Laboratories - the forgotten stakeholder
"Pathologists and laboratories are often overlooked as key stakeholders by pharma and this factor can have a considerable impact on the uptake of targ...
On March 16, 2018, the Centers for Medicare and Medicaid Services (CMS) finalized a National Coverage Determination (NCD) that covers diagnostic laboratory tests using Next Generation Sequencing (NGS) for patients with advanced cancer.
In addition to covering the FDA-approved FoundationOne CDx™ (F1CDx), CMS is now covering other FDA-approved or cleared companion in vitro diagnostics when the test has an FDA-approved or cleared indication for use in that patient’s cancer and results are provided to the treating physician for management of the patient using a report template to specify treatment options. Tests that gain FDA approval or clearance as an in vitro companion diagnostic will automatically receive full reimbursement coverage under this final NCD provided other coverage criteria are also met1.
For Medicare patients, coverage determinations for other diagnostic laboratory tests using NGS with advanced cancer will continue to be made by local Medicare Administrative Contractors (MACs). The final decision also extends coverage to repeat testing when the patient has a new primary diagnosis of cancer.
The agency left two pathways open for reimbursement coverage of NGS – either the route through the FDA, which guarantees coverage upon approval or clearance, or the Local Coverage Determination (LCD) route through the MACs. The final rule permits that LCDs, while still restrictive, can continue to provide coverage for NGS tests run as laboratory developed tests (LDTs) for advanced disease.
II. NCD Coverage Criteria
For a Next Generation Sequencing test to be covered under the NCD, all the following criteria must be met:
MACs may determine coverage of other NGS as a diagnostic laboratory test for patients with cancer only when the test is performed in a CLIA-certified laboratory, ordered by a treating physician and the patient has:
III. FDA PMA Approved vs. 510(k) Cleared Pathway
Approved and cleared tests are treated at parity, but only for patients that have a “companion diagnostic” indication.2 The FDA to date has very rarely used the 510(k)-clearance pathway for companion diagnostics. In December 2017, the FDA for the first time granted “companion diagnostic” status to a 510(k) test, the MolecularMD BCR-ABL1 assay. The FDA’s “Substantial Equivalence Determination Decision Summary” includes 27 pages of analytical and clinical validation data that shows equivalence of this test to a predicate device, the Asuragen QuantideX qPCR BCR-ABL IS Kit, which had previously received premarket approval (PMA). Test developers will be looking closely at how the MolecularMD assay received a CDx indication on a 510(k) platform. We may begin to see more LDTs going the route of seeking 510(k) clearance. F1CDx could itself be used as a predicate device for future 510(k) submissions, but such an approach may be expensive and limited by availability of tissue.
IV. Tests Approved vs. Not Approved for Coverage Under the NCD
Some analysts have claimed that Foundation Medicine has verified with CMS that the final NCD grants F1CDx national coverage not only for the test’s FDA-approved CDx indications, but for tumor profiling across any solid tumor.3 This is reasoned to be so because the FDA approved not only the test’s CDx indications across five tumor types and 17 targeted therapies, but the entire 324-gene panel that also analyzes microsatellite instability and tumor mutational burden. Medicare experts disagreed with this position, because CMS makes a point to emphasize that for national coverage the test must have an “FDA approved or cleared indication for use in that patient’s cancer”; and Foundation’s MSI and tumor mutational burden signatures are not listed among companion diagnostic indications in FDA-approved labeling.
Three other marketed NGS cancer panels – Foundation Medicine’s FoundationFocus CDx BRCA, Illumina’s Praxis Extended RAS Panel, and Thermo Fisher Scientific’s Oncomine Dx Target Test – have FDA-approved CDx indications in advanced cancer patients. Therefore, these tests automatically receive full coverage under the final NCD, provided that the five other coverage criteria listed above are also met.
