Pharmacogenomics Testing

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for pharmacogenomics testing. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for pharmacogenomics testing and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
  • Chapter 15, Section 80.1 Clinical Laboratory Services, Section 80.1.1 Certification Changes, Section 80.1.2 A/B MAC (B) Contacts With Independent Clinical Laboratories, Section 80.1.3 Independent Laboratory Service to a Patient in the Patient’s Home or an Institution, Section 80.6 Requirements for Ordering and Following Orders for Diagnostic Tests, Section 80.6.1 Definitions, and Section 280 Preventive and Screening Services
• CMS IOM Publication 100-03, Medicare National Coverage Determinations (NCD) Manual,
  • Chapter 1, Part 2, Section 90.1 Pharmacogenomic Testing to Predict Warfarin Responsiveness and Section 90.2 Next Generation Sequencing for Patients with Advanced Cancer
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
  • Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1861(ww)(1). This section defines the initial preventative physical examination which does not include laboratory tests.
• Title XVIII of the Social Security Act, Section 1861(xx)(1). This section defines cardiovascular screening blood test.
• Title XVIII of the Social Security Act, Section 1861(ddd)(1). This section defines additional preventative services. Section 1861(ddd)(2). This section describes the process for making national coverage determinations. Section 1861(ddd)(3). This section defines preventative services.
• Title XVIII of the Social Security Act, Section 1861(hhh) defines the annual wellness visit services.
• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Code of Federal Regulations (CFR) References:

• CFR, Title 42, Volume 2, Chapter IV, Part 410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions
• CFR, Title 42, Volume 2, Chapter IV, Part 410.64 Additional preventive services
• CFR, Title 42, Volume 2, Chapter IV, Part 411.15(k) Particular services excluded from coverage
• CFR, Title 42, Volume 5, Chapter IV, Part 493 Laboratory Requirements

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

Genetic testing holds the potential to provide great value in improving health outcomes for all individuals. The scope of this LCD includes testing to determine how genes affect the body's response to certain medicines, known as pharmacogenetic, or pharmacogenomic testing. Clinicians face a daunting task to individualize therapies to maximize beneficial outcomes and minimize adverse events and lack of effect. Pharmacogenomic (PGx) testing holds the hope of improved choice of drug therapy for multiple conditions for which drug therapy is appropriate.

A person’s genetic code can influence various steps in drug response. Examples of these steps where genetic variation may influence response include drug receptor type and number, increased or decreased drug uptake, and increased or decreased drug metabolism. Depending on the specific situation, these interactions can result in increased or decreased drug effectiveness as well as adverse drug reactions.

This LCD addresses single gene, multi-gene panels, and combinatorial tests aimed at determining an individual’s drug response.

Definitions

Combinatorial PGx test – a type of multi-gene panel that requires a proprietary algorithm to evaluate pharmacokinetic or pharmacodynamic relationships resulting in drug recommendations or warnings.

Actionable use – A test is considered to have an actionable use when the genotype information may lead to selection of or avoidance of a specific therapy or modification of dosage of a therapy. The selection, avoidance, or dose change must be based on the U.S. Food and Drug Administration (FDA) label for the drug, an FDA warning or safety concern, or a Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B gene-drug interaction. An intended change in therapy based on the result of a genotyping test that is not supported by one of these sources is not considered an actionable use for the purposes of this LCD.

Covered Indications

Pharmacogenetics testing will be considered medically reasonable and necessary if:

1. The patient has a condition where clinical evaluation has determined the need for a medication that has a known gene-drug interaction(s) for which the test results would directly impact the drug management of the patient’s condition; AND

2. The test meets evidence standards for genetic testing as evaluated by a scientific, transparent, peer-reviewed process and determined to demonstrate actionability in clinical decision making by CPIC guideline level A or B¹; or is listed in the FDA table of known gene-drug interactions where data support therapeutic recommendations or a potential impact on safety or response or the FDA label; https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling; https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations

Some panel/combinatorial tests may include content that has demonstrated actionability and some that has not. In these circumstances, the components of the tests that have demonstrated actionability as noted in #2 will be considered medically reasonable and necessary. Refer to the related billing and coding article for coding information.

