MEDCAC on CMS Evidence Development: Scoresheets and Video Posted

On February 13/14, 2023, CMS held a two day workshop on "coverage with evidence development."  CMS has not yet posted a transcript, but, it has posted voting scoresheets as well as Day 1 and Day 2 videos.

• Main web page here (very long vertically).
• PDF Scoresheet here. (Link from the main web page).
• Links for Video recordings, Day 1 and Day 2.  Here.  (At very bottom of the long web page, or search for "Video recordings" key word).
• Brief  meeting summary from Hogan Lovells, Langbein et al., here.
• A headline at Medtech Intelligence says that TCET policymaking will appear soon.
• TCET stands for "Transitional coverage for emerging technology" and is an umbrella term for CMS innovation policies to-be-created.

For voting questions, CMS proposed 17 features of studies under CED to rank as not important (0), important (1), or very important (2).   Most votes were "2" because the criteria are collectively necessary.    (It's like asking,"Which are important, steering or brakes or engine? (check all that are important).")  

It's unclear how some of the requirements would be enforced, for example, #15 results must be made public within 12 months of completion.  If results were made public at 15 months, what would CMS do?  Take back money from a hospital in Omaha that had been a trial site and gotten a payment 3 or 4 years prior?   Issue a fine to the association that sponsored the study (say, American Cardiology Association?)  or its P.I.?   Unclear.  

LCD Challenge: Unusual Example of a Winning Case (Glioblastoma therapy)

In 2003 (the year before I started a 4-year job as a Medicare medical director), CMS instituted regulations that govern the appeal (or "challenge") of an LCD or NCD.   Prior to this, a party could only challenge an LCD one single case at a time (claim by claim appeal), even if it always won.

CMS has an online information sheet here and the very long and detailed regulations are here at 42 CFR 426.  My blog today is a policy summary based on some online documents, and is not a legal document.  If you have any interest in this process, seek legal advice.

In the Name of a Beneficiary  

Technically, the challenges can only be in the name of a beneficiary who needs the service in question.  However, I believe in most cases a provider of the service takes over and manages the case, with permission of the beneficiary, hiring one or more attorneys to bring the case through the CMS legal system (panels of judges).

There is a single consolidated record of all NCD challenges since 2004 (almost none has ever won).  At least one way to find some LCD decisions is to simply search ALJ decisions for the exact phrase LCD challenge (search here).  For a case that got up to federal court, here.

A Winning Case for a Patient - Glioblastoma Therapy under Noridian LCD

Many cases lose and many are not filed in precisely the right way and lose on technical grounds.

I stumbled across an interestingly, lengthy, and apparently winning case, DAB CR5902 in 2021 (link below).  This involved a brain tumor patient who wanted (and whose doctor ordered) Tumor Treatment Field Therapy, TTFT.  The service was blocked by Noridian because it was started more than 7 weeks after glioblastoma diagnosis, and Noridian's LCD limited to care starting within 7 weeks, because a key clinical trial had used 7 weeks as a cut-off for starting therapy.   

• Teaching Case / Point 1.  This is a good teaching example of a MAC LCD reaching past the labeling or indication for a procedure, and imposing earlier clinical trial entrance criteria as a condition of care for all future patients.  If you ever need an example where MACs reach into the clinical trial patient criteria to write coverage, here 's one.
• Teaching Case / Point 2.  It is also a good teaching example of a MAC not backing down in the face of a court challenge it could lose (arguing that since the clinical trial enrolled to 7 weeks, therefore, a patient at 7 weeks and 1 day was invalid for care.)  

On July 9, 2021, the judge ruled that based on the MAC's arguments, their experts, publications, and the appealing party's arguments and experts, the LCD restriction to 7 weeks for start of therapy was not reasonable, and was not accepted by the neurology or neuro-oncology community in general.  It was not, for example, in NCCN guidelines.  The case is 50 pages long and has a two page summary.

https://www.hhs.gov/about/agencies/dab/decisions/alj-decisions/2021/alj-cr5902/index.html

The LCD.  Find LCD L34823 online here.  It was last revised (R8) in 1/2020, so not revised since the July 2021 case.  See the Johns Hopkins webpage about the tumor field therapy, here.

As background reading, see testimony of the attorney in this case, Debra Parrish, at a CMS public meeting in July 2019.

The case ran from February 2020 to July 2021.  A few sentences give a flavor of the case:

...On June 26, 2020, I issued an Order in which I concluded that L34823’s record, as submitted by Noridian, was insufficient to support the validity of that LCD.  Tumor Treatment Field Therapy LCD ID No. L34823, ALJ Ruling No. 2020-13 (HHS CRD June 26, 2020).  Noridian had not submitted all of the documents in the record for L34823, as required under the regulations, and Noridian had also submitted additional documents that had not been in L34823’s record.  Further, the AP submitted numerous documents and physician statements concerning the efficacy of TTFT commenced outside the seven-week period required in L34823.  .....In July 2020, Noridian declined to seek any discovery from the AP.  However, the AP served interrogatories and requests for the production of documents on Noridian.  In addition, on July 22, 2020, Noridian filed the missing documents from the record in L34823 as CMS Exhibits 51 through 73....Noridian did not object to any of the AP’s proposed exhibits but did request to cross-examine the AP’s expert witnesses....  

