Thursday, September 12, 2019

Very Brief Blog: CMS Ups Its Game on Opioid Crisis; Sets Up Town Halls and RFI's

CMS should be commended for several current actions it's taking to gather community information, best of breed practices, and new ideas for handling the opioid crisis.

  • Public Meeting.  On September 20, 2019, CMS is hosting a full day public meeting in Baltimore on the topic, agenda here.
  • Listening Session.  CMS will hold a "Listening Session" on defining and managing "outlier prescribing," here.
  • RFI.  CMS has released a very well-designed and broad-ranging "request for information" (RFI) on new ways to handle the opioid crisis.  Comments are due by October 11, 2019.  Here.

The RFI is worth reading; it's a model of its type.

Why Not an RFI on Sepsis, Antibiotics, Diagnostics?

Recently, CMS has been criticized by a low level of impactful activities on the antibiotic crisis (e.g. here and here.)   While Seema Verma, the administrator, recently wrote an article on CMS's activites in that area, it would be ideal if CMS would reach out to the community for really innovative ideas on antibiotics, diagnostics, infection, sepsis, similar to the opioid RFI above.

Very Brief Blog: BARDA Industry Day October 15-16, 2019

BARDA is the innovative and important biotech defense agency.   I've had several contacts with them in the last two years and BARDA has very impressive and proactive management.   BARDA regularly funds medical diagnostics related to sepsis and pathogen identification (see for example LexaGene here, Inflammatix here).   BARDA also supports the CARB-X industry-government partnership (here).

On October 15-16, 2019, BARDA hosts its industry days, at the Hyatt in Washington.  I attended last year and it was extremely interesting.  Registration is free; it's a big event (many hundreds of attendees) and may become fully booked as the event draws closer.  See web pages and registration here.

More About BARDA

See BARDA at Wikipedia, here.

Other Infection and Sepsis News

In other news, Friday, September 13, 2019, is World Sepsis Day, here.   For example, Thermo Fisher has a whole range of webinars and activities in September, here.     See Sepsis Alliance, here.  German Sepsis Society is currently holding its annual conference in Weimar, September 11-13, 2019, here.    ID WEEK will be held in Washington, October 2-6, 2019 - here.    Stay in DC for BARDA, October 15-16, as above.

If these topics are of interest to you, see CMS administrator Seema Verma's article in Health Affairs on CMS and antibiotic resistance, here.  (Last year, Pew Foundation called on CMS to do more, here; similar theme at APIC here.*)  Joint Commission also works in this area, here.  You may also want to track the President's Advisory Council on Antibiotic Resistance, PAC-CARB, here, and the HHS new 2020-2025 5-Year-Plan for antibiotic resistance.   See also the topic page at World Health Organization here.

DISARM Legislation in Congress

Also in Washington, this fall Congress is considering the DISARM Act, which would provide hospitals special payments for special-class antibiotics if the hospital (A) has an approved antibiotic stewardship program, and (B) contributes data to a CDC big data program on antibiotics and resistance.   Articles here and here.



* Along the theme of CMS doing something creative to push forward antibiotic management issues, I noticed that CMS just released an open-ended public request for comments and ideas on how CMS can better address opioid management.   (Here).  From my observations, it would be a good idea if CMS also did a parallel community-wide request for idea - request for information, RFI - on antibiotic management. 

Tuesday, September 10, 2019

New CMS-Funded Study Faults Cologuard Cost Effectiveness and Life-Years-Gained Effectiveness

On September 4, 2019, PLOS One published an open-access study by Naber et al. that is highly critical of the clinical effectiveness (life-years-gained, LYG) and the cost-effectiveness ("worse than any other method") for Cologuard (CPT 81528, $512).

See the paper here.  For trade news at 360DX, here.  360DX discusses potential flaws in the study; I'm not an epidemiologist and I'm discussing the study as-is.  I did notice (see also 360DX) that the costs of a Medicare colonoscopy were significantly underestimated by the authors.  See an Exact press release here; an article in MedTechDive here.

The paper is funded by HHS/CMS grant to the Mitre Corporation, but there are no Mitre authors listed.  Authors are from the Netherlands, Univ MN, Kaiser, RAND, MGH, MSK, etc.

In a key table, the authors find that a Cologuard-managed population would have 30 CRC cases and 8 deaths.   However, an FOBT poulation would have 25 cases and 6 deaths, a FIT population 27 cases and 6 deaths, and a colonoscopy population 9 cases and 2 deaths.   While the Cologuard population would have 79 life years gained per 1000, nearly all the other methods would have more LYG than that.

Authors report that Cologuard could be a dominant cost-effective strategy if cost was reduced to about $10.

CMS Asked About Cost-Effectiveness Rates

The introduction states directly that CMS requested the analysis, asking whether Cologuard was a cost-effective alternative, and if not, at what reimbursement rate or screening interval Cologuard would be cost effective.


The paper explicitly describes how the Cologuard rate was set (by crosswalking; 81315+81275+82274), a 2016 rate at circa $500 that was minimally changed by PAMA surveys in 2016 and rate setting for 2018-2020.


Note that in addition to the 20-page PDF publication, there are a number of supporting figures online, inline with the web text.

See also references to Ladabaum & Mannalithara, ref. 46, Gastroenterology 2016 151:427.


Cologuard was the highest-line-item cost in the CMS molecular payments for 2017, table:

click to enlarge

(Note in the above table, while we hear about 200,000 or 300,000 genetic tests, or 5000 new genetic tests per week, just four familiar codes captured over 50% of CMS spending.)


Lab tests for CRC in 2017 at Medicare Part B were:

click to enlarge


In Statute, at 1861(oo) and (pp)Medicare's add-on line item benefits for preventive prostate testing (which have never been used) include cost effectiveness; for colorectal preventive testing, they do not (here).  When preventive benefits are added after USPSTF approval, cost may be considered.


Over two days, Exact share price slipped about 12% (122 to 106), a market cap change of about $1.5B.


