Friday, July 12, 2024

Pathology in Action: Lundberg's "Brain to Brain Loop" from Laboratory to Clinic

George Lundberg is a pathologist and writer who was editor of JAMA for a number of years.  He wrote the book, "Managing the Patient-Focused Laboratory" in 1975, decades before "patient-focused" became a ubiquitous term.  

This week, I ran across some articles on his paradigm of a "brain to brain loop" in lab medicine and medical information.  We often remark that lab results only can have "clinical utility" to the extent they are actionable and acted on, and Lundberg contributed to this framework.

The original article was Lundberg, JAMA 1981 245:1762 "Acting on significant laboratory results."  He had a follow-up note almost twenty years later, JAMA 1998 280:565. [cited 166 and 85 times, respectively]

Plebani 2011

The 1981/1998 concept was revisited in a six-page article in 2011 by Plebani, Laposata, and Lundberg, AJCP 2011 136:829 (open access; cited 145 times).   See also a follow-up short letter by Sandhaus, AJCP 2012 137:1012.

And finally, see also a 4-page article by Lundberg in 2014, titled "Adding Outcome as the Tenth Step in the Brain to Brain Laboratory Test Loop."  AJCP 2014 141:767.  (This plea for us to "add outcomes" was less popular, cited only 22 times!)

AI Corner

Here's a Chat GPT summary of Plebani and of Sandhaus.

Summary of Plebani, Laposata, & Lundberg 2011

In the article by Plebani and colleagues, the authors review the evolution of the brain-to-brain loop concept introduced by Lundberg 40 years ago. This concept outlines the steps involved in generating a laboratory test result, from ordering to the action taken based on the test. Over the past four decades, significant changes in medical practice have impacted this loop, leading to both improvements and challenges.

Key changes highlighted include:

  1. Technological Advancements: Improvements in analytic techniques, reagents, instrumentation, and information technology have drastically reduced errors within the laboratory itself, particularly in the analytic phase.

  2. Preanalytic and Postanalytic Phases: Despite improvements in the analytic phase, errors are still prevalent in the preanalytic and postanalytic phases, especially in steps not controlled by laboratory professionals.

  3. Direct Laboratory Access (DLA): Programs allowing patients direct access to laboratory testing without clinician referral have benefits like time and cost savings but pose risks of misinterpretation and emotional distress from abnormal results.

  4. Point-of-Care Testing (POCT): While POCT offers rapid results and can improve clinical outcomes in some scenarios, it introduces new challenges and potential errors, particularly in preanalytic and postanalytic phases.

  5. Laboratory-Clinical Interface: There is a growing autonomy of clinical laboratories from the clinical context, leading to risks of inappropriate test requests and interpretation of results.

  6. Declining Workforce: There is a notable decline in students entering laboratory medicine, leading to shortages in medical technologists and laboratory directors, impacting the quality of laboratory services.

Summary of Sandhaus' Comment re Plebani

In her comment, Sandhaus acknowledges the significant contributions of the brain-to-brain loop concept over the past 40 years, as outlined by Plebani and colleagues. She agrees with their identification of five major challenges to the future relevance of the loop. Sandhaus emphasizes the irony that despite recognizing the preanalytic phase as the source of most laboratory errors and introducing effective interventions, laboratory testing is increasingly being performed by non-laboratory personnel in point-of-care settings. This shift undermines the safeguards established by laboratory professionals to ensure accurate and reliable test results.

Here's an AI read of Lundberg 2014:

In the 2014 article in AJCP, George D. Lundberg reflects on the evolution of the brain-to-brain loop concept for laboratory testing, initially introduced 40 years ago. Lundberg highlights the importance of assessing outcomes as an additional, tenth step in the loop.

Key Points:

  1. Introduction of the Brain-to-Brain Loop Concept:

    • Lundberg introduced the brain-to-brain loop in 1981, which outlines the continuum of steps from ordering a laboratory test to acting on the results.
    • The loop emphasizes the importance of minimizing errors at each step, particularly in preanalytic and postanalytic phases.
  2. Historical Context and Evolution:

    • The brain-to-brain loop was first published in JAMA and has been a recurring theme in Lundberg’s work.
    • In 1969, the critical value reporting system was introduced to ensure significant lab results are promptly communicated, which became standard practice.
  3. Challenges in Laboratory Testing:

    • Despite advancements, inappropriate laboratory utilization remains a challenge. Misbah et al. and others have highlighted the need for clinical audits to improve test appropriateness.
    • Historically, efforts to educate physicians on appropriate test usage through algorithms and decision trees have had mixed success.
  4. Adding Outcomes as the Tenth Step:

    • Lundberg proposes adding outcomes as the tenth step in the brain-to-brain loop to emphasize the importance of actionable results that benefit patients.
    • Laboratory tests should not only produce data but also lead to positive clinical actions and outcomes.
  5. Contemporary Issues in Laboratory Medicine:

    • Lundberg reflects on past and current challenges in laboratory medicine, including the difficulty in defining inappropriate utilization and the need for an outcomes research agenda.
    • He notes the ongoing need to address questions about the appropriateness, benefits, and economics of laboratory tests.
  6. Impact on Clinical Practice:

    • Effective laboratory testing should lead to actionable results, improving patient care and outcomes.
    • The article underscores the necessity of considering the final outcomes of laboratory tests to ensure their clinical relevance and utility.

In summary, Lundberg (2014) emphasizes the critical need to integrate outcomes as a fundamental part of the laboratory testing process, building on decades of work to enhance the appropriateness and effectiveness of laboratory diagnostics.

Thursday, July 11, 2024

Brief Blog: July 24 Webinar on "Clinical Utility of Pharmacogenomics"


See a webinar on July 24, 2024, titled, "Ensuring the Clinical Utility of Genomics."  It's at 10 PT, 1 ET.  Sponsored by Thermo Fisher Scientific. Led by Becky WInslow, PharmD.

Here's the link for more information.

Wednesday, July 10, 2024

CMS Releases Physician Proposed Rule CY2025

 On July 10, 2024, CMS released the inspection copy of the CY2025 proposed rule for physician services.  The Federal Register version will appear July 31.

The typescript version weighs in at 2248 pages.

Barring Congressional action, there would be a 2.9% physician payment cut due to budget neutrality laws.   Discussion at Advisory Board.


CLFS No News

There's a section for updated CLFS regulations, but it appears to be limited to routine updates to PAMA based on past Congressional line items.  Page 581-591.

Colorectal Updates

Section K, 1127-1145, discusses expanding rules for colorectal cancer screening.   CMS proposes to update regulations at 42 CFR 410.37 to delete barium enema, add computed tomography colonograph (CTC), and to define "a complete screening" to include both a blood-based biomarker test AND the subsequent screening colonoscopy.   (A complete screen is already so defined after stool-based biomarker).

Why the CRC changes? Barium enema coverage has been in place since 1998.  CMS can't delete sigmoidoscopy coverage, because it's named in statute.   Addition of CTC (colonography) is related to its positioning now in accepted screening guidelines.  

Software and AI

I don't see much about software or AI this year, although there is a section on digital mental health treatment at 377ff.  (Covered by Fierce Healthcare here).  See also some telemedicine changes (here).  See coverage at STAT here.

