Tumor Genomics: Fast vs Large Panels. Pillar RUO oncoReveal, MSK LDT "REACT"

Header:  Pillar releases a circa 22-gene kit of the popular tumor oncogenes as RUO.   MSK validates it as "MSK React."

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I was a bit confused by the title of a current Genomeweb article - 

Cancer Centers Look to New NGS-Based 'Frankenpanel' to Get Fast Info on Clinically Actionable Genes

(Subscription, here.)

I wasn't sure what a Frankenpanel was.  But I quickly linked this (see also a public press release on August 27 by Pillar) to the idea of running a few key oncogenes really fast, up front, while you are waiting for a 500-oncogene NGS CGP panel.   

From the press release, Pillar launches "oncoReveal Nexus" as an RUO kit, while Memorial Sloan-Kettering has validated it - including NYS validation - as the brand name, "MSK REACT."   

CAP Today remarked it will generally run on a MiSeq.

I was also reminded of work by Dagogo-Jack and colleagues at MGH on carefully planning the whole story-arc of coordinated interdepartmental molecular oncology, including positioning of a few tests upfront, like EGFR in lung cancer (Dagogo-Jack et al., 2023).

Genomeweb includes a comment that reimbursement is undefined yet.   MSK has a 500-gene 510(k) cleared test called MSK IMPACT which could complement REACT but on a slower timetable.

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Google offers a historical use of "frankenpanel" in the context of arcade games that are too complicated (like a 747's panel, 2013).

CAP Plans Ahead: Six Webinars from CAP on FDA LDT Topics

CAP plans ahead.   They've posted a webinar on September 18, 2024 (10 pt) on the FDA LDT Risk Classification system.   Find it   here.

But wait, there's more.  They have five more webinars on the calendar.  

• November 7, 2024 - Adverse Event Reporting
• January 9, 2025 - Correct Action Reporting
• March 20, 2025 - Quality System Processes
• May 8, 2025 - Enforcement Discretion
• July 10, 2025 - FDA LDT & Emergencies
  

See more by scrolling down on the link provided above.  The registration asks for your CAP lab number, but it doesn't seem to be a "required" field like name and email. 

Eye on Qui Tam Settlements: C-Level Executive Awarded $6M

Header:  Former C-level executive gets $6M in False Claims Act qui tam case.

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Note: This blog is based on a Policy & Medicine article online and links therein.  As stated there, the settlement is not an admission of liability and the entity denies the allegations.

See an article about a $34M false claims act settlement involving Da Vita:

https://www.policymed.com/2024/09/davita-reaches-34-million-false-claims-act-settlement.html

For more details of the allegations and settlement, see the link above.  See also (and similarly) a DOJ press release in July.

For a view into the court case, see online one of the underlying court documents:

https://www.justice.gov/opa/media/1360946/dl?inline

Policy & Medicine states:

• The case was initially brought by the former Chief Operating Officer of DaVita Kidney Care under the qui tam provisions of the False Claims Act. 
• For his role in the case, he will receive $6,370,000.

Horizon Scan: LDTs in the US vs Europe, a White Paper from Veranex

 Veranex has released a good 11-page white paper on European vs new USA FDA rules on laboratory tests - what both require, how both are being phased in.

https://veranex.com/2024/09/11/white-paper-laboratory-developed-tests-overview-of-the-regulatory-framework-in-europe-vs-usa/

FDA Highlights Value of a New Proteomic Parkinson's Disease Test

Header: FDA endorses use of alpha-synuclein assay in Parkinson's and synucleinopathy clinical development because of its very high diagnositc precision.

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Protein self-amplification into toxic configurations was established in Creutzfeldt-Jacob disease (prion protein; with Nobel prize) and this strange process applies to Parkinson's disease as well (alpha-synuclein protein).   Many dozens of research studies have validated such dysfunctional protein pathways.  For an entrance point to synucleinopathies, Wikipedia here.

The first laboratory to make a commercially available and CLIA-validated CSF synuclein assay. specific to the toxic form, is Amprion (San Diego).   (The assay involves patient abnormal protein catalyzing the formation of more abnormal protein in vitro.)  Now, FDA has issued a letter of support for this biomarker in clinical trials, so that patient groups can be identified earlier and more accurately, supporting the operation of clinical trials.  

See the FDA letter here:

https://www.fda.gov/media/181368/download?attachment

See a press release from Amprion here:

https://www.businesswire.com/news/home/20240905546394/en/FDA-Issues-Letter-of-Support-for-%CE%B1-Synuclein-Seed-Amplification-Assay-%E2%80%93-The-Core-Technology-Used-in-Amprion%E2%80%99s-First-Commercial-Test

See, for example, an 1100 patient study on the high accuracy of the alpha-synuclein test in Lancet Neurology:

https://www.discoveriesinhealthpolicy.com/2023/04/big-win-for-novel-diagnostics-clinical.html

See trade news here:

https://parkinsonsnewstoday.com/news/fda-letter-supports-use-new-alpha-synuclein-assay-trials/

https://www.clinicaltrialvanguard.com/news/fda-letter-supports-amprions-revolutionary-%ce%b1-synuclein-test/

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See a table of FDA letters of support for biomarkers here:

https://www.fda.gov/drugs/biomarker-qualification-program/letter-support-los#FDA_issued_Letters_of_Support

Journal Club: Challenge of Tech Assessments of CGP in Advanced Cancer

Header; How to evaluate the range of impacts of comprehensive genomic profiling (CGP) in advanced cancer.

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New at Critical Reviews in Oncology, and with several dozen up-to-date references, see van Shaik and colleagues for a systematic review of comprehensive genomic profiling in advanced.  How are we appraising its value?   Spoiler alert: It's messy.

The authors state it was hard to review the 83 studies collected, because of the wide differences in terminology and outcome variables.