Note that there are two required levels of compliance with fecal testing.  One is whether the test kit is ever used and returned (the ick factor).   The second is, when you have a positive test, do you advance efficiently to a colonoscopy to investigate (the oh-no colon prep factor and the day-lost factor).

Monday, September 9, 2019

Brief Blog: Understanding Concert Genetics' Two New White Papers on Genetic Coding Mess

Concert Genetics, a consultancy in Nashville, is currently hosting the annual Genetic Health Information Network Summit (GHIN Summit, September 9-11, 2019) - here.  Concert Genetics is well-known for its series of white paper on the U.S. genetic testing industry, volume, test types, and code mapping.

This week, they've also released two important new white papers on genetic coding.   I'll summarize briefly.

  • For Concert Genetics home page, here.
  • For white papers, here.  
    • A prior Concert Genetics white paper cited in Congressional testimony, here.
    • For some peer-reviewed papers Concert has written or collaborated on, here.
    • Patent, Systems and method for tracking...diagnostic testing products, here. (Cited in WP#1).
  • For blog, here.
  • For Variability in Coding white paper (#1), here.
  • For Coding Solution white paper (#2), here.

White Paper #1 - Variability

Working with a database of 35M claims and 2M genetic tests, Concert categorized by test type (for example, tumor testing, cancer risk testing, carrier testing.)  
  • Within each category, there was huge variability in coding and pricing.   
  • Those categories with the highest variability in coding had highest variability in pricing.

White Paper #2 - Coding Solution

We're all familiar with correct coding principles, some (brief ones) found in the CPT handbook, some in Medicare documents (Correct Coding Edits), some unwritten, some in payer articles, etc.   What Concert proposes is to have one uniform, systematic set of rules that are always applied as algorithms.  They are commonsensical (if there is a PLA code, use PLA code.  If there is a fit to a GSP code like Hereditary Breast and Ovarian Cancer, 81432, then apply that.   If there is a Tier 2 code, then apply that; and so on).   

It's different than today's coding because, while there is a dream that all human coders will code correctly and the same, here, a computer (or a human following iron-tight rules) will always reach the same result.   
Let's apply the idea to a dictionary.  We want to categorize the words in a dictionary.  First, categorize as English vs foreign.  Then, second, categorize as A-L or M-Z.  Then, third, categorize as one syllable, or two or more syllables, etc.   You'd have a rule set that could categorize any word, even words it hasn't seen before.  Same idea here, but for genetic coding.


One is is special rules.  Medicare MACs may have special coding rules they insist be applied (although sometimes this collides with payers; Myriad 2019 case here.)   Medicare has national special coding rules (Correct Coding Edits), although sometimes CCI rules are bizarre, as the industry has complained about some 2019 genetic coding rules therein (here, here).   MolDx has a "Test Panel" coding rule, which is dead-simple to state, but public data shows that Noridian is unable to consistently apply it.  Concert plans to have one uniform set of rules, limited in number, applied in specific order.



While it is common to hear of the 100,000 or 200,000 genetic tests, in 2017 Medicare data, 72% of volume was driven by only 10 codes.  Most of this was concentrated in the top 5 codes alone. 

While the top 5 codes did include 81479 (unlisted code) at 18%, if you went inside that unlisted code, most of the 81479 volume was driven by a few tests like Myriad Assurex Genesight, which is about half the 81479 volume.   (And almost all of the 81479 billing comes through the MolDx states, zero elsewhere).   In short, CMS data shows heavily concentrated use of a few blockbuster genomic tests.

Friday, September 6, 2019

New LCD Rules 2019: A Flow Chart View

For 2019, CMS posted new rules for the Local Coverage Determination process, the first substantial update since the 1990s.

The CMS rulebook for MACs is online (called Program Integrity Manual, Chapter 13, LCDs).  Find it at CMS, here.

However, it can be confusing to understand what is the same and what is dropped or wholly new.   I've tried to show major features of the old and new process in two slides. 

The PPT slides are open-access in the cloud here.

Old Process 1990s-2018

New Process 2019 Forward

New features include:
  • Special rules for asking for an "Informal Meeting," which MAC can grant at its discretion
  • Special rules for applying for an LCD ("New LCD Request" rules) such as "stating the benefit category"
  • MAC must acknowledge it has received, validated, and queued the LCD request, but there is no timeline for further action.  MAC should NOT say if it views coverage request favorably or unfavorably.
  • CAC meeting is OPTIONAL
  • CAC meeting may be PRIOR to any LCD, as "information gathering" for the MAC
    • MAC controls agenda, speakers, etc
    • CAC must be an open audioconference with later transcript
    • CAC meeting may be multi-MAC
  • New LCDs, LCD restriction, LCD expansion must *all* go through public process
    • This is a big change in regard to LCD expansions, which were formally quick online edits.
  • Draft LCD must be killed if not finalized in 1 year

Expect the process to take a full year. 

Example:  MAC request from stakeholder in January, with publications.  MAC holds informal meeting in February.  MAC holds CAC meeting in May.  MAC writes draft LCD in June.  Draft LCD circulated to CMS in July (in case CMS has any questions).  LCD draft posted in August.  Public meeting in September.  45 day comment period to November 1.  MAC reviews comments in November, December, January.  MAC posts revised LCD in February, effective April. 


All draft and active LCDs are in an online CMS database, here.


There was a CMS press release on the changes in October 2018, but frankly, I found it more confusing than helpful and it discussed a "faster" process which I can't see in the real world.  Here.

Thursday, September 5, 2019

Very Brief Blog: AMA Publishes Detailed RUC Minutes

Here's something new.   AMA conducts elaborate meetings of its RUC (relative valuation) committee, passes those recommendations to CMS, which heavily influence the assignment of CMS values and pricing to CPT codes. 

Very lengthy minutes are left behind online.   The RUC Minutes home page is here:

This either requires no registration or an email registration.  For example, the May 2019 RUC minutes are 376 pages of detail:

Separately, through the AMA Store, AMA sells online annual subscriptions for $320 to the RUC RBRVS Database, which gets you into definitions, RUC decisions, valuation, and utilization of every CPT code.   Search AMA Store for "RBRVS Data manager Online."  (One version here.)