Please refer to National Coverage Determination (NCD) 90.1 for anticoagulation dosing with warfarin.

Limitations

The following is considered not medically reasonable and necessary:

• Genetic testing where either analytical validity, clinical validity, or clinical utility has not been established.
• Germline testing may be performed once in a lifetime per beneficiary.
  • Any laboratory test that investigates the same germline genetic content, for the same genetic information, that has already been tested in the same Medicare beneficiary is not medically reasonable and necessary as it is duplicative. The germline sequence of an individual does not change over time, and therefore repeat testing of the same germline content for the same genetic information does not provide new clinical information.

Provider Qualifications

The ordering provider of a PGx test for a patient with a medical condition:

• Must be the treating clinician who is responsible for the pharmacologic management of the patient’s condition. The ordering provider of a PGx test is restricted to providers who have the licensure, qualifications, and necessary experience/training to both diagnose the condition being treated and to prescribe medications (the provider must be able to do both) for the condition either independently or in an arrangement as required by all the applicable state laws; and
• is considering or has already prescribed a pharmacologic treatment with actionable gene-drug interactions; and
• understands the actionability of the ordered test.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

Introduction

The focus of this evidence review is on genetic testing used to guide drug therapies, and whether the evidence is adequate to draw conclusions about improved health outcomes for the Medicare population. In general, improved health outcomes of interest include patient mortality and morbidity, as well as patient quality of life and function. Standardized evaluation of analytical validity, clinical validity, and clinical utility should be fully elucidated, and reflect the level of confidence that the performance of this test will directly benefit patients. Tests with analytic and clinical validity, with demonstrated clinical utility that provide confidence to accurately enhance clinician decision-making, have the potential to alter clinical management leading to improved patient outcomes. Ideal patient outcomes demonstrate reduced mortality and morbidity, improved patient quality of life and function.

Pharmacogenomic testing endeavors to improve patient outcomes to optimize medication choice, thereby reducing ineffective medication use and reducing adverse events. Outcomes of interest remain the patient-centered outcomes noted above.

Internal Technology Assessment

The U.S. sources of PGx test recommendations available to provide guidance to clinicians as to how available genetic test results should be interpreted for drug therapy improvement include the U.S. FDA drug labels, FDA Table of Pharmacogenetic Associations, and the CPIC.

Caudle 2014²

The CPIC publishes open-source genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. Caudle (2014) describes the CPIC guideline development process for incorporation of PGx testing into clinical practice and compares the process to the Institute of Medicine’s (IOM) Standards for Developing Trustworthy Clinical Practice Guidelines. The CPIC is a shared project between the Pharmacogenomics Knowledgebase and the Pharmacogenomics Research Network, established to address the need for practice guidelines for the translation of genetic laboratory test results into actionable decision making for specific drugs. The guidelines are developed using standardized methods. As the authors state, “Therefore, CPIC guidelines are designed to provide guidance to clinicians as to how available genetic test results should be interpreted to ultimately improve drug therapy, rather than to provide guidance as to whether a genetic test should or should not be ordered.”

A table is provided comparing the IOM standard to the CPIC Guideline development standard, listed as a point-by-point comparison. All CPIC guidelines adhere to each standard with some exceptions. One exception is IOM standard 4, the clinical practice guideline-systematic review intersection. Here, CPIC meets some but not all these standards. The explanation being that because of the nature of PGx test studies, the CPIC guideline development process often relies on published results that can vary with respect to methodological rigor and outcomes. Management of conflict of interest also does not exactly match the IOM standard. Divestiture of interests and ensuring those with conflict of interest are in the minority is not required, however the author notes in most cases, the majority of guideline authors declare no conflicts of interest. In addition, the guidelines focus on how to use the information as opposed to whether or not to order the test. Another area of deviation is IOM standard 3.2 and 3.3. While all guidelines are posted in draft form on the website for comment by CPIC members prior to publication, there is no mechanism for public representation or public comment.

