February 29: FDA Emergency Guidance on COVID-19 Testing under CLIA

On February 29, 2019, FDA issued an emergency bulletin allowing high complexity CLIA labs to performed locally developed testing for COVID-19.    The bulletin is here; open access coverage at Genomeweb is here.   See also coverage at MedTechDive, here.  For rapid FDA clearance of a New York State test, Genomeweb here.  For an update at WSJ through March 3, here.

For a March 4 update at Genomeweb, here; for a March 5 update at Genomeweb, here.

Large amounts of LDT high complexity CLIA lab testing is already routine in microbiology, and nationwide, without special permission.  With this bulletin the FDA, I think, is being sure to stay ahead of the policy skirmishes on this one.  AACC provides some backstory.

AACC has a webpage dedicated to coronavirus issues, here.   AACC specifically notes in a February 28 open letter to the FDA that an FDA Emergency Edict had not only allowed certain urgent new rules for approved emergency use [good], but proactively barred any other labs from doing tests outside that rule (here) [bad].  I believe AACC wanted CLIA-regulated LDTs and FDA emergency use tests to proceed in parallel in this urgent period.

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On Genomeweb, I noted a COVID-19 qPCR webinar scheduled for March 23, sponsored by Co-Diagnostics (Featherstone & Satterfield), here.

Brief Blog: Discordant Ratio of Private and Medicare Payments, for Hospital versus Lab Services

The March 2, 2020, issue of Business Week has an article by John Tozzi and Emma Court that compares statewide hospital prices for commercial payers versus the benchmark of Medicare prices for the same inpatient or outpatient services.

For example, in Michigan, commercial inpatient and outpatient prices are about the same as CMS prices.  Everywhere else, they're higher.  They're 80% higher in NY, but they're more like 300% higher in Indiana.  See graphic (attributed to Rand).

Why?  Well, from an armchair, you might guess that in Michigan, hospitals are fragmented and their is one highly consolidated payer, so the payer gets hospitals to bend to low prices.  You might think that in Indiana, hospitals are highly consolidated, and payers are fragmented, so hospitals can contract to high prices and make it stick.   Of course, any real-world conclusions would require a lot of analysis.

Labs and PAMA

The interesting for labs, under PAMA surveys of commercial payer prices, at least for freestanding labs, often commercial prices were lower than CMS prices, at least in CY2017.

That is, the PAMA data points would be displaced off the left-hand side of the graphic and below the 100% line which is the bottom of the chart.

Suggesting the payer-provider dynamics were very different for labs than for hospitals in most states, vis-a-vis the payer industry segment.

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From the March 2, 2020, paper issue.  The online version has the same text but not the same graphic I've shown above.  Here. I suspect the underlying source is RAND, 2019, here.

CMS Opens NCD on First FDA-Approved Blood-Based Screening Test for Colorectal Cancer

CMS covers a range of services for screening for colorectal cancer - colonoscopy, fecal occult blood testing by immunoassay, and most recently, the Cologuard FDA-approved oncogene detection test which is stool-based.

2018 payments for Cologuard (CPT 85128) were $170M, about 15% of all Medicare genomic payments [excluding virology; this blog, here.]  However, Cologuard has recently been faulted in terms of cost-effectiveness (here).

On Friday, January 28, 2020, CMS announced it was opening a review of another FDA-approved colon cancer screening test, the Epi proColon test.

• See the CMS tracking sheet here.  CMS will take public comment on the proposal to review Epi proColon from 2/28/2020 to 3/29/2020.
• CMS expected to release a draft NCD by August 28, 2020 and a final NCD by November 26, 2020.
• Epigenomics, the parent company, requested the NCD in April 2019 (here).  
• This means the duration from from request to final NCD will be about 16 months.
• BUT: I think it's clear from Epigenomics quarterly investor calls that discussions with CMS began much earlier, closer to its FDA approval in June 2016 and thus through CY2017 and CY2018.
• See Genomeweb open access summary here.
• UPDATE: See AHRQ review on this topic, June 2020, here.

A substantial proportion of US beneficiaries get no colorectal cancer screening by any method.  A blood test could provide access to screening for those who are not performing the stool tests nor undergoing outpatient colonoscopy.