After CPT meetings, with a delay of a few weeks, AMA publishes a brief table whether each code agenda item was approved, disapproved, or tabled.  AMA calls this "Summary of [CPT] Panel Actions."  See here.  May 2019 is here.

Finally, if of interest, an AMA CPT confidentiality statement sample is here.  It's aimed primarily as protecting AMA CPT copyright interests.

Genomeweb Joins Crain Communications

Rare is the day I don't see the Genomeweb website twice, and that's been true for about ten years.  Today, Genomeweb's CEO, Bernadette Toner, announced that the company has been acquired by Crain Communications.   "Operations and staff will remain unchanged."   According to Wikipedia, Crain has about 30 publications and 850 staff.   They've owned Modern Healthcare (for the hospital industry) since 1976.

Genomeweb recently diversified into three websites, with some shared stories, being (1) the original Geneomeweb, (2) 360DX (focused on the clin lab industry) and (3) Precision Oncology News.

Wednesday, September 4, 2019

Very Brief Blog; AMP Holds Molecular Pathology Economics Summit, Washington, 9/20/2019

The Association for Molecular Pathology is holding a Molecular Pathology Economics Summit in Washington, DC.   It will be on Friday, September 20, 2019.

The AMP website for the conference is here.

I've clipped partial information on the conference as text below.  At bottom of this blog, I mention a few other coming precision medicine events.

AMP September 20:
Molecular diagnostics is a rapidly evolving field with frequently changing standards for care that challenge the current paradigm for coding, coverage and payment. The Association for Molecular Pathology (AMP) is bringing together stakeholders across the healthcare spectrum in a one day summit with the goal to establish shared opportunities to improve the molecular diagnostics economic landscape.  
Attendees will participate in guided discussions to identify barriers to appropriate reimbursement for molecular pathology procedures and then explore and have the opportunity to propose solutions to critical challenges that are limiting full realization of the possibilities offered by precision medicine. The Summit will connect experts across multiple industries and professional arenas harnessing the collective effort to advance the national dialogue towards improving patient access to appropriate molecular diagnostic care. 
AMP’s Molecular Pathology Economics Summit will be a highly interactive one-day gathering focused on:
  • Identifying barriers to appropriate reimbursement for molecular pathology procedures;
  • Identifying the impact of these barriers on various stakeholders and patient access to care; and
  • Identifying potential solutions and/or novel approaches to overcoming barriers, with a goal of identifying shared policy agendas for the participating stakeholders in oncology, infectious diseases, and inherited conditions
Date: September 20, 2019
Time: 8:00am - 3:30 pm Eastern
Location: Conrad Washington DC, 950 New York Ave. NW, Washington DC, District of Columbia, 20001


A few other upcoming conferences include a trendy health modernism conference called HLTH, October 27-30, 2019, at MGM Las Vegas - here

Precision Medicine Leadership Summit (I am a speaker) October 10-11, 2019 in La Jolla, here

The 25th Annual AMP Meeting is November 7-9, 2019, in Baltimore.  Here.

The 15th Annual PMC Conference at Harvard is November 13-14, 2019, here

Brief Blog; Ubiome Files for Bankrupcy

According to the WSJ and other sources, on September 4, 2019, UBIOME filed for bankruptcy, suspended operations, and put its assets up for sale.  Story here.  Business Insider  open access, here.  Forbes here.

In particular, the company had prior raised $83M from some leading investors.  For an investigative story had Business Insider (subscription), Erin Brodwin, in August 2019, here.

Some additional press.  Exconomy, "UBiome Founders May Have Misled Investors," here.  From back in September 2018, exactly a year ago, "uBiome Jumps Into Therapeutics with $84M in Series C," TechCrunch, here.

I was briefly quoted in a WSJ story on the case, back in June (here).  I had discussed my experience with consumer testing at COLOR and at UBIOME in December 2018 (here).  I also posted some redacted multi-thousand-dollar bills that UBIOME sent to my insurer, after I had paid for the DTC test by credit card originally.  (May 2019, here.).  A teledoctor I had never heard of (NPI '768 in California) had ordered my test in the background before the Ubiome bill went to the insurer.  The insurer entirely rejected the claim.

Monday, August 26, 2019

CMS Proposes Big Heartflow Price Cut for Outpatients; MAC Proposes Detailed Coverage Rules

A couple years ago, I outlined the remarkable and serpentine saga as the Heartflow fractional flow reserve (FFR) test moved from Medicare non coverage to coverage.   (For example, at one point, Heartflow's MAC wouldn't even let it enroll in Medicare as a provider.) 

My main blog on the Heartflow topic was in April 2018, and ended with Heartflow categorized into an outpatient payment category of $1500.  Here.   (An even nerdier version of the story is here.)

Heartflow uses very sophisticated software on site to provide dynamic analyses of cardiac CT imaging taken elsewhere, leading to better and less invasive management of patients.  The company has raised several hundred million dollars over the years.  Funding includes $65M in June 2019 and $240M in February 2018 (here).

Saga Continues Summer 2019

The story continues in Summer 2019.

  • First, Palmetto GBA MAC provides a proposed LCD for coverage of Heartflow FFR, including detailed patient criteria, exclusion criteria, and technician and physician training criteria.  CMS copy here, cloud copy here
  • Second, CMS proposes to halve the outpatient Heartflow price.  CMS originally placed the Heartflow code in a New Tech Payment Category for $1500. That was for CY2018.   Now, in summer 2019, CMS says it has enough data from 840, CY2018 hospital claims to reclassify Heartflow's code in a far lower payment category.  Original APC was APC 1516 ($1450) and proposed new APC is APC 1509 ($750).  See 84 Fed Reg 39459-60 (August 9, 2019).   Here.    