FDA’s authorization of Memorial Sloan Kettering Cancer Center’s 468-gene tumor profiling test (MSK-IMPACT) demonstrates that the agency distinguishes biomarkers on NGS panels based on risk and indication. The FDA did not indicate the MSK-IMPACT test as a companion test, required for safe and effective use of a drug, but as an NGS tumor profiling panel that can be used with other data to inform patient care. Because the FDA did not indicate the MSK-IMPACT test as a companion diagnostic test, MSK-IMPACT is not included as having automatic coverage under the final NCD.4
The FDA reviewed the MSK-IMPACT test through the de novo premarket review pathway, which is designed for low-to moderate-risk devices that are novel and for which there is no legally marketed, or predicate, device. The FDA gave the MSK-IMPACT test a Class II designation and cleared it as a 510(k) device, based upon coverage with evidence development (CED) which was previously required under the draft NCD. However, according to Bruce Quinn, an industry expert, the 510(k) clearance is no longer in place2, presumably because the final NCD ruling dropped the requirement of CED.
V. Third-Party Reviewer of In Vitro Diagnostics (IVDs)
The FDA also has accredited the New York State Department of Health (NYSDOH) as an FDA third-party reviewer of IVDs, including the MSK-IMPACT and similar tumor profiling tests. A Class II designation makes these tests eligible for the 510(k)-clearance process, either by applying to the FDA directly or through an accredited third-party reviewer like NYSDOH. Labs whose NGS-based tumor profiling tests have been approved by NYSDOH no longer need to submit a separate 510(k) application to the FDA but may request that their NY state application, along with the state’s review memorandum and recommendation, be forwarded to the FDA for possible 510(k) clearance. The FDA has also stated it might accredit other third parties to conduct such reviews and to make clearance recommendations to the agency. “The goal of allowing NGS-based tumor profiling tests to undergo review by accredited third parties is to reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products”, said FDA Commissioner Scott Gottlieb in a statement. “As the field advances, we are modernizing the FDA’s approach to the efficient authorization of laboratory tests from developers that voluntarily seek 510(k) clearance,” he said.
VI. Liquid Biopsies
CMS clarified that the NCD isn\’t specific to tissue-based NGS cancer panels, which means that NGS liquid biopsy tests that have FDA-approved or -cleared CDx indications are also eligible for coverage. When liquid-based, multi-gene sequencing panel tests don\’t have FDA approval or coverage, it will be up to MACs to decide coverage2.
\”The NCD does not limit coverage to how to prepare a sample for performing a diagnostic laboratory test using NGS\”, CMS said in response to stakeholder comments, noting that the agency included four studies on liquid biopsies as part of the evidence underlying the final policy determination.
Some market analysts also interpreted this language as a positive for companies like Guardant Health, which markets liquid biopsy cancer tests. Guardant said in a statement that it has a pending local coverage decision (LCD) in advanced lung cancer for its Guardant360 assay and has previously said it also intends to submit its test for FDA premarket approval by year end.
FDA defines the recently created NYSDOH/510(k) accelerated pathway as being currently suitable only for tissue tests, not liquid biopsy tests5.
VII. The MACs
CMS has stated that coverage determinations for NGS tests for advanced cancer that are not FDA approved or cleared will be made by the local Medicare Administrative Contractors (MACs). Industry experts have opined that some MACs might tell labs to take their tests through FDA review for coverage, since there have been few positive LCDs published to date.
There are seven MACs that process Medicare Part A and Part B claims for all 50 states, along with the District of Columbia, Guam, Puerto Rico, American Samoa, the Northern Mariana Islands, and the U.S. Virgin Islands. Four of the MACS collectively participate in the drafting, evaluation and ultimately enactment of local coverage determinations (LCDs) led by one particular MAC – Palmetto GBA® and its MolDX® program.