The case record goes on like this for 50 pages.  Along the way, the judge notes that CMS challenged the expert witnesses for the patient who may have received research funding in the field.  

 

[Judge Anderson writes] Finally, I note that Noridian’s belief that the expert witnesses are financially conflicted in this case is an insufficient reason for me to disregard their testimony.  There is no evidence that any of the experts have an ownership interest in Novocure or will financially benefit from Medicare covering TTFT more broadly than it does now.  Although some of the experts have received relatively small sums personally from Novocure, and some of the experts’ academic institutions received reimbursement for conducting studies for Novocure, I find it impossible to credit such small amounts of money as a reason to discount their combined testimonies. 

--

In my search of ALJ records by keyword, there was only one hit for "MolDx," which was a dismissed LCD challenge re L36159 Factor V Leiden, in 2021, C-22-13, CR5997.

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Bonus.

This is a ChatGPT summary made with the help of Chrome Plug-in, "ChatGPT Suite."

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This article discusses the challenge process for Local Coverage Determinations (LCDs) and National Coverage Determinations (NCDs) and a winning LCD challenge case for Tumor Treatment Field Therapy (TTFT) for a patient with glioblastoma.

🏥 Challenges can only be made in the name of a beneficiary who needs the service, but providers often manage the case.

📜 There is a consolidated record of all NCD challenges since 2004, and LCD decisions can be found by searching ALJ decisions.

🤕 The winning case involved a patient with glioblastoma who needed TTFT, which was initially blocked by Noridian's LCD.

🧑‍🏫 The case is a teaching example of a MAC LCD imposing earlier clinical trial entrance criteria as a condition of care and not backing down in the face of a court challenge.

📄 The LCD can be found online and was last revised in January 2020.

🕰️ The case ran from February 2020 to July 2021 and involved a lengthy legal process.

💰 There was one dismissed LCD challenge re L36159 Factor V Leiden in 2021.

Battles over Evaluation of Science Evidence: An Evergreen Problem Since 1520

Almost every week, someone reaches out to me about a dispute related to evidence (can Product X be covered, or not covered?)    We saw this issue in headlines this week, when CMS publicly declined a request from the Alzheimer's Association to update Medicare's non-coverage of certain disease-modifying drugs in dementia (entry point here.)

At a Medicare meeting this week, a senior medical director remarked that people would like simple numeric rules for evidence (like "How many patients in a trial?") but that it's not that simple.  Some smaller trials have big effects (patients live 12 months versus 24 months) and some large  studies have minor or confusing small effects.   So, it depends on a layer of expert judgement that is contingent on circumstances.   More so probably in diagnostics, where the value is dependent on downstream events, like therapy choices.  (Emphasized recently in Soares, Establishing the Value of Diagnostic and Prognostic Tests, 2018 here.).

Disputes For Centuries, at High Temperatures

These disputes have gone on for centuries, and debates from the 1500s and 1600s seem surprisingly fresh in tone.  In the early 1500s in Italy, Tartaglia and Cardano fought bitterly and publicly, and enlisted enemies and allies, over  mathematical proofs (Hellman 2006).  William Harvey's theory of circulation of the blood, published 1628 (in Germany; banned in England!) brought hostile debates, and literally one book after another was published to tear Harvey's ideas apart (Hellman 2001).   

One of my very favorite quotes about evidence disputes I've seen only in a rare book (Stern, 1941).  Late in life, Harvey wrote:  

"Scare a day, scarce an hour, has passed since the birthday of of the circulation of the blood that I have not heard something for good or evil said of this discovery.  Some abuse it as a feeble infant, and yet unworthy to have seen the light.  Others again this the bantling deserves to be cherished and cared for.  These oppose it with much ado, those patronize it with abundant commendation.  One party holds I have completely demonstrated the circulation of the blood by experiment, observation, and ocular inspection, against all force and array of argument.  Another thinks it is scarcely, but sufficiently demonstrated, not yet cleared of all objections..."  

Stern writes, "Harvey claimed that no man over forty was found to adopt the doctrine of circulation of the blood," placing Harvey with an idea attributed to Max Planck, that scientific ideas win because their opponents eventually die.  

Medical Progress and Leadership

In a new book, biotechnology expert Brian Smith (2022) explains that the life sciences and medical technology are an ecosystem with many parts, and often not well-designed to achieve effective medical progress.   Many ecosystems have disparate goals (NIH, biopharma, investors, payors, physicians, patiens, and so on).  I was reminded of the role of leadership in these situations by page 1 of a book by Kissinger (2022).  Imagine the following paragraph in regards to the health innovation context -- such as CMS National Coverage Determinations, or CMS "Transitional Coverage for New Technologies," or the MolDx molecular test program.  