Medicare Nerd Trivia

One way that Medicare can pay for diagnostic tests is as "purchased tests," where e.g. the treating cardiologist "purchases" the technical component of a report and finalizes it (signs-it-out).  The physician can bill this "purchased test" to Medicare (by law, with no mark-up), but he has to report the entity that did the test, its location, its NPI.  CMS confirms if the test originator was validly enrolled.  See R3255CP, October 2015, Part B claim for purchased test to be handled as "unprocessable...if the [original supplier] cannot be verified as a valid, Medicare-enrolled entity" (at  Here.   

Heartflow might not be a Medicare-enrolled entity.  You can look up the NPI here, which seems to be 1982019980.  If you go to Opedge/PECOS, it comes back with a "red" rather than "green" check (see pic below) which may mean that this NPI isn't enrolled in Medicare.   See:   As noted above, CMS did process 840 Heartflow code claims at hospitals, suggesting that hospitals don't have to validate if a supplier is Medicare-enrolled or not.

The Bonanza of BRCA Policy Documents: USPSTF, OP ED Collateral, and More

Update: On September 3, 2019, JAMA and USPSTF issued updated recommendations on use of medications to reduce risk of breast cancer in women with elevated risk.  For this related, but separate, topic, see an additional set of links at BOTTOM.


On Tuesday, August 20, 2019, the regular weekly edition of JAMA brought the new USPSTF positioning on BRCA testing. 

While the changes from the last USPSTF position are not large (and there were relatively few changes from a USPSTF BRCA proposal), the changes are worth noting and the penumbra of policy documents and op eds was pretty large.  I've collated the links in this blog.

Primary Documents

2019 Final USPSTF Position
  JAMA 322:625-665.  Here.

2019 Final USPSTF Evidence Report
  JAMA 322:666-685.  Here.

Prior:  2014 USPSTF Position here.
Prior:  March 2019 USPSTF BRCA Proposal here.

Associated JAMA Documents - Same Week

Patient One-Pager.  "Should I Be Tested for BRCA Mutations?"
  JAMA 322:702.  Here.

JAMA Editorial.
  "Broadening Criteria for BRCA 1/2 Evaluation: Placing the USPSTF Recommendation in Context."
   JAMA 322:619-621.  Domchek S & Robson M.  Here.

JAMA Surgery Editorial
  Editorial on USPSTF Recommendation.
  JAMA Surg (Epub).  L Newman.  Here.

JAMA Oncology Editorial
  "Hereditary Cancer Evaluation in 2019:  A Rapidly Evolving Landscape."
  JAMA Oncol (Epub).  Yung RL & Korde Larissa.  Here.

JAMA Network Open Editorial
  "USPSTF Recommendations for BRCA1 and BRCA2 Testing in the Context of a Transformative National Cnacer Control Plan."
  JAMA Open Netw (Epub).  Rajagopal PS, Nielsen S, Olopade OI.  Here.

A Selection of Other Recent Documents

The BRCA literature is massive but here are a few articles highlighted by JAMA alongside the new USPSTF documents.

"Risk-reducing mastectomy in BRCA1 and BRCA2 Mutation Carriers: A Complex Discussion."
   JAMA 321:27. (2019).  Domchek SM.  Here.

"Evaluation of Cancer-based Criteria for Use in Mainstream BRCA1 and BRCA2 Testing in Patients with Breast Cancer."
   JAMA Netw Open 2:e194428.  (2019) Kemp Z, Turnbull A, Yost, PhD, et al. Here.

"Exome Sequencing Based Screening for BRCA 1/2 Expected Pathogenic Variants Among Adult Biobank Participants."
   JAMA Netw Open 1:182140 (2018)  Manickam K et al.  Here.

Two Other Important Policy Papers: ASBS & NAS

Earlier in 2019, the American Society of Breast Surgeons recommended that all women with breast cancer should qualify for BRCA testing.   Here.

Cited by Yung and Lorissa, above, in late June 2019, National Academy of Sciences put out a 175-page eBook policy position on national cancer control priorities.   For the eBook, Guiding Cancer Control: Path to Transformation, see press release here, book here.

Trade Journals

Genomeweb here.  Myriad supports, here.  Medscape here.  MedPage here (with CME), American Academy of Family Practice here.  Backstory from May 2019, Genomeweb subscription, "USPSTF Too Reliant on Family History," here

Guardrail Around USPSTF

The USPSTF policy doesn't cover women WITH cancer, because USPSTF policies by definition are "prevention policies" either in normal people or people with a general risk factor (like obesity for diabetes prevention benefits.)    Therefore, USPSTF will not issue a guideline for people WITH cancer, any more than it would recommend dialysis to prevent death in kidney failure patients.

USPSTF does cover the issue of breast cancer patients now "free of cancer."  They are in the domain of the USPSTF guideline, whereas breast cancer patients "with cancer" would not be.

USPTF and Copay-Free Testing

Affordable Care Act generally requires payers to cover USPSTF preventive benefits one year after the release or update or new guidelines.  Several years ago, a Health & Human Services document defining nuances of these benefits, ruled that USPSTF benefit includes both screening for BRCA risk, genetic counseling, AND the genetic testing itself.  See CMS CCIIO Fact Sheet #12 here.  My web archive here.

Medicare and NCCN vs USPSTF

Medicare LCDs in every jurisdiction cover BRCA testing in women with a personal history of breast cancer AND other qualifying factors like family cancer history.   Generally, these LCDs are just about a cut-and-paste of current NCCN guidelines for BRCA testing.   NCCN provides its guidance in two columns - the left column for patients WITH cancer (e.g. a woman with breast cancer and with two sisters with breast cancer; LCDs use the LEFT column) and a right column for patients WITHOUT cancer (the patients generally covered by USPSTF guidelines.) 

LCDs follow LEFT column (w cancer), USPSTF closer to RIGHT column (no cancer)

No Laboratory Based Nuance

The USPSTF guideline doesn't cover broader ("HBOC") gene panel testing and doesn't discuss criteria for testing, bioinformatis, etc.   It simply takes a more distant view and assumes BRCA testing is a known clinical service, like mammography or PAP smears, although the reality for molecular testing is a lot more complex.   But this occurs in other ways - for example, they simply don't define "Ashkenazi" (three grandparents?  one grandparent? etc).


