TY - JOUR
AU - Somers,, Toni
AB - Abstract Objectives We introduce regulatory terms, definitions, and the Quality System Regulation as proposed by the US Food and Drug Administration in the 2014 draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests and explore medical device requirements applicable to a laboratory environment to design, develop, and validate laboratory developed tests (LDTs). Methods We performed nine interviews with laboratory professionals to explore concerns and challenges regarding the draft, translated the results into operational factors, and surveyed professionals to test the factors that would comprise a regulatory quality management system framework. Results Nine interviewees and 35 survey respondents shared concerns of risk classification, process validation, patient safety, and general ambiguity regarding the proposed requirements for development of LDTs. Conclusions Respondents agree that a regulatory quality management system is needed in laboratories that develop LDTs, but the translation and method for design control to a clinical laboratory do not exist. As a result, laboratories are taking the wait-and-see approach. Contemporary technological advances in laboratory medicine have led to a category of laboratory diagnostics known as laboratory developed tests (LDTs). LDTs are defined as a subset of in vitro diagnostics (IVDs) that are “intended for clinical use and designed, manufactured and used within a single laboratory.”1 In recent years, the US Food and Drug Administration (FDA) has identified problems with several high-risk LDTs and has cited concerns that “patients could initiate unnecessary treatment, delay or forego treatment altogether.”1 In addition to the FDA, other governmental agencies and private organizations have challenged the validity, accuracy, oversight, and safety of LDTs. The FDA has now proposed requiring “all in-vitro diagnostic (IVD) tests intended for use in drug or biologic therapeutic decision-making be held to the same scientific and regulatory standard” as medical device firms.2 Since medical device development is held to a stringent and lengthy regulatory approval process, there is significant apprehension regarding the potential for undue delays in test development and patient access should LDTs be held to the same standard. Unlike the medical device industry, which is subject to the requirements of the FDA, clinical laboratories are under the jurisdiction of the Centers for Medicare & Medicaid Services (CMS) and the Clinical Laboratory Improvement Amendment (CLIA). The FDA has proposed that laboratories adopt a formal risk-based classification and approval process, quality system regulation (QSR), and a formalized design control structure, as described in its 2014 draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests.1 In this draft, the FDA proposes directives that are currently not mandated by CLIA or any other regulatory agency regarding laboratory oversight. Following a period of public comment, the FDA announced, in a Discussion Paper dated January 13, 2017, that it was considering possible alternatives to the original framework proposal.3 Laboratories continue to struggle to understand the implications of this additional regulatory oversight and their responsibility to comply in the event the draft guidance becomes policy. In addition, for those laboratories licensed by the New York State Department of Health (NYSDOH), the Wadsworth Center’s Clinical Laboratory Evaluations Program (CLEP) has recently adopted a three-tiered, risk-based review and approval policy for all LDT submissions, effective November 14, 2016. Risk stratification is based on an algorithm guided by three criteria: (1) well-established method, (2) key determinant of care assessment, and (3) the potential for patient impact.4 It is interesting to note that in its recent Discussion Paper, the FDA suggests the possible use of third-party collaborators, including the NYSDOH CLEP for review of LDTs. The FDA indicates that it is “exploring accepting NYSDOH review in lieu of its own.”4 Motivation for the Research The motivation for this research is to educate the laboratory community pertinent to LDTs by introducing terms, definitions, and regulatory requirements and discuss the QSR as proposed by the FDA. We compare the requirements of the 21 CFR 820 with the recommended Clinical Laboratory Standards Institute (CLSI) 12 Quality System Essentials (QSEs) for laboratories to understand how these principles may be incorporated and translated into laboratory processes that align and support the QSR. We also explore “design control” and discuss how these requirements for the medical device industry may be applicable to laboratory testing. We conducted interviews with laboratory professionals to gain an understanding of their concerns regarding the FDA draft guidance and translated that feedback into operational factors relevant for the development of a robust quality management system. Finally, we tested the factors for functionality, agility, and usefulness through a survey and propose the design of a framework to assist laboratories prepare in the event the 2014 draft guidance becomes a policy. Contribution This article contributes to the discussion about LDTs by serving as a proactive call for action by educating laboratory professionals and providing the impetus to move from a wait-and-see approach to insight, knowledge, and clarity that encompass the many facets of LDTs. We construct a means to collect substantiated data regarding the needs and gaps in laboratories and propose translation of those objectives into a vocabulary familiar to laboratorians. Finally, we translate and validate functionality and usefulness of strategic factors for design of a robust regulatory quality management system (QMS) by voice of the customer. Background The literature provides a rich background regarding the history of LDTs. The FDA, other governmental agencies, and private firms have challenged the validity, accuracy, oversight, and safety of laboratory testing. In 2008, Genentech, a private medical device manufacturer firm of oncologic pharmaceuticals and laboratory reagents, disputed laboratories or other companies selling LDTs or making statements without sufficient scientific evidence to support such claims.5 Genentech petitioned the FDA to “require all in-vitro diagnostic (IVD) tests intended for use in drug or biologic therapeutic decision-making be held to the same “scientific or regulatory review.”5 Since 2008, the FDA has identified problems with several high-risk LDTs; however, many organizations have objected to the FDA’s oversight of LDTs, including the American Hospital Association, the American Cancer Institute, and the American Clinical Laboratory Association (CLA). The American Medical Association has stated that “the FDA proposal will add an additional layer of regulatory requirements which may result in patients losing access to timely lifesaving diagnostic services and hinder advancements in the practice of medicine.”6 Certain professional organizations argue that the FDA lacks jurisdiction over LDTs, and the CLA has argued, “The FDA requirements will stifle innovation and slow patient access to critical diagnostics.”6 Moreover, the academic laboratories, if held to the 21 CFR 820 standard, may be required to perform clinical trials for each new genetic test developed. This process would require additional resources, and as explained by Evans and Watson,7 “Laboratories have insufficient resources to meet the proposed requirements and would essentially be precluded from developing or even improving tests in response to patient needs, clinician demands and changing technology.” The FDA was given oversight and authority over in vitro diagnostic medical devices in 1976; however, regulatory oversight for laboratories remains with CLIA.2,8 Regulatory Overview CLIA In this section, we highlight some of the important regulations that have led to the current framework governing LDTs. First, we discuss CLIA, the medical device amendment, and the FDA quality system regulations, and then we compare how those regulations differ from laboratory accreditation. The clinical laboratory has undergone progressive regulation over the past several decades, with key milestones depicted in Figure 1 . The current regulatory framework has evolved from the CLIA of 1967 and 1988 and is enforced under the direction of the CMS. The initial intent of the CLIA 1967 amendment was to establish licensing requirements for laboratories across state lines; however, the legislation for CLIA '88 was established to update requirements, implement performance measures, and add personnel responsibilities. Since 1988, the amendment has progressed to ensure validity, reliability, accuracy, and appropriateness of clinical laboratory testing and results.9 Figure 1 Open in new tabDownload slide Timeline of regulatory oversight spanning 50 years beginning with the Clinical Laboratory Improvement Amendment (CLIA) of 1967. FDA, US Food and Drug Administration; LDT, laboratory developed test; QSR, quality system regulation. Figure 1 Open in new tabDownload slide Timeline of regulatory oversight spanning 50 years beginning with the Clinical Laboratory Improvement Amendment (CLIA) of 1967. FDA, US Food and Drug Administration; LDT, laboratory developed test; QSR, quality system regulation. Although the aim of CLIA is to ensure that clinical laboratories operate suitably,10 Burd10 explains that CLIA lists the performance specifications as described in CFR 493 to be established but “does not specify the scientific methodology or implementation tool to be used.” CLIA instead defers selection of the appropriate method meeting these performance specifications to the laboratory director’s judgment. Useful resources include not-for-profit agencies, such as the CLSI, the College of American Pathologists, and the International Organization for Standardization, which develop and recommend clinical laboratory standards and accreditation criteria.10 To this end, the CLSI has recommended implementation of 12 QSEs Table 1 as a “framework to a systems approach to managing quality.”11 The adoption of all 12 QSEs will better ensure safe testing practices that align with governmental regulations. Table 1 Clinical Laboratory Standards Institute Quality System Essentials11 1. Organization 7. Documents and records 2. Customer focus 8. Process management 3. Facilities and safety 9. Information management 4. Personnel 10. Nonconforming event management 5. Purchasing and inventory 11. Assessments 6. Equipment 12. Continual improvement 1. Organization 7. Documents and records 2. Customer focus 8. Process management 3. Facilities and safety 9. Information management 4. Personnel 10. Nonconforming event management 5. Purchasing and inventory 11. Assessments 6. Equipment 12. Continual improvement Open in new tab Table 1 Clinical Laboratory Standards Institute Quality System Essentials11 1. Organization 7. Documents and records 2. Customer focus 8. Process management 3. Facilities and safety 9. Information management 4. Personnel 10. Nonconforming event management 5. Purchasing and inventory 11. Assessments 6. Equipment 12. Continual improvement 1. Organization 7. Documents and records 2. Customer focus 8. Process management 3. Facilities and safety 9. Information management 4. Personnel 10. Nonconforming event management 5. Purchasing and inventory 11. Assessments 6. Equipment 12. Continual improvement Open in new tab Medical