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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

January 8, 2018

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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 “Sec V” Guidance

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

Studies

– Referred to as: Draft “Dual” Guidance

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 FDA to publish guidance that:

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

Result – Accuracy” of the guidance entitled “Recommendations for Clinical

Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for

Manufacturers of In Vitro Diagnostic Devices” and dated January 30, 2008;

and

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

waived user and a moderately complex laboratory user to demonstrate

accuracy.

www.fda.gov

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The Draft Guidances Address Two CLIA Waiver Pathways

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

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

Marketing Submission (PMA, 510(k), De Novo

CR: Moderate

Pre-Submission Dual Submission (Combined 510(k) and CW)

CLIA Waiver by Regulation or Clearance for Home or OTC use

Clearance /Approval of test type listed in 42 CFR 493.15(c), or Clearance/Approval for home or Over-the-Counter (OTC) use

CLIA Record (CR): Waived

CLIA Waiver by Application (CW) Pre-Submission

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Outline

• Background

– Recent CLIA Waiver Program Improvements

• Draft Section V Guidance

• Draft Dual Guidance

• Recommendations for Semi-Quantitative Tests

www.fda.gov

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The CLIA Waiver Program Has Improved Dramatically

• In the last few years, CLIA waiver program improvements

have addressed stakeholder concerns with CLIA waiver

review times, approval rates, study design flexibility, and

transparency

www.fda.gov

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CLIA Waiver Approvals Have Increased Significantly

www.fda.gov

FY08 FY09 FY10 FY11 FY12 FY13 FY14 FY15 FY16

MDUFA III

FY08 FY09 FY10 FY11 FY12 FY13 FY14 FY15 FY16 12 7 5 5 6 3 15 14 10 5 3 2 3 2 2 11 8 8

Received Approved

Approved 80% in FY2016

Approved 42% in FY2008

MDUFA II

MDUFA = Medical Device User Fee Amendments

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Average Review Times for CLIA Waivers Have Dropped Dramatically

www.fda.gov

MDUFA III

Additional CLIA waiver resources provided by MDUFA IV will allow the FDA to reach faster performance goals and make additional CLIA waiver program improvements

0

50

100

150

200

250

300

350

400

FY2008

FY2010

FY2012

FY2014

FY2016

Average FDA days to MDUFA Decision

MDUFA II

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CLIA Waiver Decision Summaries Demonstrate Flexibility in Study Designs Supporting CLIA Waiver Approvals and Increase Transparency in the CLIA Waiver Review Process

https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm578178.htm

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Draft Sec V. Guidance

• Describes how manufacturers may leverage existing accuracy data from a marketing submission (e.g., 510(k), PMA) and conduct less costly agreement studies that compare performance of the test between a waived user and a moderately complex laboratory user to demonstrate accuracy

• Follows least burdensome principles and references recognized consensus standards for study designs

www.fda.gov

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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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Accuracy is a Widely Used and Generally Understood Term in Clinical Laboratory Science

• For example, the Clinical Laboratory Standard Institute in EP21 defines accuracy as “the closeness of an agreement between a test result and the accepted reference value”

• The more accurate a test is, the less error there is, and therefore, the more likely the test is to have an “insignificant risk of erroneous result”

• Inaccurate tests may lead to incorrect patient management decisions and inappropriate public health responses

www.fda.gov

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Why is it Important to Demonstrate Accuracy in Order for a Test to be CLIA Waived?

So that CLIA-waived laboratories don’t have to!

Under CLIA, for a non-waived test:

• The responsibility for delivering accurate results to patients is broadly shared between the test manufacturer and laboratories that choose to perform the test

• The data provided by the manufacturer to support FDA clearance/approval is only part of the data supporting that the test is accurate

• Non-waived laboratories complete additional verification or validation before performing a test for patients

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Why is it Important to Demonstrate Accuracy in Order for a Test to be CLIA Waived? Unlike non-waived laboratories, CLIA-waived laboratories do not:

1. Verify or establish the accuracy and other performance characteristics of a cleared or approved test

2. Verify or establish that the test’s reference intervals (normal values) are appropriate for the laboratory's patient population

3. Perform proficiency testing 4. Operate within a quality system

• Validation of the accuracy of a test performed by the manufacturer to support CLIA waiver saves over 180,000 CLIA-waived laboratories from having to perform comparable validation themselves

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Draft Sec V Study Options Promote Innovation While Protecting Patients

CT = Candidate Test, CM = Comparative Method: reference, traceable, or well-documented

• Potentially less costly agreement study promotes innovation and patient access

• Comparison to CM protects patients

CM CT Trained

CT Untrained

510(k)/PMA CLIA Waiver (Agreement)

Option 1:

CM CT Untrained

CLIA Waiver (Direct)

Option 2: (existing 2008 CLIA Waiver option)

• Simpler analysis and less uncertainty than Option 1

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When is Option 1 Appropriate?

1. The accuracy of the candidate test when performed by trained operators was demonstrated through comparison to an appropriate comparative method in the premarket submission (510(k), PMA, De Novo, etc.), and

2. The premarket study subjects/samples were representative of the intended use population at CLIA waived sites.

Valid statistical methods may then be used to estimate the accuracy of the test when performed by untrained operators using a combined analysis of the data from both studies

www.fda.gov

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When is Option 1 Not Appropriate?

CT = Candidate Test, CM = Comparative Method: reference, traceable, or well-documented

CM CT Trained

CT Untrained

510(k)/PMA CLIA Waiver (Agreement)

?

