CAP, AMP Release New Clinical Gene Panel Validation Guidelines; Also noted: New proposals for evidence levels in genome libraries

On March 23, 2017, CAP and AMP released a new, 25-page guideline to validation of next generation sequence panels.   The article, Jennings et al, has its journal home page here, PDF link here, and in the cloud, here.

For coverage at Genomeweb, here.

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Update December 2017:  Genomeweb article based on Ghosh et al., Genome Biology, on performance of algorithms relative to AMP guidance.  
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This is the fourth recent guidance for fundamental standards in next generation sequencing and data archiving.

See also Ritter et al. for guidelines on new standards for annotating and curating somatic tumor variants in libraries like ClinVar (here) and Li et al. on new standards for clinical reporting that is specific to somatic variants (here).  Li et al. note that most prior work has focused on clinical reporting of germline variants.   Finally, in May 2017, Strande et al. published guidelines for the firmness of validity or the evidence level of reported associations; this has relevance for both germline and tumor information archives; see Strande et al. here.

Though not related to somatic mutations, see also Richard et al., 2015, ACMG/AMP standards for reporting [germline] sequence variants (here), and a May 2017 paper by Invitae staff on SHERLOC, an interpretation system for germline variants (Nykamp et al., here) which is asserted to refine some ambiguities in AMP guidelines.

Abstract of Jennings et al. clipped after the break.

Guidelines for Validation of Next-Generation Sequencing–Based Oncology Panels

A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists

Rapid Transcript HERE: CMS Diabetes Prevention Program Webinar (3/22/2017)

The home page for the Medicare Diabetes Prevention Program is here:

https://innovation.cms.gov/initiatives/medicare-diabetes-prevention-program/

CMS is in the process of policy and rulemaking to implement the program nationally in January 2018.   CMS held a webinar on the collaborative roles of CDC and CMS on March 22, 2017.   The webpage for this webinar is here:  https://innovation.cms.gov/resources/dpp-cdc-expansion.html

CMS is expected to post slides and an official transcript in the near future.  

In addition, CMS stated it was preparing an updated and expanded FAQ.   

In the meantime, this blog provides a rapid unofficial transcript of the March 22, 2017 webinar.

The rapid unofficial online transcript is in the cloud: here.

12, 8, 4, and 2: Revisiting BRCA Policy and Pricing

Today, March 16, the USPSTF task force released for public comment the framework for an updated assessment of BRCA risk assessment, testing, and counseling (here).  It's the 12th anniversary of the USPSTF first guidance statement, in 2005 (here). Meanwhile, BRCA policy mavens will recall that this year is the 8th anniversary of AMA/ACLU filing a court case challenging the validity of some claims of the BRCA patent (here).   And in a couple months we hit the 4th anniversary of the Supreme Court decision that followed (here, here).   Meanwhile, we just crossed the 2nd anniversary of the resolution of several ongoing aspects of the patent litigation (e.g. Cook-Deegan, here), and College of American Pathologists/CAP TODAY just published an article on how the SCOTUS case has impacted diagnostic pathology (here).

I recently reviewed the cumbersome CPT/CMS approach to coding and pricing BRCA testing (here).  The flurry of anniversaries and events led me to look up some of the original SCOTUS documents this evening.

Comment Through April 12 on USPSTF BRCA Research Plan (Risk Assessment, Counseling, Testing)

USPTF has a December 2013 current recommendation on BRCA-related cancers, covering risk assessment, counseling, and genetic testing.  Based on an earlier ruling of HHS, and now pretty clearly incorporated in the 2013 guideline,  HHS and USPSTF view genetic testing as part of the preventive guideline, which makes it copay-free under most insurance plans.

On March 16, USPSTF released a new plan to update its guidance.   The public can comment through April 12.   Arising issues include restriction of preventive screening to high-risk families versus population-wide screening.  As far as the draft plan goes, it continues to focus only on increased-risk families.

Comment here:
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-research-plan/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing1

In general, under ACA, most health plans are required to provide USPSTF A and B preventive benefits and without copay.  CMS can adopt (import) USPSTF A and B benefits into Medicare via the NCD process. To date, it has done that for quite a few preventive services, but not for BRCA preventive screening.  CMS does cover BRCA testing in women already diagnosed with breast cancer, where results can guide ongoing management decisions.

Do CMS Panel Pricing Policies Apply to Gene Panels?

In a previous blog, here, we discussed that CPT and CMS had generated a complex web of coding and pricing options to pay for BRCA testing, one of Medicare's top three genetic tests (by dollar volume).

Beginning in January 2017, CMS has a fee schedule priced gene panel test that includes BRCA-1 and BRCA-2 testing, but has a much lower total price.

Does this conflict with CMS's decades-old policy to never pay more for components of a panel that it would pay for the entire panel?

