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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: ASM Books
- Sprache: Englisch
Successfully manage your laboratory accreditation and compliance audits with this easily accessible how-to resource for clinical laboratories
101 Topics for Clinical Microbiology Laboratory Leaders: Accreditation, Verification, Quality Systems, and More by Rebekah M. Martin is your roadmap to achieving and maintaining excellence in clinical microbiology laboratory administration. This quick reference guide is designed to help laboratory professionals efficiently navigate the key aspects of accreditation, regulatory compliance, and quality management. This practical resource is perfect for both new and experienced laboratory leaders who need accessible, actionable information.
Inside, you’ll find:
- Regulatory Overview: Information on the Clinical Laboratory Improvement Amendments, test complexity categories, and the roles of key agencies like the Centers for Medicare & Medicaid Services, the Centers for Disease Control and Prevention, and the Food & Drug Administration in overseeing clinical laboratories.
- Accreditation Basics: Guidance on how to obtain and maintain laboratory accreditation, including what to expect during inspections and how to respond to deficiencies.
- Test Verification & Validation: Essential tips on conducting verification and validation studies to ensure your laboratory’s test systems are accurate, reliable, and compliant with regulatory standards.
- Quality Management Essentials: Practical strategies for implementing and maintaining a quality management system, including process control, document management, and continuous improvement techniques that keep your lab running smoothly.
Presented in a user-friendly question-and-answer format, 101 Topics for Clinical Microbiology Laboratory Leaders is your go-to resource for quick, reliable guidance on leading a compliant and high-performing clinical microbiology laboratory.
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Seitenzahl: 496
Veröffentlichungsjahr: 2025
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Table of Contents
Cover
Table of Contents
Title Page
Copyright Page
Dedication Page
Foreword
Prefacepreface
Acknowledgments
About the Author
List of Abbreviations
Part I: Getting Started: Regulatory Oversight and Laboratory Accreditation
1 Clinical Laboratory Improvement Amendments (CLIA) and Regulatory Oversight
How is “clinical laboratory” defined?
What is CLIA?
What is the Code of Federal Regulations (CFR)?
What roles do the Centers for Medicare and Medicaid Services (CMS), the Centers for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA) play in regulating clinical laboratories?
What is an FDA‐cleared or FDA‐approved test?
What is a laboratory developed test (LDT)?
What does the FDA final rule mean for my laboratory?
What is Emergency Use Authorization (EUA)?
What is test complexity?
Is there a list of tests categorized by complexity?
References
2 Clinical Laboratory Improvement Amendments (CLIA) Certificates
Which laboratories need a CLIA certificate?
Which laboratories are NOT required to obtain a CLIA certificate?
What are the types of CLIA certificates?
What procedures are categorized as provider‐performed microscopy (PPM) procedures?
How does a laboratory obtain a CLIA certificate?
How many laboratories can be on one CLIA certificate?
Can one location have multiple CLIA certificates?
How many CLIA certificates can one laboratory director have?
How long is a CLIA certificate effective, and how does a laboratory renew a CLIA certificate?
What are the laboratory specialties and subspecialties?
Which states have CLIA‐exempt laboratory programs?
When can a laboratory begin testing?
Who should be notified if there are changes in the laboratory, and when?
What happens if a laboratory is out of compliance with CLIA requirements?
References
3 Waived Testing
What are waived tests?
Is there a list of tests that are waived?
Is my laboratory subject to inspection if we perform waived testing?
What are the personnel qualifications for performing waived testing in clinical laboratories?
Are there compliance exemptions for laboratories performing waived testing?
References
4 Laboratory Accreditation
What is laboratory accreditation?
What are the current CMS‐approved accrediting agencies?
How can my laboratory become accredited?
How does my laboratory maintain accreditation?
What happens during a laboratory inspection?
How does a laboratory respond when cited for deficiencies?
How is laboratory noncompliance addressed by CMS?
Can I become a laboratory inspector?
What is “ISO certification/accreditation” and does my laboratory need it?
I need some help with terms!
References
Part II: Going Live: Verification and Validation of Test Systems
5 Verification and Validation
What are verification and validation?
When should a laboratory perform a verification or validation study?
If our laboratory complies with the FDA final rule for LDTs, do we still need to perform a validation study for our LDTs?
What is a test system?
What counts as a modification to a test system?
Who is responsible for designing and implementing a verification or validation study?
Can the company who made the instrument perform the verification study?
What performance characteristics should be assessed for a verification study?
What performance characteristics should be assessed for a validation study?
Is verification/validation necessary for point of care and other CLIA‐waived assays?
My laboratory is moving an instrument. Is a verification/validation necessary?
My laboratory has five of the same instruments running the same assay. Do we have to run a verification/validation on each instrument?
My laboratory has multiple high‐complexity laboratories across the health system that run the same assays on the same platform. Does a verification/validation need to be performed at each location?
My laboratory stopped running a particular assay. Is verification/validation necessary to resume testing with this assay?
My laboratory is running a test under Emergency Use Authorization (EUA). Is verification/validation required?
Which laboratory personnel are involved in a verification/validation study?
References
6 Performance Characteristic: Precision
What is precision?
How many and what types of samples should be used to assess precision?
How does a laboratory assess precision for qualitative assays?
How does a laboratory assess precision for quantitative assays?
What calculations should be used for precision?
How can precision be assessed for matrix‐assisted laser desorption ionization–time of flight (MALDI‐TOF) identification systems?
How can precision be assessed for antimicrobial susceptibility test (AST) systems?
How can precision be assessed for multiplex molecular systems?
References
7 Performance Characteristic: Accuracy/Agreement
What is accuracy?
How many and what types of samples should be used to assess accuracy?
What calculations should be used for accuracy?
What calculations should be used for agreement?
How does disease prevalence affect test performance?
How can accuracy be assessed for matrix‐assisted laser desorption ionization–time of flight (MALDI‐TOF) identification systems?
How can accuracy be assessed for antimicrobial susceptibility test (AST) systems?
How can accuracy be assessed for multiplex molecular systems?
References
8 Performance Characteristic: Reportable Range
What is reportable range?
How many and what types of samples should be used to assess reportable range?
How does a laboratory assess reportable range for quantitative assays?
How does a laboratory assess reportable range for qualitative assays?
How can reportable range be assessed for matrix‐assisted laser desorption ionization–time of flight (MALDI‐TOF) identification systems?
How can reportable range be assessed for antimicrobial susceptibility test (AST) systems?
How can reportable range be assessed for multiplex molecular systems?
References
9 Performance Characteristic: Reference Interval
What is a reference interval?
How many and what types of samples should be used to assess the reference interval?
How does a laboratory assess the reference interval?
What calculations should be used for reference interval?
How can the reference interval be assessed for matrix‐assisted laser desorption ionization–time of flight (MALDI‐TOF) identification systems?
