Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
 
1 
Draft Guidance for Industry, Food and 
2 
Drug Administration Staff, and Clinical 
3 
Laboratories  
4 
5   
6   
Framework for Regulatory Oversight of 
7 
Laboratory Developed Tests (LDTs) 
8 
9   
DRAFT GUIDANCE 
10 
11   
12   
13  This guidance document is being distributed for comment purposes only.  
14  Document issued on: (cid:50)(cid:70)t(cid:82)ber (cid:22), 2014 
15   
16  You should submit comments and suggestions regarding this draft document within 120 days 
17  of publication in the Federal Register of the notice announcing the availability of the draft 
18  guidance.  Submit written comments to the Division of Dockets Management (HFA-305), 
19  Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  Submit 
20  electronic comments to http://www.regulations.gov.  Identify all comments with the docket 
21  number listed in the notice of availability that publishes in the Federal Register. 
22   
23  For questions regarding this document, contact LDTframework@fda.hhs.gov.  For questions 
24  regarding this document as applied to devices regulated by CBER, contact the Office of 
25  Communication, Outreach and Development in CBER at 1-800-835-4709 or 240-402-7800 or 
26  ocod@fda.hhs.gov. 
27   
28   
29   
30  U.S. Department of Health and Human Services 
31  Food and Drug Administration 
32  Center for Devices and Radiological Health 
33  Office of In Vitro Diagnostics and Radiological Health 
34   
35   
36  Center for Biologics Evaluation and Research  
37     
 
  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
38   
39   
Preface 
40 
41   
Additional Copies 
42 
43   
44  Additional copies are available from the Internet.  You may also send an e-mail request to 
45  CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance.  Please use the document 
46  number 1739 to identify the guidance you are requesting. 
47   
48  Or, contact: 
49   
50  Office of Communication, Outreach and Development 
51  Center for Biologics Evaluation and Research 
52  Food and Drug Administration 
53  10903 New Hampshire Ave., Bldg. 71, rm. 3128, Silver Spring, MD 20993-0002 
54  Internet:  
55  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/de
56  fault.htm 
57  Tel: 800-835-4709 or 240-402-7800 
58  E-mail:  ocod@fda.hhs.gov 
59   
60   
61 
 
  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
  
Table of Contents
62 
 
63 
64  A. Introduction .......................................................................................................................... 4 
65  B. LDT Definition and Scope of Guidance .............................................................................. 5 
66  C. Background .......................................................................................................................... 6 
67  1.  Regulatory History of LDTs .......................................................................................................................... 6 
68  2.  Evolution of LDT Technology, Marketing, and Business Models and the Need for Increased Regulatory 
69  Oversight of LDTs .............................................................................................................................................. 7 
70  3.  Gaps in Regulatory Oversight of LDTs ......................................................................................................... 8 
71  4.  Risk-Based Approach toward Oversight of LDTs ....................................................................................... 11 
72  D.  Framework for Regulatory Oversight of LDTs ................................................................ 15 
73  1.  Overview ..................................................................................................................................................... 15 
74  2.  Continued Enforcement Discretion in Full for Certain Categories of LDTs ............................................... 16 
75  3.  Notification to FDA of LDTs Manufactured by a Laboratory or Registration and Listing ......................... 17 
76  4.  Medical Device Reporting (MDR) Requirements ....................................................................................... 19 
77  5.  Premarket Review Requirements ................................................................................................................ 20 
78  6.  Quality System Regulation Requirements ................................................................................................... 28 
79  APPENDIX A:  LDT Oversight Framework Summary ......................................................... 30 
80  APPENDIX B:  LDT Oversight Framework; Questions and Answers .................................. 31 
81  APPENDIX C:  Regulatory Resources for LDTs ................................................................... 39 
82   
 
  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
Draft Guidance for Industry, Food and 
Drug Administration Staff, and Clinical 
Laboratories 
  
 
Framework for Regulatory Oversight of 
Laboratory Developed Tests (LDTs) 
 
This draft guidance, when finalized, will represent the Food and Drug Administration's 
(FDA's) current thinking on this topic.  It does not create or confer any rights for or on 
any person and does not operate to bind FDA or the public.  You can use an alternative 
approach if the approach satisfies the requirements of the applicable statutes and 
regulations.  If you want to discuss an alternative approach, contact the FDA staff 
responsible for implementing this guidance.  If you cannot identify the appropriate FDA 
staff, call the appropriate number listed on the title page of this guidance.  
A. Introduction  
This document describes a risk-based framework for addressing the regulatory oversight of a 
subset of in vitro diagnostic devices1 (IVDs) referred to as laboratory developed tests2 
(LDTs).  This document is intended to provide guidance to clinical laboratories that 
manufacture LDTs about how FDA (the Agency) intends to enforce authorities that apply to 
such laboratories as medical device manufacturers3 under the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act or the Act).   
 
                                                           
1 Per 21 CFR 809.3(a) in vitro diagnostic devices are those reagents, instruments, and systems intended for use 
in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, 
mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, 
preparation, and examination of specimens taken from the human body. These products are devices as defined 
in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products 
subject to section 351 of the Public Health Service Act. 
2 In the past, LDTs were referred to as home brew or in-house devices.  The term laboratory developed 
test and its acronym LDT replaced home brew over time, but the regulatory considerations are not affected 
by the change in terminology. 
3 A manufacturer is any person who engages in the manufacture, preparation, propagation, compounding, 
assembly, or processing of a device, defined as  the making by chemical, physical, biological, or other 
procedures of any article that meets the definition of device in section 201(h) of the act.  21 CFR 807.3(d); see 
also 21 CFR 803.3 (a manufacturer is any person who manufactures, prepares, propagates, compounds, 
assembles, or processes a device by chemical, physical, biological or other procedure.). 
 
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Specifically, this document describes FDAs priorities for enforcing premarket and 
postmarket requirements for LDTs as well as the process by which FDA intends to phase in 
enforcement of FDA regulatory requirements for LDTs over time.  
  
This document is not an exhaustive reference for all regulatory requirements under the 
FD&C Act or FDA regulations that may apply to medical devices, including LDTs.  
Omission of discussion of any particular regulatory requirement in this document does not 
relieve any manufacturer of the duty to comply with that requirement.  
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's 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 Agency guidances means that 
something is suggested or recommended, but not required. 
B. LDT Definition and Scope of Guidance 
FDA defines the term laboratory developed test (LDT) as an IVD that is intended for clinical 
use and designed, manufactured and used within a single laboratory. 4,5  The following is an 
example of an LDT: 
 
  A laboratory uses peer reviewed articles to guide development of a new diagnostic 
device.  The laboratory uses general purpose reagents and analyte specific reagents 
combined with general laboratory instruments and develops a testing protocol, that 
together constitute a test system which is then verified and validated within the 
laboratory.  Once validated this device is used by the laboratory to provide clinical 
diagnostic results. 
 
FDA does not consider devices to be LDTs if they are designed or manufactured completely, 
or partly, outside of the laboratory that offers and uses them.  The following are some 
examples of devices that FDA does not consider to meet the definition of an LDT: 
 
  An entity that owns several clinical laboratories develops a device in one of its 
clinical laboratories and then transfers the device to several clinical laboratories 
within its network. 
  An academic institution develops a device, which it then licenses to or signs an 
exclusivity agreement with a private corporation that owns a CLIA-certified 
laboratory. The private corporations CLIA-certified laboratory then begins 
manufacturing and using the device to provide clinical diagnostic results. 
                                                           
4 FDA generally does not exercise enforcement discretion for direct-to-consumer (DTC) tests regardless of 
whether they meet the definition of an LDT provided in this guidance.  Therefore, the enforcement policies in 
this guidance do not apply to DTC tests, and FDAs usual enforcement policies apply to DTC tests. 
5 Single laboratory refers to a facility with a single CLIA certificate as described in 42 CFR 493.43(a)-(b).  (See 
also 42 CFR 493.55).  LDTs should only be designed, manufactured, and used by laboratories that meet the 
requirements for high-complexity testing under CLIA as described in 42 CFR 493.17(c)(4) and 493.25. 
 
5  Contains Nonbinding Recommendations 
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  A laboratory contracts with a third party manufacturer to produce a key component 
(e.g., coated microtiter plate, specialized specimen collection kit) used in its device.   
  A laboratory contracts with a specification developer to design a new device.  Once 
complete, the design is then transferred to the clinical laboratory for final validation 
prior to the device being manufactured and used by the laboratory to provide clinical 
diagnostic results. 
 
FDA recognizes that some laboratories may currently be offering devices as LDTs, even 
though they do not meet FDAs definition of an LDT (e.g., they are not designed, 
manufactured, and used within a single laboratory).  Laboratory tests that are being marketed 
as LDTs but are in fact not LDTs are out of compliance with the FD&C Act6; however, in 
the interest of ensuring continuity in the testing market and avoiding disruption of access to 
these tests, FDA intends to apply the same risk-based framework, described in Section D of 
this document, to any IVD that is offered as an LDT by a CLIA-certified laboratory. 
 
For the purposes of clarity, references to LDTs in Section D of this document include IVDs 
that are offered by a CLIA-certified laboratory as an LDT (whether or not the device meets 
the FDAs definition of LDT), unless otherwise specified.   
C. Background 
1.  Regulatory History of LDTs 
In 1976, Congress enacted the Medical Device Amendments (MDA), which amended the 
FD&C Act to create a comprehensive system for the regulation of medical devices intended 
for use in humans.  At that time, the definition of a device was amended to make explicit that 
it encompasses IVDs.7  The definition of a device applies equally to IVDs manufactured by 
conventional device manufacturers and those manufactured by laboratories.  An IVD, 
therefore, meets the device definition irrespective of where and by whom it is manufactured.  
However, since the implementation of the MDA of 1976, FDA has generally exercised 
enforcement discretion so that the Agency has generally not enforced applicable provisions 
under the FD&C Act and FDA regulations with respect to LDTs.  Enforcement discretion for 
                                                           
6 As with LDTs, these tests meet the definition of device in the FD&C Act and are subject to FDA regulation. 
7 Section 201(h) of the FD&C Act provides: 
(h) The term "device" (except when used in paragraph (n) of this section and in sections 301(i), 403(f), 502(c), 
and 602(c)) means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or 
other similar or related article, including any component, part, or accessory, which is-- 
(1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to 
them, 
(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or 
prevention of disease, in man or other animals, or 
(3) intended to affect the structure or any function of the body of man or other animals, and  
which does not achieve its primary intended purposes through chemical action within or on the body of man or 
other animals and which is not dependent upon being metabolized for the achievement of its primary intended 
purposes. 
 
6  Contains Nonbinding Recommendations 
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LDTs developed as a matter of general practice, following the implementation of the 1976 
MDA.   
 
The Centers for Medicare & Medicaid Services (CMS) has regulated laboratories, including 
those that develop LDTs, under the Clinical Laboratory Improvement Amendments (CLIA) 
(42 U.S.C. 263a) since 1988.  CLIA governs the accreditation, inspection and certification 
process for laboratories.  CLIA requirements, however, address different functions than the 
requirements under the FD&C Act.  Namely, CLIA requirements address the laboratorys 
testing process (i.e., the ability to perform laboratory testing in an accurate and reliable 
manner).  Under CLIA, accreditors do not evaluate test validation prior to marketing nor do 
they assess the clinical validity of a LDT (i.e., the accuracy with which the test identifies, 
measures, or predicts the presence or absence of a clinical condition or predisposition in a 
patient).  Under the FD&C Act, the FDA assures both the analytical validity (e.g., analytical 
specificity and sensitivity, accuracy and precision) and clinical validity of diagnostic tests 
through its premarket clearance or approval process.  In addition to premarket review, FDA 
requirements provide other controls to ensure appropriate design, manufacture, and safety 
and effectiveness of the device.  As a result, while CLIA oversight is important, it alone does 
not ensure that LDTs are properly designed, consistently manufactured, and are safe and 
effective for patients. 
 
