Friday, October 4, 2024

AHRQ: Bonanza of Information Related to Sepsis

Header: AHRQ has released a Report to Congress on Sepsis, as well as supporting a bundle of new hospital policy articles on the topic.

About the last time I mentioned AHRQ, the House had proposed to de-fund it in July 2024.

Flurry of news from AHRQ about Sepsis, including a 95-page new Congressional report.

See the AHRQ capsule news page here.
See the full press release and links here.
See the 95 page report here.

See 166 page appendix here.

See the AHRQ home page for Sepsis, here.
See AHRQ highlight three new hospital policy articles:

Sankaran (2024) Identifying sources of inter hospital variation in episode spending for hospital care. Med Care 62:441.
Barbash (2024) Association between SEP-1 and documentation of sepsis in the clinical record. Med Care 62:388.
Ellenbogen (2024) Developent of a hospital coding intensity measure for sepsis. J Hosp Med 19:505.
These three articles don't appear to be open access.

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AI Corner

In its 95-page Report to Congress on the burden of sepsis in the United States, the Agency for Healthcare Research and Quality (AHRQ) offers a comprehensive analysis of hospital care related to sepsis, underscoring the significant and growing impact of the condition on the healthcare system.

The report responds to a congressional directive included in the Fiscal Year 2023 Omnibus Spending Bill, which mandated AHRQ to study morbidity, readmission, and mortality rates associated with sepsis, along with the effects of the COVID-19 pandemic on the burden of sepsis.

Key findings of the report show that sepsis-related hospitalizations increased sharply from 1.8 million in 2016 to 2.5 million in 2021, a trend accelerated by the COVID-19 pandemic. Sepsis is one of the most expensive conditions treated in U.S. hospitals, with aggregate hospital costs rising from $31.2 billion to $52.1 billion over the same period. The report provides an in-depth look at hospital utilization, mortality, and the financial strain caused by sepsis, with a focus on disparities in outcomes based on race, ethnicity, sex, geographic location, and social vulnerability.

The report also highlights key patient populations affected by sepsis, including non-maternal adults, maternal patients, and pediatric populations, and examines state-level and hospital-level variations in care. The majority of sepsis-related hospitalizations begin in the emergency department, where timely recognition and intervention are critical. The report underscores the importance of early recognition and the use of standardized sepsis care bundles, such as those promoted by the Surviving Sepsis Campaign, which have been shown to improve outcomes but remain underutilized.

AHRQ's findings emphasize the need for continued investments in surveillance and quality improvement programs to ensure better sepsis care and reduce the burden on hospitals. Disparities and geographic variations present opportunities for targeted interventions aimed at improving patient outcomes and addressing financial strains on the healthcare system.

AHRQ also highlights three new health policy articles that explore critical issues surrounding hospital management of sepsis and associated costs. These studies delve into hospital coding intensity, the impact of Medicare's sepsis reporting policy, and the variation in hospital spending on sepsis care.

"Development of a Hospital Coding Intensity Measure Based on Sepsis Diagnoses" by Michael Ellenbogen et al. explores how variations in hospital coding practices affect sepsis diagnoses. The authors developed a novel measure to compare hospital coding intensity using sepsis-related diagnoses among patients hospitalized for common infections. This measure aims to correct reimbursement inequities and improve the accuracy of risk adjustment for quality metrics, offering a more targeted approach to coding intensity evaluation across hospitals.
"Association Between Medicare's Sepsis Reporting Policy (SEP-1) and the Documentation of a Sepsis Diagnosis in the Clinical Record" by Ian Barbash et al. evaluates the effect of Medicare’s SEP-1 reporting policy on sepsis documentation in clinical records. The study found that implementation of SEP-1 modestly increased sepsis diagnosis rates, particularly among patients who did not require vasopressors. Despite the incremental increase, the study calls attention to the policy’s potential influence on documentation practices and raises questions about its clinical impact.
"Identifying Sources of Inter-Hospital Variation in Episode Spending for Sepsis Care" by Roshun Sankaran et al. investigates the factors contributing to significant variation in 90-day episode spending for sepsis care across hospitals. The study found that post-acute care spending was the primary driver of these variations, with the most expensive hospitals spending nearly double on post-acute care compared to the least expensive hospitals. The analysis points to the need for targeted policies to address these cost discrepancies, particularly in the realm of post-acute care.

These articles provide important insights for policymakers looking to improve hospital efficiency, coding accuracy, and spending management in sepsis care.

Thursday, October 3, 2024

CMS Posts Transcript of Sept. 23 TCET Webinar.

CMS held a webinar on September 23, 2024, to explain operations of the "TCET" NCD CED program which was announced on August 6, 2024.

TCET NCD CED - Transitional Coverage for Emerging Technologies; applicable only to FDA Breakthrough Devices; for National Coverage Decisions on an accelerated 6-month basis, deploying "Coverage with Evidence Development."

CMS has now released a 14 page transcript. The transcript includes a link to the archive video. There was several slides in the video that were novel to me, but CMS didn't release a separate PDF presentation deck.

Below, I provide an AI "News Story" and a full AI summary of the Q&A.

Republican health policy expert Joe Grogan listed some downsides of the TCET policy in a new article at The Hill,

https://thehill.com/opinion/healthcare/4889436-biden-harris-medical-innovation/

Grogan writes,

[Past the FDA,] innovators must still confront an uncooperative CMS, which keeps finding excuses to deny coverage at every turn.

One strategy used by the agency is “Coverage with Evidence Development,” which requires additional clinical trials on top of those conducted for the FDA.

These requirements can span decades. Of the 27 devices or procedures subjected to this procedure since 2005, only four were not still undergoing it as of April 2022. The evidence development system has been corrupted.

Originally designed to accelerate innovation, it now poses a huge obstacle. A moratorium on new Coverage with Evidence Development programs is needed until it can be fixed or scrapped.

(Not Shown: When Grogan's view was shared with Google Notebook, it said that CMS was at least trying to rebut his concerns, and provided a hotlink to paragraphs in the transcript with regard to each Grogan point.])

AI CORNER

Chat GPT writes up the transcript. Plus the Q&A.

CMS Hosts Webinar on TCET Pathway, Highlighting Changes in Coverage for Breakthrough Devices

The Centers for Medicare & Medicaid Services (CMS) held a public webinar on September 23, 2024, to educate stakeholders on its newly established Transitional Coverage for Emerging Technologies (TCET) pathway. This pathway is designed to accelerate Medicare coverage decisions for FDA-designated Breakthrough Devices. The event featured presentations by Dr. Dora Hughes, CMS Chief Medical Officer, and Dr. Steve Farmer, Chief Strategy Officer in the Coverage and Analysis Group, who elaborated on the TCET pathway’s significance and functionality.

The TCET pathway is aimed at facilitating faster Medicare access to medical innovations while ensuring safety and effectiveness for Medicare beneficiaries. It supports manufacturers by providing a predictable and transparent review process that coordinates both coverage and evidence development. This is achieved through CMS’s use of the National Coverage Determination (NCD) and Coverage with Evidence Development (CED) frameworks, allowing for the incorporation of fit-for-purpose studies into the approval process. As Dr. Hughes noted, “CMS is committed to fostering innovation while ensuring that people with Medicare have faster access to technologies that will improve their health outcomes.”

Dr. Farmer provided further insights into the operation of the TCET pathway, which builds on existing CMS authorities and emphasizes early engagement with manufacturers. The pathway is structured in different stages: premarket, near-market, and postmarket. In the premarket stage, manufacturers can engage with CMS to clarify coverage expectations, ensuring alignment with FDA requirements. A key feature of the pathway is the Evidence Preview, which assesses the available evidence on a device’s safety and effectiveness. Manufacturers can collaborate with CMS and the Agency for Healthcare Research and Quality (AHRQ) to identify and address any evidence gaps before market authorization.

One notable aspect of the TCET pathway is its capacity for flexibility in evidence generation. Manufacturers can conduct fit-for-purpose studies to provide data suited to the specific needs of the Medicare population, which typically differs from the populations included in FDA trials. “Fit-for-purpose studies, including those using real-world data, provide complementary perspectives that enhance the evidence base for coverage decisions,” explained Dr. Farmer.

The webinar also covered specific criteria for devices eligible for the TCET pathway. These include FDA Breakthrough designation, alignment with a Medicare benefit category, and the absence of an existing NCD for the device. A key advantage of the pathway is the ability to expedite the NCD process, with CMS aiming to finalize NCDs within six months of FDA market authorization.

