Journal:The US FDA’s proposed rule on laboratory-developed tests: Impacts on clinical laboratory testing

Full article title	The US FDA’s proposed rule on laboratory-developed tests: Impacts on clinical laboratory testing
Journal	Practical Laboratory Medicine
Author(s)	Smith, Leslie; Carricaburu, Lisa A.; Genzen, Jonathan R.
Author affiliation(s)	ARUP Laboratories, University of Utah Health
Primary contact	Email: jonathan dot genzen at path dot utah dot edu
Year published	2024
Volume and issue	In press
Article #	e00407
DOI	10.1016/j.plabm.2024.e00407
ISSN	2352-5517
Distribution license	Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
Website	https://www.sciencedirect.com/science/article/pii/S2352551724000532
Download	https://www.sciencedirect.com/science/article/pii/S2352551724000532/pdfft (PDF)

Abstract

Objectives: To solicit quantifiable feedback from clinical laboratorians on the U.S. Food and Drug Administration (FDA) proposed rule to regulate laboratory-developed tests (LDTs) as medical devices.

Design and methods: A ten-item questionnaire was developed and submitted to clinical laboratory customers of ARUP Laboratories, a national nonprofit clinical laboratory of the University of Utah Department of Pathology.

Results: Of 503 clinical laboratory respondents, only 41 (8%) support the FDA’s proposed rule. 67% of respondents work in laboratories that perform LDTs and were therefore asked additional questions regarding the proposed rule. 84% of these respondents believe that the proposed rule will negatively impact their laboratories, while only 3% believe that they have the financial resources to pay for FDA user fees. 61% of respondents anticipate removing tests from their laboratory menus if the proposed rule is enacted, while an additional 33% indicated that they do not yet know. Only 11% of respondents believe that they would pursue FDA submissions for all of their existing LDTs if the final rule is enacted. The vast majority of respondents (>80%) were either "extremely concerned" or "very concerned" about the impact of the proposed rule on patient access to essential testing, financial and personnel resources to comply, innovation, the FDA’s ability to implement the rule, and send-out costs and test prices.

Conclusions: The majority of clinical laboratorians surveyed do not support the FDA’s proposed rule on LDTs and report having insufficient resources to comply with the rule if it is enacted.

Keywords: laboratory-developed tests, Food and Drug Administration, Clinical Laboratory Improvement Amendments, clinical laboratory regulations

Introduction

On October 3, 2023, the U.S. Food and Drug Administration (FDA) released a proposed rule that would regulate laboratory-developed tests (LDTs) as medical devices if enacted. [1] The FDA considers in vitro diagnostics (IVDs) as “tests done on samples such as blood or tissue that have been taken from the human body.” [2] These are traditionally manufactured as reagents and/or kits that are subject to FDA-clearance/approval and are commercially distributed to clinical laboratories for clinical testing purposes. LDTs, however, are developed and performed within clinical laboratories and are not commercially distributed outside of the testing site. Additionally, the FDA has defined LDTs as IVDs that are “intended for clinical use and designed, manufactured and used within a single laboratory.” [3] While there is no legislative definition from Congress, nor any current federal regulations that create a legal definition of LDTs in the U.S., the FDA’s definition has been promulgated extensively in non-binding draft guidance documents and public-facing statements. [4, 5]

LDTs are not mentioned in the Medical Device Amendments of 1976 [6]—the law that established the current framework for medical device regulation in the U.S.—nor were LDTs discussed in Congressional hearings prior to the law’s passage. [7, 8] Thus, there is significant legal uncertainty as to whether the FDA has the authority from Congress to advance the current proposed rule. [9] Regardless, FDA leadership has signaled a commitment to move forward with LDT oversight [10], and an April 2024 tentative date for finalization of the proposed rule was posted in the fall 2023 Unified Agenda from the Biden Administration. [11, 12] (The rule was finalized on April 29, 2024.)

