Recommendations for Premarket 
Notification (510(k)) Submissions for 
Nucleic Acid-Based Human Leukocyte 
Antigen (HLA) Test Kits Used for 
Matching of Donors and Recipients in 
Transfusion and Transplantation 
____________________________________________________ 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or 
from the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
July 2015  Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  RECOMMENDATIONS FOR THE PREPARATION OF THE HLA TEST KIT 
PREMARKET NOTIFICATION (510(k)) SUBMISSION ........................................... 2 
A.  Intended Use .......................................................................................................... 2 
B.  Device Design ......................................................................................................... 3 
C.  Performance Studies ............................................................................................. 4 
D.  Software ................................................................................................................. 8 
E.  Validation of Instrumentation ............................................................................. 9 
F.  Labeling ................................................................................................................. 9 
G.  Additional Considerations ................................................................................. 10 
IV.  REFERENCES ................................................................................................................ 11 
 
 
 
 
 
i  Contains Nonbinding Recommendations 
 
Recommendations for Premarket Notification (510(k)) Submissions 
for Nucleic Acid-Based Human Leukocyte Antigen (HLA) Test Kits 
Used for Matching of Donors and Recipients in 
Transfusion and Transplantation 
_____________________________________________________________________________  
 
Guidance for Industry 
 
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 
responsible for this as listed on the title page. 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations to submitters (hereafter referred to as you) and FDA 
reviewers in preparing and reviewing premarket notification submissions (hereafter referred to as 
510(k) submission or 510(k)) for human leukocyte antigen (HLA) in vitro diagnostic (IVD) 
device test kits.  This guidance applies specifically to nucleic acid-based HLA test kits used for 
the matching of donors and recipients in transfusion and transplantation, whether testing is for a 
single locus or for multiple loci simultaneously, for which the premarket submission to FDA will 
be a 510(k).  
 
Although this guidance applies specifically to 510(k) submissions for HLA test kits, some of the 
recommendations in this guidance may also be applicable to human neutrophil antigen (HNA) 
and human platelet antigen (HPA) test kits.  We recommend that you consult the Office of Blood 
Research and Review (OBRR) in FDAs Center for Biologics Evaluation and Research (CBER) 
for specific guidance regarding premarket submission requirements for HNA and HPA test kits. 
 
This guidance provides detailed information on the types of studies FDA recommends for 
validation of HLA test kits submitted as 510(k)s and used for the matching of donors and 
recipients in transfusion and transplantation.  More specifically, the document addresses the 
types of studies and other information that FDA recommends be used in designing and 
conducting studies for validation of nucleic acid-based HLA test kits and preparing a 510(k) 
submission. 
 
This guidance finalizes the draft guidance of the same title dated November 2013 (78 FR 69693, 
November 20, 2013). 
1  Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
II.  BACKGROUND 
 
Most cells of the body bear human leukocyte antigens.  The role of the HLA system is to allow 
the human immune system to distinguish the bodys own blood, organs and tissues from foreign 
substances.  Clinical complications, such as graft rejection or graft-versus-host disease, may 
occur if the immune system recognizes transplanted cells, tissues, organs, bone marrow, or a 
transfused unit of blood or blood components as being foreign on the basis of HLA nonidentity 
or if transplanted immune system cells react in response to the recipients HLA. 
 
The science and technology upon which HLA test kits are based has become increasingly 
complex in recent years.  Testing has evolved from serology and cell-based methods with little 
instrumentation to deoxyribonucleic acid (DNA) based and multiplex assays that use complex 
instruments and software.  HLA is one of the most polymorphic systems found in humans.  This 
high degree of polymorphism and the existence of rare phenotypes found in the HLA system 
represent significant and unique challenges to develop and design studies that validate the 
accuracy of these HLA test kits.  FDAs expectations for analytical and clinical studies 
conducted in support of a 510(k) submission focus on identifying potential risks to patients if the 
kits fail to perform as expected.  The performance of these kits is critical for ensuring precise and 
successful matching between donors and recipients of blood and blood components, cells, 
tissues, bone marrow, and organs. 
 