2.  Evolution of LDT Technology, Marketing, and Business Models and the Need for 
Increased Regulatory Oversight of LDTs 
Since 1976, when Congress clarified that IVDs were medical devices under the FD&C Act 
and FDA opted to exercise enforcement discretion with respect to LDTs under this authority, 
the industry has grown and evolved in significant ways, as summarized in the discussion 
below.  FDA finds that in the absence of appropriate oversight of LDTs, there is the potential 
for increased risk for patients.  
 
In 1976, LDTs were mostly manufactured in small volumes by local laboratories.  Many 
laboratories manufactured LDTs that were similar to well-characterized, standard diagnostic 
devices, as well as other LDTs that were  intended for use in diagnosing rare diseases or for 
other uses to meet the needs of a local patient population.  LDTs at the time tended to rely on 
the manual techniques used by laboratory personnel.  LDTs were typically used and 
interpreted directly by physicians and pathologists working within a single institution that 
was responsible for the patient.  In addition, historically, LDTs were manufactured using 
components that were legally marketed for clinical use.8   
 
Although some laboratories today still manufacture LDTs in this traditional manner, the 
landscape for laboratory testing in general, and LDTs along with it, has changed dramatically 
since 1976.  Today, LDTs are often used in laboratories that are independent of the 
                                                           
8 For purposes of this guidance, components that are legally marketed for clinical use refer to general purpose 
reagents, immunohistochemical stains, and other components marketed in compliance with applicable FDA 
regulatory requirements, e.g., properly labeled for in vitro diagnostic use (21 CFR 809.10(a)(4)) and 
manufactured in compliance with quality system requirements (21 CFR Part 820). 
 
7  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
healthcare delivery entity.  Additionally, today, LDTs are frequently manufactured with 
components and instruments that are not legally marketed for clinical use and also rely more 
heavily on high-tech instrumentation and software to generate results and clinical 
interpretations.  Moreover, technological advances have increased the use of diagnostic 
devices in guiding critical clinical management decisions for high-risk diseases and 
conditions, particularly in the context of personalized medicine.   
 
Business models for laboratories have also changed since 1976.  With the advent of 
overnight shipping and electronic delivery of information, including device results, a single 
laboratory can now provide device results nationally and internationally.  Today, many new 
LDT manufacturers are large corporations that nationally market a limited number of 
complex, high-risk devices, in contrast to 1976, when hospital or public health laboratories 
used a wide range of devices that were generally either well characterized and similar to 
standard devices; used to diagnose rare diseases; or designed specifically to meet the needs of 
their local patients.  Together, these changes have resulted in a significant shift in the types of 
LDTs developed and the potential risks they pose to patients.9  
 
In summary, the FDA has determined that the following attributes of modern LDTs, which 
are not attributes of the types of LDTs offered in 1976, create potential increased risk for 
patients in the absence of appropriate oversight.  Many modern LDTs are: 
  manufactured with components that are not legally marketed for clinical use 
  offered beyond local populations and manufactured in high volume 
  used widely to screen for common diseases rather than rare diseases  
  used to direct critical treatment decisions (e.g., prediction of drug response) 
  highly complex (e.g., automated interpretation, multi-signal devices, use of non-
transparent algorithms and/or complex software to generate device results) 
 
However, FDA recognizes that, as with all IVDs, there is a wide range of risks associated 
with the wide variety of LDTs.  Thus, FDA believes that a risk-based approach to regulatory 
oversight of LDTs is appropriate and necessary to protect patient safety.  A comprehensive 
framework that describes FDAs enforcement policy for different classes and categories of 
LDTs will help provide clarity to LDT manufacturers and protect patients.  
 
3.  Gaps in Regulatory Oversight of LDTs 
Due to changes in the complexity and use of LDTs and the associated increased risks, as 
described above, FDA believes the policy of general enforcement discretion towards LDTs is 
no longer appropriate.  Although the CLIA requirements are essential for ensuring that 
laboratories and their personnel maintain standards of high quality, FDA is concerned that 
compliance with CLIA regulations alone does not ensure that the diagnostic devices 
                                                           
9 For further information, see, e.g., Report of the Secretarys Advisory Committee on Genetics, Health and 
Society, U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and 
Human Services (April 2008), at http://oba.od.nih.gov/oba/sacghs/reports/sacghs_oversight_report.pdf;  and 
FDA materials in support of the 2010 FDA public meeting on the Oversight of Laboratory Developed Tests, 
available at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm212830.htm.  
 
8  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
themselves are safe and effective as required by the FD&C Act.  Specifically, CLIA 
regulations:  
  Do not assure the safety and effectiveness of LDTs. 
  Under CLIA, the laboratorys analytical validation of a LDT is reviewed 
o
during its routine biennial survey, which means that the evaluation of 
analytical validation occurs after the laboratory has already started testing 
rather than before it markets a test to the public.   Performance of analytical 
validation (i.e., proof that the device accurately detects analytes) is required 
by CLIA regulations for a laboratorys use of its test system in its own 
laboratory prior to reporting outpatient result, but this is generally only 
assessed after the device is marketed to the public. Moreover, the routine 
CLIA survey does not include a review of the clinical validation of a LDT  
that is, the accuracy with which the test identifies, measures, or predicts the 
presence or absence of a clinical condition or predisposition in a patient. 
Accordingly, there is no assurance that the devices are clinically relevant.  
Under the FD&C Act, both analytical validation and clinical validation are 
required and assessed before the devices are offered for clinical use. 
  Do not require adverse event reporting, which makes it difficult for regulators to 
detect devices that are inaccurate, ineffective, or unsafe. 
  Do not require removal of unsafe devices from the market. 
  Do not assess quality manufacturing of devices, a critical area of device oversight.  
  CLIA regulation focuses on laboratory processes for using devices, rather than 
o
on the design and manufacture of the devices themselves. 
  Do not require informed consent for patients who participate in LDT clinical studies 
and do not establish procedures for the conduct of such studies. 
 
The Agency has serious concerns regarding the lack of independent review of the evidence of 
clinical validity of LDTs.  Clinical validity is the ability of a diagnostic device to measure or 
detect the clinical condition for which the device is intended.  Clinical validity is not 
evaluated under CLIA regulations.  LDTs that have not been properly clinically validated for 
their intended use10 and are used to make critical clinical decisions potentially put patients at 
risk of missed or incorrect diagnosis, failure to administer appropriate treatment or 
administration of potentially harmful treatment with no benefit.  
 
Further, the FDA is aware that, while clinical laboratories perform some level of analytical 
validation for LDTs to meet CLIA requirements (42 CFR 493.1253(b)(2)), the protocols used 
for that purpose are not adequate to assure the safety and effectiveness of many LDTs.  The 
CLIA survey process reviews LDT analytical validation data, but this is generally conducted 
onsite after the device is already in use for providing clinical diagnostic results.  CLIA 
oversight is not designed to ensure that LDTs are appropriately analytically validated for 
their intended use before the test is used clinically.  In addition, CLIA does not require or 
assess the clinical validity of any test.  Accordingly, with respect to LDTs, compliance with 
                                                           
10 As per 21 CFR 801.4 the term intended use refers to the objective intent of the persons legally responsible 
for the labeling of the device.  The intent is determined by their expressions or may be shown by the 
circumstances surrounding the distribution of the device. 
 
9  Contains Nonbinding Recommendations 
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CLIA regulations alone does not adequately protect patient safety.  FDA premarket review 
under the FD&C Act and FDA regulations is intended to ensure safety and effectiveness.  
 
FDA is also concerned that under the current policy of enforcement discretion, there is no 
post-market safety monitoring of serious adverse events associated with the use of LDTs.  
Although the manufacturer medical device reporting requirements (21 CFR 803.50) apply to 
laboratories that manufacture LDTs, given that FDA has generally exercised enforcement 
discretion over LDTs, adverse event reports for LDTs, including reports of serious injuries 
potentially related to LDTs, have not been systematically reported or collected.11  
 
Additionally, although compliance with CLIA requirements provides assurances that clinical 
laboratory practices are of high quality and that the methodologies selected for clinical use 
have the capability of providing the quality of results required for patient care (42 CFR 
493.1445(e)(1) and 42 CFR 493.1445(e)(3)(i  iii)), these requirements were not developed 
to provide assurances regarding the design, manufacture, and validation of the diagnostic 
device itself.  In other words, even assuming that quality laboratory practices are in place 
under CLIA (e.g., personnel are appropriately qualified and test methodology has been 
appropriately selected), problems with a device would still occur if the device were 
improperly designed or manufactured, or inadequately validated.  As a result, there is no 
assurance that those LDTs designed and manufactured by a clinical laboratory without 
premarket review and other elements of oversight are well validated or safe and effective, 
and there is no adverse event reporting to track if they are not. 
 
FDA is also concerned that LDTs that have not undergone rigorous analytical or clinical 
review are used without the knowledge of the patient or the treating physician that the device 
being used is not FDA cleared or approved.  In the case where an LDT includes a legally 
marketed analyte specific reagent (ASR), the laboratory must include a statement on the test 
report indicating that the test has not been cleared or approved by the Food and Drug 
Administration (21 CFR 809.30(e)).  However, beyond this statement on the test report 
received only after the test is conducted, there is no requirement that the patient or the 
physician be directly informed of the nature of the device prior to ordering a test, meaning 
they may not be aware that the test is an LDT and not FDA cleared or approved.  Further, 
even this limited statement would not generally be included in the test report of an LDT that 
does not use legally marketed ASRs.  As a result, treating physicians and patients who rely 
on the results from the LDT in making medical treatment decisions may be, and often are, 
unaware that the analytical and clinical validity of the LDT may not have been evaluated by 
FDA.   
 
FDA believes that it should modify its policy of enforcement discretion in a risk-based 
manner to ensure FDA oversight and provide appropriate assurances regarding safety and 
effectiveness.  There have been reports of patient harm and concerns about potential harm 
                                                           
11 See Section D.4 of this document for further discussion of the medical device adverse event reporting 
requirements under 21 CFR Part 803.   
 
10  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
due to inaccurate, unsafe, ineffective, or poor quality LDTs.12  FDA oversight of LDTs 
would provide for independent review and evaluation of LDT clinical and analytical 
performance and claims, assurances of consistent manufacturing, and postmarket controls.   
 
Premarket review would ensure that LDTs are properly designed and evaluated for analytical 
and clinical validity in the intended use population, two critical aspects of IVD performance.  
Increased oversight through enforcement of the standard device manufacturer adverse event 
reporting requirements would provide for post-market monitoring of LDTs to assist in 
identifying any new problems with device performance or quality once the device is in use.  
Further, appropriate quality controls implemented through compliance with the FDA Quality 
System regulation (QS reg) (21 CFR Part 820) would lead to more robust and reliable design 
and manufacture of LDTs with less chance of device defects leading to adverse events. 
 
A framework for oversight would also provide for greater patient protections, particularly as 
they relate to proper informed consent when investigational LDTs are being used in patient 
management. 
 
For these reasons, the FDA plans to modify its policy of enforcement discretion as described 
in this document, when finalized. 
 
