Brief Blog: Three New Popular Books on Genetics

The last several weeks have seen publication of three popular books on genetics and the genetics industry.

In The Gene Machine, Bonnie Rochman surveys how genomics - such as Ashkenazi and expanded carrier screening (here, here) and NIPT - are influencing family planning decisions.   Companies like Counsyl are profiled.   In Mercies in Disguise, experienced science journalist Gina Kolata profiles a family with the rare, fatal adult onset neurological disease Gerstmann Straussler Sheinker Syndrome.  In The Family Gene, Joselin Linder describes her family's battle with an N of 1 genetic disorder causing liver failure - known as a "private mutation."  

• Amazon hotlinks to Gene Machine, Mercies in Disguise, and The Family Gene.
• All are available as books and ebooks; Mercies and Family Gene as audiobooks too.
• NYT review of Mercies in Disguise and Family Gene, here.  Gene Machine reviewed here.
• Gina Kolata describes how she wrote her book, here.

Brief Blog: Cost Effectiveness of Gene Panels in Familial Breast Cancer

In women who have an elevated risk of breast cancer, USPSTF recommends genetic counseling to consider testing for the BRCA1-BRCA2 genes.  (And HHS guidance views the genetic testing as a USPSTF-endorsed and copay-free preventive benefit).  That's the solid ground.

Two additional topics are: 

1. Whether to extend BRCA genetic screening to women without a high-risk family history.  
2. Use and cost-effectiveness of gene panels (beyond BRCA) for a range of breast cancer risk genes.

The second topic is addressed in a new study.

In a study in Value in Health,  Li, Devlin and colleagues report that gene panel screening is cost effectiven, with costs/QALY well in the $20,000-70,000 range used for other therapies.  See Li et al. here.  The costs/QALY for gene panels were also well in the range used for screening mammography (e.g. see Pataky et al., 2014, here).   Coverage of Li et al. at Genomeweb, here.

Devil in the Details - Turning Devlin's Analysis Upside-Down

The authors state that they took costs for BRCA testing (and mammography) from the 2015 CMS fee schedules.  The cost "for the seven gene test was provided by Quest diagnostics."  The BRCA test was scored at $2178 ... and the cost of the seven gene panel as $2178 +$210 (see Devlin's Table 1, Costs [2015 US Dollars].  

However, if you use 2017 Medicare fee schedules, Medicare prices BRCA panel testing at only $932, or alternately about $1400 in states that pay for extra dup-del coding (MolDX states block payment for extra dup-del coding).   

Therefore, if you used actual Medicare panel pricing approaches, potentially the panel testing would be a savings of about $1200, literally the opposite direction than the add-on cost of +$210 over BRCA alone, carefully modeled by Li & Devlin.

Alternately, one could argue that open market available panel prices for breast cancer panels are advertised at $1500 or less, not at prices greater than $2100 for BRCA alone.   I wrote a blog about this earlier this spring.

Duration Required to Release an LCD After Its Comment Period

CMS requires MACs to provides links to CMS databases for current LCDs, for draft LCD under review, and for future effective LCDs.

I pulled data for Jurisdiction F.  Currently 6 LCDs are in "released to final" status, meaning edits have been completed following a comment period.   The interval from comment period closure to release was 92 days (four out of six LCDs), with outliers at 77 and 221 days.

Jurisdiction 6 also has 22 LCDs in draft status for which the comment period has closed.  For 14 LCDs, the comment period closed very recently (usually April 10).

Eight LCDs are now in "comment review limbo," with 8 under review for 132 days (about four and a half months) and three under review for about 250-400 days (about a year).

Eleven of all the LCDs are MOLDX LCDs.

Excel here.  Raw data online here.   Picture, click to enlarge:

In the picture, NRTF = Not Released to Final.
The meaning of RTF is left as an exercise for the reader.

The Impact of PAMA on Molecular Codes Currently Unpriced by CMS

Since the new molecular coding system was introduced in 2013, CMS has priced each year's new codes by the crosswalk or gapfill method.  However, until 2016, CMS left many of the molecular codes unpriced.

Beginning in 2016, CMS began a new policy of pricing every new molecular CPT code, whether it was used by Medicare or not.  For example, the genetic code for Ashkenazi carrier screening was priced by CMS at about $600 (81412) in 2016.  What data CMS used to set this price is unknown (it was gapfilled, so only a gapfill price result exists).

PAMA requires labs to submit commercial pricing data to CMS in 1H2017 (for tests performed in 1H2016), and CMS is to calculate median prices per test to reset its national fee schedule in 2018.  While this process is running late, and might stall-out altogether, it's interesting to note that it would convert a bevy of legacy unpriced codes to priced codes.

