Clinical Microbiolog y

The debate over federal regulation of diagnostic tests is not new, but scientific advances, societal developments, and global events over the past decade have accelerated efforts by the Food and Drug Administration (FDA) and members of Congress to revise the regulatory oversight of these devices, including laboratory-developed tests (LDTs). Despite years of congressional hearings and public meetings, legislation in the House and Senate, draft guidance from the FDA, and debate in the stakeholder community, LDT regulation remains unchanged, and the path forward remains unclear. LDTs play an essential role in infectious disease (ID) management and treatment, and changes in their regulation will have far-reaching implications for diagnostic laboratories. LDTs are widely used by clinical micro-biology laboratories for the diagnosis and monitoring of a myriad infectious diseases, and until three years ago, such testing was conducted largely out of the spotlight. The COVID-19 pandemic changed this by bringing ID tests into the forefront. As the 118th Congress gets under way, the regulation and oversight of diagnostic tests, including LDTs, remains at the forefront of health care policy discussions on Capitol Hill and with the FDA. Change is coming, and it is important that clinical microbiologists, ID physicians, and other laboratorians have a seat at the table when such changes are being discussed.


Introduction
The debate over federal regulation of diagnostic tests is not new, but scientific advances, societal developments, and global events over the past decade have accelerated efforts by the Food and Drug Administration (FDA) and members of Congress to revise the oversight framework in place for these devices, including, and perhaps most notably, laboratory-developed tests (LDTs) (Table 1).LDTs are defined as a "class of in vitro diagnostic device (IVD) (Table 1) that is designed, manufactured, and used within a single laboratory" (1).Despite congressional hearings and public meetings, multiple bills in the U.S. House and Senate, draft guidance from the FDA, and vigorous debate in the scientific, clinical laboratory, and patient advocacy communities, the regulation of LDTs remains unchanged, and the path forward for revising how these tests are regulated remains unclear as we enter the 10th year of debate on the subject and a new Congress.For those of us who work on this issue from a policy and government relations perspective, the complexity of both the process of developing LDTs and the diversity in the clinical uses of these tests makes regulation challenging, and in turn, it makes drafting and enacting effective legislation nearly impossible.Furthermore, until the COVID-19 pandemic, infectious disease (ID) testing was largely out of the public spotlight, with clinical microbiology laboratories having relied upon LDTs for decades.This article reviews the events that led to the debate over LDT oversight, discusses considerations specific to clinical microbiology and ID testing, and provides perspective on where the discussion may be headed in Washington.
how Did We Get here?
To understand the current status of IVD regulation, it is important to briefly review the recent history of the issue.While the Medical Device Amendments granted the FDA broad authority over diagnostic tests more than 45 years ago, the authority over LDTs did not really come into question until the early 2000s as the number and complexity of LDTs increased (2).Prior to that time, the FDA declined to actively regulate the safety and effectiveness LDTs through applicable statutory authority.Instead, the FDA considered enforcement discretion sufficient and focused its attention on oversight of commercial test kits, which were manufactured, broadly marketed, and sold for use in many facilities.LDTs under enforcement discretion could continue operating without FDA pre-market review unless a particular test was called into question over safety concerns.LDTs prior to the early 2000s differed significantly from those developed and implemented in laboratories today, largely because they preceded significant advances in both human and microbial genetics and genomics.Ultimately, due to the dramatic technological advancements over the past 20 years, LDTs are now more widely used, and their overall risk profile has grown.The marketplace and the availability to consumers of tests that provide information on everything from one's ancestry to one's risk for cancer evolved dramatically in the early 2000s.As early as 2007, scientific organizations, including the American Society of Human Genetics, raised concerns about the safety of direct-to-consumer (DTC) tests marketed by 23 and Me, particularly in situations where health professionals are not involved in in the interpretation of results, the laboratory is not accredited, and tests lack analytical and clinical validity (3).Eventually the FDA would issue a warning letter to 23 and Me over their DTC saliva tests.Blood tests promising early detection of colon cancer and ovarian cancer (e.g., OvaSure ™ ) were developed.Unfortunately, following commercialization of the OvaSure assay, the test demonstrated unacceptably high numbers of both false-positive and falsenegative results, which led multiple cancer advocacy organizations and public groups to express concerns over the safety and efficacy of the test (4).As a result, the manufacturers of these tests received warning letters from the FDA, which ultimately elected to use its enforcement discretion and require premarket approval of the OvaSure assay.Incredibly, the OvaSure test was pulled after just 4 months on the market.The OvaSure case became the high-profile example that patient advocacy groups embraced to highlight the need for greater regulation of such tests in the interest of public health; it was the case that instigated the push for action to regulate LDTs.More recently, the investigation surrounding Theranos, and ultimately the prosecution of founder Elizabeth Holmes and other company leadership, continues to fuel the debate over gaps in regulation of diagnostic testing and the potentially harmful effects such gaps could have on patient and consumer safety.
In 2010, the FDA announced its intent, for the first time, to regulate all LDTs in light of the scenarios and cases noted above.By 2014, following technological and scientific advancements related to genetic and biomarker testing across multiple disease areas, the agency made its intent official by notifying Congress and issuing draft guidance (1).The overarching goal was to shift the baseline standard for these tests from one of safety and effectiveness to one that increasingly focuses on clinical and analytical validity.This was also the point when congressional attention on the issue increased, spurring the House Energy and Commerce Committee to hold hearings on the topic.Members of Congress, including Representative Diana DeGette of Colorado, began considering legislative proposals to address the agency's concerns and reinforce its authority to regulate IVDs, including LDTs.
The draft guidance outlined a regulatory framework for how the FDA would move beyond enforcement discretion to requiring pre-market review of these tests.The proposed framework was risk based, and the guidance suggested that LDTs could be categorized into the following three classes: (i) tests that would be exempt from regulation, (ii) tests that would only require FDA registration and adverse event reporting, and (iii) tests that would require premarket review and a defined quality system (5).Those tests deemed "high risk" would be required to go through the full pre-market review process.Notably, while the FDA maintained it had enforcement discretion authority, congressional supporters, along with other agency leaders, believed that the FDA's position needed to be strengthened with legislation.The question of the FDA's authority to regulate these tests and how such oversight would align with current regulation of clinical laboratory operations under the Clinical Laboratory Improvement Amendments (CLIA) (Table 1) became a sticking point, however, which has in part shaped the debate for the past several years.
The FDA draft guidance, coupled with congressional attention, sparked controversy in the medical and clinical laboratory communities and incensed those who believed the guidance encroached on the practice of medicine and treated laboratories as if they were device manufacturers.On the other side of the debate, concerns centered on patient safety and the fact that patients are indifferent to what methods are used or where the test is performed-they just want it to be accurate.Concerns were also expressed that having two regulatory paths (i.e., manufacturers going through pre-market approval while LDTs do not) created an uneven playing field.By 2016, the FDA had held public meetings and received thousands of public comments on the draft guidance, but the Obama Administration was in its final weeks in office and the decision was made to delay issuance of any final guidance.At the beginning of the Trump Administration in 2017, the decision was made to halt work completely on final guidance and instead to allow time for a robust community discussion and legislative approach (1).The new legislative approach focused on creating a new definition and framework under IVDs called "in vitro clinical tests" that would ensure that all assay software and testing platforms were also regulated.The new framework would include LDTs.

