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FDA Webinar: CLIA Waiver Applications Draft Guidances

Moderator: Kemba Ford

January 9, 2019

1:00 pm ET

Coordinator: Welcome and thank you for standing by. At this time, all lines have been 

placed in listen-only mode until the question-and-answer session. Today’s call 

is being recorded. If anyone has any objections, you may disconnect at this 

time. 

I would now like to turn the call over to Kemba Ford. Thank you. You may 

begin. 

(Kemba Ford): Hello. I am Kemba Ford from FDA’s Center for Devices and Radiological 

Health Office of Communication and Education. I would like to welcome you 

to today’s webinar where we will discuss and answer questions about the two 

draft guidances published on November 28, 2018 that are intended to help 

manufacturers of in vitro diagnostic devices apply for and receive Clinical 

Laboratory Improvement Amendment waivers, also called CLIA waivers. 

The first draft is titled Select Updates for Recommendations for Clinical 

Laboratory Improvement Amendments of 1988 Waiver Applications for 

Manufacturers of In Vitro Diagnostic Devices. And the second draft guidance 
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is titled Recommendations for Dual 510(k) and CLIA Waiver by Application 

Studies. 

Today, Peter Tobin, a chemist from FDA’s Center for Devices and 

Radiological Health’s Office of In Vitro Diagnostics, will present an overview 

of these draft guidance documents. 

Following his presentation, we will open the line for any questions you may 

have related to the information provided during this presentation. 

Now, I will turn over the webinar to Peter.

Peter Tobin: Good afternoon everyone and thanks for joining us for today’s webinar on 

CLIA waiver application draft guidances. 

This webinar covers two complementary draft guidances for CLIA waivers. 

Throughout this presentation, I’ll refer to the Select Updates to the 2008 CLIA 

Waiver Guidance as the Draft Section V Guidance and the recommendations 

for Dual 510(k) and CLIA Waiver by Application Studies guidance as the 

Draft Dual Guidance. I’ll also sometimes refer to CLIA waivers by 

application as CWs. These two draft guidances are not final and not in effect 

at this time. 

Here’s the agenda for today’s webinar. I’ll start off with some background and 

then cover the highlights for each draft guidance. After my presentation there 

will also be plenty of time for questions. 

The first objective for today’s webinar is to understand the two CLIA waiver 

pathway options covered in the draft guidances -- the stepwise CLIA waiver 

pathway, which is a CLIA waiver application following clearance or approval, 
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and the dual submission or dual pathway which is a combined 510(k) and 

CLIA waiver following a Pre-Submission. 

And the second objective is to understand the FDA’s current thinking on study 

designs for both pathways. 

As background for discussing the draft guidances, I’m going to cover the 

following four areas over the next few slides -- the CLIA waiver statutory 

criteria, 21st Century Cures requirements to update the 2008 CLIA Waiver 

Guidance, CLIA waiver pathways addressed by the two drafts, and why we 

are reissuing the guidances as drafts. 

Here is the CLIA statutory criteria for waiver as modified by FDAMA. Clause 

B has only been used very rarely so I will concentrate on clause A, shown in 

bold, that a test “employ methodologies that are so simple and accurate as to 

render the likelihood of erroneous results by the user negligible,” because this 

is the clause that is primarily used and is the focus of both draft guidances. 

21st Century Cures requires an update to Section V of the 2008 CLIA Waiver 

Guidance. This section covers accuracy studies to support CLIA waiver and 

we are required to update this section to include the appropriate use of 

comparable performance between a waived user and a moderately complex 

laboratory user to demonstrate accuracy. 

The 2008 CLIA Waiver Guidance provides recommendations for meeting the 

CLIA statutory criteria for waiver described earlier, that a test should be “so 

simple and accurate as to render the likelihood of erroneous results by the user 

negligible.”
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A test that is a candidate for waiver should be simple in that it has both simple 

test characteristics and labeling that is designed for untrained waived users. 

For example, a simple test should not require complex sample or reagent 

manipulation, or complex interpretation of results or error codes.

In order to demonstrate that the likelihood of erroneous results by the user is 

negligible, the 2008 CLIA Waiver Guidance also recommends that the 

candidate test manufacturer conducts a comprehensive risk analysis, 

incorporates fail-safe and failure alert mechanisms to mitigate risks, and 

conducts flex studies and validation studies to demonstrate system robustness 

and proper functioning of incorporated risk control mechanisms. 

With the exception of Section V on accuracy studies, the rest of the 2008 

CLIA Waiver Guidance is not being reopened and will not be substantially 

changed once Section Five is finalized. 