Attendees raised several questions about the logistics of the new pathway. A significant portion of the discussion focused on how devices that are nearing FDA approval would be prioritized. Lori Ashby, a member of the CMS team, clarified that while devices close to receiving FDA market authorization might not qualify for TCET due to the expedited nature of the pathway, they can still pursue coverage through other established processes, such as Local Coverage Determinations (LCDs) by Medicare Administrative Contractors.

CMS plans to expand the transparency and efficiency of the TCET pathway with future guidance documents. These will include detailed protocols for fit-for-purpose studies and real-world data use, as well as prioritization factors for determining which devices enter the pathway. Manufacturers interested in the pathway are encouraged to submit a voluntary letter of intent up to 24 months before FDA market authorization to allow CMS to track potential candidates.

This webinar marks a significant step in CMS’s efforts to modernize the Medicare coverage process and better integrate new medical technologies into the healthcare system. As Dr. Farmer concluded, “The TCET pathway represents a balanced approach that promotes early beneficiary access to breakthrough technologies while maintaining rigorous evidence standards.”

For more information on the TCET pathway and upcoming guidance documents, visit the CMS website or review the full transcript from the September 23 webinar.

Question 1: When does the one-year clock start for nominations? Is it August 12th since that is the date the policy was effective? Or after the first quarter review? And then what happens if there are delays in FDA market authorization?

Answer: Lori Ashby explained that the one-year clock starts approximately 12 months before anticipated FDA market authorization, not tied to the August 12th policy effective date or the quarterly review. Delays in FDA authorization don’t affect acceptance into the pathway, but CMS aims to complete TCET steps within that 12-month window.

Question 2: Is there a lookback period for Breakthrough Devices nearing FDA market authorization or those recently achieving it?

Answer: There is no lookback period. Devices already in the market or nearing FDA market authorization (less than 12 months) are not eligible for TCET and are better suited for other pathways like Local Coverage Determinations (LCDs) or claim-by-claim adjudication.

Question 3: How do software as a medical device and other digital health innovations fit into the TCET pathway?

Answer: CMS clarified that such technologies could be eligible if they meet the criteria outlined in the TCET notice. However, these technologies must fit within a Medicare benefit category under Part A or Part B. CMS is actively exploring this area in policy development, with ongoing interest from Congress.

Question 4: Why are diagnostic lab tests excluded from the TCET pathway?

Answer: CMS recognizes that diagnostic lab tests are regulated as medical devices and eligible for FDA Breakthrough designation. However, diagnostic tests are considered a highly specific area of coverage, typically reviewed by Medicare Administrative Contractors (MACs). NCDs for diagnostic tests are rare, but possible if manufacturers believe additional evidence is needed for Medicare coverage.

Question 5: How will CMS prioritize TCET nominations? Will they consider the impact on Medicare beneficiaries, particularly those with high-cost or less common diseases? Will health equity be a factor?

Answer: Lori Ashby stated that until further guidance is released, CMS will prioritize based on a 2013 Federal Register notice, which considers the magnitude of impact on the Medicare program. CMS will also consider health equity, giving priority to devices that address health disparities.

Question 6: How will CMS prioritize nominations if devices are moved from one quarterly review cycle to the next?

Answer: CMS will automatically reconsider devices not selected in the first review cycle in the next cycle. However, devices within six months of FDA market authorization may not be accepted into TCET due to the short timeframe for CMS to complete the NCD.

Question 7: What level of detail will CMS provide to manufacturers whose nominations are declined for reasons other than the cap being met?

Answer: CMS will provide a justification for declined nominations, including reasons such as the absence of an FDA Breakthrough designation or an existing NCD covering the device.

Question 8: Will CMS notify manufacturers if their device is no longer automatically considered in the next review cycle due to proximity to FDA approval?

Answer: CMS is developing a web-based system to automatically notify manufacturers of their nomination status, including acceptance, reconsideration in future cycles, or withdrawal from the TCET pathway.

Question 9: How will CMS make public the number of TCET applications, device types, and classes accepted into the program after each nomination cycle?

Answer: While the nominations themselves are confidential, CMS will update the NCD dashboard with the number of devices in the pathway, the date of nomination, acceptance, and the initiation of the NCD process. This dashboard will be updated quarterly.

Question 10: How does CMS use TCET nomination material to inform the Evidence Preview? Will the manufacturer’s list of studies be the basis for the Evidence Preview?

Answer: Steve Farmer explained that the Evidence Preview is informed by a systematic literature review conducted by a contractor, which is cross-referenced with the manufacturer's bibliography. Manufacturers can propose technical edits, and the review ensures the evidence is comprehensive.

Question 11: What is the purpose of voluntary letters of intent (LOI) 18 to 24 months before FDA market authorization? How does it benefit manufacturers?

Answer: Lori Ashby clarified that the LOI allows CMS to better predict potential TCET nominations and optimize the review process. While nonbinding, it improves coordination between CMS and the FDA and helps prevent delays in reviews.

Question 12: Is CMS planning any best practice training on how to submit a nomination?

Answer: Yes, CMS plans to conduct workshops to help manufacturers considering LOIs and nominations, with details to be provided soon.

Question 13: How will CMS and FDA coordinate the TCET process, given the reliance on FDA timelines for market authorization?

Answer: CMS regularly engages with FDA and AHRQ, as well as with manufacturers, to help coordinate the process. CMS plans to initiate the TCET process approximately one year before FDA authorization, incorporating trial results and addressing evidence gaps.

Question 14: How will CMS address coding and payment for devices accepted into TCET?

Answer: CMS encourages manufacturers to proactively pursue codes during the TCET process to avoid delays. CMS has also established a Pharmaceutical and Technology Ombudsman to assist with coverage, coding, and payment decisions.

Question 15: How soon before FDA approval can the Evidence Preview and Evidence Development Plan be initiated for follow-on devices?

Answer: Follow-on devices can engage CMS about 12 months before FDA market authorization to initiate an Evidence Preview and develop an Evidence Development Plan. This helps avoid delays in NCD establishment postmarket.

Question 16: Is there noncoverage for follow-on devices until CMS approves a CED study? How can this be minimized?

Answer: Yes, follow-on devices are noncovered until a CMS-approved CED study is in place. To minimize delays, manufacturers should initiate the Evidence Preview as early as possible, ideally 12 months before FDA approval.

Question 17: How will CMS prioritize the Evidence Preview and EDP for follow-on devices?

Answer: CMS believes it has sufficient resources to conduct timely reviews for both first-to-market and follow-on devices.

Question 18: Has the use of a contractor for technical analyses reduced the processing time for NCDs? How will CMS handle the TCET workload?

Answer: CMS has streamlined processes through contractor support, allowing for specialized clinical expertise and greater efficiency. This will help accommodate the additional workload from TCET without affecting other NCDs.

Question 19: What is the anticipated timing of future CMS guidance on fit-for-purpose (FFP) studies, real-world data protocols, and prioritization guidance?

Answer: CMS expects to release guidance on fit-for-purpose studies and real-world data protocols soon. Prioritization guidance will follow after several quarterly review cycles.

Question 20: How will CMS prioritize coverage for devices within six months of FDA market authorization if they are not accepted into TCET?

Answer: Devices nearing market authorization can pursue conventional NCDs if they are not accepted into TCET. CMS will prioritize NCD requests based on their potential impact on the Medicare program and beneficiaries.

Question 21: Will Medicare Advantage plans have to cover devices under TCET?

Answer: Yes, Medicare Advantage plans must cover devices under TCET NCDs just as they do with conventional NCDs.

The news article about was written by Chat GPT4, from the transcript.

Google Notebook LM has some auto-create buttons, such as for Study Guide and Briefing. Here's how Google Notebook LM summarized the same transcript about TCET.

Timeline of Events (Google Notebook LM auto function)

2015:

Ongoing: The FDA Breakthrough Devices Program has granted over 930 Breakthrough Designations.

2022:

November: The Agency for Healthcare Research and Quality (AHRQ) publishes a report on Coverage with Evidence Development (CED).

2023:

February: The Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) holds a meeting to discuss AHRQ's CED report.

2024:

August 6: CMS issues a final procedural notice outlining the Transitional Coverage for Emerging Technologies (TCET) pathway for certain FDA-designated Breakthrough Devices.
September 23: CMS hosts a webinar to provide an overview of the TCET pathway and answer stakeholder questions.
October 31: Deadline for manufacturers to submit nominations for the first quarterly TCET review cycle.

2025:

January 31: Deadline for the second quarterly TCET review cycle.
April 30: Deadline for the third quarterly TCET review cycle.
July 31: Deadline for the fourth quarterly TCET review cycle.
Ongoing: CMS plans to publish additional guidance documents on fit-for-purpose studies, real-world data protocols, and TCET prioritization factors.