Other companies are putting blood-based CRC screening tests into large clinical trials, e.g. Guardant Health (here).   Typically, the screening studies survey circa 10,000 patients to have a 1% hit rate (100 patients) with actual colorectal cancer, to allow good statistics around that subpopulation of n=100 who are true positives.

A recent publication, supported in part by Epigenomics, found that while colonoscopy has very high theoretical health impact, at real-world reported adherence rates, other tests such as Epi proColon (methylated Sept9) may have equal or better health impacts.  See D'Andrea et al. 2019 here.

Medicare (Dys)Regulation and COVID-19 Coronavirus testing

Update March 4, 2020:  Pence announces coronavirus is a required essential health benefit under private plans, Medicare, Medicaid: here.

Update March 6:  CMS announced on March 5 it would pay for new U-codes U-0001, U-0002, separately in the hospital outpatient setting details here.

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With a rapidly emerging public health crisis emerging around COVID-19, how does molecular testing engage with CMS policy?    At least some CMS policies appear to be clearly non-helpful.

• See also a prior blog in which I discussed the promise of genomic approaches to COVID-19 - here.

CMS Bundles All Molecular Infectious Disease Testing in Most Settings!

In hospitals, molecular testing for infectious disease is bundled to the hospital's overhead costs for each patient (e.g. bundled under a Diagnosis Related Group or DRG).   Few people outside of the lab industry or Medicare policy specialists understand the further extensions of this bundling concept, however. 

Dating back many years, CMS also bundles tests performed by the hospital within three days prior to admission, even if the tests were otherwise payable.   Beginning in 2014, CMS bundles all microbiology tests performed in emergency rooms and other hospital-based outpatient encounters (e.g. an on-site or off-site hospital clinic).   The hospital gets a payment for an encounter or office visit, but any lab tests ordered and performed by the hospital get no additional payment.  (The office payments were raised a bit in 2014 to cover average lab costs.)   The only exception is human genetic tests, and a COVID-19 PCR test is not a human DNA or RNA test.

In short, hospitals are on the hook for testing for  COVID-19 and are even incented not to do so, unless absolutely necessary.   Outpatient visit G0463 (hospital outpatient clinic visit) pays about $115 (APC 5012), so ordering multiple $30 to $120 molecular virology tests could exceed CMS's payment for the whole visit, including time, nursing staff, and overhead.  Doctors would be highly disincented from ordering a viral pathogen screen for $142 (87631) if the whole payment from CMS is only $115 all-inclusive.

MolDx Policy L37713 Provides Very Limited Coverage for 

Office-Based Molecular Virology

About 30 states participate in the MOLDX policy system for molecular testing.  Policy L37713 covers molecular virology for respiratory disease, but only in the "free-standing" setting - not in the hospital inpatient setting, or emergency room, or hospital outpatient clinic (due to bundling as just explained).

Policy L37713 has very narrow coverage for any molecular testing of respiratory illness in Medicare outpatients, a position that drew stormy comments from a range of US associations, including American Society for Microbiology, Infectious Disease Society of America, and other leading organizations.   The policy and the range of association disagreements are placed in a cloud zip file here.  Net-net, when multiple pathogen and multiple pathogen testing is required, it's generally not paid for by CMS.

In L37713, CMS focuses on identifying viral illness only when a specific antiviral drug is available.  When a specific antiviral drug is not available, CMS states that the need for identify the causative organism is minimal ("viruses cause most respiratory infections, so the diagnostic role of laboratory investigation is limited.")  Specifically, monitoring outbreaks to identify the cause of the viral pneumonia and improve early detection is "not a Medicare benefit."

It appears that if or when adding coronavirus drives a test order from 5 to 6 viral pathogens, it becames unpayable (payment falls from $142 under code 87631 to $0 under code 87632).

AMA CPT Coding

Infectious agent DNA/RNA probe detection runs generally from 87471 forward.  In a nutshell, for tests for viruses not yet codified by name, payment per test is low and inadequate.  Options include 87797 (direct probe, per organism), 87798 (amplified probe, per organism), and 87799 (quantitative DNA/RNA probe, per organism.) CMS pays $30, $35, and $43 respectively.   There are test codes for multiple unique concurrent respiratory viral tests (87631 3-5 targets, 87632, 6-11 targets, and 87633 12-25 targets) which pay $142, $218, and $416, but these are generally not paid by CMS (except for 87631; for rules, see LCD zip file listed above). 

