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Application of good clinical laboratory practice reduces risks to subject safety and data integrity.
Good clinical laboratory practice (GCLP) has been applied in clinical laboratory settings for well over a decade; however, the standards governing clinical laboratory compliance and the applicability to good clinical practice (GCP) have not been clearly defined. In many cases, sponsors and sponsor representatives have applied improper standards to the qualification of clinical laboratories and in doing so have risked the safety of clinical research subjects and the integrity of clinical research data.
NOEL HENDRICKSON/GETTY IMAGES
The intent of this article is to describe the appropriate application of GCLP in a GCP driven environment; introduce the basic concept of GCLP; differentiate and define GCLP regulatory and industry standards, and to describe the three categories of laboratory practices as they relate to clinical research. An introduction to the proper conduct of a clinical/medical laboratory quality audit through the application of GCLP will also be addressed.
The three categories of laboratory practice, which support clinical research are GCLP, good laboratory practice (GLP), and bioanlaytical laboratory practice. Significant distinctions exist in the application and scope of each category of laboratory practice and relate to differences in method validation, sample type, and utilization of results. Administration of these laboratory disciplines is accomplished through the application of the following regulatory requirements and standards (see also Table 1):
Table 1. The categories of laboratory practices and the corresponding requirements/industry standards.
GCLP regulation and accreditation standards define laboratory practices, which support human sample analysis and result reporting to medical professionals (e.g., physicians) for the purpose of diagnosis and/or treatment of patients or clinical research subjects. Typically, testing methods employed in support of GCLP activity represent government approved in-vitro diagnostic devices (e.g., US FDA approved and/or CE marked medical devices).
GLP regulations and guidance define laboratory requirements, which support non-human laboratory analysis for samples that are derived, primarily, from animal host systems (i.e., analysis of animal samples, which support non-clinical research studies).
Bioanalytical guidance defines laboratory practices, which support analysis of human research samples which are not intended to be reported to physicians for the purpose of diagnosis and/or treatment. Bioanalytical samples are typically used to support clinical research and allow the sponsor of a clinical research study to evaluate research driven parameters that may support the safety and efficacy of investigational products (e.g., PK, immunogenicity, and biomarker analysis). Bioanalytical data may also be submitted to regulatory agencies to further support protocol driven endpoints of investigational products, and in exceptional circumstances, may be used in the evaluation of clinical subjects. In the latter case, the sponsor must ensure that such bioanalytical methods are clearly presented during interactions with regulatory agencies and that regulatory submissions describe the intent of the sponsor to report bioanalytical results in a clinical setting.
In summary, GCLP applies to human samples for which results will be reported to physicians in support of diagnosis and/or treatment of patients or clinical research subjects; GLP applies to animal samples which support non-clinical studies; and bioanalytical analysis is applicable to human research samples for which results will generally not be reported to physicians for use in diagnosis and/or treatment of subjects.
One of the first documented standards describing GCLP was authored in 2003 by Tim Styles of the Clinical Committee of the British Association of Research Quality Assurance (BARQA), entitled "GCLP, A Quality System for Laboratories which undertake the Analyses of Samples from Clinical Trials." Additionally, the United States National Institute of Health Division of Acquired Immunodeficiency Syndrome (US NIH DAIDS) 2008, World Health Organization (WHO) 2009, and the Medicines and Health Care Products Regulatory Agency (MHRA) 2009, also published guidance documents in support of GCLP.10, 11, 12, 14
BARQA, DAIDS, WHO and MHRA documents were created to address a perceived gap in harmonization between laboratories supporting clinical research (and in turn GCP); however, these organizations neglected to recognize existing regulatory requirements and industry standards, which by definition characterized GCLP as an existing quality standard.
In consideration of this, it is important to acknowledge that GCLP regulatory requirements and standards have been applied in clinical laboratory settings for well over a decade and are well represented by US CLIA regulation 42 CFR 493, the CAP standards, and ISO 15189 standards.1, 2, 3, 4 These requirements characterize GCLP from the perspective of a quality-driven, top-down management controlled process and are the most frequently encountered clinical laboratory standards by sponsors of clinical research.
In the United States, CLIA licensure is mandated with CAP representing the majority of voluntary clinical laboratory accreditations. CLIA licensure is enforced by the US Center for Medicaid and Medicare Services (CMS). In addition, the CMS recognizes CAP accreditation of US clinical laboratories as meeting or exceeding CLIA requirements and, by virtue of this, CMS provides CLIA licensure to laboratories that have successfully attained CAP accreditation.
