Very Very Brief Blog: AMA Posts Notice of Stakeholder BRCA Call, Feb 5 at 5 ET (4 CT 2 PT)

AMA has posted public notice allowing stakeholders to register for a call on BRCA coding, to be held Monday February 5 at 5 ET, 4 CT, 2 PT.

The registration address is here:  https://www.ama-assn.org/events/molecular-pathology-advisory-group-meeting

BRCA code set changes are on the agenda of the February 9-10 AMA CPT meeting, to be held in San Diego. 

Very Brief Blog: International Lung Cancer Genomic Testing Guidelines Updated

This week, the International Association for the Study of Lung Cancer, CAP, and AMP released new guidelines for genomic test in lung cancer.   The 27-page PDF is available open access online.

Highlights include the need for gene panel testing, dealing with small specimens, and recommended use of liquid biopsy where tissue is inadequate or unavailable.  (The latter matches NCCN guidelines, too.)

See coverage at Genomeweb here, and in other trade press here, here.  As shown in the figure below, lung cancer genomics have become vastly more complicated over several years.  (For one sample, see an article on targeting MET, here.)

click to enlarge

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See another article on new international collaborations re lung cancer staging, here.

Very Brief Blog: Invitae's Positioning for Growth (Deck + Investor Article)

Genomics labs struggle to innovate in new ways in a rapidly changing marketplace.

For industry watchers who'd like a snapshot of Invitae's strategy for innovation amongst the turbulence, see an online article at the investor website Seeking Alpha by Los Angeles-based Ophir Gottlieb of Capital Market Laboratories.  It's based on his interview with Invitae CEO Sean George.   Find the essay online here (email registration may be required).   Invitae lays out a complex, multi-dimensional strategic map involving health systems, big data, high test volume, high levels of interaction with patients, multiple routes of interaction and collaboration, etc., hence the heading, "massive disruption."

Gottlieb also posted Invitae's deck from JP Morgan, here, while including a few key screen shots within his essay.

For a Genomeweb (subscription) article on an Invitae's genetic testing pilot presented at Precision Medicine World Conference, here.  For Genomeweb's coverage of Invitae JP Morgan news, here and here.

Genome Medical, a spun-out telegenomics company, raised $11M in early January, here.  Investors include GE Ventures, Kaiser, Illumina, and Canaan Partners.  This adds to $12M raised last year.

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Not directly related except as company based genomic innovation, see a December 2017 article on Luna DNA, "offers cryptocurrency to build a community of DNA data," here and a January article  here.

Very Brief Blog: Boston Academic Lab Spinout CLARITAS Closes Doors; To Be Repurposed for Drug Discovery

In 2013, revised 2014, Harvard Business School produced a case study of Claritas Genomics (by Robert F. Higgins) which is a great profile of challenges facing independent genomics lab.  Claritas was spun out from Boston Children's Hospital.

On January 19, 2018, Genomeweb ran an article that the lab was closing its doors.  The advanced genomics independent lab environment is difficult, including now very large publicly funded companies as well as perhaps more competition from academic medical centers whose sequencing abilities may be synergized by less costly NGS platforms and outsourced pipeline software from a range of digital genomics companies (e.g. Edico, Fabric Genomics, others.)   In addition the payer environment is hard; an executive left Hudson Alpha recently reporting "the reimbursement is just not there." 

Some recent spinout labs, like NAVICAN from Intermountain, seem to be aiming to have extensive constellations of services such as telehealth genetic counselors, virtual tumor boards, etc, "more than just a genomic test."   In a recent paper I called this "Lab 3.0."

The founding CEO of Claritas, Patrice Milos, moved a couple years ago to Medley Genomics, a company where several of the co-founders are full time computer science professors.

Dark Report Jan 13, 2014

Update - A February 9, 2018 article in Genomeweb states that Claritas assets have been purchased b y "Drug discovery startup Q-State Biosciences," here.  The next phase will involve WuXi NextCode, which was also an investor in the original Claritas.  More about WuXi NextCode here in SCMP, South China Morning Post.

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Harvard Case Studies are available as PDFs for about $5.

Very Brief Blog: A Free Resource for Biomarker Proteogenomics

Attending the Precision Medicine World Congress this week, the company OLINK Proteomics had a glossy forty page magazine on proteogenomics.   Turns out it was a Sponsored Supplement to SCIENCE in Fall 2017.   The company website is here.

