Biology Reference
In-Depth Information
2.
Sample requirements: All relevant criteria and information on sampling collection,
processing, handling and storage should be clearly outlined.
3.
Analyte concentration specifications: It is recommended that, when appropriate, a range
of analyte concentrations that are measurable, detectable, or testable be established for
the assay.
4.
Cut-off: It is recommended that there be a clear rationale to support an analytical
characterization of cut-off(s) value(s).
5.
Controls and calibrators: All external and process controls and calibrators should be
clearly described and performance defined.
6.
Precision (repeatability
/
reproducibility): All relevant sources of imprecision should be
identified and performance characteristics described.
7.
Analytical specificity (interference and cross reactivity studies): Cross-reactive
and interfering substances should be identified and their effect on performance
characterized.
8.
Assay conditions: The reaction conditions (e.g., hybridization, thermal cycling
conditions), concentration of reactants, and control of nonspecific activity should be
clearly stated and verified.
9.
Sample carryover: The potential for sample carryover and instructions in labeling for
preventing carryover should be provided.
10.
Limiting factors of the device should be described, such as when the device does not
measure all possible analyte variations, or when the range of variations is unknown.
While accurate descriptions of the methods required for proper analytical validation of
a drug or biologic are clearly defined in FDA guidance
[22]
, there are not clear steps for the
device navigation process, and as such, the topic will be addressed here. For the purpose of
description, we will treat the criteria listed here as a checklist of tasks to be completed, and
describe each step in detail in the following sections.
7.4.3.3 Studies to Demonstrate Accuracy, Precision, Specificity, and Sensitivity
Appropriate studies must be designed to accurately assess the reliability and reproduc-
ibility of a device. This assessment requires two critical components. The first of these is the
production of a synthetic target to assess the ability of the assay to detect the specific analytes
involved. For example, in the case of gene expression-based diagnostic devices, this surro-
gate for the analyte of interest in a biological specimen is an
in vitro
transcribed synthetic tar-
get generated in a plasmid. These surrogates serve a number of purposes in validation. The
surrogate can assess that ability of a particular assay for its specificity to a particular analyte.
Also, the surrogate can assess the limits of quantitation and detection of each assay by accu-
rate dilution to known input concentrations. Often times these synthetic analytes can also
be utilized as run controls for the final product release. The second component necessary for
successful determination of accuracy and precision is the analytical reference method. The
analytical reference method is a previously defined method capable of assessment of the ana-
lytes of the assay in a similar or superiorly sensitive fashion yet utilizing different biological
and chemical methods. Often the analytical reference method is referred to as the gold stand-
ard. As an example, a gene expression-based microarray companion diagnostic would utilize
qPCR as an analytical reference method as it provides similar data from an equally or more
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