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Perspective: FDA/CMS Parallel Review Advances Coverage for Cancer Comprehensive Genomic Profiling

Lakshman Ramamurhty, PhD; Kristi Maxwell, MS, CGC; Bethany Sawchyn, PharmD; and Rachel Anhorn, PharmD
Authors from Foundation Medicine explain the regulatory path that led to approval of FoundationOne CDx.
Foundation Medicine's FoundationOne CDx was the second product to pursue FDA/CMS dual review, paving the way for comprehensive genomic profiling in advanced cancer patients.


Keeping up with the ongoing changes in oncology is becoming a difficult task for clinicians and payers. New relevant biomarkers and biomarker-driven treatments are introduced each year, and many more are in late-stage development. For example, 8 new biomarker-driven oncology treatments were approved in 2017 alone.Although many patients have benefited from this revolution in precision medicine by using comprehensive genomic profiling (CGP) of their tumors to help direct therapy, many others have missed this opportunity by receiving conventional testing or, worse, by failing to receive any molecular testing.

CGP refers to next-generation sequencing (NGS)–based testing of tumors that has been optimized to identify all types of cancer-relevant molecular alterations and complex genomic signatures in known cancer-related genes in a single test, using complex (often proprietary) bioinformatics. There has been substantial debate of the value of CGP in both the clinical oncology and managed care communities. Regardless, the demand for the technology exists among patients, providers, and biopharmaceutical companies alike.2

A key rationale for using CGP is the well-documented problem of low molecular testing rates and slow adoption rates for new biomarkers.3,4 Patients who receive incomplete or partial testing per guidelines may miss the opportunity to receive potentially life-extending therapies that, for some patients, have been shown to improve quality of life compared with cytotoxic chemotherapy. Alternatively, even if single-assay tests are performed, there is a high likelihood of having insufficient tissue or there being a need for repeated invasive biopsies.5 One study looking at diagnosis patterns in non–small cell lung cancer found that only 8% of patients received testing for all guideline-recommended biomarkers prior to therapy.4 Not receiving targeted therapy resulted in poorer outcomes. This is a significant area of opportunity for quality improvement in patients with advanced cancers. Unfortunately, the few established quality measures related to biomarker testing seem to be written in the reverse order, measuring if a certain test was used for patients who had received a certain drug.6 The more relevant measure might be to assess if a patient with cancer about to receive anti-oncologic therapy had received complete testing.

A CGP approach with FoundationOne CDx offers a potential solution for slow testing adoption rates and tissue exhaustion, and a 1-stop diagnostic to best leverage the rapidly changing treatment landscape. By using a platform that can accommodate additional biomarkers and companion diagnostics, FoundationOne CDx is well suited to keep pace with precision oncology. Testing patients with a CGP approach improves quality of care and offers the opportunity for patients to receive an evidence-based therapy or enroll into a clinical trial, which can be life extending but is often biomarker driven. FoundationOne CDx provides a comprehensive profile of 324 genes and is suitable for use in all solid tumors.7 It encom- passes guideline-recommended genes for testing in solid tumors and has FDA approval as a companion diagnostic for 17 targeted therapies in 5 solid tumor types. In addition, FoundationOne CDx assesses complex genomic signatures to help inform immunotherapy decisions. A comprehensive genomic profile is essential for quantifying these genomic signatures.8,9 FoundationOne CDx is an efficient way of navigating all of these established and emerging biomarkers, potentially limiting the amount of tissue and time needed to assess for multiple clinically relevant alterations compared with sequential single-gene testing.

Foundation Medicine, Inc, was founded on the premise that no mechanism existed whereby clinicians, in the day-to-day practice of clinical oncology, could systematically obtain tumor information and efficiently interpret the specific molecular alterations associated with each patient’s disease.10 This mission was a driving force in its decision to participate in the parallel review process after being approached by the FDA and CMS.