Device Amendment The medical device amendment was established in 1976 after 4.5 million Dalkon Shield intrauterine devices sold between 1971 and 1974 adversely affected 900,000 women in the United States.12 This device, which was considered faulty, was the impetus that promoted the establishment of FDA regulatory oversight to ensure the effectiveness of the intended use of medical devices and to verify safe manufacturing practices. The amendment required three classifications of medical devices: class I, low-risk medical devices; class II, moderate risk; and class III, high risk. The regulatory approval process differs significantly for each class of device. Class I devices require general controls, class II devices require premarket notification (510(k)), and class III devices require the most rigorous process of premarket approval (PMA). These classifications of medical devices had not been a concern for diagnostic laboratories until the FDAs announced the 2014 draft guidance for LDTs.13 QSR (21 CFR 820) The 21 CFR 820 or QSR is a regulatory requirement that directs the methods for the design, manufacture, packaging, labeling, storage, installation, and servicing of medical devices to ensure their safety and efficacy.1 The QSR encompasses organizational structure, management responsibilities, procedures, processes, and resources for establishing and maintaining a quality management system and serves as a guide for organizations. The 2014 LDT draft guidance proposes the use of this existing QSR. However, LDTs differ from medical devices in three respects: (1) LDTs are considered by most outside of the FDA to be a medical service, not a device; (2) medical devices may be tested on human participants, and approvals may require additional time, processes, resources, and regulatory requirements Table 213; and (3) under the FDA, a device manufacturer must demonstrate safety and efficacy of the product and may require verification through clinical trials for a PMA for new devices or substantial equivalence for a 510(k) predicate device.8 Table 2 Medical Device Requirements Regulation13 21 CFR 820 Quality System Regulation (QSR): Quality system regulation requirements International Organization for Standardization (ISO) 13485: International standard—regulatory quality management system requirements for medical device Good Manufacturing Practices (GMP): Guidelines for manufacturing, testing, and quality assurance to ensure that a product is safe for human or animal consumption or use Good Laboratory Practice (GLP): Principles to ensure the quality and integrity of nonclinical laboratory studies 21 CFR 820 Quality System Regulation (QSR): Quality system regulation requirements International Organization for Standardization (ISO) 13485: International standard—regulatory quality management system requirements for medical device Good Manufacturing Practices (GMP): Guidelines for manufacturing, testing, and quality assurance to ensure that a product is safe for human or animal consumption or use Good Laboratory Practice (GLP): Principles to ensure the quality and integrity of nonclinical laboratory studies Open in new tab Table 2 Medical Device Requirements Regulation13 21 CFR 820 Quality System Regulation (QSR): Quality system regulation requirements International Organization for Standardization (ISO) 13485: International standard—regulatory quality management system requirements for medical device Good Manufacturing Practices (GMP): Guidelines for manufacturing, testing, and quality assurance to ensure that a product is safe for human or animal consumption or use Good Laboratory Practice (GLP): Principles to ensure the quality and integrity of nonclinical laboratory studies 21 CFR 820 Quality System Regulation (QSR): Quality system regulation requirements International Organization for Standardization (ISO) 13485: International standard—regulatory quality management system requirements for medical device Good Manufacturing Practices (GMP): Guidelines for manufacturing, testing, and quality assurance to ensure that a product is safe for human or animal consumption or use Good Laboratory Practice (GLP): Principles to ensure the quality and integrity of nonclinical laboratory studies Open in new tab Differentiation Between Laboratory Developed Testing and Medical Device: Devices Cleared The FDA cleared 2,957 medical devices as 510(k) in 2012.14 The average approval time for FDA internal review in 2012 was 168 days. As of September 2012, the FDA received 2,965 devices, of which 1,715 were rejected with a refusal rate of 58%.15 In comparison, CLIA requires that tasks, activities, and processes of diagnostic testing show accuracy and reliability of testing confirmed by validation of parameters and results. The FDA clinical trials are not equivalent to CLIA validation of testing parameters. Similar to CLIA, the FDA does not provide the operational design template, detailed instruction, or translation from medical device requirements essential for interpreting, extrapolating, designing, and implementing a QSR.6 Comparing QSE to QSR Parallel to the QSR, the 12 QSEs contain most of the broad management categories and elements found in the 21 CFR 820 ( Table 3 is a side-by-side comparison of QSE to QSR, showing where they are equivalent and how they differ).11,22 However, the extent of their applicability to laboratories differ. Without a step-by-step guide for establishing the operational structure required to comply with the QSR, laboratories may feel they lack the resources and funding to develop a quality management program that meets FDA specifications. Table 3 Quality System Essentials in Comparison to 21 CFR Requirements 12 Quality System Essentials 21 CFR 820 Quality System Regulation Organization Management responsibility Customer focus Facilities and safety Personnel Personnel Purchasing and inventory Purchasing controls Equipment Process management Process controls Production and acceptance activities Design controls Identification and traceability Document and records Document controls Information management Nonconforming event management Nonconforming product Assessments Quality audit Continual improvement 12 Quality System Essentials 21 CFR 820 Quality System Regulation Organization Management responsibility Customer focus Facilities and safety Personnel Personnel Purchasing and inventory Purchasing controls Equipment Process management Process controls Production and acceptance activities Design controls Identification and traceability Document and records Document controls Information management Nonconforming event management Nonconforming product Assessments Quality audit Continual improvement Open in new tab Table 3 Quality System Essentials in Comparison to 21 CFR Requirements 12 Quality System Essentials 21 CFR 820 Quality System Regulation Organization Management responsibility Customer focus Facilities and safety Personnel Personnel Purchasing and inventory Purchasing controls Equipment Process management Process controls Production and acceptance activities Design controls Identification and traceability Document and records Document controls Information management Nonconforming event management Nonconforming product Assessments Quality audit Continual improvement 12 Quality System Essentials 21 CFR 820 Quality System Regulation Organization Management responsibility Customer focus Facilities and safety Personnel Personnel Purchasing and inventory Purchasing controls Equipment Process management Process controls Production and acceptance activities Design controls Identification and traceability Document and records Document controls Information management Nonconforming event management Nonconforming product Assessments Quality audit Continual improvement Open in new tab 21 CFR 820: Understanding Design Control “Design control” was originally established as a guiding methodology for the design, development, manufacture, and production of medical devices to ensure that accuracy, reliability, and quality are consistently built into every new device. The elements of 21 CFR 820 design control provide the manufacturing expectation of the FDA to produce a safe and effective product.16 This method is an iterative process similar to the product development method, and although historically intended as a requirement for medical devices, the development of policies, procedures, and processes as applied to test design should help with the establishment of design control specific to the laboratory. Figure 2 lists each element of design control from development to design history, and Table 4 lists each element of design control with a modified description for the practical application to organizational processes.16,17,22 Table 4 Description of Design Control16,22 Step 21 CFR 820 Design Control Description 1 Design and development planning Procedure: Set of processes that transforms requirements for an object into more detained requirements, such as the plan, design, development, execution, involvement, and interface with different groups and responsibility (ISO 9001). 2 Design input Procedure: Product characteristics, requirements, intended use, user needs, and the process to manage and resolve discrepancies are defined. The process includes responsibility approval, documentation, and rationale at every step. 3 Design output Procedure: The output consists of technical, performance, specification, and verification that the design successfully transferred into the testing environment. 4 Design review Procedure: Describes the process to review all phases of the design with documentation and approval all at each step. Establish and maintain procedures for the identification, documentation, validation, verification, review, and approval of design changes before implementation. 5 Design verificationa Procedure: Describes the process that will ensure the test is safe, is effective for use, conforms to the needs of the user, and meets its intended use. The process to ensure the design works as intended has been verified, documented, and approved at each activity. 6 Design validation Procedure: Procedure to perform validation under defined operating conditions that will ensure the test is appropriate for the intended use. 7 Design transfer Procedure: Describes the process of accurate transfer of the design into manufacturing requirements. 8 Design changes Procedure: Describes the process to identify, track, document, and approve changes prior to each activity. 9 Design history file A means to track processing information pertaining to design, development, testing, and links with all other design controls to demonstrate traceability and approval for each laboratory developed test manufactured. Step 21 CFR 820 Design Control Description 1 Design and development planning Procedure: Set of processes that transforms requirements for an object into more detained requirements, such as the plan, design, development, execution, involvement, and interface with different groups and responsibility (ISO 9001). 2 Design input Procedure: Product characteristics, requirements, intended use, user needs, and the process to manage and resolve discrepancies are defined. The process includes responsibility approval, documentation, and rationale at every step. 3 Design output Procedure: The output consists of technical, performance, specification, and verification that the design successfully transferred into the testing environment. 