4.  Risk-Based Approach toward Oversight of LDTs 
Given the concerns discussed above, the Agency believes it should no longer generally 
exercise enforcement discretion towards all LDTs.  Once finalized and implemented, this 
guidance document is intended to provide an oversight framework that will assure that 
devices used in the provision of health care, whether developed by a laboratory or a 
conventional IVD manufacturer, comply with the appropriate levels of regulatory controls to 
assure that they are safe and effective.  Highlights of the oversight framework are provided 
below in this section, and further details are provided in Section D of this guidance.  
 
Risk-Based Classification 
Medical devices are classified as Class I, II or III based upon the controls necessary to 
provide a reasonable assurance of the safety and effectiveness of the device, and factors 
relevant to this determination include the devices intended use, technological characteristics, 
and the risk to patients if the device were to fail.  Class I devices, which are subject only to 
general controls, generally represent the lowest-risk category of devices, while Class III 
devices, which are subject to general controls and premarket approval, generally represent 
the highest-risk devices.  Section 513(a)(1) of the FD&C Act (21 U.S.C. 360c(a)(1)).   
 
                                                           
12 For example, see Buchen, L. Missing the mark. Why is it so hard to find a test to predict cancer? Nature 
471, 428-432 (2011), available at www.nature.com/news/2011/110323/full/471428a.html?s=news_rss; and the 
Report of the Secretarys Advisory Committee on Genetics, Health and Society, U.S. System of Oversight of 
Genetic Testing: A Response to the Charge of the Secretary of Health and Human Services (April 2008), at 
http://oba.od.nih.gov/oba/sacghs/reports/sacghs_oversight_report.pdf. 
 
 
11  Contains Nonbinding Recommendations 
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FDA will rely upon the existing medical device classification system to evaluate the risk of a 
category of LDTs and, informed by the industrys expressed interest in participating in the 
discussion of the classification process, will use expert advisory panels to help classify 
devices not previously classified by FDA, as appropriate.  In determining the risk an LDT 
poses to the patient and/or the user, FDA will consider several factors including whether the 
device is intended for use in high risk disease/conditions or patient populations, whether the 
device is used for screening or diagnosis, the nature of the clinical decision that will be made 
based on the test result, whether a physician/pathologist would have other information about 
the patient to assist in making a clinical decision (in addition to the LDT result), alternative 
diagnostic and treatment options available to the patient, the potential consequences/impact 
of erroneous results, number and type of adverse events associated with the device, etc.  To 
provide additional clarity, FDA intends to issue draft guidance to describe what the Agency 
considers generally to be Class I, II or III within 18 months of finalization of this guidance. 
 
LDT Framework 
FDA intends to continue to exercise enforcement discretion for all applicable regulatory 
requirements for: 
  LDTs used solely for forensic (law enforcement) purposes. 
  Certain LDTs for transplantation when used in CLIA-certified, high-complexity 
histocompatibility laboratories.13   
 
FDA intends to exercise enforcement discretion for applicable premarket review 
requirements and quality systems requirements, but enforce other applicable regulatory 
requirements14 including registration and listing (with the option to provide notification15) 
and adverse event reporting, for:  
  Low-risk LDTs (Class I devices). 
  LDTs for rare diseases and Traditional LDTs.16  These types of LDTs reflect the 
types of LDTs that existed when the enforcement discretion policy was initially 
implemented.  
  LDTs for Unmet Needs, when no FDA-approved or cleared equivalent device is 
available.17 
 
For other high and moderate risk LDTs, FDA intends to enforce applicable regulatory 
requirements, including registration and listing (with the option to instead provide 
                                                           
13 These categories are described below in Section D.2. 
14 Unless otherwise exempted, general controls are applicable to all medical devices regardless of their 
classification.  General controls include, but are not limited to, the provisions of the FD&C Act pertaining to 
prohibitions on adulteration and misbranding, establishment registration and device listing, premarket 
notification, banned devices, compliance with certain remedies required through an order issued under section 
518 of the FD&C Act (e.g.,notification, repair, replacement and refund), records and reports, restricted devices 
and good manufacturing practices.  Section 513(a)(1)(A) of the FD&C Act (21 U.S.C.  360c(a)(1)(A)).   
15 Notification is described in Section D.3. 
16 LDTs for rare diseases and Traditional LDTs are discussed further below in Section D.5.(a). 
17 LDTs for Unmet Needs are discussed in Section D.5.(b). 
 
12  Contains Nonbinding Recommendations 
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notification18), adverse event reporting, premarket review, and quality system requirements, 
as follows: 
  High-risk LDTs (Class III medical devices):  Registration and listing (with the option 
to provide notification) and adverse event reporting begin six months after this 
guidance is finalized.  Premarket review requirements begin 12 months after this 
guidance is finalized for the highest risk devices19 and phase-in over 4 years for the 
remaining high-risk devices.20   Devices would remain on the market during review 
and FDAs consideration of applications.  FDAs focus on high-risk devices begins 
with the following:  a) LDTs with the same intended use as a cleared or approved 
companion diagnostic; b) LDTs with the same intended use as an FDA-approved 
Class III medical device; and c) certain LDTs for determining the safety or efficacy of 
blood or blood products. 
  Moderate-risk LDTs (Class II medical devices):  Registration and listing (with the 
option to provide notification) and adverse event reporting begin six months after this 
guidance is finalized.  Premarket review requirements begin after the high-risk (Class 
III) LDTs are completed, meaning 5 years after the guidance is finalized, and phase-
in over 4 years.21  FDA intends to utilize FDA-accredited third party review of 
premarket submissions as appropriate. 
 
In the framework described in Section D of this document, FDA seeks to provide a 
reasonable, predictable, and consistent regulatory policy for assuring the safety and 
effectiveness of LDTs and provide sufficient time for implementation.   
 
Where an LDTs analytes/markers that are measured/assessed have had their clinical validity 
already established in the literature, FDA believes it may not be necessary for sponsors to 
conduct extensive new studies to demonstrate clinical validity of the analytes/markers, but 
the sponsor will need to demonstrate that any changes in technology or methodology that 
differ from that used in the literature to assess the analyte/marker do not affect the clinical 
validity of the LDT.  FDA intends to work with the laboratory community, the health care 
professional community, and other stakeholders to identify those LDTs for which the clinical 
validity of the analyte/marker has already been established in the literature.   
 
In addition, for those LDTs that present moderate risk, FDA intends to work with interested 
parties to expand the Agencys third party review program to include these types of devices.  
If successful, FDA believes that most moderate-risk LDTs could be reviewed by a third party 
reviewer.  Under this model, FDA would generally review high-risk LDTs subject to a 
premarket approval application (PMA) (i.e., Class III medical devices), while accrediting 
                                                           
18 Notification is described in Section D.3. 
19 Highest risk LDTs are described in Section D.5.(c). 
20 Based on feedback received from industry, FDA intends to phase in the remaining high-risk LDTs and 
moderate risk LDTs based on a risk-based prioritization that will be determined through a transparent process 
including expert advisory panels, as appropriate, and opportunity for public comment.  FDA intends to publish 
the prioritization lists for high-risk LDTs within 24 months of finalization of this guidance and moderate-risk 
LDTs within 4 years.  
21 See note 19.  
 
13  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
third parties to carry out review of most moderate-risk LDTs requiring a premarket 
notification (510(k)) submission (generally Class II devices).  FDA intends to continue 
exercising enforcement discretion with respect to applicable premarket review requirements 
and quality system requirements for Class I devices, which present the lowest risk. 
 
Timeline 
Registration and Listing/Notification and Adverse Reporting:  Six months after this guidance 
becomes final, manufacturers of LDTs should notify FDA if they are developing LDTs22 and 
must begin to report significant adverse events to FDA,23 so that problems can be detected 
and corrected in a timely manner.   
 
Premarket Review: FDA intends to phase-in enforcement of premarket review requirements 
for relevant LDTs over an extended period of time. LDT categories will be phased-in for 
enforcement based on risk, and the number and type phased-in at a given time will be 
commensurate with available agency resources.  The phased-in enforcement, starting with 
the highest-risk devices (described in section D.5. (c)), will begin 12 months after the 
guidance becomes final.   
 
FDA will prioritize all other LDTs based on risk using a public process, including expert 
advisory panels as appropriate, and will provide advanced notice with respect to timing of 
enforcement to manufacturers of LDTs that fall into the high- and moderate- risk categories. 
Premarket review for the highest risk devices will begin 12 months after this guidance is 
finalized.  FDA expects to announce the priority list for the remaining high-risk devices 
within 24 months from finalization of the guidance, with enforcement for the initial 
prioritized group on this list of LDTs beginning no less than 12 months after the 
announcement of the priority list.24  FDA intends to complete phased-in enforcement of 
premarket review requirements for Class III devices first (within a period of 5 years of 
finalization of the guidance).  FDA intends to phase in enforcement of requirements for Class 
II devices once FDA has completed the phase-in of the Class III devices.  FDA expects to 
announce the prioritization of moderate-risk devices within 4 years of finalization of the 
guidance and complete phased-in enforcement of premarket regulatory requirements for 
Class II devices within 9 years of finalization of the guidance.   
 
Under the proposed framework, laboratories that manufacture LDTs would comply with 
appropriate quality controls in the FDA QS reg (21 CFR Part 820) when a PMA is submitted 
or FDA issues a 510(k) clearance order for the LDT.  Compliance with the QS reg would 
lead to more robust and reliable design and manufacture of LDTs with less chance of device 
defects leading to adverse events.  The proposed framework for LDTs would also provide for 
greater patient protections, particularly as they relate to proper informed consent when 
investigational devices are being used in patient management.   
 
                                                           
22 The notification process is described below in Section D.3. 
23 The adverse event reporting requirements are described below in Section D.4. 
24 Note that general categories of high-risk LDTs likely to be prioritized for enforcement of premarket review 
requirements are detailed in Section D.5.(d). 
 
14  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
D.  Framework for Regulatory Oversight of LDTs 
1.  Overview 
The framework for regulatory oversight of LDTs discussed below describes FDAs general 
enforcement priorities for LDTs.  As a general matter, FDA proposes a risk-based, phased-in 
approach, in combination with continued exercise of enforcement discretion for certain 
regulatory requirements and certain types of LDTs.  
 
The Agency believes that this risk-based, phased-in approach is appropriate for several 
reasons.  First, FDA believes that the health risks associated with LDTs, as with all IVDs, 
vary with each type of device and the Agencys regulatory activities should, accordingly, be 
implemented based on risk.  Second, a phased-in implementation period is meant to mitigate 
any unintended and unpredictable consequences of immediately enforcing all applicable 
requirements, such as potential shortages in the availability of these devices for clinical 
testing.  Further, the Agency recognizes that clinical laboratories may be unfamiliar with 
FDA regulations, and a phased-in implementation approach will allow those facilities time to 
learn about the requirements and to develop programs to comply with them.   
Regardless of the phase-in schedule and use of enforcement discretion, FDA maintains its 
authority to take enforcement action if necessary to protect the public health, for example, 
when the Agency determines that an LDT presents a significant risk to public health.  
Conversely, the Agency may continue to exercise its discretion by not actively enforcing 
FDA requirements for longer periods of time than described in this guidance when there are 
shortages of medically necessary devices or for other compelling reasons. 
 