The whole set of articles is online as a PDF here.  I've clipped the Table of Contents below (click to enlarge).

click t enlarge

Very Brief Blog: PLA Update; Upcoming Code Applications Can Be Reviewed

AMA CPT takes PLA code applications quarterly and either holds public comment by teleconference or (if possible) during an AMA CPT meeting.   AMA has now publicly released the PLA applications submitted by January 12, 2018.  See this webpage, for the "Feburary 2018 Agenda," and if the PDF hotlink doesn't change, this PDF link. 

Codes will be discussed at the regular February 9-10 AMA CPT meeting in San Diego.

So far, AMA has finalized 34 PLA codes; see my short review from early January here.

Code applications could be deleted but won't increase.   The proposals in the hopper are:

1. Lyme ImmunoBlots, recombinant protein method
2. Anti-Merkel Cell Panel, antibody bead assay method
3. Tick Bord IgM/IgG tests
4. Prion detection RT-PCR
5. ExACT-1 Whole Exome Test
6. Foundation One CDx (FDA PMA; 324 genes)
7. ToxLok Code Revision (0020U)
8. Sensieva Droplet 25-OH Vitamin D2/D3
9. OmniSeq Comprehensive (184 genes)
10. OmniSeq Immune Report Card (IRC; )
11. Anti-dsDNA, high salt, avidity, for SLE
12. Panorama Twins Zygosity (cfDNA)
13. MRDx BCR-ABL Test

If all are finalized, it would bring the PLA system up to circa 50 codes.

     

Very Brief Blog: Genomics Lab Executive Departs; Reimbursement "not there;" Joins Giant Biopharma Abbvie

A news item at Genomeweb picks up a story from AL.com with some interesting quotes.

Howard Jacob left Medical College of Wisconsin in 2015 to become an EVP at HudsonAlpha Institute for Biotechnology.  According to reports, they expected to supply clinical genome sequencing for about $600.  Stating to journalists that "reimbursement is just not there," he's joining biopharma giant Abbvie where he'll be VP for Genomic Research.

The interview and story at AL.com is here.   Press on the original 2015 hire is here.   Jacobs' LinkedIn page is here.

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See quotations about reimbursement problems and stock market dips at Cancer Genetics, April 2018, here.

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Very Brief Blog: A Final Visualization of the CMS NCD for NGS (and my PDF comment letter)

Medicare's wide-ranging draft NCD on the uses of NGS testing in oncology is posted for review here, and public comments are available for review here.

I offer a process chart that visualizes the NCD here:

A simpler view, summarizing just by patient types and test types, is here:

Several hundred comments will be on the CMS website, for which comments close on January 17.

I submitted a PDF public comment with these points:

The idea of catapulting Medicare oncology care into a learning healthcare system is terrific.   The specific approach, with sudden announcement of an NCD with complex and sometimes nonsensical rules, isn't the best way.   CMS should recall the Oncology Care Model was developed with many requests for information, town halls, public proposals, revisions, and stakeholder buy in.

Problems include four:

1. Blocking any use of NGS in non advanced patients is a bad idea.  This blocks the whole world of germline testing (e.g. BRAC syndromes and Lynch syndromes).  It also prevents molecular tests (such as breast cancer prognostic tests) from being ported onto NGS platforms, since they are for non late stage patients.  
2. LDTs have NO coverage except in NCI trials.   This is obviously a bad idea for many reasons, but a few concrete ones follow.   For example, FDA has freely approved cetuximab with only LDT KRAS tests, crizotinib with only LDT ROS1 tests, and Keytruda with only LDT MSI tests (the latter remains a current position of the FDA).   None of these drugs would have been available for on-label use for Medicare patients except in NCI trials, even after the on-label change at FDA.    CMS covered solid tissue panel tests on an LDT basis until a PMA test was available.  The same should occur in domains like germline testing (the whole world of ACMG and NSGC), leukemia/lymphoma panels, and liquid biopsy panels.   For germline testing, the best labeling some might ever get at FDA would be capped at 510(k) not PMA (not "high risk and life threatening devices").
3. Some nonsensical positive coverage or perverse incentives are created.   For example, a hospital could biopsy on Monday, do five, $300 tests on Tuesday, and then CMS would additionally FMI F1 CDx for $3000 on Wednesday.   Any "recurrent" cancer is covered, without being advanced, which would include millions of small skin cancers (at least under CED).  There's no limit on paraffin block age.  Take home - if they got a million ten-year-old paraffin blocks from small recurrent skin cancers, they'd cut a check for $3B.
4. Large numbers of patients are pushed into CED that makes no sense and, as written, is very invasive and costly.   If a CED project for $200M would be laughed out of the room as an NCI grant, it probably shouldn't be mandated expenditures under an NCD either.  Many patients will get hospice care, general chemotherapy, etc.   In one recent study (Tokaca 2018), only 13 of 66 lung cancer patients got a targeted therapy, but that is clearly what the CED envisions for all 66.   Patient reported outcomes won't change based on the brand of a test, any more than penicillin allergic reactions will change based on the brand of thermometer that diagnoses fever.  Simply creating a new system where genomic results are matched to drug records (Parts B & D, including time on treatment) would be a colossal improvement to what we have now.   Use best of breed stakeholder input and value-of-information design principals.  Avoid problems like patients going into multi year highly costly CED just because they are tested the day before their particular gene is converted to PMA level.  

