CARIS - Comparison to other FDA tests

Chat GPT provided this comparison of new CARIS FDA documentation, with prior FDA genomic tests.   I have no idea how accurate these tables are.   But they were auto generated by Chat GPT.

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Comparison of the Caris MI Cancer Seek Workflow with Other FDA-Approved NGS Panels

Below is a detailed comparison of Caris MI Cancer Seek with notable FDA-approved NGS panels such as FoundationOne CDx, Guardant360 CDx, and Oncomine Dx Target Test. This comparison focuses on bioinformatics workflows, biomarker validation, and clinical applications.

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1. Bioinformatics Workflows

Data Processing

Feature	MI Cancer Seek	FoundationOne CDx	Guardant360 CDx	Oncomine Dx Target Test
Sequencing Platform	Illumina NovaSeq 6000	Illumina HiSeq 4000	Illumina NextSeq 550	Ion Torrent PGM
Target Regions	Whole exome with boosted coverage of 228 genes	Comprehensive genomic profiling of 324 genes	74 genes in cell-free DNA	~50 genes for hotspot mutations
Input Material	FFPE tumor tissue	FFPE tumor tissue	Plasma (liquid biopsy)	FFPE tumor tissue
Data Alignment	Sentieon BWA to hg38	BWA-MEM to hg19	BWA to hg19	Torrent Suite alignment to hg19
Variant Calling	Custom algorithms for SNVs, indels, TMB, MSI, CNA	Custom algorithms for SNVs, indels, fusions	Custom algorithms optimized for cfDNA	Proprietary mutation detection pipeline
Reporting Levels	Companion Diagnostic (CDx), Clinically Significant, Emerging Evidence	Companion Diagnostic and Clinical Evidence Levels	Companion Diagnostic and Select Variants	Companion Diagnostic Only

Strengths of MI Cancer Seek:

• Broader Scope: The inclusion of whole exome sequencing (WES) allows for higher flexibility in adding emerging biomarkers compared to hotspot-based assays like Oncomine Dx Target Test.
• Advanced Bioinformatics: Use of synthetic RNA/DNA differentiation during library preparation enables RNA and DNA processing from the same sample, although RNA is not reported under the current approval【10†source】.

Limitations:

• FFPE Limitation: While comprehensive, MI Cancer Seek does not yet support liquid biopsies, which Guardant360 CDx offers for less invasive sampling.

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2. Biomarker Validation Criteria

Criteria	MI Cancer Seek	FoundationOne CDx	Guardant360 CDx	Oncomine Dx Target Test
Analytical Validation	≥100x read depth; ≥16 billion reads per run; ≤1% error rate	≥500x for hotspot regions; stringent quality metrics	≥5000x (cfDNA); highly sensitive for low VAFs	≥500x for hotspot regions
Clinical Validation	CDx biomarkers tied to therapies; evidence-based profiling	CDx biomarkers and investigational markers	CDx biomarkers and select investigational markers	CDx biomarkers only
Biomarker Types	SNVs, indels, CNAs (ERBB2), TMB, MSI	SNVs, indels, CNAs, MSI, TMB	SNVs, indels, CNAs, MSI	SNVs, CNAs, fusions
Companion Diagnostic Ties	Therapies for breast cancer, colorectal cancer, NSCLC, melanoma	Similar breadth with additional rare cancers	Primarily NSCLC, breast cancer, and urothelial carcinoma	Limited; specific to NSCLC

Strengths of MI Cancer Seek:

• High Biomarker Sensitivity: The inclusion of MSI, TMB, and specific CNAs (e.g., ERBB2 in breast cancer) reflects advanced tumor profiling capabilities【10†source】【11†source】.
• Emerging Evidence Layer: Reporting Level 3 biomarkers supports exploratory research and clinical trials.

Limitations:

• Narrow Clinical Implementation: While broadly validated, MI Cancer Seek's clinical utility depends on centralized testing at the Caris lab, unlike decentralized kits like Oncomine Dx Target Test.

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3. Clinical Applications

Feature	MI Cancer Seek	FoundationOne CDx	Guardant360 CDx	Oncomine Dx Target Test
Therapies Supported	15+ targeted therapies	30+ targeted therapies	10+ targeted therapies	Limited set for NSCLC
Turnaround Time	10-14 days	~2 weeks	7 days	~5 days
Specimen Type	FFPE only	FFPE only	Plasma (cfDNA)	FFPE only
MSI and TMB Assessment	Comprehensive	Comprehensive	MSI only	Not included

Strengths of MI Cancer Seek:

• Companion Diagnostic Integration: Direct linkage to therapies like PIQRAY® (alpelisib) for PIK3CA mutations and KEYTRUDA® (pembrolizumab) for MSI-H tumors【8†source】【10†source】.
• Tumor Profiling Depth: Enhanced by whole exome sequencing and comprehensive TMB calculations.

Limitations:

• Restricted Access: Centralized testing limits availability, contrasting with the Guardant360 CDx liquid biopsy model, which offers decentralized and patient-friendly access.

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Summary of Key Differentiators

• Bioinformatics Sophistication: MI Cancer Seek leads in data handling with whole exome capabilities and RNA/DNA integration.
• Comprehensive Biomarker Profile: It incorporates advanced profiling (TMB, MSI, CNAs) unmatched by some competitors like Oncomine Dx Target Test.
• Centralized Workflow: While this ensures control and consistency, it limits patient access compared to models like Guardant360 CDx.

