On this page we will give a clear overview of what the IVDR expects from validation. Information from the regulation is collected and grouped, when text is taken from the regulation it is italicized.

The IVDR prescribes that a performance evaluation must be performed, and defines that concept as follows:

“an assessment and analysis of data to establish or verify the scientific validity, the analytical and, where applicable, the clinical performance of a device”

The performance evaluation must consist of the following components (art 58 paragraph 3 IVDR):

1. Scientific Validity
2. Analytical Performance
3. Clinical Performance

Clinical performance studies are compulsory, "unless it is duly justified to rely on other sources of clinical performance data".

In addition, attention must also be paid to the stability of the product.

1. Scientific Validity

Annex XIII, part A, section 1.2.1

The manufacturer shall demonstrate the scientific validity based on one or a combination of the following sources:

relevant information on the scientific validity of devices measuring the same analyte or marker;
scientific (peer-reviewed) literature;
consensus expert opinions/positions from relevant professional associations;
results from proof of concept studies;
results from clinical performance studies.
A detailed explanation of the sources for the validation can be found in:

Annex I GENERAL SAFETY AND PERFORMANCE REQUIREMENTS
Chapter II REQUIREMENTS REGARDING PERFORMANCE, DESIGN AND MANUFACTURE
Section 9 Performance Characteristics

2. Analytical Performance

• analytical sensitivity

This Section shall include information about the study design and results. It shall provide a description of specimen type and preparation including matrix, analyte levels, and how levels were established. The number of replicates tested at each concentration shall also be provided as well as a description of the calculation used to determine assay sensitivity.

• analytical specificity

This Section shall describe interference and cross reactivity studies performed to determine the analytical specificity in the presence of other substances/agents in the specimen.

Information shall be provided on the evaluation of potentially interfering and cross-reacting substances or agents on the assay, on the tested substance or agent type and its concentration, specimen type, analyte test concentration, and results.

Interferents and cross-reacting substances or agents, which vary greatly depending on the assay type and design, could derive from exogenous or endogenous sources such as:

(a) substances used for patient treatment such as medicinal products;
(b) substances ingested by the patient such as alcohol, foods;
(c) substances added during specimen preparation such as preservatives, stabilisers;
(d) substances encountered in specific specimen types such as haemoglobin, lipids, bilirubin, proteins;
(e) analytes of similar structure such as precursors, metabolites or medical conditions unrelated to the test condition including specimens negative for the assay but positive for a condition that can mimic the test condition.

• trueness (bias)

• precision (repeatability and reproducibility)

• accuracy (resulting from trueness and precision)

(a) Trueness of measurement

This Section shall provide information on the trueness of the measurement procedure and summarise the data in sufficient detail to allow an assessment of the adequacy of the means selected to establish the trueness. Trueness measures apply to both quantitative and qualitative assays only when a certified reference material or certified reference method is available.

(b) Precision of measurement

This Section shall describe repeatability and reproducibility studies.

• limits of detection and quantitation

• measuring range

This Section shall include information on the measuring range regardless of whether the measuring systems are linear or non-linear, including the limit of detection and describe information on how the range and detection limit were established.

This information shall include a description of specimen type, number of specimens, number of replicates, and specimen preparation including information on the matrix, analyte levels and how levels were established. If applicable, a description of any high dose hook effect and the data supporting the mitigation such as dilution steps shall be added.

• linearity,

• cut-off, (including determination of appropriate criteria for specimen collection and handling and control of known relevant endogenous and exogenous interference, cross-reactions)

This Section shall provide a summary of analytical data with a description of the study design including methods for determining the assay cut-off, such as:

(a) the population(s) studied: demographics, selection, inclusion and exclusion criteria, number of individuals included;
(b) method or mode of characterisation of specimens; and
(c) statistical methods such as Receiver Operator Characteristic (ROC) to generate results and if applicable, define grey-zone/equivocal zone.

3. Clinical Performance

• diagnostic sensitivity

the ability of a device to identify the presence of a target marker associated with a particular disease or condition.

• diagnostische specificiteit

the ability of a device to recognise the absence of a target marker associated with a particular disease or condition.

• positive predictive value

the ability of a device to separate true positive results from false positive results for a given attribute in a given population.

• negative predictive value

the ability of a device to separate true negative results from false negative results for a given attribute in a given population.

• likelihood ratio

the likelihood of a given result arising in an individual with the target clinical condition or physiological state compared to the likelihood of the same result arising in anindividual without that clinical condition or physiological state.

• expected values in normal and affected populations

4. Stability

• claimed shelf-life

This Section shall provide information on stability testing studies to support the shelf life that is claimed for the device. Testing shall be performed on at least three different lots manufactured under conditions that are essentially equivalent to routine production conditions. The three lots do not need to be consecutive. Accelerated studies or extrapolated data from real time data are acceptable for initial shelf life claims but shall be followed up with real time stability studies.

Such detailed information shall include:
(a) the study report including the protocol, number of lots, acceptance criteria and testing intervals;
(b) where accelerated studies have been performed in anticipation of the real time studies, the method used for accelerated studies shall be described;
(c) the conclusions and claimed shelf life.

• in-use stability

This Section shall provide information on in-use stability studies for one lot reflecting actual routine use of the device, regardless of whether real or simulated. This may include open vial stability and/or, for automated instruments, on board stability.

In the case of automated instrumentation, if calibration stability is claimed, supporting data shall be included.

Such detailed information shall include:
(a) the study report (including the protocol, acceptance criteria and testing intervals);
(b) the conclusions and claimed in-use stability.

• shipping stability

This Section shall provide information on shipping stability studies for one lot of devices to evaluate the tolerance of devices to the anticipated shipping conditions.

Shipping studies may be done under real and/or simulated conditions and shall include variable shipping conditions such as extreme heat and/or cold.

Such information shall describe:
(a) the study report (including the protocol, acceptance criteria);
(b) the method used for simulated conditions;
(c) the conclusion and recommended shipping conditions.