Very Brief Blog: Some Cancers May Be Driven by Extrachromasomal DNA; Potential Drug Target

Over the past year or two, there's been a boom of interest in non-chromosomal oncogenes and the role they may play in some tumors.  For a number of years, we've known that tumors can be a rapidly evolution genetic mess, with missing chromosomes, extra copy numbers of oncogenes, fusions, and other alterations.

UCSD medical scientist Paul Mischel and team made a splash with a November 20 publication in Nature, documenting more about these tiny circular extrachromosomal elements (ecDNA), as well as showing they can over-express the oncogenes of interest, just like a fusion-driven oncogene that is "always on." 

Because normal tissues aren't driven by ecDNA, future drugs that eliminate ecDNA might be a magic bullet against some of the cancers, or at least, powerful assets in multi-drug regimens.

Some entry points:

• UCSD's Paul Mischel MD at Wikipedia here.
• Mischel lab at UCSD's Ludwig Cancer Center here.
• Mischel lab website here.
• Nature new paper here:   Wu et al. (2019) Circular ecDNA promotes accessible chromatin and high oncogene expression.  Nature (epub 20 November).
• Nature Reviews Cancer paper here:  Verhaak, Bafna, Mischel (2019)  Extrachrosomal oncogene amplification in tumour pathogenesis and evolution.  Nat Rev Cancer 19:283-8.
• Trade Press:
• Live Science here.
• Fierce Biotech here.
• New York Times - November 20 - here.
• Website for start-up biotech company, Boundless Bio, here.
• Raises $46M, September 2019, here.
• Mischel listed as founder; Zachary Hornby as CEO (Linked In here).

Verhaak, Nat Rev Cancer, Fig 01.  Bottom, EM of microcircular ecDNA.

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Mischel and I were just a couple years apart in the pathology residence and neuropathology fellowship at UCLA (circa 1994). MIschel's background includes college at Penn, med school at Cornell, residency at UCLA, molecular biology fellowship at UCSF, and faculty positions at UCLA and currently UCSD.

Very Very Brief Blog: FDA Posts Decision Summary for Nanthealth Tumor Exome (182pp)

On November 12, 2019, FDA approved use of the NantHealth tumor somatic, germline, and exome test.   See entry point here with additional background and links.

FDA has now released the 182-page review document - K190661 - here.   See also a deep dive article at Genomeweb here.   The FDA home page for the device is here.

I haven't read the whole FDA review, but it shows the commitment of the FDA to finding creative ways to approve very advanced NGS diagnostics with huge amounts of sequencing data.

Very Brief Blog: Seema Verma's September Blog on Program Integrity; RFI Due Nov. 20

CMS and HHS got a lot of press for wide-ranging new proposed rules regarding anti-kickback-statute and Stark laws, released for public comment October 9 (entry point here).  Generally, these aim to make value-based-contracting easier, but specifically, they usually leave out the lab industry (as if no good value-based healthcare contracts could involve the lab industry).

Here's another CMS program integrity workstream:

I had missed a lengthy Seema Verma blog on October 21 in which she discussed wide-ranging CMS efforts on the program integrity front.  Worth reading; here.  (Hint: She specifically calls out scandals in the two areas which are orthotic braces, and lab genetic testing.)

See a trade press article about Verma's blog here.

At the same time, CMS Program Integrity released a 12-page view of how they frame their changing mission, including a Request for Information (e.g. a request for public comment).  The RFI comments are due November 20, but even if you miss that deadline, the RFI may still be worth a look.

And finally, CMS Program Integrity also released a 14 page view of how they want to leverage advanced technologies, including AI or Machine Learning for medical review. 

Very Brief Blog: CMS Follows Administration Goals, Releases Price Transparency Rules

A major theme of the Trump Administration this year has been healthcare pricing, including surprise billing (here) and price transparency (for June 2019 executive order, here.) In late September, a number of stakeholder groups urged the Hill to move forward with surprise billing legislative, which had lost momentum.

For price transparency, the eagle has landed; on Friday, November 15, the Trump administration releases final and major price transparency regulations.  HHS views price transparency as a matter it can address through de novo regulation, whereas most surprise billing issue fall outside of Medicare or Medicaid and would require legislation.