A Community Divided
As mentioned above, the proposed guidance revealed divisions in the science, health care, and patient advocacy communities on whether and how the FDA should provide additional oversight of LDTs, alongside concerns around the effects that new regulations would have on providers, test developers, and patients.These divisions resulted in unexpected alliances and fell across lines not seen with other policy issues on which these groups largely agree and for which they advocate together, such as robust funding for medical research through the National Institutes of Health and funding for public health programs under the Centers for Disease Control and Prevention.The patient advocacy community, particularly organizations focused on cancer, Down's syndrome, genetic disorders, and rare diseases, took an active position in favor of the guidance.These groups were initially joined by the commercial testing community, represented by the trade group AdvaMedDx, and a number of provider groups, like the American Society for Clinical Oncology.Later, the American Clinical Laboratory Association, which represents commercial laboratories and testing facilities, would join in favor of legislation.On the other side of the debate were academic medical centers, health care providers, and scientific societies, such as the American Society for Microbiology (ASM), the Infectious Diseases Society of America (IDSA), and multiple pathology and clinical laboratory groups.Many of these groups believed that LDT regulation and oversight through CLIA was sufficient, and they provided counterproposal alternatives to FDA regulation that centered around modernization of CLIA requirements, which have not been revisited through legislation since 1988.The complexity of the issue and the stark disagreements between the commercial clinical laboratories and the patient and provider communities made proceeding on the issue through legislation or agency guidance difficult.These divisions persist as the debate continues, despite some groups softening their positions on the legislation as it has gained traction in recent years.The discord in the community has ultimately stymied supporters' ability to get a bill across the finish line.

