Contains Nonbinding Recommendations 
Recommendations for Dual 510(k) 
and CLIA Waiver by Application 
Studies 
Guidance for Industry and 
Food and Drug Administration Staff 
Document issued on February 26, 2020. 
The draft of this document was issued on November 29, 2018. 
For questions about this document, contact FDA CLIA Staff at 240-402-6169 or by email at 
CLIA@fda.hhs.gov. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health  Contains Nonbinding Recommendations 
Preface 
Public Comment 
You may submit electronic comments and suggestions at any time for Agency consideration 
to https://www.regulations.gov. Submit written comments to the Dockets Management Staff, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 
20852. Identify all comments with the docket number FDA-2017-D-5625. Comments may 
not be acted upon by the Agency until the document is next revised or updated. 
Additional Copies 
Additional copies are available from the Internet. You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance.  Please include the 
document number 16038 and complete title of the guidance in the request.  Contains Nonbinding Recommendations 
Table of Contents 
I.  Introduction ....................................................................................................................... 1 
II.  Background ....................................................................................................................... 2 
III.  Scope ............................................................................................................................... 3 
IV.  Process and Content of a Dual Submission .................................................................... 3 
V.  General Study Design Considerations .............................................................................. 6 
A.  Comparison Study Designs ........................................................................................ 7 
(1)  Quantitative Tests ................................................................................................... 8 
(2)  Binary Qualitative Tests ......................................................................................... 8 
B.  Reproducibility Study Designs................................................................................... 9  Contains Nonbinding Recommendations 
Recommendations for Dual 510(k) 
and CLIA Waiver by Application 
Studies 
Guidance for Industry and 
Food and Drug Administration Staff 
This guidance represents the current thinking of the Food and Drug Administration (FDA 
or Agency) on this topic.  It does not establish any rights for any person and is not binding 
on FDA or the public.  You can use an alternative approach if it satisfies the requirements 
of the applicable statutes and regulations.  To discuss an alternative approach, contact the 
FDA staff or Office responsible for this guidance as listed on the title page. 
I.  Introduction 
The purpose of this guidance is to assist manufacturers in using the Dual 510(k) and Clinical 
Laboratory Improvement Amendments (CLIA) Waiver by Application pathway.  It describes 
study designs for generating data that may support both 510(k) clearance and CLIA waiver.  
Use of the Dual 510(k) and CLIA Waiver by Application pathway is optional; however, FDA 
believes this pathway is in many instances the least burdensome and fastest approach for 
manufacturers to obtain a CLIA waiver at the same time as 510(k) clearance for new In Vitro 
Diagnostic (IVD) tests.  FDA believes increased use of this pathway will speed up the 
process of bringing simple and accurate IVD tests to CLIA-waived settings, which will better 
serve patients and providers. 
For the current edition of the FDA-recognized standard(s) referenced in this document, see 
the FDA Recognized Consensus Standards Database.1  For more information regarding use 
of consensus standards in regulatory submissions, please refer to the FDA guidance titled 
Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical 
Devices.2
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and 
                                                
