See an earlier blog about an important new UCSF paper on Alzheimer's tests, and payers.
Here, I highlight an automatic 12-minute podcast (with two AI voices) created by Google NotebookLM.
NotebookLM lets you make an online folder, upload one or more documents, then generate podcasts, briefing guides, study guides (lots of Q&A), and other resources.
Here is the 12 minute podcast, with a quick intro by me:
Header: My readaing of a neww UCSF paper: I would say, "Payer Plans for Blood-Based ALZ Testing Lag Guidelines and Science."
Find the JAMA article by Deverka et al. here and the UCSF press release here.
##
AI Corner (Chat GPT 4o)
Expert Analysis:
Payer Coverage Lags Behind Scientific Advancements
in Alzheimer’s Disease Blood Tests
Recent publications from UCSF TRANSPERS researchers in JAMA highlight critical coverage gaps for novel blood-based biomarker tests (BBMTs) that diagnose Alzheimer’s disease (AD). These tests, seen as a promising alternative to more invasive and costly amyloid PET scans and cerebrospinal fluid (CSF) analysis, remain unavailable to most patients due to the lack of public and private insurance coverage. This leaves patients facing out-of-pocket costs exceeding $1,000, limiting access to those who can afford it.
The UCSF study outlines that BBMTs can detect Alzheimer’s at earlier stages, potentially increasing the chances of accessing newly approved disease-modifying therapies (DMTs). However, the absence of payer coverage raises concerns about equitable access. According to the researchers, evidence of clinical utility, beyond just diagnostic accuracy, is required to shift the insurance landscape. Payers seek proof that these tests not only identify Alzheimer’s but also lead to meaningful changes in patient care.
Moreover, coverage challenges with current biomarker tools, such as amyloid PET scans and CSF testing, have already shown the complexities faced by clinicians and patients. Without consistent payer policies, regions may experience different levels of access, exacerbating health inequities. UCSF's researchers argue that preemptively addressing these issues for BBMTs is crucial to avoid repeating history.
The UCSF team, led by Dr. Patricia Deverka, stresses the importance of developing evidence-based payer guidelines for BBMTs. This includes specific clinical indications, such as the use of these tests for symptomatic patients over 60 years old, or as triage tools to determine if further amyloid PET or CSF testing is necessary. Without such guidelines, payers may hesitate to cover BBMTs, leading to further disparities in Alzheimer's diagnosis, particularly among underserved communities.
One significant equity concern is that current restrictions on specialized dementia care disproportionately affect minority populations, who already face lower rates of diagnosis. The availability of BBMTs, particularly in primary care settings, could bridge this gap. Yet, without coverage, these tools may remain inaccessible to those who need them most.
Additionally, the JAMA article points out the potential for overuse of BBMTs if introduced without clear evidence or coverage guidelines, which could strain healthcare systems. To avoid misuse, payers might consider covering BBMTs only in cases with validated clinical utility, initially limiting their use to symptomatic patients rather than for widespread screening.
The disconnect between the emerging scientific advancements in Alzheimer’s diagnostics and payer coverage is evident. BBMTs could revolutionize early diagnosis and care, but without payer adoption, they remain out of reach for many. The UCSF team’s call for proactive coverage policies that reflect the evolving landscape of AD diagnosis is timely. As the evidence base grows, so too must payer policies that promote equitable access to these critical diagnostic tools.
##
See a Google NotebookLM Automatic Podcast (two voices), 13 minutes:
##
(Back to Chat GPT)
Can you confirm that the science article, plus press release, do in fact support the point we are emphasizing (disconnect between science and coverage). Will the authors feel you (or we) draw fair conclusions albeit as our own appraisal of their work.
##
Yes, the points emphasized in your article—specifically the disconnect between scientific advancements and payer coverage—are well-supported by both the JAMA article and the UCSF press release. Here's how:
Press Release Support:
The UCSF press release clearly underscores the potential of blood-based biomarker tests (BBMTs) for Alzheimer’s disease to offer a simpler and more accessible alternative to current diagnostic methods. It explicitly states that these tests are not yet covered by insurers, leaving patients with high out-of-pocket costs, which impedes equitable access, especially for underserved populations. This indicates a direct disconnect between the availability of scientific advancements and the lack of corresponding insurance coverage.
Science Article Support:
The JAMA article elaborates on the criteria payers typically require for coverage—analytic validity, clinical validity, and clinical utility. While it acknowledges the promise of BBMTs, it emphasizes that payers are currently hesitant to cover these tests due to the need for more evidence, particularly around clinical utility. The article also highlights how the lack of coverage for existing biomarker tests (amyloid PET scans, CSF tests) has led to inequities in diagnosis and access. This further reinforces the gap between scientific progress and payer adoption.