How can the reference interval be assessed for antimicrobial susceptibility test (AST) systems?
How can the reference interval be assessed for multiplex molecular systems?
References
10 Performance Characteristic: Analytical Sensitivity
What is analytical sensitivity?
How many and what types of samples should be used to assess analytical sensitivity?
How does a laboratory assess analytical sensitivity?
What calculations should be used for analytical sensitivity?
How can analytical sensitivity be assessed for matrix‐assisted laser desorption ionization–time of flight (MALDI‐TOF) identification systems?
How can analytical sensitivity be assessed for antimicrobial susceptibility test (AST) systems?
How can analytical sensitivity be assessed for multiplex molecular systems?
References
11 Performance Characteristic: Analytical Specificity
What is analytical specificity?
How many and what types of samples should be used to assess analytical specificity?
How does a laboratory assess analytical specificity?
What should we do if cross‐reactivity or interfering substances are identified?
How can analytical specificity be assessed for matrix‐assisted laser desorption ionization–time of flight (MALDI‐TOF) identification systems?
How can analytical specificity be assessed for antimicrobial susceptibility test (AST) systems?
How can analytical specificity be assessed for multiplex molecular systems?
References
12 Additional Performance Characteristics
What additional performance characteristics could be considered, and how are they assessed?
References
13 Unacceptable Results and Resolution
What should we do if there are significant discrepancies between our new assay and the comparator assay? (Accuracy)
We are using a less sensitive method as our comparator method, and our new test is showing poor agreement and increased “false positives.” What should we do? (Accuracy)
Our assay shows significant cross‐reactivity with a particular organism. What should we do? (Analytical specificity)
References
14 Documentation for Verification and Validation Studies
What documentation is necessary for a verification or validation study?
What should be included in a verification/validation plan?
What should be included in a verification/validation summary?
How long is the laboratory required to keep verification/validation documentation?
What do I do if my laboratory’s legacy assays do not have verification/validation documentation?
References
Part III: Staying Live: Quality Management Systems
15 Quality Management Systems
What is a quality management system, and why is it essential for clinical microbiology laboratories?
What are the essentials of a quality management system?
What are some additional resources to help with developing a quality management system?
References
16 Essential: Organization
What is “organization” in a quality management system?
What are some key organization components to consider for a clinical microbiology laboratory?
What is a quality manual and how do I write one?
References
17 Essential: Laboratory Personnel
Who are the key clinical microbiology laboratory personnel?
What are the qualifications for laboratory personnel by test complexity?
Do testing personnel need to be licensed and/or certified?
How is personnel competency assessed?
What personnel records should be maintained, where, and for how long?
References
18 Essential: Customer Service
Who are the clinical microbiology laboratory’s customers?
How is customer satisfaction monitored?
How is customer dissatisfaction managed?
References
19 Essential: Facilities and Safety
How does the laboratory maintain safety?
How does the laboratory maintain security?
How does a laboratory perform a risk assessment?
What role does facilities design play in safety?
What is emergency/disaster preparedness and how can this be implemented in the laboratory?
References
20 Essential: Purchasing and Inventory
What is the purchasing and inventory quality essential?
What are key considerations for purchasing materials and services?
How is inventory managed?
What happens when there is a lack of inventory?
What are examples of external services that need to be tracked and managed?
What documents and records should be retained for purchasing and inventory?
References
21 Essential: Equipment
What is the equipment quality essential?
What are examples of equipment in the clinical microbiology laboratory?
If we use multiple instruments to perform the same test, do test results need to be compared?
What documents and records should be maintained for equipment?
How is return on investment calculated?
References
22 Essential: Process Control
What is process control?
How can the laboratory implement process control?
What is quality control (QC)?
What is an individualized quality control plan (IQCP)?
What is a Levey‐Jennings control chart?
What are calibration and calibration verification?
What documents and records should be retained as part of process control?
References
23 Essential: Document and Records Management
What are documents and records?
What is document and records management?
What are controlled and uncontrolled documents?
What is a policy versus a procedure?
What should be included in an analytical testing standard operating procedure (SOP)?
How does the laboratory store documents and records?
How long does the clinical microbiology laboratory need to retain documents and records?
References
24 Essential: Information Management
What is information management?
What are some key considerations for information management?
What is the LIS?
References
25 Essential: Occurrence Management
What is occurrence management?
What are some common laboratory errors?
How should the laboratory respond when a nonconforming event (NCE) occurs?
When and how does the laboratory perform a root cause analysis (RCA)?
What are corrective and preventive actions (CAPAs)?
References
26 Essential: Assessment
What is assessment?
How does the laboratory monitor quality processes?
What are inspections, surveys, or audits?
What indicators should the laboratory use to monitor and assess quality?
How does the laboratory implement proficiency testing (PT)?
References
27 Essential: Process Improvement
What is process improvement?
What should be included in a process improvement plan?
What does it mean for a process to be efficient and effective?
What are some common improvement models and tools?
What is a process map?
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1‐1 Intended FDA Final Rule Compliance Requirements by LDT Assay Type...
Table 1‐2 Recent Public Health Emergencies with Emergency Use Declared for ...
Chapter 2
Table 2‐1 CLIA Certificate Renewal
Table 2‐2 Laboratory Specialties and Subspecialties
Table 2‐3 Notification Requirements by CLIA Certificate
Chapter 6
Table 6‐1 Precision: Suggested Strategies
Table 6‐2.1 Intra‐Assay Results
a
Table 6‐2.2 Intra‐Assay Agreement (Repeatability)
a
Table 6‐3.1 Inter‐Assay Results
a
Table 6‐3.2 Inter‐Assay Agreement (Reproducibility)
a
Table 6‐4 Example Microbial Identification System Precision Assessment
a
Table 6‐5 Example Antimicrobial Susceptibility Test System Precision Assess...
Table 6‐6.1 Example Samples for Assessing Precision on a Multiplex Respirat...
Table 6‐6.2 Multiplex System: Intra‐Assay Results
a
Table 6‐6.3 Multiplex System: Intra‐Assay Agreement
a
Table 6‐6.4 Multiplex System: Inter‐Assay Resultsa
a
Table 6‐6.5 Multiplex System: Inter‐Assay Agreement
a
Chapter 7
Table 7‐1 Accuracy: Suggested Strategies
Table 7‐2.1 Example Microbial Identification System Accuracy Assessment—Gra...
Table 7‐2.2 Example Microbial Identification System Accuracy Assessment—Mul...
Table 7‐3.1 Example Antimicrobial Susceptibility Test System Accuracy Assess...
Table 7‐3.2 Example Antimicrobial Susceptibility Test System Accuracy Assess...
Table 7‐4.1 Example Samples for Assessing Accuracy on a Multiplex Respirato...
