monitoring procedures. Prior to conducting the study, an ethics committee must be consulted. In some cases, only notification to the member state’s competent authority will suffice, and no additional insurance to cover potential harm to patients will be required.

Opinion of Independent Ethics Committee

Article 58 of the IVDR states, “Performance studies shall be subject to scientific and ethical review. The ethical review shall be performed by an ethics committee in accordance with national law.” The organizational structure, status, and operational mode of ethics committees vary from country to country. In most cases, these committees are established by state bodies or at institutions such as hospitals, research centers, or universities. The committee’s task is to verify that the planned performance study will be conducted with due regard for the rights and well-being of its participants.

In many European Union countries, medical trials must be approved by an independent ethics committee, which evaluates the conditions and ethical criteria for conducting experiments involving human subjects, as well as the feasibility and advisability of the project. An ethics committee issues an opinion on the performance study within certain period of time of receiving the complete application documentation. The application should be submitted to the committee relevant to the location of the principal investigator or coordinator of the performance study.

If any modifications are made to the performance study that could substantially impact the safety, health, or rights of the participants, it is essential to update the documentation. The changes should be clearly marked and submitted to the ethics committee for evaluation, as per the guidelines outlined in Article 71 of the IVDR.

In summary, every medical experiment involving participants should be clearly and explicitly described in the research protocol and undergo ethical review. An independent ethics committee is required to give an objective opinion on the performance study and has the right to monitor the conduct of the trial. The sponsor and investigator are responsible for informing the committee of any significant changes within the study protocol and providing additional information and documents as needed.

Surveys, questionnaires, and database analyses are not medical experiments, but they can pose risks to participants’ well-being if improperly planned. If a researcher intends to conduct a project of this nature, they should notify the ethics committee.

Another potential scenario is the planning of a performance study utilizing residual samples. As per the IVDR, “Performance studies using left-over specimens need not be authorized. Nevertheless, the general requirements and other additional requirements with regard to data protection and the requirements applicable to procedures that are performed in accordance with national law such as ethical review should continue to apply to all performance studies, including when using left-over specimens.” Consequently, procedures utilizing residual samples will also be subject to ethics committee review.

Permission from the Competent Authority of the Member State

According to the IVDR, certain performance studies of IVDs require the submission of relevant documentation to the regulatory authority and obtaining a favorable opinion from the ethics committee before commencement. This requirement is outlined in Article 66 of IVDR. The regulatory authority has a specified period of time after validation to issue or refuse to issue a permit for the performance study mentioned in Article 58 (1) and Article 70 (1) or (2) of IVDR.

This obligation applies to interventional studies or other performance studies that require collecting an additional sample from the participant. Suppose an IVD is CE marked, and a performance study is planned, such as a post-marketing observational study, to assess the device more comprehensively. In that case, the relevant authority must be notified. Article 70 of the IVDR states, “The sponsor shall notify the Member States concerned at least 30 days prior to its commencement. […] The sponsor shall include the documentation referred to in Section 2 of Part A of Annex XIII […].”

The member state’s competent authority requires extensive documentation to authorize a performance study. As per Annex XIV of IVDR, the sponsor or their legal representative must submit a completed application form containing essential information. This includes details of the sponsor and manufacturer, study title, anticipated start date, and device description, along with its classification. The submission must also include the investigator’s brochure, performance study plan, device declaration of conformity, safety requirements, proof of insurance coverage for study participants, patient information sheet, informed consent template, and GDPR information.

The documentation submitted to the ethics committee and the competent authority must be consistent. Any substantial changes to the performance study protocol must be reported to both institutions.

Supervision of Performance Studies

According to article 76 of the IVDR, the study sponsor is required to record and report any adverse events that occur during the performance study of an IVD. These include, among others, adverse events identified in the study plan as critical to the evaluation of performance study results, serious adverse events, or device deficiency that may have led to such events if appropriate action had not been taken. The sponsor is responsible for reporting such incidents to all member states where the trial is conducted. It is essential to determine the severity of the incident. Reporting adverse events in one center does not impede other centers (or member states) from conducting independent assessments, ensuring adequate protection for trial participants. It is crucial to keep competent authorities and the ethics committee informed of the outcome of the evaluation.