Coronavirus COVID-19: Urgent need to explore the precision medicine component?

In cancer, we take it for granted that as few as 1-2 percent of patients may have distinct responses because of distinctive genomic patterns - such as lung cancer patients with ALK or ROS-1 driver mutations.

In SARS, we read that the mortality rate is around 1-2%.   The press is attributing this to generic cofactors - age, concurrent illness - but there is some risk this may be "satisficing" - stopping when we hear the first  reasonable explanation so we can move on to another question.  The first possible or even probable explanation isn't always right, however (for data on COVID-19 and age, here, here.)

According to Chen et al. in Lancet - who studied a hospital population, pre-selected for severity - of 99 patients observed for a month, 11 developed multi-organ failure and death (here).   WHO guidelines emphasize that terminal care may shift to the management of sepsis and septic shock (here).   In the earlier SARS crisis, reports of coinfections appeared (e.g. Gu & Korteweg, Am J Pathol 2007, 170:1136, here.)

It's been known since 2005 that respiratory coronaviruses can induce "hyperattack" immune responses which may be fatal - e.g. Perlman & Dandekar in Nature Rev Immun 5:917 (here).  Popular sources summarize this in 2020 as, "coronaviruses can spark a viral-induced fire through many of a person's organs" e.g. here.  An academic journal in 2020 remarks, "immunopathogenesis [in coronavirus] is associated with an immune response that is out of control" (e.g. Li et al., J Med Virol epub here.)

The facts that children are unlikely to get severe COVID-19 disease and men are more likely to die than women also suggests that subtleties of immune regulation and dysregulation are important.

Possible Precision Medicine Aspects of COVID-19: Things We Can Do Now

Molecular pathology can make many contributions to understanding the mortality pathways of the COVID-19 virus, besides access to rapid viral identification.

Do HLA or Other Innate Genomic Factors Raise the Odds of a Crisis Response?

Possibly.  Some review literature points in SARS to some reported high odds ratios (4 and higher) with some HLA genotypes (see Sun & Xi, 2014, book chapter, here).   An HLA receptor class 1 antigen can service as a receptor for some coronaviruses (Gralinski & Baric, J Pathol 2015 235:185, here.) although COVID-19 is thought to bind to the same angiotensin (ACE2) receptor as SARS-CoV (del Rio, JAMA 2/28, here).   In any case, we should also look beyond the main HLA associations and look at other genomic factors contributing to the dysfunctional immune response - we may find something much more specific than generic contributing factors like age or heart failure.

Genomics of Host Response

See an excellent open access paper by Gunsolus, Sweeney, et al., in J Clin Microbiol 2019 (here).   In a prior article (Sweeney et al., Crit Care Med 46:915, 2018, here), Sweeney and colleagues discovered and categorized three distinct molecular categories of host response to sepsis.  Each has different implications for etiology and novel immumodulatory interventions.   Potentially, patients developed a septic shock pattern after COVID-19 fall disproportionately into one of these categories, in a way that will be important to identify.

Do Coexisting Passive Infections Raise the Odds of a Crisis Response?

Another factor could be coexisting and otherwise passive infections.  (See assertions that healthcare workers do worse; here.)   One approach would be to sample the blood microbiome of patients with mild cases of SARS and looking for distinguishing associations with those who develop a fulminant COVID-19 syndrome with multiorgan failure and sepsis.   The blood microbiome can now be screened in non-selective (broad-band) ways by next-generation sequencing (e.g. one example is the commercialized Karius Test, Blauwkamp et al., 2019, here.)

Another approach would be to take patients already in multi-organ failure and sepsis and use blood microbiome screening to look for co-infections associated with death.   This lacks the predictive element but is more focused and still informative.

Funding

In a separate article, I discuss the severity of CMS policies for underfunding molecular virology (here).   CMS policies have to change quickly to meet the crisis.

However, venture capital and federal funding is flowing into this space.  Karius raised $165M in February 2020 (here), and Inflammatix (of which Sweeney is CEO; cited above) recently raised $32M (here) plus BARDA funding.

Very Brief Blog: CMS Responds to Hill re Medicare Program's Sepsis Policies

Just a week ago, there were several big-data articles, supported by CMS and BARDA, on the scope and morbidity of sepsis in the Medicare population (entry point here).

