Returning Individual Research Results to Participants Guidance for a New Research Paradigm (2018) / Chapter Skim
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3 Laboratory Quality Systems for Research Testing of Human Biospecimens
3 Laboratory Quality Systems for Research Testing of Human Biospecimens
Pages 93-146
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From page 93... ...
While the committee does not expect all research laboratories to operate under a single quality standard, the lack of certainty about the research result validity is a barrier to the return of research results. Using appropriate quality processes in scientific research will be important to ensure the validity of individual research 1 Quality management systems (QMSs)
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From page 94... ...
It highlights the total research testing process, starting with the identification of a research question followed by an investigator selecting the tests best suited to address the hypothesis; then sample collection, transport, and processing; analysis and interpretation; and finally, showing how the result can influence the development of new hypotheses or even participant care. Rigorous control measures are required throughout the pre-analytical phase to avoid errors associated with specimen handling and identification, which would result in additional errors downstream in the analytical and post-analytic phases (LabCE, 2018)
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From page 95... ...
In fact, the testing done in clinical research can affect clinical decision making or generate evidence used to gain Food and Drug Administration (FDA) approval of new drugs or devices, and therefore this testing is often performed in the regulated environment of the clinical laboratory, where protocols are more fixed and laboratory quality assurance processes are more stringent.
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From page 96... ...
This type of risk is ameliorated, although not completely avoided, in the case of clinical test results because of processes in clinical laboratories that are in place to reduce the likelihood of mislabeling or other errors and to otherwise ensure the validity and quality of individual clinical test results (Agarwal, 2014)
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These quality standards required for clinical laboratories were established by the Centers for Medicare & Medicaid Services (CMS) to protect patients.
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One challenge with research results is that the AV and CV of the tests are not always known, even when the tests are performed under a QMS; indeed, establishing AV or CV may in fact be one of the purposes of a given research study. Establishing Analytic Validity Methods for establishing the AV of a test may include (Jennings et al., 2009; NASEM, 2017a)
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From page 99... ...
. This includes detailing the controls to be run with each test or batch; the steps in the testing process, including the exact quantities of reagents and the timing of incubations or other steps; the validation of new lots of reagents; the documentation of testing steps each time that the test is run; and reporting requirements.
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From page 100... ...
LABORATORY QUALITY SYSTEMS TO INCREASE CONFIDENCE IN THE VALIDITY OF RESEARCH RESULTS Research and clinical laboratories are held to different regulatory standards because of their different recognized purposes (Burke et al., 2014; Clayton and McGuire, 2012)
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From page 101... ...
CLIA The CLIA requirements for clinical laboratories ensure the quality and integrity of clinical testing, accurate documentation of test validation and test performance, and the comparability of test results regardless of the personnel conducting the testing or the test location.7 To achieve CLIA certification, laboratories are required to have various systems in place to meet the standards for AV (American Academy of Family Physicians, 2018) ,8 but the regulations do not prescribe the design or implementation of those systems.
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. Alternative methods for proficiency testing can be used by clinical laboratories when external proficiency testing is not available.
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. The College of American Pathologists and the New York State Department of Public Health are two examples of accrediting organizations that have quality standards for NGS tests and other more complex testing methods (Aziz et al., 2014; New York State Department of Health, 2016)
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From page 104... ...
As alternatives to pursuing CLIA certification, investigators can outsource testing to a CLIA-certified laboratory, can have only those results that will be returned retested in a CLIA-certified laboratory for verification prior to disclosure, or can build or modify an existing laboratory or core facility to make it CLIA ompliant. c Not all clinical laboratories will have the resources to validate and perform research tests, and sometimes no equivalent test exists, in which case other clinical tests may not be available to assess the significance of the research result.
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From page 105... ...
.13 Consequently, adopting such standards may present hurdles similar to CLIA certification for investigators who want to return research results. For an investigator or institution considering implementing a recognized laboratory quality standard, many factors should be considered, such as legal obligations to obey state and federal laws, the type of laboratory, the type of testing, cost, institutional support, training, and other variables.
