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Clinical Laboratory Improvement

Amendments of 1998 (CLIA) Waiver 

Applications Final Guidances

Peter Tobin, Ph.D.

Chemist

Division of Program Operations and Management

OHT7: Office of In Vitro Diagnostics and Radiological Health

Office of Product Evaluation and Quality 

Center for Devices and Radiological Health

April 14, 2020
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This Webinar Covers Two Complementary

Final Guidances for CLIA Waiver Applications:

• Recommendations for Clinical Laboratory Improvement Amendments of 1988 

(CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices

– Referred to as the “CLIA Waiver” guidance

• Recommendations for Dual 510(k) and CLIA Waiver by Application Studies 

– Referred to as the “Dual” guidance

www.fda.gov
4

• Background

• Final CLIA Waiver Guidance

– Section V. Demonstrating Insignificant Risk of an 

Erroneous Result – Accuracy 

• Final Dual Guidance

Agenda
5

Objectives

• Understand CLIA waiver pathway options:

– CLIA waiver application following clearance or approval

– Dual Submission (Combined 510(k) and CLIA waiver application 

following a pre-submission)

• Understand the U.S. Food and Drug Administration’s (FDA) current 

thinking on study designs for both pathways 
6

• Background

• Final CLIA Waiver Guidance

– Section V. Demonstrating Insignificant Risk of an 

Erroneous Result – Accuracy 

• Final Dual Guidance

Agenda
7

• CLIA waiver statutory criteria

• 21st Century Cures requirements to update the 2008 CLIA Waiver Guidance

• CLIA waiver pathways addressed by the two final guidances

• Draft guidances issued in 2017 and 2018

Background
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CLIA Statutory Criteria for Waiver

CLIA, 42 U.S.C. 263a(d)(3) Examinations and Procedures, as modified by the Food 

and Drug Administration Modernization Act of 1997 (FDAMA):

“The examinations and procedures [that may be performed by a laboratory with a 

Certificate of Waiver]... are laboratory examinations and procedures that have been 

approved by the Food and Drug Administration for home use or that, as determined 

by the Secretary, are simple laboratory examinations and procedures that have an 

insignificant risk of an erroneous result, including those that −

A) employ methodologies that are so simple and accurate as to render the 

likelihood of erroneous results by the user negligible, or 

B) the Secretary has determined pose no unreasonable risk of harm to the patient if 

performed incorrectly.”

www.fda.gov
9

21st Century Cures Requires an Update to

Sec V. of the CLIA Waiver Guidance

• Sec. 3057, CLIA Waiver Improvements, requires the FDA to publish guidance that:

(1) revises “Section V. Demonstrating Insignificant Risk of an Erroneous Result –

Accuracy” of the [2008 CLIA Waiver Guidance*]

(2) includes the appropriate use of comparable performance between a waived 

user and a moderately complex laboratory user to demonstrate accuracy

www.fda.gov

* “Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver 

Applications for Manufacturers of In Vitro Diagnostic Devices,” issued January 30, 2008
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The Final Guidances Address Two CLIA Waiver 

Pathways

Stepwise CLIA Waiver by Application (CLIA Waiver Guidance)

Dual 510(k) and CLIA Waiver by Application (Dual Guidance)

Marketing Submission 

(Premarket Approval 

[PMA], 510(k), De Novo)

CLIA Record: 

Moderate

Pre-Submission Dual Submission (Combined 510(k) and CLIA Waiver)

CLIA Waiver by Regulation or Clearance/Approval for Home Use

Clearance or Approval of test type listed 

in 42 CFR 493.15(c), or

Clearance or Approval for home use

CLIA Record: Waived

CLIA Waiver by 

Application Pre-Submission
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• Initial drafts of both guidances were issued in November 2017:

– The draft CLIA Waiver guidance was entitled “Select Updates for 

Recommendations for Clinical Laboratory Improvement Amendments of 

1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic 

Devices” and included draft revisions to Section V of the 2008 CLIA 

Waiver Guidance.

– The draft Dual guidance had the same title as the current final guidance.

• Based on comments received, and multiple meetings with stakeholders, 

significantly revised drafts were issued in November 2018.

Draft Guidances Were Issued in 2017 and 2018
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• Background

• Final CLIA Waiver Guidance

– Section V. Demonstrating Insignificant Risk of an 

Erroneous Result – Accuracy 

• Final Dual Guidance

Agenda
13

• Provides study design recommendations for CLIA waiver applications

– Addresses the stepwise CLIA waiver pathway following marketing 

submission clearance/approval

• Significant changes were not made from the 2018 draft

– Only limited edits to address minor technical comments and to 

incorporate the 2018 draft Section V into the 2008 final guidance

Final CLIA Waiver Guidance
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CLIA Waivers Focus on Two Questions

• Is the test system simple?

– Simple test characteristics

– Labeling for waived users (for example, a Quick Reference Guide at 7th

grade level)

• Does the test system have an insignificant risk of erroneous 

result?