Cast of Characters

Centers for Medicare & Medicaid Services (CMS)

Dr. Dora Hughes: CMS Chief Medical Officer and Director for the Center for Clinical Standards and Quality. Provides opening remarks at the TCET webinar, emphasizing CMS's commitment to innovation and timely patient access.
Dr. Steve Farmer: Chief Strategy Officer in the Coverage and Analysis Group. Presents a detailed overview of the TCET pathway at the webinar.
Lori Ashby: CMS representative who answers stakeholder questions during the TCET webinar.

Other Organizations

Food and Drug Administration (FDA): Responsible for granting Breakthrough Device designations and overseeing the premarket review process for medical devices. Works closely with CMS on the TCET pathway.
Agency for Healthcare Research and Quality (AHRQ): Collaborates with CMS on the CED pathway and provides feedback on Evidence Previews and Evidence Development Plans.
Medicare Administrative Contractors (MACs): Process Medicare claims and make local coverage determinations. May continue to review diagnostic lab tests, even if they receive Breakthrough Device designation.
Medicare Evidence Development and Coverage Advisory Committee (MEDCAC): Provides CMS with independent advice on coverage issues. Reviewed AHRQ's CED report in February 2023.

Key Terms

Breakthrough Devices: Medical devices that demonstrate the potential to offer a more effective treatment for a life-threatening or irreversibly debilitating disease or condition, for which no approved or cleared alternatives exist.
Transitional Coverage for Emerging Technologies (TCET): A Medicare coverage pathway that provides expedited coverage for certain FDA-designated Breakthrough Devices.
National Coverage Determination (NCD): A national Medicare policy that determines whether a particular item or service is covered by Medicare.
Coverage with Evidence Development (CED): A Medicare coverage pathway that allows for coverage of promising new technologies while requiring manufacturers to conduct additional clinical studies to demonstrate long-term safety and effectiveness.
Evidence Preview: A focused literature review that provides early feedback on the strengths and weaknesses of the available evidence for a particular technology.
Evidence Development Plan (EDP): A plan developed by the manufacturer to address any evidence gaps identified in the Evidence Preview. May include traditional clinical studies and/or fit-for-purpose studies using real-world data.
Fit-for-purpose study: A study where the design, analysis plan, and data sources are appropriate to address the specific research question at hand.
Real-world data: Data collected from sources outside of traditional clinical trials, such as electronic health records, claims databases, and patient registries.

This timeline and cast of characters should provide a good starting point for understanding the key events and players involved in the TCET pathway.

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Briefing Doc: CMS Transitional Coverage for Emerging Technologies (TCET) Pathway

Date: October 26, 2024

Subject: Overview of the TCET Pathway and Key Takeaways from the September 23rd Webinar

Background:

The Centers for Medicare & Medicaid Services (CMS) has finalized the Transitional Coverage for

Emerging Technologies (TCET) pathway to accelerate Medicare coverage for innovative medical devices designated as "Breakthrough Devices" by the FDA. This briefing document summarizes the key themes and important details of the TCET pathway based on two CMS sources:

CMS Fact Sheet (August 6, 2024): Provides an overview of the TCET pathway, its goals, eligibility criteria, and the process for manufacturers.
CMS Webinar Transcript (September 23, 2024): Offers deeper insights into the TCET pathway, addressing specific questions from stakeholders.

Main Themes:

Accelerated Coverage: The TCET pathway aims to reduce the time lag between FDA market authorization and Medicare coverage for Breakthrough Devices, improving patient access to cutting-edge treatments.
Predictability and Transparency: The pathway provides manufacturers with a clear and predictable process, outlining evidence requirements and timelines for coverage decisions.
Collaboration and Engagement: CMS emphasizes collaboration with FDA, AHRQ, manufacturers, and other stakeholders throughout the process.
Evidence Development: TCET encourages the generation of real-world evidence through fit-for-purpose studies to support coverage decisions.

Key Ideas and Facts:

1. TCET Pathway Overview:

Target: Certain FDA-designated Breakthrough Devices that fall within a Medicare benefit category.
Goal: To finalize a National Coverage Determination (NCD) within six months of FDA market authorization.
Process:Pre-Market: Manufacturers submit a nomination, CMS conducts an Evidence Preview and, if necessary, develops an Evidence Development Plan (EDP) with the manufacturer.
Post-Market: CMS finalizes an NCD, which may include Coverage with Evidence Development (CED) requirements.
Post-TCET: CMS will reconsider the NCD based on the EDP timeline and evidence generated.

2. Device Eligibility:

FDA-designated Breakthrough Devices.
Within a Medicare benefit category.
Not already subject to an existing NCD.
Not excluded from coverage by law or regulation.

3. Nominations and Prioritization:

Manufacturers self-nominate approximately 12 months before anticipated FDA market authorization.
CMS accepts nominations quarterly and prioritizes them based on potential impact on the Medicare program and beneficiaries.
A non-binding letter of intent can be submitted 18-24 months before anticipated FDA market authorization.

4. Evidence Development:

Evidence Preview: A collaborative review of existing evidence, conducted by CMS, AHRQ, and the manufacturer.
Evidence Development Plan (EDP): If evidence gaps exist, an EDP is developed to outline fit-for-purpose studies.
Fit-for-Purpose Studies: Studies designed to address specific evidence needs using appropriate designs and data sources, including real-world data.

5. Coverage Duration and Transition:

Transitional Coverage: Tied to the completion of the EDP, typically lasting five or more years.
Post-TCET Coverage: CMS will reconsider the NCD and make a final coverage determination based on the generated evidence.

6. Key Takeaways from the September 23rd Webinar:

Lookback Period: Devices already on the market are not eligible for TCET.
Software as a Medical Device: Eligibility depends on meeting the TCET criteria and falling within a Medicare benefit category, which is still under development for SaMD.
Diagnostic Lab Tests: Generally excluded from TCET, but manufacturers can contact CMS for individual consideration.
Prioritization: CMS considers beneficiary impact, health equity, and available resources when prioritizing nominations.
Letters of Intent: Help CMS predict demand and can potentially alleviate delays in the review process.
Coordination with FDA: CMS emphasizes regular communication and collaboration with the FDA.
Coding and Payment: CMS encourages proactive pursuit of codes and offers resources to assist manufacturers.

Quotes:

"CMS is committed to fostering innovation while making sure that people with Medicare have faster access to technologies that will improve their health outcomes." - Dr. Dora Hughes, CMS Chief Medical Officer.
"TCET aims to reduce uncertainty about coverage options through a premarket evaluation of potential harms and benefits of technologies while identifying any important evidence gaps." - Dr. Dora Hughes, CMS Chief Medical Officer.
"We believe that manufacturers will be better positioned for multiple product development stages if they anticipate both FDA and CMS requirements when developing clinical studies." - Dr. Dora Hughes, CMS Chief Medical Officer.

Next Steps:

Review the full CMS Fact Sheet and Webinar Transcript.
Submit a letter of intent if you have a device that may be eligible for TCET.
Review upcoming CMS guidance documents on fit-for-purpose studies, real-world data protocols, and prioritization factors.

Conclusion:

The TCET pathway represents a significant shift in Medicare's approach to covering emerging medical technologies. By emphasizing early engagement, collaboration, and evidence development, CMS aims to accelerate patient access to innovative treatments while ensuring the safety and effectiveness of care for the Medicare population.

Transitional Coverage for Emerging Technologies (TCET) Pathway

Study Guide

Purpose of TCET:

The TCET Pathway is designed to expedite Medicare coverage for innovative medical devices designated as "Breakthrough Devices" by the FDA.
It aims to balance timely access for Medicare beneficiaries with the need for robust evidence supporting the safety and effectiveness of new technologies.

Key Features:

Voluntary: Manufacturers can choose to participate.
Pre-market Engagement: CMS and manufacturers collaborate early to identify evidence gaps and develop Evidence Development Plans (EDPs).
Expedited NCD Process: CMS aims to finalize NCDs within six months of FDA market authorization.
Coverage with Evidence Development (CED): Coverage can be provided while evidence is being gathered through fit-for-purpose studies, including real-world data.
Transitional Coverage: Coverage under TCET is time-limited, tied to the EDP, and typically lasts five or more years.
Post-TCET Coverage: CMS will reconsider the NCD based on the generated evidence, leading to either continued coverage, modified coverage, or non-coverage.

Eligibility:

FDA-designated Breakthrough Devices.
Devices within a Medicare benefit category.
Devices not already subject to an existing NCD.
Devices not excluded from coverage by law or regulation.

