Personalized Medicine Education and Advocacy

Thought leadership in personalized medicine


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Collaborations, Data, and Policies: Insights From the Personalized Medicine & Diagnostics Track at the 2018 BIO International Convention

by David L. Davenport, Manager of Public Policy, Secretary to the Board, Personalized Medicine Coalition

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David L. Davenport

Citing decreasing genetic sequencing costs, the development of new targeted therapies, and the ability to bring together genetic and clinical information with new technologies, Harvard Medical School’s Paul C. Cabot Professor of Genetics Raju Kucherlapati, Ph.D., who also serves as Scientific Director, Partners HealthCare Personalized Medicine, opened the Personalized Medicine & Diagnostics Track at the 2018 BIO International Convention by asserting that “the field of personalized medicine [is positioned to] have an even greater impact on patients and the health of the human population [in the future].”

The Personalized Medicine & Diagnostics Track, held in Boston from June 5 – 7, was co-organized by the Personalized Medicine Coalition (PMC) and sponsored by Thermo Fisher Scientific. The track brought together thought leaders to discuss the latest innovations and policies in personalized medicine. From those conversations several themes emerged:

1. Innovative, multi-stakeholder collaborations promise to bring personalized medicines to patients faster.

With thoughtful approaches to multi-stakeholder collaborations, patients stand to benefit. In Partnerships Power Precision Health: Collaborative Models for Advancing Personalized Medicine, moderated by the University of North Carolina School of Medicine’s Terry Magnuson, Ph.D., and featuring representatives from the BlueCross BlueShield Association, the National Institutes of Health (NIH)’s All of Us Research Program, and Color Genomics, panelists concluded that collaboration between and within multiple sectors of the health care system will be crucial to advance personalized medicine. Several collaborative models were discussed during the conversation, including: providers partnering with other providers to share data; multiple community stakeholder groups partnering with the NIH’s All of Us Research Program to collect a million genomes; and joint research endeavors involving industry, payers, providers, and patient groups.

2. Advances in data science will help integrate genomic, clinical, and economic information that is necessary to deliver new personalized medicines to patients.

During Personalized Medicine in Action: Examples of Clinical Implementation, moderated by Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, PMC, and featuring representatives from Agendia, the Swedish Cancer Institute, and Stanford Health Care, panelists discussed constraints to delivering holistic, value-based personalized medicine and concluded that reimbursement paradigms must evolve to facilitate this approach. Building and combining genomic, clinical, and economic data sets would help provide evidence not just for clinical utility but for cost effectiveness, the latter of which is crucial to coverage and reimbursement. First and foremost, however, data must be “accurate” and “complete” to be useful.

Echoing Dr. Kucherlapati’s opening comments, panelists during the session Is Biotechnology Drowning in Health-Related Data? agreed that analyzing many kinds of data will be the next step in advancing personalized medicine. They pointed to artificial intelligence and machine learning as new tools that could help identify promising personalized medicine strategies. The panel, moderated by Damian Garde, National Biotech Reporter, STAT News, and featuring representatives from Novartis Institutes for Biomedical Research, GNS Healthcare, and Sema4, discussed the need to develop new personalized medicines for unmet medical needs and acknowledged the benefit of existing diagnostic strategies that help determine who will not benefit from a treatment.

Moderated by Alan Sachs, M.D., Ph.D., Chief Scientific Officer, Thermo Fisher Scientific, and featuring representatives from Metabolon, King Faisal Specialist Hospital and Research Center in Saudi Arabia, and the University of Pittsburgh, a discussion of large-scale public and private research programs aimed at screening healthy populations for actionable genetic risk factors reiterated that while some data already show the value of personalized medicine, the generation of additional evidence, along with provider education, is needed to facilitate clinical implementation. Panelists coalesced on implementation strategies that keep a broad vision for personalized medicine in mind but focus first on screening for genetic risk factors where evidence of value is strongest.

In a session titled Bridging the Gap: Adding Dynamics to the Diagnostic/Therapeutic Interface, moderated by Alice Jacobs, M.D., Advisor, Third Rock Ventures; Entrepreneur-in-Residence, Caltech, and featuring representatives from Cedars-Sinai Medical Center, Ceres Nanosciences, and Genome Profiling LLC, panelists discussed the potential for ongoing monitoring of biomarkers and patient data through wearables and direct-to-consumer genomics to develop dynamic wellness and treatment plans, and suggested that this may be the future of personalized medicine.

