Senate RFI on LDTs
Below is the full text of a response we wrote to Senator Cassidy in response to his RFI on tests.
April 3, 2024
Dear Senator Cassidy,
Thank you for your attention to the need for well-regulated and well-performing laboratory tests. The importance of accurate and useful diagnostics tests cannot be overstated, and the bifurcation of the regulatory system between in vitro diagnostics (IVDs) and laboratory developed tests (LDTs) has been a long-standing public health concern. Numerous attempts, from the 2007 IVDMIA guidance,[1] to the 2014 LDT guidance[2] to the 2022 VALID Act[3] have been forwarded to address this. None have succeeded.[4]
The history of the FDA’s efforts regarding this should not go unnoticed. FDA has held public convenings,[5],[6] opened dockets, and met with stakeholders for years.[7] Some of these stakeholders have been intransigent, blocking FDA and Congress’s attempts at compromise.[8] With no other options left, FDA has asserted its rulemaking authority. Those who claim that FDA cannot or should not do so are being disingenuous at best, having stymied all progress on LDT regulation for more than a decade, and complaining when FDA continues to assert its authority in the interest of public health. Congress should support FDA regulation of all tests, putting all test manufacturers on an even playing field.
As part of an overarching framework, the clinical utility of the test, while outside FDA’s scope, is of the utmost importance. How the test functions, how well it detects analytes, what its limitations are, how test results are returned and what the results of the test mean are critical to the appropriate deployment of these potentially powerful tools. However, we have seen these be used inappropriately, drawing concern from the public[1] and Congress.[2]
Due to a lack of systemic, overarching regulation, there are many unknowns regarding tests. We do not fully know what tests are offered, by whom, for what.[3] We do not have accurate information about what custom tests are offered or how often. We do not have a way to know the performance of many tests. We have no real way to know if there are adverse events associated with tests. For example, if a patient’s cancer does not respond to a targeted therapy, we don’t currently know if it is due to an inaccurate test, misinterpretation of a test, or if the patient is one of the unlucky people for whom the markers indicate the targeted therapy but the tumor nonetheless fails to respond.
While outside the scope of this particular request, the cost of tests to the healthcare system is staggering. Medicare alone spent $5.5 billion on only the top 25 tests in 2021.[4] The direct costs of tests, and therefore the direct and indirect costs of tests with unknown or poor performance, is immense. The cost of a regulatory system that provides accurate testing may be large, but a system that provide little, disparate or no oversight of tests is more expensive.
However, one of the hallmarks of science is transparency. Therefore, proposals that include publication of information regarding test performance, ideally in a centralized and easy-to-use fashion, support those principles. Proposals that consider characteristics of tests -- including follow-on-tests -- as secretive, are not appropriate.
Another key principle is that the regulatory burden, particularly the administrative burden, must be minimal. Manufacturers, including laboratories, should be required to do no more than is necessary to ensure the development of safe and accurate tests. To be clear, good tests are integral to our medical system. Despite laboratories claiming that they are fundamentally different from test kit manufacturers,[5] that is not how providers and patients see it. If tests are indeed important to healthcare, there is no reason they should not provide accurate information.
In the absence of sufficient federal oversight regarding clinical validity, other programs have been developed.
The Clinical Laboratory Improvement Act was originally enacted to ensure proper laboratory functions regarding Pap tests.[6] CLIA, implemented by CMS, still governs laboratory procedures, and ensures analytical validity of the test in that laboratory;[7] CMS “does not have the expertise to assure that tests work”.[8]
New York State’s Department of Health has established a Clinical Laboratory Evaluation Program. The program requires enrollment for any laboratory that seeks to use samples from New York State, regardless of where the test is performed.[9] Modifications of tests have to be re-reviewed.[10] Labs that have clinical laboratory permits from the New York program are exempt from CLIA.[11] The program has been ongoing, in some form or another, since 1991.
MolDx was established in 2011 to ensure that a CMS contractor (MAC) was paying for tests meeting the statutory requirement of reasonable and necessary.[12] The program reviews non-FDA approved/cleared tests and modified FDA approved/cleared tests.[13] States covered by MACs participating in the program include: West Virginia, Virginia, North Carolina, South Carolina, California, Nevada, Washington, Oregon, Idaho, Montana, Wyoming, North Dakota, South Dakota, Arizona, Utah, Ohio, Kentucky, Michigan, Indiana, Iowa, Missouri, Kansas, Nebraska, Alabama, Tennessee and Georgia.[14],[15]
A single database -- one that can both pull data from multiple sources and allow numerous users to run reports -- could be a solution. The potential of cloud storage and interoperability of data, as well as tagging/segmenting data, can yield, together with willing players, at least one powerful part of the solution.
