Translating Biomarker Discovery into Companion Diagnostics through Validation and Regulatory Consideration - Genomic Biomarkers for Pharmaceutical Development - page 170

ideally the ultimate commercial distributor should appropriately control all aspects of the
assay. If multiple vendors are used to source different portions of the assay, then risk mitiga-
tion and identification of alternative vendors can become quite complex.
7.4.3 Assay Validation
A key component of any assay is the ability to demonstrate that it provides reliable and
accurate assessment of the analyte of interest. In order to demonstrate that this is true, the
assay must by analytically validated. While the components of an analytical validation
may vary depending on the type of assay, a systematic approach to validation is required
to ensure that all necessary components are addressed. The analytical validation of a device
can be broken into two distinct steps. First, the performance characteristics of an assay are
established during assay characterization or qualification. This process allows for the identi-
fication of characteristics and standards that the assay must meet in the second step, formal
analytical validation. The actual validation tests the assay in a realistic setting to assess the
device's ability to meet the specifications laid out in the assay characterization.
7.4.3.1 Assay Characterization or Qualification
Assay qualification and characterization are keys to a successful device analytical valida-
tion, as this step lays the groundwork for the formal validation procedures. Often an assay
is developed or utilized in a research setting during hypothesis generation and following
the assessment of the predictive value of the proposed companion diagnostic in early tri-
als. This logistical issue leads to an insufficient understanding of the assay's performance
characteristics prior to its migration to a more clinically applicable version. In addition, suf-
ficient changes to a research assay to accommodate a better clinical design necessitate that
performance characteristics will need to be redefined. During assay performance characteri-
zation, the assay should be subjected to conditions outside of what is expected in the clini-
cal setting. This testing at the extreme ends of expected conditions allows the investigator
and assay developer to assess the breaking points of the assay and evaluate a reliable range
of performance. To ensure appropriate criteria setting for all aspects of validation, each
of these aspects should be thoroughly assessed. A complete list of parameters to assess is
dependent upon each assay, and a more thorough description of the validation parameters
is covered in the following section.
7.4.3.2 Analytical Validation of a Companion Diagnostic
The analytical validation of a companion diagnostic can be a complicated process, but
is simplified utilizing a systematic approach to its completion. The aspects of an analytical
validation are defined in the draft Drug Diagnostic Co-Development Concept Paper [3] as
the following:
1. Studies to show that test performance can be applied to expected clinical use as
a diagnostic with acceptable accuracy, precision, specificity and sensitivity: A
demonstration of the device's ability to accurately and reproducibly detect the analyte(s)
of interest at levels that challenge the analyte concentration specifications of the device
should be provided (see point 3 below).