In the U.S., rulemaking from federal agencies must follow requirements outlined in the Administrative Procedure Act. [13] The FDA’s proposed rule on LDTs is considered "notice-and-comment" rulemaking, where the public is notified of a proposed rule and provided with the opportunity to provide open comments, and the agency is required to consider this feedback from the public in its deliberation and rulemaking. [14] The public comment period for the FDA’s proposed rule was limited to 60 days, and it officially closed on December 4, 2023, with approximately 6,700 comments submitted. [15] The FDA declined numerous requests for extensions of the public comment period. [16] These requests included a letter signed by leaders of 89 laboratories and professional organizations [17], as well as a request from the American Medical Association House of Delegates. [18] Extension of public comment periods can provide members of the public more time to evaluate the implication of a proposed rule, and they are often granted by agencies for rules with significant potential impact to the public. The FDA has hosted no public workshops or hearings on LDT oversight since 2015. [19]

An important aspect of the public comment process is to assist a federal agency in understanding whether different sectors of the public support or oppose a proposed rule and for which reasons. While the Federal Register’s comment submission system for the proposed rule on LDTs included a drop-down menu for submitters to select the industry, corporate type, career, or setting most applicable to them—presumably to assist federal agencies in categorizing comments by sector—"clinical laboratory" or "clinical laboratorian" were not available options, even though this setting and career type is most impacted by the proposed rule. As such, it will be difficult for the FDA to conduct an accurate quantitative analysis of public opinion in a key sector directly impacted by its proposed rule.

To provide a quantitative assessment of clinical laboratorian opinions on the FDA’s proposed rule and its anticipated impact on clinical laboratory operations and patient care, a survey was distributed in February 2024 to customer contacts of ARUP Laboratories. ARUP is a national, nonprofit clinical laboratory enterprise of the University of Utah Department of Pathology, with community hospital and academic medical center laboratory customers across all 50 states. [20] As such, recipients of this survey are directly involved in clinical laboratory testing and have occupational roles for which FDA-cleared/approved IVDs and LDTs are relevant and familiar. Survey results demonstrate that there is strong opposition among clinical laboratory respondents to the proposed rule and significant concerns regarding its anticipated negative impacts on clinical laboratory testing and patient care across laboratories.

Materials and methods

A ten-item questionnaire regarding the potential impact of the FDA’s proposed rule on LDTs was developed (see Survey Questionnaire). The study received an exemption determination (Category 2) from the University of Utah Institutional Review Board (IRB 00174067). [21] An invitation to participate in this survey was distributed to customer contact email addresses from ARUP’s customer relationship management system (CRM) (Salesforce; San Francisco, CA). The survey was opened on January 31, 2024 and closed on February 21, 2024. Documentation of informed consent was waived by the IRB for this exempt protocol. A cover letter outlining the study was provided in the invitation email for this anonymous questionnaire, and individuals who chose to not complete the survey could disregard this invitation. Individual survey links could only be used for one submission. As ARUP Laboratories operates the University of Utah Health clinical laboratories and also serves as the health system’s primary reference laboratory, surveys were not distributed to either ARUP or University of Utah Health email addresses to avoid the potential for respondent bias regarding expectations of reference laboratory services. Contacts at national reference laboratories were also excluded to avoid similar bias regarding reference laboratory services. Research trial contacts were also excluded as not all studies require Clinical Laboratory Improvement Amendments (CLIA) certification. The survey was administered using the Experience Management XM platform (Qualtrics; Provo, UT), and no identifiers were collected from survey respondents. Respondent institution type (i.e., community hospital, academic hospital, pediatric hospital, Veterans Administration / federal hospital, independent reference laboratory, pathology group or clinic) and institution location (i.e., U.S. state, territory, or country) was available for a subset of customers in the CRM for summary analysis. A geographic map of institutions in each U.S. state was created using a template from SlideQuest in PowerPoint (Microsoft 365; Redmond, WA).

Data was tabulated within Qualtrics and further analyzed and displayed using Excel (Microsoft 365; Redmond, WA). Percentages are rounded to whole numbers throughout the manuscript. Statistical analyses were performed using R Statistical Software (v4.3.3; R Core Team, 2024). Thematic analysis of free text comments was also conducted and included both semantic themes (e.g., the precise wording of a comment) and latent themes (e.g., an underlying concept in a comment) [22]. Respondent text was assigned to thematic categories and tabulated in Excel, as previously described. [23] Respondent comments displayed in the manuscript were edited for spelling and minor grammatical corrections only.

Results

Of survey invitations distributed by email to 15,513 individuals, 532 questionnaires (3% response rate) were either fully or partially completed. Information on respondent institution’s state, territory, or country was known for 429 respondents (81%), with 421 institutions in this subset (98%) located in the U.S. across 45 states. Eight additional respondents were affiliated with institutions outside the U.S. Distribution of respondent institution location by U.S. state is shown in Figure 1.

Figure 1. Respondent institution by U.S. state. Map showing respondent institution by state (where available).

