Performance studies are a key element of the EU In Vitro Diagnostic Medical Devices Regulation (IVDR). Clinical performance studies establish aspects of device performance that cannot be determined by analytical performance studies, literature or previous experience from routine diagnostic testing, and demonstrate safety and clinical relevance. The data feed into the performance evaluation and form part of the clinical evidence – a key step towards certification. The requirements are set out in Annex XIII, Part A, Section 2 IVDR.
Purpose of clinical performance studies
A clinical performance study aims to establish or confirm aspects of device performance that cannot be determined otherwise. The information is used to demonstrate compliance with the general safety and performance requirements relating to clinical performance, and the data obtained are used in the performance evaluation process as part of the clinical evidence.
Ethical considerations
Every step of a clinical performance study – from the first consideration of the need for and justification of the study to the publication of the results – must be carried out in accordance with recognised ethical principles.
Study design and methods
Clinical performance studies should be designed to maximise the relevance of the data while minimising potential bias. They may be prospective or retrospective, observational or interventional. Device use, specimen collection and other operational details must be strictly controlled and the influence of all relevant factors on the results taken into account.
The clinical performance study plan (CPSP)
Every clinical performance study must be based on a clinical performance study plan (CPSP) defining the rationale, objectives, design, proposed analysis, methodology, monitoring, conduct and record-keeping. In particular, the CPSP must contain:
- the single identification number of the clinical performance study referred to in Article 66(1);
- identification of the sponsor, including name, registered place of business and contact details and, where applicable, those of its contact person or legal representative under Article 58(4);
- information on the investigator(s), their qualifications and contact details, and the investigation site(s); for self-testing devices, the location and number of lay persons involved;
- the starting date and scheduled duration of the study;
- identification and description of the device, its intended purpose, the analyte(s) or marker(s), metrological traceability and the manufacturer;
- information about the type of specimens under investigation;
- an overall synopsis of the study, its design type (e.g. observational, interventional), the objectives and hypotheses, with reference to the current state of the art in diagnosis and/or medicine;
- a description of the anticipated risks and benefits of the device and the study in the context of the state of the art in clinical practice and – except for studies using leftover samples – the medical procedures involved and patient management;
- the instructions for use of the device or test protocol, the necessary training and experience of the user, appropriate calibration and quality control procedures, details of any other devices, medical devices, medicinal products or other articles to be included or excluded, and the specifications of any comparator or comparative method used as reference;
- a description and justification of the study design, its scientific robustness and validity, including the statistical design and the measures taken to minimise bias (e.g. randomisation) and to manage potential confounding factors;
- the analytical performance under Annex I, Section 9.1(a), with justification for any omission;
- the clinical performance parameters to be determined under Annex I, Section 9.1(b), with justification for any omission and – except for studies using leftover samples – the specified clinical outcomes/endpoints (primary/secondary) with justification, and the potential implications for individual health and/or public health management decisions;
- information on the study population: subject specifications, selection criteria, size of the study population, representativeness of the target population and, where applicable, information on vulnerable subjects (e.g. children, pregnant women, immunocompromised or elderly subjects);
- information on the use of data from leftover specimen banks, genetic or tissue banks, patient or disease registries, etc., with a description of reliability and representativeness and the statistical analysis approach, and assurance of a relevant method for determining the true clinical status of patient specimens;
- the monitoring plan;
- data management;
- decision algorithms;
- the policy on any amendments to the CPSP, including those under Article 71, or deviations from it, with a clear prohibition of waivers from the CPSP;
- accountability for the device, in particular control of access to it, follow-up of devices used in the study and the return of unused, expired or malfunctioning devices;
- a statement of compliance with recognised ethical principles for medical research involving humans, the principles of good clinical practice for clinical performance studies and the applicable regulatory requirements;
- a description of the informed consent process, including copies of the patient information sheet and consent forms;
- procedures for safety recording and reporting, including definitions of recordable and reportable events and the procedures and timelines for reporting;
- criteria and procedures for suspending or terminating the study early;
- criteria and procedures for follow-up of subjects after the study, for subjects in case of suspension or early termination, for subjects who have withdrawn consent and for subjects lost to follow-up;
- procedures for communicating test results outside the study, including to the study subjects;
- a policy on the establishment of the clinical performance study report and the publication of results in accordance with the legal requirements and ethical principles;
- a list of the technical and functional features of the device, specifying those covered by the study;
- a bibliography.
If part of this information is submitted in a separate document, it must be referenced in the CPSP. For studies using leftover samples, points (u), (y) and (z) do not apply. If any element is considered not appropriate for inclusion because of the specific study design (for example studies using leftover samples versus interventional studies), a justification must be provided.
The clinical performance study report
The clinical performance study report, signed by a medical practitioner or another authorised responsible person, must contain documented information on the study protocol, results and conclusions, including negative findings. Results and conclusions must be transparent, free of bias and clinically relevant. The report should contain enough information to be understood by an independent party without reference to other documents, and include any protocol amendments or deviations and data exclusions with appropriate justification.
Other performance studies
By analogy, the plan and report for other performance studies (for example analytical performance studies) must be documented in the same way, although their nature and methods differ from clinical performance studies.
How EVERBIZ can help
EVERBIZ supports IVD manufacturers in planning performance studies, drafting CPSPs and study reports and preparing the performance evaluation under the IVDR. Contact us.
This article is for general information only and does not constitute legal advice. The text of Regulation (EU) 2017/746 is authoritative.