Within the European Union (EU), many countries either mandate medical (clinical) laboratory accreditation to ISO 15189 standards or will require medical laboratories to be accredited to ISO 15189 in the near future (e.g., ISO 15189 accreditation is required by medical laboratories in Germany and, as of January 2010, the Sanitary Safety of Health Products Agency (AFSSAPS) of France will require that all medical laboratories within France be ISO 15189 certified by 2012).
The United Kingdom's Clinical Pathology Accreditation (CPA) is also aligned both by reference and function to ISO 15189 requirements.13 The CPA accreditation is mandated for the National Health Systems (NHS) medical laboratories and is also offered as an optional accreditation to independent laboratories within the United Kingdom.
Globally, CAP and ISO 15189 clinical laboratory accreditations predominate; however, in recent years ISO 15189 has overtaken CAP as the leading accrediting organization of clinical laboratories. One reason for the success of the ISO 15189 GCLP standard can be attributed to the fact that ISO and CAP have aligned their efforts. The CAP, in addition to their own clinical laboratory accreditation program, now provides ISO 15189 accreditation services.
To emphasize the extent of clinical laboratory accreditation, an illustration of the global scope of CAP accreditation is presented in Table 2.
Table 2. In 1964 the first US laboratory was awarded CAP accreditation.
From a GCP industry perspective, the need to develop standards which support clinical laboratory auditing has become evident in recent years. Although clinical laboratory regulatory requirements and standards have been applied in clinical laboratory settings for many years (e.g., CLIA and CAP), the applicability of these standards to sponsors of clinical research utilizing clinical laboratory services has not been clearly defined.
In the arena of clinical research, sponsor audits of clinical laboratories have typically focused upon perceived GCP issues of relevance (i.e., can the laboratory manage a project, produce a result of analysis, and provide the sponsor with this result in a timely manner). While these aspects are important to GCP compliance, they do not effectively represent the comprehensive audit scope that must be considered when evaluating a clinical laboratory in support of clinical research.
In addition, due to poorly defined audit scope, many sponsor auditors have improperly evaluated clinical laboratory vendors by application of inappropriate regulatory standards (e.g., use of GLP regulations in a clinical laboratory setting rather than GCLP). It is important to note that sponsor ignorance of clinical laboratory requirements and poorly defined audit scope can have far reaching consequences and can directly impact subject safety and data integrity. It is, therefore, imperative that sponsors and sponsor representatives (i.e., CROs) clearly understand GCLP standards and application.
In order to define the appropriate scope of a clinical laboratory audit, the major phases of clinical laboratory analysis must be considered. These phases are defined by CLIA and ISO 15189, and referenced in the CAP checklists and include:4, 5, 6
The pre-analytical/pre-examination phase of clinical laboratory analysis represents all variables that can impact sample integrity prior to the analysis/examination phase. These variables include, but are not limited to the following: phlebotomy and sample collection methods, specimen transport, environmental control of shipping containers, specimen requisition and accessioning, analytical method and electronic system validation, sample storage, and sample containment vessels and interfering substances.
The analytical/examination phase of clinical laboratory analysis represents all variables that can impact sample integrity and analysis during the testing phase. These variables include, but are not limited to the following: preparation of slides, solutions, calibrators, controls, proficiency testing materials, reagents, stains, quality of water and other materials used in testing, references to manufacturer's test system instructions, package inserts and operator manuals, and identification of panic or alert values (as applicable).2, 3
The post-analytical/post-examination phase of clinical laboratory analysis represents all variables that can impact result reporting and follow-up. These variables include, but are not limited to: report formatting (i.e., electronic or paper formats which are associated with unique patient identifiers, laboratory identifiers, and identification of test reference intervals and normal ranges); review, approval, and release of result reports and corrected reports; verification of accurate and timely final report receipt; and post-analysis sample storage and result retention.
A failure of any one of these critical phases of clinical laboratory testing can significantly affect the integrity of a clinical result and, again, directly impact clinical subject safety and data integrity (Table 3).15, 16, 17, 18, 19, 20
Table 3. Failure in any phase of clinical laboratory testing can directly impact the integrity of results.
When planning a vendor qualification audit of a clinical laboratory, basic quality systems must be evaluated by an auditor with experience both in GCLP and GCP. The auditor must ensure that all clinical laboratory systems and testing phases meet the minimum requirements set forth by GCLP.
