Wednesday, December 4, 2024

JAMA Articles Highlight Massive Molecular UTI Testing in Medicare - MolDx Got There First

This week, JAMA has two articles discussing a recent "boom" in molecular UTI testing.  The articles were highlighted in Genomeweb.    Notably, over the past couple years, the MolDx program saw a "boom" in molecular pathogen testing several years ago, and brought out a strictly-limited LCD on the topic, including blocking most molecular testing on routine UTIs.

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The JAMA articles are worthwhile reading.   Neither Hatfield or Fitzpatrick pick up on another track of the story, which was LCD respones and 180 degree turnarounds in the payment velocity.  I believe this would have been most striking in MolDx policy regions.   More about MolDx, next.

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MolDx noted an explosion in molecular pathogen codes (including one for "other pathogen" billed in high multiples) several years ago.   The responded with a strict LCD, a voluminous billing and coding article, and even a Palmetto website FAQ.   These policy activiites led to a marked drop in payments for the now-controlled codes in MolDx regions (28 states).

  • Find the FAQ here.
  • Find the LCD here.
  • Find the billing/coding article here.
  • Anticipating requests for coverage based on prior literature, MolDx even published a 9-page PDF of hundreds of molecular UTI articles that "HAVE NOT adequately met the clinical validity and clinical utility criteria for UTI panels."   Here.
If I recall correctly, early versions of the LCD focused on CPT panel codes (e.g. a single code for "pulmonary pathogen x 12") and did not control alternative billing tricks, like the same test coded creatively as "other pathogen" which is then billed x12.

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While the work of Hatfield et al is important, leading to a JAMA publication with high visibility, I'd also note that much of the data is not secret, but is published annually and openly by CMS, so that anyone in the public could also have tracked the explosive growth in these codes in a matter of an hour or two.  (An example from my own work here.)   The Hatfield work had a higher level of specificity, by pairing pathogen procedures with UTI ICD-10 codes, which requires researcher-level access.   But the take-home lesson which is massive payment growth on uncontrolled codes would be publicly available.

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You can also identify the specific labs that were billing some of these codes, and how much they were paid per year, in a CMS public data source here.



Monday, December 2, 2024

Now Online: The Closing Briefs in FDA LDT Lawsuit (ACLA, AMP)

Thanks to CAP Advocacy News for providing links to final closing briefs newly filed by ACLA and AMP in the FDA LDT court case.

https://documents.cap.org/documents/acla-closing-brief2024.pdf

https://documents.cap.org/documents/amp-closing-brief2024.pdf

They weigh in at 32pp and 34pp, respectively, dated-stamped 11-25-2024.

The AMP brief discusses MolDx (p. 20).  

ACLA writes (p2) "Unable to defend the agency's untenable position, FDA's lawyers double down on a strategy of obfuscation and definitional sleight of hand."

They note that 1976 device law specific limited FDA control to "devices" and "in vitro reagents" [less than a device], and not "processes" like LDTs.

They emphasize than at LDT is not an object or item placed into interstate commerce.  They distinguish lab procedures from software (SaMD) because software is actually tangible, e.g., a downloaded computer file transferred from one place to another [w/ citations to court cases on SaMD].

Much is made of the legislative intent of CLIA vs FDA; CLIA specifically allows for FDA IVD's to be modified and become LDTs under CLIA; that ability doesn't make sense if it is simultaneously illegal to do so under FDA law.

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[Particularly colorful is the ACLA's 9/2024, 51-page entertaining and lively motion for summary judgement including their hatchet job on FDA's attempts to defend itself - here.  Discussed at bottom of blog.]

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AI Corner - Chat GPT 4o

Summary Argument: 

FDA’s Overreach on Laboratory-Developed Tests (LDTs)

Introduction: A Health Law Perspective

The U.S. Food and Drug Administration (FDA) has overstepped its statutory authority by asserting that Laboratory-Developed Tests (LDTs) constitute "medical devices" under the Federal Food, Drug, and Cosmetic Act (FDCA). This unprecedented move disrupts decades of regulation under the Clinical Laboratory Improvement Amendments (CLIA), which govern laboratory services as professional healthcare activities. The FDA’s Final Rule embodies what legal scholars term a “major questions” case—an agency claiming vast, newfound authority with no clear Congressional mandate. This interpretation risks undermining medical innovation and threatening access to vital diagnostic services​.

