Tuesday, January 15, 2019

Very Brief Blog: CMS Slightly Updates Its New 2019 Rules for LCDs

On October 3, 2018, CMS released a major update of its rules for new LCDs and for LCD reconsiderations.  This was a major change (including large deletions) in the longstanding processes found in Program Integrity Manual, Chapter 13, LCDs.  My original article here.

On January 11, 2019, CMS released a minor revision or tweak to this large update.  The new January updates seem minor, but are hard to discern, because all the new pages of text are in "red" (including this week's tweaks).   The new document is Changer Request 10901, Transmittal 854, Released January 11, 2019, with effective date of September 26, 2018 and implementation date of January 8, 2019. 

Find the document here.

Find the changes in context in PIM Chapter 13 as a whole, here.

Nerd Note!

I found at least one typo.  In the online full chapter (here),  refers the reader to the listing of specialties in a Contractor Advisory Committee/CAC in Exhibit 3. And in the Transmittal, 10901, Business requirement 7.1 states that MACs shall endeavor to have full CAC specialist panels in every state.   But if you go to the separate PDF for all exhibits, Exhibit 3 (which should be a specialties list, like surgeon, psychiatrist, internist, etc) is simply missing.

Very Brief Blog: MSK Paper Highlights Clinical Impact of TMB, Clinical Differences Among Cancer Types

Total mutation burden (TMB) has an increasingly high profile among cancer biomarkers and can be calculated several different ways. 

A new paper by Samstein et al. (Memorial Sloan Kettering) reports findings in 1600 patients over a range of cancer types. 

Key findings include high overall value of TMB as a predictive biomarker of response, but also, substantial differences among cancer types.  Expressing TMB as mutations per megabase, the threshold for decisions may vary considerably among cancers.  They recommend setting different cutoffs based on quintiles for different cancer types.   In addition, Samstein et al. found that above a certain level, TMB's predictive impact asymptotes.
  • Samstein et al. here (Nature Genetics).
  • Coverage at STAT PLUS (subscription), here.  Also Genomeweb (subscription), here.
  • Prior landmark paper by Chalmers et al. with 100,000 patients, here.
Harmonization.  A TMB harmonization project is at Friends of Cancer Research, FOCR, here.  Somewhat comically, Genomeweb notes there are multiple different harmonization committees at work in different places, here.  I think my first blog on TMB was about two years ago, here.

Tidbit.  Regarding FDA's position in November 2017, in FMI F1 CDx test paperwork, P170019C, statement that "the clinical validity of TMB defined by this panel has not been established." Here.

Top, Kaplan Meier, TMB levels set "within histology" then recombined.
Bottom, TMB impact flattens out (as hazard ratio) above 15-20.

Forest Plots for whole cohort (top line) and subgroups

Thursday, January 10, 2019

Very Brief Blog: CMS Offers PAMA Tutorial Call on January 22, 2019

CMS has announced a one-hour PAMA Private Payor Rates Call, Tuesday, January 22, 2019, at 2-3 ET.

See the CMS outreach page here.  See the registration page here.  See the registration for THIS call on that webpage, for January 22.

Register for this Medicare Learning Network (MLN) event:

Clinical Diagnostic Laboratories to Collect and Report Private Payor Rates Call
Tuesday, January 22, 2019
2:00 - 3:00 PM Eastern Time

Do you need to submit data required by the Clinical Diagnostic Test Payment System final rule? Laboratories, including physician offices laboratories and hospital outreach laboratories that bill using a 14X TOB are required to report laboratory test HCPCS codes, associated private payor rates, and volume data if they:

  • Have more than $12,500 in Medicare revenues from laboratory services on the Clinical Laboratory Fee Schedule (CLFS), and
  • Receive more than 50 percent of their Medicare revenues from CLFS and physician fee schedule services during a data collection period

This call provides a refresher on how to collect and submit required data. CMS will use this data to set Medicare payment rates effective January 1, 2021.

Email Questions in Advance
A question and answer session follows the presentation; however, you may email questions in advance to CLFS_Inquiries@cms.hhs.gov with “January 22 Call” in the subject line. These questions may be addressed during the call or used for other materials following the call. For more information, visit the PAMA Regulations webpage.

Target Audience
Clinical diagnostic laboratories, including physician offices and hospital outreach laboratories

Presentation: Available prior to the event
Audio recording and transcript: Available approximately 2 weeks after the event

Very Brief Blog: FDA Issues Recall for Some Foundation One CDx Test Reports re TMB

Update:  This blog appeared 7 am on January 10.  