4 Design review Procedure: Describes the process to review all phases of the design with documentation and approval all at each step. Establish and maintain procedures for the identification, documentation, validation, verification, review, and approval of design changes before implementation. 5 Design verificationa Procedure: Describes the process that will ensure the test is safe, is effective for use, conforms to the needs of the user, and meets its intended use. The process to ensure the design works as intended has been verified, documented, and approved at each activity. 6 Design validation Procedure: Procedure to perform validation under defined operating conditions that will ensure the test is appropriate for the intended use. 7 Design transfer Procedure: Describes the process of accurate transfer of the design into manufacturing requirements. 8 Design changes Procedure: Describes the process to identify, track, document, and approve changes prior to each activity. 9 Design history file A means to track processing information pertaining to design, development, testing, and links with all other design controls to demonstrate traceability and approval for each laboratory developed test manufactured. ISO, International Organization for Standardization. aVerification pertaining to design control and validation holds two separate meanings in the laboratory.19 Open in new tab Table 4 Description of Design Control16,22 Step 21 CFR 820 Design Control Description 1 Design and development planning Procedure: Set of processes that transforms requirements for an object into more detained requirements, such as the plan, design, development, execution, involvement, and interface with different groups and responsibility (ISO 9001). 2 Design input Procedure: Product characteristics, requirements, intended use, user needs, and the process to manage and resolve discrepancies are defined. The process includes responsibility approval, documentation, and rationale at every step. 3 Design output Procedure: The output consists of technical, performance, specification, and verification that the design successfully transferred into the testing environment. 4 Design review Procedure: Describes the process to review all phases of the design with documentation and approval all at each step. Establish and maintain procedures for the identification, documentation, validation, verification, review, and approval of design changes before implementation. 5 Design verificationa Procedure: Describes the process that will ensure the test is safe, is effective for use, conforms to the needs of the user, and meets its intended use. The process to ensure the design works as intended has been verified, documented, and approved at each activity. 6 Design validation Procedure: Procedure to perform validation under defined operating conditions that will ensure the test is appropriate for the intended use. 7 Design transfer Procedure: Describes the process of accurate transfer of the design into manufacturing requirements. 8 Design changes Procedure: Describes the process to identify, track, document, and approve changes prior to each activity. 9 Design history file A means to track processing information pertaining to design, development, testing, and links with all other design controls to demonstrate traceability and approval for each laboratory developed test manufactured. Step 21 CFR 820 Design Control Description 1 Design and development planning Procedure: Set of processes that transforms requirements for an object into more detained requirements, such as the plan, design, development, execution, involvement, and interface with different groups and responsibility (ISO 9001). 2 Design input Procedure: Product characteristics, requirements, intended use, user needs, and the process to manage and resolve discrepancies are defined. The process includes responsibility approval, documentation, and rationale at every step. 3 Design output Procedure: The output consists of technical, performance, specification, and verification that the design successfully transferred into the testing environment. 4 Design review Procedure: Describes the process to review all phases of the design with documentation and approval all at each step. Establish and maintain procedures for the identification, documentation, validation, verification, review, and approval of design changes before implementation. 5 Design verificationa Procedure: Describes the process that will ensure the test is safe, is effective for use, conforms to the needs of the user, and meets its intended use. The process to ensure the design works as intended has been verified, documented, and approved at each activity. 6 Design validation Procedure: Procedure to perform validation under defined operating conditions that will ensure the test is appropriate for the intended use. 7 Design transfer Procedure: Describes the process of accurate transfer of the design into manufacturing requirements. 8 Design changes Procedure: Describes the process to identify, track, document, and approve changes prior to each activity. 9 Design history file A means to track processing information pertaining to design, development, testing, and links with all other design controls to demonstrate traceability and approval for each laboratory developed test manufactured. ISO, International Organization for Standardization. aVerification pertaining to design control and validation holds two separate meanings in the laboratory.19 Open in new tab Figure 2 Open in new tabDownload slide All steps throughout the process of design controls as stated in 21 CFR 820 quality system regulation. Figure 2 Open in new tabDownload slide All steps throughout the process of design controls as stated in 21 CFR 820 quality system regulation. Verification Confirmation is made, through the provision of objective evidence, that specified requirements have been fulfilled (design output meets the design input requirements). Validation Confirmation is made through the provision of objective evidence that the requirements for a specific intended use or application have been fulfilled.18,19 Research Method Now that we have covered the regulatory background, we turn to the technique conducted in this study as a mixed-method approach to research employed in two sequential phases: phase I consisted of qualitative interviews to capture the understanding of laboratory professionals in all aspects of LDTs and to determine if adherence to FDA regulatory requirements was achievable in a laboratory environment to design, develop, and test LDTs. If not, why not, and what would be the limiting steps? In addition to the interviews, proceedings from the 2-day FDA workshop, “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs),”20 held January 8-9, 2015, also contributed to this study. The intent of the workshop was for the FDA to provide the rationale for the 2014 draft guidance, as well as invite feedback and participation from peers within the laboratory community to state their case for or against the 2014 framework in the context of the proposed regulatory requirements. The interview and workshop information assisted the researchers in identifying factors that would serve as the building blocks for a regulatory laboratory framework. During phase II, a quantitative survey was conducted to test the factors identified during the interviews to determine agility, functionality, and usefulness as a proxy in the absence of implementation in a live environment. The study was designed as follows: Phase I—Interview A qualitative phone interview protocol was designed based on results of a review of the literature and was initially conducted to explore the potential challenges and constraints for laboratory compliance to the 2014 draft guidance. A convenience sampling strategy was used to select subject matter experts well versed in the historic, political, and practical perspective of LDTs. The nine interview participants selected were professionals from the fields of laboratory, regulatory, accreditation, and medical device segments of the industry and who had the time or the availability to participate. The names of the interviewees and associated organizations are retained as confidential. Secondary Data The presentations obtained from the two-day FDA workshop in 2015 pertaining to QSR were documented, described, and incorporated in this research. The public workshop was particularly helpful for this research and clarified issues and concerns as well as provided insight about future regulatory direction, produced a strategy, and explained how FDA recommendations may affect future laboratory operations. Constructing the Interview Protocol The interviewees were asked the questions in the following protocol and were encouraged to discuss their knowledge of LDTs. The 30-minute confidential interview protocol consisted of nine questions Table 5 . Table 5 Interview Questions 1. What is your role, title, and responsibility in the organization? 2. Tell me about the history and your knowledge about LDTs? 3. What are some of the regulatory challenges associated with LDTs? 4. How does genetic testing influence regulatory oversight? 5. Describe the current scrutiny associated with regulatory guidelines for LDTs. 6. What is the role of the FDA in LDTs? 7. Explain the intent of the FDA guidance framework for LDTs released in December 2014. 8. In your opinion, what would the implications(s) be if the FDA mandated regulatory guidelines for the process of LDTs? 9. How would you describe the “outcome and view of the future” if the FDA mandates regulatory oversight for LDTs? 1. What is your role, title, and responsibility in the organization? 2. Tell me about the history and your knowledge about LDTs? 3. What are some of the regulatory challenges associated with LDTs? 4. How does genetic testing influence regulatory oversight? 5. Describe the current scrutiny associated with regulatory guidelines for LDTs. 6. What is the role of the FDA in LDTs? 7. Explain the intent of the FDA guidance framework for LDTs released in December 2014. 8. In your opinion, what would the implications(s) be if the FDA mandated regulatory guidelines for the process of LDTs? 9. How would you describe the “outcome and view of the future” if the FDA mandates regulatory oversight for LDTs? FDA, US Food and Drug Administration; LDT, laboratory developed test. Open in new tab Table 5 Interview Questions 1. What is your role, title, and responsibility in the organization? 2. Tell me about the history and your knowledge about LDTs? 3. What are some of the regulatory challenges associated with LDTs? 4. How does genetic testing influence regulatory oversight? 5. Describe the current scrutiny associated with regulatory guidelines for LDTs. 6. What is the role of the FDA in LDTs? 7. Explain the intent of the FDA guidance framework for LDTs released in December 2014. 8. In your opinion, what would the implications(s) be if the FDA mandated regulatory guidelines for the process of LDTs? 9. How would you describe the “outcome and view of the future” if the FDA mandates regulatory oversight for LDTs? 1. What is your role, title, and responsibility in the organization? 2. Tell me about the history and your knowledge about LDTs? 3. What are some of the regulatory challenges associated with LDTs? 4. How does genetic testing influence regulatory oversight? 5. Describe the current scrutiny associated with regulatory guidelines for LDTs. 6. What is the role of the FDA in LDTs? 7. Explain the intent of the FDA guidance framework for LDTs released in December 2014. 