Information on respondent institution type was available for 327 respondents (62%). Distribution of these institutions by category is shown in Table 1.

Table 1. Respondent institution by category. Institution category Number Percent Hospital (community) 179 55% Hospital (academic) 64 20% Independent reference laboratory 40 12% Hospital (children’s) 25 8% Hospital (Veterans Administration/federal) 10 3% Pathology group or clinic 9 3%

Respondents were asked in the questionnaire to specify a job that best describes their roles within their respective organization. A categorized list of respondent job roles is shown in Table 2. The most common job categories selected by respondents included lab manager or supervisor (153, 29%), lab director (97, 18%), lab employee (med tech, lab tech, lab assistant; 83, 16%), and medical director, pathologist, physician, clinician, or PhD scientist (68, 13%).

Table 2. Job categories of survey respondents. CEO, chief executive officer; CFO, chief financial officer; IT, information technology; LIS, laboratory information system. Job category Number Percent Lab manager or supervisor 153 29% Lab director 97 18% Lab employee (med tech / lab tech / lab assistant) 83 16% Medical director, pathologist, physician, clinician, or PhD scientist 68 13% Send-out / referral testing 29 6% Quality and compliance 25 5% Executive (CEO, CFO, etc.) 23 4% IT / LIS 13 2% Customer service / support service 10 2% Office: executive assistant, administrative assistant, etc. 4 1% Specimen processing / receiving 1 0% Supply chain / ancillary services 1 0% Other 25 5% Total 532

503 respondents then answered a question regarding whether they support the FDA’s proposed rule to regulate LDTs as medical devices. A majority (360, 72%) responded "no," 41 (8%) responded "yes" and 102 (20%) responded that they either had no opinion (69, 14%) or did not know whether they support the proposed rule (33, 7%) (Fig 2a). Distribution of responses according to job category is presented in Table 3. The highest percentage of "no" responses were in the "medical director, pathologist, physician, clinician, or PhD scientist" job category (91%), the "quality and compliance" job category (91%), the "executive (CEO, CFO, etc.)" job category (86%), and the "lab director" job category (83%). The Fisher’s exact test was used to examine the differences in response by job category. Although the test indicated statistical differences within the dataset, pairwise examination of responses by job category found no statistical differences. These conflicting results may be due to a loss of power due to smaller sample sizes in the pairwise analysis.

Figure 2. Responses to survey questions. Respondents were asked (a) whether they support the FDA proposal to regulate LDTs, (b) whether they perform LDTs within their laboratories, (c) if their laboratories would be negatively impacted by the proposed rule if enacted, (d) if they anticipate having to remove tests from their laboratory menus if the proposed rule is enacted, and (e) whether they have the financial resources to pay for FDA user fees. Questions for (c), (d), and (e) were asked only of respondents whose laboratories performed LDTs.

Table 3. Responses to "Do Your Support the FDA's Proposed Rule to Regulate Laboratory-Developed Tests and Medical Devices?" CEO, chief executive officer; CFO, chief financial officer; IT, information technology; LIS, laboratory information system. Job category Yes No Don't know No opinion Total Number % Number % Number % Number % Number Lab manager or supervisor 16 11 101 68 8 5 24 16 149 Lab director 4 4 78 83 4 4 8 9 94 Lab employee (med tech / lab tech / lab assistant) 10 13 45 58 10 13 13 17 78 Medical director, pathologist, physician, clinician, or PhD scientist 0 0 62 91 2 3 4 6 68 Send-out / referral testing 3 12 11 44 4 16 7 28 25 Quality and compliance 1 5 20 91 0 0 1 5 22 Executive (CEO, CFO, etc.) 0 0 19 86 0 0 3 14 22 IT / LIS 2 18 3 27 2 18 4 36 11 Customer service / support service 2 22 6 67 0 0 1 11 9 Office: executive assistant, administrative assistant, etc. 2 67 1 33 0 0 0 0 3 Specimen processing / receiving 0 0 0 0 0 0 1 100 1 Supply chain / ancillary services 1 100 0 0 0 0 0 0 1 Other 0 0 14 70 3 15 3 15 20 Total 41 360 33 69 503

489 respondents then answered a question regarding whether their laboratory performs LDTs. 327 (67%) responded "yes," 117 (24%) responded "no," and 45 (9%) responded "don’t know" (Fig 2b). As the survey was intended to assess how laboratories that perform LDTs would respond to the proposed FDA rule if enacted, a response of "no" or "don’t know" ended the survey for those respective respondents.