A day later, on January 11, Genomeweb reported that FMI had resolved the issue (here).  The FMI announcement clarified the error described on the FDA website was related to total mutational burden (TMB) reporting.   



FDA issues innumerable notices on device recalls.   FDA current shows an open recall notice on certain FMI FoundationOne CDx test reports.

Date Initiated by FirmOctober 31, 2018
Create DateDecember 20, 2018
Recall Status1Open3, Classified
Recall NumberZ-0649-2019
Recall Event ID81614
PMA NumberP170019 
Product ClassificationNext generation sequencing oncology panel, somatic or germline variant detection system - Product Code PQP
ProductFoundationOne CDx, Model TG-HS4000 Seq Kit Test  
Recalling Firm/
Foundation Medicine, Inc.
150 2nd St
Cambridge MA 02141-2115
For Additional Information ContactNicole Green
617-418-2200 Ext. 7337
Manufacturer Reason
for Recall
An incorrect test result for a single analyte may have been reported for up to 800 physician reports
FDA Determined
Cause 2
ActionOn October 31, 2108, an outreach program was implemented by Foundation Medicine's Medical Affairs team to advise ordering physicians who received reports of possibility that the relevant reports could contain an incorrect test result.
Quantity in Commerce800 reports
DistributionUS nationwide

Wednesday, January 9, 2019

Very Brief Blog: CardioDx Shuts Down

In a short item written based on SF Chronicle, Genomeweb reports:
CardioDx, a medical diagnostic company that makes a blood test for heart disease, is shutting down, the San Francisco Chronicle reports....Chronicle adds that though the firm's closing appears sudden, it comes after Medicare stopped paying for the firm's test, Corus CAD, in November. One notice posted by the US Centers for Medicare and Medicaid Services argued that the test, which gauges whether patient with chest pain might need additional testing to rule out coronary artery disease, is not medically necessary. "Data regarding its clinical usefulness in elderly (Medicare-aged) patients, particularly males, is significantly lacking in all scientific articles," it said, according to the Chronicle.
The Chronicle newspaper also refers to whistleblower lawsuits.  Article here.

CMS 2016 data for labs and doctors shows CardioDx was paid $1050 for 22,451 tests, or about $23M.  Chronicle states that CardioDx raised in total $297M, including $22M in January 2017, with platinum investors like Kleiner Perkins and GE and Intel.

Medicare had reversed a previous favorable decision after Medicare had been one of the few or major coverers of the test, private insurers generally and major guidelines did not follow suit. As the LCD states, "The Corus CAD test is not included in any professional society management or treatment guidelines."  The LCD also notes the predominance of company-funded, company-authored studies.

Since the company is gone, the LCD L37673, may not be permanent, so I have put a PDF cloud copy here.

Tuesday, January 8, 2019

Very Brief Blog: Decibio Issues Market Report on Liquid Biopsy

With my offices being based in SF and Los Angeles, I frequently have a chance to work with Decibio, a Santa Monica-based life sciences consultancy.  I had a chance to contribute to their new report on liquid biopsy markets both US and world wide, and covering both cfDNA and other modalities like circulating tumor cells.  

Read more about the offering here.

Very Brief Blog: Suzanne Belinson's Shift from BCBS Evidence Street to TEMPUS Commercial Markets

While this is not new-news, last fall Suzanne Belison PhD, the founding director of the BCBS Evidence Street tech assessment program, shift to a commercial Vice President role at TEMPUS, the relatively new Chicago-based genomics lab valued at two billion dollars during a recent $110M round.  Linked-In gives her transfer date to Tempus as September, 2018.

TEMPUS particularly emphasizes its genomic big data and analytics capabilities.   This has been an exceptionally active area in the past week, with Sophia Genetics raising $77M, Qiagen buying N-of-1, and Illumina partnering with PierianDx.

Evidence Street was launched by BCBS in December 2016, just two years ago, as a replacement for the prior TEC (technology evaluation center).*   While TEC generally had assessments available open access, Evidence Street is using a subscription model.   See a Summer 2018 interview with Belinson about her goals for Evidence Street here.

In early 2017, there were published rumors, or announcements, or claims, (which I was always skeptical of) that Evidence Street would formally and contractually assist MolDx with evidence evaluations.  That was never finalized.

Belinson will be a speaker at the Precision Medicine World Conference in Santa Clara, January 20-23, 2019.


* Evidence Street was announced in December 2016, but BCBS filed for the trademark in May 2015.