 
III.  RECOMMENDATIONS FOR THE PREPARATION OF THE HLA TEST KIT 
PREMARKET NOTIFICATION (510(k)) SUBMISSION 
 
A.  Intended Use 
 
A 510(k) submission must contain, among other things, proposed labels and labeling and 
advertisements sufficient to describe the device, its intended use, and the directions for its 
use (21 CFR 807.87(e)).  In the case of HLA test kits, the intended use should specify the 
marker the device is intended to detect.   
 
We recommend that the following statement be included in the intended use statement in 
your 510(k) submission for HLA test kits:   
 
To be used to determine {indicate HLA locus or loci}, to aid in transfusion and 
transplantation donor and recipient matching. 
 
Please consult CBER for specific guidance regarding HLA test kits that have a different 
intended use than the one recommended in this section.    
2  Contains Nonbinding Recommendations 
 
 
B.  Device Design 
 
We recommend that you carefully characterize the design of your HLA test kits.  For 
example, you should describe the following elements in your 510(k) submission, where 
applicable: 
 
  Test platform (e.g., flow cytometry, instrumentation for multiplex test systems). 
  Composition and layout in spatially-fixed platforms, including feature (e.g., 
probe) identity and placement, where applicable. 
  Methods used for attaching the capture or probe material to a solid surface, if 
applicable. 
  Hybridization conditions, washing procedures, and drying conditions (e.g., 
temperature, length of time). 
  Assay components such as buffers, enzymes, fluorescent dyes, chemiluminescent 
reagents, other signaling and signal amplification reagents, instruments, software, 
etc. 
  Methodology for DNA extraction that you provide or that you recommend for 
users, and other applicable preanalytical elements.  If you do not provide sample 
preparation reagents in your test kits, you should provide specifications (including 
justification for these specifications) for assessing the quality of the assay input 
sample so that users can validate their own sample preparation method and 
reagents. 
  Range of input sample concentrations that meet performance specifications. 
  Internal controls and external controls, and calibrators that you recommend or 
provide.  Validation of controls and calibrators. 
  Stability and reproducibility of the entire test procedure when used for its 
intended use. 
  For multiplex tests in which the target molecules will contact a number of 
different probes, the methods used to mitigate the risk for probe cross-
hybridization. 
  The methods used to address the potential for probe cross-contamination. 
  The maximum number of samples that can be simultaneously processed.  
 
We recommend that you describe in detail the test kits methodology for detecting alleles 
and genotypes, including a detailed description of algorithms and decision trees, as 
applicable.  You should also briefly outline your risk analysis relating to the test kits 
methodology for detecting alleles and genotypes. 
 
We also recommend that you include illustrations or photographs of non-standard 
equipment or methods because these can be helpful in understanding novel 
methodologies, including the incorporation of features to minimize potential device 
failures and user errors. 
 
3  Contains Nonbinding Recommendations 
 
C.  Performance Studies 
 
Performance studies should demonstrate with a high level of confidence that the test kit 
performs within the established specifications.  You should identify the performance 
characteristics that are to be assessed and establish validation methods and acceptance 
criteria.   
 
The following subsections include specific recommendations for accuracy studies, 
precision studies including reproducibility and repeatability, and clinical comparison 
studies, including recommendations for the study design, samples, and a description of 
concordance.  
 
1.  Accuracy Studies 
 
Accuracy studies for molecular detection methods should address all 
probes and/or primers included in the HLA test kit.  However, due to the 
large number of polymorphisms within the HLA system, we realize that it 
may be impractical to individually measure the accuracy of each 
polymorphism that a test kit claims to detect.  Therefore, we recommend 
that the accuracy study, which may be conducted in-house, challenge the 
performance parameters of the test system as follows: 
 
  The study should use nationally or internationally recognized well-
characterized DNA samples (described in this section) that 
represent the most prevalent HLA alleles, and, if possible, also 
include rare alleles. 
  The sample size for each locus should meet the following criteria:  
use a sufficient number of well-characterized DNA samples such 
that you can demonstrate that the one-sided 95% lower confidence 
limit of overall agreement (i.e., concordance) exceeds 0.95 for 
each test kit (locus) in the submission.  The samples in this study 
should be tested once and cover a reasonable range of genotypes.  
Sponsors are encouraged to discuss sample selection with FDA in 
advance to reach an agreement on this process  
  Results should be reported using statistically appropriate practices 
as outlined in the FDA guidance document entitled, Guidance for 
Industry and FDA Staff:  Statistical Guidance on Reporting Results 
from Studies Evaluating Diagnostic Tests, dated March 13, 2007 
(Ref. 1).  That guidance provides recommendations on the 
handling of equivocal results, discrepant result resolution and how 
comparison of the results to non-reference standards and methods 
should be reported. 
 