Developed in 2011, the MolDX program performs the following functions6:
Positive Final NGS LCDs to Date
Recent relevant NGS positive coverage determinations from MolDX include7: APC and MUTYH gene testing for individuals suspected to have familial adenomatous polyposis (FAP), attenuated FAP (AFAP) or MYH-associated polyposis (MAP) with a personal history of ≥20 adenomas over a lifetime; BRCA1 and BRCA 2 tests for hereditary breast and/or ovarian cancer; Genetic testing for BCR-ABL negative myeloproliferative disease; Genetic testing for Lynch Syndrome.
There has been one non-MolDX NGS positive coverage decision from National Government Services, a MAC that has not associated itself with any MolDX LCDs. This test, a Genomic Sequential Analysis Panel represented by CPT 81450, is for the evaluation of blood or bone marrow samples in patients with clinical signs or symptoms of myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative overlap syndromes (MDS/MPN), in whom clinical, laboratory, and pathologic assessment are non-diagnostic. The LCD also provides coverage for newly diagnosed MDS or MDS/MPN patients either:
Currently Pending NGS LCDs
Early in 2017, four MolDX-affiliated MACs collaborated to draft three separate LCDs for non-proprietary comprehensive genomic profiling (CGP) tests for guiding treatment in patients with specific cancer types. These MACs put forth comment periods for each of these LCDs, which started and ended before mid-year. No final decision was made on any of them. In late March 2018, approximately 2 weeks after the CMS final NCD was published, Palmetto GBA re-activated these three LCDs, initiating comment periods that will end on 5/10/2018. Palmetto re-activated these LCDs as a result of the final NCD, and published coverage requirements that meet the criteria set forth by the NCD. These LCDs are illustrated in the table below8. Coverage decisions by Palmetto are expected by mid-2018 after the close of the comment period, but such a timeline is by no means guaranteed.
2018 Draft LCDs for Comprehensive Genomic Profiling
|Title||LCD ID#||Contractor Name||Status||Comment Period Start||Comment Period End||Date of Release for Notice|
|Comprehensive Genomic Profiling to Guide Treatment in Patients with Advanced Primary Peritoneal, Fallopian Tube and Ovarian Cancer||DL37128||CGS Administrators, LLC||E||2/16/2017||4/13/2017|
|Noridian Healthcare Solutions, LLC||E||2/8/2017||4/10/2017|
|DL37203||Wisconsin Physician Service Insurance Corporation||E||5/8/2017||6/22/2017|
|Comprehensive Genomic Profiling to Guide Treatment in Patients with Metastatic Colorectal Cancer||DL37136||CGS Administrators, LLC||E||2/16/2017||4/13/2017|
|Noridian Healthcare Solutions, LLC||E|
|DL37222||Wisconsin Physician Service Insurance Corporation||E||5/8/2017||6/22/2017|
|Comprehensive Genomic Profiling to Guide Treatment in Patients with Metastatic Melanoma||DL37138||CGS Administrators, LLC||E||2/16/2017||4/13/2017|
|Noridian Healthcare Solutions, LLC||E|
|DL37220||Wisconsin Physician Service Insurance Corporation||E||5/8/2017||6/22/2017|
Proposed/Draft Status Legend
C=Proposed/Draft LCD released for comment
E=Formal comment period has ended; comments now being considered
MolDX Draft LCDs for CGP Policy Summary7
CGP analysis using multiplex or next generation sequencing (NGS) technology is proven to be reasonable and necessary to guide targeted and/or immuno-oncology therapy in patients with advanced ovarian, primary peritoneal, or fallopian tube cancer when ALL of the following criteria are met:
The above policy summary published by the MolDX-affiliated MACs pertains to advanced ovarian, primary peritoneal, or fallopian tube cancer. The published summaries for metastatic colorectal cancer and metastatic melanoma are identical, except for the identity of the biomarkers listed.
