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.

___

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.

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.

___

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.

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.

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.

___

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

CMS Innovation: Innovation Officer Leaves; Congress Proposes Fences for CMMI

Innovation Officer Dr. Anand Shah Leaves CMS, Joins FDA

In January 2019, CMS created a new position of Senior Medical Advisor for Innovation.  The first holder of this position was Dr. Anand Shah, a Columbia University-trained radiation oncologist with NIH and FDA background.

In January 2020, Dr. Shah departed CMS for the FDA, taking the position of Deputy Commissioner for Medical and Scientific Affairs.   I've clipped the FDA's description of Dr. Shah's background as a footnote.

Track his FDA/Twitter account here.  For example, from his FDA position, he endorsed the NGS NCD expansion at CMS which occurred about the time he left.


Congress Proposes Legislative Guardrails for CMMI

The Affordable Care Act created the CMMI, the Center for Medicare and Medicaid Innovation, through Section 1115A of the Social Security Act (here).    Previously, demo projects at CMS were created one legislated project at a time, and could represent either good ideas or some pork belly shenanigan snuck into the bottom of a long bill.

Section 1115A allows the CMMI to create any demo project it wants, waive any law it needs to, to do so, and the demo can be as large as it wants and run as long as it wants.   (Yup - you think, "Woah?!") 

In fact, Republicans in 2016, before the election, were quite agitated about CMMI as it was expanding under the Obama administration (here).  Riding that wave, CMS under the new administration called a temporary halt to CMMI initiatives.  And the value and quality of CMMI's work was criticized by GAO.

Seems like a long time ago.  In fact, the administration recognized that CMMI's broad powers could allow it do to major initiatives, like block grants for Medicaid, drug pricing reform, etc.    There's also a complicated section that allows CMMI to put in play processes that permanently replace existing laws with new ones developed by CMMI projects.

As noted in Healthcare Dive here, and in a press release from Congr. Sewell here, at least some lawmakers on the Hill don't want CMS to have the authority to suspend any legislated rule in the name of a demo that could run nationwide and be of unlimited duration.   While it seems like a long and awkward bill, read H.R. 5741 to see what they came up with.   It deals both with (A) how demo programs can be established (guardrails) and (B) how the results of demo projects can interact permanently with Congressional laws (very complicated.)

There's a lot of health policy media about H.R. 5741; rather than list a lot of links, see for yourself by going to Google and search Sewell and CMMI together; such as here.

See a detailed blog at Health Affairs on February 12 by Micklos, Pierce-Wobel, and Traylor, about reforms needed to make CMMI more useful and viable - here.

____

Schrodinger AI (supports biopharma)

Although not directly related to CMS innovation or FDA-AI-diagnostics, in today's IPO news, Schrodinger, a software company that assists drug discovery, had a $230M IPO this past week; for its market cap check Yahoo Finance here.  (Google gives its market cap as $1.2B.)    The prospectus I found listed the share price as $17 but as of today it traded at $26 (over several days, it rose to $32 and slipped back down to $26).  What's interesting about the IPO is that it generates a 262 page prospectus about its business model, IP, and business plans - here.  Its revenue is running about $70M a year.

See a Nature Reviews Drug Discovery article by Schneider et al. here; see Nature Reviews collection for AI and digital health here.  See an article calling for FDA regulation of AI in pharma R&D; here.

_____

Footnote - FDA Describes Dr. Anand Shah's Background

Dr Shah co-led and scaled Information Exchange and Data Transformation (INFORMED), a science and technology incubator designed to harness the power of big data and advanced analytics to improve disease outcomes.

Dr. Shah developed organizational and technical infrastructure for modern approaches to evidence generation in support of regulatory decisions.

He is a widely recognized authority on how innovative medical products are developed, regulated, financed, and delivered. Dr. Shah’s efforts have focused on the development and implementation of innovative approaches to value-based health care delivery and expanding competition and consumer choice. He recently served in two senior leadership roles at the Centers for Medicare & Medicaid Services (CMS).


####

I'm not an attorney, but note that on February 14, 2020, CMS lost a case that would have authorized work as a requirement for some Medicaid enrollees in Arkansas (article here, ruling here).  (The court notes it was applying the same reasoning as a prior ruling on the same topic in Kentucky.)  As far as I can tell, CMS attempted to allow the work waiver under the CMS "Medicaid waiver" authority, which Court rejected.   But if CMS had created the work demo program instead under its CMMI authority, it might have worked, since "any" program can be created there under current law.   