1 Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. 
2 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-
voluntary-consensus-standards-premarket-submissions-medical-devices. 
1  Contains Nonbinding Recommendations 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited. The use of the word should in Agency guidance means that 
something is suggested or recommended, but not required.  
II.  Background 
Typically, in an application for CLIA waiver (CLIA Waiver by Application) a manufacturer 
submits evidence to FDA that a previously cleared or approved test, initially categorized as 
moderate complexity, meets the CLIA statutory criteria for waiver3 and requests that FDA 
categorize the test as waived.  This means that, historically, a CLIA Waiver by Application 
has followed clearance or approval of an IVD test.  For additional information about FDAs 
procedures for determination of CLIA categorization, please see FDAs guidance 
Administrative Procedures for CLIA Categorization.4  
While a premarket notification (510(k)) and CLIA Waiver by Application each include 
discrete elements not required in the other, both submissions generally include comparison 
and reproducibility studies.  For a 510(k), such studies are often performed by trained 
operators (i.e., test operators who meet the qualifications to perform moderate complexity 
testing;5 sometimes referred to as moderate complexity users).  For a CLIA Waiver by 
Application, we believe such studies should be conducted by the intended user (i.e., test 
operators in waived settings and with limited or no training or hands-on experience in 
conducting laboratory testing; sometimes referred to as untrained operators or waived 
users).6  
An applicant may choose to conduct a single set of comparison and reproducibility studies 
with untrained operators to satisfy certain requirements to establish both substantial 
equivalence under section 513(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
for 510(k) clearance and simplicity and insignificant risk of erroneous results under 42 
U.S.C.  263a(d)(3) for CLIA waiver.  To streamline the review of such data, the Dual 
510(k) and CLIA Waiver by Application (Dual Submission) pathway was established as part 
of the Medical Device User Fee Amendments of 2012 (MDUFA III).7 The Dual Submission 
pathway is a mechanism for the review of both a 510(k) and CLIA Waiver by Application 
                                                
3 Tests may obtain a CLIA waiver if the tests have been approved by the [FDA] 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.  42 U.S.C.  263a(d)(3). 
4 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/administrative-
procedures-clia-categorization. 
5 See 42 CFR 493.1423. 
6 42 U.S.C.  263a(d)(3); See also FDAs guidance Recommendations for Clinical Laboratory Improvement 
Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices, 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-
clinical-laboratory-improvement-amendments-1988-clia-waiver-applications. 
7 For more information regarding MDUFA III, please see Medical Device User Fee Amendments 2012 
(MDUFA III), available at https://www.fda.gov/industry/medical-device-user-fee-amendments-
mdufa/medical-device-user-fee-amendments-2012-mdufa-iii. 
2 Contains Nonbinding Recommendations 
within a single submission, with a reduced overall review time compared to separate, 
sequential submissions.  
III.  Scope 
This guidance is intended to aid manufacturers in developing study designs for Dual 
Submissions.  A Dual Submission is especially appropriate for devices that are simple, have 
fail-safe and failure alert mechanisms, have few pre-analytical steps, and are subject to 
premarket notification requirements.  
This guidance focuses on recommendations for designing a single set of comparison and 
reproducibility studies, such that the data generated will support both 510(k) clearance and 
CLIA waiver. 
While the study design recommendations in this guidance were developed with a Dual 
Submission in mind, they may also be utilized in a sequential submission approach in which 
a CLIA Waiver by Application follows marketing authorization.  In such cases, the applicant 
may utilize the studies described herein to support marketing authorization and reference 
such data in their subsequent CLIA Waiver by Application. 
IV.  Process and Content of a Dual Submission 
A Dual Submission should be submitted following a Pre-Submission.8  As described in the 
Medical Device User Fee Amendments of 2017 (MDUFA IV) Commitment Letter,9 an 
applicant should inform FDA that it plans to submit a Dual Submission during a Pre-
Submission.  FDA recommends using this Pre-Submission to discuss planned study designs 
for comparison and reproducibility studies that support both 510(k) clearance and CLIA 
waiver.  
A Dual Submission should contain the same information as a complete 510(k) and CLIA 
Waiver by Application.10  Content related to the comparison and reproducibility studies may 
                                                
8 For administrative details regarding the submission process, please see FDAs guidance Administrative 
Procedures for CLIA Categorization, available at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/administrative-procedures-clia-categorization.  A Pre-Submission is a type of Q-
Submission.  For additional information on Pre-Submissions, please refer to FDAs guidance Requests for 
Feedback on Medical Device Submissions: The Q-Submission Program, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program. 
9 Available at https://www.fda.gov/media/100848/download.  For more information regarding MDUFA IV, 
please see Medical Device User Fee Amendments 2017 (MDUFA IV), available at  
https://www.fda.gov/industry/medical-device-user-fee-amendments-mdufa/medical-device-user-fee-
amendments-2017-mdufa-iv. 
10 For information about the content of each type of submission see 21 CFR 807, subpart E; Administrative 
Procedures for CLIA Categorization, available at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/administrative-procedures-clia-categorization and Recommendations for Clinical 
Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro 
 