"Any society is perpetually in transit between a past that forms its memory, and a vision of the future that inspires its evolution.  Along this route, leadership is indispensible...to help people reach from where they are to where they have never been,and, sometimes, can scarcely imagine going.  ...[Leaders] must balance what they know, which is drawn from the past, with what they intuit about the future, which is inherently conjectural and uncertain.  It is this intuitive grasp of direction that enables leaders to set objectives and lay down a strategy...communicating objectives and rallying support."

Although I didn't have this quote at that time, it's this thought I had in mind when I wrote that I was disappointed that a recent CMS two-day workshop on "Evidence Development" focused its expert panel on answering only questions about methodology and not where we should be going and  why.   To me, this is like a focus on how thick the asphalt on a road should be, displacing a chance to focus on to where the road should be built and why.  The "methods-only" focus (or any other single-minded focus) there in the payor silo powers the separately-spinning and inefficient medtech ecosystem that Smith (2022) writes about.  

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By the way, in the field of diagnostic testing, the concept of "value" as clinical utility is not new.  When I was in medical school in the 1980s, we students were asked, "Why order that test, and how will it impact this patient's care?"   And in 1800 when Laennec discovered the stethoscope, one naysayer immediately took the position, "You will learn nothing by it, and, if you do, you cannot treat the disease any better," which is pretty good for a 223-year-old definition of clinical utility from a diagnostic procedure.  (Hellman, 2001, p X).  

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Hellman H (2001)  Great Feuds in Medicine.

Hellman H (2006) Great Feuds in Mathematics.

Kissinger H (2022) Leadership.

Smith B (2022) Darwin's Medicine: How Business Models in the Life Sciences are Evolving.

Stern B (1941)  Society and Medical Progress.

Planck's original quote, 1948 (Gegner allmählich aussterben).

 

Very Brief Blog: CMS Turns Down Alzheimer Association Request on Drug NCD

In December 2022, the Alzheimer Associated submitted a detailed formal request to CMS, asking for reconsideration of a current, extremely limiting coverage of FDA-approved Alzheimer drugs.  See my blog with links here.

On February 22, 2023, CMS issued a press release that the request would not be accepted; the status quo remains.   Here.

CMS writes in the press release, 

At this time, CMS is not reconsidering the national coverage determination (NCD) for Food and Drug Administration (FDA)-approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. We recognize that these medications are a unique, new class of drugs, and we regret that the decision could not be more favorable.  After careful review of the request and supporting documentation, we are making this decision because, as of the date of this letter, there is not yet evidence meeting the criteria for reconsideration.

CMS also refers to "CMS's letter to the Alzheimer's Association," suggesting that there's a letter circulating behind this press release.

Alzheimer's Association released its own press release and therein, linked to the 3-page CMS response letter in PDF.

See Reuters here.  See Fierce Pharma here.  See "New Drug is Game Changer" at Nature here.  A pivotal study for lecanemab appeared last month in NEJM here.

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CMS in its response said it was waiting for FDA  confirmation of "clinical improvement" but the FDA accelerated approval, and NEJM publication, including significant impact on clinical memory scales, which to my ear, IS clinical improvement (in a disease which is a cognitive disorder).   

See a trade journal article on Alzheimer measurement scales by Annalee Armstrong who is a senior editor at Fierce Biotech - here.

AMA Posts May CPT Meeting Registration and Lab Codes for Early Comment

 AMA has posted a registration and agenda page for the May 4-6 2023 hybrid CPT meeting in Chicago.   Registration will open February 27.

AMA posts lab code applications very early to allow time for public comment prior to the subcommittees meetings.   

Lab codes here:

https://www.ama-assn.org/system/files/may-2023-path-lab-mo-path-agenda.pdf

If you want to comment on a lab code, you must request an information packet by March 3, and return it by March 6.

There are lab applications big and small:

• Acetylcholine receptor antibody
• About twenty MORE Cat III codes relative to glass slide digitization (there were already quite a few prior to these new ones)
• Revision of MAAA code 81528 to include protein markers.  This is the Cologuard code (Exact Sciences).
• Applications for Cat I, optical genome mapping (OGM) for tumor and for germline (2 codes)
• Yet again an application for "gadolinium serum level" 
• Hep D q-PCR
• An Admin MAAA code for CV disease risk
• Cat I code for patient-normal sequence variants to match a tumor sequencing procedure
• Two Cat I codes for molecular testing for microbial resistance
• 5 codes for "ultra sensitive protein detection procedures"

Natera Signatera Test Gets MolDx Coverage as 'Minimal Residual Disease' (MRD) Test

Big news on February 15, 2023, that Natera receives MolDx MRD coverage for its circulating tumor DNA test "Signatera" in the indication, breast cancer.

• See the Natera press release, here.
• Open access at Genomeweb here.
• Investors Business Daily here.
• See a pending "Empowered with Meg Ryan" cancer information episode on the topic here.
• From back in December, see a San Antonio Breast Conference press release here.

