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 (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.

Individual Flocked Sampling Swab

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.

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, 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.

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 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 life-threatening 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 long-term 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 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] Q-submissions,^[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 well-understood 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.