Key Legal and Regulatory Issues

  1. Misinterpretation of "Device": The FDCA defines a device as a tangible, manufactured product intended for use in medical contexts. FDA's attempt to include intangible testing procedures or protocols under this definition stretches the statutory language beyond recognition. Laboratory protocols are services, not manufactured goods, and cannot reasonably be categorized as "devices"​.

  2. Violation of the Commercial Distribution Requirement: LDTs are created and used within a single laboratory, lacking the commercial distribution element required under FDCA’s regulatory scope. By targeting these tests, the FDA misrepresents the statutory requirement for regulating goods in interstate commerce​.

  3. CLIA’s Authority over LDTs: Congress explicitly designated CLIA as the regulatory framework for laboratory services, focusing on accuracy and reliability through licensure and professional oversight. FDA's encroachment disregards this statutory division, conflating manufacturing oversight with clinical practice regulation​.

FDA’s Deficient Legal Justifications

FDA’s arguments rely on definitional manipulation and unsupported analogies:

  • Redefining "Manufacturing": FDA contends that developing or using testing protocols equates to manufacturing a device. This conflation ignores that protocols do not create a tangible product; they represent professional expertise and procedural development​.
  • Shifting Interpretations: FDA asserts that it has historically claimed authority over LDTs since the 1970s, yet this claim lacks enforcement history. Courts should not legitimize what amounts to "regulatory adverse possession"—an agency retroactively asserting long-dormant authority​.

Major Questions Doctrine

The Supreme Court has consistently held that transformative regulatory claims require explicit Congressional authorization. FDA’s assertion fails this test:

  • Economic and Professional Impact: The rule disrupts a significant healthcare sector, imposing billions in compliance costs while criminalizing longstanding medical practices​.
  • Legislative Silence: Congress has repeatedly declined to grant FDA authority over LDTs, further highlighting the agency’s overreach​.

Arbitrary and Capricious Rulemaking

FDA's reliance on non-binding “enforcement discretion” policies demonstrates the weakness of its legal interpretation. By admitting that laboratories could be prosecuted at any time for routine activities, FDA injects uncertainty into essential diagnostic services. This ambiguity underscores the arbitrary nature of the Final Rule​.

Conclusion

FDA’s Final Rule represents a sweeping and legally unfounded attempt to regulate professional healthcare services as if they were manufactured goods. By conflating laboratory-developed protocols with tangible devices, the agency jeopardizes patient care, medical innovation, and the integrity of administrative law. Courts must vacate this rule, as it exceeds statutory limits, disregards Congressional intent, and undermines the longstanding division between CLIA and FDCA authority.

As the plaintiffs aptly summarize: “Unable to defend the agency's untenable position, FDA's lawyers double down on a strategy of obfuscation and definitional sleight of hand.” \

This Court should reject this overreach to preserve the integrity of laboratory services​.


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AI Corner (Chat GPT 4o)

ACLA Closing Brief

The American Clinical Laboratory Association (ACLA)'s closing brief presents a robust critique of the FDA's final rule, centered on the legal interpretation of whether laboratory-developed tests (LDTs) and testing protocols constitute "devices" under the Federal Food, Drug, and Cosmetic Act (FDCA). 

Key Arguments from the ACLA Brief

  1. Definition of a Device:
    ACLA argues that the FDCA's definition of a "device" is limited to tangible, manufactured products, such as instruments or test kits. Laboratory testing protocols, by contrast, involve professional services and the use of physical tools but do not constitute a "device" themselves. The brief emphasizes the inconsistency of FDA's claims with statutory language and historical interpretation of the FDCA.

  2. CLIA vs. FDCA Jurisdiction:
    ACLA asserts that the Clinical Laboratory Improvement Amendments (CLIA) already provide a comprehensive regulatory framework for laboratory services, focusing on analytical and clinical validity. CLIA's regulatory scope, combined with its professional licensing standards, highlights the professional-service nature of LDTs, further distinguishing them from the FDA-regulated manufacturing of devices.