I suggest limited scope of the NCD to solid cancers, for somatic gene testing, in tissue.  This leaves a grand and broad NCD in place.  90% of Medicare cancers are solid cancers, the NCD is solely and wholly designed for PMA gene-drug tests in somatic mutations, and 95% of the market or more is tissue biopsy.   In one swoop, for now, this avoids rolling avoid leukemia patients (or requiring absurd types of solid tumor CED), avoids a blockade of liquid biopsy coverage (which is working through FDA, commercial, NCCN, and LCD pathways), and germline testing.

There needs to be some safety valve for LDTs.   For example, the NCD could grant PMA test coverage (where they are available), grant CED coverage merely for the price of CED participation, but allow specific clear cut scenarios to be carved out of CED by having an LCD pathway.    MACs have been rigorous, tough, and slow to cover gene panel testing, so this is a narrow safety valve for narrow situations where CED would be unnecessary.   A two year moratorium on the non coverage paragraph would also be workable.

Simplify the CED.   Consider value of information strategies and allow rich public debate and comment on the minimum criteria set that has the biggest bang for the buck and burden.  Remember that some kinds of CED, like cardiac valve surgery CED, are primarily watchful: is the patient readmitted, does he have a stroke, must the valve be removed?   Oncology trial management is invasive and proactive, like monthly RECIST scans for PFS.   

Consider a CED pathway for liquid biopsy.   All solid tumors tests have a pathway to 510(k) status if they benchmark as NYS approved.   No such pathway yet for leukemia or liquid biopsy.  If CMS must, create additional entry points to the CED arm, one of which is NYS-510(k)-solid tissue, but another is NYS-liquid biopsy (since no 510(k) pathway exists).  The treatment is justified since liquid biopsy tests are in FDA pipelines, specific clinical uses are endorsed by NCCN, and some tests are NYS approved and are meeting commercial and MAC criteria for medical utility.

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Added note (1/23/2018).   FDA has been markedly revamping its diagnostic test policies, including self-certification for some types of germline genetics, the NYSDOH-510K merged process for gene panel tests (MSK IMPACT), and the mere fact it now suddenly allows reporting of dozens or hundreds of "off label" genes in the Oncomine and FMI F1CDx tests.   Another trade wind:  On March 21-22, FDA will hold panels on whether it can downclassify tests like HIV diagnostic tests and HCV viral load tests from PMA to de novo 510K.  That's big.  Panel info here.

Very Brief Blog: United Healthcare Comments on the CMS NGS NCD (aka "Foundation Medicine NCD")

CMS's Next Gen Sequencing NCD is on the CMS website here with public comments here.  Public comments close January 17.

A particular interesting comment is from United Healthcare, as clipped below.

Commenter:

Malin, Jennifer

Title:

Senior Medical Director, Oncology and Genetics

Organization:

UnitedHealthcare

Date:

12/27/2017

Comment:

Ms. Tamara Syrek-Jensen
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

December 27, 2017

RE: Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N)

Dear Ms. Syrek-Jensen:

On behalf of UnitedHealthcare, we appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N).

Advances in molecular diagnostic testing have contributed to an improved understanding of the biology of cancer and the development of many new innovative therapies. The rapid pace of change in the methodology for performing genetic testing, including the development of Next Generation Sequencing (NGS) addressed in the Proposed Decision Memo, has led to widespread variation in the types of tests for genetic alterations that are available and bundling of tests into cancer-type agnostic panels that may include numerous tests for genetic alterations that have limited clinical utility for any one cancer type. However, due to lack of evidence supporting the tests’ clinical utility, there are limited clinical guidelines on when and how to use multi-gene panels to guide the management of a patient’s cancer treatment.

