68006 Federal Register / Vol. 88, No. 190 / Tuesday, October 3, 2023 / Proposed Rules 

NAV CANADA is amending RNAV 

route Q–801 in their airspace to ensure 

continuity and cross-border 

connectivity with the new RNAV route 

Q–801 proposed in this NPRM. The 

proposed Air Traffic Service (ATS) 

route actions are described below. 

J–133: Jet route J–133 currently 

extends between Galena, AK, VOR/DME 

and Sitka, AK, NDB. The FAA proposes 

to revoke the portion between the 

Anchorage, AK, VOR/DME and the 

Sitka, AK, NDB. As amended, Jet route 

J–133 would extend between Galena, 

AK, VOR/DME and Anchorage, AK, 

VOR/DME. 

Q–801: Q–801 would extend between 

the Anchorage, AK, VOR/DME and the 

HARPR, OR, WP. The new route would 

remain within United States airspace 

between the Anchorage VOR/DME and 

the EEVER, AK, Fix and between the 

CYVIC, WA, WP and the HARPR WP. 

The new EEVER route point is being 

established on the Alaska/Canada 

border north of the MOCHA, AK, Fix. 

The new CYVIC route point is being 

established on the United States/Canada 

border in Washington state replacing, 

the CFPXC computer navigation fix 

(CNF) currently charted. This action is 

part of an ongoing FAA initiative to 

replace CNF and unpronounceable 

border fix/waypoint names with 

standard, pronounceable, five-letter 

names. This proposed action would 

establish RNAV route Q–801 within the 

United States and exclude the airspace 

in Canada. 

Regulatory Notices and Analyses 

The FAA has determined that this 

proposed regulation only involves an 

established body of technical 

regulations for which frequent and 

routine amendments are necessary to 

keep them operationally current. It, 

therefore: (1) is not a ‘‘significant 

regulatory action’’ under Executive 

Order 12866; (2) is not a ‘‘significant 

rule’’ under DOT Regulatory Policies 

and Procedures (44 FR 11034; February 

26, 1979); and (3) does not warrant 

preparation of a regulatory evaluation as 

the anticipated impact is so minimal. 

Since this is a routine matter that will 

only affect air traffic procedures and air 

navigation, it is certified that this 

proposed rule, when promulgated, will 

not have a significant economic impact 

on a substantial number of small entities 

under the criteria of the Regulatory 

Flexibility Act. 

Environmental Review 

This proposal will be subject to an 

environmental analysis in accordance 

with FAA Order 1050.1F, 

‘‘Environmental Impacts: Policies and 

Procedures’’ prior to any FAA final 

regulatory action. 

List of Subjects in 14 CFR Part 71 

Airspace, Incorporation by reference, 

Navigation (air). 

The Proposed Amendment 

In consideration of the foregoing, the 

Federal Aviation Administration 

proposes to amend 14 CFR part 71 as 

follows: 

PART 71—DESIGNATION OF CLASS A, 

B, C, D, AND E AIRSPACE AREAS; AIR 

TRAFFIC SERVICE ROUTES; AND 

REPORTING POINTS 

■ 1. The authority citation for 14 CFR 

part 71 continues to read as follows: 

Authority: 49 U.S.C. 106(f), 106(g); 40103, 

40113, 40120; E.O. 10854, 24 FR 9565, 3 CFR, 

1959–1963 Comp., p. 389. 

§ 71.1 [Amended] 

■ 2. The incorporation by reference in 

14 CFR 71.1 of FAA Order JO 7400.11H, 

Airspace Designations and Reporting 

Points, dated August 11, 2023, and 

effective September 15, 2023, is 

amended as follows: 

Paragraph 2004 Jet Routes 

* * * * * 

J–133 [Amended] 

From Galena, AK to Anchorage, AK. 

* * * * * 

Paragraph 2007 Canadian Area Navigation 

Routes. 

Q–801 HARPR, OR to Anchorage, AK (TED) [NEW] 

HARPR, OR WP (Lat. 42°28′50.00′′ N, long. 122°53′01.54′′ W) 

FELIX, OR WP (Lat. 43°19′13.98′′ N, long. 123°05′39.51′′ W) 

ECTOF, OR WP (Lat. 44°10′49.55′′ N, long. 123°18′57.87′′ W) 

WAPTO, WA FIX (Lat. 47°28′19.54′′ N, long. 124°13′50.38′′ W) 

Tatoosh, WA (TOU) VORTAC (Lat. 48°17′59.64′′ N, long. 124°37′37.36′′ W) 

CYVIC, WA WP (Lat. 48°29′59.97′′ N, long. 124°54′39.80′′ W) 

GOVAD, Canada FIX (Lat. 49°02′48.65′′ N, long. 125°42′15.09′′ W) 

FINGS, Canada FIX (Lat. 50°15′00.00′′ N, long. 127°34′00.00′′ W) 

SIMSU, Canada FIX (Lat. 50°46′56.00′′ N, long. 128°25′37.00′′ W) 

CAFTA, Canada FIX (Lat. 51°17′43.00′′ N, long. 129°05′19.00′′ W) 

EEVER, AK FIX (Lat. 54°35′01.79′′ N, long. 133°05′54.23′′ W) 

MACIE, AK WP (Lat. 57°43′38.87′′ N, long. 137°50′47.74′′ W) 

LAIRE, AK FIX (Lat. 58°48′14.67′′ N, long. 140°31′43.36′′ W) 

FROZN, AK WP (Lat. 59°40′34.90′′ N, long. 143°29′31.48′′ W) 

Johnstone Point, AK (JOH) VOR/DME (Lat. 60°28′51.43′′ N, long. 146°35′57.61′′ W) 

Anchorage, AK (TED) VOR/DME (Lat. 61°10′04.32′′ N, long. 149°57′36.52′′ W) 

* * * * * 

Issued in Washington, DC, on September 

28, 2023. 

Karen L. Chiodini, 

Acting Manager, Rules and Regulations 

Group. 

[FR Doc. 2023–21811 Filed 10–2–23; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 809 

[Docket No. FDA–2023–N–2177] 

RIN 0910–AI85 

Medical Devices; Laboratory 

Developed Tests 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is proposing to amend its 

regulations to make explicit that in vitro 

diagnostic products (IVDs) are devices 

under the Federal Food, Drug, and 

Cosmetic Act (FD&C Act) including 

when the manufacturer of the IVD is a 

laboratory. In conjunction with this 

amendment, FDA is proposing a policy 

under which FDA intends to phase out 

its general enforcement discretion 

approach for laboratory developed tests 


ddrumheller on DSK120RN23PROD with PROPOSALS1
Federal Register / Vol. 88, No. 190 / Tuesday, October 3, 2023 / Proposed Rules 68007 

(LDTs) so that IVDs manufactured by a 

laboratory would generally fall under 

the same enforcement approach as other 

IVDs. FDA is proposing this phaseout to 

better protect the public health by 

helping to assure the safety and 

effectiveness of LDTs. If finalized, this 

phaseout may also foster the 

manufacturing of innovative IVDs for 

which FDA has determined there is a 

reasonable assurance of safety and 

effectiveness. 

DATES: Either electronic or written 

comments on the proposed rule must be 

submitted by December 4, 2023. 

ADDRESSES: You may submit comments 

as follows. Please note that late, 

untimely filed comments will not be 

considered. The https://

www.regulations.gov electronic filing 

system will accept comments until 

11:59 p.m. Eastern Time at the end of 

December 4, 2023. Comments received 

by mail/hand delivery/courier (for 

written/paper submissions) will be 

considered timely if they are received 

on or before that date. 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit a comment 

with confidential information that you 

do not wish to be made available to the 

public, submit the comment as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand Delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper comments 

submitted to the Dockets Management 

Staff, FDA will post your comment, as 

well as any attachments, except for 

information submitted, marked and 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2023–N–2177 for ‘‘Medical Devices; 

Laboratory Developed Tests.’’ Received 

comments, those filed in a timely 

manner (see ADDRESSES), will be placed 

in the docket and, except for those 

submitted as ‘‘Confidential 

Submissions,’’ publicly viewable at 

https://www.regulations.gov or at the 

Dockets Management Staff between 9 

a.m. and 4 p.m., Monday through 

Friday, 240–402–7500. 

• Confidential Submissions—To 

submit a comment with confidential 

information that you do not wish to be 

made publicly available, submit your 

comments only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ The 

Agency will review this copy, including 

the claimed confidential information, in 

its consideration of comments. The 

second copy, which will have the 

claimed confidential information 

redacted/blacked out, will be available 

for public viewing and posted on 

https://www.regulations.gov. Submit 

both copies to the Dockets Management 

Staff. If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://

www.govinfo.gov/content/pkg/FR-2015- 

09-18/pdf/2015-23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

FOR FURTHER INFORMATION CONTACT: 

Toby Lowe, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Silver Spring, MD 20993, 301– 

796–6512, LDTProposedRule@

fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Executive Summary 

A. Purpose of the Proposed Rule 

B. Summary of the Major Provisions of the 

Proposed Rule 

C. Legal Authority 

D. Costs and Benefits 

II. Table of Abbreviations/Commonly Used 

Acronyms in This Document 

III. Background 

A. Introduction 

B. Need for the Rule 

C. FDA’s Current Regulatory Framework 

D. History of the Rulemaking 

IV. Legal Authority 

V. Description of the Proposed Amendment 

to the Definition of In Vitro Diagnostic 

Products 

A. Proposed Amendment 

B. Legal Basis for the Proposed 

Amendment 

VI. Description of the Proposed Enforcement 

Policy 

A. Scope 

B. Stages 

VII. Proposed Effective Date 

VIII. Preliminary Economic Analysis of 

Impacts 

IX. Analysis of Environmental Impact 

X. Paperwork Reduction Act of 1995 

XI. Federalism 

XII. Consultation and Coordination With 

Indian Tribal Governments 

XIII. Other Issues for Consideration 

XIV. References 

I. Executive Summary 

A. Purpose of the Proposed Rule 

FDA is proposing to amend its 

regulations to make explicit that IVDs 

are devices under the FD&C Act 

including when the manufacturer of the 

IVD is a laboratory. This amendment 

would reflect that the device definition 

in the FD&C Act does not differentiate 

between entities manufacturing the 

device, and would provide further 

clarity, including for stakeholders 

affected by the accompanying changes 

to FDA’s general enforcement discretion 

approach for LDTs. In connection with 

amending the regulation, FDA intends 

to phase out its general enforcement 

discretion approach for LDTs so that 

IVDs manufactured by a laboratory 

would generally fall under the same 

enforcement approach as other IVDs. 

For purposes of this document, we use 

‘‘manufacture’’ and related terms as a 

shorthand for the various activities that 

constitute manufacturing as described 

in FDA regulations (e.g., design, 


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1See discussion of ‘‘IVDs offered as LDTs’’ in 

section VI.A below. 

2This proposed rule would result in compliance 

costs for laboratories that are ensuring their IVDs 

offered as LDTs are compliant with applicable 

statutory and regulatory requirements. These costs 

overlap somewhat with effects associated with this 

rule in the form of user fees including annual 

registration fees, fees for premarket submissions, 

and annual fees for periodic PMA reporting, which 

are paid from laboratories to FDA. These fees are 

paid by laboratories but are considered revenue for 

FDA. The approach to estimating fee effects is 

distinct from the approaches for either benefits or 

costs, so they will be presented as transfers. 

preparation, propagation, assembly, and 

processing). 

In 1976, the Medical Device 

Amendments of 1976 (the MDA) 

amended the FD&C Act to create a 

comprehensive system for the regulation 

of devices intended for human use. In 

implementing the MDA, FDA has 

generally exercised enforcement 

discretion such that it generally has not 

enforced applicable requirements with 

respect to most LDTs. Enforcement 

discretion for LDTs developed as a 

matter of general practice. However, the 

risks associated with LDTs are much 

greater today than they were at the time 

of enactment of the MDA. As discussed 

more fully in section III.B, today’s LDTs 

are generally, among other things, used 

more widely, by a more diverse 

population, with an increasing reliance 

on high-tech instrumentation and 

software, and more frequently for the 

purpose of guiding critical healthcare 

decisions. In this regard, today’s LDTs 

are similar to other IVDs that have not 

been under this general enforcement 

discretion approach. Given these 

changes, and for the additional reasons 

discussed in section III.B, phasing out 

the general enforcement discretion 

approach for LDTs is important to 

protect the public health. The phaseout 

of FDA’s general enforcement discretion 

approach for LDTs is intended to help 

assure the safety and effectiveness of 

LDTs, and may also foster the 

manufacturing of innovative IVDs for 

which FDA has determined there is a 

reasonable assurance of safety and 

effectiveness. 

B. Summary of the Major Provisions of 

the Proposed Rule 

This rulemaking would amend the 

definition of ‘‘in vitro diagnostic 

products’’ in FDA regulations to state 

that IVDs are devices under the FD&C 

Act ‘‘including when the manufacturer 

of these products is a laboratory.’’ In 

conjunction with this amendment, FDA 

is also proposing a policy under which 

FDA intends to phase out its general 

enforcement discretion approach for 

LDTs so that IVDs manufactured by a 

laboratory would generally fall under 

the same enforcement approach as other 

IVDs. Additional details regarding the 

proposed phaseout policy are discussed 

further in section VI. 

C. Legal Authority 

FDA is proposing to issue this rule 

under the Agency’s general rulemaking 

authorities and statutory authorities 

relating to devices. These authorities 

include sections 201(h)(1), 301, 501, 

502, 510, 513, 514, 515, 518, 519, 520, 

701, 702, 704, and 801 of the FD&C Act 

(21 U.S.C. 321(h)(1), 331, 351, 352, 360, 

360c, 360d, 360e, 360h, 360i, 360j, 371, 

372, 374, and 381). 

D. Costs and Benefits 

We quantify benefits to patients from 

averted health losses due to problematic 

IVDs offered as LDTs.1 Due to 

limitations in the data, we quantify 

health benefits only with respect to 

IVDs for certain diseases and 

conditions; however, we would expect 

additional health benefits associated 

with averted health losses for other 

diseases and conditions. We estimate 

that the annualized benefits over 20 

years would range from $2.67 billion to 

$86.01 billion at a 7 percent discount 

rate, with a primary estimate of $31.41 

billion, and from $1.81 billion to $61.41 

billion at a 3 percent discount rate, with 

a primary estimate of $22.33 billion. 

Additional benefits would include 

averted non-health losses from the 

quantified reduction in costs of 

problematic IVDs offered as LDTs and 

unquantified reduction in costs from 

lawsuits and costs to healthcare 

systems. We quantify costs to affected 

laboratories for complying with 

applicable statutory and regulatory 

requirements. Additional costs would 

include some costs to FDA, which we 

include in our estimates. The 

annualized costs would range from 

$2.52 billion to $19.45 billion at a 7 

percent discount rate, with a primary 

estimate of $5.87 billion, and from $2.39 

billion to $18.55 billion at a 3 percent 

discount rate, with a primary estimate of 

$5.60 billion. The annualized transfers 2

would range from $100 million to $452 

million at a 7 percent discount rate, 

with a primary estimate of $226 million, 

and from $121 million to $538 million 

at a 3 percent discount rate, with a 

primary estimate of $269 million. The 

annualized costs to FDA would range 

from $265 million to $1.06 billion at a 

7 percent discount rate, with a primary 

estimate of $530 million, and from $251 

million to $1.00 billion at a 3 percent 

discount rate, with a primary estimate of 

$501 million. These estimates do not 

include anticipated offsets from user 

fees. Factoring in offsets from user fees 

at current levels, estimated costs to FDA 

are reduced to $165 million to $607 

million at a 7 percent discount rate, 

with a primary estimate of $304 million, 

and to $103 million to $465 million at 

a 7 percent discount rate, with a 

primary estimate of $233 million, 

covering approximately half of the 

estimated costs to FDA. 

II. Table of Abbreviations/Commonly 

Used Acronyms in This Document 

Abbreviation/acronym What it means 

510(k) .................................................................. Premarket Notification. 

AMC .................................................................... Academic Medical Center. 

ASR ..................................................................... Analyte Specific Reagent. 

CFR ..................................................................... Code of Federal Regulations. 

CGMP ................................................................. Current Good Manufacturing Practice. 

CLIA .................................................................... Clinical Laboratory Improvement Amendments of 1988. 

CMS .................................................................... Centers for Medicare & Medicaid Services. 

EUA ..................................................................... Emergency Use Authorization. 

FDA ..................................................................... Food and Drug Administration. 

FD&C Act ............................................................ Federal Food, Drug, and Cosmetic Act. 

HCT/Ps ............................................................... Human Cells, Tissues, and Cellular and Tissue-Based Products. 

HLA ..................................................................... Human Leukocyte Antigen. 

IDE ...................................................................... Investigational Device Exemption. 

IVD ...................................................................... In Vitro Diagnostic Product. 

IVDMIA ................................................................ In Vitro Diagnostic Multivariate Index Assay. 

LDT ..................................................................... Laboratory Developed Test. 


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3Although FDA’s general enforcement discretion 

approach continues today, it does not apply to 

LDTs in all contexts; for example, it does not apply 

to, among other LDTs, those used for declared 

emergencies/potential emergencies/material threats 

under section 564 of the FD&C Act (21 U.S.C. 

360bbb–3). 

4See, e.g., Refs. 1 to 3. These observations are also 

informed by FDA’s own experience, including the 

review of submissions and site visits, and staff with 

prior experience in the laboratory industry 

developing and running LDTs. 

5As discussed further in section V, FDA is also 

proposing to amend the statutory citation for the 

device definition included in § 809.3 (21 CFR 809.3) 

to reflect that it is now codified at section 201(h)(1) 

of the FD&C Act (21 U.S.C. 321(h)(1)). 

Abbreviation/acronym What it means 

MDA .................................................................... Medical Device Amendments of 1976. 

MDR .................................................................... Medical Device Report. 

MDUFA ............................................................... Medical Device User Fee Amendments. 

NIPS .................................................................... Non-Invasive Prenatal Screening. 

PMA .................................................................... Premarket Approval Application. 

QS ....................................................................... Quality System. 

III. Background 

A. Introduction 

FDA’s regulations define IVDs as 

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, and intended for 

use in the collection, preparation, and 

examination of specimens taken from 

the human body. IVDs include test 

systems (also referred to in this 

preamble as ‘‘tests’’) that are performed 

on samples taken from the human body, 

such as blood or tissue, for the purpose 

of detecting diseases or other 

conditions, monitoring a person’s 

overall health, identifying patients who 

are likely to benefit from specific 

therapies, or otherwise helping to 

diagnose, cure, mitigate, treat, or 

prevent disease or its sequelae. Some 

IVDs are manufactured by conventional 

manufacturers for use by other entities 

such as laboratories, healthcare 

providers, or, in some cases, patients. 

Such IVDs may include ‘‘test kits,’’ 

containing packaged sets of components 

that are part of or comprise a test 

system. Other IVDs are manufactured by 

laboratories for use by the same or other 

laboratories. Such IVDs include LDTs. 

FDA has generally considered an LDT to 

be an IVD that is intended for clinical 

use and that is designed, manufactured, 

and used within a single laboratory that 

is certified under the Clinical 

Laboratory Improvement Amendments 

of 1988 (CLIA) and meets the regulatory 

requirements under CLIA to perform 

high complexity testing. Section V.B 

sets forth the legal reasoning for FDA’s 

position that IVDs manufactured by 

laboratories, including LDTs, are 

devices. 

However, in implementing the MDA, 

FDA generally has exercised 

enforcement discretion such that it 

generally has not enforced applicable 

requirements with respect to most LDTs. 

At the time of passage of the MDA, 

LDTs were mostly manufactured in 

small volumes by laboratories that 

served their local communities. They 

were typically intended for use in 

diagnosing rare diseases or for other 

uses to meet the needs of a local patient 

population, or were generally similar to 

well-characterized, standard tests. They 

also tended to employ manual 

techniques (and did not use automation) 

performed by laboratory personnel with 

specialized expertise; to be used and 

interpreted by physicians or 

pathologists in a single institution 

responsible for the patient (and who 

were actively involved in patient care); 

and to be manufactured using 

components legally marketed for 

clinical use, such as general purpose 

reagents or immunohistochemical stains 

marketed in compliance with FDA 

regulatory requirements. Due to these 

and other factors, FDA generally 

exercised enforcement discretion such 

that it generally has not enforced 

applicable requirements for most LDTs.3

However, the LDT landscape has 

evolved significantly since 1976. Today, 

many LDTs rely on high-tech or 

complex instrumentation and software 

to generate results and clinical 

interpretations. They are often used in 

laboratories outside of the patient’s 

healthcare setting and are often 

manufactured in high volume for large 

and diverse populations. Many LDTs are 

manufactured by laboratory 

corporations that market the tests 

nationwide, as they accept specimens 

from patients across the country and run 

their LDTs in very large volumes in a 

single laboratory. Today’s LDTs are also 

more commonly manufactured with 

instruments or other components not 

legally marketed for clinical use and are 

more often used to inform or direct 

critical treatment decisions, to widely 

screen for common diseases, to predict 

personal risk of developing certain 

diseases, and to diagnose serious 

medical conditions such as cancer and 

heart disease.4 The risks associated with 

most modern LDTs are therefore much 

greater today than they were at the time 

FDA began implementing the MDA, and 

most LDTs today are similar to other 

IVDs that have not been under FDA’s 

general enforcement discretion 

approach. In addition, FDA is 

concerned that firms are offering IVDs 

as ‘‘LDTs’’ even when they are not 

LDTs, because they are not actually 

designed, manufactured, and used 

within a single laboratory (see, e.g., 

Refs. 4 and 5). 

As a result of this evolution in the 

testing landscape, FDA has long 

recognized the need for a change in the 

Agency’s general enforcement discretion 

approach for LDTs. The history of FDA’s 

efforts with respect to LDTs is set forth 

in the ‘‘History of the Rulemaking’’ 

section below (section III.D). Over the 

past few years, FDA has accumulated 

even more information supporting the 

need for a change, as discussed below. 

In light of these developments, FDA is 

proposing to amend FDA’s regulations 

to make explicit that IVDs are devices 

under the FD&C Act including when the 

manufacturer is a laboratory.5 FDA is 

also proposing a policy under which 

FDA intends to phase out FDA’s general 

enforcement discretion approach for 

LDTs so that IVDs manufactured by a 

laboratory would generally fall under 

the same enforcement approach as other 

IVDs. 