3 Contains Nonbinding Recommendations 
overlap and, 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. 
In addition to the information required in a 510(k) provided in 21 CFR 807.87, the following 
FDA guidances are applicable: 
  Format for Traditional and Abbreviated 510(k)s,11
  Refuse to Accept Policy for 510(k)s,12
  And, as available,device-specific guidances.
Additionally, FDA recommends you include the following in a Dual Submission:
  Device Description and Determination That Device is Simple
A description of your device that demonstrates it is simple to use.  See Section III 
of FDAs guidance Recommendations for Clinical Laboratory Improvement 
Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro 
Diagnostic Devices.13
 Risk Analysis
The results of a risk analysis, including the identification of potential sources of 
error for your device.  See Section IV of FDAs guidance Recommendations for 
Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver 
Applications for Manufacturers of In Vitro Diagnostic Devices14 and ISO 14971 
Medical devices--Application of risk management to medical devices.
 Failure-Alert and Fail-Safe Mechanisms
The results of risk evaluation and control, including a description of (1) measures 
you have implemented to mitigate the risk of errors, and (2) validation and/or 
verification studies demonstrating the ability of failure alerts, fail-safe 
mechanisms, and other control measures that you have incorporated into your 
device to mitigate the risk of errors, even under conditions of stress.  See Section 
IV of FDAs guidance Recommendations for Clinical Laboratory Improvement 
                                                
Diagnostic Devices, available athttps://www.fda.gov/regulatory-information/search-fda-guidance-
documents/recommendations-clinical-laboratory-improvement-amendments-1988-clia-waiver-applications. 
11Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/format-traditional-
and-abbreviated-510ks-guidance-industry-and-fda-staff. 
12Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/refuse-accept-
policy-510ks. 
13Availableat https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-
clinical-laboratory-improvement-amendments-1988-clia-waiver-applications.
14 Ibid. 
4 Contains Nonbinding Recommendations 
Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro 
Diagnostic Devices.15
  Flex Studies 
The results of flex studies demonstrating insensitivity of the test system to 
environmental and usage variations under conditions of stress.  See Section IV of 
FDAs guidance Recommendations for Clinical Laboratory Improvement 
Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro 
Diagnostic Devices.16
  Analytical Studies 
A description of the design and results of analytical studies of the device 
conducted at an internal site including, but not limited to, the following: 
  Analytical sensitivity (Limit of Detection (LoD) or C5-C95 for qualitative 
tests); 
  Measuring interval (Limit of Quantitation (LoQ) and Limit of Blank 
(LoB)/LoD, if applicable, for quantitative tests); 
  Analytical specificity (interferences, cross-reactivity, etc.); 
  Linearity (for quantitative tests); 
  Precision (if needed for lot-to-lot variability and/or other issues); 
  Carry-over (if applicable); 
  Reagent stability; and 
  Sample stability. 
  Comparison Study 
A description of the study design and results of comparison studies you conducted 
to demonstrate that the device has an insignificant risk of an erroneous result 
when performed by untrained operators.  See Section V, General Study Design 
Considerations below. 
  Reproducibility Study 
A description of the study design and results of reproducibility studies of the 
device performed by untrained operators.  See Section V, General Study Design 
Considerations below. 
  Clinical Performance Study 
Most IVD 510(k) submissions do not include a clinical performance study.  
However, for some devices, a clinical performance study may be needed for either 
                                                