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. By returning the research result with this qualification, the investigator is not providing information for use in clinical decision making on the basis of the research test alone.
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From page 107... ...
CONCLUSION: When individual research results are intended for use in clinical decision making, tests must be performed in laboratories that are CLIA certified. CONCLUSION: When individual research results are not intended for use in clinical decision making in a study protocol, CLIA certification may not be an appropriate or necessary mechanism to ensure that research test results are of sufficient quality to permit their return.
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From page 108... ...
. However, the widely reported concerns regarding the lack of reproducibility in science may drive changes in the requirements for research laboratories and motivate the development of quality standards or the training of PIs in basic quality management (Begley et al., 2015; Calabrese and Palm, 2008; Collins and Tabak, 2014; Davies et al., 2017; Loew et al., 2015; McNutt, 2014; NIH, 2017b; Titus and Bosch, 2010)
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From page 109... ...
2) Several ongoing initiatives in Europe are aimed at producing guidance and recommendations to assist investigators in meeting quality management essentials (EQIPD, 2017; PAASP, 2018b)
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110 TABLE 3-1 Quick-Reference Biospecimen Reporting for Improved Study Quality Summary/Checklist: Tier 1 Items to Report If Known and Applicable DATA ELEMENTS EX AMPLES • Biospecimen type Serum, urine Solid tissue, whole blood, or another product derived from a human being • Anatomical site Liver, antecubital area of the arm Organ of origin or site of blood draw • Disease status of patients Diabetic, healthy control Controls or individuals with the disease of interest • Clinical characteristics of patients Premenopausal breast cancer patients Available medical information known or believed to be pertinent to the condition of the biospecimens • Vital state of patients Postmortem
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From page 111... ...
Alive or deceased patient when biospecimens were obtained • Clinical diagnosis of patients Breast cancer Patient clinical diagnoses (determined by medical history, physical examination, and analyses of the biospecimen) pertinent to the study • Pathology diagnosis HER2-negative intraductal carcinoma Patient pathology diagnoses (determined by macro- and/or microscopic evaluation of the biospecimen at the time of diagnosis and/or prior to research use)
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TABLE 3-1, Continued 112 The make-up of any formulation used to maintain the biospecimens in a nonreactive state • Storage temperature −80°C, 20°C to 25°C The temperature or range thereof at which the biospecimens were kept until distribution/analysis. • Storage duration 8 days, 5–7 years The time or range thereof between biospecimen acquisition and distribution or analysis • Shipping temperature −170°C to −190°C The temperature or range thereof at which biospecimens were kept during shipment or relocation • Composition assessment and selection Minimum 80 percent tumor nuclei and maximum 50 percent necrosis Parameters used to choose biospecimens for the study SOURCE: Moore et al., 2011.
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From page 113... ...
. But while this would improve research, it is important to note that any results that were to be used in clinical decision making in a study protocol would still need to be generated in a CLIAcertified laboratory in order to protect patient safety.
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, provides scientific and technical advice and guidance to the Department of Health and Human Services (HHS) related to improvement in clinical laboratory quality and laboratory medicine practice, as well as revision of the CLIA standards.
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. A central element of established quality management systems, such as CLIA, is a method for evaluation and external accountability to demonstrate that quality standards are being met by a laboratory.
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Implementing this type of review process will likely require training and funding for IRBs and their institutions as IRBs may not have the necessary expertise to review laboratory quality. When expertise in quality essentials is lacking, institutions will need to hire staff with the appropriate expertise, solicit training in quality management practices for their current staff, consult with an external advisor with expertise in quality practices, or work with scientific review committees so that they are able to review laboratory practices.
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In addition to the quality practices of a laboratory, the characteristics of the tests being used will be important for IRBs to consider. Tests in the development phase (intended for either research use or clinical use)
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. In addition, numerous documents exist that may provide guidance to laboratories considering the adoption of quality practices.