In digital genomics, above I cited Tempus's fund-raising and new deals concerning Qiagen/Nof1, Illumina/PierianDx, and Sophia Genetics.  Another example is Mayo's collaboration with Nference (the collaboration titled Qrative), announced in late 2017.

Archive of quoted sources here.

Very Brief Blog: The Startup Health Festival in SF, Adjacent to JP Morgan

This morning I was having breakfast at 7 am adjacent to my SF office and I noticed banners for a "Startup Health Festival" - one of the conferences adjacent to JP Morgan this week.   The conference website says it was invitation-only and is sold out - from the venue, it looks like a pretty large event.

I've captured the 2019 conference website here, and in case it goes dark at some point, I put a PDF of the conference agenda and speakers in the cloud here

Top name speakers including Jill Biden, Sanjay Gupta, Bernard Tyson (CEO of Kaiser), and Esther Dyson.  There are high level government speakers as well like Mona Siddiqui, Chief Data Officer of HHS, and Lord Prior, Chair of NHS England.

There are many, many startups represented; additional large company speakers included Bertrand Bodson, Chief Digital Officer of Novartis, and Heather Bell, SVP of Global Digital at Sanofi.  Bell has an unusual resume, including a PhD in modern history from Oxford and ten years at McKinsey; she then managed international outreach strategies for Oxford.


Monday, January 7, 2019

Very Brief Blog: FDA Releases Self-Certification "Working Model" For Digital Health

On January 7, 2019, FDA released a position statement from Commissioner Dr Scott Gottlieb, as well as a raft of links to new webpages and documents on software self certification.

This effort has been one of the highlight efforts of the FDA under Dr. Gottlieb.   It's worth tracking because FDA often mentions this as a concept it wants to apply in the diagnostics/genomics space as well.  (And if fact, some path-breaking approvals for 23andMe a couple years ago (update here) were themselves close to self-certification with open data, as opposed to either the known 510(k) or PMA pathways).

See Gottlieb announcement here; it contains numerous internal links to resources.  Coverage at MedCity here; their further analysis here. RAP News here.

I've also cut/pasted below the break.


Separately, for articles on UK NHS investments in digital health and clinical roll-outs, here and here.

Sunday, January 6, 2019

Could CMS Open NCD on Genesight? Coding Implications.

In a major advance, last week Myriad Genetics announced the publication of its GUIDED clinical trial of the impact of psychiatric pharmacogenetics on healthcare outcomes in depression (Greden et al., here).  In particular, the beneficial impact was largest in patients switched from a "red" to a better drug after testing - and you only know which patients those are, by testing a larger group.  See discussion in Genomeweb here.

However, the publication passed through at least two journals.  Last November, Myriad announced that a "first journal" where the trial was reviewed had "notified the company that as a condition of publication, the proprietary GeneSight algorithm would need to be disclosed."

Myriad resubmitted to a different journal, the well-respected Journal of Psychiatric Research.  Myriad noted in November that on publication of GUIDED, it would submit a request to Medicare to expand access to primary care physicians (currently only psychiatrists).   See Myriad transcript here.

CMS Could Open an NCD on GeneSight

CMS could open an NCD on Genesight, which is one of the largest branded molecular tests CMS covers and may be about the largest single branded or proprietary test covered that does not have a PLA code, which has implications for PAMA rate-setting.  CMS created an NCD in 2017 for tumor gene panel testing, at a time when those tests were only about 1% of CMS molecular spending, based on codes 81445+81455 (spending on those codes $6M; molecular spending about $600M).   As a proportion of CMS molecular spending, GeneSight would be several times that (e.g. several percent).  In addition, other psychiatric gene panel tests with good data are also entering the market, and CMS may want to promote uniformity of coverage (see  Bradley et al, an open access paper on a large psychiatric pharmacokinetic RCT, with favorable outcomes, supported by Althea).  Another published lab in this space is Genomind.  For comparison, CMS undertook the recent NGS cancer NCD when there were similarly  three tests for it to review (FMI F1 CDx, Thermo Fisher Oncomine, Illumina Praxis Extended Ras). 

Mixed Private Coverage.  The pivotal publication, Greden et al., is now available, and that is definitely the sort landmark that CMS waits for.  For now, CMS covers GeneSight through its LCD (of which I've been a strong supporter).  However, private payer non-coverage is easy to find (e.g. example at Anthem here) which CMS is likely aware of both at the local and national level.