The conclusions you are drawing—that there is a disconnect between science and payer coverage—are consistent with the data and concerns raised by the authors. Both the press release and the JAMA article highlight payer hesitation due to a lack of proof of clinical utility, despite the promising science behind BBMTs. By pointing out this gap in your appraisal, you are not overstating their conclusions but rather expanding on the implications of their work from a policy perspective.
The authors are likely to view this assessment as a fair extrapolation of their work. You are aligning with their emphasis on the need for clear coverage policies, evidence development, and equitable access, while making the case that current payer policies lag behind the advancing science.
Thus, your analysis remains well within the bounds of their findings and provides a reasonable interpretation of the implications regarding payer coverage gaps.
...with some errors.
I've been hearing that Google Notebook now has a feature where it can generate an automatic, two-voice audio podcast by AI, from any article or documents you feed it. (Here)
A friend used by CMS crossswalk/gapfill article - quite a long one - and produced a two-voice podcast from it. I've loaded YouTube with a second version (from the final article version).
Is It Accurate? Is It Worth 30 Seconds?
Is it completely accurate, and does it get all the emphases correct? NO.
Is it worth listening to, for 30 or 60 seconds, to get the look and feel? For me, DEFINITELY.
Find It
I loaded the Google AI Podcast up into YouTube, with a brief intro by me.
You can also find the shorter and longer podcasts as a Transcript. (The first is styled as Adam and Brenda, the second as Charles and Deanna).
TRANSCRIPT (#2, LONGER) https://docs.google.com/document/d/1ZOcgKZXzZByOqNBLY01aFZbaPe6wyuVV/edit?usp=sharing&ouid=110053226805181888143&rtpof=true&sd=true
TRANSCRIPT (#1, SHORTER)https://docs.google.com/document/d/1UGA4rhE-Ym4D91dEKjjXT0I6wXNVFlbh/edit?usp=sharing&ouid=110053226805181888143&rtpof=true&sd=true
Three news items this morning.
FOIA: Because it can be cryptic why and how CMS disagrees with the majority panel recommendations, I requested FOIA information in February 2023 on the November 2022 final decisions. Today I got a FOIA response (020320237062) that 3 spreadsheets exist and contain more information on CMS's search for crosswalks and development of rationales, but CMS declined to release them to me.
 |
| click to enlarge |
 |
| click to enlarge |
MolDx rationales. The most frequent terms in the rationale descriptions include "price," "based," "service," "similar," "comparable," and "existing," suggesting a strong emphasis on the following key patterns in how Medicare MolDx sets prices for molecular lab tests:
Comparison to Existing Services: The pricing often references similarity to existing services, suggesting that new tests are frequently evaluated in relation to established codes and methodologies. This ensures that new services are aligned with already established pricing structures (e.g., "comparable services").
Price Justification Based on Service Complexity: Many rationales are based on the complexity of the service. Tests described as offering additional or more complex features compared to current offerings are given appropriate adjustments in price, but only if justified by the scope and complexity of the service.
Genomic and DNA Testing: The frequent mention of "DNA" and "genomic" suggests a focus on tests related to genetic or molecular diagnostics, where pricing might be informed by the complexity of the analysis and the amount of genomic information provided.
Use of Existing Laboratory Fee Schedule (CLFS): The term "CLFS" (Clinical Laboratory Fee Schedule) indicates that the Medicare MolDx program often refers to existing price frameworks in making determinations for new tests, likely aiming for consistency across similar diagnostic services.
These patterns indicate that the MolDx program prioritizes comparability with existing tests, complexity of the new test, and uses established frameworks like the CLFS when setting prices for new molecular lab tests.
From the frequency analysis of the rationale descriptions where CMS disagreed with the expert panel’s recommendations, several key patterns emerge:
Crosswalk Disagreements: The term "crosswalk" appears frequently, suggesting that CMS often disagrees with the panel on how new tests should be priced relative to existing tests. Crosswalks are used to establish equivalency between new and existing tests for pricing, and CMS seems to place a different emphasis on how closely a new test aligns with a specific code than the panel does.
Emphasis on CMS Judgment: The term "CMS" is frequently mentioned, indicating that CMS is explicit in asserting its judgment over the panel’s recommendations. CMS consistently provides its rationale when it diverges from expert advice, signaling transparency in decision-making.
Existing Codes and Test Comparability: CMS's rationale often revolves around the existence of a comparable test or code. When CMS disagrees, it frequently states that there is a more appropriate or similar code that better fits the test in question, suggesting CMS prioritizes consistency with existing pricing models.
Precision in Test Descriptions: CMS often disagrees with recommendations when the test description does not explicitly match the proposed crosswalk analysis or when key details like risk scores are missing. This highlights a strong focus on detailed descriptors and clinical content as critical factors in pricing decisions.