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Would you like further detail on clinical validation examples for specific biomarkers (e.g., MSI or PIK3CA mutations) or an analysis of the implications of centralized versus decentralized testing models?

MolDxOlogy: Two Tables for TA Listings

 I was puzzled by different entry points for TA documents?

(1)
If I start at Palmetto MolDx home page

   https://www.palmettogba.com/moldx

I click on Technology Assessments and go here:

   https://www.palmettogba.com/palmetto/moldxv2.nsf/DID/9W2LPH1487

Then I click on Technology Assessments Forms Updated 7 17 2024 and get here

   https://www.palmettogba.com/palmetto/moldxv2.nsf/DIDC/TJ4XC2M5IX~Technical%20Assessment

For example the first form GEN-CQM-003 Checklist, seems to be V1 2023.

I count 13 TA entries.

(2)
But if I use Google I get here:

https://www.dexzcodes.com/palmetto/dex.nsf/T/Technical%20Assessment

https://www.dexzcodes.com/palmetto/dex.nsf/DID/UMPUJNFSV0

And the first form is GEN CQM 003 Checklist, but now, it is updated 10 17 2024 and it is V4 October 2024.

I tally 17 TA entires (plus "gapfill").

Extra ones here include venous thromboembolism screening and prenatal carrer screening and prenatal cell free dna screening

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I could understand if the Dexzcodes.com included public facing forms like prenatal, not on Palmetto Medicare, but why would things like Checklist have different versions?  

CMS Updates Certain Medical Audit Rules (PIM Chapter 3)

 https://www.cms.gov/files/document/r13008pi.pdf

Unrelated:
Certain very tedious audits for NCDs (re: Comment on Med Adv using "only NCDs."

https://www.cms.gov/files/document/r12990cp.pdf

Moldx and "patients without cancer"

The MRD TA form at MOLDX inquires about presurgical patients and post surgical patients.  Post surgical patients are divided into those with cancer and those without cancer.   How does it define the latter?

Not on the TA form.   

Go to the LCD itself, as MolDx explains below.

• As per L38779, a patient without cancer is a patient with “no clinical, radiographical, or other biological evidence that tumor cells remain post treatment and subsequently the patient is no longer being subjected to therapeutic interventions for cancer.”
• If treatment is ongoing, then the patient is considered to still have cancer. So, a patient who had a lumpectomy is considered to be “without cancer” IF the above statement is true - for example, she is also not undergoing radiation or other treatments and there is no evidence that cancer cells exist (i.e. margins and scans are negative, etc.).

MolDx defines e.g. postsurgical adjuvant radiation or chemo as "treatment for cancer" but a 5 or 10 year treatment with e.g. tamoxifen is NOT considered a treatment for cancer.

If the patient qualifies as treatment for cancer period, then MRD testing would be either one time testing, or, in some cases, a series of several assays defined as one test.   If the patient qualifies as POST cancer, NO cancer, as above, then MRD tests can be billed individually as it is a "patient without cancer."   (This paragraph is inference to the one-test-per-patient clause in NCD 90.2)

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tagNCD90_2  tagpatientswithoutcancer

Medicare Advantage and Out of Network Rates

 tagmedicareadvantage, tagoutofnetowork

Labs Often Get Paid CMS Rate for Out of Network Lab Claims

Why?

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Rule 422.214 on Out of Network M.A. Payments

Where this comes from is 42 CFR 422.214.   This rule does not directly state that Medicare Advantage must pay the FFS rate to non contracted (out of network ) providers.  However, it says that out of network providers must accept the FFS rate.   That is, the provider can appeal any rate paid that is less that the FFS rate.   Also, there is a clause that when an out of network provider submits a claim to Med Adv, it is "deemed" to be for the Medicare FFS payment rate. (422.214(c).)

https://www.ecfr.gov/current/title-42/chapter-IV/subchapter-B/part-422/subpart-E/section-422.214

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There is also a Medicare Advantage policy manual (Internet only manual 16) with about 20 chapters on different aspects of Medicare Advantage.  Chatper 4 section 100 manualizes a reference to 422.214.

https://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/mc86c06.pdf   see section 100 for reference to 422.214.

It's cited to SSA 1852(a)(2) and to 1852(k)(1), and to a preamble that appeared June 29, 2000.   The June 29, 2000, rulemaking is presented at 65 FR 40325 (and alter amended; see 422.214 webpage, bottom).

https://www.federalregister.gov/documents/2000/06/29/00-15648/medicare-program-medicarechoice-program#page-40325

Discusson at:

https://www.federalregister.gov/d/00-15648/p-1066

The preamable text which helps interpret the intenton of the regulations, is here:

Special Rules for Services Furnished by Noncontract Providers (§ 422.214) 

Consistent with sections 1852(k)(1) and 1866(a)(1)(O) of the Act, § 422.214 requires that any health care provider that does not have in effect a contract establishing payment amounts for services furnished to a beneficiary enrolled in an M+C coordinated care plan must accept, as payment in full, the amounts that they could collect if the beneficiary were enrolled in original Medicare (less the amounts specified in §§ 412.105(g) and 413.86(d) of the regulations on hospital graduate medical education payments, when applicable). Any statutory provisions (including penalty provisions) that apply to payment for services furnished to a beneficiary not enrolled in an M+C plan also apply to the payment described in § 422.214(a)(1) of our regulations. We received three comments regarding this section. 

