Tuesday, July 30, 2024

AI Corner: Scite.Ai Writes Instant Articles From PubMed

Header: Scite.ai autogenerates short, fully referenced articles on the topic of your choice, even kind of obscure ones.   If you think "AI writing is unusable because of hallucinations," you haven't used Scite.ai.

Here, I update an April 2024 blog.

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I've referred before to a subscription AI service called SCITE.AI.   When you have an index paper (Smith et al. 2022), it gives you all the papers that have cited it, AND, in most cases, the paragraph of text that makes the citation.   

You get other data, like how many citations a paper has, how many are neutral citations, which citations are confirmatory vs negative, etc.  Click on any paper citing Smith et al. 2022, or any paper in the bibliography of Smith et al. 2022, and replicate the same info instantly.

SCITE has full-text access to all public articles, plus licenses that allow it to present short quotes even from many firewalled articles.

Assistant by SCITE

Scite.ai has got another trick called ASSISTANT BY SCITE.  Here, you give it a question or a topic, and it searches PubMed for relevant articles and builds an AI summary out of them.

POLE?

Someone asked me about the gene, POLE (dna polymerase epsilon), which contributes to hypermutations in some cancers.   New to me.   I checked the AMA CPT codebook, and while there are codes that mention POLG and POLG2 (gamma and gamma-2), nothing for POLE.

I gave this request to ASSISTANT BY SCITE:

"What are the clinical purposes in clinical oncology 
for testing the gene POLE?"

In about a minute, it rolled back with this response.

Testing the gene POLE in clinical oncology serves several important purposes. POLE mutations have been identified in various cancers, including colorectal cancer, endometrial cancer, and lung adenocarcinoma. Detecting pathogenic variants in the POLE gene is crucial for identifying patients with a good prognosis and guiding treatment decisions (Heerik et al., 2023). In endometrial cancer, POLE mutations are associated with a favorable outcome and high PD-L1 expression, indicating a potential benefit from immunotherapy (Liu et al., 2018). Furthermore, POLE mutations have been linked to increased tumor mutation burden (TMB) and have shown promise in predicting response to immune checkpoint inhibitors (Li et al., 2022).

The clinical significance of POLE mutations extends to different cancer types, such as colorectal cancer and stomach adenocarcinoma. POLE mutations have been associated with distinct clinicopathological characteristics and outcomes, emphasizing the importance of distinguishing POLE category tumors for tailored management (Hino et al., 2019). Additionally, assessing POLE and POLD1 mutations in stomach adenocarcinoma has been proposed as a valuable prognostic and immunotherapy biomarker (Zhu et al., 2022).

Moreover, POLE mutations have implications beyond prognosis and treatment response. Studies have highlighted the role of POLE mutations in activating cancer-cell-intrinsic immunity and suppressing tumorigenesis through specific pathways (Tang, 2024). Furthermore, the identification of germline POLE mutations in pediatric patients with hypermutated medulloblastoma underscores the importance of genetic testing for early detection and management of hereditary cancer syndromes (Lindsay et al., 2019).

In conclusion, testing for POLE mutations in clinical oncology is essential for risk assessment, treatment stratification, and predicting response to immunotherapy across various cancer types. Understanding the clinical implications of POLE mutations can aid in personalized cancer care and improve patient outcomes.

References: 

Heerik, A., Haar, N., Vermij, L., Jobsen, J., Brinkhuis, M., Roothaan, S., … & Bosse, T. (2023). qpole: a quick, simple, and cheap alternative for pole sequencing in endometrial cancer by multiplex genotyping quantitative polymerase chain reaction. Jco Global Oncology, (9). https://doi.org/10.1200/go.22.00384 

Hino, H., Shiomi, A., Kusuhara, M., Kagawa, H., Yamakawa, Y., Hatakeyama, K., … & Yamaguchi, K. (2019). Clinicopathological and mutational analyses of colorectal cancer with mutations in the pole gene. Cancer Medicine, 8(10), 4587-4597. https://doi.org/10.1002/cam4.2344 

Li, S., Zhang, J., Du, W., Ren, X., & Zhang, X. (2022). Pathologic complete response to immune checkpoint inhibitor in a stage iiib ovarian clear cell carcinoma patient with pole mutation resistant to platinum-based chemotherapy: a case report. Gland Surgery, 11(9), 1562-1567. https://doi.org/10.21037/gs-22-420 

Lindsay, H., Scollon, S., Reuther, J., Voicu, H., Rednam, S., Lin, F., … & Roy, A. (2019). Germline pole mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency. Molecular Case Studies, 5(5), a004499. https://doi.org/10.1101/mcs.a004499 

Liu, L., Ruiz, J., O’Neill, S., Grant, S., Petty, W., Yang, M., … & Zhang, W. (2018). Favorable outcome of patients with lung adenocarcinoma harboring pole mutations and expressing high pd-l1. Molecular Cancer, 17(1). https://doi.org/10.1186/s12943-018-0832-y 

Tang, M. (2024). The p286r mutation of dna polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cgas-sting pathway. Cell Death and Disease, 15(1). https://doi.org/10.1038/s41419-023-06418-3 

Zhu, M., Cui, H., Zhang, L., Zhao, K., Xing, J., & Jin, H. (2022). Assessment of pole and pold1 mutations as prognosis and immunotherapy biomarkers for stomach adenocarcinoma. Translational Cancer Research, 11(1), 193-205. https://doi.org/10.21037/tcr-21-1601

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Let's ask a follow up.

"Going back to the POLE gene, when it is mutated, 
the cancer cell genome may be hypermutated. 

It seems like hypermutated cancers may be good candidates for checkpoint inhibitor therapy. TMB, tumor mutational burden, is a marker for checkpoint inhibitor drug response. 

Is there evidence that POLE itself, is a biomarker for better checkpoint inhibitor response?"

Among the references provided, Reference (Garmezy et al., 2022) by in "Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers" stands out as a relevant source for investigating whether POLE mutations serve as biomarkers for improved response to checkpoint inhibitor therapy. This study delves into the association between mutations in the POLE exonuclease domain, hypermutated cancers, and the potential for enhanced responses to immunotherapy agents, suggesting a trend towards improved prognosis (Garmezy et al., 2022). The findings from this research shed light on the predictive value of POLE mutations in guiding treatment decisions involving immune checkpoint inhibitors, indicating a potential benefit for patients with POLE-mutated cancers. Moreover, Reference Wang (2023) by et al. provides additional insights into the immune signatures of POLE mutations in endometrial carcinomas. The study demonstrates that tumors with POLE mutations exhibit significantly higher tumor mutational burden (TMB) and microsatellite instability (MSI) scores, suggesting a more favorable response to immune checkpoint inhibitors (Wang, 2023). This evidence further supports the notion that POLE mutations may serve as predictive biomarkers for better responses to immunotherapy, emphasizing the potential clinical implications of POLE status in guiding treatment strategies for cancer patients. Furthermore, Reference Durando et al. (2022) by presents a case study highlighting a patient with POLE mutation-associated colorectal cancer who achieved a four-year disease-free remission following anti-PD-1 therapy. This case underscores the clinical significance of POLE mutations and their impact on treatment outcomes, particularly in the context of immune checkpoint blockade (Durando et al., 2022). The successful response to anti-PD-1 therapy in this case suggests that POLE mutations may indeed be associated with improved checkpoint inhibitor responses, supporting the hypothesis that POLE status could serve as a biomarker for favorable treatment outcomes. In conclusion, the references provide compelling evidence suggesting that POLE mutations may serve as predictive biomarkers for better responses to immune checkpoint inhibitor therapy in various cancers. The studies highlight the association between POLE mutations, hypermutated phenotypes, increased TMB, and enhanced antitumor immune responses, indicating the potential utility of POLE status in guiding immunotherapy strategies for cancer patients.