Infectious Disease Testing Concerns: "One size Does not Fit All"
LDTs play an essential role in ID management and treatment, and changes in their regulation would have far-reaching implications for the clinical laboratories offering such testing.LDTs are widely used by clinical microbiology laboratories for the diagnosis and monitoring of a myriad IDs.Results from an unpublished 2022 ASM survey of 111 clinical microbiology laboratory members revealed that 90% of the respondents used LDTs and that the numbers of LDTs offered per laboratory ranged from less than 5 to over 100.LDTs are used to evaluate tens of thousands of samples each year for detection of a wide range of infectious organisms and conditions.Importantly, their uses go beyond just patient care diagnostics and antimicrobial stewardship purposes; they are also used for public health surveillance and outbreak mitigation.Microbiologic testing is inherently different than other diagnostic disciplines.Often, ID tests are not used as a "standalone" diagnostic, but rather, are part of a larger diagnostic workup for a patient.ID diagnostics are used not only to identify a pathogen, but also to determine the pathogen's antimicrobial susceptibility pattern and to identify the organism burden (i.e., viral load), which in turn help clinicians guide and select appropriate antimicrobial therapy and monitor treatment response.ID LDTs also play an important role when testing for uncommon infectious agents and for detection of new or emerging pathogens, and many are developed with specific patient populations in mind, including pediatric and immunocompromised individuals, who can be at risk for different types of pathogens than the general population.The 2022 ASM survey also found that the reasons for using LDTs varied, but the lack of FDA-cleared or -approved alternatives, the convenience and need to utilize existing platforms already present in the laboratory, and improved performance over available IVDs were the top three driving factors for laboratories to use LDTs.
The unique aspects of how and why LDTs are used in ID diagnostics make pre-market approval untenable, and the proposed risk-based framework, with strict definitions of "low," "moderate," and "high" risk, is concerning to medical microbiologists.How would these tests be classified, and would risk mitigation measures really lower the risk?As an example, for patients undergoing organ or bone marrow transplantation, testing for select transplant-related viruses almost always involves LDTs because there are no commercially available tests for establishing the viral load for a number of these pathogens, which is a necessary part of clinical management (5).Other concerns include how any LDT modifications would be addressed, including the addition of new sample sources or the need to modify primers/probes for molecular assays in cases of pathogen evolution.There are many situations for which exemptions may be necessary, given the inherent unpredictability of IDs, and consideration needs to be taken for non-commercial microbiology laboratories, which are already financially strapped and would not be able to hire additional staff to assist with new regulatory requirements or otherwise support submission of LDTs for FDA review.These and other concerns were communicated throughout 2014 and 2020 to Congress by ASM and partner organizations, including the IDSA, with some success.Ultimately however, the language in the VALID Act did not change sufficiently to alleviate the clinical microbiology and ID communities' concerns.As a result, ASM and peer organizations representing clinical laboratory professionals have not supported this legislation and have in some cases actively advocated against it.