House Commitee Proposes Defunding the AHRQ ($0); Notes on CMS budget

 It's budget and politicking time again.  Each year, various House committees propose budgets for government agencies for the coming fiscal year (FY2025).   Actual budgets are worked out being House and Senate over a period of months.

The 349-page budget plan for House Labor & Health has been released.   

Notably, it suggests not funding the AHRQ (page 141).   I don't see any separate remark for USPSTF; as far as I know, USPSTF is embedded in the AHRQ and its budget.   The recent budget was $369M.

The document proposes dropping the federal budget for Medicaid from $406B to $383B.  

The Medicare trust funds expenditures are expected to rrise from $476B to $521B.

However, they suggest that CMS "program management" drop from $3.7B to $3.4B (4.3B was requested).

Numerous specific comments and recommendations for CMS operations follow, from page 142ff.

A sampling of topics mentioned include 

  • algorithm-based health services; 
  • AI in Prior Auth; 
  • Cancer care planning; 
  • chronic kidney disease guidelines incl Dx; 
  • making organ recovery financing less opaque; 
  • providing more frequent screening for CRC after finding known polyps; 
  • some negative comments about "blatant political activism" at CMS such as in contact centers; 
  • better coverage of digital mammography esp across States; 
  • improved diagnostic testing for neurodegenerative disease including skin tests [147] [ALZ]; 
  • timely payment under No Surprises Act situations; 
  • better access for non-opioid pain relief; 
  • nuclear diagnostics / adverse packaging of nuclear scan ligands [including ALZ]; 
  • a section about "overestimating utilization of new codes in the fee schedule," 
  • reduce false positives (skin) in sepsis blood cultures; 
  • avoid over-reliance on death certificiates in organ transplant measures; 
  • issues with radiosurgery codes; introduce self-sampling for cervical screening; 
  • update Stark Laws (re fair market value); 
  • ensure timely access to treatments and diagnostics for Alzheimer's disease [155] [ALZ]; 
  • whole genome sequencing for Medicad [156], 
  • a note that Federal Administration funding is reduced $100M (155).

CMS Releases Outpatient Proposed Rule CY2025 - Big Day for Radiopharmaceuticals

 As usual for early July, CMS releases the proposed hospital outpatient rule on July 10, 2024.

See the fact sheet here.   The press release is here.

The typescript inspection copy is here.  It weighs in at 984 pages.

The typeset version will appear July 22 in Federal Register.

Early coverage at Fierce Healthcare here. At Advisory Board.


There are new quality and conditions of participation rules for obstetric services, including E.R.


Scanning for words like "molecular" and "laboratory" I did not see anything noteworthy.


CMS proposed to revised its longstanding bundling of radiopharmaceuticals, whatever cost, into single average charges for the PET or other nuclear scan.  See the radiology website "aunt minnie."  See also an AI discussion of the proposal at sidebar.

  • Diagnostic radiopharmaceuticals with a per-day cost more than $630 would be paid for separately under CMS’ newly-proposed rule, rather than being bundled with nuclear medicine tests.
  • “This update should address challenges for patients in accessing these prescribed nuclear medicine tests with higher-cost radiopharmaceuticals,” CMS wrote in its press release describing the rule.
  • Similar changes have been proposed a few times by legislation, but hasn't passed [FIND Act].


At PDF pages 189ff, Section (g), there is a rather comical dance around range of prices that could be assigned to AI-assisted imaging services (From $3 to $900) related to APC 1511 and codes 0623ff.   

CMS writes,  it is unlikely that a service with a current payment rate of $950.50 would have a geometric mean of $4.20, an arithmetic mean of $6.60, and a median of $3.52.  These findings lead to uncertainty about the appropriate payment rate for the service described by CPT code 0625T...


Sunday, July 7, 2024

Is MolDx Doing Amazing New Things with Z Codes?

Header:  MolDx is proliferating the number of separate Z codes that may be used with a single CPT code (even a single PLA code).  This allows the Z code to describe patient pre-conditions and scenarios that can't be captured under one code.   


Part One: 

Many-to-One Mappings of Z codes to Regular Codes

Z codes date back to 2012, a prehistoric time period when there were only a few molecular codes (such as, "DNA extraction, $20" and "DNA amplification, $20.")  Z codes could make such descriptors specific for, say, EGFR mutations.

By 2014, AMA CPT was pouring out more specific codes (one for BRCA, one for EGFR, and so on), and Z codes now allowed MolDx to distinguish between MolDx-approved and MolDx-disapproved LDT versions of tests under each of those early CPT codes.

By 2024 - well, it's 2024 now.  MolDx is proliferating the numer of Z-codes, and this allows them to process claims based on very specific patient preconditions or scenario factors exist for a given test.

  • While CMS has occasionally ventured into verbose and hyper-specific Z codes (G0023, G0033, with G0023 being a Henry-Jamesian 431 words long), there's never been a profusion of scenario-based codes like Z codes today.   
  • And it could be that MolDx is just getting started.


Log on to the DEX code registry and check out recent Z-codes for CareDx.  (Actually, you don't see Z codes themselves, but each test page in the registry represents a (hidden) unique Z code).

There's an entry labeled, Allosure Kidney (a donor DNA test) for cause ,and an entry labeled, Allosure Kidney for surveillance.

For Cause The AlloSure assay is a clinical-grade targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms to accurately quantify dd-cfDNA in transplant recipients without separate genotyping of donor or recipient. The assay quantifies the fraction of dd-cfDNA in both unrelated and related donor-recipient pairs and can be completed within 3 days of blood draw, thereby providing the practical turnaround time preferred for management of transplant recipients. The AlloSure assay is performed in the CareDx CLIA laboratory and has received conditional approval by the New York State Department of Health.

For Surveillance The AlloSure assay is a clinical-grade targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms to accurately quantify dd-cfDNA in transplant recipients without separate genotyping of donor or recipient. The assay quantifies the fraction of dd-cfDNA in both unrelated and related donor-recipient pairs and can be completed within 3 days of blood draw, thereby providing the practical turnaround time preferred for management of transplant recipients. The AlloSure assay is performed in the CareDx CLIA laboratory and has received conditional approval by the New York State Department of Health.

Here, the body of the text is similar, although in other cases it could differ.  The key convention, the name, is separately coded for "Surveillance" (e.g. quarterly in asymptomatic transplants) and "For Cause" (e.g. to work up signs and symptoms of rejection.)

The text has a different style in the equivalent Natera test, called "Prospera".

Prospera Kidney For Cause, Cell free DNA found in plasma of kidney transplant recipients is isolated, amplified, sequenced, and analyzed to calculate the donor-derived cell-free DNA fraction. This fraction is indicative of kidney status. Assay intended for use as an aid in the for-cause detection of renal allograft injury and rejection.

Prospera Kidney For Surveillance, Cell free DNA found in plasma of kidney transplant recipients is isolated, amplified, sequenced, and analyzed to calculate the donor-derived cell-free DNA fraction. This fraction is indicative of kidney status. Assay intended for surveillance purposes when done as an alternative to surveillance biopsy for renal allograft injury and rejection.