[Additional citations omitted].

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Find A Review Article

Here I asked for a POLE review article.   The third one, YAO, sounds like that most on-point.  Even though HEERIK is about technology, it might have a good overview about why you'd bother to test POLE in cancer patients.  A side bar in the SCITE reference sections tells me that each of these is "open access."

"Find review articles about the gene POLE (dna polymerase epsilon) in clinical oncology. Focus on 2022, 2023, 2024 papers."


The references provided focus on the clinical characteristics, detection, and sequencing of POLE mutations in endometrial cancer. They offer valuable insights into the significance of POLE mutations in endometrial carcinoma, emphasizing the importance of accurate detection and characterization for improved clinical management and treatment outcomes.

  • Heerik, A., Haar, N., Vermij, L., Jobsen, J., Brinkhuis, M., Roothaan, S., … & Bosse, T. (2023). qpole: a quick, simple, and cheap alternative for pole sequencing in endometrial cancer by multiplex genotyping quantitative polymerase chain reaction. Jco Global Oncology, (9). https://doi.org/10.1200/go.22.00384
  • Lawson, N. and Chung, B. (2023). Clinical characteristics and detection of polymerase epsilon mutant endometrial carcinoma. Science Insights, 42(4), 903-908.
  • https://doi.org/10.15354/si.23.re295
  • Yao, X. (2024). The clinical and pathological characteristics of pole-mutated endometrial cancer: a comprehensive review. Cancer Management and Research, Volume 16, 117-125. https://doi.org/10.2147/cmar.s445055






Here's another one, from the headlines.
ALZ blood tests.

I understand there have been big advances in the accuracy of TAU and other BLOOD tests for Alzheimer diagnosis. Please review this topic focusing on 2023 and 2024 papers.

In recent years, there has been a significant advancement in the accuracy and utility of blood tests for diagnosing Alzheimer's disease (AD), particularly focusing on biomarkers like tau and amyloid-beta (Aβ) proteins. The development of blood biomarker tests for AD has progressed rapidly, with these tests now being increasingly utilized in research studies, clinical trials, and clinical practice (Hansson et al., 2023). Detecting readily available blood biomarkers such as Aβ42 peptides, phosphorylated tau proteins, and total tau proteins has emerged as a promising strategy for AD diagnosis (Abukuri, 2024). These accessible blood tests measure biomarkers associated with AD pathology, including amyloid-beta and tau, which are key features of the disease, along with assessing neurodegeneration (Warmenhoven, 2024). Recent studies have highlighted the shift from low-sensitive plasma assays to new ultra-sensitive assays like single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) for determining plasma biomarkers of AD with higher accuracy (Pais et al., 2023). The accurate detection of AD pathology, including Aβ plaques and hyperphosphorylated tau aggregates, through blood tests is crucial for both research and clinical trials, with implementation in clinical settings already underway (Colvee-Martin, 2024). Plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have shown utility in screening and diagnosing the earliest stages of AD (Datta, 2024). Plasma pT217‐tau, among multiple tau species and other biomarkers, has demonstrated high accuracy in predicting the presence of AD neuropathology, including aggregated tau pathology (González‐Ortiz et al., 2023). Additionally, plasma phosphorylated tau (p-tau) has shown specificity to AD compared to non-AD neurodegenerative diseases, making it a valuable biomarker for clinical diagnosis and eligibility for approved therapies (Kac, 2023). The development of blood biomarkers targeting the principal pathological hallmarks of AD, such as Aβ and p-tau, has provided new diagnostic and prognostic opportunities that were not feasible with cerebrospinal fluid (CSF) or neuroimaging biomarkers (Garcia-Escobar, 2024). These blood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of AD in clinical practice (Hansson et al., 2023). Recent advances in blood-based biomarkers offer a less invasive alternative to current CSF measures, enhancing the feasibility of widespread screening and monitoring for AD (Garcia-Escobar, 2024). In conclusion, the advancements in blood tests for AD, particularly focusing on tau and Aβ biomarkers, have significantly improved the accuracy and accessibility of AD diagnosis. These blood-based biomarkers offer a less invasive and more practical approach to screening, diagnosing, and monitoring AD, with the potential to revolutionize the field of AD research and clinical practice.

Abukuri, D. (2024). Novel biomarkers for alzheimer’s disease: plasma neurofilament light and cerebrospinal fluid. International Journal of Alzheimer S Disease, 2024, 1-15. https://doi.org/10.1155/2024/6668159
Colvee-Martin, H. (2024). Neuropathology, neuroimaging, and fluid biomarkers in alzheimer’s disease. Diagnostics, 14(7), 704. https://doi.org/10.3390/diagnostics14070704
Datta, D. (2024). Nanoscale imaging of pt217‐tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: evidence of interneuronal trafficking and early‐stage neurodegeneration. Alzheimer S & Dementia, 20(4), 2843-2860. https://doi.org/10.1002/alz.13737
Garcia-Escobar, G. (2024). Blood biomarkers of alzheimer’s disease and cognition: a literature review. Biomolecules, 14(1), 93. https://doi.org/10.3390/biom14010093
González‐Ortiz, F., Kac, P., Brum, W., Zetterberg, H., Blennow, K., & Karikari, T. (2023). Plasma phospho-tau in alzheimer’s disease: towards diagnostic and therapeutic trial applications. Molecular Neurodegeneration, 18(1). https://doi.org/10.1186/s13024-023-00605-8
Hansson, O., Blennow, K., Blennow, K., & Dage, J. (2023). Blood biomarkers for alzheimer’s disease in clinical practice and trials. Nature Aging, 3(5), 506-519. https://doi.org/10.1038/s43587-023-00403-3
Kac, P. (2023). Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of alzheimer’s disease neuropathology.. https://doi.org/10.1101/2023.12.11.23299806
Pais, M., Forlenza, O., & Diniz, B. (2023). Plasma biomarkers of alzheimer’s disease: a review of available assays, recent developments, and implications for clinical practice. Journal of Alzheimer S Disease Reports, 7(1), 355-380. https://doi.org/10.3233/adr-230029
Warmenhoven, N. (2024). A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests.. https://doi.org/10.1101/2024.07.02.24309629

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SCITE writes about "tests that report intermediate zones."






The "Braidwood" Case Canceling USPSTF Preventive Benefits: Still Alive

How time flies.  In September 2022, the "Braidwood" federal court case found that ACA preventive benefits based on USPSTF recommendations was void, because the USPSTF (and its volunteer panel of experts) was not an allowabe entity to set federal government policies.