Sample Types - We recommend the use of well-characterized DNA 
samples recognized in the United States ( U.S.) or abroad that have been 
extensively tested using a variety of HLA testing methods, including DNA 
4  Contains Nonbinding Recommendations 
 
sequence-based typing.  The term well-characterized DNA sample will 
be used henceforth in this document to describe the abovementioned 
samples. 
 
Concordance Description - The HLA typing results from your test are 
concordant with the well-characterized DNA sample if one pair of the 
reported alleles is the same as the typing results of the well-characterized 
DNA sample. 
 
2.  Precision Studies including Repeatability and Reproducibility 
 
Precision studies should capture possible sources of variation including 
within run, run-to-run, day-to-day, operator-to-operator, instrument-to-
instrument, site-to-site and lot-to-lot variation.  Because within run 
variability can be captured using a measure of how closely measurements 
within the same run agree (e.g., percent agreement of results within the 
same run), we refer to this as the repeatability estimate.  The repeatability 
estimate can be captured using data from an internal study or by 
combining results collected at multiple sites in a reproducibility study.  A 
reproducibility study should be performed at multiple sites using multiple 
operators with skill levels similar to those of your intended users.  You 
should also perform testing over several weeks and at different times of 
the day to maximize detection of potential sources of variability.  For 
reagents recommended to be used with automated instruments, the 
submission should include testing on three separate instruments, one at 
each site. 
 
You may choose to combine the repeatability study and the reproducibility 
study into a single study. 
 
We recommend the following precision study design: 
 
  Three study sites, including at least two external sites, with two 
operators at each site.  If feasible, each operator should perform 
two runs per day. 
  Each sample is run in duplicate (for repeatability), on five 
nonconsecutive days over 20 days using one lot of the test kit.  
NOTE:  Kit and component lot-to-lot studies, using three different 
lots, may be conducted in-house using the same panel as the 
external sites. 
  The study outlined in this section should be used on each 
instrument for which you are seeking clearance. 
  If you plan to submit a bundled submission, conduct a precision 
study for each test kit. 
  Operator experience may have an impact on test system 
performance; therefore, operator training is an important 
5  Contains Nonbinding Recommendations 
 
consideration when designing validation studies.  Your precision 
study protocol should include training requirements for the 
operators.  If applicable, operators should be certified prior to 
participating in the study and the protocol should include 
certification acceptance criteria.  The training program should 
reflect the training to be received by operators once the product is 
marketed. 
  In general, complete agreement should be expected.  Sponsors 
should perform an investigation and provide justification if there is 
disagreement. 
 
Sample Types - Perform precision studies using well-characterized DNA 
samples (precision panel) that ideally should cover every genotype 
reported by the device.  However, due to the large number of possible 
HLA alleles that may be detected by your test kit, it may not be possible to 
cover every genotype in the precision panel; therefore, we recommend the 
following: 
 
  The precision panel should be blinded and should consist of well-
characterized DNA samples representing significant diversity of 
the detectable alleles represented in the test kit.  It is preferable that 
the panel samples differ from those used in the accuracy study.   
  The lowest DNA concentration suggested by the test kits 
Instruction for Use should be used with all samples in the panel, 
though additional testing using higher concentrations of DNA can 
also be added. 
 
Concordance Description - The precision study results are concordant 
with the well-characterized DNA sample results if one pair of the reported 
alleles is the same as the typing results of the well-characterized DNA 
sample.  In addition, any uncertainty in the typing assignment (i.e., the list 
of ambiguities) should be reported and compared between operators, sites, 
runs, repeats, and days. 
 