Inivata (a liquid biopsy company now within Neogenomics) has 25 use cases for its RaDaR MDR minimal residual disease detection test, for different diseases (like breast cancer, lung cancer, etc) as well as numerous different use cases and situations. Click to enlarge.

25 Alternate Descriptors for Inivata RaDaR

I looked at MRD codes of 6 companies, Adaptive, Guardant, Inivata, Natera, Naveris.  I tallied 54 total MRD codes, of which about 30 were inactive or nonpayable (perhaps awaiting more data).  By my tally, 5 of 25 Inivata codes were rated in DEX as covered, compared to 19 of 22 under Natera.

DEX MRD codes (7/2024)

MRD descriptors varied from 38 to 124 words long. 18 MRD descriptors were over 100 words long.

As a side bar to a tabular listing of 54 Z codes for "MRD," see Chat GPT try to figure the table out - here.

Part Two:  From Z Codes Back to LCDs Again

Could Z-code logic helped shape easier to understand LCDs?

Over the past year, there have been debates in the WSJ about MolDx's coverage regarding donor DNA testing (the saga started in March 2023 and reached WSJ September 10September 22September 26February 22April 18) and along the way, see also at least one CMS press release (February 29).  No question, the CMS coverage for Allosure is more intricate to read than the SC BCBS coverage.  Click to enlarge.

MolDx issued a revision of the LCD (DL38568) on August 10, 2023, currently pending finalization. I posted a cloud-copy redline of the draft compared to the prior active version - here.   The effective coverage rules are intertwined and reach circa 900 words long in the proposal.  MolDx noted in August 2023 that the  various revisions (here) were "clarity" only and that "no change in coverage" was implied by the new text and definitions and rules (stated as "synopsis of changes" in DL38568).

DL38568 (click to enlarge). Changes for clarity only (per synopsis).

Could Z Codes Help the LCD Writer?

The Z codes for "surveillance" and "for cause" coverage reveal a basic logical structure that would be difficult for a new reader to quickly extract from the numerous allograft LCD rules.

For example, based on the Z code logic, the LCD coverage structure might be styled as,

"MolDx covers donor DNA transplant tests for rejection for two purposes, "surveillance" and "for cause".

     1.  "Surveillance" testing is covered when A,B,C,D, and  not covered if E, F.

    2.  "For Cause" testing is covered when G, H, I, J, and not covered if K. L.

This would bring the clarity of coverage statements more into alignment with the structure of the transplant Z codes.



Saturday, July 6, 2024

Trade Journals Headline the "UNCERTAINTY" of FDA LDT policymaking

Within a few days of each other, both 360DX and CAPTODAY feature articles on FDA LDT regulation, and the headlines announce, "UNCERTAINTY" and "UNKNOWNS."

Here is the June 26 article at 360DX by Adam Bonislawski [subscription]:

Here is the July article at CAP TODAY by Karen Titus [open access]:


Neither article directly calls out the presidential election, and if we just say neutrally that DJT has a low end 25% and high end 75% [The Economist this week] odds of winning, that's a big wild card.  


On an exploratory note, in May, I wrote a blog how labs could reckon with a huge ruling that could, however, be "canceled, changed, or delayed."  The blog was based on feeding key facts and scenarios to Chat GPT 4.  Here.


AI Corner

For curiousity only!  I have not fact-checked this but it gives an idea of verbal reasoning that AI is on the path to doing.   (Similarly, a few days ago I asked Chat GPT to pull out and cluster groups of related tests from the new AMA PLA codes, which are numbered randomly).

So, for an unvalidated skim, here's the result.  If I actually needed this, I could use the AI as a starting point but validate it point by point against the 2 articles.   Without validation, as here, just for fun.


[Chat GPT 4 ]  Here is a reasoned analysis of the two articles by Adam Bonislawski and Karen Titus regarding the uncertainty surrounding the FDA's regulation of laboratory-developed tests (LDTs):

1. Facts or Situations Mentioned by Both Authors:

  • FDA Final Rule on LDTs: Both articles discuss the FDA's final rule regulating LDTs as medical devices, highlighting the phased approach for implementation and the mixed reactions from the laboratory community.
  • ACLA Lawsuit: Both articles mention the American Clinical Laboratory Association (ACLA) filing a lawsuit against the FDA, arguing that the FDA does not have the authority to regulate LDTs as medical devices.
  • Enforcement Discretion: Both articles highlight the FDA's use of the phrase "exercise enforcement discretion," indicating the agency's flexibility in enforcing the new regulations and its intention to issue further guidance.
  • Industry Concerns: Both articles address the concerns of the laboratory community regarding the increased regulatory burden, potential impact on lab operations, and the need for clarification on various aspects of the final rule.

2. Facts and Situations Mentioned Only by Adam Bonislawski:

  • Legal Landscape and Chevron Doctrine: Bonislawski's article delves into the broader legal landscape, discussing the potential impact of the Supreme Court's reconsideration of the Chevron doctrine on the FDA's authority and regulatory actions.
  • Specific Legal Arguments: The article by Bonislawski provides detailed insights into the legal arguments presented by the ACLA, including the contention that LDTs are professional healthcare services, not medical devices, and the historical context of the FDA's regulatory authority.
  • Carve-Outs and Regulatory Response: Bonislawski discusses the various carve-outs included in the FDA's rule and how they were established in response to public comments. He also touches on the potential vulnerabilities these carve-outs might introduce to the FDA's legal position.
  • District Court for the Eastern District of Texas: The article mentions that the ACLA filed its lawsuit in this specific court, which has historically been more receptive to arguments of regulatory overreach, indicating a strategic choice by the ACLA to potentially delay the implementation of the rule.

3. Facts and Situations Mentioned Only by Karen Titus:

  • Lab Responses and Preparations: Titus provides specific examples of how laboratories, such as those at Duke University Medical Center, responded to the release of the final rule, including efforts to validate LDTs before the rule took effect.
  • Stakeholder Reactions: The article includes reactions from various stakeholders, such as Jane Pine Wood and Dr. Diana Cardona, who provide detailed commentary on the implications of the rule for lab operations, the potential impact on patient care, and the challenges of navigating the new regulatory environment.
  • Impact on Digital Pathology and AI: Titus's article specifically addresses concerns about the impact of the FDA's rule on digital pathology and the integration of artificial intelligence in lab tests, highlighting the regulatory uncertainties and potential hesitations in adopting new technologies.
  • Economic and Operational Burdens: The article discusses the economic and operational burdens imposed by the new regulations, including the need for labs to hire additional staff or create new positions to manage compliance and validation processes.

By analyzing both articles, it is clear that while they cover similar ground regarding the FDA's final rule on LDTs and the ACLA's lawsuit, they offer unique perspectives and additional details that complement each other. Bonislawski's article focuses more on the legal and regulatory framework, while Titus provides a closer look at the practical and operational challenges faced by laboratories. 

[END Chat GPT]

Friday, July 5, 2024

HHS Creates Policy for SAHS: "Significant, Anomalous, Highly Suspect Charges"

There was a brouhaha this spring that some areas had massive, likely illegitimate charges and spending for "catheters," and this was messing with ACO accounting rules and shared savings results.