For example, it took me a moment to realize that the point of this chart is to display 20 different ways of defining "turnaround time."  

click to enlarge

This chart catalogs factors clinicians may be considering when ordering CGP:

click to enlarge

Thanks to the HE&G blog for highlighting.

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AI Corner

Here's a Chat GPT 4o summary.

The article "Factors for a Broad Technology Assessment of Comprehensive Genomic Profiling (CGP) in Advanced Cancer" systematically reviews the various factors influencing the adoption of CGP in advanced cancer. While CGP offers extensive genomic insights, particularly through methods like whole genome sequencing (WGS) and whole exome sequencing (WES), its higher costs, compared to targeted molecular diagnostics, complicate reimbursement decisions. 

This review shines a light on key non-clinical factors—such as feasibility, patient test journey, wider diagnostic implications, laboratory organization, and scientific spillover—that should be integrated into health technology assessments (HTA).

The study highlights that while health benefits and cost-effectiveness remain central to decision-making, empirical evidence on other crucial factors is limited. Most studies reviewed in this article focus on "test journey" and "wider implications" of CGP, such as turnaround times, actionable mutations, and matched treatments. Yet, the data’s variability and lack of uniform outcome definitions across studies pose challenges to drawing strong conclusions. Furthermore, factors like laboratory organization and scientific spillover are acknowledged but lack robust empirical evidence in current literature.

In conclusion, the study advocates for a more holistic and comparative strategy for evaluating CGP, urging the inclusion of qualitative and real-world evidence to complement clinical utility data. It recommends future research prioritize generating standardized, outcome-based evidence across broader factors to support clearer reimbursement and policy decisions.

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I find that asking Chat GPT for 10 or 15 key bullet points can be helpful.

Cute: See why Chat GPT chose this order of bullets in a sidebar.

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Here are 12 key takeaways from the study, focusing on its findings, frustrations, and conclusions about the utility of CGP in advanced oncology:

Here’s a re-ordered version of the 12 key takeaways, prioritized for clarity and importance:

1. Actionable Mutations Were Common, but Impact Was Unclear: Although 78.1% of studies reported finding actionable mutations, this did not consistently translate into improved patient outcomes due to barriers like access to treatments and patient health status.

2. Limited Diagnostic Impact: Only 18% of studies reported that CGP had a significant impact on refining or revising diagnoses. This low emphasis on diagnostic benefits frustrated the authors, as it could have been a clearer measure of CGP’s utility.

3. Matched Treatments Had Inconsistent Results: While 83% of studies reported patients receiving matched treatments, the percentage ranged from 1.5% to 75%, making it difficult to gauge CGP’s utility in ensuring appropriate treatments.

4. Clinical Utility Limited by Treatment Access: Even when actionable mutations were identified, logistical barriers such as lack of access to trials or insurance denials often prevented patients from receiving matched treatments, limiting the practical utility of CGP.

5. No Randomized Controlled Trials (RCTs): The lack of well-designed RCTs specifically comparing CGP to targeted profiling was a major frustration, as such studies are essential for demonstrating clear clinical utility.

6. Turnaround Time Variability: Turnaround times for CGP ranged from 11 to 116 days, with no standardization in how they were measured. This inconsistency made it hard to evaluate the efficiency of CGP in a clinical setting.

7. Lack of Standardization in Outcomes: The wide variability in outcome definitions (e.g., actionable mutations, matched treatments) across studies was a major limitation, preventing the authors from making robust conclusions about CGP’s effectiveness.

8. Difficulty in Assessing Long-Term Benefits: The authors found it challenging to assess the long-term benefits of CGP, particularly regarding potential hereditary findings, which could have generational impacts but are not often included in health technology assessments (HTAs).

9. Observational Study Design Challenges: The predominance of observational studies limited the ability to draw strong conclusions about CGP’s utility, as these designs often lack the controls necessary for definitive assessments.

10. Lack of Cost-Effectiveness Data: The absence of detailed cost-effectiveness analyses left a significant gap, making it difficult to assess CGP’s financial viability and overall value in routine oncology care.

11. Limited Empirical Evidence: Factors such as laboratory organization and scientific spillover, while important, were rarely addressed with empirical evidence, leaving critical gaps in understanding CGP’s broader value.

12. Need for Real-World Evidence and Comprehensive Assessments: The authors concluded that future research should focus on real-world evidence and more comprehensive assessment strategies to better capture CGP’s full value in advanced oncology.

In summary, while CGP shows promise, the lack of standardized outcomes, RCTs, and comprehensive data on real-world utility left the authors cautious in their conclusions about its current utility in advanced oncology.

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For more articles on a rolling basis, see "Health Economics & Genomics" blog here.

For those with subscription access to Genomeweb, a new story about a CGP "Frankenpanel".

For the idea of more systematic, integrated assessments, see a new FDA initiative to systematize the review of drugs, which may be >300 pages long.  Here.

Linked In: Xander van Wijk, See a Range of FDA LDT Resources

I don't believe I've met Xander van Wijk, a Houston-based regulatory consultant.  His Linked-In postings include some great resources on the FDA LDT issue.

23 Slide Deck on FDA LDT

Earlier this summer, he posted an excellent (right-sized) 23-slide deck on the FDA LDT final rule.  It's a good balance of digestible size and yet incorporated many great-to-know details.  Read all the way through to Slide 23 for an excellent table of all the requiresments x all the numerous test categories.

https://www.linkedin.com/posts/xandervanwijk_navigating-fdas-final-rule-on-ldts-activity-7204406695085637633-PtBj

Webinars What's Up

See also a new post by van Wijk that summarizes some very recent activiies (like the FDA August 22 webinar) and also, provides a guide to upcoming webinars in the field.

https://www.linkedin.com/posts/xandervanwijk_ampfda-suit8192024finalpdf-activity-7239399183181303808-Zq_c

At this latter link, you can get to... 