FDA.  Additionally, quite recently the FDA criticized claims of non-FDA-reviewed pharmacogenetic tests citing particularly those for antidepressants [see detail at foonote*], Genomeweb here.  Do the FDA and CMS talk?  Yes.  Recall that the first version of the CMS NGS NCD in November 2017 acted to block LDT testing in the tumor domain from CMS payment, and cover only FDA-based testing, and some conspiracy theorists argued this was FDA getting its way regarding LDTs via CMS.

APA.  Another issue is that an APA task force in 2018 seemed to warn that psychiatric pharmacogenetics had "insufficient data to support widespread use of pharmacogenomic tests in clinical practice to guide antidepressant treatment," here; see also here.   Both CMS and MACs look to guidelines in coverage decisions (e.g. here).  There are also cases on record where MACs have used company-funded or -authored studies as a part of a non-coverage decision (e.g. here).

CMS Interest in TRD.  CMS has previously tracked the treatment resistant depression area and written NCDs on it (here, here, here).

Collectively, these factors such as quite mixed private coverage, FDA positioning, and APA (among others), together with the very high dollar volume under an unlisted code that loops around PAMA, make GeneSight's status with CMS more complicated than the average test under the average LCD.

Algorithms are Intellectual Property, But Are Drug Categories Printed on Reports?

Myriad, quoted above, stated that it changed journals to ensure its algorithm remains private.  APA, which would surely weigh in on a CMS NCD, stated in 2018 that "there is a lack of transparency with regard to the algorithms used by the companies to derive treatment recommendations from tests looking at multiple genetic variations," here.  While the workings of an algorithm are private, outcomes are face-valid on the test report (e.g. drugs in bins for green, yellow, red).   Given the patient's CYP genotype, the same genotype could be input into other software and one could compare how the outputs match or vary.  (There are hundreds of thousands of GeneSight tests out there, so collecting 500 for consented in silico research might be feasible).  For example, an open-access algorithm or a different branded algorithm might produce bin outputs quite close to GeneSight, or quite different.  The point is that this is an empirical question that can be easily tested, just as you can empirically test whether or not one lab's BRCA sequence interpretations match another (on the same mutation).  An organization could tell CMS, we don't know how GeneSight gets from genotype 12345 to classifying drugs A,B,C as green, yellow, and red, but our software will also input genotype 12345 and usually classify the same drugs the same way.

NCD Would Lead To Specific Coding

An NCD would most likely lead to specific code issuance by CMS, as occurred with the Cologuard approval (e.g. a CMS G-code).  While such a code would be subject to PAMA, note that the issue of PAMA is pretty distant - any codes coming out in 2H 2019 will not be PAMA-priced til January 2024. 

However, the new G code would go into the CMS CLFS pricing cycle (the CMS "crosswalk/gapfill" process.)   This could simply confirm the current CMS MAC price of Genesight  (around $2000, based on public CMS data).  However, the CMS crosswalk process would overrule the local price and lock down the CMS administrator's price for several years.  In contrast, the MAC price with code 81479 could change arbitrarily either up or down as it is not registered on the national annual fee schedule.**   But the CMS national pricing process can be frugal compared to MAC pricing; AMP recently asserted CMS had mispriced BRCA components under some new AMA CPT codes by factor of three, here.

CMS has publicly flagged concerns about 81479 coding (see here).  In January 3, 2019 investor report, Barclay's asserted the average commercial payer price of GeneSight was in the several hundred dollar range (see also quotes here), but that is not the same as the PAMA median price, which ignores the $0 dollar claims.  On the other hand, if the answer is there are lots and lots and lots of $0 commercial clinical claims for a test CMS pays $2000 for, that data too could also make CMS a little edgy.

Anyone Could Request NCD

Anyone could request a CMS NCD; famously, United Healthcare requested one on CAR-T therapies last year (here and here).   Alternatively, CMS could initiate one without an outside request.


*  The FDA's pharmacogenetic warning had a mixup of messages between concerns about non-FDA-reviewed claims, which were pretty strong concerns, and what I see as entirely separable issues about patients changing their own meds without intervention of a physician, which would be very unlikely for GeneSight. That said, the FDA did state directly that:

"The FDA is aware of genetic tests that claim results can be used to help physicians identify which antidepressant medication would have increased effectiveness or side effects compared to other antidepressant medications. However, the relationship between DNA variations and the effectiveness of antidepressant medication has never been established. The FDA is aware that health care providers may have made inappropriate changes to a patient's medication based on the results from genetic tests that claim to provide information on the personalized dosage or treatment regimens for some antidepressants."


** In CY2017, CMS spent $32M on 14,858 uses of 81479 in Ohio, at $2,158 per use, which is likely a pretty close match to Assurex GeneSight testing.  The national use of 81479 in 2017 was 74,657 uses at $115M.