B. Need for the Rule 

FDA is proposing a policy under 

which FDA intends to phase out the 

general enforcement discretion 

approach for LDTs because that 

approach has led to an oversight scheme 

that does not best serve the public 

health. LDTs that are under the general 

enforcement discretion approach are 

treated differently from other IVDs. 

However, there is no longer a sound 

basis for this distinction. In FDA’s 

experience, including with COVID–19 

tests and IVDs that are offered as LDTs 

after FDA’s approval of a comparable 

companion diagnostic, many test 

systems made by laboratories today are 

functionally the same as those made by 

other manufacturers of IVDs. They 


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6The references cited are examples of the 

described practice. Their inclusion does not 

represent FDA support for or approval of the 

activities described. 

7FDA has initiated a pilot program for certain 

oncology diagnostics as one step that may be 

helpful in reducing the risks associated with using 

certain LDTs to identify cancer biomarkers (see 88 

FR 40273 (June 21, 2023)). 

involve the same materials and 

technologies, are intended for the same 

or similar purposes, are developed by 

and for individuals with similar 

expertise, and are marketed to the same 

patients, sometimes on a national scale. 

For these reasons, tests made by 

laboratories are often used 

interchangeably by healthcare providers 

and patients with tests made by other 

manufacturers. In fact, today, the testing 

industry has come to view FDA’s 

general enforcement discretion 

approach as an alternative pathway to 

market for test systems, such that test 

systems are often ‘‘launched as LDTs’’ 

with no assurance that they meet 

requirements under the FD&C Act and 

its implementing regulations (see, e.g., 

Refs. 6 and 7).6 These tests lack the 

characteristics and institutional 

safeguards that originally justified 

FDA’s general enforcement discretion 

approach, as discussed above, and may 

directly compete with FDA-authorized 

kit-based test systems. FDA views this 

bifurcated system of oversight as 

untenable and inconsistent with FDA’s 

public health mission. 

The proposed phaseout of FDA’s 

general enforcement discretion 

approach is designed to redress the 

imbalance in oversight and protect the 

public health. Diagnostic testing is a 

cornerstone of modern medicine; CDC 

estimates that 70 percent of medical 

decisions are based on laboratory test 

results (Ref. 8). IVDs offered as LDTs are 

a growing sector of that market (Ref. 1). 

Moreover, these tests are proliferating in 

some of the most complicated and 

sensitive areas of medical practice, 

where the presence of a valid test can 

be most important. 

As the testing landscape has evolved, 

information about these tests in the 

scientific literature, news articles, and 

anecdotal reports submitted to the 

Agency, among other sources, has 

exposed evidence of problems 

associated with these tests. This 

evidence is discussed in more detail 

below. Particularly over the last few 

years, this evidence has been growing 

and likely does not reflect the full scale 

of the problems. (Until FDA 

systematically collects information on 

these tests, such as adverse event 

reports, it will not be able to assess more 

fully the extent of the risks to patients 

in the manner it does for other devices.) 

Based on current safety signals, FDA is 

proposing to phase out the general 

enforcement discretion approach to help 

assure that patients are receiving 

accurate and reliable diagnostic test 

results regardless of where the tests are 

made. 

1. IVDs Offered as LDTs Have a 

Significant Impact on Modern Medical 

Care 

Today, IVDs offered as LDTs are 

ubiquitous, and are intended to 

diagnose a broad range of diseases and 

conditions (see Ref. 2). In many cases, 

these IVDs are meant for use in complex 

areas of medicine involving lifethreatening diseases, such as cancer, 

neurological diseases, cardiovascular 

illness, infectious diseases, and rare 

diseases. They can proliferate in areas 

where diagnosis is difficult, and the 

healthcare community has few points of 

reference for determining test validity. 

Sometimes, they use complex 

algorithms to calculate ‘‘scores’’ for 

diagnosis with little transparency to the 

user about the basis for these 

algorithms. Increasingly, these IVDs are 

intended to inform drug treatment, 

directing physicians to choose certain 

drugs based on a patient’s genetic or 

other information. FDA has witnessed 

an explosion in the volume, complexity, 

and scope of IVDs offered as LDTs for 

use in determining cancer treatments,7

and as discussed below, news coverage, 

including as recently as this year, has 

drawn attention to the use of IVDs 

offered as LDTs for non-invasive 

prenatal screening (NIPS), which 

evaluate fetal DNA circulating in a 

pregnant individual’s blood. In general, 

IVDs offered as LDTs are occupying a 

growing share of the testing market and 

are used in some of the most complex 

areas of medicine (see, e.g., Refs. 1 and 

2). 

Given the role these IVDs play in 

modern medical care, their validity has 

a significant impact on the public 

health. False positive test results, which 

erroneously indicate that a patient has 

a certain disease or condition, can delay 

diagnosis and treatment of the true 

disease or condition, lead to 

unwarranted interventions, and cause 

needless distress. Interventions may 

involve medication with serious side 

effects or risky medical procedures. 

False negative results can lead to 

progression of disease, in some cases 

without the opportunity for life-saving 

treatment, and the spread of infectious 

disease. The harms to patients from 

false positive and negative results can 

be significant. For example, the 

application of an ineffective oncology 

treatment due to a false positive for a 

patient already weakened from disease, 

or the failure to receive a life-saving 

medication due to a false negative, can 

be fatal. These false results can stem 

from an analytical error or from a lack 

of clinical validity where a measured 

result is incorrectly associated with a 

particular clinical state. Flaws in a test’s 

algorithm can mean the difference in 

whether a patient with cancer receives 

a beneficial immunotherapy. Pregnant 

people may use screening tests to make 

decisions without obtaining appropriate 

confirmatory testing. In 2016, FDA 

learned of a false positive result from a 

genetic test for long QT syndrome (a 

heart signaling disorder) that led to the 

erroneous implantation of a defibrillator 

in a healthy individual. In addition to 

the risks associated with the 

implantation procedure, the defibrillator 

delivered inappropriate shocks to the 

patient, which posed the risk of sudden 

cardiac death (Refs. 9 and 10). These are 

just a few examples of how diagnostic 

tests can and do have significant longterm consequences for patients. 

2. Current Information Raises Serious 

Questions About Whether Patients Can 

Rely on IVDs Offered as LDTs 

FDA has highlighted the risks 

associated with IVDs offered as LDTs for 

decades, and our concerns have grown 

in recent years. As described in the 

‘‘History of the Rulemaking’’ section, we 

first took steps to address the issue in 

the late 1990s, followed by a series of 

different proposed strategies for 

increasing oversight. In 2015, the 

Agency published a report of 20 case 

studies involving inaccurate, unsafe, 

ineffective, or poor quality LDTs that 

caused or may have caused patient harm 

(‘‘2015 Report’’) (Ref. 11). More recent 

evidence suggests that the situation is 

getting worse. This evidence cuts across 

test types and laboratories and is from 

a variety of sources, including 

published studies in the scientific 

literature, allegations of problematic 

tests reported to FDA, FDA’s own 

experience in reviewing IVDs offered as 

LDTs, news articles, and class-action 

lawsuits. Overall, the evidence points to 

fundamental uncertainty in the 

marketplace about whether IVDs offered 

as LDTs provide accurate and reliable 

results. 

Scientific literature is one source of 

evidence. Over time, FDA has become 

aware of various publications that 

describe problems with IVDs offered as 

LDTs. In the past 3 years, four different 

studies have documented high 

variability in performance among these 

IVDs (Refs. 12 to 15). In one study, the 


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8These submissions have been for a wide variety 

of indications, including tests intended to detect 

nucleic acids from viruses associated with head and 

neck cancers; to identify patients with obesity due 

to rare genetic conditions to inform treatment 

eligibility; to aid in the management of therapy for 

patients taking certain anticoagulants; and tests for 

breast cancer prognosis, tumor profiling, and 

treatment selection, for patients with cancer. 

9For discussion of FDA’s Q-submission program, 

see FDA’s guidance document issued on June 2, 

2023, entitled ‘‘Requests for Feedback and Meetings 

for Medical Device Submissions: The QSubmissions Program,’’ available at https://

www.fda.gov/media/114034/download. 

10FDA has not confirmed the veracity of the 

allegations or facts in every complaint, report, and 

allegation. Nevertheless, collectively this 

information points to potential problems among 

IVDs offered as LDTs. 

same samples were sent to 19 

laboratories for testing using their own 

manufactured test and only 7 of those 

laboratories correctly reported all results 

(Ref. 12). For almost half of the tests 

studied, analytical accuracy was 

significantly lower than that of the 

parallel test approved by FDA. In 

another study, researchers sent identical 

samples to two different laboratories to 

detect tumor mutations and found over 

70 percent discordance in the results 

from their tests (Ref. 13). A study by 

Friends of Cancer Research found 

substantial variability among tumor 

mutational burden (TMB) tests 

manufactured by laboratories and used 

to identify patients with cancer most 

likely to benefit from immunotherapy 

(Ref. 14). A fourth study highlighted 

validity concerns specific to early 

cancer detection tests, including one 

IVD offered as an LDT that delivered 

nine false positive results for every true 

cancer diagnosis (Ref. 15). An article 

published earlier this year detailed an 

oncologist’s experience with false 

results from an unapproved blood-based 

multi-cancer early detection IVD offered 

as an LDT and intended to screen for 

more than 50 types of cancer (Ref. 16). 

A 2016 study published in the New 

England Journal of Medicine reported 

false positive results from genetic IVDs 

offered as LDTs for hypertrophic 

cardiomyopathy in multiple patients of 

African American descent (Ref. 17). 

These studies do not mean that every 

laboratory is manufacturing bad tests or 

that no patient can rely on IVDs offered 

as LDTs. Instead, they reflect a level of 

variability, including the potential for 

inaccurate or incomplete results, that 

highlights the need for changes to the 

basic oversight scheme. 

FDA’s own experience has reinforced 

concerns regarding IVDs offered as 

LDTs. FDA has gathered information 

about IVDs offered as LDTs through its 

review of submissions. Although the 

Agency generally has not enforced 

requirements for LDTs, it has received 

premarket submissions from some 

laboratories seeking authorization for 

their tests. We have received numerous 

submissions for such tests, including 

premarket review submissions,8 Qsubmissions,9 and investigational use 

submissions for IVDs offered as LDTs, as 

well as many emergency use 

authorization (EUA) requests from 

laboratories (which are discussed 

further below). FDA’s review of these 

submissions has provided insight into 

laboratory test development and, in 

some cases, revealed significant 

concerns. For example, FDA has 

observed that many laboratories fail to 

perform appropriate or adequate 

validation studies, have data 

demonstrating their test does not work 

as intended but offer the test anyway, or 

use instruments and other components 

that are not adequately controlled for 

clinical use. The tests described in these 

submissions have been intended for a 

range of diseases or conditions, some of 

which are very serious. FDA has 

received submissions for IVDs offered as 

LDTs to diagnose Alzheimer’s disease, 

predict heart disease risk, diagnose 

Fabry disease (a rare neurological 

disorder), and inform treatment 

considerations for a rare blood cancer, 

all of which lacked adequate validation 

to support authorization. 

In addition, given that FDA’s general 

enforcement discretion approach for 

LDTs has not applied to IVDs for 

emergency use (though FDA has issued 

enforcement policies for such IVDs 

during specific emergencies, as 

explained elsewhere in this preamble), 

FDA has received EUA requests for tests 

from laboratories, including many for 

COVID–19 diagnostics. Of the first 125 

EUA requests for COVID–19 molecular 

diagnostic tests submitted from 

laboratories, 82 showed test design or 

validation problems (Ref. 18). In one 

case, the approach to validation was so 

poor that when redone correctly, there 

was a 400-fold difference in 

performance, leading the laboratory to 

take the test off the market. In another 

example, an academic medical center 

(AMC) laboratory purported to validate 

its test with only 12 positive samples, 

showing perfect performance. FDA 

requested evaluation of additional 

specimens to confirm. When an 

additional 12 samples were evaluated, 

the cumulative performance revealed an 

unacceptably high false negative rate, 

where the test identified only 71 percent 

of known positive specimens as positive 

and falsely identified 29 percent of 

known positive samples as negative, 

and the EUA request was withdrawn. In 

addition, multiple laboratories that 

offered their tests as described in FDA’s 

COVID–19 test guidance (see discussion 

in Ref. 19) did not provide any 

analytical and/or clinical validation 

data in the EUA requests that they 

submitted after the tests were in use. 

This experience provided a window 

into the approach that many laboratories 

may take to test validation, and not only 

confirmed but increased FDA’s concerns 

about the validation of IVDs offered as 

LDTs. The experience also showed that 

even tests involving relatively wellunderstood techniques (here, the 

polymerase chain reaction, or PCR, 

technique) may not perform well. In all, 

test performance seen in this subset of 

submissions from laboratories was far 

worse than we expected. To the extent 

that this sample represents larger trends 

in the performance of IVDs offered as 

LDTs, it underscores the need for greater 

FDA oversight. 

FDA has also received multiple 

complaints, adverse event reports, and 

other allegations identifying problems 

with IVDs offered as LDTs.10 One 

complaint alleged that an IVD offered as 

an LDT to diagnose autism had 

insufficient clinical validation to 

support this use. In another complaint, 

an informant alleged that a laboratory 

was forging results when its liquid 

biopsy test did not work. Additionally, 

FDA has received multiple voluntary 

medical device reports (primarily from 

patients) of inaccurate NIPS test results, 

as well as inaccurate results from an 

oncology IVD offered as an LDT that 

predicts risk of breast cancer recurrence 

and informs the decision to pursue 

chemotherapy, both of which can pose 

serious, irreversible harm to patients. 

Another report described a false 

negative result from a BRCA test 

marketed to predict one’s risk of breast 

cancer. The patient was later diagnosed 

with breast cancer and found to be 

BRCA1 positive by another test. A 

separate report from a healthcare 

provider described a different patient 

that received discrepant results from 

testing with this BRCA test and with 

another IVD offered as an LDT for 

hereditary cancer risk prediction. In yet 

another report, a patient described a 

false positive breast cancer result from 

an oncology blood IVD offered as an 

LDT and that led to invasive followup 

procedures, emotional anguish, and 

unnecessary monetary expenses. FDA 

also received a report regarding a bloodbased test for lung cancer that 

underestimated cancer in about 40 

percent of patients. Additionally, FDA 

has received medical device reports 


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regarding infectious disease genetic 

IVDs offered as LDTs without 

validation, from which inaccurate 

results could lead to limb loss or 

women’s health issues, and regarding 

inaccurate results from an IVD offered 

as an LDT to assess medication 

adherence. As noted above, collectively, 

this information, though anecdotal, 

points to potential problems among 

IVDs offered as LDTs, the scope and 

scale of which FDA cannot fully assess 

or address without phasing out the 

general enforcement discretion 

approach for applicable requirements 

(such as adverse event reporting). 

Aside from the scientific community 

and FDA, the general public is coming 

to recognize concerns with the current 

scheme, in which most LDTs are 

generally not overseen by FDA. General 

news sources and other outlets have 

reported on such concerns (see, e.g., 

Refs. 20 to 26). For example, the New 

York Times recently conducted an 

indepth investigation into NIPS tests 

and found that positive results from the 

tests are incorrect about 85 percent of 

the time (Ref. 22). NIPS tests are 

screening tests, so they should be 

followed up with confirmatory 

diagnostic testing, but the New York 

Times article reported that patients and 

healthcare providers are making 

healthcare decisions based on results 

from these screening tests alone due to 

manufacturers’ marketing claims. A 

device whose labeling is false or 

misleading in any particular manner is 

misbranded under the FD&C Act; 

however, under the general enforcement 

discretion approach, FDA generally has 

not enforced this proscription for IVDs 

offered as LDTs. As another example, 

ProPublica reported on a COVID–19 test 

offered by a laboratory under contract 

with a university without EUA 

authorization from FDA, which, 

according to the report, missed 96 

percent of the positive cases from the 

university campus, and routinely sent 

people infected with COVID–19 back 

into the community (Ref. 26). In 

addition, consumers, shareholders, and 

investors are filing lawsuits against 

laboratory manufacturers for false and 

misleading statements about test 

efficacy, including lawsuits related to 

pharmacogenetic tests (genetic tests 

intended to inform drug selection) and 

NIPS (see, e.g., Complaint, In re Myriad 

Genetics, Inc. Sec. Litig., No. 2:19–cv– 

00707–PMW (D. Utah 2019); Complaint, 

Hickok v. Capone, No. 2021–0686 (Del. 

Ch. 2021); Complaint, Davis v. Natera, 

Inc., No. 3:22–cv–00985 (N.D. Cal. 

2022); Complaint, Carroll v. Myriad 

Genetics Inc., No. 4:22–CV–00739 (N.D. 

Cal. 2022); Biesterfeld v. Ariosa 

Diagnostics, Inc., No. 1:21–CV–03085, 

2022 WL 972281 (N.D. Ill. 2022); and 

Complaint, Kogus v. Capone, No. 2022– 

0047–SG (Del. Ch. 2022)). The overall 

picture presented by this evidence 

indicates that a change in oversight is 

needed to better assure the safety and 

effectiveness of IVDs offered as LDTs. 

3. Greater FDA Oversight is Needed To 

Protect the Public Health 

As described above, the evidence FDA 

has collected points to flaws in 

laboratory manufacturing of tests that 

need to be addressed to protect the 

public. Greater oversight by FDA would 

help address these flaws. 

In the past, FDA has communicated 

with the public when it is particularly 

concerned about a type of IVD offered 

as an LDT. For example, in addition to 

the 2015 Report, FDA has issued safety 

communications about pharmacogenetic 

tests, NIPS tests, ovarian cancer 

screening tests, nipple aspirate tests, 

and instruments used in the design of 

many different LDTs (Refs. 27 to 31). 

FDA has also taken compliance action 

in some circumstances, such as issuing 

a warning letter to a laboratory 

manufacturing a pharmacogenetic test 

in April 2019 (Ref. 32). However, more 

structural change is needed. FDA’s 

general enforcement discretion 

approach emerged at a time when the 

typical IVD offered as an LDT looked 

very different from how it looks today. 

FDA has made a preliminary 

determination that this approach has 

become outdated, and the proposed 

steps to end this approach in this 

rulemaking would better protect the 

public health. 

Increased oversight would help to 

ensure the safety and effectiveness of 

IVDs offered as LDTs. More accurate 

diagnoses would lead to better care, 

which would advance public health 

overall. Through increased oversight, 

the public, including patients and 

healthcare professionals, could have 

more confidence that the test results 

they rely on are accurate. Greater FDA 

oversight of IVDs offered as LDTs has 

become particularly important as more 

and more novel treatments require use 

of a specialized test to identify patients 

likely to benefit from them. This, in 

turn, has led to increased development 

of tests used as the primary driver for 

therapeutic decisions. These include 

tests to determine whether to administer 

a therapeutic, which therapeutic to 

administer, and at what dose to 

administer the therapeutic. For 

example, recent approvals of drug 

products to treat diseases in their early 

stages, such as for early-stage 

Alzheimer’s patients, make accurate and 

early diagnosis of these diseases more 

critical today than ever before. As 

another example, gene therapy is an 

emerging field with incredible potential 

to treat many diseases or conditions. 

Testing is required to identify patients 

with the defective gene targeted by the 

treatment and, in some cases, to assess 

whether the patient has antibodies to 

the vector delivering the treatment that 

would prevent it from working. In these 

and other cases, accurate and reliable 

test results are essential for safe and 

effective use of a therapeutic. 

Increased oversight would also 

address business strategies that take 

advantage of the current bifurcated 

system. For example, in a number of 

cases, laboratories that have submitted 

premarket submissions for their tests, 

but whose tests did not meet applicable 

requirements for authorization, have 

still offered these IVDs as ‘‘LDTs.’’ Some 

of these tests, such as a test intended to 

diagnose Alzheimer’s disease, had 

inadequate validation data to support 

authorization (see Ref. 33). A 

genotyping test purported to predict 

heart disease risk, but FDA found that 

there was no association between the 

genetic information the test identified 

(KIF6) and heart disease. A third test, 

intended to diagnose Fabry disease, 

showed a high level of false negatives. 

The public health is not served by a 

scheme in which tests that have these 

types of problems are still offered to 

patients simply because the 

manufacturer is a laboratory. FDA is 

also aware that some industry players 

have created business models that claim 

a connection to laboratories and offer 

IVDs as LDTs. The increase in firms 

using these business models, as well as 

their substantial magnitude of reach, 

underscores the need for more 

oversight. 

In addition, FDA anticipates that 

consistent oversight would bring more 

stability to the testing market overall, 

which could help to encourage the 

manufacture of IVDs for which there is 

a reasonable assurance of safety and 

effectiveness. FDA is aware of 

arguments that better assuring the safety 

and effectiveness of LDTs would foster 

test innovation. FDA is also aware of 

arguments that IVD manufacturers that 

are not laboratories may currently be 

discouraged from investing time and 

resources into developing novel tests 

due to the concern that once the 

manufacturer receives marketing 

authorization for its test, laboratories 

will develop similar tests and market 

their tests without complying with FDA 

requirements. We anticipate that 

applying the same oversight approach to 


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laboratories and non-laboratories that 

manufacture IVDs would better assure 

the safety and effectiveness of LDTs, 

and would remove a disincentive for 

non-laboratory manufacturers to 

develop novel tests, thereby spurring 

innovation and access to IVDs for which 

there is a reasonable assurance of safety 

and effectiveness. As a result, we 

anticipate that phasing out the general 

enforcement discretion approach for 

LDTs would advance responsible 

innovation by both laboratory and nonlaboratory IVD manufacturers alike, 

rather than discouraging it. 

FDA is aware of other arguments that 

ending the general enforcement 

discretion approach for LDTs would 

interfere with test innovation and 

patient access due to the potential need 

for premarket review of new tests. 

However, under FDA’s device 

authorities, FDA premarket review is 

only required for certain tests (generally 

those classified into class II or class III), 

and FDA estimates that approximately 

50 percent of IVDs offered as LDTs 

would not require premarket review (see 

section II.F.4 of the Preliminary 

Economic Analysis of Impacts (Ref. 34)). 