Details after the break.

MolDx announces new Medical Director, Dr James Almas

On April 20, 2017, the MolDX program announced Dr. James Almas has joined as a Medical Director.   Dr. Almas is a board-certified pathologist who has also served as a medical officer with the CMS coverage group in Baltimore.

The MolDx announcement is here.  Dr. Almas' Linked-In is here.

Very Brief Blog: When will the July 2017 CLFS Meeting Be?

Each July, CMS holds a public meeting for discussion of pricing issues for new CLFS codes.  For the past two years, the meeting has also included a public session of the PAMA Clinical Laboratory Advisory Panel (which also discusses new code pricing recommendations.)  Webpage for these meetings is here.

Occasionally, CMS has locked and announced the July date as early as the first quarter.  This year, it's almost May and we don't know yet.

Here's for the betting person:

2016: July 18, 3rd Monday
2015: July 16, 3rd Thursday
2014: July 14, 2nd Monday
2013: July 10, 2nd Wednesday

With that landscape, looks like the 2017 date will fall between Monday July 10 at the earliest and Thursday July 20 at the latest.  ...When it is announced.

Brief Blog: S. 794: Legislation for LCD Process Clarity

LCD Legislation Re-Introduced in New Congress

"Local Coverage Determinations Clarity Act of 2017"

In both 2016 and 2017, legislation supported by AdvaMed has been introduced which would improve the clarity and independence of MAC LCD policymaking.

For the text of 2017's S.794 bill, see here.  For a 2017 press release, here.  For 2016 trade press, here.

Introduction was by Sen. Isakson of Georgia.  Full text of the legislation is also cut/pasted below the break.  The bill would largely implement in statute guidelines that are already on the CMS website, but would carry "force of law."  There are currently 8 MAC companies making policies for 12 different CMS Medicare geographies or jurisdictions (here).

S. 794 requires:

• Publish LCD proposal, PLUS a written rational and description of all evidence relied upon.
• Within 60 days, convene a public meeting, receive public comments, and use an expert panel (as now exists; the "CAC" panel).
• Post a record of meeting minutes within 14 days.
• Provide for written comment as well.
• Provide a response to all issues raised and finalize the LCD, adding descriptions of any additional qualifying evidence.
• Effective date "not less than" 30 days.
• A MAC may not finalize an LCD that applies outside its geographic area, and if importing an LCD, the new MAC must independently "evaluate and consider the qualifying evidence."
• A specific CMS ombudsman for LCD disputes is to be appointed.

The bill also makes some small modifications to the existing LCD definition and reconsideration process.  For example, during reconsideration, the MAC must consider if it "did not apply or inaccurately applied" the relevant evidence.

After the break, I walk through the bullet points with comments in regard to current policy, and then provide a cut/paste of the legislation.

Note that the changes in S.794 are much larger than a few sentences about LCD process clarity that have already appeared as Section 4010 of the 21st Century Cures Act.   

Those sections are effective as law in June 2017, and required that:  (1) Final LCDs be posted at least 45 days prior to the effective date, (2) Trackback to the proposal LCD date and original proposed text, (3) Provide discussion of all comments received and (4) rationale for LCD decision.  See pp. 408-409 of 21CC in the cloud, here.

Brief Blog: CMS MACs by Jurisdiction and by Contractor

CMS provides a website with detailed information on its Medicare Administrative Contractors (MACs) for traditional fee for service Parts A and B.   The website is here.

I recently needed to consolidate the information for a project, and provide the Excel spreadsheet in the cloud, here.  Dates and figures are current as of April 2017.

A snapshot summary is below - click to enlarge.   There are four numbered MACs (the old system), and eight lettered MACs, so there are twelve contracts.  However, four MACs (Novitas, NGS, Noridian, WPS) hold two contracts, so there are only eight MAC companies.

While I do not understand the full corporate structures, I believe that two pairs of MACs have some type of higher level joint ownership or umbrella corporation (Palmetto, CGS; and Novitas, FCSO).*  This would leave six MACs or sets of MACs that are unrelated.

Together, four multi-jurisdiction MACs, Novitas (24%), NGS (20%), Noridian (15%) and WPS (11%) have about 65% of Medicare beneficiaries.  A CMS MAC Map is here.

LCD Legislation Re-Introduced in New Congress

In both 2016 and 2017, legislation supported by AdvaMed has been introduced which would improve the clarity and independence of MAC LCD policymaking.  For the text of 2017's S.794 bill, see here.  For a 2017 press release, here.  For 2016 trade press, here.  For more detail, my blog here.