I have blogs from September 2022, December 2022, March 2023.

Fast forward to July 2024.  

The US Circuit Court of Appeals, Fifth Circuit, "affirmed a court order invalidating" the USPTF mandate, but found that a national injunction was not valid.   (The news article notes that the injunction might still be valid within the jurisdiction geography of the original federal district court, though).

See also the July 2024 article at Commonwealth.  41-page PDF here.

The take home lessons are,

1.  BRAIDWELL is still alive, from 2022 into 2024.   And it's still winning (that is, it's still defeating the USPSTF benefits law.)

2. Now the case was remanded back to the federal court, from which it may be appealed again back up to the same federal appealscourt. ("pingpong").

3.  This timeline (2022, 2023, 2024, 2025...) back and forth with motions and countermotions gives you some idea how "fast" the ACLA/FDA case may move...

The court addressed whether or not the Secretary of HHS could "cure" the defect by officially legally endorsing the USPTF recommendations as each came out.  The court felt this would be superficial and cosmetic.


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AI Corner

[Chat GPT 4 writes...]

In the case Braidwood Management, Inc. v. Xavier Becerra, the Fifth Circuit Court of Appeals addressed the constitutionality of the mandates under the Affordable Care Act (ACA) that require private insurers to cover certain preventive-care services without cost-sharing. The plaintiffs, comprising individuals and businesses, challenged these mandates on religious grounds, arguing that compulsory coverage for services like contraception and HIV-prevention drugs violated their religious beliefs.

A significant aspect of the case involved the Appointments Clause of the U.S. Constitution. The plaintiffs contended that members of the United States Preventive Services Task Force (Task Force), Advisory Committee on Immunization Practices (ACIP), and Health Resources and Services Administration (HRSA) were acting as principal officers of the United States without proper presidential appointment and Senate confirmation. The district court had found the structure of the Task Force unconstitutional, resulting in the vacating of agency actions enforcing the mandates and issuing an injunction.

The Fifth Circuit's ruling was mixed. It agreed that the Task Force held unreviewable power, making its members principal officers not properly appointed under Article II of the Constitution. 

However, the court found that the district court erred in universally vacating all agency actions and enjoining enforcement based on these recommendations. The court affirmed part of the district court’s judgment, reversed the universal relief, and remanded for further proceedings regarding the proper scope of the injunction and other unresolved issues, such as the ratification memo by Secretary Becerra.

This case has critical implications for health policy and administrative law, particularly concerning the constitutionality of agency structures and their authority under federal law. It emphasizes the need for proper appointments of federal officers and the potential for significant changes in the enforcement of preventive-care mandates depending on the court's final decisions​


I believe the lower court felt it had authority to issue a bold, nationwide injunction against the USPSTF preventive services measures.    What does the new decision say about the status of local or national injunctions?

The Fifth Circuit Court of Appeals in Braidwood Management, Inc. v. Xavier Becerra addressed the use of local or national injunctions in the context of agency actions and preventive-care mandates. The lower court had issued a nationwide injunction and vacated all agency actions enforcing the preventive-care mandates based on the recommendations of the United States Preventive Services Task Force (USPSTF), arguing that the structure of the Task Force violated the Appointments Clause of the U.S. Constitution.

However, the Fifth Circuit found that the district court erred in granting such broad relief. The appellate court emphasized that universal (nationwide) injunctions are not typically required or the norm and should only be issued when absolutely necessary to provide complete relief to the plaintiffs. The Fifth Circuit cited skepticism from several Supreme Court justices regarding the authority of lower courts to issue nationwide injunctions and highlighted that such injunctions can prevent legal questions from being fully developed across different jurisdictions​(2024 COURT 0501 Braidwo…)​.

The court also noted that vacatur under § 706 of the Administrative Procedure Act (APA), which was granted by the lower court, operates on the status of agency action rather than being party-specific. This means vacatur can have nationwide effects even though it is not a traditional equitable remedy. However, for vacatur to be granted, there must be a proper APA claim, which was not present in this case​(2024 COURT 0501 Braidwo…)​.

Ultimately, the Fifth Circuit reversed the universal injunction and vacatur of all agency actions, concluding that the relief granted by the district court was broader than necessary to address the plaintiffs' injuries. The case was remanded for further proceedings to determine the appropriate scope of relief, emphasizing that the remedy should be no more burdensome than necessary to provide complete relief to the plaintiffs​(2024 COURT 0501 Braidwo…)​.


Much is made of the USPSTF not being properly federally appointed.   But it has always seemed to me, if the Secretary of Health took their reports, and officially adopted and signed and published them, then they WOULD be the opinions of a federally appointed official, and have better standing.   Even though in another sense the maneuvers would be cosmetic.

The idea that the Secretary of Health and Human Services (HHS) could adopt and officially endorse the recommendations of the United States Preventive Services Task Force (USPSTF) to lend them the authority of a federally appointed official was discussed in the case. However, the Fifth Circuit found that this approach would not cure the constitutional issues identified.

The court emphasized that while the Secretary of HHS has the authority to endorse and publicize the recommendations, the fundamental problem is that the USPSTF, as an advisory body, is making binding decisions about preventive-care mandates without proper oversight or review by a principal officer of the United States. The mere endorsement or publication of these recommendations by the Secretary would not suffice to provide the necessary supervisory authority required by the Constitution.

The court pointed out that the USPSTF members are required by statute to be "independent and, to the extent practicable, not subject to political pressure." This statutory independence means that the USPSTF's recommendations cannot be directly supervised, reviewed, or altered by the Secretary of HHS or any other higher-ranking official. Thus, even if the Secretary adopted the recommendations, it would not change the fact that the original decision-making power lies with the USPSTF, which is not composed of principal officers properly appointed under Article II of the Constitution.

Therefore, while the Secretary's adoption of the USPSTF's recommendations might appear to lend them federal authority, it would not address the underlying constitutional issue. The problem is not just one of formality or appearance but of substantive oversight and accountability within the federal government's constitutional framework .


Plaintiffs argued they were bringing the case for religious freedom violations. But the judge decided by simply tossing the preventive services (due to the USPSTF problems). Do I understand correctly that the court found, since the USPSTF recommendations were invalid in the first place, for anyone, there was no need to reach the religious objections.

Yes, you understand correctly. The Fifth Circuit Court found that the United States Preventive Services Task Force (USPSTF) members' status as principal officers who were not properly appointed under the Constitution rendered their recommendations invalid. Since the court concluded that the USPSTF lacked the authority to make binding recommendations, it ruled that these recommendations could not be enforced against anyone.

As a result, the court did not need to address the plaintiffs' religious freedom objections. The court focused on the constitutional issue of the USPSTF's structure and the Appointments Clause violation, which made the preventive-care mandates unenforceable regardless of any religious objections​(2024 COURT 0501 Braidwo…)​. This approach effectively resolved the case without delving into the specific religious objections raised by the plaintiffs​(2024 COURT 0501 Braidwo…)​.

If the court found that rubberstamping the USPSTF decisions would fail, why did it "remand regarding the Becerra ratification memo?"