In addition, FDA review is only 

required for device modifications in 

certain circumstances. For devices that 

are subject to PMA requirements, a PMA 

supplement is required only for changes 

that affect the safety or effectiveness of 

the device, and in some cases the 

change may be made prior to FDA 

approval (see 21 CFR 814.39(d)); may be 

made 30 days after a supplement has 

been filed, unless FDA takes certain 

action (see 21 CFR 814.39(e)); or may be 

made 30 days after FDA receives a 

notice describing the change (in lieu of 

a supplement), unless FDA takes certain 

action (see 21 CFR 814.39(f)). For 

devices that are subject to 510(k) 

requirements, a new 510(k) is only 

required for a significant change or 

modification in design, components, 

method of manufacture, or intended 

use, where a significant change or 

modification is one that could 

significantly affect the safety or 

effectiveness of the device or that is a 

major change or modification in the 

device’s intended use (21 CFR 

807.81(a)). FDA has published several 

guidance documents to help 

stakeholders determine whether a 

certain change or modification may 

require a PMA supplement, new 510(k), 

or other submission to FDA, and FDA 

has several mechanisms available 

through which manufacturers may seek 

FDA assistance in making this 

determination. In addition, under 

section 515C of the FD&C Act (21 U.S.C. 

360e–4), a PMA supplement or new 

510(k) is not required for a change to a 

device that would otherwise require a 

supplement or new 510(k) if the change 

is consistent with a predetermined 

change control plan previously 

approved or cleared by FDA. We also 

note that as described in section VI.B, 

FDA is proposing to phase out the 

general enforcement discretion 

approach for LDTs with respect to 

premarket review requirements on a 

date that aligns with or follows the 

beginning of a new user fee cycle, such 

that FDA’s review timelines and goals 

would be reflected in commitments 

newly negotiated with industry. For all 

of these reasons, FDA does not 

anticipate that ending the general 

enforcement discretion approach for 

LDTs would unduly impair test 

innovation and patient access. 

Furthermore, FDA’s approach was 

never intended to selectively foster 

laboratory innovation at a cost to public 

health. Rather, the approach arose based 

on certain test characteristics and 

institutional safeguards that at the time 

adequately protected patients. In 

general, those characteristics and 

safeguards are no longer present, putting 

public health at risk. Further, FDA is 

aware that this scheme is in some cases 

fostering unfounded claims of 

innovation rather than responsible 

innovation. These claims are concerning 

to FDA because they can mislead the 

public, undermine legitimate 

competition, and disincentivize 

responsible, science-based innovation. 

Finally, increased oversight may help 

to advance health equity. FDA is aware 

of concerns that IVDs offered as LDTs 

may exacerbate health inequities due to 

higher rates of inaccurate results among 

underrepresented patient populations, 

particularly racial and ethnic minorities 

undergoing genetic testing (see, e.g., 

Refs. 17 and 35 to 38). Some IVDs 

offered as LDTs have not been validated 

for use in all patient populations within 

a disease state, meaning that it is 

unknown how well the test may 

perform across diverse patient 

populations expected to use the test and 

the test may be less accurate in 

underrepresented patient populations, 

potentially contributing to health 

disparities (see, e.g., Ref. 39). Increased 

FDA oversight may help to ensure that 

information is available pertaining to 

device safety and effectiveness for 

specific demographic characteristics if 

performance differs within the target 

population, through the enforcement of 

applicable labeling requirements. In 

addition, when FDA conducts 

premarket review of a device, FDA may 

ask that sponsors provide data for 

different intended patient populations, 

and with new authorities under the 

Food and Drug Omnibus Reform Act of 

2022 (FDORA), sponsors generally are 

required to submit diversity action 

plans to FDA, including the sponsor’s 

goals for enrollment in device clinical 

studies. In contrast, with limited 

oversight over these tests, FDA does not 

know whether diverse patient 

populations are being included in 

validation studies for these IVDs. FDA 

has made a preliminary determination 

that increased oversight for these IVDs 

would help ensure adequate 

representation of the intended use 

population in validation studies and 

transparency regarding potential 

differential performance, helping to 

advance health equity. FDA also 

recognizes that IVDs offered as LDTs 

may serve communities in rural, 

medically underserved areas with 

disparities in access to diagnostic tests. 

However, the benefits of test access 

directly depend on the ability of tests to 

work as intended. Thus, to the extent 

that access to IVDs offered as LDTs may 

benefit patients in rural, medically 

underserved communities, the harms of 

unsafe or ineffective IVDs offered as 

LDTs may also be realized among these 

underserved patient populations. By 

increasing its oversight, FDA may better 

prevent and mitigate such harms, 

thereby better protecting the health of 

these underserved populations. 

We are aware of arguments that other 

mechanisms—such as the medical 

expertise of laboratorians or 

requirements under CLIA—already 

provide adequate oversight of IVDs 

offered as LDTs. However, our review of 

the evidence indicates otherwise. 

Evidence suggests that under the current 

scheme, the healthcare community lacks 

adequate assurances about the safety 

and effectiveness of IVDs offered as 

LDTs. Although laboratories that offer 

LDTs are also subject to CLIA, which is 

primarily administered by the Centers 

for Medicare & Medicaid Services 

(CMS), CLIA is not a substitute for FDA 

oversight. CLIA establishes 

requirements for laboratories and 

laboratory personnel pertaining to 

operations, inspections, and 

certification, with a focus on the 

proficiency with which laboratories 

perform clinical testing (see 42 U.S.C. 

263a and 42 CFR part 493). Among 

other requirements, clinical laboratories 

generally must have a CLIA certificate 

that corresponds to the complexity of 

tests performed prior to accepting 

human samples for testing. However, 

under CLIA, CMS does not regulate 

critical aspects of laboratory test 


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11When ‘‘QS’’ requirements are discussed 

throughout this preamble, FDA is referring to the 

current good manufacturing practice (CGMP) 

requirements set forth in part 820 (21 CFR part 820). 

Generally, the requirements are referred to as QS 

requirements, but that terminology may change 

when amendments to part 820 are finalized. See 87 

FR 10119 (February 23, 2022) and section VI.B.3 for 

a further discussion of FDA’s proposed 

amendments to part 820. 

development; does not evaluate the 

performance of a test before it is offered 

to patients and healthcare providers; 

does not assess clinical validity (i.e., the 

accuracy with which a test identifies, 

measures, or predicts the presence or 

absence of a clinical condition or 

predisposition in a patient); does not 

regulate certain manufacturing 

activities, such as design controls and 

acceptance activities; does not provide 

human subject protections for patients 

who participate in test clinical research 

trials; and does not require adverse 

event reporting. As such, CMS has 

described the FDA and CMS ‘‘regulatory 

schemes’’ as ‘‘different in focus, scope 

and purpose, but they are intended to be 

complementary’’ (Ref. 40). Where CLIA 

does play a role (as discussed further 

below, compliance with CLIA may 

provide certain assurances relating to 

quality system (QS) requirements), FDA 

has tailored its proposed phaseout 

policy accordingly.11

We are also aware of arguments that 

any additional oversight of LDTs should 

be accomplished by granting new 

statutory authorities to CMS. However, 

this would cause a problematic split in 

oversight, with the same types of tests 

being reviewed by different Agencies 

depending on where the test was made. 

For example, a cancer diagnostic test 

developed by a conventional 

manufacturer would be reviewed by 

FDA while a similar cancer diagnostic 

test (using the same sample type and 

testing for the same analytes) developed 

by a laboratory would be reviewed by 

another Agency. Further, with that 

divided oversight, an IVD developed by 

a conventional manufacturer could even 

be reviewed and cleared by FDA and 

subsequently reviewed by another 

Agency if a laboratory made certain 

modifications to it. However, if those 

same modifications were made by the 

original manufacturer, they would be 

reviewed by FDA. This could lead to 

confusion and inconsistency. 

FDA has both the authority and the 

expertise to perform the necessary 

oversight of IVDs offered as LDTs and is 

the only Agency for which that is the 

case. One of FDA’s most basic and wellunderstood responsibilities is helping to 

ensure the safety and effectiveness of 

medical products. FDA employs staff 

across a wide range of disciplines, 

including physicians, statisticians, 

engineers, biologists, chemists, 

geneticists, and others, to evaluate the 

science behind medical products before 

they reach the market. Understanding 

the complex technical information in 

applications, such as clinical trial data, 

bench testing results, and product 

manufacturing and design 

characteristics—and putting that 

information in context to assess whether 

a product can be marketed—is within 

the unique expertise of FDA. This type 

of expertise is no less important for 

IVDs, which can have a wide variety of 

public-health consequences, as 

described elsewhere in this rule. During 

review of an application for an IVD, 

FDA reviewers closely examine data 

relevant to analytical validity, clinical 

validity, and safety, and draw on their 

expertise and experience to understand 

both the product and the science 

supporting the product. 

Review of the underlying science 

behind an IVD is based on what the IVD 

does and is in no way related to where 

the IVD is made. Thus, FDA’s 

experience and expertise with respect to 

oversight of other IVDs is directly 

applicable to oversight of LDTs. In fact, 

FDA has already applied its expertise to 

the review of some IVDs offered as 

LDTs—for example, during public 

health emergencies. As stated above, 

FDA has reviewed many EUA requests 

for tests from laboratories during the 

public health response to COVID–19. 

Entities outside FDA have also 

recognized that FDA should oversee 

LDTs, and that greater oversight is 

needed. For example, the Secretary’s 

Advisory Committee on Genetics, 

Health, and Society, in its April 2008 

report entitled ‘‘U.S. System of 

Oversight of Genetic Testing,’’ stated 

that ‘‘FDA should address all laboratory 

tests, regardless of how they are 

produced (i.e., as a commercial test kit 

or laboratory-developed test), in a 

manner that takes advantage of its 

current experience’’ (Ref. 41). The 

American Cancer Society Cancer Action 

Network has taken a similar position, 

noting in a November 2016 statement 

that ‘‘[c]urrent oversight of LDTs falls 

short of ensuring these tests produce 

accurate and meaningful results . . . 

[t]he FDA is the most appropriate 

agency to evaluate the analytical and 

clinical validity of diagnostic tests, 

along with their safety, to help ensure 

that cancer patients and their doctors 

are able to make appropriate treatment 

decisions based on accurate 

information’’ (Ref. 42). Likewise, the 

Advanced Medical Technology 

Association (AdvaMed) stated in 

November 2021 that the association has 

‘‘long supported the idea that all 

diagnostic test developers . . . should 

be subject to the same FDA standards 

and processes’’ (Ref. 43). 

4. FDA Should Increase Oversight in a 

Manner That Recognizes the Current 

State of the Testing Market 

As discussed throughout this section, 

increased oversight of IVDs offered as 

LDTs is needed. However, FDA has also 

made a preliminary determination that 

our general enforcement discretion 

approach should be phased out in a 

manner that accounts for the level of 

public health concern and the 

importance of avoiding undue 

disruption to the testing market, 

including undue disruption to the 

provision of care. Therefore, we are 

proposing a gradual phaseout to occur 

in stages over a total period of 4 years, 

as described in section VI.B. FDA 

anticipates that this phaseout policy 

should ultimately enable IVDs offered as 

LDTs that are supported by sound 

science to remain on the market. FDA 

also recognizes that some IVDs may 

need to come off the market, because, 

for example, the IVD cannot meet 

applicable requirements under the 

FD&C Act and its implementing 

regulations, or the laboratory chooses 

not to invest resources to meet those 

requirements. To the extent that 

withdrawal from the market of these 

IVDs implicates any reliance interests, 

FDA has made a preliminary 

determination that the public-health 

benefits associated with the reasonable 

assurance of safety and effectiveness of 

IVDs offered as LDTs outweigh any such 

interests. In addition, in the long run, it 

is possible that any reduction in the 

number of current IVDs offered as LDTs 

may be offset by the market entry of 

IVDs from other manufacturers who will 

have benefitted from a more consistent 

oversight approach and increased 

stability spurring innovation. 

C. FDA’s Current Regulatory Framework 

The FD&C Act, as amended by the 

MDA and subsequent statutes, 

establishes a comprehensive system for 

the regulation of devices, defined in 

section 201(h)(1) of the FD&C Act, that 

are intended for human use. Section 513 

of the FD&C Act (21 U.S.C. 360c) 

establishes three categories (classes) of 

devices depending on the regulatory 

controls needed to provide reasonable 

assurance of their safety and 

effectiveness. The three categories of 

devices are class I (general controls), 

class II (special controls), and class III 

(premarket approval). 

Class I devices are those devices for 

which the general controls of the FD&C 


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Act (controls authorized by or under 

section 501, 502, 510, 516, 518, 519, or 

520 (21 U.S.C. 351, 352, 360, 360f, 360h, 

360i, or 360j) or any combination of 

such sections) are sufficient to provide 

reasonable assurance of safety and 

effectiveness of the device; or those 

devices for which insufficient 

information exists to determine that 

general controls are sufficient to provide 

reasonable assurance of safety and 

effectiveness or to establish special 

controls to provide such assurance, but 

because the devices are not purported or 

represented to be for a use in supporting 

or sustaining human life or for a use 

which is of substantial importance in 

preventing impairment of human 

health, and do not present a potential 

unreasonable risk of illness or injury, 

are to be regulated by general controls 

(section 513(a)(1)(A) of the FD&C Act). 

General controls include, but are not 

limited to, provisions that relate to 

establishment registration and device 

listing; premarket notification; 

prohibitions against adulteration and 

misbranding (e.g., labeling that fails to 

bear adequate directions for use); 

recordkeeping and reporting, including 

adverse event reporting and reporting of 

corrections and removals initiated to 

reduce a risk to health posed by the 

device or to remedy a violation of the 

FD&C Act caused by the device which 

may present a risk to health; and current 

good manufacturing practice (CGMP) 

requirements. These controls apply to 

all devices unless an exemption applies. 

Class II devices are those devices for 

which general controls by themselves 

are insufficient to provide reasonable 

assurance of safety and effectiveness, 

but for which there is sufficient 

information to establish special controls 

to provide such assurance, including the 

promulgation of performance standards, 

post-market surveillance, patient 

registries, development and 

dissemination of guidelines, 

recommendations, and other 

appropriate actions the Agency deems 

necessary to provide such assurance 

(section 513(a)(1)(B) of the FD&C Act). 

Class III devices are those devices for 

which insufficient information exists to 

determine that general controls and 

special controls would provide a 

reasonable assurance of safety and 

effectiveness, and are purported or 

represented for a use in supporting or 

sustaining human life or for a use which 

is of substantial importance in 

preventing impairment of human 

health, or present a potential 

unreasonable risk of illness or injury 

(section 513(a)(1)(C) of the FD&C Act). 

Under section 513(d)(1) of the FD&C 

Act, devices that were introduced or 

delivered for introduction into interstate 

commerce for commercial distribution 

before the enactment of the MDA on 

May 28, 1976 (generally referred to as 

‘‘preamendments devices’’) are 

classified after FDA: (1) receives a 

recommendation from a device 

classification panel (an FDA advisory 

committee); (2) publishes the panel’s 

recommendation, along with a proposed 

regulation classifying the device, and 

provides an opportunity for interested 

persons to submit comments; and (3) 

publishes a final regulation classifying 

the device. A preamendments device for 

which a classification regulation has not 

been promulgated is known as an 

‘‘unclassified device.’’ Until an 

unclassified device type has been 

formally classified by regulation, the 

marketing of new devices within the 

device type requires FDA premarket 

review through a premarket notification 

(510(k)) under section 510(k) of the 

FD&C Act. 

Devices that were not introduced or 

delivered for introduction into interstate 

commerce for commercial distribution 

before May 28, 1976 (generally referred 

to as ‘‘postamendments devices’’) are 

classified automatically by section 

513(f) of the FD&C Act into class III 

without any FDA rulemaking process. 

Those devices remain in class III and 

require approval of a premarket 

approval application (PMA), unless and 

until: (1) FDA classifies or reclassifies 

the device into class I or II under section 

513(f)(2) or (3) of the FD&C Act, or (2) 

FDA issues an order finding the device 

to be substantially equivalent, in 

accordance with section 513(i) of the 

FD&C Act, to a predicate device that 

does not require premarket approval. 

The Agency determines whether new 

devices are substantially equivalent to 

predicate devices by means of 

premarket notification procedures in 

section 510(k) of the FD&C Act and part 

807 of the regulations (21 CFR part 807). 

In addition, under section 520(g) of 

the FD&C Act and part 812 of FDA’s 

regulations (21 CFR part 812), a clinical 

investigation to determine the safety 

and effectiveness of certain devices 

must be the subject of an approved 

investigational device exemption (IDE) 

before such investigation may 

commence. If an IDE has been granted, 

a failure to comply with a requirement 

under which the device was exempted 

for investigational use renders the 

device adulterated (see section 501(i) of 

the FD&C Act). 

Failure to comply with applicable 

requirements of the FD&C Act and FDA 

regulations may render the device 

adulterated and misbranded under 

sections 501 and 502 of the FD&C Act 

and may constitute a prohibited act 

under section 301 of the FD&C Act (21 

U.S.C. 331). 

IVDs, as defined in § 809.3 (21 CFR 

809.3), are devices intended for human 

use and are subject to the FD&C Act. 

They include class I, class II, and class 

III devices, as well as both 

preamendments and postamendments 

devices. Like other devices, IVDs are 

subject to general controls, including 

premarket notification, reporting 

requirements regarding adverse events 

and corrections and removals, IDE 

requirements (though most 

investigations of IVDs are exempt from 

most provisions of the IDE regulation), 

and other applicable requirements 

under the FD&C Act and FDA’s 

regulations. IVDs are also subject to 

specific labeling requirements in part 

809 of the regulations (21 CFR part 809). 

D. History of the Rulemaking 

1. FDA’s Longstanding Recognition That 

IVDs Manufactured by Laboratories Are 

Devices 

FDA has made clear, on many 

occasions and over many years, that 

LDTs are devices under the FD&C Act 

(for the legal reasoning for this 

conclusion, see section V.B). Over 25 

years ago, FDA explained that clinical 

laboratories that develop tests are acting 

as manufacturers of medical devices (62 

FR 62243 at 62249 (November 21, 

1997)). FDA reiterated that position in a 

citizen petition response a year later 

(Ref. 44), and in the preamble to a final 

rule 3 years after that (65 FR 18230 at 

18231 (April 7, 2000)). In 2006, FDA 

again cited its prior statement that 

clinical laboratories that develop tests 

are acting as manufacturers of medical 

devices (Ref. 45 (quoting 62 FR 62243 at 

62249)). In 2014, FDA expressly 

considered and rejected arguments that 

LDTs are not devices under the FD&C 

Act, stating in a citizen petition 

response that ‘‘LDTs are devices within 

the plain language of the [statutory] 

definition’’ (Ref. 46). Five years later, 

FDA issued a warning letter stating that 

‘‘FDA has not created a legal ‘carve-out’ 

for LDTs such that they are not required 

to comply with the requirements under 

the Act that otherwise would 

apply. . . . Although FDA has 

generally exercised enforcement 

discretion for LDTs, the Agency always 

retains discretion to take action when 

appropriate, such as when it is 

appropriate to address significant public 

health concerns’’ (Ref. 47). A wide range 

of other FDA documents, including 

guidance documents, safety 

communications, compliance letters, 

and other public statements, have 


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12As defined in the draft guidance document, 

IVDMIAs are ‘‘test systems that employ data, 

derived in part from one or more in vitro assays, 

and an algorithm that usually, but not necessarily, 

runs on software to generate a result that diagnoses 

a disease or condition or is used in the cure, 

mitigation, treatment, or prevention of disease.’’ 

The draft guidance document further characterized 

IVDMIAs as having the following three features: 

they use clinical data to empirically identify 

variables and derive weights/coefficients used in an 

algorithm; they employ that algorithm to calculate 

a patient-specific result, which cannot be 

independently derived and confirmed by another 

laboratory (absent access to proprietary information 

used in the development and derivation of the test); 

and they report that result, which cannot be 

interpreted by a well-trained healthcare practitioner 

using prior knowledge of medicine in the absence 

of information from the test developer regarding 

clinical performance and effectiveness. 

13HHS also posted an accompanying document 

entitled ‘‘FAQs on Laboratory Developed Tests 

(LDTs)’’ on its website (Ref. 58). 

indicated or otherwise taken as their 

premise that IVDs are devices even 

when the manufacturer is a laboratory 

(see, e.g., Refs. 11, 18, 27, 28, and 48 to 

56). 

FDA has also taken regulatory actions 

consistent with these statements and 

documents. Since 2017, the Agency has 

reviewed over 40 PMAs, 510(k)s, and De 

Novo classification requests for tests 

identified by the manufacturer as LDTs, 

and has approved, cleared, or granted 

De Novo classification for roughly half 

of those tests under authorities in the 

FD&C Act specifically reserved for 

‘‘devices.’’ FDA has also received many 

EUA requests from laboratories and has 

authorized over 150 such tests for 

emergency use, an authority that is also 

limited to ‘‘devices’’ or other FDAregulated medical products. 

2. Past FDA Initiatives To Address LDTs 

In light of FDA’s recognition that 

LDTs are devices and our increasing 

concerns about IVDs offered as LDTs (as 

detailed in the ‘‘Need for the Rule’’ 

section, section III.B of this document), 

over the years the Agency has 

considered various ways to address 

IVDs manufactured by laboratories that 

raise safety or effectiveness concerns. In 

1997, FDA sought to address these 

concerns by establishing restrictions on 

the sale, distribution, and use of analyte 

specific reagents (ASRs), which the 

Agency described as the ‘‘primary 

ingredients’’ of most LDTs (62 FR 62243 

at 62249). In 2006, FDA issued a draft 

guidance outlining a different 

enforcement approach for a type of LDT 

known as an in vitro diagnostic 

multivariate index assay (IVDMIA),12

which raised particular safety and 

effectiveness concerns (Ref. 45). FDA 

later determined that it should engage in 

a more comprehensive effort to oversee 

LDTs, in part due to stakeholder 

feedback. 

Consistent with this determination, in 

2010, FDA announced plans to develop 

a broader approach to the oversight of 

LDTs. The Agency held a 2-day public 

meeting and opened a docket for public 

comment (75 FR 34463 (June 17, 2010)). 

Input received through those 

proceedings informed two draft 

guidance documents issued by FDA on 

October 3, 2014, entitled ‘‘Framework 

for Regulatory Oversight of Laboratory 

Developed Tests (LDTs)’’ (79 FR 59776) 

and ‘‘FDA Notification and Medical 

Device Reporting for Laboratory 

Developed Tests (LDTs)’’ (79 FR 59779) 

(Refs. 48 and 49). In those draft 

guidance documents, FDA proposed to 

implement a risk-based oversight 

framework for IVDs offered as LDTs, 

with a phased enforcement strategy. 

