Journal:The regulatory landscape of precision oncology laboratory medicine in the United States: Perspective on the past five years and considerations for future regulation

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Full article title The regulatory landscape of precision oncology laboratory medicine in the United States:
Perspective on the past five years and considerations for future regulation
Journal Practical Laboratory Medicine
Author(s) Konnick, Eric Q.
Author affiliation(s) University of Washington
Primary contact Email: konnick at uw dot edu
Year published 2020
Volume and issue 21
Article # e00172
DOI 10.1016/j.plabm.2020.e00172
ISSN 2352-5517
Distribution license Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Website https://www.sciencedirect.com/science/article/pii/S2352551719301040
Download https://www.sciencedirect.com/science/article/pii/S2352551719301040/pdfft (PDF)

Abstract

The regulatory landscape for precision oncology in the United States is complicated, with multiple governmental regulatory agencies with different scopes of jurisdiction. Several regulatory proposals have been introduced since the Food and Drug Administration released draft guidance to regulate laboratory developed tests in 2014. Key aspects of the most recent proposals and discussion of central arguments related to the regulation of precision oncology laboratory tests provides insight to stakeholders for future discussions related to regulation of laboratory tests.

Keywords: oncology, regulation, testing, LDTs, FDA, CLIA, CMS

The current regulatory environment in the United States

The current state of laboratory test regulation in the United States (U.S.) is complex, and the prospect of changes in the current paradigm has been continually on the horizon since 2014. Briefly, clinical laboratories in the U.S. are regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ′88)[1] of the Public Health Services Act, which are administered by the Centers for Medicare and Medicaid Services (CMS). These regulations were put in place to improve the quality of the processes in clinical laboratories, but the regulations allow for organizations that have received certification from CMS to inspect laboratories as a deemed entity. This status allows deemed entities to place additional requirements in place, so long as the underlying CLIA requirements are met.

CLIA regulations have a flexible framework that allows individual medical directors and laboratories to have some leeway in how the specific requirements are met, which allows for accommodation of unique population-, laboratory-, and test-level factors that can improve the overall quality of testing, while also allowing for the development of tests by laboratory medicine practitioners within certain bounds. Testing kits that are manufactured and shipped across state lines are regulated by the U.S. Food and Drug Administration (FDA) via the Medical Device Amendments of 1976[2], which amended the Federal Food, Drug, and Cosmetic Act of 1938. The FDA has several review and approval pathways where the manufacturer submits documentation and data to the FDA for review, and if the data fulfill the FDA’s requirements, the test recieves marketing authorization. Manufacturers can then sell their products to laboratories, who wish to perform that testing.

Testing kits which are cleared or approved by the FDA are regulated under CLIA when they are performed in a certified laboratory. In addition, under the current structure, laboratories are expected to verify the performance of these products and, under CLIA, are allowed to modify them if deemed necessary by medical leadership. If a manufactured product is modified by the user's laboratory, the test is considered a "laboratory developed test." Such modifications are frequently made to improve assay performance, use the assay in a way different from the use claimed by the manufacturer (e.g., diagnostic instead of screening applications), or allow acceptance of additional sample types that were not submitted to the FDA for approval. This regulatory flexibility allows clinical laboratories to offer tests that are accurate and medically relevant to their patients. Currently, many high-complexity clinical laboratories are accredited by the College of American Pathologists (CAP), which conducts unannounced biannual laboratory inspections and administers a multitude of proficiency testing programs to evaluate the accuracy and agreement between laboratories across the spectrum of laboratory tests.

The FDA has maintained that they have the statutory authority to regulate all laboratory tests, including tests that are developed and offered in a single lab, but have chosen to operate under a policy of enforcement discretion.