The Fifth Circuit Court addressed the Becerra ratification memo, which attempted to ratify the recommendations made by the United States Preventive Services Task Force (USPSTF) and other agencies. The Government argued that Secretary Becerra's memo from January 21, 2022, effectively ratified these recommendations, thus curing any constitutional issues related to the Task Force's recommendations.

However, the court expressed skepticism about the effectiveness of this ratification as a remedy for the Appointments Clause issues. The court highlighted that Secretary Becerra does not have statutory authority to review, revise, or issue the preventive-care recommendations himself, which is critical for a valid ratification. The court emphasized that for ratification to be valid, the ratifying official must have the authority to make the decision both at the time of the original act and at the time of the ratification.

Moreover, the court acknowledged that the plaintiffs raised compelling arguments that there were significant procedural problems with the ratification memo, including the lack of notice-and-comment rulemaking, arbitrary and capricious reasoning, and improper retroactivity. These arguments had not been fully considered by the district court, leading the appellate court to remand the case for further proceedings on these issues. This remand was necessary to determine whether the ratification memo could indeed remedy the constitutional issues, given the procedural concerns and the lack of explicit authority for the Secretary to ratify these recommendations​

Did the appellate court have to "remand" the Becerrra ratification memo for lower court review?   It sounds like both the lower court and appeals court found the ratification memo failed.   What was left to review at that point?   I would have concluded the opposite (no issues remained after both lower court and then appellate court had both rejected Becerra.)

The appellate court's decision to remand the issue regarding the Becerra ratification memo indicates that there were specific procedural and substantive aspects that the lower court had not fully addressed. While the appellate court did express skepticism about the effectiveness of the ratification memo, it acknowledged that the district court had not thoroughly examined several key arguments presented by the plaintiffs.

The remand was necessary because:

Procedural Issues: The appellate court noted that the plaintiffs raised concerns about procedural flaws in the ratification memo, such as the lack of notice-and-comment rulemaking, which are required for significant regulatory actions under the Administrative Procedure Act (APA).

Substantive Authority: The appellate court pointed out that there were unresolved questions about whether Secretary Becerra had the legal authority to ratify the recommendations in the first place. The court found that the lower court needed to explore whether the Secretary's action was consistent with statutory requirements and whether it constituted a valid ratification under administrative law principles.

Further Analysis Required: The appellate court believed that a more detailed analysis was required to determine the extent and impact of the ratification memo, particularly regarding whether it could indeed cure the constitutional defects. This includes considering whether the memo could have retrospective effect or if the ratification addressed all necessary legal and procedural requirements.

Thus, the remand was not necessarily a disagreement with the lower court's conclusion but rather a directive to ensure that all legal and procedural issues were fully considered and documented. This thorough examination would provide a comprehensive basis for any final decisions and potential further appeals.


With regard to the ratification we discussed early, I realize now, while the Secretary could "replicate" or "reprint and sign" the USPSTF decisions, the ACA itself gives preventive coverage authority to "USPSTF A B Decisions" - Not to ad hoc documents written and signed by the Secretary.

You're correct. The Affordable Care Act (ACA) specifically grants the authority to mandate preventive-care coverage based on the recommendations rated "A" or "B" by the United States Preventive Services Task Force (USPSTF). The statutory language does not provide for the Secretary of Health and Human Services (HHS) to directly create or issue these preventive-care guidelines; rather, it mandates that insurers cover services based on the USPSTF's ratings.

Therefore, even if the Secretary were to replicate, endorse, or ratify the USPSTF's recommendations, the statutory authority for requiring coverage comes explicitly from the USPSTF's determinations, not from a separate or subsequent action by the Secretary. This distinction is critical because it means that the USPSTF's decisions must comply with constitutional requirements, such as proper appointments under the Appointments Clause, without the possibility of retroactive correction or ratification by the Secretary.

Thus, the legal and constitutional issues surrounding the USPSTF's structure and appointment of its members remain central, as the Secretary's endorsement cannot substitute for the statutory requirement that coverage mandates are based directly on USPSTF ratings. This reinforces the significance of the appellate court's scrutiny of the Task Force's authority and the limitations on the Secretary's ability to cure any deficiencies through ratification.



Monday, July 29, 2024

Journal Club: McKinsey White Paper on MCED and LBX

Header: McKinsey has a new, 9 page white paper on cancer early screening and liquid biopsy.  At the home page, they have a very brief overview:

https://www.mckinsey.com/industries/life-sciences/our-insights/liquid-biopsy-charting-innovation-in-early-cancer-screening#/

Register to download the PDF.   


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Here's an AI summary of it.

SIDEBAR:  

  • See also an article by Robbins published July 20, 2024, at NEJM.  "MCED - Keeping a High Bar for Evidence of Benefit."  Here.

AI Corner

Chat GPT summarizes McKinsey.

The new white paper titled "Liquid Biopsy: Charting Innovation in Early Cancer Screening" from McKinsey & Company explores the transformative potential of liquid biopsy (LBx) in oncology diagnostics. The document provides an in-depth analysis of LBx technology, which involves sampling and analyzing biological fluids such as blood to detect cancer cells or tumor-derived DNA, RNA, and other molecules.

Key Highlights:

  1. Technology and Market Growth: LBx offers a less invasive alternative to traditional tissue biopsies, providing faster turnaround and better capturing of tumor heterogeneity. The global LBx market, valued at over $4 billion in 2022, is expected to grow by 16% annually from 2020 to 2030.

  2. Use Cases: LBx has applications in early cancer screening, therapy selection, and monitoring during and after treatment. While it is well-established for therapy selection and monitoring, its use in early cancer screening is still emerging but holds significant potential.

  3. Challenges and Opportunities:

    • Technological Maturity and Clinical Evidence: LBx technology has matured, with increasing evidence supporting its clinical utility. Multi-cancer early-detection (MCED) tests like Grail’s Galleri have demonstrated the ability to detect multiple cancer types with high accuracy.
    • Physician Acceptance and Affordability: Challenges remain in gaining physician acceptance and making LBx tests affordable and accessible. The high costs and limited reimbursement pose significant barriers.
  4. Four Strategies for Adoption: The paper suggests several strategies to overcome these challenges, including (1) forming partnerships for guideline inclusion, (2) engaging with physicians through data, (3) exploring innovative payment models, and )4_ leveraging direct-to-consumer channels. McKinsey also emphasizes the importance of strategic mergers and acquisitions to gain scale and enhance market penetration.

  5. Impact and Future Directions: The report projects that with the right strategies and collaborations, LBx could become a pivotal tool in early cancer detection, significantly improving patient outcomes and survival rates.

Implications for Genomics and Commercialization: For experts in genomics and commercialization, this white paper offers valuable insights into the current state and future potential of LBx. It underscores the need for continuous technological advancements, evidence generation, and stakeholder engagement to drive broader adoption. The discussion of market dynamics, regulatory challenges, and innovative business models provides a comprehensive overview for those interested in the commercialization of novel diagnostic technologies.

This summary can serve as a basis for further exploration of specific topics relevant to your readers, such as the integration of multiomics approaches in LBx and the impact of new reimbursement models on the adoption of advanced diagnostic tools.