There are currently three pathways to CLIA waived categorization. In the first 

pathway, shown at the top of the slide, if a test is cleared or approved through 

one of the nine test types -- this is, excuse me, in 42 CFR 493.15(c) -- such as 

urinalysis dipstick or non-automated fecal occult blood, or if the test is cleared 

or approved for home use, then the test will be categorized as waived 

following clearance or approval. 

Otherwise, following clearance or approval, tests may be categorized either as 

moderate or high complexity according to the CLIA categorization criteria 

listed in 42 CFR 493.17. 

The two CLIA waiver pathways that are addressed by the draft guidances are 

shown in the bottom half of the slide. The stepwise CLIA waiver pathway is 

covered by the 2008 CLIA Waiver Guidance and the draft Section Five 
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update. In this pathway, the manufacturer first obtains clearance or approval 

and a moderate categorization prior to submitting a CLIA waiver application. 

In the Dual pathway, a manufacturer first submits a Pre-Submission to inform 

FDA that it plans to submit a Dual Submission. This Pre-Submission provides 

a forum for the applicant and the FDA to discuss the proposed study designs 

for the Dual Submission. 

Following the Pre-Submission, the manufacturer submits a complete 510(k) 

and CLIA waiver application in a single submission package. The draft Dual 

guidance addresses recommendations for study designs for this CLIA waiver 

pathway. 

Previous drafts of both CLIA waiver guidances were issued in November 

2017, and we held a webinar on these drafts in January 2018. Based on 

comments received and multiple meetings with stakeholders, the new drafts 

have been thoroughly revised. Because of the significant changes that were 

made to address stakeholder comments, we are reissuing both guidances in

draft to allow stakeholder comments before finalizing. 

Before getting into the highlights of the two draft guidances, I want to 

mention two definitions that are used in both guidances. An “Untrained 

Operator or Waived User” is a test operator in waived settings who has 

limited or no training or hands-on experience in conducting laboratory testing. 

And a “Trained Operator or Moderate Complexity Laboratory User” is a test 

operator who meets the qualifications to perform moderate complexity testing 

and with previous training in performing the test.

These definitions connect the “untrained operator” and “trained operator”

terminology used in the draft guidances with the “waived user” and 
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“moderately complex laboratory user” terminology from section 3057 of 21st

Century Cures. 

The revised Section V guidance provides study design recommendations for 

demonstrating that a test is accurate in the hands of the intended CLIA-waived 

users as part of a CLIA waiver application following clearance or approval. 

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

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

In response to stakeholder comments, the draft Section V guidance focuses in 

on study design aspects directly related to meeting the statutory criteria for 

waiver. Specifically, this draft emphasizes validating that the accuracy of a 

candidate test is not meaningfully impacted by differences between nonwaived and waived use, including: user training and experience, testing 

environment, or patient populations.

General information on test accuracy issues that are not specific to CLIAwaived tests has been replaced with references to FDA-recognized consensus 

standards. The availability of publicly posted CLIA waiver decision 

summaries complements this approach because they provide study design 

details from successful CLIA waiver applications for a wider variety of test 

types and circumstances than it would be possible to cover as examples in the 

guidance. 

At the end of fiscal year 2017, FDA began piloting the release of CLIA 

waiver decision summaries on the CDRH transparency webpage. CLIA 

waiver decision summaries allow the public to learn how the FDA reviewed 

an applicant’s data to make a CLIA waiver approval determination and 

promote consistency and predictability in the CLIA waiver review process. 
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In response to stakeholder comments, two additional study design options

were added to the revised draft Section V guidance for a total of four study 

design options. The revised draft also provides additional flexibility regarding 

how manufacturers may leverage existing accuracy data from previous 

marketing submissions such as 510(k)s, PMAs, or De Novo marketing 

submissions. 

Options 1-3 are appropriate when sufficient valid scientific evidence to 

demonstrate that a test candidate test meets the CLIA statutory criteria for 

waiver can be derived from the combination of the performance studies 

included in previous marketing submissions, and the new CLIA waiver

studies described for each option in the revised Section V draft guidance. 

Now I’ll describe each of the four options. 

Option 1, commonly called agreement studies, includes 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. Since pre-market performance studies generally include 

data establishing the accuracy of the candidate test in the hands of trained 

operators, the FDA believes that Option 1 will be appropriate for the majority 

of candidate tests.

Option 2 is one of the new options. Option 2 includes agreement studies 

modeled after approaches in the FDA guidance on Assay Migration Studies 

for In Vitro Diagnostic Devices. Under this option, these studies compare 

performance of the candidate test between untrained and trained users instead 

of comparing performance between new and old systems as described in the 

assay migration guidance. 
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Option 3 is the second new option and it includes flex and human factors 

engineering studies. As an alternative to comparative study designs for certain 

test systems, flex and human factors engineering studies may provide 

sufficient assurance that the change in user populations and environment of 

use between non-waived and waived settings will not adversely impact the 

results provided by the candidate test. 