In addition to expertise in the application of GCLP and GCP requirements, an auditor must also be proficient in electronic system and software validation techniques. The majority of clinical laboratories use laboratory information management systems (LIMS) or laboratory information systems (LIS). LIMS/LIS systems must be assessed and this evaluation should include: review of validation summary reports and supporting data; system hardware and interfaces; system security, maintenance, back-up and restore capabilities; and data reporting, retrieval, and preservation capabilities.21, 22, 23, 24, 25, 26
The following is a list of critical clinical laboratory systems that should be included in the scope of a clinical laboratory audit:
As evidence to the complexity of scope, which defines a clinical laboratory audit, any one of the above categories could warrant an extensive discussion. This fact serves to emphasize that only auditors proficient in the application GCLP should perform such audits or, at the very least, less seasoned GCLP auditors should be directed by an experienced team lead.
Table 4. A list of acronyms utilized in this article.
As clinical research studies continue to expand globally, it is imperative that sponsor's of clinical research develop an acute understanding of the application of GCLP to clinical laboratory vendor qualification and oversight. Sponsors of clinical research must also recognize the inherent risks of not applying a comprehensive GCLP process and country specific mandates to the scope of clinical laboratory qualification and the direct impact that aberrant clinical laboratory results can have on GCP compliance.
Editor's Note: The term clinical laboratory has been used to describe a clinical/medical laboratory throughout this article.
Tobin C. Guarnacci, CQA, CBA, M(ASCP), President, CLINIQAL, 4104 24th Street, Suite 711, San Francisco, CA, USA. In Asia Pacific, CLINIQAL International, No. 82/37 Chang Khien, T. Chang Phuek, A. Muang, Chiang Mai 50300, Thailand, e-mail: email@example.com.
1. US Code of Federal Regulations Title 42, Part 493, "Clinical Laboratories Improvement Act of 1988 (CMS)," http://www.access.gpo.gov/nara/cfr/waisidx_04/42cfr493_04.html.
2. College of American Pathologists, "Accredited Laboratory Directory," http://www.cap.org/apps/ cap.portal?_nfpb=true&_pageLabel=accrlabsearch_page.
3. College of American Pathologists, "CAP History Timeline," http://www.cap.org/apps/cap.portal? _nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow& _windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=cap%2Finformation%2Ftimeline.html&_state=maximized&_pageLabel=cntvwr
4. International Standards of Operation, "Medical laboratories—Particular Requirements for Quality and Competence," ISO 15189 (2007), www.ISO.org.
5. Clinical and Laboratory Standards Institute (CLSI), http://www.clsi.org/.
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12. World Health Organization, "Good Clinical Laboratory Practice," (2009), http://apps.who.int/tdr/publications/tdr -research-publications/gclp-web/pdf/gclp-web.pdf.
13. Clinical Pathology Accreditation (CPA), http://www.cpa-uk.co.uk.
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15. Food and Drug Administration, Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance, (FDA, Rockville, MD 1996.
16. Code of Federal Regulations Title 21, Part 50, "Protection of Human Subjects," http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=50.
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18. US Code of Federal Regulations Title 21, Part 56, "Institutional Review Boards," http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=56
19. US Code of Federal Regulations Title 21, Part 312, "Investigational New Drug Application," http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=312.
20. US Code of Federal Regulations Title 21, Part 812, "Investigational Device Exemptions," http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=812.
21. US Department of Health and Human Services, "General Principles of Software Validation; Final Guidance for Industry and FDA Staff," (FDA, Rockville, MD, 2002).
22. International Organization of Standardization, "Quality Systems—Model for Quality Assurance in Design, Development, Production, Installation, and Servicing," ISO 9001:1994, http://www.iso.org/iso/catalogue_detail.htm?csnumber=16534.
23. International Organization of Standardization, "Software Engineering—Product Quality—Part 4: Quality in Use Metrics," ISO 9126: 2010, http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm?csnumber=39752.
24. D. Cowan, R. Gray, and B. Campbell, "Validation of Laboratory Information Systems," Archives of Pathology and Laboratory Medicine, (122) 239-244 (1998).
25. P. Valenstein, C. P. Treling, and R. D. Aller, "Laboratory Computer Availability. A College of American Pathologists Q Probes Study of Computer Downtime in 422 Institutions," Archives of Pathology and Laboratory Medicine, (120) 626-632 (1996).
26. CLSI, "Laboratory Automation: Communications with Automated Clinical Laboratory Systems, Instruments, Devices, and Information Systems; Approved Standard—Second Edition" NCCLS document, (21) 29,http://www.clsi.org/source/orders/free/AUTO03-a2.pdf.