Process:

Pre-Market Stage: CMS publishes guidance documents to clarify evidence expectations and manufacturers submit a Letter of Intent 18-24 months before anticipated FDA market authorization.
Near-Market Stage: Manufacturers formally nominate their device 12 months before anticipated FDA market authorization. CMS conducts an Evidence Preview and holds a stakeholder meeting.
Early Post-Market Stage: If sufficient evidence exists, an expedited NCD is issued. If not, a CED NCD is issued with an agreed-upon EDP.
Post-Market Stage: CMS reviews evidence generated through the EDP and reconsiders the NCD.

Benefits:

For Medicare Beneficiaries: Faster access to potentially life-saving or life-improving technologies.
For Manufacturers: Reduced uncertainty about Medicare coverage, clear evidence expectations, and a streamlined review process.
For the Healthcare System: Encourages innovation and promotes the development of high-value, evidence-based medical technologies.

Quiz

Instructions: Answer the following questions in 2-3 sentences each.

What is the primary purpose of the TCET Pathway?
Which medical devices are eligible for the TCET Pathway?
Describe the role of the Evidence Development Plan (EDP) in the TCET process.
How does the TCET Pathway benefit Medicare beneficiaries?
What is the typical duration of coverage under a TCET NCD?
What are the potential outcomes of the CMS NCD reconsideration after the completion of the EDP?
How does the TCET Pathway encourage the use of real-world data in evidence generation?
Explain the difference between an expedited NCD and a CED NCD under the TCET Pathway.
What is the significance of the "Breakthrough Device" designation in the context of TCET eligibility?
How does the TCET Pathway streamline the process for manufacturers seeking Medicare coverage for their devices?

Answer Key

The TCET Pathway aims to expedite Medicare coverage for FDA-designated Breakthrough Devices, balancing timely patient access with the need for robust evidence.
Eligible devices are FDA-designated Breakthrough Devices that fall within a Medicare benefit category, are not already subject to an NCD, and are not excluded from coverage by law or regulation.
The EDP outlines a plan for addressing evidence gaps identified in the Evidence Preview and typically includes fit-for-purpose studies. It provides a roadmap for evidence generation that will inform the future NCD reconsideration.
The TCET Pathway benefits Medicare beneficiaries by providing them with faster access to potentially life-saving or life-improving technologies that may not be covered through traditional Medicare pathways.
Coverage under a TCET NCD is time-limited and tied to the EDP, typically lasting for approximately five or more years.
After the completion of the EDP, the NCD will be reconsidered. Potential outcomes include: an NCD without evidence development requirements, an NCD with continued evidence development requirements, a non-coverage NCD, or rescinding the NCD.
The TCET Pathway encourages the use of real-world data through fit-for-purpose studies, recognizing its value in generating evidence that reflects real-world patient populations and treatment settings.
An expedited NCD is issued when sufficient evidence already exists to support coverage, while a CED NCD is issued when there are evidence gaps that need to be addressed through further studies. The CED NCD allows for coverage while evidence is being gathered.
The "Breakthrough Device" designation is a prerequisite for TCET eligibility, as it indicates that the device has the potential to offer significant improvements over existing treatments for serious or life-threatening conditions.
The TCET Pathway streamlines the process for manufacturers by providing clear evidence expectations, a defined timeline for review, and opportunities for early collaboration with CMS, reducing uncertainty and expediting coverage decisions.

Essay Questions

Discuss the potential benefits and challenges of the TCET Pathway for Medicare beneficiaries, manufacturers, and the healthcare system as a whole.
Explain the rationale for including coverage with evidence development (CED) as a key component of the TCET Pathway. How does CED balance the need for timely access to new technologies with the importance of evidence-based coverage decisions?
Analyze the role of real-world data in the evaluation of emerging medical technologies. How can real-world data studies be designed to generate meaningful evidence to support coverage decisions under the TCET Pathway?
Describe the collaboration between CMS and the FDA in the TCET process. How do the different mandates and regulatory frameworks of these agencies influence their respective roles in evaluating new medical technologies?
Explore the potential long-term impact of the TCET Pathway on the innovation landscape for medical devices. How might the pathway influence the development, clinical trial design, and market access strategies for future Breakthrough Devices?

Glossary of Key Terms

Breakthrough Device: A medical device designated by the FDA as offering significant improvements over existing treatments for serious or life-threatening conditions.
CED (Coverage with Evidence Development): A CMS coverage pathway that allows for Medicare coverage of a new technology while additional evidence is being collected to support its safety and effectiveness.
CMS (Centers for Medicare & Medicaid Services): The federal agency responsible for administering Medicare, Medicaid, and other healthcare programs.
EDP (Evidence Development Plan): A plan outlining the studies and data collection activities that will be conducted to address evidence gaps identified in the Evidence Preview.
Evidence Preview: A focused literature review conducted by CMS to assess the available evidence on a new technology.
FDA (Food and Drug Administration): The federal agency responsible for regulating the safety and effectiveness of medical devices, drugs, and biologics.
Fit-for-Purpose Study: A study designed to address specific evidence gaps relevant to Medicare coverage, often incorporating real-world data.
NCD (National Coverage Determination): A national policy that determines whether Medicare will cover a particular item or service.
Real-World Data: Data collected outside of traditional clinical trials, reflecting real-world patient populations, treatment settings, and clinical practices.
TCET (Transitional Coverage for Emerging Technologies): A CMS pathway that provides expedited Medicare coverage for certain FDA-designated Breakthrough Devices.

Automatic Podcast with 2 Voices: FDA's PDL1 Ad-Comm Last Week

Header: We copy a few major documents about the PDL1 workshop at FDA, and Google Notebook LM makes an AI podcast from it, with two voices.

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Last week, FDA held a much-discussed Ad Comm on what the future labeling shouold be for some major cancers regarding checkpoint inhibitor drugs in the presence of low or high PDL1 staining.

Two lead documents were circa 50 pages, one from FDA, one from BMS.

I uploaded these two major documents plus a Genomeweb article plus a "Washington Analysis" article, and finally, a review published online at Friends of Cancer Resarch. So here were five articls in one Google Notebook LM folder.

Google autogenerates four work products, three written ones and the fourth is an AI audio podcast.

1. A timeline of events (basck to 2021)

2. A "briefing guide" to all 5 documents.

3. A "study guide," largely in Q&A format.

4. A audio podcast with 2 AI voices in a "Dialog" over the material.

Find the TIMELINE, BRIEFING GUIDE, and STUDY GUIDE below in sequence.

Find a VIDEO that introduces the AI PODCAST, including the whole AI PODCAST.
https://youtu.be/ULY_c02saos

FDA briefing document
https://www.fda.gov/media/182143/download
Other briefing documents at far bottom of webpage
https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-26-2024-meeting-oncologic-drugs-advisory-committee-meeting-announcement-09262024
Genomeweb (Kanski)
https://www.precisionmedicineonline.com/regulatory-news-fda-approvals/fda-panel-finds-limited-immunotherapy-benefit-pd-l1-negative-gastric
Friends of Cancer Research
https://friendsofcancerresearch.org/blog/stakeholder-connect-insights-from-the-september-26-2024-meeting-of-the-oncology-drugs-advisory-committee/

TIMELINE

Timeline of Main Events

This timeline focuses on the development and FDA review of PD-L1 inhibitors in combination with chemotherapy for the first-line treatment of advanced or metastatic HER2-negative gastroesophageal adenocarcinoma (GC/GEJC/EAC).

Unknown Date (Prior to 2020):

CHECKMATE-649 (CA209649) study begins. This international, multicenter, randomized, double-blind, placebo-controlled trial investigates nivolumab plus chemotherapy vs. chemotherapy alone in previously untreated patients with advanced or metastatic GC/GEJC/EAC.

May 27, 2020:

Primary analysis data cutoff for CHECKMATE-649.

Unknown Dates (Between 2020 and 2024):

FDA approves nivolumab plus chemotherapy for first-line GC/GEJC/EAC. The approval is not restricted by PD-L1 expression levels.
FDA approves pembrolizumab plus chemotherapy for first-line GC/GEJC/EAC. The approval is not restricted by PD-L1 expression levels.
BeiGene submits a Biologics License Application (BLA) for tislelizumab plus chemotherapy for the treatment of GC/GEJC/EAC.
FDA reviews data from CHECKMATE-649, KEYNOTE-859, and RATIONALE-305. Concerns arise regarding the benefit-risk profile of PD-L1 inhibitors in patients with low PD-L1 expression levels.

September 26, 2024:

FDA Oncologic Drugs Advisory Committee (ODAC) meeting convened. The meeting focuses on the emerging risk-benefit analysis of PD-L1 inhibitors as a class in GC/GEJC/EAC, particularly in patients with low PD-L1 expression.
Bristol-Myers Squibb (BMS) submits a supplemental BLA (sBLA) for nivolumab plus chemotherapy for first-line GC/GEJC/EAC. The sBLA includes data from longer-term follow-up of CHECKMATE-649.

