Saturday, August 16, 2025

NCI MATCH Final Concordance Study: High Accuracy Among 26 Labs

 NCI and Clinical Cancer Research publish a large-scale concordance study of tumor comprehensive genomic profiling across 26 NGS laboratories.   Results were very good.

See a blog by Howard McLeod here.

See the full paper by Zane et al., released August 15, here.

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I have not seen the full paper, but I'll include the remarks and the abstract below.

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McLeod

Howard McLeod, Center Director at Center for Precision Medicine and Functional Genomics, shared a post on LinkedIn:

  • “The National Cancer Institute (NCI) MATCH study gave an opportunity to assess concordance of comprehensive genomic profiling across 11 commercial and 14 academic laboratories (with the NCI central lab being the standard). 
  • As many of us have seen in practice, high concordance for SNV, insert, deletion, and copy number variants in therapeutically relevant driver genes for NGS across the labs (not as good for hybridization capture assays). 
  • Gives confidence for using the NGS lab that gives you the genes you need, at the turn around time that is needed.”
  • Title: A Concordance Study among 26 NGS Laboratories Participating in the NCI Molecular Analysis for Therapy Choice Clinical Trial Available to Purchase
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Zane

Purpose:
NCI selected a network of Clinical Laboratory Improvement Amendments–certified laboratories performing routine next-generation sequencing (NGS) tumor testing to identify patients for the NCI Molecular Analysis for Therapy Choice (NCI-MATCH) trial. This large network provided a unique opportunity to compare variant detection and reporting between a wide range of testing platforms.

Experimental Design:
Twenty-eight NGS assays from 26 laboratories within the NCI-MATCH Network, including the NCI-MATCH central laboratory (CL) and 11 commercial and 14 academic designated laboratories (DL), were used for this study. DNA from eight cell lines and two clinical samples were sequenced. Pairwise comparisons in variant detection and reporting between each DL and CL were performed for single-nucleotide variant, insertion and deletion, and copy-number variant classes.

Results:
We observed high concordance in variant detection between CL and DL for single-nucleotide variants and insertions and deletions [average positive agreement (APA) > 95.4% for all pairwise comparisons] but lower concordance for variant reporting after analysis pipeline filtering. 

We observed much higher agreement between CL and assays using amplification as the target enrichment method (84.2% < APA ≤ 95.7%, average APA = 88.7%) than other assays using hybridization capture (69.7% < APA ≤ 93.8%, average APA = 77.4%) due to blacklisting of actionable variants in low complexity regions. 

For copy-number variant reporting, we observed high agreement (APA > 82%) except between CL and two assays (APA = 76.9% and 71.4%) due to differences in estimation of copy numbers. Notably, for all variants, differences in variant interpretation also contributed to reporting discrepancies.

Conclusions:
This study indicates that different NGS tumor profiling tests currently in widespread clinical use achieve high concordance between assays in variant detection. For variant reporting, observed discrepancies are mainly introduced during the bioinformatic analysis.

Friday, August 15, 2025

AMA CPT - Detailed Deck on PLA Code Rules and Processes

For PLA Codes, find the AMA's 36-slide deck and FAQ at links provided.

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There are now over 600 AMA CPT PLA codes (proprietary laboratory analyses), and more are issued quarterly.

PLA codes are issued both for single-lab proprietary tests, and for distributed FDA approved or cleared tests.

Unfortunately, there is no master categorization of PLA codes: they are issued serially.  So there's no index to which are genomic sequencing procedures, which are minimal residual disease, which are pharmacogenetic, and so on.   

AMA CPT Speaker at Conference

On August 18, 2025, in Washington, hear two talks about lab codes to kick off the Next Generation Dx Summit, reimbursement track.  On that Monday, Zach Hochstetler of AMA CPT Editorial & Regulatory Services, describes "Critical Updates to Lab CPT Codes."   He's followed by Victoria Pratt (Indiana School of medicine and AMA PLA committee), on "PLA Codes and the CLFS Rate Setting Process."

Find agenda and registration here.

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There's a home page for all things PLA at the AMA CPT - here.  

I was looking for some updates and ran across a detailed 36-page slide deck by AMA on PLA, as well as a detailed FAQ.

The 36-page deck is here.  The FAQ is here.


sample slide


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I noted in a July blog that, by inspecting PLA codes released over the last several quarters, they seemed to stop issuing digital-only lab PLA codes (blog here).  For example, you could track some that were being applied-for but not finalized.  I didn't see any direct confirmation of that in the AMA instructions.

Monday, August 11, 2025

Brief Blog: RFK Jr Requests Journal Retraction - Finding the Links

You may have heard that HHS has asked a top journal to retract a recent paper.  Find the links below.

The original study (Andersson) mined the records of 1.2M persons vaccinated over 24 years for certain risk/benefit issues.

  • See an August 11, 2025, Reuters article on the journal retraction issue, by Erman & Rigby, here.
  • See the August 1, 2025, Op Ed from HHS leadership here.
    • See an August 7, 2025, entry point to additional debate at TrialSiteNews here.
  • See the original Andersson et al. at Ann Intern Med here.   See July coverage at Stat here.

Ted Cho and Brian Miller: CMS and the (Innovation) Valley of Death

Last winter, Brian Miller and Ted Cho published a 15-page white paper on the Innovation Valley of Death.  Here, here.  American Enterprise Institute; Cho is at UCSF, Miller at Hopkins.

In July, Miller announced a two-part series on CMS & Valley of Death, followed by FDA & Valley of Death.   Linked In here.  Find Part 1, Coverage Reform, online at Hoover Institution here.

The authors' key takeaways are three:

  1. Delays in Access to Innovation: Differing regulatory standards between FDA approval and Centers for Medicare and Medicaid Services (CMS) coverage delay access to the life-changing innovations in medical devices and health technology over the past several decades, with a median 5.7-year lag.
  2. Prior Regulatory Reform Efforts Have Lagged: For 30 years, policymakers and regulators have introduced advisory committees, new coverage pathways, and other process improvements, but access remains limited—underscoring the failure of these reforms.
  3. Urgent Need for CMS Reform: Policymakers and CMS can provide clarity of coverage principles, improve local coverage determination processes, and expand transparency to facilitate access to innovation.
What Do I Think?

I like the paper, the body of which is only about 8 pages.  It gives a good history and overview.   It notes the decades of attempts at improvement and reform, and it notes the stasis of the once-lauded MEDCAC process.  

I'd add that when CMS does hold a MEDCAC, the voting questions are almost always so vague that the panel wastes a lot of time, inconclusively, debating what is meant.  There are a host of reasons that innovation gets imperiled, one of the worst being the years of delay before truly novel NCDs or LCDs appear.   I track the CMS policy website weekly and truly new LCDs are very, very rare.   

As far as CED goes, I see little evidence of benefit, and a new complex (byzantine) CED proposal for renal denervation for hypertension looks very messy to me (blog).   CMS does only 4 NCDs per year, yet if its TCET plan was fully implemented, it would be doing 12 (4 NCDs, 4 TCET NCDs, and 4 TCET NCDs coming up for re-appraisal.)  No way.

Forgotten but Important:  Death by Coding
Discussions of reimbursement and innovation generally go in this direction - coverage policy.  However, there is also the less-remarked on area of "death by coding."   While I haven't check these two areas lately, for many years, there was one HCPCS code for "insulin pump," one HCPCS code for "sleep apnea pump."   No matter if you developed one that was twice as clinically effective, twice as high compliance, twice as important new features, there was no  incentive - there was one code, one price for the field.   This also can be an important disincentive to innovation.

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AI Corner

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Here's an AI summary (Chat GPT 5).

The Hoover Institution brief “Crossing the Valley of Death, Part 1: The Innovation Imperative and Medicare Coverage Reform” describes the persistent gap between FDA approval of new medical technologies and Medicare coverage sufficient to ensure patient access—a delay averaging about 5.7 years. This “Valley of Death” arises because innovators face two sequential regulatory hurdles: FDA’s safety and efficacy review, followed by CMS’s coverage determination under its “reasonable and necessary” standard. The agencies operate under different statutory mandates, resulting in misaligned processes and timelines that slow adoption of innovations and reduce their potential impact on patient care.

The authors frame the case for reform as both an innovation imperative and a moral obligation. While 45 percent of Medicare beneficiaries experience impairments in activities of daily living and over 6,000 rare diseases lack treatments, the United States has a strong history of medical innovation—producing more than 1,200 new drugs in the past 60 years and transforming care for conditions such as HIV and heart disease. Despite these successes, many conditions still impose enormous human and economic costs, such as insulin-dependent diabetes, which affects millions and drives billions in health care expenditures. The authors argue that U.S. policy should focus on removing inefficiencies that hinder timely adoption of proven innovations.