September 3, 2019 Update

JAMA and USPSTF released a set of documents related to medication for reducing risk of breast cancer.    The recommendations are "preventive" e.g. primary prevention, in women who do not personally HAVE breast cancer.  While the same meds can be used to reduce breast cancer recurrence after a lumpectomy, that is a medical (not preventive) use that is outside scope of USPSTF.

USPSTF Statement
JAMA 2019 322:857-67, here.

The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects. (B recommendation) 

USPSTF Evidence Review
JAMA 2019 322:868-886, here.

Op Ed, Pace & Keating.
JAMA 2019 322:821-3, here.

JAMA Oncol Op Ed, Daley & Ross
JAMA Oncol epub, here.

Patient Page.
JAMA 2019 322:900, here.


Not related to BRCA, but MedPage also highlighted a new 8/2019 article on uses of genomic testing in breast cancer with positive nodes (Gnanajothy, here, Macias here.)

Thursday, August 22, 2019

OPKO, 4KScore, PMA Status of "Risk Tests," VALID, and Regulatory Uncertainty

Let me show that the title of this blog is more than a word salad.

Opko 4KScore

On August 7, 2019, OPKO released its Q2-2019 results, and including remarks about its adventure with the FDA and its 4KScore test, a multi biomarker MAAA test that helps evaluate the risk of men with intermediate PSA levels (above normal but single digits).   The 4KScore test has suffered some published negative LCDs, for several years, but a favorable LCD is currently pending.

New News re 4KScore and FDA

Here's the transcript.

OPKO announced in June it had submitted 4KScore to FDA as a de novo 510(k) test.  Here.   That makes sense.  The FDA has reviewed breast cancer prognostic risk tests under 510(k) - see the Mammaprint test (K070675) and the similar Nanostring Prosigna test (K130010).    See the FDA's 2007 guidance document for these MAAA risk tests here.

Not gonna work for 4KScore.   OPKO informs us, 4KScore has to be PMA:
Based on comments received from the FDA, in July, we withdrew that submission and plan to resubmit the application as a PMA, after [...] having to meet the PMA submission guidelines. We anticipate the resubmission will occur in the next few weeks...There is a different test already approved by FDA as a PMA route application. So, in this case they wouldn't allow us to do it as a de novo....We expect to submit the PMA later this month and we have a typical review timeline for PMA, it’s somewhere around nine months to a year.
Risk Categories: Experts Have Low Concordance

Recently, the trade journal 360Dx had a long interview with ARUP regulatory expert Jonathan Genzen (here), which tracks back to his 2019 article on FDA/LDT regulatory issues (here and open access) and his 2017 article (here). 

Genzen also was co-author on a very interesting 2019 article on how noisy "risk categorization" is, how much disagreement there is on an expert-to-expert basis (in other words, there is low concordance).  See Mohlman, Genzen, Weiss, Schmidt, 2019, here

4KScore this summer seems to be a case study of this -  similar prognostic MAAA's are variably classified as 510(k) or PMA based on relatively small clinical scenario differences.

DAIA, VALID and Risk Categories

New efforts at Congressional FDA diagnostics reform hinge importantly on separation of regulatory workload by risk category.   E.g., see articles on VALID here, here.  (See also a little-known 18 page HHS comment on VALID from March 2019, here.)

But:  If regulatory "risk" categories are intrinsically noisy and inconsistent - asserted with data by Mohlman et al - we should all be aware of that in forming views about what it will be likely putting LDTs under the umbrella of VALID.



The FDA-reviewed Mammaprint and Prosigna tests cited above are 510(k) tests that help physicians make major decisions in breast cancer, such as giving or not giving adjuvant chemotherapy.   Tests that refine or hope to refine decision-making in regards to prostate cancer/elevated PSA (like 4KScore) are, however, PMA tests.  See e.g. the free-PSA test (P060005), the Hologic Progensa test (P100033), the Beckman PHI test (P090026).

While there are a bonanza of specialty tests to handle prostate risk, recent articles and letters in Arch Path Lab Med tout the value of simply reflexing an intermediate PSA (4-10) into free-PSA testing.  See Ferraro here,  Schifman here; original lead article here.

MolDx Proposed LCDs and Resulting First-Day Equity Market Reactions

One August 22, 2019, the MolDx program released 13 new molecular test LCDs, four of which directly involved publicly-held companies.  (Discussion here.)

How did the market react, and how fast?


Natera gained new coverage of its Signatera test, for minimal disease monitoring in colon cancer.   The stock price was quiet for about about three hours, then popped circa 5% (market value $130M).   This was a predictable gain, and could probably have been a profit opportunity for anyone watching this throughout the morning hours.


This small publicly held company had a favorable LCD on new products, and the market value popped on market opening at 9:30 am - by about 14% or circa $50M market value.  Unlike Natera, the reaction was immediate and the armchair investor had no opportunity with CSTL.


Myriad had opined on an investor call a few days ago that it was "optimistic" that a forthcoming LCD would remove a restriction of psychiatrist-only ordering for its GeneSight test.*

No such luck - the restriction remained, at least in this draft at this time.  The LCD involved is pretty verbose and confusing even to experts, and the market didn't react til 10 am.  Then, the stock slid 8% in two stages, one in morning and one after 2 pm.  Market cap value lost, circa $130M.


This company gained coverage for its donor organ circulating DNA test in heart patients; it already had coverage for AlloSure in renal transplant patients.  The cardiac transplant market is pretty tiny, and if anything, AlloSure new sales might be at parity with existing AlloMap sales.  Given the small market, there wasn't much reaction.

click to enlarge**
Take Home Lesson

To my eye, either the Castle or Natera rise in market values were easily foreseeable by a normal reading of each new LCD.  There wasn't time for an LCD reader to take advantage of the information with CSTL, but there was plenty of time for Natera. 