The study sponsor’s obligation to inform the ethics committee and the competent authority of the member state about any significant changes to the study is a crucial aspect of overseeing medical device performance studies. Substantial modifications of the study protocol may include taking additional samples from participants or extending the study duration.

Monitoring of the Study

Monitoring clinical study performance is crucial for ensuring data accuracy and reliability. In order to adhere to the Good Clinical Practice principles outlined by ICH E6 (R2) Good clinical practice – Scientific guideline and ISO 20916:2019, it is recommended to conduct monitoring before, during, and after the study.

The primary goal of monitoring is to safeguard the participants’ rights and verify the accuracy and completeness of the results. ISO 20916:2019 mandates that the IVD performance study must adhere to a predetermined protocol, and the data collected must align with the source data. Study data analysis and reporting should align with the study plan while prioritizing ethical considerations throughout the project.

As per ISO 20916:2019, the sponsor is primarily responsible for overseeing the study. However, they may delegate clinical performance study duties, including monitoring, to an external organization. It is essential to recognize that the sponsor bears ultimate accountability for the quality and accuracy of the trial data. ISO 20916:2019 emphasizes the sponsor’s role in evaluating the scope and nature of monitoring the performance study and the source data verification strategy. Additionally, the IVDR highlights the sponsor and investigator’s role in conducting the trial. Article 68 states, “The sponsor and the investigator shall ensure that the performance study is conducted in accordance with the approved performance study plan.” and “In order to verify that the rights, safety, and well-being of subjects are protected, that the reported data are reliable and robust […] the sponsor shall ensure adequate monitoring of the conduct of a performance study.” As per the IVDR, the sponsor is responsible for assigning an independent study monitor, who is not affiliated with the trial site, to ensure that the clinical performance study adheres to the study plan and GCP guidelines.

The study initiation stage is crucial, especially regarding the monitoring aspect. At this point, it is necessary to ensure that the study team and investigator are well-versed with the study’s scope and have comprehensively familiarized themselves with the approved study protocol, investigator brochure, and informed consent form. ISO 20916:2019 emphasizes the need for a study initiation visit at each study site. This visit is conducted and documented during the project’s initial phase. During this stage, research team members’ details and functions are documented, and the study plan and relevant documentation are thoroughly discussed.

Monitoring the performance study diligently throughout its execution at the study site is imperative. This requires periodic documentation review and verification of the trial results. The study sponsor is responsible for safety assessment and oversight of study monitoring. As per ISO 20916:2019, the sponsor is mandated to classify adverse events and conduct the safety assessment of the clinical performance study. Analyzing study participants’ informed consent and systematically reviewing reported adverse events is essential during the trial. This is also to conduct a thorough review of the study documentation and results to ensure they are current and stored appropriately.

The last stage of the performance study involves carefully monitoring and verifying the quality and completeness of all documents and data gathered. The procedures need to be rechecked to ensure compliance with the study protocol. In accordance with ISO 20916:2019, all activities related to closing the study are performed in compliance with the protocol’s terms and adequately documented. All documents related to monitoring, monitoring visits, corrective actions, and other supervisory activities, should be appropriately archived and stored.

Notifications After the End of the Trial

By article 72 of IVDR, the sponsor is required to notify the member state of the timely or early termination or suspension of the trial. It is of utmost importance to communicate the reason for halting or terminating any clinical trial to the competent authorities in all member states where the study was conducted within 15 days. If the trial is terminated early for safety reasons, the sponsor must notify all member states where the trial was conducted within 24 hours.

The clinical performance study report must be submitted to the relevant institutions. This report should encompass the study’s protocol, results, conclusions, and executive summary. The sponsor or its legal representative should submit the documents to each member state where the trial was conducted within one year after completion or within three months after early termination or temporary suspension. Additionally, it is crucial to notify the relevant ethics committee about the study’s termination.