Medicare coverage reform has been attempted before. In 1999, under Administrator Nancy-Ann DeParle, CMS restructured its coverage analysis group and created the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC). In 2021, the Trump administration introduced the Medicare Coverage of Innovative Technologies (MCIT) rule, which granted automatic four-year coverage for FDA-designated breakthrough devices. The Biden administration repealed MCIT in 2022 and replaced it with the Transitional Coverage for Emerging Technologies (TCET) pathway, which accepts only five devices per year and excludes diagnostics. In 2023, legislation (H.R. 1691) was introduced to restore MCIT-like transitional coverage.

The current coverage process includes National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs) by Medicare Administrative Contractors (MACs), and Coverage with Evidence Development (CED).   

(BQ: See Joe Grogan's WSJ Op Ed, nix CED, from June 2025.)  (See also a WSJ op ed, nix CED for amyloid drugs, August 2025.)

MEDCAC’s activity has declined sharply in recent years, and the number of NCDs has dropped from a peak of 20 in 2003 to just four in 2022. CED, intended to accelerate coverage while gathering evidence, often stretches for years, drains resources, and rarely leads to full coverage—only three of 26 CED programs since 2005 have transitioned to routine coverage. The authors recommend a moratorium on new CED programs until CMS establishes defined milestones, completion criteria, and timelines. They also criticize CMS’s increasingly skeptical stance toward drugs granted FDA accelerated approval, noting that states like Oregon have sought to exclude such drugs from Medicaid coverage.

A central policy concern is the lack of a statutory definition for “reasonable and necessary.” CMS currently defines this administratively as safe and effective, not experimental or investigational, and appropriate for the Medicare population. Without a national definition, MACs apply their own interpretations, leading to inconsistent access based on geography. The authors recommend codifying broad evaluative principles in rulemaking, clarifying the division of responsibility between NCDs and LCDs, and maintaining local flexibility for positive customization.

Finally, the report proposes improvements to the LCD process, including imposing transparent timeframes for key steps, enhancing CAC membership with MEDCAC experts, posting CAC membership and technical questions at least 30 days before meetings [*], and holding annual CMS public meetings with MACs to review policy and operational lessons. The authors conclude that innovation is both an economic and moral imperative, and that streamlining, standardizing, and making coverage decisions more transparent can reduce inequities, improve access, and provide innovators with greater certainty, all in a way that should attract bipartisan support.

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* Noridian has posted a meeting on molecular cancer tests, but by 8/11 offered no meaningful agenda for the 9/4 meeting.

HHS to Nix the LDT Final Rule

 At Linked In, Karin Hughes is one of the first to report that Executive Order #12866 will be used to reverse the FDA LDT rule.  It will formally retract the FDA LDT rule, which lost in federal court in Texas back in May 2025.

It looks to me like the document was "received August 6" but may be in regulatory review, it may be titled but not released.  It will be interesting if it just briefly retracts the LDT rule or if it elaborates on a new agency direction.  

https://www.reginfo.gov/public/do/eoDetails?rrid=1044563

The title is, Medical Devices; Laboratory Developed Tests; Rescission, and the status seems to be "pending."

The "meetings" tab shows no related meetings.

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EO12866 is not new; it represents a 1993 regulatory framework.   The new document would, I think, be a new document or rule issued under the authority of 12866.  I think FDA Law Blog also indicates the rule is written but under review as of August 11.

https://www.reginfo.gov/public/jsp/EO/eoDashboard.myjsp



See comments at Linked In by Christine Bump here.


Prior Authorization in Fee for Service Medicare: More Follow-up

On July 8, 2025, I had a blog discussing the CMMI plan to introduce Prior Authorization into Medicare Part B.   Prior-auth companies would bid for the right to interpose their Prior Auth software between the provider and the MAC.   I noted (and you had to dig for this) that the Prior Auth companies would be paid based on charges avoided (ie, the volume of denials they could generate.)

I also noted that the PA computers were supposed to simply implement the rules for existing LCDs/NCDs, but that some of the topics to be authorized actually had no meaningful guidance at CMS.

Some follow-up a month later.

At Linked In, Brian Miller highlights the potential problems, pointing us to a new Op Ed by Donald Berwick and Andrew Ducas.

See the STAT article by Berwick & Ducas here.

See also an opinion piece by Jessica Hall at Marketwatch here.



Saturday, August 9, 2025

MolDx Greenlights "Pathlight," the New MRD Test from Saga Diagnostics

On August 5, 2025, we highlighted Decibio's latest update on MRD coverage (here).  I mentioned late-breaking coverage by MolDx of the SAGA "Pathlight" MRD test.  Here's some more.

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  • SAGA Diagnostics is a spin-out from Lund University in Sweden.  See an article at Lund University, June 2025, here.
  • See a July 30 press release from SAGA about its MolDx coverage here.  
    • The coverage is for all breast cancer subtypes and  recurring monitoring (surveillance) for "up to six years."
    • See coverage at Genomeweb.
  • See a Linked In article by Achyut Saroj on August 8, here.  
    • The Linked In article includes an embedded Elliott article.
  • See the full article by Elliott et al. in Clinical Cancer Research here.  
    • While the webpage is dated April 14, internal text says editorial approval was February 7 and online publication February 9.  
    • February would have been the earliest date for a MolDx coverage submission, which requires MRD publication(s).
  • The executive chairman is Roopom Banerjee.  He holds a Master's from the Harvard Kennedy School and  has been on the board since 2021.

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MolDx DEX Registry lists the lab as Morrisville, NC.  It lists Pathlight (their only test entry on MolDx as of now) as $3652 and "covered."  I suspect that is for an initial test plus set-up genomics, but I can't be sure.   

  • dPCR vs NGS and CMS Policy
    • Since the recurring test is digital PCR rather than NGS, I think it falls outside of restrictions of CMS NGS NCD 90.2.
  • The test is described as genome-informed.  
    • Natera recently got MolDx coverage for a genome-informed Signatera test.  So this is a trend.

As of August 9, the MolDx DEX descriptor is:

  • The test is a dPCR-based, tumor-informed liquid biopsy assay that is designed to detect circulating tumor DNA (ctDNA) in the blood for the purpose of detecting molecular residual disease (MRD), monitoring treatment response, or detecting cancer recurrence.  
  • The test entails whole genome sequencing of a patient's tumor specimen, which is then used to generate a customized multiplex dPCR assay (fingerprint) for up to 16 structural variants (SVs).  This unique patient fingerprint is then used to detect the presence or absence of ctDNA. 
  • The test is intended to be used for patients diagnosed with solid tumor malignancies, initially focused in breast cancer (all subtypes), for multiple purposes, including neoadjuvant treatment monitoring, post-surgical MRD detection, adjuvant treatment monitoring, and post-treatment surveillance for recurrence.

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The DEX text includes "adjuvant treatment monitoring," and Elliott et al. has some data on this, but the press release on coverage doesn't seem to directly include "adjuvant treatment monitoring" (or for what chemotherapy classes).

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On July 19, I published a popular blog on a new proposed MolDx LCD about DCIS breast cancer test coverage (non-coverage), suggesting it might be used as a "teaching case study" for how MolDx thinks.   

You can't say the same for the Pathlight coverage, "how MolDx thinks."  MolDx releases no info on its thought process other than (1) the original, four-year-old LCD and the (2) binary status of "covered" for Pathlight at DEX registry..  

However, you can on your own put together coverage statements in the press release from the company, with a detailed view of the Elliott et al. publication.  This lets you infer what MolDx found acceptable.

  • Analytical performance accurately classified 217 tumor and 217 control cases.  
  • Breast-cancer retrospective performance had 100 cases, across several BC types, and found ctDNA ahead of known distal recurrence 19/19 recurrences.  (This includes postsurgical positives).

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AI CORNER

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Google Notebook LM writes a single 400 word article based on the links provided.

Direct AI output.  Do not quote without checking details against original sources.

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SAGA Diagnostics has launched Pathlight MRD, an ultrasensitive liquid biopsy test designed to transform cancer care by enabling early detection of cancer recurrence. Originating from research at Lund University in Sweden, this groundbreaking test is now commercially available in the U.S. and has received Medicare coverage.