FDA solicited public feedback on the 

draft guidance documents and held a 

public workshop on January 8 and 9, 

2015 (79 FR 69860 (November 24, 

2014)). 

From October 2014 through 2016, 

FDA analyzed more than 300 sets of 

comments on the draft guidance 

documents, as well as discussion from 

the public workshop, and engaged 

extensively with stakeholders in 

meetings and conferences. A number of 

interested parties provided feedback, 

including laboratories, healthcare 

providers, patients, conventional IVD 

manufacturers, government agencies, 

and Congress. The feedback ranged 

generally from strong opposition to 

strong support for FDA’s proposed 

increased oversight of LDTs and 

addressed a wide range of topics, 

including FDA’s authority to regulate 

LDTs, the risks posed by LDTs without 

increased FDA enforcement, the effect 

of a new enforcement approach on test 

access and innovation, the potential 

interplay between FDA regulation and 

CLIA, and the implications of increased 

FDA oversight for competition in the 

IVD market. 

On January 13, 2017, FDA issued a 

discussion paper (2017 Discussion 

Paper) synthesizing the feedback that 

had been provided to the Agency, 

following a choice by FDA not to 

finalize the draft guidance documents to 

allow for further public discussion and 

to provide an opportunity for Congress 

to develop legislation for a new 

regulatory framework encompassing all 

IVDs that appropriately balances patient 

protection with continued access and 

innovation (Ref. 50). 

In August 2020, HHS posted a 

statement on its website entitled 

‘‘Rescission of Guidances and Other 

Informal Issuances,’’ which stated, 

among other things, that ‘‘the 

department has determined that the 

Food and Drug Administration (‘FDA’) 

will not require premarket review of 

laboratory developed tests (‘LDT’) 

absent notice-and-comment 

rulemaking’’ (Ref. 57).13 This statement 

was informed by advice in a legal 

memorandum from the HHS Office of 

General Counsel (see Ref. 59). In 

November 2021, based on new advice 

from the HHS Office of General Counsel, 

HHS leadership determined that the 

August 2020 statement no longer 

represented the Department’s policy or 

legal views (Ref. 59). HHS Secretary 

Xavier Becerra publicly announced the 

withdrawal of the statement on 

November 15, 2021 (Ref. 60). Various 

news outlets have reported on these 

events (Refs. 61 to 64). 

IV. Legal Authority 

FDA is proposing to issue this rule 

under the Agency’s general rulemaking 

authorities and statutory authorities 

relating to devices. These authorities 

include sections 201(h)(1), 301, 501, 

502, 510, 513, 514, 515, 518, 519, 520, 

701, 702, 704, and 801 (21 U.S.C. 

321(h)(1), 331, 351, 352, 360, 360c, 

360d, 360e, 360h, 360i, 360j, 371, 372, 

374, and 381). In particular: 

• Under section 201(h)(1) of the 

FD&C Act, a device is defined as ‘‘an 

instrument, apparatus, implement, 

machine, contrivance, implant, in vitro 

reagent, or other similar or related 

article, including any component, part, 

or accessory, which is (A) recognized in 

the official National Formulary, or the 

United States Pharmacopeia, or any 

supplement to them, (B) 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 (C) 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.’’ 

• Section 701(a) of the FD&C Act 

authorizes FDA to issue regulations for 

the efficient enforcement of the FD&C 

Act. 

For additional descriptions of some of 

the authorities referenced above, see 

‘‘FDA’s Current Regulatory Framework’’ 

section (section III.C.). For additional 

discussion of how these legal authorities 

apply to LDTs, see ‘‘Legal Basis for the 

Proposed Amendment’’ section (section 

V.B.). 


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V. Description of the Proposed 

Amendment to the Definition of In Vitro 

Diagnostic Products 

A. Proposed Amendment 

We are proposing to amend part 809, 

subpart A, specifically § 809.3, by 

updating the definition of ‘‘in vitro 

diagnostic products’’ to make explicit 

that IVDs are devices under the FD&C 

Act including when the manufacturer of 

the IVD is a laboratory. IVDs are defined 

as ‘‘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’’ (§ 809.3). This 

amendment would reflect FDA’s 

longstanding view that LDTs are devices 

under the FD&C Act, and would reflect 

the fact that the device definition in the 

FD&C Act does not differentiate 

between entities manufacturing the 

device. In other words, whether an IVD 

is a device does not depend on where 

or by whom the IVD is manufactured. 

FDA is also proposing to amend the 

statutory citation for the device 

definition included in § 809.3 to reflect 

amendments to section 201(h) of the 

FD&C Act as a result of the enactment 

of the Safeguarding Therapeutics Act 

(Pub. L. 116–304, 134 Stat. 4915). For 

many years, the definition of ‘‘device’’ 

had been codified at section 201(h) of 

the FD&C Act. Upon enactment of the 

Safeguarding Therapeutics Act, the 

definition of ‘‘device’’ was redesignated 

as paragraph (h)(1) and a new definition 

of ‘‘counterfeit device’’ was codified at 

paragraph (h)(2). 

B. Legal Basis for the Proposed 

Amendment 

If amended as proposed, § 809.3 

would express in plain terms that IVDs, 

including test systems, fall within the 

definition of a device in section 

201(h)(1) of the FD&C Act when they 

have been manufactured by laboratories. 

In this subsection, FDA sets forth the 

legal reasoning for this position. 

1. In Vitro Diagnostic Test Systems Are 

Devices 

The FD&C Act defines a device as, in 

relevant part, ‘‘an instrument, 

apparatus, implement, machine, 

contrivance, implant, in vitro reagent, or 

other similar or related article, 

including any component, part, or 

accessory, which is . . . intended for 

use in the diagnosis of disease or other 

conditions, or in the cure, mitigation, 

treatment, or prevention of disease’’ (see 

21 U.S.C. 321(h)(1); see also 21 U.S.C. 

360j(o) (identifying circumstances under 

which software is and is not within the 

device definition)). This definition 

includes IVD test systems. Test systems 

are sets of IVDs—for example, reagents, 

instruments, specimen collection 

devices, software, and other related 

materials—that function together to 

produce a test result. See, e.g., 

§ 809.10(a)(9)(iii) (21 CFR 

809.10(a)(9)(iii)) (discussing ‘‘multiple 

unit products which require the use of 

included units together as a system’’); 

id. § 809.10(b) (referring to reagents and 

instruments within a system). 

According to a straightforward reading 

of the statutory text, these systems are 

‘‘apparatus[es],’’ ‘‘contrivance[s],’’ and 

articles that are ‘‘similar or related’’ to 

‘‘instrument[s]’’ and ‘‘in vitro 

reagent[s],’’ that are intended for use in 

the diagnosis of disease or other 

conditions or in the cure, mitigation, 

treatment, or prevention of disease. 

They consist of individual parts that 

have their own regulatory identity, but, 

when combined, constitute a new 

device. 

The device definition expressly 

contemplates this scenario because it 

provides that both an overall article and 

each of its ‘‘components’’ and ‘‘parts’’ 

are devices subject to regulation. (21 

U.S.C. 321(h)(1); cf. Shuker v. Smith & 

Nephew, PLC, 885 F.3d 760, 768 (3d Cir. 

2018) (describing the distinct status of a 

‘‘system that is itself a ‘device’ but that 

is comprised of Class II [device] 

components in addition to one or more 

Class III [device] components’’).) The 

word ‘‘apparatus,’’ which is defined as 

‘‘a set of materials or equipment 

designed for a particular use,’’ 

encompasses test systems by its plain 

terms. (See Apparatus, MerriamWebster.com (last accessed June 28, 

2023); see also United States v. BactoUnidisk, 394 U.S. 784, 798 (1969) 

(‘‘Congress fully intended that the 

[FD&C] Act’s coverage be as broad as its 

literal language indicates’’).) Consistent 

with this analysis, FDA’s definition of 

an ‘‘in vitro diagnostic product,’’ which 

was first promulgated in 1973 and is 

still in effect today, identifies a 

‘‘system’’ as a type of IVD and a device 

under the FD&C Act. (Section 809.3 

(IVDs include ‘‘reagents, instruments, 

and systems’’); see 38 FR 7096 at 7098 

(March 15, 1973).) 

The regulation of test systems is 

important because test systems are 

generally the IVDs that produce a 

result—a ‘‘positive’’ or ‘‘negative’’ (such 

as what patients receive in the context 

of COVID–19 diagnostic tests), a 

quantitative value (such as a 

concentration of glucose), or perhaps a 

more detailed report of results. The 

quality of test results is generally what 

defines both the risks and benefits of 

IVDs: the risks stem from inaccurate, 

unreliable, incomplete, or misleading 

test results, and the benefits stem from 

accurate, reliable, and complete test 

results. For that reason, test systems and 

their results are a key focus of FDA’s 

regulation of IVDs. FDA has issued over 

350 regulations classifying different 

types of test systems (see generally 21 

CFR parts 862, 864, 866) and has 

evaluated the performance and results 

of innumerable test systems over the 

course of decades. Patients and 

healthcare professionals rely on FDA to 

help ensure the validity of test systems, 

and conventional IVD manufacturers 

have built their business around this 

premise. 

The focus on test systems and their 

results is not new; it has been a 

consistent theme throughout the history 

of FDA’s regulation of IVDs. Congress 

expressly granted FDA authority over 

diagnostic products in 1938. (Federal 

Food, Drug and Cosmetic Act (June 25, 

1938), Pub. L. 75–717, 52 Stat. 1040 

(defining ‘‘drug’’ and ‘‘device’’ with 

reference to an intended use in 

‘‘diagnosis,’’ among other things).) 

Following the 1938 Act, FDA took 

action against diagnostic products, 

including against a system intended to 

diagnose illness based on human blood 

samples. (See Drown v. United States, 

198 F.2d 999, 1001 (9th Cir. 1952).) 

And, in the early 1970s, FDA 

established a specific IVD regulatory 

program in response to ‘‘rapid growth in 

development of in vitro diagnostic 

products combined with the increasing 

use and reliance on the results by 

physicians, hospital personnel, and 

clinical laboratories.’’ (37 FR 819, 

January 19, 1972). This program 

addressed the ‘‘need [for] closer scrutiny 

because of the possibility that 

inaccurate and unreliable results may be 

obtained.’’ Id. FDA issued final 

regulations establishing controls over 

IVDs, including ‘‘systems,’’ in 1973 (38 

FR 7096 at 7098) (creating, among other 

things, ‘‘product class standards’’ to set 

‘‘performance requirements necessary to 

assure accuracy and reliability of 

results’’). FDA’s increasing concerns 

about these products was evident from 

the fact that—even before Congress 

expanded the Agency’s device 

authorities in 1976—it applied the drug 

authorities to certain IVDs. The 

Supreme Court upheld that application 

in Bacto-Unidisk, 394 U.S. at 800–01. 

In 1976, Congress enacted the MDA, 

sweeping legislation meant to broaden 

and strengthen FDA’s authority over 


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14These exemptions apply when a practitioner (1) 

is licensed by law to prescribe or administer a 

device such as an IVD, (2) manufactures that device, 

and (3) does so ‘‘solely for use in the course of [his 

or her] professional practice.’’ Thus, these 

exemptions apply to practitioners, not entities such 

as corporate or hospital laboratories that employ 

licensed practitioners. For example, FDA has long 

held that hospitals that reprocess single-use devices 

are subject to registration and other requirements 

under the FD&C Act because they are the owners/ 

operators, manufacturers, etc. even though those 

hospitals employ licensed practitioners. See 

Frequently-Asked-Questions about the Reprocessing 

and Reuse of Single-Use Devices by Third-Party and 

Hospital Reprocessors; Final Guidance for Industry 

and FDA Staff (July 2001), available at https://

www.fda.gov/media/71057/download (stating 

‘‘Third-party and hospital reprocessors of single-use 

devices (SUDs) are subject to all the regulatory 

requirements currently applicable to original 

equipment manufacturers, including premarket 

submission requirements’’ and including a Q&A 

that provides instructions on how to register and 

list for such entities). 

devices. (See, e.g., H.R. Rep. 94–853 at 

11 (February 29, 1976).) The MDA 

included revisions to the definition of 

‘‘device’’ to clarify that IVDs should be 

regulated under the new, more robust 

device authorities. (Medical Device 

Amendments of 1976, Pub. L. 94–295, 

90 Stat. 539 (adding the term ‘‘in vitro 

reagent’’ to the definition of a device); 

S. Rep. No. 93–670 at 16 (January 29, 

1974) (‘‘The Committee recognizes that 

there is confusion at the present time 

about whether certain articles are to be 

treated as devices or drugs under the 

Food, Drug and Cosmetic Act. 

Therefore, the Committee reported bill 

has carefully defined ‘device’ so as to 

specifically include implants, in vitro 

diagnostic products, and other similar 

or related articles.’’). The legislative 

history shows that Congress had serious 

concerns about test systems and sought 

to empower FDA to address them. (See, 

e.g., S. Rep. No. 93–670 at 3–4 (January 

29, 1974) (describing with concern 

‘‘quack devices’’ such as a ‘‘diagnostic 

service’’ in which ‘‘[p]ractitioners . . . 

mailed in the blood spots taken from 

their patients,’’ ‘‘[t]he blood-spotted 

paper was put into a slot of the 

electrical device called the ‘Radioscope’ 

while the operator stroked with a wand 

the abdomen of a person holding metal 

plates connected to the device,’’ and 

‘‘the operator determined from this the 

identity, kind, location, and significance 

of any disease present’’).) Congress also 

contemplated performance standards 

relevant to test systems, such as 

required labeling with ‘‘ranges of 

accuracy of diagnosis.’’ (H.R. Rep. 94– 

853 at 27.) Thus, in the MDA, Congress 

endorsed FDA’s focus on test systems 

and their results. 

2. Test Systems Manufactured by 

Laboratories Are Devices 

The definition of ‘‘device’’ in the 

FD&C Act encompasses test systems 

regardless of where or by whom they are 

manufactured. (See 21 U.S.C. 321(h)(1).) 

In particular, the definition contains no 

exception or limitation for devices 

manufactured by laboratories. ‘‘Congress 

expresses its intentions through 

statutory text passed by both Houses 

and signed by the President (or passed 

over a Presidential veto).’’ (Oklahoma v. 

Castro-Huerta, 142 S. Ct. 2486, 2496 

(2022).) If Congress had intended such 

a limitation, it could have said so. 

Instead, Congress made clear that the 

definition does not turn on the type of 

entity manufacturing the device: for 

example, the statute expressly 

recognizes that even ‘‘practitioners 

licensed by law to prescribe or 

administer . . . devices’’ (the 

professionals most closely associated 

with traditional medical practice) can 

‘‘manufacture . . . devices,’’ though 

they may be exempt from certain 

requirements when they do so ‘‘solely 

for use in the course of their 

professional practice.’’ 14 (See 21 U.S.C. 

360(g)(2); see also 21 U.S.C. 360i(c)(1), 

374(a)(2)(B).) 

Courts have repeatedly recognized 

that articles manufactured by medical 

professionals fall within FDA’s 

jurisdiction (e.g., United States v. 

Regenerative Sciences, 741 F.3d 1314 

(D.C. Cir. 2014) (holding that doctors 

‘‘producing, as part of their medical 

practice,’’ a ‘‘drug’’ under the FD&C Act 

violated the FD&C Act); Drown v. 

United States, 198 F.2d 999, 1001 (9th 

Cir. 1952) (upholding FDA action 

against chiropractor who 

‘‘manufacture[d] certain photographic, 

therapeutic and diagnostic instruments 

of her own design which she use[d] in 

her practice’’)). As the D.C. Circuit in 

Regenerative Sciences observed, an 

approach that rejects ‘‘the [FD&C Act]’s 

regulation of doctors’’ would ‘‘create an 

enormous gap in the [FD&C Act]’s 

coverage.’’ (741 F.3d at 1320.) 

The inclusion of articles in the FD&C 

Act’s definition of a device without 

regard to the identity of their 

manufacturer makes particular sense in 

the context of test systems. Today, in 

FDA’s experience, there is little 

distinction between the test systems 

manufactured by laboratories and other 

manufacturers. These systems generally 

consist of highly specialized 

components with complex functionality 

working in combination; they rarely 

resemble the ‘‘1976-type’’ tests 

discussed in this rule. For example, a 

modern-day next generation sequencing 

(NGS) test system for genetic testing 

typically consists of (among other 

things) a DNA extraction kit to extract 

nucleic acids from a human sample; an 

NGS instrument that analyzes the 

nucleic-acid output and (after days) 

generates gigabytes of sequencing raw 

data; and multiple pieces of computer 

software that translate that raw data into 

a test report. The systems look the same, 

and function the same way, regardless 

of who manufactures them. And 

although not all systems look exactly 

like an NGS system, they do typically 

involve sophisticated instruments with 

advanced software that, when used in 

conjunction with other test components, 

produce the system’s results. Their 

manufacture generally requires 

knowledge of bioinformatics, software 

development, and an underlying 

specialty, such as medical genetics— 

knowledge that is neither traditionally 

associated with nor unique to 

laboratories. FDA understands that 

many test systems offered as LDTs are 

designed at Fortune 500 companies (see 

Ref. 65) by a ‘‘development team,’’ 

similar to how systems from 

conventional manufacturers are 

designed. And in FDA’s experience, the 

individuals on these development teams 

generally have the same training and 

expertise regardless of whether they are 

employed by a ‘‘laboratory’’ 

organization or a conventional 

manufacturer. Even smaller laboratories 

use the same complex equipment for 

their systems, although they may 

purchase and use components that are 

labeled by other companies for 

‘‘research use only.’’ In short, there is 

nothing inherent in the nature or design 

of laboratory developed test systems 

that would justify exclusion from FDA’s 

jurisdiction. 

That is not to say that laboratories and 

conventional IVD manufacturers are 

identical. Laboratories do occupy a 

distinct role in diagnostic testing 

because they are the entities that 

generally perform the tests. Like many 

devices, such as a magnetic resonance 

imaging unit used by a trained 

technician, test systems are usually used 

by trained professionals. Laboratories 

that are certified under CLIA and that 

meet the regulatory requirements under 

CLIA to perform high complexity testing 

employ trained laboratorians to ‘‘run’’ 

test systems, and CLIA is the statutory 

scheme that governs that work, as 

discussed in more detail in section III.B. 

However, a laboratory’s role in 

performing test systems does not change 

its obligations under the FD&C Act 

when it is manufacturing test systems. 

As previously noted, the FD&C Act does 

not exclude medical professionals who 

manufacture devices from its scope, and 

the mere fact that a device is 

manufactured in connection with a 


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medical service or procedure does not 

eliminate FDA’s jurisdiction. (See 

United States v. Regenerative Sciences, 

741 F.3d at 1319 (‘‘Notwithstanding 

appellants’ attempt to characterize this 

case as an effort by the FDA to ‘restrict[ ] 

the use of an autologous stem cell 

procedure,’ the focus of the FDA’s 

regulation is on the Mixture [that is, the 

product that is created in connection 

with the procedure].’’).) 

Although some commentators have 

argued that laboratory manufacturing is 

immune from regulation because it is 

within the ‘‘practice of medicine,’’ that 

argument misconstrues the scope of the 

FD&C Act’s ‘‘practice of medicine’’ 

provision. Section 1006 of the FD&C Act 

(21 U.S.C. 396) provides: ‘‘Nothing in 

this [Act] shall be construed to limit or 

interfere with the authority of a health 

care practitioner to prescribe or 

administer any legally marketed device 

to a patient for any condition or disease 

within a legitimate health care 

practitioner-patient relationship.’’ 

Section 1006 carves out a specific zone 

of protected conduct that does not reach 

laboratory manufacturing of test 

systems. The purpose of the provision is 

to ‘‘ensure[ ] that once the FDA permits 

a device to be marketed for one use, 

health care practitioners have the 

flexibility to draw on their expertise to 

prescribe or administer the device’’ for 

other uses. (Judge Rotenberg Educ. Ctr., 

Inc. v. United States, 3 F.4th at 395 

(emphases added); see also Conf. Rep. 

105–399 at 97 (November 9, 1997) 

(provision intended to cover ‘‘off-label 

use of a medical device by a physician 

using his or her best medical judgment 

in determining how and when to use the 

medical product for the care of a 

particular patient’’).) The statutory 

provision applies only in the context of 

use of a ‘‘legally marketed device’’—that 

is, a device that is already manufactured 

and lawfully on the market—and only 

applies to ‘‘prescrib[ing] or 

administer[ing] . . . within a legitimate 

health care practitioner-patient 

relationship.’’ It does not apply to the 

manufacture of new test systems. The 

manufacture of a new device falls 

squarely within FDA’s realm. Cf. United 

States v. Regenerative Sciences, 741 

F.3d at 1320 (‘‘[W]hile the [FD&C Act] 

was not intended to regulate the 

practice of medicine, it was obviously 

intended to control the availability of 

drugs for prescribing by physicians.’’) 

(quoting United States v. Evers, 643 

F.2d 1043, 1048 (1981)). The fact that 

healthcare practitioners may prescribe a 

device, such as a test system, in the 

context of a healthcare practitionerpatient relationship does not mean that 

entities manufacturing that device can 

escape regulation. If that were the case, 

few devices would be regulated, because 

most are intended for use by healthcare 

practitioners in the context of a 

healthcare practitioner-patient 

relationship. 

Furthermore, contrary to what some 

commentators have suggested, CLIA did 

not repeal FDA’s authority over IVDs 

manufactured by laboratories, which 

dates back to at least 1938. CLIA does 

not expressly repeal FDA’s authority, 

nor was FDA’s authority repealed by 

implication. ‘‘An implied repeal will 

only be found where provisions in two 

statutes are in irreconcilable conflict, or 

where the latter Act covers the whole 

subject of the earlier one and is clearly 

intended as a substitute.’’ (Branch v. 

Smith, 538 U.S. 254, 273 (2003) 

(cleaned up).) Here, as CMS itself has 

explained, ‘‘the regulatory schemes of 

the two agencies are different in focus, 

scope and purpose’’ and ‘‘are intended 

to be complementary’’ (Ref. 40). As 

explained in section III.B, CLIA puts a 

focus on the proficiency with which 

laboratories perform clinical testing, and 

the FD&C Act puts a focus on the 

manufacturing of test systems. CMS and 

FDA have different areas of expertise, 

and CLIA does not address a wide range 

of activities regulated under the FD&C 

Act, such as clinical validation and 

design activities. Thus, ‘‘CLIA does not 

preempt the FDA’s authority to regulate 

facilities like [Clinical Reference 

Laboratory]. When two statutes are 

‘capable of co-existence, it is the duty of 

the courts, absent a clearly expressed 

congressional intent to the contrary, to 

regard each as effective.’ ’’ (Clinical 

Reference Lab. v. Sullivan, 791 F. Supp. 

