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Palmetto GBA Issues Three Draft LCDs on Multi-marker Tests; MolDx Lays out Review Criteria, Process

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NEW YORK (GenomeWeb) – Medicare contractor Palmetto GBA has issued draft local coverage determinations stipulating reimbursement criteria for three multi-marker molecular diagnostics: Assurex Health's pharmacogenetic test for refractory depression, MDxHealth's ConfirmMDx epigenetic prostate cancer test, and bioTheranostics' Breast Cancer Index test for gauging disease recurrence.

Stakeholders may comment on the draft LCDs from July 8 to August 25.

These proposed LCDs from Palmetto offer a view into the types of evidence that diagnostics developers need to submit to Medicare contractors in order to secure coverage for multi-marker tests. The LCDs also demonstrate flexibility on the part of the Medicare contractor to consider a variety of schemes under which it is willing to furnish coverage for lab tests, factoring in evolving clinical evidence and treatment guidelines.

According to Medicare policy expert Bruce Quinn these LCDs were a long time in the making, involving months of deliberations, explanations, and dialogue between Palmetto staff and test providers. "The three new Palmetto MolDx LCDs should be read closely by anyone who is tracking trends in the coverage of new tests that are not directly tied" to primary US Food and Drug Administration drug trials, Quinn, senior health policy advisor at the law firm Foley Hoag, told PGx Reporter. "Each LCD contains a fairly detailed literature review, which may be less than a commercial health technology assessment, but which reflects a much higher standard of evidence understanding and evaluation than most … LCDs under most Medicare administrative contractors."

Palmetto released these draft LCDs the same week as documents outlining the evidence that diagnostics developers must submit for coverage reviews under its MolDx program. CMS launched MolDx and placed Palmetto in charge of the program in 2011, aiming to better capture the molecular diagnostics Medicare was paying for and ensure that it was only paying for tests with proven clinical validity and utility. "The three LCDs should be viewed in context of the full-fledged dossier and evidence guidance documents that MolDx released on its website last week after six months of preparation," Quinn noted.

A document entitled "Clinical Test Evaluation Process," or CTEP, lays out the methodology by which MolDx experts and its executive committee consider new tests. In a second document, Palmetto outlines the guidelines that diagnostics firms must follow to prove the analytical and clinical validity of their tests. A third document provides a technical assessment checklist that laboratory staff can use "to ensure that all required documents/information has been included prior to submission" to MolDx.

Once MolDx determines a submitted test package is complete, its experts place the test into one of three tracks: a fast track review for companion tests that have been approved by the FDA as part of a new drug application or are deemed appropriate based on FDA approved drug labeling; expedited review for tests that have been formally evaluated by a MolDx specialty society and deemed to be a "standard of care;" and traditional reviews for tests that are considered based on data from published, peer-reviewed trials. The three draft LCDs issued by Palmetto all concern tests that haven't been approved or cleared by the FDA and aren't considered "standard of care," and likely fall into the "traditional review" category.

Finally, after MolDx completes its technical assessment and determines that a test meets Medicare criteria for coverage, the test will then be evaluated for pricing. Palmetto instructs test developers to provide the list price of the test, as well as what other insurers are paying for it; to detail what it costs to perform the test; and to provide any published health economics studies on the diagnostic.

Importance of prospective studies

The draft LCD on GeneSight highlights the importance of conducting prospective analysis on genetic tests when possible.

Assurex Health's GeneSight Psychotropic analyzes 50 alleles from six genes that have been shown in studies to affect a person's response to antidepressant and antipsychotic treatments. Included on the panel are pharmacokinetic genes from the CYP450 family and pharmacodynamic genes implicated in the serotonin system.

In granting the draft LCD in the North Carolina jurisdiction, Palmetto specified that in order for GeneSight testing to be reimbursed, patients must have refractory depression and have failed at least one neuropsychiatric medication, and doctors must be contemplating alternative treatment strategies. The Medicare contractor cited data from three prospective studies, one retrospective health economic trial, and a meta-analysis to justify its LCD proposal for GeneSight. In the cost effectiveness study, Assurex was able to show that by using GeneSight to determine the psychiatric drugs that depressed patients are likely to respond well to, doctors can cut more than $5,000 per patient each year in healthcare utilization costs.

Furthermore, after reviewing the medical necessity of GeneSight for the Medicare population specifically, Palmetto determined that the test has potential utility in this setting since, as people get older, the risk of drug-drug interactions increases as their mental health begins to decline.

Palmetto estimated that 26 percent of the Medicare population suffers from a mental health condition each year. Six out of 10 disabled Medicare beneficiaries under 65 years of age have a mental disorder. Meanwhile, according to the American Psychiatric Association, among those 65 and older, depression is the most common mental disorder.

"[Depression] frequently appears as a co-morbid symptom to other conditions and can even mimic the symptoms of dementia," Palmetto states in the draft LCD. "As a group, seniors generally take more medications than other age groups, increasing their risk of drug-drug interactions and adverse drug events."

Coverage under registry programs

When it comes to MDxHealth's ConfirmMDx prostate cancer test, Palmetto proposes limiting coverage for the test only when it is performed by doctors enrolled in a MolDx-approved certification and training registry program, or CTR.

"The MDxHealth CTR program serves as a control to assure the appropriate selection of patients, compliance with management decisions, and stringent follow up to ensure the benefits of the test outweigh its risks," Palmetto states in the draft LCD, granted in its South Carolina jurisdiction.