Table 7‐4.2 Example Samples Known Positive and Negative for Each Analyte
a
...
Table 7‐4.3 Mutliplex System: Example 2x2 Table to Assess Accuracy or Agreem...
Table 7‐4.4 Multiplex System: Example 2x2 Table to Assess Overall Accuracy ...
Chapter 8
Table 8‐1 True and Measured Values for Linearity Study Example
a
Chapter 9
Table 9‐1 Reference Interval: Suggested Strategies
Chapter 17
Table 17‐1 Required Personnel by Laboratory Test Complexity
a
Chapter 23
Table 23‐1 Revision Table Example
Table 23‐2 CLIA Retention Requirements
a
,
b
List of Illustrations
Chapter 6
Figure 6‐1 Precision and Accuracy. Precision and accuracy can be visualized ...
Chapter 7
Figure 7‐1 Example Antimicrobial Susceptibility Test System Accuracy Assessm...
Chapter 8
Figure 8‐1 Analytical Measurement Range. An example of the analytical measur...
Figure 8‐2 Linearity, Linear Range, and Analytical Measurement Range. Linear...
Figure 8‐3 Example Linearity Study for Establishing the Analytical Measureme...
Chapter 19
Figure 19‐1 Organism Risk Groups and Biosafety Levels. The initial step in a...
Figure 19‐2 Risk Matrix. A risk matrix is a tool to aid in a laboratory’s ri...
Chapter 22
Figure 22‐1 Levey‐Jennings Control Chart. An example Levey‐Jennings co...
Chapter 25
Figure 25‐1 NCE Response Process. This figure outlines the NCE response proc...
Figure 25‐2 NCE Risk Matrix and Course of Action Chart. This figure shows bo...
Figure 25‐3 Fishbone Diagram Analysis. A fishbone diagram is shown. This dia...
Chapter 27
Figure 27‐1 SWOT Analysis Table. This table is used as part of the SWOT (stre...
Figure 27‐2 Process Map Symbols. This figure shows common, standardized symb...
Figure 27‐3 Process Map Example. Shown here is an example of a process map f...
Guide
Cover Page
Table of Contents
Title Page
Copyright Page
Dedication Page
Foreword
Preface
Acknowledgments
About the Author
List of Abbreviations
Begin Reading
Index
Wiley End User License Agreement
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101 TOPICS FOR CLINICAL MICROBIOLOGY LABORATORY LEADERS
ACCREDITATION, VERIFICATION, QUALITY SYSTEMS, AND MORE
Rebekah M. Martin, PhD, D(ABMM), MLS(ASCP)CM
Medical Affairs Manager, Molecular Solutions
BD Life Sciences ‐ Integrated Diagnostic Solutions
Becton, Dickinson and Company
Copyright © 2025 American Society for Microbiology. All rights reserved.Copublication by the American Society for Microbiology and John Wiley & Sons, Inc.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted by law. Advice on how to reuse material from this title is available at http://wiley.com/go/permissions.
The right of Rebekah M. Martin to be identified as the author of this work/the editorial material in this work has been asserted in accordance with law.
Limit of Liability/Disclaimer of WarrantyWhile the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy of completeness of the contents of this book and specifically disclaim any implied warranties or merchantability of fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The publisher is not providing legal, medical, or other professional services. Any reference herein to any specific commercial products, procedures, or services by trade name, trademark, manufacturer, or otherwise does not constitute or imply endorsement, recommendation, or favored status by the American Society for Microbiology (ASM) or by the author. The views and opinions of the author(s) expressed in this publication do not necessarily state or reflect those of ASM, and they shall not be used to advertise or endorse any product.
Editorial Correspondence:ASM Press, 1752 N Street, NW, Washington, DC 20036‐2904, USA
Registered Offices:John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA
For details of our global editorial offices, customer services, and more information about Wiley products, visit us at www.wiley.com.
Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand.
Some content that appears in standard print versions of this book may not be available in other formats.
Library of Congress Cataloging‐in‐Publication Data Applied for:Hardback ISBN: 9781683674450
Cover Design: WileyCover Image: © Golden Sikorka/Shutterstock
For BenLife with you is my favorite adventurexxx
Excellence, then, is not an act but a habit.—Will Durant (1926) The Story of Philosophy: The Lives and Opinions of the World's Greatest Philosophers (often misattributed to Aristotle)
Foreword
As I settle into the later phase of my career in diagnostic and medical microbiology, I occasionally reflect on my activities, which I hope have had a special impact on or significance to the field. Two notable examples that stand out are mentoring the next generation of laboratory medicine leaders and serving as a subject matter expert on the topic of verification and validation of laboratory tests. (I fondly remember being referred to by colleagues as the “V and V guy.”) In these areas, I have had the pleasure of collaborating with Rebekah Martin, coauthoring manuscripts on the verification and validation of laboratory tests. Martin has demonstrated a deep knowledge and understanding of this complex subject, for which written regulations are relatively sparse. This often leaves details open to interpretation and forces laboratorians to consult supplemental materials authored by subject matter experts.
In this book, Martin provides a concise overview and practical guidance for several topics that are important responsibilities of laboratory leaders. These topics include laboratory accreditation, verification and validation of laboratory tests (of course), and essential elements of a laboratory quality management system—such as personnel qualifications, competency assessments, equipment maintenance, information management, document control, process control (including individualized quality control programs), nonconforming event investigation, and process improvement. These are challenging topics, because (as previously mentioned) the laboratory regulations often lack granularity. Much is left to the discretion and expertise of the laboratory director, whether designing a test verification study, developing a competency assessment program, investigating nonconforming events, or establishing an external quality assessment program for nonregulated analytes. While there are resources available for these topics, Martin has skillfully tied it all together in one practical, insightful, and informative guide. Concise and addressing the key points, this book serves as a pocket guide that I’m confident laboratory leaders will frequently consult. Keep it in a handy location—a hard copy will likely be well worn.
Several chapters deserve special mention. The book appropriately begins with a comprehensive description of the Clinical Laboratory Improvement Amendments (CLIA), which includes a nice description of emergency use authorization (EUA) and the important distinction between an EUA and a declared public health emergency. Martin does a great job of defining test complexity designations, and her chapter on waived testing is particularly timely given the recent explosion in point‐of‐care testing for infectious diseases, driven largely by COVID‐19, as well as sexually transmitted infections, hepatitis C virus, and others. Most point‐of‐care testing in the United States is performed with CLIA‐waived tests, and this chapter addresses some key considerations such as personnel qualifications and training requirements.
A chapter near and dear to my heart is the one on verification and validation, which provides important definitions for ambiguous concepts such as a test system and what represents a test modification. Martin also helps to sort out an ongoing source of confusion: when is it necessary to perform a verification or validation study? The chapter on quality management systems (QMS) discusses each of the essential elements of a QMS and describes important resources such as the Clinical and Laboratory Standards Institute (CLSI). The chapter on personnel clearly lays out the CLIA definitions of laboratory personnel, distinguishing, for examples, between individuals who might be titled “laboratory director” by their institution but are actually usually either a technical or general supervisors under CLIA’s definitions—an important distinction.