  3. Major Questions Doctrine:
    The brief invokes the doctrine to argue that the FDA's reinterpretation of its authority to regulate LDTs represents a "transformative" change that lacks explicit Congressional authorization. Such a significant expansion of regulatory scope requires clear statutory language, which is absent here.

  4. Economic and Practical Impacts:
    ACLA critiques the rule as imposing massive compliance costs and regulatory burdens on laboratories, disrupting established practices. The brief points out that FDA's own carveouts and "enforcement discretion" policies demonstrate the impracticality and overreach of its interpretation.

  5. Ad Hoc Enforcement Policies:
    The brief challenges FDA's reliance on non-binding enforcement discretion to mitigate the rule's harsh impacts, calling it arbitrary and an acknowledgment of the rule's flaws.

Analysis and Insights

  • Tangible vs. Intangible:
    A central theme in ACLA's argument is the distinction between tangible goods (e.g., test kits) and professional services. This distinction is crucial for laboratories to argue that the development of LDTs involves the application of expertise and established protocols, not the creation of new devices.

  • Historical and Statutory Context:
    By contrasting the FDA's current claims with decades of regulatory practice, ACLA underscores the absence of precedent for treating laboratory protocols as devices. This lends credibility to its assertion that FDA's action is a regulatory overreach.

  • Broader Implications for the Lab Industry:
    If the FDA's final rule stands, laboratories may face dual regulatory burdens under CLIA and the FDCA, leading to increased costs and delayed innovation. This could particularly impact smaller labs and their ability to offer customized tests for unique clinical needs.

Takeaway for the Lab Industry

  • Regulatory Advocacy: Laboratories must actively engage in the regulatory process, emphasizing the professional nature of their work and the existing adequacy of CLIA oversight.
  • Compliance Strategy: Lab directors should prepare for potential changes by evaluating their current practices in light of FDA's final rule while also contributing to industry efforts to challenge or clarify regulatory boundaries.
  • Legal Vigilance: The use of doctrines like major questions and rule of lenity reflects the high stakes and legal complexity of this issue, suggesting a need for continued monitoring of judicial outcomes.

ACLA's brief frames a compelling argument for rejecting FDA's final rule, portraying it as an unlawful expansion of authority with significant adverse consequences for the lab industry. The industry should draw on these arguments to advocate for clear and practical regulatory distinctions between devices and professional laboratory services.


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AMP


Review of the AMP Closing Brief

The Association for Molecular Pathology (AMP)'s closing brief offers a detailed critique of the FDA’s final rule asserting regulatory authority over laboratory-developed tests (LDTs). 


Key Arguments from the AMP Brief

  1. Major Questions Doctrine:

    • Unprecedented Scope: AMP argues that the FDA’s claim to regulate LDTs under the FDCA invokes the “major questions doctrine,” requiring clear Congressional authorization. The brief emphasizes that the FDA has overstepped by attempting to regulate an area traditionally left to CLIA and professional discretion.
    • Economic and Political Significance: AMP underscores that subjecting LDTs to FDA regulation will impose extraordinary costs (estimated in billions) and stifle innovation, directly impacting patient care. Congress has repeatedly declined to authorize such regulation, highlighting the legislative void.
  2. Conflict with FDCA:

    • Definition of a Device: AMP asserts that LDTs, which involve professional services rather than tangible, commercial products, fall outside the statutory definition of a "device" under the FDCA.
    • Commercial Distribution Requirement: LDTs are developed and used within the same lab, without being distributed commercially. AMP argues that the FDA’s attempt to apply the FDCA to non-commercial activities misinterprets the statute.
    • Practice of Medicine Exemption: The brief highlights statutory protections for healthcare practitioners under the FDCA, asserting that the FDA’s rule violates these exemptions by penalizing laboratories for using and modifying diagnostic tools.
  3. CLIA vs. FDCA Jurisdiction:

    • Separate Regulatory Schemes: AMP contends that Congress designed CLIA to oversee the quality and validity of laboratory tests, including LDTs, making FDA oversight duplicative and unnecessary. The brief highlights that CLIA already ensures analytical and clinical validity through proficiency testing and quality controls.
    • No Overlap in Authority: AMP emphasizes that FDA's regulation of LDTs would disrupt CLIA’s comprehensive framework, creating regulatory conflicts that Congress never intended.
  4. Arbitrary and Capricious Rulemaking:

    • Lack of Evidence: AMP critiques the FDA for failing to provide adequate justification for the rule, particularly in light of the agency’s historical non-enforcement and the existing oversight under CLIA.
    • Economic Burden: The brief emphasizes the disproportionate costs of the rule, which would force laboratories to abandon innovative tests, disrupt patient care, and overburden the FDA itself with regulatory demands.

Analysis and Insights

  • The Legal Foundation of LDTs as Professional Services:

    • AMP effectively distinguishes LDTs from commercial devices by framing them as integral to the practice of medicine. This argument positions laboratories as extensions of clinical decision-making rather than as manufacturers of products.
  • Historical and Statutory Context:

    • By referencing Congress’s repeated refusal to grant FDA authority over LDTs, AMP strengthens its claim that the FDA’s final rule lacks statutory support. The reliance on legislative history and previous regulatory practice supports AMP’s interpretation of Congressional intent.
  • Regulatory Overlap Between CLIA and FDA:

    • The brief convincingly argues that CLIA adequately regulates the reliability and safety of LDTs. AMP’s position that FDA oversight would disrupt existing processes resonates with stakeholders wary of redundant regulation.
  • Economic and Practical Consequences:

    • AMP’s detailed cost analysis highlights the real-world implications of FDA overreach. The estimated financial burden and potential harm to patient access and innovation amplify the argument that FDA regulation is unjustified.

Takeaway for the Lab Industry

  • Advocacy for Legislative Clarity: The lab industry should continue to advocate for clear statutory boundaries, emphasizing the professional and non-commercial nature of LDTs.
  • Collaboration with CLIA: Laboratories should highlight the efficacy of CLIA’s regulatory framework in ensuring test quality, while showcasing its flexibility for innovation.
  • Preparing for Potential Changes: Even as AMP’s arguments challenge the FDA’s authority, laboratories should assess compliance strategies in the event of regulatory shifts, while supporting industry-wide litigation efforts.

The AMP brief underscores a cohesive argument against FDA overreach, emphasizing the role of LDTs in advancing patient care under existing CLIA oversight. Its detailed analysis provides a strong foundation for resisting the final rule, with significant implications for the lab industry.


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Here is the September 2024 ACLA motion for summary judgment, MSJ, which seems more legalistic than the closing memoradum.   Discuss?

The ACLA’s Motion for Summary Judgment is indeed more detailed and legalistic than the ACLA’s Closing Brief, which is consistent with their distinct purposes. Below is a detailed comparison and analysis based on the content of the Motion for Summary Judgment (MSJ):


Nature of the Motion for Summary Judgment (MSJ)

The Motion for Summary Judgment is a legal document filed mid-case to argue that the court should rule in the plaintiff's favor on specific issues because there are no disputed material facts requiring a trial. It is highly focused on statutory interpretation, precedent, and administrative law principles, often citing detailed legal authorities to demonstrate why the agency’s actions are invalid.


Comparison of Content with the Closing Brief

  1. Legalistic Framework and Depth of Analysis:

    • The MSJ engages deeply with the statutory text, legislative history, and judicial precedent, often invoking specific Supreme Court cases (e.g., West Virginia v. EPA, FDA v. Brown & Williamson Tobacco Corp.) and applying principles like the major questions doctrine.
    • The Closing Brief, while still grounded in legal arguments, is broader and more rhetorically persuasive, summarizing key arguments made earlier in the litigation and focusing on policy impacts and the broader narrative of FDA overreach.
  2. Focus on Administrative Procedure Act (APA) Violations:

    • The MSJ details the procedural flaws in the FDA’s rulemaking, including its failure to justify the rule adequately under the APA. It heavily critiques the FDA’s reliance on "enforcement discretion" to defend its regulation, arguing that this creates arbitrary and capricious standards.
    • The Closing Brief mentions APA violations but in a more summary fashion, emphasizing their impact on the laboratory industry rather than the technicalities of administrative law.
  3. Reliance Interests and Economic Analysis:

    • The MSJ emphasizes reliance interests, discussing how laboratories, clinicians, and patients have operated under CLIA’s framework for decades. It quantifies the economic burden of the FDA’s rule (e.g., billions in compliance costs, reduction in test availability).
    • The Closing Brief simplifies these arguments for persuasive effect, using them as evidence of the rule's impracticality.
  4. Statutory Interpretation:

    • The MSJ dedicates substantial effort to dissecting the FDCA’s definition of “device” and arguing that laboratory-developed tests (LDTs) are professional services, not tangible products. It also critiques the FDA’s use of enforcement discretion as a means to bypass statutory limits.
    • The Closing Brief echoes these points but frames them in the context of broader consequences for the healthcare system.
  5. Major Questions Doctrine:

    • The MSJ elaborates extensively on this doctrine, arguing that the FDA’s rule represents a transformative expansion of authority without clear Congressional authorization, making it a textbook case for judicial skepticism.
    • The Closing Brief includes this argument but with less technical analysis, focusing on the doctrine's broader implications for agency overreach.

Notable Legalistic Features in the MSJ

  • Specific Legal Citations: The MSJ cites over 50 cases, statutes, and regulatory texts to support its arguments, demonstrating a meticulous legal foundation.
  • Detailed Legislative History: It reviews decades of legislative efforts (e.g., failed attempts to pass the VALID Act) to argue that Congress deliberately chose not to grant FDA authority over LDTs.
  • Analytical Structure: The MSJ breaks arguments into fine-grained subpoints (e.g., textual interpretation, legislative intent, reliance interests), providing a systematic roadmap for the court.

Conclusion

The ACLA’s Motion for Summary Judgment is substantially more legalistic, detailed, and technical than its Closing Brief. While the Closing Brief synthesizes and highlights key arguments for persuasive effect, the MSJ digs deeply into the statutory, procedural, and doctrinal aspects of the case to build a strong foundation for judicial review. This depth is necessary at the summary judgment stage to demonstrate that the facts and law conclusively favor the plaintiff without requiring a trial.


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If the ACLA argues that a device must be a tangible, physical product, where does that leave a separate topic, the FDA's extensive regulation of software as a medical device?   This isn't of issue to ACLA, but it would be salient to a judge or FDA.

The FDA’s extensive regulation of Software as a Medical Device (SaMD) presents a potential counterpoint to the ACLA’s argument that a “device” under the FDCA must be a tangible, physical product. This issue, while not directly addressed by ACLA, could be salient for a judge or the FDA as it relates to the broader interpretation of the FDCA’s scope. Here’s an analysis of how this might influence the case:


1. FDA’s Approach to Software as a Medical Device

The FDA has long regulated certain types of software as medical devices, particularly under its SaMD framework, which encompasses:

  • Standalone software designed to diagnose, treat, or prevent disease.
  • Clinical decision support systems (CDSS), when they meet the FDCA’s definition of a device.

This regulatory framework has been upheld because software, although intangible, can have medical functionality comparable to traditional devices. Courts and regulators have accepted this broader interpretation of “device” under the FDCA when it aligns with the statute’s purpose of protecting public health.


2. Potential FDA Argument Based on SaMD Precedent

The FDA could argue:

  • Functional Equivalence: Like SaMD, LDTs may not be tangible products, but their functions—diagnosing or guiding treatment—align with the FDCA’s purpose to regulate devices that impact patient care.
  • Broad Definition of “Device”: The FDCA defines a device as an “instrument, apparatus, implement, machine, contrivance...or other similar or related article,” which could encompass intangible processes or services if they perform equivalent functions to regulated devices.
  • Precedent for Intangible Products: The regulation of SaMD demonstrates that the FDCA is not limited to physical, tangible items.