Somewhat confusingly, today's release has two different components, and one part is a second and "final" part to the annual OPPS final rule, most of which was released November 1 (here).  In that rule, CMS merely stated concisely that "We intend to [issue] a forthcoming final rule."  Here it is.

Then, there is also a separate PROPOSED rule, which has its own website and its own fact sheet.

Headline:  The OPPS Final Rule "F2" governs hospital requirements for publishing price transparency.  While I believe past state legislation has defined this as chargemasters, CMS defines this as per payor negotiated rates.   All rates need to be available to a patient, but 300 key rates need to the public.  Meanwhile, the PROPOSED rule is about insurers posting negotiated rates.

• For CMS/HHS press release, here.
•    For CMS fact sheet on the rule (CMS-1717-F2), here.
•      Those who want to read the 1717-F2 rule (in typescript form, 331pp), here.
•         CMS webinar on the final rule here (Dec. 3).
• Now, there is also separate from that, a PROPOSED rule.
•    For fact sheet on PROPOSED rule, (CMS-9915-P) here.
•      Those who want to read the 9915-P rule (in typescript form, 219pp), here.
•    Since 9915-P is a PROPOSED rule, it has a 60 day comment period (to mid January).
• For WSJ article, here.
• For a September background WSJ article, here.  ("Push Sparks Furor")
• For a November 20 update, WSJ, hospitals vow to sue CMS, here.
• The Economist, Nov. 23 issue, Op Ed here.  Deep dive article, same issue, here.
• Healthcare Dive here.  Medcity News here.  Pro's and Con's article at Vox, here.
• Health Affairs here.
• AHA and other hospital groups issued a joint statement that they disliked the rules here.
• Opponents gear up for the courtrom, here.

Puzzler:

I haven't read these line by line.  But for hospitals, CMS clearly asks them to post negotiated rates per payor, and CMS then asks them to post lowest and highest negotiated rate "anonymously."  If I've listed ten payer rates by name from 1 to 10 for cost, then posting the lowest & highest rates anonymously seems impossible.

Footnotes:

With all the fuss about transparency, all CMS prices have been posted online for a decade or two, physician offices, imaging, lab tests, hospital based surgery, inpatient, outpatient, drug prices, and so on.   Nothing secret about all of that.

And with commercial insurers, while there has never been mandatory posting of contracted rates, either from the hospital side nor from the payer side, there's one thing hiding in plain site.  These rates are sent out by the millions, tens of millions, hundreds of millions, into the public space via Explanations of Benefits.   I know if my imaging center charged BCBS $1200, got paid $319, and my copay was $35.   I know if my doctor charged BCBS $225 for an office visit, got paid $87, and my copay was $20.   While these circulate by email, by postal mail, such agreements and rates circulate in society in hundreds of millions of documents.  Easy to access?  No.  But different in a fundamental way from a true "secret."

Very Brief Blog: CDC Releases Antibiotic Resistance Report; CMS Tie-Ins

Watching the 6 am cable news in a Boston hotel prior to today's Personalized Medicine Coalition conference held at Harvard Medical School, local news provides a 30 second clip about a new CDC report on antibiotic resistance in the US.

Some sources for New CDC Report:

• STAT summary of new CDC report on antibiotic resistance, here.
• CDC homepage for the new 2019 report, here.
• Download the actual 148-page report from CDC, here.
• The new report updates the prior 2013 report.
• Pages 41-47 focus on diagnostics.

Some policy tie-ins at CMS:

• CMS administrator Seema Verma had an Op Ed in Stat last wek on CMS efforts on antibiotic resistance.
• November 6 Op Ed in Stat, here.
• August 2 Op Ed by Verma in Health Affairs, here.

As detailed in her November 6 Op Ed, recent CMS efforts to encourage antibiotic best practices and drug development include (1) raising the New Technology Add-on Payment for inpatient costly drugs (albeit only for 2-3 years per new drug), (2) upgrading the DRG payment for some DRGs that involve sepsis, and (3) finalizing Conditions of Participation to require hospital antibiotic stewardship committees.   Updates 1 and 2 were in August final inpatient rulemaking (entry point here); the CoP requirement was a special rule issued September 25 (entry point here).