September 27, 2024:

ODAC overwhelmingly recommends against the off-label use of PD-L1 inhibitors in combination with chemotherapy for patients with PD-L1 negative GC/GEJC/EAC.
Pharma sponsors agree to consider expanded access programs specifically for PD-L1 negative patients. This is in response to concerns raised by the FDA and patient advocacy groups about the potential for restricted access to these therapies if the indication is narrowed.

Cast of Characters

Richard Pazdur, MD: Director of the FDA's Oncology Center of Excellence (OCE). Dr. Pazdur led the ODAC meeting and expressed concerns about the use of PD-L1 inhibitors in patients with low PD-L1 expression.

Representatives from Bristol-Myers Squibb (BMS), Merck, and BeiGene: These companies presented data from their respective clinical trials and responded to questions from the ODAC members.

ODAC Members: A panel of experts in oncology, biostatistics, and other relevant fields. They reviewed the data presented by the FDA and pharmaceutical companies and voted on their recommendations.

Patient Advocates: Representatives from patient advocacy groups voiced concerns about the potential impact of restricting the indication for PD-L1 inhibitors on patient access.

BRIEFING GUIDE

FDA Panel Rejects PD-L1 Inhibitors for Low Expressors in Gastric Cancer

This briefing document reviews the FDA's Oncologic Drugs Advisory Committee (ODAC) meeting held on September 26, 2024, concerning the use of PD-L1 inhibitors in combination with chemotherapy for patients with gastroesophageal adenocarcinoma (GC/GEJC/EAC).

Main Themes:

Limited Efficacy in PD-L1 Low Patients: The committee focused on the risk-benefit profile of PD-L1 inhibitors in patients with low PD-L1 expression. Analyses from three pivotal trials (CHECKMATE-649, KEYNOTE-859, and RATIONALE-305) and a pooled patient-level analysis revealed limited efficacy in patients with low PD-L1 expression (CPS <1 or TAP <1).
Potential for Harm: While combination therapies showed clear benefits for patients with higher PD-L1 expression, the panel expressed concern about the potential for harm in low expressors. These harms include serious immune-related adverse events, coupled with the significant impact of GC/GEJC/EAC on quality of life.
Harmonization of PD-L1 Testing: The use of different PD-L1 assays and cutoff points across trials raised concerns regarding consistent treatment algorithms and future drug development.

Important Ideas/Facts:

No benefit in Low Expressors: The FDA analysis concluded: "Addition of ICIs to standard of care chemotherapy for the treatment of patients with PD-L1 <1 does not appear to result in benefit."
Magnitude of benefit tied to PD-L1 levels: All three trials consistently showed greater benefit with increasing PD-L1 expression levels. As stated in the FDA analysis: "Benefit for patients with PD-L1 ≥10 have the greatest magnitude of benefit."
Testing inconsistencies: Different PD-L1 assays and cutoffs across trials complicate data interpretation and could lead to inconsistencies in treatment recommendations.
Impact on Future Research: Varying testing methodologies may hinder the design and interpretation of future clinical trials.
Patient Access: The FDA acknowledged concerns about restricting access to potentially beneficial therapies and requested pharmaceutical companies consider expanded access programs, particularly for PD-L1-negative patients.

Quotes:

FDA Briefing Document: "FDA believes a contemporary risk:benefit discussion evaluating the available data is required to further define the indication for these products for the treatment of gastric cancer to better match patients with a treatment that is likely to provide them benefit."
Washington Analysis: "FDA’s Oncologic Drugs Advisory Committee (ODAC) overwhelmingly supported FDA’s view that PD-L-1 inhibitors... should not be used in combination with standard chemotherapy in patients with PD-L-1 negative tumors."
Genomeweb: "Pazdur also sought commitment from pharma sponsors to establish expanded access... specifically for PD-L1 negative patients for these indications."

Conclusion:

The ODAC voted against recommending the use of PD-L1 inhibitors in combination with chemotherapy for patients with low PD-L1 expression in GC/GEJC/EAC. This decision reflects growing concern about the lack of demonstrated benefit and potential for harm in this specific patient population. The FDA highlighted the need for further research and emphasized the importance of harmonizing PD-L1 testing for future drug development and consistent treatment strategies. The agency also encouraged pharmaceutical companies to consider expanded access programs to ensure patient access to potentially beneficial therapies

A STUDY GUIDE (Q*&A)

Gastroesophageal Adenocarcinoma Treatment: Navigating PD-L1 Expression Levels in the Era of ICIs

Short-Answer Quiz

What are the two main PD-L1 scoring methods discussed in the FDA briefing documents, and what are their key differences?
Based on the FDA analysis of CHECKMATE-649, KEYNOTE-859, and RATIONALE-305, what overall trend emerges regarding the efficacy of ICI+chemo across different PD-L1 expression levels?
What are two challenges in PD-L1 testing highlighted in the FDA documents?
According to the FDA briefing document "2024 FDA 0926 PDL1 Low 41pp.pdf," what is the main reason for FDA's concern regarding off-label use of ICIs in PD-L1 low patients, despite the absence of PD-L1 restrictions on current approvals?
Briefly describe the two potential labeling options for ICIs in first-line gastroesophageal adenocarcinoma that the sponsor presents in "2024 FDA 0926 BMS on PDL1 Low Issues 50p.pdf".
What are the implications of having different PD-L1 cut-offs for different ICI drugs, as highlighted in the FDA document "2024 FDA 0926 PDL1 Low 41pp.pdf"?
According to "2024 FDA 0926 PDL1 Low 41pp.pdf," what significant action did the FDA take in 2009 regarding EGFR inhibitors in colorectal cancer, and what is its relevance to the current discussion on PD-L1 in gastroesophageal adenocarcinoma?
Based on the Washington Analysis report, what was the outcome of the FDA's ODAC meeting concerning the use of PD-L1 inhibitors in combination with chemotherapy?
What commitment did Dr. Pazdur seek from pharmaceutical companies during the ODAC meeting, as reported in "2024 Genomeweb 0927 Kanci on PDLA debates at AD COMM.pdf"?
Why is the inclusion/exclusion of esophageal adenocarcinoma (EAC) patients in clinical trials for gastric/GEJ adenocarcinoma a point of consideration, according to the FDA document "2024 FDA 0926 PDL1 Low 41pp.pdf"?

Answer Key

TPS (Tumor Proportion Score): Evaluates the percentage of viable tumor cells showing membrane staining at any intensity (0-100% scale). CPS (Combined Positive Score): Considers the number of PD-L1 positive tumor cells and immune cells in relation to the total number of viable tumor cells, providing a score (e.g., 1, 5, 10).
The FDA analysis consistently reveals that the efficacy of ICI+chemo generally increases with higher PD-L1 expression levels. Patients with higher PD-L1 scores consistently demonstrate greater benefit compared to those with lower scores, suggesting a predictive role of PD-L1 expression.
Tumor heterogeneity: PD-L1 expression can vary within a tumor, potentially leading to inaccurate scoring from a single biopsy. Interobserver variability: Pathologists might interpret PD-L1 staining differently, leading to discrepancies in scoring.
The FDA is concerned that off-label use in PD-L1 low patients might expose them to potential harms associated with ICI therapy, such as serious immune-related adverse events, without clear evidence of clinical benefit. This is particularly concerning as data suggests these patients may not benefit from this treatment.
Option 1: Indication based on individual trial results. This option would consider each trial's specific PD-L1 testing methodology and statistical analysis plan, potentially leading to different PD-L1 cut-offs for different ICIs. Option 2: Indication based on totality of data. This option would analyze data across trials to determine a single PD-L1 cut-off for all ICIs, acknowledging potential differences in PD-L1 tests used.
Different cut-offs could create inconsistencies in patient treatment, potentially leading to confusion among healthcare providers and impacting insurance coverage for specific tests. It could also complicate the design of future clinical trials aiming to improve patient outcomes.
In 2009, the FDA restricted the use of EGFR inhibitors (cetuximab and panitumumab) in metastatic colorectal cancer to patients with KRAS wild-type tumors, based on the analysis of multiple clinical trials. This decision underscores the FDA's willingness to refine indications based on accumulating data to ensure that treatments are directed towards patients most likely to benefit.
The ODAC overwhelmingly supported the FDA's view that the use of PD-L1 inhibitors should not be expanded off-label for patients with low PD-L1 expression in combination with chemotherapy.
Dr. Pazdur urged pharmaceutical companies to consider establishing expanded access programs specifically for patients with PD-L1 negative tumors, recognizing potential access challenges if labeling were to be restricted based on PD-L1 status.
While there are anatomical differences between EAC and gastric/GEJ adenocarcinomas, they share histological similarities. This raises questions about the appropriateness of combining or separating these patient populations in clinical trials, as it may impact the generalizability of findings and subsequent treatment recommendations.