Friday, January 4, 2019

Very Brief Blog: AMP Asks CMS Reconsider BRCA Pricing in 2019

Genomeweb reports today that AMP has asked CMS to reconsider the pricing of new BRCA codes established through the 2018 summer comment and fall decision periods.
  • Genomeweb article here.
  • AMP letter online here.
CMS has an ongoing and unchanged code for 81162, BRCA 1/2 full sequencing with dup del analysis.   AMA CPT 2019 institutes a new code system (largely developed by AMP or CAP) with new code 81163 for BRCA 1/2 sequencing alone, and 81164 for BRCA 1/2 dup del analysis alone.  Another is 81164 for BRCA 1 sequencing alone.

Principally, regarding CMS pricing of 81162, AMP argues that CMS acted inappropriately when it priced for sequencing BRCA 1 and separately for BRCA 2.  This yielded prices of several hundred dollars per gene.  However, AMP argues that labs run both genes together therefore a different, very large procedure crosswalk is more appropriate. This points to code 81408, $2000.

But this will yield other inconsistencies; for example, in next year in 2021 the composite code 81162 will pay only $1825, less than one of its components, if AMP's proposal is adopted.

In addition, the crosswalk code CMS used for BRCA2 sequencing was continuing code BRCA2 (81216, $185), which CMS used as a reference price for sequencing BRCA2, which seems clear enough.  AMP avoids this rabbit hole by simply stating that 81408, $2000, is the most direct single crosswalk.

Current CMS prices are shown:

Two code numbers at far left = services in the two columns.
The appeal issue will be an agenda item at the CMS summer new code pricing meeting, which typically occurs either circa June 30 or else after the July 4 holiday such as July 8-20.

AMP also lodges a second appeal.   AMP argues for higher pricing of 81165, BRCA 1 sequencing alone, based on the concern that an exon count crosswalk to 81406 is too low because some exons are really big.   PAMA commercial payer data, as well as CMS data, indicates that individual codes like "BRCA 1 sequencing alone" are virtually never used. 

Very Brief Blog: Two Big Digital Genomics, Digital Pathology Investments

Two news items on digital laboratory medicine -

$68M for Digital Pathology in UK

The December 24, 2018 Dark Report (subscription, but you can read 1 free article per month) reports that the UK is making a $68M investment in digital pathology, which will take the shape of five major regional centers (London and four other cities).   Here.

I haven't found a similar open access source (hey, you should subscribe to Dark Report), but a March 2018 article on teh rapid growth and high goals for digital pathology in UK is here.

UK also announced a ten year plan to boost digital health and sequencing; at New Scientist, here.

$77M For Digital Genomics: Sophia

In a second story, Swiss- and Boston-based Sophia Genetics raised a remarkable $77M for its digital genomics and bioinformatics services.  This brings its total funding to $140M.  See the press release here.  Sophia writes,
"The company combines deep expertise in life sciences and medical disciplines with mathematical capabilities in data computing. Today, its universal platform, SOPHiA AI, is utilized by more than 850 hospitals across 77 countries and has already supported the diagnosis of over 300,000 patients. The platform enables healthcare professionals to make sense of complex genomic and radiomic data through advanced analysis in order to better diagnose and treat patients, both for oncology and hereditary disorders."


Footnotes and Updates

Also around January 1, 2019...

  Qiagen buys N-Of-One clinical bioinformatics service, here.

  Illumina and PierianDx ink multi year, non exclusive collaboration deal, here.


Last August, TEMPUS, which provides a genomics lab but strongly emphasizes its bioinformatics potential, raised $110M

For an open access 2018 article on software for somatic tumor variants, Tamborero in Genomic Medicine, here.

Brief Blog: CMS Extends Lab Date of Service Rule, Again, to July 2019

On December 26, 2018, CMS released an announcement that it was again delaying required implementation of new Date of Service rules that had been slated for January 1, 2018.   The new implementation date is July 1, 2019.

The announcement is released as a zip file on the CMS Date of Service web page.  The ZIP file includes a 1 page announcement of the delay, and a 2 page Q&A document.

See the CMS DOS web page here.  You should be able to access the zip file directly here.

What Happened

The DOS rule, dating back almost ten years, requires hospital outpatient specimens to be billed by the hospital if that's where the tissue was biopsied or the blood was drawn on a registered outpatient.   In Fall 2017, CMS created a mandatory exception effective January 1, 2018, that the performing laboratory must bill for such a specimen if it was a molecular pathology test or an ADLT (most ADLTs will also be molecular pathology tests.) 