####

See an article on Medicare Advantage plans that could be designed as "special needs" plans for homeless people - here.

Very Brief Blog: Trump Administration Posts "Budget in Brief" For HHS for FY2021

With much fanfare, the Trump administration released its government-wide budget plans on February 10, 2020, WaPo here.

As part of this, HHS released a 188-page FY2021 budget in brief.   Find it here.  See also the HHS budget home page here.

Example: Kidney Disease

The budget reflects priorities that President Trump launched in July 2019 with a coordinated roll-out of initiates in kidney disease and transplant care. 

Writing:

The Budget includes $39 million across multiple HHS
agencies and requests new legislative authority in
support of the initiative’s three goals:
   * Reduce the number of Americans developing
End-Stage Renal Disease (ESRD) by 25 percent
by 2030.
   * Have 80 percent of new ESRD patients in 2025
receive dialysis at home or a transplant.
   * Double the number of kidneys available for
transplant by 2030.

Adding, "The Budget invests $31 million in HRSA for the Organ Transplantation program, including $18.3 million for the Organ Procurement Transplantation Network, Scientific Registry of Transplant Recipients, and public and professional education efforts to increase public awareness about the need for organ donation...The Budget also advances legislative proposals to revolutionize the way patients with chronic kidney disease and kidney failure are diagnosed, treated, and supported."  The plan also includes efforts to keep kidney transplant patients on anti-rejection drugs, which currently terminate (along with the rest of their Medicare) 36 months after transplant (unless the patient is otherwise Medicare-eligible.)

I've used renal care as an example; many other proposals are found in the 188-page document.


Example: Medicare Coverage Policy & Processes

In October 2020, President Trump issued an executive order for improving coverage and processes at Medicare.  This was echoed in a pair of December 18, 2019, long blogs in Health Affairs on improving Medicare coverage rules and processes (entry point here).

Several paragraphs in the FY2021 plan also address Medicare:

Provide Price and Quality Transparency -  

Improve Clarity and Transparency of the Medicare
Coverage Process
Many stakeholders find the process and standards for the Medicare coverage determination process lack clarity. This proposal requires CMS to issue additional
guidance around the Medicare coverage process, including sub-regulatory guidance on the evidence standards that CMS utilizes in assessing coverage and the process to appeal coverage determinations, in an effort to improve clarity around Medicare coverage.
[Budget Neutral] 

Strengthen the Parallel Review Process to Streamline Medicare CoverageThe Parallel Review program is a collaborative effort between the Food and Drug Administration (FDA) and CMS that reduces the time between FDA approval of a device and Medicare coverage of that item. This proposal strengthens the existing parallel review process to improve device manufacturer participation and increase transparency. [Budget Neutral]

Thanks to a former senior CMS official who pointed out to me, these FY2021 paragraphs, while echoing the recent October 2019 Executive Order, are also very close to improvements captured in a 2012 Obama "Bioeconomy Blueprint" which is still online - here.


___

While not directly related to healthcare, Trump also proposes raising spending on AI and quantum computing to $2B per year within 2 years (WSJ here).


 

Very Brief Blog: Teaching in Dx Reimbursement Intro Course; Tuesday March 3, SF

I'm looking forward to participating in #TRICON in San Francisco the first week of March - I am one of the instructors in the "Coverage and Reimbursement for Advanced Diagnostics" workshop organized for Tuesday March 3, 6.30-9.30PM.

Learn about things to know - and mistakes to avoid

Webpage here.

SC25: Coverage and Reimbursement for Advanced Diagnostics

TUESDAY, MARCH 3 | 6:30 - 9:30 PM  

ABOUT THIS COURSE:

Market access for diagnostics developers is more complex and challenging than ever. New compliance requirements and payer demands for more detailed information compel companies/laboratories to be as good at communicating the value of their products as they are at developing them. We will discuss some of the intricacies and realities of proving long-term value to stakeholders including clinical data and real-world evidence on the benefits of testing.

TOPICS TO BE COVERED:

• Investigating the Background, Implications and Future Outlook of Medicare Reforms to the Clinical Laboratory Fee Schedule
• Development of the value proposition for commercial payers: Key evidence requirements
• Trends in laboratory benefits
• The role of national guidelines in establishing commercial payer coverage
• Know key decision points for optimization of your revenue cycle operations
• Strategically meet industry billing requirements head-on, while minimizing your costs and boosting your bottom-line

COURSE AGENDA:

6:00 pm Dinner Buffet

6:30 Course Welcome and Introductions

6:40 Latest Updates on Medicare Coverage: Local and National

Bruce Quinn, MD, PhD, Principal, Bruce Quinn Associates

7:10 How Do I Get a CPT Code and What are My Options?