Possible study design approaches that may be suitable include flex study 

designs described in Section IV of the 2008 CLIA Waiver Guidance and 

human factor study designs described in FDA’s guidance Applying Human 

Factors and Usability Engineering to Medical Devices. 

This approach is appropriate for test systems for which collection of a 

specimen is always performed by a professional -- for example, an 

endocervical swap collected by a doctor -- or collection of a specimen is 

always performed by a patient -- for example, a urine specimen collected by 

the patient, and other pre-analytical steps are very simple -- for example, 

placement of the entire specimen in the analyzer --, and the intended patient 

populations are sufficiently similar. 

Another possible scenario where this option may be appropriate is a CLIA 

waiver application for a modification of a previously waived test system 

where the Quick Reference Instructions were not modified or minimally 

modified. 

Option 4 is the approach included in Section V of the 2008 CLIA waiver 

guidance and was called “Option 2” in the November 2017 Section V draft. 

Option 4 includes comparison study designs in which the results of the 

candidate test in the hands of untrained operators are directly compared to the
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results of an appropriate comparative method in the hands of trained 

operators.

Another aspect of the section V guidance that stakeholders requested 

additional clarity about was FDA’s approach to benefit-risk considerations for 

CLIA waiver applications. To address this in the revised Section V draft, 

we’ve added a new section called “Considerations in Satisfying CLIA Waiver 

Requirements” that discusses this issue and how we are harmonizing our 

approach to benefit-risk considerations for CLIA waivers with other FDA 

benefit-risk guidances. 

Thinking about benefit risk considerations for CLIA waivers, we need to go 

back to the statutory criteria for CLIA waiver, that a test should be “so simple 

and accurate as to render the likelihood of erroneous results by the user 

negligible.”

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 and use environment --, and 

the probable benefits and probable risks or harms 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. 

One aspect of the revised Section V guidance that has not changed are general 

CLIA waiver study design considerations. FDA recommends that applicants 
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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. 

Finally, Pre-Submissions are highly recommended to get feedback from the 

FDA on study designs for any of the four options before conducting the 

studies. FDA also welcomes discussion of additional study design approaches 

besides the four options presented in the guidance. 

For additional information on Pre-Submissions, please refer to FDA’s 

guidance Requests for Feedback on Medical Device Submissions: The PreSubmission Program and Meetings with Food and Drug Administration Staff. 

So now, moving on to the revised draft Dual guidance. In contract to the 

stepwise CLIA waiver pathway covered by the draft Section V guidance, the 

draft Dual guidance is intended for new in vitro diagnostic tests that have not 

yet been cleared, and so there is not generally accuracy data available yet for 

these tests. 

The draft Dual guidance describes a more efficient single set of comparison 

and reproducibility study designs with untrained users for a Dual Submission. 

Similarly to the revised draft section V, in the revised Dual guidance, general 

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

been replaced with references to FDA-recognized consensus standards. 

We’ve also referenced general study design considerations in the draft Section 

V guidance rather than repeating similar information in the draft Dual 

guidance. 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.
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Over the next few slides, I’m going to compare the types of studies conducted 

for the Stepwise and Dual CLIA waiver pathways starting with a little more 

background on the Stepwise pathway. 

Historically, under the Stepwise CLIA waiver pathway, manufacturers have 

conducted separate accurate studies in different clinical settings -- first to

support 510(k) clearance and later to support CLIA waiver. Specifically, 

manufacturers generally conducted comparison and reproducibility studies 

with trained users at non-waived point of care sites as part of the support for 

510(k) clearance, and then later conducted similar studies with untrained users 

at waived sites to support their CLIA waiver application.

This slide shows a summary of the different types of studies typically 

performed under the Stepwise and Dual CLIA waiver pathways. For the 

Stepwise CLIA waiver pathway, the left column shows typical study types for

a point-of-care 510(k) -- including the point-of-care comparison and 

reproducibility studies under the red X --, and the right column shows 

additional study types typically included in a CLIA waiver application. 

The basic idea behind the Dual approach is that it is reasonable to assume that 

test performance in the hands of trained users will be equal to or better than 

test performance in the hands of untrained users. Therefore, a single set of 

comparison and reproducibility studies conducted at sites representative of 

CLIA waived sites and with intended untrained users can be used as part of 

the support for both 510(k) clearance and CLIA waiver approval. 