CMS's deferral of the mandatory exception means that for now, either the hospital or the lab can bill for the qualifying molecular pathology test.  CMS notes in the FAQ that "in no case should both the hospital and the performing laboratory bill for the same test," just in case that wasn't clear from context or the meaning of "either."

Thursday, January 3, 2019

Pittsburgh Authors Publish Review of National CMS SEP-1 Data

I have previously published two articles on CMS SEP-1 performance data, one in August when 3-quarter 2017 data was first released (here) and one in November when full year 2017 data was released (here).  The second article focuses on the poor performance of top US academic medical centers on SEP-1.

SEP-1 has been criticized elsewhere; see references in the above blogs and for two simple entry points here and here.  For more detail see Faust & Weingart here.

Barbash, David, and Kahn of University of Pittsburgh School of Medicine have published a late December 2018 article which is a peer-reviewed assessment of the CMS raw data.  (For an earlier report see Venkatesh, here.)

I quote the full abstract below.  In my November blog, Pittsburgh was in the top 20 academic hospitals for which I pulled SEP-1 data; Pittsburgh scored 42, below the national average but about the median of the top 20 academic centers.  The authors believe their data shows that the overall value of SEP-1 is "supported by providing additional construct validity," and quote other work suggesting that early identification saves lives.  If this is the case, it should be more upsetting that many hospitals score so poorly and in the open public record.  However, the authors conclude that overall associations between SEP-1 scores and other quality scores was weak, consistent with other weak or negative data for SEP-1 (here, here, here).

Crit Care Med. 2018 Dec 21.   [Epub ahead of print]
National Performance on the Medicare SEP-1 Sepsis Quality Measure.
Barbash IJ1,2, Davis B2,3, Kahn JM1,2,3.
   https://insights.ovid.com/pubmed?pmid=30585827       https://journals.lww.com/ccmjournal/Abstract/onlinefirst/National_Performance_on_the_Medicare_SEP_1_Sepsis.96060.aspx

The Centers for Medicare and Medicaid Services requires hospitals to report compliance with a sepsis treatment bundle as part of its Inpatient Quality Reporting Program. We used recently released data from this program to characterize national performance on the sepsis measure, known as SEP-1.

Cross-sectional study of United States hospitals participating in the Centers for Medicare and Medicaid Services Hospital Inpatient Quality Reporting Program linked to Centers for Medicare and Medicaid Services' Healthcare Cost Reporting Information System.

General, short-stay, acute-care hospitals in the United States.

We examined the hospital factors associated with reporting SEP-1 data, the hospital factors associated with performance on the SEP-1 measure, and the relationship between SEP-1 performance and performance on other quality measures related to time-sensitive medical conditions. A total of 3,283 hospitals were eligible for the analysis, of which 2,851 (86.8%) reported SEP-1 performance data. SEP-1 reporting was more common in larger, nonprofit hospitals. The most common reason for nonreporting was an inadequate case volume.

Among hospitals reporting SEP-1 performance data, overall bundle compliance was generally low, but it varied widely across hospitals (mean and SD: 48.9% ± 19.4%). Compared with hospitals with worse SEP-1 performance, hospitals with better SEP-1 performance tended to be smaller, for-profit, nonteaching, and with intermediate-sized ICUs. Better hospital performance on SEP-1 was associated with higher rates of timely head CT interpretation for stroke patients (rho = 0.16; p < 0.001), more frequent aspirin administration for patients with chest pain or heart attacks (rho = 0.24; p < 0.001) and shorter median time to electrocardiogram for patients with chest pain (rho = -0.12; p < 0.001).

The majority of eligible hospitals reported SEP-1 data, and overall bundle compliance was highly variable. SEP-1 performance was associated with structural hospital characteristics and performance on other measures of hospital quality, providing preliminary support for SEP-1 performance as a marker of timely hospital sepsis care.

PMID: 30585827 

Wednesday, January 2, 2019

Has Medicare Canceled Much of Germline BRCA Testing, Including for Ashkenazi Populations? New 2019 MolDx LCD

Today I was scanning 2019 LCDs for updates and found an unusual one in the MolDx program.

