Analytical Performance Characteristics for IVDs: What Manufacturers Need to Know

While ‘analytical performance’ is not a novel concept in the transition from the IVDD to the IVDR, it has been greatly expanded upon under the new EU IVD regulatory framework and is defined under the IVDR as ‘the ability of a device to correctly detect or measure a particular analyte’.

What is an Analytical Performance report under the IVDR?

The IVDR builds upon the list of specific analytical performance characteristics established under the IVDD with the following examples provided under GSPR 9.1(a):

• • Analytical sensitivity
  • Analytical specificity
  • Trueness (bias)
  • Precision (repeatability and reproducibility)
  • Accuracy (resulting from trueness and precision)
  • Limits of detection and quantitation
  • Measuring range
  • Linearity
  • Cut-off
  • Determination of appropriate criteria for specimen collection and handling
  • Control of known relevant endogenous and exogenous interference, cross-reactions

Metrological traceability of calibrator and control material values are described in Annex III of the IVDR as analytical performance information to be included in the Technical Documentation File, and thus should also be considered as a specific analytical performance characteristic, where applicable.

How are these characteristics defined within the IVDR?

None of these specific analytical performance characteristics are defined under the IVDR, however MDCG 2022-2 does establish definitions for several of them. Where no clear source is described in MDCG 2022-2 for a specific definition or where no definition is established in this guidance, an internationally recognized source for specific analytical (and clinical) performance characteristics is the Clinical and Laboratory Standards Institute (CLSI) Harmonized Terminology Database.

Changes in performance evaluation requirements for IVDs under the IVDD and IVDR

Under the IVDD, specifically in Annex III, the manufacturer’s technical documentation was required to include adequate performance evaluation data and test reports. Under the IVDR, it is now a requirement for manufacturers to establish an analytical performance report (APR) as one of the reports supporting the performance evaluation report (PER). The IVDR establishes that manufacturers shall demonstrate analytical performance of their IVDs in relation to all parameters described under GSPR 9.1(a), unless any omission can be justified as not applicable. Subsequently, it is critical that manufacturers document such justification within the scope of the performance evaluation documentation (typically documented in either the Performance Evaluation Plan (PEP) or APR).

Analytical performance characteristics for different types of IVDs

One of the most common questions from manufacturers is subsequently “Which specific analytical performance characteristics apply to my device?” While BS ISO 16142-2:2017 (not harmonized under the IVDR) directs manufacturers to international guidance documents, which are most appropriate for study design (including relevant CLSI guidance), it does not provide an explicit indication of the types of parameters applicable for different types of IVDs, as the combination of device type/characteristics (e.g. quantitative, qualitative, semi-quantitative) and intended purpose can result in a diverse array of IVDs. However, MedEnvoy has the observed the following examples of the types of analytical performance parameters that have been included with different types of IVDs:

BS EN ISO 18113-3:2009 (not harmonized under the IVDR) does provide some guidance on analytical performance characteristics that should be described in the labeling for instruments and in the case of Class D IVDs, it is even easier to identify the relevant analytical performance parameters (and minimum testing requirements) with the publication of the Common Specifications in Commission Implementing Regulation (EU) 2022/1107. While this regulation is currently in a transition period until 25 July 2024, during the transition IVDs that conform with the common specifications under Decision 2002/364/EC shall be presumed to be in conformity with the IVDR common specification (which includes the relevant analytical performance parameters and testing requirements).

Alternative approaches for demonstrating trueness in novel markers under the IVDR

The IVDR also establishes that for novel markers or other markers for which certified reference materials / measurement procedures are not available, it may not be possible to demonstrate trueness. In such scenarios, different approaches may be used if demonstrated to be appropriate, such as comparison to some other well-documented methods or the composite reference standard. In the absence of such approaches, a clinical performance study comparing performance of the novel device to the current clinical standard practice (i.e. state of the art clinical practice). An example of non-novel IVDs for which the latter approach has been widely applied is fecal immunochemical tests (FITs) / Fecal Occult Blood Tests (FOBTs) whose ability to detect bleeding from colorectal cancer is typically compared against colorectal cancers detected by the non-IVD “gold standard” (colonoscopy).

Analytical performance and its relationship to literature search data under the IVDR

Lastly, in contrast to scientific validity and clinical performance, it is not possible to demonstrate analytical performance though literature search data. The IVDR clearly establishes that, as a general rule, analytical performance is to be based on analytical performance studies. Therefore, once all such studies have been completed, their results should be described in the APR, and it is strongly recommended that the APR include references to the protocols and reports generated for these analytical performance studies, and be aligned with the content descriptions under the respective analytical performance characteristics listed under Section 6.1, Annex II of the IVDR.

Consulting services for analytical performance under the IVDR

If you have any additional questions about analytical performance under the IVDR in regarding performance evaluations or require relevant training / consulting services, get in touch.