In response, CMS has released a new proposed rule that would exclude defined "anomalous spending" from such calculations.   Find it here:

American Hospital Association writes about it:

The new acronym is SAHS, significant, anomalous, and highly suspect billing.  

  • See also HealthLeaders and RevCycle and Fierce Healthcare.

  • I've said for years that most Medicare fraud doesn't require super algorithms or (now) AI, but can be picked up by a 12 year old using Excel.

The proposal has a truncated comment period to July 29.


AI Corner

Here's a Chat GPT summary of the 13-page rule.

The rule you uploaded focuses on addressing significant anomalous billing activities that could impact Medicare Shared Savings Program financial calculations. Specifically, it proposes revisions for the 2023 financial performance assessments of Medicare Shared Savings Program Accountable Care Organizations (ACOs), setting benchmarks for new agreement periods starting from 2024 onwards, and adjusting the factors used in the application and change request cycles for ACOs.

Here are the key points:

  1. Anomalous Billing Activity Detection: The proposal highlights an increase in billing for selected intermittent urinary catheter supplies under Durable Medical Equipment, Prosthetics, Orthotics, and Supplies (DMEPOS) claims in 2023, which is suspected to be fraudulent. This has led to concerns about inflated Medicare Parts A and B payment amounts, potentially skewing ACO financial performance and benchmark calculations.

  2. Proposed Adjustments: CMS proposes to exclude the affected DMEPOS claims from the financial calculations of ACOs to prevent inaccurate payment adjustments and shared savings or losses determinations. This exclusion is intended to ensure that ACO performance evaluations and financial reconciliations are based on legitimate and representative service use.

  3. Operational Changes: The rule suggests adjustments to several operational aspects of the Shared Savings Program, including how performance year expenditures are calculated and benchmarks are set. These changes aim to mitigate the impacts of anomalous billing activities on ACO financial outcomes.

  4. Public and Stakeholder Impact: The proposal also considers the potential impacts on various stakeholders, particularly how it could affect the financial operations of ACOs. It discusses the need for timely adjustments to maintain the integrity and trustworthiness of the Shared Savings Program.

This proposed rule underscores the importance of accurate financial reporting and the need for mechanisms to adjust calculations when unexpected or fraudulent activities distort the expected expenditures of ACOs.

"It sounds like an embarassing situation at CMS..."

The issue of fraud, particularly in complex systems like Medicare, is a challenging one for CMS, and they are certainly aware of the implications and risks associated with fraudulent activities. Here’s how CMS generally handles these situations:

  1. Detection and Investigation: CMS uses various data analytics and monitoring systems to detect unusual billing patterns that deviate from normal activities. When a significant, anomalous, and highly suspect (SAHS) billing activity is identified, as described in the document you uploaded, CMS investigates these patterns further to determine if they are indeed fraudulent.

  2. Actions Taken: If fraud is suspected or confirmed, CMS takes several actions:

    • Referral to Law Enforcement: Suspect activities are referred to appropriate law enforcement agencies for further investigation and potential prosecution.
    • Recovery of Funds: CMS attempts to recoup any payments that were made fraudulently.
    • Exclusion of Providers: Entities found to be involved in fraudulent activities can be excluded from participating in Medicare and other federal health programs.
  3. Policy Adjustments: To prevent future occurrences, CMS often revises policies and introduces new measures. This can include adjusting how payments are calculated and benchmarks are set for ACOs to ensure that anomalous billing activities do not unfairly influence financial outcomes.

  4. Public Transparency and Rulemaking: Through the notice and comment rulemaking process, CMS provides transparency about issues and gathers feedback from various stakeholders. This process helps refine the strategies for handling and preventing fraud, demonstrating an effort to be transparent rather than to "whitewash" any issues.

While the discovery of fraud can be seen as an embarrassment, it is also a part of the ongoing challenge of managing a vast and complex healthcare system. CMS's proactive adjustments and transparency in handling these issues are part of their commitment to maintaining the integrity of the Medicare program.

MolDx Nixes Coverage of Castle Squamous Stratification Test

On July 4, 2024, MolDx released a final LCD L39583 with non-coverage of the Castle Biosciences squamous test.  This non-coverage matched the position of a draft LCD released on June 8, 2023.   The coverage was requested, per an included letter, on July 1, 2020 by Castle.  

Castle share price, which has been around $22 in recent months, slipped from $21 to $17 on Friday (roughly $100M of market cap).   See coverage 7-11 at 360Dx.  This was updated to include Castle comments, e.g. "robust validation data...overlooked by Palmetto" and [Quoting Castle] pointing to two high-quality validation studies addressing MolDx concerns.  [See SIDEBAR on the two "overlooked" papers, ARRON 2024 and WYSONG 2024].

Q&A Document

The final LCD was released along with a question-and-answer article on the public comment period (A59815), which prints as a 128-page PDF for me.  The main MolDx reebuttal section runs 6300 words and is organized on 11 topics.


MolDx's conclusory non coverage remark states:

In conclusion, the current evaluated tests at the time of drafting this policy have not yet demonstrated definitive additional risk stratification beyond that provided by available clinical, pathological, and staging criteria within the NCCN risk framework. Promising evidence is in development for use in selection of patients for adjuvant RT. This contractor will continue to monitor the evidence and may modify coverage based on new information in the pertinent literature and society recommendations.

MolDx was also concerned the populations studied did not include enough persons of color, stating:

Test performance of the 40-GEP has been reported in a population that is predominantly male and essentially all Caucasian, which is representative of the majority of patients with cSCC. Although incidence is highest in non-Hispanic white populations, the risk of metastasis is greater in patients of color. Further studies should include representation of test performance characteristics inclusive of and addressed in patients of color.

I include a PDF-format redline version of Draft LCD and Final LCD in the cloud here.  The LCD has 83 bibliographic citations and the body is 8900 words.



Readers should review the full final LCD and the Q&A article, as linked above.  

Solely for curiousity, I include a  Chat GPT analysis below.


Summarize the "response to comments" document.

Below is a concise summary of the 12 points addressed by MolDx in their rebuttal to the non-coverage policy for Castle Bioscience's GEP-40 test for squamous cell carcinoma risk stratification:

  1. Complexity of cSCC and Staging Inaccuracies: MolDx acknowledges that current staging systems for cutaneous squamous cell carcinoma (cSCC) have limitations in accurately predicting outcomes. The GEP-40 test claims to offer improved risk stratification, but its clinical utility and validation need further evidence.

  2. Validation of GEP-40: The GEP-40 test has been validated in cohorts representing the intended use population. However, MolDx emphasizes that this validation should be more comprehensive and consistent with broader clinical evidence.

  3. Focus on Metastasis: MolDx recognizes metastasis as a critical outcome for Medicare beneficiaries. They point out that the GEP-40 test should demonstrate significant impact on patient management and outcomes, especially considering the low metastatic rates in high-risk cSCC groups.

  4. Independent Risk Information: GEP-40 provides additional quantifiable risk information beyond current clinical and pathological criteria. Nonetheless, its added value in improving patient management and outcomes over existing measures needs clearer demonstration.