Caudle 2016³

The purpose of this article is to describe the state of PGx test evidence and evidence-based resources that facilitate the uptake of PGx testing into clinical practice. The authors state the threshold for evidence needed for clinical implementation of PGx testing is controversial and good quality randomized controlled trials (RCTs) are rarely available. A standardized approach to evaluate the literature and provide guidance to clinicians is essential in facilitating the implementation of PGx testing into routine practice. The CPIC believes there is a critical need to provide classification of gene/drug groupings based on being actionable in clinical decision making based on reliable standardized criteria. A prioritization algorithm for considerations for new gene/drug groups is provided for review. CPIC levels of evidence for genes and drugs, Table 2:

CPIC Level Definitions for Genes and Drugs

U.S. Food and Drug Administration (FDA)⁴

The FDA states that “pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose.” Drug labeling may contain information on genomic biomarkers and can describe the following as listed per the FDA: “Drug exposure and clinical response variability, risk for adverse events, genotype-specific dosing, mechanisms of drug action, polymorphic drug target and disposition genes, trial design features.”⁴

FDA safety communications have been published that warn against the use of many genetic tests with unapproved claims to predict patient response to specific medications. According to the FDA, the number of cases are limited for which at least some evidence does exist to support a correlation between a genetic variant and drug levels within the body, and this is described in the labeling of FDA cleared or approved genetic tests and FDA approved medications. The FDA provides descriptions for how to use genetic information to manage therapeutic treatment and can appear in different sections of the labeling depending on the actions.⁵ For instance, from an October 31, 2018 communication:

“The FDA is alerting patients and health care providers that claims for many genetic tests to predict a patient's response to specific medications have not been reviewed by the FDA, and may not have the scientific or clinical evidence to support this use for most medications. Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient.”

And:

“There are a limited number of cases for which at least some evidence does exist to support a correlation between a genetic variant and drug levels within the body, and this is described in the labeling of FDA cleared or approved genetic tests and FDA approved medications. The FDA authorized labels for these medical products may provide general information on how DNA variations may impact the levels of a medication in a person's body, or they may describe how genetic information can be used in determining therapeutic treatment, depending on the available evidence."

Coverage of items and services in the Medicare program is based on reasonable and necessary services. This concept is operationalized by application of evidentiary standards. Evidence thresholds for coverage are a careful balance of benefits and harms in the consideration of net health outcomes.

Selection of pharmacologic therapies in the management of disease involves a complicated decision-making process which is ultimately based on individual patient attributes. A patient’s genetic makeup is potentially one of those tools to aid in clinician decision-making. In order to rely upon genetic testing as a decision-making tool in pharmacologic management of the patient’s condition, a treating clinician must have not only knowledge of the potential for gene-drug interaction but confidence in the test result, and there must be a potential for actionability. The PGx testing is rapidly evolving not only in volume of knowledge but in approach to testing. As would be expected, what began as limited content testing continues a path to broader and more encompassing testing, with seemingly infinite variations. It is in this context that the use of PGx testing for clinical decision making to improve a Medicare patient’s health outcome is examined.

Confusion at the level of the patient’s treating clinician may exist due to the difficulty of translating results to actionability. Rapid change also creates difficulty, particularly for clinicians who are not experts in the specific area of PGx. Furthermore, inconsistencies in recommendations between sources of information and access to information can be problematic, or even create differential health outcome effects in different patient populations.

Consistent with the evidence framework for all genetic testing, PGx tests must demonstrate analytical validity, clinical validity, and clinical utility to be considered medically reasonable and necessary for coverage. However, analytical validity and clinical validity are not enough to produce improved health outcomes. Simply knowing a test result is not enough. For true improved health outcomes, the test must be actionable and then be successfully intergraded into patient care by the clinician.