The track’s emphasis on data echoed thought leaders’ conclusions about the field during other Convention sessions outside of the track. In a fireside chat between U.S. Food and Drug Administration (FDA) Commissioner Scott Gottlieb, M.D., and BIO President and CEO James Greenwood, for example, Commissioner Gottlieb commented on the growing importance of managing data. In particular, he pointed to the increasing potential of real-world evidence (RWE) in product approvals or authorizations as the tools for establishing statistical significance of large RWE data-sets are improved and as investments are made in large data-set models.

3. Reforms to regulatory and coverage decision-making processes are needed to keep pace with the rapid development of new personalized medicine products, services, and technologies.

During The Next Generation of Personalized Medicine: A New Regulatory Paradigm for Next-Generation Sequencing Panels, moderated by Cynthia A. Bens, Senior Vice President, Public Policy, PMC, representatives from the American Cancer Society Cancer Action Network (ACS-CAN), FDA’s Center for Devices and Radiological Health, the U.S. Centers for Medicare & Medicaid Services (CMS)’ Coverage and Analysis Group, and Thermo Fisher Scientific discussed the parallel review process for medical devices and diagnostics at CMS and FDA, and how the agencies are working together to improve transparency and to help companies that approach FDA for clearance avoid common pitfalls in bringing to market new technologies facilitating personalized medicine. According to Tamara Syrek Jensen, J.D., Acting Director, Coverage and Analysis Group, CMS, “parallel review is important for how it is changing the communications between CMS and developers going into regulatory review [from retrospective] to prospective communication.” ACS-CAN Policy Principal Mark Fleury, Ph.D., said parallel review is the first step in “harmonizing” an oversight system that “doesn’t quash innovation.”

In Precision Diagnostics: Trends in Evidence Development for Medicare and Commercial Payers, moderated by Brian P. Carey, J.D, Partner, Foley Hoag LLP, with representatives from ADVI, CareFirst BlueCross BlueShield, and Foundation Medicine, panelists addressed the emerging need for more evidence of personalized medicine’s value. Parallel review, coverage with evidence development, and joint studies between commercial payers and diagnostic companies will be key in developing that evidence. Referencing Foundation Medicine’s recent experience with parallel review, the company’s Senior Director for Payer Policy and Health Outcomes Ingrid Marino encouraged other developers considering parallel review to prepare for contrasting points of view and bring solutions to their discussions with the government agencies.

During a panel on business models providing clinical and consumer genomic services, moderated by Vivek Mittal, Ph.D., Partner, Health Advances LLC, with representatives from Helix, MindStrong Health, and Canaan Partners, speakers agreed that companies must secure and protect the privacy of patient data, as well as help establish the clinical utility of reported variants in order to drive progress in consumer-directed personalized medicine. Panelists commended FDA for being progressive and trying to keep pace with innovation, particularly as it relates to digital health.

A New Age of Personalized Medicine

As PMC President Edward Abrahams, Ph.D., contended in his opening remarks, “one-size-fits-all medicine has taken us about as far as it can.” Recent innovations in multi-stakeholder collaborations, data science, and regulation discussed at this year’s BIO Convention will continue to help usher in a new age of personalized medicine that brings greater health system efficiency and, most importantly, better outcomes for patients.

PMC would like to thank all of the speakers for their contributions to the track, many of whom are PMC members (in bold above). The complete track agenda can be downloaded here.


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Recent US Policy Developments Improve Outlook for Personalized Medicine

by Cynthia A. Bens, Senior Vice President, Public Policy, PMC

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Cynthia A. Bens

The U.S. Congress, the Food and Drug Administration (FDA), and the Centers for Medicare and Medicaid Services (CMS) recently moved to support funding for ongoing research in the field, clarify the regulatory pathway for digital health products, and collect feedback on a proposal to cover chimeric antigen receptor (CAR) T-cell therapies nationwide, respectively.

As explained below, each of these developments stands to improve the outlook for personalized medicine.