Unlike many other circulating tumor DNA (ctDNA) assays that primarily target single-nucleotide variants (SNVs), Pathlight focuses on structural variants (SVs). SVs are stable, highly tumor-specific genomic changes that reflect underlying genomic instability and provide a clearer, earlier indication of disease recurrence. This approach allows for precise molecular residual disease (MRD) tracking, especially in ER-positive (ER+) low-shedding tumors, where other assays often fall short. The assay uses whole genome sequencing (WGS) of tumor tissue to create a customized "fingerprint" of up to 16 structural variants for each patient, which is then used in digital PCR (dPCR) to detect ctDNA in blood samples.

Clinical validation, primarily through the cTdna evaluation in eaRly breAst canCER (TRACER) study published in Clinical Cancer Research, demonstrated remarkable performance. Pathlight achieved 100% sensitivity and 100% specificity in detecting early breast cancer recurrence. It provides a median lead time of 417 days (or 13.7 months) before recurrence is detected by standard clinical methods, including imaging. The test also boasts a high baseline detection rate of 96% across all early-stage breast cancer subtypes, notably 94% in ER+ disease. Furthermore, clearance of ctDNA during neoadjuvant therapy was associated with improved outcomes, enhancing residual cancer burden prognostication.

The Pathlight MRD test is now covered for Medicare beneficiaries for recurrence monitoring in the surveillance setting for up to six years in patients with stage II-III breast cancer, including all subtypes (HR+/HER2-, HER2+, and TNBC). This coverage decision, issued by Palmetto GBA’s MolDX Program, reflects a rigorous review of Pathlight’s analytical and clinical validity. The currently listed cost on the MolDX DEX Registry is $3652. This development aims to empower patients and clinicians with ultra-sensitive tools for more personalized and informed treatment decisions, moving towards smarter surveillance and long-term monitoring programs.

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Is the company a "spin-out?"

Yes, SAGA Diagnostics is a spinout company from Lund University in Sweden.

Specifically:

  • It was founded in 2016 from research conducted at Lund University.
  • SAGA Diagnostics is described as a "portfolio company of LU Ventures" and "a brilliant example of how research from Lund University can reach the world and improve healthcare," having started as a spinout with support from LU Ventures and LU Innovation.
  • While its origins are in Sweden, SAGA's headquarters and CLIA-certified laboratory are located in Research Triangle Park, North Carolina, U.S..
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Summarize Elliott et al; do not just repeat the abstract, we have that.

The "Ultrasensitive Detection and Monitoring of Circulating Tumor DNA Using Structural Variants in Early-Stage Breast Cancer" study, published in Clinical Cancer Research by Elliott et al., describes the development and validation of a novel circulating tumor DNA (ctDNA) assay, Pathlight, that utilizes structural variants (SVs) for molecular residual disease (MRD) detection in early-stage breast cancer (EBC).

The study addresses the need for improved biomarkers in cancer diagnosis, treatment selection, and monitoring, moving beyond invasive tissue biopsies to liquid biopsies. Unlike many existing ctDNA assays that primarily target single-nucleotide variants (SNVs), this study highlights the potential of SVs, which are stable, highly tumor-specific genomic changes reflecting underlying genomic instability. The Pathlight assay workflow involves whole genome sequencing (WGS) of tumor tissue to generate a personalized "fingerprint" of up to 16 SVs per patient, followed by multiplex digital PCR (dPCR) analysis of plasma-derived cell-free DNA (cfDNA) to detect ctDNA.

Analytical validation demonstrated the assay's ultrasensitivity, achieving a 95% limit of detection (LoD95) of 0.00052% (5 parts per million) with standard cfDNA inputs, and even lower (0.00011% or 1.1 ppm) with higher inputs. It also showed 100% analytical specificity across 217 cancer-free donor samples and 217 genomic DNA samples, testing 5,268 SVs.

In a retrospective clinical evaluation of 100 EBC patients (28 TNBC, 33 ER+, 39 HER2+) undergoing neoadjuvant systemic therapy, the assay successfully generated fingerprints for 95% of participants. Key findings include:

  • High baseline ctDNA detection: 96% of evaluable baseline samples showed ctDNA, with similar rates across all receptor subtypes, including 94% in ER+ disease where other assays often struggle.
  • Prognostic value of on-treatment dynamics: Clearance of ctDNA prior to cycle 2 of neoadjuvant therapy was associated with improved outcomes, and persistent ctDNA detection enhanced prognostication when combined with residual cancer burden (RCB) status.
  • Early detection of recurrence: ctDNA was detected prior to distant recurrence in 100% of cases (19/19) with evaluable samples, providing a median lead time of 417 days (13.7 months) before clinical detection by standard methods. Any ctDNA detection after surgery or during follow-up was strongly associated with recurrence.

The study concludes that this novel SV-based approach offers sensitive and specific ctDNA detection for treatment monitoring and prognostication in EBC. The uniqueness of SV breakpoints minimizes false positives and the selection of amplified SVs enhances sensitivity. While acknowledging limitations such as its retrospective nature, the study supports prospective trials to evaluate ctDNA-guided treatment strategies.

Vinay Prasad: Restored to FDA, Head of CBER: Key Timelines

In news that seemed to break on Saturday, August 9, Vinay Prasad is returning to the FDA to head CBER - biologicals & vaccines.   He was gone from Tuesday, July 29, to Friday, August 8.


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Timeline includes - 

NYT

May 20 - Prasad published article in NEJM (Prasad & Markary) that the best approval for COVID vaccines would be for over-age-65 and younger persons with predisposing illnesses. At NEJM: Here.  Immediate coverage at NYT here.

July 2 - NYT article that in fact FDA staff had endorsed open-ended approval of new COVID vaccines, but Prasad 5-page memorandum overruled staff.  Here.  The NYT article includes the 5-page memorandum. PDF here (dated May 16, ahead of NEJM release).

Op Eds

July 20 - Laura Loomer op ed as "left wing saboteur of President Trump."  Also Loomer, July 28.

July 25 - example of a follow-on anti-Prasad op ed.

WSJ Op Eds

July 27 - "Digging the grave" op ed - "Prasad is a Bernie Sanders Acolyte."

July 30 - "Dancing on the grave" op ed - "Why Prasad Had to Go."

EXIT

July 29 - Prasad leaves FDA.  See coverage the next day at Reuters here

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August 4 - At conference, Dr Makary publicly invites Prasad to return to FDA ASAP.  (Inside Health Policy here, and other sources).

August 5 - In my hands, Chat GPT predicted Prasad was unlikely to return, as the event lacked any clear precedents.  Here.

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August 9 (Saturday) - Many sources, Prasad is back. Open access article at The Hill.  NYT here.  WaPo and others quote HHS as saying the whole episode was "fake news."

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August 7, 2025

JAMA Network Open publishes Prosser et al. on cost-effectiveness of mRNA COVID vaccine.  Here.

  • Vaccine was cost-saving over age 65.
  • Vaccine was $25,787 per QALY age 50-64.
  • Vaccine was $115,588 per QALY age 18-49.
While one could say "That is dollars not health," the dollarized values are based on QALYs and one could have stopped and just compared net QALYs across age brackets.

It is supportive of Prasad's cut-offs that risk-benefit seems much higher over age 65.   

It is alternatively supportive of broader coverage, in that younger persons still had favorable (though less strongly favorable) results. 

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For his official photo, Prasad used neither a comb nor a razor.


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AI Corner

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I asked Google Notebook LM to compare the NEJM Covid article by Prasad (Prasad & Makary) with the May FDA internal memo released by NYT on the same topic.

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Here is a summary of the arguments presented in each PDF, followed by a comparison of where they particularly agree or differ:


NEJM

Summary of "2025 NEJM 0520 Prasad Makary Why COVID VAX is Bad 3p.pdf"

This article, a "Sounding Board" piece by Vinayak Prasad, M.D., M.P.H., and Martin A. Makary, M.D., M.P.H., published in the New England Journal of Medicine on May 20, 2025, critiques the U.S. approach to COVID-19 vaccination.