  5. Risk Stratification Within Stages: The test claims to stratify metastatic risk within stages effectively. However, MolDx notes that its clinical utility must be proven within the context of national guidelines and current risk assessment tools.

  6. Correlation of GEP Results with Staging: MolDx argues that merely correlating GEP results with existing stages or risk factors is insufficient. The test must show independent value and lead to meaningful management changes that improve patient outcomes.

  7. Incorporation into Patient Management: GEP-40 has shown consistent integration into management plans aligning with national guidelines. However, MolDx calls for more robust evidence to support these claims and their impact on clinical practice.

  8. Identifying ART-Eligible Patients: The test helps identify patients with high biological risk of metastasis who may benefit from adjuvant radiation therapy (ART). Yet, MolDx stresses the need for further validation and evidence of its efficacy in special populations like immunosuppressed patients.

  9. Healthcare Cost Savings: Appropriate use of GEP-40 for informing ART decisions can potentially save healthcare costs for Medicare. Nonetheless, MolDx clarifies that cost savings alone do not justify coverage without strong evidence of clinical benefit.

  10. CMS Review and Validation: MolDx disputes claims that CMS's Division of New Technology has validated the GEP-40 test's clinical validity and independence. They assert that coverage decisions are based on medical value and reasonable necessity criteria. [SEE NOTE RE #10]

  11. Criteria for Medical Necessity: The test's medical reasonableness and necessity must be demonstrated within the specific clinical context of cSCC. MolDx emphasizes that each test and disease state requires distinct evidentiary support for coverage.

  12. Overall Evidence and Recommendations: MolDx concludes that the GEP-40 test currently lacks comprehensive evidence of clinical validity and utility. They recommend further studies and peer-reviewed publications to substantiate its claims and impact on patient outcomes.

This summary provides a clear and concise overview of MolDx's rebuttal points, highlighting their key arguments and concerns regarding the GEP-40 test.

[RE #10: BQ notes that MolDx's response to Comment Topic 10, the ADLT status of the test, was an anaphylatic reaction.  MolDx writes in this context, "Statements alluding to this [ADLT] process as one that establishes the medical appropriateness of a test, or that it even considered such evidence are false and wholly without merit."  Ouch.]


Which MolDx arguments seem most important [based on Q&A responses]?

The most important and contributory concerns of MolDx leading to the final non-coverage decision for the Castle Bioscience GEP-40 test can be identified as follows:

  1. Lack of Demonstrated Clinical Utility and Validity: MolDx emphasized the need for comprehensive evidence showing that the GEP-40 test improves patient management and outcomes. They pointed out that the test must demonstrate clinical validity and utility beyond current staging and risk assessment tools. This concern is crucial as it directly impacts the perceived value and effectiveness of the test in real-world clinical settings.

  2. Inadequate Evidence of Added Value: MolDx noted that while the GEP-40 test adds quantifiable risk information, its independent value over existing clinical and pathological criteria has not been sufficiently demonstrated. They stressed that the test needs to show a meaningful reclassification of patients that leads to significant changes in clinical management and improved outcomes.

  3. Questionable Impact on Management and Outcomes: MolDx highlighted that the test's proposed management changes based on GEP-40 results have not been validated independently. They questioned whether the test leads to clinically impactful decisions, particularly in patients with low baseline metastatic risk. This concern undermines the argument that GEP-40 significantly enhances clinical decision-making.

  4. Discrepancies in Metastasis Rates and Validation Cohorts: MolDx pointed out inconsistencies between the metastasis rates reported in the GEP-40 validation studies and other independent studies. They raised concerns about the generalizability of the patient populations used to validate the test, suggesting that the test's predictive value might not be as robust in broader clinical practice.

  5. Inconsistencies in Utilization and Guidelines: MolDx mentioned that the incorporation of GEP-40 into clinical practice, as proposed by Castle Biosciences, lacks consistent support from independent experts and national guidelines. They emphasized that the test must align with established guidelines and demonstrate clear benefit in a standardized clinical context.

Overall, the most critical concern was the lack of comprehensive and independent evidence demonstrating that the GEP-40 test provides significant clinical utility and improves patient outcomes. This fundamental issue directly impacted the decision against coverage, as MolDx requires robust proof that any new test meaningfully enhances current medical practices and benefits patients.


Now discuss the full Q&A document, including access to all 128 pages of public incoming comments.

Based on the detailed comments and responses in the document, the most significant and contributory concerns raised by MolDx that led to the final non-coverage decision for Castle Bioscience's GEP-40 test for cutaneous squamous cell carcinoma (cSCC) can be summarized and discussed as follows:

  1. Lack of Demonstrated Clinical Utility: One of the primary reasons for non-coverage was the insufficient demonstration of clinical utility of the GEP-40 test. MolDx emphasized that the test needed to show that its use leads to significant improvements in patient management and outcomes. The comments highlight that although the test provides additional risk stratification information, it has not been conclusively shown to impact clinical decision-making in a way that improves patient outcomes.

  2. Inadequate Evidence of Added Value: MolDx pointed out that the GEP-40 test needed to demonstrate definitive value above and beyond existing clinical, pathological, and staging criteria. They critiqued that the test did not consistently show statistically significant, independent risk stratification beyond what is already provided by current staging systems.

  3. Validation Cohorts and Generalizability: MolDx raised concerns about the generalizability of the validation cohorts used for the GEP-40 test. They argued that the cohorts used did not adequately represent the broader population of patients with cSCC. This was particularly important as it questioned the test's applicability and reliability across diverse patient groups, including those treated in community settings versus academic centers.

  4. Independent Risk Information: While the GEP-40 test added quantifiable risk information, MolDx noted that its independent value in improving patient management and outcomes was not clearly demonstrated. They emphasized that merely providing additional risk information is not sufficient unless it leads to actionable changes in clinical practice.

  5. Correlation with Current Risk Assessment Tools: MolDx pointed out that the test's performance needed to be evaluated in combination with current risk assessment tools to demonstrate added improvement. They criticized the lack of robust evidence showing that GEP-40 significantly reclassifies patients within existing staging systems in a clinically meaningful way.

  6. Consistency in Clinical Practice: MolDx highlighted discrepancies in the use of formal staging systems among clinicians, noting that not all physicians consistently use these systems to inform management decisions. This inconsistency undermines the argument that the GEP-40 test provides a necessary improvement over current practices.

  7. Healthcare Cost Savings: Although Castle Biosciences argued that the GEP-40 test could lead to healthcare cost savings by informing ART decisions, MolDx countered that cost savings alone do not justify coverage. They stressed that the primary criterion for coverage is the demonstration of clinical benefit and medical necessity.

  8. Impact on Patient Management: MolDx questioned whether the GEP-40 test leads to meaningful changes in patient management, especially given the low metastatic rates in high-risk cSCC groups. They noted that even if the test stratifies risk, it must show that this stratification translates into improved outcomes through altered management strategies.

  9. CMS Review and Validation: MolDx disputed claims that the CMS Division of New Technology validated the GEP-40 test’s clinical validity and independence. They clarified that the coverage decision relies on demonstrating medical value and reasonable necessity, which was not sufficiently shown for the GEP-40 test.