In presenting its disagreement, CMS appears to focus on maintaining price consistency with existing codes and requiring a strong match between the test’s description and the proposed pricing mechanism. These disagreements are framed as corrections to ensure appropriate alignment with established Medicare pricing principles, which reflects CMS’s priority for precise and comparable test categorization.
How should a lab frame its comments to CMS?
If a lab prefers the expert panel’s recommendation or other public recommendations over CMS’s decision and seeks to challenge CMS’s rationale, the lab should carefully structure its comment letter to maximize its effectiveness. Here are steps to prioritize and frame the letter:
By presenting an evidence-based, well-reasoned argument that aligns with CMS’s broader goals, the lab can increase the likelihood that its comment will be seriously considered.
##
Based on the pasted rationales where CMS disagreed with the expert panel and recommended gapfill, we can draw several insights about CMS's decision-making process when it diverges from the expert panel recommendations.
Focus on Resource Estimation by MACs:
Lack of Public Input:
Specificity of Test Methods:
Minority Panel Recommendations:
Avoidance of Redundancy:
Historical Precedents and Consistency:
When CMS disagrees with the expert panel, its rationales seem to hinge on several core principles:
CMS’s preference for gapfill over expert panel crosswalk recommendations in certain cases seems to stem from its desire to avoid blanket pricing decisions when it feels that MACs are better suited to determine the local costs associated with a test. This approach allows for flexibility and adjustment based on real-world data. Moreover, CMS’s frequent reference to past decisions and consistency suggests that it values long-term stability in pricing over potentially more aggressive changes suggested by the panel.
By frequently citing resource estimation by MACs, CMS emphasizes the importance of regionalized cost analysis, which may reflect the variability in lab testing across different regions of the country. This approach also allows CMS to remain cautious and conservative in pricing, especially when faced with incomplete information or uncertainty.
Hi Maria,
As you're preparing to take over the gapfill pricing process, I want to give you a solid foundation on how CMS approaches these issues and what our priorities are. The gapfill process is a critical part of CMS’s role in setting fair and sustainable pricing for new molecular diagnostic tests, especially in a constantly evolving space like laboratory diagnostics.
The gapfill method allows us to price new lab tests based on the resources needed to perform the test, as assessed by the local Medicare Administrative Contractors (MACs). When we don't have a clear equivalent test or “crosswalk” to base pricing on, gapfill lets us gather data over time to arrive at a fair and accurate price.
The gapfill process is different from crosswalking, where we match a new test to an existing code with similar complexity or use, and then adopt its price. Gapfill is used when no such direct match is available, allowing us to start fresh.
CMS approaches gapfill pricing with several key priorities in mind:
Accuracy and Fairness: We want to make sure that the price reflects the actual resources needed to perform the test. This includes technical factors, such as the type of analysis involved (e.g., DNA vs. RNA), the labor required, and the technology used.
Cost Containment: While we aim for accuracy, we also have to ensure that prices are sustainable. We are balancing innovation in molecular diagnostics with the responsibility to prevent runaway costs in the healthcare system.
Consistency Across the Board: We aim to keep our pricing consistent, not just with past decisions but also across similar tests. This ensures fairness and stability for laboratories, payers, and patients alike. For example, if we’ve already gapfilled or crosswalked a similar test in the past, we aim to stick close to those decisions unless something has significantly changed.
When a new code comes in, the process starts with evaluating whether a crosswalk exists. This is when we ask: Does this test have a near equivalent that is already priced? If yes, we lean toward crosswalking. But when there’s no clear match—either because of new technology or complexity—we turn to the gapfill process.
Why Gapfill? Gapfill lets the MACs get involved, because they are closer to the realities of running these tests in their regions. They can assess what labs are charging and what the real resource needs are. This ensures that the pricing reflects what's happening on the ground, not just in theory.
We value public input and the recommendations from our expert advisory panel. Their expertise and stakeholder perspectives are invaluable. However, you’ll notice that CMS doesn’t always agree with the majority opinion.
When We Agree with the Panel: These are usually cases where the panel’s recommendation aligns well with the existing framework, past pricing decisions, and the principles we follow. In these cases, you’ll see that the rationales are relatively simple, as there’s a clear consensus.
When We Disagree with the Panel: This often happens when CMS has concerns about the sustainability of the panel’s recommendation or when we believe there’s a better way to determine pricing through gapfill. For example, if the panel suggests a crosswalk but CMS believes the test requires a unique approach, we might opt for gapfill. Here, our rationale tends to be more specific, citing factors like insufficient data or public input, or the need for MACs to provide a more localized resource estimate.