Emergence of new regulatory proposals

2014 draft guidance and evolution to legislation

In October of 2014, the U.S. FDA released draft guidance[3] that proposed to dramatically change the regulatory landscape of tests that were developed and offered in a single laboratory, formally referred to as "laboratory developed tests" or LDTs. There was a large amount of feedback from academic, community, commercial, and professional stakeholders, with several hundred comments submitted to the FDA docket.[4] After the 2016 presidential election, the FDA publicly stated that the agency will defer to the legislative branch of the U.S. government to update the regulatory landscape of LDTs and manufactured laboratory tests, also know as in vitro diagnostic devices.[5] Although the FDA has stated that it will not wholesale change the regulatory requirements for LDTs in the interim, the agency has continued to release guidance documents, in both draft and final forms, that touch on the regulation of laboratory diagnostics that are used in the care of oncology patients.

During this same period of time, a variety of stakeholders, including the CAP[6] and the Association for Molecular Pathology (AMP)[7], proposed alternative regulatory approaches. In addition, a consortium of commercial laboratories, test manufacturers, and large reference laboratories with academic affiliations helped draft the basis for the proposed Diagnostic Accuracy and Innovation Act (DAIA)[8], which was made available for red-line comments by representatives in the U.S. House of Representatives in 2017. This proposal introduced the new term "in vitro clinical tests" (IVCTs) as a common term for both commercial manufactured tests and LDTs, and as a term to differentiate such tests from medical devices. As part of the feedback process, the legislative sponsors requested technical assistance (TA) and comments from the FDA.

VALID Act of 2020 and VITAL Act of 2020

The process of obtaining the FDA's TA document for the DAIA took over a year, and the TA document that was received by the sponsors was not a commentary on the draft legislation that was provided to them, but rather it was an entirely new legislative discussion draft that outlined an almost entirely different regulatory scheme from DAIA. The legislative sponsors quickly evaluated the TA document and released the Verifying Accurate, Leading-edge IVCT Development (VALID) Act. Over the following years, the VALID Act was the topic of many meetings among stakeholders, the FDA, and legislative staff, and a final version was introduced into the U.S. House of Representatives and U.S. Senate on March 5, 2020[9], during the early days of the SARS-CoV-2 pandemic in the United States. On March 17, 2020, an alternative regulatory bill, the Verified Innovative Testing in American Laboratories (VITAL) Act of 2020[10], was introduced into the Senate.

The approach outlined in the VALID Act of 2020 continues the FDA’s long-standing assertion that the agency be the central arbiter of a laboratory developed test's analytical accuracy and validity. Key components of VALID include extensive grandfathering of existing LDTs, a new classification scheme for new tests, and a framework for a precertification scheme that is designed to allow laboratories to create, validate, and offer certain tests without FDA review in certain circumstances. While many previous approaches to regulation included three risk levels for tests (low, moderate, and high), the VALID Act of 2020 only has two categories: low- and high-risk. Tests in the low-risk categorization would be allowed to be developed and used for patient care through individual submission to the FDA or through use of the precertification pathway. Tests considered to be in the high-risk category would not be eligible for using the precertification pathway and would require the test to be submitted to the FDA via a pathway similar to the current premarket approval (PMA) pathway. Given that many current molecular oncology LDTs are used to select therapy regimens or could be used to decide prophylactic surgeries, most of these tests are expected to be classified in the high-risk category, requiring a time-consuming and expensive PMA should VALID become law. While there is the provision for high-risk tests to use “mitigating measures” that would allow a different regulatory pathway, it is unclear how this might work in practice, and none of the examples cited in the legislation reference professional practice or expertise.