Essay Questions

Critically analyze the ethical implications of restricting ICI treatment based on PD-L1 expression levels, considering potential benefits and harms to patients, as well as implications for healthcare resource allocation.
Considering the FDA's concerns about potential harms in the PD-L1 low population, propose a research agenda to better understand the risk-benefit profile of ICI+chemo in this patient group, outlining specific research questions, study designs, and ethical considerations.
Compare and contrast the two potential labeling options for ICIs in first-line gastroesophageal adenocarcinoma presented in the sponsor briefing document, discussing the advantages and disadvantages of each approach in terms of scientific rigor, clinical practicality, and patient access.
Given the challenges and variability inherent in PD-L1 testing, discuss strategies to improve standardization and accuracy in PD-L1 assessment for gastroesophageal adenocarcinoma.
Drawing parallels with the FDA's past decisions on biomarker-driven therapies (e.g., EGFR inhibitors in colorectal cancer), analyze the potential future implications of the ODAC's recommendations regarding PD-L1 and ICIs in gastroesophageal adenocarcinoma.

Glossary of Key Terms

ICI (Immune Checkpoint Inhibitor): A type of drug that blocks proteins called immune checkpoints, which normally help prevent the immune system from attacking healthy cells. By blocking these checkpoints, ICIs allow the immune system to recognize and attack cancer cells more effectively.
PD-1 (Programmed Death Protein 1): A protein found on the surface of T cells (a type of immune cell) that helps regulate immune responses. Cancer cells can exploit PD-1 to evade immune detection.
PD-L1 (Programmed Death Ligand 1): A protein often found on the surface of cancer cells that binds to PD-1 on T cells, inhibiting the immune response and allowing cancer cells to escape destruction.
CPS (Combined Positive Score): A method used to quantify PD-L1 expression on tumor cells and immune cells within a tumor sample, providing a score that can guide treatment decisions.
TPS (Tumor Proportion Score): A method that measures the percentage of tumor cells in a sample that express PD-L1, regardless of the staining intensity.
Gastroesophageal Adenocarcinoma: A type of cancer that occurs in the esophagus, the tube that connects the mouth to the stomach, or in the gastroesophageal junction, the area where the esophagus meets the stomach.
ODAC (Oncologic Drugs Advisory Committee): A panel of independent experts who provide recommendations to the FDA on the approval of cancer drugs.
Expanded Access Program: A pathway for patients with serious or life-threatening conditions who cannot participate in clinical trials to access investigational drugs not yet approved by the FDA.
Biomarker: A measurable characteristic (e.g., a protein) that can be used to indicate the presence of a disease, predict the likelihood of treatment response, or assess disease progression.
Off-label Use: The use of a drug for a medical condition or in a dosage or manner not specifically approved by the FDA.
Risk-Benefit Profile: An assessment of the potential benefits and harms associated with a particular medical intervention or treatment.
Tumor Heterogeneity: The presence of genetic and phenotypic differences between cancer cells within a tumor, which can influence treatment response and disease progression.
Interobserver Variability: The extent to which different observers, such as pathologists interpreting biopsy results, may arrive at different conclusions or assessments.

Direct link to FOCR Essay

https://friendsofcancerresearch.org/blog/stakeholder-connect-insights-from-the-september-26-2024-meeting-of-the-oncology-drugs-advisory-committee/

OTTER.ai Summary of Auto Transcript of PODCAST

This is a Google link to the podcast audio file; you may need to be signed into a google account to play it. Earlier in this essay I also provided the audio podcast as a YouTube link.

https://notebooklm.google.com/notebook/0f6f27ad-9002-42cb-96e8-a45988986f52/audio

Google Notes "PODCAST" PLD1 REVIEW

The discussion delves into the complexities of PDL1 testing for gastric and esophageal cancers, focusing on the immunotherapy drug OPDIVO. The FDA's briefing document highlights the critical need for accurate PDL1 testing, as its inconsistency across labs and pathologists can lead to life-or-death decisions. Despite OPDIVO showing overall survival benefits, its efficacy is strongly linked to PDL1 levels, raising questions about its use in patients with low PDL1. The conversation also touches on the broader implications for personalized medicine, emphasizing the importance of informed consent, second opinions, and patient advocacy.

Transcript

https://otter.ai/u/6TD_3GzDaOXLmQpTG6h_qAUJdXU?view=transcript

Action Items

[ ] Advocate for the right PD-L1 test to be used and ensure it is interpreted correctly.
[ ] Discuss the risks and potential benefits of immunotherapy treatment based on individual PD-L1 levels.
[ ] Consider other biomarkers, such as MSI and TMB, in the treatment decision-making process.
[ ] Obtain a second opinion, especially for complex cancer treatments.

Issues & Risks

Inconsistency in PDL1 testing results between different labs and pathologists.
Potential overtreatment of patients with low PDL1 expression.
Lack of PDL1 testing for about 40% of patients.
Concerns about the smaller survival benefit for low PDL1 patients versus the risks of immunotherapy.
Ethical concerns about limiting access to treatment based on an inconsistent test.

Next steps

More research needed on PDL1 testing and immunotherapy efficacy.
Development of more consistent testing methods.
Creation of clearer guidelines for doctors.

Questions discussed

What is PDL1 and how does it relate to immunotherapy?
How reliable is PDL1 testing?
What should patients ask their doctors about PDL1 testing and immunotherapy?
Should drug approval be based on overall benefit to a larger group or push for truly personalized medicine?

Outline

FDA Briefing on OPDIVO and PDL1 Testing

Speaker 1 introduces the topic of cancer treatment, focusing on gastric and esophageal cancers, and mentions PDL1 testing.
Speaker 2 emphasizes the importance of PDL1 testing for real patients and life-or-death decisions.
Speaker 1 and Speaker 2 discuss the FDA briefing document on OPDIVO, a key drug, and the implications of PDL1 testing.
The document paints a grim picture for gastric and esophageal cancers, highlighting the critical nature of first-line treatment.

Understanding PDL1 and Immunotherapy

Speaker 1 and Speaker 2 explain that PDL1 is a signal on cancer cells that attracts the immune system, making it a target for immunotherapy.
Speaker 2 describes how different tests and labs measure PDL1 levels, leading to inconsistent results.
Speaker 1 and Speaker 2 discuss the potential life-or-death consequences of these inconsistencies in PDL1 testing.
The conversation shifts to the real-world impact of PDL1 testing on patients, emphasizing the need for accurate and consistent results.

FDA Meeting and Expert Panel Discussion

Speaker 2 mentions the FDA meeting coverage by Geno Webb, which raised serious doubts about OPDIVO's effectiveness.
The expert panel noted that OPDIVO showed a stronger survival benefit in patients with higher PDL1 levels.
Speaker 1 and Speaker 2 discuss the debate over whether a smaller benefit for low PDL1 patients justifies the risks of immunotherapy.
The conversation highlights the importance of informed consent and the challenges of making life-or-death decisions based on unreliable testing.

Challenges in PDL1 Testing and Patient Advocacy

Speaker 1 and Speaker 2 discuss the Flatiron data showing that 40% of patients are not tested for PDL1, leading to decisions without crucial information.
The conversation emphasizes the need for patients to be informed about their PDL1 levels and the potential risks and benefits of treatment.
Speaker 1 and Speaker 2 stress the importance of open communication with doctors and advocating for oneself.
The discussion includes the need for consistent testing and clear guidelines for doctors to ensure accurate and reliable results.

Broader Implications and Personalized Medicine

Speaker 1 and Speaker 2 discuss the broader implications of PDL1 testing and the need for personalized medicine.
The conversation touches on the importance of considering other biomarkers like MSI and TMB in treatment decisions.
Speaker 1 and Speaker 2 emphasize the need for second opinions and the importance of feeling confident in one's treatment plan.
The discussion highlights the complexities of cancer treatment and the need for ongoing research and better testing methods.

FDA's Consideration of Immunotherapy Drugs

Speaker 2 mentions that the FDA meeting also considered three HP immunotherapy drugs: OPDIVO, Keytruda, and Tevimbra.
The expert panel voted on whether the data supported using these drugs in patients with low or no PDL1 expression.
For all three drugs, the majority of experts voted no, raising concerns about the smaller survival benefit in low PDL1 patients.
Speaker 1 and Speaker 2 discuss the potential narrowing of immunotherapy access based on PDL1 testing and the ethical and medical complexities involved.