U.S. Congress’ FY 2019 Appropriations Bills Would Enhance Infrastructure for Innovation in Personalized Medicine Through NIH Budget Boost

On June 28, 2018, the U.S. Senate Appropriations Committee approved its FY 2019 spending bill. The bill would provide $39.1 billion for the National Institutes of Health (NIH), an increase of $2 billion above FY 2018. One week prior, on June 15, the U.S. House of Representatives Labor-Health and Human Services-Education Appropriations Subcommittee approved its own appropriations bill, which would provide $38.3 billion for NIH, an increase of $1.25 billion above FY 2018.

Both congressional proposals include significantly higher amounts than the $34.2 billion budget request for NIH put forward by the Trump Administration.

In addition to the increases every NIH Institute and Center would receive to advance fundamental scientific knowledge that will speed the development of personalized medicine therapies, diagnostics, and preventive interventions, the House and Senate bills make specific investments in the All of Us Program and implementation of the 21st Century Cures Act, both of which were supported in testimony PMC provided to Senate and House subcommittees earlier this year.

FDA Launch of Software Pre-Certification Model for Digital Health Tools May Help Facilitate Personalized Care Regimens

FDA released an updated working model for the Software Pre-Certification (Pre-Cert) Pilot Program on June 19, 2018. Dr. Adam Berger from FDA’s Personalized Medicine Staff within the Center for Devices and Radiological Health briefed PMC’s Public Policy Committee later that day on the changes to the model.

Software is increasingly used in health care to treat and diagnose disease, aid in clinical decision-making, and manage patient care. FDA has acknowledged that its traditional approach for the regulation of hardware-based medical devices is not well suited for software device functions that feature faster design and development timelines and require different types of validation. The Pre-Cert Program creates a voluntary pathway for digital health developers to demonstrate excellence based on software development, validation and maintenance practices and to provide faster patient access to these technologies. Version 0.2 of the working model clarifies the scope of the Pre-Cert Program, provides additional details on the program’s excellence appraisal framework, and further highlights elements of the program’s pathway determinations, streamlined pre-market review processes, and real-world performance.

FDA has an open docket for the pilot program. The agency is calling for public comment and is particularly interested in feedback from the patient and health care provider communities. Dr. Berger’s presentation to the PMC Policy Committee included asks for additional information that would be most helpful to FDA as it advances this novel approach to digital health regulation. FDA will continue developing and informally testing various components of this program through December of 2018.

CMS’ Updates to Current Coverage Policies and Consideration of National Coverage for CAR T-cell Therapies Signals Agency’s Willingness to Explore Innovative Approaches to Reimbursement for Personalized Medicines

CMS presented two opportunities this month for input on payment policy issues for CAR T-cell therapies. CMS’ FY 2019 Medicare Hospital Inpatient Prospective Payment System (IPPS) and Long Term Acute Care Hospital (LTCH) Prospective Payment System Proposed Rule included important considerations for reimbursing hospitals that administer these treatments. Updates for coverage of CAR T-cell therapies included in the proposed rule specifically related to the review of New Technology Add On Payments (NTAPs) for these treatments and the potential creation of a new Medicare Severity Diagnosis Related Group (MS-DRG) for procedures using CAR T-cell therapies.

CMS also opened a National Coverage Analysis (NCA) for CAR T-cell therapies for cancer at the request of United Health Group. The NCA is the first step in the path to developing a National Coverage Decision that would impose a uniform national coverage policy. If the process moves forward, CMS anticipates that it will release a proposed coverage decision by February 16, 2019, and a final decision by May 17, 2019.

PMC submitted comments on the IPPS Proposed Rule and comments on the NCA, both highlighting the impact CAR T-cell therapies have had in the treatment of some cancers with poor prognoses and the importance of thoughtful coverage policies to match these innovations. PMC also signed a group letter urging CMS to approach coverage of CAR T-cell therapy with vision and flexibility that can transfer to other transformative cell and gene therapies in the future.