1499, 1509 (D. Kan. 1992) (quoting 

Ruckelshaus v. Monsanto Co., 467 U.S. 

986, 1018, (1984)), aff’d in part and 

rev’d in part on other grounds sub nom., 

United States v. Undetermined No. of 

Unlabeled Cases, 21 F.3d 1026 (10th 

Cir. 1994).) 

In fact, Congress has affirmed that test 

systems manufactured by laboratories 

are devices under the FD&C Act. In the 

Protecting Access to Medicare Act of 

2014 (PAMA) (Pub. L. 113–93), 

Congress listed 510(k) clearance or 

premarket approval under the FD&C Act 

as one of several bases for Medicare 

payment for an ‘‘advanced diagnostic 

laboratory test,’’ which is defined in 

part as a clinical diagnostic laboratory 

test ‘‘that is offered and furnished only 

by a single laboratory and not sold for 

use by a laboratory other than the 

original developing laboratory (or a 

successor owner)’’ (section 216(a) of 

PAMA). If such laboratory tests were not 

devices, the 510(k) clearance and 

premarket approval provisions would 

not apply to them and the inclusion of 

such provisions would be pointless and 

ineffectual. In addition, Congress 

indicated that clinical laboratory tests 

are devices in 2016 amendments to the 

FD&C Act. (21 U.S.C. 360j(o)(1)(D) 

(repeatedly referring to ‘‘clinical 

laboratory test or other device data’’) 

(emphasis added).) 

The FD&C Act confers jurisdiction on 

FDA to regulate test systems, a point 

that has been codified in FDA’s 

regulations for more than half a century. 

And nothing in the text, history, or 

purpose of the statute suggests that test 

systems manufactured by laboratories 

are excluded from that jurisdiction. This 

interpretation is not only the most 

straightforward reading of the statute, it 

is also the most reasonable: any other 

interpretation would create a bifurcated 

scheme in which systems that are 

functionally identical are treated 

differently under the law. 

3. FDA’s Jurisdiction Over IVDs 

Manufactured by Laboratories Is Not 

Altered by the FD&C Act’s Provisions 

Related to Interstate Commerce and 

Commercial Distribution 

Modern Commerce Clause 

jurisprudence holds that Congress has 

‘‘authority to regulate even purely local 

activities that are part of an economic 

‘class of activities’ that have a 

substantial effect on interstate 

commerce.’’ (United States v. 

Regenerative Sciences, 741 F.3d at 1320 

(quoting Gonzales v. Raich, 545 U.S. 1, 

17 (2005)).) Thus, few have disputed 

that Congress possesses the power to 

grant FDA authority to regulate even 

purely intrastate activities. However, 

some commentators have asserted that 

language in the FD&C Act referencing 

‘‘interstate commerce’’ and ‘‘commercial 

distribution’’ precludes FDA from 

regulating IVDs that are designed, 

manufactured, and used in a single 

laboratory. As discussed below, these 

assertions lack merit. 

a. Interstate commerce. There is no 

overarching requirement in the FD&C 

Act that FDA-regulated articles have a 

particular nexus with interstate 

commerce. Interstate commerce is not a 

prerequisite to FDA jurisdiction (beyond 

the constitutional minimum). Rather, 

under the FD&C Act, a limited number 

of provisions include specific interstate 

commerce ‘‘elements,’’ and thus require 

a particular connection with interstate 

commerce in order for those provisions 

to apply. For example, certain of the 

FD&C Act’s ‘‘prohibited acts’’ contain an 

interstate commerce element that must 

be satisfied before the government can 

bring an enforcement action under those 


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provisions (e.g., 21 U.S.C. 331(a), (c), 

(d), and (k)). But relatively few of the 

FD&C Act’s device provisions include a 

specific interstate commerce element, 

and most of the device-related 

prohibited acts do not. (See, e.g., 21 

U.S.C. 331(e) (prohibiting the failure to 

establish or maintain any record, or 

make any report, required under the 

device adverse-event reporting 

requirements without reference to 

interstate commerce); id. 331(p) 

(prohibiting the failure to register a 

device establishment without reference 

to interstate commerce); id. 331(q)(1) 

(prohibiting the failure to comply with 

device investigational-use requirements 

without reference to interstate 

commerce); id. 331(fff)(3) (prohibiting 

the doing of any act which causes a 

device to be a counterfeit device, or the 

sale or dispensing, or holding for sale or 

dispensing, of a counterfeit device 

without reference to interstate 

commerce); see generally United States 

v. Walsh, 331 U.S. 432, 434–36 (1947) 

(finding no interstate commerce element 

to 21 U.S.C. 331(h), which prohibits 

false guaranties) (‘‘[21 U.S.C. 331(a)] is 

directed to illegal interstate shipments, 

while [21 U.S.C. 331(h)] is directed to 

the giving of false guaranties’’).) If an 

FD&C Act provision does not contain an 

interstate commerce element, ‘‘interstate 

commerce’’ imposes no limit on FDA’s 

powers beyond the constitutional 

minimum. For devices, the FD&C Act 

imposes obligations even where there is 

no interstate commerce element and 

likewise gives FDA authority to take 

action when there is a violation of those 

obligations. Thus, FDA does not, for 

example, somehow lose jurisdiction if a 

particular device has not been 

‘‘introduced’’ into interstate commerce. 

In fact, Congress intentionally revised 

a provision of the FD&C Act to ensure 

that FDA could take action against 

devices without satisfying any 

particular interstate commerce element. 

In the MDA, Congress revised the 

seizure provisions in section 304 of the 

FD&C Act to ‘‘permit seizure of devices 

without reference to interstate 

commerce’’ because the previous 

interstate commerce requirement ‘‘ha[d] 

been a burden to the effective 

enforcement of existing authorities’’ and 

‘‘whether or not a medical device 

actually crosses state lines has nothing 

to do with the principal intent of this 

proposal: to assure the safety and 

effectiveness of medical devices.’’ (H.R. 

Rep. 94–853 at 15; see 21 U.S.C. 

334(a)(2).) In other words, Congress 

recognized that the interstate commerce 

element in this provision did not 

advance the goals of the MDA. 

Consistent with that view, the FD&C Act 

grants FDA wide-ranging authority over 

devices, including IVDs, and that 

general authority does not turn on a 

connection with interstate commerce 

above the constitutional minimum. 

In addition, one of the key prohibited 

acts on which FDA relies, section 301(k) 

of the FD&C Act (21 U.S.C. 331(k)), 

contains an interstate commerce 

element, but applies even when a 

problematic device has not been 

introduced in interstate commerce. That 

provision prohibits ‘‘the doing of any 

. . . act with respect to[ ] a . . . device 

. . . if such act is done while such 

article is held for sale (whether or not 

the first sale) after shipment in interstate 

commerce and results in such article 

being adulterated or misbranded.’’ 

Courts have held that even if a product 

is wholly manufactured and sold 

intrastate, the interstate commerce 

element is satisfied if the components 

used in manufacturing the product have 

traveled in interstate commerce. (See 

United States v. Regenerative Sciences, 

741 F.3d at 1320–21 (upholding FDA 

enforcement action under 331(k) 

because a drug component had traveled 

in interstate commerce); Baker v. United 

States, 932 F.2d 813, 815 (9th Cir. 1991); 

United States v. Dianovin Pharm., Inc., 

475 F.2d 100, 102 (1st Cir. 1973).) At 

least some components of test systems, 

such as general purpose reagents, ASRs, 

instruments, and collection devices, are 

usually shipped in interstate commerce 

even if the system itself is designed, 

manufactured, and used solely in the 

laboratory (i.e., intrastate). And section 

709 of the FD&C Act (21 U.S.C. 379a) 

establishes a presumption of interstate 

commerce in enforcement actions, 

meaning that the burden is on regulated 

parties to demonstrate, for example, that 

no component of a system traveled 

across State lines. (‘‘In any action to 

enforce the requirements of this Act 

respecting a device . . . the connection 

with interstate commerce . . . shall be 

presumed to exist.’’). 

Some commentators have cited the 

interstate commerce element in section 

510(k) of the FD&C Act to raise 

questions about FDA’s authority over 

LDTs. Section 510(k) provides that a 

person who is required to register and 

‘‘proposes to begin the introduction or 

delivery for introduction into interstate 

commerce’’ of a device ‘‘shall’’ submit a 

premarket notification. Under this line 

of argument, laboratories that design, 

manufacture, and use an IVD in a single 

laboratory are not proposing to 

introduce their IVD into interstate 

commerce, and therefore section 510(k) 

does not apply to them. That argument, 

however, does not lead to the 

conclusion that FDA lacks jurisdiction 

over LDTs or that none of the FD&C Act 

requirements apply to LDTs. It would 

mean only that section 510(k) does not 

apply. And if accepted, the only 

practical consequence of that assertion 

would be that affected laboratories are 

subject to more burdensome 

requirements under the FD&C Act. 

In particular, if section 510(k) is 

construed to mean that such IVDs are 

not eligible for the premarket 

notification pathway, that would only 

mean that those IVDs (unless they are 

510(k)-exempt, in which case section 

510(k) would not apply anyway, or are 

for investigational use) would be forced 

into the more rigorous review pathways 

of premarket approval or authorization 

through the De Novo pathway. That is 

because under section 513(f)(l) of the 

FD&C Act, a postamendments device, 

i.e., a device that was ‘‘not introduced 

or delivered for introduction into 

interstate commerce for commercial 

distribution before [May 28, 1976],’’ is a 

class III device by operation of law (21 

U.S.C. 360c(f)(1)). If such a device 

cannot be found to be substantially 

equivalent through the premarket 

notification pathway, it must either 

have an approved PMA (21 U.S.C. 

360e(a)), or be reclassified and gain 

authorization through a pathway such 

as the De Novo process (21 U.S.C. 

360c(f)(2)(A)(ii)). Thus, under this 

theory, laboratories would not escape 

FDA regulation—they would face 

heavier regulation. However, because 

section 510(k) does not, in fact, preclude 

regulated entities from submitting 

premarket notifications even assuming 

their devices are not introduced into 

interstate commerce, and because 

laboratories have every incentive to take 

the less burdensome path to market of 

510(k) notification, the 510(k) pathway 

should play the same role in device 

reclassification (21 U.S.C. 360c(f)) for 

IVDs offered as LDTs as for any other 

device. Regardless, the inclusion of an 

interstate commerce element in section 

510(k) in no way affects FDA’s overall 

authority to regulate IVDs manufactured 

by laboratories. 

b. Commercial distribution. The 

phrase ‘‘for commercial distribution’’ 

also appears in various device 

provisions of the FD&C Act, and some 

commentators have asserted that this 

phrase, too, signals that FDA lacks 

authority over LDTs. For example, they 

point to the 510(k) premarket 

notification requirement, which is 

triggered when a person who is required 

to register ‘‘proposes to begin the 

introduction or delivery for introduction 

into interstate commerce for commercial 

distribution of a device intended for 


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15Other laboratories would be out of compliance 

with CLIA regulations if they were developing and 

performing tests that are not FDA authorized. Such 

tests have never fallen within FDA’s general 

enforcement discretion approach (see, e.g., Refs. 32, 

40, and 54). 

16As discussed elsewhere in this preamble, FDA 

has generally considered the term ‘‘laboratory 

developed test (LDT)’’ to mean an IVD that is 

intended for clinical use and that is designed, 

manufactured, and used within a single CLIAcertified laboratory that meets the regulatory 

requirements under CLIA to perform high 

complexity testing. 

human use’’ (21 U.S.C. 360(k)). As with 

‘‘interstate commerce,’’ the presence of 

this phrase in that provision and certain 

other specific device provisions does 

not bear on the Agency’s overall 

jurisdiction. Furthermore, LDTs are for 

commercial distribution, so the 

presence of the phrase does not change 

the operation of those provisions with 

respect to these IVDs. 

Under our longstanding, judicially 

endorsed interpretation, ‘‘commercial 

distribution’’ does not require the 

physical transfer of an object, as some 

commentators have argued. Instead, the 

legislative history, FDA’s nearcontemporaneous regulation, and at 

least one judicial decision reflect that 

the phrase ‘‘commercial distribution’’ 

means ‘‘on the market.’’ A House Report 

issued 3 months before enactment of the 

MDA contains an unusually clear 

statement of the intended meaning of 

the phrase: ‘‘‘Commercial distribution’ 

is the functional equivalent of the 

popular phrase ‘on the market.’ ’’ (H.R. 

Rep. No. 94–853 at 36) FDA’s 

regulations implementing the 

registration, listing, and 510(k) 

provisions, which were finalized in 

1977 (soon after enactment of the MDA), 

similarly define commercial distribution 

as ‘‘any distribution of a device 

intended for human use which is held 

or offered for sale.’’ (21 CFR 807.3(b)) In 

the preambles to the proposed and final 

rule, FDA equated the term with the 

phrase ‘‘on the market’’ (41 FR 37458 at 

37459 (September 3, 1976); 42 FR 42520 

at 42524 (August 23, 1977)). A court has 

also endorsed this interpretation of the 

term (United States v. An Article of 

Device Consisting of 1,217 Cardboard 

Boxes, 607 F. Supp. 990, 994–95 (W.D. 

Mich. 1985) (giving deference to FDA’s 

reasonable interpretation of 

‘‘commercial distribution’’ to mean, ‘‘in 

its popular sense, ‘on the market’ ’’)). 

These sources show that the term does 

not relate to physical movement, and 

because IVDs manufactured by 

laboratories (including LDTs) generally 

are ‘‘on the market,’’ they are for 

commercial distribution. 

VI. Description of the Proposed 

Enforcement Policy 

Based on the considerations set forth 

in this preamble, FDA is proposing to 

end the general enforcement discretion 

approach for LDTs. However, FDA also 

recognizes that many IVDs 

manufactured by laboratories are 

currently being marketed as LDTs, and 

that a sudden change could negatively 

affect the public, including patients and 

industry. In particular, FDA 

understands that the healthcare 

community and patients have been 

using these IVDs, and that coming into 

compliance will take time for 

manufacturers. FDA also recognizes that 

we should consider Agency resources. 

For additional information regarding the 

estimated costs associated with this 

rulemaking, see the Preliminary 

Economic Analysis of Impacts (Ref. 34). 

To achieve greater oversight in a 

manner that accounts for the various 

considerations, FDA is proposing to 

gradually end its general enforcement 

discretion approach in stages, as 

described below (hereinafter ‘‘the 

phaseout policy’’). FDA’s intent is that, 

following a 4-year phaseout period, 

IVDs offered as LDTs generally would 

be expected to meet applicable 

requirements. 

Although FDA is proposing to 

gradually end its current general 

enforcement discretion approach over a 

period of years, the phaseout policy 

does not in any way alter the fact that 

it is illegal to offer IVDs without 

complying with applicable 

requirements. Regardless of the 

phaseout timeline and continued 

enforcement discretion approach for 

certain IVDs discussed below, FDA 

retains discretion to pursue enforcement 

action at any time against violative IVDs 

when appropriate. 

Moreover, FDA has adopted and 

intends to continue adopting 

enforcement discretion policies for 

certain types of IVDs in certain 

circumstances, as appropriate. For 

example, FDA issued guidance 

documents with enforcement discretion 

policies for certain COVID–19 and 

Mpox tests at the beginning of each 

declared emergency (as described 

further below), and intends to issue a 

draft guidance with an enforcement 

policy for IVDs for emerging outbreaks 

offered prior to FDA review to address 

the immediate public health need. FDA 

will seek public comment on such draft 

guidance in accordance with good 

guidance practices (see 21 CFR 10.115). 

With this notice of proposed 

rulemaking, FDA seeks public comment 

on whether specific enforcement 

discretion policies would be appropriate 

for IVDs offered as LDTs for other public 

health scenarios. If so, please provide a 

description of those scenarios, an 

explanation of why enforcement 

discretion policies with respect to those 

scenarios would be appropriate, and any 

relevant evidence to support such 

policies. FDA would also appreciate 

public comment on what, if any, 

unintended consequences may result 

from the proposed phaseout policy to 

certain patient populations (for 

example, Medicare beneficiaries, rural 

populations, etc.) and what steps could 

be taken to mitigate those consequences. 

FDA’s proposed phaseout policy, 

including the scope and phaseout 

timeline, is set forth below. 

A. Scope 

While FDA’s general enforcement 

discretion approach has been focused 

on LDTs, FDA is proposing a broader 

scope for the phaseout policy. 

Specifically, FDA is proposing to apply 

the phaseout policy to IVDs that are 

manufactured and offered as LDTs by 

laboratories that are certified under 

CLIA and that meet the regulatory 

requirements under CLIA to perform 

high complexity testing,15 even if those 

IVDs do not fall within FDA’s 

traditional understanding of an LDT 

because they are not designed, 

manufactured, and used within a single 

laboratory.16 Throughout this preamble, 

these IVDs are referred to as ‘‘IVDs 

offered as LDTs.’’ FDA is proposing this 

scope because it recognizes that not all 

laboratories have understood the limited 

nature of FDA’s general enforcement 

discretion approach and have been 

offering IVDs based on the approach 

even when they do not fit what FDA 

generally considers to be an LDT. As 

previously discussed, FDA has made a 

preliminary determination to structure 

the phaseout in a way that avoids undue 

disruption to the testing market. This is 

important even for certain IVDs 

currently on the market that do not fall 

within the scope of FDA’s general 

enforcement discretion approach. 

Although FDA is proposing this 

broader scope for the phaseout policy, it 

does not intend to sweep in certain tests 

that were excluded from the general 

enforcement discretion approach, as 

reflected in compliance patterns, 

multiple public FDA actions and 

communications, or both. These tests 

are: 

1. Tests that are intended as blood 

donor screening or human cells, tissues, 

and cellular and tissue-based products 

(HCT/Ps) donor screening tests required 

for infectious disease testing under 21 

CFR 610.40 and 1271.80(c), 

respectively, or for determination of 


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blood group and Rh factors required 

under 21 CFR 640.5. Under the cited 

regulations, a blood or HCT/P 

establishment must not use a test for the 

purposes listed here unless the test is 

licensed, approved, or cleared by FDA 

for such use. Blood and HCT/P 

establishments must register with FDA 

and are subject to FDA inspection (see 

21 CFR parts 207, 607, 807 and 1271). 

FDA’s general enforcement discretion 

approach for LDTs has never applied to 

these tests because these tests are a 

critical part of the overall process of 

ensuring the safety of blood and blood 

components and HCT/Ps by preventing 

infectious disease transmission and 

incompatible blood transfusions which 

can have life-threatening consequences. 

Based on FDA experience, 

establishments have been generally 

complying with these requirements (see, 

e.g., Refs. 66 and 67). 

2. Tests intended for emergencies, 

potential emergencies, or material 

threats declared under section 564 of 

the FD&C Act. After all previous 

declarations under section 564(b), FDA 

has generally expected LDTs to comply 

with applicable requirements in the 

FD&C Act and FDA regulations. FDA’s 

general enforcement discretion 

approach has not applied to these tests 

because of the significant risk posed by 

the disease (as signified by the unusual 

step of issuing a declaration) and 

because false results can have serious 

implications for disease progression and 

public health decision-making, in 

addition to the individual patient’s care. 

As it has done in other areas, FDA has 

adopted (and may continue to adopt) 

specific enforcement discretion policies 

for such tests (see, e.g., Refs. 51 and 52). 

In addition, consistent with the 

Government Accountability Office’s 

2022 recommendation that ‘‘FDA 

should develop a policy for the use of 

enforcement discretion regarding 

unauthorized tests in future public 

health emergencies,’’ FDA intends to 

issue guidance on factors to consider in 

adopting such enforcement discretion 

policies (Ref. 68). FDA has 

communicated its expectations 

regarding tests for emergency use in 

guidance and elsewhere, including ‘‘It 

has come to our attention’’ letters posted 

on FDA’s website and other public 

communications (see, e.g., Refs. 51 to 

54, 69, and 70). 

3. Direct-to-consumer tests. FDA’s 

general enforcement discretion 

approach has not applied to tests 

intended for consumer use (without 

meaningful involvement by a licensed 

healthcare professional), given the 

greater risks to patients presented by 

these tests (see, e.g., Refs. 48, 55, and 71 

to 75). FDA’s enforcement discretion 

approach for LDTs was originally 

premised, in part, on the participation 

of medical professionals to help 

determine whether a particular test was 

appropriate, counsel patients on the 

significance and limitations of a test, 

assist in interpreting results, assess how 

the results fit in the overall clinical 

picture, and consider next steps. When 

patients order tests, receive results, and 

make decisions (such as a decision to 

stop medication) without this expert 

intermediary, there is a heightened need 

for FDA oversight. 

For these categories of tests, FDA has 

generally expected applicable 

requirements to be met, and we are not 

proposing to change that approach. 

FDA notes that the manufacturing of 

test components outside of a 

laboratory—for example, when the same 

entity owns both the laboratory and a 

manufacturing facility separate from the 

laboratory—does not fall within FDA’s 

general enforcement discretion 

approach. FDA’s approach has long 

been specific to laboratory development 

(e.g., 61 FR 10484 (‘‘in-house developed 

tests have not been actively regulated by 

the Agency’’) (emphasis added); Ref. 48 

(describing an LDT as an IVD that is 

‘‘designed, manufactured, and used 

within a single laboratory’’). The 

proposed phaseout policy would not 

change FDA’s longstanding expectation 

that IVD manufacturing activities 

occurring outside of a CLIA-certified 

laboratory comply with applicable 

device requirements. 

In addition, for certain categories of 

tests manufactured by laboratories, FDA 

is proposing to continue to apply the 

current general enforcement discretion 

approach going forward. One such 

category of tests is referred to in this 

preamble as ‘‘1976-Type LDTs.’’ Such 

tests have the following characteristics 

common among LDTs offered in 1976: 

use of manual techniques (without 

automation) performed by laboratory 

personnel with specialized expertise; 

use of components legally marketed for 

clinical use; and design, manufacture, 

and use within a single CLIA-certified 

laboratory that meets the requirements 

under CLIA for high complexity testing. 

