MolDX Response to Comments on CYP Testing

https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=54236&ver=3&ContrId=353&ContrVer=1&LCDId=36311&name=353*1&UpdatePeriod=654&IsPopup=y&

Article ID 54236


Response to Comments

COMMENT	RESPONSE
Cover CYP2C19 for Clopidogrel on a case by case basis; all Clopidogrel treated patients after acute myocardial infarct; expand coverage to patients with high risk characteristics. We request that the LCD recognize individual medical review to allow coverage for CYP2C19 testing in the patient on clopidogrel who would be considered high risk based on clinical characteristics.	From the latest CPIC statement on CYP2C19 and CLOPIDOGREL (Scott, 2013), “Current data do not support the use of CYP2C19 genotype data to guide treatment in other scenarios”.
Cover CYP2C19 for Amitriptyline We recommend coverage of CYP2C19 testing for use in patients being treated with amitriptyline, nortriptyline, and the tricyclic anti-depressants.	While the literature is promising and it is likely that CYP-based drug dosing will eventually become the standard of care, the evidence does not yet support that drug selection or dosing based on CYP genotype improves patient outcomes outside of the scenarios described in the Covered Indications section of the LCD. We agree that CPIC guidelines are useful in evaluating the strength of clinically relevant pharmacogenetic data and attempt to incorporate these recommendations when evidence is strong and shows a significant clinical impact. CPIC classified the level of evidence to support an initial dose reduction for CYP2C19 poor metabolizers as moderate based on a lack of randomized trials. Further studies of amitriptyline, nortriptyline, and other TCAs are necessary to strengthen the robustness of this recommendation.
Cover CYP2C19 for Proton Pump Inhibitors We recommend coverage for CYP2C19 testing in conjunction with initiating therapy with omeprazole, lansoprazole, pantoprazole, or esomeprazole at standard dosing as first line therapy unless other evidence is submitted; we request for expansion of coverage to patients being treated with a PPI for GERD and H. Pylori.	We agree that the medical literature supports an association between CYP2C19 genotype and response to PPIs; however, the lack of risk of adverse effects and the simple recommendation to increase the dose in patients who do not respond does not support clinical utility for this testing at this time.
Cover CYP2D6 and/or CYP2C19 for Antidepressants for numerous diagnoses Multiple commenters recommended coverage of CYP2D6 testing for all TCAs and for all FDA-labeled indications and off-label indications accepted as medical practice and covered by Medicare, e.g. use of amitriptyline for treatment of neuropathic pain.	Although tricyclic antidepressants have similar pharmacokinetic properties, there is limited data regarding CYP2D6 genotyping and other TCAs. Evidence to support the use of genetic testing prior to initiating certain TCA due to the effects of genotype on drug efficacy and safety was reviewed and covered in this policy. However, there is insufficient evidence for CYP2D6 genotyping for individuals considering antipsychotic medications or other antidepressants. While the literature is promising and it is likely that CYP-based drug dosing will eventually become the standard of care, the evidence does not yet support that drug selection or dosing based on CYP genotype improves patient outcomes outside of the scenarios described in the Covered Indications section of the LCD. We agree that CPIC guidelines are useful in evaluating the strength of clinically relevant pharmacogenetic data and attempt to incorporate these recommendations when evidence is strong and shows a significant clinical impact. CPIC classified the level of evidence to support an initial dose reduction for CYP2C19 poor metabolizers as moderate based on a lack of randomized trials. Further studies of amitriptyline, nortriptyline, and other TCAs are necessary to strengthen the robustness of this recommendation.
Cover CYP2D6 for Codeine A commenter requested that the required level of evidence be applied uniformly, e.g. the strength of evidence for CYP2D6 for codeine is the same in the CPIC guidelines as that for CYP2C19 for clopidogrel and CYP2D6 for amitriptyline/ nortriptyline, which Noridian has determined have a sufficient level of evidence to cover. A commenter requested that Medicare provide coverage for medically necessary testing for ALL beneficiaries, regardless of age or reason for eligibility for Medicare, e.g. disability and that coverage for CYP2D6 genotyping for codeine (and related drugs) based on presence of national guidelines, the strength of evidence cited in the guidelines and the presence of an FDA black box warning.	The efficacy and toxicity, including severe or life-threatening toxicity after normal doses of codeine has been linked to an individual’s CYP2D6 genotype (Crews 2014). However, FDA warnings related to the highest risk patients (breastfed neonates and children) recommend against the use of codeine regardless of CYP2D6 genotype. CYP2D6 genotyping patients would indicate avoidance of codeine due to risk of adverse events in only 1-2% of the population, and there is considerable variation in the degree of severity of adverse events, with most not classified as serious. Codeine has been widely used without genotyping and is universally available so access to medical care is not limited. There is insufficient evidence to support clinical utility of genotyping for management of codeine therapy.