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New FDA Guidances on NGS-Based Testing May Bolster Personalized Medicine

Guest Blog
by Neil A. Belson, J.D., of Counsel, Potomac Law Group

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Neil A. Belson

The U.S. Food and Drug Administration (FDA)’s recently issued final guidance documents related to next-generation sequencing (NGS) may encourage the development of personalized medicine by streamlining the regulatory pathway for NGS-based tests and expanding the role of real-world evidence for regulatory purposes.

Most observers believe NGS technologies, which can examine millions of DNA variants at a time related to numerous conditions and detect previously unidentified variants, will accelerate personalized medicine by allowing clinicians to match patients to suitable treatments with increased efficiency and precision. FDA recognizes that regulatory approaches developed for conventional diagnostics, which measure only a limited number of analytes, are not appropriate for reviewing NGS technologies. FDA is therefore seeking a more “flexible and adaptive” approach that accommodates the rapidly evolving nature of NGS technologies, while providing reasonable assurance of safety and effectiveness.

Streamlining Regulation of NGS-Based Tests

The first guidance, entitled Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics, seeks to encourage the expanded use of genetic variant databases in pre-market testing of NGS-based (and other genomic-based) diagnostics. FDA considers a “genetic variant database” to be a “publicly accessible database of human genetic variants that aggregates and curates reports of human genotype-phenotype relationships to a disease or condition” and includes publicly available documentation of evidence supporting such linkages.

FDA believes that evidence from publicly available databases could support clinical validity of genetic variant assertions if the database meets the following criteria:

  1. Operates in a manner which provides adequate information and assurances to assess the quality of its source data, evidence review and assertions regarding variants;
  2. Transparency, including its data sources and how it evaluates variant evidence
  3. Complies with data privacy and security requirements; and
  4. Contains genetic variant information generated using validated methods.

FDA believes that data and genetic variant assertions from databases that satisfy the agency’s guidance would generally constitute scientifically valid evidence to support clinical validity for FDA approvals. At present, potentially useful genetic variant data is often not stored in a publicly accessible manner. With its guidance, FDA hopes to encourage increased deposition of genetic data into public databases. This, in turn, would provide additional data for developers of NGS-based diagnostic tests to utilize in developing and gaining regulatory approvals for their products. Ultimately, the agency seeks a “well-defined process … to promote more rapid translation of genetic information into useful clinical evidence.”

FDA’s second guidance, Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases, seeks to streamline FDA’s pre-market review of NGS-based tests for germline diseases “through a process that leverages appropriate standards, quality systems controls and community assessment of clinical validity.” FDA considers “germline diseases” to encompass genetic diseases arising from inherited or de novo germline variants.

With this guidance, FDA seeks to promote the development of consensus standards that can provide guidance to developers of NGS-based tests intended to diagnose suspected germline diseases. Test developers could certify conformity to such standards in their pre-market submissions, if such standards develop.

There are currently no legally marketed devices with a general intended use of aiding in diagnosis of suspected germline diseases. This absence of predicate devices would normally mean that NGS-based tests aimed at diagnosing suspected germline diseases would automatically have to meet pre-market approval requirements for Class III devices. FDA believes, however, that its recommendations, or standards that address them, could provide the reasonable assurance of safety and effectiveness that would allow such NGS-based tests (aimed at diagnosing suspected germline diseases) to be eligible for classification as Class II devices through the de novo process. The de novo process authorizes FDA to classify new devices which present low-to-moderate risks as Class I or Class II even where no predicate device exists. By making the de novo process available, FDA is streamlining regulatory approval and commercialization of NGS-based tests which meet the agency’s standards of safety and effectiveness. Furthermore, once FDA utilizes the de novo process to classify an initial NGS-based test aimed at diagnosing suspected germline disease as a Class II device, such a device could then become a predicate for future 510(k) submissions of NGS-based tests with similar intended uses.

Expanding the Role of Real-World Evidence for Regulatory Purposes

The guidances also create new incentives for the expanded use of real-world evidence in obtaining medical device approvals, which may lead to more efficient approval of personalized medicine tests. FDA issued a final guidance in 2017 stating that it would consider real-world evidence when making regulatory decisions relating to medical devices in both pre-market and post-market contexts.