According to the press release, the coverage applies to both adjuvant therapy decisions and MRD monitoring, and applies to patients with IIb or higher breast cancer stage. It applies across HR positive, or Her2 positive, or Triple Negative cases.  Interestingly, the press release in particular highlights data published in 2019 as Coombes et al.  But they also remark, "This study is one of several that support the use of Signatera in breast cancer, and one of over 40 peer-reviewed publications across solid tumors."

Natera presented at JP Morgan in mid January, and their year-end investor call will be February 28, 2023.

The stock shot up vertically from $42 to $49 on Thursday morning.  The jump in market cap was roughly from $4.5B to $5.4B, or a billion dollars upward.

MolDx's LCD for MRD allows coverage in both solid tumors and hematopoietic cancers, and both for MRD (unexpected recurrence) monitoring and drug-therapy decisions.   However, MolDx grants coverage slowly and carefully on a test-by-test basis.  Most of the known coverage to date is for the Signatera bespoke tumor detection test (for colorectal cancer, for bladder cancer, and now for breast cancer.)   Guardant has coverage for colorectal cancer, and Adaptive Biotechnologies for some hematopoietic cancers.   

There are also negatives.  In October 2022, Neogenomics announced it was dropping out of the MRD coverage race for its colorectal RaDaR product, but continuing to pursue MRD for a breast cancer project - here.  We know that Neogenomics had submitted from MRD coverage in January, per another press release.

 

Catching Up with OIG: Their take on NCD-LCD Confusion & Bariatric Surgery

The CMS NCD for bariatric surgery dates back more than a decade without revision.  It's worth noting for two reasons.   One, there is a contorted policy twist apparently to make bariatric surgery covered.  It's not enough to have severe obesity (like a BMI of 40 or 50).  You have to ALSO have "a disease" that is being "treated" by bariatric surgery - such as knee pain or diabetes.  This always seemed strange to me.  It's like a smoking cessation benefit that predated a later benefit, the first one required tobacco addiction "and a disease" like emphysema.    Regarding the bariatric surgery NCD, a second factor was its vagueness on some key points.

In February 2022, OIG issued a report on Medicare and implementation of bariatric surgery policy.  

The OIG noted that some sections of the NCD were highly vague, and therefore, required supplementation by LCDs.   However, the OIG then noted the LCDs varied quite a lot, and even taken them at face value, the rules weren't always followed by hospitals and payment systems.  OIG recommended modernizing the NCD to include rules that LCDs were adding post-hoc, and if possible, reduce discrepancies among LCDs.

In an unusual move, CMS took NONE of the OIG suggestions; it rejected all of them.  The rejections didn't always make sense;  CMS retorted that statute did not require LCDs to be uniform.  No, replied OIG, but we never said it did.

You can read the full report, including the quarrel back and forth with CMS, here:

https://oig.hhs.gov/oas/reports/region9/92003007.asp

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I poked fun at CMS's oddly convoluted reasoning that even grave obesity (BMI 50) is 'not a disease' and can only be medically treatable if the bariatric surgery "treats another disease" like knee failure.  See two current news articles on obesity viewpoints,

https://www.clinicaladvisor.com/home/topics/obesity-information-center/obesity-organizations-release-consensus-statement/

and

https://www.axios.com/2023/02/18/obesity-treatments-drugs-insurance-coverage-stigma

 

CMS Reverses Another Policy Decision: Advanced Wheelchairs as Benefit Category

Today is the second time in several months that CMS has reversed (or radically changed) a position on benefit category and policy.   The first involved the connection between a stool colon screening test and a colonoscopy, and the second (new) involves a new decision on advanced wheelchair functions being a part of durable medical equipment (DME).

The Colonoscopy Copay Flip

In the earlier decision, in November final rule-making, CMS determined that a colon cancer stool test and a follow-on colonoscopy were part of a continuous process of diagnosis, with the goal that the colonoscopy did not require a  copay.  (87 FR 69760, 11/18/2022; also stated on p.4 here).  (This was separate from lawmaking that a tissue biopsy did not make the colonoscopy require a copay any more).  

The CMS decision was interesting because a positive FIT or COLOGUARD test had been triggering a "diagnostic colonoscopy" with a copay, for years and years.  

Separately from Medicare, HHS had earlier ruled that a stool-triggered colonoscopy in private insurance did not require a copay (ACA FAQ12-Q5).

The Mobility Device Flip

In the new decision, we turn to power wheelchairs.  IN a Benefit Category Determination on July 26, 2006, CMS determined that an "iBOT 4000" had lifting and stair climbing functions that were not medical and therefore not DME.   In the new decision - here - CMS rules instead that seat lifting systems ARE a medical function, for example, by preventing shoulder injury caused by stretching up. [*]  While the decision is framed as a "Coverage Analysis" a large part of the decision is in fact a "benefit category analysis."

NCDs: Don't Hold Your Breath

The NCD released today, in draft form, is based on a formal 90-page request accessioned in September 2020 (from the ITEM, the Independence Through Enhancement of Medicare & Medicaid Coalition.)  So from request to draft, about 2.5 years.

The Moral

I guess at least one moral could be drawn, if CMS has a formal decision against something, as a matter of law and policy, it's still subject to a 180 degree reversal in a future year.