  10. Appropriateness of Risk Stratification: MolDx emphasized that the GEP-40 test should demonstrate improved risk stratification within the context of current guidelines and risk assessment tools. They highlighted that the test's performance should be validated within a standardized clinical context to ensure it meets the unmet clinical need.

In summary, the most significant concerns from MolDx that led to the non-coverage decision centered around the lack of robust evidence demonstrating the GEP-40 test's clinical utility, added value, and impact on patient outcomes. These concerns underscored the need for more comprehensive validation and proof that the test leads to meaningful improvements in clinical practice and patient management.


The above AI analysis is based on the Q&A document.  

Switching to the LCD document.  Next, Chat GPT discusses the actual final LCD.

For those avidly interested in understanding how decisions regarding Medicare coverage for molecular biomarker tests are made, the provided document offers a detailed example, specifically focusing on the non-coverage decision for the Castle Biosciences GEP-40 test for cutaneous squamous cell carcinoma (cSCC). Here’s a TLDR summary of the key points, organized into the coverage decision, the review of evidence, and the analysis of evidence:

Coverage Decision

The Medicare Molecular Genomics Program (MolDx) decided not to cover the GEP-40 test. The primary reason for this decision is the lack of sufficient evidence demonstrating that the test provides additional clinical utility beyond existing risk stratification methods.

Review of Evidence

  1. Clinical Background of cSCC:

    • cSCC is the second most common skin cancer, with increasing incidence.
    • While most cases are treatable, a subset can metastasize, leading to poor outcomes.
  2. Current Risk Stratification and Staging Systems:

    • Existing systems include the National Comprehensive Cancer Network (NCCN) Guidelines, the American Joint Committee on Cancer (AJCC) 8th Edition, and the Brigham and Women’s Hospital (BWH) staging system.
    • These systems aim to categorize tumors into low, high, and very high-risk groups to guide treatment.
  3. Development and Validation of the GEP-40 Test:

    • The GEP-40 test was designed to stratify metastatic risk using gene expression profiling.
    • Validation studies showed the test could categorize patients into low, moderate, and high metastatic risk groups, but these studies had limitations in their design and population.

Analysis of Evidence (Rationale for Determination)

  1. Clinical Utility and Validity:

    • For a new biomarker to be covered, it must demonstrate additional risk stratification and improve patient outcomes within the framework of existing guidelines.
    • The GEP-40 test has not shown definitive clinical utility beyond current staging and risk assessment tools.
  2. Population and Metastatic Rates:

    • The intended use population for GEP-40 is too broad, including many patients unlikely to benefit from the test.
    • The metastatic rates in the test’s validation cohorts are higher than those observed in broader NCCN-validated populations, questioning the generalizability of the results.
  3. Integration with Current Guidelines:

    • The test must work in combination with existing guidelines to reclassify patients in a way that impacts clinical decisions meaningfully.
    • Current analyses do not adequately separate high-risk from very high-risk groups within the NCCN framework, which undermines the test’s proposed utility.
  4. Consistency and Validation of Proposed Frameworks:

    • Proposed management strategies integrating GEP-40 results with current guidelines have not been validated or widely supported outside Castle Biosciences.
    • Most metastases still occur in tumors classified as low or moderate risk by the test, raising concerns about its predictive accuracy.
  5. Representation in Studies:

    • Test performance has predominantly been reported in a demographic not fully representative of all cSCC patients, particularly those of color, who may have higher metastatic risks.


The evidence presented does not sufficiently demonstrate that the GEP-40 test provides additional, reliable risk stratification or improves clinical outcomes compared to existing methods. Consequently, the test has not been granted coverage. MolDx will continue to monitor emerging evidence and may adjust coverage decisions based on new, robust data.

This summary encapsulates the key considerations and rationales behind the non-coverage decision, offering policy experts a clear view of the stringent requirements and rigorous evaluation process employed by Medicare.


Thursday, July 4, 2024

The "Nth" Flip Flop in HHS Transgender Law - A Post-Chevron Case Study

This is one of the strangest chains of decisions I've ever seen in Health & Human Services policy - yet another "flip flop" in HHS law and regulation regarding transgender healthcare.  I'll briefly summarize.

  • In March 2010, the Affordable Care Act passed.
  • Section 1557 bars healthcare sex discrimation, but does so by referring the reader to text found in the 1972 Title IX federal education act.   (No person shall, on the basis of sex, be subject to discrimination...etc).
  • The Obama administration got around to writing regulations on this in 2016 (the summer Hilary Cinton was running for president).  They defined "sex discrimination" to include gay & transgender.  81 FR 31375 (5 18 2016).  
    • This received a federal court injunction, in Texas, in 2016 (Franciscan v Burwell).
  • The Trump administration (2017-2021) was prepared to let the proposed regulation expire unfinished in 2019.
    • However, the 2016 rule also included several pages establishing antibiotic stewardship programs.
    • In Summer 2019, the Trump administration extended the review period of the 2016 rule, and split apart the sex and antibiotic components.
    • The antibiotic stewardship components were finalized in early 2020.
  • Later in 2020, the Trump administration repealed the sex policy components (85 FR 37160, 6 19 2020, proposed 5 24 2019).
  • On June 15, 2020, Supreme Court ruled in Bostock that in Title VII (not Title IX), the term sex discrimination includes homosexual or transgender.
  • The Biden administration proposed, and later finalized, its enactment of ACA 1557, by determining or "re-determining" that in Title IX, sex refers to both homosexual and transgender.  (89 FR 37522, 5 6 2024).  This was to become active in 60 days, being 7 5 2024.)
  •   On July 3, 2024, Judge Luis Guirola of Soutern District of Mississippi, ruled that in Title IX (and therefore, by reference, in sectioni 1557 of ACA), "sexual" means male, female, and homosexual, but NOT transgender.   UPI here.   Court decision here.
    • The judge starts with the recent striking-down of the Chevron principal, that courts should defer to agencies in interpreting vague statutes.
    • The judge makes much of whether, in 1972, when writing the Title IX education act, Congress and dictionaries (p 15)and common usage intended the word "sex" [discrimination] to commonly include "transgender."  That is, much about textual originalism.
    • The judge includes an immediately-effective national injunction.
      • (I believe Biden HHS could go to the next-higher court to, first, repeal the injunction, then continue the case).
I am not a lawyer or a politician, but I believe the election comes into play, because a new Trump administration could reverse the regulation over a year or two (as occurred in 2020) but also could decline to oppose court rulings against the regulation, which have already occured, or decline to protest the injunction.


(On the latter point.  Some years ago there was a legal action to "throw out" an old NCD banning coverage of gender surgery, and CMS handled it by declining to file in opposition to the action - sort of a pocket veto).


The fact that Bostock included "homosexual and transgender," but, referred to Title VII and not Title IX, plays into Guirola's decision in ways that are over my head.

Some extra links.  July 3, Fierce Healthcare, judge blocks rule.   April 29, Fierce Healthcare, administration restores nondiscrimination rule.  June 2020, Trump tosses nondiscrimination rule.    