FDA defines real-world evidence as “clinical evidence regarding the usage and potential benefits of a medical product derived from analysis” of real-world data, such as electronic health records, insurance claims, and data from disease registries (italics added). As the italicized words suggest, real-world evidence signifies something more than anecdotal data to the agency. Rather, like traditional randomized clinical trials, real-world evidence requires careful study designs. The main difference is that real-world evidence focuses on actual patient and health care delivery data in generating clinical evidence to support regulatory approvals. Real-world evidence can be faster, less costly and a better indication of a product’s performance under real-life conditions than randomized clinical trials.

The new guidances create incentives for NGS-based test developers to generate clinically valid real-world evidence in genetic variant databases or in conformance with consensus standards, which can guide the development of new products.


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CMS Acts to Enhance Patient Access to Innovative Personalized Medicine Diagnostics and Support Laboratories Furnishing Tests

by Cynthia A. Bens, Senior Vice President, Public Policy, PMC

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Cynthia A. Bens

On November 30, 2017, the U.S. Food and Drug Administration (FDA) and the Centers for Medicare & Medicaid Services (CMS) announced the approval and preliminary coverage of Foundation Medicine’s FoundationOne CDx. As part of its announcement, CMS released a draft proposed decision memo for the FoundationOne CDx and similar next-generation sequencing (NGS) tests for use in the diagnosis of advanced cancer.

The draft coverage proposal was scrutinized by numerous stakeholders during an extended public comment period that resulted in CMS receiving nearly 400 pages of feedback. Many of these interest groups, including the Personalized Medicine Coalition (PMC), requested clarification from CMS on different aspects of the proposed decision memo. PMC’s comments highlighted the need to extend coverage for NGS testing to earlier stages of cancer and make allowances for retesting during the course of a patient’s life. In addition, PMC called on CMS to expand full coverage beyond FDA-approved NGS tests and consult with stakeholders to define a rigorous but less burdensome pathway to coverage with evidence development (CED) for NGS tests that do not meet CMS’ proposed criteria for full coverage.

Fortunately, CMS addressed many of the community’s concerns in the resulting national coverage determination (NCD) that was released on March 16, 2018. The following is a summary of what we view as major changes from the draft NCD.

  • Coverage granted for FDA-approved and FDA-cleared NGS-based in vitro companion diagnostic tests. FDA-cleared NGS tests for advanced cancer would have fallen under a CED program in the original program. The final NCD expands the scope of coverage to NGS tests that are cleared as in vitro companion diagnostics through FDA pathways, such as 510(K), in addition to tests that are FDA-approved as in vitro companion diagnostics. Because the final determination does not specify sample type, FDA-cleared or -approved NGS liquid biopsy tests that are in vitro companion diagnostics will be covered as they become available, provided that all of the required patient and test indications are met.
  • NGS tests indicated for use outside of advanced cancer not at risk of immediate non-coverage as previously thought. Under the proposed NCD, Medicare coverage was uncertain for tests that did not meet the narrow categories of FDA-approved or -cleared tests, and even these tests would have been subject to CED. Coverage decisions for both NGS-based in vitro diagnostics and laboratory-developed tests (LDTs) in areas such as hereditary testing, screening, and other non-cancer conditions will remain with local Medicare Administrative Contractors (MACs). Under the final NCD, coverage for NGS-based tests in patients with cancer without FDA-approved or -cleared companion diagnostic indications may be handled through the local coverage determination process, subject to the restrictions set forth in the final NCD.
  • CED dropped. CED was an important but problematic feature of CMS’ draft. In the proposed coverage decision, CED programs would have been required for all other NGS-based cancer tests that were not FDA-approved NGS-based in vitro companion diagnostic tests for advanced cancer. Further, CED for LDTs was limited only to those participating in an NIH-NCI National Clinical Trial Network. CED was not included in the final CMS determination, and instead, non-FDA-approved NGS tests will need to be evaluated by the MACs to determine coverage status.
  • Additional cancer indications included for coverage and one-time testing limitation removed. The proposed decision memo only provides pathways to coverage for NGS testing for Medicare beneficiaries with recurrent, metastatic, and stage IV cancer. In addition to coverage for these patients, the final NCD also covers NGS testing for patients with either relapsed, refractory, or stage III cancer when the NGS test meets the diagnostic assay requirements for coverage. The final NCD precludes coverage for patients with stage II or earlier cancer. In the final NCD, CMS also expanded the frequency of testing allowed, from using the same diagnostic laboratory test once to using the same diagnostic laboratory test once for each new primary diagnosis of cancer. Repeat testing for the purposes of treatment monitoring is not included in the final NCD.