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. While not every one of these elements may be essential in every research setting, these factors are the minimum to be considered in the development of the research quality management system.
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• Data quality management (source documentation and electronic records) , assessment of reporting system.
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As noted in Chapters 2 and 4, participants have the right to request their results, and when individual research results are offered, participants have the right to decide whether to receive or to share their results. CONCLUSION: For investigators conducting research testing on human biospecimens, the adoption of an externally accountable quality management system would improve confidence in result validity and help ensure that the results returned to participants are of high quality.
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From page 123... ...
This flowchart is also applicable to a situation in which an investigator has an unanticipated result and is considering whether to return it to a participant. CLIA = Clinical Laboratory Improvement Amendments of 1988; DRS = designated record set; HIPAA = Health Insurance Portability and Accountability Act of 1996; NIH = National Institutes of Health; QMS = quality management system.
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From page 124... ...
Allowing research laboratories to return results will not affect the conduct of clinical laboratories or investigators who will generate results for clinical decision making in the study protocol, as the committee emphasizes that it is of the utmost importance that tests used for clinical decision making need to be performed in a CLIA-certified laboratory to protect participant safety. ADDRESSING RESOURCE AND INFRASTRUCTURE NEEDS IN RESEARCH LABORATORIES TO ENABLE RETURN OF HIGH-QUALITY INDIVIDUAL RESEARCH RESULTS Given that few research laboratories currently operate under a QMS with external accountability, significant investment in infrastructure will be needed in order to substantially increase the number of laboratories that meet quality standards necessary for the return of individual research results to participants.
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From page 125... ...
. Specifically, the development of such systems requires commitment and investment on the part of the investigators, buy-in from staff and faculty across all levels of the organization, extensive training in quality practices, and the commitment and support of general management, the department, or the institution (Vermaercke, 2000)
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From page 126... ...
Quality management systems have been shown to make work more efficient, facilitate the training of new staff, improve reproducibility, increase p atient safety, and enhance data integrity (Davies, 2013; Global Biological Standards Institute, 2013)
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From page 127... ...
COMPETENT PERSONNEL SAFETY REQUIREMENTS REAGENT TRACEABILITY (TO NIST TRAINING PROGRAM AND ONGOING CONTINUING EDUCATION STANDARD) AND MANAGEMENT CONTINUING EDUCATION METHOD AND PROCESS SECURE INFORMATION, DATA RECURRENT AND SECURE VALIDATION AND VERIFICATION MANAGEMENT AND ARCHIVE QMS FUNDING ACCREDITATION OR CERTIFICATION COSTS BIOREPOSITORY EQUIPMENT FIGURE 3-3 Costs, infrastructure, and resources needed to implement a quality management system.
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From page 128... ...
, it would be prudent for institutions to begin initial groundwork intended to support investigators as they work to adopt the laboratory quality practices necessary for return of individual research results. This may include providing training programs in quality management for investigators, assisting
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From page 129... ...
ACADEMIC GOVERNMENT & JOURNALS & INDUSTRY & LABORATORIES & NONPROFIT PROFESSIONAL INVESTORS INSTITUTIONS FUNDERS SOCIETIES • Ensure best practices • Reduce target validation • Facilitate grant review • Facilitate peer-review incorporated into and development failures process process research process • Improve translateability • Optimize use of financial • Protect reputation • Produce more and commercialization of resources reproducible results discoveries • Decrease misinformation • Protect reputation • Decrease misinformation • Enhance collaboration • Improve public with academia • Improve public perception of life science • Protect reputation perception of life science research • Improve return on research • Enhance collaboration investment with industry • Optimize use of funds STANDARDS = REPRODUCIBILITY MORE EFFICIENT USE OF RESOURCES AND TIME PROTECTION OF REPUTATION MORE FAVORABLE PUBLIC OPINION OF RESEARCH FIGURE 3-5 Systemic benefits of standards. NOTE: This figure, developed by the Global Biological Standards Institute, highlights the fact that "research standards can be a unifying driver of quality improvement efforts and have the potential to benefit all stakeholders." 129 SOURCE: Global Biological Standards Institute, 2013, p.