Can you provide more color about the "four channels" that might be creatively leveraged?

The white paper outlines four creative channels that diagnostics companies might leverage to overcome the challenges associated with the adoption and commercialization of advanced liquid biopsy (LBx) technologies:

  1. Partnerships with Employer Groups and Benefit Platforms: Diagnostics companies can partner with employer groups and digital healthcare platforms to provide tests as part of employee health benefits. For example, Grail partnered with Carrum Health to offer the Galleri test to employees through employer health plans. This channel helps in reaching a large number of potential patients efficiently and may include a broader range of tests within employee health packages​​.

  2. Direct-to-Consumer (DTC) Channels: The increased consumer awareness of diagnostic testing due to the COVID-19 pandemic has created an opportunity for DTC marketing of LBx tests. Companies like Labcorp have launched DTC digital health platforms, such as Labcorp OnDemand, to offer wellness tests directly to consumers. In China, New Horizon Health offers screening test packages online at different price points for premium customers. This approach can serve as a separate revenue stream while regulatory and reimbursement barriers are being addressed​​.

  3. Collaborations with Biopharma Companies: LBx companies can partner with biopharma companies to leverage their expertise and data for drug discovery and patient stratification. Such collaborations can provide LBx companies with long-term genetic data across multiple patient populations, helping to build real-world evidence linking cancer screening with early-stage treatment and demonstrating survival benefits. For instance, Grail has collaborated with AstraZeneca, and Johnson & Johnson has partnered with Optellum for lung cancer diagnostics​​.

  4. Strategic Mergers and Acquisitions: To gain scale and enhance market penetration, diagnostics companies may explore mergers and acquisitions. Recent examples include Thermo Fisher Scientific's acquisition of Olink and Standard BioTools' merger with SomaLogic. These strategic moves can provide the necessary resources for generating clinical evidence, supporting consumer and physician education, and achieving payer adoption​​.

While these channels offer potential avenues for increasing the adoption of LBx, the success of DTC strategies, in particular, remains uncertain, especially given the high costs and complexity of advanced genomic tests compared to lower-cost consumer genetic tests like 23andMe​.

Guardant SHIELD Approved by FDA for CRC Screening

FDA has approved Guardant SHIELD as the first blood-based colorectal cancer screening test that meets Medicare's NCD criteria for this class of test.  As such, it will be covered by Medicare retroactive to today, the date of approval.

See the Guardant press release here:

https://investors.guardanthealth.com/press-releases/press-releases/2024/Guardant-Healths-Shield-Blood-Test-Approved-by-FDA-as-a-Primary-Screening-Option-Clearing-Path-for-Medicare-Reimbursement-and-a-New-Era-of-Colorectal-Cancer-Screening/default.aspx

See the 14-page provider-facing labeling:

https://shieldcancerscreen.com/wp-content/uploads/LBL-000351-R1-Shield-Provider-Labeling.pdf

Track its FDA approval page for further documents as they're released (PMA 230009):

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P230009

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Coverage at NYTimes.  At Bloomberg.  At Reuters.


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Here's the Guardant press release in part:

  • Shield is first blood test approved by FDA as a primary screening option for colorectal cancer and that meets performance requirements for Medicare coverage
  • Blood test offers easy, convenient and pleasant screening option with potential for improving colorectal cancer screening rates

PALO ALTO, Calif.--(BUSINESS WIRE)-- Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, today announced the U.S. Food and Drug Administration (FDA) has approved the company’s Shield™ blood test for colorectal cancer (CRC) screening in adults age 45 and older who are at average risk for the disease. It is the first blood test to be approved by the FDA as a primary screening option for CRC, meaning healthcare providers can offer Shield in a manner similar to all other non-invasive methods recommended in screening guidelines. Shield is also the first blood test for CRC screening that meets the requirements for Medicare coverage. (fn1)

Colorectal cancer is the second-leading cause of cancer-related death in the U.S., even though it is highly treatable if caught early. fn2 The American Cancer Society estimates that more than 150,000 people will be diagnosed with CRC in 2024 and the disease will be responsible for more than 53,000 deaths. fn3 More than three out of four individuals who die from CRC are not up to date with their screening. fn4 Early detection is critical. When colon cancer is found at an early stage before it has spread, the five-year relative survival rate is 91%. If the cancer has spread to distant parts of the body, the five-year relative survival rate is 14%. fn5

The CRC screening rate in the U.S. is only about 59%, which falls well below the National Colorectal Cancer Roundtable’s goal of 80% for eligible individuals. fn6 More than one out of three eligible Americans – over 50 million people – do not complete CRC screening, often due to the perception that other available options, such as colonoscopy or stool-based tests, are invasive, unpleasant or inconvenient. fn7

“The persistent gap in colorectal cancer screening rates shows that the existing screening options do not appeal to millions of people,” said Daniel Chung, MD, gastroenterologist at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School. “The FDA's approval of the Shield blood test marks a tremendous leap forward, offering a compelling new solution to close this gap. This decision will help make screening tests more broadly accessible and propel blood-based testing and CRC screening into a new era. With increased screening rates and early cancer detection, many more lives can be saved.”

The Shield blood test is the result of over 10 years of research and development, including collaboration between Guardant Health and leading health organizations globally. Since the commercial introduction of the LDT (laboratory developed test) version in May 2022, the overall adherence rate for the Shield test has been more than 90%, meaning more than 90% of patients who were prescribed the test in a real-world clinical setting completed it. fn8 In contrast, studies show only 28-71% of patients who are prescribed other screening methods, such as colonoscopy or a stool test, complete them. fn9-12 Primary care physicians can have patients complete a Shield test with a simple blood draw during a routine office visit, providing a convenient and more pleasant alternative screening method that doesn’t require the special preparation, dietary changes, time and discomfort associated with colonoscopy or the unpleasantness of handling stool.

“The FDA approval of the Shield test is a significant victory for patients and an important milestone in Guardant Health’s mission to conquer cancer with data. Shield can help improve colorectal cancer screening rates so we can detect more cancers at an early stage, when they are treatable,” said AmirAli Talasaz, Guardant Health co-CEO. “We are now getting ready to launch this test in the near future and are very excited to empower physicians with a viable blood-based screening option to tailor the screening regimen to the unique needs of their patients.”

The FDA decision follows a strong recommendation for approval by an Advisory Committee panel in May 2024. The approval was based on results of ECLIPSE , a 20,000+-patient registrational study evaluating the performance of the test for detecting CRC in average-risk adults. Designed to reflect the diverse population of the U.S., the study was conducted at more than 200 clinical trial sites in rural and urban communities across 37 states. Results from the study, published in the March 14, 2024, issue of The New England Journal of Medicine , showed that Shield demonstrated 83% sensitivity for the detection of CRC, with 90% specificity for advanced neoplasia. This performance is within range of current guideline-recommended non-invasive screening methods, in which overall CRC sensitivity ranges from 74% to 92%. fn13

Sunday, July 28, 2024

FDA Reminds Us: In 2026 It Will Watch & Regulate LDT "Claims" Including "Comparisons"

Header:  FDA wants an elaborate assessment of your LDT validity by May 2026 and will "take action" against any claims that are not substantiated enough, in the eyes of the FDA.  This includes NY State and Grandfathered tests.