3.  Clinical Comparison Studies 
 
Clinical comparison studies are performed to evaluate the proposed 
devices performance in a clinical setting, using random clinical 
specimens and the assay instructions outlined in the proposed labeling.  
Clinical comparison studies of investigational IVD devices are subject to 
the investigational device exemption (IDE) provisions of section 520(g) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360j(g)), and related 
implementing regulations.  You should consider how FDA regulations at 
21 CFR Part 812 (Investigational Device Exemptions) apply to your 
particular study, and also refer to 21 CFR Part 50 (Informed Consent) and 
6  Contains Nonbinding Recommendations 
 
21 CFR Part 56 (Institutional Review Boards) for other applicable 
requirements. 
 
Informed Consent 
 
For studies of an investigational device, the definition of a (human) subject includes 
an individual on whom or on whose specimen an investigational device is used (see 
21 CFR 812.3(p)).  Because section 520(g)(3)(D) of the Federal Food, Drug, and 
Cosmetic Act and the regulations in 21 CFR Part 812 require informed consent under 
21 CFR Part 50 for FDA-regulated human subject research, informed consent must be 
obtained before specimens can be used, except in limited circumstances as specified 
in the regulations.1  Note that the guidance document entitled, Guidance for 
Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff:  
Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are Not Individually Identifiable, dated April 25, 
2006 (Ref. 2) provides that FDA intends to exercise enforcement discretion, under 
certain circumstances, with regard to the regulations governing the requirement for 
informed consent when human specimens are used for FDA-regulated IVD device 
investigations.  As described in that guidance document, FDA does not intend to 
object to the use, without informed consent, of leftover human specimens (i.e., 
remnants of specimens collected for routine clinical care or analysis that would 
otherwise have been discarded) in investigations that meet the criteria for exemption 
from the IDE regulation in 21 CFR 812.2(c)(3), as long as subject privacy is protected 
by using only specimens that are not individually identifiable.  
 
Note that sponsors must comply with the requirements for institutional review board 
review, if applicable, as set forth in 21 CFR Part 56 unless they meet the exemption 
criteria outlined in 21 CFR 56.104 or 56.105.  
 
Study Design for Clinical Comparison Studies 
 
We recommend the following study design: 
 
  The study should include three sites, including at least two external sites of 
which at least one is in the U.S. The sites should cover different geographic 
regions and include a representation of major ethnic groups found in the U.S. 
in order to increase the probability of covering the many HLA genotype 
variants found in the U.S. population.  You can refer to published literature for 
the U.S. prevalence of HLA alleles.  For example, the National Marrow Donor 
Program (http://www.bethematch.org) provides frequency information for 
HLA haplotypes found in the U.S. population.  
  Your protocol should include training requirements for the operators involved 
in the studies.  If applicable, operators should be certified prior to participating 
in the study and the protocol should include certification acceptance criteria.  
The certification/training requirements should reflect those that will be 
                                                 
1 21 CFR 50.23 and 50.24. 
7  Contains Nonbinding Recommendations 
 
implemented once the device is marketed in order to best assess the device 
performance under actual use conditions. 
  Sample size  sufficient number of samples should be tested that would allow 
one to establish that the one-sided 95% lower confidence limit for the overall 
agreement with the comparison device exceeds 0.95 for each HLA locus in 
the submission. 
  In your study, you should compare two distinct lots of your product either to a 
device legally marketed in the U.S. or to results obtained by bi-directional 
sequencing.  Bi-directional sequencing entails sequencing both strands of 
amplified genomic DNA.  Include all test kits that will be described/listed in 
your submission in the study.  The statistical analysis plan should be defined 
prior to the start of the study and should be consistent with FDAs guidance 
document entitled, Guidance for Industry and FDA Staff:  Statistical 
Guidance on Reporting Results from Studies Evaluating Diagnostic Tests, 
dated March 13, 2007 (Ref. 1). 
  The protocol should include evaluation of sample preparation reagents 
provided with the test kit.  If you do not include sample preparation reagents 
in the test kit, each site should use and validate its own specimen processing 
procedures and demonstrate that the resulting sample meets the HLA kit 
manufacturer-supplied specifications. 
  Discordant results should be investigated and the results of your investigation 
should be reported in the submission.  However, calculations should be 
performed on the original results, not the resolved results.  Please refer to 
FDAs guidance document entitled, Guidance for Industry and FDA Staff:  
Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic 
Tests, dated March 13, 2007 (Ref. 1). 
 