The Centralized Test Database could leverage data – such as CLIA inspection data, MolDx application information, New York State data and FDA’s existing IVD data – to provide necessary oversight. Since many of these databases already exist, we would need to determine what is already interoperable and can be easily combined, versus what needs to be amended.
By tagging and segmenting data, the Centralized Test Database could allow any user, from payers to competitors to patients, access to appropriate data regarding tests. An insurance company could use the data to ensure coverage for tests that are clinically valid; providers could research the various performance characteristics of tests they are considering ordering; patients could use the database to understand the limitations of a test result; and, laboratories could compare the performance of their tests and their competitors, thereby understanding best practices.
Further, the Centralized Test Database may make adverse event reporting simpler; adverse events could be funneled back into test performance, reported to the CDC when necessary, and reported to FDA to monitor. Laboratories should not have to fill out multiple forms to multiple HHS agencies for a single event.
The Centralized Test Database is not the single answer to ensuring well-regulated and well-performing tests, but could be a large part of a multi-prong effort.
Answers to some of your specific questions are on the following pages.
FDA Regulatory Framework for Diagnostics
1. How well is FDA’s medical device framework working for the regulation of diagnostic products? Are there improvements that should be made? a. Of these specific changes, which would require Congressional action, and which can be effectuated by FDA alone?
The regulation of tests by FDA is split into two distinct categories which are functionally irrelevant to providers or patients. The difference between an IVD and LDT in terms of manufacturing has led to a potential difference in accuracy and utility of these tests. Tests should meet the same clinical standards notwithstanding their type of locality in which they are run. Whether an academic medical center, a local hospital, a reference laboratory or anywhere else, patients and providers deserve the same accuracy of test results; no additional burden should be placed on patients to ensure the validity of their test results.
Recent legislative proposals sought to establish a tailored approach to regulating all tests similarly, based on risk rather than place of manufacture. While those specific bills may not be the solution, the approach was correct. All tests, regardless of where they are manufactured, run or developed, should be regulated the same way.
If Congress believes that FDA’s IVD regulation is not appropriately tailored, it must change that. However, if the IVD regulation is appropriate, then FDA can, on its own, remove enforcement discretion for LDTs and regulate them the same as IVDs. A consistent approach is required.
2. Does the current device regulatory framework support the review of diagnostics that are developed using AI or that incorporate AI?
Even FDA has stated that it does not have the appropriate authority or review pathways to regulate products with AI.[16] This is something that other health agencies, including the EU and Australia, have already addressed. Congress should act on this with all due haste.
3. What, if anything, makes diagnostics distinct among FDA-regulated medical products to warrant specific attention to how AI may be used in the review of product submissions?
Laboratory based diagnostics may not be significantly different than other diagnostics, such as digital pathology or AI in radiology. A tailored approach to regulating diagnostics should be used. The longer Congress and FDA do not act, the more patients are exposed to the risk of false results; however, digital pathology and radiology devices are currently regulated under FDA’s device authorities, as are IVDs. So Congress should consider the diagnostic reform which may include tools other than laboratory tests, but with respect to laboratory tests, what we now call IVDs and LDTs should be regulated consistently.
Many LDTs are already reviewed by New York State or CMS’s MolDx program. Leveraging these existing programs which aim to ensure clinical and analytical validity -- and, in the case of MolDx, clinical utility[17] -- has not hindered innovation. HHS should leverage these existing programs and any other potential data sources for a Centralized Test Database that can serve the needs of CMS, FDA, CDC and other operating divisions. This Centralized Test Database could also be a resource for providers and patients to understand the performance characteristics of tests or find where specific tests are offered. It could provide a consolidated way to report adverse events and allow enforcement actions to protect public health.
4. Are the regulatory pathways intended to evaluate diagnostics for special populations (i.e. rare diseases or genetic disorders) working? a. How could they be enhanced to accelerate and authorize products for special populations, for example, certain companion diagnostics for rare biomarkers?
People with rare diseases do not deserve inaccurate tests. Tests for rare disorders, further, may be used widely and therefore the risk of an inaccurate result could be widespread. Therefore, tests for rare disorders should also be reasonably accurate.
7. Does FDA’s current risk classification framework properly measure risk versus regulatory controls for diagnostics products? a. If not, how can FDA’s risk-based regulatory approach to diagnostics be improved to better align the degree of regulatory oversight with patient risk and benefit?
FDA’s risk classification is by and large accurate; however, the risk of the test and the type of studies FDA needs are not closely aligned. For example, NGS tumor sequencing tests, which can determine the anti-cancer medication a patient receives, is high risk. But FDA does not need to examine each marker individually if the platform is analytically valid and the ever-evolving scientific data as properly referenced to interpret the utility of those markers. Therefore, FDA has classified these tests as Class II, which falsely indicates that these are moderate risk.[18] FDA has done the best it can under its existing authorities.