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On April 29, 2024, FDA announced its final rule for regulating LDT's over a period of several years (a staged roll-in).   In Stage 2, by May 2026, FDA expects compliance with all "labeling" requirements.  

Remember that for drugs and devices, "labeling" is not just the outside of a box, but the full instructions for use and validated clinical support data which underlie "claims."  Drug advertisements are cautious not to make "claims" that aren't supported by labeling (package inserts, etc) which have been scrutinized by FDA.  (There are some exceptions related to first amendment.)

FDA has an elaborate website for its LDT regulatory plans - https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests

Amid the lengthy webpage, don't miss the little link for FAQs:

https://www.fda.gov/medical-devices/laboratory-developed-tests/laboratory-developed-tests-faqs

Here's the FAQ for labeling.  Remember, being an New York State-approved or a "grandfathered" test only relieves the lab from a 510(k) or PMA submission - it doesn't relieve the lab from the 2026 requirements like "labeling."  And you can't just have "labeling" on file - it has to be summited to FDA.  For example, for the Pillar "Onco Reveal" test, PMA 200011, the safety and effectiveness is 45 pages long, while the "labeling" for labs is 85 pages long and even the "physician" labeling is 8 pages long (with several pages for detailed test performance characteristics).

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Q: FDA states that the Agency intends to request submission of labeling for certain IVDs offered as LDTs. What does this mean, and what is the scope of FDA review of this labeling?

A: For IVDs that fall within the NYS CLEP, unmet needs or “currently marketed IVDs offered as LDTs” (i.e., those that were first marketed prior to May 6, 2024) enforcement discretion policy, FDA intends to request that manufacturers submit certain labeling information to the Agency in connection with the listing of the IVD as provided in 21 CFR 807.26(e). 

Labeling includes IVD performance information and a summary of supporting validation, as applicable. This information will help FDA more closely monitor currently marketed IVDs offered as LDTs and identify those that may lack analytical validity, clinical validity, or safety. 

As part of its review of labeling for currently marked IVDs offered as LDTs, FDA intends to look closely at claims of "superior performance" and whether those claims are adequately substantiated

FDA generally intends to take action where the labeling of a currently marketed IVD offered as an LDT is false or misleading, and/or the IVD offered as an LDT lacks the appropriate assurance of safety and effectiveness for its intended uses as a result of any such claims that are not adequately substantiated.

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AI Corner

I am not an attorney, and that includes not being an attorney for FDA promotions and labeling law and case law.  I did ask Chat GPT to weigh in, and include that below.

Chat GPT 4 writes:

The FDA views claims made in advertising or promotional materials as "claims" if they represent the product's attributes, effects, or benefits. These claims must be supported by validated data that has been reviewed and approved by the FDA for inclusion in the product's official labeling. If promotional claims exceed what is validated and approved by the FDA, they may be considered misleading and could result in regulatory action. Therefore, companies must ensure that all claims in their promotional materials align with the approved labeling and are supported by robust evidence.

Are there some exceptions under First Amendment or for publications?  For example, can I make an advertising claim substantiated by a new New England Journal article?

While the First Amendment protects free speech, including commercial speech, the FDA maintains stringent regulations on advertising claims for drugs and medical devices to ensure they are not misleading and are supported by substantial evidence.

Even if a claim is substantiated by a new article in a reputable journal like the New England Journal of Medicine, it cannot be used in advertising unless it is consistent with the FDA-approved labeling. Here are some key points regarding exceptions and publications:

  1. First Amendment Considerations: While the First Amendment protects commercial speech, this protection is not absolute. The FDA can regulate commercial speech to prevent misleading or false claims, ensuring public health and safety.

  2. Scientific Publications: Manufacturers can disseminate peer-reviewed scientific journal articles that discuss off-label uses, but this dissemination must be done in a non-promotional context and should follow specific guidelines set by the FDA.

  3. Promotional Claims: Any promotional claim, even if substantiated by new research, must be consistent with the FDA-approved labeling. If a new study supports a claim that is not included in the labeling, the manufacturer must seek FDA approval to update the labeling before using the claim in advertising.

  4. Dissemination of Information: The FDA allows certain scientific information to be shared with healthcare professionals, provided it is balanced and not misleading. This includes reprints of peer-reviewed scientific articles, which should be distributed in a manner that does not appear promotional.

In summary, while new scientific articles can inform clinical practice and be shared in educational contexts, advertising claims must remain within the boundaries of FDA-approved labeling to ensure they are not misleading.


Journal Club: Scott Gottlieb, JAMA: "Congress must update FDA regulations for Medical AI"

In a July 11, 2024 article at JAMA FORUM, Scott Gottlieb, former commisioner of FDA, writes that FDA's approach to AI must be updated.  He anticipates it will require Congressional action, and it could come in a model that is akin to the lab medicine VALID Act.

###

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2821274



See also: From May 2024, Senate bipartisan committee releases 30 page roadmap to USA "Innovation in AI."   Here or here or here.

See a quite-long article at 360Dx by Greg Cima on regulatory trends in AI diagnostics, here.

AI CORNER

The article doesn't have an abstract, a Chat GPT 4 summary is below.

Congress Must Update FDA Regulations for Medical AI

In a recent op-ed, former FDA Commissioner Scott Gottlieb advocates for modernizing FDA regulations to keep pace with the rapid advancements in medical artificial intelligence (AI). Highlighting the successful regulation of the Apple Watch's heart rhythm detection feature, Gottlieb emphasizes the need for a firm-based regulatory approach for AI medical devices.

Key Points:

  1. Firm-Based Regulation:

    • The FDA's shift from product-focused to firm-based regulation emphasizes the quality systems of manufacturing firms over the individual mechanics of products.
    • This approach involves routine inspections and audits of firms’ processes to ensure consistent production quality and safety of medical devices.
  2. The VALID Act:

    • The Verifying Accurate Leading-edge IVCT Development Act (VALID Act), currently before Congress, seeks to codify this firm-based regulatory approach.
    • The Act aims to modernize the oversight of in vitro diagnostics, similar to the challenges faced in regulating medical AI devices that undergo constant innovation.
  3. AI Medical Devices:

    • AI models, such as OpenAI's ChatGPT, can manage patient interactions and assist in clinical decision-making, requiring regulatory oversight.
    • The complex, opaque nature of AI models makes it difficult for the FDA to fully understand their functionality, posing regulatory challenges.
  4. Risks and Challenges:

    • AI systems trained on unreliable datasets can yield incorrect answers, highlighting the need for robust regulatory frameworks.
    • Developers are cautious, often classifying AI tools as non-device clinical decision support software to avoid stringent FDA regulations.
  5. Proposed Reforms:

    • Gottlieb suggests a modern approach where the FDA focuses on the developer’s processes and systems rather than dissecting the AI models.
    • Third-party certification for lower-risk AI devices and creation of large, reliable datasets for AI development and validation are recommended.
  6. Legislative Action Needed:

    • The FDA cannot fully implement firm-based regulation without new laws.
    • Congress must enact legislation to adapt FDA policies to the unique characteristics of AI medical devices, ensuring efficient and effective oversight.