Stakeholders, from laboratories to clinicians to advocacy groups, are part of the process, and we review their input carefully. While we don’t always follow their recommendations, their perspectives provide context on the test's value and usage in the real world. If we don’t receive much public input, as happens sometimes, it can push us to default to gapfill, as we’d prefer more data to make a final crosswalk decision.
One of the trickiest parts of the job is balancing the need to support innovation in diagnostics with the goal of keeping Medicare costs in check. Laboratories are constantly developing more sophisticated and personalized tests, but those tests come with costs. By using gapfill, CMS can take the time to evaluate the test properly, ensuring the price reflects both the clinical value and the actual resources required without prematurely inflating costs.
As you take on this role, keep these priorities in mind. We are here to ensure that pricing is fair, accurate, and sustainable, both for CMS and for the broader healthcare system. Always look for consistency with past decisions but be open to adjusting as technology advances and new data comes in. And finally, remember the importance of MACs and public input—they play a vital role in making sure our pricing reflects the real-world environment in which these tests are performed.
I’ll be here to help you with specific cases and guidance as you take over, but these principles should guide you through the bulk of the decisions you’ll need to make.
Good luck!
##
She asks, what are some the most likely pitfalls and headaches in the job?
##
Great question! There are definitely some challenges and potential pitfalls that come with managing the gapfill pricing process. Here are some of the most common ones to watch out for:
A major pitfall is not having enough data to make informed decisions. Whether it’s the lack of public input, limited clinical data, or missing financial impact information from laboratories, this can put you in a position where decisions feel more speculative than evidence-based.
How to manage: Always advocate for more data collection and better stakeholder input. Push for MACs and public parties to provide detailed resource usage information.
There can be significant pressure from various stakeholders—laboratories, clinicians, patient advocacy groups, and even your own advisory panel. Each party has its own interests, and sometimes these conflict with CMS’s goals of cost containment or fairness.
How to manage: Stick to CMS principles and maintain transparency. Clearly communicate the reasons behind your decisions, whether you agree or disagree with a panel or stakeholder. Being clear about CMS’s broader goals can help smooth out tension.
Disagreeing with the majority recommendation of the expert panel can sometimes be politically tricky. The panel members are experts in their fields, and openly diverging from their recommendations could lead to questions about CMS’s judgment.
How to manage: Be clear and specific in your rationale. CMS is focused on sustainability, consistency, and cost management—these priorities should drive your decision-making. When you disagree with the panel, it’s important to justify the decision based on solid, defendable principles, like resource estimation by MACs or inconsistency with past crosswalks.
Molecular diagnostics and other lab tests are becoming more complex, especially with the rise of personalized medicine and next-gen sequencing technologies. The rapid pace of innovation can make it difficult to assess where a new test fits into the existing pricing framework.
How to manage: Stay up to date on emerging technologies, and lean on expert opinions, even if CMS ultimately doesn’t follow the majority. Engaging with industry experts and MACs early on helps to get a clearer sense of the test’s complexity and where it might fit.
Finding a balance between pricing that encourages innovation and ensuring that Medicare doesn’t overpay for new diagnostics is always a challenge. Tests that are very innovative or groundbreaking often come with higher costs, and setting a price too low could discourage their use, but setting it too high can lead to excess costs.
How to manage: Use gapfill to your advantage in these cases. It allows for a flexible, data-driven approach to set pricing over time, rather than rushing to a crosswalk decision that might not fully account for the test’s value.
The gapfill process can be slow and cumbersome, especially when relying on MACs to assess resources and costs over time. Gathering the data needed to justify a final price can take longer than anticipated, and delays can frustrate stakeholders.
How to manage: Set clear expectations early on about the time frame for the gapfill process. Regular check-ins with MACs and stakeholders can help keep things moving along.
Some codes go through multiple rounds of reconsideration, especially if there’s disagreement between CMS and the expert panel or public stakeholders. Revisiting the same code multiple times can be frustrating and may lead to perceived indecision or inconsistency.
How to manage: Document decisions thoroughly so that if a code comes back for reconsideration, you have a clear record of why CMS made the initial decision. This also helps justify CMS’s consistency in its approach.
This job requires a careful balance between clinical innovation, cost control, and fairness. You’ll likely find that the pressure from various parties and the complexity of new technologies are the biggest challenges, but by staying grounded in CMS’s core principles—accuracy, sustainability, and transparency—you’ll be able to navigate these effectively. Just keep your cool, rely on data, and make decisions based on the best information available, even when you face uncertainty or pushback.
We’ll go over specific cases and best practices over the next few months, but this overview should give you a sense of the common issues and how to handle them.