9. Is the “safety and effectiveness” standard against which diagnostics are reviewed the most appropriate review standard to assign risk management for clinical tests?
When considering the risk of a test, it is not the risk of the device itself, but of a bad result. We often use the term “high-stakes” rather than “high-risk” to convey this information.
10. Do the proposed reforms to FDA’s device framework warrant the establishment of a new regulatory pathway specific to diagnostics? If yes, what are the principles that should guide such a new framework, as it would be applied to diagnostics currently subject to FDA premarket review?
Yes. This framework should be built on the scientific principle of transparency, as well as a regulatory principle of fairness. Tests should be regulated based on the risk the patient of a false result, not where the test is manufactured or run.
CLIA Regulatory Framework for LDTs
6. Where does redundancy exist, if at all, within the current CLIA regulatory structure with respect accreditation standards under federal and state licensure programs, as well as through CMS approved accreditation organizations?
There is a way to deploy technology to leverage existing data frameworks in a way that reduces administrative burden and provides much-needed transparency. HHS could create and house a Centralized Laboratory Database of information about what tests are available, for which indications, and what the performance characteristics are. All stakeholders, including FDA, CMS, MolDx, NYS, payers, individual providers and patients could have access to some version of the Centralized Laboratory Database. Each regulatory body could pull a report about whatever test they need information on, and the manufacturers would not have to fill out redundant forms.
7. In considering legislative reforms to CLIA, should LDTs be defined in statute? What aspects of test development would characterize such a definition?
A test should not be regulated differently based on where it is manufactured. A test used on a patient to provide information, regardless of being run at an academic medical center, a local laboratory, a reference laboratory or a provider’s office, should provide accurate and clinically useful results. Any definition must encompass all tests – now known as LDTs and IVDs – as one class of medical products.
8. How should Congress consider issues relating to the practice of medicine and its relationship with labeling for LDTs? Should there be additional oversight of the information conveyed to patients serviced by LDTs?
Patients should have access to accurate information about the performance of the test, and what the results mean. These types of issues, addressed by FDA for medical products, could be addressed through the use of a database such as the one discussed above.
Thank you again for the opportunity to provide comments regarding the regulation of diagnostic products. I would be pleased to continue this discussion; I can be reached at [email].
Sincerely,
Cara Tenenbaum, Principal
Strathmore Health Strategy
[1] Sarah Kliff and Aatish Bhatia, When They Warn of Rare Disorders, These Prenatal Tests Are Usually Wrong, New York Times, Jan 1, 2022 available at https://www.nytimes.com/2022/01/01/upshot/pregnancy-birth-genetic-testing.html.
[2] Letter from Members of Congress to FDA regarding NIPT, January 21, 2022, available at https://roy.house.gov/sites/evo-subsites/roy.house.gov/files/wysiwyg_uploaded/Final%20Roy-Daines-Fischbach%20Pro-Life%20Letter%20to%20FDA%20on%20NIPT.pdf.
[3] We do have some of this data from the New York State and MolDx programs, discussed later.
[4] Department of Health and Human Services Office of the Inspector General, Data Brief: Medicare Part B Spending on Lab Tests Increased in 2021, Driven By Higher Volume of COVID-19 Tests, Genetic Tests, and Chemistry Tests, OEI 09 22 00400, December 2022 available at https://oig.hhs.gov/oei/reports/OEI-09-22-00400.pdf.
[5] Remarks of Dara Eisner, March 21, 2024. I do not believe that a uniform approach, ie a so called “level playing field “is the thing we should be focusing on here. A level playing field assumes we are all playing the same sport. When in fact we’ve got different leagues.” See https://energycommerce.house.gov/events/health-subcommittee-hearing-evaluating-approaches-to-diagnostic-test-regulation-and-the-impact-of-the-fda-s-proposed-rule
[6] “In the 1960s, many women received false negative results of their Papanicolaou smear—a then-annual test for cervical cancer— now often referred to as a Pap test or Pap smear…In response to the obvious failure, Congress created the Clinical Laboratory Improvement Amendments (CLIA) of 1967 to regulate hospitals and independent laboratories and the tests these labs analyze. Continued concerns regarding the accuracy of Pap tests, as well as other laboratory test results, led to CLIA’s further amendment in 1988, expanding regulation to all laboratories, including those in doctors’ offices.” Grabman, G. and Tenenbaum, C. FDA Regulation Must Uphold Women’s Health, 77 Food and Drug L. J. 3 (2022) available at https://www.fdli.org/wp-content/uploads/2022/12/Grabman-Tenenbaum-FDLJ-77-3.pdf.
[7] CLIA Overview, CMS (2013) available at https://www.cms.gov/regulations-and-guidance/legislation/clia/downloads/ldt-and-clia_faqs.pdf.
