REGULATORY COMPLIANCE AND METHOD VALIDATION - Flow Cytometry in Drug Discovery and Development - page 238

The internationally accepted principles of GLP were developed by the Organiza-
tion for Economic Co-operation and Development (OECD), outlining principles and
quality assurance standards for nonclinical laboratory research performed by its
member countries in the Dangerous Substances Directive 67/548/EEC [9]. OECD
also issued a supplemental advisory document to address the application of GLP
principles to the uniquely different characteristics of in vitro systems: positive and
negative controls and benchmarks; care and maintenance of test systems; and quality
assurance monitoring [10]. Following the extensive guidelines of GLP is often costly
and resource intensive; however, research not conducted under these restrictions may
render data inadmissible in support of a new drug filing.
Laboratories in compliance with GLP regulations are globally recognized as
promoting trustworthy data supporting compounds for government regulation,
although some international requirements differ in proof of compliance [11]. Some
countries require laboratory accreditation for claiming GLP compliance; however,
the United States does not have a GLP accreditation program in place [12]. In all
cases, compliance with GLP requires extensive documentation and laboratory
audits.
To supplement GLP regulations, the FDA released guidance for bioanalytical
method validation in support of preclinical and clinical pharmacology studies [13].
The document provides general recommendations for performing precision, accu-
racy, selectivity, sensitivity, reproducibility, and stability assessments required in
regulated method validation to ensure it is suitable and reliable for its intended
application. In addition, this guidance describes the level of validation required for
new and modified methods: full validation, partial validation, and cross validation.
The provisions and acceptance criteria are sometimes difficult to directly apply to
novel biomarker assays; nonetheless, the general recommendations can be modified
as applicable to flow cytometric methods [14].
12.2.2 CLIA
In the United States, all testing performed on human specimens used for patient
diagnosis, disease monitoring, health assessment, and subsequent decision making is
subject to CLIA regulations. Although CLIA actually does not apply to clinical
research testing, during clinical trials safety parameters and patient enrollment testing
are likely to be conducted in CLIA-certified laboratories. The reason for this is two-
fold: one is that data will be reported in real time to the clinical investigator, and thus
might be used for patient care, and the other is that CLIA-certified laboratories abide
by high-quality standards to positively impact data reporting [14]. The CLIA
regulations define a quality system for laboratory testing to ensure the accuracy and
reliability of results. They apply to all hospital, independent, and physician office
laboratories performing analyses on human samples. Specific operational require-
ments are included for personnel credentials, continuing education, proficiency
testing, method performance specifications, and reference range requirements. All
aspects of laboratory operation and result reporting required under CLIA authority are
outlined in 42CFR493. The Division of Laboratory Services, under the Center for