The characteristics associated with 

LDTs offered in 1976 resulted in the 

emergence of FDA’s general 

enforcement discretion approach for 

LDTs, and the specific characteristics 

listed above provide the greatest risk 

mitigation among the characteristics 

that were commonly associated with 

LDTs offered in 1976 (discussed in 

section III.A). Based on changes to the 

LDT landscape since 1976, the risks 

associated with most modern LDTs are 

generally much greater today than they 

were in 1976; however, for tests that 

share the characteristics listed above, 

FDA has made a preliminary 

determination that the risks are 

sufficiently mitigated such that FDA’s 

general enforcement discretion 

approach for LDTs should continue to 

apply. These tests might include, for 

example, immunohistochemistry tests 

that involve no automated preparation 

or interpretation, but would not include, 

for example, lateral flow tests, as they 

do not generally rely on laboratory 

personnel expertise. 

FDA is also proposing to continue to 

apply the general enforcement 

discretion approach to Human 

Leukocyte Antigen (HLA) tests that are 

designed, manufactured, and used in a 

single laboratory certified under CLIA 

that meets the requirements to perform 

high-complexity histocompatibility 

testing when used in connection with 

organ, stem cell, and tissue 

transplantation to perform HLA allele 

typing, for HLA antibody screening and 

monitoring, or for conducting real and 

‘‘virtual’’ HLA crossmatch tests. FDA 

has made a preliminary determination 

that HLA LDTs for transplantation used 

in histocompatibility laboratories that 

meet the regulatory requirements under 

CLIA to perform high complexity 

testing, when used in connection with 

organ, stem cell, and tissue 

transplantation for certain purposes as 

described in this paragraph, are unique 

in that they are generally developed, 

and the testing is generally performed, 

in urgent, life-saving situations for the 

patient. Physicians must often make 

prompt decisions about transplantation 

based on medical judgment regarding 

their patient’s condition and degree of 

mismatch between the donor and 

patient should an organ, stem cells, or 

tissue become available. Further, these 

tests are often individualized within 

each medical facility, for example, they 

include reagents that reflect local HLA 

polymorphisms and patient 

demographics. Note that the general 

enforcement discretion approach does 

not apply to HLA tests used for blood 

transfusion as such tests are highly 

standardized across institutions; FDA 

intends to continue to enforce 

applicable requirements for HLA tests 

used for blood transfusion. 

FDA also intends to maintain its 

longstanding enforcement discretion 

approach for tests intended solely for 

forensic (law enforcement) purposes. 

This approach has been in place for over 

20 years and applies to such tests 

regardless of whether they are offered as 

an LDT. See, e.g., 65 FR 18230 (April 7, 

2000). Tests used in the law 


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enforcement setting are subject to 

protections and requirements associated 

with the judicial process that mitigate 

risk related to test accuracy and sample 

collection and that generally are not 

available in the home, workplace, 

insurance, and sports settings. These 

protections include the use of rules of 

evidence in judicial proceedings and 

legal representation of the accused (i.e., 

the person being tested) through the 

judicial process during which the 

accuracy of the test may be raised 

during the adjudication. We seek 

comment on any implications of 

continued enforcement discretion with 

regard to LDTs used for law 

enforcement purposes and any factors 

that FDA should consider—particularly 

as it relates to civil rights and equity— 

related to the scientific validity and 

accuracy of these tests. 

In addition, tests exclusively used for 

public health surveillance are distinct 

from other tests where: (1) they are 

intended solely for use on 

systematically collected samples for 

analysis and interpretation of health 

data in connection with disease 

prevention and control, and (2) test 

results are not reported to patients or 

their healthcare providers. These tests 

would not be affected by the phaseout 

policy. The results of these tests are 

generally used for trending on a 

population basis. Public health 

authorities also have access to test 

results from non-surveillance tests that 

are FDA approved, cleared, or 

authorized and that are reported under 

State reporting laws for infectious and 

other diseases. In addition, during a 

public health emergency, if there was a 

564 declaration (as there was for past 

public health emergencies), FDA could 

require test result reporting to public 

health authorities under emergency use 

authorizations, as appropriate. 

In 2017, FDA indicated support for 

less oversight of other categories of tests, 

such as low-risk tests (class I devices), 

tests currently on the market, and tests 

for rare diseases. However, FDA has 

accumulated information in the 

intervening years that suggests we 

should treat these categories of tests 

similarly to other FDA-regulated tests. 

For example, as discussed above in 

section III.B, FDA has gained additional 

information showing that there is a high 

variability in the performance of IVDs 

offered as LDTs that are currently on the 

market, including in circumstances 

where the test technology is relatively 

simple and well-understood, where the 

tests are for rare diseases, and where the 

tests are low risk. Among other things, 

FDA’s recent experience with tests for 

COVID–19 suggests that many tests 

manufactured by laboratories are not 

appropriately validated. Compliance 

with premarket review requirements 

(when applicable), QS requirements, 

and registration and listing 

requirements would help assure that 

these IVDs work as intended, enable 

FDA to keep track of IVDs offered as 

LDTs (and, for example, help FDA 

locate IVDs that are raising concerns or 

independently evaluate the risk status of 

marketed IVDs), assist with FDA’s 

inspection and planning efforts, and 

make information available to patients 

and healthcare providers that may 

inform the selection of particular IVDs 

for use. Therefore, FDA is now 

proposing to end the general 

enforcement discretion approach, via a 

phaseout approach, with respect to 

premarket review requirements (as 

applicable), QS requirements, and 

registration and listing requirements for 

these tests, in addition to medical 

device reporting (MDR) requirements 

(i.e., reporting of adverse events), 

correction and removal reporting 

requirements, and other requirements 

applicable to such tests. Based on the 

information available at this time, FDA 

has made a preliminary determination 

that this proposal appropriately 

balances the relevant considerations 

with respect to these tests, including 

currently marketed IVDs offered as 

LDTs. 

However, FDA expects that some 

stakeholders will suggest that FDA 

continue to maintain the current general 

enforcement discretion approach with 

respect to premarket review and some or 

all QS requirements for currently 

marketed LDTs or a subset of currently 

marketed LDTs (i.e., what some 

previously referred to as 

‘‘grandfathering’’). To the extent 

commenters suggest such an approach 

for FDA’s consideration, FDA requests 

information to support such an 

approach, including the following: 

• Given the information in the ‘‘Need 

for the Rule’’ section of this preamble in 

particular, what would be the public 

health rationale for generally exercising 

enforcement discretion with respect to 

premarket review and some or all QS 

requirements, for LDTs that are being 

offered as of the date of issuance of this 

proposed rule and are not changed with 

respect to indications for use or 

performance after that date? Please 

provide data to support such an 

approach. Also, if you think there are 

steps that might help support such an 

approach, including ideas that might 

help to address the public health 

concerns discussed in the ‘‘Need for the 

Rule’’ section, please describe them, and 

include a rationale and any supporting 

evidence. 

• If commenters suggest maintaining 

the general enforcement discretion 

approach with respect to premarket 

review and QS requirements for a subset 

of LDTs (e.g., low and moderate risk 

LDTs) currently on the market that are 

being offered as of the date of issuance 

of this proposed rule and are not 

changed with respect to indications for 

use or performance after that date, what 

would be the public health rationale to 

support such an approach? Please 

provide any data supporting such an 

approach. Also, if you think there are 

steps that might help support such an 

approach, including ideas that might 

help to address the public health 

concerns discussed in the ‘‘Need for the 

Rule’’ section, please describe them and 

include a rationale and any supporting 

evidence. 

FDA recognizes that the phaseout of 

the general enforcement discretion 

approach described in this section may 

have a relatively greater impact on small 

laboratories. Therefore, FDA seeks 

comment on the following: 

• Is there a public health rationale to 

have a longer phaseout period for IVDs 

offered as LDTs by laboratories with 

annual receipts below a certain 

threshold (e.g., $150,000) (see Table 43 

in the Preliminary Economic Analysis of 

Impacts (Ref. 34))? If so, please provide 

relevant data and comment specifically 

on an alternative recommended 

timeline. 

In addition, FDA is aware that some 

AMCs have claimed that their 

laboratories operate under unique 

circumstances (such as being integrated 

into direct patient care) and therefore 

their tests should be treated differently 

than tests manufactured by other 

laboratories. Although FDA is not aware 

of an established definition of an AMC 

laboratory, one possible description is: a 

laboratory for which a certificate is in 

effect under CLIA and that meets the 

requirements under CLIA to perform 

tests of high-complexity; that is part of 

an accredited public or nonprofit 

private AMC that has a medical 

residency training program or 

fellowship program related to test 

development, application, and 

interpretation; and that is integrated 

into the direct medical care for a 

patient, including specimen collection, 

testing, interaction with the treating 

provider, and, as appropriate, patient 

treatment based on the test, all at the 

same physical location. FDA seeks 

comments on the following: 

• What are the characteristics of AMC 

laboratories? Do the characteristics 

included above accurately describe 


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AMC laboratories and in fact distinguish 

them from other laboratories? 

• Should FDA continue the general 

enforcement discretion approach with 

respect to any requirements, such as 

premarket review requirements, for tests 

manufactured by AMC laboratories? 

• If FDA should continue the general 

enforcement discretion approach with 

respect to any requirements, such as 

premarket review requirements, for tests 

manufactured by AMC laboratories, are 

there any additional considerations that 

should be taken into account with 

respect to this approach, for example, 

whether an FDA cleared or approved 

test is available for the same intended 

use as the test manufactured by an AMC 

laboratory? Please provide a rationale 

and other information (e.g., data) to 

support any additional considerations. 

• If FDA should have a different 

policy for AMC laboratories, what 

would be the public health rationale to 

support such a policy? For example, if 

integration of an AMC laboratory into 

direct patient care is included as a basis 

for a different policy, please include a 

public health rationale when explaining 

why and how such integration supports 

the different policy, and how integration 

could ensure that there is a reasonable 

assurance of IVD safety and 

effectiveness. 

• If FDA should have a different 

policy for AMC laboratories, is there 

evidence to support such a policy? 

FDA also is interested in and seeks 

comment on leveraging programs such 

as the New York State Department of 

Health Clinical Laboratory Evaluation 

Program (NYSDOH CLEP) or those 

within the Veterans Health 

Administration (VHA), as appropriate. 

In particular, FDA requests comment on 

whether it may be appropriate to 

continue the general enforcement 

discretion approach, such that FDA 

generally would not enforce any 

applicable device requirements, where 

outside programs can be leveraged. If 

FDA should continue to exercise 

enforcement discretion under these 

circumstances: 

• What specific characteristics of and 

activities within these programs justify 

such an approach? 

• Should the scope of such a policy 

be more limited for each program in 

question? For example, should FDA 

continue enforcement discretion for 

premarket review requirements and 

intend to enforce other requirements, 

such as reporting adverse events? 

• Are there any additional 

considerations that should be taken into 

account? 

Please provide a rationale and other 

information (e.g., data) to support any 

suggestions. 

B. Stages 

As previously discussed, FDA is 

proposing to gradually phase out its 

current general enforcement discretion 

approach so that most IVDs offered as 

LDTs would generally fall under the 

same enforcement approach as other 

IVDs. In developing the proposed 

phaseout policy, FDA has considered a 

number of factors, including the public 

health importance of better assuring the 

safety and effectiveness of IVDs offered 

as LDTs, the desire to avoid undue 

disruption to the testing market, the 

time it may take for laboratories to come 

into compliance with FDA 

requirements, the need for adequate 

resources to implement the phaseout 

policy in a manner that does not 

undermine reasonable expectations with 

regards to premarket review timing (per 

the Medical Device User Fee 

Amendments (MDUFA) V agreement), 

and the benefits of a relatively simple 

policy that can be easily understood and 

implemented. Keeping these factors in 

mind, FDA has structured the phaseout 

policy to contain five key stages: 

• Stage 1: End the general 

enforcement discretion approach with 

respect to MDR requirements and 

correction and removal reporting 

requirements 1 year after FDA publishes 

a final phaseout policy, which FDA 

intends to issue in the preamble of the 

final rule. 

• Stage 2: End the general 

enforcement discretion approach with 

respect to requirements other than MDR, 

correction and removal reporting, QS, 

and premarket review requirements 2 

years after FDA publishes a final 

phaseout policy. 

• Stage 3: End the general 

enforcement discretion approach with 

respect to QS requirements 3 years after 

FDA publishes a final phaseout policy. 

• Stage 4: End the general 

enforcement discretion approach with 

respect to premarket review 

requirements for high-risk IVDs 31⁄2

years after FDA publishes a final 

phaseout policy, but not before October 

1, 2027. 

• Stage 5: End the general 

enforcement discretion approach with 

respect to premarket review 

requirements for moderate risk and low 

risk IVDs (that require premarket 

submissions) 4 years after FDA 

publishes a final phaseout policy, but 

not before April 1, 2028. 

Each of these stages is discussed in 

further detail below. For each stage, 

FDA is proposing a period of time for 

laboratories to come into compliance 

before FDA intends to end the general 

enforcement discretion approach. FDA 

encourages laboratory manufacturers to 

begin early and work toward 

compliance with requirements sooner 

than the end of the specified 

timeframes. FDA also intends to 

consider providing more targeted 

guidance and/or making additional 

resources available on specific topics, 

such as compliance with applicable 

labeling requirements, over the course 

of the phaseout period. 

1. Stage 1: End the general 

enforcement discretion approach with 

respect to MDR requirements and 

correction and removal reporting 

requirements 1 year after FDA publishes 

a final phaseout policy. 

FDA has structured the phaseout 

policy to obtain information about 

potentially harmful IVDs offered as 

LDTs as soon as feasible. As detailed 

elsewhere in this preamble, FDA is 

concerned that some of the IVDs offered 

as LDTs may be posing risks to patients. 

Therefore, FDA is prioritizing the 

phaseout of the general enforcement 

discretion approach for requirements 

that would help FDA identify and 

monitor significant issues with IVDs 

offered as LDTs, consistent with other 

considerations described in this 

proposed policy. 

Enforcement of the MDR requirements 

under 21 U.S.C. 360i(a) through (c) and 

21 CFR part 803, in particular, would 

enable FDA to systematically monitor 

significant adverse events to identify 

problematic IVDs offered as LDTs, such 

as those with poor performance or other 

safety issues. FDA has made a 

preliminary determination that 

gathering this information is important 

for IVDs that do not have the safeguards 

associated with compliance with other 

FDA requirements, such as 

manufacturing under QS requirements 

or confirmation of analytical and 

clinical validity through premarket 

review. 

For similar reasons, FDA is 

prioritizing the collection of information 

about when a manufacturer has initiated 

a correction or removal of its IVD to 

reduce a risk to health or to remedy a 

violation of the FD&C Act that may 

present a risk to health. Under 21 U.S.C. 

360i(g) and part 806 (21 CFR part 806), 

manufacturers are required to report 

such corrections or removals to FDA, 

and FDA intends to phase out the 

general enforcement discretion 

approach for these requirements at the 

same time it does so for MDR 

requirements. Because FDA intends for 

the phaseout of the general enforcement 

discretion approach with respect to 


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17For example, FDA stated in the ‘‘Framework for 

Regulatory Oversight of Laboratory Developed Tests 

(LDTs)’’ draft guidance that ‘‘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’’ (Ref. 48). 

correction and removal reporting 

requirements to occur before phaseout 

of the general enforcement discretion 

approach with respect to registration 

and listing requirements, FDA intends 

to exercise enforcement discretion, such 

that it generally does not intend to 

enforce, the requirement to use the 

establishment registration number on 

such reports (21 CFR 806.10) when 

laboratories use their CLIA certificate 

number instead prior to registering. 

FDA’s proposal to phase out 

enforcement discretion for MDR 

requirements within 1 year after 

finalization of the policy is informed by 

comments FDA received in response to 

the draft guidance documents that FDA 

issued in 2014 proposing to implement 

an oversight framework for IVDs offered 

as LDTs. In 2014, FDA proposed a 6- 

month timeline for laboratory 

compliance with MDR requirements 

(Ref. 48), and we received comments 

suggesting that a longer period may be 

appropriate for the establishment of a 

system to identify, review, and report 

adverse events. Based in part on those 

comments, FDA is now proposing a 1- 

year time period for laboratories to come 

into compliance with the MDR 

requirements. In conjunction with the 

phaseout of the general enforcement 

discretion approach with respect to the 

MDR requirements, FDA is also 

proposing to end the general 

enforcement discretion approach with 

respect to the requirements of part 806, 

concerning reports of corrections and 

removals. Because MDRs frequently are 

a basis for corrections and removals, 

FDA views these requirements as 

working together to provide information 

to FDA about issues with device 

performance or quality. We anticipate 

that this 1-year time period is adequate, 

particularly given that laboratories 

should already have some processes in 

place for detecting problems with their 

IVDs to comply with CLIA regulations. 

2. Stage 2: End the general 

enforcement discretion approach with 

respect to requirements not covered 

during other stages of the phaseout 

policy 2 years after FDA publishes a 

final phaseout policy. 

FDA is proposing to end the general 

enforcement discretion approach for 

requirements besides MDR, correction 

and removal reporting, QS, and 

premarket review requirements 2 years 

after the final policy is published. These 

other requirements include registration 

and listing requirements under 21 

U.S.C. 360 and part 807 (excluding 

subpart E); labeling requirements under 

21 U.S.C. 352 and parts 801 and 809, 

subpart B; and investigational use 

requirements under 21 U.S.C. 360j(g) 

and part 812. We have included 

compliance with investigational use 

requirements at this stage, in 

recognition that there has been some 

confusion about our enforcement 

approach in this area. Our 

understanding is that laboratories often 

are not complying with investigational 

use requirements currently, even though 

FDA has generally expected compliance 

with these requirements.17 We are 

therefore including these requirements 

in the phaseout policy. 

FDA recognizes that this proposal is 

different from FDA’s prior statements in 

the 2017 Discussion Paper regarding 

oversight of IVDs manufactured by 

laboratories with respect to certain 

requirements, for which the timing of 

FDA’s expectations for compliance 

generally depended on the type of 

premarket review applicable to the 

device. However, upon review, FDA 

anticipates that it would better serve the 

public health and be simpler to phase 

out the general enforcement discretion 

approach for these requirements at the 

2-year mark. For example, under this 

timeline, laboratories could work 

toward compliance with the stage 2 

requirements without necessarily 

determining the risk category of their 

IVDs until later stages of the proposed 

phaseout policy. Another advantage of 

this timeline is that FDA would obtain 

registration and listing information 

before the enforcement discretion 

phaseout date for premarket review 

requirements, which could give the 

Agency an initial understanding of the 

universe of IVDs offered as LDTs to 

facilitate premarket review of those 

IVDs. Based on its experience, FDA 

anticipates that 2 years is adequate time 

to come into compliance with the 

various requirements. 

3. Stage 3: End the general 

enforcement discretion approach with 

respect to QS requirements 3 years after 

FDA publishes a final phaseout policy. 

At the 3-year mark, FDA would 

expect compliance with the device 

CGMP requirements of the QS 

requirements under 21 U.S.C. 360j(f) 

and part 820 (21 CFR part 820). 

However, for IVDs for which all 

manufacturing activities occur within a 

single CLIA-certified laboratory that 

meets the regulatory requirements to 

perform high complexity testing and for 

which distribution of the IVD does not 

occur outside that single laboratory, 

FDA would expect compliance at the 3- 

year mark with some, but not all, of the 

QS requirements. Although FDA and 

CMS regulation are different and 

complementary, compliance with CLIA 

requirements provides some quality 

assurances that may be relevant to 

laboratories’ manufacturing practices. In 

particular, laboratories may in practice 

be able to apply concepts set forth under 

CLIA requirements for laboratory 

operations to manufacturing activities 

regulated by FDA. For FDA to 

effectively leverage the CLIA 

assurances, this proposed approach 

would apply only when all 

manufacturing activities occur within a 

single laboratory and the IVD is not 

distributed outside that laboratory. 

However, even in the context of this 

approach, there are certain QS 

requirements for which CLIA 

regulations do not provide the 

assurances that FDA requirements 

would provide. These requirements 

include design controls under 21 CFR 

820.30; purchasing controls (including 

supplier controls) under 21 CFR 820.50; 

acceptance activities (receiving, inprocess, and finished device 

acceptance) under 21 CFR 820.80 and 

21 CFR 820.86; corrective and 

preventative actions (CAPA) under 21 

CFR 820.100; and records requirements 

under part 820, subpart M. Because 

CLIA does not provide assurances 

relevant to these requirements, FDA is 

proposing to end the general 

enforcement discretion approach for 

these specific requirements for IVDs for 

which all manufacturing activities occur 

within a single CLIA-certified laboratory 

that meets the regulatory requirements 

to perform high complexity testing, and 

which are not distributed outside that 

laboratory, 3 years after finalizing this 

policy. For all other IVDs offered as 

LDTs and subject to this phaseout 

policy, FDA is proposing to end the 

general enforcement discretion 

approach for all QS requirements 3 

years after finalizing this policy. 

Based on its experience, FDA 

anticipates that 3 years is adequate time 

for laboratories to come into compliance 

with QS requirements. In addition, 

based on the discussion above regarding 

concerns with the quality and validation 

of IVDs offered as LDTs, FDA has made 

a preliminary determination that 

phasing out the general enforcement 

discretion approach for QS 

requirements later than 3 years would 

not be in the best interest of the public 

health. Compliance with QS 

requirements is critical to the quality 

and validity of IVDs offered as LDTs. 


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18Under the proposed phaseout policy, 

laboratories that intend to submit an HDE 

application should do so within the same 31⁄2-year 

timeframe provided for submission of PMAs. As in 

the case of PMAs, under FDA’s proposed policy, 

FDA generally would not intend to enforce against 

IVDs after an HDE application has been submitted 

(within the 31⁄2-year timeframe) until FDA 

completes its review of the application. 

For example, under the design controls 

of the QS requirements, laboratories 

would, among other things, generally 

have better procedures for validating the 

design of their tests, which would help 

to ensure that they are analytically and 

clinically valid (see Ref. 76). 

FDA also notes that on February 23, 

2022, FDA proposed to amend the 

device QS regulation, part 820, to align 

more closely with international 

consensus standards for devices (87 FR 

10119). As stated in that proposed rule, 

the requirements, if finalized, would be 

substantially similar to the requirements 

of the current part 820, providing a 

similar level of assurance in a firm’s 

quality management system, and FDA 

intends for this phaseout policy to apply 

with respect to any regulations 

promulgated through that rulemaking. 