1. A CAP webinar on the FDA LDT rule on September 18.
2. An FDA webinar on LDT labeling requirements on September 24.
3. An ADLM webinar on "Complying with FDA" on September 25.

The FDA webinar doesn't require pre-reg and the FDA fully archives its webinars and decks on the LDT subject.

WPS MAC and Million-Patient Data Breach

 On September 6, 2024, CMS released a press release regarding a possible compromise of private data of up to a million people.   The data incident occurred at the WPS MAC.  "CMS and WPS apologize for the inconvenience..."

Find the CMS press release here:

https://www.cms.gov/newsroom/press-releases/cms-notifies-individuals-potentially-impacted-data-breach

See coverage at HealthCareDive here:

https://www.healthcaredive.com/news/cms-wisconsin-physicians-service-insurance-corporation-moveit-data-breach/726416/

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See a summary below [Chat GPT 4o].  

CMS Notifies Nearly 1 Million Individuals of Data Breach Linked to MOVEit Vulnerability

September 6, 2024—In a critical development for those monitoring Medicare-related cybersecurity, the Centers for Medicare & Medicaid Services (CMS) and its contractor, Wisconsin Physicians Service Insurance Corporation (WPS), have begun notifying nearly 950,000 individuals about a data breach that may have compromised their personally identifiable information (PII). The breach stems from vulnerabilities in the MOVEit file transfer software, a third-party solution used by WPS in connection with its Medicare administrative services.

The breach, which is part of a broader cybersecurity issue impacting numerous organizations across the U.S., specifically affected data managed by WPS on behalf of CMS. The compromised data includes sensitive information from Medicare beneficiaries and potentially other individuals whose PII was processed as part of CMS's audit functions.

Scope and Timeline of the Incident

According to CMS, the vulnerability in MOVEit software was exploited between May 27 and May 31, 2023. Despite a patch being applied shortly after Progress Software, MOVEit’s developer, disclosed the vulnerability in June 2023, subsequent investigations revealed that unauthorized parties accessed and copied certain files before the patch was implemented. It wasn't until a second, more detailed review in May 2024 that the full extent of the breach was identified, with WPS confirming that some of the compromised files contained Medicare beneficiaries' PII.

The breach has raised significant concerns, particularly for CMS policy experts who oversee regulatory compliance and data security measures tied to Medicare administration. As a result, 946,801 individuals have been mailed notices about the incident, with CMS also issuing public substitute notices for those whose contact information may be out of date.

Information Compromised and Immediate Steps

The compromised data includes a range of personal information, such as:

• Names
• Social Security Numbers (SSNs) or Individual Taxpayer Identification Numbers (ITINs)
• Medicare Beneficiary Identifiers (MBIs)
• Dates of birth
• Health Insurance Claim Numbers (HICNs)
• Hospital account numbers
• Dates of service

While there is currently no confirmed evidence of identity fraud linked to the breach, CMS and WPS are taking precautionary measures. These include offering complimentary identity protection and credit monitoring services for 12 months, and the issuance of new Medicare cards with updated MBIs for affected individuals. CMS has emphasized that Medicare benefits themselves remain unaffected.

Broader Implications for Medicare Contractors and Data Security

For policymakers, this incident underscores the challenges in securing third-party software used by contractors handling Medicare claims and related audits. The breach not only puts the spotlight on MOVEit and similar software but also raises questions about the oversight and rapid response protocols for protecting Medicare beneficiaries' sensitive data.

In particular, the breach highlights the need for ongoing collaboration between CMS, its contractors, and law enforcement agencies, as well as the importance of proactive cybersecurity audits and breach disclosure transparency.

As the regulatory landscape around health data protection tightens, this breach will likely serve as a key case study in shaping future policies on third-party vendor risk management, with potential ripple effects across both Medicare Part A/B claims contractors and broader healthcare data security frameworks.

Moving Forward

CMS and WPS are continuing to work with law enforcement and cybersecurity experts to investigate the incident and safeguard affected systems. This breach is likely to fuel ongoing discussions among Medicare policy experts about the balance between efficiency in claims processing and the imperative of ensuring data security in outsourced services.

For stakeholders, the MOVEit breach represents a pivotal moment, reminding all actors involved in Medicare administration of the critical importance of robust cybersecurity safeguards and rapid response mechanisms. As more details emerge, the policy community will be watching closely to understand how CMS and its contractors address the long-term implications of this breach for data privacy and Medicare's operational integrity.

AI Corner: Can Scite.AI Write a History of FDA LDT Regulation?

In this blog, I've referred several times to Scite.AI, a subscription service that brings specialized AI and writing skills to PubMed.

One feature is "Scite Assistant" which drafts initial articles on a requested topic.  Here's the request:

Provide a summary of major historical policy articles that review the FDA's authority and history in efforts to regulate Laboratory Developed Tests.

Here's the output back to me, generated by Scite in a few seconds. 

Its initial response didn't include 2023-2024 citations, so I asked again and got that.  I print the original essay below, and then, the 2023-2024 update.  I show one comprehensive bibliography at bottom.  (Scite.AI cited a paper where I'm a coauthor; Huang).  Note that SCITE knows it should spell out terms before using abbreviations.

OUTPUT PART ONE

Provide a summary of major historical policy articles that review the FDA's authority and history in efforts to regulate Laboratory Developed Tests.

The regulation of Laboratory Developed Tests (LDTs) by the U.S. Food and Drug Administration (FDA) has evolved significantly over the years, reflecting the complexities of balancing innovation in diagnostic testing with the need for patient safety and test efficacy. 

Historically, LDTs have been developed and utilized within individual laboratories without the stringent oversight that applies to commercially manufactured in vitro diagnostics (IVDs). This regulatory landscape began to shift notably in the early 2010s when the FDA expressed intentions to assert its authority over LDTs, which had previously been largely unregulated under the Clinical Laboratory Improvement Amendments (CLIA) of 1988 (Vance, 2011; Sharfstein, 2015; Genzen et al., 2017).