####
CMS Prepares for Meeting with Angry Stakeholders
You continue to be the CMS policymaker. Several large organizations are upset that you (CMS) make different choices than the Federal advisory panel (lab expert advisory panel) around 40% of the time. Disconcertingly, they also have data that in the recent round of over 100 decisions, you agreed with the advisory panel 70% of the time on low cost codes, and disagreed 70% of the time with high cost codes (>$1000). Your boss, the senior director of the Center for Medicare, will attend the meeting but expects you (the director responsible for lab pricing). Discuss your thinking and preparation for the challenging meeting.
As we prepare for this meeting, we need to acknowledge that one of the most critical concerns for stakeholders is why CMS disagrees with the advisory panel of experts about 40% of the time, particularly for high-cost codes. This issue, especially the trend of more disagreements for higher-priced tests, will likely be a central focus of the discussion. We need to approach this with transparency and an emphasis on CMS’s broader mission.
The central issue of disagreement with the advisory panel, particularly for high-cost tests, needs to be handled with transparency and clear communication about CMS’s broader fiscal responsibilities. By preparing to explain the reasoning behind these decisions—focusing on sustainability, consistency, and the need for data-driven pricing—we can demonstrate that CMS is acting in the best interests of both Medicare beneficiaries and the program’s long-term viability.
From the free email newsletter Politico Pulse:
https://www.politico.com/newsletters/politico-pulse/2024/09/13/inside-hhs-ai-purchases-00178902
ARTIFICIAL INTELLIGENCE AT HHS — HHS, one of the federal government’s top users of artificial intelligence, has spent nearly $129 million on AI and AI-related purchases in the past five years, Chelsea and POLITICO’s Mohar Chatterjee report. That’s according to a POLITICO analysis of government data, which found that the top spenders within HHS include: — The Office of the Assistant Secretary for Management and Budget at $53 million — The NIH at $26 million — The FDA at $32 million Why it matters: AI experts who spoke with POLITICO said the investments, which accelerated before President Joe Biden’s October executive order directing federal agencies to be more intentional about how they use and regulate AI, aim to sort through massive datasets and advance research at the FDA and the NIH. “This is encouraging,” said Dr. Don Rucker, who was HHS’ National Coordinator for Health IT in the Trump administration. As the health care industry works out what the proliferation of AI means for the sector, “HHS is sort of working out a version of the same question,” Rucker added. |
|
Some ways HHS agencies use AI: — To date, the OASMB purchased from AI company Spectral MD more than $39 million in optical imaging devices that use machine-learning algorithms to classify burns, which can be used to handle wounds in mass-casualty events. — In 2020 and 2021, the Centers for Medicare and Medicaid Services awarded tech consulting firm ESimplicity nearly $4 million to plan how to efficiently transition its data to cloud services that could support AI use. — Last year, the National Institutes of Health awarded a nearly $3.5 million contract to AI company BelleTorus for the experimental development of telehealth AI tools that could digitally assess a child’s throat and airways. According to a GAO report from December, HHS is one of the top federal government agencies using AI — fourth only to NASA and the Commerce and Energy departments. Just last month, HHS merged two tech offices and increased its focus on AI, posting job listings for three new roles related to creating AI policy: A chief AI officer, a chief technology officer and a chief data officer. |
Update: Panel supported FDA plan for narrower labeling (votes 10-2, 11-1). Here.
Friends of Cancer Research summarizes.
##
I posted a blog a few weeks ago that FDA had a pending AdComm on PDL1 and immuno-oncology (blog here).
The meeting is now imminent and Endpoints covers briefing materials from FDA and from BMS.
Endpoints
FDA (41pp)
https://www.fda.gov/media/182138/download
BMS (50pp)
https://www.fda.gov/media/182140/download
As quoted by Endpoints, FDA writes,
The agency said that “approvals for all randomized patients may not be in the best interest of patients with tumors with low PD-L1 expression” and that giving the drugs to patients with low or no PD-L1 expression “has the potential for harm including serious immune related adverse events on top of a malignancy that can markedly affect a patient’s quality of life.”
Opposite Issues for Her2 Drugs
Note that in other quarters, we are looking at the value of Her2 drugs for patients with low and "ultra low" Her2 expression, e.g. this month in ASCO Post.
##
Note that debates about PDL1 confusion and harmonization go back for years; e.g. Karim 2017 and Adam 2018.
One response is to focus on better-defined cutoffs or reading methods for PDL1. Entirely different approaches would attempt to make algorithms combining PDL1, TMB, MSI, or other biomarkers relevant to the checkpoint inhibitor pathways.
##
AI Corner
##
I asked Chat GPT 4 to read both the FDA and BMS documents and discuss.
##
This document outlines the FDA's review and considerations regarding the use of immune checkpoint inhibitors (ICIs) like nivolumab (Opdivo) and pembrolizumab (Keytruda) for the first-line treatment of HER2-negative metastatic or unresectable gastric adenocarcinoma. The FDA focuses on the relevance of PD-L1 expression as a biomarker for treatment efficacy, particularly in the context of selecting patients for ICI treatment.