BARDA and PAC-CARB

For those who aren't familiar with it, the national biodefense agency BARDA provides substantial funding for antibiotic resistance technologies (including diagnostics as well as drugs), and an international public-private funding agency, CARB-X, is an innovative approach to funding.

There is a President's Advisory Commission on Antibiotic Resistance (PAC-CARB), which last spring held a special session to urge HHS to finalize the Conditions of Participation for hospitals to require antibiotic stewardship committees.   HHS also is producing a second five-year National Action Plan for coordinated federal efforts in antibiotic resistance policy and investments (here).

Antibiotic Stewardship Programs: JC, CMS, CDC

Antibiotic Stewardship Programs (ASPs) are required both by the Joint Commission on hospital accreditation and CMS, but CMS worked to insure its requirements were met by meeting JC requirements.   Both sets of rules are predicated on Core Elements of ASP's, produced several years ago by CDC.  CDC is said to be in the midst of revising the Core Elements in the next month or two.

IDSA, Pew Foundation

Two of the independent organizations heavily involved in antibiotic stewardship policy are Infectious Disease Society of America (IDSA) and Pew Foundation.

Diagnostics and Hospital Budgets

On October 31, 2019, 360Dx ran an excellent (subscription) article discussing how "one of the hottest categories in diagnostics is antibiotic resistance testing," while such new molecular tests frequent collide against fixed hospital inpatient budgets.  And fixed outpatient budgets too - Medicare since 2014 bundles all clinical chemistry and microbiology tests to hospital outpatient visits or surgeries (with an exception only for human genetic tests). 

DISARM Bill and AdvamedDx

On the Hill, the DISARM bill has been introduced in both houses.  This is the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms Act of 2019, see press release here and full bill here (S. 1712).  DISARM would pay for certain priority antibiotics on an average-sales-price basis for Medicare inpatients, on the requirement that hospitals participate (1) in the CDC national data registry for antibiotic resistance (NHSN) and (2) have ASP in place [the latter is now required by CMS, which it wasn't when the bill was introduced]. 

In a six-page public letter to the Senate, in July 2019, AdvamedDx suggested that the DISARM bill should have more policy initiatives related to diagnostics (here).  Advamed's proposed revisions include requiring a lab director on ASP committees, and upgrading lab technology with faster turnaround times and clearer reports with better decision support capabilities electronically integrated. 

(On the latter point, Biomerieux is supporting advanced analytics software to take the diagnostics lab far beyond historic "sensitivity and resistance" reporting; here. BARDA is also supporting Beckman Coulter to integrate advanced EHR-based algorithms with lab test reporting in sepsis, here.)

Medicare Won't Cover FDA-Approved HIV-1 Genotyping Due in Cancer Patients, Due to Stupid Policy Glitch

In March 2018, CMS released a blanket policy for all uses of NGS testing in Medicare patients with cancer.  The policy limits NGS testing to patients with "advanced cancer" (metastatic, recurrent, stage 3 or 4).   By my reading of the NCD, and I think most readings, the limits are absolute, as the policy is worded, it applies to all NGS tests and doesn't distinguish by type of NGS test.  Therefore, if you had a small skin cancer and a doctor ordered the FDA "Sensa" HIV-1 NGS-based resistance test, Medicare wouldn't pay for it. 

Obviously, CMS staff were thinking of tests like NGS Foundation One test (which they were reviewing at the time) when they limited all NGS test payment exclusively to "advanced cancers."   The policy really has got to be updated to only control testing in areas the NCD actually reviews (I read Medicare law this way; here).   If an NCD reviews A and B, they can then create policy cover A and perhaps not cover B; but they can't non-cover topics C or D that they never reviewed.

Very Brief Blog: Digital Therapeutics Alliance Release Suite of Documents

In September, the FDA released a number of documents in its continuing efforts to stay abreast of digital health (entry point here).

This week, the Digital Therapeutics Alliance issues a press release and its own suite of documents.