The main elements of FDAs framework for regulatory oversight include: 
 
  Either notification to FDA of LDTs manufactured by a laboratory or Registration 
and Listing  
  Medical Device Reporting Requirements (MDR) for LDTs (e.g., adverse event 
reporting) 
  Continued enforcement discretion with respect to premarket review requirements 
for low-risk LDTs, Traditional LDTs, LDTs used for rare diseases, and LDTs 
for Unmet Needs 
  Risk-based, phased-in approach to enforcing the premarket review requirements 
for other high-risk and moderate-risk LDTs 
  Use of clinical literature to support a demonstration of clinical validity, which 
FDA expects would reduce the need for additional clinical studies to show clinical 
validity for LDTs where the analytes/markers that are measured/assessed have 
had their clinical validity established in the literature 
  Facilitation of third-party review for many moderate risk LDTs 
  Phased-in approach to enforcing the Quality System regulation 
 
The elements of this framework for regulatory oversight of LDTs are described in detail 
below, along with their rationale and time frames for implementation. 
 
15  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
 
For those LDTs that are already FDA approved or cleared, it is FDAs expectation that 
manufacturers will continue to follow the regulations.  Manufacturers of tests that are used 
solely for in-process quality control testing in the manufacture of FDA-regulated articles 
should consult with FDA to determine applicable regulatory requirements.   
 
2.  Continued Enforcement Discretion in Full for Certain Categories of LDTs   
FDA intends to continue to exercise enforcement discretion in full for certain categories of 
diagnostic devices as described below.  For the following devices, FDA does not intend to 
enforce applicable registration and listing (nor is FDA requesting notification), adverse event 
reporting, premarket review, or quality system requirements:   
 
(a)  LDTs Used Solely for Forensic (Law Enforcement) Purposes 
FDA intends to continue to exercise enforcement discretion in full for IVDs used 
solely for forensic (law enforcement) purposes whether or not they are LDTs, 
consistent with current Agency policy.25  
 
(b)  LDTs Used in CLIA-Certified, High-Complexity Histocompatibility Laboratories 
for Transplantation 
Consistent with a 2011 recommendation from the Secretarys Advisory Committee on 
Organ Transplantation, FDA intends to continue to exercise enforcement discretion in 
full over LDTs used in CLIA-certified, high-complexity histocompatibility 
laboratories, when those LDTs are used in connection with organ, stem cell, and 
tissue transplantation:  
-  to perform high resolution allele typing;  
-  for antibody screening and monitoring; or 
-  for the purpose of conducting real and virtual crossmatch tests. 
 
These devices are often individualized within each medical facility, e.g., use of 
reagents that reflect local HLA polymorphisms and patient demographics.  They also 
are rapidly evolving.  These attributes raise significant concern that enforcement of 
FDA regulatory requirements for these devices could lead to the unavailability of 
testing used in transplants to sensitized transplant candidates, and in virtual 
                                                           
25 For example, see 65 FR 18230 (April 7, 2000) (final rule for OTC test sample collection systems for drugs of 
abuse testing) (However, FDA will continue to exercise its enforcement discretion with respect to the use of 
these products in the law enforcement setting because there are protections to ensure sample integrity and test 
accuracy that are not generally available in the home, workplace, insurance and sports settings. The additional 
protections include the use of rules of evidence in judicial proceedings and the representation of the accused 
(i.e., the person being tested) through the judicial process.); FDA draft guidance, Premarket Submission and 
Labeling Recommendations for Drugs of Abuse Screening Tests (Dec. 2003), at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070612.htm (At 
this time, FDA will continue to defer oversight of the use of these tests in the forensics (law enforcement) 
setting to the existing system of legal controls, such as the rules of evidence in judicial proceedings and other 
protections afforded through the judicial process.). 
 
16  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
crossmatching of donors and recipients at different locations, and could make 
desensitization and post-transplant monitoring less available.  However, this 
enforcement discretion policy is limited to LDTs used in organ, stem cell, and tissue 
transplantation, and does not extend to LDTs used in HLA testing for blood 
transfusion, which is highly standardized across institutions (see Section D.5.(c)).  
 
3.  Notification to FDA of LDTs Manufactured by a Laboratory or Registration and 
Listing 
With the exception of the categories of devices identified above in Section D.2 (forensic (law 
enforcement) LDTs and certain LDTs used in connection with organ, stem cell, and tissue 
transplantation), for laboratories that manufacture, prepare, propagate, compound, assemble, 
or process26 LDTs, FDA intends to continue to exercise enforcement discretion with respect 
to registration and listing requirements (21 CFR Part 807) provided that such laboratories 
notify FDA that they are manufacturing LDTs and provide basic information regarding each 
of these LDTs.  Notification is expected to occur once for each LDT, although if significant 
changes are made to an LDT, additional notification should be provided. 
 
Collection of such data is critical in the implementation of the risk-based framework 
described in this guidance given that this data will be used to classify LDTs, inform the 
classification guidance that FDA intends to issue within 24 months of finalizing this 
guidance (see Classification of LDTs in Section D.5.(d)), and prioritize enforcement of 
premarket review requirements.   Specifically, FDA plans to utilize advisory panels to 
provide recommendations to the Agency on LDT risks, classification, and prioritization of 
enforcement of applicable regulatory requirements on certain categories of LDTs, as 
appropriate.   Notification data will be useful for advisory panels in developing these 
recommendations and for FDA in carrying out the activities described in this guidance (e.g., 
developing the priority list).  Additionally, FDA intends to make the notification data 
publically available (after removing any information for which public disclosure is 
prohibited), because FDA believes that this information will be helpful to stakeholders, 
including industry, patients and physicians.    
 
Laboratories should provide notification information to the FDA within 6 months of the date 
of publication of the final version of this guidance document with respect to their LDTs on 
the market on the date of publication of the final version of this guidance document, and any 
new LDTs on the market in the 6 months following publication of this document. Starting 6 
months after publication of the final version of this guidance, laboratories offering new LDTs 
should provide notification prior to offering the LDT for clinical use.  It should be noted that 
when a laboratory makes a significant change to the marketed intended use of an LDT for 
which they have previously provided notification, the LDT will be considered by the FDA to 
be a new LDT.27  Therefore, a new notification should be provided prior to offering that LDT 
                                                           
26 See 21 CFR 807.3(d) for definition of these terms.  This guidance document uses manufacture to 
encompass all of these terms. 
27 For purposes of this guidance, FDA uses the term marketed intended use to refer to the use(s) of a test that 
a laboratory promotes or includes in any applicable labeling.  Although FDA generally considers new devices to 
 
 
17  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
for clinical use; this is especially important for those changes in marketed intended use that 
increase the risk of the device.  Additionally, following initial notification, FDA urges 
laboratories that make other significant modifications to LDTs after notification to re-submit 
notification data to FDA to communicate such changes (see section D.5.(e) of the guidance 
for additional information on significant device modifications). Given that notification data 
will be used to classify LDTs and prioritize enforcement of premarket review requirements 
based on risk, it will benefit laboratories to provide the most accurate information possible to 
ensure that appropriate classification is made.   
 
This notification does not constitute compliance with registration and listing requirements, 
nor will the laboratory be considered to be registered or to have listed its devices with the 
FDA.  Therefore, such laboratories are not required to submit registration fees to FDA with 
the notification. 
 
Laboratories that do not opt to notify the Agency that they are manufacturing LDTs or 
provide basic information regarding each of the LDTs manufactured in their laboratory 
within the abovementioned timeframes will have opted not to be within the scope of FDAs 
enforcement discretion policy with respect to the registration and listing requirements.  Such 
laboratories would fall within the agencys normal enforcement approach with respect to the 
registration and listing requirements.  Registration and listing requirements include 
registration of each establishment28 with the FDA and listing of the devices manufactured in 
these facilities (21 CFR 807.20(a)).  Submission of the registration and listing information 
must be accompanied by payment of the registration fee (Section 738(a)(3) of the FD&C Act 
(21 U.S.C. 379j(a)(3))). 
   
Further, FDA does not intend to enforce registration and listing requirements for an 
establishment that manufactures, prepares, propagates, compounds, assembles or processes 
one or more LDTs until a premarket submission (e.g., PMA (21 U.S.C. 360e(c); 21 CFR Part 
814) or a 510(k) submission (21 U.S.C. 360(k); 21 CFR Part 807, Subpart E)) has been made 
to the Agency for any one LDT.  
 
Proposed specific instructions on how laboratories should appropriately notify the FDA 
regarding LDT manufacture and provide basic information regarding the LDTs are provided 
in the draft guidance document titled FDA Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).  
 
The notification system described above will be a critical element of the LDT oversight 
framework, as it will provide the Agency with the necessary information on the LDTs being 
currently manufactured by clinical laboratories to assist the Agency in implementing the 
enforcement of premarket requirements for LDTs based on their risk, as described below in 
Section D.5.   
 
                                                                                                                                                                                    
include other types of modifications to an existing device (e.g., technological changes), for the purposes of this 
subsection only, new LDTs do not include other types of modifications to an existing LDT.   
28 See 21 CFR 807.3(c) for definition of establishment. 
 
18  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
FDA does not intend to exercise enforcement discretion with respect to registration and 
listing requirements for an establishment that manufactures, prepares, propagates, 
compounds, assembles or processes medical devices other than or in addition to LDTs, even 
if the establishment is a laboratory. 
 
4.  Medical Device Reporting (MDR) Requirements  
With the exception of the categories of tests identified above in Section D.2 (forensic (law 
enforcement) LDTs and certain LDTs used in connection with organ, stem cell, and tissue 
transplantation), FDA intends to enforce the manufacturer reporting requirements of the 
Medical Device Reporting (MDR) regulation (21 CFR Part 803, Subpart E) for laboratories 
manufacturing LDTs.29  The MDR regulation requires the manufacturer of a medical device 
to submit reports to the FDA whenever they become aware30 of information that reasonably 
suggests that a device they market may have caused or contributed to31 a death or serious 
injury,32 or has malfunctioned and the malfunction would be likely to cause or contribute to a 
reportable death or serious injury should it recur.   21 CFR 803.50.   
 
One objective of the MDR regulation is to provide a mechanism for FDA and device 
manufacturers to identify and monitor significant adverse events involving medical devices 
so that problems may be detected and corrected in a timely manner.  This information is 
particularly important in the case of LDTs, as many of these devices have not undergone 
premarket review.  MDR reporting for LDTs will provide for an important risk mitigation 
measure to detect, track, and help address serious problems related to LDT performance 
should they occur.  
 
Therefore, beginning six months following publication of the final version of this guidance 
document, FDA intends to cease its exercise of enforcement discretion with respect to the 
MDR reporting requirements in 21 CFR Part 803, Subpart E, for laboratories that 
manufacture LDTs. A description of the specific requirements in 21 CFR Part 803, Subpart 
E, as well as further information on how the MDR requirements apply to laboratories is 
described in the guidance document FDA Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).  
 
                                                           
29 With respect to clinical laboratories, FDA has already been enforcing the provisions of the MDR regulation 
applicable to device user facilities (21 CFR 803.3 and Subpart C).  User facilities are required to report to FDA 
information that reasonably suggests that a device has caused or contributed to the death of a patient and to the 
manufacturer information that reasonably suggests a device may have caused or contributed to a death or 
serious injury (21 CFR 803.30). 
30 A manufacturer has become aware of an event when an employee of the entity required to report has 
acquired information to reasonably suggest a reportable adverse event has occurred. (21 CFR 803.3). 
31The term caused or contributed to means that a death or serious injury was or may have been attributed to a 
medical device, or that a medical device was or may have been a factor in a death or serious injury, including 
events occurring as a result of failure, malfunction, improper or inadequate design, manufacture, labeling, or 
user error. (21 CFR 803.3) 
32Serious Injury means an injury or illness that is life-threatening, results in permanent impairment of a body 
function or permanent damage to a body structure, or necessitates medical or surgical intervention to preclude 
permanent impairment of a body function or permanent damage to a body structure. (21 CFR 803.3) 
 
19  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
5.  Premarket Review Requirements 
With the exception of the categories of devices identified above in Section D.2 (forensic (law 
enforcement) LDTs and certain LDTs used in connection with organ, stem cell, and tissue 
transplantation) and those identified in paragraphs (a) and (b) below, FDA intends to phase in 
the enforcement of applicable premarket requirements over time based upon the risk 
associated with that device.  FDA intends to focus its efforts on the highest risk devices first 
and gradually phase in enforcement for other devices over time.  In this manner, it is FDAs 
intention to avoid undue disruption of medical testing while seeking to assure patient safety 
and to assure that health care practitioners are relying on device results that are meaningful 
and accurate when making medical decisions.  
 
