What Every Clinical Virologist Should Know About The VALID Act

Abstract

In 2018, a bi-partisan proposed draft legislation called the Verifying Accurate, Leading-edge IVCT Development (VALID) Act was released by Representative Larry Bucshon (Republican-Indiana) and Diana DeGette, (Democrat-Colorado). The VALID Act attempts to create a new framework for the oversight and regulations of both laboratory-developed testing procedures (commonly known as laboratory-developed tests) and In vitro diagnostic tests by the U.S. Food and Drug Administration. The potential impact of this new law if passed may be significant for clinical laboratories in terms of diagnostic test development and implementation. In this report, we review the background and key information that every clinical virologist should know about the VALID Act.

1. Background

In the United States, the Food and Drug Administration (FDA) regulates all in vitro diagnostics (IVD) tests. IVD tests are defined as any product (e.g. reagents, instruments, and systems, biological products) whose intended use is for the diagnosis and/or management of disease or other health conditions (1). IVD tests are categorized into three classes: class I, class II and class III devices ranging from low risk and least regulation (class I) to highest risk and premarket approvals prior to distribution (classes II and II devices). Unlike IVD tests, laboratory-developed testing procedures (LDPs), commonly referred to as laboratory-developed tests (LDTs )have generally not been subject to FDA regulations, but are rather regulated by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88) with tests categorized based on the complexity of the method, e.g. waived testing (low complexity), moderate testing and high complexity testing (2). Each of these categories are subject to laboratory standards and regulations with more stringent regulations for the higher complexity tests. LDPs are defined as tests that are designed, developed, and validated for use within a single CLIA-certified laboratory. The use of the term LDP instead of LDT better highlights that these tests are medical procedures and services that are developed and used in conjunction with the expertise of laboratory medical professionals for patients care (3). LDPs are developed using a variety of reagents ranging from locally developed reagents to GMP produced reagents and commercially available analyte-specific reagents (ASR).

Other test classifications including RUO (research-use only) tests or IUO (investigation-use only) tests may represent testing in various stage of development into IVD tests. They are not intended for clinical diagnostics and as such are not subjected to FDA regulations. However, if the manufacturer intent changes, these tests have to follow the regulatory pathway for IVD tests.

2. Timeline of Events Leading to VALID

An excellent review of the development of FDA’s oversight of medical devices, the evolution of the CLIA regulations and the intersection of both regarding LDPs was published by Genzen, et al. in Clinical Chemistry in 2017 (4). Until 2010, the FDA exercised enforcement discretion over LDPs-meaning it had decided not to exercise its legal oversight. Many Laboratory professional organizations maintain that clinical laboratories develop and implement LDPs as part of the practice of medicine, over which the FDA has no jurisdiction. From this clinical laboratory perspective, the legal oversight should be under CMS through enforcement of CLIA (5). The historical reasons for these polar points of view are beyond the scope of this paper.

With rapid development in technologies that were being applied to laboratory testing, and for which traditional commercial/FDA approval processes were not adequate, concerns for public health and safety regarding the use of laboratory developed procedures without oversight beyond the CLIA regulations was discussed in the government and in public forums. Further, concern over the proprietary algorithms associated with some of the new multiparameter risk prediction and disease progression tests, prompted the FDA to issue a draft guidance for IVDMIA’s (In Vitro Diagnostic Multivariate Index Assays ) in 2007 (6). Though the guidance was never finalized, some organizations voluntarily submitted to the FDA and received approval for their IVDMIA’s. MammaPrint® (Agendia, Amsterdam, The Netherlands), AlloMap® (CareDx, Brisbane, CA) and OVA1 ® (Vermillion, Inc, Austin Tx) are three examples of these multiparameter predictive tests that received approvals as IDVMIAs. A few laboratories received approval for their tests under this guidance. Public comments and pressure from those organizations supporting FDA oversight of LDPs continued. For example, Genentech filed a citizen’s petition with the FDA in 2008 requesting that the FDA “initiate rulemaking to exercise regulatory jurisdiction over all LDPs and use its current risk-based classification to determine the level of regulatory oversight and review that is necessary and appropriate for these tests”(7).

In June 2010 the FDA announced a public meeting to be held that July to discuss the regulation of LDPs (8). At that time, FDA was re-evaluating its practice of enforcement discretion and wanted input from stakeholders. Because the FDA was now considering broad coverage of LDP’s, including multivariate assays, it did not finalize the draft IVDMIA guidance. After several public meetings and discussions – including those determining whether the establishment of the rules of oversight were new regulation, meaning the FDA should follow a more rigorous rulemaking process, or clarification of existing regulation -meaning the FDA could issue guidance documents- the FDA in 2014, notified Congress via the Federal Register that it would be publishing guidance documents for the oversight of LDPs. Two Guidance documents were published in October 2014: 1) Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories. Framework for Regulatory Oversight of Laboratory developed tests (LDTs) (9) and 2) Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories. FDA Notification and Medical Device Reporting for Laboratory developed tests (LDTs) (10). Together these documents outlined the history of the enforcement discretion, the gaps in current regulation, the regulatory framework for FDA oversight, the risk-based categories, and registration, notification and reporting requirements for LDPs.

