Biology Reference
In-Depth Information
sensitive chemistry. This allows for the assessment of accuracy as required in this section.
Not all methods will have an easily identified analytical reference method. In these cases it
becomes quite difficult to assess the accuracy of a diagnostic device when there is no true
answer against which to compare results. While assay performance characteristics of indi-
vidual assays can be established utilizing controls, it is important that the validation itself is
carried out with patient samples identical to the intend-to-treat population if at all possible.
This will be practical data that reviewers can utilize to assess the performance of the device
in a real world setting. Analytical studies utilized here include specificity, accuracy, precision,
and robustness.
7.4.3.4 Sample Requirements
There must be clear criteria laid out for the collection and storage of all sample types uti-
lized for the device. This includes collection methodology, stabilization methods, appropriate
storage conditions, and stability of the analytes at the stated storage. Ideally a method will be
employed that has been previously cleared. In utilizing a previously cleared sample collec-
tion and extraction product, the storage conditions will have been previously defined. Also
of note on this aspect of analytical validation is that the sample type should be stable in order
to accommodate the test. At a minimum, samples will have to be stable from the collection
time through shipping to the clinical testing site. The stability of the samples at the stated
storage conditions will need to be demonstrated to achieve successful validation.
7.4.3.5 Analyte Concentration Specifications
Upon establishment of assay performance characteristics relative to a synthetic target in
assay qualification, further study during validation is required to understand the potential
and ideal range of input from a true clinical sample. First, a significant history of established
data on the expected yield of the analyte helps lay the groundwork and ensure that sufficient
material will exist to run the device. This range of expected values can then be expanded
upon to push the limits of the assay and applied to the studies required in this section. Studies
encompassed by this portion of validation include establishment of upper limit of detection
and quantitation, lower limit of detection and quantitation, linearity, and range. Data gained
from these studies will help determine if additional clinical sample concentration or clinical
sample dilution methods will be necessary for the sample prior to analysis. To further address
the earlier ease of use section, ideally the assay will accommodate a range of expected concen-
trations and yields to avoid additional dilution or concentration of the samples.
7.4.3.6 Cut-off Establishment
The establishment of an assay cut-point is a key element of the device and determines how
robust the performance will be. The identification of a strong cut-point utilizing the training
set to assign the threshold and test set, to evaluate the accuracy, has been described previously
in this chapter, and thresholds that clearly partition the scores from the patient populations
allow the determination of a robust predictive value of the device. Positive or negative shifts
to the cut-point will shift the predictive value in either positive or negative favor, which can
modify the preferred patient profile. For example, the profile of patients targeted from an
assay that has a high negative predictive value based on concordance between low test scores
and negative clinical outcome and a more modest positive predictive value based on high test
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