1. The Proposed Decision Memo has broad and vague criteria regarding coverage for cancer therapies and we urge CMS to revise the criteria to specify that NGS results may not be used as a basis for coverage of a drug or combinations of drugs that would not be supported by the drug(s) FDA label or statutorily approved compendia.

The proposed coverage criteria state that CMS will cover the NGS test “including the test results.” This would result in a broad expansion of coverage criteria for cancer therapies beyond their current FDA approved or compendia supported indications because it implies that any therapies with a mechanism of action that may theoretically have a biological impact on a genetic alteration identified by the test will be covered regardless of evidence of safety or efficacy in the clinical scenario in which the test is being performed. Such a broad expansion will undermine efforts to conduct the necessary clinical studies to determine the safety and efficacy of therapies targeted to genetic alterations in different cancer types, greatly increase healthcare costs, and potentially expose beneficiaries to treatments where the benefits and harms are unknown.

2. CMS should provide coverage for all of the marketed tests that meet the coverage criteria outlined in the Proposed Decision Memo not just the tests that are the proprietary tests linked with a particular type of therapy. This would not disrupt access to the most clinically appropriate and cost-effective diagnostic test to determine if a beneficiary’s tumor harbors a genetic alteration that can be targeted by a specific therapy.

By limiting its scope to the FDA-approved companion in vitro diagnostic tests, the Proposed Decision Memo may have the unintended consequence of limiting beneficiary access to more clinically appropriate and/or more cost-effective diagnostic tests. For example, BRCA1 and BRCA2 gene testing is used to target therapy for various treatments and there are many available tests but the Proposed Decision Memo would limit coverage specifically to the FoundationFocusTM diagnostic test. FoundationFocusTM is a proprietary NGS test marketed by Foundation Medicine that detects alterations in the BRCA1 and BRCA2 genes. The FoundationFocusTM was used in the trial that led to the FDA approval of RubracaTM (rucaparib) and was approved as a companion diagnostic.(1) There are currently two other PARP inhibitors on the market that are approved for the treatment of patients with ovarian cancer, LynparzaTM (olaparib) and ZejulaTM (niraparib), for which testing for BRCA1 and BRCA2 is also recommended to determine if a patient with advanced breast or ovarian cancer will benefit from treatment.(2) The Proposed Decision Memo would limit coverage for diagnostic testing for BRCA1 and 2 to only the FoundationFocusTM test if treatment to be used is RubracaTM whereas there are many other tests available and other treatments that would necessitate this type of testing.

Additionally, many laboratories have the capability of performing the diagnostic testing to determine whether a patient caries a somatic or germline mutation in BRCA1 or BRCA2, either using NGS or other methodologies for assessing genetic alterations. Will this Proposed Decision Memo supersede the LCD(3) that provides coverage criteria for all BRCA1 and BRCA2 genetic tests, not just the FoundationFocusTM? An unintended consequence of the Proposed Decision Memo will be to restrict access to the most cost-effective testing for BRCA1 and BRCA2. Coverage should be based upon evidence-based clinical criteria that can be applied irrespective of the laboratory performing the test.

3. CMS should ensure that coverage criteria for multi-gene panels are evidence-based and that there is clinical utility for all of the genes included in a proprietary panel.

In order to determine whether the expanded multi-gene panel tests meet coverage, CMS should consider whether the incremental information beyond that available in targeted testing (NGS or other methods) has clinical utility.

Expanded multi-gene NGS panels such as the F1CDx (Foundation Medicine, Inc.) include many more genes than are needed to determine the appropriateness of therapy with no clinical utility for the additional genes. As described in the Proposed Decision Memo, the F1CDx is a NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB), using DNA isolated from FFPE tumor tissue specimens. This test is currently not specified in any of the FDA labels of cancer therapies. The application for F1CDx approved by the FDA includes data supporting indications for five cancer types, non-small cell lung cancer, melanoma, colorectal cancer, ovarian cancer, and breast cancer.