Coverage of CYP2C9 and VKORC1 according to NCD 90.1 Both CYP2C9 and VKOCR1 should be covered within the context of a clinical study/coverage with evidence development according to NCD 90.1; if significant reductions in hospitalizations have been conclusively proven through CYP2C9 and VKORC1 genotyping, why does the draft policy limit testing to patients who are “enrolled in a prospective, randomized, controlled study when the study meets the following standards	Noridian covers CYP2C9 and VKORC1 genotyping for warfarin as described under NCD 90.1. All other uses not specifically listed in the NCD or this LCD are considered experimental, investigational, and unproven. If Noridian has missed publications that clearly demonstrates reductions in hospitalizations, the commenter needs to provide this information via a reconsideration request.
Delay postponement of this LCD until 2016; delay implementation until further evidence confirming or negating the clinical utility of pharmacogenetic (PGx) testing is collected; advancements in medicine will be hindered without continued reimbursement for PGx testing; restricting coverage will greatly reduce availability of test data in coming years and considerably delay test inclusion in standard of care practices; LCD is clearly a cost control measure because it excludes all but a narrow subset of the conditions and providers that currently benefit for the testing; delay LCD so that the evidence regarding the true impacts of this decision can be thoroughly reviewed, analyzed and understood Commenters requested postponement of this LCD until additional data was forthcoming.	Noridian will reconsider published evidence when it becomes available. Coverage requires evidence of demonstrated clinical utility – that a test result improves patient outcomes, and/or changes physician management that improves patient outcomes. Clinical utility has only been established for a narrow subset of conditions. Evidence of improved patient outcomes will quickly establish standard of care.
Cover ICD-9 995.2 (Other and unspecified adverse effect of drug, medicinal and biologic substance), beneficiaries accepted into approved studies or participating in Medicare Innovations Programs (CPCI or Shared Savings), and for patients at high risk of gene-based adverse drug events. A commenter requested coverage for the above groups for the above patient groups if the LCD is implemented prior to 2016.	There is no published evidence to support coverage for CYP testing for the above patient groups.
Reconsider coverage of cytochrome P450 gene metabolizer status in relation to limited coverage for GeneSight Psychotropic Panel.Noridian should reconsider their current position on the utility of individual cytochrome P450 gene metabolizer status in relation to limited coverage provided for Genesight® Psychotropic Panel.	GeneSight is multiplex pharmacogenomic test involving the analysis of fifty alleles (SNPs) from six different genes and a clinical outcomes-based decision support modeling tool that weights the influence of the various alleles/SNPs with respect to thirty-two different psychotropic pharmaceutical agents. The test results in the differentiation of psychoactive drugs that are likely to be effective and well-tolerated by a particular patient versus those that are not. In multiple prospective clinical studies, the use of GeneSight® to guide neuropsychiatric pharmaceutical selection and prescription has demonstrated an increased patient response to treatment from 60% to 250% (as measured by the standardized 17-item Hamilton Rating Scale for Depression or HAM-17; response is defined as = 50% reduction in HAM-D17 score) versus unguided, empirical treatment (or treatment as usual). Prospective evidence is required to demonstrate the effectiveness and utility for individual or P450 gene combination testing.
LCD is inconsistent with expert panel recommendations The Noridian Proposal is inconsistent with expert panel recommendations that were based on evaluation of the scientific literature that was used to develop drug-gene specific guidelines.	Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. They are not binding and intended only to assist clinicians in decision making.
The FDA has issued Black Box Warnings for over 100 medications recommending pharmacogenomic markers need to be assessed before and if patients are placed on these medications.	There is clear evidence of the clinical validity of CYP450 genotyping. However, there is limited evidence that genotyping and subsequent alterations to patient management improve patient outcomes for many scenarios; the clinical utility of CYP450 genotyping is proven in limited scenarios only. The draft LCD does not conflict with the FDA’s assessment of the clinical validity of CYP450 genotyping and potential relationship between genotype and drug response. FDA labeling as referenced does not mandate genotyping, but rather serves to warn clinicians that certain patient subgroups may exhibit altered drug response, and clinicians should be aware of alternative treatment strategies when appropriate. The draft LCD defines clinical scenarios where genotyping improves patient outcomes compared to outcomes when genotyping is not performed, which is not addressed by the FDA.
Who and what establishes “insufficient” data? Exactly who and what defines the term “insufficient” data to support coverage of any and all CYP450 and VKORC1 genetic mutation tests utilized in the practice of medicine; if significant reductions in hospitalizations have been conclusively proven through CYP2C9 and VKORC1 genotyping,	For Medicare coverage purposes, Medicare Administrative Contractor (MAC) Medical Directors establish sufficiency of data. A well characterized hierarchy of evidence is recognized by trained clinicians and scientists. In the absence of published scientific evidence that demonstrates clinical utility, the data is “insufficient”.