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)
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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 Several regulatory proposals have been introduced since the Food and Drug Administration released draft guidance to regulate laboratory developed tests in 2014.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.


References

  1. ↑ "Public Law 100-578 - Clinical Laboratory Improvement Amendments of 1988" (PDF). U.S. Government Publishing Office. 31 October 1988. https://www.govinfo.gov/content/pkg/STATUTE-102/pdf/STATUTE-102-Pg2903.pdf. Retrieved 30 August 2019. 
  2. ↑ "Public Law 94–295 - Medical Device Amendments of 1976" (PDF). U.S. Government Publishing Office. 28 May 1976. https://www.govinfo.gov/content/pkg/STATUTE-90/pdf/STATUTE-90-Pg539.pdf. Retrieved 31 August 2019. 
  3. ↑ Food and Drug Administration (3 October 2014). "Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) - Draft Guidance". Food and Drug Administration. https://www.fda.gov/media/89841/download. Retrieved 31 August 2019. 
  4. ↑ Food and Drug Administration (2 February 2015). "Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)". Regulations.gov. https://www.regulations.gov/docket?D=FDA-2011-D-0360. Retrieved 31 August 2019. 
  5. ↑ Food and Drug Administration (13 January 2017). "Discussion Paper on Laboratory Developed Tests (LDTs)". Food and Drug Administration. https://www.fda.gov/media/102367/download. Retrieved 31 August 2019. 
  6. ↑ Vance, G.H. (2011). "College of American Pathologists Proposal for the Oversight of Laboratory-Developed Tests". Archives of Pathology & Laboratory Medicine 135 (11): 1432–5. doi:10.5858/arpa.2011-0304-SA. PMID 22032569. 
  7. ↑ Ferreira-Gonzalez, A.; Emmadi, R.; Day, S.P. et al. (2014). "Revisiting Oversight and Regulation of Molecular-Based Laboratory-Developed Tests: A Position Statement of the Association for Molecular Pathology". Journal of Molecular Diagnostics 16 (1): 3–6. doi:10.1016/j.jmoldx.2013.10.003. PMID 24331365. 
  8. ↑ Food and Drug Administration (3 August 2018). "FDA's views on the Diagnostic Accuracy and Innovation Act (DAIA)" (PDF). Food and Drug Administration. http://www.fdalawblog.net/wp-content/uploads/2018/08/FDA-LDT-Draft-Leg.pdf. Retrieved 31 August 2019. 
  9. ↑ Burr, R. (5 March 2020). "S.3404 - VALID Act of 2020". Congress.gov. Library of Congress. https://www.congress.gov/bill/116th-congress/senate-bill/3404/text. 
  10. ↑ Paul, R. (17 March 2020). "S.3512 - VITAL Act of 2020". Congress.gov. Library of Congress. https://www.congress.gov/bill/116th-congress/senate-bill/3512/text. 
  11. ↑ Wadsworth Center (August 2019). "History: NYSDOH Wadsworth Center’s Clinical Laboratory Evaluation Program (CLEP)" (PDF). Wadsworth Center. https://www.wadsworth.org/sites/default/files/WebDoc/Tiered_LDT_Review_Policy_June2019_REVISED_Aug%202019.pdf. Retrieved 31 August 2019. 

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. Many 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.

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