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.