In summary, we make the following observations:
There is no requirement in the draft LCDs that the tests be approved or cleared by the FDA. However, a laboratory that gains coverage through this regulatory path and obtains test approval from NYSDOH could have the option to request that their NY state application, along with the state’s review memorandum and recommendation, be forwarded for possible 510(k) clearance by the FDA.
According to industry sources, MolDX may decide to not require laboratories operating outside the state of New York to obtain the same degree of NYSDOH approval as laboratories operating within the state. However, NYSDOH approval would assist MolDX in evaluation of analytical and clinical validity. The role of NYSDOH in these draft LCDs needs to be clarified. In any case, approval from NYSDOH will not assure reimbursement coverage. All MACs will require proof of clinical utility before coverage is approved.
While there is no requirement that these CGP tests be FDA companion diagnostic tests, the disease indications covered under the draft LCDs all have FDA-approved targeted therapies. Therefore, Diaceutics views the re-activation of these draft LCDs under the Palmetto GBA MolDX program as a positive next step after the recent rendering of the CMS final NCD.
VIII. The Commercial Payors
GenomeWeb recently reported9 that 12 medical directors affiliated with commercial payors were surveyed before the final NCD was announced in mid-March. Results of the survey revealed that they viewed CMS’s draft national coverage proposal with caution, and many questioned whether NGS testing had demonstrated sufficient clinical utility to warrant broad coverage. Also, some of the medical directors had serious concerns about the methodology CMS used to develop the coverage determination. Importantly, CMS entirely eliminated coverage with evidence development (CED) proposals from the final NCD. Other industry observers, including some oncologists, have pointed out that current evidence supports the use of NGS in relatively few cancer indications. They further predict that CMS’s coverage policy will drive greater NGS utilization and potentially harm cancer patients by directing them to off-label drugs that don’t work or are too toxic.
Now that the MACs under MolDX are actively considering three CGP tests for advanced cancers that are tied to specific therapies, commercial payers are likely to focus on the final decisions arising from the MACs’ deliberations. Their decisions may take additional time beyond mid-2018, are not guaranteed to be positive, and will hinge upon evidence of clinical utility.
IX. Clinical Databases
On April 12, 2018, the FDA finalized two guidances10. The first guidance, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics,” describes an approach where test developers may rely on clinical evidence from FDA-recognized public databases to support clinical claims for their tests and help provide assurance of the accurate clinical evaluation of genomic test results. The guidance describes how product developers can use these databases to support the clinical validation of NGS tests that they are developing. These public databases may include resources like ClinGen, which is maintained by the National Institutes of Health (NIH). Using FDA-recognized databases will provide test developers with an efficient path for marketing clearance or approval of a new test.
FDA intends to implement a recognition process for publicly accessible genetic variant databases that choose to participate in an effort to streamline premarket review of genetic and genomic-based tests (including PCR, NGS and other sequencing methodologies). For such genetic variant databases, FDA may consider utilizing third parties to assist with the recognition process in the future.
For premarket submissions that rely upon genetic variant databases recognized by FDA, the Agency may determine that submission of any additional valid scientific evidence for certain variant assertions found in these genetic variant databases is not necessary, depending on the sufficiency of the evidence for these assertions.
The second concurrently issued 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,” provides recommendations for designing, developing, and validating NGS-based tests used to diagnose individuals with suspected genetic diseases. It describes what the FDA would look for in premarket submissions to determine a test’s analytical validity, including how well the test detects the presence or absence of a particular genomic change. The document’s scope however does not apply to NGS-based tests intended for use as a companion or complementary diagnostic.
Diaceutics is optimistic about the industry’s recent regulatory and reimbursement progress with NGS. We point to clear evidence of benefit provided by diagnostic-dependent immunotherapies, the efficacy of drugs tied to known driver mutations and fusions, the growing recognition of clinical utility of microsatellite instability and tumor mutational burden, and the recognition by the FDA regarding the importance of clinical databases. Publicly available registries will play a key role in future coverage determinations. Such registries need to be accessible to high-quality, analytically and clinically validated genomic oncology tests. Development and implementation of additional solutions will be required to break through the barriers that keep such data siloed. This will be a prerequisite for extensive clinical utility and health economics outcome studies to prove the necessity of NGS testing and support adequate reimbursement in the setting of many other cancers.