– Risk Analysis 

– Flex Studies

– Accuracy Studies
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Test Should be Designed to be Simple to Use

Examples of “Simple” Test Characteristics:

• Automated instrument or unitized test system

• Uses direct unprocessed samples (such as, fingerstick blood, venous whole blood, 

nasal or throat swabs, or urine) 

• Easy to read instructions (such as, a Quick Reference Guide at 7th grade level) 

• No operator intervention during analysis

• No technical or specialized training – troubleshooting or complex error codes

• Easy to read test results (positive, negative, invalid, direct value, etc.) 
16

A Systematic Risk Analysis Should be Conducted

• Recommended resource: ANSI AAMI ISO 14971, Medical Devices - Application 

of Risk Management to Medical Devices (FDA recognized standard) 

• Examples of potential sources of error to consider include:

 Operator error/human factors 

 Specimen handling and integrity – clotted specimen, short sample, interfering 

substances 

 Reagent integrity – improperly stored, outdated 

 Hardware, software and electronics integrity - power failures, bugs, physical trauma 

to unit 

 System stability - calibration 

 Environmental factors – temperature, humidity, atmospheric pressure, surface angle, 

device movement
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Fail-Safe and Failure Alert Mechanisms Should be 

Incorporated to Mitigate Risks

Examples of Fail-safe and Failure Alert Mechanisms:

• Lock-out features

 No result if QC fails

 No result if reagents expired

 No result if outside instrument temperature range

 No result if internal electronic checks or procedural controls fail

• Physical features to ensure correct placement of components

• Monitors of the environment

 Indicator desiccants that alert when outside storage conditions
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Flex and/or Validation Studies are Conducted Based 

on the Risk Analysis

Potential source of 

error

Example of flex studies Example of validation 

studies

Procedure: 

Add 3 drops.

What happens when too 

many or too few drops 

are added?

Study adding 1, 2, 3, 4, 

5, 6 drops – Observe 

when incorrect results 

occur.

Device fails at 1 & 6 

drops.

Studies to validate fail-safe 

or QC or failure alert when 

< 2 drops and > 5 drops.
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• Test instructions intended for untrained operators should be simple and written at 

no higher than a 7th grade level: 

– Quick Reference Guide (QRG): A short (usually one or two page) version of 

the test instructions, preferably laminated and attached to the test system. It is 

intended for untrained operators and contains the step by step instructions 

needed to perform the test with a negligible likelihood of erroneous results.

– Operator’s Instrument Manual: A short version of the instrument manual that 

is intended for untrained operators and includes instructions for start-up of the 

instrument, long term maintenance including calibration (if applicable), error 

codes, etc.

• Note: For waived test systems, the package insert should be intended for the 

medical professional prescribing the test and does not need to be written at a 7th

grade reading level.

Labeling for Waived Devices
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• Background

• Final CLIA Waiver Guidance

– Section V. Demonstrating Insignificant Risk of an 

Erroneous Result – Accuracy 

• Final Dual Guidance

Agenda
21

• Emphasizes validating that the accuracy of a candidate test is not meaningfully 

impacted by differences between non-waived and waived use, including: 

– user training and experience;

– testing environment; or 

– patient populations.

• General information on test accuracy issues not specific to CLIA-waived tests 

has been replaced with references to FDA-recognized consensus standards.

– Additionally, examples of successful CLIA waiver study designs can be found in 

publicly posted CLIA Waiver Decision Summaries.

The Revised Section V Focuses on Study Design 

Aspects Directly Related to Meeting the Statutory 

Criteria for CLIA Waiver
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• Untrained Operator or Waived User:

– A test operator in waived settings and with limited or no training or 

hands-on experience in conducting laboratory testing.

• Trained Operator or Moderate Complexity Laboratory User:

– A test operator who meets the qualifications to perform moderate 

complexity testing (42 CFR 493.1423).

• Note: also see Section V.C.(2) Operators for additional recommendations.

Definitions
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• Option 1: Agreement Studies

– Comparison study designs in which the results of the candidate test in the 

hands of untrained operators are compared to the results of the candidate 

test in the hands of trained operators

– The FDA believes Option 1 will be appropriate for the majority of candidate 

tests

• Option 2: Agreement studies modeled after approaches in the FDA guidance 

on Assay Migration Studies for In Vitro Diagnostic Devices

• Option 3: Flex and human factors engineering studies

• Option 4: Direct Comparison to an Appropriate Comparative Method

– Comparison study designs in which the results of the candidate test in the 

hands of untrained operators are directly compared to the results of an 

appropriate comparative method in the hands of trained operators

Additional Study Design Options Provide Flexibility
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• All tests have some likelihood of erroneous results, but whether the likelihood of 

erroneous results in the hands of waived test users is negligible will vary from test 

to test depending on a number of factors, including: 

– intended use; 

– context of use (for example, patient population, use environment); and

– probable benefit(s) and probable risk(s) or harm(s) associated with waived use 

of the test.