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[*] For example, writing:  Users of wheelchairs long term reported that the greatest degree of shoulder pain occurred when performing non-level transfers (Curtis and Roach 1995) while one recent study (Barabareshci and Holland 2019) found that 66% of subjects felt that transfer activity exacerbated their underlying shoulder pain.  This hardly seems like major new information since 2006, the negative decision.

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See a white paper from HHS on preventive services under the ACA.

The ACA decision about colonoscopy copays following a positive FIT is FAQ 12 Q5.

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Basically, a screening colonoscopy used to trigger a copay if there was a tissue biopsy during the procedure.   This was changed by law, which took its stakeholders years of jawboning.  However, a colonoscopy was still "diagnostic" with a copay if it was triggered by FIT/Cologuard.  Which was changed in 11/2022.  

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One might ask, if a Cologuard and a Colonoscopy are part of one continuous process for CRC screening, why isn't the same true for LDCT and a follow up CT for cause (or biopsy), or a cervical Pap smear and a follow-up cervical biopsy, or a high PSA and a follow up biopsy for cause.   The best I can come up with is, well, they ARE all similar in many ways, part of a continuous work up from cancer screening test to cancer diagnostic.  However, Colonoscopy is the only one of these that ALSO overlaps and exists in parallel as a standalone, copay-free screening test, which is not true for, say, a lung biopsy.

Speaking Event: TRI-CON SAN DIEGO (MTW, March 6-8, 2023)

I'm speaking and chairing a panel at the 30th annual "TRI CON" conference for Molecular & Precision Medicine, in San Diego March 6-8, 2023.

There are multiple tracks, some of which partially share events.  I'm in the Tuesday-Wednesday track, "Diagnostics Innovation and Market Access," and on Wednesday afternoon our topic is "Reimbursement Strategies for Advanced Diagnostics."  Nicholas Halzack of Roche will discuss PAMA Reform and parallel efforts; I'll discuss Medicare's plans for better coverage of transitional technology; and Dr Bien-Willner of MolDx will "Demystify Molecular Diagnostics Coverage & Reimbursement in Medicare - MolDx."  

A partial list of speakers in this track on Tuesday-Wednesday will include Lon Castle of eviCore, Mathew Fickie of Highmark, John Fox and Damon Hostin of Illumina, Mara Aspinall of ASU and Bluestone Ventures, Ajit Singh of RA Artiman Ventures, John Szajka of BD, Bruce Tromberg of NIH/RADx, Lauren Feldman of ADVI, Suzaane Belinson of Tempus, Shaunna Kobilis of Adaptive Biotechnologies..  

More info here including a discount code:

CHI’s 30th International Molecular & Precision Med Tri-Con, March 6-8, 2023 in San Diego. Visit www.triconference.com for detailed program and to register, plus you can use my code “LI200” for additional $200 discount.

UCSF: Outstanding "Grands Rounds" on the State of AI in Medicine

UCSF has an outstanding online grand rounds series - here - and this week it posts an excellent one-hour, five-speaker review of some newest trends for AI in Medicine.  The Grand Rounds makes CHAT GPT its focus, but includes other topics.  Find the video at YouTube here:

https://www.youtube.com/watch?v=j-aOCuzfxUI

Faculty speakers are Drs. Bob Wachter (chairman), Aaron Neinstein, Sara Murray, Dan Lowenstein, and Atul Butte.

One of the most arresting moments for me was when Dr Butte gave Chat GPT - which isn't even specifically trained on medicine - an oncology unstructured record, and asked it to summarize the biomarkers in the record. Which it instantly could do:

Just as rapidly, Chat GPT could summarize all the diagnostics - imaging & pathology - and structure them in a table:

I couldn't resist the urge to turn AI on itself.  

I ran an autotranscript of the audio, and fed it into Chat GPT (10,000 words, but no more than the limit of 1500 words at a time).  This gave the whole hour summarized by AI into ten-minute segments.  Last, I asked Chat GPT to summarize this collection of six mini-summaries into one single summary of the whole hour.     This is what I got:

• The discussion on Chat GPT is part of the UCSF Medical Grand Rounds and is hosted by Dr Bob Wachter, Chair of the Department of Medicine at UCSF. The session focuses on the current and potential uses of Chat GPT in healthcare and its implications. 
• Four experts in the field, Drs Aaron Neinstein, Sara Murray, Dan Lowenstein, and Atul Butte, present on different aspects of the topic. Dr. Neinstein discusses the slow adoption of AI in healthcare and suggests that AI can augment the patient-doctor relationship and help with administrative tasks. Dr. Murray talks about GPT-3 and mentions potential applications in healthcare, including clinical documentation, streamlining literature review, and task automation, but also highlights risks such as bias and hallucination. Dr. Lowenstein discusses the potential of Chat GPT in medical education and research, but also highlights the need for improvement in knowledge processing. Dr. Butte discusses the advancements in AI technology and the importance of caution and ethical considerations. 
• The speakers in the panel discussion touch upon the impact of AI on education and healthcare, the ethical implications of using these tools, and the potential for misinformation with the use of GPT. They have mixed feelings about the topic, with some being both excited and scared, while others are optimistic or cautious. They agree that the use of GPT in healthcare is complex and important, and will require ongoing discussion and careful consideration.

