by Lindsay Stephens, Senior Operations Coordinator, Personalized Medicine Coalition

Lindsay Stephens

In his opening remarks during the 2019 Biotechnology Innovation Organization (BIO) International Convention’s “Personalized Medicine & Diagnostics Track,” which was co-hosted by BIO and the Personalized Medicine Coalition (PMC) from June 3 – 6, PMC Senior Vice President of Science Policy Dr. Daryl Pritchard contended that “the case for personalized medicine has been made.”

As evidence to support his claim, Dr. Pritchard noted that PMC classified 42 percent of the new drugs the U.S. Food and Drug Administration (FDA) approved in 2018 as personalized therapies.

The field’s champions, he suggested, are turning their attention to an even more important problem: how to integrate personalized medicine strategies into health care practice.

The track demonstrated that innovative business models and policy solutions, as well as the development of evidence showing the clinical utility and economic value of diagnostic testing and targeted therapies, will be instrumental to clinical adoption.

Three themes emerged.

1. Partnering and innovative collaborations across stakeholder groups are crucial for developing an ecosystem that brings diagnostic tests and personalized treatments to patients faster and at a reasonable cost.

Panelists across sessions agreed that tackling clinical adoption challenges will necessitate collaborating with other stakeholders. “Nobody can do this by themselves,” Art Swanson, Vice President, Genomics Product Management, Optum, argued during a session titled “Innovative Models for Real-World Evidence: Creating Value-Based Precision Health.”

Aurélie Deleforge, Associate Consultant, Bionest Partners, added during “Precision Medicine Beyond Oncology” that pharmaceutical companies and diagnostic companies, along with payers, providers, and patient groups, are necessary partners because access to diagnostic tests is a prerequisite to access to personalized treatments. She predicted that these types of partnerships will become more prominent as stakeholders continue conversations about how they can mutually benefit each other and how their partnerships can drive health care decisions that result in better patient outcomes.

Arguably the most needed partnership right now is with payers. During a session on the “Clinical and Economic Value of Personalized Cancer Treatment,” Ammar Qadan, Vice President, Global Head of Market Access, Illumina, acknowledged that without payer recognition of the value of next-generation sequencing (NGS), the technology will go nowhere. Qadan and Dr. Michael Sherman, Chief Medical Officer of Harvard Pilgrim Health Care, highlighted a partnership between Harvard Pilgrim and Illumina that is designed to facilitate improved access to genomic testing for previously non-covered individuals.

2. Health care decision-makers require evidence of the utility of personalized medicine. Large amounts of real-world and clinical data exist, but it’s still unclear how to unlock the power of this data to build the evidence that will result in more widespread patient access.

During “From Diagnostics to Treatment and Back Again in the Digital Era,” Kristen Pothier, Global Head of Life Sciences Strategy, Ernst & Young Parthenon, summed up issues that were raised throughout the track sessions by asking how we can “take the best data and put it to work.” With many datasets available, the opportunity is there, but as Elizabeth Donley, CEO, NeuroPointDX, mentioned in “Precision Medicine Beyond Oncology,” so much data makes it “difficult to draw meaningful conclusions” and “get your hands around it all.”

Another concern — How do we involve consumers in data collection and storage while convincing them that their data are in good hands? Art Swanson mentioned that some data are “ripe for misuse,” and as we begin looking for ways to convert this information into real-world evidence, it is important that the “consumer [has] confidence, trust and control over data.”

3. To remain innovative, policies will need to be flexible to keep up with new technologies and treatments.

With personalized medicine technology and treatments developing rapidly, it is important that regulatory and reimbursement policies keep up so as to ensure appropriate access and continued innovation. As Elizabeth Hillebrenner, Associate Director for Scientific and Regulatory Programs at FDA’s Center for Devices and Radiological Health, explained during “Precision Medicine and the FDA: Prospects for Regulation of Laboratory-Developed Tests (LDTs),” FDA is working with Congress to propose new regulatory oversight processes that proponents believe will “level the playing field” for LDTs and in vitro diagnostics (IVDs) to help assure safety and reliability while providing an environment that will allow for tests to rapidly come to market.

During “Coverage for Advanced Diagnostics and the Impact on Patient Access to Personalized Medicine,” panelists discussed how the Centers for Medicare and Medicaid Services (CMS) re-opened a National Coverage Decision (NCD) applicable to NGS-based tests amidst concerns over language that could be interpreted to mean non-coverage of germline testing. PMC Senior Vice President of Public Policy Cynthia A. Bens remarked that CMS’ decision to reconsider the policy demonstrates the importance of policy and science working together. Bens hopes all government agencies will continue to demonstrate such flexibility as health care evolves toward personalized medicine.

The Way Forward

These conversations underline that the field is filled with promise and dedicated leaders. To accelerate progress, personalized medicine’s advocates are shifting attention to implementation challenges, building evidence of value, innovative business models, and flexible policy solutions that can align health care toward a future of better patient outcomes and a more efficient health system.

by Brad Power, Process Innovator and Cancer Treatment Re-engineer; diagnosed with lymphoma in July of 2018

Brad Power

Summary: The potential of next-generation sequencing to revolutionize cancer treatment by enabling personalized therapies is still more promise than reality. Despite the best intentions of leaders at academic cancer centers, the translation of sequencing technology’s potential into medical practice remains in its infancy, and adoption is excruciatingly slow for people like me with a cancer diagnosis. What is the hold up? Where can the disruptive breakthrough occur? The greatest hope for accelerating personalization in cancer treatment is for people with a cancer diagnosis to educate themselves about their treatment options and be an advocate for their treatment.