Comment:

Several commenters suggested that we revise § 422.214 to provide that payment to a noncontracting provider must equal the amount that provider would be allowed to collect under original Medicare. These commenters believe that M+C organizations should only be permitted to pay the billed amount when this is the same amount that Medicare would pay under original Medicare. 

Response:

Section 422.214 implements section 1866(a)(1)(O) of the Act, with respect to services furnished by a “provider of services” as defined in section 1861(u), and section 1852(k)(1), with respect to other services. Neither of these provisions requires an M+C organization to pay a provider more than the amount of the provider's bill, or even impose obligations on M+C organizations at all. Rather, these provisions serve as a limit on the amount the provider can collect from the M+C organization. Specifically, each of these provisions states that a provider “shall accept as payment in full” the amount (less the amounts specified in §§ 412.105(g) and 413.86(d) of the regulations) that it would receive under original Medicare, including cost sharing and permitted balance billing (“the Medicare payment amount”). While this means that under these provisions the provider cannot collect 

more than the Medicare payment amount if its billed amount is 

higher, this obligation to “accept” the Medicare amount as payment in full does not obligate the M+C organization to pay this amount if the provider's bill is 

lower. Thus, in the case of emergency services and certain other services referred to in section 1852(d)(1)(C) of the Act furnished to an enrollee in a coordinated care plan, the provider or providers must accept the Medicare payment amount for the services if their billed amount is higher, but would have no right under sections 1852(k)(1) or 1866(a)(1)(O) to be paid more than the amount of their bill if the billed amount is lower than the Medicare payment amount. 

We note, however, that a provision in the BBA does give providers furnishing services to coordinated care plan enrollees the right to be paid the Medicare payment amount under certain circumstances. Section 1852(a)(2) provides that where an M+C organization chooses to furnish services through providers that do not have contracts with the organization in order to meet its obligation under section 1852(a)(1) to make Medicare services available, it must provide for payment “equal to at 

least

” the Medicare payment amount. (Emphasis added.) This new provision, unlike section 1866(a)(1)(O) or section 1852(k)(1), establishes a “floor” for payment when it applies. This “floor,” combined with the “ceilings” under sections 1866(a)(1)(O) and 1852(k)(1), essentially requires that the Medicare payment amount be paid where section 1852(a)(2) applies. Because section 1852(a)(2) refers to an M+C organization's furnishing services in fulfillment of its obligations under section 1852(a)(1), we are interpreting section 1852(a)(2), in the coordinated care plan context, as providing M+C organizations with the opportunity to arrange to provide nonemergency services through noncontracting providers. Under this interpretation, the “minimum payment” requirement in section 1852(a)(2) would only apply where the M+C organization has arranged for the services in question to be provided by a noncontracting provider...

Google Notebook LM: Marxist Review of Lancet Special Issue on USA Health Policy (12/2024)

 Examining Health Through a Marxist Lens

SOURCE:  https://www.discoveriesinhealthpolicy.com/2024/12/lancet-devotes-special-issue-to-us.html

These sources provide a lens through which to examine health and healthcare disparities in the United States from a Marxist perspective, revealing how social and economic structures shape health outcomes.

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Marxism analyzes how social class, determined by one's relationship to the means of production, influences various aspects of life. A Marxist perspective would scrutinize the role of capitalism in generating health disparities. For example, the Prison Policy Initiative report cited in source highlights the immense financial resources invested in the carceral system. A Marxist analysis would question how these resources are diverted from social programs and healthcare initiatives that could address underlying socioeconomic factors contributing to crime and poor health in marginalized communities.

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Marxism argues that societal institutions, including healthcare systems, function to reproduce existing power structures and maintain inequalities. This view is evident in source, which points out that providing healthcare to incarcerated populations should not be seen as a solution but as an indication of societal failures to address health needs in communities. This point of view aligns with the Marxist concept of alienation, where individuals are separated from the products of their labor and from each other. The focus on treating health issues within the carceral system, rather than investing in community-based solutions, exemplifies this alienation.

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Source further reinforces this perspective by emphasizing the importance of identifying and addressing inequalities in well-being. From a Marxist viewpoint, this unequal distribution of well-being is a direct consequence of the capitalist system, which prioritizes profit accumulation over human needs.

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The concept of "structural racism" (as mentioned in sources) intersects with Marxist analysis by highlighting the ways in which historical and ongoing racial discrimination, rooted in capitalist exploitation, creates and perpetuates inequalities. Source explicitly points out that interventions to address social determinants of health could significantly reduce or eliminate racial health disparities. This argument aligns with the Marxist understanding of class struggle, where racial divisions are often exploited to divide the working class and maintain capitalist control.

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A Marxist perspective would view the privatization of healthcare and the influence of pharmaceutical companies as further manifestations of capitalist exploitation within the healthcare system. This is illustrated in source, where the authors discuss the California prison system's "complete care" model, highlighting potential concerns about the role of private corporations in delivering healthcare services within the carceral system.

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Source underscores the fundamental Marxist principle that true freedom is contingent upon fulfilling basic needs, including healthcare. The statement that "health care is a right, one of the most basic" resonates with the Marxist critique of bourgeois rights, which often prioritize individual liberties over collective well-being.

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A Marxist interpretation of these sources would advocate for a radical restructuring of healthcare systems and societal priorities to ensure equitable access to quality healthcare for all, regardless of socioeconomic status.

Overall, a Marxist analysis of these sources would emphasize the interconnectedness of health disparities with broader social, economic, and political structures. It would challenge the notion that healthcare inequalities are merely individual failures and instead point to the systemic issues inherent in capitalism that perpetuate these disparities.