(a) Continued Enforcement Discretion with Respect to Premarket Review 
Requirements for LDTs Used for Rare Diseases and Traditional LDTs 
The FDA believes that it is appropriate to continue to exercise enforcement discretion 
with respect to premarket review requirements for the two categories of LDTs 
described below.  However, laboratories that manufacture these LDTs should notify 
the FDA as described in Section D.3 of this guidance and in the guidance document, 
FDA Notification and Medical Device Reporting for Laboratory Developed Tests 
(LDTs).  FDA intends to enforce registration and listing requirements for 
laboratories that manufacture these LDTs if they have not notified the Agency, as 
described above.  In addition, FDA intends to enforce the MDR reporting 
requirements, including 21 CFR Part 803, Subpart E, for laboratories that 
manufacture these LDTs, as described in Section D.4 of this document.   
 
LDTs Used for Rare Diseases 
The Humanitarian Use Devices (HUD)/Humanitarian Device Exemption (HDE) 
provisions of the Act (21 U.S.C. 360j(m)) and regulations (21 CFR 814, Subpart H) 
provide an abbreviated regulatory pathway as an incentive for the development of 
devices for use in the treatment or diagnosis of rare diseases or conditions.   
 
FDA recognizes that some LDTs may qualify as HUDs.  An IVD device may qualify 
for HUD designation when the number of persons who may be tested with the device 
is fewer than 4,000 per year.  FDA recognizes that one patient may be tested multiple 
times with the same device; when this occurs, the multiple uses are counted as one 
use for purposes of defining which devices may qualify as HUDs.  
 
If an IVD is being developed to diagnose or to help diagnose a disease or condition 
with an incidence of fewer than 4,000 patients per year, but there are more than 4,000 
patients a year who would be subject to testing using the device, then the device does 
not qualify as a HUD (21 CFR 814.102(a)(5)). 
 
While FDA encourages laboratories manufacturing LDTs for rare diseases to seek 
approval under the HDE provisions, FDA plans to continue to exercise enforcement 
discretion with regard to premarket review requirements for LDTs that meet the 
definition in this guidance and the definition of an HUD under 21 CFR 814.102(a)(5).   
 
20  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
 
Traditional LDTs 
FDA intends to continue to exercise enforcement discretion with respect to premarket 
review requirements for Traditional LDTs, which are those IVD devices that reflect 
the types of LDT available when FDA began its policy of generally exercising 
enforcement discretion over LDTs in 1976.  In considering whether to exercise 
enforcement discretion for Traditional LDTs, FDA intends to consider the following 
factors: 
 
(1) Whether the device meets the definition of LDT in this guidance (a device 
designed, manufactured and used by a single laboratory); and 
(2) Whether the LDT is both manufactured and used by a health care facility 
laboratory (such as one located in a hospital or clinic) for a patient that is being 
diagnosed and/or treated at that same health care facility or within the facilitys 
healthcare system33; and 
(3) Whether the LDT is comprised  only of components and instruments that are 
legally marketed for clinical use (e.g., analyte specific reagents (21 CFR 
864.4020), general purpose reagents (21 CFR 864.4010), and various classified 
instruments); and 
(4) Whether the LDT is interpreted by qualified laboratory professionals, without the 
use of automated instrumentation or software for interpretation. 
 
FDA believes that the factors described above help to mitigate the risks associated 
with these LDTs in several ways.  First by meeting the definition of an LDT in this 
guidance, the laboratory that develops and validates an LDT is the same location with 
the personnel and appropriate expertise needed to run and interpret the test result.  
Further, the manufacture and use of LDTs within a facilitys healthcare system 
ensures common responsibility for patient outcomes that may result from the clinical 
decisions informed by those device results, while providing patient access to any 
LDT used in a laboratory within that healthcare system.  Also, the factors for 
Traditional LDTs ensure a certain level of quality through the use of only components 
and instruments legally marketed for clinical use.  When these three factors are in 
place and CLIA regulations ensure that laboratory personnel are appropriately 
qualified and trained for their role in the laboratory, FDA believes that the 
circumstances described above allow for appropriate controls to manage risks 
specifically related to manual techniques and interpretation in Traditional LDTs.  In 
contrast, automated instrumentation and use of software requires appropriate 
                                                           
33 The term healthcare system refers to a collection of hospitals that are owned and operated by the same 
entity and that share access to patient care information for their patients, such as, but not limited to, drug order 
information, treatment and diagnosis information, and patient outcomes. Please note that in this case, FDA does 
not consider a contracted diagnostic laboratory to be included in the facilitys healthcare system.  FDA would 
consider an owned and operated diagnostic laboratory to be included in the facilitys healthcare system.  Please 
also note that the term hospital is defined as:  a distinct entity that operates for the primary purpose of 
providing diagnostic, therapeutic (such as medical, occupational, speech, physical), surgical, and other patient 
services for specific and general medical conditions. Hospitals include general, chronic disease, rehabilitative, 
psychiatric, and other special-purpose facilities. 21 CFR 803.3. 
 
21  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
instrument and software validations to be performed, which are not evaluated under 
the CLIA regulations.  FDA believes that where an LDT relies on manual 
interpretation by qualified laboratory professionals, rather than the use of automated 
instrumentation or software for interpretation, and the other factors above are also 
present, it is appropriate and consistent with the LDTs available when FDA initiated 
its policy of enforcement discretion over these devices in 1976. FDA believes that 
these factors appropriately mitigate risks associated with Traditional LDTs being used 
on patients so that continued enforcement discretion with respect to premarket review 
requirements is appropriate. 
 
(b) Continued Enforcement Discretion with Respect to Premarket Review 
Requirements for LDTs for Unmet Needs When No FDA-cleared or -approved 
Alternative Exists 
FDA recognizes the role that LDTs can play in meeting urgent unmet healthcare 
needs.  FDA believes it is important to maintain the availability of LDTs that serve 
unmet needs (but that are not LDTs for rare diseases or Traditional LDTs) until a 
comparable FDA-cleared or -approved device becomes available.  For this reason, 
FDA intends to exercise enforcement discretion with respect to premarket review 
requirements for LDTs for Unmet Needs.  In determining whether an LDT is an 
LDT for Unmet Needs, FDA intends to consider the following factors:  
  
(1) Whether the device meets the definition of LDT in this guidance (a device 
designed, manufactured and used by a single laboratory);  and 
(2) Whether there is no FDA cleared or approved IVD available for that specific 
intended use; and 
(3) Whether the LDT is both manufactured and used by a health care facility 
laboratory (such as one located in a hospital or clinic) for a patient that is being 
diagnosed and/or treated at that same health care facility or within that facilitys 
healthcare system. 
 
For LDTs for Unmet Needs, FDA does not intend to consider factors such as whether 
the LDT is comprised of only legally marketed components and instruments or 
whether the LDT is interpreted by qualified laboratory professionals, without the use 
of automated instrumentation or software for interpretation.  FDA believes that 
greater flexibility is appropriate for LDTs for Unmet Needs because there is no FDA-
cleared or approved alternative for the device on the market.  
 
As with Traditional LDTs, FDA believes that the manufacture and use of LDTs for 
Unmet Needs within a facilitys healthcare system will help to mitigate risks because 
the healthcare system manufacturing and using the test is also responsible for treating 
the patient, and is thereby responsible for patient outcomes that may result from the 
clinical decisions informed by that device result. 
 
Note:  However, once FDA clears or approves an IVD for the same intended use, 
FDA will no longer consider the LDT to be an LDT for Unmet Needs.  Therefore, 
following FDA clearance or approval of a device with the same intended use as an 
 
22  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
LDT for Unmet Needs, FDA intends to enforce the premarket review requirements if 
the LDT falls within FDAs enforcement priorities.  For example, if the LDT is Class 
III, then it falls within the initial priorities described in Section D.5.(c), meaning that 
if FDA approves a Class III test, laboratories offering LDTs with the same intended 
use would be expected to submit a premarket approval application within 12 months.   
 
If the LDT is Class II and not within one of the categories described in Section 
D.5.(c), then FDA intends to enforce following the process for prioritizing the Class 
II LDTs as described in Section D.5.(d), meaning that FDA intends to enforce 
premarket review when the LDT category is called in and FDA clears a test in that 
category.  FDA will provide adequate public notice through the priority list discussed 
in Section D.5.(d) that would describe when a new category of LDT is being called 
in, after which the laboratory will have 12 months to submit a premarket application 
for their LDT if FDA clears a test in that category.  If the appropriate premarket 
submission is made within the 12-month period, FDA intends to continue to exercise 
enforcement discretion while that submission is under Agency review to ensure 
continued availability of the device until FDA makes a final decision on the 
submission.   
 
Given that laboratories should have already conducted appropriate studies to 
demonstrate analytical and clinical validity or be able to reference support in the 
literature to justify device use for clinical decision-making, FDA does not anticipate 
that premarket submissions to FDA for these tests would be overly burdensome.  
Exercising enforcement discretion with respect to LDTs for Unmet Needs until a 
device with the same intended use is cleared or approved would encourage the 
makers of such LDTs to gather appropriate data, without delaying patient access in 
the absence of a cleared or approved diagnostic device.  It also would provide patients 
and providers with the confidence that once a test is cleared or approved by FDA, all 
such devices, regardless of who makes them, are safe and effective because all such 
devices will need to comply with premarket review requirements. 
 
Laboratories that manufacture one or more LDTs for Unmet Needs should notify the 
FDA, as described in Section D.3 of this guidance.  FDA intends to enforce 
registration and listing requirements for laboratories that manufacture these LDTs if 
they have not opted to notify the Agency, as described above.  In addition, FDA 
intends to enforce the MDR reporting requirements, including 21 CFR Part 803, 
Subpart E, for laboratories that manufacture these LDTs, as described in Section D.4 
of this document. 
 
(c) Enforcement of Premarket Submission Requirements for Companion Diagnostics 
and Other High-risk Diagnostic Device Category LDTs  
FDA intends to initially focus its enforcement priorities by generally enforcing the 
premarket review requirements beginning 12 months after this guidance is finalized 
for the following LDTs: a) LDTs with the same intended use as a cleared or approved 
 
23  Contains Nonbinding Recommendations 
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companion diagnostic34; b) LDTs with the same intended use as an FDA-approved 
Class III medical device; and c) certain LDTs for determining the safety or efficacy of 
blood or blood products. 
 
FDA believes that these diagnostic device categories are among the highest risk LDTs 
currently available on the market because the device either is used to direct patient 
therapy (as in the case of LDTs with the same intended use as a cleared or approved 
companion diagnostic) or has the same intended use as a device that FDA has already 
determined to be in the highest risk classification (Class III). 
 