The COVID-19 effect
The COVID-19 pandemic changed the landscape for clinical microbiology testing, bringing ID LDTs into the public spotlight as never before.In early 2020, SARS-CoV-2 emerged in the United States and immediately presented diagnostic testing challenges, from lack of immediately available assays, necessitating the development of SARS-CoV-2 LDTs, to limited reagents and supplies to perform even routine patient care testing.Clinical microbiology laboratories worked tirelessly, however, to develop SARS-CoV-2 LDTs to support the rapidly growing pandemic.
With the declaration of a public health emergency, the emergency use authorization (EUA) policy kicked into gear, which required all SARS-CoV-2 tests, including LDTs, to receive FDA approval before being sold or implemented for clinical use.This policy, coupled with an imperfect assay from the Centers for Disease Control and Prevention that was initially used by many laboratories, resulted in significant delays to implementing SARS-CoV-2 diagnostic tests for routine patient care at a critical juncture early in the pandemic and set the U.S. back in terms of early testing availability.ASM and its members mobilized to bring these challenges to the attention of FDA officials (6).The agency listened to ASM's concerns and temporarily lifted the restrictions on LDTs and adjusted the EUA requirements to allow laboratories performing SARS-CoV-2 LDTs to submit requests for retroactive approval after deploying the tests for clinical care.Without this flexibility, rapid diagnosis of SARS-CoV-2 and the implementation of subsequent mitigation measures could not have proceeded.Even with this adjustment, however, many academic medical centers that had worked to develop tests were unable to use them for weeks in February and March 2020 while this change was being implemented.
For laboratories unable to validate their own LDTs, there were no approved commercial tests available until mid-March 2020.
As the pandemic worsened over the course of 2020, hundreds of SARS-CoV-2 LDTs, along with commercial assays, were approved through the EUA process.This process connected clinical laboratory directors and their staff to the FDA in vitro diagnostic staff; these were two groups of individuals who had not previously interacted.In an effort to mitigate confusion and misunderstandings, ASM facilitated many conversations between clinical laboratory leaders and FDA officials during this time, and the interactions were collaborative and productive.Unfortunately, not all SARS-CoV-2 LDTs successfully completed the regulatory review process, and as might be expected, some LDTs submitted by academic medical centers were not approved due to both design and validation problems (7).The fact that not all tests made it through approval is not surprising, but it had the unfortunate result of placing microbiology testing in a harsh light and further justifying to supporters the need for increased FDA oversight and regulatory changes.Microbiology testing is now in the spotlight and not immune from criticism that previously only other (i.e., non-ID) diagnostic and prognostic assays had received.In recent months, FDA officials have publicly cited problematic SARS-CoV-2 tests as another reason why a new regulatory framework with pre-market approval is needed, now more than ever, to ensure that high-risk tests are clinically valid (8).

What's next?
As the 118th Congress gets under way, the regulation and oversight of diagnostic tests, including LDTs, remains at the forefront of health care policy discussions on Capitol Hill and within the FDA.In conversations with community stakeholders and in testimony before the House Energy and Commerce Committee, FDA officials have expressed continued support for a legislative approach, such as the VALID Act, which is the latest iteration of legislation, noting that there may be a need for an exemption for certain academic medical centers (9).With the support of the agency, Rep. DeGette (D-CO) remains committed to reform through legislation, and along with Rep. Bucshon (R-IN), reintroduced the VALID Act on 29 March 2023.Rep. Bucshon has also secured the Energy and Commerce Committee Chair's commitment to holding a hearing on the legislation.Upon re-introduction of the legislation, Rep. DeGette specifically included a microbiology testing example, saying, "Whether it's an at-home test for COVID-19 or a cancer screening done in a hospital, diagnostic tests are used by millions of patients every single day in this country to make important health care decisions.We have a responsibility to ensure that these tests are as accurate as possible, and that the patients using them can rely on their results" (10).
There has also been some speculation that the bill could be attached to "must pass" reauthorizing legislation, the Pandemic and All-Hazards Preparedness Act (PAHPA) (Table 1), which expires in September 2023, and will be under the purview of the same committees in Congress.However, support in the Senate is unclear given that the primary Republican champion in that chamber, Sen. Richard Burr, retired at the end of 2022.Sen. Michael Bennet (D-CO), the Democratic lead on the VALID Act, has not indicated whether he will reintroduce it and who from the Republican side of the aisle may join him.Furthermore, one of the biggest supporters in that chamber, Sen. Patty Murray (D-WA), is no longer Chair of the Senate Health, Education, Labor and Pensions (HELP) Committee, all of which could slow the bill's movement through the committee.
At ASM, we anticipate revived discussions around LDT regulation in the coming months and a renewed effort to push the bill across the finish line, including using PAHPA as a vehicle, citing the importance of these regulations in emergency situations.If congressional action stalls again, many stakeholders have discussed whether the FDA may go the route of rulemaking to address the concerns, a move that Commissioner Califf suggested in 2022 was an option should Congress ultimately fail to pass the bill (11).However, in the months since Califf's comments, FDA officials have backtracked from this position, stating that new authorities are needed to establish a framework for IVDs and the only way to accomplish this, and ensure that the FDA has the resources it needs to fulfill this role, is through legislative action.
ensuring a seat at the Table ASM continues to engage with government officials and entities on the issue of LDT regulatory oversight and has formed strong partnerships with IDSA and other clinical laboratory organizations with the goal of developing a mutually beneficial path forward.Advocacy by our members has been instrumental in highlighting the concerns of medical microbiologists and ID physicians around the new proposed regulatory framework for LDTs, and they have been directly interacting with policymakers in an effort to have a constructive dialogue and effect change.Such advocacy is essential, since in Washington, if you are not at the table, you are on the table.We cannot afford to remove ourselves from the center of the discussion even if we continue to disagree with the details of the approach.At the heart of ASM's concerns is that a "one size fits all" approach does not work well in the field of diagnostic testing, and it is crucial that the needs of clinical microbiology laboratories, including academic, not-for-profit, and commercial facilities, be taken into consideration when developing any new regulatory framework.
As these conversations have continued, we have seen important changes made to the legislation in an effort to address these concerns.The definitions of "high risk," "moderate risk," and "low risk" have been repeatedly adjusted to meet stakeholder needs, although the devil remains in the details.Exemptions have been modified to address many concerns, including those of the clinical microbiology community.For example, antimicrobial susceptibility tests, "first of a kind" assays, and those for which there are no viable commercial options or that are classified as an "unmet need and humanitarian use" are exempt from the abovementioned risk stratification.Language has been added to ensure that the proposed FDA oversight aligns with and does not duplicate authorities for the Centers for Medicare and Medicaid Services under CLIA.While the authors of the new LDT regulatory bill continue to reject language that would exempt disease-specific areas (e.g., ID), momentum has grown to exempt academic medical centers from the provisions.While not a panacea for clinical microbiology laboratories, such an exemption would provide regulatory relief for many members and laboratories associated with ASM.Howwever, there is still work to be done.