Given the books (Flash Boys) and movies (The Hummingbird Project) about millisecond and microsecond trading, Natera today was a case where that wasn't necessary.   Despite the usual warnings about risks of out-thinking the market, about the market immediately incorporating new information (here), at least one of these stocks lagged in a surprising way.


Myriad:  "There's also the Medicare LCD that would potentially provide expansion into primary care that we're excited about, and we feel optimistic about that as well, which would be another significant opportunity."

Data charts are noisy and numbers are only approximate.

Very Brief Blog: MolDx Releases Bonanza of New Proposed LCDs

On August 21, 2019, MolDx released a bonanza of new LCDs for public review and comment.   See further below where I put a ZIP file of all 13 LCDs in the cloud for downloading.

How to find the LCDs directly:
  • Start on the PalmettoGBA MAC Policy Page, here.
  • Click on "Proposed LCD Status Report"
  • This takes you to a web page with several dozen proposed or recently completed LCDs.
  • I suggest clicking on the column header, "Comment Period Start Date" and setting the View Items Per Page to 100.
  • While it looks like there are 19 new LCDs of all types, there are specifically about 13 that are MolDx molecular LCDs.
    • Note in particular there are two interacting LCDs on pharmacogenomics, both DL35633 and DL38294.
Here's a short tally:
  1. DL38255, AlloSure cfDNA Testing (Heart, Kidney)
  2. DL35633, Combinatorial Pharmacogenomics
  3. DL38292, Decipher Prostate, Favorable Intermediate Risk
  4. DL37725, DecisionDx Melanoma
  5. DL38240, Molecular Erythrocyte Typing
  6. DL38258, "Molecular Microscope" [transplant], Heart
  7. DL37701, Oncotype DX AR V7, Prostate
  8. DL38294, PGx Test [non combinatorial]
  9. DL38238, "Razor 14 Gene Lung Cancer Assay"
  10. DL38274, Repeat Germline Testing
  11. DL38242, SelectMDX, Prostate
  12. DL38290, Signatera Minimum Residual Disease, Colon Cancer
  13. DL38260, Allograft Kidney Biopsy Tissue: Genomic Tests for Rejection
Cloud Zip File for You

Saving readers a huge amount of clicking and pecking, I put all 13 LCDs in a public Zip file in the cloud, HERE.

What It Means

It will take time to assess all of these.  A few early take home lessons:
  • In psychiatric gene panel testing, both Myriad GeneSight and Althea NeuroIDGenetix are covered.   
    • It appears restrictions on psychiatrist ordering are continued (coverage for GeneSight, NeuroIDGenetix, when ordered by a psychiatrist.)
    • In contrast, United Healthcare will newly cover this type of testing ordered by any provider (here).
    • The FDA-based kerfuffle about PGx testing (here) occurred well after these LCDs were locked down.
    • While it's unclear if FDA could/would actually require Myriad to strip drug recommendations out of GeneSight and report only CYP* genotypes, if FDA did that, the test wouldn't really continue to be the test as studied in trials (with red/green/yellow bins and guidance.)
  • Revised CareDx AlloSure LCD covers both kidney and heart testing using the donor organ cfDNA model..
  • Natera Signatera LCD covers serial use of MRD monitoring in colorectal cancer.  
    • This is a big deal for molecular diagnostics in clinical oncology.
    • Interestingly, Natera stock hadn't really moved by late morning eastern time, suggesting either the market had already incorporated this news in past weeks or a market inefficiency.
    • The Natera stock did pop around 5%, but not until after lunch Eastern Time - given LCD watchers a several hour window to use the buying opportunity.  
      • It doesn't take millisecond fiber optics.(*)
    •   (By 10:15 Myriad hadn't moved significantly either).
Note that since January 2019, all changes in LCDs must go into a public comment process, therefore, even relatively small expansions in coverage trigger a new draft LCD.  For example, I can't tell what the update is to DL38292, I'm pretty sure I've seen this LCD title before.

The LCD authors, particularly in PGx LCDs, place a lot of weight on trial population > 65, and a lot of adverse weight on any changes in analysis plan relative to original study design.  They will look up your 5-year-old entry and read it with a magnifying glass.


These LCDs will go through the several MolDx MACs (Noridian, etc) for public comment.  There will be a public open meeting for Palmetto JM on October 7, 2019, which will trigger a 45 day public comment period October 7-November 21. 

It usually takes at least several months after the close of public comment for MolDx to post final LCDs, which in turn, have a 45 day period before they are effective.  Therefore, expected typical effective dates could easily begin in February or March 2020, although MolDx could (hypothetically) move somewhat faster.

Timelines for LCDs

Generally, these LCDs would have been under review at MolDx by April or May 2019.  They would have been finalized in June or early July.  They would have been reviewed by CMS for up to 21 days in July 2019.   They would be completely locked down several weeks before the August 22 posting.   Considering public comment at multiple MACs, the final effective dates are very likely to go out into 1Q2020 or even 2Q2020

Add these up, and the total timeline from meetings and presentations and dossiers, to final active LCDs, approaches a full year.

Fun Facts

The LCDs average 12 pages long (12.3 ±  SD 4.3) with a range of 9pp to 24 pp. There are 160 pages of draft LCDs here.

In the Signatera policy, it is noted that "a series of assays comprises a single test."  Similarly, in article A56322 for ClonoSEQ, a series of assays comprise a single test.

In the Signatera policy, there is also language that defines certain postsurgical patients as "not known to be with cancer."   This relates to the CMS NGS NCD 90.2, which governs NGS testing in patient "with cancer" and provides rules about possible LCD NGS coverage in advanced (stage 3,4) versus non advanced cancer. 

Presumably, by analogy between CRC and breast cancer, a patient with Stage 1 or 2 personal history of breast cancer and post lumpectomy, would not be a patient "known to be with cancer" at the time of BRCA testing.   This would mean a Stage 1/2 breast cancer patient could get NGS testing, postsurgically, since she is "not known to be with cancer," but if she was known to be with cancer post lumpectomy, it would not be local cancer, it would be advanced, and therefore she could also get NGS testing.  (Whew).