MolDX States & MACs

MolDX is a multi-MAC policy system for genomic test LCDs and pricing.   There are six MolDX jurisdictions (JE, JF, J5, J8, JM, J15) under four different MACs (Noridian, WPS, Palmetto, CGS.)   Therefore, MolDX spans 24 states and 41% of US claims (16.4M of 37M Medicare beneficiaries).  (Click to enlarge).

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*  E.g. Celerian Group "is a consortium of companies" including MAC CGS and MAC Palmetto GBA, here.  Similarly, in a 2012 press release, "Diversified Service Options, a wholly owned subsidiary of Florida BCBS, acquired MAC [Novitas Solutions] from its parent company..." - here.

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For economics nerds, the MACs have a Herfindahl or oligopoly index of 0.15.  The Herfindahl  index varies from 0 to 1, with 1 representing monopoly.  It is mostly driven by at least one company having a very large share (e.g. 1 company has 70% or 80%).  (Calculated by summing the squares of each participant's market share.)    Wikipedia.

Brief Blog: Gene Test Management for Payers and Others: ECRI-GENE

I recently gave a talk in Berlin and talked about US payer reactions over the last four years to what they perceived, fairly or not, as a "Versicherungsblitzkrieg" (Insurance Blitzkrieg) coming from rapidly growing pharmacogenetic and cardiac testing labs.   (Several such labs fell equally rapidly into bankruptcy amidst commerical payer, DOJ, or CMS actions).

Companies developing to help payers manage genomic test policies include BeaconLBS (covered frequently by Dark Report); the former NextGxDx, now Concert Genetics; and eviCore, which developed for other types of benefit management, like imaging.  To my knowledge, BCBS Evidence Street is another major HTA, but focuses on providing the evidence assessments* rather than outsourceable payer claims handling functions.

Add a specialized service at nonprofit HTA firm, ECRI, called ECRIgene.  Website here.  It's not brand new; see a July 2016 press release, here.

Their homepage states:

Think of ECRIgene as your genetic test control center with experts constantly monitoring activities in this rapidly evolving universe. Our  analysts, nurses, clinicians, and medical librarians research, analyze, and synthesize the key features and evidence on each relevant test using the GRADE-based evidence-rating system. These experts are dedicated to researching your custom requests and answering your specific questions. 

We can imagine sales reps from large and small labs lined up to talk to a clinician; and sales reps from Beacon, Concert, eviCore, and ECRIGene lined up to talk to the patient's health plan. (For a few years, I've used a slide that refers to the growing HTA medical-industrial complex.)

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It's been reported that at some point in 2017, BCBS Evidence Street and MolDX will use a common portal, here.

Foundation Publishes 100,000 Patient Study on "Total Mutational Burden" (TMB)

Very early on, before sequencing 200 or more genes in tumors was really commercialized, it occurred to me that from a business strategy perspective you would need to come up with a clinical reason for assessing 200+ genes.   Even today there are a very finite number of effective drugs for targeted mutations (EGFR, ALK, BRAF, etc), not anywhere near 200-500.   Adding referral to clinical trials will have limited impact; although tallies count "hundreds, or even thousands" of oncology clinical trials, they are likely counting things like phase I drug dosing arms.

Two approaches to making use of all 500 genes are being discussed.

• One use would be to make very complex in silico models of tumor cell biology.  Companies like Cellworks and Darwin Health are exploring this.  I think of this as a growing industry for "digital genomics."  
• Another use is finding something about those 500 sequenced genes that can be assessed and applied clinically -- but requiring the exponential jump in gene data and unrelated to the small number of approved drug-gene pairings.  
• An approach here is Total Mutational Burden (TMB), and Foundation Medicine has just published a large new study.

Note that while either or both of these areas may prove to be clinically effective and important, you would come across these kinds of ideas, just by working backwards, Sherlock Holmes-style, from assuming you already have built the 500- or 1000-gene test and want to reverse-engineer applications for it.  As an if-then statement;  if one of these ideas proves important, then the market for 500 gene tests would rise while not depending on the trickle of a few new individual FDA-approved gene-drug pairs.

Total mutational burden is being cited as a potential biomarker for the effectiveness of immuno-oncology checkpoint drugs.   Chalmers et al. report the results from 100,000 patient studies conducted in a wide range of tumors from the FMI archives (Genome Medicine, Open Access, here.) FMI finds that:

• They confirmed the previous understanding that lung cancer and melanoma are most likely to have rampant mutations, but found that rampant mutations also occurred at lower rates in many cancers.
• You get most of the information for 0.5MB DNA; an exome confirms the high or low mutation burden you already low, whereas accurate assessment falls off below 0.5MB.
• PMS2 mutations tend to be associated with rampant mutations, as is aging.

