Navigating IVDR Compliance: Applicability of Scientific Validity for IVDs

While established over ten years ago as a concept by the precursor to the International Medical Device Regulators Forum (IMDRF), the Global Harmonization Task Force (GHTF), scientific validity is a novel concept in the EU regulatory framework in the transition from the IVDD to the IVDR.

Understanding scientific validity for IVDs

The first step in establishing the scientific validity for an IVD or determining if scientific validity is applicable to an IVD is understanding exactly what ‘scientific validity’ means for the specific IVD of interest.

While the IVDR defines ‘scientific validity of an analyte’ as ‘the association of an analyte with a clinical condition or a physiological condition’, the following definitions are also established in the respective sources indicated:

• • The extent to which the analyte, or marker to be determined by the IVD is associated with the targeted physiological state or clinical condition (MDCG 2022-2)
  • For IVD medical device software (MDSW): The extent to which the claimed intended purpose is associated with the targeted physiological state or clinical condition (derived from MDCG 2022-2)
  • For IVD MDSW: The association of an MDSW output with a clinical condition or physiological state (MDCG 2020-1)

While these definitions are (relatively) easily applied to reagent-based IVDs (including reagent-containing kits) and standalone MDSW, they are less easily applied to other types of IVDs.

Applicability of scientific validity for Class A devices under Rule 5(b) of IVDR

Certain Class A devices, such as those that fall under Rule 5(a) (e.g. products for general laboratory use intended by the manufacturer to make them suitable for in vitro diagnostic procedures relating to a specific examination) or Rule 5(c) (i.e. specimen receptacles) do not perform analyte or marker determination and are not IVD MDSW. Therefore, it is reasonable for manufacturers of such IVDs to justify the non-applicability of scientific validity.

However, in the case of Class A devices that fall under Rule 5(b) (i.e. instruments intended by the manufacturer specifically to be used in vitro diagnostic procedures), critical considerations regarding the applicability of scientific validity include:

• • Does the instrument determine an analyte or marker without the use of any additional reagents? If the answer is yes, in all likelihood the instrument is in fact not a Class A IVD based upon guidance provided in MDCG 2020-16, and scientific validity would be applicable unless due justification is provided.
  • Does the instrument incorporate IVD MDSW?

Identification of applicable software models and scientific validity for IVD MDSW

For the second consideration, it’s important to clearly identify which of the software models described in MDCG 2020-1 is applicable, i.e.

• • MDSW with an intended purpose and claimed clinical benefit related to driving or influencing a medical device for a medical purpose, in which case scientific validity would be applicable and would need to encompass the MDSW and the driven or influenced instrument.

NOTE: If the MDSW is intended to drive/influence more than one IVD, an independent scientific validity report (and performance evaluation) is required for each foreseen and clinically viable software-device combination.

• • Software driving or influencing the use of a medical device with no independent intended purpose or independent claimed clinical benefit, in which case scientific validity would be applicable to the instrument including the software as either a component or accessory.

Applicability of scientific validity for calibrators and control materials in IVDs

Other types of IVDs for which the applicability of scientific validity is not clearly established are calibrators and control materials, as they do not determine an analyte or marker but are actually themselves measured by the IVD that they are intended to calibrate or serve as a control. MDCG 2022-2 notes that “…for certain devices intended to be used together, for example a reagent intended to be used with calibrators and controls, it may be more appropriate to establish the scientific validity in the context of this combination.” In our experience, Notified Bodies expectations during performance evaluation review of standalone calibrators and control material is that these include a scientific validity report demonstrating the association of the analyte or marker for the assay(s) they are supporting (all analytes/markers in the case of multiparametric controls/calibrators).

Types and sources of evidence for establishing scientific validity in IVDs

Once a manufacturer has determined the type and applicability of scientific validity to their device, the next step is to determine the type/level of evidence necessary to support scientific validity which will largely be driven by the IVDs degree of novelty. Annex XIII of the IVDR establishes that manufacturers shall demonstrate scientific validity based on one or a combination of the following sources:

1. Relevant information on the scientific validity of devices measuring the same analyte or marker.
2. Scientific (peer-reviewed) literature.
3. Consensus expert opinions/positions from relevant professional associations.
4. Results from proof-of-concept studies.
5. Results from clinical performance studies.

In the case of well-established scientific validity, for which the generally acknowledged state of the art has been characterized, manufacturers will typically establish scientific validity based upon data from options 1-3 due to the existence of high-quality evidence in the public domain (refer to our article on best practices for performance evaluation literature searches here). For novel devices, or where manufacturers are unable to identify sufficient data from options 1-3, a scientific rationale will need to be provided and the manufacturer will need to generate new or additional data, in most cases from options 4-5.

Establishing a literature search protocol and report for IVD clinical performance

As scientific peer-reviewed literature is also among the data sources to demonstrate IVD clinical performance, and Section 1.2, Annex XIII of the IVDR states that as a general methodological principle, manufacturers shall identify through a systematic scientific literature review the available data relevant to the device and its intended purpose and identify any remaining unaddressed issues or gaps in the data, both a literature search protocol and report including scientific validity among their objectives should be established. Only once this literature search has been completed and any gaps identified and addressed should manufacturers then proceed with compilation of the scientific validity report (it is recommended that the literature search protocol and report be included as annexes to the performance evaluation report as it will typically support scientific validity, clinical performance and state of the art data analyzed within the scope of the performance evaluation).

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