15 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-
clinical-laboratory-improvement-amendments-1988-clia-waiver-applications. 
16 Ibid. 
5 Contains Nonbinding Recommendations 
a 510(k) or Dual Submission (please contact FDA through a Pre-Submission17 for 
further discussion). 
  Labeling 
Proposed device labeling, including instructions for use consistent with a device 
that is simple.  See Section VI of FDAs guidance Recommendations for 
Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver 
Applications for Manufacturers of In Vitro Diagnostic Devices.18
V.  General Study Design Considerations 
When designing comparison and reproducibility studies to support a Dual Submission, FDA 
recommends that applicants evaluate test performance in settings designed to replicate, as 
closely as possible, the actual CLIA-waived settings, patients/samples, and test operators.  
Therefore, study designs should include the following: 
  Testing sites that are representative of the intended use of the waived test. 
  Subject populations that are representative of the intended patient population(s). 
  Intended sample type and matrix.  
  Untrained operators representative of those at intended waived settings.  We 
encourage you to enroll operators with the least amount of training that might be 
encountered at the types of sites for which this device is intended.  
  Testing should be integrated into the daily workflow of the site where the 
operators are often multitasking between patient care, testing, and other duties. 
General study design considerations for CLIA waiver studies are provided in Section V of 
FDAs guidance Recommendations for Clinical Laboratory Improvement Amendments of 
1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices.19  We 
recommend that manufacturers consider the general recommendations in Sections V.B, V.C, 
and specific recommendations in Section V for Option 4 studies (i.e., comparison studies 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) when designing studies in support of a Dual Submission.  Additional general study 
design considerations for Dual Submissions are described below. 
The appropriate design of the studies and data analysis is strongly influenced by the type of 
the candidate test.  For the purposes of this guidance: 
                                                
17 For additional information on Pre-Submissions, please refer to FDAs guidance Requests for Feedback on 
Medical Device Submissions: The Q-Submission Program, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-
submission-program. 
18 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-
clinical-laboratory-improvement-amendments-1988-clia-waiver-applications. 
19 Ibid. 
6 Contains Nonbinding Recommendations 
  A quantitative test is a test that gives numerical results (e.g., concentration of an 
analyte in a patient sample) which are referenced to a measuring interval and 
standards. 
  A binary qualitative test is a test that provides only two outputs (e.g., 
positive/negative or yes/no). 
This Section includes recommendations for quantitative and binary qualitative tests.  If your 
test is a different type of test from the two types described above (e.g., qualitative with 
multiple nominal categories, semi-quantitative, a multi-analyte assay with algorithmic 
analyses), please contact FDA through a Pre-Submission20 for discussion of study designs. 
If the candidate test is intended to be used at Point-of-Care (POC) non-waived sites in 
addition to waived sites and the intended use patient population at the CLIA-waived sites in 
the comparison study does not sufficiently represent the intended use patient population at 
POC non-waived sites, FDA recommends that you address this issue by also including one or 
a few POC non-waived sites in the study.  At any included POC non-waived sites, trained 
operators representative of those at intended POC non-waived sites should perform testing 
with the candidate test. 
The recommendations for comparison and reproducibility studies described in this guidance 
are for studies that include the type of samples that are typical of CLIA-waived devices (for 
example, capillary whole blood samples).  If you plan to pursue a 510(k) clearance for POC 
non-waived use for additional sample types beyond those for which you are requesting a 
CLIA waiver in your Dual Submission, please contact FDA through a Pre-Submission for 
discussion of study designs.21
A.  Comparison Study Designs 
For comparison study design and analysis to establish performance characteristics related to 
the accuracy of the candidate test, we recommend you follow appropriate FDA-recognized 
consensus standards, such as: 
  For quantitative tests: Clinical Laboratory Standards Institute (CLSI) EP21,22 CLSI 
EP2723
  For qualitative tests: CLSI EP1224
These standards include discussion of the importance of selecting an appropriate comparative 
method (CM) and describe quality hierarchies of preferred CM types for quantitative and 
                                                