• See the DTA website here.
• See the new press release here, with a series of links therein.
• Topics include:
• Code of Ethics here.
• Product Best Practices here.
• Categorization of Digital Health (umbrella), Digital Medicine, Digital Therapeutics here.
• Another product categorization table here.

Partial screenshot of DTx table

I've put today's document versions into a zip file in the cloud here, but check DTxA website for updates.

FDA Clears Whole Exome Tumor Test for NantHealth; 510(k)

On November 12, 2019, NantHealth announced it had received a first in class FDA clearance for an NGS-based whole exome test.   In addition to sequencing some 19,000 genes and 39 million base pairs, the test reports the same 468 cancer-relevant genes reported by the Memorial Sloan-Kettering IMPACT test, a predicate test for NantHealth.  IMPACT was a de novo clearance in November 2017.  Nanthealth's test also reports tumor mutational burden (TMB.)

The branded name is OMICS CORE.

• See NantHealth press release here.
• See open access summary at Genomeweb here.
• See open access at Clinical Omics here.
• FDA tracks the test as K190661 here.
• See the 180-page FDA decision summary, K190661, here.
• See Genomeweb on the decision summary, here.

The 57-page 2017 FDA evaluation of MSK IMPACT (DEN 170058) is online here.  it will be very interesting to see the FDA's published validation requires for whole exome in Nanthealth's FDA review.

It's hard to be sure from the short press releases, but it may be that the test reports the 468 genes (like IMPACT) but uses exome to calculate TMB (or for research data).

NantHealth's most recent investor call, November 7, is online here.  NantHealth was up 10% today, to $0.76 with a market cap of $85M.  (Current assets are about $28M; retained earnings are -$918M; initial valuatoin was $1.7B.)  In 2017 and 2018, each year NantHealth had about $85-90M revenue against net lincome (loss) of about $175-190M.

Horizon Watch: The FDA's Payer Communications Page (Includes CMS Parallel Review)

I noticed that the FDA has updated its consolidated Payor Communications webpage, with multiple sections and links, as of September 2019.

• See the FDA Payor Communications Page here.
• See the FDA Drug & Device Payor Communications Guidance, here.
• 26 pages, PDF, June 2018.
• See Gottlieb statement about the value of FDA-Payor interactions, here.
• See an archived commercial webinar on FDA's package of  payor communications at Icon, here.

Sections on the FDA Payor Communications Page include:

• An overview and background section; 
• A voluntary Commercial Payor section
• Includes Aetna, Kaiser, Cigna, Humana, etc., and evidence groups like ECRI; 
• Instructions and contact information for the "CMS-FDA Parallel Review" process.  

Note that the CMS Parallel Review process is very rare, used in full only twice in a decade. 

At the bottom of the webpage are a number of links to various Commissioner statements, Federal Register publications, etc.    For example, FDA last held a "Payor Summit for Medical Devices" three years ago, in 2016.

You can also request an FDA speaker to come talk about these policies at an event or conference (instructions on the webpage).

CMS Updates PAMA and ADLT Pages; Offers to Create G Codes in Lieu of PLA Codes

I don't have screen shots of every CMS page edition, but I think they've significantly revamped their webpages for PAMA regulations, PAMA reporting, ADLT applications, and rapid quarterly HCPCS codes.

They now have a sort of consolidated PAMA Regulations page under the Clinical Lab Fee Schedule division that offers one-stop shoping, usually to online documents but sometimes to other web pages.

See the CLFS home page here.

See the PAMA regulations home page here.

There are successive sections, each with a few links, for PAMA reporting rules, PAMA reporting computer system, ADLT applications, and an application for a quarterly CMS code (in lieu of a PLA code.)

Of note, there is a webpage, updated 10/15/2019, that I hadn't seen before.  Here, CMS welcomes your quarterly application of a lab code, which will start with "U" (rather than G).  The codes move as fast as PLA codes; for a January 1 deadline, you get an April decision and a July effective date.  CMS won't give you a unique HCPCS code if you have, or if you are applying for, an AMA CPT code.

CMS will issue codes for ADLTs and FDA cleared or approved tests.  The 7 page PDF application is here.