Search the Medicare Coverage Database for the BRCA panel code 81432.  You'll get quite a set of LCDs:

Click on the L36082 LCD for BRCA/BRCA2 genetic testing, which are frequently performed by NGS sequencing or panel testing.   Find the Palmetto LCD L36082 at this link.  The new text is clipped for you here:

Multigene Panels***

^ The indications and limitations of coverage listed in National Coverage Determination (NCD) 90.2 (Next Generation Sequencing- NGS) apply to genetic testing for susceptibility to breast or ovarian cancer. While the NGS NCD Section 90.2 B describes specific coverage criteria for nationally covered tests, Section 90.2 D permits coverage of other NGS as a diagnostic laboratory test for patients with cancer when performed and ordered according to the requirements described by the NCD. According to Section D of the NGS NCD AB Medicare Administrative Contractors (AB MACs) may cover next generation sequencing tests in patients with cancer. As such, genetic testing for susceptibility to breast or ovarian cancer with multi­-gene NGS panels (not otherwise covered under NCD 90.2 Section B) may be covered by this AB MAC as reasonable and necessary when ALL of the NCD criteria are met in addition to the following... (next section unchanged)

This referral to "coverage requirements described in the NCD...ALL of the NCD criteria are met..." acts to allow NGS based testing only in women with Stage III/IV cancer, excluding women with Stage I/II cancer.   See the CMS NGS NCD here.

According to Cancer.net, 60% of breast cancer cases are localized, e.g. stage 1/2, suggesting the rule if applied this way will impact a lot of testing.

The NCD, somewhat bizarrely, would act to block NGS based testing but allow sequencing and reporting of the same genes, in the same Stage 1/2 women under the LCD, with Sanger or PCR testing. 

BRCA and Ashkenazi Populations

BRCA mutations are far more common in Ashkenazi-heritage populations.  Brandt-Rauf and colleagues write, "Lack of awareness about the possibility of hereditary breast cancer in the Jewish population which . . . has enormous risk compared with other populations—maybe ten-fold higher of having a mutation—makes it rather disadvantageous to not talk about it...The truth demographically is that over 90% of Jews in North America are of Ashkenazi origin."

Similarly, in 2017 CDC reports that "Women who had Ashkenazi panel testing accounted for approximately 5% of women who had any BRCA testing during the study period and ≤0.1% of all women aged 18–64 years."  This was age 18-64 related to employer preventive benefits under ACA; rates >65 are similar.

The USPSTF also reported about a 10X increase in prevalence of BRCA carriers in the Ashekenazi population, 2013, here.   


As of January 2, 2019, the same CMS database did not list this change in the MolDx LCD for Noridian Jurisdiction E or F.   (Those LCDs haven't been updated for routine new 2019 BRCA codes either, though).  See here.

There are several reasons why it hasn't made sense, to me, to apply the March 2018 NCD to germline testing like this.   (And no MAC has come up with this explicit application to germline testing until this week, showing it is not an obvious reading of the full NCD.)

  1. The NCD was based on an application by Foundation Medicine for FDA-approved CDx tumor testing.  All the literature and discussion is on tumor testing.  Targeted drugs are nearly always used only in metastatic disease, where the Stage III/IV rule makes sense.  That rule makes no sense applied to germline testing, and germline testing wasn't discussed in the NCD.  Germline testing couldn't even get into the main NCD coverage rule, since it isn't a CDx.   It seems more like a semantic unintended effect, given the whole body of evidence.
  2. In response to concerns from several stakeholders that the NCD (in draft form) might be misapplied to germline testing, CMS intentionally inserted explicit new text directly into the body of the NCD that it can be applied only to a certain type of NGS testing, for targeted therapies.  This would seem to exclude application of the rules to germline testing and narrow them only to targeted therapy testing.  (I wrote about this on April 18, 2018).  
    1. CMS also states in the NCD, "BRCA is discussed in familial risk assessment (Daly et al. 2017) which is outside the scope of this decision."
  3. NCDs are based on the Medicare statute for reasonable & necessary medical care.  It makes no sense the exact same mutation would be legally medically necessary (under the same CPT code and cost) if found by one method rather than another.  Here, CMS would be saying that it is legal and medically necessary to pay $2000 for 81162 BRCA testing by Sanger method, but not to pay exactly the same $2000 for same code 81162 BRCA testing by NGS in the same patient.   There can't possibly be any rationale there, given the identical results and identical cost to CMS.


In addition to the links above, in the cloud I've put a PDF copy of the Palmetto January 2019 LCD, and a copy of a Word-based redline of recent changes.  Here and here, respectively.

Additional Considerations

Shift to Sanger Testing for Ridiculous Reasons?

Nothing in the new LCD prevents gene testing by non-NGS methods in Stage 1-2 patients.  To the extent NGS testing for germline risk mutations is allowed only in Stage 3-4 patients, this is probably counterproductive since most benefit for BRCA-adherent longitudinal management is going to be in the longest-surviving patients, not those terminally ill or entering hospice care with Stage 4 cancer.