Finally, the chapter on occurrence (or error, or nonconforming event) management is essential reading. Some of these laboratory errors can lead to adverse events and patient harm and Martin does a superb job explaining the process for managing errors, including monitoring, investigating, determining root cause, and implementing corrective and preventive actions. I especially note the inclusion of a risk matrix table in this chapter that highlights the probability and risk of patient harm.
Martin’s book will be extremely valuable not only for laboratory leaders—medical and technical directors, managers, supervisors —but also for trainees in laboratory medicine fellowship programs, for whom board examinations are right around the corner. As a current representative of the diagnostic device industry, I also strongly believe this book will be a great resource for my industry colleagues, helping them better understand the laboratory customer environment and the regulatory guard rails in which they operate.
Michael Loeffelholz
Vice President, Scientific Affairs
Cepheid
Sunnyvale, CA
Preface
The purpose of this book is to act as a guide for navigating some of the complexities of clinical microbiology laboratory administration. As we all know, maintaining compliance in the clinical laboratory can be challenging. Not only are regulations and requirements numerous, but they can sometimes be confusing or vague—and on occasion there may be updates or events that introduce new requirements and unfamiliar processes. Additionally, terms like “CLIA,” and activities such as “verification” and “document control” are often casually referred to, but are also often unaccompanied by definitions, context, or an explanation of how to fulfill related requirements. It is therefore unsurprising that it may be daunting to develop—or even to work within—a laboratory management and administrative system when there are gaps in practical knowledge.
When I began working on this project, I wanted to create something that would help fill these gaps for laboratory administrators and employees, but that would also be something I would have actually used in the clinical laboratory. I also wanted to consolidate information into a single, digestible resource. My goal was therefore to develop an easy‐to‐use, accessible reference that could provide readers across experience levels with context for various requirements as well as some specific suggestions for best practices. The product of these contemplations is what you now hold in your hands.
While the focus of this text is on activities for the clinical microbiology laboratory in particular, a great deal of what is included will be applicable to or adaptable for other specialties in the clinical laboratory. It should be noted that the requirements and suggestions included throughout the book are intended for clinical laboratories based in the United States that must comply with U.S. federal and/or state requirements1.
As a final note, this book is meant to be an aid for YOU. Whether you are a new (or seasoned!) laboratory director, a microbiology fellow or pathology resident, a laboratory manager, a medical laboratory scientist, a student, or you just happen to be interested in these topics, my hope is that you find this text useful (and perhaps even a little bit engaging) and that you come away with more knowledge than when you started.
Rebekah M. MartinOctober 2024
Note
1
This book is comprehensive but not exhaustive. Laboratory personnel both within and outside of the United States are responsible for identifying and complying with all applicable regulations and requirements.
Acknowledgments
It is perhaps cliché—but nonetheless true—to say that this book would never have happened without the support of a whole host of people. I’ve been incredibly lucky to have a fantastic group of colleagues, friends, and family who have assisted in getting me to this point. I wish to extend particular thanks to those listed here.
Michael J. Loeffelholz, for recommending me to write this book. When you passed the torch of expertise, I never dreamed it would lead to this!
Christine Charlip, for taking a chance on me. My thanks for your faith and trust.
Megan Angelini, my editor, for really everything! But especially for showing endless encouragement and patience, and for believing in this book as much as I do.
Michael J. Loeffelholz, Susan E. Sharp, Linoj Samuel, Paige M.K. Larkin, Eileen M. Burd, Lars F. Westblade, Alessandro Rossi, Lauren Cooper, and Max Louzon for providing critical feedback on the book proposal, outline, and manuscripts.
Bob Tibbetts, for ushering me into the world of verification and validation, and importantly, for your mentorship and friendship.
Linoj Samuel, for inviting me to write the V&V chapter with Mike and for your guidance and support over the years.
All the Beautiful Micro Mamas: Mel, Paige, Jocelyn, Lauren, Thess, Phyu, and Dona! For sharing wisdom, experience, frustration, and laughter. You women inspire me.
Lola, my cat, for providing all the snuggles during writing sessions.
Elisa, my sibling, for being a source of delight, encouragement, and support; both in writing and in life.
Bob and Kathy, my parents, for being interested in and proud of everything I’ve accomplished. And of course, thank you for regularly asking about how “the book” is going. Good news mom and dad…it’s finally finished!!
Ben, my husband. As an historian and archivist, you probably care very little about the regulations governing clinical micro labs. But you care about me, and you know that I care about this. Thank you for reading every single chapter and providing feedback prior to submission, and for putting up with me while I fretted about deadlines and brooded over specific wording. You are always the first to tell me “You can do it”. You encourage me to reach for my dreams—whether those dreams involve writing a book, moving across the ocean, or taking time to do absolutely nothing—and I would not have made it as far as I have without your partnership and support.
And finally, thanks to you, the reader, for taking the time to engage with this book.
About the Author
Rebekah (Bekah) M. Martin, PhD, D(ABMM), MLS(ASCP)CM has enjoyed working in or adjacent to the clinical microbiology laboratory throughout a career that spans the health care, academic, and industry sectors. After graduating with a clinical laboratory science degree from Michigan State University (Go Green!), she worked as a medical laboratory scientist in the microbiology division at Henry Ford Hospital in Detroit. She then went on to receive her PhD in molecular and cellular pathology from the University of Michigan where her dissertation focused on identifying bacterial and host risk factors for clinical infection with Klebsiella pneumoniae. She has completed a medical microbiology fellowship at the University of Utah School of Medicine and ARUP Laboratories, worked as an associate technical director of microbiology at Labcorp, taught as an assistant professor both in the Clinical and Diagnostic Sciences department at Oakland University and in the Biomedical Laboratory Diagnostics program at Michigan State University, and is currently the regional medical affairs subject matter expert for molecular solutions at Becton, Dickinson, and Company (BD) in the Europe, Middle East, and Africa region. Bekah is certified as a Diplomate of the American Board of Medical Microbiology, and also maintains certification as a Medical Laboratory Scientist through the American Society for Clinical Pathology Board of Certification. She is passionate about good food and wine. She also enjoys traveling, spending time outdoors hiking and kayaking, and spending time indoors reading. Bekah currently lives in the East Riding of Yorkshire in the United Kingdom with her husband Ben and their cat Lola.
List of Abbreviations
Unless otherwise stated, all government regulations and bodies refer to those in the United States.