20 For additional information on Pre-Submissions, please refer to FDAs guidance Requests for Feedback on 
Medical Device Submissions: The Q-Submission Program, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-
submission-program. 
21 Ibid. 
22 CLSI EP21 Evaluation of Total Analytical Error for Quantitative Medical Laboratory Measurement 
Procedures. 
23 CLSI EP27 How to Construct and Interpret an Error Grid for Quantitative Diagnostic Assays. 
24 CLSI EP12 User Protocol for Evaluation of Qualitative Test Performance. 
7 Contains Nonbinding Recommendations 
binary qualitative tests.  Comparison to higher quality CMs (e.g., reference methods or 
methods traceable to higher order references), when available, provides more absolute 
information about the accuracy of the candidate test while comparison to lower quality CMs 
may provide only relative performance information.  Where there is no generally accepted 
CM for an IVD device type, the use of a legally marketed predicate device or other well-
documented method as the CM would generally be appropriate.  We recommend discussing 
the selection of an appropriate CM as part of a Pre-Submission25 prior to conducting the 
comparison study. 
(1)  Quantitative Tests 
  An appropriate type of regression analysis should be performed and biases at the 
medical decision levels and at the lower and upper limits of the measuring 
interval should be calculated along with the confidence interval of each bias 
estimate. 
  Total error (central 95% region of observed differences between the candidate test 
and CM) should be estimated for the entire measuring interval of the candidate 
test, and for 3 subintervals (low, medium and high), as described in CLSI EP21. 
  The measuring interval of the CM should be at least as wide as the measuring 
interval of the candidate test.  If there are samples with either candidate test or 
CM values outside of the corresponding measuring intervals, these samples 
should be analyzed separately. 
  If one of the medically important points of the candidate test includes the Limit of 
Blank (LoB)/Limit of Detection (LoD)/Limit of Quantitation (LoQ), then some 
additional calculations for samples with very low levels of analyte may be needed 
for appropriate evaluation and comparison of the LoB/LoD/LoQ of the candidate 
test in the hands of untrained operators (see CLSI EP17)26. 
(2)  Binary Qualitative Tests 
  Binary qualitative tests with an analytical cutoff: For some qualitative tests (e.g., 
when non-diseased subject samples have a true zero concentration of the analyte 
of interest), clinical performance and analytical accuracy of the qualitative tests 
are the same concepts, and, therefore, in most situations, a study for evaluation of 
analytical accuracy can be considered as a study for clinical performance 
evaluation with measures such as clinical sensitivity, clinical specificity, positive 
and negative likelihood ratios, and positive and negative predictive values for a 
binary qualitative test.  When certain types of CMs are used in the study, 
measures such as positive percent agreement (PPA) and negative percent 
agreement (NPA) should be estimated instead.27
                                                
25 For additional information on Pre-Submissions, please refer to FDAs guidance Requests for Feedback on 
Medical Device Submissions: The Q-Submission Program, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-
submission-program. 
26 CLSI EP17 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. 
27 See CLSI EP12 for additional details. 
8 Contains Nonbinding Recommendations 
  Binary qualitative tests with a clinical cutoff: For some qualitative tests, clinical 
performance related to the target condition (for example, cancer present or absent) 
and analytical accuracy related to the amount of the analyte detected are different 
concepts and the cutoff for the qualitative test is chosen to optimize clinical 
sensitivity and clinical specificity of the test based on a clinical data set.  Note that 
the scientific evidence recommended to support a CLIA waiver for a qualitative 
test in this Section is related to the analytical accuracy of the qualitative test.  
Issues related to the clinical performance of a qualitative test are out of the scope 
of the guidance (please contact FDA through a Pre-Submission28 for further 
discussion). 
  Each untrained operator should run the candidate test with a minimum of 5 
samples that are positive by the CM and 5 samples that are negative by the CM. 
B.  Reproducibility Study Designs 
We recommend conducting the reproducibility study at a minimum of 3 of the same sites that 
were included in the comparison study29 and are representative of the intended use of the 
waived test.  To facilitate statistical analysis, the same number of untrained operators (likely 
2 or 3) should be included at each site of the reproducibility study.  For reproducibility study 
design and analysis, we recommend you follow FDA-recognized consensus standards (e.g., 
CLSI EP05,30 CLSI EP12).  We recommend that you include the following sources of 
variability: different sites, different untrained operators, different days, different runs, 
different lots (if applicable), and a few replicates.  If the candidate device is a unitized 
device, contact FDA through a Pre-Submission31 to discuss how you should evaluate 
repeatability. 
Two possible study designs for evaluation of lot-to-lot variability are described below: 
  Design 1:  Include three different lots at each of three sites in the reproducibility 
study in such a way that the between-lot component can be evaluated. 
  Design 2:  Evaluate lot-to-lot variability in a separate small study at one internal 
site where patient (or surrogate) samples and controls are tested over a few days.
                                                