The NCD is a net positive for NGS testing, as it now guarantees Medicare coverage at a national level for FDA-approved or -cleared NGS-based companion in vitro diagnostic tests for advanced cancer. PMC applauds CMS for recognizing that NGS testing is a breakthrough technology that is critical to advancing personalized medicine. We will continue to work with policymakers to advance diagnostics regulations and legislation that we believe will further improve patient care.

The featured speaker at PMC’s Policy Committee Meeting on April 24 will address the scope of CMS’ final coverage determination and its implementation. Ongoing federal activities related to diagnostics will also be the focus of a BIO 2018 session moderated by PMC. The panel, “Regulatory Oversight of Personalized Medicine: Today and Tomorrow,” will take place in Boston, Massachusetts, on June 6, 2018.


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A Precision Paradigm for Value Assessment: How Frameworks Can Account for Personalized Medicine to Inform Payers, Providers, Innovators and Patients

by Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, PMC

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Daryl Pritchard, Ph.D.

The Personalized Medicine Coalition’s most recent white paper, Personalized Medicine and Value Assessment Frameworks: Context, Considerations, and Next Steps, contends that to improve clinical outcomes and facilitate more cost-effective health care, value assessment frameworks (VAFs) must incorporate the principles of personalized medicine. The report examines the characteristics of U.S.-centered VAFs and identifies how each integrates or, as in most cases, fails to integrate personalized medicine.

Health insurance companies have been conducting health technology assessments for years. As part of these processes they may or may not have considered value assessment reports from independent organizations.  Recent indications from both public and private payers, however, have suggested a greater interest in the use of VAFs for coverage and payment decision-making.  Health care delivery organizations and physician groups have also taken a greater interest in using frameworks to help quantify the value of various treatments and interventions. This has increased the likelihood that VAFs will impact access to care.

Several frameworks are already in use by different end-users. ICER’s framework, the Drug Abacus developed by Memorial Sloan Kettering, and frameworks developed by the American Society for Clinical Oncology (ASCO) and the National Comprehensive Cancer Network focus primarily on value to payers and providers at a health system level, while newer VAFs, including FasterCures’ Patient Perspective Value Framework and the Innovation and Value Initiative, were developed with patients in mind.

To facilitate access to treatment options of highest value at both the individual patient and health care system levels, however, VAFs must consider all of these perspectives. PMC’s report argues that to assess the value of new treatments in a way that meets the needs of patients and innovators as well as payers and providers, VAFs must integrate personalized medicine.

By identifying which medical treatments and procedures will work best for each patient, personalized medicine improves efficiency at both the individual and health system levels. But as they are currently designed, most VAFs involve static comparisons based on population health, and therefore neglect to adequately consider patient-level efficiencies learned through ongoing clinical practice. PMC’s report highlights five personalized medicine considerations — namely diagnostic testing, heterogeneity of treatment effects, treatment efficiency, individual values and circumstances, and emerging or evolving value elements, which, if accounted for in VAF methodologies, would help ensure that value is considered at both the health system and patient levels.

In a panel discussion to launch the report, Kristen Migliaccio-Walle, who was the report’s lead author from Xcenda, Dan Leonard, President of the National Pharmaceutical Council, Alan Balch, CEO of the National Patient Advocate Foundation, and Dana Wollins, Director of Health Policy at ASCO, agreed that alignment of VAFs with the goals and benefits of personalized medicine is critical to ensure informed decision making.

Other VAF developers concur. ICER’s President, Steven Pearson, for example, recently noted in an email to PMC that he is “convinced that we share the same vision: a health care system in which insurers and drug makers can continue the progress toward even more [personalized] tests and treatments while making them more affordable and more accessible for the patients who need them.”