Very Brief Blog: CMS Posts Final PFS, OPPS Annual Rules On Time

Despite not posting proposed annual policymaking for the physician fee schedule and hospital outpatient policy until late July, with comment periods running until ;ate September, CMS was able to release final rulemaking for CY2020 on November 1, giving the public the required 60 days notice before January 1.

CMS releases "inspection copies" or typescripts now; typeset Federal Register versions will appear around November 12 (OPPS) and November 15 (PFS).

• The consolidated Federal Register page for CMS announcements is here.
• Hospital Outpatient Policy page here.
• OPPS inspection copy typescript here. 1113pp.
• Federal Register Final Rule, Nov 12, 84FR61142, 351pp, here.
• OPPS Fact Sheet here.
• OPPS Addendum ZIP Files (Such as APC rates and CPT to APC assignments) here.
• Physician Fee Schedule Policy page here.
• PFS inspection copy typescript here.  2475pp.
• Federal Register Final Rule, Nov 15, 84FR62568, 996pp, here.
• PFS Fact Sheet here.  Quality Program Fact Sheet here (28pp PDF).
• A PFS press releases emphasizes reducing provider burden and improved quality metrics, here.
• PFS addendum ZIP files online here.
• Consolidated Discoveries Zip File
• To save hunting and pecking, I've putting the several rules, press releases, OPPS Zip Excel files into one 32 MB open access zip file in the cloud - here.

The PFS rules includes several new opioid abuse policy programs, one for general outpatient care, one for new bundled payments for Opioid Treatment Programs (OTP, aka methadone centers).   The latter program had threated to bundle all monthly urine tox lab fees into a single payment of a few dollars but CMS revised this to include more sophisticated testing.  See a public letter from Aegis, a leading tox lab, on the problems CMS would have caused with the original proposal (here).  The opioid test policies get their own press release here.

The OPPS rule, for the lab industry, was notable for proposed changes to the infamous and complex outpatient hospital Date of Service rule.  CMS is making no significant changes except to add an exclusion re blood banks at 42 CFR 414.510(b)(5) [typescript p. 1105].  (Text here).  Within the 1-14 day time period after an outpatient blood draw or biopsy, the lab that performs a human molecular test must bill for the test and the date of service is the date of test performance.  This means that whether a hospital or an outside reference lab performs, for example, an EGFR test on a lung biopsy, it must be billed as "date of performance" not "date of collection" which is the usual CMS DOS.  Said differently, if a hospital runs an EGFR gene test and a PSA test on the same vial, the EGFR test has "DOS" as date of performance, while the PSA test would have DOS as date of collection, except that in the OPPS setting the PSA but not the EGFR is bundled.  Note the same distinction of two DOS from one vial applies also for a physician origin blood sample handled and run the same day at Quest or Labcorp.  

CMS proposed to start a new Part A/B program for prior authorization with several surgeries that CMS feels are likely to be abused, like blepharoplasty.  Despite complaints, CMS is finalizing this.  I had my doubts that this was likely a program that CMS could implement well, due to the very minimalistic staffing of its MACs with RN or MD staff, but maybe it can if volumes are low.  Prior auth services will be CPT codes associaited with blepharoplaty, botulinum injections, panniculectomy, rhinoplasty, vein ablation.  Particular providers can be released from prior auth rules if they have high pass rates on submitted cases.  There were questions whether CMS had authority to institute Part A/B prior auth (see inspection copy, 992ff).  

Also in the OPPS system, CMS proposed cutting payments for the Heartflow advanced digital imaging service from $1500 to $750; the final price chosen will be around $900.  (Earlier article here). (Inspection copy, 255ff).   Flipping from the OPPS to the PFS rule, CMS proposes that some 3D imaging rendering CPT codes (e.g. 76376, 76377) may be misvalued (inspection copy, 174ff).

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CMS floated a plan for hospitals to push standard charges for increased transparency; CMS deferred action on this topic (inspection copy, 926ff).  Much ink had been spilled since July on this topic; entry point here.

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Related to the July announcement of multi-modal programs to improve CKD, ESRD, and renal transplant care, CMS proposed changes to the "expected donation rate" which is part of qualifying as a transplant procurement center; see OPPS inspection copy 927ff.