The different types of studies typically performed for a Dual Submission 

incorporates both the left and right columns but does not include the point-of-
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care comparison and reproducibility studies with trained users under the large 

red X. 

The Dual pathway can provide considerable study efficiencies compared to 

the Stepwise approach to CLIA waiver. Additionally, overall FDA review 

time is also generally shorter for Dual Submissions with a maximum of 180 

FDA days versus potentially up to 250 FDA days for the Stepwise route of a 

traditional 510(k) followed by a CLIA Record and then a CLIA waiver 

application. 

We’ve seen increasing interest in the Dual Submission pathway over the last 

few years, and in fiscal year 2018 Duals became the preferred CLIA waiver 

pathway, accounting for almost three-quarters of the CLIA waivers received. 

Due to the study efficiencies possible with Dual Submissions, we expect that 

Duals will continue to be popular. We hope that the Dual guidance, when 

finalized, will help more manufacturers use this pathway to bring new simple

and accurate in vitro diagnostic tests to CLIA-waived settings. 

Greater access to these tests is expected to benefit patients and public health 

by allowing faster diagnosis and treatment decisions and reduced loss to 

follow-up. 

I’ve now finished the highlights of the two revised draft guidances. Here are 

some resources for you, including links to the draft guidances covered today 

and the docket numbers and links to the pages in Regulations.gov where you 

can comment on these draft guidances through February 27, 2019. 
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Links to the two final CLIA waiver guidances which are currently in effect are 

also provided, specifically the 2008 CLIA Waiver Guidance and the 

Administrative Procedures Guidance which was updated in 2017. 

I’ve also included a link to the CDRH transparency page where CLIA waiver 

decision summaries are posted. 

Thank you again for your interest in these draft guidances. We are interested 

in your feedback and I would be happy to answer any questions you have 

about the CLIA waiver draft guidances. 

Coordinator: Thank you. At this time if you’d like to ask a question, please press star 1 and 

please record your name when prompted. If you’d like to withdraw the 

request, you may press star 2. Again, to ask a question please press star 1 and 

please record your name when prompted. One moment please for the first 

question. 

Peter Tobin: While the Q&A portion is getting set up, I’d just like to encourage you again 

to comment on the draft CLIA waiver guidances. Also, if you think of 

questions later on after the webinar, please send them to CLIA@fda.hhs.gov. 

It’s on the screen. 

If you have other CLIA waiver or CLIA categorization questions that are not 

related to the draft CLIA waiver guidances, please also feel free to email us at 

CLIA@fda.hhs.gov and we’d be happy to help you. 

Coordinator: Thank you. We do have a question from I believe it’s (Martha). Please go 

ahead with your question. 
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(Martha): Hi. My question is regarding the Section V draft guidance and pursuing option 

one or an agreement study demonstrating accuracy. Will ATE and LER zones 

still need to be defined under that option? 

Peter Tobin: So one of the things that we’re doing with this revised draft is we’re trying to 

broaden available possibilities of study types and approaches that are 

available. And across different types of devices, certain approaches may be 

more common than others. And we’re also trying to sort of harmonize 

approaches to how we evaluate tests across different submission types. 

So as you’ll see, we still are recommending various CLSI guidelines that 

include discussion of ATE and LER. But we are also open to the possibility of 

other approaches perhaps where you’re looking separately at, you know, 

different elements of accuracy such as looking, you know, at bias and 

precision elements separately.

There can be a number of different possible approaches and we want to leave 

open various possibilities although the, you know, the ATE and LER 

approach is a good approach and continues to be one of the approaches we 

recommend. But we do recognize that for certain types of tests, other 

approaches are common and we welcome discussion of those other 

approaches through the Pre-Submission process. 

(Martha): Thank you. 

Coordinator: Thank you. And once again if you’d like to ask a question, please press star 1 

and please record your name when prompted. One moment, please. And at 

this time I’m showing no further questions. 
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Kemba Ford: Thank you. This is Kemba Ford. We appreciate your participation and 

thoughtful questions during today’s webinar. Today’s presentation and 

transcript will be available on the CDRH Learn Web page at 

www.fda.gov/training/cdhrhlearn on Thursday, January 17. 

If you have additional questions about today’s presentation, please contact us 

using the information on the screen. 

As always, we appreciate your feedback. Following the conclusion of the 

webinar, please complete a short 13 question survey about your FDA CDRH 

webinar experience. The survey can be found at www.fda.gov/cdrhwebinar 

immediately following the conclusion of this live webinar. 

Again, thank you for your participation in today’s webinar and this concludes 

our webinar. 

Coordinator: Thank you. This concludes today’s conference. You may disconnect at this 

time.

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