Separately, one of the controversies in the academic literature has been around CMS's mandatory measurement of a measure called SEP-1, which has had a conflicting range of positive and negative articles (entry point here; see also PubMed for SEP-1 here.)

In 2020, the House asked HHS to report on its interventions for sepsis and its management of the SEP-1 quality measure.  CMS has now responded.

See the Fiscal Year 2021 CMS Justification of Budget, 346pp, online here.  (This is the mandatory 300 page bedtime reading for Medicare-ologists until the Hospital Rule comes out in April 2020 and the Physician and Outpatient rules come out in June 2020).   CMS's response flags that it may prefer to replace SEP-1 (a complex process measure) with a simpler and more direct outcome measure (such as % survival in sepsis.)

Scrolling head to page 260, here is the House request of CMS, issued last summer:

Sepsis.—The Committee is concerned that sepsis and antibiotic resistant bacteria continue to be leading public health threats that are responsible for a significant number of deaths, as well as rising costs within the healthcare system. According to the most recent data, the national average compliance rate for CMS’s sepsis treatment measure, known as SEP–1, is only 49 percent. The Committee urges CMS to issue a Request for Information to gather views on proposals to modernize and optimize CMS’s current SEP– 1 measure.

The Committee requests an update on these activities in the fiscal year 2021 Congressional Budget Justification.

CMS responds:

CMS agrees that ensuring proper sepsis treatment and antibiotic stewardship is crucial to protecting patients in healthcare facilities and in the community at large.

As stated in CMS’Measure Inventory Tool
(https://cmit.cms.gov/CMIT_public/ReportMeasure?measureRevisionId=300 ),
a principle of sepsis care is that clinicians must rapidly treat patients with an unknown causative organism and unknown antibiotic susceptibility. Since patients with severe sepsis have little margin for error regarding antimicrobial therapy, initial treatment should be broad spectrum to cover all likely pathogens. CMS continues to work closely with the Sepsis (SEP-1) quality measure stewards and stakeholders on measure updates.

Since measure inception in 2015, the stewards have made many updates to the measure to improve abstraction, reduce burden, and address concerns raised by clinicians and stakeholders. Measure updates have taken into account evolving clinical practice and current measure specifications align with the Surviving Sepsis Campaign guidelines. The SEP-1 measure is up for National Quality Forum re-endorsement next year and CMS plans to continue close collaboration with the measure
stewards and stakeholders on potential updates and/or changes to the SEP-1 measure.

Additionally, CMS expects to begin working on a sepsis outcome measure and has formed a Technical Expert Panel that will help inform development of this new measure

CMS shares the Committee’s concern about antibiotic resistance. The consequences resulting from misuse of antibiotics are severe, leading to life-threatening infections, adverse drug events, and increasing the prevalence of drug-resistant bacteria. In recognition of the importance of proper antibiotic stewardship, on September 30, 2019, CMS finalized requirements that will ensure that all participating hospitals and critical access hospitals implement antibiotic stewardship programs following nationally recognized guidelines (84 FR 51732). Specifically, the final rule includes important requirements for the implementation of antibiotic stewardship programs as part of the Conditions of Participation for hospitals and critical access hospitals in the Medicare and Medicaid programs. We believe that these antibiotic stewardship programs will provide a critical tool for hospitals and critical access hospitals to use in the fight against the emergence of new strains of antibiotic-resistant bacteria and in the defense of our currently effective antimicrobials.

Jeff Bezos Says: Give Strategic Decisions Time, and Don't Overuse PowerPoint

While both PowerPoint and Word memoranda can be the right way to deliver a message, I've seen that sometime PowerPoint is more likely to hide flaws and gaps in the reasoning or the argument.

It's been said for many years that "Amazon Bans PowerPoint" and that they start meetings off with written memos and a five minute reading session. 

In his 2018 letter to shareholders, Bezos devoted some additional thinking to these topics.   He begins by using the example of someone who wants to do free handstands (no wall).  Experts say this takes six months to do perfectly, not a week or two.  Bezos says if you think it takes a week, the project is dramatically under-resourced.   He refers to handstands in the following section.  See the full letter online at SEC (here).