See my Google Doc summary to access the summary above, then, the six transcript sections that led to the summary, and if of interest, the Otter auto text used as input to the AI.

https://docs.google.com/document/d/1PFYtW_fhucpjkO9lUzAe4I2fVd2rczLyBnXY3O7QE6Q/edit?usp=sharing

Precision Medicine: Are We Seeing More Rigorous Papers, With More Reasonable Claims?

One of the factors that has plagued precision medicine has been claims of big benefits that aren't often clearly justified, made numerical, or which seem to defy the reader's own "back of envelope" calculations of benefit.  (For example, big claims that promise of future clinical utility and benefits, that may or may not occur at that scale for a range of reasons.)

Recently, I've seen a trend to impressively designed papers with quantitative benefit claims, rather that loosely forecast ones.   Here are a few examples.

Swen et al. (2023) Lancet:  12 gene PGx panel in RCT

Swen et al. report in Lancet a multi-institution, cluster-randomized study of 12 pharmacogenetic genes.  In some 1500 patients with actionable  results, adverse events were 28% in the control group and 21% in the PGx arm.   The study has a reasonable panel (12 genes), a rigorous design (cluster-randomized means randomized by clinic location), and good outcomes measurement.   This resulted not in vague claims of some kind of massive benefit, but rather, in demonstrated data for a reasonable and solid benefit (28% to 21%).  

Tafazzoli et al. (2022) Pharmacoeconomics: Projected Outcomes of Multi-Cancer Screening

In a rigorous pharmacoeconomic model, Tafazzoli et al. report projected outcomes based on real-world stage of discovery today for 19 cancers, projected changes (some larger, some smaller) from Stage 3/4 to Stage 1/2, and average expected impact on costs and survival for patients in a commercial health plan (e.g. per 100,000 patients).   A wide range of factors are considered, including costs of false positives, missed cases (between screening intervals), and missed cases (due to sensitivity to detect in Stage 1/2).  Of note, there are exceptional valuable and detailed per-cancer tables in the Supplementary Materials.  The authors report realistic stage shifts (e.g. demographics of 20% stage IV esophageal cancers today, become 10% stage IV esophageal cancers with population screening; Figure 2.)  Overall, costs of stage 3/4 cancers fall by about half, while on a population-wide basis, this is offset by the costs of annual plasma screening for many years.   The model becomes more favorable as the costs of cancer care rise and if the costs of per annum molecular screening lower with testing at scale and new tech.  

• Besides the invaluable supplementary tables in Taffazoli, see the supplementary "CHEERS" checklist for writing excellence, which I mentioned in an earlier blog.

Wong et al. (2022) Personalized Medicine: Health Plan Coverage vs Major Guidelines

Rather than hand-waving about difficulties with payors, Wong et al. rigorously surveyed major health plan coverage for multi-gene tumor panel testing, compared one-to-one with major guidelines.   71% of 38 plans reviewed were "more restrictive" than current major guidelines, for that plan's effective date.   The authors recommend better guideline clarity, and the possibility of state-level policies for guideline-endorsed access.   

Bonus Citation:
Lennerz et al. (2023) Clin Chem Lab Med: Diagnostic quality model (includes AI/ML)

I mentioned this briefly since I'm still working through this new article, but it provides an excellent example of rigorous systems thinking for quality management in a lab field that increasing depends on software, machine learning, AI, and integration with the clinical sphere via EMRs and other feedback loops.   The paper supports a gap analysis as well as pointing the way toward quality metrics.   This is important as a recent Genomeweb survey found that many institutions are aware of substantial precision oncology process gaps, yet very few of them had any kind problem-reduction plan [!].   

All four of the papers (Swen, Tafazzoli, Wong, Lennerz) are open access.

Very Brief Blog: An Interesting Tool for Sharper Publication & Dossier Writing ("CHEERS")

This week, I was reading a recent detailed publication on cancer screening using plasma DNA, its costs & effectiveness (see Tafazzoli, 2022, open access, PMID 36038710).  

Like most papers, it has supplemental files online.   I was surprised, and intrigued, to see an Excel file that is not the usual background data, but a structured infrastructure of how the paper is written.

Checklist from CHEERS: Worth a Glance

The Excel spreadsheet is online here.  I'm sure some readers will have heard of it, although I hadn't.  It's called "Checklist from CHEERS."   (It's a standard for health economics, but 90% of it could be adapted to other uses).   It provides a list of about 30 topics or issues the paper should cover, and the authors provide a verification that each item was discussed (e.g. item 19 is discussed on manuscript lines 191-200, 209-215).   

It would probably be a godsend if this type of crystal-clear plan or structure was used more commonly.   Whatever type of scientific or persuasive writing you do, probably worth a look.

Screenshot in part; click to enlarge.