Nazi Medicine: In NEJM 2024 (Retro to 1935)

In 2024, NEJM had two articles on Nazism and 1930s medicine, as covered by NEJM.

NEJM 2024 Abi-Rached

The first 2024 article was, Abi-Rached & Brandt, Nazism and the Journal, 390:1157-61.  

https://www.nejm.org/doi/full/10.1056/NEJMp2307319 

• NEJM 1935 Davis
• Abi-Rached's article focused on a 1935 article, Recent Changes in German Health Insurance under the Hitler Government, May 30, 1935, Davis, NEJM 212:1037-42.
• https://www.nejm.org/doi/full/10.1056/NEJM193505302122206
• The Davis article broadly discussed features and emphases of Nazi social medicine and policy, with one mention that Jewish physicians were excluded.  (There was also 1 follow-up letter & reply).

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NEJM 2024 REEDE

The second 2024 NEM article was, Reede JY et al., Eugenics, Nazism, and the Journal, 391:e50 [published as a transcript].

https://pubmed.ncbi.nlm.nih.gov/39536237/

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Harvard Gazette covered the Abi-Rached & Brandt article in May 2024.   "How do you read organization's silence over the rise of Nazism?" by Alvin Powell.

https://news.harvard.edu/gazette/story/2024/05/how-do-you-read-organizations-silence-over-rise-of-nazism/

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The two 2024 NEJM articles (with shared authorship) focus on the relative silence of NEJM on German medicine, save for the single Davis article.   

A comparison was made with JAMA (which had somewhat more articles on Nazism).

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First, I hope that the citation to Davis led some readers to the 1935 original article, easily available via the NEJM archive.   Many themes in German medicine of the 1930s echo today - urban versus rural, public health vs treatment of disease, politics of physician organizations, specialists vs generalists, funding, etc.

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Second, the deliberate 2024 focus on what is found inside of medical journal archives may miss an important point.  

There have a been a number of popular history books in the last few years about Nazism and pro-German sentiment in the US during the 1930s.   (Lindbergh vs Roosevelt, Duffy, 2010; Those Angry Days 1939-1941, Olson, 2013, Hitler's American Friends, Hart, 2018, others).

Since NEJM is an academic journal, of special interest is the late Stephen Norwood's book, "The Third Reich in the Ivory Tower," Cambridge Univ Press, 2011.     

And focusing on Boston and Massachusetts - Available open access is a 2008 chapter by Norwood in the journal, American Jewish History, Johns Hopkins MUSE, page 38, "Legitimzing  Nazis: Harvard University and the Hitler Regime 1933-1937."

https://www.scribd.com/document/212918635/Harvard-e-Hitler-33-37

https://drive.google.com/file/d/1jF0W51YVlSdKZ0jlnY5u0bSHkWmtimxW/view?usp=sharing

Cf. debates about when to continue exchanges with German universities, are in some ways mirrored by debates or swings on political correctness today; WSJ 2024.

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The relative silence of NEJM, and the brevity of Davis' reference to Jewish physicians, becomes clearer in the context of work like Norwood's.    

It is difficult to view 1934 except through the lens of the Hoocaust and 1945.   However, when 1933 and 1934 were  unfolding, Nazism had a smaller role in world politics.  Even the frightful early persecution of Jewish physicians in 1933, 1934, might have been compared to the treatmentt of Black physicians in the US (among numerous examples), which also likely had minimal if any coverage in JAMA and NEJM in 1935.  

[Re Black persecution in the US and Jewish persecution in Germany, see Hitler's American Model, Whitman, 2017].

In summary.   The limited coverage of Nazism in NEJM during 1935, could have been compared to pro-Nazism at the same time at Harvard (Norwood), although this takes us out of the narrow domain of medical journal studiesm the boundary set by Abi-Rached for their essay.   See also, in the Powell Harvard Gazette interview, Brandt comments, "The Davis piece is remarkable for its opacity, its ability to focus on a [economic] reform and not have any context around it."   But the Abi-Rached Brandt article also takes a rather narrow focus, focusing on NEJM with relatively little on the more general partly pro-Nazi society as documented by Norwood, Hart, and others.   That is, we could say Abi-Rached and Brandt were remarkable for their ability to focus only on the contents of NEJM, and not set a broader mileu of events that year for the reader.

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One could also say, Abi-Rached is concerned that Davis 1935 talked primarily on German social medicine, and said very little about Jewish exclusion and persecution.   But, Abi-Rached was very concerned with publications in the 1935 NEJM, and could have taken a broader stance discussing the pro-Nazi movements in academia and society at the same time.  

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There is a recent book on quite sharp leftward and rightward swings in AMA politics, 1880s-1980s, in which the 1930s chapter is pertinent.  Peter A Swenson, 2021, Disorder: A history of reform, reaction, and money in American medicine.   

Cut FDA Final Brief Text

 

Where do the two briefs have the tightest overlap?

The ACLA and AMP briefs overlap significantly in their critiques of the FDA's final rule regulating laboratory-developed tests (LDTs). The key areas of overlap include:

1. Major Questions Doctrine:

   • Both briefs assert that the FDA’s regulation of LDTs represents a significant expansion of regulatory authority requiring clear Congressional authorization, which is absent.
   • Both highlight that Congress has repeatedly declined to authorize such regulation, underscoring the overreach.