Bezos: 

Unrealistic beliefs on scope – often hidden and undiscussed – kill high standards. To achieve high standards yourself or as part of a team, you need to form and proactively communicate realistic beliefs about how hard something is going to be – something the [gymnastics] coach understood well. 

Six-Page Narratives 

We don’t do PowerPoint (or any other slide-oriented) presentations at Amazon. Instead, we write narratively structured six-page memos. We silently read one at the beginning of each meeting in a kind of “study hall.” Not surprisingly, the quality of these memos varies widely. Some have the clarity of angels singing. They are brilliant and thoughtful and set up the meeting for high-quality discussion. Sometimes they come in at the other end of the spectrum. 

In the handstand example, it’s pretty straightforward to recognize high standards. It wouldn’t be difficult to lay out in detail the requirements of a well-executed handstand, and then you’re either doing it or you’re not. The writing example is very different. The difference between a great memo and an average one is much squishier. It would be extremely hard to write down the detailed requirements that make up a great memo. Nevertheless, I find that much of the time, readers react to great memos very similarly. They know it when they see it. The standard is there, and it is real, even if it’s not easily describable. 

Here’s what we’ve figured out. Often, when a memo isn’t great, it’s not the writer’s inability to recognize the high standard, but instead a wrong expectation on scope: they mistakenly believe a high-standards, six-page memo can be written in one or two days or even a few hours, when really it might take a week or more! They’re trying to perfect a handstand in just two weeks, and we’re not coaching them right. The great memos are written and re-written, shared with colleagues who are asked to improve the work, set aside for a couple of days, and then edited again with a fresh mind. They simply can’t be done in a day or two. The key point here is that you can improve results through the simple act of teaching scope – that a great memo probably should take a week or more.

Bezos summarizes, great work "simply can't be done in a day or two."  Years ago, in a quote I've forgotten, one of the famous 20th century judges, like Cardozo or Brandeis, made the same point in an essay about hard judicial opinions.  His strong point was, after hearing the case, after reading the briefs, the final decision ...just...took...time.  Pretty much the same point Bezos is making in a business context above.

Karius Raises $165M for Microbial NGS Sequencing

From Reuters and other newswires, Bay Area molecular diagnostics startup KARIUS raises $165M in a Series B funding round.   Karius provides overnight assessment of the complete blood microbiome (1200 pathogens).    

Reuters here.
TechCrunch here.
Fierce Biotech here.
The company's website is here - https://www.kariusdx.com/

See a detailed 2019 paper on analytical and clinical validation in Nature Microbiology, open access, Blauwkamp et al., here.

Excerpt from Tech Crunch:

“What Karius is good at is identifying those novel microbes before they become an outbreak like coronavirus,” says Mickey Kertesz, a chief executive whose life sciences startup just hauled in $165 million in new funding.

While the new money may have been raised under the looming threat of Covid 19, the company’s technology is already being used to test for infection-causing pathogens in immunocompromised pediatric patients, and for potential causes of complex pneumonia, fungal infections and endocarditis, according to a statement from the company. 

Liquid biopsy technology has been widely embraced in cancer treatments as a way to identify which therapies may work best for patients based on the presence of trace amounts of genetic material in a patient’s bloodstream that are shed by cancer cells.

Karius applies the same principles to the detection of pathogens in the blood — developing hardware and software that applies DNA sequencing and machine learning techniques to identify the genetic material that’s present in a blood sample.
As the company explains, microbes infecting the human body leave traces of their DNA in blood, which are called microbial cell-free DNA (mcfDNA). The company’s test can measure the cell-free DNA of more than 1,000 clinically relevant samples from things like bacteria, DNA viruses, fungi and parasites. These tests indicate the types of quantities of those pathogens that are likely affecting a patient. 

“We’re through the early stages of adoption and clinical studies show that the technology literally saves lives,” says Kertesz.

click to enlarge.  OGrady/Nature here.

Very Brief Blog: Proposed Pathology CPT Codes Reviewable - on Whirlwind Schedule

The AMA CPT editorial panel meets three times a year - roughly February, May, October - and posts abbreviated descriptions of each proposed code some six weeks in advance (March 13, 2020), allowing stakeholders to request code application packets and submit comments.