8. In your opinion, what would the implications(s) be if the FDA mandated regulatory guidelines for the process of LDTs? 9. How would you describe the “outcome and view of the future” if the FDA mandates regulatory oversight for LDTs? FDA, US Food and Drug Administration; LDT, laboratory developed test. Open in new tab Data Collection The interviews were conducted by telephone over a 2-year period from April 2015 to May 2017. The process was explained prior to the interview and audio-recorded when possible, and the results were compiled. In addition to interview data, secondary data were collected from discussions that pertained to the quality system regulation during the public workshop to capture concerns with the 2014 draft guidance. Data Analysis The interviews were conducted with nine participants, and the discussions were manually transcribed. The topics of the conversations were tallied for frequency and coded manually. As depicted in Table 6 , the interview and secondary data were categorized into codes and subcodes, and a relational analysis was conducted to identify patterns of the most frequent theme and trends in both the interviews and the workshop discussion. Table 6 Leading Interview Codes Code Category General  GEN-HT History of LDTs  GEN-TN Technology  GEN-PT Patient safety concerns  GEN-DIR The laboratory need for direction  GEN-BM Change business model  GEN-UCT Uncertainty of requirements and path forward Laboratory  LAB-Org Hardship to organization  LAB-ACC Accreditation requirements  LAB-QS Quality management systems FDA  FD-RC Risk classifications  FD-PV Process validation  FD-FRW FDA 2014 framework proposal  FD-OS Outsource may be necessary  FD-RS Resources are needed to comply with regulations  FD-CFR 21 CFR 820 QSR requirements Code Category General  GEN-HT History of LDTs  GEN-TN Technology  GEN-PT Patient safety concerns  GEN-DIR The laboratory need for direction  GEN-BM Change business model  GEN-UCT Uncertainty of requirements and path forward Laboratory  LAB-Org Hardship to organization  LAB-ACC Accreditation requirements  LAB-QS Quality management systems FDA  FD-RC Risk classifications  FD-PV Process validation  FD-FRW FDA 2014 framework proposal  FD-OS Outsource may be necessary  FD-RS Resources are needed to comply with regulations  FD-CFR 21 CFR 820 QSR requirements FDA, US Food and Drug Administration; LDT, laboratory developed test; QSR, quality system regulation. Open in new tab Table 6 Leading Interview Codes Code Category General  GEN-HT History of LDTs  GEN-TN Technology  GEN-PT Patient safety concerns  GEN-DIR The laboratory need for direction  GEN-BM Change business model  GEN-UCT Uncertainty of requirements and path forward Laboratory  LAB-Org Hardship to organization  LAB-ACC Accreditation requirements  LAB-QS Quality management systems FDA  FD-RC Risk classifications  FD-PV Process validation  FD-FRW FDA 2014 framework proposal  FD-OS Outsource may be necessary  FD-RS Resources are needed to comply with regulations  FD-CFR 21 CFR 820 QSR requirements Code Category General  GEN-HT History of LDTs  GEN-TN Technology  GEN-PT Patient safety concerns  GEN-DIR The laboratory need for direction  GEN-BM Change business model  GEN-UCT Uncertainty of requirements and path forward Laboratory  LAB-Org Hardship to organization  LAB-ACC Accreditation requirements  LAB-QS Quality management systems FDA  FD-RC Risk classifications  FD-PV Process validation  FD-FRW FDA 2014 framework proposal  FD-OS Outsource may be necessary  FD-RS Resources are needed to comply with regulations  FD-CFR 21 CFR 820 QSR requirements FDA, US Food and Drug Administration; LDT, laboratory developed test; QSR, quality system regulation. Open in new tab Phase II Survey: Testing the Functionality of the Framework Constructing the Survey Protocol A confidential Qualtrics Survey consisting of three sections was developed for this study. Section I includes survey statements derived from extensive literature searches, the qualitative interviews, and a review of the 2-day FDA workshop in 2015 pertinent to the QSR on LDTs. Based on feedback, we translated the findings into a taxonomy comprising eight strategic factors and 40 statements that serve as building blocks for a laboratory regulatory quality management system. As depicted in the supplement (all supplemental materials can be found at American Journal of Clinical Pathology online), each statement contains five statements totaling 40 outcomes ranked on a 5-point Likert scale from “extremely important” to “not important at all.” The strategic factors identified are as follows: Leadership commitment Training Preassessment of the current QMS Design control Document control Process control Development of a QMS framework Process validation Section II contained two open-ended questions regarding the functionality, agility, and usefulness of the strategic factors listed in the study. The feedback was instrumental in determining if the participants agreed with the factors included in the survey or in assessing their opinion about what factors would be more appropriate. “Do you agree with the strategic factors identified in the proposed framework for a Quality Management System of LDTs? If not, please suggest additional factors pertinent to develop a robust framework.” “Do you think the establishment of a Quality Management System framework will assist LDT laboratories incorporate regulatory requirements such as design control more readily? If not, why and what else is necessary?” Section III included two questions to substantiate the understanding of the respondents regarding LDT design, development, validation, and delivery in a laboratory environment and to document their professional role. The questions were as follows: What is your professional role? a. Senior leader b. Medical director c. Medical doctor d. Technical supervisor e. Manager/supervisor f. Quality professional g. Other Do you consider yourself a subject matter expert on the topic of LDT? a. Definitely yes b. Probably yes c. Might or might not d. Probably not e. Definitely not Data Collection The quantitative survey was distributed to 767 laboratory professionals from April to July 2017. The respondents included all attendees from the Executive War College Laboratory Conference held in May 2017 in New Orleans, Louisiana. The survey was also distributed to randomly selected laboratory professionals demonstrating expert knowledge regarding the field of LDTs from LinkedIn with titles in the fields of regulatory, quality, and medical laboratory. Survey Demographics The responses from the Qualtrics survey resulted in 51 started surveys and 35 completed surveys, with a 69% completion rate of those who responded to the survey. The respondents included 10 senior leaders, four medical directors, 13 quality professionals, two technical supervisors, one manager, and five other professionals. To ensure the appropriate expertise in the field of LDTs, each participant was asked a critical qualifying question: Do you consider yourself a subject matter expert in the topic of LDT? The participants responded as follows: “definitely yes” (n = 9), “probably yes” (n = 9), “might or might not” (n = 6), “probably not” (n = 7), and “definitely not” (n = 2), as depicted in Figure 3 . Figure 3 Open in new tabDownload slide Laboratory developed test (LDT) expert classification of survey respondents using question 12: do you consider yourself a subject matter expert on the topic of LDT? Figure 3 Open in new tabDownload slide Laboratory developed test (LDT) expert classification of survey respondents using question 12: do you consider yourself a subject matter expert on the topic of LDT? Data Analysis The statistical software SPSS Version 24 (SPSS, Chicago, IL) was used to calculate and analyze the scores for significance across all eight factors and 40 statements. The descriptive statistics include the mean, standard deviation, and variance. Additional statistical analyses are as follows. Principal Axis Factoring Extraction Method The data were further analyzed by the principal axis factoring extraction method—more specifically, principal component analysis with the rotation method: varimax with Kaiser normalization. According to Williams et al,21 isolating factors with high loadings can reduce the variables into a smaller set of factors, remove variation, and cluster the relationships into patterns. This method was helpful to identify patterns consisting of high loadings with significant factors and statements exceeding 0.623, as depicted in Table 7 . Table 7 Survey Statements Under the Corresponding Strategic Factor Chosen From Expert Participants Ranked by Mean Values and Further Divided Into Quartiles From Extremely Important (1.28) to Not Important at All (2.28) Mean Mean Results: All Groups Q1: Leadership Commitment Q2: Training Q3: Preassessment of Existing QMS Q4: Design Control Q5: Document Control Q6: Process Control Q7: Development of a QMS Framework Q8: Process Validation 1.3 Q1_2 1.33 Q1_5 1.33 Q1_1 1.48 Q1_3 1.53 Q6_4 1.64 Q3_5 Q8_2 1.66 Q5_5 Q6_3 1.67 Q2_5 Q4_1 Q8_1 1.68 1.69 1.7 Q2_2 Q8_3 1.71 Q7_5 1.72 Q7_1 1.79 Q8_5 1.82 Q2_4 Q4_3 Q5_2 Q8_4 1.88 Q3_2 Q4_2 1.9 Q6_1 1.91 Q5_4 1.97 Q2_1 Q4_4 Q6_5 Q7_3 2 Q5_1 Q7_2 2.03 Q2_3 Q3_1 Q7_4 2.06 Q3_3 2.12 Q5_3 2.15 Q3_4 2.16 Q6_2 2.24 Q1_4 2.39 Q4_5 Mean Mean Results: All Groups Q1: Leadership Commitment Q2: Training Q3: Preassessment of Existing QMS Q4: Design Control Q5: Document Control Q6: Process Control Q7: Development of a QMS Framework Q8: Process Validation 1.3 Q1_2 1.33 Q1_5 1.33 Q1_1 1.48 Q1_3 1.53 Q6_4 1.64 Q3_5 Q8_2 1.66 Q5_5 Q6_3 1.67 Q2_5 Q4_1 Q8_1 1.68 1.69 1.7 Q2_2 Q8_3 1.71 Q7_5 1.72 Q7_1 1.79 Q8_5 1.82 Q2_4 Q4_3 Q5_2 Q8_4 1.88 Q3_2 Q4_2 1.9 Q6_1 1.91 Q5_4 1.97 Q2_1 Q4_4 Q6_5 Q7_3 2 Q5_1 Q7_2 2.03 Q2_3 Q3_1 Q7_4 2.06 Q3_3 2.12 Q5_3 2.15 Q3_4 2.16 Q6_2 2.24 Q1_4 2.39 Q4_5 QMS, quality management system. Open in new tab Table 7 Survey Statements Under the Corresponding Strategic Factor Chosen From Expert Participants Ranked by Mean Values and Further Divided Into Quartiles From Extremely Important (1.28) to Not Important at All (2.28) Mean Mean Results: All Groups Q1: Leadership Commitment Q2: Training Q3: Preassessment of Existing QMS Q4: Design Control Q5: Document Control Q6: Process Control Q7: Development of a QMS Framework Q8: Process Validation 1.3 Q1_2 1.33 Q1_5 1.33 Q1_1 1.48 Q1_3 1.53 Q6_4 1.64 Q3_5 Q8_2 1.66 Q5_5 Q6_3 1.67 Q2_5 Q4_1 Q8_1 1.68 1.69 1.7 Q2_2 Q8_3 1.71 Q7_5 1.72 Q7_1 1.79 Q8_5 1.82 Q2_4 Q4_3 Q5_2 Q8_4 1.88 Q3_2 Q4_2 1.9 Q6_1 1.91 Q5_4 1.97 Q2_1 Q4_4 Q6_5 Q7_3 2 Q5_1 Q7_2 2.03 Q2_3 Q3_1 Q7_4 2.06 Q3_3 2.12 Q5_3 2.15 Q3_4 2.16 Q6_2 2.24 Q1_4 2.39 Q4_5 Mean Mean Results: All Groups Q1: Leadership Commitment Q2: Training Q3: Preassessment of Existing QMS Q4: Design Control Q5: Document Control Q6: Process Control Q7: Development of a QMS Framework Q8: Process Validation 1.3 Q1_2 1.33 Q1_5 1.33 Q1_1 1.48 Q1_3 1.53 Q6_4 1.64 Q3_5 Q8_2 1.66 Q5_5 Q6_3 1.67 Q2_5 Q4_1 Q8_1 1.68 1.69 1.7 Q2_2 Q8_3 1.71 Q7_5 1.72 Q7_1 1.79 Q8_5 1.82 Q2_4 Q4_3 Q5_2 Q8_4 1.88 Q3_2 Q4_2 1.9 Q6_1 1.91 Q5_4 1.97 Q2_1 Q4_4 Q6_5 Q7_3 2 Q5_1 Q7_2 2.03 Q2_3 Q3_1 Q7_4 2.06 Q3_3 2.12 Q5_3 2.15 Q3_4 2.16 Q6_2 2.24 Q1_4 2.39 Q4_5 QMS, quality management system. Open in new tab t Test The t test was performed to determine whether the means of experts and nonexperts had distinct, differing priorities and were statistically different regarding the adoption of a QMS. Since the participants rated four of five factors within leadership commitment as the most relevant category, the assumption was