REGULATORY COMPLIANCE AND METHOD VALIDATION - Flow Cytometry in Drug Discovery and Development - page 240

A new approach to bridge the regulatory gap for human trials considered clinical
research is the proposal of GCLP recommendations. The British Association of
Research Quality Assurance (BARQA) wrote initial GCLP guidelines in 2003,
blending GCP trial conduct standards and GLP facility and procedural requirements
to create a framework for laboratory analysis in support of clinical trials [28].
Although drafted in a generic format, the goal of GCLP was to facilitate comparison
of laboratory data generated in global clinical research trials [29].
More specific GCLP recommendations were later put forth by the National
Institute of Allergy and Infectious Disease (NIAID) and PPD, Inc. to address data
comparability concerns in immunogenicity assays between phase I and II vaccine
studies conducted in global HIV trials [30, 31]. Guidelines specifically address flow
cytometry analyses including diagnosis of HIV-1 infection, blood processing im-
munogenicity, and cellular immunogenicity assays for trials supported by the
Division of Acquired Immune Deficiency Syndrome (DAIDS) [32]. These GCLP
guidelines embraced both research and clinical aspects of FDA compliance:
21CFR58 and 21CFR493. Recommendations from other accrediting agencies, such
as CAP and the International Organization for Standardization (ISO), were also
incorporated: CAP CLIA-based Laboratory Accreditation Program, CAP Accred-
itation to ISO 15189 Standard Program; ISO 15189 Quality Management and
Competence of Medical Laboratories; ISO 17015 Quality of Laboratory Data; and
ISO 17025 Requirements for Testing and Calibration [33-35].
ConsistentGCLPapplication in researchanddevelopment laboratorieswill provide
reliable andcomparabledata, paramount toa successful clinical trial. Thekeyelements
of GCLP in laboratory testing include organization and personnel, laboratory equip-
ment, testing facility operations, quality control program, verification of performance
specifications, records and reports, physical facilities, specimen transport andmanage-
ment, personnel safety, laboratory information systems, and quality management.
Conduct of clinical trials within the GCLP guidelines will harmonize clinical-trial
flow cytometry operations among multiple laboratories producing high-quality data
and ensure smooth transition of a compound in drug development [29, 31, 34].
12.3 METHOD DEVELOPMENT AND VALIDATION
FOR DRUG DEVELOPMENT
Flow cytometric assays in drug discovery and clinical development not only provide
valuable information pertaining to the population of cells targeted by the drug,
binding of drug to its receptors or ligands, and modulation of the antigen by the drug
but also contribute to the understanding of drug effects on cellular functions. Various
assays, such as immunophenotyping, apoptosis, activation, proliferation, cell signal-
ing, intracellular cytokines, and receptor occupancy are being extensively performed
in the drug development process utilizing different types of flow cytometers. Flow
cytometry is not only becoming more widely applied in a clinical diagnostic setting
for disease diagnosis and monitoring but also being used in biomarker research and
pharmacodynamic marker evaluation during drug treatment [36-39].