Sample Types - Use blinded random samples. 
 
Concordance Description - HLA typing results are concordant with the results from 
the comparison device if at least one pair of alleles at a specific locus is the same 
between the two devices, either by allele group or by full allele name.  We 
recommend that you provide an explanation if the list of ambiguities for the predicate 
device includes a common and well documented (CWD) allele(s) that is not also 
reported by your device.   
 
  NOTE:  The term allele group refers to those groups of alleles with identical 
sequences in the exons that encode for the domains of the antigen recognition site 
(ARS).  These HLAs likely present similar or identical peptide binding and 
immunologic characteristics. 
 
D.  Software 
 
If your HLA test kit includes software, you should perform validation as recommended in 
the FDA guidance document entitled, General Principles of Software Validation; Final 
8  Contains Nonbinding Recommendations 
 
Guidance for Industry and FDA Staff, dated January 11, 2002 (Ref. 3) in preparing your 
510(k) submission. 
 
You should determine the level of concern of your software and submit the 
documentation recommended for that level of concern as discussed in the FDA guidance 
document entitled, Guidance for Industry and FDA Staff:  Guidance for the Content of 
Premarket Submissions for Software Contained in Medical Devices, dated May 11, 
2005 (Ref. 4).  If applicable, you should describe how your software addresses concerns 
such as background correction, normalization, etc. 
 
If your test kit uses off-the-shelf software, you should follow the recommendations 
contained in the FDA guidance document entitled, Guidance for Industry, FDA 
Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices dated 
September 9, 1999 (Ref. 5). 
 
Algorithms contained in the design of the device are critical to determining the correct 
genotype and phenotype; therefore, these algorithms should be described in the 510(k) 
submission. 
 
E.  Validation of Instrumentation  
 
If you provide, or recommend, specific instrumentation for your test kit, whether 
manufactured by you or by another company, you should include specific information 
about the instrument(s) in your submission. 
 
If you provide the instrument to the end-user as part of your test kit, your demonstration 
of substantial equivalence will need to address the inclusion of this instrument in your 
device.  You should address this by submitting instrument validation data in the 510(k).  
The instrument may be included in the 510(k) for the HLA test kit or the instrument may 
be submitted as a stand-alone device under a separate 510(k) submission.  In the latter 
case, the HLA test kit and the instrument are reviewed at the same time.   
 
F.  Labeling 
 
Under 21 CFR 807.87(e), the 510(k) submission must include proposed labels, labeling, 
and advertisements sufficient to describe the device, its intended use, and the directions 
for its use.  Where applicable, photographs or engineering drawings should be supplied. 
 
IVDs, including the HLA test kits covered in this guidance, are subject to labeling 
requirements under 21 CFR Part 809 (In Vitro Diagnostic Products for Human Use).  
You must label the product in accordance with these provisions.  Furthermore, in addition 
to the information required in 21 CFR 809.10(b)(2), you should include in the labeling 
the following statement:   
 
Should not be used as the sole basis for making a clinical decision. 
 
9  Contains Nonbinding Recommendations 
 
G.  Additional Considerations 
 
Bundling - You may bundle the test kits for different HLA loci in a single 510(k) 
submission.  However, as is true for any 510(k), you must provide the information 
required by 21 CFR 807.87.  This includes appropriate supporting information for each of 
the devices or indications for use, as well as data from performance studies under  
21 CFR 807.92(b), when applicable.  See Guidance for Industry and FDA Staff:  
Bundling Multiple Devices or Multiple Indications in a Single Submission, dated June 
22, 2007 (Ref. 6). 
 
Changes to the Device - Section 807.81(a)(3) requires a new 510(k) for any change or 
modification that could significantly affect either the safety or the effectiveness of a 
device.  See the FDA guidance document entitled, Deciding When to Submit a 510(k) 
for a Change to an Existing Device (K97-1), dated January 10, 1997 (Ref. 7). 
 
