October 3, 2023 Medical Device - Regulatory

European Union in Vitro Diagnostic Regulation (EU IVDR) 2017/746 is the European law concerning placing in vitro diagnostic medical devices for human use and their accessories on the market. Manufacturers of medical devices that wish to place in vitro diagnostic medical devices on the EU market must comply with EU IVDR requirements. The IVDR was introduced in May 2017 to improve the safety and efficacy of in vitro diagnostic medical devices available in the EU market.

A comprehensive quality management system (QMS) supports Manufacturers of in vitro diagnostic medical devices to compi.ly with the IVDR requirements regarding quality.
It defines an in vitro medical devices as any device used in vitro to examine samples derived from the human body to provide relevant information for material, software, or system used alone or in combination.

The regulation was introduced in May 2017 and has a transition period for manufacturers to comply with the requirements until May 2025 to May 2028, depending on device classification.

IVDR Device Classification:

Based on patient and public health risk due to transmissible agents within the biological materials IVDR classification rules in Annex VIII specify four classes for in vitro diagnostic devices: A, B, C, or D. These classes are based on the intended purpose of the devices and potential risk for end-users.

  • Class A: Have low patient and public health risks eg. laboratory instruments, buffer solutions, specimen receptacles etc.
  • Class B: Have moderate patient risk and low public health risk these devices include IVDs for self-testing with less risk to the patient than those in Class C eg pregnancy tests, fertility tests, glucose level tests etc.
  • Class C: Have high patient risk and moderate public health risk. IVDs under this classification include devices that are used for detecting infectious agents without any risk of propagation, or for detecting the presence of an infectious agent with the potential to cause death or severe disability in case of erroneous result e.g. sexually transmitted infection tests, cancer markers, human genetic tests etc.
  • Class D: Devices with high patient risk and high public health risk are classified under this category. This class includes IVDs that detect or are exposed to life-threatening transmissible agents or transmissible agents and infectious diseases with high risk of propagation e.g. blood group typing, tissue typing (for transplants) etc.

Under the IVDR, only Class A non-sterile devices can be self-certified by the manufacturer.

Before marketing, in vitro diagnostic devices from the remaining classes must be audited and certified by a Notified Body.

Performance Evaluation Under IVDR:

A Performance Evaluation (PE) is required for any in vitro diagnostic device (IVD) that a manufacturer wants to place on the EU market.PE is explained in Article 56 of the new In Vitro Diagnostics Regulation (IVDR), and its goal is to demonstrate that the IVD in question achieves its intended purpose and is both safe and effective.

IVDR defines Performance Evaluation as “an assessment and analysis of data to establish or verify the scientific validity, the analytical and, where applicable, the clinical performance of a device.” Thereby PE is a continuous process that must be carried out throughout the life cycle of the device. Furthermore, regulation describes evaluation of three distinct sets of performance characteristics.

  • Scientific Validity: IVDR defines scientific validity as “the association of an analyte with a clinical condition or physiological state.” The literature or data has to be summarized in the scientific validity report (SVR) as it pertains to the specific claims stated by the manufacturer in the intended purpose of the device. For Scientific validity and performance evaluation, the evidence for scientific validity has to be appraised for its relevance and quality, with references, justifications and conclusions, which provides some guidance on the layout of the report. So for SVR following claims are considered:

a) Analyte Claims: All analytes must be listed with distinct literature or data to support the association with the listed conditions

b) Condition Claims: All conditions must be specified with appropriate measuring ranges/cut-offs for clinical diagnosis. • Justification must be provided in SVR for broad or generic conditions described in the intended purpose. Reference international clinical guidance when describing the clinical condition

c) Testing Populations Claims: Describe any limitations on the testing population such as patients outside specified age range or patients with particular condition. Provide literature or device data demonstrating suitability for testing on these patient types.