*Natera.  Stock popped at least +4% several hours after the LCD news was released.  That's circa $100M of market cap.  You would not have needed nanosecond fiber optic cables to catch that particular wave.

For more about trading responses on Day 1, here.

Natera, 8/22/2019

For an August 27 article at MedTechDive on how payers are reacting to an earlier favorable psychiatry PGx policy from United Healthcare, here.

Wednesday, August 21, 2019

Very Brief Blog; CMS Posts CY2019 Gapfil; See the MAC Price Proposals

CMS prices new codes for a given calendar year by one of two processing, "Crosswalk" or "Gapfill."  The "Crosswalk" process assigns a known price, by crosswalk to a comparable CPT code, during the prior year, e.g. with public meetings and public comment from June to November.    Codes that don't get "crosswalked" enter "Gapfill" during the next year.   T

Yhis year, for example, 18 live active codes are in the "gapfill" process for CMS, because they didn't get crosswalked last fall.

Under "gapfill," MACs are supposed to send their proposed pricing decisions on the new codes to CMS by March, CMS post in March or April for public comment.   This year, the whole process was radio silent in April...May....June...July.   Today, August 21, 2019, CMS posted the proposed prices for 60 days of public comment.  Whew.

  • The home page for pricing postings is here.
  • The cloud file for August 2019 Gapfill is here.
    • It's called "2019 CLFS Gapfill Preliminary Determinations."
    • I've put my own cloud copy, slightly modified for clarity, directly in the cloud here.
Summaries web-posted below.  For the full range of prices and MAC rationales see the cloud Excel spreadsheets.

Click to enlarge.

  • There were about 10 codes where the multiple between the highest and lowest rationale was 1.6X or less.   
    • There were only 3 codes with 100% agreement.
  • There were four infectious disease codes where the high/low multiple was over 4x, but the absolute dollars small ($15, $68).   
  • The wildest multiple was 11X, from $328 to $3675.  For 19U, Columbia OncoTarget, Columbia/DarwinHealth, the MACs said "their was a lack of direct resource requirements" or "data was not received."  One rationale pulled out of this vacuum was the median of several four-figure 815xx codes, the other was crosswalk to 81445 for $600 or less.
  • 0053U, a Mayo prostate test, had a multiple of 2.7X with rationales from "Similar to ConfirmMDx" to "data not received."
What Happens Next?

CMS tells us: 
"Preliminary 2019 Gapfill recommendations have been posted. Public comments will be accepted for 60 days, until Monday October 21, 2019. Please submit comments to Glenn McGuirk;"
CMS will post final decisions after circulating the above comments to MACs, who will "consider" the comments, and potentially "revise" the prices.    My best bet is, allow a minimum of a month, suggesting CMS final gapfill prices will be posted sometime after November 21, 2019 (TBD).

Accounting Rationales

If you see the accounting rationales (see cloud Excel files) the MACs have some confusion about accounting principles.

CMS *definitely* pays for overhead - whether DME, hospital outpatient, RVU Part B calculations, inpatient, hospice, anything. 

Here, the MACs seem to sometimes take a position "CMS doesn't pay for overhead" and subtract it out as a line item in costs provided.   Well, if you don't "pay" for overhead, then overhead has to be baked into the direct costs.  If you have $100 direct cost A, $100 direct cost B, $100 direct cost C, and $200 overhead, the correct CMS price may be $500.   If you say "no overhead is paid separately," then that only makes sense if overhead is already baked into the listed build up of direct prices, which aren't really direct prices anymore.

My point, it's similar to e.g. CMS rules for controls in immunohistochemistry, where CMS doesn't pay for "controls" separately - true - but the costs of control slides are very clearly and explicitly baked into (listed among) the public tables of CMS RVU direct costs of the tests in the first place, which are then also multiplied by CMS for overhead. 

Infectious Codes and High Multiple Crosswalks

Codes 0041U-0044U in infectious disease by a specialty lab are an interesting case.  As I recall from June 2018, the lab wanted high crosswalk multiples (e.g. 10X).   CMS proposed very low crosswalk multiples in September 2018 (e.g. 1X or 2X) and the codes ended up in gapfill.   However, the MACs under gapfill have proposed very low prices again.  I suspect these codes will get some aggressive public comment in the next weeks.


0018U Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences, utilizing fine needle aspirate, algorithm reported as a positive or negative result for moderate to high risk of malignancy A3  $      3,002 ThyraMIR (Interpace)
0019U Oncology, RNA, gene expression by whole transcriptome sequencing, formalinfixed paraffin embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents.  $      3,675 OncoTarget/Columbia
0021U Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5’-UTRBMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score.  $          760 Apifiny, Armune
0022U Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence/absence of variants and associated therapy(ies) to consider.  $      1,950 Oncomine /Dx Target (FDA),Thermo Fisher
0023U Oncology (acute myelogenous leukemia), DNA, genotyping of internal tandem duplication, p.D835, p.I836, using mononuclear cells, reported as detection or non-detection of FLT3 mutation and indication for or against the use of midostaurin.  $          249 LeukoStrat, Invivoscribe
0029U Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (ie, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823).  $          451 PGx Panel, Mayo
0030U Drug metabolism (warfarin drug response), targeted sequence analysis (ie, CYP2C9, CYP4F2, VKORC1, rs12777823).  $          134 Warfarin Resp, Mayo
0035U Neurology (prion disease), cerebrospinal fluid, detection of prion protein by quaking-induced conformational conversion, qualitative  $          541 Prion, National Prion Ctr
0041U Borrelia burgdorferi, antibody detection of 5 recombinant protein groups, by immunoblot, IgM.  $            17 Lyme, IGeneX
0042U Borrelia burgdorferi, antibody detection of 12 recombinant protein groups, by immunoblot, IgG.  $            17 Lyme, IGeneX
0043U Tick-borne relapsing fever Borrelia group, antibody detection to 4 recombinant protein groups, by immunoblot, IgM.  $            15 Tick, IGeneX
0044U Tick-borne relapsing fever Borrelia group, antibody detection to 4 recombinant protein groups, by immunoblot, IgG.  $            15 Tick, IGeneX
0048U Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)  $      2,920 MSK IMPACT
0050U Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements  $      2,279 MyAML, Invivoscribe
0053U Oncology (prostate cancer), FISH analysis of 4 genes (ASAP1, HDAC9, CHD1 and PTEN), needle biopsy specimen, algorithm reported as probability of higher tumor grade  $      2,030 Prostate Risk, Mayo
0055U Cardiology (heart transplant), cell-free DNA, PCR assay of 96 DNA target sequences (94 single nucleotide polymorphism targets and two control targets), plasma  $      3,240 MyTaiHeart, TAI
0056U Hematology (acute myelogenous leukemia), DNA, whole genome next generation sequencing to detect gene rearrangement(s), blood or bone marrow, report of specific gene rearrangement(s).  $      2,516 MatePair, Mayo
0057U Oncology (solid organ neoplasia), mRNA, gene expression profiling by massively parallel sequencing for analysis of 51 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as a normalized percentile rank.  deleted  RNA, NGS, OmniSEeq, Life Tech