• Accordingly, the appropriate acceptance criteria for CLIA waiver accuracy studies 

will vary from test to test.

• For details about the FDA’s current thinking about benefit-risk considerations for 

medical devices, CDRH benefit-risk guidances are referenced rather than 

repeating similar material.

We’re Harmonizing Our Approach to CLIA Waiver BenefitRisk Considerations with Other FDA Benefit-Risk Guidances 
25

• The FDA recommends that applicants evaluate test performance in settings 

designed to replicate, as closely as possible, intended:

– CLIA-waived testing sites;

– Patients, sample type and matrix; and

– Untrained operators.

• Testing should be integrated into the daily workflow of the facility where the 

operators are often multitasking between patient care, testing, and other duties.

• Include at least 3 sites and at least 9 untrained operators (across all sites).

• Pre-Submissions are highly recommended to get feedback from the FDA on study 

designs before conducting the studies.

General CLIA Waiver Study Design 

Considerations Have Not Changed
26

• Background

• Final CLIA Waiver Guidance

– Section V. Demonstrating Insignificant Risk of an 

Erroneous Result – Accuracy 

• Final Dual Guidance

Agenda
27

• Describes an efficient single set of comparison and reproducibility study 

designs with untrained users for a Dual 510(k) and CLIA Waiver by 

Application (“Dual Submission” or Dual”)

– The Dual study design recommendations in this guidance may also be 

utilized in a sequential submission approach in which a CLIA Waiver by 

Application follows marketing authorization (such as, PMA, De Novo)

• Significant changes were not made from the 2018 draft, only minor edits to 

harmonize with technical edits to the CLIA Section V guidance

Final Dual Guidance
28

Historically, Separate 510(k) and CLIA Waiver Studies 

Have Been Conducted in Different Clinical Settings

www.fda.gov

510(k) Point of Care (POC) 

Sites & Trained Users

CLIA Waiver 

by 

Application

Waived Sites & 

Untrained Users

• In this two step approach, 

manufacturers conduct 

separate comparison and 

reproducibility studies, in 

different clinical settings, first to 

support 510(k) clearance and 

later to support CLIA Waiver by 

Application.
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• Inform the FDA that you plan to submit a Dual Submission in a Pre-Submission 

prior to submitting the Dual Submission.

• A Dual Submission should contain the same information as a complete 510(k) and 

CLIA Waiver by Application: 

– Content related to the comparison and reproducibility studies may overlap.

• Therefore, a single set of comparison and reproducibility studies may be 

used to support both 510(k) clearance and CLIA Waiver by Application.

– All other content that would otherwise be included in separate, sequential 

510(k) and CLIA Waiver by Application submissions should be included in a 

Dual Submission.

Process and Content of a Dual Submission
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The Dual Approach Provides Time and Study Efficiencies

510(k) – POC CLIA Waiver Application

• Analytical studies as

• analytical sensitivity,

• analytical specificity,

• linearity,

• reagent stability,

• sample stability, and so on

• Simple,

• Flex studies

• Comparison study

(POC sites & trained users)

• Comparison study

(CLIA waived sites and untrained users)

• Reproducibility study

(POC sites & trained users)

• Reproducibility study

(CLIA waived sites and untrained users)
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• For comparison study design and analysis we recommend you follow 

appropriate FDA-recognized consensus standards, such as:

– For quantitative tests: 

• Clinical Laboratory Standards Institute (CLSI) EP21, CLSI EP27

– For qualitative tests: 

• CLSI EP12.

• See Section V of the CLIA Waiver guidance for general study design 

considerations. 

Comparison Study Design Recommendations
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• For reproducibility study design and analysis, we recommend you follow 

appropriate FDA-recognized consensus standards (such as, CLSI EP05, 

CLSI EP12).

• Include a minimum of 3 of the same sites that were included in the 

comparison study. 

• To facilitate statistical analysis, include the same number of untrained 

operators (likely 2 or 3) at each site.

• Include the following sources of variability: different sites, different 

untrained operators, different days, different runs, different lots (if 

applicable), and a few replicates.

Reproducibility Study Design Recommendations
33

• Final Guidances:

– Administrative Procedures for CLIA Categorization

– Recommendations for Clinical Laboratory Improvement Amendments of 1988 

(CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices

– Recommendations for Dual 510(k) and CLIA Waiver by Application Studies

– Requests for Feedback and Meetings for Medical Device Submissions: The QSubmission Program

• CLIA Waiver Decision Summaries

Resources
34

Questions?

CLIA@fda.hhs.gov

Slide Presentation, Transcript and Webinar Recording 

will be available at:

http://www.fda.gov/training/cdrhlearn

Under the Heading: Specialty Technical Topics; Subheading: In Vitro Diagnostics