Victoria Pratt, PhD, FACMG, Director, Pharmacogenomics and Molecular Genetics Laboratories, Medical and Molecular Genetics, Indiana University School of Medicine; President, Association of Molecular Pathology


7:45 Dessert Break

8:00 Payer Presentation Prep: Successful Strategies

Lon Castle, MD, CMO, Lab and Specialty Drug Services, eviCore healthcare

8:30 Healthcare Storytelling for Clinical Diagnostics – How to Do It…

Katherine Tynan, PhD, CEO, President, Tynan Consulting LLC

9:00 Q&A with Attendees and Speakers

9:30 Course Ends

Very Brief Blog: Myriad Describes Reimbursement Challenges

In October, Health Affairs published a major article on the growing power of Laboratory Benefit Managers, and I used it as an opportunity to link back to August investor calls at Myriad, such as their August investor call, describing growing impact of claims processing edits, prior authorization, and LBMs - entry point here.

Here, I'm flagging their February 6, 2020 investor call, where they continue to describe challenges with edits, prior authorizations, inappropriate denials, and other barriers to revenue.   (Open access tp transcript here). 

In something called after-hours trading (which I don't fully understand) share price was reported as falling from circa $30 to circa $20.   More information when Friday's markets open.

Here's a remarkable paragraph:

Reductions in average selling price are largely unrelated to lower contract prices or ineligible patients. Instead, they are a result of shifting preauthorization rules, inappropriate denials, new documentation requirements and fluctuating coding directions. 

To address these challenges, we have made significant organizational changes, including establishing a new department, which we have called revenue operations. This organization has the responsibility to develop new approaches and to coordinate resources across the enterprise to attack the highest priority opportunities.

For example, in the second quarter, we developed and deployed an early warning system powered by artificial intelligence to detect billing anomalies earlier so we can act on them immediately. 

Amazing stuff. Reimbursement matters, and requires increasing agility and resourcing.

In other news, the CEO resigned and they are awaiting a potential improved coverage policy for Genesight from MolDx.   (Private payer edits have been slowing Genesight revenue, possibly due to edits on CYP gene codes). 

They also remark, "Prenatal cash collections were negatively impacted by issues in billing operations that occurred during the transition of the homegrown Counsyl billing system to an industry standard system used by Myriad. While the issues will be resolved this quarter, the disruption in cash collections necessitated a negative adjustment..."

For an intro-to-reimbursement course I'm teaching in early March in SF, here.

___

One of the bugaboos for Myriad and other labs is "improper prior authorization."  There's an article in the February 3, 2020, JAMA on improper authorization, which is based on pharma, but probably has learnings relevant for the diagnostics industry too.  Here.

Medicare's Revised NCD For Next Gen Sequencing in Cancer: Highlights and Quirks

On January 27, 2020, CMS released a revised NCD for next generation sequencing.

• See the full CMS analysis here.
• 41 pages as PDF; 33,000 words.
• See my initial blog quoting the main decision points here.
• In the cloud, see my lightly annotated extract of CMS's discussion of public comments, here.

In this blog, I'll recapitulate the highlights of the decision then describe some of the oddities.

DECISION IN BRIEF

Avoiding some details, let's summarize.  In February 2018, CMS issued an NCD guaranteeing coverage of FDA-approved NGS tests used on label in advanced cancer as companion diagnostics(e.g. the Foundation Medicine FDA-approved F1 test).   The NCD contains language implying that no NGS testing was covered (neither under LCD nor NCD) in non-advanced cancer.   CMS reiterated this stance in a transmittal in November 2018.  By early 2019, many stakeholders complained to CMS this would inadvertently block NGS testing of germline risk genes under guidelines (e.g. BRCA in high risk women post lumpectomy).   

In October 2019, CMS revised the NCD in a draft for public comment.  The revision included new sections on germline testing.   After public comments, CMS finalized the NCD on January 27, by inserting new language in and around the prior language, and by revising some of the prior language as well.     With the new language, germline hereditary risk testing is guaranteed national coverage in breast and ovarian cancer, if the NGS test is FDA approved or cleared (no genes are named).   For other cancers and for non-FDA tests, MACs can create coverage (or continue existing coverage).