Screenshot in part; click to enlarge

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By the way, this journal Springer/Nature had a helpful guide to authors online, "get your manuscript ready for editors" - here.

"Can ChatGPT Summarize It?" A Litmus Test for Clarity?

Starting Point:  On January 20, 2023, I published a new white paper on trends in coding and reimbursement in solid tumors - find it here.

I used this as the basis for some AI research on Chat GPT's ability to summarize key points.

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Computer Summary of Executive Summary

The white paper has a page-long executive summary, and about 10 pages of text.   

I gave the executive summary to ChatGPT to summarize, and it did a pretty good job.  (Clipped at bottom; 615 words to 165).

And...Summary of Half of Paper

Next, ChatGPT can't absorb 10 pages of text, so I cut and pasted  the second half of the paper into ChatGPT, for a summary.   This also came out pretty well.   (Clipped at bottom; 1700 words to 163).

What's the Point?  Could This be a Clarity Litmus Test?

So it occured to me, people often think of ChatGPT in forward-mode:  Can it write a paper?  Can it write a discussion section?   In today's essay, I am using it the opposite way, as a sort of instantaneous cross-check after the writing's done.  

Proposed: If you have written a paper, essay, op ed, or executive summary, can ChatGPT "understand it" and summarize it clearly?  If so, you've written clearly enough that even a computer (basically a pile of tin cans and some batteries) can understand it, then it's probably fairly clear.

And on the other hand, if you give your essay to ChatGPT to summarize, and it returns with a confusing, conflicted mess, maybe - just maybe - your human writing isn't as clear as you thought it was.

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The Computer Summary of my own Executive Summary:

Comprehensive Genomic Profiling (CGP) in cancer is widely recognized as having clinical utility and is included in updated guidelines, Medicare coverage policies, and white papers. The newer plasma-based CGP technology is preferred by some cancer patients as it is available when solid tumor tissue is not and can be performed serially to determine therapy resistance. The AMA code set for genomics does not distinguish between specimen sources but the newer PLA code set does and there are already codes for plasma-based tumor testing. Reimbursement for plasma-based testing requires codes specifying it as the underlying technology and there are already codes for two FDA-approved tests. The cost of plasma-based testing is higher due to the depth of sequencing required, but it offers cost offsets compared to tissue-based testing. The AMA CPT has recently introduced new specificity codes for RNA sequencing in cancer and is working on updating the coding system for cancer genomics. 2023 is expected to be an exciting period for policy around plasma-based CGP.

Computer Summary of Second Half of My White Paper:

The coding system for genomics in the US, the AMA CPT codes, has seen a rise in codes related to genomics in recent years, including the creation of the "Proprietary Laboratory Analysis" (PLA) codes. There are currently only a few codes for tumor genomics and these codes have not yet been specific to sample source such as plasma or paraffin. The AMA CPT has recently revised codes for DNA and RNA analyses but more needs to be done to keep up with the latest advancements. The coding system has not yet recognized the coding for plasma-based comprehensive genomic profiling (CGP) testing, which is an important area now seeing FDA-approved tests and rapid innovation from laboratory-developed tests. The resources for plasma-based CGP tests are different and higher than for FFPE-based tests, but there are cost offsets obtained from using a plasma-based approach. There is still time to debate these topics and develop the best consensus strategies through the AMA CPT meeting in May 2023.

Lessons from OPPS Rule: Downgrading Payment for a Pathology Test

Here's a brief case study on how hospital outpatient payment is different from "physician fee schedule" payment, and how sudden changes can occur in the former.

Way back in 2011, AMA CPT created a new FISH code 88121 specifically for urine FISH with 3-5 biomarkers.   (Prior to this, FISH from any source was paid in multiples of the number of markers, and CPT felt that urine FISH with 5 biomarkers should be priced as a single service.  This resulted in a significant price cut, something like 50%, for applicable services).

In the non-facility setting, a pathology code is priced by RVU's, physician materials and work units.  In the facility setting, the technical component of the code is priced by administrative assignment of the code to an "APC," an ambulatory payment category.  This results in one price for any of a basket of services in that APC.  

OK, so 88121 has been paid as 5673 "Level III Pathology' for $333.  CMS found the median hospital charges calculate to $175.  So CMS re-assigned 88121 down to 5672 "Level II Pathology" at $162.

This was a proposed rule in July 2022 and finalized in November 2022.   

CMS received a number of protest letters, arguing that the APC Level II price was too low.  CMS responded patiently that it prices hospital services by taking the geometric mean of claims charges (using a chart-to-cost deflation value) and that gave median hospital values of $175 which fits an APC whose payment is $162.

The moral is, a successful and high enough APC assignment for a new code can decay into a lower APC reassignment based on CMS's annual review of incoming hospital claims and charges. 

I've put the CMS discussion (87 FR 71871) in a cloud PDF here.

  

Very Brief Blog: Dr. Karen Nakano Retires from CMS

Many in the lab community have appreciated the hard work of Dr. Karen Nakano as one of the CMS senior policy staff responsible for laboratory payment issues.   It's announced she reached retirement from CMS, at the end of January 2023.