• For non-small cell lung cancer, Foundation One provided data supporting the utility of only 5 alterations in the 324 genes in the panel (EGFR exon 19 deletions, EGFR exon 21 L858R, EGFR exon 20 T790M alterations, ALK rearrangements, BRAF V600E) to determine the appropriateness of Gilotrif® (afatinib), Iressa® (gefitinib), Tarceva® (erlotinib), Tagrisso® (osimertinib), Alecensa® (alectinib), Xalkori® (crizotinib), Zykadia® (ceritinib) Tafinlar® (dabrafenib) in combination Mekinist® (trametinib).
• For melanoma, there are therapies targeting 2 alterations in 1 of the 324 genes in the Foundation One panel (BRAF V600E and V600K: Tafinlar® (dabrafenib), Zelboraf® (vemurafenib), or Mekinist® (trametinib) or Cotellic® (cobimetinib) in combination with Zelboraf® (vemurafenib).
• For colorectal cancer, there are indications for testing for 2 of the 324 genes (KRAS and NRAS) in the F1CDx to determine the efficacy of Erbitux® (cetuximab) or Vectibix®(panitumumab).
• Similarly for ovarian cancer, there are indications for testing just 2 of the 324 genes included in the F1CDx (BRCA1 and BRCA2) to determine efficacy of the FDA approved therapy Rubraca® (rucaparib).
• Finally for breast cancer, Foundation One provided data on the amplification of ERBB2 (HER2) which correlates with the expression of HER2 antigen, the target for Herceptin® (trastuzumab), Kadcyla® (adotrastuzumab-emtansine), or Perjeta® (pertuzumab); however this would be of limited clinical utility since breast cancer specimens are routinely evaluated for HER2 expression by immunocytochemistry or in situ hybridization.(4)

Given the limited number of genetic alterations needed to determine appropriateness of therapy for these cancers, most of the genes included in the F1CDx lack clinical utility.

Summary

The Proposed Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer provides broad coverage for select proprietary genetic tests with limited evidence of clinical utility and may also result in restricting access to the most cost-effective testing by promoting the selected proprietary tests. This establishes a dangerous precedent of creating coverage criteria that prioritize the manufacturer of a test or therapy instead of a careful and deliberate consideration of the test itself, along with the scientific evidence, balancing the benefits and harms to a clearly defined population of beneficiaries. The final National Coverage Determination should allow Medicare Advantage Plans such as UnitedHealthcare to continue making evidence based determinations so that beneficiaries have access to the appropriate care.

Thank you for the opportunity to provide comments on this Proposed Decision Memo. If you have any questions or would like to discuss this issue further, please contact me at (763) 283-2401.

Sincerely,

Jennifer Malin, M.D.
Senior Medical Director, Oncology and Genetics

Cc: Sam Ho, M.D.
UnitedHealthcare Chief Medical Officer

(1) Rucaparib Approved for Ovarian Cancer. Cancer Discov. 2017 Feb;7(2):120-121
(2) PARP inhibitors: Clinical utility and possibilities of overcoming resistance. Benjamin G. Bitler, Zachary L. Watson, Lindsay J. Wheeler, and Kian Behbakht. Gynecologic Oncology 2017; 147:695-704.
(3) MolDX: BRCA1 and BRCA2 Genetic Testing (L36082)
(4) Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. Antonio C. Wolff, M. Elizabeth H. Hammond, David G. Hicks, Mitch Dowsett, Lisa M. McShane, Kimberly H. Allison, Donald C. Allred, John M.S. Bartlett, Michael Bilous, Patrick Fitzgibbons, Wedad Hanna, Robert B. Jenkins, Pamela B. Mangu, Soonmyung Paik, Edith A. Perez, Michael F. Press, Patricia A. Spears, Gail H. Vance, Giuseppe Viale, and Daniel F. Hayes. Journal of Clinical Oncology 2013; 31:3997-4013.

Very Brief Blog: CMS To Consider Revisions to CLIA Regulations

On Friday January 12, CMS released a "Request for Information," notifying the public that it is considering a major update to CLIA regulations.   CLIA is a public health law that is implemented via lengthy regulations written by CMS.   In general, the regulations are quite dry: specifying requirements such as years of experience for staff and management, and specifying that controls, records, and accuracy of tests must be appropriate.   Much implementing detail is left to customs, guidelines, and standards of practice even after both the statute and regulations are considered. 

The CMS request for information is here, and is open until for sixty dates, until mid March.   See coverage at Modern Healthcare here, JDSupra(by ReedSmith) here, and 360DX here.   

A limited number of topics are being posted.   One is the equivalency or not of various associates' and bachelors' degrees, such as those in Nursing versus those in biology or lab science.   Another is penalties for abuses of proficiency testing.   Another is the methodology for crossmatch histocompatibility in transplant science. 