My answer is "probably so," but CMS has not faced the issue yet.  Research on the topic indicates that CMS's lab panel pricing policies are memorialized in varies program documents, but not fixed in law or regulation.

Because PAMA is a law, and raises some thorny issues for CMS regarding the interaction of PAMA law and CMS internal lab test policies, CMS should probably put its panel policies into formal, enforceable regulations.   When doing so, CMS should assess the fit of its panel policies to gene test panels.  It looks like this could quickly become a multi-hundred-million dollar issue for CMS.  Details after the break.

It's a Chaotic Mess: CMS Pricing of BRCA Testing

When assessed by CY 2015 payments in the fee-for-service Medicare Part B system, BRCA testing is the third-largest expenditure, at about $52M per year.  However, the situation for CY 2017 is going to be much more complex, as there are now three different coding approaches, all recognized by CMS, resulting in drastically different Medicare expenditures for BRCA testing.

Depending on which set of rules and codes are applied,  payments could be anyone from $931 all-in for a BRCA panel including full dup-del analysis, all the way up to $2,780 for individual genetic components of BRCA 1 and BRCA 2 testing.

Assuming similar test utilization in 2017 as in 2015, Medicare's total payments could be as low as $17.9M this year or as high as $51M.   This article discusses how Medicare backed itself into this mess.   A shorter second blog (here) asks whether CMS panel pricing rules can or should apply to BRCA testing.

Brief Blog: A Large Scale Private Payer CED Project: Genetically Informed Mammography

On March 14, 2017, Health Affairs runs a detailed blog by Rosenberg-Wohl et al. (here) about a "Coverage with Evidence Development" study supported through the collaboration of diverse stackholders, including multiple University of California campuses, Blue Shield of California, and other collaborators.

The study, WISDOM (see website here), looks to assess the impact of randomized use of a genetic breast cancer risk profile on mammography outcomes.   The idea is simple: if breast cancer is risk based, then one-size-fits-all screening based on projected risk/benefit is like one-size-fits-all clothing or shoes.   The authors describe the study as benefiting from the use of $225 breast cancer genetic risk testing.  There will be 100,000 total participants, with half of them receiving the test.

The authors explain that imposing numbers of hurdles that had to be maneuvered to launch the program.   The 5-year study is new and will be enrolling into 2017.

Brief Blog: Seema Verma Confirmed As Head of CMS

On March 13, the Senate voted to confirm Seema Verma as head of CMS.

Coverage at Medscape here, at Becker's Hospital Review here, at New York Times, here.

Verma built an Indiana-based healthcare consulting helping multiple states redesign their Medicaid programs.   For a full transcript of her Senate interview testimony, here.   For an earlier blog on her background, here.  For her August 2016 blog on Indiana's Medicaid reform, in Health Affairs, here.

CMTP/Green Park Issues White Paper on Genomics, Liquid Biopsy

On February 7, we covered a Real World Evidence information center set up by the Green Park Collaborative and the Center for Medical Technology Policy (CMTP).

On March 13, the GPC and CMTP issued a 19 page white paper summarizing their November 2016 two-day stakeholder workshop on the adoption of genomic technologies.  One focus of the workshop was Liquid Biopsy.   See the web page here, the white paper here.  Table of contents is clipped below the break.

Brief Blog: Could GINA's Genetic Privacy Protections Change?

This week, a flurry of articles on an obscure legislation proposal that could chip away at GINA's protections regarding genetic privacy in the workplace and with health insurance.

See coverage at PLOS.ORG here, at Genomweb here, at STAT here, at Dark Daily, here.

STAT writes,

A little-noticed bill moving through Congress would allow companies to require employees to undergo genetic testing or risk paying a penalty of thousands of dollars, and would let employers see that genetic and other health information.

Giving employers such power is now prohibited by legislation including the 2008 genetic privacy and nondiscrimination law known as GINA. The new bill gets around that landmark law by stating explicitly that GINA and other protections do not apply when genetic tests are part of a “workplace wellness” program.

The PLOS article quotes from a letter from the President of the American Society for Human Genetics to the Hill.

Nancy J. Cox, PhD, ASHG president, in a letter to the U.S. House Committee on Education and the Workforce, provides a frightening overview:

“If enacted, this legislation would undermine fundamentally the privacy provisions of the Genetic Information Nondiscrimination Act (GINA) and the Americans with Disabilities Act (ADA). It would allow employers to ask employees invasive questions about their and their families’ health, as well as genetic tests they and their families have undergone. It would further allow employers to impose stiff financial penalties on employees who choose to keep such information private, thus empowering employers to coerce their employees into providing their health and genetic information.”