A2LA
American Association for Laboratory Accreditation
AABB
Association for the Advancement of Blood & Biotherapies (formerly the American Association of Blood Banks)
ABB
American Board of Bioanalysis
ABCC
American Board of Clinical Chemistry
ABFT
American Board of Forensic Toxicology
ABMGG
American Board of Medical Genetics and Genomics
ABMLI
American Board of Medical Laboratory Immunology
ABMM
American Board of Medical Microbiology
ACHC
Accreditation Commission for Health Care
ACHI
American College of Histocompatibility and Immunogenetics (formerly American Board of Histocompatibility and Immunogenetics [ABHI])
ACLA
American Clinical Laboratory Association
AMP
Association for Molecular Pathology
AMR
Analytical measurement range
ANAB
ANSI National Accreditation Board
ANSI
American National Standards Institute
APHL
Association of Public Health Laboratories
ASCP BOC
American Society for Clinical Pathology Board of Certification
ASHI
American Society for Histocompatibility & Immunogenetics
ASM
American Society for Microbiology
ASR
Analyte specific reagents
AST
Antimicrobial susceptibility test
BSL
Biosafety level
BLA
Biologics License Application
BV
Bacterial vaginosis
CA
Categorical agreement
CAP
College of American Pathologists
CAPA
Correction and preventive action
CDC
Centers for Disease Control and Prevention
CE
Continuing education
CFR
Code of Federal Regulations
CFU
Colony forming units
CI
Confidence interval
CLIA
Clinical Laboratory Improvement Amendments
CLIAC
Clinical Laboratory Improvement Advisory Committee
CLSI
Clinical and Laboratory Standards Institute
CMS
Centers for Medicare and Medicaid Services
COA
Certificate of Accreditation
COC
Certificate of Compliance
COLA
The Commission on Office Laboratory Accreditation
COVID‐19
Coronavirus disease 2019
COW
Certificate of Waiver
CRE
Carbapenem‐resistant Enterobacterales
CSF
Cerebrospinal fluid
CT/NG
Chlamydia trachomatis
/
Neisseria gonorrhoeae
CV
Coefficient of variation
DCLS
Doctor of Clinical Laboratory Science
DMAIC
Define, measure, analyze, improve, control
DMLI
Diplomate in Medical Laboratory Immunology
DNA
Deoxyribonucleic acid
DO
Doctor of Osteopathic Medicine
DoD
Department of Defense
DOT
Department of Transportation
EA
Essential agreement
EHR
Electronic health care record
EOP
Emergency operations plan
EPA
Environmental Protection Agency
EQA
External quality assessment
ESBL
Extended‐spectrum beta‐lactamase
EUA
Emergency use authorization
FDA
Food and Drug Administration
FD&C Act
Federal Food, Drug, and Cosmetic Act
Flu
Influenza/influenza virus
FMEA
Failure modes and effects analysis
FN
False negative
FP
False positive
FRACAS
Failure reporting, analysis, and corrective action system
GPR
General purpose reagents
HAN
Health Alert Network
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HLA
Human leukocyte antigen
HHS
Department of Health and Human Services
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HHS
Department of Health and Human Services
hMPV
Human metapneumovirus
HPV
Human papillomavirus
HR
Human resources
I
Intermediate
ID
Identification
IFU
Instructions for use
IQ
Installation qualification
IQCP
Individualized quality control plan
IRB
Institutional review board
ISO
International Organization for Standardization
IT
Information technology
IU
International units
IVCT
In vitro
clinical tests
IVD
In vitro
diagnostic
JCAHO
The Joint Commission on Accreditation of Healthcare Organizations (former name and acronym). Currently known as The Joint Commission.
KPI
Key performance indicator
LAI
Laboratory‐acquired infection
LDT
Laboratory developed test
LIS
Laboratory information system
LIMS
Laboratory information management system
LLoQ
Lower limit of quantification
LoD
Limit of detection
LoQ
Limit of quantification
LRN
Laboratory Response Network
MALDI‐TOF
Matrix‐assisted laser desorption ionization–time of flight
MD
Doctor of Medicine
MD
Major discrepancy rate
MinD
Minor discrepancy rate
MDR
Medical device reporting
ME
Major error rate
MIC
Minimum inhibitory concentration
MinE
Minor error rate
MIS
Microbial identification system
mL
Milliliter
MLS
Medical laboratory scientist
MLT
Medical laboratory technician
MSA
Master service agreement
MSM
Men who have sex with men
N/A
Not applicable
NCE
Nonconforming event
NPA
Negative percent agreement
NPV
Negative predictive value
NRCC
National Registry of Certified Chemists
NS
Nonsusceptible
NYS
New York State
NYS CLEP
New York State Clinical Laboratory Evaluation Plan
OQ
Operational qualification
OSHA
Occupational Safety and Health Administration
PDCA
Plan‐do‐check‐act
PFU
Plaque forming units
PGCM
Practical Guidance for Clinical Microbiology
PHE
Public health emergency
PHI
Protected health information
PI
Package insert
PIV
Parainfluenza virus
PMA
Premarket approval
PO
Purchase order
POCT
Point‐of‐care test
PPE
Personal protective equipment
PPM
Provider‐performed microscopy
PPA
Positive percent agreement
PPV
Positive predictive value
PQ
Performance qualification
PT
Proficiency testing
QA
Quality assessment
QA
Quality assurance
QC
Quality control
QCP
Quality control plan
QMS
Quality management system
QNS
Quantity not sufficient
QSE
Quality system essential
R
Resistant
RBC
Red blood cell
RCA
Root cause analysis
RFI
Request for information
ROI
Return on investment
RSV
Respiratory syncytial virus
S
Susceptible
SAMSHA
Substance Abuse and Mental Health Services Administration
SARS‐CoV‐2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SDD
Susceptible‐dose dependent
SE
Standard error
SMART
Specific, measurable, achievable, relevant, and time‐bound
SOP
Standard operating procedure
SPC
Statistical process control
SWOT
Strengths, weaknesses, opportunities, and threats
TAT
Turnaround time
TCID
50
Tissue culture infectious dose
TLA
Total laboratory automation
TN
True negative
TP
True positive
ULoQ
Upper limit of quantification
U.S
United States
USPS
United States Postal Service
VALID
Verifying Accurate Leading‐Edge IVCT Development Act
VHA
Veterans Health Administration
VMD
Very major discrepancy rate
VME
Very major error rate
VV
Verification/validation
WHO
World Health Organization
Part IGetting Started: Regulatory Oversight and Laboratory Accreditation
1Clinical Laboratory Improvement Amendments (CLIA) and Regulatory Oversight
How is “clinical laboratory” defined?