One proposed use of this type of data is predicting immunotherapy outcomes with a biomarker (TMB) orthogonal to markers like PDL1.   Last December, MolDX providing coverage of comprehensive genomic profiling in several additional cancer types (colon, melanoma, ovarian) based in part on the contributory value of TMB to therapy choices.

The authors also used Cancer Genome Atlas (TCGA) data.  Coverage at Genomeweb, here.

Update May 9:  FMI emphasized the growing role and value of TMB in its May 9 investor call, here.
Update October 6:   For a UCSD paper on TMB clinical impact (Khagi et al.) here.
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For AACR news with a re-analysis of Opdivo data using TMB, BiopharmaDive, here.

For an earlier FMI paper on 63,220 tumors, see Hartmaier et al., Genome Med 9:16, February 2017, here.

Brief Blog: DC Conference on Tumor Heterogeneity, May 11-13, 2017

The classic paper in the US literature on tumor heterogeneity remains Gerlinger et al, in NEJM 2012 (here.)   On May 11-13, there will be a (free) international conference in Washington DC on the topic.  The conference is sponsored by the Menarini Foundation, the University of Hamburg, and MD Anderson.

See the website here and here the PDF brochure here.  It's at the "Congress Center of the Old Post Office Building," which I believe is now Trump International Hotel.

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New papers appear regulary across a range of cancers, e.g. new work by Morissy on medulloblastoma heterogeneity in Nature Genetics, April 2017, here.

Brief Blog: CMS Publishes CY2018 Inpatient Rulemaking; Six New Technologies Seek Add On Payments

CMS has released its Inpatient Proposed Rule for FY2018.

The typescript version is online here (1832 pp).
On April 28, the typeset Federal Register version will appear here.
The CMS press release is here.

Update: Final Rule appears in Federal Register, April 14, 2017, here.

New Technology in Brief Review

In addition to the annual rejuggling of some DRG codes, an area of recurring interest is the "new" New Technology applications - beginning on page 349 of the current public review version.  CMS received 9 applications, of which 3 were withdrawn before publication.   The remaining six new technologies for add-on payments are:

1. ZINPLAVA (bezlotoxumab)
2. Edwards INTUITY ELITE Valve and Liva Nova PERCEVAL Valve
3. STELARA (ustekinumab)
4. KTE-C19 / Axicabtagene ciloleucel
5. VYXEOS (cytarabine/daunorubicin liposomes)
6. GammaTile

Drugs must be costly enough to substantially exceed the inpatient DRG for the conditions where they will be used, the same standard as for devices.   The products must be "literally new" (meeting carefully defined dates and rules) as well as technologically new, and must have have clinically impactful new benefits, and it must also fail to be "substantially similar" to existing therapies.  

Qualifying new technologies earn hospitals a bonus to each DRG for which the product qualifies, for 2-3 years.

Brief summaries of each product below the break.

ACLA Generally Supportive of Statutory FDA Reform for CLIA Labs and IVDs

On March 21, Dr. Larry Bucshon (R-IN) and Diana DeGette (D-CO) released a discussion draft of the Diagnostic Accuracy and Innovation Act (DAIA), along with summary documents.  In general, this is built on the Diagnostic Test Working Group (DTWG) approach circulated in the previous session of Congress.  ACLA has come out as generally supportive.  Details follow.

Hill Lab Proposal Released in Late March

An initial press release for the legislation is here, with a 2-page summary here, a 5-page summary here. and the whole 215-page statutory proposal here.

ACLA Generally Supportive in Early April

On April 7, ACLA issued a generally favorable press release in support, here, also releasing ACLA's detailed letter to the Hill, here (should open in window) or here (should open in Google docs) or here.

Get all six documents in one cloud zip file here.

In March, ADVAMED initially released a rapid, generally favorable short press release, here.  Similarly, Labcorp, here.  For an initial summary at RAPS, here, and for early coverage at Genomeweb, here.   For the AMP 5-page letter on DAIA, here.

Scott Gottlieb Senate Testimony; Unique Transcript HERE

On Wednesday, April 5, Scott Gottlieb testified before the Senate HELP committee for two and a half hours.

For a unique unofficial transcript of the hearing: click HERE. 

The Senate website is here.   (Click on "Open in New Window" for video).

Gottlieb's 5-page prepared statement is here.

Video also archived at CSPAN, here.

The Senate vote on Gottlieb's confirmation is scheduled for April 26, here.

Open access coverage at:

• Xconomy, here.
• Healthcare IT News, here.
• BioPharma Dive, here.
• The Hill, here.
• Endpoints, here.
• Health Affairs, here.
• Heritage Foundation "thumbs up," here.
• Endpoints also excerpted and published later responses from Gottlieb to the committee, here.