The Devil Is in the Details
For clinical microbiology laboratories, legislation that leaves the details to the FDA to sort out and implement, with stakeholder input, may be the best option to ensure that the unique needs of ID testing and use of LDTs to detect pathogens are considered.The VALID Act as reintroduced continues to take a highly prescriptive approach, which remains a sticking point.The FDA Center for Devices and Radiological Health (CDRH) has the technical expertise and subject matter experts to sort through the complexity of a risk-based framework to ensure the safety and accuracy of tests and is better able to understand the distinct differences between testing methods and the clinical impact of results.To date, legislators have been unwilling to distinguish between different types of disease testing in the introduced bills, saying that requests for specific disease exemptions are "non-starters."But legislation that is overly prescriptive and takes a one size fits all approach risks tying the agency's hands, making it difficult for subject matter experts to implement the law with flexibility, which has been a hallmark of CDRH's approach to recent testing challenges.It is important for medical microbiologists, ID physicians, and most of all patients that any new regulations allow for the nuance associated with clinical microbiology diagnostic testing, including the widespread utilization of LDTs in clinical ID practice.

Conclusions
Change is coming, and clinical microbiology laboratories need to be prepared.The status quo is untenable for reasons that largely have nothing to do with the quality of testing offered through these laboratories, but there is a compelling case being made that LDTs as a whole category of tests cannot continue to operate independent of premarket review.ASM does not reject this position.As we learned through the SARS-CoV-2 testing experience, there are situations where it is best for laboratories and for patients that tests receive review and approval through the FDA, in addition to the regulations under CLIA.There is an old saying that sometimes one should "be for what's going to happen."While it may take 10 more years, chances are that legislation in some form will pass, and the regulations will change.Most importantly, however, the clinical microbiology community must continue to have a seat at the table and provide input when these changes are being discussed.ASM and its clinical and public health microbiology leaders have established relationships with members of Congress and their staffs, and we have been able to forge an open dialogue and productive working relationship with the FDA CDRH staff.Working together, policymakers and stakeholders can achieve policy changes that protect patients and consumers and minimize disruptions and regulatory burdens that additional oversight could bring to microbiology testing.ASM will continue to advocate for the needs of its members and the patients they serve, alone and in concert with likeminded stakeholders.

Table 1 . Key terms and definitions Term (acronym) Definition
Pandemic and All-Hazards Preparedness Act (PAHPA) Legislation, first enacted in 2006, that authorized funding to improve bioterrorism and other public health emergency preparedness and response activities and established the Biomedical Advanced Research and Development Authority within the Department of Health and Human Services for the advanced research and development of medical countermeasures.The legislation is reauthorized every 5 years and currently expires on 30 September 2023.
The bill that has gotten the most traction to date and nearly passed in late 2022 was the Verifying Accurate and Leading-edge In Vitro Diagnostics (VALID) Act (Table1), sponsored by Representatives Diana DeGette (D-CO) and Larry Bucshon (R-IN) in the House of Representatives and Senators Michael Bennet (D-CO) and Richard Burr (R-NC) in the Senate.This legislation has evolved over the past two Congresses to try to address community concerns while maintaining the goal of pre-market review for high-risk IVDs.