For 12 months following publication of this guidance document in final form, FDA 
intends to exercise enforcement discretion with respect to premarket review 
requirements for currently marketed LDTs in the three abovementioned categories.  
FDA intends to begin enforcing premarket review requirements for these categories 
of currently marketed LDTs at the end of that 12-month period.  If the appropriate 
premarket submission (generally a PMA) is made within the 12-month period, FDA 
intends to continue to exercise enforcement discretion while the premarket 
submission is under FDA review, so as not to interrupt patient access.  FDA intends 
to begin enforcing premarket review requirements immediately upon publication of 
this guidance document in final form for all new LDTs (i.e., those that become 
available for patient testing after final publication of this guidance document) in these 
categories.  FDA will expect manufacturers of these new LDTs to make an 
appropriate premarket submission and obtain approval or clearance for their devices 
prior to use. 
 
Blood Donor, Transfusion Compatibility, and HCT/P Donor LDTs  
Devices used for blood donor screening are regulated by the Office of Blood 
Research and Review (OBRR) in the Center for Biologics Evaluation and Research 
(CBER).  FDA regulations require that blood donor screening testing be performed, 
and that the donor screening devices used be approved for such use and performed 
in accordance with the manufacturers instructions (21 CFR 610.40(a), (b)).  For 
some time now, FDA has enforced these regulatory requirements with respect to 
LDTs that are donor screening devices.   
 
FDA considers other devices used in determining the safety or efficacy of blood or 
blood products to be high-risk devices, including devices used for HLA testing for 
transfusion compatibility and those used for blood donor infectious disease 
supplemental or confirmatory testing, or for red blood cell compatibility testing (i.e., 
phenotyping and/or genotyping of donors and recipients or mother and fetus).  As 
                                                           
34 Companion Diagnostics (also referred to as in vitro companion diagnostic devices or IVD companion 
diagnostic devices) are in vitro diagnostic devices that provide information that is essential for the safe and 
effective use of a corresponding therapeutic product. Further information regarding companion diagnostics can 
be found in the guidance document entitled In Vitro Companion Diagnostic Devices. 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262
327.pdf 
 
24  Contains Nonbinding Recommendations 
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such, similar to the other high-risk LDTs noted above, FDA intends to begin 
enforcing premarket review requirements for these types of devices at the end of 12 
months of the finalization of this guidance.   
 
The regulations also require that donors of human cells, tissues, and cellular and 
tissue-based products (HCT/Ps) be screened for evidence of relevant communicable 
diseases using licensed, approved, or cleared donor screening devices (21 CFR 
1271.80).  FDA intends to continue to enforce this requirement for HCT/P donor 
screening devices, including for any LDTs intended for this use. 
 
(d) Phased-In Enforcement of Premarket Requirements for Other LDT Categories 
After FDA collects and analyzes notification data, it will prioritize the remaining 
device categories based on risk using a public process.  FDA plans to utilize advisory 
panels to provide recommendations to the Agency on LDT risks and prioritization of 
enforcement of applicable regulatory requirements on certain categories of LDTs, as 
appropriate.  FDA intends for there to be ample opportunity for public comment.   
 
FDA intends to provide adequate notice about the risk-based prioritization of 
categories of LDTs to increase transparency and so that laboratories may be able to 
prepare well in advance of enforcement. FDA anticipates that this phased-in 
enforcement of premarket review requirements for LDTs will take place over a 
number of years. 
 
For the high risk devices identified in section (c), FDA intends to begin enforcing 
premarket review requirements 12 months after this guidance is finalized.  FDA 
expects to announce the priority list for the remaining Class III LDTs within 24 
months from finalization of this guidance.  In the priority list, FDA plans to describe 
the order in which the Agency intends to enforce the Class III LDT categories and 
when the Agency intends to start enforcing the different categories.  FDA intends to 
start enforcing the premarket review requirements for the Class III LDT categories in 
the highest priority group beginning no less than 12 months after the priority list is 
announced.35  If a premarket submission (i.e., PMA (21 CFR Part 814) or biologics 
license application (BLA) (21 CFR Part 601)) or if appropriate, an investigational 
device exemption (IDE) (21 CFR Part 812), is submitted within the 12-month period, 
FDA intends to continue to exercise enforcement discretion while the submission is 
under FDA review.  After FDA begins enforcing the premarket review requirements 
for LDTs in a particular category, FDA will expect laboratories that develop new 
LDTs in these categories to comply with premarket review requirements before 
marketing of such LDTs.  
 
                                                           
35 Note that general categories of high-risk LDTs likely to be in the highest priority group for  prioritized for 
enforcement of premarket review requirements are detailed below in this Section under the heading LDTs of 
Higher Concern to the Agency. 
 
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FDA intends to complete phased-in enforcement of premarket review requirements 
for Class III devices first (within a period of 5 years of finalization of the guidance).  
FDA intends to phase-in enforcement of premarket review requirements for Class II 
devices once FDA has completed the phase-in of the Class III devices.  FDA expects 
to announce the enforcement prioritization of Class II devices within 4 years of 
finalization of the guidance and complete phased-in enforcement of premarket 
regulatory requirements for Class II devices within 9 years of finalization of the 
guidance.   
 
It should be noted that the Agency will accept premarket submissions for LDTs at any 
point for those laboratories seeking to come into regulatory compliance, even prior to 
FDA enforcing premarket review requirements for those laboratories LDT devices.  
 
Classification of LDTs  
To provide additional clarity, FDA intends to issue guidance to describe what the 
Agency considers generally to be Class I, II or III within 24 months of finalization of 
this guidance.36  
 
FDA intends to enforce premarket submission requirements beginning with highest 
risk LDTs (i.e., FDA intends to address the highest risk Class III devices before 
addressing lower risk Class II devices).  FDA intends to continue exercising 
enforcement discretion with respect to applicable premarket submission requirements 
for LDTs that are Class I devices, which present the lowest risk.  Once enforcement 
of a set of LDTs has been completed, FDA intends to enforce premarket submission 
requirements for the next set of LDTs (based on their risk).  The appropriate type of 
premarket submission (i.e., PMA, 510(k), de novo, etc.) will depend on the device 
classification.   
 
FDA recognizes that some LDTs with new intended uses may automatically be 
classified in the highest risk class, Class III, as a matter of law.  Section 513(f)(1) of 
the FD&C Act (21 U.S.C. 360c(f)(1)).  Where warranted, FDA plans to down classify 
such LDTs into the appropriate lower risk class on its own initiative or using the de 
novo process, with input from advisory panels where appropriate.  Section 513(b)(1), 
513(f)(2), and 513(f)(3) of the FD&C Act (21 U.S.C. 360c(b), 21 U.S.C. 360c(f)(2), 
and 21 U.S.C. 360c(f)(3)).   
 
LDT Devices of Higher Concern to the Agency 
FDA has identified several categories of LDTs that have not yet been classified that it 
believes generally pose a higher risk to patients than other LDTs, and for which 
enforcement of premarket review requirements likely commence earlier (following 
adequate public notice as described above), as follows:  
 
(1) Devices that act like companion diagnostics.   
                                                           
36 FDA intends to issue a draft version of this guidance for comment prior to an advisory panel meeting on LDT 
risks and enforcement prioritization.   
 
26  Contains Nonbinding Recommendations 
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These diagnostics include those devices that claim to enhance the use of a specific 
therapeutic product, through selection of therapy, patient population, or dose, but 
which are not included in the therapeutic product labeling (e.g., devices developed 
by laboratories that claim to predict who will respond to a therapy approved for 
use in a larger population).  FDA believes these devices represent higher risk to 
patients given that they provide a direct, often standalone, recommendation for 
use of a specific therapeutic product that is not supported by the therapeutic 
product labeling. 
 
(2) Screening devices for serious diseases and/or conditions intended for use in 
asymptomatic patients with no other available confirmatory diagnostic product or 
procedure, such as screening device for malignant cancers  
 
(3) Diagnostic devices for certain infectious diseases with high-risk intended uses37 
 
(e) Modifications to FDA Cleared/Approved Devices 
As in the case of any other entity, a clinical laboratory that modifies an FDA 
cleared/approved device in a way that affects device performance or intended use is 
considered to be a device remanufacturer (21 CFR 820.3(w)). Such modifications 
may include change in specimen type or sample matrix (e.g., saliva vs. whole blood), 
type of analysis performed (e.g., qualitative vs. quantitative), the purpose of the assay 
(e.g. screening, diagnosis, prognosis, monitoring, surveillance, and confirmation), the 
target population(s), etc.  These modified devices must meet premarket submission 
requirements under 21 CFR 807.81(a)(3) and 21 CFR Part 814.  FDA intends to begin 
enforcing premarket requirements for these modified devices as the Agency begins 
enforcing premarket requirements for the LDT category under which the modified 
device falls.  
 
(f) Clinical Investigations 
FDA intends to continue to enforce investigational device requirements under 21 
CFR Part 812 for all clinical investigations of LDTs that are conducted under clinical 
protocols that require institutional review board approval. Before conducting an 
investigation, clinical laboratories must follow applicable requirements in 21 CFR 
Part 56 for institutional review board (IRB) approval as well as applicable 
requirements in 21 CFR Part 50 for informed consent from the study subjects at the 
time of their enrollment in the study.  See In Vitro Diagnostic (IVD) Device Studies 
- Frequently Asked Questions, 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guid
                                                           
37 Diagnostic devices for certain infectious diseases with high-risk intended uses are considered to be of higher 
concern to the Agency.  For example, currently available cytomegalovirus and/or Epstein-Barr virus serological 
devices, intended to detect and differentiate the presence of viral antibodies or antigens to diagnose a viral 
infection, are generally considered low-risk devices.  However, new molecular devices intended to monitor 
levels of cytomegalovirus or Epstein-Barr virus in infected, immunocompromised, or transplant patients are 
expected to fall into a higher-risk category because patients in these categories are at greater risk of death from 
infection, especially if a false negative or low viral load is recorded by the test at the beginning of treatment. 
 
27  Contains Nonbinding Recommendations 
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anceDocuments/UCM071230.pdf.  Currently, the vast majority of IVD development 
programs involve studies that are considered exempted investigations as defined in 
21 CFR 812.2. However, if the LDT to be studied in the investigation meets the 21 
CFR 812.3 definition of a significant risk device, the investigation can only be 
conducted under an approved investigational device exemption (IDE).  21 CFR 812.2.  
IDE requirements include labeling the LDT for investigational use in accordance with 
21 CFR 809.10(c) or 21 CFR 812.5, as applicable, if the laboratory intends to conduct 
an investigation to pursue FDA clearance or approval.   
 
Further information regarding investigational device requirements can be found on 
the FDA website at:  
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYo
urDevice/InvestigationalDeviceExemptionIDE/ucm046164.htm 
 
(g) Evaluation of Clinical Validity of LDTs 
FDA expects that for many LDTs, clinical validity has already been established in 
literature.  FDA emphasizes that it is the Agencys practice to leverage such 
information from the literature in lieu of requiring additional studies to demonstrate 
clinical validity.  In these cases FDA may still require studies demonstrating device 
performance (e.g., analytical evaluations) but generally intends to rely on the 
scientific literature to support clinical validity if appropriate. FDA intends to work 
with the laboratory community, the healthcare professional community and other 
stakeholders to determine whether an LDTs clinical validity has already been 
established in the literature. 
 
(h) Third Party Review 
FDA has an established third party review program for eligible medical devices38.  
For LDTs, FDA envisions that the Agency would generally review PMAs for high-
risk (Class III) LDTs, whereas third parties would generally review the 510(k)s for 
lower risk (Class II) LDTs.  FDA seeks to work with interested parties that have 
experience with laboratories and can meet FDA requirements for third party 
reviewers. FDA anticipates that inclusion of such groups will facilitate a more 
efficient review process for LDTs. If this approach is successful, most 510(k)s for 
LDTs could be reviewed by appropriate third parties.   
 