Key Arguments and Proposed Framework:

  • Critique of U.S. Policy: The authors argue that the U.S. has adopted an aggressive "one-size-fits-all" annual COVID-19 booster program, recommending boosters for every American, unlike other high-income nations which confine recommendations to older adults or those at high risk. They reject the view that Americans are not sophisticated enough for age- and risk-based recommendations.
  • Uncertain Benefit and Declining Trust: The benefit of repeat dosing, especially for low-risk persons with prior doses or infections, is uncertain. This uncertainty, coupled with declining public trust, has led to poor booster uptake (less than 25% of Americans, less than 10% for children <12 in 2024-2025 season). This has also contributed to a general decline in trust in vaccination, affecting other vital programs like MMR.
  • New FDA Regulatory Framework: The FDA will adopt a new framework moving forward:
    • Immunogenicity-Based Approval: Favorable benefit-risk findings based on immunogenicity data are anticipated for adults over 65 years and all persons over 6 months with one or more CDC-defined risk factors for severe COVID-19 outcomes. This group is estimated to include 100 million to 200 million Americans.
    • Randomized Controlled Trial (RCT) Requirement: For healthy persons (no risk factors) between 6 months and 64 years, the FDA anticipates the need for randomized, controlled trial data evaluating clinical outcomes before Biologics License Applications can be granted.
  • Preferred Study Design for RCTs:
    • Ideal Population: The 50–64-year-old age group without risk factors is considered an ideal population for future trials due to global equipoise regarding yearly boosters.
    • Endpoints: The primary endpoint should be symptomatic COVID-19, with secondary endpoints including severe COVID-19, hospitalization, and death.
    • Trial Features: Sample size calculations should aim for a lower confidence interval bound ideally above 30%. Trials should include people with past COVID-19, extend follow-up for a minimum of 6 months, and the control group could receive a saline placebo to document the full adverse-event profile.
  • Balancing Competing Values: The new policy balances the need for timely approval for high-risk populations with the need for evidence in low-risk groups, acknowledging the uncertainty of benefit for healthy individuals.
  • COVID-19 vs. Influenza: COVID-19 is distinct from influenza in that its vaccine-induced immunity may not require annual updates, it has summer transmission that facilitates studies, and natural immunity against severe disease appears robust.
  • Commitment to Gold-Standard Science: The new FDA philosophy represents a balance of regulatory flexibility and a commitment to "gold-standard science," aiming to provide information craved by healthcare providers and the American public.

FDA Memo

Summary of "2025 FDA 0516 Prasad memo on restricted vaccine approval 5pp.pdf"

This document is a Center Director Decisional Memorandum from Vinayak Prasad, M.D., MPH, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, dated May 16, 2025. It explains CBER's decision regarding Novavax's Biologics License Application (BLA) for NUVAXOVID (COVID-19 Vaccine, Adjuvanted).

Key Arguments and Decision:

  • Restricted Approval: Dr. Prasad's memo approves NUVAXOVID for active immunization to prevent COVID-19, but only for individuals 65 years of age and older, and those 12 through 64 years who have at least one underlying condition that puts them at high risk for severe outcomes from COVID-19. This is a narrower indication than Novavax's original request for individuals 12 years of age and older.
  • Reasons for Restriction: CBER's decision to limit the BLA is based on several factors:
    • Limitations of Submitted Data: There was an overreliance on potentially confounded observational data, and a diminishing risk of severe COVID-19 outcomes in the general American population.
    • Unclear Efficacy from Immunogenicity Data: The ability to estimate clinical efficacy against novel COVID-19 variants from immunogenicity data and observational/real-world data is limited because the amount of protection conferred by an increase in neutralizing antibodies is unclear. A causal relationship between rising neutralizing antibody titers and diminished severe COVID-19 outcomes has not been established.
    • Differences from Influenza: SARS-CoV-2 differs from influenza; natural SARS-CoV-2 infection provides durable protection against future severe disease and death, which may outlast vaccine-conferred protection. The viral evolution rate of SARS-CoV-2 is markedly slower than influenza.
    • Observational Data Bias: Observational data supporting risk reduction from additional vaccine doses is subject to multiple biases, including the "healthy vaccinee bias," which makes it difficult to draw reliable conclusions about vaccine efficacy. This bias has been thoroughly documented for both COVID-19 and influenza vaccines.
    • Decreased Risk of Severe Outcomes: The risk of severe outcomes from COVID-19 has dramatically decreased over the past four years, with the infection fatality rate estimated to have decreased approximately 10-fold. As a result, individuals previously at low risk now have minimal risk of death from COVID-19.
    • Benefit-Risk Calculation Altered: Given the decreased risk of severe COVID-19, the potential for absolute benefit from vaccination has also decreased. Even rare known and unknown vaccination-related harms, such as myocarditis, now have a higher chance of outweighing potential benefits in non-high-risk populations.
  • Post-Marketing Commitment (PMC): Novavax has agreed to a PMC to assess the efficacy of the product among 50- to 64-year-old individuals in a randomized controlled trial. This study aims to determine if other patient populations have a favorable benefit-risk profile, as there is "equipoise" for such a study in individuals 50-65 years of age without risk factors.
  • Divergence from U.S. Policy: The memo notes that the U.S. COVID-19 vaccine schedule of recommending annual vaccinations to children and non-high-risk adults under 65 diverges from international consensus.
  • Emerging Consensus: The memorandum highlights an emerging consensus in the American medical community for this approach, referencing former FDA commissioner Robert Califf's statements supporting placebo-controlled trials for updated boosters in non-high-risk individuals.

Comparison: Agreement and Differences

The two documents, while serving different purposes, show significant alignment, particularly due to the shared authorship of Dr. Vinayak Prasad.

Points of Agreement:

  • Restricted Vaccination Recommendations: Both sources strongly advocate for limiting broad COVID-19 vaccine recommendations (especially annual boosters) to older adults (typically 65+) and those with specified underlying high-risk conditions [Prasad memo: 1, 3, 4, 5, 23; NEJM article: 30, 32]. They explicitly criticize the U.S.'s "one-size-fits-all" approach that extends recommendations to healthy, low-risk individuals [NEJM article: 30].
  • Need for Randomized Controlled Trials (RCTs) in Low-Risk Groups: A core tenet in both documents is the critical need for robust, randomized, placebo-controlled trials to evaluate clinical outcomes (efficacy and safety) for healthy, low-risk populations before granting broad marketing authorization [Prasad memo: 3, 26; NEJM article: 32, 34, 35, 41].
  • Target Population for RCTs: Both identify the 50-64-year-old age group without underlying risk factors as an ideal population for future RCTs, citing "global equipoise" regarding the benefit of yearly boosters for this group [Prasad memo: 26; NEJM article: 34].
  • Diminished Risk of Severe COVID-19: Both acknowledge the dramatic decrease in the risk of severe outcomes from COVID-19 over time [Prasad memo: 14, 19, 20]. This fundamental shift alters the benefit-risk calculation for low-risk individuals, making the potential for absolute benefit minimal [Prasad memo: 20].
  • Limitations of Observational and Immunogenicity Data: Both documents express concerns about the reliance on observational data, noting biases like the "healthy vaccinee bias," and the limited ability of immunogenicity data alone to reliably predict clinical efficacy, especially against novel variants [Prasad memo: 5, 6, 7, 8, 13, 14; NEJM article: implicitly, by stating the need for RCTs focused on clinical outcomes (32, 35)].
  • Distinction from Influenza: Both clearly articulate that SARS-CoV-2 differs significantly from influenza in terms of viral evolution speed and the durability of natural immunity against severe disease [Prasad memo: 9, 12; NEJM article: 37, 40].
  • Transparency and Evidence Generation: Both emphasize the importance of generating robust, "gold-standard" evidence to inform future vaccine policies and provide clarity to healthcare providers and the public [Prasad memo: 27, 28; NEJM article: 41].

Points of Difference (primarily in scope and emphasis):

  • Document Type and Purpose:
    • The Prasad memo is an internal FDA decisional memorandum explaining a specific regulatory approval decision for a single product (NUVAXOVID BLA) based on the presented evidence. Its focus is on the rationale for that specific, restricted approval.
    • The NEJM article is a published "Sounding Board" opinion piece outlining a broader "new FDA Covid-19 philosophy" and a proposed general regulatory framework for future COVID-19 vaccine approvals. It sets out a policy vision.
  • Scope of Application:
    • The Prasad memo directly applies its rationale to the approval of NUVAXOVID and its specific indication.
    • The NEJM article lays out a general policy for all future COVID-19 vaccine approvals and booster recommendations, applicable to a wider range of products and populations.
  • Discussion of Public Trust and Vaccine Uptake:
    • The NEJM article explicitly addresses the issue of poor booster uptake and the decline in public trust in vaccination generally, including a "ripple effect" on vital immunization programs like MMR. It highlights this as a significant contextual factor for the FDA's new approach.
    • While the Prasad memo mentions the divergence of the U.S. vaccine schedule from international consensus, it does not delve into the broader implications of declining public trust or poor uptake as a direct reason for its decision, though it aligns with the philosophy that might address such issues.
  • Detail on Specific Harms/Harm-Benefit Analyses:
    • The Prasad memo explicitly cites specific "harm-benefit analyses" suggesting net harm of ongoing vaccination for low-risk populations and discusses "unfavorable imbalances in rates of neurological, cardiac and thrombotic adverse events" linked to the Novavax vaccine.
    • The NEJM article acknowledges that the policy "balances competing values" and that the benefit for low-risk individuals is "uncertain", but it does not detail specific harms or refer to particular harm-benefit analyses as extensively as the memo.