Key points include:
Bristol-Myers Squibb (BMS) presents its position on nivolumab (Opdivo) combined with chemotherapy for treating gastroesophageal adenocarcinoma, emphasizing the flexibility needed in prescribing decisions. BMS advocates that existing labeling provides sufficient information for clinicians to make informed decisions, including the potential benefits for PD-L1-positive patients and those whose PD-L1 status is unknown.
Key points include:
PD-L1 Testing and Cutoffs:
Risk-Benefit Analysis:
Regulatory Perspective:
For oncologists, interpreting both FDA and BMS viewpoints involves navigating complex clinical and regulatory landscapes:
Patient Selection: Oncologists must weigh FDA's potential move toward more restrictive labeling based on PD-L1 expression against BMS's more flexible approach. In practice, this means that oncologists need to carefully evaluate each patient's pathology report and PD-L1 status to decide whether ICIs are appropriate.
PD-L1 Testing: With differing assays and cutoffs used in clinical trials, oncologists will need to ensure that the PD-L1 testing method used is appropriate and reliable. Differences in assay performance may affect patient selection for treatment, complicating decision-making.
Safety Considerations: Oncologists must also consider the risk of immune-related adverse events, particularly in patients with low or no PD-L1 expression. They may have to balance the potential for benefit against the risk of harm, especially as FDA highlights that patients with low PD-L1 expression may not see significant survival benefits.
Literature and Label Interpretation: Given the evolving regulatory landscape, oncologists must stay informed about updates to drug labeling and clinical guidelines. They may need to consult both FDA guidance and manufacturer recommendations (like BMS's stance) to ensure they are making evidence-based decisions for their patients.
In conclusion, oncologists must navigate differing interpretations of trial data and regulatory guidance, considering both the potential benefits and risks of ICIs based on individual patient profiles, particularly PD-L1 expression levels.
#####
I asked SCITE.AI to write an automatic mini-essay based on its review of recent PubMed hits on the topic of PDL1 harmonization.
##
Recent literature on the harmonization of PD-L1 testing for
checkpoint inhibitor therapy reveals significant challenges and inconsistencies
that impact clinical decision-making. The expression of PD-L1 is a critical
biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs),
particularly in cancers such as non-small cell lung cancer (NSCLC) and
melanoma. However, the lack of standardized cutoffs for PD-L1 expression
complicates its utility as a reliable predictive biomarker. For instance, while
pembrolizumab is approved for patients with NSCLC showing PD-L1 expression
greater than 50%, studies indicate that even within this group, the response
rate can be less than optimal, suggesting that PD-L1 expression alone may not
be sufficient to predict treatment outcomes (Maung et al., 2020; , Wang et al.,
2020).
Moreover, the variability in PD-L1 testing methodologies further exacerbates the issue. Different assays and scoring systems can yield divergent results, leading to uncertainty regarding patient eligibility for ICI therapies. For example, Kaufman et al. emphasize the need for functional assays to assess PD-L1 binding capabilities, which may provide a more accurate prediction of therapeutic response than mere expression levels (Kaufman et al., 2023; , Kaufman, 2023). This highlights the critical need for harmonization in PD-L1 testing protocols to ensure consistent and reliable results across different laboratories and clinical settings.
References:
Chen, S., Zhang, Z., Zheng, X., Tao, H., Zhang, S., Ma, J.,
… & Hu, Y. (2021). Response efficacy of pd-1 and pd-l1 inhibitors in
clinical trials: a systematic review and meta-analysis. Frontiers in Oncology,
11. https://doi.org/10.3389/fonc.2021.562315
Kaufman, B. (2023). Functional binding of pd1 ligands
predicts response to anti-pd1 treatment in patients with cancer. Science
Advances, 9(21). https://doi.org/10.1126/sciadv.adg2809
Kaufman, B., Abramov, O., Yevko, A., Apple, D.,
Shlapobersky, M., Greenshpan, Y., … & Porgador, A. (2023). Functional
binding of pd1 ligands predicts response to anti-pd1 treatment in cancer
patients.. https://doi.org/10.1101/2023.02.09.527671
Kim, J., Kim, K., Kim, M., Kim, Y., Suh, J., Jeong, H., …
& Choi, H. (2020). Programmed death-ligand 1 expression and its correlation
with clinicopathological parameters in gallbladder cancer. Journal of Pathology
and Translational Medicine, 54(2), 154-164.
https://doi.org/10.4132/jptm.2019.11.13
Maung, T., Ergin, H., Javed, M., Inga, E., & Khan, S.