2. Definition of a Device under the FDCA:

   • Both argue that LDTs are not “devices” as defined by the FDCA because they involve professional services rather than tangible, manufactured products. They emphasize that LDTs are not commercially distributed and are used within a single laboratory.

3. Conflict with CLIA:

   • Both emphasize that CLIA already provides comprehensive oversight for LDTs, regulating their validity and reliability.
   • They argue that FDA regulation would create unnecessary duplication, conflict with CLIA, and undermine its well-established framework.

4. Economic and Practical Consequences:

   • Both highlight the severe financial and operational burdens the FDA’s rule would impose on laboratories, including billions in compliance costs, disruption of innovation, and reduced patient access to LDTs.
   • They underscore the likelihood of laboratories exiting the market, further harming patient care.

5. Arbitrary and Capricious Rulemaking:

   • Both briefs argue that the FDA’s rule is arbitrary and capricious, lacking a clear rationale or evidence to justify the dramatic shift in regulatory oversight.
   • They critique the FDA’s reliance on enforcement discretion policies as inadequate and inconsistent.

6. Practice of Medicine Exemption:

   • Both highlight statutory protections for healthcare professionals under the FDCA, arguing that the FDA’s rule unlawfully infringes on the practice of medicine by regulating professional services.

These shared arguments reflect a unified stance from the lab industry, emphasizing that the FDA’s final rule oversteps statutory boundaries, conflicts with existing regulation, and would harm patient care and innovation.

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I don't have access to the government's response, that is, the FDA's response and final brief.   However, what can we infer about the FDA's responses and counter-arguments, from the moving parties' final briefs.

While the FDA’s final brief is not available, we can infer key aspects of its arguments and counterpoints based on how the ACLA and AMP briefs respond to and refute them. Here’s an analysis of what the FDA likely argued and how the moving parties addressed those points:

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1. Authority to Regulate LDTs

FDA’s Likely Argument:

• The FDA likely argued that LDTs qualify as "devices" under the FDCA because they involve in vitro diagnostic (IVD) systems, which the agency has historically regulated.
• The FDA may have claimed it has continuously asserted authority over LDTs since the 1970s but has exercised enforcement discretion until now.

Response by ACLA and AMP:

• Both briefs dispute the FDA’s historical authority, emphasizing that LDTs are professional services, not commercially distributed devices.
• They point out that the FDA has inconsistently applied its claimed authority, with decades of non-enforcement undermining its position.
• The AMP brief argues that relying on broad definitions of terms like "device" (e.g., “apparatus” or “contrivance”) would sweep in unrelated medical procedures, exceeding statutory intent.

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2. Commercial Distribution Requirement

FDA’s Likely Argument:

• LDTs involve “commercial distribution” because laboratories provide testing services for a fee, and the FDA’s statutory authority covers commercially provided services.

Response by ACLA and AMP:

• Both briefs argue that “commercial distribution” under the FDCA applies to tangible goods transferred to third parties, not internal laboratory procedures.
• AMP highlights that applying this interpretation to LDTs would render the statutory language meaningless, as procedures cannot be “distributed.”

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3. Compatibility with CLIA

FDA’s Likely Argument:

• The FDA likely argued that CLIA and FDA regulation target different aspects of test oversight: CLIA focuses on laboratory operations and analytical validity, while the FDA focuses on clinical validity and patient safety.

Response by ACLA and AMP:

• Both briefs reject this distinction, asserting that CLIA already ensures both analytical and clinical validity through proficiency testing and other mechanisms.
• AMP argues that FDA regulation would create unnecessary duplication and conflict, effectively undermining the existing CLIA framework.

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4. Major Questions Doctrine

FDA’s Likely Argument:

• The FDA likely attempted to downplay the significance of its rule under the major questions doctrine, arguing that its regulation of LDTs is consistent with its long-standing statutory authority.

Response by ACLA and AMP:

• Both briefs counter that the FDA’s sudden assertion of broad regulatory authority over LDTs constitutes a “transformative expansion” requiring explicit Congressional authorization, which has not been granted.
• They highlight Congress’s repeated refusal to authorize such regulation, suggesting that the FDA’s actions lack clear statutory backing.

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5. Economic and Practical Impacts

FDA’s Likely Argument:

• The FDA may have argued that the costs associated with compliance are justified by the need to ensure the safety and efficacy of LDTs, given their critical role in patient care.

Response by ACLA and AMP:

• Both briefs emphasize the disproportionate costs and practical burdens, projecting billions in compliance costs, laboratory closures, and diminished patient access to innovative tests.
• They argue that these impacts are avoidable under the current CLIA framework, which effectively regulates test quality without stifling innovation.

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6. Practice of Medicine Exemption

FDA’s Likely Argument:

• The FDA may have argued that the practice of medicine exemption under the FDCA does not shield laboratories or affiliated entities from regulation, as it is narrowly tailored to individual practitioners.

Response by ACLA and AMP:

• Both briefs assert that the exemption protects not only individual practitioners but also their affiliated entities (e.g., laboratories), as regulation of one inevitably impacts the other.
• AMP emphasizes that holding laboratories liable for LDT practices would undermine Congress’s intent to shield healthcare providers from regulatory overreach.

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7. FDA’s Rulemaking Process

FDA’s Likely Argument:

• The FDA likely defended its rulemaking as consistent with administrative law principles, claiming it carefully considered stakeholder input and based the rule on statutory mandates.

Response by ACLA and AMP:

• Both briefs argue the rule is arbitrary and capricious, citing inadequate justification for the regulatory shift and failure to address the historical reliance on CLIA oversight.
• AMP specifically critiques the FDA’s reliance on non-binding enforcement discretion policies, calling them insufficient and inconsistent.