(Commenters must have a direct relationship to the code in question, however, which AMA reviews before sending the packet out to the stakeholder.  For example, my status as a consultant interested in CPT trends doesn't qualify me to get copies of new digital health codes.  However, if I was a digital health company with a product or service that would likely use the code, that would qualify as a stakeholder.)

However, pathology codes are on a whirlwind schedule.  Path/Lab codes, which were due at AMA around February 12, have been posted already and if you want to comment, you must state your intent in an email to AMA by Wednesday February 26 at the latest.

AMA will send you materials, which you can comment on by March 2.

The PDF agenda (and comment instructions) for the May 2020 CPT meeting are online here.  Again, you must respond to AMA by Feb 26 if you want your input considered.  If you are interested in non-path non-lab codes, check back with AMA around March 15 when those codes will appear online.

Codes include:

• Carbamazepine drug assay
• Felbamate drug assay
• Drug assays for flecainide, itraconazole, leflunomide, methotrexate, rufuinamde.
• MAAA code for adrenal cortex malignancy risk
• MAAA code for 70 gene breast cancer risk panel by microarray OR by NGS
• MAAA for bladder cancer subtyping
• MAAA for bacterial vaginosis
• MAAA for allograft rejection
• GSP (genomic sequencing eg NGS) code for solid tumors editing coding and placement of RNA analysis
• Cat III code 0500T HPV genotyping elevate to Cat I
• Campylobacter antigen
• Free estradiol test (multiple revisions)

Comments will be circulated  to the Pathology Coding Caucus, a group that includes CAP, AMP, ACLA, Advamed, and other major organizations.  They will also become part of the file available to the CPT committee of the whole.

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Some CPT dates (here).  Applications were due Feb. 12 for CPT Chicago May 14-16, 2020.  Applications will be due June 30 for CPT New Orleans October 1-3, 2020.   Applications will be due November 4, 2020, for the AMA CPT in Phoenix February 4-6, 2021.   In each case, Path/Lab codes open for comment about 7-10 days after they are due, while other codes open for comment about 60 days prior to the CPT meeting.

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The results of panel actions are posted at:
https://www.ama-assn.org/about/cpt-editorial-panel/summary-panel-actions

The September 2019 Seattle meeting has been posted, but not yet the February 2020 SF meeting.
https://www.ama-assn.org/system/files/2019-11/september-2019-summary-panel-actions.pdf

FDA Creates New Pharmacogenetics Websites, More

It's notorious that in November 2018 and in first-half 2019, the FDA had a number of aggressive tactics against pharmacogenetics laboratories.   (E.g. see background facts inside a recent February 14 report in Genomeweb, here.)  See also a Citizen's Petition filed against the FDA and its regulatory actions in mid-January, here and 19-page PDF document here.  (See similarly a deck about FDA at CPIC, the PGx consortium, here.)

On February 20, 2020, FDA released a long press release about new websites and initiatives at FDA regarding pharmacogenetic testing and reporting.

• See FDA press release here.
• See new FDA webpage for PGx associations - here.
• See the public comment docket here.
• FDA has been discussing whether or how it might joint a multi-stakeholder "collaborative community" on PGx - here.
• Article about FDA at RAPS, here.
• Article about FDA at Genomeweb, here.
• Article about FDA at Endpoints (echoes RAPS), here.
• 
  
• See separately a January 2020 article at Genomeweb about Translational Software, a vender of advanced PGx software, entering into the 510K process at FDA, here.
• Separately, CAP TODAY features PGX for February 2020 - here.

Very Brief Blog: Center for Connected Medicine's 2020 "Top of Mind" Healthcare Innovation Report

I saw several press releases recently that pointed back to the same source, a 26-page survey report of how hospitals and providers are thinking about innovation, released by the Pittsburgh-based Center for Connected Medicine (CCM).

Some quick links:

• Read about the CCM here.
• See their blog/news page here.
• See their view on the fits-and-starts roll-out of digital health here.
• See their summary of precision medicine findings in the 26-page report here.
• Download the 26-page Top of Mind report here.

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By the way, in Southern California, where I'm based, this month both UC-Irvine and UCLA hold interesting health innovation conferences.   See the the 2020 Health Forecast conference at Irvine here (Feb. 20-21) and the UCLA medtech/digital health conference here (March 3).