The Code of Federal Regulations in the United States defines a laboratory as follows:
“…a facility for the biological, microbiological, serological, chemical, immunohematological, hematological, biophysical, cytological, pathological, or other examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings. These examinations also include procedures to determine, measure, or otherwise describe the presence or absence of various substances or organisms in the body. Facilities only collecting or preparing specimens (or both) or only serving as a mailing service and not performing testing are not considered laboratories.” (42 CFR §493.2) (1)
Laboratories that operate as defined above are subject to regulation by the Clinical Laboratory Improvement Amendments (CLIA) and are often referred to as clinical laboratories. The term clinical laboratories will be used throughout this book to refer to laboratories regulated by CLIA.
There are some key aspects that help identify a clinical laboratory based on the definition above:
What is occurring in the laboratory? Laboratories must be involved in testing. If a location is handling specimens for other purposes but is not performing any testing, they are not considered a clinical laboratory.
What is being tested? The laboratory must examine human specimens, which refers to any materials that are obtained from humans. These include but are not limited to blood, body fluids and secretions, tissues, urine, stool, hair and nails, and swabs from various body sites. Human samples collected postmortem during an autopsy may also be tested in clinical laboratories (2).
What is the purpose of testing? The purpose of testing in the laboratory must be for patient management. This can include testing to assist in diagnosis, monitor disease progress, track treatment impact, engage in preventative care, or assess potential organ donors (3).
Other laboratories may perform testing on human samples, but not for the purposes of health assessment and patient management. These are not considered clinical laboratories and they are not subject to CLIA requirements. Examples of such laboratories include research laboratories, forensic laboratories, and laboratories certified by the Substance Abuse and Mental Health Services Administration (SAMSHA) that perform only drug testing (other testing performed in SAMSHA certified laboratories may require a CLIA certificate) (4).
What is CLIA?
CLIA stands for Clinical Laboratory Improvement Amendments. When someone mentions “CLIA” they may be talking about either CLIA law or CLIA regulations. CLIA law refers to the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88) (Public Law 100‐578), which were amendments to the Clinical Laboratories Improvement Act of 1967 (CLIA’67) and were signed into law in 1988. CLIA regulations, on the other hand, are requirements codified in the Code of Federal Regulations (42 CFR §493 Laboratory Requirements). CLIA regulations were issued by the Centers for Medicare and Medicaid Services (CMS) in 1992 in order to enact CLIA’88. From 1992 to 1994, CLIA regulations were phased in. Amendments to these regulations have occurred periodically since then. For further information on CLIA regulations see section What is the Code of Federal Regulations (CFR)? The section here will discuss CLIA law.
The Clinical Laboratories Improvement Act of 1967 (Public Law 90‐174)
In 1967, a new section (Sec. 353) was added to the Public Health Service Act (5). Titled Licensing—Biological Products and Clinical Laboratories, the purpose of this addition was briefly noted as “to improve the performance of clinical laboratories.” Also known as The Clinical Laboratories Improvement Act of 1967 (CLIA’67), this brief section represented the establishment of quality standards for clinical laboratories in the United States.
CLIA’67 required interstate laboratories performing testing on human samples for the purposes of diagnosis, prevention, treatment, or assessment of a disease or condition to obtain a license to operate. In order to obtain and maintain a license, laboratories needed to demonstrate adherence to certain standards meant to improve clinical laboratory quality and ultimately ensure patient safety. Specifically, the standards were meant to ensure: 1) maintenance of a quality control program, 2) maintenance of records, equipment, and facilities, 3) qualifications of the laboratory’s director(s) and other personnel, and 4) participation in a proficiency testing program.
CLIA’67 had a relatively limited reach, however. It only applied to laboratories that took part in “interstate commerce” i.e., only laboratories that did business across state lines. Laboratories accredited by any accrediting agency with requirements equal to or more stringent than those found in CLIA’67 were exempt from the licensing requirement, as were smaller laboratories and labs whose activities remained within one state. CLIA’88 would widen that reach.
The Clinical Laboratory Improvement Amendments of 1988 (Public Law 100‐578)
In late 1987, two articles were published in The Wall Street Journal by journalist Walt Bogdanich detailing false negative Papanicolaou (Pap) smear results that led to missed diagnoses in cervical cancer screening (6, 7). Bogdanich’s articles suggested that the inaccurate Pap smear results were due to overwork, lack of quality control, and lack of appropriate education for testing personnel (). In response to the resulting public upset and in order to strengthen and improve existing laws governing clinical laboratories, Congress passed the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88) (8).
CLIA’88 outlined several amendments to Public Health Service Act section 353. Important among these changes was the establishment of minimum standards for all clinical laboratories in the U.S., not just those involved in interstate commerce (9). Also included in CLIA’88 was the requirement for development of standards for: laboratory personnel qualifications, quality control (QC) and quality assurance (QA) procedures, and proficiency testing requirements. CLIA’88 also introduced waived and nonwaived test categorization.
Two amendments to CLIA’88 were later implemented, one in 1997 to update the criteria for waived testing and one in 2012 related to proficiency testing referral (10, 11). Despite these recent amendments, CLIA law is still referred to as CLIA’88.
What is the Code of Federal Regulations (CFR)?
The Code of Federal Regulations (CFR) is the codification of regulations set forth by federal departments and agencies in the United States. The official CFR is reviewed and published annually by the Office of the Federal Register. An unofficial “point in time” version can be found online and is known as the Electronic Code of Federal Regulations (e‐CFR) (https://www.ecfr.gov/).
The CFR provides regulations for a wide range of industries and sectors, including clinical laboratories. Specifically, Title 42 Part 493 (42 CFR §493), titled “Laboratory Requirements,” details the regulations all clinical laboratories must follow in order to acquire and maintain certification to perform human specimen testing under CLIA ’88 (1). In other words, the CFR contains the federal requirements a clinical laboratory must comply with in order to legally test human samples for health care purposes. 42 CFR §493 provides regulations for all clinical laboratories, including those performing microbiology and serology testing on human specimens. As with CLIA law, the purpose of 42 CFR §493 is to provide quality standards that clinical laboratories must meet, with a mind toward ensuring quality testing and patient safety.
42 CFR §493 provides regulations on several topics ranging from how clinical laboratories acquire and maintain certification, to personnel qualifications, to details on how to maintain a quality system for every type of system. Several topics within 42 CFR §493 will be covered in this book, however readers are advised to read through 42 CFR §493 for official information (https://www.ecfr.gov/current/title‐42/chapter‐IV/subchapter‐G/part‐493). Though the CFR is an excellent resource for clinical laboratory administrators, it can sometimes be unclear. To aid laboratories in interpreting how to fulfill various requirements, the Centers for Medicare and Medicaid Services (CMS) publishes interpretive guidelines that accompany 42 CFR §493 (12).
What roles do the Centers for Medicare and Medicaid Services (CMS), the Centers for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA) play in regulating clinical laboratories?
Three federal agencies are responsible for administering CLIA in the United States: the Centers for Medicare and Medicaid Services (CMS), the Centers for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA). Each agency has distinct but complementary roles in administering CLIA and providing support and oversight for clinical laboratories (4, 13‐15).