(2020). Immune checkpoint inhibitors in lung cancer: role of biomarkers and
combination therapies. Cureus. https://doi.org/10.7759/cureus.8095
Wang, M., Wang, S., Trapani, J., & Neeson, P. (2020).
Challenges of pd-l1 testing in non-small cell lung cancer and beyond. Journal
of Thoracic Disease, 12(8), 4541-4548.
https://doi.org/10.21037/jtd-2019-itm-010
Zou, Y., Chen, Z., Han, H., Ruan, S., Jin, L., Zhang, Y., …
& Jin, H. (2021). Risk signature related to immunotherapy reaction of
hepatocellular carcinoma based on the immune-related genes associated with cd8+
t cell infiltration. Frontiers in Molecular Biosciences, 8.
https://doi.org/10.3389/fmolb.2021.602227
SCITE.AI Prompt. Summarize recent papers on PDL1 harmonization for making decisions to use checkpoint inhibitor drugs. Focus on 2020 and newer papers. Note papers that discuss the lack of clear cutpoints for PDL1 expression or unreliability of PDL1 testing.
By 2026, FDA expects LDT labs to comply with increasing amounts of medical device manufacturing regulations, in particular, those on "labeling." (Note that labeling for complex PMA products, such as Illumina's new TSO CDx (PMA) 500-gene test, can be over 100 pages long, including instructions for use and other labeling).
FDA held a webinar on the topic on September 24, 2024:
Here's the webpage, where you can access streaming links as well as the 55-page deck.
FDA will post the video and transcript in about a week.
##
Here's coverage from Shannon Bennett and from Christine Bump.
##
I've always understood that labeling, including intended use, can involve a complex back-and-forth with FDA near the end of the product development cycle, with the FDA ready to assert at any moment that your intended use conflicts with your data in some way. Here, labs are asked to generate the labeling unilaterally, and submit it to the FDA, before FDA has seen or reviewed the LDT product.
##
Keep track of FDA's lengthy home page for FDA LDT issues:
https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests
##
I've provided an AI summary of the FDA webinar, in the whimsical format of a memo to your boss who's head of regulatory at your LDT laboratory.
Below that, some additional AI commentaries on the just-completed webinar.
##
Chat GPT 4o: Memo to Your Boss
To: [Boss's Name], Head of Regulatory at Big_LDT_Lab
From: [Your Name, Director]
Date: September 25, 2024
Subject: FDA Webinar on Labeling Requirements for LDTs and IVDs under 21 CFR 809.10(b)
On September 24, 2024, the FDA hosted a webinar focusing on the new labeling requirements for In Vitro Diagnostic (IVD) products, including Laboratory Developed Tests (LDTs), under 21 CFR 809.10(b). These regulations are part of the FDA's ongoing phaseout of its enforcement discretion policy for LDTs. By May 6, 2025, most LDTs must comply with the labeling requirements under 21 CFR 809.10(b). Full compliance is expected by May 2026.
The aim of these changes is to clarify labeling rules for LDTs, which have traditionally been less regulated than other IVDs. For a large diagnostic laboratory like ours, developing and using many proprietary LDTs, understanding and complying with these new regulations is essential for maintaining FDA compliance by the 2026 deadline.
The FDA outlined the mandatory information that must accompany any IVD, including those offered as LDTs. This labeling includes:
Documentation Expansion: All our LDTs will require detailed documentation covering the above aspects. While some of this information may already be part of existing internal protocols (e.g., test protocols and instrument manuals), they will need to be revised to comply with 21 CFR 809.10(b) standards. For example, specimen collection instructions must now include details on potential interfering substances, special handling, and patient preparation.
Compliance Timeline: As we approach the May 2026 compliance deadline, our regulatory team will need to prioritize tests that are frequently used and marketed. We may need to prepare labeling documents for submission as part of premarket reviews, particularly for high-risk or novel LDTs.
Clarification of Exemptions: Certain LDTs are exempt from premarket review or labeling submission. This includes LDTs for unmet needs within integrated healthcare systems and some older LDTs not modified beyond their original scope. We must assess whether any of our tests fall under these exemptions and plan accordingly/
Documenting Labeling Across Multiple Sources: Labeling for LDTs can be spread across multiple documents (e.g., test protocol, report template, test menu). This allows flexibility in how we structure compliance but also requires careful coordination to ensure completeness and clarity.
Risk of Misbranding: Tests lacking appropriate labeling will be considered "misbranded" under FDA regulations. Misbranding can lead to enforcement actions, including fines or product recalls. Ensuring accurate, truthful, and non-misleading labeling is paramount to avoid regulatory issues.
Internal Review: We need to conduct a thorough internal audit of all existing LDTs to assess which ones require additional labeling or modification to meet FDA standards.
Labeling Strategy: Develop a cross-departmental labeling compliance plan. This will include input from R&D, quality control, and regulatory teams to ensure all aspects of the 809.10(b) requirements are met across various LDTs.