the experts may have answered the statements differently due to their roles and responsibilities within the organization. The nonexperts were operationally oriented rather than occupying a leadership role. To test this assumption, the data were analyzed to determine if experts and nonexperts chose statements within the eight strategic factors differently. Open-Ended Questions The responses to the open-ended questions were analyzed using SPSS Version 24 to determine the number of participants considered an expert (Figure 3) and to tally acceptability and satisfaction with the suggested factors as explained in the survey results section. Results Interviews The tone expressed by the interviewees was ambiguity and uncertainty regarding all aspects of the LDT process, and similar concerns were articulated, including (1) risk classification, (2) process validation to ensure the accuracy and precision of tests results, (3) ambiguity of the 21 CFR 820 requirements translated to the laboratory, (4) lack of clarity from the FDA and other governmental agencies (eg, CMS), (5) patient safety concerns of the FDA, and (6) lack of clarity and direction regarding the 2014 draft guidance. The lack of coordination, clarity, and guidance from CLIA and the FDA has created confusion and a lack of motivation on behalf of the laboratory community. The general feedback received through the interviews showed substantial ambiguity across laboratory professionals regarding terms, definitions, and how to transfer operational requirements into regulatory terms. In addition, it is unclear how the draft guidance would translate from medical device to the laboratory. The development of a laboratory application of 21 CFR 820 quality systems regulation that would meet the LDT manufacturing requirements has not been addressed by regulatory agencies and has left laboratory leaders unprepared to be proactive. Ambiguity also existed during the interviews regarding the definition of design control and how to appropriately address and translate these requirements into the laboratory environment. Interview Results The discussion with the interviewees was instrumental to gain an understanding of the challenges faced by laboratory leaders, accreditation agencies, and regulatory policy makers. The interview findings depicted in Figure 4 illustrate the basis for the development of an operational framework for LDTs. Figure 4 Open in new tabDownload slide The results of nine interviews with laboratory developed test (LDT) experts from the field of regulatory, accreditation, diagnostic laboratory, and medical device. Figure 4 Open in new tabDownload slide The results of nine interviews with laboratory developed test (LDT) experts from the field of regulatory, accreditation, diagnostic laboratory, and medical device. The top five most significant concerns are identified as follows: FD-RC: Risk Classifications FD-PV: Process Validation FD-21 CFR 820 QSR Requirements GEN-UCT: Uncertainty GEN-PT: Patient Safety Secondary Data FDA Public Workshop The information shared during a 2-day FDA webinar held January 8-9, 2015, made a significant contribution to this research.20 The FDA began the conference by addressing areas of concern regarding the overview of the LDT draft guidance and the implication of adverse test results for the patients and the laboratories, as well as how the guidance would affect regulatory agencies already lacking appropriate resources. The director of the Centers for Devices and Radiological Health, Jeffrey Shuren, stated that the “FDA is transparent and does not claim they got it all right and some say they didn’t get anything right.” However, the FDA is acting on the behalf of patient safety, which has made its way into the popular press.20 In fact, adverse patient safety concerns associated with LDTs were published in the New York Times on August 28, 2008, July 7, 2011, and January 22, 2011. Guest speakers shared their support and apprehension of the draft guidance and addressed the importance of test accuracy for appropriate therapies. Katherine Tynan, a presenter, stated, “Quality systems vary significantly in terms of scale and complexity, and one of my concerns with the current dialogue between the FDA and laboratories developing LDTs is that quality means very different things to the stakeholders.”20 Research and development firms stressed the importance of laboratories outside of manufacture to be held to the same regulatory oversight and stated that a major cause of the inaccuracies of laboratory test development is improper design and lack of validation to verify the result is as intended. This topic was substantiated by consistent feedback mentioned 12 times from all nine interviewees, who also expressed test validation concerns. Liz Lison, president of Advocea Consulting firm and a conference speaker, explained, “Most of the failures that I have seen in LDTs may have been averted if design controls had been in place. Therefore, I urge the agency not to delay the enforcement of design controls for high-risk tests and potentially introduce a two -tier system for pre-market review.”20 The oversight of laboratory testing remains with CLIA. However, a gap exists regarding the regulation of test development. Due to the advances in genomic medicine, the interviewees expressed that the oversight by CLIA is no longer adequate to manage the compliance needs of laboratories. There is a significant difference in the oversight of the FDA and CLIA. The FDA does not mandate the operation of testing as stated in CFR 493; CLIA does not ensure the safety and effectiveness of test protocols as described in 21 CFR 820.20 Interpretation of Findings The interview and secondary findings validated the motivation for this study Figure 5 . The laboratory professionals illustrated the struggle to understand how to develop and organize a framework adaptable to their organization. The participant response from the 2-day workshop was more directive and outlined the need of laboratories vs the uncertainty noted during the interviews. As a result, the participants substantiated the need for a regulatory vocabulary translated to operational laboratory terms. In addition, the feedback describing gaps in processing was instrumental to the development of strategic factors developed from interview and workshop feedback and proposed as the precursor to a quality systems framework that would serve as the foundation for LDT development, as depicted in Table 8 . Table 8 Suggested Strategic Factors Necessary for a Regulatory QMS Framework Topic Interview/Conference Discussion Strategic Factors Developed as a Result of the Interviews Interview topic Leaders are unclear regarding how 21 CFR 820 requirements apply to laboratory testing considered by many to be a service, not a product. Leadership commitment Interview topic Laboratories lacked the rigor that is present in the manufacture of medical devices. Training FDA public workshop It is essential that the FDA harmonize the QSR requirements with CLIA requirements at a more granular level to prevent duplicate efforts and to ease the regulatory burden because governmental agencies have not provided the necessary guidance for struggling laboratories. Preassessment of the existing quality management system FDA public workshop Laboratory failures due to lack of process control Design control FDA public workshop Change is necessary to raise the level of quality, prioritize tasks, and dedicate the time and resources necessary to understand regulatory requirements to attain process standardization. Document control Interview topic The major cause of the inaccuracies of laboratory test development is improper design and lack of validation to verify the result is as intended. Process control FDA public workshop Laboratories need guidance documents and a defined process to simplify and translate the FDA proposal. Development of a QMS framework Interview topic The importance of test systems to validate protocols, processes, and test development that will consistently ensure the effectiveness and accuracy of test results Process validation Topic Interview/Conference Discussion Strategic Factors Developed as a Result of the Interviews Interview topic Leaders are unclear regarding how 21 CFR 820 requirements apply to laboratory testing considered by many to be a service, not a product. Leadership commitment Interview topic Laboratories lacked the rigor that is present in the manufacture of medical devices. Training FDA public workshop It is essential that the FDA harmonize the QSR requirements with CLIA requirements at a more granular level to prevent duplicate efforts and to ease the regulatory burden because governmental agencies have not provided the necessary guidance for struggling laboratories. Preassessment of the existing quality management system FDA public workshop Laboratory failures due to lack of process control Design control FDA public workshop Change is necessary to raise the level of quality, prioritize tasks, and dedicate the time and resources necessary to understand regulatory requirements to attain process standardization. Document control Interview topic The major cause of the inaccuracies of laboratory test development is improper design and lack of validation to verify the result is as intended. Process control FDA public workshop Laboratories need guidance documents and a defined process to simplify and translate the FDA proposal. Development of a QMS framework Interview topic The importance of test systems to validate protocols, processes, and test development that will consistently ensure the effectiveness and accuracy of test results Process validation CLIA, Clinical Laboratory Improvement Amendment; FDA, US Food and Drug Administration; QMS, quality management system; QSR, quality system regulation. Open in new tab Table 8 Suggested Strategic Factors Necessary for a Regulatory QMS Framework Topic Interview/Conference Discussion Strategic Factors Developed as a Result of the Interviews Interview topic Leaders are unclear regarding how 21 CFR 820 requirements apply to laboratory testing considered by many to be a service, not a product. Leadership commitment Interview topic Laboratories lacked the rigor that is present in the manufacture of medical devices. Training FDA public workshop It is essential that the FDA harmonize the QSR requirements with CLIA requirements at a more granular level to prevent duplicate efforts and to ease the regulatory burden because governmental agencies have not provided the necessary guidance for struggling laboratories. Preassessment of the existing quality management system FDA public workshop Laboratory failures due to lack of process control Design control FDA public workshop Change is necessary to raise the level of quality, prioritize tasks, and dedicate the time and resources necessary to understand regulatory requirements to attain process standardization. Document control Interview topic The major cause of the inaccuracies of laboratory test development is improper design and lack of validation to verify the result is as intended. Process control FDA public workshop Laboratories need guidance documents and a defined process to simplify and translate the FDA proposal. Development of a QMS framework Interview topic The importance of test systems to validate protocols, processes, and test development that will consistently ensure the effectiveness and accuracy of test results Process validation Topic Interview/Conference Discussion Strategic Factors