CMS regulates clinical laboratory testing in the United States under CLIA. Specifically, CMS does the following:
Develops and publishes CLIA regulations
Issues CLIA certificates to clinical laboratories
Approves accreditation agencies that perform inspections
Performs inspections
Approves state exemptions for state programs deemed equivalent to CLIA (currently only Washington state and New York state are exempt from CLIA program requirements)
(16)
Enforces regulatory compliance
The CDC supports the administration of CLIA through its Clinical Laboratory Improvement Advisory Committee (CLIAC) and provides several services that aid clinical laboratories in improving quality. The CDC supports clinical laboratories by:
Advising the U.S. Department of Health and Human Services (HHS) on scientific and technical issues pertaining to clinical laboratories, with a focus on improving quality and practices. This is achieved through the CDC’s CLIAC. CLIAC also provides guidance on revisions to CLIA standards
(17)
. Committee members represent all disciplines of the clinical laboratory and are professionals working in clinical, academic, and industry spaces. CLIAC meetings are open to the public and can be viewed virtually.
Publishing guidelines and recommendations for testing and treatment of diseases, including infectious diseases
Providing online training courses and videos for laboratory professionals. Training activities can be found here:
https://www.cdc.gov/lab‐training/php/onelab/
The FDA is responsible for:
Reviewing applications for authorization of
in vitro
diagnostic (IVD) devices and subsequently clearing, approving, or granting manufacturers the ability to market IVDs
Designating IVDs into one of three CLIA categorizations. In order of least to most complex, tests are categorized as either waived tests, moderate‐complexity tests, or high‐complexity tests.
The FDA also has authority to regulate laboratory developed tests (LDTs), and, until recently, they have chosen to exercise “enforcement discretion” such that they did not require premarket notification or approval for these assays. However, the FDA has announced they will be phasing out this enforcement discretion in conjunction with their issuance of the final rule. The final rule amends FDA regulations to state that IVDs that are developed by clinical laboratories are now subject to the Federal Food, Drug, and Cosmetic (FD&C) Act (18). See sections What is a laboratory developed test (LDT)? and What does the FDA final rule mean for my laboratory? for additional information of the FDA’s role in overseeing LDTs.
What is an FDA‐cleared or FDA‐approved test?
Tests that are performed on human samples (e.g., blood, body fluids or secretions, tissue) for the purpose of screening, diagnosis, or monitoring of diseases or other conditions are known as in vitro diagnostic (IVD) products. Before a manufacturer introduces an IVD to the market, they are required to notify the FDA of their intent to put that device on the market. To do this, manufacturers must submit premarket notification (510(k))1 applications, premarket approval (PMA) applications, or De Novo classification requests to the FDA, who will then review applications to ensure that the device is both safe and effective before its introduction to the market (19).
Class I or II2 IVDs being introduced to the market for the first time and that are considered “substantially equivalent” to another device already on the market (also known as a predicate device) are required to go through the 510(k) premarket notification review process. If the 510(k) review process is successful, these devices are cleared by the FDA (FDA cleared) and may be legally placed on the market (20, 21).
IVDs that are classified as class III devices—which are considered the most high‐risk devices and therefore require the most stringent regulatory control—and are introduced to the market for the first time are required to go through the premarket approval (PMA) process. If the PMA review process is successful, these devices are approved by the FDA (FDA approved) and may be legally placed on the market (22, 23).
De Novo classification requests may be submitted for IVDs being introduced to the market for the first time and that meet the standards for low‐ or moderate‐risk devices (likely to be classified as class I or II), but that do not have a substantially equivalent (predicate) device already on the market3 . If the De Novo review process is successful, the FDA grants the manufacturer the right to legally place the device on the market. The device can then be used as a predicate device for future 510(k) submissions.
As a point on terminology, the various submissions result in scenarios where the FDA may clear (510(k)), approve (PMA), or grant (De Novo) a manufacturer’s ability to legally market a device.
What is a laboratory developed test (LDT)?
The FDA defines a laboratory developed test (LDT) as “…an IVD that is intended for clinical use and designed, manufactured and used within a single laboratory.” (24). In other words, if a clinical laboratory develops their own test for use in patient testing, it is considered an LDT. Additionally, if a clinical laboratory makes any modifications to an FDA‐cleared or FDA‐approved test, the modified test is also considered an LDT. The FDA considers a single laboratory to be a facility with a single CLIA certificate4. Therefore, if an LDT is being used under multiple CLIA certificates, it is not considered an LDT under the FDA definition and is out of compliance. Similarly, if a test is developed or manufactured partially or completely outside of a single laboratory, it is not considered an LDT and is out of compliance. Components of LDTs should include general purpose reagents (GPRs), analyte specific reagents (ASRs), or in‐house materials (25). ASRs and GPRs manufactured outside of the laboratory do not violate the FDAs requirement for a test to be manufactured completely within a single laboratory (26). LDTs may only be used in laboratories that meet the CLIA requirements for high‐complexity testing (see 42 CFR §493.17(c)(4) and 42 CFR §493.25) (1).
The FDA has authority to regulate LDTs, and, until recently, they have chosen to exercise “enforcement discretion” such that they did not require premarket notification or approval for these assays. Throughout the past decades, the FDA has written several draft guidances and documents regarding the regulation of LDTs. In May 2024, the FDA announced they were amending their regulations with regard to LDT oversight, such that LDTs are now subject to certain FDA regulations, including premarket notification or approval (with some exceptions) (18). See What does the FDA final rule mean for my laboratory? below for additional information on this announcement and how it affects clinical laboratories in the United States.
What does the FDA final rule mean for my laboratory?
In May 2024, the FDA published details of the previously announced final rule regarding their oversight of LDTs (18). This rule updated FDA regulations such that the definition of IVDs under the Federal FD&C Act includes IVDs that are “manufactured” by laboratories5. In other words, it unequivocally gives the FDA oversight of the regulation of LDTs. In addition to this update, the FDA also announced they would be phasing out the “enforcement discretion” they have previously implemented for LDTs, meaning that in most instances clinical laboratories that develop and use LDTs must now comply with several regulations that are applicable to IVD manufacturers (18). A high‐level overview of the applicable FDA requirements, the expected implementation stages and compliance start dates, and the affected LDT types will be discussed in this section. As a reminder, only clinical laboratories that meet the CLIA requirements for high‐complexity testing may develop and use LDTs.