CMS, BARDA, Support Deep-Dive Study of Sepsis Prevalence in Medicare

Sepsis is a major cause of death nationally and world-wide, and threatens to rise even higher because of the rise in highly antibiotic-resistant pathogens.

In a series of six papers appearing this week in the journal Critical Care Medicine, we have one of the largest-ever real-world evidence studies using diverse Medicare fee-for-service and Medicare Advantage data.  Sepsis-related admissions rose 40% during a period when the Medicare program grew 22%. 

Costs per year are in the $50B range while six-month mortality is 60% for septic shock and 36% for severe sepsis.  Comorbidities like cancer market elevate the mortality statistics.  (Medicare benefit payments in 2018 were $730B).

The articles appear in the March 2020 issues of Critical Care Medicine, timed with the 49th Annual Critical Care Conference being held in Orlando.  In addition, the set of articles triggered a lengthy press release from the Department of Health and Human Services, including comments from BARDA head and study co-author Dr. Rick Bright.

(For those who track Washington and infectious disease, note that the President's Advisory Council on antibiotic resistances, PAC-CARB, is meeting later this month - here.)

The Six Papers

All three of the main data analysis papers, clocking in at 13, 13, and 17 pages, are first-authored by Dr. Timothy Buchman, a prolific academic who is also professor of anesthesiology and professor of surgery at Emory.   Several BARDA staff are also co-authors, along with staff at the Bay Area consultancy ACUMEN.

The three main papers are titled:

Sepsis Among Medicare Beneficiaries:
   1.  The Burdens of Sepsis (48:276)
   2.  The Trajectories of Sepsis (48:289)
   3.  The Methods, Models, and Forecasts of Sepsis (48:302)

Note that the same issue of the journal also includes two adjacent articles on the mortality and trajectory of pediatric septic shock, Zimmerman et al. (48:319, 48:329). 

On the Buchman et al. Medicare publications, see also a set of three Op Eds.   The first is by Rhee et al. on the "eye popping costs of sepsis" (48:420); the second by Levy on the use of big data (48:422); and the third by Busch et al. on the amount of data coaxed out of Medicare claims from diverse data sets (48:424).

On a special visualization page, click down the left headers for data views.  See toggle settings on the right.

click to enlarge

Trade Press and HHS's Press Release
h
The HHS press release brings together CMS and HHS/BARDA voices, is fairly lengthy at 1300 words.  The press release uses the data as a springboard for noting CMS efforts in quality of care improvement, CMS payment advances for antibiotics, BARDA investments in sepsis, and CDC investments in antibiotic and sepsis issues.   The press release also links through to DRIVE, a BARDA biotechnology investment program that includes diagnostics for sepsis (here).

For example, the press release states: "CMS continues to clear away regulatory obstacles and financial disincentives that have long inhibited the development of life-saving antibiotics capable of treating sepsis patients. Patients suffering from sepsis deserve to see America’s full innovative potential mobilized to address this devastating condition.” 

Another quote:  "Most patients with sepsis arrived at the hospital with the condition, rather than developing sepsis in the hospital, a possible indicator of success for CMS efforts to reduce hospital-based cases of sepsis [iatrogenic infection]."

HHS Assistant Secretary for Preparedness and Response Dr. Robert Kadlec states, “Any infection can lead to sepsis, including infections caused by influenza or emerging diseases like coronaviruses, which makes sepsis a significant concern in public health emergencies.”

For a trade press story at Fierce Healthcare, here.

Since the papers are all open-access, I've also bundled them in a cloud zip file, here.





 

Offbeat: NEJM, CAP Weigh In on CMS Autopsy Policy; CAP on MolDx Unlisted Codes

I trained in pathology at UCLA in the 1990s (I was doing an elective at the coroner's office during the 1994 LA earthquake), and was intrigued by the policy and process around autopsies.

Here's a letter in today's NEJM that leads to CAP viewpoints on CMS policy.   The letter highlights for NEJM readers that CMS recently deleted its autopsy rule.   U Vermont's Dr. Rueckert notes that in a new 1,037 case series, autopsies found major actionable missed findings in 2%.

Back story -

On September 30, 2019, CMS removed a historical hospital condition of participation requiring autopsies.  (It was the same rulemaking that creating a new condition of participation for antibiotic stewardship programs.)  CAP highlighted the issue in its November 2019 policy report to members (here).