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Thursday, August 7, 2025

History Corner: Those Giant Free CMS Physician Payment Datasets - Where Did They Come From?

History Corner: Those Huge Free CMS Physician Payment Datasets - Where Did They Come From?

At Data.cms.gov, one of many data sets is complete 2013-2023 data on claims paid by Medicare Part B, by provider and by CPT code.  "Provider" includes physicians, as well as independent labs.   (Hospital labs are not included.)

Find the data here:

https://data.cms.gov/provider-summary-by-type-of-service/medicare-physician-other-practitioners/medicare-physician-other-practitioners-by-provider-and-service

It's a little tricky at first to search and filter and download the data, but it just takes a little time and practice with the filter and download menus.

Where Did This Come From?

I "lived through this" - working in policy consulting since 2008, and especially, during the active years of court cases around 2010-2013.

I asked Chat GPT to write a history essay.   It may not be perfect in detail, but gives you a good entry point.

###

AI CORNER

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Here is a consolidated article based on your notes and prior research:


From Secrecy to Sunshine: The Legal Journey Behind CMS’s Physician Payment Data Releases (2013–2023)

In 2014, the Centers for Medicare & Medicaid Services (CMS) made a historic move: it released a massive public dataset detailing what individual physicians and other healthcare providers were paid by Medicare, broken down by CPT code, number of services, and total reimbursements. The data, covering payments for services rendered in 2012, marked a turning point in federal transparency. But the road to that moment spanned more than three decades of legal battles, privacy concerns, and shifting public policy.

The 1979 Injunction: A Curtain of Confidentiality

The story begins in the late 1970s, when the Department of Health, Education, and Welfare (now HHS) planned to release names and Medicare reimbursement amounts for physicians earning over $100,000. The Florida Medical Association (FMA), joined by the American Medical Association (AMA) and several individual physicians, sued to block the release.

In 1979, a federal court agreed with the physicians and issued a permanent injunction (Florida Medical Ass’n v. HEW, 479 F. Supp. 1291), citing FOIA Exemption 6, which protects personal privacy. The ruling barred HHS from disclosing any lists of Medicare reimbursement amounts that would identify physicians. For more than 30 years, this injunction sealed physician-level Medicare payment data from public view.

Early Challenges and the FOIA Push (2003–2011)

In 2003, Real Time Medical Data (RTMD), a private analytics firm, requested Medicare claims under the Freedom of Information Act (FOIA). HHS released limited data but withheld anything that could identify individual physicians, citing the 1979 injunction. A subsequent appeal by RTMD was rejected by the Eleventh Circuit Court, which upheld the injunction but suggested that the proper route was to challenge the injunction directly in the issuing court.

At the same time, the landscape was changing. Medicare was growing rapidly—both in cost and complexity—and concerns about fraud, waste, and provider overbilling were intensifying. Meanwhile, CMS was expanding its Health Data Initiative, releasing large datasets on hospital charges and quality measures. In this environment, the case for transparency gained traction.

Dow Jones and WSJ Enter the Fray

In 2011, Dow Jones & Company, parent of The Wall Street Journal, formally intervened in the 1979 case. Alongside RTMD, they argued that the injunction was outdated and inequitable. HHS also reversed its position and joined the effort to vacate the injunction, citing evolving FOIA case law and public interest arguments.

Dow Jones emphasized that Medicare had grown twenty-fold since 1979 and now represented a significant portion of the federal budget. They submitted expert declarations—such as that of Harvard’s Malcolm Sparrow—highlighting the public value of the data in uncovering Medicare fraud.

The Legal Turning Point: Injunction Vacated in 2013

On May 31, 2013, the U.S. District Court for the Middle District of Florida vacated the 1979 injunction. The court ruled that:

  • The Privacy Act does not support long-term prospective injunctions against government agencies,

  • Injunctive relief under the Act only applies in narrow circumstances (e.g., denying access to one’s own records),

  • And broad “reverse FOIA” restrictions could harm the public interest.

The ruling didn’t mandate data release—but it removed the legal barrier. CMS was now free to decide whether to release physician-level payment data under FOIA standards.

CMS Requests Comments—and Signals Intent

In August 2013, CMS posted a Request for Public Comments, seeking input on how to balance physician privacy with public interest. The notice asked whether individual payment data should be released, how it might improve healthcare delivery, and what formats would best serve researchers and stakeholders. CMS emphasized its alignment with the Obama administration’s data transparency agenda and its goal to reduce waste and abuse.

The First Release: April 2014

On April 9, 2014, CMS released physician-level Medicare payment data for calendar year 2012. The dataset included over 880,000 individual providers, listing:

  • CPT/HCPCS codes billed

  • Number of services performed

  • Average submitted and allowed charges

  • Total Medicare payments

The dataset covered physicians, nurse practitioners, podiatrists, and independent labs.

WSJ Leads the Media Response

The Wall Street Journal was the first major news outlet to fully capitalize on the release. It built a searchable interactive database that allowed the public to look up any physician by name or NPI, view their most common procedures, and compare billing patterns.

The WSJ's investigative coverage spotlighted top billers, regional anomalies, and specialties with unusually high payments (e.g., ophthalmology and oncology). Its reporting series included:

  • “How Much Medicare Pays Doctors”

  • “Medicare’s Top Billers”

  • “Taxpayer-Funded Millions”

Impact and Backlash

The release was praised by watchdogs, policymakers, and health economists for its potential to:

  • Uncover fraud and overutilization

  • Encourage provider accountability

  • Inform research on spending patterns

But the medical community pushed back. The AMA and other groups warned that the data lacked nuance. Gross payments didn’t reflect provider costs, group practice billing, or medically necessary high volumes. There were concerns about reputational harm and patient confusion.

A New Era of Data Transparency (2014–2023)

Despite the controversy, CMS affirmed its intent to release physician-level data annually. Each year since 2014, CMS has published updated datasets, now covering services from 2013 through 2023. These releases are hosted at data.cms.gov and have become essential tools for:

  • Journalists

  • Academic researchers

  • Policy analysts

  • Healthcare watchdogs

The data has been used to flag inappropriate billing, compare specialties, and inform healthcare reform discussions.

Each year's data appears about 18 months after the close of the year.  At least in part, because physicians have one year to submit final claims as each year closes in December.  


Conclusion

The release of Medicare physician payment data was not a one-time event—it was the product of a 35-year legal journey that pitted privacy against transparency. Thanks to media pressure, shifting FOIA jurisprudence, and CMS’s evolving role in healthcare stewardship, the 2014 release marked the beginning of an ongoing transformation in how government healthcare data is shared.

Today, what was once legally forbidden is a public resource. The result is a new era in which anyone—from a patient to a policymaker—can explore how billions in Medicare funds are spent, one CPT code at a time.


 

New York Times: Lobbying for Healthcare in the New Administration?

At the New York Times, August 7, 2025, see Vogel, Kliff, and Thomas for their review of lobbying and health policy for new technologies in the current administration.

https://www.nytimes.com/2025/08/07/us/politics/trump-medicare-bandages-donors.html

##

While the article focuses on a delay in a skin substitutes price cut (linking to an LCD pushed forward to 1/1/2026), it eventually includes the important facts that:

  • The [skin substitute] industry was caught off guard in July
  • The Trump administration changed course and proposed a new plan that would lower skin substitute reimbursements to a flat fee of $806 per square inch, a small fraction of what some companies currently earn. 
  • The proposal could go into effect next year if it is finalized.
Delay LCD to 2026

July new rulemaking
##

While NYT writes about political dollars and skin grafts, WSJ has an article on "millions of dollars" in donations to encourage DEA re-classification of marijuana. Also at Medpage in more detail.

Dr Paul Gerrard Co-Hosts Multi-faceted New Podcast "HealthTech Remedy"

Many readers of this blog will be familiar with the name of Dr Paul Gerrard, who has served as a MolDx medical director and as a physician executive with Veracyte and  ArteraAI.  (See Gerrard et al. validating its prostate model here.)

