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Clinical Laboratory Improvement

Amendments of 1998 (CLIA) Waiver 

Applications Draft Guidances

Peter Tobin, Ph.D.

Chemist

Division of Program Operations and Management

Office of In Vitro Diagnostics and Radiological Health

Center for Devices and Radiological Health
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This Webinar Covers Two Complementary

Draft Guidances for CLIA Waiver Applications:

• Select Updates for Recommendations for Clinical Laboratory Improvement 

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

Diagnostic Devices

– Referred to as: Draft “Section V” Guidance

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

– Referred to as: Draft “Dual” Guidance

• These draft guidances are not final and not in effect at this time

www.fda.gov
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• Background

• Revised Draft Section V Guidance

• Revised Draft Dual Guidance

Agenda
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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 FDA’s current thinking on study designs for both 

pathways 
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• CLIA waiver statutory criteria

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

• CLIA waiver pathways addressed by the two drafts

• Why we are re-issuing the guidances as drafts

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
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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
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Summary of 2008 CLIA Waiver Guidance

• Is the test system simple?

– Simple test characteristics

– Labeling for waived users (for example: 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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The Draft Guidances Address Two CLIA Waiver 

Pathways

Stepwise CLIA Waiver by Application (2008 CLIA Waiver Guidance & Draft Section V)

Dual 510(k) and CLIA Waiver by Application (Draft 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 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 (CR): Waived

CLIA Waiver by 

Application Pre-Submission
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• Previous drafts of both guidances were issued in 

November 2017

• Based on comments received, and multiple meetings with 

stakeholders, the new drafts have been thoroughly revised

• Because of the significant changes made, we are reissuing in draft to allow stakeholder comments before 

finalizing

Re-Issuing Significantly Revised CLIA Waiver 

Guidances in Draft to Allow Stakeholder Comments 
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• Untrained Operator or Waived User:

– A test operator in waived settings who has 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) and with previous training in 

performing the test.

Definitions
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• Provides study design recommendations for demonstrating that a test is 

accurate in the hands of intended CLIA-waived users

– as part of a CLIA waiver application following clearance/approval

• The FDA believes this guidance will reduce barriers to bringing simple and 

accurate tests to CLIA-waived settings, such as doctor’s offices

Revised Draft Section V Guidance
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• 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 now be found in 

publicly posted CLIA Waiver Decision Summaries

The Revised Draft Section V Focuses on Study 

Design Aspects Directly Related to Meeting the 

Statutory Criteria for CLIA Waiver
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CLIA Waiver Decision Summaries Promote 

Consistency and Predictability
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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 (New): Agreement studies modeled after approaches in the FDA 

guidance on Assay Migration Studies for In Vitro Diagnostic Devices

• Option 3 (New): 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), 

– 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 
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• The FDA recommends that applicants evaluate test performance in settings 

designed to replicate, as closely as possible:

– intended CLIA-waived settings

– patients/samples, 

– test operators, and

– testing over time, as in the typical intended use setting

• 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
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• Describes a more efficient single set of comparison and reproducibility 

study designs with untrained users for a Dual Submission 

• Similar to Section V, general information on test accuracy issues not 

specific to CLIA-waived tests has been replaced with references to FDArecognized consensus standards

• The FDA believes the Dual pathway is in many instances the least 

burdensome and fastest approach for manufacturers to obtain a CLIA 

waiver in addition to 510(k) clearance for new tests

Revised Draft Dual Guidance
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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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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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Dual Submissions Became the Preferred 

CLIA Waiver Pathway in FY18

FY13 FY14 FY15 FY16 FY17 FY18

Standalone CLIA Waivers 3 14 11 9 7 4

Dual Submissions 0 1 3 1 6 11

0% 7%

21%

10%

46%

73%

Submissions

Fiscal Year Received

Duals accounted 

for nearly 3/4 of 

the CLIA Waiver 

Program in FY18
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• Draft guidances: Please Comment (Due Feb 27, 2019)

– Select Updates for Recommendations for Clinical Laboratory Improvement Amendments 

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

Guidance for Industry and FDA Staff, Comment Here: FDA-2017-D-5570

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

Guidance for Industry and FDA Staff, Comment Here: FDA-2017-D-5625

• Final guidances:

– Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) 

Waiver Applications for Manufacturers of In Vitro Diagnostic Devices

– Administrative Procedures for CLIA Categorization

• CLIA Waiver Decision Summaries

Resources
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Questions?

CLIA@fda.hhs.gov

Slide Presentation, Transcript and Webinar 

Recording will be available at:

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

Under the Heading: In Vitro Diagnostics