In 2014, the FDA released draft guidance proposing a framework for the regulation of LDTs, which sparked considerable debate among stakeholders, including laboratory professionals and public health advocates. The guidance aimed to ensure that LDTs meet the same standards of safety and effectiveness as other medical devices, particularly in light of concerns regarding the accuracy and reliability of these tests (Ratner, 2014; Caliendo et al., 2016). The Infectious Diseases Society of America and other professional organizations voiced apprehensions that stringent regulations could limit access to essential diagnostic tests, particularly in the context of infectious diseases (Caliendo et al., 2016; Sidawy, 2015).

The FDA's approach has been characterized by a recognition of the unique role that LDTs play in clinical practice, particularly in areas where commercial tests are unavailable or inadequate. For instance, the FDA has acknowledged that LDTs are often tailored to meet specific patient needs and can provide critical diagnostic information, especially in rapidly evolving fields such as pharmacogenomics and infectious disease testing (Adashi & Cohen, 2022; Gill et al., 2021; Hillebrenner et al., 2015). However, the lack of uniform oversight has raised concerns about variations in test quality and the potential for misleading results, which can have serious implications for patient care (Genzen, 2019; Huang et al., 2021).

Recent developments, particularly during the COVID-19 pandemic, have further highlighted the need for a regulatory framework that can adapt to emerging public health needs. The FDA's Emergency Use Authorization (EUA) process allowed for the rapid deployment of LDTs for SARS-CoV-2 testing, demonstrating the agency's capacity to exercise oversight in urgent situations (Marble et al., 2021; Schreier et al., 2019). This experience has prompted discussions about the future of LDT regulation, including potential legislative reforms such as the Verifying Accurate Leading-edge In Vitro Clinical Test Development (VALID) Act, which seeks to create a more cohesive regulatory environment for both LDTs and traditional IVDs (Hillebrenner et al., 2015; Peaper et al., 2021; Rychert et al., 2022).

In summary, the historical trajectory of FDA regulation of LDTs reflects a growing recognition of the need for oversight that balances innovation with patient safety. As the landscape continues to evolve, ongoing dialogue among stakeholders will be crucial in shaping a regulatory framework that supports the development of high-quality diagnostic tests while ensuring their reliability and accessibility in clinical practice.

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2023 2024

Do you have access to any articles about the FDA LDT regulations proposed in 2023 and finalized in 2024?

OUTPUT PART TWO

The regulatory landscape surrounding Laboratory Developed Tests (LDTs) has undergone significant changes with the FDA's proposed rule released in October 2023, which aims to end the enforcement discretion that has historically allowed LDTs to operate outside the stringent regulatory framework applied to commercial in vitro diagnostics (IVDs). This proposed rule has been met with a mix of support and criticism from various stakeholders, reflecting the complexities of ensuring patient safety while fostering innovation in laboratory testing (Miller, 2024; Smith, 2024; Offit et al., 2023).

The proposed rule outlines a phased implementation plan that would require LDTs to undergo the same regulatory scrutiny as commercially available tests. This shift is intended to address concerns regarding the quality and reliability of LDTs, which have been developed and validated under the Clinical Laboratory Improvement Amendments (CLIA) but without the comprehensive oversight that the FDA applies to IVDs (Miller, 2024; Bogdanoski, 2024). Critics of the FDA's approach have expressed concerns about the potential impact on patient access to essential diagnostic tests, particularly in specialized areas where LDTs have historically filled gaps left by commercial offerings (Saitman, 2023; Smith, 2024).

In addition to the proposed rule, the ongoing discussions surrounding the Verifying Accurate Leading-edge IVCT Development (VALID) Act further complicate the regulatory environment for LDTs. This legislation aims to create a more cohesive regulatory framework that would encompass both LDTs and traditional IVDs, addressing some of the fragmentation in oversight that has characterized the field (Saitman, 2023; Offit et al., 2023). The VALID Act has been viewed as a potential solution to harmonize regulations and ensure that all diagnostic tests meet high standards of safety and efficacy (Offit et al., 2023).

The implications of these regulatory changes are profound, particularly in light of the COVID-19 pandemic, which highlighted both the critical role of LDTs in public health and the challenges associated with their regulation. The FDA's experience during the pandemic, where it granted Emergency Use Authorizations (EUAs) for numerous LDTs, has informed its current regulatory stance and the proposed rule (Miller, 2024; Bogdanoski, 2024). Stakeholders are now grappling with the balance between ensuring rigorous testing standards and maintaining access to innovative diagnostic solutions that are essential for patient care (Miller, 2024; Saitman, 2023).

In conclusion, the FDA's proposed rule and the discussions surrounding the VALID Act represent a pivotal moment in the regulation of LDTs. As the FDA seeks to assert greater oversight, the ongoing dialogue among clinicians, laboratory professionals, and regulatory bodies will be crucial in shaping a regulatory framework that supports both patient safety and the advancement of diagnostic testing.