In support of the need for their regulatory oversight, the FDA published a white paper the following year in which they described twenty case studies illustrating the possible public health/safety threat of “unregulated” LDPs (11). A commentary paper produced by the Association of Molecular Pathology (AMP) precisely discussed and rebutted the FDAs presentation, case by case (12, 13). The discussion of real and potential risks versus benefits of LDPs regulated by current CLIA processes (such as flexibility in test improvement with new data, rapid development in outbreaks. and accessibility to all sectors) is still debated (13).

In 2015, at least three different organizations worked with Congress on regulatory proposals: the College of American Pathologists (CAP) proposal focused on CLIA/CMS strengthening, AMP proposed CLIA- strengthening programs as well as a reflex process to FDA for some categories of tests, and the Diagnostic Test Working Group (DTWG), a coalition of some laboratories and manufacturers, proposed a structure facilitating the regulation in vitro clinical tests (IVCTs) based on the test and risk- as opposed to the entity that made and produced them (14).

In December 2016, shortly after the national election, the FDA communicated that it would suspend plans to issue final LDP oversight guidance documents and continue to work with Congress, the newly elected administration, and stakeholders. This was followed in January 2017 by their “Discussion Paper on Laboratory developed tests (LDTs)”. In this paper they summarized many of the comments and discussions that they had received over the years of developing the guidance documents as well as the main principles of their proposed approach (15).

In 2017, Representative Larry Bucshon (R-IN) and Diana DeGette (D-CO) publicly released the discussion draft Diagnostic Accuracy and Innovation Act (DAIA), which had the elements of the framework developed by the DTWG in 2015 with further input from additional stakeholders including patient groups, other developers and manufacturers (16). Release of the document was intended to evoke responses from FDA, and public and professional stakeholders. As with the DWTG plan, the DAIA plan proposed a new regulatory category for IVCTs- separate from medical devices and inclusive of tests developed by manufacturers (IVD) and clinical laboratories (LDP). An IVCT would be defined as a test used in the collection, analysis, or clinical examination of specimens for the purpose of diagnosis, screening, disease monitoring, or treatment monitoring (17). The IVCT category further specified oversight of test development and validation to be conducted by FDA, supplanting the currently existing arrangement of clinical laboratory LDP oversight by CLIA. The role of CLIA would be relegated to supervision of test performance within laboratories. Under the new IVCT category, both IVD’s and LDP’s would be placed under a common regulatory pathway, regardless of whether the test was designed to be used in a single laboratory, or commercially distributed. All IVCT developers would be required to register with the FDA on an annual basis, submit descriptions of each IVCT offered, and be subject to FDA inspection (17). This rearrangement would potentially enhance the levels of test accuracy and clinical validity through more stringent oversight of test validation data. However, the potential downside of revamping the test categories was that of significantly higher regulatory burden to laboratories and possible inhibition of test development to meet ever-changing diagnostic needs due to the onerous regulatory requirements (18).

3. The Verifying Accurate Leading-Edge IVCT Development (VALID) Act

a. The Legislation

In an attempt to address the significant backlash (pro and con) associated with the DAIA and definition of IVCT’s during the initial period of stakeholder input during March 2017-June 2018, a new version of the DAIA draft, entitled The Verifying Accurate Leading-Edge IVCT Development Act (VALID), was released in December 2018 (19). In this version the authors of the original DAIA draft, House Representatives Larry Bucshon (R-IN) and Diana DeGette (D-CO), also gained support from US Senators Michael Bennet (D-CO) and Orrin Hatch (R-UT). In December 2018, with the additional support of House Energy and Commerce committee Chairman Frank Pallone (D-NJ) and Greg Walden (R-OR), a new discussion draft was released for feedback. This new draft bill incorporated many FDA recommendations on regulation of diagnostic tests, and importantly emphasized a new regulatory framework for oversight of IVCT’s by the FDA.

b. Risk-based Classification

Under VALID, classification of IVCT’s using a risk-based approach is a fundamental driver of the downstream need for premarket review, test precertification, adverse event reporting, and other additional regulatory requirements. A high-risk test would be defined as “a test in which an undetected inaccurate result would likely cause serious or irreversible harm or death to a patient or patients or would otherwise cause serious harm to the public health.” (Example: HIV testing, BRAF biomarkers). A low-risk test is defined as “a test in which an undetected inaccurate result would cause minimal or no harm or disability, or immediately reversible harm, or would lead to only a remote risk of adverse patient impact or adverse public health impact; or could cause non-life-threatening injury or injury that is medically reversible or delay necessary treatment (Example: Influenza A).