In the new NCD, NGS tests for RNA (and oddly, "NGS tests for proteins" [sic]) are outside of scope.  Non-cancer tests, e.g. HIV genotyping tests by NGS methods, are also out of scope.

QUIRKS OF THE NEW NCD

It's helpful to read the NCD analysis as a whole, and in particular you get insights into CMS thinking by reviewing the Q&A to public comments (here).

1. The Title

The revisions were put forward in October under the old title, Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer.   The new final version shows the same title at top of page.  However, Appendix B of the final revision this week shows us the new title is actually changed to:  Next Generation Sequencing (NGS) for Patients with Somatic (Acquired) and Germline (Inherited) Cancer.

We don't usually categorize patients as "Somatic Acquired Cancer" and "Germline Inherited Cancer."  See also my point below #6.  

2. "Scope" Language New in Section A

Scope language was added to the top of the NCD, Section A.  

"This National Coverage Determination (NCD) is only applicable to diagnostic lab tests using NGS for somatic (acquired) and germline (inherited) cancer.  

Medicare Administrative Contractors (MACs) may determine coverage of diagnostic lab tests using NGS for RNA sequencing and protein analysis.  

MACs also have discretion to determine coverage of diagnostic lab tests using NGS for any non-cancer (e.g., infectious disease and heart disease) use.  These uses are outside the scope of this NCD."

The first sentence is a little quirky.  Tests using NGS aren't "for somatic cancer" or "for inherited cancer" but rather "for somatic mutations" or "for germline mutations."   

Test for for RNA expression levels by NGS (a technology which is increasingly usable)are excluded from scope because it's NGS for RNA and NGS for RNA is "out of scope," period.  Good, and clearly written.   For example, if the Mammaprint or Oncotype Dx tests are converted to NGS RNA expression platforms, they are out of scope.   

But I think such tests are also excluded since the scope is only for NGS based somatic acquired ^mutation tests, though the word somatic acquired [^mutation] is missing.  Still, the wording is a little odd.

2B.  NGS for Protein Analysis [sic]

It's  unusual to refer to "NCS for protein analysis" although at least this is "out of scope" so one need to worry about it further.

3. Single Test Use Language

The prior NCD had this restriction on repeat testing.  A test could be covered only if: 

[Prior Statement: patient] "either not been previously tested using the same NGS test for the same primary diagnosis of cancer, or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician."

The new language on repeat testing is found in both the germline and somatic mutation sections, and reads differently:

"[NEW: patient] not been previously tested [A] with the same test using NGS [and B] for the same cancer genetic content."

This is a little redundant.  If you are previously tested with literally the SAME test "A", then it was for the SAME genetic content "B," because the test was the SAME.   If the test is the SAME then the content of the test is the SAME.   Vice versa, if the genetic content of the test "B" is different, then the test "A" is not the SAME.    

I also wondered if this could be interpreted that you could use the SAME test but expecting DIFFERENT genetic content test results, for example, because the tumor has relapsed and therefore the tumor must have different genomic status now (different genomic content ^of the tumor), which we have to test for.  This fits the grammar and follows the legal rule that you should try to interpret a law so that no part is redundant and all parts matter (Scalia).   

4.  NCCN as a Guideline

The NCD analysis has two categories of guideline, "Evidence Based Guidelines" and "Professional Society Guidelines."  The draft in October placed the NCCN guideline under "Evidence Based Guideline" and then immediately criticized it for not being an evidence based guideline.  This was a little head-spinning.  They now acknowledge the NCCN guideline is "evidence based."

I think what happened is, there is indeed a kind of rigorous evidence based review that uses defined keywords, controlled literature searches, evidence admissibility criteria, meta-analyses, and so on.  NCCN would use that as an input, when available, but wouldn't produce it.  In addition, a comprehensive clinical guideline for physicians like an NCCN or ASCO guide has to consider all types of patients and situations, even those with less evidence.

5.  Lynch Syndrome "Not Enough Evidence"

CMS says it got submissions about Lynch Syndrome but there was not enough evidence.   Obviously, Lynch syndrome testing is included in all guidelines, covered by all MACs, by private insurers and so on.  So what gives?

I think the missing link here is that CMS was filtering only for Lynch syndrome evidence SPECIFICALLY conducted solely on NGS platforms.   That's not how the rest of the oncology and genetics community would sort the evidence for Lynch.

6. Weird Phrasing re Topics and Policy Categories

As noted earlier, the NCD refers to "acquired somatic cancer" and "germline hereditary cancer" rather than TESTS.