FDA intends to finalize amendments 

to the QS regulation expeditiously, such 

that the amended QS requirements 

would be in effect before the proposed 

beginning of stage 3. Upon the start of 

stage 3, or if the laboratory complies 

with QS requirements prior to the start 

of stage 3, FDA would expect 

compliance with the QS requirements 

that are in effect at that time. For further 

information on the QS requirements that 

would be established pursuant to the 

amendments to the QS regulation, if 

finalized as proposed, please refer to the 

proposed codified at 87 FR 10119 at 

10133 and 10134. Notably, the 

requirements relating to design controls, 

purchasing controls, acceptance 

activities, CAPA, and records 

requirements are set forth in the 

following ISO 13485 clauses as 

modified by the proposed codified for 

part 820: Clause 4. Quality Management 

System, Subclause 4.2.5; Clause 6. 

Resource Management; Clause 7. 

Product Realization, Subclause 7.1, 

Subclause 7.3, Subclause 7.4, and 

Subclause 7.4.3; and Clause 8. 

Measurement, Analysis, & 

Improvement, Subclause 8.2.5, 

Subclause 8.2.6, and Subclause 8.3. 

In addition, FDA notes that under 

section 515(d)(2) of the FD&C Act, the 

Agency may not approve a PMA if the 

applicant fails to demonstrate 

conformity with the QS requirements. 

Therefore, compliance with the QS 

requirements is needed to support 

approval of a PMA. As provided in 

section 520(f)(2) of the FD&C Act, any 

person subject to the QS requirements 

may petition for an exemption or 

variance from any QS requirement (see 

also 21 CFR 820.1). 

4. Stage 4: End the general 

enforcement discretion approach with 

respect to premarket review 

requirements for high-risk IVDs 31⁄2

years after FDA publishes a final 

phaseout policy, but not before October 

1, 2027. 

FDA proposes that the phaseout date 

for the general enforcement discretion 

approach with respect to premarket 

review requirements for high-risk IVDs 

offered as LDTs (IVDs that may be 

eligible for classification into class III) 

should occur 31⁄2 years from the time 

that FDA issues a final phaseout policy. 

The premarket review requirements are 

set forth in 21 U.S.C. 360e and 21 CFR 

part 814. FDA is proposing this time 

period because it is mindful that 

phasing out the general enforcement 

discretion approach on a timeline that is 

too short could cause undue disruption 

in the testing market. Among other 

things, we anticipate that 31⁄2 years 

would provide sufficient notice and 

opportunity for laboratories 

manufacturing IVDs to plan for and 

prepare PMAs and would appropriately 

account for any reliance interests. We 

note that 31⁄2 years is a longer time 

period than was discussed in either the 

2014 draft guidance documents or the 

2017 Discussion Paper for the phaseout 

of the general enforcement discretion 

approach for premarket review 

requirements. 

This timeline is also intended to align 

the phaseout date for the general 

enforcement discretion approach for 

premarket review requirements for highrisk IVDs offered as LDTs with the start 

of fiscal year 2028, which coincides 

with the beginning of a new user fee 

cycle. This alignment would provide an 

opportunity for industry participation in 

negotiations regarding the next user fee 

cycle with the knowledge that 

laboratory manufacturers would be 

expected to comply with premarket 

review requirements. (Although a trade 

association representing laboratories 

previously has participated in MDUFA 

negotiations, the prior negotiations have 

not incorporated similar expectations 

regarding laboratory compliance with 

premarket requirements.) Thus, we 

propose that this amount of time is 

appropriate to foster stability and 

consistency in the marketplace for the 

current MDUFA cycle, and would take 

into account the need for adequate FDA 

resources to implement the phaseout 

policy in a manner that does not 

compromise the capacity to achieve 

MDUFA V performance expectations. 

FDA anticipates that during this 31⁄2- 

year period, laboratories would work 

with FDA to determine whether PMAs 

should be submitted for their IVDs. 

Under FDA’s proposed policy, FDA 

generally would not intend to enforce 

against IVDs offered as LDTs after a 

PMA has been submitted (within the 

31⁄2-year timeframe) until FDA 

completes its review of the application. 

Given that such IVDs may already be on 

the market and available to patients, 

FDA generally does not intend to 

interrupt access at the point when a 

submission is made. 

Finally, FDA recognizes that the 2017 

Discussion Paper described a possible 

premarket-review approach specific to 

LDTs for unmet needs. FDA has not 

included such an approach in this 

proposed policy because we anticipate 

that the 31⁄2-year timeframe should be 

sufficient for laboratories to meet 

premarket review requirements for each 

of their marketed IVDs, as applicable, 

including IVDs for unmet needs. FDA 

also anticipates that programs currently 

in place may facilitate the development 

and premarket authorization of IVDs for 

unmet needs. These programs include 

the Humanitarian Use Devices (HUD)/ 

Humanitarian Device Exemption (HDE) 

program,18 which, among other things, 

provides an exemption from the 

requirement to establish a reasonable 

assurance of effectiveness for devices 

intended for use in the treatment or 

diagnosis of rare diseases or conditions 

(21 U.S.C. 360j(m); 21 CFR part 814, 

subpart H), and the Breakthrough 

Devices program, which is intended to 

help expedite the development and 

review of certain devices that provide 

for more effective treatment or diagnosis 

of life-threatening or irreversibly 

debilitating diseases or conditions (21 

U.S.C. 360e–3). 

5. Stage 5: End the general enforcement 

discretion approach with respect to 

premarket review requirements for moderate 

risk and low risk IVDs (that require 

premarket submissions) 4 years after FDA 

publishes a final phaseout policy, but not 

before April 1, 2028. 

FDA is proposing to end the general 

enforcement discretion approach with 

respect to premarket review 

requirements for moderate risk IVDs 

offered as LDTs (IVDs that may be 

eligible for classification into class II) 

and low risk IVDs offered as LDTs (IVDs 

that may be eligible for classification 

into class I) that require a premarket 

submission 4 years after FDA publishes 

the final phaseout policy. These 

premarket submissions include 510(k) 

submissions, the requirements for 

which are set forth at 21 U.S.C. 360(k), 


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Federal Register / Vol. 88, No. 190 / Tuesday, October 3, 2023 / Proposed Rules 68027 

360c(i), and part 807, subpart E. These 

submissions also include De Novo 

requests, which laboratories may submit 

for IVDs offered as LDTs for which there 

is no legally marketed device upon 

which to base a determination of 

substantial equivalence, and for which 

the laboratory seeks classification into 

class I or class II. These requirements 

are set forth at 21 U.S.C. 360c(f)(2) and 

21 CFR part 860, subpart D. 

FDA intends this stage to begin no 

earlier than April 1, 2028. FDA’s 

reasons for proposing this time period to 

phase out the general enforcement 

discretion approach with respect to 

premarket review requirements for 

moderate risk and low risk IVDs offered 

as LDTs are similar to those for the 

‘‘stage 4’’ time period, except that FDA 

has lengthened the time period by 6 

months in order to prioritize the review 

of applications for high-risk IVDs 

offered as LDTs (subject to premarket 

approval requirements), so that FDA can 

focus first on IVDs for which the 

consequences of a false result are most 

significant. FDA also recognizes that a 

greater number of IVDs are subject to the 

510(k) requirements, as compared with 

premarket approval requirements, so a 

longer period of time for laboratories to 

come into compliance with these 

requirements may be appropriate, 

particularly for laboratories with large 

test menus. 

FDA generally would not intend to 

enforce against IVDs offered as LDTs 

after a 510(k) or De Novo request has 

been submitted (within the 4-year 

timeframe) until FDA completes its 

review of the submission. 

FDA also anticipates that laboratories 

may seek to utilize FDA’s Third Party 

review program. FDA currently operates 

a Third Party review program for 

medical devices, and multiple 

organizations are accredited to conduct 

reviews of 510(k) submissions for 

certain IVDs (see Ref. 77). We anticipate 

interest in the Third Party review 

program among test manufacturers, as 

well as potential new Third Party 

review organizations. In particular, FDA 

is aware of certain CLIA accreditation 

organizations that may be interested in 

potentially becoming Third Party 

reviewers under FDA’s program, and to 

the extent laboratories are already 

familiar with these organizations, 

laboratories may be inclined to use the 

Third Party review program. In 

addition, under the MDUFA V 

agreement, FDA is currently working to 

enhance the Third Party review 

program, which may make it more 

attractive to manufacturers including 

laboratories. 

VII. Proposed Effective Date 

The Agency proposes that any final 

rule based on this proposed rule will 

become effective 60 days after the date 

of publication of the final rule in the 

Federal Register. 

VIII. Preliminary Economic Analysis of 

Impacts 

We have examined the impacts of the 

proposed rule under Executive Order 

12866, Executive Order 13563, 

Executive Order 14094, the Regulatory 

Flexibility Act (5 U.S.C. 601–612), and 

the Unfunded Mandates Reform Act of 

1995 (Pub. L. 104–4). 

Executive Orders 12866, 13563, and 

14094 direct us to assess all benefits, 

costs, and transfers of available 

regulatory alternatives and to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). Rules 

are ‘‘significant’’ under Executive Order 

12866 Section 3(f)(1) (as amended by 

Executive Order 14094) if they ‘‘have an 

annual effect on the economy of $200 

million or more (adjusted every 3 years 

by the Administrator of [the Office of 

Information and Regulatory Affairs 

(OIRA)] for changes in gross domestic 

product); or adversely affect in a 

material way the economy, a sector of 

the economy, productivity, competition, 

jobs, the environment, public health or 

safety, or State, local, territorial, or tribal 

governments or communities.’’ OIRA 

has determined that this proposed rule 

is a significant regulatory action under 

Executive Order 12866 Section 3(f)(1). 

The Regulatory Flexibility Act 

requires Agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because most facilities that will 

be affected by this rule are defined as 

small businesses and the proposed rule 

is likely to impose a substantial burden 

on the affected small entities, we find 

that the proposed rule will have a 

significant economic impact on a 

substantial number of small entities. 

We prepared an analysis consistent 

with the Unfunded Mandates Reform 

Act of 1995 (section 202(a)), which 

requires us to prepare a written 

statement that includes estimates of 

anticipated impacts, before proposing 

‘‘any rule that includes any Federal 

mandate that may result in the 

expenditure by State, local, and tribal 

governments, in the aggregate, or by the 

private sector, of $100,000,000 or more 

(adjusted annually for inflation) in any 

one year.’’ The current threshold after 

adjustment for inflation is $177 million, 

using the most current (2022) Implicit 

Price Deflator for the Gross Domestic 

Product. This proposed rule would 

result in an expenditure in at least one 

year that meets or exceeds this amount. 

This proposed rule, if finalized, 

would amend FDA’s regulations to 

make explicit that IVDs are devices 

under the FD&C Act including when the 

manufacturer of the IVD is a laboratory. 

As discussed in section VI, FDA intends 

to phase out its general enforcement 

discretion approach for LDTs so that 

IVDs manufactured by a laboratory 

would generally fall under the same 

enforcement approach as other IVDs. 

We anticipate that the benefits of 

phasing out FDA’s general enforcement 

discretion approach for LDTs would 

include a reduction in healthcare costs 

associated with unsafe or ineffective 

tests, including tests promoted with 

false or misleading claims, and from 

therapeutic decisions based on the 

results of those tests. Quantified benefits 

are the annualized sum of both health 

and non-health benefits. Unquantified 

benefits would include the reduction in 

costs from lawsuits and reduction in 

costs to healthcare systems. 

Table 1 summarizes the annualized 

benefits, costs, and transfers of the 

proposed rule. At a 7 percent discount 

rate, 20-year annualized benefits range 

from $2.67 billion to $86.01 billion, 

with a primary estimate of $31.41 

billion per year. At a 3 percent discount 

rate, 20-year annualized benefits range 

from $1.81 billion to $61.41 billion, 

with a primary estimate of $22.33 

billion per year. At a 7 percent discount 

rate, 20-year annualized costs range 

from about $2.52 billion to $19.45 

billion, with a primary estimate of $5.87 

billion per year. At a 3 percent discount 

rate, annualized costs range from about 

$2.39 billion to $18.55 billion, with a 

primary estimate of $5.60 billion per 

year. At a 7 percent discount rate, 20- 

year annualized transfers range from 

$100 million to $452 million, with a 

primary estimate of $226 million per 

year. At a 3 percent discount rate, 20- 

year annualized transfers range from 

$121 million to $538 million, with a 

primary estimate of $269 million per 

year. 


ddrumheller on DSK120RN23PROD with PROPOSALS1
68028 Federal Register / Vol. 88, No. 190 / Tuesday, October 3, 2023 / Proposed Rules 

TABLE 1—SUMMARY OF BENEFITS, COSTS AND TRANSFERS OF THE PROPOSED RULE

[Millions of 2022 U.S. dollars] 

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(%) 

Period 

covered 

(years) 

Benefits: 

Annualized Monetized 

($m/year).

$31,408 

22,332 

$2,670 

1,810 

$86,013 

61,413 

2022 

2022 

7 

3 

20 

20 

Annualized Quantified .. .................. .................. .................. .................. 7 

3 

Qualitative .....................

Costs: 

Annualized Monetized 

($m/year).

5,874 

5,598 

2,522 

2,394 

19,452 

18,549 

2022 

2022 

7 

3 

20 

20 

A portion of foreign costs could be passed on to domestic consumers. We estimate that up to $30.73 

million in annualized costs (7%, 20 years) to foreign facilities could be passed on to domestic consumers. 

Annualized Quantified .. .................. .................. .................. .................. 7 

3 

Qualitative .....................

Transfers: 

Federal Annualized 

Monetized ($m/year).

226 

269 

100 

121 

452 

538 

2022 

2022 

7 

3 

20 

20 

From: Device Industry To: FDA 

Other Annualized Monetized ($m/year)................... .................. .................. .................. 7 

3 

From: To: 

Effects: 

State, Local, or Tribal Government: 

Small Business: The proposed rule is likely to have a significant economic impact on a substantial number of small laboratories that manufacture IVDs offered 

as LDTs. 

Wages: 

Growth: 

We have developed a comprehensive 

Preliminary Economic Analysis of 

Impacts that assesses the impacts of the 

proposed rule. The full preliminary 

analysis of economic impacts is 

available in the docket for this proposed 

rule (Ref. 34) and at https://

www.fda.gov/about-fda/economicsstaff/regulatory-impact-analyses-ria. 

IX. Analysis of Environmental Impact 

We have determined under 21 CFR 

25.30(h) that this action is of a type that 

does not individually or cumulatively 

have a significant effect on the human 

environment. Therefore, neither an 

environmental assessment nor an 

environmental impact statement is 

required. 

X. Paperwork Reduction Act of 1995 

FDA tentatively concludes that this 

proposed rule contains no new 

collections of information. However, 

FDA does assume that there will need 

to be corresponding adjustments to the 

burden estimates for relevant approved 

collections of information before the 

relevant phaseout stage begins and any 

such collection of information would 

not be as a result of the implementation 

of the proposed rule. FDA tentatively 

concludes that the following 

information collections will need 

adjustment before the relevant phaseout 

stage begins: Office of Management and 

Budget (OMB) control number 0910– 

0437, Medical Device Reporting; OMB 

control number 0910–0359, Corrections 

and Removals; OMB control number 

0910–0625, Device Registration and 

Listing; OMB control number 0910– 

0485, Labeling; OMB control number 

0910–0078, Investigational Device 

Exemption; OMB control number 0910– 

0073, Quality Systems; OMB control 

number 0910–0231, Premarket 

Approval; OMB control number 0910– 

0332, Humanitarian Device Exemption; 

OMB control number 0910–0756, QSubmissions; OMB control number 

0910–0120, Premarket Notification; and 

OMB control number 0910–0844 De 

Novo. Such adjustments will be 

submitted for review and clearance by 

OMB under the Paperwork Reduction 

Act of 1995 (PRA) (44 U.S.C. 3501– 

3521). 

XI. Federalism 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. We 

have determined that this proposed rule 

does not contain policies that have 

substantial direct effects on the States, 

on the relationship between the 

National Government and the States, or 

on the distribution of power and 

responsibilities among the various 

levels of government. Accordingly, we 

conclude that the rule does not contain 

policies that have federalism 

implications as defined in the Executive 

order and, consequently, a federalism 

summary impact statement is not 

required. Through publication of this 

proposed rule, we are providing notice 

and an opportunity for State and local 

officials to comment on this rulemaking. 

XII. Consultation and Coordination 

With Indian Tribal Governments 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13175. We 

have tentatively determined that the 

rule does not contain policies that 

would have a substantial direct effect on 


ddrumheller on DSK120RN23PROD with PROPOSALS1
Federal Register / Vol. 88, No. 190 / Tuesday, October 3, 2023 / Proposed Rules 68029 

19See, e.g. H.R.4128—117th Congress (2021– 

2022): VALID Act of 2021, H.R.4128, 117th Cong. 

(2021), https://www.congress.gov/bill/117thcongress/house-bill/4128/text; S.2209—117th 

Congress (2021–2022): VALID Act of 2021, S.2209, 

117th Cong. (2021), https://www.congress.gov/bill/ 

117th-congress/senate-bill/2209. 

one or more Indian Tribes, on the 

relationship between the Federal 

Government and Indian Tribes, or on 

the distribution of power and 

responsibilities between the Federal 

Government and Indian Tribes. The 

Agency solicits comments from tribal 

officials on any potential impact on 

Indian Tribes from this proposed action. 

XIII. Other Issues for Consideration 

FDA anticipates that this proposed 

rule, if finalized, may require 

conforming amendments to other FDA 

regulations, including provisions 

regarding IVD labeling and ASRs in part 

809. FDA intends to consider and 

propose conforming amendments, 

where appropriate, at a future date. 

In addition, we note that various bills 

have been introduced in Congress that 

would change the legal status of IVDs as 

devices (under these bills, IVDs would 

generally be regulated as ‘‘in vitro 

clinical tests’’ and would be subject to 

new statutory authorities).19 We 

recognize that the enactment of such 

legislation would directly impact this 

rule, given that it is being proposed 

under the statutory device authorities 

and other authorities under the FD&C 

Act. 

XIV. References 

The following references marked with 

an asterisk (*) are on display at the 

Dockets Management Staff (see 

ADDRESSES) and are available for 

viewing by interested persons between 

9 a.m. and 4 p.m., Monday through 

Friday; they also are available 

electronically at https://

www.regulations.gov. References 

without asterisks are not on public 

display at https://www.regulations.gov 

because they have copyright restriction. 

Some may be available at the website 

address, if listed. References without 

asterisks are available for viewing only 

at the Dockets Management Staff. FDA 

has verified the website addresses, as of 

the date this document publishes in the 

Federal Register, but websites are 

subject to change over time. 

1. Grand View Research, ‘‘Laboratory 

Developed Tests Market Size, Share & Trends 

Analysis Report By Technology 

(Immunoassay, Molecular Diagnostics), By 

Application (Oncology, Nutritional & 

Metabolic Disease), By Region, and Segment 

Forecasts, 2023–2030: Report Summary,’’ 

available at https://

www.grandviewresearch.com/industryanalysis/laboratory-developed-tests-marketreport (last accessed on April 28, 2023). 

2. The Pew Charitable Trusts, ‘‘The Role of 

Lab-Developed Tests in the In Vitro 

Diagnostics Market,’’ October 2021. Available 

at https://www.pewtrusts.org/en/researchand-analysis/reports/2021/10/the-role-of-labdeveloped-tests-in-the-in-vitro-diagnosticsmarket. 

* 3. Congressional Research Service, ‘‘FDA 

Regulation of Laboratory-Developed Tests 

(LDTs),’’ December 7, 2022. Available at 

https://crsreports.congress.gov/product/pdf/ 

IF/IF11389. 

* 4. Warning Letter to deCODE Genetics re: 

deCODEme Complete Scan (June 10, 2010). 

Available at https://www.fda.gov/media/ 

79216/download. 

* 5. Warning Letter to 23andMe, Inc. re: 

23andMe Personal Genome Service (June 10, 

2010). Available at http://web.archive.org/ 

web/20191214010336/https:/www.fda.gov/ 

media/79205/download. 

6. ThermoFisher Scientific, ‘‘Demystify 

Molecular Test Development and 

Implementation: How Do Labs Implement 

Molecular Tests To Meet Complex Clinical 

Needs?’’ Available at https://

www.thermofisher.com/us/en/home/clinical/ 

clinical-genomics/molecular-diagnostics/ 

molecular-diagnostic-education.html (last 

accessed on March 28, 2023). 

7. Lighthouse Lab Services, ‘‘Industry 

Insights: Paths To Consider When 

Commercializing Your LDT,’’ December 19, 

2022; available at https://

www.lighthouselabservices.com/paths-toconsider-when-commercializing-your-ldt/ 

(last accessed on March 31, 2023). 

* 8. Centers for Disease Control and 

Prevention, Division of Laboratory Systems 

(DLS), ‘‘Strengthening Clinical Laboratories,’’ 

November 15, 2018, available at https://

www.cdc.gov/csels/dls/strengtheningclinical-labs.html (last accessed on March 31, 

2023). 

9. Ackerman, J.P., DC Bartos, J.D. 

Kapplinger, et al., ‘‘The Promise and Peril of 

Precision Medicine: Phenotyping Still 

Matters Most,’’ Mayo Clinic Proceedings, 

91(11):1606–1616, 2016. Available at https:// 

doi.org/10.1016/j.mayocp.2016.08.008. 

10. Begley, S., ‘‘Genetic Testing Fumbles, 

Revealing ‘Dark Side’ of Precision Medicine,’’ 

STAT, October 31, 2016. Available at https:// 

www.statnews.com/2016/10/31/genetictesting-precision-medicine/. 

* 11. FDA, ‘‘The Public Health Evidence for 

FDA Oversight of Laboratory Developed 

Tests: 20 Case Studies,’’ November 16, 2015, 

available at http://web.archive.org/web/ 

20151122235012/https://www.fda.gov/ 

downloads/AboutFDA/Reports

ManualsForms/Reports/UCM472777.pdf. 

12. Pfeifer, J.D., R. Loberg, C. Lofton-Day, 

et al., ‘‘Reference Samples To Compare NextGeneration Sequencing Test Performance for 

Oncology Therapeutics and Diagnostics,’’ 

American Journal of Clinical Pathology, 

157(4):628–638, 2022. Available at https://

doi.org/10.1093/ajcp/aqab164. 

