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 2014 2  
  
**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 2016 3  
  
**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  
  
**

CPIC Level

|

Clinical Context

|

Level of Evidence

|

Strength of Recommendation  
  
---|---|---|---  
  


A

|

Genetic information should be used to change prescribing of affected drug

|

Preponderance of evidence is high or moderate in favor of changing prescribing

|

At least one moderate or strong action (change in prescribing) recommended  
  
B

|

Genetic information could be used to change prescribing of the affected drug
because alternative therapies/dosing are extremely likely to be as effective
and as safe as non-genetically based dosing

|

Preponderance of evidence is weak with little conflicting data

|

At least one optional action (change in prescribing) is recommended  
  
C

|

There are published studies at varying levels of evidence, some with
mechanistic rationale, but no prescribing actions are recommended because (a)
dosing based on genetics makes no convincing difference or (b) alternatives
are unclear, possibly less effective, more toxic, or otherwise impractical or
(c) few published studies or mostly weak evidence and clinical actions are
unclear. Most important for genes that are subject of other CPIC guidelines or
genes that are commonly included in clinical or DTC tests.

|

Evidence levels can vary

|

No prescribing actions are recommended  
  
D

|

There are few published studies, clinical actions are unclear, little
mechanistic basis, mostly weak evidence, or substantial conflicting data. If
the genes are not widely tested for clinically, evaluations are not needed.

|

Evidence levels can vary

|

No prescribing actions are recommended  
  
**  
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.