Cumulative References (Both Original and 2023 Update)

References:

Adashi, E. and Cohen, I. (2022). Sars-cov-2 laboratory-developed tests. Jama, 327(13), 1229. https://doi.org/10.1001/jama.2022.3382

Bogdanoski, G. (2024). Translating the regulatory landscape of medical devices to create fit‐for‐purpose artificial intelligence (ai) cytometry solutions. Cytometry Part B Clinical Cytometry, 106(4), 294-307. https://doi.org/10.1002/cyto.b.22167

Caliendo, A., Couturier, M., Ginocchio, C., Hanson, K., Miller, M., Walker, K., … & Frank, G. (2016). Maintaining life-saving testing for patients with infectious diseases: infectious diseases society of america, american society for microbiology, and pan american society for clinical virology recommendations on the regulation of laboratory-developed tests. Clinical Infectious Diseases, 63(2), 151-154. https://doi.org/10.1093/cid/ciw260

Genzen, J. (2019). Regulation of laboratory-developed tests. American Journal of Clinical Pathology, 152(2), 122-131. https://doi.org/10.1093/ajcp/aqz096

Genzen, J., Mohlman, J., Lynch, J., Squires, M., & Weiss, R. (2017). Laboratory-developed tests: a legislative and regulatory review. Clinical Chemistry, 63(10), 1575-1584. https://doi.org/10.1373/clinchem.2017.275164

Gill, P., Yu, F., Porter-Gill, P., Boyanton, B., Allen, J., Veerapandiyan, A., … & Schaefer, G. (2021). Implementing pharmacogenomics testing: single center experience at arkansas children’s hospital. Journal of Personalized Medicine, 11(5), 394. https://doi.org/10.3390/jpm11050394

Hillebrenner, E., Litwack, E., Bradley, P., Donigan, K., Lowe, T., Serrano, K., … & Gutiérrez, A. (2015). Fda oversight of laboratory‐developed tests will facilitate adoption of pharmacogenetic testing into routine clinical care. The Journal of Clinical Pharmacology, 55(7), 728-730. https://doi.org/10.1002/jcph.521

Huang, R., Lasiter, L., Bard, A., Quinn, B., Young, C., Salgado, R., … & Lennerz, J. (2021). National maintenance cost for precision diagnostics under the verifying accurate leading-edge in vitro clinical test development (valid) act of 2020. Jco Oncology Practice, 17(11), e1763-e1773. https://doi.org/10.1200/op.20.00862

Marble, H., Bard, A., Mizrachi, M., & Lennerz, J. (2021). Temporary regulatory deviations and the coronavirus disease 2019 (covid-19) pcr labeling update study indicate what laboratory-developed test regulation by the us food and drug administration (fda) could look like. Journal of Molecular Diagnostics, 23(10), 1207-1217. https://doi.org/10.1016/j.jmoldx.2021.07.011

Miller, M. (2024). Fda’s proposed rule for the regulation of laboratory-developed tests. Journal of Clinical Microbiology, 62(2). https://doi.org/10.1128/jcm.01488-23

Offit, K., Sharkey, C., Green, D., Wu, X., Trottier, M., Hamilton, J., … & Stadler, Z. (2023). Regulation of laboratory-developed tests in preventive oncology: emerging needs and opportunities. Journal of Clinical Oncology, 41(1), 11-21. https://doi.org/10.1200/jco.22.00995

Peaper, D., Rhoads, D., Sullivan, K., Couturier, M., Humphries, R., Martin, I., … & Wojewoda, C. (2021). Considerations from the College of american pathologists for implementation of an assay for sars-cov-2 testing after a change in regulatory status. Journal of Clinical Microbiology, 59(10). https://doi.org/10.1128/jcm.01167-21

Ratner, M. (2014). Fda pushes for control over laboratory-developed tests. Nature Biotechnology, 32(9), 855-855. https://doi.org/10.1038/nbt0914-855a

Rychert, J., Schmidt, R., & Genzen, J. (2022). Laboratory-developed test orders in an academic health system.. https://doi.org/10.1101/2022.12.12.22283358

Saitman, A. (2023). How the VALID act could affect patient access to laboratory developed testing for therapeutic drug monitoring. Journal of Mass Spectrometry and Advances in the Clinical Lab, 28, 56-59. https://doi.org/10.1016/j.jmsacl.2023.02.004

Schreier, J., Feeney, R., & Keeling, P. (2019). Diagnostics reform and harmonization of clinical laboratory testing. Journal of Molecular Diagnostics, 21(5), 737-745. https://doi.org/10.1016/j.jmoldx.2019.04.002

Sharfstein, J. (2015). FDA regulation of laboratory-developed diagnostic tests. Jama, 313(7), 667. https://doi.org/10.1001/jama.2014.18135

Sidawy, M. (2015). US food and drug administration regulatory oversight of laboratory‐developed tests: commentary on the draft guidance. Cancer Cytopathology, 123(10), 573-575. https://doi.org/10.1002/cncy.21566

Smith, L. (2024). The us FDA's proposed rule on laboratory-developed tests: impacts on clinical laboratory testing. Practical Laboratory Medicine, 40, e00407. https://doi.org/10.1016/j.plabm.2024.e00407

Vance, G. (2011). College of american pathologists proposal for the oversight of laboratory-developed tests. Archives of Pathology & Laboratory Medicine, 135(11), 1432-1435. https://doi.org/10.5858/arpa.2011-0304-sa

Novitas: No LCD, But Burdensom Documents Required for Genomic Codes

 On July 26, 2024, Novitas MAC announced it was delaying the finalization of a new LCD for oncology biomarkers:

https://www.discoveriesinhealthpolicy.com/2024/07/novitas-oncology-lcd-carnival-continues.html

On August 16, 2024, Novitas announced a number of pathology/laboratory codes that would require documentation for payment.  Find the announcement here:

https://www.novitas-solutions.com/webcenter/portal/MedicareJH/pagebyid?contentId=00294519

The text announcement is brief but it links to an Excel file of specific codes (click on the headline, "Pathology and laboratory codes" on the web page.

Apparently Novitas intends this page to be "evergreen" as it states the associated clickable link for documentation codes "may be updated quarterly."

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New process for pathology and laboratory codes

Important billing information

Effective September 19th, when medical records are not submitted to support the code billed (for the laboratory and pathology codes linked below), the service will reject. The claim must then be resubmitted with the appropriate documentation.