[8] Shuren, J. and Hughes, D., FDA and CMS: Americans Deserve Accurate and Reliable Diagnostic Tests, Wherever They Are Made (2023) available at https://www.fda.gov/medical-devices/medical-devices-news-and-events/fda-and-cms-americans-deserve-accurate-and-reliable-diagnostic-tests-wherever-they-are-made.
[9] “The Clinical Laboratory Evaluation Program (CLEP) seeks to ensure the accuracy and reliability of test results in clinical laboratories located in or accepting specimens from New York State (NYS) through on-site inspections, proficiency testing and evaluation of the qualifications of personnel of state permit-holding clinical laboratories and blood banks. The proper performance of diagnostic laboratory tests is a matter of vital concern, affecting the public health, safety and welfare of all NYS residents.” New York State Department of Health, About the Program available at https://www.wadsworth.org/regulatory/clep/about-the-program.
[10] CLEP Releases LDT Review Data, Nov. 8, 2023, available at https://www.wadsworth.org/news/clep-releases-ldt-review-data.
[11] “The excellence of the center's Clinical Laboratory Evaluation Program has been acknowledged by CMS through their granting of exempt status from the federal Clinical Laboratory Improvement Amendments of 1988 for laboratories located in and holding NYS clinical laboratory permits.” New York State Department of Health, About the Program available at https://www.wadsworth.org/regulatory/clep/about-the-program.
[12] See CMS’s LCD page at https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=35025.
[13] Id.
[14] “Although Palmetto “owns” the MolDX program, several other MACs also participate in the program. These include Noridian JE and JF, CGS J15, and WPS J5 and J8.” Medical Management Plus, The Molecular Diagnostic Services (MolDX) Program, Nov. 17, 2017, available at https://www.mmplusinc.com/kb-articles/the-molecular-diagnostic-services-moldx-program.
[15] CMS MAC map available at https://www.cms.gov/files/document/ab-jurisdiction-map03282023pdf.pdf
[16] “However, FDA officials said updated authorities would help it regulate medical devices enabled with artificial intelligence (AI), in particular. Members of Congress are currently considering enhancing oversight of AI, including in medical devices, and congressional members have discussed barriers with FDA. However, FDA has not clearly identified, documented, and communicated to Congress the specific legislative changes that would help it address these challenges. Without this information, Congress may not be able to appropriately update FDA's authorities, and FDA may miss opportunities to fully realize the public health benefits of this technology.” GAO, Selected Emerging Technologies Highlight the Need for Legislative Analysis and Enhanced Coordination, Jan. 25, 2024 available at https://www.gao.gov/products/gao-24-106122.
[17] “In order to receive favorable review results, the assay must demonstrate clinical utility (CU), fulfill the CMS "reasonable and necessary" criteria, and meet analytical and clinical validity (AV/CV) standards.“ Technical Assessment, MolDx available at https://www.palmettogba.com/palmetto/moldxv2.nsf/DID/9W2LPH1487.
[18] 21 CFR 866.6080
[1] Federal Register Notice, Draft Guidance for Industry and Food and Drug Administration Staff; In Vitro Diagnostic Multivariate Index Assays; Availability, July 26, 2007, 72 FR 41081, available at https://www.federalregister.gov/documents/2007/07/26/07-3660/draft-guidance-for-industry-and-food-and-drug-administration-staff-in-vitro-diagnostic-multivariate.
[2] Food and Drug Administration, Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), October 3, 2014 available at https://www.fda.gov/media/89841/download
[3] S.2209/H.R. 4128, 117th Congress
[4] “Burr said he's confident that lawmakers will support the lab measure, which was dropped from omnibus talks late last year over concerns from House members. ‘I don't think anybody in the House was opposed to VALID,’ he said. ‘I think there were a lot of people in the House that didn't know what the hell it was or what it did or the impact it was going to have. That may be my fault to some degree, because maybe we should have done more outreach.’” CQ Morning News, February 8, 2023.
[5] Federal Register Notice, Framework for Regulatory Oversight of Laboratory Developed Tests; Public Workshop; Request for Comments, November 24, 2014, 79 FR 69860 available at https://www.federalregister.gov/documents/2014/11/24/2014-27713/framework-for-regulatory-oversight-of-laboratory-developed-tests-public-workshop-request-for
[6] Federal Register Notice, Oversight of Laboratory Developed Tests; Public Meeting; Request for Comments, June 17, 2010, 75 FR 34463, available at https://www.federalregister.gov/documents/2010/06/17/2010-14654/oversight-of-laboratory-developed-tests-public-meeting-request-for-comments.
[7] FDA Discussion Paper on LDTs, January 13, 2017, available at https://www.fda.gov/media/102367/download
[8] Anna Clark, The Tests Are Vital. But Congress Decided That Regulation Is Not., ProPublica, Jan. 24, 2023, available at https://www.propublica.org/article/prenatal-screening-cancer-tests-regulation.