As a sidebar (separate link) see an AI discussion of the case, and a discussion of how the Bostock Title VII decision includes (sex, gay, transgender) while the new HHS court decision includes only (sex, gay).


Tuesday, July 2, 2024

Very Brief Blog: AMA Publishes July 1 New PLA Codes

AMA publishes new Proprietary Laboratory Analysis (PLA) codes quarterly, and here's the batch submitted circa April 1 and ratified at the May 2024 AMA CPT editorial meeting.  The new list appears July 1.   

The list also includes PLA codes from recent quarters that are too recent to be in teh CY2024 AMA code book.

The codes run from 0476U (OneOme mental health / pharmacogenomic genes) to 0520U (Sync View drug monitoring from Phenomics).  That suggests there are nearly 50 new PLA codes in the July 1 batch.   I assume all of these were covered in the June 25, 2024 CMS public meeting for new code pricing (here).


AI Corner

One of the problems with PLA codes is that they have no organizing structure, and there are now over 500 of them.

I exported the PDF into Excel, and then copied the resulting 7 Excel sheets into 1 sheet.   I asked CHAT GPT to make some categories and list the relevant tests.  I cut and paste these below, but I have NOT manually checked them for accuracy.   Initially, it happily put the Transplantation tests into its Oncology category, and I asked it to fix that.



CodeTest and CompanyTest Description
0478ULung HDPCRTM, Protean BioDiagnosticsOncology (non-small cell lung cancer), DNA methylation...
0485UCaris AssureTM, Caris MPI, Inc d/b/aOncology (solid tumor), cell-free DNA and RNA...
0486UNorthstar ResponseTM, BillionToOne LabsOncology (pan-solid tumor), next-generation sequencing...
0487UNorthstar SelectTM, BillionToOne LabsOncology (solid tumor), cell-free circulating tumor DNA...
0490UCELLSEARCH® Circulating Melanoma CellOncology (cutaneous or uveal melanoma), circulating melanoma cells...
0491UCELLSEARCH® ER Circulating Tumor Cell (CTC)Oncology (solid tumor), circulating tumor cells, estrogen receptor...
0492UCELLSEARCH® PD-L1 Circulating Tumor CellOncology (solid tumor), circulating tumor cells, PD-L1 expression...
0495UStockholm3, BioAgilytix DiagnosticsOncology (prostate), analysis of circulating tumor DNA...
0496UColoScapeTM PLUS, DiaCarta, IncOncology (colorectal), cell-free DNA, 8 gene mutations...
0497UOncoAssureTM Prostate, DiaCarta, IncOncology (prostate), mRNA gene-expression profiling...
0498UOptiSeqTM Colorectal Cancer NGS Panel, DiaCarta, IncOncology (colorectal), next-generation sequencing...
0499UOptiSeqTM Dual Cancer Panel Kit, DiaCarta, IncOncology (colorectal and lung), DNA from formalin-fixed tissue...
0501UQuantiDNATM Colorectal Cancer Triage Test, DiaCarta, IncOncology (colorectal), blood, quantitative cell-free DNA...
0507UAvantect Ovarian Cancer Test, ClearNote® HealthOncology (ovarian), DNA, whole-genome sequencing...
0510UPurISTSM, Tempus AI, IncOncology (pancreatic cancer), augmentative data integration...
0511UPARIS, Tempus AI, IncOncology (solid tumor), tumor cell culture and response profiling...
0512UTempus p-MSI, Tempus AI, IncOncology (prostate), augmentative algorithm for microsatellite instability...
0513UTempus p-Prostate, Tempus AI, IncOncology (prostate), augmentative algorithm for prognostic profiling...



  • 0493U: ProsperaTM, NateraTM

    • Transplantation medicine, quantification of donor-derived cell-free DNA (cfDNA) using next-generation sequencing, plasma, reported as percentage of donor-derived cell-free DNA.
  • 0508U: VitaGraftTM Kidney Baseline + 1st Plasma Test, Oncocyte Corporation

    • Transplantation medicine, quantification of donor-derived cell-free DNA using 40 single-nucleotide polymorphisms (SNPs), plasma, and urine, initial evaluation reported as percentage of donor-derived cell-free DNA with risk for active rejection.
  • 0509U: VitaGraftTM Kidney Subsequent, Oncocyte Corporation

    • Transplantation medicine, quantification of donor-derived cell-free DNA using up to 12 single-nucleotide polymorphisms (SNPs) previously identified, plasma, reported as percentage of donor-derived cell-free DNA with risk for active rejection. ​

Infectious Diseases:

  • 0480U: Bacteria, Viruses, Fungus, and Parasite Metagenomic Sequencing, Spinal Fluid (MSCSF), Mayo Clinic
    • Infectious disease (bacteria, viruses, fungi, and parasites), cerebrospinal fluid (CSF), metagenomic next-generation sequencing (DNA and RNA), bioinformatic analysis, with positive pathogen identification.
  • 0483U: Ciprofloxacin Susceptibility of Neisseria gonorrhoeae, MedArbor Diagnostics, SpeeDx, Inc
    • Infectious disease (Neisseria gonorrhoeae), sensitivity, ciprofloxacin resistance (gyrA S91F point mutation), oral, rectal, or vaginal swab, algorithm reported as probability of fluoroquinolone resistance.
  • 0484U: Macrolide Resistance of Mycoplasma genitalium, MedArbor Diagnostics, SpeeDx, Inc
    • Infectious disease (Mycoplasma genitalium), macrolide sensitivity (23S rRNA point mutation), oral, rectal, or vaginal swab, algorithm reported as probability of macrolide resistance.
  • 0502U: QuantiVirusTM HPV E6/E7 mRNA Test for Cervical Cancer, DiaCarta, Inc
    • Human papillomavirus (HPV), E6/E7 markers for high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), cervical cells, branched-chain capture hybridization, reported as negative or positive for high risk for HPV.
  • 0504U: Urinary Tract Infection Testing, NxGen MDx LLC
    • Infectious disease (urinary tract infection), identification of 17 pathologic organisms, urine, real-time PCR, reported as positive or negative for each organism.
  • 0505U: Vaginal Infection Testing, NxGen MDx LLC
    • Infectious disease (vaginal infection), identification of 32 pathogenic organisms, swab, real-time PCR, reported as positive or negative for each organism.

Monday, July 1, 2024

New in JAMA! Lee Fleisher, Robert Califf, Others, on "Payers and Evidence Generation"

Update - This is one of a pair of articles this summer in JAMA by FDA on clinical evidence.

This paper, this blog, is Abbasi et al., with Lee Fleisher, on payers and evidence.

There was also a slightly earlier paper by Abbasi, Curtis, Califf, "Why should FDA focus on pragmatic clinical research?"  In print June 3, 2024, 332:103-104.  

JAMA also links these two FDA op eds to a consensus essay by Angus et al., "Integration of clinical trials with the practice of medicine."  June 3, 2024, 332:153-162.


 Have you wondered when CMS will finalize 2023's proposed rule on new technologies, the TCET rule (here)?  

Here's a joint article in JAMA, July 1, authored by the head of FDA (Califf) and the prior Chief Medical Officer of CMS (Fleisher).   