Once a test was classified as high or low risk, this would define the need for premarket approval. Under VALID, the pathway for premarket review would be much the same as the current requirements for premarket application (PMA) under 21 CFR 814.20. A description of the intended use of the test, risk assessment, description of function and performance, manufacturing information, quality system information, and raw data would typically be required for submission to the FDA.

Certain tests would not be subject to the premarket review requirements of VALID. Law enforcement and public health surveillance tests would be exempt, in addition to low volume (< 5 patients /year) and single patient tests, tests for rare diseases (< 8,000 individuals per year), manual tests, and LDP’s marketed 90 days or more before enactment of VALID (17). Test developers would be required to establish and maintain a quality system consisting of design controls, purchasing controls, supplier controls, corrective and preventive actions (CAPA), adverse event reporting, post-market surveillance, and processes for corrections or test recalls in order to demonstrate IVCT’s function as designed, and assure methodology is available to detect quality problems and address issues.

c. Pre-certification

One of the major changes to the current FDA approval paradigm under VALID is the concept of precertification. As an alternative to the premarket review, a developer of a low-risk test may file a “precertification application”, which would include information on the test methods, test controls, analytical and clinical validation. The information required for precertification would essentially be the same as a traditional premarket review, except that raw data would not need to be submitted to the FDA (17). All IVCT’s falling within the precertification order would be exempt from the requirement for premarket review for two years, with application for renewal every 4 years. An eligible organization could hold multiple precertification orders, which could theoretically exempt multiple tests based on multiple technologies from the necessity of premarket review (20). Application for precertification is voluntary; a test developer may choose to forgo this approach and utilize the traditional single test-specific premarket approval pathway via a streamlined process (17).

The precertification approach would be a significant change from the current FDA method in that oversight would shift from premarket to post-market review. Potentially, once pre-certified, IVCT developers could market tests which have not been subjected to full FDA review. Conversely, this new approach offers developers more rapid access to the test market and extends utilization of limited regulatory resources for test review. At this juncture, a major concern with VALID in its current form is that exact policies and information needed for precertification application are not well defined (21).

4. FDA Technical Guidance Document

In April of 2019, the U.S. Department of Health and Human Services (HHS) issued a technical assistance (TA) review document addressing the VALID act. In the TA, the HHS position was largely supportive of the VALID approach, endorsing the need for FDA as the body charged with oversight of IVCT’s, re-vamped regulatory approval structures (premarket review, precertification), provisions for premarket review exemptions, and the use of third-party reviewers to assist with IVCT oversight activities such as application review, quality system review or inspections.

One of the issues raised by the FDA was that of regulatory premarket review of analytical platforms. As defined by VALID, a “platform” refers to hardware (e.g. instrument and/or software) intended to be used with an IVCT in order to generate a clinical test result (19). Under current FDA guidelines, a clinical test composed of both a reagent and instrument system are considered a combination device and subject to current requirements for FDA clearance. Instrument platforms are reviewed with the submission of the assays. As proposed by VALID, individual assays, i.e. assay/instrument combination devices, falling under the precertification pathway may not be subject to any premarket review.

5. The Challenges with the VALID Act

One of the major concerns with VALID is the significant change in the methods and degree of regulatory oversight applied to IVCT’s in both the diagnostic industry and clinical laboratories. Although numerous changes to the components of the current FDA test approval pathway have been proposed, VALID currently lacks sufficient detail to describe the oversight process. Although IVCT oversight is an agreed upon need, new regulations as applied to pathways to FDA test approval, including premarket review and precertification have not been clearly stated in the current VALID draft document. Monetary and personnel resources required to support increased levels of regulation will be a significant expense to the FDA, diagnostic industry, and laboratories, potentially inhibiting new test development and leading to increased test cost.

As designated in VALID, all test developers would be required to establish and maintain a Quality System (QS) for all IVCT’s. As currently written, definitions in VALID overlap with CMS activities enforced by CLIA (22). In many cases QS would be duplicative of activities already in place under CLIA, and an added expense to clinical laboratories in order to support new processes, procedures and personnel (23). This would lead to increased regulatory burden on clinical laboratories, with the potential of inhibition of new test development.