Predicate Trained

Unknown Relationship to True Value – Can’t determine if the candidate test performed by untrained users has an insignificant risk of erroneous results

When data are not available to support accuracy of the test with trained operators compared to an appropriate comparative method

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When is Option 2 Appropriate?

• Option 2 is always accepted and is also used in the Dual approach

• Option 2 is recommended for sponsors who want the best study to determine accuracy with less uncertainty and simpler analysis then Option 1

www.fda.gov

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Draft Dual Guidance

• Describes study designs for generating data to support both 510(k) clearance and

CLIA Waived categorization

• Intended to assist manufacturers in using the optional Dual 510(k) and CLIA

Waiver by Application pathway (Dual pathway), formalized and piloted at the

request of industry groups in MDUFA III

• FDA believes the Dual pathway is in many instances the least burdensome and

fastest approach for manufacturers to obtain a CLIA waived categorization in

addition to 510(k) clearance for new In Vitro Diagnostic (IVD) devices

www.fda.gov

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Historically, Separate 510(k) and CLIA Waiver Studies Have Been Conducted in Different Clinical Settings

www.fda.gov

Two Step: Direct (Existing 2008 and Draft Sec V: Option 2)

510(k) Candidate Test by Trained Users vs. Comparative Method or Predicate

CLIA Waiver by Application

Candidate Test by Untrained Users vs. Comparative Method

• 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 Draft Dual Guidance Describes a More Efficient Single Study Approach for New IVDs

www.fda.gov

Two Step: Agreement (Draft Sec V: Option 1)

Two Step: Direct (Existing 2008 and Draft Sec V: Option 2)

Dual Study (Draft Dual)

510(k) Candidate Test (CT) by Trained Users vs. Comparative Method (CM)

CT by Trained Users vs. CM or Predicate

CLIA Waiver by Application

CT by Untrained Users vs. CT by Trained Users

CT by Untrained Users vs. CM

CT by Untrained Users vs. CM

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Recommendations for Semi-Quantitative Tests Are a New Feature of the Draft Guidances

• The appropriate design of the studies and data analysis is

strongly influenced by whether the candidate test is quantitative,

qualitative or semi-quantitative

• For the purpose of these guidances, a semi-quantitative test is a

test with a few ordinal categories (e.g., negative, trace, +, ++,

+++) in which the order of categories together with the

definitions of these categories contain information used during

the interpretation of the test results

www.fda.gov

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• For example, consider a semi-quantitative test for Albumin with 4 categories (bins), each covering a concentration range:

Neg 1+ 2+ 3+

Near Cutoff Region 2

Near Cutoff Region 3

Near Cutoff Region 1

• Even when comparing a semi-quantitative test to itself: – Some level of disagreement is expected for samples in the near

cutoff regions

– The extent of disagreement will increase with increased numbers of samples in the near cutoff regions

Why is a Quantitative Comparative Method Recommended for Semi-Quantitative Tests?

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Hypothetical Data: Comparative Method (Semi-Quantitative)

Neg 1+ 2+ 3+ Candidate Test (Semi-Quantitative)

Neg 143 8 1+ 19 114 26 2+ 5 136 24 3+ 5 161

Agreement: 88.3% 89.8% 81.4% 87.0% Total Agreement: 86.4%

– Cannot determine whether samples with discordant results are close to bin cutoffs (where some level of disagreement would be expected) because quantitative sample values are not known

– Therefore not possible to evaluate whether levels of disagreement between bins are acceptable

Using a Semi-Quantitative Comparative Method Provides Less Information than a Quantitative Comparative Method and therefore Candidate Test Performance May Appear Worse

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– Can determine whether samples are close to candidate test bin cutoffs (where some level of disagreement would be expected)

– Allows separate evaluation of agreement in 7 regions: • The 3 near cutoff regions where some disagreement is expected (grey

regions below)

• The 4 regions near the center of the bins where near 100% agreement is expected (white regions below)

Using a Quantitative Traceable Comparative Method is Advantageous

CM provides Analyte Concentration Traceable to References of Higher Order

3+ 1+ 2+ Neg

Near Cutoff Region 2

Near Cutoff Region 3 (108-123)

Near Cutoff Region 1

CT

CM 118

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The % Coefficient of Variation (CV) of the Quantitative Traceable Comparative Method can be used to establish Allowable Total Error for a Semi-Quantitative Candidate Test

• Establishing Allowable Total Error for the difference between comparative method and candidate test

– Consider a quantitative test with acceptable level of % CV and % bias close to 0

– If one performs 2 measurements of the same sample with the quantitative device:

• there will be some difference in these two values because of random measurement errors.

– One can construct boundaries based on % CV that 95% of the differences between two repeated measurements are inside of these boundaries

– This method is used to determine near cutoff concentration ranges with acceptable variability

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Example with a Quantitative Traceable Comparative Method

Comparative Method (Quantitative Traceable)

Range 0-16 17-20 21-49 50-56 57-107 108-123

124-4,700

Predicted Bins With At Least 95%

Probability

Neg Neg or 1+

1+ 1+ or 2+

2+ 2+ or 3+

3+

Candidate

Test

Neg 143 7 1 151 1+ 5 14 114 25 1 159 2+ 1 4 136 21 3 165 3+ 2 3 161 166

148 22 115 29 138 25 164 641

Percent of Candidate Results

With Predicted Bins

96.6% (143/148)

95.5% (21/22)

99.1% (114/115)

100% (29/29)

98.6% (136/138)

96.0% (24/25)

98.2% (161/164)

ATE: 98.0% (628/641) with 95% CI: 96.6%-98.8% LER: 0.0% (0/641) with 95% CI:0.0%-0.6%

12% (76/641) samples were around the cutoffs

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