Biomedical Engineering Reference
In-Depth Information
choice could be to conduct a separate non-GLP study to define the need to validate a
flow cytometry assay for legitimate inclusion in a (subsequent) GLP study.
As lead compounds proceed to early clinical trials (phase I/II), “fit-for-purpose”
validation is regarded by most to be sufficient provided the data are not diagnostic or
representative of a safety measurement (in which case CLIA standards become
enforceable). In later trials (phase III registrational studies and phase IV studies of
commercialized products), Good Clinical Laboratory Practice (GCLP) and Clinical
Laboratory Improvement Amendment (CLIA) guidelines are applied, where deci-
sions reflect the intended utility of the data. So, a flow cytometric method may be used
in more than one stage of the drug development process with the proviso that
revalidation is exercised to meet regulatory requirements at the next stage [1].
Although validation and regulatory requirements may evolve as compounds progress
to filing, the goal in all cases is to achieve reliable results that are calibrated and
appropriate for the intended application of the data [2, 3]. Assay development,
whether on a flow cytometer or other platform, is an iterative process where both the
regulatory oversight and the need to formally document the reliability of the
measurements are tethered to the context of the effort.
It cannot be understated that a key consideration in application of flow cytometry
assays in the biopharmaceutical industry is the intended purpose of the assay.
Exploratory data are sometimes not subject to the high precision and accuracy
requirements of clinical data; clinical standards may not be rigorous enough to
support identification and qualification of a new biomarker [4]. There is a very
important distinction to bemade, however, when assays are defined by the exploratory
moniker in the clinical setting because in the true (clinical) sense an exploratory assay
is one where the data are not a clinically validated end point or a surrogate marker of
efficacy. Stated another way, “exploratory” sometimes means that the assay is the
subject of scientific exploration, but in other cases an alternative definition that
considers the measurement to represent a clinical end point of nonestablished
meaning is intended. Although those in the field have this awareness and compensate
for the potential confusion the terminology may bear, invention of a more precise
terminology would be of benefit to all.
12.2.1 GLP
GLP guidelines were developed in the 1970s frombest practices to improve reliability
in toxicology data submitted to the U.S. Food and Drug Administration (FDA) [7].
The original documents werewritten for animal studies; however, revisions have been
published to fit the unique characteristics of nonanimal-based in vitro methods, such
as cell culture systems [5, 8]. The specific guidelines of GLP applicable to all aspects
of nonclinical laboratory studies are outlined in Title 21 Part 58 of the Code of Federal
Regulations (21CFR58). It provides an outline to justify a testing environment and its
operations addressing facilities, personnel, equipment, standard operating procedures
(SOPs), assay controls, records, and reporting requirements. In addition, GLP
compliance requires an independent quality assurance component including formal
internal audits.
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