The proposed precertification process is similar in concept to some existing programs, including the conditional approval process utilized by the New York State Department of Health (NYDOH)[11], but it uses a technology classification system to allow laboratories or manufacturers to develop within a certain scope of expertise. The technological categories have underlying scientific principles that are considered generally similar by the FDA. The technology categories are clot detection, colorimetric, enzymatic, fluorometry, immunoassay, mass spectrometry/chromatography, microbial culture, nephlometric/turbidimetric, next generation sequencing (NGS), non-NGS nucleic acid analysis, slide-based technology, and spectroscopy. The VALID Act of 2020 stipulates that a laboratory would become precertified for a specific technology by submitting an initial assay through the stand-alone pathway, and, if successful, the lab would obtain a multi-year permission to develop and modify tests within that technology class. At the end of a certification term, the lab could submit a new assay for review and could receive an extension of the precertification. While tests developed in the precertification window would not need to be submitted for review, documentation would have to be maintained for inspection by the FDA or third-party reviewers.

A key provision of VALID is the extensive grandfathering provision that is included in the legislation, where tests that are available before the legislation enactment can continue to be offered after the law is in effect. This grandfathering was included to prevent the sudden loss of laboratory tests as the law is enacted. A key aspect of this grandfathering is that tests cannot be modified after VALID becomes law, and the FDA has the authority to order any test off the market if they choose.

While the VALID Act of 2020 has numerous provisions—weighing in at over 245 pages—and ensconces many aspects of regulation of LDTs in statute, the VITAL Act of 2020 takes the opposite approach. The VITAL Act of 2020 is only seven pages in length and simply states that all development and performance of LDTs will be under the jurisdiction of the Public Health Services Act and cannot be regulated under the Medical Device Act. These two legislative bills are indicative of the extreme differences that people, companies, and institutions have taken on the issue of regulation of laboratory services and the methods that are used to provide data to inform patient care. The key regulatory proposals and legislation are presented in Table 1.

Table 1. Timeline of key developments in the regulation of laboratory testing
Date Document Relevant statute
1976 Medical Device Regulation Act Food, Drug, and Cosmetic Act of 1938
1998 Clinical Laboratory Improvement Amendments (42 USC 263a) Public Health Services Act
2014 Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) Food, Drug, and Cosmetic Act of 1938
2017 Diagnostic Accuracy and Innovation Act (DAIA) Food, Drug, and Cosmetic Act of 1938
2018 Verifying Accurate Leading-edge IVCT Development Act of 2018 (FDA technical assessment of DAIA) Food, Drug, and Cosmetic Act of 1938
2019 Verifying Accurate Leading-edge IVCT Development Act of 2018 (FDA technical assessment of DAIA) Food, Drug, and Cosmetic Act of 1938
March 2020 Verifying Accurate Leading-edge IVCT Development Act of 2020 Food, Drug, and Cosmetic Act of 1938
March 2020 Verified Innovative Testing in American Laboratories Act of 2020 Food, Drug, and Cosmetic Act of 1938

The fates of the current legislation are uncertain, given the current state of the U.S. political climate, but evaluation of key underlying concepts related to the logic of regulation may benefit the stakeholders who are interested in this regulation.

Commentary on the scope of regulation

There are numerous manufacturers who have developed targeted precision oncology tests and companion diagnostics that have achieved FDA approval. Despite the availably of these manufactured tests, many laboratories continue to develop and use LDTs for oncology testing, especially at academic institutions. There are several examples of specific comprehensive tests that were developed and used as LDTs that have sought both PMA (Foundation medicine) and 510(k) (MSK-IMPACT) approval.[12] While the existing FDA regulatory pathways are clearly available to all laboratories that develop LDTs, the observation that these pathways have not been used except by a handful of large and well-funded organizations suggests that the burdens of seeking such approvals are sufficiently large and complex[13][14] to dissuade laboratories from undertaking, despite any benefits. Laboratories that develop LDTs often state that the ability to modify tests without needing to seek regulatory approval allows for tests to be continuously improved and updated to meet patient needs. In the setting of precision oncology, laboratory tests are undergoing constant revision and updating as new discoveries in science and medicine are applied to routine patient care.

In many discussions and talking points related to the need for regulation of LDTs, several topics are consistently raised as key reasons for increased LDT regulation. These factors include the risk of patient harm, the changing nature of LDTs, accuracy and interchangeability of results, the need to encourage innovation, and the requirement for a single regulatory pathway.