  • Analytical Performance: Analytical performance report (APR) refers to how well your IVD measures or detects your analyte. To evaluate the analytical performance of your IVD, you’ll need to carry out bench studies like cross-reactivity, interference, and stability testing. The full list of characteristics you’ll need to measure can be found in Annex I, Section 9.1 of IVDR. Assays, Controls/Calibrators and Instruments are typical studies that are considered for Analytical Performance. Therefore, APR link back to PEP, describe the studies performed in sufficient detail, provide an explanation of why certain performance characteristics are not applicable and support the claims being made in the instructions for use (IFU).
  • Clinical Performance: IVDR defines clinical performance as “the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state in accordance with the target population and intended user.” In other words, clinical performance is a measure of your device’s diagnostic accuracy. You’ll likely need to conduct a clinical performance study to prove this, though you may use literature as supporting evidence. For devices measuring analytes that are associated with a clinical condition that have medical decision points, clinical performance data and a corresponding clinical performance report (CPR) are required. Typical clinical performance data could be diagnostic sensitivity and specificity, area under the curve, negative predictive value and positive predictive value.

The results of all three of these items must be documented in individual reports. IVDR addresses scientific validity, analytical performance, and clinical performance in a comprehensive manner in Annex XIII, and I’d strongly encourage you to read through it carefully.

Pre-Market Performance Evaluation (PE) requirements

The activities within the PE can be broken up into pre-market and post-market stages. The pre-market stage will consist of two main items: your Performance Evaluation Plan and your Performance Evaluation Report.

Performance Evaluation Plan (PEP)

The Performance Evaluation Plan lays out all the information you have about your device and the activities you plan on carrying out to prove its performance.

IVDR states that the Performance Evaluation Plan should include:

  • The intended purpose and characteristics of your device
  • The analyte or marker you’re using
  • Intended use, user, and indications for use
  • General Safety and Performance Requirements (GSPR) supported by your PE
  • The methods you’re using to examine the analytical and clinical performance of the device
  • An outline of your development phases, including the methods for determining the scientific validity and the analytical and clinical performance.
  • A description of the current State of the Art
  • Benefit-risk considerations
  • Your Post-Market Performance Follow-up (PMPF) plan
Performance Evaluation Report (PER)

The PER is where all the clinical evidence—including your scientific validity report, analytical performance report, and clinical performance report—will be documented.

The Performance Evaluation Report must include:

  • Your justification for the approach you took to gather your clinical evidence
  • The literature search methodology, protocol, and report
  • The technology behind the device, its intended purpose, and any claims you’re making about its performance or safety
  • The nature and extent of the scientific validity and the analytical and clinical performance data you’ve evaluated
  • A comparison of the clinical evidence with the State of the Art
  • Any updates from your PMPF Evaluation Reports

Post-Market Performance Evaluation (PE) requirements

IVDR also states clearly that “the clinical evidence and its assessment in the performance evaluation report shall be updated throughout the life cycle of the device.” In order to fulfill the post-market requirements, you’ll need to conduct a Post-market Performance Follow-up (PMPF).

The PMPF is meant to be a continuous collection of clinical data on the performance of your device after it has been placed on the market.

Like the initial Performance Evaluation, you’ll need to create a plan for your PMPF and document your outputs in a PMPF Evaluation Report. IVDR states that the plan should specify the methods and procedures you’ll use to proactively collect and evaluate scientific, performance, and safety data.

The goals of your PMPF should be to:

  • Confirm the safety and performance of the device throughout its expected lifetime
  • Identify previously unknown risks, limits to performance, or contra-indications
  • Identify and analyze any emergent risks
  • Ensure the continued acceptability of the benefit-risk profile
  • Identify any possible systemic misuse

If your IVD is Class C or D, your PMPF Evaluation Report will need to be updated annually. For lower risk devices, an annual update may not be necessary, but the schedule for updating it should be justified. Some low-risk devices without residual risk may not need a PMPF; however, the decision to forgo one must also be justified in the PE Evaluation Report.

Additionally, if your device is Class C or D, you’ll be required to issue a Periodic Safety Update Report (PSUR). The PSUR is another part of your post-market surveillance activities, and you are required to update it annually.