Conclusion:

Gottlieb calls for Congress to update FDA regulations to effectively manage the rapid evolution of AI in healthcare. A firm-based regulatory approach, codified through legislation like the VALID Act, is essential for ensuring the safety and efficacy of AI medical devices while fostering innovation.

Published in JAMA Health Forum, July 11, 2024.

NCI Algorithm Promises to Improve Checkpoint Inhibitor Accuracy

One of the dilemmas in checkpoint inhibitor therapy - which can be quite toxic - is predicting who is the best candidate for a strong response.

An NCI Press release highlights a new tool, LORIS, which is an AI-based algorithm and was developed by Ruppin et al. at NCI and Morris et al. at Sloan-Kettering.

See a Linked In blog by Josie Hayes, here.

See the NCI press release here.

See the Nature Cancer article by Chang et al. (June 3) here.

See a summary algorithm online at NCI here.

##

Here's the abstract from Nature Cancer (PMID 38831056):

Despite the revolutionary impact of immune checkpoint blockade (ICB) in cancer treatment, accurately predicting patient responses remains challenging. Here, we analyzed a large dataset of 2,881 ICB-treated and 841 non-ICB-treated patients across 18 solid tumor types, encompassing a wide range of clinical, pathologic and genomic features. 

We developed a clinical score called LORIS (logistic regression-based immunotherapy-response score) using a six-feature logistic regression model. LORIS outperforms previous signatures in predicting ICB response and identifying responsive patients even with low tumor mutational burden or programmed cell death 1 ligand 1 expression. LORIS consistently predicts patient objective response and short-term and long-term survival across most cancer types. Moreover, LORIS showcases a near-monotonic relationship with ICB response probability and patient survival, enabling precise patient stratification. 

As an accurate, interpretable method using a few readily measurable features, LORIS may help improve clinical decision-making in precision medicine to maximize patient benefit. LORIS is available as an online tool at https://loris.ccr.cancer.gov/

##

See a July 11 article at JAMA FORUM, "Congress must update FDA regulations for Medical AI," by Scott Gottlieb:

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2821274

 

July 11, 2024   Congress Must Update FDA Regulations for Medical AI   -  Scott Gottlieb, MD

 JAMA Health Forum. 2024;5(7):e242691. doi:10.1001/jamahealthforum.2024.2691

When the US Food and Drug Administration (FDA) cleared the Apple Watch in 2018 for use in detecting irregular heart rhythms, many observers were worried that the agency would become mired by its need to dismantle the device to affirm its functionality. Instead, when Apple came to the FDA with a proverbial mountain of data proving its reliability in real-world settings, it bolstered a regulatory concept that was already forming among the agency’s policymakers: taking a firm-based approach to the regulation of lower-risk medical devices. This approach shifted the regulatory focus from scrutinizing the product itself to the results it generated and the developer’s overall approach to confirming the device’s reliability......



Friday, July 26, 2024

Novitas Oncology LCD: The Carnival Continues

 In mid-2022, Novitas MAC proposed a new LCD for oncology tests.   In June 2023, it issued the final version, which was much longer with many topics not covered in the proposal.  After stakeholder protests that this was "bait and switch," Novitas withdrew the final LCD.

And, days later, Novitas issued the "final LCD" of the 2022 proposal, as a new, "proposal" for 2023. Entry point here - from July 27, 2023.  

This triggered a new round of public comments.  I used AI to summarize the 21 presentations at a public hearing.  Here.  

Now, the clock has run out on the one-year time period to finalize the July 2023 draft LCD (which, recall, was the June 2023 final LCD of the 2022 proposal).

What's New?  Still Thinking!

Novitas posts that CMS has granted it an extension (of unstated duration) to continue considering the public comments.  Find it here:

https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00006150

July 26, 2024

Novitas is considering all the feedback received from interested parties regarding the Genetic Testing for Oncology LCD. An extension has been granted by CMS in order for all comments to be considered thoroughly. Future updates will be published to this website and the Medicare Coverage Database. Please watch our website and consider subscribing to our mailing list for the most timely updates.

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AI Corner

I asked Chat GPT to read this blog, and then, provide an illustration of its own choosing.

Chat GPT 4




Thursday, July 25, 2024

CMS CLFS Experts (July 25-26): Links to Transcript, Video, and a Chat GPT Analysis

On July 25, 2024, CMS held its "expert panel" providing advice on the pricing of over 100 new lab codes.

Original blog here.

Agenda for meeting here.

Flash-blog on the "process" discussion held during the panel - here.

CMS will post the voting results during August.

##

In this blog, I first provide links to the auto transcript and video links to YouTube.

Then, in the second half, I present discussion of the meeting by Chat GPT 4.


##

Auto Transcript (segmented to match the 4 videos)

https://docs.google.com/document/d/1NiSAfNe4ilIzYzbcPBIiQeW4Gyo4icjO/edit?usp=sharing&ouid=110053226805181888143&rtpof=true&sd=true

##

Here is a video archive and autotranscripts segmented for the 4 videos.

20240725 CLFS FACA VIDEO ONE (About 1-58)

https://youtu.be/TjA51_WikNM  

20240725 CLFS FACA VIDEO TWO (About 62-70)

https://youtu.be/Favgw6rdwpw

20240725 CLFS FACA VIDEO THREE (About 70-103)

https://youtu.be/356m3mmeYX0

20240725 CLFS FACA VIDEO FOUR (About 103-132 & Holdovers)

https://youtu.be/xvDjMtOwf9g

20240726 CLFS FACA VIDEO FIVE (0726, MISC)

https://youtu.be/nw64rEx1kDU


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AI CORNER


I gave the entire transcript to Chat GPT and asked it to open.  I have preserved my prompts as I wrote them.   Note that at first, it gave a shallow summary, then a better one.  Then, I asked it what evidence it saw in the transcript, for how panelists made pragmatic decisions between "crosswalk" and "gapfill".

##

PROMPT #1

Please provide a summary of this transcript.  A ten-person advisory expert panel advises CMS (Medicare) on how to price about 100 new tests.   Primarily by the "crosswalk" method to a smilar test, if none available, then by "gapfill."   Do not try to summarize the individual decisions, as there are >100 of them.

##

  • The transcript from the CMS CLFS FACA Advisory Panel meeting outlines the process and discussions involved in pricing new lab tests for Medicare. The ten-person expert panel advises CMS on pricing approximately 100 new tests using primarily the "crosswalk" method, which involves comparing a new test to an existing similar test to set a price. If a comparable test is not available, the "gap fill" method is used, where the price is determined based on the cost of resources and technology used for the test.
  • The panel's recommendations are based on subcommittees' reviews, public comments, and supporting information. Each new test is reviewed for its methodology, resources, and indications, with the panel voting on whether to use a crosswalk or gap fill approach. The process includes public input, and final decisions are made after considering preliminary recommendations and additional comments.
  • For a detailed summary, specific test decisions were not included as the content involves over 100 individual decisions and discussions. Instead, the focus is on the general procedure and methodology applied by the panel in making their pricing recommendations.