Documentation submitted from the medical record to support the initial claim submission for the pathology and lab codes linked below may include one or more of the following:

• Orders and test results for the test performed
• History and physical examination
• Progress or office notes for the test performed
• Any additional documentation in the medical record that supports the need for the service

Pathology and laboratory codes [see hot link on original Novitas web page]

Avoid negative impacts to your claims by providing medical records with your initial claim submission for the pathology and lab codes linked above. Please consult this list frequently as it may be updated quarterly.

##

Here, I've cut-pasted from the Excel as accessed on 9/08.  It looks like many are PLA codes since 1/1/2024 (e.g. not in the 2024 annual book).  But some codes in the range over 419U appear omitted, too.  

Procedure code	Description
0020M	Oncology (central nervous system), analysis of 30000 DNA methylation loci by methylation array, utilizing DNA extracted from tumor tissue, diagnostic algorithm reported as probability of matching a reference tumor subclass
0421U	Oncology (colorectal) screening, quantitative real-time target and signal amplification of 8 RNA markers (GAPDH, SMAD4, ACY1, ARe.g., CDH1, KRAS, TNFRSF10B, EGLN2) and fecal hemoglobin, algorithm reported as a positive or negative for colorectal cancer risk (BQ Colosense)
0422U	Oncology (pan-solid tumor), analysis of DNA biomarker response to anti-cancer therapy using cell-free circulating DNA, biomarker comparison to a previous baseline pre-treatment cell-free circulating DNA analysis using next-generation sequencing, algorithm reported as a quantitative change from baseline, including specific alterations, if appropriate
0425U	Genome (e.g., unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis, each comparator genome (e.g., parents, siblings)
0426U	Genome (e.g., unexplained constitutional or heritable disorder or syndrome), ultra-rapid sequence analysis
0428U	Oncology (breast), targeted hybrid-capture genomic sequence analysis panel, circulating tumor DNA (ctDNA) analysis of 56 or more genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability, and tumor mutation burden
0429U	Human papillomavirus (HPV), oropharyngeal swab, 14 high-risk types (i.e., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68)
0434U	Drug metabolism (adverse drug reactions and drug response), genomic analysis panel, variant analysis of 25 genes with reported phenotypes
0435U	Oncology, chemotherapeutic drug cytotoxicity assay of cancer stem cells (CSCs), from cultured CSCs and primary tumor cells, categorical drug response reported based on cytotoxicity percentage observed, minimum of 14 drugs or drug combinations
0436U	Oncology (lung), plasma analysis of 388 proteins, using aptamer-based proteomics technology,predictive algorithm reported as clinical benefit from immune checkpoint inhibitor therapy
0437U	Psychiatry (anxiety disorders), mRNA, gene expression profiling by RNA sequencing of 15 biomarkers, whole blood, algorithm reported as predictive risk score
0438U	Drug metabolism (adverse drug reactions and drug response), buccal specimen, gene-drug interactions, variant analysis of 33 genes, including deletion/duplication analysis of CYP2D6, including reported phenotypes and impacted gene-drug interactions
0439U	Cardiology (coronary heart disease [CHD]), DNA, analysis of 5 single-nucleotide polymorphisms (SNPS) (rs11716050 [loc105376934], rs6560711 [wdr37], rs3735222 [scin/loc107986769], rs6820447 [intergenic], and rs9638144 [esyt2]) and 3 DNA methylation markers (cg00300879 [transcription start site {tss200} of cnksr1], cg09552548 [intergenic], and cg14789911 [body of spatc1l]), qPCR and digital PCR, whole blood, algorithm reported as a 4-tiered risk score for a 3-year risk of symptomatic CHD
0441U	Infectious disease (bacterial, fungal, or viral infection), semiquantitative biomechanical assessment (via deformability cytometry), whole blood, with algorithmic analysis and result reported as an index
0442U	Infectious disease (respiratory infection), myxovirus resistance protein a (MXA) and c-reactive protein (CRP), fingerstick whole blood specimen, each biomarker reported as present or absent
0443U	Neurofilament light chain (NfL), ultra-sensitive immunoassay, serum or cerebrospinal fluid
0445U	B-amyloid (abeta42) and phospho tau (181p) (ptau181), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
0448U	Oncology (lung and colon cancer), DNA, qualitative, next generation sequencing detection of single-nucleotide variants and deletions in egfr and kras genes, formalin-fixed paraffin-embedded (FFPE) solid tumor samples, reported as presence or absence of targeted mutation(s), with recommended therapeutic options
0449U	Carrier screening for severe inherited conditions (e.g., cystic fibrosis, spinal muscular atrophy, beta hemoglobinopathies [including sickle cell disease], alpha thalassemia), regardless of race or self-identified ancestry, genomic sequence analysis panel, must include analysis of 5 genes (cftr, smn1, hbb, hba1, hba2)
0450U	Oncology (multiple myeloma), liquid chromatography with tandem mass spectrometry (LCMS/MS), monoclonal paraprotein sequencing analysis, serum, results reported as baseline presence or absence of detectable clonotypic peptides
0451U	Oncology (multiple myeloma), LCMS/MS, peptide ion quantification, serum, results compared with baseline to determine monoclonal paraprotein abundance
0452U	Oncology (bladder), methylated PENK DNA detection by linear target enrichment-quantitative methylation-specific real-time PCR (LTE-qMSP), urine, reported as likelihood of bladder cancer
0453U	Oncology (colorectal cancer), cell-free DNA (cfDNA), methylationbased quantitative PCR assay (SEPTIN9, IKZF1, BCAT1, Septin9-2, VAV3, BCAN), plasma, reported as presence or absence of circulating tumor DNA (ctDNA)
0454U	Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping
0455U	Infectious agents (sexually transmitted infection), Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, multiplex amplified probe technique, vaginal, endocervical, gynecological specimens, oropharyngeal swabs, rectal swabs, female or male urine, each pathogen reported as detected or not detected
0456U	Autoimmune (rheumatoid arthritis), next-generation sequencing (NGS), gene expression testing of 19 genes, whole blood, with analysis of anticyclic citrullinated peptides (CCP) levels, combined with sex, patient global assessment, and body mass index (BMI), algorithm reported as a score that predicts nonresponse to tumor necrosis factor inhibitor (TNFi) therapy
0459U	β-amyloid (Abeta42) and total tau (tTau), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
0460U	Oncology, whole blood or buccal, DNA single-nucleotide polymorphism (SNP) genotyping by real-time PCR of 24 genes, with variant analysis and reported phenotypes
0461U	Oncology, pharmacogenomic analysis of single-nucleotide polymorphism (SNP) genotyping by real-time PCR of 24 genes, whole blood or buccal swab, with variant analysis, including impacted gene-drug interactions and reported phenotypes
0464U	Oncology (colorectal) screening, quantitative real-time target and signal amplification, methylated DNA markers, including LASS4, LRRC4 and PPP2R5C, a reference marker ZDHHC1, and a protein marker (fecal hemoglobin), utilizing stool, algorithm reported as a positive or negative result [BQ Cologuard Plus]
0465U	Oncology (urothelial carcinoma), DNA, quantitative methylationspecific PCR of 2 genes (ONECUT2, VIM), algorithmic analysis reported as positive or negative
0466U	Cardiology (coronary artery disease [CAD]), DNA, genomewide association studies (564856 single-nucleotide polymorphisms [SNPs], targeted variant genotyping), patient lifestyle and clinical data, buccal swab, algorithm reported as polygenic risk to acquired heart disease
0467U	Oncology (bladder), DNA, nextgeneration sequencing (NGS) of 60 genes and whole genome aneuploidy, urine, algorithms reported as minimal residual disease (MRD) status positive or negative and quantitative disease burden
0468U	Hepatology (nonalcoholic steatohepatitis [NASH]), miR-34a5p, alpha 2-macroglobulin, YKL40, HbA1c, serum and whole blood, algorithm reported as a single score for NASH activity and fibrosis
0469U	Rare diseases (constitutional/heritable disorders), whole genome sequence analysis for chromosomal abnormalities, copy number variants, duplications/deletions, inversions, unbalanced translocations, regions of homozygosity (ROH), inheritance pattern that indicate uniparental disomy (UPD), and aneuploidy, fetal sample (amniotic fluid, chorionic villus sample, or products of conception), identification and categorization of genetic variants, diagnostic report of fetal results based on phenotype with maternal sample and paternal sample, if performed, as comparators and/or maternal cell contamination
0471U	Oncology (colorectal cancer), qualitative real-time PCR of 35 variants of KRAS and NRAS genes (exons 2, 3, 4), formalin-fixed paraffin-embedded (FFPE), predictive, identification of detected mutations
0472U	Carbonic anhydrase VI (CA VI), parotid specific/secretory protein (PSP) and salivary protein (SP1) IgG, IgM, and IgA antibodies, enzyme-linked immunosorbent assay (ELISA), semiqualitative, blood, reported as predictive evidence of early Sjögren syndrome
0474U	Hereditary pan-cancer (e.g., hereditary sarcomas, hereditary endocrine tumors, hereditary neuroendocrine tumors, hereditary cutaneous melanoma), genomic sequence analysis panel of 88 genes with 20 duplications/deletions using nextgeneration sequencing (NGS), Sanger sequencing, blood or saliva, reported as positive or negative for germline variants, each gene
0475U	Hereditary prostate cancerrelated disorders, genomic sequence analysis panel using next-generation sequencing (NGS), Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (CGH), evaluation of 23 genes and duplications/deletions when indicated, pathologic mutations reported with a genetic risk score for prostate cancer