The home page for CLIA statute and regulations is here.   The earliest version of CLIA covered labs billing CMS and labs with interstate businesses (e.g. federal authorities under the Interstate Commerce Clause).  This was CLIA 1967, and followed "scandals" in areas like PAP testing.   CLIA 88 broadened authorities to all labs.   CLIA statute  is only a few pages long, defining laboratory testing and laboratories, giving CMS the authority to establish standards, inspect, regulate, etc.    CLIA regulations are very dry and procedural, walking through staffing, proficiency testing, and quality systems for non waived testing in about a dozen historical areas (microbiology, virology, chemistry, toxicology, cytology, etc.)   For example, at 493.1254, for maintenance checks of equipment developed in-house, "the laboratory must establish a maintenance protocol that ensures equipment, instrument, and test system performance that is necessary for accurate and reliable test results and reporting." 

Very Brief Blog: JPM and Biotech Leadership: The "Men Named MIchael" Quote

Seen at Boston Globe STAT:   "There are more men named Michael presenting at JP Morgan, that there are female CEOs."

https://www.statnews.com/2018/01/07/jpm-gender-diversity/

Very Brief Blog: The Halteres Consultancy Deck on "Why Dx Companies Fail"

Email this morning brought a citation to a 2015, 20 page deck by Halteres Associates on "Why Diagnostic Companies Fail?"  It's online at their website, here.

One of the take home lessons for me is page 7, where they rate a couple dozen companies against about a dozen performance metrics or key competencies.   The point is, if you miss almost any of the dozen metrics, you won't succeed.   It's like an electric circuit in series where every step has to be active. 

click to enlarge

Is the FDA FMI CDx Approval "Really" A Very Elaborate Analytical Validity Assessment?

In mid-December, the FDA released its main safety & effectiveness review document on the Foundation Medicine CDX 384-gene test (here).   As commentators have noted, CMS gives very high priority to FMI's PMA approval - "This tells us that it really has clinical utility."   Far lower status is given to tests with published data, NYSDOH approval, or the new 510(k) somatic gene panel approval.   As proposed, those tests get coverage only if $10,000 or more, such as RECIST studies, are deployed for each test paid by CMS. 

The 58-page FDA review is worth reading in detail, which probably few people have invested several hours in doing.   The review is mostly an exhaustive analytical validity assessment.   FMI CDx is verified to have 700-800X coverage for targeted regions; which was information already used in publications, its website, I assume its CAP validations, NYS approval, and MolDX approval.   FMI CDx has a net sequencing error rate of .003 percent (below the FDA's stated threshold of .01 percent or 1 base in 10,000).   But again, this is sequencing accuracy level that is known to be met for clinical genetic tests.    And it's analytical data.

The heart of the review assesses the performance of six very specific outputs of the FMI CDx test against six prior art PMA comparators, as diverse as the Ventana ERBB2/Her2 FISH test and the Roche EGFR T790M point mutation test. 

Two of the comparisons involved clinical blocks, but these were much noisier (with missing blocks, differing results, etc) than the four comparisons that involved running the predicate test on merely available tumor blocks. 

The two comparisons that are cross-modality (between ALK FISH and ERBB2 FISH and sequencing)  are much noisier than accuracy between an FMI point mutation and a PMA kit point mutation.  I summarize the results in the first figure below by gene reviewed, and give representative examples of "very tight" and "noisier" concordance in the second figure below.

My Brief Informal Summary of Results from FDA S&E Document

Examples of Tight (Left) and Noisier (Right) Concordance

I provide a more detailed, but still informal, summary of the S&E key findings in a sidebar blog, here.  In general, whether clinical trial or "available" blocks were used, about 100-150 positive blocks and a similar number of negative blocks were required.    However, even when clinical trial archives were used, the assessing for a passing grade is based on the analytical validity concordance of FMI and prior art results.

The FDA approval is, no question, an exhaustive view that gives a great deal of confidence in the test.  But few commenters actually read it.   The key pivotal tables are mostly based on "available" blocks.  All the data on concordance to prior art is "analytical" and "statistical."   The bar is within 10% noninferior to a comparator. 

It's a big, big achievement.   But I'm unconvinced it's light-years and night and day different than an academic NGS test which has, say, 99%  concordance to Sanger in hundreds of specimens and 95-99% concordance to an IVD in dozens of specimens.   Or for that matter, the 99.9% accurate MSK IMPACT test with its new 510(k) approval.

As I noted earlier (here), the FDA review defines away any issues about accuracy outside the claims.   The FDA tested accuracy in some cases to match a single point mutation; in writing up its pivotal risk-benefit decision, FDA states that: the test matches those several cases of prior PMA art and therefore the whole test (which also reports sequencing on some 377 other genes and things like Total Mutational Burden) introduces no new medical issues or risks beyond the prior art such as a point mutation T790M test or a point mutation L858R test.   