Introduction

In November, I attended the Annual Personalized Medicine Conference at Harvard Medical School, which is organized by the Personalized Medicine Coalition and attended by “the world’s leading researchers, investors, industry executives, policy experts, payers, clinicians, and patient advocates.” I was attending in my role as a journalist, someone who has written over 75 articles for The Harvard Business Review. My specialty is process re-engineering (how technology can enable new ways of work). Following my diagnosis of lymphoma in July, I have focused my research on cancer treatment. For me, improving cancer treatment is personal. I was in the last cycle of my chemotherapy treatment during the time I attended the conference.

One conference attendee went to the microphone during a panel discussion to say that at his institution, they are sequencing all of their patients (with the implication that more institutions should make such a commitment). It happened to be the same institution at which I was getting treatment. I quickly went to the microphone and said, “I am a patient there, and I’m currently getting chemotherapy (as I motioned to my bald head) for lymphoma. I have a deep respect for your institution, and while I’m sure that every patient there is supposed to get sequenced in theory, I must tell you that it is not happening in practice. I had to ask my oncologist three times to get my tumor biopsy sequenced, and on the fourth time I brought it up, he handed me a brochure and said it would be done in the next batch.” I’ve followed up several times to find out when I will get my results, and I’ve been told that it may be three months. About eight or 10 people approached me in the remainder of the conference to tell me that they really appreciated my comments showing the reality vs. the hype of actual patient experiences. Several of these people shared similar stories about a loved one who they were helping navigate through a cancer diagnosis. They, too, faced a lack of interest and dismissal of their attempts to use sequencing information to tailor treatment.

The Slow Adoption of Sequencing to Tailor Treatments

The promise of next-generation sequencing to tailor treatments to everyone with a cancer diagnosis faces the reality of slow adoption as a standard approach. The current system isn’t delivering the potential of personalized cancer treatment — patients aren’t being directed to the best options for them. Adoption is being slowed by (1) the conservatism of health care providers; (2) patients who aren’t aware of next-generation sequencing technology and personalized therapies; and (3) payers who aren’t reimbursing patients and providers for next-generation sequencing.

The Need for Leadership from Health Care Providers, Patients, and Payers

Making sequencing of adequate breadth and depth and the associated personalization of cancer treatment the “standard of care” will require leadership from health care providers, patients, and payers.

• Health care providers must make sequencing and personalization the standard of care, even though it may disrupt their “tried-and-true” processes, overwhelm them with data, face resistance from payers, raise some costs (while saving others), and challenge their traditional patient relationships. They must trust in a process to find the optimal therapy in a more consultative, peer-to-peer relationship.
• Patients and their support teams must educate themselves about treatment options and be advocates for their treatment, including asking for sequencing of adequate depth and breadth (including clinical level whole-genome sequencing of their healthy and tumor tissue, sequencing of their transcriptome RNA, and sequencing of their microbiome).
• Payers must reimburse these sequencing costs, including repetitions, ideally for everyone with a cancer diagnosis but at minimum for everyone with a late-stage cancer diagnosis. While the federal government — The Centers for Medicare and Medicaid Services (CMS) — is paying for sequencing, many commercial insurers haven’t yet followed suit.

Accelerating Personalization in Cancer Treatment

What can we do to accelerate the use of sequencing and personalization in cancer treatment?

Getting providers or payers to change their processes will continue to be a slow road to widespread adoption. I’m hoping that consumer empowerment can be the disruptive force that our health care system needs. At the Personalized Medicine Conference, panelist Michael Pellini, M.D., Chairman of Foundation Medicine and Managing Partner of venture capital fund Section 32, argued that, “​Patients are going to force us to figure this out.”

Many patients aren’t equipped to lead their cancer treatment, but people with a late-stage cancer diagnosis get up the learning curve fast since they are motivated to become engaged leaders of their care. As another panelist, Susan McClure, Founder of Genome magazine, asserted at the Personalized Medicine Conference, “Never underestimate a person’s ability to grasp complex information when their life depends on it.” She led a discussion with Bryce Olson, who is a good example. He said, “I’m a country boy from a small town in Montana. But I came up the learning curve very fast when I was diagnosed with metastatic prostate cancer.” For informed and engaged patients with a cancer diagnosis like Bryce Olson or myself there is no structured process or legal, insurance, or regulatory framework — as there is for oncologists — for us to make critical decisions, even though we are the ones directly affected. So, we must carve our own path.

Here’s what I’m doing, and what I recommend to anyone (a friend or family member) with a late-stage cancer diagnosis:

First, I’m going to capture my health data. The data will include raw sequencing data of sufficient depth and quality for my whole healthy cell genome, my whole cancer cell genome, my microbiome, and my cancer “transcriptome” (RNA). After several requests, my provider is sequencing my tumor sample that came from my biopsy. I’ll get the other data from additional service providers. And I’ve signed up for a clinical trial with a new blood biopsy company to get personalized biomarkers to track my cancer’s progress.

Second, I will release my data to several service providers that specialize in treatment recommendations to get a variety of personalized treatment options.

Who knows what I will find? Hopefully there will be a therapy that is precise, with few toxic side effects, and that supports my native immune system (e.g., tumor-infiltrating leukocytes). Right now, it seems like a personalized vaccine may be the best option. Stay tuned!

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

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.

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

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.

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

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.