The CTR program aims to avoid missing diagnoses of early prostate cancer patients; inform doctors and patients on appropriate use of ConfirmMDx; and collect long-term outcomes information. As such, MDxHealth must submit to Palmetto data every six months ensuring that its test is being appropriately used, such as the total number of tests submitted for Medicare payment; the number of patients tested who are enrolled and not enrolled in clinical trials; the patients' PSA test scores at initial testing; and patients' biopsy results and cancer status.

The draft LCD stipulates that MDxHealth will also maintain a database of ConfirmMDx CTR-certified physicians and ensure that only doctors on the list are ordering the test. Palmetto is holding MDxHealth responsible for "prevent[ing] a certified provider from ordering the test if the provider is found to be non-compliant with the ConfirmMDx CTR program."

The ConfirmMDx test gauges the methylation status of GSTP1, RASSF1, and APC, which are biomarkers associated in the published literature with prostate cancer. The test has been developed as a tool that doctors can use to gain further prognostic insights on patients with high risk factors for prostate cancer, such as elevated PSA scores, abnormal digital rectal exams, and negative histopathology findings in a biopsy leading to consideration for rebiopsy.

However, these standard tests and measures are imprecise, and can be abnormal in men at low risk for prostate cancer. Noting that the test had a negative predictive value of 90 percent in a large clinical validation study, Palmetto said it is proposing coverage for ConfirmMDx as a useful test for reducing unnecessary repeat biopsies.
 
In terms of evidence supporting use of ConfirmMDx, Palmetto acknowledges that the use of the test is supported by retrospective analyses. However, as the contractor also points out, MDxHealth is conducting a prospective study, called PASCUAL, to gauge the impact of the test on patient outcomes.  

"Although limited coverage of this assay does support data collection within the PASCUAL trial, participation in the PASCUAL trial is not a prerequisite to the limited coverage," Palmetto states. "Coverage is limited to providers enrolled in the MDxHealth CTR program." Palmetto estimates that MDxHealth will perform 1,200 tests in the PASCUAL study over three years, which will be covered through the proposed LCD.

In order to have ConfirmMDx testing reimbursed through Medicare under the CTR, doctors must fit one of the following criteria: be registered as an investigator in the PASCUAL trial; follow patients in a manner similar to the methodology in the trial; provide documentation of how patients were counseled about ConfirmMDx, its capabilities and risks; or provide data on how the test impacted care of patients who received the test but aren't part of the trial or a registry where outcomes data are being collected.

Palmetto stipulates a number of other coverage criteria in the draft LCD for ConfirmMDx, including that the patient must be between 40 and 70 years old; have had a negative biopsy where a minimum of eight tissue cores were collected; is being considered for a repeat biopsy based on consistent elevated risk factors for prostate cancer; does not have a prior diagnosis of prostate cancer; and isn't being managed by active surveillance.  

Coverage in tune with latest guidelines

In the draft LCD for BioTheranostics' Breast Cancer Index test, Palmetto seems to have carefully factored in the nuances of the most up-to-date treatment guidelines. "The body of evidence for the adjuvant endocrine treatment of estrogen receptor-positive breast cancer is continuing to evolve," the contractor states in the draft LCD, noting that the National Comprehensive Cancer Network now recommends that patients should be treated with adjuvant tamoxifen for five years, in addition to standard-of-care regimens, to reduce late recurrences.

"The BCI LCD shows the most sophisticated approach to coverage with ongoing trial data that has occurred at any Medicare contractor to date," Quinn reflected.

Although there are side effects associated with prolonged therapy, guidelines-making bodies strongly advise additional years of hormone therapy, reasoning that the benefits outweigh the risks. Still, tools such as BCI that help doctors gain more insights into which women are at high risk of late relapse, and therefore should receive additional hormonal therapy, are necessary since the optimal duration and impact of hormonal treatment beyond 10 years is not yet known, according to Palmetto.

"The BCI assay … uses PCR to interrogate selected proliferation genes, and may identify a subset of postmenopausal women who are at increased risk of late relapses for ER-positive breast cancer and who may derive a greater benefit from extended hormone therapy," Palmetto states. The draft LCD, granted in Palmetto's North Carolina jurisdiction, limits coverage of BCI for post-menopausal women with ER-positive breast cancer; for a patient who is completing five years of tamoxifen treatment; when the doctor or patient is concerned about toxicities related to anti-hormonal therapy; and when test results, the risk and benefits of testing, and treatment guidelines are discussed with the patient.

The contractor warns in the proposed LCD that BCI cannot be used by itself, and that doctors must consider patients' clinical factors when gauging their recurrence risk after five years. Moreover the test has not shown convincingly in studies that it can pick out low recurrence risk patients who can forgo hormone therapy completely. "A significant concern exists as to whether the assay can identify any group at such a low risk that it is safe to depart from a strong expert recommendation and safely stop therapy," the contractor states.

Palmetto cites data suggesting that all patients, whether having high or low risk of recurrence, harbor a risk for late recurrence, and that risk increases "steadily" annually after a patient has stopped adjuvant endocrine therapy after five years. "Given the substantial number of patients at risk in the BCI-Low group (over 60 percent), the total number of women at risk that may benefit from extended hormone therapy at the end of five years of tamoxifen therapy is not negligible," Palmetto said in the LCD.

Additionally, the Medicare contractor will not reimburse for BCI if doctors use it to identify newly diagnosed breast cancer patients who could most benefit from chemotherapy. More studies are needed to confirm the use of this test in this setting, Palmetto concluded.

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