Brief Blog: Scott Gottlieb Announced as FDA Nominee

Early on March 10, Bloomberg ran an article citing Scott Gottlieb as the leading candidate for head of FDA.   See the open access article here.   Around noon, WSJ stated that Gottlieb is the expected FDA nominee, here.   And the NYT also, here.  WaPo. here.  At around 5 eastern, Reuters posted that the White House has confirmed that Gottlieb "is" the nominee.  Further analysis at Endpoints, here, and Vox, here.  A later update at Endpoints (on March 29, here) covers some of Gottlieb's pharma connections that have to be unwound.

Wall Street Journal hails the nomination as potentially "one of Trump's most important appointments" (here).  See a detailed analysis of Gottlieb's views on drug pricing is providing by the DrugChannels blog (here), with a callout to Gottlieb's insightful 10/2016 Hill testimony (here).

This blog highlighted Gottlieb's promising candidacy on December 13, January 21, and February 6.

For MedCityNews, "Statistical Guide to Scott Gottlieb," March 15, 2017, here.

A interesting pre-election (9/2016) interview with Gottlieb is online, here.

A colorful article about the new administration, Peter Thiel, and FDA, at Vox, here.  A negative article on Gottlieb at LA Times, here.

Brief Blog: AMA Releases Results of February 2017 CPT Meeting

The AMA CPT Editorial Panel meets three times per year, most recently in early February in New Orleans.  A number of molecular codes were on the agenda, for single genes, for MAAA tests, and for genomic sequencing procedure panels.   

• The results of the AMA panel were posted today by the AMA, on this webpage, here.  
• See the document, 2017 February: CPT® Editorial Summary of Panel Actions.

Brief Blog: Comparing the FDA BRCA Approvals for Myriad & Foundation Medicine

Myriad Genetics received FA approval for its BRCA1/BRCA2 companion diagnostic (BRACAnalysis CDx (TM)), on December 19, 2014.

Foundation Medicine received FDA approval its its NGS-based BRCA1/BRCA2 companion diagnostic (FoundationFocus CDx[BRCA] Assay (TM)), on December 19, 2016.

The tests fall under different FDA PMA classifications (Cancer Germline Detection System, for Myriad; and Next Generation Sequencing Oncology Panel, Somatic or Germline Variant Detection System, for Foundation.)

Each has detailed Safety & Effectiveness documentation and Labeling documentation online at FDA (these are 34 and 16 pages, respectively, for Myriad, and 31 and 18 pages, for Foundation).

• The FDA homepage for FoundationFocus (P160018) is online at FDA here.
• 
  
• The FDA homepage for BRACAnalysis (P140020) is online at FDA here.  
• This approval also has 8 links to minor supplements (such as changes in software or polymerase reagents.)

The FMI approval order is linked directly to clinical use with Rubrca, and the Myriad approval is linked directly to clinical use with Lynparza.

• A collated ZIP file with the five core FDA documents for each product (and the 8 minor supplements for Myriad) is in the cloud, here.

Update: An April 27, 2017 article in Genomeweb discusses that FMI's test is less-validated for longer insertions and deletions or large rearrangements, and that Clovis Oncology is getting approval for on-label use of the Myriad test with its PARP inhibitor Rubraca (here).

Brief Blog: PMC Releases 2017 Policy Report, Holds Hill Briefing

Last month, on February 7, the Personalized Medicine Coalition released a report on barriers and disincentives to personalized medicine (here).  The report was based on multi-stakeholder workgroups and interviews, and appeared as a 5-page summary plus a 12-page academic paper in the journal Personalized Medicine.   The paper by Pritchard et al. is entitled, "Strategies for Integrating Personalized Medicine into Healthcare Practice."

Now, on March 7, PMC released its annual full-length report on the personalized medicine movement in healthcare (64 page PDF, here.)

Also today, PMC will hold a 90 minute Hill briefing on issues in personalized medicine (here).   The Hill briefing, co-hosted by Sen. Markey (D-MA), will include four panelists:

• Stephen D. Eck MD PhD, Astellas Pharma
• Emily Kramer-Golinkoff, Co-Founder, Emily's Entourage
• Miachel Sherman MD, Harvard Pilgrim Health Care
• Jay Wohlgemuth MD, Quest Diagnostics

[Update, Coverage of the Hill hearing by "Science & Enterprise," here.]

The 64-page annual report discusses opportunities and challenges.  Opportunities include medical benefits and the fast past of science.  Challenges include regulatory policy, coverage/payment policy, clinical adoption rates, and health information technologies.

Coverage at Genomeweb, here.  At STAT, here.

Brief Blog: Grail Raises $900M For Advanced Liquid Biopsy Sequencing

As it promised to do at the beginning of the year, GRAIL has raised almost a billion dollars to push the horizons of next-generation sequencing from blood samples.   The press release is clipped after the break.

Grail recently announced it was hiring Elizabeth Mansfield PhD, one of the senior leadership team for precision medicine at the FDA over the past decade (here).