6.  Quality System Regulation Requirements  
The Quality System Regulation (21 CFR Part 820) was developed to define the minimal 
quality system requirements that medical device manufacturers must implement in order to 
assure that the finished device will be safe and effective.  FDA intends to continue to 
exercise enforcement discretion with respect to QS reg requirements, codified in 21 CFR Part 
                                                           
38 Further information regarding FDAs current third party review program can be found at:  
http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissio
ns/thirdparyreview/default.htm 
 
28  Contains Nonbinding Recommendations 
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820, until a manufacturer of a given LDT submits a PMA or FDA issues a 510(k) clearance 
order for the LDT.  Under this enforcement policy, the clinical laboratory manufacturing and 
using the LDT will be responsible for having a quality system in place that meets the 
minimum requirements codified in 21 CFR Part 820, either at the time of PMA submission 
(the facility that makes the device must pass an inspection as a condition of PMA approval as 
a matter of law (21 CFR 814.45(a)(3))), or prior to market launch for cleared devices, as 
applicable.  This initial period of continued exercise of enforcement discretion for QS reg 
requirements is intended to allow time for laboratories to learn about their regulatory 
obligations under the Act, as well as to develop programs to comply with them.  FDA intends 
to assist laboratories in understanding these and other applicable requirements prior to 
enforcing those requirements. 
 
FDA recognizes that there may currently be low-risk LDTs that, based upon intended use and 
technology, would be classified as Class I diagnostic devices that are not exempt from 510(k) 
submission requirements, or Class I or II diagnostic devices that are exempt from 510(k) 
submission requirements.39  FDA intends to continue exercising enforcement discretion with 
respect to QS reg requirements for these LDTs at this time.  The Agency intends to provide 
adequate notice before it begins enforcing QS reg requirements for these LDTs, should it 
decide to enforce these requirements for these tests in the future. 
 
The Agency encourages laboratories to begin working toward building elements of the QS 
reg requirements into their practices as these requirements apply to the design and 
manufacture of LDTs.  Specifically, the Agency encourages laboratories developing new 
LDTs to implement design controls (21 CFR 820.30(a)-(j)).  When applied appropriately, the 
design control elements described by the QS reg ensure a more robust device design with 
fewer device defects and recalls.   
 
FDA also intends to expand its third party inspection program for surveillance inspections, 
and to explore opportunities to coordinate with and leverage existing programs, for example, 
to minimize or avoid additional inspections as a result of implementation of the framework 
described in this guidance. 
                                                           
39 The majority of Class I medical devices are exempt from 510(k) premarket notification requirements under 
current regulations; however, a small number of Class I devices are not exempt and therefore, are subject to 
510(k) premarket notification requirements.  Conversely, only a small number of Class II devices are exempt 
from 510(k) premarket notification requirements under the current regulations, and therefore, most Class II 
devices are subject to 510(k) premarket notification requirements.   
 
29  Contains Nonbinding Recommendations 
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APPENDIX A:  LDT Oversight Framework Summary 
 
The following table provides a summary of the draft framework for regulatory oversight of LDTs.   
 
Requirements FDA Intends to Enforce 
Registration and 
Manufacturer 
Listing (Section 
Reporting 
510) of the  Premarket Review  Quality System 
Requirements for 
FD&C Act; 21  Requirements (Sections  Regulation 
Medical Device 
Category  CFR Part 807)   510(k) and 515 of the  Requirements 
Reporting 
where no FDA  FD&C Act; 21 CFR Part  (Section 520(f) of 
(Section 519(a) of 
Notification has  807, Subpart E; 21 CFR  the FD&C Act; 21 
the FD&C Act; 
been provided  Part 814)  CFR Part 820) 
21 CFR Part 803 
by the 
Subpart E) 
laboratory 
LDTs solely used for forensic (law         
enforcement) purposes 
 
LDTs used in CLIA-certified, high-
complexity histocompatibility 
laboratories for transplantation 
LDTs used for Rare Diseases  X  X     
Traditional LDTs   X  X     
LDTs for Unmet Needs  X  X     
LDTs with the same intended use  X  X   Enforced for currently   Enforced once 
as a cleared or approved  marketed LDTs that  PMA submitted or 
Companion Diagnostic   have not made a  FDA issues 
  premarket submission  clearance order  
LDTs with the same intended use  within 12 months of 
as an approved Class III medical  finalization of this 
device  guidance document 
   Enforced for new LDTs 
Certain LDTs used to determine  initially marketed after 
safety/efficacy of blood or blood  finalization of this 
products   guidance document  
LDTs for Infectious Agents (donor 
screening tests) used in blood and   All requirements currently enforced  
blood components and HCT/Ps  
Class III (high risk) LDTs  X  X   Enforced on a risk-  Enforced on a risk-
based, phased-in basis  based, phased-in 
 FDA plans to announce  basis  until a 
the priority list within  manufacturer of a 
24 months of  given LDT submits 
finalization of this  a PMA. 
guidance 
Class II (moderate risk) LDTs  X  X   Enforced on a risk-  Enforced on a risk-
based, phased-in basis  based, phased-in 
 Enforced after FDA has  basis  until FDA 
completed the phase-in  issues a 510(k) 
of Class III  clearance order  for 
  FDA plans to announce  the LDT 
the priority list for class 
II within 4 years of 
finalization of this 
guidance 
Class I (low risk) LDTs  X  X     
 
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APPENDIX B:  LDT Oversight Framework; Questions 
and Answers 
 
Question 1:  I am a laboratory that makes LDTs for rare disease testing 
that meet the definition of a Humanitarian Use Device, as described in 
Section D.5.(a) of this document.  What are the relevant enforcement 
policies under the framework for greater regulatory oversight of LDTs? 
 
Response: 
FDA Notification:  FDA intends to continue to exercise enforcement 
discretion with respect to Registration and Listing 
requirements (21 CFR Part 807), provided that you 
notify the FDA that you are manufacturing LDTs and 
provide basic information regarding each of these LDTs 
within 6 months of finalization of this guidance 
document or prior to offering a new LDT for clinical 
use after that date.   
 
Specific instructions on how you should appropriately 
notify the FDA regarding LDT manufacture and 
provide basic information regarding the LDTs are 
provided in the draft guidance document entitled FDA 
Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).   
 
Medical Device Reporting:  FDA intends to continue to enforce the medical device 
reporting requirements for user facilities (21 CFR Part 
803, Subpart C) for all diagnostic tests used in your 
facility. 
 
  If you are a laboratory that makes LDTs (excluding the 
categories outlined in Section D.2 of this guidance 
document), FDA intends to enforce the medical device 
reporting requirements for medical device 
manufacturers (21 CFR Part 803, Subpart E) beginning 
6 months after finalization of this guidance only for 
those LDTs manufactured by your laboratory. 
 
Further instructions on how you may meet your MDR 
reporting obligations as both a user facility as well as a 
medical device manufacturer are provided in the draft 
guidance document entitled FDA Notification and 
 
31  Contains Nonbinding Recommendations 
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Medical Device Reporting for Laboratory Developed 
Tests.   
 
 
Question 2:  I am a laboratory that makes Traditional LDTs as described 
in Section D.5.(a) of this document.  There is an equivalent FDA 
cleared/approved device with the same intended use as my LDT on the 
market.  What are the relevant enforcement policies under the framework 
for greater regulatory oversight of LDTs? 
 
Response:   
FDA Notification:  FDA intends to continue to exercise enforcement 
discretion with respect to Registration and Listing 
requirements (21 CFR Part 807), provided that you 
notify the FDA that you are manufacturing LDTs and 
provide basic information regarding each of these LDTs 
within 6 months of finalization of this guidance 
document or prior to offering a new LDT for clinical 
use after that date.   
 
Specific instructions on how you should appropriately 
notify the FDA regarding LDT manufacture and 
provide basic information regarding the LDTs are 
provided in the draft guidance document entitled FDA 
Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).   
 
Medical Device Reporting:  FDA intends to continue to enforce the medical device 
reporting requirements for user facilities (21 CFR Part 
803, Subpart C) for all diagnostic tests used in your 
facility. 
 
  If you are a laboratory that makes LDTs (excluding the 
categories outlined in Section D.2 of this guidance 
document), FDA intends to enforce the medical device 
reporting requirements for medical device 
manufacturers (21 CFR Part 803, Subpart E) beginning 
6 months after finalization of this guidance only for 
those LDTs manufactured by your laboratory. 
 
Further instructions on how you may meet your MDR 
reporting obligations as both a user facility as well as a 
medical device manufacturer are provided in the draft 
guidance document entitled FDA Notification and 
 
32  Contains Nonbinding Recommendations 
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Medical Device Reporting for Laboratory Developed 
Tests.  
 
Premarket Review Requirements: While FDA has indicated that it intends to enforce 
premarket review requirements for LDTs that have the 
same intended use as an FDA cleared/approved device, 
considering the factors described in Section D.5.(a) of 
this document, FDA intends to exercise enforcement 
discretion with respect to medical device premarket 
requirements for your Traditional LDTs.  
 
Question 3:  I am a laboratory that makes LDTs that have the same 
intended use as a cleared or approved Companion Diagnostic and/or that 
have the same intended use as an approved Class III medical device.  What 
are the relevant enforcement policies under the framework for greater 
regulatory oversight of LDTs? 
 
Response:   
FDA Notification:  FDA intends to continue to exercise enforcement 
discretion with respect to Registration and Listing 
requirements (21 CFR Part 807), provided that you 
notify the FDA that you are manufacturing LDTs and 
provide basic information regarding each of these LDTs 
within 6 months of finalization of this guidance 
document.   
 
Specific instructions on how you should appropriately 
notify the FDA regarding LDT manufacture and 
provide basic information regarding the LDTs are 
provided in the draft guidance document entitled FDA 
Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).   
 
Registration and Listing:  If you are a laboratory that is engaged in the 
manufacture, preparation, propagation, compounding, 
assembly, or processing of an LDT intended for human 
use, FDA intends to enforce all applicable registration 
and listing requirements (21 CFR Part 807) once a 
premarket submission has been made to the Agency for 
that LDT. 
 
 
Medical Device Reporting:  FDA intends to continue to enforce the medical device 
reporting requirements for user facilities (21 CFR Part 
 
33  Contains Nonbinding Recommendations 
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803, Subpart C) for all diagnostic tests used in your 
facility. 
 
  If you are a laboratory that makes LDTs (excluding the 
categories outlined in Section D.2 of this guidance 
document), FDA intends to enforce the medical device 
reporting requirements for medical device 
manufacturers (21 CFR Part 803, Subpart E) beginning 
6 months after finalization of this guidance only for 
those LDTs manufactured by your laboratory.   
 
Further instructions on how you may meet your MDR 
reporting obligations as both a user facility as well as a 
medical device manufacturer are provided in the draft 
guidance document entitled FDA Notification and 
Medical Device Reporting for Laboratory Developed 
Tests (LDTs).  
 
Premarket Review Requirements: If you are a laboratory that makes the types of LDTs 
described in this question, FDA intends to exercise 
enforcement discretion with respect to premarket 
submission requirements for these LDTs for 12 months 
following finalization of this guidance document. 
 
If you are a laboratory that will be manufacturing and 
using a new LDT (i.e., an LDT initially marketed for 
use after the date of finalization of this guidance 
document) that has the same intended use as a cleared 
or approved companion diagnostic or that has the same 
intended use as an approved Class III device, you may 
be subject to enforcement action if you market the 
device prior to FDA clearance/approval.  FDA intends 
to enforce the premarket requirements (21 CFR Part 
807, Subpart E, and 21 CFR Part 814) for these new 
LDTs. 
 
