Clinical Evidence for In-Vitro Diagnostic Medical Devices

Clinical evidence – What is this?

Clinical evidence for in-vitro diagnostic devices (IVDs) is gathered through performance evaluations, assessing scientific validity, analytical performance, and clinical performance (Article 2 (44).) It is essential to have clinical expertise in every step of this process, ensuring each claimed benefit is supported by appropriate evidence.

Given that many healthcare decisions rely on IVDs, their results can significantly affect patient care. Therefore, clinical evidence must demonstrate that an IVD achieves its claimed benefits safely and in compliance with general safety and performance requirements (GSPRs) in Annex I. This evidence must support the IVD’s intended purpose and performance, addressing residual risks to patients and users. Evaluate clinical evidence for accessories used with IVDs alongside the corresponding IVDs.

Evidence-based medicine principles should guide the assessment, focusing on the strength, robustness, and quality of the data to ensure the clinical benefit outweighs residual risks.

The performance evaluation process

Performance evaluation for in vitro diagnostic devices (IVDs) is an ongoing, structured process integral to the quality management system, detailed in Article 56 and Annex XIII of the IVDR. It involves:

  1. Planning: Developing a performance evaluation plan (PEP) tailored to the device’s characteristics and intended purpose.
  2. Data Establishment:
    • Assessing available data for relevance and suitability.
    • Identifying and generating additional data if needed.
  3. Analysis and Documentation: Analyzing data, documenting conclusions in the performance evaluation report (PER), and preparing the summary of safety and performance for Class C and D devices.
  4. Continuous Monitoring and Updates: Updating the PER, summary of safety and performance, and other documents like the Periodic Safety Update Report (PSUR) based on post-market performance follow-up (PMPF) data.

Key pillars of performance evaluation include:

  • Scientific Validity: The association between the analyte and the targeted condition.
  • Analytical Performance: The IVD’s accuracy in detecting or measuring the analyte.
  • Clinical Performance: Correlation of IVD results with clinical conditions.

Have a plan!

The performance evaluation of an IVD begins with creating a Performance Evaluation Plan (PEP), which specifies the device’s characteristics, performance criteria, and evaluation process. Key factors to consider include:

  • Intended purpose (e.g., specific disorder or condition detected)
  • Novelty and innovation
  • Scientific validity of the analyte
  • Methods and assay technology
  • State-of-the-art
  • Patient risk
  • Intended users and disease states
  • Device classification and study population variability
  • Availability of reference materials and methods
  • Target population and specimen stability

Find the the requirements for the PEP in Annex XIII of the IVDR. You need to plan, conduct, and document the performance evaluation continuously, updating the PEP and performance evaluation report with data from Post-Market Performance Follow-up (PMPF). The PEP should clearly outline applicable General Safety and Performance Requirements (GSPRs) and include a benefit-risk assessment using predetermined thresholds. Additionally, compliance testing results (e.g., electromagnetic compatibility or electrical safety) must be included in the performance evaluation report.

The holy trinity.

As already mentioned, the scientific validity, analytical performance and clinical clinical performance together demonstrate the clinical evidence of an IVD. Let’s look closer into each field.

Scientific Validity – Is it true?

Scientific validity, crucial for each IVD, establishes the association of an analyte with a clinical condition or physiological state. This demonstration is vital for devices providing such information. For devices used together, like a reagent with calibrators and controls, validity can be established in combination. Existing data may support this, but for novel analytes or purposes, new data may be required. I advise systematic literature reviews, to ensure thoroughness and documentation. Examples of existing data sources include peer-reviewed literature and clinical data. New evidence generation may involve clinical performance studies. 

Analytical Performance – What can it do?

Analytical performance, as defined by IVDR Article 2(40), ensures that your IVD reliably and accurately measures or detects analytes. This involves demonstrating performance characteristics through analytical performance studies, with routine diagnostic testing data as supporting evidence. Assess all specified specimen types and sampling conditions, including stability considerations. Information on specimen collection, storage, and analysis timeframes should be provided. Analytical performance indicators, outlined in IVDR Annex I and II, include sensitivity, specificity, accuracy, precision, and stability. For IVD software, characteristics like confidentiality and reliability are important. 

Clinical Performance – How is the performance in the field?

Clinical performance, defined by IVDR Article 2 (41), refers to an in vitro diagnostic device’s ability to produce results correlated with specific clinical conditions or processes, as intended for the target population. You will need to demonstrate that the software achieves clinically relevant results through testing in various conditions and environments. While certain devices may not require clinical performance data, justification is necessary. The MDCG 2020-1 takes you by the hand and provides some very good examples. Interestingly, for software it might be sufficient to demonstrate clinical performance by usability studies and bench testing. 

Let’s wrap it up ! – The performance evaluation report

You need to compile evidence, assess benefit-risk, and document the performance evaluation in the Performance Evaluation Report (PER). This includes evaluating scientific validity, analytical, and clinical performance data to ensure conformity with safety and performance requirements. Annex XIII allows for studies other than clinical performance studies, such as analytical performance or Post-Market Performance Follow-up (PMPF), which should also be reflected in the PER.

The assessment considers factors like intended users, condition severity, risk estimation, adverse events, and available alternatives. Additionally, performance evaluation is a continuous process, with data actively monitored and collected over the IVD’s lifecycle. Changes to the IVD, such as intended purpose or design, require reevaluation and updating of clinical evidence to ensure ongoing safety and effectiveness. Developments in the state-of-the-art or standards may trigger further updates to the clinical evidence.

Frequency for updates of plans and reports

The following overview will help you understand the individual update cycles depending on the risk class.

Device ClassDocumentRequired frequency of updateArticle
AllPerformance Evaluation and associated documentationThroughout the life cycle of the device.From implementation of the manufacturer’s Post Market Performance Follow up (PMPF) plan in accordance with Part B of Annex XIII and the post-market surveillance plan referred to in Article 79Continuously through product’s lifetime based on input from PMS and PMPF for all classes.Article 56 (6)
AllPost Market Surveillance PlanAs necessaryArticle 79
AllPost-Market Performance Follow-Up (PMPF)Continuously through product’s lifetime based on input from post market surveillance plan (Annex III)As necessary, unless specific justification is given.Annex XIII Part B
A & BPerformance Evaluation ReportContinuously through product’s lifetime based on input from PMS and PMPF for all classes.As necessary and as defined in the PMS planArticle 56(6)
A & BPost Market Surveillance ReportWhen necessary and made available to the notified body and the competent authority upon requestArticle 80
C & DPerformance Evaluation ReportAs necessary and at least annuallyArticle 56(6)
C & DPeriodic Safety Update Report (PSUR)At least annuallyArticle 81 (1)
C & DSummary of Safety and Performance (SSP)As soon as possible, where necessaryArticle 29Article 56 (6)

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