FDA Requirements
The FD&C Act is a set of laws that grant the FDA the authority to regulate the production, sale, and distribution of medical devices6 (as well as other products) in the United States. These laws are codified within Title 21 of the CFR. The regulations specifically governing medical devices are found in Title 21 Parts 800–898. Under the amended regulations, clinical laboratories that produce and “market”7 LDTs must now comply with a subset of these requirements, specifically the following (18):
Medical Device Reporting (MDR) (21 CFR Part 803)
Correction and Removal Reporting (21 CFR Part 806)
Registration and Listing (21 CFR Part 807)
Labeling (21 CFR §809.10)
Investigational Use (21 CFR Part 812)
Premarket Review Submission for High‐Risk IVDs (21 CFR Part 814)
High‐risk IVDs are reviewed through the PMA process
Premarket Review Submission for Low‐ and Moderate‐Risk IVDs (21 CFR Part 807 Subpart E for 510(k) submissions; and 21 CFR Part 860 Subpart D for De Novo submissions)
8
Low‐ and moderate‐risk IVDs are reviewed through the premarket notification (510(k)) or De Novo processes
Quality System Regulations
Only a subset of the quality system regulations (found in Part 820) is applicable to clinical laboratories. Specifically, clinical laboratories must comply with the following requirements:
Design Controls (21 CFR §820.30)
Purchasing Controls (21 CFR §820.50)
Acceptance Activities (21 CFR Part 820 Subpart H)
Corrective and Preventive Actions (21 CFR §820.100)
Records (21 CFR §820.180‐186)
Complaint Files (21 CFR §820.198)
These requirements are substantial, and most are significantly different than the requirements clinical laboratories are familiar with. It will take time to implement processes for meeting these requirements within clinical laboratories. Laboratories that currently develop and use LDTs, or intend to do so in the future, should therefore familiarize themselves with these requirements as soon as possible and reach out to the FDA with questions.
Implementation Stages and Compliance Start Dates
The FDA is implementing a phaseout policy wherein they are phasing out the general enforcement discretion they previously applied. This phaseout policy is being undertaken in five stages over four years. For each stage, there is an accompanying date that identifies when clinical laboratories are expected to be compliant with the regulations in each stage. This date is designated as the compliance start date in this book. Each stage is described below, including the compliance start date and the regulations included in that stage (18). This information is also shown in Table 1–1.
Stage 1: Clinical laboratories that produce IVDs must comply with the medical device reporting, correction and removal reporting, and complaint files requirements. Compliance with these requirements is expected starting May 6, 2025.
Stage 2: Clinical laboratories that produce IVDs must comply with the registration and listing, labeling, and investigational use requirements. Compliance with these requirements is expected starting May 6, 2026.
Stage 3: Clinical laboratories that produce IVDs must comply with the remaining quality system requirements not already addressed in stage 1. This includes the design controls, purchasing controls, acceptance activities, corrective and preventive actions, and records requirements. Compliance with these requirements is expected starting May 6, 2027.
Stage 4: Clinical laboratories that produce IVDs must comply with the premarket review requirements for high‐risk IVDs by submitting a PMA. Compliance with this requirement is expected starting November 6, 2027.
Stage 5: Clinical laboratories that produce IVDs must comply with the premarket review requirements for low‐ or moderate‐risk IVDs by submitting a premarket notification (510(k)) or a De Novo request. Compliance with these requirements is expected starting May 6, 2028.
LDT Categories
There are several categories into which the FDA has organized LDTs, each of which is described here (18). It is important for laboratory personnel to have a good understanding of what types of LDTs are included in each category since the above‐mentioned requirements will be applicable to some but not all categories (see the discussion on targeted enforcement discretion below).
1976‐type LDTs: This category includes tests that have certain characteristics in common with LDTs that were offered in 1976, when the original enforcement discretion came into effect. These characteristics include
(18)
:
Techniques are performed manually (with no automation) by laboratory personnel with specialized expertise
Components used for the test are legally marketed for clinical use
The test is developed and used within a single clinical laboratory that meets the CLIA requirements for high‐complexity testing
Human leukocyte antigen (HLA) LDTs for transplantation: This category refers to HLA tests that are considered LDTs (i.e., developed and used within a single laboratory that meets the CLIA requirements for high‐complexity testing), and that are used to perform HLA allele typing, HLA antibody screening and monitoring, and HLA crossmatch tests (real or virtual) in order to aid in organ, tissue, and/or stem cell transplantation
(18)
.
Table 1‐1 Intended FDA Final Rule Compliance Requirements by LDT Assay Type. This table lists each of the FDA compliance requirements for LDTs manufactured in clinical laboratories, as well as the expected stage and compliance start dates for each requirement, and where in Title 21 of the CFR each requirement is detailed. For each LDT category, the applicable requirements are also identified. Note that for 1976‐type LDTs, HLA LDTs for transplantation, forensic tests, and DoD and VHA LDTs, the FDA intends to continue applying enforcement discretion, such that compliance is not expected for any of the listed requirements. Clinical laboratories must comply with the requirements for the remaining LDT categories as applicable. Applicable requirements for each category are indicated as “Yes” in the table. For information on each type of LDT category, see section What does the FDA final rule mean for my laboratory? main text. LDTs that must comply with premarket submission requirements should submit an application for only one of the pathways (PMA, 510(k), or De Novo) depending on the device’s expected risk level and whether there is a predicate device.
FDA Requirements for Laboratory Developed Test Compliance
Stage
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
Compliance Start Date
May 6, 2025
May 6, 2026
May 6, 2027
Nov 6, 2027
May 6, 2028
Requirement
Medical Device Reporting
Correction and Removal Reporting
Quality System: Complaint files
Registration and Listing
Labeling
Investigational Use
Quality System
Premarket Review Submission (PMA)
Premarket Review Submission (510(k), De Novo)
Design Controls
Purchasing Controls
Acceptance Activities
Corrective & Preventive Actions
Records
21 CFR Section
Part 803
Part 806
§820.198
Part 807
§809.10
Part 812
§820.30
§820.50
Part 820, Subpart H
§820.100
§820.180‐186
Part 814
Part 807, Subpart E (510(k)) Or Part 860 Subpart D (De Novo)
LDT Categories & Applicable Requirements
1976‐Type LDTs
The FDA intends to exercise enforcement discretion for these LDTs. Laboratories are not required to comply with any of the above requirements for these LDT assays.
HLA for Transplant
The FDA intends to exercise enforcement discretion for these LDTs. Laboratories are not required to comply with any of the above requirements for these LDT assays.
Forensic Tests
The FDA intends to exercise enforcement discretion for these LDTs. Laboratories are not required to comply with any of the above requirements for these LDT assays.
DoD and VHA
The FDA intends to exercise enforcement discretion for these LDTs. Laboratories are not required to comply with any of the above requirements for these LDT assays.
NYS CLEP‐Approved
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Rare RBC Antigens
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Unmet Needs
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Currently Marketed
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Minor Modifications (Marketed LDT)
a
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Significant Modifications
(Marketed LDT)
a
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Minor Modifications (510(k) or De Novo)
b
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Significant Modifications