We will continue to closely monitor and periodically update our guidance on how the newest regulatory developments will impact payer decision-making.
XI. Considerations for Pharma
The CMS final NCD paradoxically clarifies and complicates the decision-making process as to which regulatory pathway to pursue for optimal NGS test commercialization and payer coverage. As a result of the NCD, there are now two pathways that can lead to acceptable reimbursement for NGS tests: either through the FDA (or by proxy, a third-party review process such as NYSDOH) or alternatively by the MACs via LCDs. At the same time there are still significant unknowns within the complete payer landscape such as if MAC coverage decisions will be influenced by the NCD and whether commercial insurers will follow suit. Layered on top of this is the complexity of other testing methodologies that can be ancillary to, or in some cases replace NGS to ameliorate other important hurdles to optimum patient testing
Given this uncertainty, a single go-to-market testing strategy will not fit all targeted therapeutics in development and each pharmaceutical asset should have a specific and cohesive diagnostic testing plan that enhances commercialization of the associated therapeutic and minimizes patient leakage. From mapping of the diagnostic landscape to creating, implementing and tracking the results of an optimal testing strategy, Diaceutics can assist our clients with a tightly integrated end-to-end suite of service offerings to ensure launch success.
Jeff Schreier, MBA
Robert Feeney, PhD
XIII. Appendix: Explanation of Terminology
FDA-Cleared vs. FDA-Approved
All manufacturers who seek to market medical devices in the United States must first pass a very thorough process with the FDA through one of two pathways—the Section 510(k) process, where a device is “cleared” for distribution, or the Premarket Approval (PMA) process, where a device is “approved” by the FDA.
The FDA puts medical devices into three different buckets, creatively listed as Class I (low risk), Class II (higher risk), and Class III (highest risk). What classification bucket the medical device falls into will determine the applicable FDA “label” for the product — from FDA registered or listed, to FDA cleared, and finally to FDA approved. It is primarily a measure of risk that decides how a device ends up marketed as FDA listed or FDA approved or somewhere in-between.
The following is a breakdown of the different classes of medical devices:
Class I products: Class I devices are generally not subject to any premarket review by the FDA but still must register with the FDA. These products are sometimes marketed as “FDA registered” or “FDA listed”.
Class II products: Before a Class II product can be sold it must show the FDA that it is “substantially equivalent” to another product that the FDA has already given clearance. These products are often marketed as “FDA cleared”.
Class III products: Class III products are subject to a rigorous review process by the FDA, and are eventually known as “FDA approved” devices. These devices usually sustain or support life, are implanted, or present potential unreasonable risk of illness or injury.
LDT Regulation by CLIA
A laboratory developed test (LDT) is a type of in vitro diagnostic test that is designed, manufactured and used within a single laboratory.
The Centers for Medicare & Medicaid Services (CMS) regulates all laboratory testing (except research) performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA). In total, CLIA covers approximately 260,000 laboratory entities. The Division of Laboratory Services, within the Survey and Certification Group, under the Center for Clinical Standards and Quality (CCSQ) has the responsibility for implementing the CLIA Program.
The FDA does not consider diagnostic devices to be LDTs if they are designed or manufactured completely, or partly, outside of the laboratory that offers and uses them.
All CLIA-regulated laboratories and test developers have the option of submitting their LDTs to the FDA for approval or clearance. The process is laborious, time-consuming and costly. Laboratories and test developers ultimately decide to go down the FDA path in order to attain a strategic market advantage or more favorable reimbursement.
For the past several years, the FDA has been seeking to develop and institute a framework by which the FDA would attain legal responsibility for oversight of LDTs.