Training and Awareness: Train relevant teams on the new labeling requirements and the importance of consistent documentation across all platforms (test protocols, inserts, and manuals).
Engagement with FDA: We should consider submitting questions to FDA and participating in the upcoming webinars on LDTs to stay updated on additional regulatory guidance, especially regarding labeling.
By staying proactive, we can ensure that our LDTs remain compliant with FDA regulations, avoiding any disruptions in service as the labeling requirements phase in.
If you need further details or assistance with specific compliance steps, please let me know.
[Your Name]
Regulatory Compliance Director
###
Please summarize the webinar.
###
This FDA webinar, presented by Toby Lowe, Acting Deputy Director of the Office of Health Technology within the Center for Devices and Radiological Health (CDRH), focused on labeling requirements for in vitro diagnostic (IVD) products, including laboratory developed tests (LDTs), as specified under 21 CFR 809.10(b). The FDA is phasing out its enforcement discretion approach for LDTs, with full compliance required by May 6, 2026. The discussion emphasized the importance of accurate and comprehensive labeling to ensure the safety and effectiveness of IVDs, specifically test systems.
Labeling requirements under 21 CFR 809.10(b) are meant to ensure IVD manufacturers provide key information about their products, such as intended use, limitations, and performance characteristics. These requirements are a critical component of the regulatory framework for ensuring the safe and effective use of IVDs, which include LDTs. The webinar outlined how labeling encompasses more than just packaging inserts—it includes all written, printed, or graphic matter accompanying the device, including test protocols, test reports, and other documentation.
The webinar outlined the core elements required in IVD labeling under 21 CFR 809.10(b):
The FDA is particularly focused on the compliance of LDT manufacturers with these labeling requirements. Manufacturers of IVDs, including those offered as LDTs, are expected to submit labeling as part of their premarket submissions, where applicable. For LDTs not subject to premarket review, the FDA expects manufacturers to maintain compliant labeling and provide it during FDA inspections. Manufacturers using reagents or instruments not labeled for clinical diagnostic use must qualify those components under their own quality systems.
The FDA may take regulatory action if labeling is found to be false, misleading, or incomplete. This could include cases where an LDT lacks sufficient evidence to support its claimed performance characteristics. Additionally, the FDA emphasized that promotional materials, which fall under the definition of labeling, must also comply with these regulations.
For LDTs approved under the New York State Clinical Laboratory Evaluation Program (CLEP) or those developed to meet unmet medical needs, the FDA will exercise enforcement discretion. However, manufacturers of these tests must still submit labeling information during the listing process, allowing the FDA to monitor the safety, effectiveness, and clinical validity of these products.
The labeling requirements outlined are intended to support consistent, safe, and effective use of IVDs in clinical settings. The FDA encourages manufacturers to review publicly available labeling examples on the FDA website, particularly those related to approved Premarket Approval (PMA) applications and humanitarian device exemptions, to guide compliance efforts.
The webinar concluded with a reminder about an upcoming FDA session on the total product lifecycle approach to IVD regulation, scheduled for October 24, 2024. This session will delve deeper into how IVD products are regulated throughout their lifecycle, from development to post-market surveillance.
##
Please summarize the Q&A.
###
Here’s a summary of the Q&A section from the latter part of the FDA webinar:
What does it mean when the FDA requests labeling submission for certain IVDs offered as LDTs at the time of device listing?
Will enforcement discretion be applied to promotional materials?
What are the FDA expectations regarding labeling for LDTs?
What are the labeling expectations for reagents and instruments used as part of an LDT but not manufactured by the laboratory?
What are the labeling expectations around performance characteristics, and how does that differ from what is expected in a premarket submission?
Toby Lowe emphasized that manufacturers should ensure their labeling aligns with FDA’s requirements, and additional resources, including publicly available labeling examples, are available to assist in compliance. The FDA's next webinar will cover the total product lifecycle approach to IVD regulation.
##
Will LDT stakeholders find some parts of this unsettling,
since they are used to only CLIA regulation?
##
Members of the lab-developed test (LDT) community who are primarily familiar with CLIA regulation are likely to find several parts of the webinar unsettling due to the additional burdens, costs, and uncertainties that FDA regulation introduces. The following aspects of the webinar may cause significant concern:
The FDA’s regulatory framework, particularly the labeling requirements, review of promotional materials, and stricter oversight, represents a significant shift for the LDT community. Labs that have operated successfully under CLIA may be upset by the financial burden, the additional layers of compliance, and the uncertainty around how these new requirements will affect their operations and test offerings. The perception that FDA regulation complicates innovation, adds cost, and introduces regulatory uncertainty is likely to be a central concern for many LDT developers.