Respondents whose laboratories perform LDTs were then asked whether the FDA’s proposed rule would negatively impact their laboratories (n=322 responses). 270 (84%) responded "yes," 11 (3%) responded "no," and 41 (13%) responded "don’t know" (Fig 2c). Respondents were also asked whether they anticipate having to remove tests from their menu if the proposed rule is enacted (n=304 responses). A majority, 185 (61%) responded 'yes,' 101 (33%) responded 'don’t know,' and 18 (6%) responded 'no' (Fig 2d). Respondents were also asked whether their laboratories have the financial resources to pay for FDA user fees, with fiscal year 2024 medical device user fees displayed in the question stem: $21,760 per “moderate risk” 510(k) submission and $483,560 per “high risk” premarket authorization submission [24] (n=303 responses). 238 (79%) responded "no," 56 (19%) responded "don’t know," and 9 (3%) responded "yes" (Fig 2e).

High levels of concern regarding the potential impact of the proposed rule were expressed by respondents in this survey (Fig 3), with answers of "extremely concerned" or "very concerned" provided across all topics queried, including patient access to essential testing (269 of 305, 88%), availability of financial resources to comply with the proposed regulations (264 of 305, 87%), impact on innovation (261 of 306, 86%), future laboratory send-out costs (252 of 304, 83%), increase in test prices (248 of 303, 82%), availability of personnel resources to comply with the proposed regulations (247 of 305, 81%), and FDA’s ability to implement the proposed regulations (245 of 305, 80%). Only a small percentage of respondents (≤6%) chose either "not concerned at all" or "slightly concerned" for any of the topics queried.

Figure 3. Ratings for level of concern. Stacked bar chart showing respondent level of concern about seven topic areas if the FDA’s proposed rule is adopted. Rating scale: extremely concerned, very concerned, moderately concerned, slightly concerned, not at all concerned, don’t know. Percentages rounded to zero decimal places.

When asked how their laboratories would likely respond to the new regulatory requirements if the FDA adopts the proposed rule, respondents reported the following distribution of strategies regarding potential FDA submissions (n=303 responses): discontinue all existing LDTs that require submissions (48, 16%); or alternatively pursue FDA submissions for "only a few" of existing LDTs (50, 17%), "less than half" of existing LDTs (29, 10%), "more than half" of existing LDTs (41, 14%), or "all" existing LDTs (34, 11%) (Fig 4). One third of respondents (101, 33%) chose "don’t know" to this question, demonstrating that further clarification on the proposed regulations and associated costs will be required to formulate a laboratory’s strategy.

Figure 4. Anticipated response to the proposed rule. Respondents were asked how they think their laboratories would respond to the new regulatory requirements regarding their existing LDTs if the FDA adopts the proposed rule.

Respondents were then asked a question regarding expectations of their reference laboratories if the FDA adopts the proposed rule (n=295 responses; Fig 5). Respondents were asked to select their top two types of support. An equal majority of respondents expected their reference laboratories to advocate on behalf of laboratories to change the FDA rule (175, 59%) and to offer testing options for all LDTs that their laboratories discontinue (175, 59.3%), whereas 92 respondents (31%) would like consulting services on how to pursue FDA clearance/approval, and 57 respondents (19%) would like their reference laboratory to serve as a resource for education about the FDA rule and its implementation. 12 respondents (4%) selected "other" and included a variety of additional ideas including participation in litigation against a final rule, manufacturing and distribution of kits, partnership for specialty testing, sharing of protocols and residual specimens for LDT validation purposes, and physician education to alter LDT ordering practices.

Figure 5. Expected support from reference laboratories. Respondents were asked which types of support they would need from their reference laboratories if the FDA were to adopt the proposed rule. Respondents were instructed to please select their top two types of support.

Respondents were then provided an open text comment field to solicit additional feedback. Additional comments were received from 63 respondents. Of these 63 respondents, 1 (2%) was in support of the FDA’s proposed rule, 49 (78%) expressed opposition to the proposed rule, and 13 (21%) provided feedback that did not address either support or opposition. Multi-part comments were further subdivided by content to reveal a total of 123 distinct comment topics from respondents for thematic analysis. These were then categorized by semantic and latent thematic categories (Table 4). Representative examples of comments are shown in Table 5.