Along with Drs Timothy Showalter and Trevor Royce, Gerrard is now co-hosting the podcast HealthTech Remedy.

  • Find the home page here.  Find "About" here.
  • Find the episode list here.
    • You'll find a high quality transcript as well as the podcast audio.
Here's the website description:

  • Welcome to the HealthTech Remedy podcast, where three physician leaders explore healthcare innovation. Drawing on our backgrounds from academic medical centers to leadership roles in health technology, we provide unique insider perspectives on the industry. 

  • Each episode features the real stories of both emerging and established health technology companies transforming patient care. We also interview the pioneering leaders driving change, sharing their journeys and insights.

  • Join us as we uncover breakthrough solutions, discuss their real-world impact, and reflect on the challenges and successes of health tech. We navigate the arcane interface of healthcare and technology, offering a blend of expert analysis and personal reflections.
In recent podcasts, Dr. Aron D'Souza discussed biotechnology & performance enhancement, Alex Dyle discussed faster clinical research at Flatiron, Dr. Yousuf Zafar discussed bridging local and specialized oncology expertise, and Dr. Brigham Hyde discussed new approaches to facilitate real-world evidence.

###
Re biotech and longevity, see Tad Friend's review of Peter Diamandis and others, New Yorker, August 11.

####
AI CORNER
####

Google Notebook LM reads the four transcripts and summarizes for us.
(Direct AI output - do not quote without checking details)

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The four podcasts at HealthTech Remedy" highlight innovative health technology companies.

  • Enhanced aims to redefine human potential through a direct-to-consumer telehealth platform for performance optimization and the Enhanced Games, where athletes openly use enhancements.
  • Flatiron Health is transforming oncology clinical trials by leveraging EHR data and AI to design smarter protocols, accelerate patient recruitment, and streamline data collection, making trials faster and more representative.
  • AccessHope tackles cancer care inequity by remotely connecting local oncologists and patients with subspecialists from top cancer centers, offering expert reviews and support as an employee benefit.
  • Atropos Health provides physicians with rapid, patient-specific real-world evidence by analyzing de-identified EHR data in response to natural language clinical questions, addressing the lack of timely evidence in medical decisions.
###

Here is a detailed summary of each podcast transcript, tailored for health tech and health policy experts:

PODCAST ONE: DR D’SOUZA PERFORMANCE ENHANCEMENT

This episode delves into Enhanced, a company founded by CEO Dr. Aron D'Souza, which aims to revolutionize human performance through a dual-pronged approach: a revolutionary sporting event and a direct-to-consumer health platform. Dr. D'Souza, with a background in law and complex problem-solving, describes his current mission as ushering in an "enhanced age" where technology fundamentally augments the human experience across physical, mental, cultural, and civilizational domains, even framing aging as a treatable disease.

Key Business Models & Vision:

  • The Enhanced Games: An audacious alternative to the Olympics, set to launch in 2026, where athletes are openly permitted to use performance enhancements. The goal is to showcase the true limits of human capability. The concept gained viral attention, leading to significant venture capital interest. Early successes include Kristian Gkolomeev, who, at 31 years old and after just three weeks on the program, broke a 16-year-old world record, demonstrating the potential for enhanced athletes to surpass prime-age performance. The company believes sports serve as the "greatest proving ground" for validating human enhancements due to rapid, measurable results.
  • Direct-to-Consumer (DTC) Health Platform: This platform focuses on performance optimization and aims to democratize access to cutting-edge therapies for longevity, strength, and focus, moving beyond the exclusive realm of billionaires. The business model involves consumer-paid services, including a monthly prescription fee (around $399/month), diagnostics, and coaching subscriptions. Products include enhanced therapies for testosterone levels and longevity. Dr. D'Souza explicitly critiques the traditional sports business model (e.g., FIFA, Olympics) as inefficient, contrasting it with Red Bull's successful sports marketing approach to sell high-margin products. Enhanced aims to sell prescription medicines, supplements, and fast-moving consumer goods (FMCG) supporting human enhancement.

Ethical and Regulatory Landscape:

  • The discussion highlights the "fuzzy boundaries" of enhancement, using the real-world case of runner Caster Semenya, whose naturally elevated testosterone was deemed "too enhanced" for competition. Examples like LASIK surgery and GLP-1 drugs are cited as normalized enhancements that do not trigger societal alarms, unlike other forms of performance enhancement. Dr. D'Souza draws an analogy to cosmetic medicine, where non-therapeutic surgical enhancements (e.g., silicone implants) are accepted, but pharmacological enhancements for similar goals (e.g., anabolic steroids for muscle growth) are not, highlighting perceived inconsistencies.
  • The company acknowledges the controversial nature of the topic but emphasizes its scientific rigor. Enhanced has assembled a respectable medical advisory board, expanded its scientific panel to 38 members, hosted scientific conferences, and generated extensive research and academic interest. A survey by FIMS (the Olympic Doctors' Own Association) indicated that 74% of Olympic doctors are willing to treat enhanced athletes, and 30% are willing to prescribe performance enhancements if legal and ethical, suggesting a growing scientific acceptance.

Strategic Positioning & Future:

  • Enhanced is backed by prominent figures like Peter Thiel, Christian Angermeyer, and Balaji Srinivasan, known for controversial bets in biotech, crypto, and frontier technology.
  • The company views itself as a category-defining entity in human enhancements, aiming to create a paradigm shift in medicine by solving aging and building a lifestyle brand around the concept of "Human 2.0". Dr. D'Souza asserts that healthcare spending will increasingly be dedicated to making humans healthier and more capable, pointing to the willingness of middle-class Americans to pay for GLP-1 drugs as a market indicator.
  • For entrepreneurs, Dr. D'Souza advises solving complex coordination problems and prioritizing finding distribution before building a product. He stresses the importance of a "magnetic mission" (e.g., "build superhumanity") to attract top talent, emphasizing that talent density is paramount for achieving "miracles" and extraordinary things.

PODCAST TWO: DR DEYLE AND FLATIRON AND TRIALS

This episode focuses on Flatiron Health's groundbreaking efforts to address the inherent inefficiencies of clinical trials, led by Alex Deyle, VP & General Manager of Clinical Research. Flatiron Health, a pioneer in real-world evidence (RWE) and a Google Ventures success story acquired by Roche in 2018 for approximately $2 billion, has deep integrations with oncology-specific EHRs across 280 cancer centers in the U.S. and internationally.

The Problem & Flatiron's Foundation:

  • Clinical trials are universally recognized as slow, costly, and inefficient, creating a significant bottleneck in bringing life-saving cancer treatments to patients. Data within the traditional trial ecosystem is often siloed, unstructured, and requires burdensome manual transcription from EHRs to Electronic Data Capture (EDC) systems. This inefficiency is likened to "building buildings for a single clinical trial," where infrastructure is rebuilt for each new study without reusability.
  • Flatiron's strength lies in its established EHR network in community oncology and its decade-plus experience in processing high-quality structured and unstructured data from EHRs. The company's prior success in defining RWE methodologies and enabling regulatory-grade evidence from real-world data positions it uniquely to disrupt clinical research.

Flatiron's Three-Pronged Approach to Clinical Trial Transformation:

  1. Designing Smarter Protocols: Flatiron leverages its extensive RWE datasets to provide analytics that make protocols more operationally and scientifically feasible. This includes optimizing eligibility criteria, potentially expanding patient eligibility from less than 50% to up to 75% in oncology trials with minimal impact on endpoints. This also helps improve the representativeness of trial populations.
  2. Accelerating Patient Recruitment: Flatiron uses data, AI (including LLMs and machine learning models), and point-of-care software to identify the right sites and surface eligible patients to clinical staff in real-time. This approach can reduce site screening effort by 95%, significantly streamlining the patient identification process for narrow, precision medicine populations.
  3. Lowering Data Collection Burden (EHR to EDC): Through its Flatiron ClinicalPipe™ technology (enabled by a prior acquisition), Flatiron automates the direct transfer of data from EHRs to EDC systems. This automation reduces manual transcription errors, minimizes source data verification, and accelerates data collection with higher quality. Flatiron also builds workflows within the EHR to facilitate structured capture of trial-specific data not typically found in routine care (e.g., adverse events) for seamless transfer.