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Inferred Strategy of the FDA

• The FDA likely sought to expand the statutory definitions and historical interpretations of the FDCA to encompass LDTs, focusing on patient safety as a justification for regulatory oversight.
• It probably downplayed the potential conflicts with CLIA and the economic impacts of the rule, while asserting that it has the authority to act in the absence of explicit Congressional prohibition.

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Conclusion

From the ACLA and AMP responses, it is clear that the FDA’s arguments hinge on broad statutory interpretations, historical assertions of authority, and a separation of regulatory focus between CLIA and the FDCA. However, both briefs effectively challenge these positions by emphasizing statutory text, legislative history, and the practical consequences of the FDA’s actions. This alignment suggests a strong unified opposition to the FDA’s rule within the lab industry.

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What arguments are unique to ACLA or unique to AMP?

there are several noteworthy arguments unique to either the ACLA or AMP closing briefs, reflecting their differing emphases and approaches to opposing the FDA’s final rule:

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Arguments Unique to the ACLA Closing Brief

1. FDA's Inconsistent Enforcement History:

   • ACLA places significant emphasis on the FDA’s inconsistent enforcement of its purported authority over LDTs, using this as evidence that the agency itself has historically acknowledged its limited authority in this area.

2. Focus on Economic Disruption:

   • While both briefs discuss economic impacts, ACLA provides a broader analysis of how the rule would disrupt the entire clinical laboratory sector, emphasizing the financial burden on smaller labs and its chilling effect on innovation.

3. Role of Laboratories as Service Providers:

   • ACLA delves deeper into the distinction between laboratories as service providers (under CLIA) versus manufacturers (under the FDCA). This framing underscores that LDTs are services, not products, and challenges the FDA’s attempt to conflate the two.

4. Critique of FDA’s Ad Hoc Enforcement Policies:

   • ACLA specifically critiques the FDA’s reliance on non-binding "enforcement discretion" policies to mitigate the rule's effects, arguing that such policies highlight the rule’s impracticality and lack of clarity.

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Arguments Unique to the AMP Closing Brief

1. Practice of Medicine Exemption:

   • AMP places greater emphasis on the FDCA’s practice of medicine exemption, arguing that the FDA’s rule undermines this long-standing protection for healthcare professionals and their affiliated entities.
   • AMP highlights how the exemption applies to individual practitioners and their associated laboratories, reinforcing that the rule would unlawfully penalize laboratories for activities intrinsic to medical practice.

2. Conflict with CLIA’s Comprehensive Regulation:

   • While ACLA critiques the overlap between FDA and CLIA oversight, AMP goes further by arguing that the FDA’s rule would render key CLIA provisions superfluous, creating direct regulatory conflicts.
   • AMP specifically points to how CLIA already addresses both analytical and clinical validity, undermining the FDA’s justification for additional oversight.

3. Detailed Examination of the Major Questions Doctrine:

   • AMP provides a more in-depth discussion of the major questions doctrine, analyzing how Congress’s repeated refusal to grant the FDA authority over LDTs highlights the absence of clear Congressional authorization for the rule.

4. Use of Analogies to Surgical Procedures:

   • AMP draws a novel analogy between the development of LDTs and the design of surgical procedures, arguing that the FDA’s expansive interpretation of “device” could criminalize standard medical practices like surgery, thereby demonstrating the unworkability of the FDA's position.

5. Critique of FDA’s Statutory Interpretation:

   • AMP takes a nuanced approach to challenging the FDA’s interpretation of statutory terms like “apparatus” and “contrivance,” employing canons of statutory construction to argue that the FDA’s definitions are overly broad and inconsistent with Congressional intent.

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Summary of Unique Contributions

• ACLA focuses on the practical and economic impacts of the rule, emphasizing the financial and operational burdens on laboratories, and critiques the FDA’s historical inconsistencies in asserting its authority.
• AMP, on the other hand, provides a more legalistic critique, emphasizing statutory construction, the practice of medicine exemption, and the conflict with CLIA, while employing analogies and canons of interpretation to challenge the FDA’s arguments.

These distinctions reflect complementary strategies, with ACLA targeting the rule’s real-world implications and AMP focusing on the legal framework. Together, they form a robust opposition to the FDA’s final rule.

Law School Questions

 

Write three essay questions for a third-year law student course on health & regulatory law, where this case was a major teaching case this semester.

Essay Question 1: Regulatory Jurisdiction and Statutory Interpretation

The FDA's assertion of regulatory authority over laboratory-developed tests (LDTs) has been challenged by both ACLA and AMP on statutory and jurisdictional grounds. Drawing from their arguments and relevant statutory language, address the following:

• Discuss the jurisdictional boundaries between CLIA and the FDCA. How does this case illustrate the challenges of overlapping regulatory frameworks?
• Evaluate the FDA’s interpretation of LDTs as "devices" under the FDCA. Is this interpretation consistent with the statutory language and legislative intent? Why or why not?
• Apply the major questions doctrine to this case. Should the FDA’s regulation of LDTs fall under this doctrine, and if so, why does it matter?

In your response, consider both the practical implications for laboratories and the legal principles governing agency authority.