13. Quy, P.N., K. Fukuyama, M. Kanai, et 

al., ‘‘Inter-Assay Variability of NextGeneration Sequencing-Based Gene Panels,’’ 

BMC Medical Genomics, 15: 86, 2022. 

Available at https://doi.org/10.1186/s12920- 

022-01230-y. 

14. Vega, D.M., L.M. Yee, L.M. McShane, 

et al., ‘‘Aligning Tumor Mutational Burden 

(TMB) Quantification Across Diagnostic 

Platforms: Phase II of the Friends of Cancer 

Research TMB Harmonization Project,’’ 

Annals of Oncology, 32(12):1626–1636, 2021. 

Available at https://doi.org/10.1016/ 

j.annonc.2021.09.016. 

15. Offit, K., C.M. Sharkey, D. Green, et al., 

‘‘Regulation of Laboratory-Developed Tests in 

Preventive Oncology: Emerging Needs and 

Opportunities,’’ Journal of Clinical Oncology, 

41(1): 11–21, 2023. Available at https://

doi.org/10.1200/jco.22.00995. 

16. Coffey, D., ‘‘Blood Test Positive for 

Cancer, but Is There Really a Tumor?’’ 

Medscape, February 17, 2023. Available at 

https://www.medscape.com/viewarticle/ 

988431. 

17. Manrai, A.K., B.H. Funke, H.L. Rehm, 

et al., ‘‘Genetic Misdiagnoses and the 

Potential for Health Disparities,’’ New 

England Journal of Medicine, 375(7):655– 

665, 2016. Available at https://doi.org/ 

10.1056/NEJMsa1507092. 

18. Shuren, J. and T. Stenzel, ‘‘Covid-19 

Molecular Diagnostic Testing—Lessons 

Learned,’’ New England Journal of Medicine, 

387:e97, 2020. Available at https://doi.org/ 

10.1056/nejmp2023830. 

* 19. FDA, ‘‘Policy for Coronavirus Disease2019 Tests During the Public Health 

Emergency (Revised)*; Guidance for 

Developers and Food and Drug 

Administration Staff,’’ November 15, 2021. 

20. Clark, A., ‘‘For a Host of Vital Lab 

Tests, No FDA Oversight Exists,’’ Undark 

Magazine, February 1, 2023. Available at 

https://undark.org/2023/02/01/for-a-host-ofvital-lab-tests-no-fda-oversight-exists/. 

21. Clark, A., A. Gallardo, J. Deam, et al., 

‘‘They Trusted Their Prenatal Test. They 

Didn’t Know the Industry Is an Unregulated 

‘Wild West,’’’ ProPublica, December 6, 2022. 

Available at https://www.propublica.org/ 

article/how-prenatal-screenings-haveescaped-regulation. 

22. Kliff, S. and A. Bhatia, ‘‘When They 

Warn of Rare Disorders, These Prenatal Tests 

Are Usually Wrong,’’ New York Times, 

January 1, 2022. Available at https://

www.nytimes.com/2022/01/01/upshot/ 

pregnancy-birth-genetic-testing.html. 

23. Robinson, S.A., A.R. Carter, and D.A. 

Brindley, ‘‘The Changing Regulatory 

Landscape for Laboratory Developed Tests,’’ 

Regulatory Focus, August 30, 2021. Available 

at https://www.raps.org/news-and-articles/ 

news-articles/2021/8/the-changingregulatory-landscape-for-laboratory-d. 

24. Adashi, E.Y. and I.G. Cohen, ‘‘SARSCoV–2 Laboratory-Developed Tests: Integrity 

Restored,’’ JAMA, 2022;327(13):1229–1230. 

Available at https://doi.org/10.1001/ 

jama.2022.3382. 

25. Rogus, S. and P. Lurie, ‘‘FDA Is Letting 

Harmful Lab-Developed Tests Fall Through 

the Cracks,’’ MedPage Today, December 9, 

2022. Available at https://

www.medpagetoday.com/opinion/secondopinions/102161. 

26. Damon, A., ‘‘The COVID Testing 

Company That Missed 96% of Cases,’’ 

ProPublica, May 16, 2022. Available at 

https://www.propublica.org/article/covidtesting-nevada-false-negatives-northshore. 


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* 27. FDA, ‘‘The FDA Warns Against the 

Use of Many Genetic Tests With Unapproved 

Claims To Predict Patient Response to 

Specific Medications: FDA Safety 

Communication,’’ October 31, 2018. 

Available at http://web.archive.org/web/ 

20190909184258/https://www.fda.gov/ 

medical-devices/safety-communications/fdawarns-against-use-many-genetic-testsunapproved-claims-predict-patient-responsespecific. 

* 28. FDA, ‘‘Genetic Non-Invasive Prenatal 

Screening Tests May Have False Results: 

FDA Safety Communication,’’ April 19, 2022. 

Available at https://www.fda.gov/medicaldevices/safety-communications/genetic-noninvasive-prenatal-screening-tests-may-havefalse-results-fda-safety-communication. 

* 29. FDA, ‘‘Ovarian Cancer Screening 

Tests: Safety Communication—FDA 

Recommends Against Use,’’ September 7, 

2016. Available at http://web.archive.org/ 

web/20160912081959/https:/www.fda.gov/ 

Safety/MedWatch/SafetyInformation/ 

SafetyAlertsforHumanMedicalProducts/ 

ucm519540.htm?source=govdelivery&utm_

medium=email&utm_source=govdelivery. 

* 30. FDA, ‘‘FDA Safety Communication: 

Breast Cancer Screening—Nipple Aspirate 

Test Is Not an Alternative to Mammography,’’ 

December 12, 2013. Available at http://

web.archive.org/web/20131217065913/https:/ 

www.fda.gov/MedicalDevices/Safety/ 

AlertsandNotices/ucm378389.htm. 

* 31. FDA, ‘‘Mass Spectrometers by Sciex: 

Safety Communication—Incorrect 

Assignment of Test Results,’’ September 1, 

2016. Available at https://wayback.archiveit.org/7993/20161021235406/http://

www.fda.gov/Safety/MedWatch/ 

SafetyInformation/SafetyAlertsforHuman

MedicalProducts/ucm518907.htm. 

* 32. FDA, ‘‘FDA Issues Warning Letter to 

Genomics Lab for Illegally Marketing Genetic 

Test That Claims To Predict Patients’ 

Responses to Specific Medications,’’ April 4, 

2019. Available at https://www.fda.gov/newsevents/press-announcements/fda-issueswarning-letter-genomics-lab-illegallymarketing-genetic-test-claims-predictpatients. 

* 33. Memorandum to File from Brittany 

Schuck, Ph.D., Deputy Office Director, Office 

of In Vitro Diagnostics (OHT7), Center for 

Devices and Radiological Health (CDRH), 

U.S. Food and Drug Administration, RE: 

Examples of In Vitro Diagnostic Products 

(IVDs) Offered as Laboratory Developed Tests 

(LDTs) that Raise Public Health Concerns 

(September 22, 2023). 

* 34. Preliminary Regulatory Impact 

Analysis; Initial Regulatory Flexibility 

Analysis; Unfunded Mandates Reform Act 

Analysis.’’ 2023. Information available at 

https://www.fda.gov/about-fda/reports/ 

economic-impact-analyses-fda-regulations. 

35. Gerhard, G.S., S.G. Fisher, and A.M. 

Feldman, ‘‘Genetic Testing for Inherited 

Cardiac Diseases in Underserved Populations 

of Non-European Ancestry: Double 

Disparity,’’ JAMA Cardiology, 3(4):273–274, 

2018. Available at https://jamanetwork.com/ 

journals/jamacardiology/fullarticle/2673291. 

36. Martin, A.R., M. Kanai, Y. Kamatani, et 

al., ‘‘Clinical Use of Current Polygenic Risk 

Scores May Exacerbate Health Disparities,’’ 

Nature Genetics, 51, 584–591, 2019. 

Available at https://doi.org/10.1038/s41588- 

019-0379-x. 

37. Wang, Y., K. Tsuo, M. Kanai, et al., 

‘‘Challenges and Opportunities for 

Developing More Generalizable Polygenic 

Risk Scores,’’ Annual Review of Biomedical 

Data Science, 5:293–320. Available at https:// 

doi.org/10.1146%2Fannurev-biodatasci111721-074830. 

38. Duncan L., H. Shen, B. Gelaye, et al., 

‘‘Analysis of Polygenic Risk Score Usage and 

Performance in Diverse Human Populations,’’ 

Nature Communications, 10(1):3328, 2019. 

Available at https://doi.org/ 

10.1038%2Fs41467-019-11112-0. 

39. Hoskins, K.F., O.C. Danciu, N.Y. Ko, et 

al., ‘‘Association of Race/Ethnicity and the 

21-Gene Recurrence Score With Breast 

Cancer-Specific Mortality Among U.S. 

Women,’’ JAMA Oncology, 7(3):370–378, 

2021. Available at https://doi.org/ 

10.1001%2Fjamaoncol.2020.7320. 

* 40. CMS, ‘‘Laboratory Developed Tests 

(LDTs) Frequently Asked Questions,’’ 

available at https://www.cms.gov/regulationsand-guidance/legislation/clia/downloads/ldtand-clia_faqs.pdf (last accessed on April 14, 

2023). 

* 41. Teutsch, S. and R. Tuckson, ‘‘U.S. 

System of Oversight of Genetic Testing: A 

Response to the Charge of the Secretary of 

Health and Human Services: Report of the 

Secretary’s Advisory Committee on Genetics, 

Health, and Society,’’ 2008. Available at 

https://repository.library.georgetown.edu/ 

bitstream/handle/10822/512822/SACGHS_

oversight_

report.pdf?sequence=l&isAllowed=y. 

42. American Cancer Society Cancer 

Action Network, ‘‘Administration Declines to 

Issue FDA Guidance on LDT Oversight,’’ 

November 16, 2016. Available at https://

www.fightcancer.org/releases/ 

administration-declines-issue-fda-guidanceldt-oversight. 

43. Advanced Medical Technology 

Association, ‘‘AdvaMed Statement on HHS 

Reversal of LDT Rescission Notice,’’ 

November 16, 2021. Available at https://

www.advamed.org/industry-updates/news/ 

advamed-statement-on-hhs-reversal-of-ldtrescission-notice/. 

* 44. Letter from D. Bruce Burlington, M.D., 

Director, FDA/CDRH, to Jeffrey N. Gibbs, 

Esq., Hyman, Phelps & McNamara, P.C., 

Docket No. 92P–0405 (August 12, 1998). 

Available at https://www.regulations.gov/ 

document/FDA-1992-P-0047-0001. 

* 45. FDA, ‘‘In Vitro Diagnostic 

Multivariate Index Assays; Draft Guidance 

for Industry, Clinical Laboratories, and FDA 

Staff,’’ September 7, 2006. Available at 

https://downloads.regulations.gov/FDA2006-D-0233-0002/attachment_1.pdf. 

* 46. Letter from Leslie Kux, Assistant 

Commissioner for Policy, FDA, to Alan 

Mertz, American Clinical Laboratory 

Association, Docket No. FDA–2013–P–0667 

(July 31, 2014). Available at https://

www.regulations.gov/document/FDA-2013-P0667-0008. 

* 47. Warning Letter to Inova Genomics 

Laboratory re: MediMap Tests (April 4, 

2019). Available at https://www.fda.gov/ 

inspections-compliance-enforcement-andcriminal-investigations/warning-letters/ 

inova-genomics-laboratory-577422-04042019. 

* 48. FDA, ‘‘Framework for Regulatory 

Oversight of Laboratory Developed Tests 

(LDTs); Draft Guidance for Industry, Food 

and Drug Administration Staff, and Clinical 

Laboratories,’’ October 3, 2014. Available at 

https://www.fda.gov/media/89841/download. 

* 49. FDA, ‘‘FDA Notification and Medical 

Device Reporting for Laboratory Developed 

Tests (LDTs); Draft Guidance for Industry, 

Food and Drug Administration Staff, and 

Clinical Laboratories,’’ October 3, 2014. 

Available at https://www.fda.gov/media/ 

89837/download. 

* 50. FDA, ‘‘Discussion Paper on 

Laboratory Developed Tests (LDTs),’’ January 

13, 2017. Available at https://www.fda.gov/ 

media/102367/download. 

* 51. FDA, ‘‘Policy for Monkeypox Tests To 

Address the Public Health Emergency; 

Guidance for Laboratories, Commercial 

Manufacturers, and Food and Drug 

Administration Staff,’’ September 7, 2022. 

Available at https://www.fda.gov/media/ 

161443/download. 

* 52. FDA, ‘‘Policy for Coronavirus 

Disease-2019 Tests (Revised); Guidance for 

Developers and Food and Drug 

Administration Staff,’’ January 12, 2023. 

Available at https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/ 

policy-coronavirus-disease-2019-testsrevised. 

* 53. ‘‘It Has Come to Our Attention’’ Letter 

to Texas Children’s Hospital and Houston 

Methodist Hospital re: Zika Direct Test 

(March 4, 2016). Available at https://

public4.pagefreezer.com/browse/FDA/22-02- 

2023T10:21/https://www.fda.gov/media/ 

96740/download. 

* 54. FDA, ‘‘Monkeypox (mpox) and 

Medical Devices,’’ January 27, 2023, available 

at https://www.fda.gov/medical-devices/ 

emergency-situations-medical-devices/ 

monkeypox-mpox-and-medical-devices (last 

accessed on March 9, 2023). 

* 55. Untitled Letter to Navigenics Corp. 

(June 10, 2010). Available at https://

public4.pagefreezer.com/browse/FDA/22-02- 

2023T10:21/https://www.fda.gov/media/ 

79235/download. 

* 56. FDA, ‘‘Laboratory Developed Tests,’’ 

September 27, 2018. Available at https://

www.fda.gov/medical-devices/in-vitrodiagnostics/laboratory-developed-tests (last 

accessed on April 12, 2023). 

* 57. HHS, ‘‘Rescission of Guidances and 

Other Informal Issuances,’’ August 19, 2020. 

* 58. HHS, ‘‘FAQs on Laboratory 

Developed Tests (LDT).’’ 

* 59. Memorandum to File from Stephen 

Cha, Counselor to the Secretary, HHS, RE: 

Withdrawal of August 2020 Policy Regarding 

Laboratory-Developed Tests (November 14, 

2021). 

* 60. HHS, ‘‘Statement by HHS Secretary 

Xavier Becerra on Withdrawal of HHS Policy 

on Laboratory-Developed Tests,’’ November 

15, 2021. 

61. Diamond, D. and D. Lim, ‘‘Memo 

Details HHS Push To Upend FDA’s Testing 

Oversight,’’ Politico, October 2, 2020. 

Available at https://www.politico.com/news/ 

2020/10/02/hhs-memo-fda-testing-oversight425139. 


ddrumheller on DSK120RN23PROD with PROPOSALS1
Federal Register / Vol. 88, No. 190 / Tuesday, October 3, 2023 / Proposed Rules 68031 

62. Kaplan, S., ‘‘Trump Administration 

Says Some Coronavirus Tests Can Bypass 

F.D.A. Scrutiny,’’ New York Times, August 

24, 2020. Available at https://

www.nytimes.com/2020/08/21/health/ 

coronavirus-tests-fda.html. 

63. Baumann, J., ‘‘Virus Testing Push 

Leaves FDA Lab Oversight in ‘a Bizarre 

Limbo,’’’ Bloomberg Law, August 26, 2020. 

Available at https://news.bloomberglaw.com/ 

pharma-and-life-sciences/virus-testing-pushleaves-fda-lab-oversight-in-a-bizarre-limbo. 

64. Howard, J., ‘‘HHS Withdraws Trump 

Administration Policy That Limited FDA 

Review of Certain Covid-19 Tests,’’ CNN, 

November 15, 2021. Available at https://

www.cnn.com/2021/11/15/health/covid-labtests-hhs-withdraws-policy-bn/index.html. 

65. Fortune, ‘‘Fortune 500—The Largest 

Companies in the U.S. by Revenue,’’ 2023. 

Available at https://fortune.com/ranking/ 

fortune500/. 

* 66. FDA, ‘‘Compliance Program Guidance 

Manual 7341.002; Inspection of Human Cells, 

Tissues, and Cellular and Tissue-Based 

Products (HCT/Ps).’’ Available at https://

www.fda.gov/media/73949/download. 

* 67. FDA, ‘‘Compliance Program Guidance 

Manual 7342.002; Inspection of Source 

Plasma Establishments, Brokers, Testing 

Laboratories, and Contractors,’’ January 31, 

2019. Available at https://www.fda.gov/ 

media/80179/download. 

* 68. Government Accountability Office, 

‘‘COVID–19: FDA Took Steps to Help Make 

Tests Available; Policy for Future Public 

Health Emergencies Needed,’’ May 2022. 

Available at https://www.gao.gov/assets/gao22-104266.pdf. 

* 69. ‘‘It Has Come to Our Attention’’ Letter 

to MD Biosciences re: the Zika Virus RNA by 

RT–PCR Assay (March 4, 2016). Available at 

https://public4.pagefreezer.com/browse/ 

FDA/22-02-2023T10:21/https://www.fda.gov/ 

media/96214/download. 

* 70. ‘‘It Has Come to Our Attention’’ Letter 

to First Diagnostic Corp. re: ATFirst One Step 

Zika Antibody Test (March 10, 2016). 

Available at https://public4.pagefreezer.com/ 

content/FDA/04-10-2022T10:19/https://

www.fda.gov/media/96739/download. 

* 71. FDA, ‘‘Direct-to-Consumer Tests,’’ 

December 20, 2019, available at https://

www.fda.gov/medical-devices/in-vitrodiagnostics/direct-consumer-tests (last 

accessed on March 9, 2023). 

* 72. Untitled Letter to Interleukin 

Genetics, Inc. (November 4, 2015). Available 

at https://public4.pagefreezer.com/browse/ 

FDA/22-02-2023T10:21/https://www.fda.gov/ 

media/94365/download. 

* 73. Untitled Letter to Pathway Genomics, 

Inc. (September 21, 2015). Available at 

https://public4.pagefreezer.com/browse/ 

FDA/30-12-2022T07:46/https://www.fda.gov/ 

media/93493/download. 

* 74. Transcript of the Molecular and 

Clinical Genetics Panel meeting, March 8, 

2011. Available at https://wayback.archiveit.org/7993/20170404140959/https://

www.fda.gov/downloads/ 

AdvisoryCommittees/CommitteesMeeting

Materials/MedicalDevices/MedicalDevices

AdvisoryCommittee/Molecularand

ClinicalGeneticsPanel/UCM249857.pdf. 

* 75. Transcript of the Molecular and 

Clinical Genetics Panel meeting, March 9, 

2011. Available at https://wayback.archiveit.org/7993/20170404141000/https:/ 

www.fda.gov/downloads/Advisory

Committees/CommitteesMeetingMaterials/ 

MedicalDevices/ 

MedicalDevicesAdvisoryCommittee/ 

MolecularandClinicalGeneticsPanel/ 

UCM249858.pdf. 

76. Bradley, P.L., J.S. Dickey, J.D. Levin, et 

al., ‘‘Complex Clinical Laboratory Tests Can 

Benefit From Design Controls,’’ Health 

Affairs Forefront, June 3, 2022. Available at 

https://www.healthaffairs.org/do/10.1377/ 

forefront.20220601.318288. 

* 77. FDA, ‘‘510(k) Third Party Review 

Program,’’ August 19, 2022. Available at 

https://www.fda.gov/medical-devices/ 

premarket-submissions-selecting-andpreparing-correct-submission/510k-thirdparty-reviewprogram(lastaccessedonSeptember22,2023). 

List of Subjects in 21 CFR Part 809 

Labeling, Medical devices. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, FDA proposes to 

amend 21 CFR part 809 as follows: 

PART 809—IN VITRO DIAGNOSTIC 

PRODUCTS FOR HUMAN USE 

■ 1. The authority citation for part 809 

is revised to read as follows: 

Authority: 21 U.S.C. 321(h)(1), 331, 351, 

352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 

371, 372, 374, 381. 

■ 2. In § 809.3, revise the last sentence 

of paragraph (a) to read as follows: 

§ 809.3 Definitions. 

(a) * * * These products are devices 

as defined in section 201(h)(1) 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, including 

when the manufacturer of these 

products is a laboratory. 

* * * * * 

Dated: September 27, 2023. 

Robert M. Califf, 

Commissioner of Food and Drugs. 

[FR Doc. 2023–21662 Filed 9–29–23; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 117 

[Docket No. USCG–2023–0530] 

RIN 1625–AA09 

Drawbridge Operation Regulation; 

Long Creek, Nassau County, NY 

AGENCY: Coast Guard, Department of 

Homeland Security (DHS). 

ACTION: Notice of proposed rulemaking. 

SUMMARY: The Coast Guard proposes to 

temporarily modify the operating 

schedule that governs the Loop Parkway 

Bridge across Long Creek, mile 0.7, 

Nassau County, NY. The bridge owner, 

New York State Department of 

Transportation (NYSDOT), submitted a 

request to operate the bridge under 

single leaf openings to perform bridge 

deck replacement. We invite your 

comments on this proposed rulemaking. 

DATES: Comments and related material 

must reach the Coast Guard on or before 

November 2, 2023. 

ADDRESSES: You may submit comments 

identified by docket number USCG– 

2023–0530 using Federal Decision 

Making Portal at https://

www.regulations.gov. 

See the ‘‘Public Participation and 

Request for Comments’’ portion of the 

SUPPLEMENTARY INFORMATION section 

below for instructions on submitting 

comments. 

FOR FURTHER INFORMATION CONTACT: If 

you have questions on this proposed 

rule, call or email Ms. Stephanie E. 

Lopez, First Coast Guard District, 

Project Officer, telephone 212–514– 

4335, email Stephanie.E.Lopez@

uscg.mil. 

SUPPLEMENTARY INFORMATION: 

I. Table of Abbreviations 

CFR Code of Federal Regulations 

DHS Department of Homeland Security 

FR Federal Register 

OMB Office of Management and Budget 

NPRM Notice of proposed rulemaking 

(advance, supplemental) 

§ Section 

U.S.C. United States Code 

NYSDOT New York State Department of 

Transportation 

II. Background, Purpose, and Legal 

Basis 

The Loop Parkway Bridge across Long 

Creek, mile 0.7, Nassau County, NY, has 

a vertical clearance of 21 feet at mean 

high water and a horizontal clearance of 

75.5 feet at mean high water. Waterway 


ddrumheller on DSK120RN23PROD with PROPOSALS1