Table 4. Thematic analysis of open comments. Thematic categories displayed in the table were mentioned by a minimum of three respondents. CLIA, Clinical Laboratory Improvement Amendments; LDT, laboratory-developed test; NYSDOH, New York State Department of Health; TAT, turn-around-time. Theme Number Percent Negative impact to patients- General 18 15 Negative impact to patients- Pediatric 4 3 Cost & negative economic impact 17 14 Benefits of alternative regulatory structures (e.g., CLIA, CMS, NYSDOH) 12 10 FDA and government overreach 9 7 FDA-specific concerns 8 7 Discontinuation of testing & laboratory closures 6 5 Discipline-specific comments 5 4 Gratitude for survey opportunity 5 4 LDTs are not medical devices / labs are not manufacturers 5 4 Benefits of additional LDT oversight 4 3 Supplier challenges with proposed rule 3 2 Industry disruption 3 2 Other 24 20 Table 5. Example comments from respondents. CAP, College of American Pathologists; CLIA, Clinical Laboratory Improvement Amendments; COLA, Commission on Laboratory Accreditation; LDT, laboratory-developed test; NYSDOH, New York State Department of Health; TAT, turn-around-time. Patient care, cost, and economic impact • If this rule is finalized it is going to adversely impact patient care and health equity. • The rule would even be worse for children's hospitals, as many biochemical tests are performed locally because national reference labs cannot provide the same TATs. • The negative economic impact of the FDA’s proposed rule would be immense and has not been accurately or properly represented by the FDA. • Will add significantly to operational costs and lab workforce burnout, thereby creating a significant undue burden, with no data to indicate that this approach will substantively improve safety, efficacy, or utility. • We could not stay in business if we had to pay fees for every test on our menu and then new fees when a test has to be modified because a reagent is no longer available from supplier or in a form it is used in the original procedure. Regulatory comments • The NYSDOH system for LDT approval is a much better and more reasonable solution to LDT risk assessment. If followed, it would mitigate possible harm from the few LDT's on the market that cause a clinical risk due to poor performance or clinical validity. The FDA proposed rule is akin to a sledgehammer approach to a problem that requires scalpel intervention. • There is a need for oversight of LDTs, but it should be done with updating and modification of CLIA regulations and use that infrastructure. Modernization of CLIA is needed anyway since landscape of all testing (including even point of care) has changed markedly since the 1980s. • LDTs need reasonable regulation, but the FDA is taking a step in the wrong direction. I don't understand why this can't be part of the lab accreditation process, which is already highly scrutinized. Additional burdens to the LDT process make our country less prepared to handle the inevitable next pandemic. • I believe that quality laboratory test validation studies are verified by accrediting organizations (like CAP, COLA, etc.) that have deemed status by CMS. If there is rigor around the inspection process, then FDA oversight of LDTs in an accredited lab is not necessary. • I think having more oversite of LDT's may be warranted, but I am not sure the FDA's approach of requiring approval is reasonable or the most effective way to do this. FDA-specific comments and government overreach • I am most concerned that the FDA has no genuine interest in listening to the experts (scientists and pathologists) in laboratory medicine. • I don't feel adding FDA oversight would truly improve LDTs, rather it will only increase cost, delay innovation and the speed at which new tests can be put into use which hurts and harms the very persons they are "trying to protect." • I also believe there is no good evidence for the claims or basis of patient harm by LDTs. Again, this appears to be highly misrepresented by the FDA. • The FDA did not fully evaluate the impact this rule would have on labs and to patients. • I am afraid this is another instance of government overreach that does more harm than good. We have CLIA which is currently a way to oversee more closely a laboratory's quality of testing. Adding more layers of bureaucracy and costs does not help anyone. • The FDA is overstepping its mandate and must be curtailed and reined in. Discontinuation of testing, laboratory closures, and impact on innovation • The negative impact on our patients will be astounding if we have to divert to send out testing or stop testing all together. • If this regulation were to go into effect, there would be very few tests in our catalog that we could still perform. This would have a significant impact to the community we serve and to public health as a whole. • Due to time and cost constraints, we would likely have to discontinue these tests and stop much of our next generation sequencing tests that serve our complicated patient population which is at a large academic institution. • We truly do not know if we will be able to continue providing local, quality test results to the already under-served patient population. • The financial burdens on small and middle-sized laboratories will be significant and cause many labs to drop important LDTs from their menus. • This will be catastrophic to diagnostic innovation. • This rule could destroy our lab. Discussion References Notes This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. A note (and citation) indicating that the final rule was announced at the end of April was added. No other changes have been made, in accord with the "NoDerivs" portion of the license.