PROMPT #2

Could you write a description of the meeting that is about twice as long, going into additional highlights and factors.


The CMS CLFS FACA Advisory Panel meeting held on July 25-26, 2024, focused on establishing payment amounts for new or substantially revised Healthcare Common Procedure Coding System (HCPCS) codes for the upcoming calendar year. The ten-person expert panel, consisting of members with extensive backgrounds in various medical and scientific fields, provided recommendations to the CMS on how to price approximately 100 new laboratory tests. These recommendations were primarily based on the "crosswalk" method and, when necessary, the "gap fill" method.

Key Highlights:

  1. Meeting Structure and Process:

    • The meeting began with introductions and housekeeping items, led by Rashida Arthur, the designated federal officer. The process was virtual, allowing broader participation.
    • Two subcommittees were established: the Molecular Pathology Genomic Sequencing (MOG) Subcommittee and the Chemistry, Hematology, Immunology, and Microbiology (CHIMP) Subcommittee. These groups aimed to streamline discussions and leverage panel members' expertise efficiently.
  2. Crosswalk Method:

    • The crosswalk method involves comparing the new test to an existing test with similar methodology, resources, and clinical utility. If a suitable comparable test was found, the panel recommended using its established price for the new test.
    • For example, the test code 0445U, related to Alzheimer’s disease, was crosswalked to 0358U due to similar descriptors and methodologies, ensuring consistent pricing based on established precedents.
  3. Gap Fill Method:

    • When no comparable test was available, the gap fill method was employed. This method involves determining the payment amount based on the resources and technology required for the new test. This method takes longer as it involves gathering cost data from multiple sources.
      • The code 86041 for acetylcholine receptor binding antibody, lacking a precise comparable test, was recommended for gap fill pricing.
  4. Public and Panel Input:

    • The meeting allowed for real-time public comments and responses to questions from the panel, ensuring a transparent and inclusive process.
    • Discussions often included detailed questions about the specifics of the tests, such as the methodologies used, the type of specimens analyzed, and the clinical relevance of the tests.
  5. Technical Clarifications:

    • The panel frequently sought technical clarifications to ensure accurate recommendations. For instance, there were detailed discussions on whether certain tests measured qualitative versus quantitative results and how these differences impacted resource use and pricing.
      • For example, discussions around code X0103U for therapeutic drug monitoring involved clarifications about whether the test provided qualitative or quantitative data, impacting the decision to recommend gap fill or crosswalk to an existing code.
  6. Complexity of Test Categories:

    • The panel reviewed tests across various categories, such as molecular pathology, immunology, and microbiology. Each category had unique considerations, reflecting the diversity and complexity of modern diagnostic testing.
    • The use of advanced technologies like liquid chromatography-tandem mass spectrometry (LC-MS/MS) and multiplex assays highlighted the evolving nature of laboratory diagnostics.
  7. Voting and Decision Making:

    • Each test was individually discussed, followed by panel voting on the recommended pricing method. Votes were cast electronically, and results were immediately shared.
    • Some tests required additional follow-up or were moved to the end of the agenda for further discussion, ensuring thorough consideration of all options.

Additional Factors Considered:

  • Methodological Consistency: Ensuring that similar tests were priced consistently to avoid discrepancies and ensure fairness in pricing across the board.
  • Resource Utilization: Evaluating the resources required for each test, including equipment, reagents, and labor, to accurately reflect the cost in the pricing recommendation.
  • Clinical Utility: Considering the clinical importance and utility of the tests in patient care, influencing the prioritization and pricing decisions.
  • Technological Advances: Acknowledging the rapid advancements in diagnostic technologies and how they impact the complexity and cost of new tests.

Conclusion:

The CMS CLFS FACA Advisory Panel meeting was a meticulous and inclusive process aimed at ensuring fair and accurate pricing for new and revised laboratory tests. By leveraging the expertise of the panel members, incorporating public input, and thoroughly evaluating each test's methodology and clinical relevance, the panel provided CMS with well-founded recommendations for the upcoming year.


PROMPT #3

That was excellent! Thanks for the additional insight and color. One of the persistent topics is how to decide if a crosswalk is "close enough" to use, or whether to turf the decision to the gapfill process instead. This was discussed in the panel discussion segment about process, noting there were no objective rules for a "comparable" test. Could you review the whole document and draw any insights into how the panel approached the practical or pragmatic decision of whether a crosswalk was "close enough to use" or whether no such close crosswalk existed, forcing a referral to gapfill instead. How did panelists pragmatically handle this dilemma, as suggested by their transcribed thinking and remarks.


The CMS CLFS FACA Advisory Panel meeting highlighted several discussions around the challenge of determining whether a crosswalk is "close enough" to use or if the decision should be deferred to the gap fill process. This decision-making process lacks objective rules, and the panel often relies on practical and pragmatic considerations, as evidenced by their transcribed remarks and thought processes.

Key Insights from the Panel's Approach:

  1. Criteria for Comparability:

    • The panel frequently debated what makes a test "comparable" enough to justify a crosswalk. Factors such as intended use, methodology, number of targets, and resources required were considered. For instance, panelists discussed whether tests with similar methodologies but different targets could still be crosswalked effectively.
  2. Information and Documentation:

    • A recurring theme was the necessity of detailed information from sponsors. Panelists emphasized the need for comprehensive descriptions of assays, methodologies, resources, and outcome reports to make informed decisions. When such information was lacking, it often led to recommending the gap fill method due to insufficient data to establish a direct crosswalk .
  3. Examples of Decision-Making:

    • For complex assays, such as next-generation sequencing for colorectal cancer, the lack of a direct comparable test led to a recommendation for gap fill​.
    • In cases where a test had a similar methodology and specimen type but differed in complexity or number of analytes, the panel might opt for a crosswalk with a multiplier to account for these differences.
      •  For example, a neurofilament light chain test was crosswalked with a 0.5 multiplier due to its methodological similarity to an existing test with more analytes .
  4. Consistency and Precedent:

    • The panel aimed to maintain consistency in their recommendations year over year. This was particularly important for tests that had undergone similar reviews in previous years. Consistent application of crosswalks helps in maintaining fairness and predictability in pricing decisions.
  5. Panel Discussions and Votes:

    • The panel’s discussions often involved multiple options for crosswalks, with detailed justifications for each. When no clear crosswalk was identified, and no substantial input was received from labs or stakeholders, the gap fill method was recommended. This approach ensures that the pricing process remains rigorous and justified even in the absence of direct comparability .

Practical Handling of the Dilemma:

The panel's pragmatic handling of the crosswalk versus gap fill dilemma is illustrated by their reliance on detailed comparisons and thorough discussions. They consider:

  • The specific methodologies and technologies used in the tests.
  • The intended clinical use and outcome measures.
  • The completeness and quality of the information provided by test developers.
  • Historical decisions and established precedents to ensure consistency.

In conclusion, the panel's approach to deciding whether a crosswalk is "close enough" involves a detailed examination of each test's characteristics, a reliance on thorough documentation, and an emphasis on maintaining consistency. When faced with insufficient information or clear differences in methodology, the panel pragmatically opts for the gap fill method to ensure fair and accurate pricing decisions