Developed as a Result of the Interviews Interview topic Leaders are unclear regarding how 21 CFR 820 requirements apply to laboratory testing considered by many to be a service, not a product. Leadership commitment Interview topic Laboratories lacked the rigor that is present in the manufacture of medical devices. Training FDA public workshop It is essential that the FDA harmonize the QSR requirements with CLIA requirements at a more granular level to prevent duplicate efforts and to ease the regulatory burden because governmental agencies have not provided the necessary guidance for struggling laboratories. Preassessment of the existing quality management system FDA public workshop Laboratory failures due to lack of process control Design control FDA public workshop Change is necessary to raise the level of quality, prioritize tasks, and dedicate the time and resources necessary to understand regulatory requirements to attain process standardization. Document control Interview topic The major cause of the inaccuracies of laboratory test development is improper design and lack of validation to verify the result is as intended. Process control FDA public workshop Laboratories need guidance documents and a defined process to simplify and translate the FDA proposal. Development of a QMS framework Interview topic The importance of test systems to validate protocols, processes, and test development that will consistently ensure the effectiveness and accuracy of test results Process validation CLIA, Clinical Laboratory Improvement Amendment; FDA, US Food and Drug Administration; QMS, quality management system; QSR, quality system regulation. Open in new tab Figure 5 Open in new tabDownload slide Secondary data results complied from discussions pertinent to quality system regulations obtained from the 2015 US Food and Drug Administration public workshop on laboratory developed tests. Figure 5 Open in new tabDownload slide Secondary data results complied from discussions pertinent to quality system regulations obtained from the 2015 US Food and Drug Administration public workshop on laboratory developed tests. Survey Results Exploratory Factor Analysis and Factor Reliability The factor analysis was conducted to explore the data set, determine the importance of the relationships between the variables, and isolate the factors with high loadings to reduce variables into a smaller set of factors. As described by Williams et al,21 an appropriate factor loading of 0.50 is optimal for factor analysis. However, due to the smaller sample size, a significant factor loading would be 0.60 or larger. The analysis eliminated 17 variables with smaller loadings, as shown in Table 9 . The loadings analyzed and clustered the relationships into patterns. The clusters illustrated the importance of leadership, clinical validity, process validation, and procedures to provide guidance for accuracy and consistency of processes. The weak factors removed clarified the reluctance to perform a preassessment of the existing operation to determine if the organization was prepared to operate within a regulatory environment. Table 9 Exploratory Factor Analysis and Factor Reliability Performed on Each Categorya Rotated Component Matrixb Component Statement Statement Description 1 2 3 4 5 6 7 8 9 Q2_4 Staff training 0.822 Q3_3 Crosswalk of current processes 0.772 Q3_5 Clear understanding of QSR requirements 0.701 Q2_5 The assignment of responsible persons 0.691 Q7_3 Preassessment of current processes 0.635 Q5_4 Documentation of tasks and activities at each step 0.626 Q2_3 The program includes value stream mapping to demonstrate the significance of handoffs 0.614 Q3_2 ISO 15189 will assist the organization in complying with requirements 0.612 Q7_4 Q7_5 Q6_4 Clinical validity is performed as validation 0.811 Q6_3 Documentation of analytic validity will demonstrate accuracy and reliability 0.765 Q6_1 Responsibility for every handoff to ensure LDT accuracy 0.615 Q1_3 Q5_5 Q8_3 Process qualification ensures design specification 0.871 Q8_2 Validation to ensure all steps meet regulatory requirements 0.779 Q8_4 Operational qualification will ensure the process is operating as intended 0.675 Q7_1 Q5_2 Clearly written procedures remove ambiguity in the process 0.859 Q5_1 Updated and accurate operating procedures 0.761 Q1_4 Q3_1 Q8_5 Performance qualification produces the same result and operates correctly 0.696 Q2_1 Training includes introduction to LDTs 0.659 Q8_1 Process validation is performed to ensure effectiveness 0.626 Q2_2 Q1_2 Q4_3 Design control that is well implemented and documented will ensure quality 0.759 Q4_2 Design control described in laboratory terms will clarify requirements 0.724 Q7_2 Q4_4 Q6_5 Data collection and clearly communicating requirements 0.863 Q6_2 The consistent uninterrupted flow of material will demonstrate user-friendliness of the framework 0.764 Q5_3 Q1_1 Leadership institutes key performance indicators 0.699 Q4_5 A procedure that addresses adverse events 0.665 Q3_4 Q4_1 Q1_5 Leadership consistently communicates change 0.734 Rotated Component Matrixb Component Statement Statement Description 1 2 3 4 5 6 7 8 9 Q2_4 Staff training 0.822 Q3_3 Crosswalk of current processes 0.772 Q3_5 Clear understanding of QSR requirements 0.701 Q2_5 The assignment of responsible persons 0.691 Q7_3 Preassessment of current processes 0.635 Q5_4 Documentation of tasks and activities at each step 0.626 Q2_3 The program includes value stream mapping to demonstrate the significance of handoffs 0.614 Q3_2 ISO 15189 will assist the organization in complying with requirements 0.612 Q7_4 Q7_5 Q6_4 Clinical validity is performed as validation 0.811 Q6_3 Documentation of analytic validity will demonstrate accuracy and reliability 0.765 Q6_1 Responsibility for every handoff to ensure LDT accuracy 0.615 Q1_3 Q5_5 Q8_3 Process qualification ensures design specification 0.871 Q8_2 Validation to ensure all steps meet regulatory requirements 0.779 Q8_4 Operational qualification will ensure the process is operating as intended 0.675 Q7_1 Q5_2 Clearly written procedures remove ambiguity in the process 0.859 Q5_1 Updated and accurate operating procedures 0.761 Q1_4 Q3_1 Q8_5 Performance qualification produces the same result and operates correctly 0.696 Q2_1 Training includes introduction to LDTs 0.659 Q8_1 Process validation is performed to ensure effectiveness 0.626 Q2_2 Q1_2 Q4_3 Design control that is well implemented and documented will ensure quality 0.759 Q4_2 Design control described in laboratory terms will clarify requirements 0.724 Q7_2 Q4_4 Q6_5 Data collection and clearly communicating requirements 0.863 Q6_2 The consistent uninterrupted flow of material will demonstrate user-friendliness of the framework 0.764 Q5_3 Q1_1 Leadership institutes key performance indicators 0.699 Q4_5 A procedure that addresses adverse events 0.665 Q3_4 Q4_1 Q1_5 Leadership consistently communicates change 0.734 ISO, International Organization for Standardization; LDT, laboratory developed test; QSR, quality system regulation. aExtraction method: principal component analysis. Rotation method: varimax with Kaiser normalization. bRotation converged in 15 iterations. Open in new tab Table 9 Exploratory Factor Analysis and Factor Reliability Performed on Each Categorya Rotated Component Matrixb Component Statement Statement Description 1 2 3 4 5 6 7 8 9 Q2_4 Staff training 0.822 Q3_3 Crosswalk of current processes 0.772 Q3_5 Clear understanding of QSR requirements 0.701 Q2_5 The assignment of responsible persons 0.691 Q7_3 Preassessment of current processes 0.635 Q5_4 Documentation of tasks and activities at each step 0.626 Q2_3 The program includes value stream mapping to demonstrate the significance of handoffs 0.614 Q3_2 ISO 15189 will assist the organization in complying with requirements 0.612 Q7_4 Q7_5 Q6_4 Clinical validity is performed as validation 0.811 Q6_3 Documentation of analytic validity will demonstrate accuracy and reliability 0.765 Q6_1 Responsibility for every handoff to ensure LDT accuracy 0.615 Q1_3 Q5_5 Q8_3 Process qualification ensures design specification 0.871 Q8_2 Validation to ensure all steps meet regulatory requirements 0.779 Q8_4 Operational qualification will ensure the process is operating as intended 0.675 Q7_1 Q5_2 Clearly written procedures remove ambiguity in the process 0.859 Q5_1 Updated and accurate operating procedures 0.761 Q1_4 Q3_1 Q8_5 Performance qualification produces the same result and operates correctly 0.696 Q2_1 Training includes introduction to LDTs 0.659 Q8_1 Process validation is performed to ensure effectiveness 0.626 Q2_2 Q1_2 Q4_3 Design control that is well implemented and documented will ensure quality 0.759 Q4_2 Design control described in laboratory terms will clarify requirements 0.724 Q7_2 Q4_4 Q6_5 Data collection and clearly communicating requirements 0.863 Q6_2 The consistent uninterrupted flow of material will demonstrate user-friendliness of the framework 0.764 Q5_3 Q1_1 Leadership institutes key performance indicators 0.699 Q4_5 A procedure that addresses adverse events 0.665 Q3_4 Q4_1 Q1_5 Leadership consistently communicates change 0.734 Rotated Component Matrixb Component Statement Statement Description 1 2 3 4 5 6 7 8 9 Q2_4 Staff training 0.822 Q3_3 Crosswalk of current processes 0.772 Q3_5 Clear understanding of QSR requirements 0.701 Q2_5 The assignment of responsible persons 0.691 Q7_3 Preassessment of current processes 0.635 Q5_4 Documentation of tasks and activities at each step 0.626 Q2_3 The program includes value stream mapping to demonstrate the significance of handoffs 0.614 Q3_2 ISO 15189 will assist the organization in complying with requirements 0.612 Q7_4 Q7_5 Q6_4 Clinical validity is performed as validation 0.811 Q6_3 Documentation of analytic validity will demonstrate accuracy and reliability 0.765 Q6_1 Responsibility for every handoff to ensure LDT accuracy 0.615 Q1_3 Q5_5 Q8_3 Process qualification ensures design specification 0.871 Q8_2 Validation to ensure all steps meet regulatory requirements 0.779 Q8_4 Operational qualification will ensure the process is operating as intended 0.675 Q7_1 Q5_2 Clearly written procedures remove ambiguity in the process 0.859 Q5_1 Updated and accurate operating procedures 0.761 Q1_4 Q3_1 Q8_5 Performance qualification produces the same result and operates correctly 0.696 Q2_1 Training includes introduction to LDTs 0.659 Q8_1 Process validation is performed to ensure effectiveness 0.626 Q2_2 Q1_2 Q4_3 Design control that is well implemented and documented will ensure quality 0.759 Q4_2 Design control described in laboratory terms will clarify requirements 0.724 Q7_2 Q4_4 Q6_5 Data collection and clearly communicating requirements 0.863 Q6_2 The consistent uninterrupted flow of material will demonstrate user-friendliness of the framework 0.764 Q5_3 Q1_1 Leadership institutes key performance indicators 0.699 Q4_5 A procedure that addresses adverse events 0.665 Q3_4 Q4_1 Q1_5 Leadership consistently communicates change 0.734 ISO, International Organization for Standardization; LDT, laboratory developed test; QSR, quality system regulation. aExtraction method: principal component analysis. Rotation method: varimax with Kaiser normalization. bRotation converged in 15 iterations. Open in new tab Overall Mean of Categories To determine if factors were viewed differently by experts vs nonexperts, the aggregate mean for the items associated with each factor was analyzed. As shown in Table 10 , experts vs nonexperts chose similar responses for all