Patient Advocacy and Personalized Medicine

Speaker 1 and Speaker 2 emphasize the importance of patients advocating for themselves and asking tough questions.
The conversation highlights the need for clear and consistent guidelines for doctors to ensure accurate and reliable testing.
Speaker 1 and Speaker 2 discuss the broader implications of PDL1 testing and the need for personalized medicine.
The discussion underscores the importance of being informed and confident in one's treatment plan, emphasizing the need for ongoing research and better testing methods.

Final Thoughts and Next Steps

Speaker 1 and Speaker 2 summarize the key points of the discussion, emphasizing the importance of knowledge and advocacy.
The conversation highlights the need for ongoing research and better testing methods to ensure accurate and reliable results.
Speaker 1 and Speaker 2 encourage listeners to keep asking questions and advocating for themselves.
The discussion concludes with a reminder of the importance of being informed and confident in one's treatment plan.

FINALLY, Transcript of PODCAST

Speaker 1 0:00

All right, buckle up listeners, because today's deep dive is taking us straight into the world of cancer treatment,

Speaker 2 0:06

straight into you said it no sugarcoating here,

Speaker 1 0:09

absolutely not. We're going deep specifically for gastric and esophageal cancers. And we're talking PDL one testing, which, let me tell you, it's a mouthful. It is a mouthful, but it's way more interesting, and honestly, way more important than it might sound at first. You're

Speaker 2 0:24

not kidding. This isn't just some technical jargon. We're talking about real people here.

Unknown Speaker 0:28

Real people, real decisions, exactly

Speaker 2 0:30

whether a patient gets the right treatment, the wrong treatment, or maybe even no treatment at all.

Speaker 1 0:36

And those are life and death decisions. No two ways about it. So where are we jumping in from? We've got excerpts from an FDA briefing document on a drug called OPDIVO key drug, yep. Plus, we've got some coverage of the actual FDA meeting from Geno Webb. Now I know this is your bread and butter, day in day out, but even for me, just skimming these documents, I felt like

Unknown Speaker 0:57

a detective, ha,

Speaker 1 0:58

ha, yeah, like we're on the trail of some big medical mystery. Well,

Speaker 2 1:02

you're not wrong. The FDA is trying to figure out this whole thing with PDL one, and who should be eligible for these immunotherapies. And

Unknown Speaker 1:09

what are the implications there?

Speaker 2 1:11

The implications huge, both for patients and the whole field. It's really something.

Speaker 1 1:16

Okay, so let's set the scene the document. It doesn't really sugarcoat things, does? It paints a pretty snark picture for gastric and esophageal cancers. It's

Speaker 2 1:26

a tough landscape treatment options, especially later on, very limited. We're

Speaker 1 1:30

talking what? Fifth deadliest globally. That's right. Fifth deadliest globally.

Speaker 2 1:34

So that first line treatment, critical, absolutely critical. The

Speaker 1 1:37

FDA isn't messing around, and neither are we. Which brings us to immunotherapy, immunotherapy. Now I'm hearing immunotherapy more and more these days. It's like this big. It's huge. It feels almost like a medical revolution, right? Yeah, using your own wn body to fight cancer. It's a game changer, for sure. Optivo That falls under this umbrella, right?

Speaker 2 1:57

Got it? Optivo? It's an immunotherapy drug, specifically what we call an immune checkpoint inhibitor. Okay, so

Unknown Speaker 2:03

there's a butt coming. I

Speaker 2 2:04

can feel it. Well, there's always a but in medicine, isn't there? It's given alongside chemo, which, as you know, chemo not exactly a walk in the park Exactly. And right now, OPDIVO is approved regardless of your PDL one level. But like you said, the FDA, they're taking a second look, and this, this is where things get really interesting, because

Speaker 1 2:23

it all hinges on this, this Pdl, one thing. So what is PDL one? I got to be honest, the document all the acronyms, CPS, TPS, different cutoff points a lot, right? It was like I needed a decoder ring just to understand what I was reading. I

Speaker 2 2:37

hear you think of it this way. Imagine PDL one is like a signal on these cancer cells,

Unknown Speaker 2:42

a signal like a warning sign, not

Speaker 2 2:45

quite more like a like a come get me. Flag waving to

Speaker 1 2:49

the immune system. I see so the immune system is like, send a security guard patrolling around, and the flags are saying, hey, problem over here? Exactly, more flags,

Speaker 2 2:57

stronger signal, and potentially a better response to these immunotherapy drugs. Okay,

Speaker 1 3:02

that makes sense. So, CPS, TPS, these are just different ways of different ways

Speaker 2 3:06

of measuring those flags. But, and this is a big but, oh boy, there we go, measuring those flags. It's not an exact science. We're talking different tests, different labs. I've even seen cases, and this is wild, where two pathologists, two

Unknown Speaker 3:21

pathologists. So the people who actually analyze the samples the very same.

Speaker 2 3:24

They can look at the same sample and come to different conclusions about the PDL. One,

Speaker 1 3:29

Wait, seriously. So it's not like sending a blood test to two labs and they might be off by a point of two. Sometimes it's more than that. This is like, positive versus negative kind of different.

Speaker 2 3:39

It could be that different? Yes, and that's why this whole thing is such a big deal. We're not talking about a subtle difference in measurement. Here.

Speaker 1 3:46

We're talking about life or death decisions. Exactly, life

Speaker 2 3:50

or death decisions based on what, at least right now seems like a shaky foundation. You're

Speaker 1 3:55

not mincing words, and I appreciate that this isn't just some scientific headache. This

Speaker 2 4:00

is real world stuff. This is impacting real

Speaker 1 4:03

patients right now, I think it's time we dive into those real world consequences. What do you say?

Unknown Speaker 4:09

Let's do it. This is where it gets really eye opening. It's

Unknown Speaker 4:12

like we're talking about two different universes here.

Speaker 2 4:14

It's true. You've got this FDA briefing document painting this really optimistic picture of OPDIVO, even for patients with low Pdl, one

Speaker 1 4:23

which, and maybe I'm jumping the gun here, but that doesn't exactly scream reliable testing. To me, you're

Speaker 2 4:29

not wrong to be thinking that I've got inconsistent testing, different labs, different results, and then you've got the Gina web coverage of the FDA meeting itself, a whole other story. Okay,

Speaker 1 4:37

hold on so the FDA meeting, they weren't exactly sold on optivo for everyone.

Speaker 2 4:42

Let's just say the expert panel, they brought up some serious doubts, doubts

Unknown Speaker 4:46

like, what? Give me the rundown. So

Speaker 2 4:47

optivo, it did show a survival benefit overall, but, and this is a big but, that benefit was much stronger in the patients with higher PDL one the

Speaker 1 4:57

come get me. Flags are waving loud and clear. In this case. This Exactly. So

Speaker 2 5:00

now the question becomes, is a smaller benefit for the low Pdl, one patients, is it worth the extra risks that come with immunotherapy? That's the debate. Man,

Speaker 1 5:11

that is a tough one. If it's your life on the line, you want every fighting chance, right? But not if the treatment might do more harm than good, then that's the tightrope they're walking, and it's not even like everyone at is getting this. PDL one, testing didn't we see something about that in the data? Oh,

Speaker 2 5:25

yeah, you're remembering correctly. The flatiron data, it showed something like 40% of patients didn't even get tested for Pdl, one, 40% we're

Speaker 1 5:33

talking almost half the patients. So they're making these huge decisions, life or death decisions, without even having this one piece of information,

Speaker 2 5:42

it's happening. And it's not just about getting the treatment or not. It's also about being informed about understanding the potential risks and benefits based on your individual situation. Imagine

Speaker 1 5:53

being that patient, you have cancer, there's this treatment, but this one test, this Pdl, one thing, it's like a gatekeeper.

Speaker 2 6:00

It's a gatekeeper to a potentially life saving treatment. That's exactly right, and it might not even be about your cancer itself, but about all this messiness around the test. I feel

Speaker 1 6:07

like we've stumbled onto something really important here. This isn't just about optivo or even just these types of cancer. This is bigger. Oh,

Speaker 2 6:14

absolutely. This is about the reliability of testing. It's about informed consent. It's about patients being able to advocate for their own health.

Speaker 1 6:21

And speaking of advocating, put yourself in that patient's shoes for a second. What would you want to know? What would you ask your doctor?