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From page 130... ...
. Other institutional responsibilities may include • educating laboratory leadership and other laboratory staff about QMS expectations; • establishing platforms, templates, and access to expert consultants to evaluate and assess investigators' current level of quality management practices, advise the IRB, and implement quality standards; • developing a system for laboratory inspection to support compliance with the external review of quality standards; and • advising the investigators, IRBs, and institution as to the required compli ance with the QMS, which has implications for the potential alidity of v research results and the ability to return research results to participants.
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From page 131... ...
; B. adopting the externally accountable quality management system for research laboratories once established for relevant laboratories (see Recommendation 2) ; or C. ecoming CLIA certified or facilitating access to core, affiliated, b or third-party CLIA-certified laboratories for sample testing, re testing, or a confirmatory testing process when research results are for use in clinical decision making in a study protocol.
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From page 132... ...
The quality of the research results will be a crucial factor to be weighed as investigators and institutions consider whether to return results to participants, but it is only one element in the decision-making process. The next chapter addresses two additional dimensions, value and feasibility, that will help investigators make decisions on what to return, and it describes the need for a plan and process that includes engaging participants and communities in making these determinations.
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From page 133... ...
ORGANIZ ATIONS 15189 STANDARD (NY) STANDARD a External Quality Control External inspections required ✓ ✓ ✓ External inspections voluntary ✓ Participation in proficiency testing from an approved tester required for regulated ✓ ✓ ✓ ✓ analytes Alternative performance assessment required for ✓ ✓ ✓ ✓ unregulated analytes 133 continued
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ORGANIZ ATIONS 15189 STANDARD (NY) STANDARD a Internal Quality Control Internal quality control checks required ✓ ✓ ✓ ✓ ✓ Documentation describing policies and procedures necessary to assure the quality ✓ ✓ ✓ ✓ ✓ of test results Methods, supplies, equipment, and testing are appropriate to provide results within stated performance specifications and ✓ ✓ ✓ ✓ ✓ type and volume of testing Requirements for specimen collection ✓ ✓ ✓ ✓ ✓ Established and reviewed procedures for specimen transport to and from reference laboratories (timing, record ✓ ✓ ✓ ✓ ✓ keeping, environmental conditions, communications)
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TABLE 3-2, Continued 136 CLIA NON WAIVED (HIGHLY CLIA COMPLEX ACCREDITATION ISO CLIA EXEMPT STATE VOLUNTARY ✓= REQUIRED LABOR ATORIES)
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ORGANIZ ATIONS 15189 STANDARD (NY) STANDARD a Personnel are trained, qualified, and there is sufficient staff for ✓ ✓ ✓ ✓ ✓ the work required Qualified laboratory director (a role with responsibility over d the administrative oversight of ✓ ✓ ✓ ✓ ✓ the laboratory)
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From page 138... ...
A research laboratory voluntarily adopts a research quality management system that applies to research activity throughout the research life cycle. ᵇ For CLIA this includes a "Quality assessment system to monitor, assess, and correct problems, review the effectiveness of corrective actions, revise SOPs to prevent reoccurrence, and discuss QA reviews with appropriate staff." c This includes the need for written, clear, and explicit delegation of responsibilities by the laboratory director to individuals qualified to assume those duties.
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defines the clinical laboratory director as the individual responsible for administration of the technical and scientific operation of a clinical laboratory or blood bank. • 10 NYCRR Section 58-1.2(a)
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From page 140... ...
2017. Laboratory quality assurance and standard ization programs.
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clinical laboratories? Clinica Chimica Acta 346(1)
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2012. Assuring the quality of next-generation sequencing in clinical laboratory practice.
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2017. A model for the departmental quality management infrastructure within an academic health system.
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2016. Quality management.
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. Scientific Working Group on Quality Practices in Basic Biomedical Research.
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2011. Laboratory quality managment system: Handbook.
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