In addition, while most BRCA testing would be equal dollars under the NCD (e.g. 81162 for BRCA sequencing and dup deletion costs no more or less to CMS with either method) - some costly loopholes are opened up.  For example, every MAC except the NGS MAC (ironic name) covers 81432, a ten-gene panel for breast cancer.  MACs aren't covering "the code," they are signally they are covering all ten genes, including BRCA1/2.  This means if a lab performs 9 genes, they are separately billable.  Here, you hit an NCCI new rule that you aren't supposed to stack Category I genes with NGS methods, but use 81479 instead.   However, that NCCI rule doesn't apply to Sanger or PCR, so it seems you CAN stack the nine HBOC genes, and starting with $2000-plus for BRCA.

MolDx LCD Instruction Is Ambiguous

The new LCD instruction tells people doing HBOC testing they must refer to the NGS NCD if they are using NGS methods. 

But they don't tell you how to interpret the NCD when you get there.  Do you follow the sentence that says only recurrent/metastatic cancers can be covered, or, do you follow the sentence in the NCD that says the NCD only applies to one subset of NGS testing, the kind for targeted chemotherapy? 

What If Your Stage I Breast Cancer Is Gone?

The NCD says that for patients with cancer, NGS testing can be covered by LCDs only if the patient has advanced cancer.  However, a patient who has stage 1 breast cancer and a lumpectomy no longer has any cancer - no signs and symptoms of cancer.  She had cancer before the lumpectomy that removed the stage I cancer.  So does the NGS NCD apply to her - no longer an obvious cancer patient - or does the LCD concept apply (a person with "a personal history of cancer," which she does have?)

Are Medicare Advantage Plans at Compliance Risk?

Medicare Advantage plans can cover services non-covered by CMS, like vision, dental, or in this case, stage 1/2 HBOC testing with NGS.  However, Medicare Advantage plans must meet compliance rules and regulations when they cover non-covered services, like separate notification to the patient in advertising materials and separate budgeting reporting to CMS.  Have Medicare Advantage plans been legally out of compliance since March 18, 2018, for reporting Stage 1/2 HBOC testing within their covered costs under Medicare?

Interpreting the NCD Ambiguity

There is a concept in law that regulations should be interpreted, if possible, in a way they make sense.  One sentence of the NCD says that NGS testing can only be covered in cancer patients if they have advanced cancer.  Another sentence says that the NCD as a whole applies only to a subclass of NGS tests for targeted therapies.   The only way to coherently interpret these is to assume the second sentence modifies the meaning of the first.   That's logical.  The other way around doesn't work.  (See Justice Scalia's book on interpretation of laws, here.)

Which Is Controlling?  The Header Coverage Section of the NCD or the Sentence Restricting Its Scope to Targeted Therapy Testing?

I've heard that CMS argues that the "header section" of the NCD is the operative section, and nothing in the body can modify the header section.  (The header section says only advanced cancer patients can be tested by NGS, but the body says the scope of the NCD is only targeted therapy testing.)   Let's assume that the header section is the "operative" section.  Where is that written down?   Is that in the statute?  Is that in any regulation?  Is that even in the CMS manuals - anywhere?   Maybe it's just a subregulatory concept at CMS.  But if a subregulatory concept can modify the interpretation of an NCD, then why can't a written statement in the body of the NCD modify the NCD?  Even the Supreme Court frequently uses the intention of a law as a whole in order to interpret it.

CMS Subregulatory Language Frequently Modifies Regulatory Language

Even if you argue the header of the NCD has the status of "regulatory language" and the body of the NCD the status of "subregulatory language," the latter frequently modifies for the former. 

For one example, in the 14-day-rule, the regualatory language (42 CFR 414.500ff) states parts of the rule apply to molecular pathology tests.  You can't tell from the term "molecular pathology tests" if this applies to molecular microbiology or not.  You have to look to the context and explanations in subregulatory rulemaking to find it only applies to human molecular tests - you can't tell from the regulation, and in fact, the regulation might more easily imply the opposite. 

Similarly, the regulation about a recent required exception to the 14 day rule (for genomic tests) took effect January 1, 2018, and that regulatory text hasn't changed.  However, subregulatory (PDF) announcements from CMS have extended implementation, most recently updated on December 26, 2018, until July 1, 2019.   CMS regulations would fall apart and be unusable, resulting in chaos, if subregulatory definitions and clarifications did not exist and couldn't modify regulatory language.