CAP had protested the issue a year earlier, in November 2018, in a CAP letter to CMS which is online here.

The  now-deceased regulation, 42 CFR 482.22(d), recommended hospital staff secure autopsies in cases of "unusual deaths, medical legal, and educational interest."   It's expunged as of September 30, 2019.  CAP argued that CMS's regulation was redundant in medico-legal cases - those follow a legal pathway with or with a CMS rule.  But CAP liked the encouragement from CMS to hospital management to perform autopsies for unusual cases and educational interest.

The dearly departed regulation looked like this before it expired:

Side Story - Autopsies and Precision Medicine?  Yes!

There's also a side story connecting autopsies in cancer patients with precision medicine, since the autopsy provides a chance for unlimited sampling of widespread tissue mets, or parts of one tumor mass, that's not possible with FNA, LBx, or other low-invasiveness measures.  Turna Ray at Genomeweb discussed this in an article in September 2019 - here.   See a representative research article based on rapid-autopsy genomics here.  The rapid autopsy can also provide unlimited tissue for research such as ex vivo explant tumor models.

Side Story - Shortage of Autopsy Pathologists (Medical Examiners)

Around the same time, February 25, 2020, NYT ran a health policy article on the severe national shortage of autopsy pathologists (e.g. forensic medical examiners) - by Jordan Kisner; here.

Other CAP Priorities - LCDs and Unlisted Codes

CAP suggested some priorities where it DID want CMS to pursue regulatory relief.  CAP complained about the LCD process (page 2-3 of its letter.) 

CAP also complained about burdensome use of unlisted codes (topic 7 and page 5 of its letter.)

When You Say Unlisted Codes, You Mean MolDx

Nationally the use of a few pathology (anatomic pathology) unlisted codes is almost nil.   In the wetlab, use of molecular unlisted code 81479 is about 12% of MoPath payments at $135M in 2018 (here).

But those payments for 81479 are almost entirely (>95%) from MolDx MACs.  81479 is virtually unused by MACs outside of MolDx.

Insight from FOIA

Based on additional data via FOIA, MolDx has edits on about 13,000 Z codes, of which 38% or 4,937 track to the unlisted code 81479. 

Among all 13,000 Z codes in the MolDx inventory, 8,545 or 66% were listed as nonpayable.

Nature Publishes Bonanza of Open-Access Papers on Advanced Genomics of Tumors

Genomeweb currently has a headline article on a new publication regarding advanced genomics of tumors - here.  The trackback is to an article by Paczkowska et al. on multiomic-genomics of tumors and advanced bioinformatics insights - here.

But the bigger story for me is that the Paczkowska article was just one of a set of 21 similar articles, all published open access by Nature on February 5, 2020.   View the full set of articles here.

The project is supported by the International Cancer Genome Consortium, where you can find the Pan Cancer Analysis of Whole Genomes data portal (ICGC/PCAWG).

Very Brief Blog: FDA Pushes AI in Radiology; Will Hold Two Day Conference

Pathology, Radiology, and AI

We think of radiology and pathology as the two diagnostic specialities.  We talk about AI in both (on the pathology side, see e.g. Sloan Kettering's spinout PAIGE-AI which raised $45M this winter.  Not to be out-done, New York's nearby Mt Sinai also has a lab AI spinout, Renalytics_AI.) 

On the radiology side, literally, hardly a single issue of Journal of American College of Radiology (JACR) gets published without an article on AI-related policy and science issues for its industry and its physician membership.

FDA Produces De Novo Ultrasound/AI Clearance; Issues White Papers; Will Hold Public Meeting Feb 25-26, 2020

FDA has produced a De Novo clearance of a novel ultrasound-AI device for cardiology.   See MedCityNews here, see Healthcare Dive here.  The product comes from Caption Health here, and the FDA press release is here.   The FDA 5-page DN approval is here; DN190040.

The FDA has a whole new regulatory category for these devices, AI in Imaging - Product code QJU, category 891.2100, here, and FDA produced a major white paper on the topic last year.

FDA Conference: AI in Imaging, February 25-26, 2020

See the FDA's web page, with extensive agenda, for a February 25-26, 2020, conference on AI in imaging - here.

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Separate from AI in radiology, see an article about non-radiologists interpreting advanced imaging; here.