Unknown Speaker 6:30

Okay, deep breath. Put myself in those shoes. It'd be terrifying. But like you said, knowledge is power. So first off, if they're recommending op, devo or something like it, another

Unknown Speaker 6:41

immunotherapy in this class. Yeah,

Speaker 1 6:42

I'd want to know, have I been tested with the right PDL one test? What's the point of a test? If it's not even the right one for the job, you're hitting on

Speaker 2 6:51

something crucial there. There are so many variations on this test. It's wild, and they're not all created equal, that's for

Speaker 1 6:56

sure. Okay, so right test, check. What else is on this hypothetical checklist for our listeners. Next

Speaker 2 7:02

up, risk versus benefit? This is a big one. You'd want to have a real conversation with your doctor about your own personal risk tolerance,

Speaker 1 7:10

especially given my PDL one level, right? Because if it's low, those potential benefits, they might be smaller too.

Speaker 2 7:16

And are you willing to take on more risk from the immunotherapy if the potential upside might be smaller,

Speaker 1 7:22

so much to weigh, and this is all assuming you even get the test in the first place, and that's the right one.

Speaker 2 7:28

It really highlights the importance of that open communication with your doctor. Don't be afraid to ask those tough questions, voice your concerns, make sure you really understand what those risks and potential benefits look like for you specifically,

Speaker 1 7:42

two big things. Then write test and write for Emmy based on risks and all that is there a third thing our listener should keep in mind, don't leave us hanging, right? So

Speaker 2 7:51

we've talked about Pdl, one, but remember those other biomarkers, MSI, TMB, all those. They can be part of the conversation too.

Speaker 1 7:57

So it's not just about one piece of the puzzle. It's about how it all fits together,

Speaker 2 8:02

exactly and honestly. Don't ever hesitate to get a second opinion, especially with something as complex as cancer, a second opinion can be invaluable, like

Speaker 1 8:11

getting a second mechanic's opinion before a major car repair, right? Better safe than sorry. 100%

Speaker 2 8:17

it's your health, your life. You deserve to feel totally confident in your treatment plan, whatever that

Speaker 1 8:23

looks like. Zooming back out a bit, it seems like this FDA meeting, it was grappling with something even bigger than just OPDIVO, wasn't it?

Speaker 2 8:29

Oh, for sure, we've been talking about optivo, but they were actually looking at three HP immunotherapy drugs, optivo, Keytruda and tevimbra, all being used with chemo for these advanced gastric and esophageal cancers. Wow. Okay,

Speaker 1 8:43

so triple the impact then and this whole PDL one debate, this testing dilemma, it's swirling around all of them. All of

Speaker 2 8:49

them. They asked the expert panel to vote on whether the data supported using these drugs in patients with low or even no PDL one expression.

Speaker 1 8:58

So those patients where the flags are either super faint or non existent. That's right.

Speaker 2 9:03

And for all three drugs, the majority of experts actually voted no. Wow.

Speaker 1 9:08

Okay, so it sounds like the FDA might actually be moving towards narrowing who gets these immunotherapies, at least for these types of cancer, it's definitely

Speaker 2 9:15

on the table. They voiced real concerns about that smaller survival benefit in the low PDL one group, they felt the risks might outweigh the benefits in those cases. You

Speaker 1 9:25

know, logically, I get it. But then there's this other layer, this whole testing issue. It almost feels like a catch 22 right? It's

Speaker 2 9:31

incredibly complex. You've got a test with no limitations, inconsistencies, and they're considering limiting access based on that test. It's a tough call, ethically, medically, all of it, and

Speaker 1 9:41

even if you do get the test, there's no guarantee it'll be the right one, or that it'll even be interpreted the same way by different doctors. It

Speaker 2 9:49

just shows how much we still don't know and how much work still needs to be done, more research, more consistent testing, clearer guidelines for doctors. But. Whole Nine Yards.

Speaker 1 10:01

In the meantime, it's the patients who are stuck in this incredibly difficult position. You're facing a serious illness. There's this potentially life saving treatment, and then this test which

Unknown Speaker 10:10

which might not be the magic bullet we

Speaker 1 10:12

wish it was exactly. It really underscores how important it is to be your own advocate. Ask the tough questions. Don't be afraid to get a second opinion. Push for clarity and information. It's your health on the line. Couldn't set it better myself. You know, what's really got me thinking is this goes way beyond just this one test or these particular drugs. This brings up a much bigger question. What's that? Should drug approval be based solely on the overall benefit to a larger group, or should we be pushing for truly personalized medicine, even if it's Messier, more complex? That's

Unknown Speaker 10:45

the million dollar question, isn't it?

Speaker 1 10:47

No easy answers there, not at all, but definitely a conversation worth having. Well, this

Speaker 2 10:51

has been one heck of a deep dive. We've covered a lot of ground. We went from dense FDA documents to questioning the very foundation of how we made treatment decisions. Hopefully our listeners still with us, and

Speaker 1 11:03

hopefully we feel a little more equipped to navigate this whole complex landscape. Knowledge is power. Never forget that couldn't agree more. Big. Thanks to you, as always, for breaking it all down and to our listener, keep asking those questions, keep advocating for yourself, and we'll catch you on the next deep dive. So we've talked about PDL one, but remember those other biomarkers we touched on earlier? MSI, TMB, all those, they can be part of the conversation too. Absolutely,

Unknown Speaker 11:27

it's not just about PDO one and isolation.

Speaker 1 11:30

So it's not just about one piece of the puzzle. It's about how it all fits together exactly

Speaker 2 11:34

and honestly, don't ever hesitate to get a second opinion, especially with something as complex as cancer, a second opinion can be invaluable, like getting

Speaker 1 11:44

a second mechanic's opinion before a major car repair. Better safe than sorry. 100%

Speaker 2 11:49

it's your health, your life. You deserve to feel totally confident in your treatment plan, whatever that

Speaker 1 11:54

looks like. Zooming back out a bit, it seems like this FDA meeting, it was grappling with something even bigger than just OPDIVO, wasn't it? Oh, for sure,

Speaker 2 12:02

we've been talking about OPDIVO, but they were actually looking at three each immunotherapy drugs, OPDIVO, Keytruda and tevimbra, all being used with chemo for these advanced gastric and esophageal cancers. Wow. Okay,

Speaker 1 12:14

so triple the impact then, and this whole PDO one debate, this testing dilemma, it's swirling around all of

Speaker 2 12:21

them. All of them. They asked the expert panel to vote on whether the data supported using these drugs in patients with low or even no Pdl, one expression,

Speaker 1 12:29

so those patients where the flags are either super faint or non existent, that's

Speaker 2 12:33

right. And for all three drugs, the majority of experts actually voted no. Wow. Okay,

Speaker 1 12:38

so it sounds like the FDA might actually be moving towards narrowing who gets these immunotherapies, at least for these types of cancer, it's

Speaker 2 12:44

definitely on the table. They voiced real concerns about that smaller survival benefit in the low PDL one group. They felt the risks might outweigh the benefits in those cases,

Speaker 1 12:54

which logically, I get it. But then there's this other layer, this whole testing issue, it almost feels like a catch 22 right? It's

Speaker 2 13:00

incredibly complex. You got a test with known limitations, inconsistencies, and they're considering limiting access based on that test. That's a tough call, ethically, medically, all of it.

Speaker 1 13:11

And even if you do get the test, there's no guarantee it'll be the right one, or that it'll even be interpreted the same way by different doctors. It

Speaker 2 13:18

just shows how much we still don't know and how much work still needs to be done, more research, more consistent testing, clearer guidelines for doctors the whole nine yards.

Speaker 1 13:27

In the meantime, it's the patients who are stuck in this incredibly difficult position. You're facing a serious illness. There's this potentially life saving treatment, and then this test, which

Unknown Speaker 13:38

might not be the magic bullet, we wish it was exactly

Speaker 1 13:41

it really underscores how important it is to be your own advocate. Ask the tough questions. Don't be afraid to get a second opinion. Push for clarity and information. It's your health on the line.

Unknown Speaker 13:52

Couldn't have said it better myself. You know? What's

Speaker 1 13:54

really got me thinking is this goes way beyond just this one test or these particular drugs. This brings up a much bigger question, what's that? Should drug approval be based solely on the overall benefit to a larger group, or should we be pushing for truly personalized medicine, even if it's Messier, more complex? That's

Speaker 2 14:13

the million dollar question, isn't it? No easy answers there. Not at all,

Speaker 1 14:17

but definitely a conversation worth having. While, this has been one heck of a deep dive, we've covered a lot of ground. We went from dense FDA documents to questioning the very foundation of how we make treatment decisions. Hopefully our listeners still with us, and hopefully

Speaker 2 14:32

they feel a little more equipped to navigate this whole complex landscape. Knowledge is power. Never forget that couldn't

Speaker 1 14:39

agree more big. Thanks to you as always for breaking it all down and to our listener, keep asking those questions, keep advocating for yourself, and we'll catch you on the next deep dive. You.

Transcribed by https://otter.ai