The report concludes with five strategic recommendations for developers of VAFs:

  1. Consider diagnostic testing as an explicit and integral part of the value assessment of treatment options where efficacy and/or safety information can be obtained;
  2. Include a formal mechanism for consideration of heterogeneity of treatment response appropriately balanced with population-based considerations;
  3. Develop methods for the consideration of emerging or evolving elements of value over time to fully account for emergent benefits at the health system and individual patient levels;
  4. Ensure appropriate awareness and education about the use of value assessment frameworks in personalized medicine to reduce the risk of inappropriate restriction of reimbursement and/or access to individualized care; and
  5. Consider the perspectives of all stakeholders, especially patients.

As VAFs have gained prominence and become a focus of discussion by decision-makers within the health care community, it has become more important than ever to realize that patient-level efficiencies convey real value at the health system level. Currently, the value assessment viewpoints of payers and providers are often not aligned with those of patients. Following the recommendations in PMC’s report will help bridge that gap.
Personalized Medicine and Value Assessment Frameworks: Context, Considerations, and Next Steps


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Precision Pathways: The Significance of Comprehensive Immune Profiling and the Tumor Microenvironment for Personalizing Immunotherapy

Guest Blog
by Mark Gardner, CEO, OmniSeq

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Mark Gardner

Immunotherapies, specifically checkpoint inhibitors (CPIs), are an exciting new class of drugs for advanced-stage cancer patients. Unlike patients treated with chemotherapy and targeted therapies, a significant percentage of patients receiving CPIs experience durable responses, with progression-free survival often measured in years.1

Absent a more clearly defined target population, however, the incremental costs of CPIs may strain resources available for treating an aging population. Given the potential benefits of these drugs, CPIs cost over $100,000 per year, and these costs are rapidly adding up. The U.S. will likely spend more than $6 billion on CPIs in 2017, and an analysis by L.E.K. Consulting suggests that these costs may grow to exceed $16 billion by 2021. Unfortunately, CPIs do not work for approximately 60 – 80 percent of patients, depending on histology.2

In order to assist physicians with their decisions to treat patients with CPIs, there are several biomarkers in use today. Physicians may measure PD-L1 expression by immunohistochemistry (IHC) and potentially by fluorescent in situ hybridization (FISH) to find PD-L1 copy number gains. Recently, FDA also approved the use of pembrolizumab for patients with high microsatellite instability (MSI-H) regardless of histology, and it is likely that other measures of DNA instability and mismatch repair damage (such as high mutational burden) will gain traction as companion or complementary diagnostics.

Unfortunately, while biomarkers such as MSI-high3-5 and PD-L1 copy number gain6-8 are highly correlated with response, they are prevalent for only a small percentage of patients. In contrast, PD-L1 expression of greater than 1 percent of tumor cells is found in a high proportion of all patients, but meeting this cutoff is not highly correlated with response.

In July of 2017, scientists at Merck published a paper highlighting the promise of gene expression signatures related to the IFN pathway with promising results and an “area under the curve” (AUC) better than both mutational burden and PD-L1 IHC.9 Merck scientists have generally presented a case to use all three categories of biomarkers (PD-L1 expression, DNA damage and gene expression signatures) to best inform treatment decisions.

Given the imperfect state of biomarkers today, the best method to assist oncologists with their decisions to treat with CPIs is through a three-pronged comprehensive immune profile that assesses PD-L1 IHC/FISH, MSI/mutational burden and RNA-seq.

Clinicians should not settle, however, for identifying only the 20 – 40 percent of patients who will respond to CPIs alone. OmniSeq believes gene expression biomarkers can be used to fully assess the cancer adaptive immune response cycle, and patient response rates can be increased by identifying candidates for appropriate combination therapies. This is especially needed in the subset of over 1,000 total immunotherapy trials10 that are testing combinations of novel agents with existing drugs, such as anti-PD-1 drugs like pembrolizumab and nivolumab.

Indeed, as we interviewed physicians running clinical trials across the country, we did not observe an obvious logic as to how patients are being assigned to experimental combination immunotherapies. Given the complexity of the cancer immune cycle, patients should be guided toward trials primarily based on the biology at work in each patient’s tumor microenvironment. OmniSeq hypothesizes specifically that over-expression of targeted genes relative to a reference population is the most rational method for guiding patients onto combination therapy clinical trials.