 

CMS Updates NCD Wait List: Adds "Colorectal Cancer Screening" as Future NCD Revision

Header:  CMS adds "colorectal cancer screening" as an update to its "waitlist" for National Coverage Decisions.   Relevant to several products, "Colosense" (approved by FDA 5/2024) and "Cologuard Plus" (FDA approval pending soon).

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A few weeks ago I wrote about CMS's notorious backlist or waitlist for NCD revisions, including new information I obtained by FOIA - here.

John Leppard at Washington Analysis has been one of the first to pick up, that CMS has updated its "NCD Wait List," dated as 8/15/2024, by adding Colorectal Cancer Screening to the top of the list (no other changes.)   The document was posted later, as the 5/15/2024 version was online when I wrote my blog on August 26.

Here's a screen shot of May versus August: 

click to enlarge

Different Parts of NCD in Different Styles

Here's NCD 210.3 for CRC screening.  Different parts are written in different styles.  

• Part 1 covers fecal occult blood tests, immunoassays that superceded previous "guaiac" tests.  This part simply says FOBT tests are covered annually, and doesn't refer to FDA, although the tests couldn't be sold without FDA approval. No names or branding.
• Part 2 is for the Cologuard test, effective October 9, 2014 and refers to "Cologuard" as a "proprietary" test.   Whether CMS could automatically cover a successor Cologuard test ("Cologuard II, Cologuard Plus, Cologuard New, etc") is a question I'll leave to attorneys expert in the art.
• Part 3 is for blood-based biomarker tests, January 19, 2021.  This one clearly anticipates successor tests, predicating CMS coverage on FDA approval and certain performance standards.   

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CMS could have written Part 2 in a broader way; for example, at about the same time, a non-coverage decision blocked coverage of amyloid PET testing in Alzheimer's disease, and applied both to all current FDA amyloid PET biomarkers and even to future ones not yet approved by FDA (and even if they had better performance).  CMS's more recent NCD for amyloid-altering drugs in Alzheimer's also applies to the whole class of drugs, including future ones, with coverage not varying by product.