3. Distinction Between SaMD and LDTs

ACLA could counter this argument by emphasizing distinctions between SaMD and LDTs:

  • Tangible Input: SaMD often operates on tangible data from physical devices (e.g., imaging systems, wearables). LDTs, however, involve laboratory protocols applied to patient samples, aligning more closely with professional services.
  • Service vs. Product: LDTs are embedded in laboratory services and involve clinical expertise, making them fundamentally different from standalone software products designed for commercial use.
  • Historical Scope of Regulation: Unlike SaMD, which has been explicitly addressed in FDA guidance and international standards (e.g., IMDRF SaMD documents), LDTs have been historically regulated under CLIA as professional services, not devices.

4. Judicial Considerations

A judge might consider:

  • Consistency in Regulation: Does regulating LDTs as devices create inconsistencies with FDA’s approach to SaMD or does it harmonize with the broader regulatory framework?
  • Legislative Intent: The FDCA’s application to SaMD has been accepted partly because software serves as a direct surrogate for traditional devices. Does Congress intend the same logic to apply to LDTs, which have historically been treated as professional services?
  • Regulatory Overreach: Courts have upheld SaMD regulation within limits. However, applying the SaMD analogy to LDTs might be seen as overreach, particularly if it conflicts with CLIA and established reliance interests.

Conclusion

While the FDA’s regulation of SaMD provides a precedent for applying the FDCA to intangible products, LDTs are distinguishable as professional services rather than products. This distinction may allow ACLA to argue that the functional equivalence between SaMD and tangible devices does not extend to LDTs. However, judges may find the SaMD precedent persuasive if they adopt a broader view of the FDCA’s scope, potentially creating a challenge for ACLA’s narrower, tangible-product interpretation of “device.”


CAP Asks FDA a Question about LDT Rule; The Missing Key Answer

 College of American Pathologists publishes a newsletter about advocacy issues, which is open-access.  Here, they asked FDA a question about LDTs that appear after the issuance date of the rule (after May 2024).

CAP NEWSLETTER LINK

The CAP question is,

There is confusion about the regulatory obligations for LDTs developed after the issuance dates. We have received many questions about how to classify the tests, what documentation is needed, and can laboratories bring these systems online now.

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FDA gives the CAP a completely boilerplate (pro forma) answer about general device classificatioin - PMA, 510k, etc.  

The FDA didn't even answer what I took to be the main point of the question [issuance date].  In general, LDTs before June 2024 must comply with paperwork rules in 2025, 2026, but no PMA/510k.  LDTs launched after June 2024 must comply with those paperwork rules PLUS PMA/510k.    

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Here's the interesting answer, for me.  Tests around before May 2024 are "grandfathered" except for various requirements in May 2025, May 2026, and May 2027.  Then come the deadlines for actual PMA/510k filing.  If those documents are filed, FDA will allow tests to remain on the market until the documents are reviewed (anticipated a backlog approaching infinity).   That's filing PMA by November 2027, or 510k by May 2018.

Here's what's interesting.  If your PMA or 510k is filed later, like June 2018, you can't stay on the market (since you don't have on-file PMA or 510k by the staged deadlines), and, your PMA or 510k will be reviewed - god knows when, since it will be queued behind howeer many 10,000, or 50,000, PMAs or 510ks that the FDA lacks the staff to process.   So an LDT with paperwork filed in, say, June 2018, would be allowed for use....ever?  never?   2028?





ADVAMED Supports Bipartisan Senate Bill: Breakthrough Device Coverage at CMS


ADVAMED supports a bipartisan Senate bill to support Medicare coverage of FDA-reviewed Breakthrough products.

The Senate bill, from Sen. Todd Young (R IN) and Sen. Alex Padilla (D CA), parallels HR 1691, which passed the House Ways and Means committee in June 2024.

In a nutshell, the bill would restore the short-lived "MCIT" policy at the end of the "Trump I" administration, which was replaced by a much weaker "TCET" policy during the Biden administration.

Read more about the ADVAMED position here:

https://www.advamed.org/industry-updates/news/advamed-welcomes-bipartisan-senate-bill-to-expedite-medicare-coverage-of-breakthrough-medical-technologies-diagnostic-tests/?utm_source=chatgpt.com

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June 2024 press release on House bill HR 1691, from ADVAMED.