Guided by these insights, OmniSeq is excited to participate in a new era of precision immunotherapy, and is actively seeking collaborators to generate data to test whether over-expression of a target in a tumor’s microenvironment represents the most logical method for assigning patients to combination immune therapy clinical trials. We believe this approach may shape the future of precision immunotherapy.

References

1. Harris, S. J., Brown, J., Lopez, J. & Yap, T. A. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol. Med. 13, 171–93 (2016).
2. Grady, D. A Sickened Body as Cancer Weapon: Harnessing the Power of the Immune System. The New York Times CLXV, (2016).
3. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).
4. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
5. Cortes-Ciriano, I., Lee, S., Park, W.-Y., Kim, T.-M. & Park, P. J. A molecular portrait of microsatellite instability across multiple cancers. Nat. Commun. 8, 15180 (2017).
6. Inoue, Y., Osman, M., Suda, T. & Sugimura, H. PD-L1 copy number gains: a predictive biomarker for PD-1/PD-L1 blockade therapy? Transl. Cancer Res. 5, S199–S202 (2016).
7. Guo, L. et al. PD-L1 expression and CD274 gene alteration in triple-negative breast cancer: implication for prognostic biomarker. Springerplus 5, 805 (2016).
8. Inoue, Y. et al. Clinical significance of PD‑L1 and PD‑L2 copy number gains in non‑small‑cell lung cancer. Oncotarget 7, (2016).
9. Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
10. Kolata, G. A Cancer Conundrum: Too Many Drug Trials, Too Few Patients. The New York Times 1 (2017).


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FDA’s Approval of First NGS-Based IVD for NSCLC Raises New Question: Where Does This Leave LDTs?

Guest Blog
by Joydeep Goswami, President, Clinical Next-Generation Sequencing and Oncology, Thermo Fisher Scientific

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Joydeep Goswami

FDA’s recent decision to grant premarket approval of the first next-generation sequencing (NGS)-based companion diagnostic for non-small cell lung cancer (NSCLC) marks an important milestone in precision medicine. Patients and their oncologists now have access to an in vitro diagnostic (IVD) that can help expedite the selection of targeted therapies in days, a key advancement considering traditional testing methods can take several weeks for an answer — time that many NSCLC patients simply don’t have.

While this is great news for one segment of the more than 1.6 million estimated new cases of cancer that will be diagnosed in 2017,1 what options are available for the rest of the patients battling this disease and for which there is no approved IVD? There has been a lot of debate about laboratory-developed tests (LDTs) versus IVD testing, particularly as to whether to stop the use of LDTs or to regulate them. In the fast-moving field of oncology, where the power of understanding the disease and the selection of precision treatments are being improved rapidly by technologies like NGS, clinicians and oncologists want to be able to incorporate these latest advancements into their clinical diagnostic practices.

While IVD tests undoubtedly are the gold standard in terms of demonstrating clinical validity and utility, developing an IVD can take several years. Patients and doctors dealing with fast moving and fatal diseases like cancer do not have the luxury of waiting until an IVD test is developed and approved in order to have access to a viable test. On the other hand, LDTs allow clinicians and pathologists to validate a diagnostic much faster under the appropriate controls and quality guidelines from the Clinical Laboratory Improvement Amendments (CLIA) and the College of American Pathologists (CAP).

Although LDTs do not meet the same gold standard achieved by FDA-approved IVD tests, they do provide patients and clinicians with a much-needed option and quicker access to the latest advances in science while an equivalent IVD test is being developed. LDTs thus speed the path and utilization of the latest biological discoveries and technological innovations for the benefit of patients. Banning them or over-regulating them could have a negative impact both on innovation and, more importantly, patient access.

But there may be a solution that would enable patients to reap the benefits provided by both testing approaches. In one scenario, FDA could mandate labs to switch from an LDT to an equivalent IVD once one is approved. Alternatively, considering the much more rigorous validation process that an IVD product has to undergo, the Centers for Medicare & Medicaid Services and FDA could work together to encourage their use by setting reimbursement levels for IVDs higher than those associated with LDTs. Such measures could more effectively balance patient safety concerns with the right to benefit from cutting-edge science immediately.

1. American Cancer Society. Cancer Facts & Figures. 2017. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Accessed July 11, 2017.