A final example of challenges as related to VALID is that of the requirement for review of IVCTs and periodic renewal of approvals. This requirement would apply to pre-certified new tests and modifications to existing tests subjected to premarket approval (19). For IVCT’s that go through the precertification pathway to FDA approval, an initial application approval would expire after 2 years; renewal would be contingent upon FDA review of a different test (within a single technology) than used in the prior application (19). A subsequent renewal would be effective for four years after the renewal date of the repeat application (17). Any IVCT with premarket approval, as defined by VALID, undergoing modification or change to test performance or safety would require annual review (23). Although the intent under VALID is intended to enhance the ability of FDA to monitor procedures for IVCT development and validation by developers, the additional effort required for periodic re-application and filing of IVCT renewals may prove to be inhibitory to test development by both diagnostic industry and clinical laboratories.

An additional aspect to the VALID IVCT application/renewal process is the ability of FDA to support the process of application review. VALID has proposed the use of third-party reviewers to assist with the application process, allowing FDA to extend its internal resources for this purpose. The question as to exactly what third party organizations would be used for this process has not been clearly defined, nor are there guidelines addressing potential conflicts of interest that may exist if this approach is utilized. The requirement for standardization of application review methodology is also essential if third-party assessors are used but is not currently addressed in VALID.

6. The VITAL Act - March 2020

The 2020 designation of the SARS CoV-2 pandemic by the US Department of Health and Human Services as a public health emergency (PHE) has resulted in a significant change to the legislative trajectory of VALID. Because of the designation of a PHE, laboratory-developed procedures currently require submission of requests for use to FDA for review and approval under Emergency Use Authorization (EUA) prior to use in diagnostic testing. Due to perceived delays in approval of diagnostic tests for SARS CoV-2 under the current FDA EUA structure, on March 19^th ,2020 Senators Rand Paul (Republican, Kentucky) and Ted Cruz (Republican, Texas) introduced the Verified Innovative Testing in American Laboratories Act of 2020 (VITAL)(24, 25). Under VITAL, the regulation of LDP’s would be shifted away from FDA, and back to CMS oversight under CLIA. As specifically stated in the text of the VITAL bill:

“ All aspects of a laboratory-developed testing procedures shall be regulated by the Secretary of Health and Human Services under section 353 of the Public Health Service Act, and no aspects of laboratory-developed testing procedures shall be regulated under the Federal Food, Drug, and Cosmetic Act, including during a public health emergency declared under section 319 of the Public Health Service Act”(24, 25).

This requirement would result in an exemption of LDP’s from FDA oversight, with the intent of reducing delays in development of and access to diagnostic testing. The VITAL proposal counters the current public health emergency environment in which LDPs must be submitted to FDA for agency review within 15 working days of test implementation. The proposed CMS regulatory oversight by VITAL is also in stark contrast to VALID, which mandates specific oversight by FDA. Professional organizations such as AMP and AACC have endorsed VITAL, with the opinion that it differentiates LDP’s from in vitro diagnostic tests and streamlines the current regulatory framework for LDP oversight (26, 27). In March of 2020, VITAL was assigned for review by the Senate Health, Education, Labor, and Pensions Committee, but did not proceed to roll call vote and was cleared from the books at the end of the 116th Congressional session on January 3rd, 2021 (25).

Summary

The Coronavirus pandemic has highlighted the significant impact of the FDA regulation of LDP’s in the ability of clinical laboratories to rapidly implement laboratory testing to readily care for their patients (22). On March 5^th, 2020, the VALID Act was introduced in Congress to the Senate Health, Education, Labor and Pensions committee by Richard Burr (R-NC). In its current version, the VALID Act makes exemption for testing developed during public health emergency. However, while the VALID Act has yet to be considered for approval and the VITAL Act might also be reconsidered for discussion, clinical virologists and other laboratorians should remain aware and participate in the discussions to potentially change the current landscape of LDP regulation.

Table 1.

Selected Key Events in the Development of LDP Oversight.

Year	Event
2007	FDA IVDMIA draft guidance published
2008	Genentech Citizen’s Petition to FDA
2009	ADVAMED proposal to FDA
2010	FDA Notice in Federal Register(June 17) announcing a public meeting to discuss Oversight of Laboratory Developed Tests.’’ (19/20 July)5 Public meetings held with stakeholders.
2014	Publication of two FDA Guidance Documents: Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories. Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories. FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs).
2015	Public meetings Alternate regulatory proposals : CAP/ AMP/ DTWG
2017	Notification from FDA that oversight through guidance documents would not be pursued FDA publishes “Discussion Paper on Laboratory Developed Tests. (LDTs) Release of DAIA discussion draft by Representatives Bucshon (R-IN) and DeGette (D-CO)
2018	Responses to DAIA by FDA and stakeholder groups Release of a revised DAIA as the VALID ACT by Representatives Bucshon (R-IN) and DeGette (D-CO) with support of Senators Bennet (D-CO) and Hatch ( R-UT)
2020	Introduction of the VALID Act to Congress Introduction of the VITAL Act to Congress