Risks to patients and the changing nature of LDTs

A commonly cited reason for additional regulation of laboratory testing is to reduce the risk of patient harm due to tests that do not perform as expected.[15] Although many assertions of patient harm due solely to laboratory developed tests are often easily debunked[16], the possibility of patient harm is a serious possibility that should be considered. Manufactured products that are produced and shipped across state lines may require more extensive regulatory oversight because the manufacturer has no control over the specific skills or expertise of the laboratory staff and directors who are implementing the test. As such, having a test that can be understood and used by novices and experts alike may be a reasonable requirement, which is the current state of manufactured tests in the United States.

LDTs are often developed and implemented in laboratories that have specific expertise and patient needs that require specialized testing. LDTs are also commonly used in areas of medicine where there is a rapid increase in knowledge (e.g., oncology), or where testing methods must be nimble due to changing analytes (e.g., infectious disease). The ability to rapidly adapt testing methods and implement new scientific and medical findings with LDTs stands in contrast to the extensive and costly process required for tests pased through the FDA processes, which have been estimated to result in multiple years delay in test availability compared to other Western countries, with potential costs of tens of millions of dollars per FDA sumission.[17] Given the costs associated with obtaining FDA approval for laboratory tests, there will be significant costs that laboratories will have to bear under the proposed VALID Act, both in terms of submitting tests for consideration of precertification and in maintaining that certification. In addition, tests that are in the high-risk classification will be less likely to be laboratory developed and will either need a commercial solution or require referral to an outside laboratory.

A concern that has been repeatedly raised by the FDA and other groups is that the nature of LDTs has changed over past decades. Where LDTs were once mostly performed in hospital laboratories for local patients, in the present day, LDTs are often performed in central laboratories that are removed from the site of patient care. These labs can fall into several general categories: reference laboratories for hospital systems, regional reference laboratories, national reference laboratories, and commercial for-profit entities. While these laboratories are all likely to adhere to high standards and perform analytically sound tests, the change of LDTs from a primarily local to a regional or national scale has been suggested by the FDA to be a rationale for no longer applying enforcement discretion. Although not explicitly stated in the FDA’s statements, the implication lies in the potential for decreased patient safety, not due to the type of test performed (LDT vs. FDA-approved), but due to decreased interaction of laboratory experts with the team caring for individual patients.

When any tests are performed in centralized laboratories with limited access to clinical records, there is a higher risk of making pre-analytical, post-analytical, and cognitive errors that can impact patient care. In addition, incentives such as the payment structure of the laboratory can incentivize behaviors that are divergent from the best interest of patients and the health system. Many decentralized laboratories use a fee-for-service payment model, which has been suggested to increase overutilization[18][19] and can potentially lead to situations where analytical and clinical validity claims may overreach the available data.[20] Research has also suggested that laboratory testing done remotely from the patient may lead to increases in cost, turnaround time, duplicative orders, unnecessary studies, and errors.[21][22] Ironically, the addition of additional and costly regulations via the VALID Act may actually drive further consolidation of the centralization model of laboratory testing, which could lead to additional errors as previously described. As complex testing is removed from regional and academic centers and concentrated in centralized laboratories, the ability of laboratory medicine experts to interact with their patient-facing colleagues is likely to decrease, resulting in further degradation in care.


References

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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. The original article appears to accidentally duplicate citation #8 for citation #7; what is believed to have been the intended citation has been substituted for citation #7 in this version. Several of the original article's citations are completely out of order or nonsensical. For example, the original citations #9 and #10 in no way verify the statement about the VALID Act and were removed for this version. In fact, original citation #10 should have been original citation #13 (used here), and it's not clear where original citation #13 was intended to go (omitted here). Otherwise, in accordance with the NoDerivatives portion of the original license, nothing else has been changed.