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Essay Question 2: Economic and Public Health Implications of Regulatory Overreach

Both ACLA and AMP emphasize the economic and public health impacts of the FDA’s rule. In a well-structured essay, analyze:

• How does the rule’s potential economic burden on laboratories weigh against the FDA's stated goals of ensuring patient safety and test accuracy?
• Do the existing CLIA regulations adequately address concerns about the analytical and clinical validity of LDTs, or is there a compelling need for FDA oversight?
• Consider how the rule might disproportionately affect smaller laboratories or those serving underserved populations. What broader public health issues could arise?

Use examples from the briefs and discuss whether the FDA adequately justified its position in light of these consequences.

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Essay Question 3: The Role of Enforcement Discretion in Administrative Law

The FDA has historically used enforcement discretion to regulate LDTs, a point heavily critiqued in the ACLA and AMP briefs. Write an essay discussing:

• What is the legal and practical role of enforcement discretion in administrative law?
• How does the FDA's reliance on enforcement discretion to mitigate the impacts of its LDT rule affect its credibility and the clarity of its regulatory framework?
• Should courts view reliance on enforcement discretion as a strength or a weakness in agency rulemaking? Justify your position with reference to this case and broader principles of administrative law.

In your response, address how the courts might balance the flexibility of enforcement discretion with the need for predictability and fairness in regulation.

DE LAAT Exercise PD

 https://www.nature.com/articles/s41531-024-00641-1

Heart-rate chest-strap Participants wore chest straps with a Polar H7 heart rate (HR) monitor (Polar Electro Oy, Kempele, Finland) starting five minutes before, and continuing throughout every exercise session. The target HR for each participant was defined as 80% of his/her maximum HR. Maximum HR was determined according to the formula: Maximum HR = 220-age. Beat-to-beat interval data were collected with the EliteHRV app and filtered using a Butterworth filter to minimize high frequency art

220-70 = 150    220-60 = 160.

nature  npj parkinson's disease  articles  article

Article

Open access

Published: 09 February 2024

Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson’s disease

Bart de Laat, Jocelyn Hoye, Gelsina Stanley, Michelle Hespeler, Jennifer Ligi, Varsha Mohan, Dustin W. Wooten, Xiaomeng Zhang, Thanh D. Nguyen, Jose Key, Giulia Colonna, Yiyun Huang, Nabeel Nabulsi, Amar Patel, David Matuskey, Evan D. Morris & Sule Tinaz 

npj Parkinson's Disease volume 10, Article number: 34 (2024) Cite this article

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Abstract

Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated the dopaminergic system of patients with mild and early PD before and after a six-month program of intense exercise. Using 18F-FE-PE2I PET imaging, we measured dopamine transporter (DAT) availability in the striatum and substantia nigra. Using NM-MRI, we evaluated the neuromelanin content in the substantia nigra. Exercise reversed the expected decrease in DAT availability into a significant increase in both the substantia nigra and putamen. Exercise also reversed the expected decrease in neuromelanin concentration in the substantia nigra into a significant increase. These findings suggest improved functionality in the remaining dopaminergic neurons after exercise. Further research is needed to validate our findings and to pinpoint the source of any true neuromodulatory and neuroprotective effects of exercise in PD in large clinical trials.

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Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN)1. A growing literature has demonstrated the benefits of exercise programs for controlling motor symptoms of PD2,3,4,5. The reported benefits vary according to the type, intensity, and duration of the exercise. Moderate-to-high-intensity exercise multiple times per week for prolonged periods (e.g., 6 months) has been shown to ameliorate the motor severity of PD in clinical trials6,7,8.

Rodent models of PD have shown that exercise-induced improvements in motor performance were accompanied by neuroprotective effects on the dopaminergic neurons in the SN9,10,11,12,13,14,15,16. These neuroprotective effects of exercise are thought to be mediated through neurotrophic, anti-inflammatory, and angiogenic factors. It has been suggested that the interplay between these factors facilitates rescuing of the dopaminergic neurons and increased signaling capacity of healthy dopaminergic neurons17,18. In humans, indirect clinical evidence suggests that exercise may be neuroprotective. Exercise studies in patients with PD support the mediator role of neurotrophic and anti-inflammatory factors in clinical improvement19,20,21. Low pro-inflammatory microglial activation has been proposed as a pathway linking physical activity to brain health based on postmortem examination of older adults without PD but with varying degrees of physical activity22. Postmortem nigral volumes and white matter integrity have been found to be positively correlated with physical activity in older adults without PD23. A positron emission tomography (PET) study using [11C]-raclopride in people with PD demonstrated that a single bout of vigorous cycling by habitual exercisers released significantly more dopamine in the caudate nucleus than the same activity performed by those who were sedentary24. These findings suggest that the benefits of exercise may be due to neuromodulatory effects, such as the preservation of the dopaminergic reserves and enhanced dopamine transmission. However, these putative effects have not been directly investigated in humans with PD in vivo.

High Intensity Exercise

High-intensity Exercise May Reverse Neurodegeneration in Parkinson’s Disease

February 23, 2024

by Isabella Backman

High-intensity exercise induces brain-protective effects that have the potential to not just slow down, but possibly reverse, the neurodegeneration associated with Parkinson’s disease, a new pilot study suggests.

Prior research has shown that many forms of exercise are linked to improved symptoms of Parkinson’s disease. But there has been no evidence that hitting the gym could create changes at the brain level. Now, a small proof-of-concept study involving 10 patients showed that high-intensity aerobic exercise preserved dopamine-producing neurons, the brain cells that are most vulnerable to destruction in patients with the disease.