CMS Transmittal Resolves Madcap Federal Register Errors on Date of Service 2018: Ignore CMS Errors

In final rulemaking for CY2018, CMS revised its date of service rules for hospital outpatient biopsies, in a manner that requires the performing laboratory to bill for molecular tests.   This may be the hospital's own molecular lab but often may be an outside independent lab. 

However, CMS did some really weird twists, turns, and misstatements in finalizing the rule.  For example, they stated point blank it referred to "molecular pathology tests" and equally point blank it did not apply to "genomic sequencing procedures or PLA tests."    This is like saying a rule applies to household pets, including cats and dogs, except not dogs. 

In producing its operating instructions to providers and MACs, on December 22, 2017, CMS simply ignored the weirder misstatements in its own rule and provides simple instructions.   If it's a molecular pathology test, then it has "OPPS Status Indicator A" in a policy spreadsheet called Appendix B which is mainly issued annually but gets small updates quarterly.   See the CMS webpage, "Addendum B Updates," here.

If the CPT code is paired with Status Indicator A, then that CPT code is billed by the providing lab (be it hospital or independent.) 

See Medline Matters MM10417, here.   See also Instructions to Contractors, CR10417 (Transmittal CP3941), here.

They left one quirk, which is that the new DOS for Status "A" tests is "the date they are performed."  Is that the date they are signed out?   Probably?  We think?   CMS declined to specify for us, and even declined to say it was in fact the date of sign out or the date of final report, it's "the date they are performed" whatever that is (rule, pp 52538-9). 

See new 2018 regulation at 42 CFR 414.510 here.  For final rulemaking, see 82 FR 52533ff, here.

AMA Reaches 34 PLA Codes; Next Deadline Friday January 12

The AMA released an update of its active Proprietary Laboratory Analyses (PLA) codes on December 20, 2017, bringing the total published codes to 34, with two already-deleted codes (0004U, 0015U).   The PLA homepages are here; see the full table online here.   11 of the 34 codes were applied for by Mayo (0004U, 0010U, 0012U-14U, 0027U-32U).

PLA deadlines for CY2018 are on  January 12, April 11, July 12, and October 9.  The PLA application portal is here (I believe you must be signed in to the AMA website itself to access that.)

Key parts of the application are currently:

1. PMA, 510K, or Non FDA?
2. Link for how providers can order the test.
3. Terminology for the code.
1. Disease; chemistry (RNA, DNA), number of markers, methods (e.g. qPCR), number of functional domains if indicated; specimen type; algorithmic result (e.g. if prognostic0, report type (e.g. risk score).
4. Are any CPT codes currently used to report the test?
5. Are existing codes "integral to" the test (e.g. do not report duplicatively).
6. For what diagnoses does the test have clinical utility?
7. Provide a clinical vignette (short template provided; a sentence or two).
8. Provide a brief description of the service (short template provided; a couple sentences).
9. Attach documentation via file upload.
1. CLSI lab protocol.
2. FDA insert if relevant.
3. Copies of positive and negative reports

(Note that I have summarized the questions; see the full AMA website for the full questions).   Authors can prepare their application via online forms and store and revise until it's ready to submit.

The Strangest Ever: FMI CDx at MAC, FDA, and CMS Without Review of Panel Utility

On November 30, 2017, CMS released a draft blanket coverage determination for the Foundation Medicine F1CDx test for all cancer patients with tumors for which it is on-label, expanding on a rolling basis with label expansion. 

There are some unusual follow-on aspects of the decision.  For example, if the F1CDx covers one PMA gene in a certain cancer, and even if that gene is already known positive or negative based on the prior IVD that F1CDx is itself based on, F1CDx is still covered.   (Let's say for a million patients at $3000, or $3B).   This seems to imply F1CDx has some value beyond its on-label genes.   However, neither FDA nor CMS ever broached that conclusion.   Also puzzlingly, there will be some cancers where the F1CDx points only to off-label drugs for 95% of patients (especially if common mutations like EGFR have already been filtered out by prior testing).  Despite requiring CED for all other testing approaches, the NCD doesn't require (or misses the opportunity to require) any form of records, tracking or CED for this huge cancer population, as long as their pathway to off-label drugs was via "failing to have an on-label drug on the F1CDx test."