Quality System Requirements:    FDA intends to enforce the QS reg requirements in 21 
CFR Part 820 upon submission of a PMA or FDA 
clearance of a 510(k).  
 
Question 4:  I am a laboratory that makes LDTs for Infectious Agents 
(donor screening tests) used in blood and blood components.  What are the 
relevant enforcement policies under the framework for greater regulatory 
oversight of LDTs? 
 
 
34  Contains Nonbinding Recommendations 
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Response:   
FDA Requirements:    FDA intends to continue to enforce all FDA 
requirements for LDTs in this category. 
 
Question 5:  I am a laboratory that makes LDTs that do not fit into any of 
the categories described in this document.  What are the relevant 
enforcement policies under the framework for greater regulatory oversight 
of LDTs? 
 
Response:   
FDA Notification:  FDA intends to continue to exercise enforcement 
discretion with respect to Registration and Listing 
requirements (21 CFR Part 807), provided that you 
notify the FDA that you are manufacturing LDTs and 
provide basic information regarding each of these LDTs 
within 6 months of finalization of this guidance 
document or prior to offering a new LDT for clinical 
use after that date. 
   
Specific instructions on how you should appropriately 
notify the FDA regarding LDT manufacture and 
provide basic information regarding the LDTs are 
provided in the draft guidance document entitled FDA 
Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).   
 
Registration and Listing:  FDA intends to enforce the registration and listing 
requirements in a risk-based, phased-in manner.  If you 
are a laboratory that is engaged in the manufacture, 
preparation, propagation, compounding, assembly, or 
processing of an LDT intended for human use, FDA 
intends to enforce all applicable registration and listing 
requirements (21 CFR Part 807) once a premarket 
submission has been made to the Agency for that LDT. 
 
 
Medical Device Reporting:  FDA intends to continue to enforce the medical device 
reporting requirements for user facilities (21 CFR Part 
803, Subpart C) for all diagnostic tests used in your 
facility. 
 
  If you are a laboratory making such LDTs, FDA intends 
to enforce the medical device reporting requirements 
for medical device manufacturers (21 CFR Part 803, 
Subpart E) beginning 6 months after finalization of this 
 
35  Contains Nonbinding Recommendations 
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guidance only for those LDTs manufactured by your 
laboratory. 
 
Premarket Review Requirements: FDA intends to enforce premarket review requirements 
in a risk-based, phased-in manner.  The Agency plans 
to announce its intent to enforce premarket 
requirements for a given category of LDTs well in 
advance of implementation.  FDA intends to start 
enforcing premarket requirements for the LDT 
categories described in Section D.5.(c) of this guidance 
12 months after finalization of this guidance; and for all 
other Class III and Class II LDTs, as described in the 
priority list for Class III LDTs that FDA intends to 
announce 24 months after finalization of this guidance 
and as described in the priority list for Class II LDTs 
that FDA intends to announce 4 years after finalization 
of this guidance. 
 
If you are a laboratory that will be manufacturing and 
using a new LDT in an area where the Agency has 
begun enforcing premarket requirements under 21 CFR 
Part 807, Subpart E, and 21 CFR Part 814, you may be 
subject to enforcement action if you market the device 
prior to FDA clearance/approval.   
 
Quality System Requirements:    FDA intends to enforce the QS reg requirements in 21 
CFR Part 820 upon submission of a PMA, or upon 
premarket clearance, as applicable.  
 
Question 6:  I am a principal investigator developing a new LDT in a lab at 
an academic medical center.  What are the relevant requirements for 
compliance with FDAs investigational device exemption regulation and 
what are the relevant enforcement policies under the framework for 
greater regulatory oversight of LDTs?  
 
Response:   
The regulatory requirements for investigational devices are the same for academic medical 
center investigators as for other investigators.  Investigational IVDs, including LDTs, are 
reagents, instruments, and systems intended for use in the diagnosis of disease or other 
conditions that are the object of an investigation, and are subject to the Investigational 
Device Exemption (IDE) regulation (21 CFR Part 812), which is intended to protect the 
safety of study subjects. Unless exempted under 21 CFR 812.2, an approved IDE is required 
 
36  Contains Nonbinding Recommendations 
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to allow the shipment of investigational IVDs and their use in investigations.40 The vast 
majority of IVD development programs involve IVD studies that are defined as exempted 
investigations under 21 CFR 812.2.  However, if the device is non-exempt (e.g., if invasive 
sampling is performed to obtain the specimen in a way that may pose significant risk to 
patients, or if test results are returned to patients without confirmation by a medically 
accepted diagnostic product or procedure), the IDE regulation requirements apply.  For 
general information on IDEs, see Guidance on IDE Policies and Procedures, at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc
m080202.htm, or if you would like to discuss specific questions with FDA through the Pre-
submission program regarding IVD development or application preparation, see FDA 
guidance The Pre-Submission Program and Meetings with Food and Drug Administration 
Staff, found at 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo
cuments/UCM311176.pdf.   
 
As with other LDT manufacturers, when an academic medical center offers an LDT for 
clinical use, the following are the relevant enforcement policies: 
 
FDA Notification:  FDA intends to continue to exercise enforcement 
discretion with respect to Registration and Listing 
requirements (21 CFR Part 807), provided that you 
notify the FDA that you are manufacturing LDTs and 
provide basic information regarding each of these LDTs 
within 6 months of finalization of this guidance 
document or prior to offering a new LDT for clinical 
use after that date.   
 
Specific instructions on how you should appropriately 
notify the FDA regarding LDT manufacture and 
provide basic information regarding the LDTs are 
provided in the draft guidance document entitled FDA 
Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs).   
 
Registration and Listing:  FDA intends to enforce the registration and listing 
requirements in a risk-based, phased-in manner.  If you 
are a laboratory that is engaged in the manufacture, 
preparation, propagation, compounding, assembly, or 
processing of an LDT intended for human use, FDA 
intends to enforce all applicable registration and listing 
requirements (21 CFR Part 807) once a premarket 
submission has been made to the Agency for that LDT. 
                                                           
40 Investigations of significant risk devices, as defined in 21 CFR 812.3(m), require FDA approval of an IDE 
application.  Investigations of nonsignificant risk devices that meet the conditions described in 21 CFR 812.2(b) 
are considered to have an approved IDE without FDA review and approval of an application. 
 
37  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
 
Medical Device Reporting:  FDA intends to continue to enforce the medical device 
reporting requirements for user facilities (21 CFR Part 
803, Subpart C) for all diagnostic tests used in your 
facility. 
 
  If you are a laboratory making such LDTs, FDA intends 
to enforce the medical device reporting requirements 
for medical device manufacturers (21 CFR Part 803, 
Subpart E) beginning 6 months after finalization of this 
guidance only for those LDTs manufactured by your 
laboratory. 
 
Premarket Review Requirements: FDA intends to enforce premarket review requirements 
in a risk-based, phased-in manner.  The Agency plans 
to announce its intent to enforce premarket 
requirements for a given category of LDTs well in 
advance of implementation. FDA intends to start 
enforcing premarket requirements for the LDT 
categories described in Section D.5.(c) of this guidance 
12 months after finalization of this guidance; and for all 
other Class III and Class II LDTs, as described in the 
priority list for Class III LDTs that FDA intends to 
announce 24 months after finalization of this guidance 
and as described in the priority list for Class II LDTs 
that FDA intends to announce 4 years after finalization 
of this guidance. 
 
If you are a laboratory that will be manufacturing and 
using a new LDT in an area where the Agency has 
begun enforcing premarket requirements under 21 CFR 
Part 807, Subpart E, and 21 CFR Part 814, you may be 
subject to enforcement action if you market the device 
prior to FDA clearance/approval.   
 
Quality System Requirements:    FDA intends to enforce the QS reg requirements in 21 
CFR Part 820 upon submission of a PMA, or upon 
premarket clearance, as applicable.    
 
38  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
APPENDIX C:  Regulatory Resources for LDTs 
 
1.  Registration and Listing  
Applicable Laws and Regulations:  Section 510 of the FD&C Act (21 U.S.C. 360); 21 
CFR Part 807 
 
Applicable Resources: 
  Implementation of Medical Device Establishment Registration and Device 
Listing Requirements Established by the Food and Drug Administration 
Amendments Act of 2007  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm185871.htm) 
  Device Advice:  Registration and Listing 
(http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomark
etyourdevice/registrationandlisting/default.htm)  
 
 
2.  Medical Device Reporting 
Applicable Laws and Regulations:  Sections 519(a),(b), and (c) of the FD&C Act (21 
U.S.C. 360i); 21 CFR Part 803 
 
Applicable Resources:   
  Device Advice:  Reporting Adverse Events (Medical Devices) 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Postmar
ketRequirements/ReportingAdverseEvents/default.htm) 
 
3.  Medical Device Corrections and Removals 
Applicable Laws and Regulations:  Section 519 of the FD&C Act (21 U.S.C. 360i); 21 
CFR Part 806 
 
Applicable Resources: 
  Device Advice:  Recalls Corrections and Removals (Devices) 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Postmar
ketRequirements/RecallsCorrectionsAndRemovals/default.htm) 
 
4.  Quality System Regulation 
Applicable Laws and Regulations:  Section 520(f) of the FD&C Act (21 U.S.C. 360j); 21 
CFR Part 820 
 
 
5.  Labeling 
 
39  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
Applicable Laws and Regulations:  Section 502 of the Act (21 U.S.C. 352); 21 CFR Part 
809 
 
Applicable Resources:   
  Device Advice:  In Vitro Diagnostic Device Labeling Requirements 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overvie
w/DeviceLabeling/InVitroDiagnosticDeviceLabelingRequirements/default.ht
m) 
 
6.  Premarket Requirements  
Applicable Laws and Regulations:  Sections 510, 513, and 515 of the FD&C Act (21 
U.S.C. 360, 360c, and 360e); 21 CFR Part 807, 
Subpart E, and 21 CFR Part 814; Section 351 of the 
Public Health Service Act; 21 CFR Parts 600-680  
 
Applicable Resources: 
 
General Device Requirement Resources 
  Device Advice:  How to Market Your Device 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Howto
MarketYourDevice/default.htm) 
  CDRH LEARN ( http://www.fda.gov/Training/CDRHLearn/default.htm) 
  CDRH Sponsored Workshops, Training Conferences and Other Meetings 
(http://www.fda.gov/http://www.fda.gov/MedicalDevices/NewsEvents/Works
hopsConferences/default.htmMedicalDevices/NewsEvents/WorkshopsConfer
ences/default.htm) 
 
Resources Associated with Modifications to Devices  
  "Modifications to Devices Subject to Premarket Approval (PMA) - The PMA 
Supplement Decision-Making Process  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm089274.htm)  
  Deciding When to Submit a 510(k) for a Change to an Existing Device 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm080235.htm) 
  30-Day Notices and 135-Day PMA Supplements for Manufacturing Method 
or Process Changes, Guidance for Industry and CDRH 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm080192.htm) 
 
IDE and Investigational Studies for IVDs Resources: 
  Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are Not Individually Identifiable 
(http://www.fdahttp://www.fda.gov/MedicalDevices/DeviceRegulationandGui
 
40  Contains Nonbinding Recommendations 
Draft - Not for Implementation 
 
dance/GuidanceDocuments/ucm078384.htm.gov/MedicalDevices/DeviceReg
ulationandGuidance/GuidanceDocuments/ucm078384.htm) 
  In Vitro Diagnostic (IVD) Device Studies  Frequently Asked Questions 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidan
ce/GuidanceDocuments/UCM071230.pdf) 
 
41