Compelling Results & Partnerships:

  • Flatiron's end-to-end model has demonstrated the ability to enroll studies 4 to 6 times faster and at 20-30% lower costs compared to traditional approaches, also accelerating time to database lock.
  • Exact Sciences Partnership: Flatiron facilitated a molecular residual disease (MRD) study that went from concept to first patient in just six months—a process that typically takes years. This was achieved by leveraging existing master clinical trial agreements and parent protocols across Flatiron's tech-enabled network.
  • NRG Oncology Collaboration: Flatiron is deploying ClinicalPipe™ with NRG, one of the NCI's cooperative groups, to measure the utility of EHR-to-EDC technology on a large oncology trial, proving its value in streamlining data acquisition for NCI-funded research.

Challenges & Strategic Outlook:

  • The biggest challenge identified is overcoming the "status quo" in clinical trials, where the significant investments involved often lead stakeholders to prioritize playing it safe over adopting innovative, though more efficient, models.
  • Flatiron aims to create a new model for Contract Research Organizations (CROs), deeply embedded within the EHR ecosystem. Alex Deyle's advice for health tech innovators is to "solve problems that matter" and to build multidisciplinary teams, as healthcare innovation requires diverse expertise and understanding of complex frameworks.

PODCAST THREE: DR ZAFAR ACCESSHOPE CONNECTING EXPERTS

This episode highlights AccessHope, a company co-founded by City of Hope in 2019, that is fundamentally rethinking cancer care delivery by bridging geographic and expertise gaps. Dr. Yousuf Zafar, Chief Medical Officer and a recognized expert in cancer care quality, innovation, and financial toxicity, explains AccessHope's mission to address the inequity in cancer care delivery that often leads to varied outcomes and higher costs based on where patients live.

Core Problem & Solution:

  • Cancer is presented as an infinitely complex and costly condition with treatment variations based on region, physician training, and the burden on local generalist oncologists to stay current across numerous disease sites. This creates a "fragmentation of expertise," where specialized subspecialist insights are not uniformly accessible.
  • AccessHope's solution is to democratize access to specialized oncology expertise from the nation's top cancer centers (e.g., City of Hope, Dana-Farber, Johns Hopkins). Crucially, this is achieved without requiring patients to travel or change their local providers. Instead, timely insights and second opinions are provided to community oncologists, empowering them to deliver cutting-edge, evidence-based care closer to home.

Business Model & Products:

  • AccessHope offers its services as an employee benefit to large employers and health plans, serving nearly 7 million members through over 400 employers (including 60+ Fortune 500 companies) and two of the largest U.S. health plans. The revenue model is primarily through contracts with these entities, appealing to employers who want to ensure their employees receive optimal cancer care. Customers seek transparency and alignment of care with evidence.
  • AccessHope offers two main products and a support service:
    1. Accountable Precision Oncology (APO): An automated, technology-based expert opinion service that runs in the background for employers. When an employee is diagnosed with cancer, AccessHope obtains, collates, and summarizes their medical records, sending them to an expert reviewer for remote analysis. The review is then sent to the treating oncologist. This "behind-the-scenes" approach overcomes the common barrier of low member engagement associated with opt-in services.
    2. Expert Advisory Review: This is a similar subspecialist review but requires active member request.
    3. Cancer Support Team: Offers oncology nurses to provide direct support, education, and psychosocial assistance to members navigating their cancer journey.

Impact & Strategic Growth:

  • AccessHope focuses on four key stakeholders: customers, foundational academic partners, treating oncologists (the end-users), and patients. The relationship with community oncologists is built on "deep respect," acknowledging their knowledge and workload, with AccessHope providing specialized insights to complement their practice.
  • The company aims to standardize treatment approaches, lead to more uniform care, and ultimately improve patient outcomes. A compelling patient case highlighted how AccessHope's remote review and direct engagement with a community oncologist realigned care for an advanced kidney cancer patient, even identifying a nearby clinical trial option, underscoring the company's multi-level impact.
  • The COVID-19 pandemic significantly impacted AccessHope's growth, with a "huge peak" in case volume in early/mid-2020, as the value of remote expert opinions became evident.
  • A major area of future growth is clinical trials, with AccessHope actively exploring capabilities to match patients to trials, navigate the enrollment process, educate patients, and provide just-in-time information on trial slot availability. This also includes helping community oncologists determine when travel to a trial site is most beneficial for a patient.
  • Dr. Zafar's advice for clinicians moving into health tech emphasizes: first, identify the problem to solve (don't confuse technology with the solution); second, align incentives with stakeholders; and third, leverage clinical experience as a "superpower", spending time to understand the nuances of practice and patient challenges.

PODCAST FOUR: DR BRIGHAM HYDE, ATROPOS, and REAL WORLD EVIDENCE

This episode explores Atropos Health, a company co-founded and led by Dr. Brigham Hyde, dedicated to making real-world evidence (RWE) accessible to physicians at the point of care. Atropos addresses a critical gap in medicine where approximately 90% of clinical decisions lack high-level evidence, leading to variable and potentially suboptimal care.

Origin, Innovation, and Problem-Solving:

  • Atropos Health, founded in 2020, originated from Stanford University's "Green Button" initiative. The Green Button was an early system that allowed physicians to submit clinical questions and receive rapid, tailored analyses of de-identified EHR data within days (now often minutes). This rapid turnaround was a significant challenge for RWE studies, which traditionally take months or years. Dr. Hyde described his initial reaction as "black magic" due to the speed and methodological quality achieved.
  • The company's core innovation stems from the necessity to be "99% faster" to address real-time clinical dilemmas. This pressure led to developing their own Temporal Query Language (TQL), designed to overcome the limitations of traditional SQL in calculating time-based relationships crucial for observational research. Post-LLM, Atropos introduced ChatterWD, an LLM interface that allows users to chat in natural language to formulate queries and run studies in minutes on millions of patients.

Key Solutions and Business Model:

  • Natural Language Querying: Clinicians can ask plain language questions, enabling broad usability without requiring RWE expertise.
  • Rapid, Rigorous Analysis: Atropos delivers insights quickly, often within minutes, using "academic grade methods" including triplicate statistical analyses (unmatched, basic match, high-dimensional propensity score match) to remove confounders inherent in real-world data.
  • Geneva OS: This "full operating system for real-world evidence generation" provides a next-generation infrastructure for leveraging RWE quickly and efficiently across diverse data sources.
  • Atropos Evidence Network: This network leverages federated data across multiple health systems while ensuring patient privacy. Data remains behind the health system's firewall, with Atropos's compute layer accessing de-identified data (or identified under BIA when necessary). Health systems can passively monetize their data through aggregate analysis without relinquishing control. A "real-world fitness score" helps users determine which dataset is most appropriate for a given query, optimizing data utility.
  • The revenue model is primarily subscription-based (user-based SaaS) for health systems, evidence generation projects with life sciences companies, and potential government/payer partnerships.

Use Cases and Impact:

  • Clinical Practice: Atropos is highly utilized in academic medical centers, especially for cases where literature or guidelines are insufficient, stakes are high, or treatments are expensive. This includes specialties like hemonc, orthopedics, anesthesia, and significantly, geriatrics and pediatrics, where clinical trial data is often lacking. An example highlighted a rapid analysis for a diabetic patient with liver disease, comparing GLP-1s and metformin, demonstrating that GLP-1s were still more effective for BMI reduction despite trial exclusions.
  • Life Sciences: Atropos empowers pharma teams to accelerate research, from trial design and understanding patient populations to health economics and outcomes research (HEOR) studies. For a pilot at J&J, Atropos enabled a team to perform 150 studies in six months (5x their typical volume), saving consultant costs.
  • Policy & Regulatory Influence: Atropos's analyses support changes in institutional policies (e.g., formulary, guidelines). There is increasing acceptance of RWE by regulatory bodies like the FDA and CMS, with examples like palbociclib's label expansion for men with breast cancer based on RWE, indicating a positive trend for data-driven personalized medicine.

Challenges and Outlook:

  • Key barriers include building trustworthiness and robust privacy infrastructure for data access, ensuring accurate data curation from massive datasets, and overcoming clinician resistance to change.
  • Dr. Hyde expressed excitement about deeper integrations, such as ambient workflow integration where real-time, personalized evidence "pops right up" for physicians during visits. He emphasizes the company's role in unlocking demand for RWE by enabling quick answers, benefiting the entire RWE ecosystem.
  • Dr. Hyde's career advice stresses curiosity and relentlessness for entrepreneurs, focusing on solving meaningful problems, prioritizing user experience in health tech, and strategically aligning with broader technological advancements (e.g., leveraging improving LLM models rather than building foundational ones).
  • [End AI from Google Notebook LM]

Wednesday, August 6, 2025

FOCR Study Links ctDNA Clearance with Overall Survival in Lung Cancer TKI Therapy

 There have been many studies of ctDNA clearance (or relapse) with cancer immunotherapy.  Here is a 940-patient meta-study in TKI treated NSCLC, part of the Friends of Cancer Research (FOCR) portfoilio.