Everybody "Defined-Away" the Clinical Utility of Large Panels

There has been huge debate in the US and world oncology literature on the value of large gene panel tests, and Vinay Prasad of OHSU has publicly protested that the F1CDx coverage decision is premature (here).

In succession, MolDX, FDA, and CMS defined away this question in their reviews. 

MolDx Decision 
The MOLDX LCD for FMI F1 (L36198) doesn't state that 300- or 400 gene panel tests are medically necessary.   Rather, the LCD discusses that for one or two identified genes, like EGFR, if you do an FDA IVD point mutation test, it will pick up certain common mutations, and if you sequence that known PMA biomarker gene, you will pick up several extra actionable mutations (e.g. 17% more).  What is done with, or why, regarding the other 300 or 400 genes that the test reports simply isn't brought into the question.


FDA Decision
Go to the FDA F1CDx webpage (P170019, here) and look up the safety and effectiveness review document.   In the pivotal risk-benefit determination, page 55, section C, FDA states that "F1CDx assay has demonstrated non inferiority to companion diagnostics [reviewed in Section X] and therefore, does not introduce additional risks above [the] other approved devices."   FDA has been able to define away any actions with any of the additional several hundred genes since they are not on-label claims, so, as judges say, FDA need not reach or speculate towards any conclusion on the large panel, in order to approve F1CDx. 

FDA also comments that the F1CDx was not referred to an advisory panel because all questions or issues in the F1 PMA duplicate information already reviewed (e.g. the prior review of the single EGFR gene for erlotinib.)

CMS Decision
Finally, while CMS's NCD is 40 to 60 pages long, depending how you print it, the pivotal decision for coverage of F1CDx at the end is extremely brief, and merely states because F1CDx includes PMA on label genes, F1CDx is "reasonable and necessary."   Any emergent or associated collateral risks or benefits, or whether the test "meets but does not exceed the patient's need" (a traditional CMS metric), simply don't enter into the final decisional sentences.

Is This Good Or Bad?

I mostly see the NCD as having a lot of weird consequences that people will look back in in 3, 6 or 12 months and say, "Wow."   For example, leukemia seems to be under the NCD (it's oncology), but there are no PMA gene panel tests, and no 510(k) tests, so coverage of genetic testing is available only in NCI trials, and for the most common genes and drugs, those trials won't even exist any more.  (Alternately, leukemia patients must be in C.E.D., for which CMS mandates RECIST imaging testing for participation, which leukemia patients can't do, so they can't get the C.E.D. arm.)   Another "wow" is that very soon, massive numbers of Medicare patients without any on-label genetic results will get lots and lots and lots of off-label genetic results, for which no plan is made.

My main point is that one would think that along the pathway to this decision, CMS or FDA would have "had to have" looked at clinical utility (or net risk benefit) of large gene panel tests, and they didn't, at least not in the pivotal decisional parts of their documents. 

____

I posted a very informal, freehand summary of the FDA concordance studies for F1 CDx, here.

Very Brief Blog: Tracking JP MORGAN HEALTHCARE CONFERENCE

The JP Morgan Healthcare conference 2018 (36th Annual) is meeting this week in San Francisco, with satellite events Sunday, January 7, and the main invitation-only conference running all week at the St Francis Hotel Convention Center at Union Square. 

Even the agenda of the conference is not readily available.  JP Morgan publishes a very short website for JPMHC18 here, and JP Morgan Global publishes a somewhat longer website here.  (IT has a rather curt FAQ section, such as: Q: Where can I get an agenda?   A: Agendas are available only to attendees.") 

JPMorgan seems to endorse #JPMHC18 as the official Twitter hashtag, although there is also a lot of usage of #JPM18 too. 

See a webfeed on Twitter for #JPMHC18 by clicking here.    (Hardcore Twitter fans that also want to see #JPM18 can find it here.) 

There is a long list of activities (including listing for many marked as "private"like the Harvard Business School JPM recewiption) at: JPM.HEALTH, here. 

Update.

From the public INVIDIOR.COM investor web site, here, there is a public link to the JP Morgan webpage for agenda and links to most all presentations on the conference as archived streaming audio or video, here.  Email registration required for entry.

Very brief blog: MobiHealthNews Summarizes 224 DHealth Investments ($5B)

In a year-end article for 2017, MobiHealthNews summarizes 224 investments in digital health, ranked in tiers ($100M or more; $50M-100M, etc).   Each investment is briefly summarized and carries a link to more information.  Online here.

Investments tallied $1.3B in Q1, $2.6B in Q2, and about $550M in Q3 and Q4 each.

click to enlarge