Wednesday, August 14, 2019

Very Brief Blog: Myriad Genetic's Unusual Share Price Spike and Fall


Myriad Genetics' share price spiked around June 19, 2019, when the company announced it had resolved (expected to resolve) a qui tam case for about $9M.  The spike suggested that the market might have expected worse, and the settlement removed an overhang.   Links and backstory here.


On July 31, the share price shot upward again, on news that United Healthcare planned to cover the Genesight test. 


However, on August 13/14, the share price shot downward on news of reduced revenue and an FDA action regarding its GeneSight test. 

Reduced revenue was attributed in part to the rising activity of lab benefit managers (which raise the denial rate on claims the payers receives.) 

Myriad also reported that FDA had directly asked it to change its reports for GeneSight, which Myriad believes it should not have to do.  Myriad also dropped some specialized forms of the GeneSight test because of what it said was evidence that did not live up to its standards. 

Open access news at 360DX here, subscription story at Business Insider here.  Earnings call transcript here.   

Genomeweb did a deeper-dive story on August 16 here, it doesn't seem to have a subscription flag so it may be open access.  Suggestions that FDA would like drug advice stripped out, leaving just gene reports.  If that happened (and Myriad protests), it would hardly be "the" Genesight report, which was a page of drug advice listings; the impact of this report is what was studied in clinical trials.

What's Next?

Myriad also commented it was "optimistic" about wider coverage in a Medicare LCD "in this fiscal year."   The Medicare MolDx program is likely to release its various new LCDs for its autumn public meeting within the next several weeks, which will trigger a 45 day public comment period.  MolDx held a public workshop on psychiatric pharmacogenetics evidence in June (here).  CMS releases new-draft LCDs only on Thursday, so August 22, 29, and September 5 are among the possible dates.

Myriad also was optimistic about Genesight's status under a BCBS Evidence Street evaluation, and hoping to get some extra facts and corrections into an "off-cycle" reprint of that evaluation.

Tuesday, August 13, 2019

Very Brief Blog: Association of Molecular Pathology's Elaborate Position Statements Page

The Association of Molecular Pathology (AMP) has a long record of producing active, detailed policy statements and position letters, some on its own, some in collaboration with other groups (such as College of American Pathologists, CAP). 

It's worth checking out form time to time, and the webpage is in a clear and accessible format.

  • Find the open access AMP policy page here.
Just a few of the recent comments on that webpage include:
  • July 25:  Opposition to Patent Reform Legislation; see also June 3
  • June 20:  Comments on MolDx LCD DL38047 for NGS in myeloid malignancies
  • June 20:  Comments on MolDx LCD DL38045 for NGS in solid tumors
  • June 10:  Position on DTC genetic testing
  • May 29:  Comments on Medicare NCD for NGS Testing in Cancer
  • March 18:  Comments on USPSTF Proposed BRCA Update
  • March 4:  Comments on NCCI Edits for Multiple Tests
The June 20 comments wrestle with MolDx's attempt to craft reasonable policies under some of the poorly written or even ridiculous aspects of the CMS NCD on NGS testing.   After much protest in early 2019 (see trade journal articles and AMP's February 1 letter to CMS), CMS took a comment period May 29-April 29 on how the NCD could be revised.  CMS will issue proposed revisions for another round of public comment by October 29.

In solid tumors, the CMS NCD covers an NGS test only if it has not been used before in the same primary diagnosis of cancer...that sounds like coverage x1.   AMP/CAP note that when tumors are relapsed, recurrent, or simply metastatic, they often show gains and losses in mutations, "rendering them, in effect, new cancers."   MolDx may have been thinking this too, since it seemed to narrow the CMS instruction to apply only to tests performed "on the same tumor specimen." 

On the other hand, the LCD might seem to provide coverage more narrow than the NCD (a scenario which is not allowed), since the NCD covers "any FDA approved NGS test" as long as it has not been performed before.  Seemingly the NCD might be read to allow two different FDA NGS tests to be performed on the same specimen, since, simply, neither has been performed before.  While the LCD says that a CGP (comprehensive genomic profiling) test won't be allowed if another CGP has been performed on the case.  Technical!

AMP Meetings

AMP's annual meeting will be November 7-9, 2019, in Baltimore.  Here.  It looks like registration is $675 member, $850 non-member.  (That's a $175 delta; for $200 you can become a member, so a net cost of $25 if you're going to the meeting anyway).

AMP will also host a "Molecular Pathology Economics Summit" in Washington, Friday, September 20, 2019.  Here.  It look like registration is $975 for for-profit organizations, $375 for non-profit. The preliminary agenda is online here.