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Andrews et al. publish a 940-patient meta-analysis of TKI-treated lung cancer (total of 8 studies).  Clearance of ctDNA is correlated with overall survival, with a hazard ratio of 2.12 (p<.0001).

  • See post at Linked In here.
  • See longer summary at FOCR here.
  • See Andrews et al. 2025 here - open access.
  • See more about the FOCR ctDNA portfolio - here.

###

See the abstract and "translational relevance," from the article.  Below these sections directly from the authors, I also provide an AI summary and ten AI "key takeaways" for policy experts, clinicians, and invstors.

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ctDNA Clearance as an Early Indicator of Improved Clinical Outcomes in Advanced NSCLC Treated with TKI: Findings from an Aggregate Analysis of Eight Clinical Trials - Andrews et al, 2025, Clinical Cancer Research.

Authors: 

Purpose:

Circulating tumor DNA (ctDNA) holds promise as an early endpoint to predict overall survival (OS). The creation and structured interrogation of aggregated datasets inform the hypothesis that ctDNA is reasonably likely to predict treatment benefit. Friends of Cancer Research convened a diverse working group to establish and implement an analysis plan assessing patient-level associations between changes in ctDNA levels with OS and progression-free survival (PFS).

Experimental Design:

The aggregate dataset included eight clinical trials representing 940 patients with biomarker-positive advanced non–small cell lung cancer treated with tyrosine kinase inhibitors. Detection of baseline and on-treatment ctDNA was assessed for associations with OS and PFS. Additionally, combinations of ctDNA detection and RECIST measurements up to 10 weeks on treatment were considered.

Results:

Patients with detected ctDNA at baseline that became nondetected on treatment (“clearance”) experienced improved OS compared with patients with persistently detected ctDNA (adjusted HR = 2.12, P < 0.001). 

This pattern was also seen in the subset of patients with stable disease as measured by RECIST within 10 weeks of treatment initiation (adjusted HR = 4.15, P < 0.001). Results were similar for PFS.

Conclusions:

In patients with oncogene-driven advanced non–small cell lung cancer treated with tyrosine kinase inhibitors, ctDNA clearance within 10 weeks of treatment initiation was associated with improved OS and PFS. These patient-level results support the growing evidence that demonstrates a change in ctDNA levels during treatment is associated with clinical benefit. Future prospective trials should include predefined thresholds of molecular response to advance the utility of ctDNA as an early endpoint.

Authors:

Translational Relevance

ctDNA holds promise as an early endpoint in solid tumor oncology trials; however, patient- and trial-level meta-analyses demonstrating associations between changes in ctDNA and long-term outcomes, such as overall survival and progression-free survival, are necessary before ctDNA can be used in regulatory decision-making. A patient-level aggregate analysis of eight previously completed clinical trials of patients with advanced non–small cell lung cancer treated with tyrosine kinase inhibitors showed that clearance of ctDNA was associated with improved overall survival and progression-free survival compared with those who had persistently detected ctDNA. Additional work is necessary to establish ctDNA as an early endpoint, but this study supports the growing body of evidence that decreased ctDNA levels are associated with improved outcomes.

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Summary and Commentary

This multi-trial patient-level analysis—led by the Friends of Cancer Research ctMoniTR collaboration—marks a significant step in validating circulating tumor DNA (ctDNA) clearance as a promising early surrogate endpoint for overall survival (OS) and progression-free survival (PFS) in patients with advanced non–small cell lung cancer (aNSCLC) receiving tyrosine kinase inhibitors (TKIs).

Drawing on de-identified data from eight clinical trials involving 940 patients with oncogene-driven aNSCLC (e.g., EGFR, ALK, RET, MET alterations), the study demonstrated that ctDNA clearance within 10 weeks of treatment initiation was strongly associated with improved OS and PFS, even after adjusting for confounding clinical variables.

Key Novel Contributions

  1. Cross-Trial Patient-Level Evidence:
    Unlike prior single-trial reports, this is among the first studies to aggregate and harmonize patient-level data from multiple pharma-sponsored trials across different assay platforms (NGS and ddPCR), enhancing the generalizability of the findings.

  2. Stratified Prognosis by ctDNA Status:

    • Patients with persistently detected ctDNA had the worst outcomes (OS HR = 6.25 vs. ctDNA never detected).

    • Patients with ctDNA clearance (D to ND) showed significantly better survival than those with persistent ctDNA (OS HR = 2.12, P < 0.001).

    • Patients with undetectable ctDNA at both timepoints had the best prognosis—a reminder that pretreatment ctDNA status is also prognostic.

  3. ctDNA Surpasses Early RECIST:
    While early RECIST-based radiographic response was not strongly associated with long-term outcomes, ctDNA clearance added predictive value even among patients with stable disease (SD) by imaging. Notably, among SD patients, persistent ctDNA detection conferred a 4.15-fold higher risk of death compared to those with ctDNA clearance.

  4. Implications for Trial Design and Drug Development:
    The study supports incorporating early molecular response metrics—specifically ctDNA clearance—as supplementary endpoints in clinical trials. This may be especially impactful in settings with ambiguous imaging findings (e.g., SD or non-measurable disease) and for informing early go/no-go decisions.

Limitations and Future Direction

The analysis is retrospective and exploratory, and while it adjusts for multiple variables, it is not designed to establish causality. Assay heterogeneity and variable sampling schedules across trials add complexity, underscoring the need for:

  • Standardized ctDNA assays and response thresholds

  • Prospective validation of ctDNA-based surrogate endpoints

  • Regulatory consensus on how ctDNA can support accelerated approval frameworks


Conclusion

This rigorous, multi-trial patient-level analysis adds momentum to the use of ctDNA clearance as a molecular response biomarker in NSCLC. By showing a robust association with survival outcomes, independent of radiographic response, the study contributes critical evidence toward positioning ctDNA as a regulatory-grade early endpoint—potentially transforming the pace and precision of oncology drug development.

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SIDEBAR - TEN POINTS

Here is a sidebar-style list of ten key takeaways from the study, categorized by audience—policy/coverage, clinical oncology, investors, and general science insights.


📌 Sidebar: 10 Key Takeaways from the FOCR ctDNA Clearance Study

🏛️ For Policy & Coverage Stakeholders

  1. Regulatory Readiness: This large, multi-trial analysis supports ctDNA clearance as a reasonably likely surrogate for survival outcomes—aligning with FDA guidance for accelerated approval in solid tumors.

  2. Coverage Implications: If ctDNA clearance becomes a validated early endpoint, payors may face increasing pressure to cover serial liquid biopsy testing—not just for mutation detection, but for on-treatment response monitoring.

🩺 For Clinical Oncologists

  1. ctDNA vs. Imaging: ctDNA clearance at 10 weeks outperformed early RECIST response in predicting OS and PFS, especially in patients with stable disease—suggesting it could refine treatment decisions.

  2. Prognostic Stratification: Even among partial responders or SD patients by imaging, ctDNA status stratified prognosis, offering an early molecular readout of benefit vs. futility.

💼 For Investors in Oncology Diagnostics & Therapeutics

  1. Market Opportunity: The study creates a compelling clinical use case for repeat liquid biopsy platforms, particularly in TKI-treated NSCLC—an early and growing segment of precision oncology.

  2. Differentiation Signal: Diagnostics firms with sensitive and reproducible ctDNA quantification capabilities (NGS or ddPCR) may benefit from emerging demand for treatment-response monitoring tools.

🔬 General Scientific Highlights

  1. Broad Applicability: The analysis includes patients treated with EGFR-, ALK-, MET-, and RET-targeted TKIs, suggesting platform-agnostic utility across oncogene-driven NSCLC.

  2. ctDNA Clearance = Survival Signal: Among patients with detectable ctDNA at baseline, clearance within 10 weeks led to a 2-fold improvement in OS vs. persistent detection (HR 2.12, P < 0.001).

  3. Independence from RECIST: ctDNA clearance and RECIST response had low redundancy—the former added predictive value even when imaging was ambiguous.

  4. Step Toward Standardization: This study pushes the field toward harmonizing ctDNA assays and response definitions, a necessary precursor to regulatory validation and routine clinical use.