Brief Blog: NGS MAC Updates Molecular Pathology LCD: Oddities and Errors

On February 2, 2022, the NGS MAC released a proposed update of its broad molecular services LCD, L35000.  Here.

First, the updates are narrow and involve a few codes for cytogenetics.  However, I noticed a few other aspects of the LCD.

Odd "Issue Description"

First, LCDs online at CMS are now required to post an ISSUE DESCRIPTION for each new LCD or revision.   However, for L35000, NGS MAC has simply filled this box in by using some old cut and paste boilerplate tht "LCDs address circumstances under which an item may be reasonable and necessary."  Surely CMS intended this mandatory box "Issue Description" to orient the reader to the new LCD, not merely to fill with unchanging boilerplate that LCDs define covered services.   

Request Letter Posted

Second, the request came from Mayo Clinic in October 2022, so the lag to the draft update was just 3 1/2 months.   (I've seen other requests lag a year or more).

Third, the request letter is posted online, it's brief at two pages, but readers can reference it for style and content.  

Process

In the "Proposed Process Information / Synopsis of Changes" NGS MAC notes that IGH and TP53 genes will be covered, and that this matches to NCCN guidance.

In a "Document Note," NGS MAC notes that only IGH and TP53 gene coverage in CLL is open for comment.

LCD Structure is Unusual

The LCD has a lengthy section with typically one-sentence coverage statements, and an even longer section of non covered genes, the latter showing the gene name only and no remarks.

Although the LCD deals with a very large numbers of genes, the required "Summary of Evidence" and "Analysis of Evidence" sections are very brief and only deal tersely with a couple topics.

LCD Has Major Errors

The LCD has a section that even 5-50 gene panels are not covered in cancer (except 5-50 genes in lung cancer.)  The LCD then refers to LCD L36376.  

However, L36376 was deleted four years ago (2019).  In fact, they have coverage for 5-50 gene and also 51+ gene panels in their LCD L37810.   

I submitted a comment that this section of LCD L3500 was out of date, out of sync, and confusing.  

Pharmacogenetics

Readers may note that the coverage here for PGx cods (CYP2C6 etc) is exceedingly narrow, far narrower than PGx LCDs at MolDx and Novitas/FCSO MACs.

CMS Gears Up for Feb 13/14 MedCAC on CED: Download Background, Speakers, Presentations

Update: See a Hogan Lovells summary of the MedCAC days, here.

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Back in September 2022, CMS announced a MedCAC (public panel workshop) on Coverage with Evidence Development.  Back in November 2022 they pushed the date from December 2022 to February 2023.  Now, they've posted details, agenda, panelists, speakers,  and background materials.

Although we don't read the word "TCET" on the page, the meeting is widely viewed as part of the Biden administrations to boot up a program or policy package called "Transitional Coverage for Emerging Technologies."   This has been proposed to develop and be defined, as a replacement for "MCIT" Medicare Coverage for Innovative Technologies under the Trump administration.  The MCIT, which was never put in effect, linked coverage to FDA breakthrough status.

Find it all here:

https://www.cms.gov/medicare-coverage-database/view/medcac-meeting.aspx?medcacid=79&year=all&sortBy=meetingdate&bc=15

See a wide range of materials:

• Registration link (your email)
• Roster
• Questions
• Agenda
• Speakers
• Written public comments
• Background materials (incl. tables for AHRQ review)
• Presentations [includes 58 p AHRQ deck]
• AHRQ review document "Requirements for Coverage with CED"
• Original Federal Register notice

Some of the above resources like "Agenda" are simply downward extensions of the webpage.

The agenda includes a summary of the AHRQ question review by Jodi Segal MD of Johns Hopkins.  Public comments run from 11:30 to 12:50.  There are 14 speakers, such as Medtronic, AdvaMed, American College of Cardiology, MITA, SNM, and others.  There are a few minutes for open mic public comments after lunch, then the panel discusses the key questions.

Panelists are asked to score the importance of the following aspects of CED:

• Sponsor
• Communication
• Governance
• Context ("Rationale for study is well supported," "Study is not unnecessarily duplicative," etc.)
• Protocol ("registered with Clinical Trials.gov")
• Population
• Generalizable
• Data quality
• Data use
• Design - Subpopulations ("Must discuss subpopulations...")
• Reproducibility (e.g. analysis is robust to alternative analyses)
• Reporting
• Sharing
• Legal (e.g. medical care, not simply testing toxicity in health individuals)

The panel, chaired by Joseph Ross MD of Yale, includes guest members Dr. Caños of CDRH, Dr. Umscheid of AHRQ, and Dr. Hodes, NIA/NIH.

Part of the AHRQ pre-work was to have 9 experts rate about 20 bullet points as "2" (essential) "1" (important) or "0".   See the webpage link "background materials" or click to enlarge the figure below.  4 were rated "2" by all reviewers, and 3 more were rated "2" by almost all reviewers.

AHRQ / Click to enlarge / Background materials