The  committee bill passed by 36 yeas, 5 nays.

The bill contains a clause that CMS is not blocked from affecting coverage if the device is shown to have no benefit (or to have harms) to Medicare beneficiaries.   There is a special category called "specified breakthrough device" [SBTD] which is one with no prior benefit category.  SBTD's get special reports-to-congress.  The June 2024 House passage refers to amendments, but the Congress.gov home page doesn't list any.

Sunday, December 1, 2024

Brief Blog; FDA Posts Final Guidance re ctDNA in Drug Development

 FDA posts 20 page finao guidance on use of ctDNA as a biomarker in drug development.

See the 20 page PDF here:

https://www.fda.gov/media/183874/download

See an essay from Josie Hayes at Linked In here:

https://www.linkedin.com/posts/josie-hayes-phd-pccc_ctdna-drugdevelopment-fdaguidance-activity-7268283780929392642-8Xk-/?utm_source=share&utm_medium=member_ios

And subscription coverage at Genomeweb here.

"Big Three" Use Cases

The guidance encompasses "the big three" use cases - ctDNA for oncogene selection; for MRD; and for drug response.   For MRD, the FDA notes that tumor-informed and tumor-naive methods have various advantages.

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AI Corner (Chat GPT 4o)

FDA's Draft Guidance on ctDNA in Drug Development

The FDA's November 2024 Draft Guidance focuses on using circulating tumor DNA (ctDNA) as a biomarker in curative-intent drug development for early-stage solid tumors. It highlights key roles for ctDNA, including patient selection, molecular residual disease (MRD) enrichment, response measurement, and early endpoints in clinical trials. This framework is part of the FDA's ongoing effort to improve precision in oncology and reduce treatment toxicity for patients unlikely to benefit from therapy.

Key Points and Takeaways:

  • Comment Period: The guidance allows a 60-day comment period for industry feedback.
    • [About January 20]
  • ctDNA in Trials:
    1. Can be used to select patients with specific molecular alterations, especially when tumor tissue is unavailable.
    2. MRD detection via ctDNA identifies patients at high risk of recurrence, enabling tailored escalation or de-escalation of therapy.
    3. ctDNA trends (e.g., clearance or reduction) could act as surrogate early endpoints, potentially predicting long-term outcomes like disease-free survival (DFS) or overall survival (OS).
  • Validation and Standardization:
    • Robust assay validation (e.g., sensitivity, specificity) is critical for regulatory acceptance.
    • [For MRD] Tumor-informed (mutation-specific) and tumor-naïve (general panel) assays each have advantages and limitations, depending on the study design.
  • Regulatory Synergy:
    • Emphasizes harmonization between ctDNA assays and broader regulatory requirements for investigational devices.

Broader Context: FDA and MRD Testing

  • The guidance builds on the FDA's 2020 Hematologic Malignancies Guidance, where MRD was validated in blood cancers. Applying similar principles to solid tumors remains a challenge due to variable ctDNA levels influenced by tumor type, stage, and biology.
  • For drug development, ctDNA could complement imaging or pathological assessments, streamlining early signals of efficacy in trials.

Final Thought:

The draft highlights the FDA's cautious optimism for ctDNA as a transformative biomarker in oncology, but it underscores the need for robust clinical evidence and assay consistency before ctDNA can achieve routine regulatory and clinical utility. Experts should consider contributing comments during the review window to refine these pivotal recommendations.

Brief Blog: BloodPac Webinar on Thursday December 5, 2024

 Watch for a new BLOODPAC  seminar, the Third Annual New Frontiers seminar.  This one is called, "Beyod ctDNA: Multiomics and Multimodal AI in Liquid Biopsy."   (And arriving just when you thought you had figured out ddPCR).   

It's 2-4pm ET on Thursday December 5.   11-1 PT.

https://www.eventbrite.com/e/bloodpac-2024-new-frontiers-seminar-tickets-1055858383849?aff=oddtdtcreator