28 For additional information on Pre-Submissions, please refer to FDAs guidance Requests for Feedback on 
Medical Device Submissions: The Q-Submission Program, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-
submission-program. 
29 For recommendations regarding sites included in the comparison study, see Section V.C.(1) of FDAs 
guidance Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver 
Applications for Manufacturers of In Vitro Diagnostic Devices, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/recommendations-clinical-laboratory-improvement-amendments-
1988-clia-waiver-applications. 
30 CLSI EP05 Evaluation of Precision of Quantitative Measurement Procedures. 
31 Please see https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-
and-meetings-medical-device-submissions-q-submission-program. 
9 Contains Nonbinding Recommendations 
An example of this study with 3 days and reagent lots A, B, and C is presented in 
Table 1 below: 
Table 1. Example of Design 2: Single Site Lot-to-Lot Variability Study Design32
Day  Reagent lots 
1  A  B  C 
2  B  C  A 
3  C  A  B 
A reproducibility study design where each site uses a different lot is generally undesirable, 
especially for new technologies, because it would be impossible to determine whether 
observed differences are lot-related or site-related. 
If specimens used with the candidate test are not stable (for example, capillary whole blood), 
attempts to use small-scale repeatability/reproducibility studies that use the intended use 
clinical samples should be explored (please contact FDA through a Pre-Submission33 to 
discuss study designs for precision/reproducibility studies).  
We recommend that you include in the reproducibility study the following samples: 
  For quantitative tests, the following levels of analyte should be included: close to 
the lower limit of the measuring interval, below the medical decision level 
(MDL), around the MDL, above the MDL, and close to the upper limit of the 
measuring interval.  If the candidate device has more than one MDL, then 
samples with concentrations around these MDLs should be evaluated.  It is 
understood that some tests will not have specific MDLs, but rather a range of 
values; in such cases, the reproducibility panel should contain samples scattered 
throughout the measuring interval of the candidate test. 
  For binary qualitative tests with an analytical cutoff: true negative, close to the 
LoD, and moderate positive samples should be included.  For binary qualitative 
tests with a clinical cutoff: true negative, high negative (close to C5), low positive 
(close to C95) and moderate positive samples should be included.  C5 is a sample 
concentration which yields a positive result 5% of the time (and a negative result 
95% of the time), and C95 is a sample concentration which yields a positive result 
95% of the time (and a negative result 5% of the time).34
  In addition, you should run the appropriate quality control samples associated 
with the candidate test. 
We recommend discussing reproducibility study design as part of a Pre-Submission prior to 
conducting the reproducibility study. 
                                                
32 Note that the same lot is then included at each site in the main reproducibility study. 
33 For additional information on Pre-Submissions, please refer to FDAs guidance Requests for Feedback on 
Medical Device Submissions: The Q-Submission Program, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-
submission-program. 
34 See CLSI EP12 for additional details. 
10