statements within the survey from an average of close to 1 (extremely important) to slightly over 2 (very important). This result suggests both groups considered all factors to be equally important for the development of a QMS. Table 10 Overall Mean of Factors Factor No. Range Descriptive Statistics Mean (SD) Variance Minimum Maximum AverQ3_Preassess 33 2.40 1.00 3.40 1.9515 (0.58101) 0.338 AverQ4_DesignContrl 33 2.20 1.00 3.20 1.9455 (0.60472) 0.366 AverQ5_DocuentContrl 33 2.00 1.00 3.00 1.9030 (0.58335) 0.340 AverQ7_Development 32 1.80 1.00 2.80 1.8844 (0.42435) 0.180 AverQ6_ProcesContrl 32 1.60 1.00 2.60 1.8453 (0.45497) 0.207 AverQ2_training 33 1.40 1.00 2.40 1.8364 (0.40452) 0.164 AverQ8_ProcessValid 33 1.80 1.00 2.80 1.7212 (0.48718) 0.237 AverQ1_Leadership 33 1.20 1.00 2.20 1.5333 (0.32275) 0.104 Valid N (listwise) 32 Factor No. Range Descriptive Statistics Mean (SD) Variance Minimum Maximum AverQ3_Preassess 33 2.40 1.00 3.40 1.9515 (0.58101) 0.338 AverQ4_DesignContrl 33 2.20 1.00 3.20 1.9455 (0.60472) 0.366 AverQ5_DocuentContrl 33 2.00 1.00 3.00 1.9030 (0.58335) 0.340 AverQ7_Development 32 1.80 1.00 2.80 1.8844 (0.42435) 0.180 AverQ6_ProcesContrl 32 1.60 1.00 2.60 1.8453 (0.45497) 0.207 AverQ2_training 33 1.40 1.00 2.40 1.8364 (0.40452) 0.164 AverQ8_ProcessValid 33 1.80 1.00 2.80 1.7212 (0.48718) 0.237 AverQ1_Leadership 33 1.20 1.00 2.20 1.5333 (0.32275) 0.104 Valid N (listwise) 32 Open in new tab Table 10 Overall Mean of Factors Factor No. Range Descriptive Statistics Mean (SD) Variance Minimum Maximum AverQ3_Preassess 33 2.40 1.00 3.40 1.9515 (0.58101) 0.338 AverQ4_DesignContrl 33 2.20 1.00 3.20 1.9455 (0.60472) 0.366 AverQ5_DocuentContrl 33 2.00 1.00 3.00 1.9030 (0.58335) 0.340 AverQ7_Development 32 1.80 1.00 2.80 1.8844 (0.42435) 0.180 AverQ6_ProcesContrl 32 1.60 1.00 2.60 1.8453 (0.45497) 0.207 AverQ2_training 33 1.40 1.00 2.40 1.8364 (0.40452) 0.164 AverQ8_ProcessValid 33 1.80 1.00 2.80 1.7212 (0.48718) 0.237 AverQ1_Leadership 33 1.20 1.00 2.20 1.5333 (0.32275) 0.104 Valid N (listwise) 32 Factor No. Range Descriptive Statistics Mean (SD) Variance Minimum Maximum AverQ3_Preassess 33 2.40 1.00 3.40 1.9515 (0.58101) 0.338 AverQ4_DesignContrl 33 2.20 1.00 3.20 1.9455 (0.60472) 0.366 AverQ5_DocuentContrl 33 2.00 1.00 3.00 1.9030 (0.58335) 0.340 AverQ7_Development 32 1.80 1.00 2.80 1.8844 (0.42435) 0.180 AverQ6_ProcesContrl 32 1.60 1.00 2.60 1.8453 (0.45497) 0.207 AverQ2_training 33 1.40 1.00 2.40 1.8364 (0.40452) 0.164 AverQ8_ProcessValid 33 1.80 1.00 2.80 1.7212 (0.48718) 0.237 AverQ1_Leadership 33 1.20 1.00 2.20 1.5333 (0.32275) 0.104 Valid N (listwise) 32 Open in new tab t Test Factor Analysis Table 11 shows the results of all statements chosen from experts vs nonexperts with corresponding means. Both groups choose the options of (1) extremely important and (2) very important statements, resulting in consistency and a small variance between all responses. The hypothesis was that experts and nonexperts had different and distinct priorities regarding adoption of a QMS due to their roles and responsibilities within the organization and may have answered statements differently. We found that there was no significant difference between experts and nonexperts on average importance attributed to the strategic factors (Table 10). Table 11 t Test Independent Samples Test Characteristic Levene’s Test for Equality of Variances t Test for Equality of Means F Significance t df Significance (Two-Tailed) Mean Difference Std. Error Difference 95% Confidence Interval of the Difference AverQ1_Leadership  Equal variances assumed 1.026 .321 –0.258 25 .798 –0.03333 (0.12910) –0.29922 to 0.23255  Equal variances not assumed –0.280 19.907 .783 –0.03333 (0.11921) –0.28208 to 0.21542 AverQ2_training  Equal variances assumed 0.082 .777 0.543 25 .592 0.08889 (0.16366) –0.24818 to 0.42596  Equal variances not assumed 0.572 18.466 .574 0.08889 (0.15549) –0.23718 to 0.41496 AverQ3_Preassess  Equal variances assumed 0.032 .859 0.504 25 .619 0.12222 (0.24273) –0.37769 to 0.62214  Equal variances not assumed 0.528 18.308 .604 0.12222 (0.23135) –0.36324 to 0.60768 AverQ4_DesignContrl  Equal variances assumed 0.293 .593 –0.946 25 .353 –0.24444 (0.25843) –0.77669 to 0.28780  Equal variances not assumed –0.886 13.663 .391 –0.24444 (0.27581) –0.83737 to 0.34848 AverQ5_DocuentContrl  Equal variances assumed 0.928 .345 –0.828 25 .415 –0.20000 (0.24148) –0.69733 to 0.29733  Equal variances not assumed –0.893 19.659 .383 –0.20000 (0.22406) –0.66790 to 0.26790 AverQ6_ProcesContrl  Equal variances assumed 1.221 .280 0.088 24 .931 0.01667 (0.18916) –0.37374 to 0.40708  Equal variances not assumed 0.100 18.558 .921 0.01667 (0.16651) –0.33240 to 0.36574 AverQ7_Development  Equal variances assumed 0.003 .958 –0.310 24 .759 –0.05556 (0.17922) –0.42545 to 0.31434  Equal variances not assumed –0.327 15.388 .748 –0.05556 (0.16980) –0.41669 to 0.30558 AverQ8_ProcessValid  Equal variances assumed 0.901 .352 –0.272 25 .788 –0.05556 (0.20443) –0.47659 to 0.36548  Equal variances not assumed –0.244 12.335 .812 –0.05556 (0.22808) –0.55100 to 0.43989 Independent Samples Test Characteristic Levene’s Test for Equality of Variances t Test for Equality of Means F Significance t df Significance (Two-Tailed) Mean Difference Std. Error Difference 95% Confidence Interval of the Difference AverQ1_Leadership  Equal variances assumed 1.026 .321 –0.258 25 .798 –0.03333 (0.12910) –0.29922 to 0.23255  Equal variances not assumed –0.280 19.907 .783 –0.03333 (0.11921) –0.28208 to 0.21542 AverQ2_training  Equal variances assumed 0.082 .777 0.543 25 .592 0.08889 (0.16366) –0.24818 to 0.42596  Equal variances not assumed 0.572 18.466 .574 0.08889 (0.15549) –0.23718 to 0.41496 AverQ3_Preassess  Equal variances assumed 0.032 .859 0.504 25 .619 0.12222 (0.24273) –0.37769 to 0.62214  Equal variances not assumed 0.528 18.308 .604 0.12222 (0.23135) –0.36324 to 0.60768 AverQ4_DesignContrl  Equal variances assumed 0.293 .593 –0.946 25 .353 –0.24444 (0.25843) –0.77669 to 0.28780  Equal variances not assumed –0.886 13.663 .391 –0.24444 (0.27581) –0.83737 to 0.34848 AverQ5_DocuentContrl  Equal variances assumed 0.928 .345 –0.828 25 .415 –0.20000 (0.24148) –0.69733 to 0.29733  Equal variances not assumed –0.893 19.659 .383 –0.20000 (0.22406) –0.66790 to 0.26790 AverQ6_ProcesContrl  Equal variances assumed 1.221 .280 0.088 24 .931 0.01667 (0.18916) –0.37374 to 0.40708  Equal variances not assumed 0.100 18.558 .921 0.01667 (0.16651) –0.33240 to 0.36574 AverQ7_Development  Equal variances assumed 0.003 .958 –0.310 24 .759 –0.05556 (0.17922) –0.42545 to 0.31434  Equal variances not assumed –0.327 15.388 .748 –0.05556 (0.16980) –0.41669 to 0.30558 AverQ8_ProcessValid  Equal variances assumed 0.901 .352 –0.272 25 .788 –0.05556 (0.20443) –0.47659 to 0.36548  Equal variances not assumed –0.244 12.335 .812 –0.05556 (0.22808) –0.55100 to 0.43989 Open in new tab Table 11 t Test Independent Samples Test Characteristic Levene’s Test for Equality of Variances t Test for Equality of Means F Significance t df Significance (Two-Tailed) Mean Difference Std. Error Difference 95% Confidence Interval of the Difference AverQ1_Leadership  Equal variances assumed 1.026 .321 –0.258 25 .798 –0.03333 (0.12910) –0.29922 to 0.23255  Equal variances not assumed –0.280 19.907 .783 –0.03333 (0.11921) –0.28208 to 0.21542 AverQ2_training  Equal variances assumed 0.082 .777 0.543 25 .592 0.08889 (0.16366) –0.24818 to 0.42596  Equal variances not assumed 0.572 18.466 .574 0.08889 (0.15549) –0.23718 to 0.41496 AverQ3_Preassess  Equal variances assumed 0.032 .859 0.504 25 .619 0.12222 (0.24273) –0.37769 to 0.62214  Equal variances not assumed 0.528 18.308 .604 0.12222 (0.23135) –0.36324 to 0.60768 AverQ4_DesignContrl  Equal variances assumed 0.293 .593 –0.946 25 .353 –0.24444 (0.25843) –0.77669 to 0.28780  Equal variances not assumed –0.886 13.663 .391 –0.24444 (0.27581) –0.83737 to 0.34848 AverQ5_DocuentContrl  Equal variances assumed 0.928 .345 –0.828 25 .415 –0.20000 (0.24148) –0.69733 to 0.29733  Equal variances not assumed –0.893 19.659 .383 –0.20000 (0.22406) –0.66790 to 0.26790 AverQ6_ProcesContrl  Equal variances assumed 1.221 .280 0.088 24 .931 0.01667 (0.18916) –0.37374 to 0.40708  Equal variances not assumed 0.100 18.558 .921 0.01667 (0.16651) –0.33240 to 0.36574 AverQ7_Development  Equal variances assumed 0.003 .958 –0.310 24 .759 –0.05556 (0.17922) –0.42545 to 0.31434  Equal variances not assumed –0.327 15.388 .748 –0.05556 (0.16980) –0.41669 to 0.30558 AverQ8_ProcessValid  Equal variances assumed 0.901 .352 –0.272 25 .788 –0.05556 (0.20443) –0.47659 to 0.36548  Equal variances not assumed –0.244 12.335 .812 –0.05556 (0.22808) –0.55100 to 0.43989 Independent Samples Test Characteristic Levene’s Test for Equality of Variances t Test for Equality of Means F Significance t df Significance (Two-Tailed) Mean Difference Std. Error Difference 95% Confidence Interval of the Difference AverQ1_Leadership  Equal variances assumed 1.026 .321 –0.258 25 .798 –0.03333 (0.12910) –0.29922 to 0.23255  Equal variances not assumed –0.280 19.907 .783 –0.03333 (0.11921) –0.28208 to 0.21542 AverQ2_training  Equal variances assumed 0.082 .777 0.543 25 .592 0.08889 (0.16366) –0.24818 to 0.42596  Equal variances not assumed 0.572 18.466 .574 0.08889 (0.15549) –0.23718 to 0.41496 AverQ3_Preassess  Equal variances assumed 0.032 .859 0.504 25 .619 0.12222 (0.24273) –0.37769 to 0.62214  Equal variances not assumed 0.528 18.308 .604 0.12222 (0.23135) –0.36324 to 0.60768 AverQ4_DesignContrl  Equal variances assumed 0.293 .593 –0.946 25 .353 –0.24444 (0.25843) –0.77669 to 0.28780  Equal variances not assumed –0.886 13.663 .391 –0.24444 (0.27581) –0.83737 to 0.34848 AverQ5_DocuentContrl  Equal variances assumed 0.928 .345 –0.828 25 .415 –0.20000 (0.24148) –0.69733 to 0.29733  Equal variances not assumed –0.893 19.659 .383 –0.20000 (0.22406) –0.66790 to 0.26790 AverQ6_ProcesContrl  Equal variances assumed 1.221 .280 0.088 24 .931 0.01667 (0.18916) –0.37374 to 0.40708  Equal variances not assumed 0.100 18.558 .921 0.01667 (0.16651) –0.33240 to 0.36574 AverQ7_Development  Equal variances assumed 0.003 .958 –0.310 24 .759 –0.05556 (0.17922) –0.42545 to 0.31434  Equal variances not assumed –0.327 15.388 .748 –0.05556 (0.16980) –0.41669 to 0.30558 AverQ8_ProcessValid  Equal variances assumed 0.901 .352 –0.272 25 .788 –0.05556 (0.20443) –0.47659 to 0.36548  Equal variances not assumed –0.244 12.335 .812 –0.05556 (0.22808) –0.55100 to 0.43989 Open in new tab Survey Results: Expert Response per Quartile All participants agreed that leadership commitment was extremely important as illustrated by top ranking statements 1, 2, 3, and 5 with corresponding means from 1.3 to 1.48 (Table 7). The commitment of leadership to institute key performance indicators, conduct direct regulatory initiatives, and maintain and consistently communicate change in the organization was considered significant. However, a poorly rated statement was the task of an organizational preassessment to determine missing processes, lack of procedures, and deficiencies and create a list of necessary guidance documents to comply with regulatory requirements. This outcome was unanticipated due to laboratory accreditation agency practices of a crosswalk between laboratory current processes in comparison to requirements. Statements depicting design control were not considered extremely important, with all five statements located on the second, third, and fourth quartile, despite the proposal for QSR by the FDA. There were no significant results for the following statements: (1) the statement suggesting a procedure to address the process for identification, documentation, and reporting of an adverse event in the laboratory and the (2) establishment of an LDT quality committee to quickly approve changes and provide support. Note: Mean scores with identical values may fall within the same placement across several categories of strategic factors. Respondent Feedback Open-ended questions were presented to the survey respondents in question 9: “Do you agree with the strategic factors identified in the proposed framework for Quality Management System of LDTs? If not, please suggest additional factors pertinent to develop a robust framework.” This question resulted in positive feedback for the development of a QMS framework, and 20 of 35 participants agreed with the strategic factors proposed by the researcher. The respondents agreed that all the factors and statements listed were indeed important. However, leadership buy-in was considered imperative for implementation and to ensure the proper resources to address development of the QMS. Feedback: The Establishment of a QMS Framework The following questions were presented to the survey respondents in question 10: “Do you think the establishment of a Quality Management System framework will assist LDT laboratories incorporate regulatory requirements such as design control more readily? If not, why and what else is necessary?” Out of 35 respondents, 23 answered this question with yes, I agree and strongly agree, and nine of 35 respondents scripted favorable feedback. The respondents agreed that a fully functional QMS is needed to meet accreditation requirements, and document control is critical in this process. An accepted framework will provide the laboratory community with “structure, uniformity and integrity” (survey respondent) and the documentation discipline for all laboratories. The process is not only beneficial for the development of LDTs but in the general laboratory as well to comply with accreditation requirements. A crosswalk of each clause of Part 21 CFR 820 can be performed in comparison to the elements of each QSE. The QSE can be used as the QMS framework; however, the most difficult topic discussed in the draft guidance is clinical significance and how the results derived from an LDT are being used or will be used to guide therapy. Discussion The impetus for change within the laboratory community began with the awareness of patients who were adversely affected by the results of LDTs. Historically, the design and development of LDTs were not under the jurisdiction of CLIA, and testing operations are formally not within the oversight of the FDA. Many articulated that the FDA has no jurisdiction over LDTs. In addition, before synergistic legislation can occur, the agencies must bridge the gap between required regulations. Shelia Walcoff of Goldbug Strategies and an FDA workshop speaker stated, “It is essential that FDA harmonize the QSR requirements with CLIA requirements at a more granular level to prevent duplicate efforts and to ease the regulatory burden” because governmental agencies have not provided the necessary guidance for struggling laboratories.20 The adoption of a laboratory structure that would satisfy accreditation and regulation requirements in the event the 2014 draft guidance becomes a policy is perplexing. The interviewees expressed that laboratories may be required to change business strategies, outsource, or terminate many of the current tests if the FDA proposal becomes a policy. However, interviewees also expressed that laboratory leaders are taking the wait-and-see approach because the laboratory community considers test development a service, not a product. The interviewees shared their concerns about CLIA and the FDA collectively developing standards and guidance documents prior to a policy release. The current regulations for medical devices include requirements for design control geared for product development, and the meaning of design control, methodology, and the translation of these regulations from the medical device industry to a clinical laboratory do not exist. The survey respondents agreed that a regulatory-oriented framework for the development of LDTs is needed in the laboratory, and it is interesting to note that the survey respondents did not consider design control as extremely or very important despite the proposal for a QSR by the FDA. These findings support the conclusion of ambiguity in interpreting the meaning of design control and how this requirement would be adapted to the laboratory environment. Liz Lison, president of Advocea Consulting firm and a FDA workshop speaker, explained, “Most of the failures that I have seen in LDTs may have been averted if design controls had been in place.”20 The eight suggested strategic factors and 40 statements derived from the literature, qualitative interviews, and the FDA workshop provide the impetus for the design of an QMS. The respondents agreed with all statements relevant to the design of a QMS based on needs and gaps expressed by laboratory professionals. This finding aligns with the results of the survey as there was no significant difference in the way the experts vs nonexperts responded to factors and associated statements. All respondents chose statements as extremely important or very important. This finding directly aligns with the recommendation by Katherine Tynan, an independent regulatory consultant from the 2015 FDA workshop, who offered advice to governmental agencies as follows: “Develop a common vocabulary that laboratories can understand.” “Simplify the cumbersome QSR and assist laboratories translate the directives.” “Develop a “QSR fit for purpose and harmonize the standard.” Tynan’s advice to laboratories was to “invest in a quality management system, implement all factors of design control, and be proactive and prepare for future regulatory requirements.”20 Consequently, the preparation of a QMS requires the understanding of where gaps exist to develop appropriate processes that would adhere to requirements. Moreover, this survey statement suggesting review of current policies and procedures to identify gaps was not considered important by all groups. This was an interesting conclusion because this is general practice within laboratory accreditation agencies. The future research includes design of an agile, robust quality management system that will incorporate the suggested factors as follows: leadership commitment, training, preassessment, design control, document control, and development of a QMS framework. References 1. US Food and Drug Administration (FDA) . Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: Framework for Regulatory Oversight of Laboratory Developed Tests . Rockville, MD : Food and Drug Administration ; 2014. WorldCat COPAC 2. Vance , GH . College of American Pathologists proposal for the oversight of laboratory-developed tests . Arch Pathol Lab Med . 2011 ; 135 : 1432 - 1435 . Google Scholar Crossref Search ADS PubMed WorldCat 3. US Food and Drug Administration , Center for Devices and Radiological Health. Discussion paper on laboratory developed tests (LDTs) . https://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/LaboratoryDevelopedTests/UCM536965.pdf. Accessed January 13, 2017 . 4. New York State Department of Health, Wadsworth Center. Laboratory standards . https://www.wadsworth.org/regulatory/clep/clinical-labs/obtain-permit/on-site-survey/laboratory-standards. Accessed February 6, 2016. 5. Genentech Legal Department . Citizens Petition, Regulation of In Vitro Diagnostic Tests . 2008 . WorldCat COPAC 6. Erickson E , Britt E . Lab-developed tests come under fire . Chem Eng News . 2010 ; 88 : 24 - 25 . 7. Evans JP , Watson MS . Genetic testing and FDA regulation: overregulation threatens the emergence of genomic medicine . JAMA . 2015 ; 313 : 669 - 670 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Weiss RL . The long and winding regulatory road for laboratory-developed tests . Am J Clin Pathol . 2012 ; 138 : 20 - 26 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Centers for Medicare & Medicaid Services (CMS) . CLIA overview . https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html. Accessed November 6, 2015. 10. Burd EM . Validation of laboratory-developed molecular assays for infectious diseases . Clin Microbiol Rev . 2010 ; 23 : 550 - 576 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Clinical and Laboratory Standards Institute (CLSI) . Quality Management System Model for Laboratory Services; Approved Guideline . 4th ed. Wayne, PA : CLSI ; 2011 . CLSI document QMS01-A4. WorldCat COPAC 12. Boonstra H , Duran V , Northington Gamble V et al. The “boom and bust phenomenon”: the hopes, dreams, and broken promises of the contraceptive revolution . Contraception . 2000 ; 61 : 9 - 25 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Medical device and radiological health regulations come of age . https://www.fda.gov/aboutfda/whatwedo/history/productregulation/medicaldeviceandradiologicalhealthregulationscomeofage/default.htm. Accessed April 2, 2016. 14. Emergo Group. How long will it take my 510(k) to be cleared by the US FDA?http://www.emergogroup.com/resources/research/fda-510k-review-times-research. Accessed January 10, 2015. 15. Medical Device & Diagnostic Industry . FDA’s refuse to accept policy hit hard in 2013 . http://link.galegroup.com/apps/doc/A374100070/ITOF?u=lom_waynesu&sid=ITOF&xid=e77e0641. Accessed March 14, 2016. 16. FDA Centers for Devices and Radiological Health . Design Control Guidance for Medical Device Manufactures . Rockville, MD : Food and Drug Administration ; 1997 . WorldCat COPAC 17. Clinical Laboratory Standards Institute . Quality System Regulations for Laboratory Developed Tests: A Practical Guide for the Laboratory . Wayne, PA : Clinical Laboratory Standards Institute ; 2015 . WorldCat COPAC 18. World Health Organization . Laboratory Quality Management System . Geneva, Switzerland : World Health Organization ; 2011 . WorldCat COPAC 19. International Organization for Standardization (ISO) . Medical Laboratories: Requirements for Quality and Competence . ISO 15189. Geneva, Switzerland : ISO ; 2012 . WorldCat COPAC 20. Food and Drug Administration. FDA Public Workshop to discuss FDA’s proposal for a risk-based framework for addressing the regulatory oversight of a subset of in vitro diagnostic devices (IVDs) . January 8-9, 2015. http://wayback.archive-it.org/7993/20170112083608/http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm423537.htm. Accessed April 17, 2016. 21. Williams B , Onsman A , Brown T . Exploratory factor analysis: a five-step guide for novices . Austral J Paramed . 2010 ; 8 : 3 . WorldCat 22. US Food and Drug Administration (FDA) . Code of Federal Regulations 21 CFR Part 820 . Washington, DC : Food and Drug Administration ; 1997 . WorldCat 23. Klein R. FDA, CMS and the oversight of laboratory developed tests . Paper presented at ARUP Laboratories, University of Utah ; September 23, 2016 ; Salt Lake City, UT. Google Preview WorldCat COPAC © American Society for Clinical Pathology, 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
TI - Facing the InevitableBeing Prepared for Regulatory Requirements for Laboratory Developed Tests
JO - American Journal of Clinical Pathology
DO - 10.1093/ajcp/aqy014
DA - 2018-04-25
UR - https://www.deepdyve.com/lp/oxford-university-press/facing-the-inevitablebeing-prepared-for-regulatory-requirements-for-csItD09l2Q
SP - 484
VL - 149
IS - 6
DP - DeepDyve
ER -