Weird things follow.   For example, look at new Section C, restrictions:

C. Nationally Non-Covered Indications
Somatic (Acquired) Cancer
Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with acquired (somatic) cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above.

This suggests like a patient getting the FMI test who has acquired non hereditary breast or colon cancer is targeted under "C" non-coverage, but a patient getting the FMI test who has BRCA- or Lynch-driven breast or colon cancer is outside the scope of restriction section "C."  I would have thought CMS referred to somatic acquired tumor mutation tests but they specificallyemploy the words "patients with" not the words "tests for."

CMS Posts Revised NCD for NGS Sequencing in Advanced Cancer

On January 20, 2020, CMS posted a revised NCD for uses of NGS testing in patients with cancer.

The original NCD, in February 2018, focused on companion diagnostic tumor tissue tests (e.g. the Foundation Medicine F1 test).   It gave special coverage benefits to tumor tests that were approved as FDA companion diagnostics. 

Stakeholders complained during 2018 and in early 2019 that the NCD inadvertently tended to block coverage of germline NGS tests, since the NCD focused coverage boundaries on "advanced cancer" patients.   CMS posted a draft revision of the NCD in October 2019, and the final revision now.

See the full NCD here:
https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=296

CMS also issued a press release, here.

See coverage at Genomeweb here.  At MedCity News here.  HealthtechDive here.  Healthcare Finance News here.   Health Payer Intelligence here.  Becker's Hospital News, here.

In the press release, CMS Administrator Seema Verma is quoted: “We recognize that cancer patients shoulder a heavy burden, so we’re leaving no stone unturned in supporting women’s health and getting all patients the care they need. NGS testing provides clinically valuable information to guide patients and physicians in developing a personalized treatment plan....Innovative technologies are transforming medicine, and at every turn, President Trump has shown a dogged determination to give Americans access to them”

##
###

Below, I primarily quote the text.  For a later blog that dissects some of the quirks and weirdness, here.

I've cut and pasted the pivotal text (the coverage text) below.  This is the NEW text, the text that is related to germline sequencing. 

A.  The Centers for Medicare & Medicaid Services (CMS) has determined that Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

1. The patient has:
   • ovarian or breast cancer; and
   • a clinical indication for germline (inherited) testing for hereditary breast or ovarian cancer; and
   • a risk factor for germline (inherited) breast or ovarian cancer; and
   • not been previously tested with the same germline test using NGS for the same germline genetic content.
2. The diagnostic laboratory test using NGS must have all of the following:
   • Food and Drug Administration (FDA) approval or clearance; and
   • results provided to the treating physician for management of the patient using a report template to specify treatment options.

B.  Other

Medicare Administrative Contractors (MACs) may determine coverage of Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when the patient has:

• any cancer diagnosis; and
• a clinical indication for germline (inherited) testing of hereditary cancers; and
• a risk factor for germline (inherited) cancer; and
• not been previously tested with the same germline test using NGS for the same germline genetic content.

We are making other technical, clarifying, and conforming changes in Section 90.2 of the National Coverage Determinations Manual.  We are clarifying the existing policy related to diagnostic tests for Somatic (Acquired) Cancer. 

See Appendix B for the draft manual language.

For ease of the reader, this National Coverage Determination (NCD) is only applicable to diagnostic lab tests using NGS for somatic (acquired) and germline (inherited) cancer.  

Medicare Administrative Contractors (MACs) may determine coverage of diagnostic lab tests using NGS for RNA sequencing and protein analysis.  

MACs also have discretion to determine coverage of diagnostic lab tests using NGS for any non-cancer (e.g., infectious disease and heart disease) use.  These uses are outside the scope of this NCD.

My head is spinning a bit from the fact they refer to "Patients with Somatic (Acquired) and Germline (Inherited) Cancer."   Normally you would refer to germline sequencing tests for inherited mutations and somatic sequencing tests for acquired mutations - not "germline and acquired cancers."

###

The full NCD coverage section, including both old and new text, 

is clipped below (as provided by CMS in its "Appendix B."

###

90.2 Next Generation Sequencing (NGS) for Patients with Somatic (Acquired) and Germline (Inherited) Cancer [New title]

A.  General

Clinical laboratory diagnostic tests can include tests that, for example, predict the risk associated with one or more genetic variations.  In addition, in vitro companion diagnostic laboratory tests provide a report of test results of genetic variations and are essential for the safe and effective use of a corresponding therapeutic product.  Next Generation Sequencing (NGS) is one technique that can measure one or more genetic variations as a laboratory diagnostic test, such as when used as a companion in vitro diagnostic test.