FDA's Risk-Based Regulation of Diagnostics

Laboratory developed tests (LDTs) traditionally have not been required to receive approval by the FDA prior to being used. Additionally, the FDA process for medical devices (including LDTs) is somewhat less well defined and slightly more complex compared with the well-established regulatory path for small molecules and biologic therapies. The 1976 Medical Device Amendment provided a comprehensive regulatory framework for medical devices and established a risk-based regulatory classification system, as described in Figure 1.11 Diagnostics are medical devices and are classified based on the risk posed to the patient using the device. The lowest risk devices are deemed Class I and are mostly exempt from any requirements prior to marketing within the United States. Examples of Class I devices include arm slings, latex examina- tion gloves, and most hearing aids.

Premarket notification or 510(k)

Most medical devices and diagnostics fall in the Class II category, and manufacturers of such devices are required to notify the FDA prior to marketing those devices via a 510(k) submission (premarket notification [PMN]).12 The 510(k) application allows the manufacturer to demonstrate that its device is “substantially equivalent” in terms of its intended use, safety, and effectiveness to an already legally marketed “predicate” medical device in the United States.

Premarket approval

Class III is reserved for devices deemed high risk and subject to a premarket approval (PMA) procedure, like that for new drugs. By statute, the PMA process is reserved for medical devices that “support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury.”13 For this reason, almost all companion diagnostics that may direct treatment are also categorized as Class III and require FDA approval, based on clinical experience, before a product can be marketed.

Pre-market approval is the most involved and expensive process that a medical device manufacturer typically pursues. This type of approval is based on a determination by the FDA that the applicant has submitted sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). For example, Figure 2 shows the types of evidence submitted by Foundation Medicine for FoundationOne CDx.

Path to Market for LDTs

Rigorous FDA evaluations, as shown in Figure 2, are in stark contrast to the path to market for LDTs, although many valuable diagnostic assays have come to market via the LDT pathway. To date, the FDA has exercised a policy of enforce- ment discretion wherein LDTs have not been required to seek authorization in advance of being clinically offered as a test. LDTs are regulated by CMS’ Clinical Laboratory Improvement Amendments (CLIA), which is administered through various accreditation bodies, including the College of American Pathologists. Additionally, various state agencies, including the New York State Department of Health, have their own requirements for laboratories accepting patient samples originating in their states. Although CLIA establishes quality standards for laboratories to ensure the accuracy, reliability, and timeliness of patients’ test results, they do not cover how to perform a pre-market review of analytic validation or require clinical validity data. This contrasts with the FDA review process for Class III PMAs where both analytic and clinical validity are evaluated. Moreover, whereas medical devices and diagnostics must register with the FDA and are also required to submit adverse events, recalls, and user complaints, LDTs have no such requirement. This can lead to lack of awareness of potential safety signals with a given LDT.

Medicare Coverage Determination

To be covered by CMS, medical products must fall into one of the statutorily defined “benefit categories” and be “reasonable and necessary” for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. To meet the “reasonable and necessary” standard, a product or service must improve health outcomes, be safe and effective, and not be deemed experimental or investigational. The reasonable and necessary provisions are not defined explicitly in regulation and remain at the discretion of Medicare. For Medicare, FDA-approved devices with therapeutic indica- tions are presumed to meet this definition unless directly addressed through a Local Coverage Determination (LCD) or National Coverage Determination (NCD). Public payers are often subject to requirements to develop their coverage policies in an open and transparent manner. For example, LCDs and NCDs must undergo opportunities for public comment and are open to more political scrutiny given the nature of publicly funded programs.14

FDA/CMS Parallel Review Process

The FDA and CMS have clearly different objectives: safety and effectiveness of a device and whether the device is reasonable and necessary, respectively. Therefore, neither agency is usually influenced by the other’s findings or decisions, nor has there been coordination between the individual review processes. To support medical device innovation, the FDA and CMS entered a memorandum of understanding, which led to a pilot FDA/CMS parallel review process.15 The purpose of this program was mainly to minimize the time between regulatory authorization and reimbursement, an important barrier to patient access for the latest medical device innovation.16 Creating accelerated approval processes or breakthrough device designations would be insufficient if there was no comparable innovation in reimbursement policies. This is particularly unique to the medical device/diagnostic space in contrast to the oncology therapeutic space where FDA approval of a drug or biologic is sufficient for reimbursement and therefore access by the patient. Medical device/diagnostics must pursue reimbursement separately via an LCD or NCD following FDA review.17 The pilot project has since been made permanent.18

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