In fact, after six months of exercise, the neurons actually had grown healthier and produced stronger dopamine signals. Dopamine is a chemical that helps brain cells communicate with each other. The researchers published their findings in npj Parkinson’s Disease on February 9.

The medications we have available are only for symptomatic treatment. They do not change the disease course. But exercise seems to go one step beyond and protect the brain at the neuronal level.

Sule Tinaz, MD, PhD

“This is the first time imaging has been used to confirm that the biology of the brain in those suffering with Parkinson’s disease is changed by intense exercise,” says Evan D. Morris, PhD, professor of radiology and biomedical imaging at Yale School of Medicine and co-principal investigator of the paper.

What causes Parkinson’s disease?

Parkinson’s disease is a neurodegenerative disorder caused by the misfolding of alpha synuclein protein that is naturally present in our cells. The misfolded protein accumulates within neurons and damages them.

The dopamine-producing cells that are most affected reside in the part of the brain known as the substantia nigra, an area near the base of the brain. As these cells die off, the lack of dopamine creates the physical symptoms of the disease, particularly motor symptoms such as tremors and slowed movement. It’s a gradual progression, and at the time of diagnosis, typically patients have already lost over half of their dopamine-producing neurons.

“By the time patients clinically manifest the typical motor symptoms of Parkinson’s, you can assume that the neurodegenerative process actually started much earlier, maybe a decade or two,” says Sule Tinaz, MD, PhD, associate professor of neurology and co-principal investigator.

The most common available medication, levodopa, replaces the missing dopamine. While the drug is effective in alleviating motor symptoms, it does not prevent the ongoing neurodegeneration and can cause undesirable side effects with long-term use such as uncontrolled excessive movements [dyskinesia]. There is currently no cure for the disease.

Exercise plays a vital role in treating Parkinson’s disease

Exercise is an essential component of Parkinson’s disease management. In fact, some gyms offer exercise programs specifically for the condition. “I always tell patients that exercise is a part of their treatment,” says Tinaz. “The same way I prescribe medication, I also prescribe exercise.”

In Connecticut, Michelle Hespeler is the founder of Beat Parkinson’s Today, an evidence-based non-profit exercise program that offers online and in-person classes throughout the state. Hespeler was inspired to create her program after being diagnosed with the disease herself. “She took all of the elements of high-intensity interval training and combined it with the needs of people with Parkinson’s disease,” says Tinaz.

Previously, two well-designed clinical trials have shown that engaging in high-intensity exercise—in which participants reach around 80% to 85% of their age-appropriate maximum heart rate—three times a week for six months is correlated with less severe motor symptoms. “These trials suggested that exercise really is disease-modifying in a clinical sense,” says Tinaz. The Yale team used these clinical trials as a model for its new study.

Using brain imaging to study impact of high-intensity exercise

For their study, the Yale researchers recruited patients who had been diagnosed with Parkinson’s disease for less than four years. At this early stage of their disease, the patients had not yet lost all of their dopamine-producing neurons. All participants initially went through a two-week trial period to ensure they could handle the intensity of the exercise classes before enrolling.

After the trial period, the participants received their first round of brain scans. One was an MRI scan that measured the amount of neuromelanin—a dark pigment found in dopamine-producing neurons—in the substantia nigra. The second scan was a PET scan that measured dopamine transporter (DAT) availability. DAT is a protein that helps the neurons maintain proper dopamine levels.

Ten participants completed a six-month high-intensity exercise program through Hespeler’s Beat Parkinson’s Today program. Due to the COVID-19 pandemic, the classes took place online. These classes involve High Intensity Functional Intervals [HIFI] designed to keep participants’ heart rates elevated for the majority of the workout. Participants wore heart rate monitors to ensure they were reaching their target heart rates and other wearables (e.g., a Fitbit) to record their movements. After the six months, the researchers repeated the MRI and PET scans.

High-intensity exercise reverses neurodegeneration

Following the six-month program, brain imaging showed a significant increase in both the neuromelanin and DAT signals in the substantia nigra. This suggests that high-intensity exercise not only slowed down the neurodegenerative process, but also helped the dopaminergic system grow healthier.

“Where we would have ordinarily expected to see a decline in the DAT and neuromelanin signals, we saw an increase,” says Bart de Laat, PhD, associate professor adjunct in psychiatry and the study’s first author. “We had hoped to see that the neurodegeneration would not progress as quickly or stop temporarily, but instead we saw an increase in nine out of 10 people. That was remarkable.”

The study highlights the importance of including an exercise regimen as part of one’s Parkinson’s treatment plan. “The medications we have available are only for symptomatic treatment. They do not change the disease course,” says Tinaz. “But exercise seems to go one step beyond and protect the brain at the neuronal level.”

While this is an exciting finding, additional research will be needed to fully understand the neuroprotective effects of exercise. The team hopes that its work will inspire other scientists to prioritize research into exercise and its disease-modifying potential.

Parkinson’s disease is the fastest-growing neurological disease. By 2040, researchers estimate that over 12 million people worldwide will be living with the condition. The new study holds promise that exercise can help mitigate the enormous personal and economic costs the disease poses. “Exercise is accessible to everyone, is relatively cheap, and is safe [if your health care provider approves],” says Tinaz. “If it also has this neuroprotective effect with the potential to reverse the disease course, that is something to celebrate and to study.”

Featured in this article

• 

  Evan Morris, PhD

  Professor of Radiology and Biomedical Imaging and of Biomedical Engineering
• 

  Sule Tinaz, MD, PhD

  Associate Professor of Ne