All We Know is the Topic

All we know for sure about the pending CRC NCD is the name of the topic - preventive screening in colorectal cancer.   But note in a parallel track, in Physician Fee Schedule rulemaking this summer, CMS proposed to add a benefit for CT colonography and remove a (antique) benefit for barium enema.

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The CMS NCD against amyloid PET scans (though now deleted) did not apply to coverage of tau PET scans, where FDA approvals began in 2020.

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"Cologuard Plus" had a publication in NEJM in March 2024, and is currently undergoing pricing by CMS (the annual crosswalk/gapfill process for all new tests).

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The August 2024 NCD dashboard shows 3 NCDs completed in the rolling 12 months, including merely deleting the amyloid PET one.  Under the TCET plan, CMS would add 10 NCD decisions per year to the 3-4 it does now.  It would add 5 new TCET decisions, and over time, that requires a re-evaluation of 5 per year to achieve steady state.  

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CMS posts the new August list with a new link, while leaving the May list posted concurrently under a different link.  

August 2024  https://www.cms.gov/files/document/ncddashboard2024.pdf

Old May 2024 https://www.cms.gov/files/document/ncd-dashboard.pdf 

Myriad Issues 8-K Notice re GeneSight Clin Trial Design; General Issue on "Pragmatic Trials"

 Myriad Genetics issued an interest 8-I (impactful news update) that it was discontinuing a planned analysis of GeneSight pharmacogenetic clinical data.   The data design involved using an administratively constructed comparator arm (aka "control" arm) with claims data.  

They write,  the Company directed the third-party vendor to review its data warehouse to identify a group of patients that best matched the characteristics of the GeneSight patient group.... the Company concluded that any data comparing the GeneSight patient group against this non-GeneSight control group were not reliable. Therefore, the Company has determined to discontinue the analysis for this part of the study.

SEC notice here.    

See also a 2024 Am J Psychiat publication by Baum et al., The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder.   It updates the "American Psychiatric Association Council of Research Workgroup on Biomarkers" position.

MYGN has a share price dip + recovery:

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Don't Over-hype "Administrative Virtual Control Arms"

The issue is the limits of using administratively constructed databases as a comparator arm as opposed to using actual tracked patients (randomized) as a comparator arm.   I have heard senior CMS staff in the past year tout the potential expansion of "Coverage with Evidence Development" in non randomized trials due to use of administrative control arms, and how that science had developed so much.  

Well....

My impression it is still very difficult to rely on administratively implied or virtual control groups, especially when outcome differences are relatively small.   The CMS YMCA pre-diabetes intervention study (published in Health Affairs, not the most rigorous scientific/economic journal) used an administratively constructed comparator group and got outlandishly favorable outcomes, even if a prediabetes patient had a single brief YMCA session.   I would have concluded that if that was the case, the YMCA treatment group (people showing up at gyms!!!) was probably simply different than the unobserved, imputed control group (people the same age but sitting in their cardiologist's office). 

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See also a May 2024 article in JAMA on inferring causality from observational trials; Dahabreh et al.

STAT: Neumann et al. on Greatly Expanding CED/TCET

Header: Neumann et al. (TUFTS) propose wide expansion on Coverage with Evidence Development (CED) at CMS.   Entry point for them is the recent TCET announcement.

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In early August, CMS finalized its plan for Transitional Coverage for Emerging Technologies (TCET, here).  Basically, medical devices under FDA review by the Breakthrough Pathway can apply for early review by CMS and expect, usually, a National Coverage Determination with Coverage with Evidence Development (TCET-CED) within six months of final FDA approval.  Entry point here.  The online Federal Register document explains that, in general, clin lab diagnostics are excluded (a statement which is followed by several paragraphs about MolDx).  CMS gives the TCET NCD program a bandwidth of 5 NCDs per year.

At STAT, Peter Neumann et al, of Boston University, describe the TCET program as-is, and make a number of recommendations for its expansion, and the wider use of CED.   Find it here:

https://www.statnews.com/2024/08/28/medicare-ced-tcet-coverage-emerging-technologies-devices/

The authors write, Medicare should broaden the TCET program’s scope and ambitions. In practice, this could allow for new studies examining how emerging treatments for diabetes, heart failure, or Alzheimer’s disease affect the health and quality of life of Medicare beneficiaries in real-world settings.  Such efforts would require additional resources for CMS. The Bipartisan Policy Commission has recommended up to $10 million per year to modernize the Medicare coverage process — a modest figure in light of Medicare’s trillion-dollar annual outlays, and [$10M is] an order of magnitude too small to make any meaningful difference.

Documented Bandwidth

One problem I covered recently, based in part on a FOIA request, CMS only produces about 4 total NCDs per year (including simple ones like deletions), and has a backlog of several years for NCD requests (my blog here.)  

Which Means...

Let's bring this all together.  Effective and impactful pragmatic trials (e.g. most CED) are among the hardest types of trial to design, raising questions about how much bandwidth CMS has to widen that program and follow-up 5 additional programs per year (20 would be open at once by Year 4).   At equilibrium, CMS would be opening 5 CED NCDs per year and reviewing and closing the same number, so handling 10 NCDs per year for TCET alone.

Economics of CED Vary Widely

To quote from a section of my own August 7 blog. 

• You rarely see a discussion of the economics of CED, but it works much better with high cost, high margin products.   Consider a $50,000 drug.   $5000 to manufacture, $3000 per patient per trial for management, gross margin is $42,000 per reimbursement.
• Now pivot to a $100 genetic test.  $50 to manufacture.  $300 per patient per trial for management, gross margin is NEGATIVE -$2950.   I have never heard a CMS speaker who seemed to "get it" or be remotely aware of this policy aspect of CED.

Pragmatic Trials Tricky

CED registries often hinge on comparing results of participants to "virtual controls" or "administrativey matched controls."  This can be fraught with difficulties and complexities - example from current new is here.