This National Coverage Determination (NCD) is only applicable to diagnostic lab tests using NGS for somatic (acquired) and germline (inherited) cancer.  Medicare Administrative Contractors (MACs) may determine coverage of diagnostic lab tests using NGS for RNA sequencing and protein analysis.  MACs also have discretion to determine coverage of diagnostic lab tests using NGS for any non-cancer (e.g., infectious disease and heart disease) use.  These uses are outside the scope of this NCD.

B. Nationally Covered Indications

1. Somatic (Acquired) Cancer

Effective for services performed on or after March 16, 2018, the Centers for Medicare & Medicaid Services (CMS) has determined that Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician, and when all of the following requirements are met:

1. Patient has:
   1. either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; and
   2. not been previously tested with the same test using NGS for the same cancer genetic content, and
   3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).
2. The diagnostic laboratory test using NGS must have:
   1. Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,
   2. an FDA-approved or -cleared indication for use in that patient’s cancer; and,
   3. results provided to the treating physician for management of the patient using a report template to specify treatment options.

2. (NEW) Germline (Inherited) Cancer

Effective for services performed on or after [DATE], CMS has determined that NGS as a diagnostic laboratory test is reasonable and necessary and covered nationally for patients with germline (inherited) cancer, when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

1. Patient has:
   1. ovarian or breast cancer; and,
   2. a clinical indication for germline (inherited) testing for hereditary breast or ovarian cancer; and,
   3. a risk factor for germline (inherited) breast or ovarian cancer; and
   4. not been previously tested with the same germline test using NGS for the same germline genetic content.
2. The diagnostic laboratory test using NGS must have all of the following:
   1. FDA-approval or clearance; and,
   2. results provided to the treating physician for management of the patient using a report template to specify treatment options.

C. Nationally Non-Covered Indications

1. Somatic (Acquired) Cancer

Effective for services performed on or after March 16, 2018, NGS as a diagnostic laboratory test for patients with acquired (somatic) cancer are non-covered if the cancer patient does not meet the criteria noted in section B.1. above.

D. Other

1. Somatic (Acquired) Cancer

Effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of NGS as a diagnostic laboratory test for patients with advanced cancer only when the test is performed in a CLIA-certified laboratory, when ordered by a treating physician, and when the patient has:

a. either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and,
b. not been previously tested with the same test using NGS for the same cancer genetic content, and
c. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

2. (NEW) Germline (Inherited) Cancer

Effective for services performed on or after [DATE], MACs may determine coverage of NGS as a diagnostic laboratory test for patients with germline (inherited) cancer only when the test is performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the patient and when the patient has:

1. any cancer diagnosis; and,
2. a clinical indication for germline (inherited) testing of hereditary cancers; and,
3. a risk factor for germline (inherited) cancer; and,
4. not been previously tested with the same germline test using NGS for the same germline genetic content.

(This NCD last reviewed XX.)

Very Brief Blog: Chief Medical Officer, Chief Innovation Officer, Both Depart CMS

Two departures from CMS announced in January, and one from HHS.

CMS Chief Medical Officer, Dr. Kate Goodrich, will leave for an executive position at Humana.  Story at Modern Healthcare here, Healthcare Finance News here, Lousville Business Journal here.  Prior to CMS, Dr. Goodrich had been a senior hospitalist at George Washington University.  Goodrich joined CMS in 2012. 

CMS Chief Innovation Officer, Dr. Anand Shah, will leave for a full-time policy position at FDA.   Dr. Shah joined CMS in early 2019 (here, here).  He will be FDA Deputy Commissioner for Medical and Scientific Affairs (here).   Current FDA chief Dr. Stephen Hahn, sworn in to replace Scott Gottlieb on December 24, 2019, is trained in both medical oncoloogy and radiation oncology; Shah is a radiation oncologist.  Follow Shah on Twitter for FDA at https://twitter.com/AnandShahFDA .

And a departure from HHS.  

Dr. Mona Siddiqui, Chief Data Officer in the HHS Officer of the Chief Technology Officer, also is leaving HHS (here).  Siddiqui (Linked-In here) holds an MD from Johns Hopkins, an MPH from Harvard, and an MSE in Engineering from Stanford; she'd held a number of policy staff positions in government since 2010.