Controversy does exist regarding the evidence threshold needed for clinical application of PGx testing and can be a further source of difficulty for the clinician seeking information. Good quality RCTs are rare. While alternate study designs may currently be necessary to understand the clinical utility of PGx testing, a rigorous, standardized approach to the evidence is necessary to demonstrate with any level of confidence the goal of improved health outcomes in all Medicare beneficiaries.

Therefore, it remains important to approach PGx testing with a rigorous, standardized approach to evidence, that is not a barrier, but facilitates appropriate testing uptake for all eligible Medicare beneficiaries. The IOM Standards for Developing Trustworthy Clinical Practice Guidelines provides a rigorous, standardized approach for guideline development. This approach is consistent with CPIC guideline generation. In addition, these guidelines do not suggest test ordering or medication selection, but they provide a level of confidence in gene-drug interactions that have actionability in specific circumstances. The guidelines are clear and understandable by non-PGx specialists.

The FDA guidance for the safety and efficacy of drugs is uniquely relied upon. An individual’s genetic construct has the potential to affect drug safety and effectiveness. Therefore, the FDA authorized labels “may provide general information on how DNA variations may impact the levels of a medication in a person's body, or they may describe how genetic information can be used in determining therapeutic treatment, depending on the available evidence.” Furthermore, the FDA has issued safety warnings when genetic tests claim to predict a patient’s response to medical therapy. The issuance of this alert by the FDA cautions against unapproved use of gene testing for recommendations that have little evidence but attempt to direct medication therapy:

“The FDA is alerting patients and health care providers that claims for many genetic tests to predict a patient's response to specific medications have not been reviewed by the FDA, and may not have the scientific or clinical evidence to support this use for most medications. Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient.”⁵

The FDA is a source of reliable information.

In summary, PGx testing has the potential to improve patient outcomes through assisting the clinician in pharmacologic treatment decision-making, however given the rapidly evolving test climate, a reliable, rigorous, standardized approach to evidence is necessary to realize improved health outcomes in the Medicare population. At this time, only FDA label, including the FDA Table of Pharmacogenetic Associations, and CPIC guidelines meet these criteria.

Please refer to the related Local Coverage Article: Billing and Coding: Pharmacogenomics Testing (A58801) for documentation requirements, utilization parameters and all coding information as applicable.

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1. Clinical Pharmacogenetics Implementation Consortium (CPIC). Guidelines. 2020: https://cpicpgx.org/. Accessed November 5, 2020.
2. Caudle KE, Klein TE, Hoffman JM, et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline development process. Curr Drug Metab. 2014;15(2):209-217. doi:10.2174/1389200215666140130124910.
3. Caudle KE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Relling MV, Klein TE. Evidence and resources to implement pharmacogenetic knowledge for precision medicine. Am J Health Sys Pharm. 2016;73(23)1977-1985. doi:10.2146/ajhp150977.
4. U.S. Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. 2020. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling. Accessed Nov 4, 2020.
5. The FDA Warns Against the use of Many Genetic Tests with Unapproved Claims to Predict Patient Response to Specific Medications: FDA Safety Communication. 2018. https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific#actions. Accessed Nov 5, 2020.
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9. National Human Genome Research Institute. Coverage and Reimbursement of Genetic Tests. 2019. https://www.genome.gov/. Accessed November 5, 2020.
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12. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Board on the Health of Select Populations; Committee on the Evidence Base for Genetic Testing. An Evidence Framework for Genetic Testing. Washington (DC): National Academies Press (US); 2017 Mar 27. https://doi.org/10.17226/24632.
13. Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines. Clinical Practice Guidelines We Can Trust. Graham R, Mancher M, Miller Wolman D, Greenfield S, Steinberg E, editors. Washington (DC): National Academies Press (US); 2011.