Please note, for the addition of a new test kit locus, submit a traditional 510(k).  For 
example, if your HLA kit was cleared to provide resolution of Class II DRB locus, you 
need to submit a new 510(k) if you are modifying your kit to include the resolution of 
Class II DQB locus.  We recommend validation testing in accordance with the 
recommendations described in this guidance.  For further information on traditional 
510(k)s, see the FDA guidance document entitled Guidance for Industry and FDA Staff:  
Format for Traditional and Abbreviated 510(k)s, dated August 12, 2005, and corrected 
on November 17, 2005 (Ref. 8).   
10  Contains Nonbinding Recommendations 
 
IV.  REFERENCES 
 
1.    Guidance for Industry and FDA Staff:  Statistical Guidance on Reporting 
Results from Studies Evaluating Diagnostic Tests, March 13, 2007.  
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm071148.htm  
2.    Guidance for Sponsors, Institutional Review Boards, Clinical Investigators 
and FDA Staff:  Guidance on Informed Consent for In Vitro Diagnostic 
Device Studies Using Leftover Human Specimens that Are Not 
Individually Identifiable, April 25, 2006. 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm078384.htm  
3.    General Principles of Software Validation; Final Guidance for Industry 
and FDA Staff, January 11, 2002.   
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm085281.htm 
4.    Guidance for Industry and FDA Staff:  Guidance for the Content of 
Premarket Submissions for Software Contained in Medical Devices, May 
11, 2005.  
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGui
dance/GuidanceDocuments/UCM089593.pdf  
5.    Guidance for Industry, FDA Reviewers and Compliance on Off-the-Shelf 
Software Use in Medical Devices, September 9, 1999. 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm073778.htm  
6.    Guidance for Industry and FDA Staff:  Bundling Multiple Devices or 
Multiple Indications in a Single Submission, June 22, 2007. 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm089731.htm 
7.    Deciding When to Submit a 510(k) for a Change to an Existing Device 
(K97-1), January 10, 1997.   
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm080235.htm 
8.    Guidance for Industry and FDA Staff:  Format for Traditional and 
Abbreviated 510(k)s, August 12, 2005, corrected on November 17, 2005.  
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm084365.htm  
9.    The International Immunogenetics (IMGT) Information System, 
http://www.imgt.org  
10.    Guidance for Industry and FDA Staff:  Pharmacogenetic Tests and Genetic Tests for 
Heritable Markers, June 19, 2007.   
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm077862.htm  
11  Contains Nonbinding Recommendations 
 
11.    Guidance for Industry and FDA Staff:  In Vitro Diagnostic (IVD) Device 
Studies  Frequently Asked Questions, June 25, 2010.  
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGui
dance/GuidanceDocuments/UCM071230.pdf  
12.    Guidance for Industry and FDA Staff:  Use of Symbols on Labels and in 
Labeling of In Vitro Diagnostic Devices Intended for Professional Use, 
November 30, 2004. 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guid
anceDocuments/ucm085404.htm   
13.   D.W. Tholen, A. Kallner, J.W. Krouwer, and K. Meier.  Evaluation of 
Precision Performance of Quantitative Measurement Methods; Approved 
Guideline - Second Edition, Clinical Laboratory Standards Institute, EP05-
A2, August 20, 2004.  http://www.clsi.org/  
14.   R.J. McEnroe, M.F. Burritt, D.M. Powers, D.W. Rheinheimer, and B.H. 
Wallace.  Interference Testing in Clinical Chemistry; Approved Guideline 
- Second Edition, Clinical Laboratory Standards Institute, EP07-A2, 
November 23, 2005. http://www.clsi.org/ 
15.   C.J. Brown and C.V. Navarrete.  Clinical Relevance of the HLA System in 
Blood Transfusion.  Vox Sanguinis (2011); 101(2): 93-105.  
16.   J. Klein and A. Sato.  The HLA System (Part I).  The New England 
Journal of Medicine (2000); 343:702-709.  
17.   J. Klein and A. Sato.  The HLA System (Part II).  The New England 
Journal of Medicine (2000); 343:782-786.  
18.   U. Shankarkumar.  The Human Leukocyte Antigen System.  International 
Journal of Human Genetics (2004); 4(2):91-103. 
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