Not Much of a Link to TCET

I was interested from a TCET perspective, because a publication like this might suggest that the final version of TCET is about to appear.  But on further review, it's not so clear.  The article is primarily by FDA authors, taking an FDA perspective (albeit on medical insurance).     

The TCET proposal is mentioned but only tangentially.  Had TCET been carefully summarized and praised in this essay, I would have tagged that, as a sign that TCET's finalization was imminent.  See also an earlier, 8/2023 article in JAMA Health Forum by Fleisher and colleagues on TCET, here.

FDA Authors Take on Payers

So take the FDA-and-payers article on its own.   FDA reports several ways in which private payers are, or could be, pivotal to post-FDA-approval evidence generation, including the simple fact that they hold all the claims data.   See the FDA's detailed website about its collaborations with payors here.

CMS CMMI and the "ACE"

The FDA article mentions TCET, coverage with evidence development (CED), and a proposal from the CMMI innovation center called "ACE, Accelerating Clinical Evidence," which would be related to different payments for drugs that have and have not completed post-approval trials.  New to me; see also here, page 3.


Nerd note - the FDA article says that CMS first got the authority to cover routine costs of devices in clinical trials in 2003, in the Medicare Modernization Act, but it actually goes back to the Clinton-era NCD (2000) on clinical trials.  And the even earlier 1995 joint CMS-FDA regulation on Medicare coverage of IDE Category B trials (60 FR 48417) which itself developed at least in part from a legal case dating to 1994 (2nd Circuit, Yale New Haven Hosp v Leavitt, 11/16/2006).

Unlike many policy articles, this one DOES have an abstract, which I clip below.


Importance  The US leads the world in bringing new medical products to market, but the ability to generate evidence to inform clinical practice in postmarket settings needs improvement. Although a diverse group of stakeholders is working to improve postmarket evidence generation, the role of private payers has been underappreciated.

Observations  Payers are crucial allies in improving evidence generation because better data would better inform coverage decisions, their policies and practices influence the conduct of care and research, and their claims data are a source of real-world evidence used in medical product evaluation. In addition, payers have a stake in improving evidence generation because the kinds of evidence needed to inform health care and coverage decisions are often not available when a product enters the market and may not be generated without their involvement. Here, we describe several key steps payers could take to improve evidence generation, including participating in efforts to reduce administrative and financial barriers to the conduct of clinical trials, directly incentivizing evidence generation on high-priority questions by funding potential cost-saving trials, increasing engagement with the medical products industry on evidentiary needs for coverage decisions, and improving usability of claims data by reducing data lags and routinely recording unique device identifiers. Broad payer engagement with US Food and Drug Administration recommendations regarding evidence generation will ensure that the opportunities to participate in clinical research are extended to all communities and that evidence needed to inform care is generated in trials and surveillance systems that reflect the clinical reality across the US.

Conclusions and Relevance  Increasing payer involvement in evidence generation can benefit all participants in the medical innovation ecosystem. The importance of payers in these efforts will continue to grow in response to imperatives to increase integration of care and research, engage a diverse set of communities in clinical research, and move toward alternative payment models.


FDAs Arguments, Payers, Data, and MolDx

Just like a famous criminal said he robbed banks, "Because that's where the money is," FDA looks to payers for real world evidence, because that's where the claims are.  CMS has tons of Medicare data, from claims forms, some free, some available on payment for data runs.   But in diagnostics, more and more claims fall under the MolDx unlisted code 81479, plus a Z code.   (81479 is virtually unused outside of MolDx MACs).   But if you buy that data, you won't know the Z codes, and can't do public health research.  Even if CMS is able to sell you the claim field containing the Z code, the Z code is confidential, so you won't know what test, or category of test, was used for large proportions of molecular test claims.


AI Corner

I also pulled an AI-generated summary (Chat GPT 4).


Summary of the Article: "Why Evidence Generation Should Matter to Payers and How They Can Help"

Authors: Ali B. Abbasi, MD; Lesley H. Curtis, PhD; Lee A. Fleisher, MD; Robert M. Califf, MD

Main Points:

  1. Current State of Evidence Generation:

    • The US excels in bringing new medical products to market but lags in generating postmarket evidence that informs clinical practice and policy.
    • Postmarket evidence is crucial for understanding comparative effectiveness, cost-effectiveness, and optimal sequencing of treatments.
  2. Role of the FDA:

    • The FDA is working on enhancing real-world evidence (RWE) in regulatory decisions, promoting pragmatic clinical trials, improving trial diversity, and integrating care with research.
    • The agency collaborates with federal and external partners but sees an underappreciated role for private payers in supporting evidence generation.
  3. Importance of Payers:

    • Private payers are critical for generating evidence to improve health outcomes and guide coverage decisions.
    • They influence care and research through their policies and practices, and their claims data is a valuable source of RWE.
  4. Proposed Steps for Payers:

    • Reduce Barriers: Streamline administrative and financial barriers to conducting clinical trials.
    • Incentivize Evidence Generation: Fund trials addressing high-priority questions and cost-saving interventions.
    • Engage with Industry: Collaborate with medical product developers on evidentiary needs for coverage decisions.
    • Improve Claims Data: Enhance usability of claims data by reducing lags and recording unique device identifiers.
  5. Benefits of Payer Involvement:

    • Increased payer involvement can lead to better evidence generation, ultimately benefiting all stakeholders in the medical innovation ecosystem.
    • This involvement aligns with broader goals of integrating care and research, engaging diverse communities in clinical trials, and transitioning to alternative payment models.
  6. Case Studies and Examples:

    • Historical precedents and current initiatives illustrate the potential for payer-supported trials to provide valuable evidence and cost savings.
    • Examples include CMS’s coverage with evidence development policy and the Enhancing Oncology Model, which emphasize the importance of payer engagement in research.
  7. Operational Considerations:

    • Improving claims data quality can enhance postmarket surveillance and support the efficient conduct of clinical trials.
    • Initiatives like the FDA’s Sentinel Initiative and the Biologics Effectiveness and Safety System demonstrate the utility of high-quality claims data in regulatory decisions.
  8. Conclusion:

    • Increasing payer engagement in evidence generation is essential for the future of medical innovation and healthcare delivery.
    • Collaboration among stakeholders, including payers, is necessary to ensure that evidence generation is integrated with clinical practice and addresses public health priorities.

Author Information:

  • Ali B. Abbasi, MD: Affiliated with the US Food and Drug Administration (FDA).
  • Lesley H. Curtis, PhD: Affiliated with the US Food and Drug Administration (FDA).
  • Lee A. Fleisher, MD: Affiliated with the University of Pennsylvania, Philadelphia.
  • Robert M. Califf, MD: Commissioner of the US Food and Drug Administration (FDA), based at the White Oak Campus in Silver Spring, Maryland.

Article Citation:

  • JAMA. doi:10.1001/jama.2024.7616
  • Published online July 1, 2024.

This article emphasizes the pivotal role of private payers in generating postmarket evidence to improve healthcare outcomes and support effective medical innovation. The authors argue for a collaborative approach involving payers, the FDA, and other stakeholders to address gaps in evidence and enhance the quality and applicability of clinical research.