ModifiedColorado Rocky Mountain Health PlansPolicy MMP391.16

Pharmacogenomics Testing

Policy governing coverage and medical necessity criteria for pharmacogenetic/pharmacogenomic testing (single-gene, multi-gene panels, and combinatorial tests) that inform drug selection or dosing; applies to Colorado Rocky Mountain Health Plans members and providers. Establishes covered and non-covered indications, definitions, and applicable CPT codes.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyPharmacogenomics Testing

Policy CodePolicy MMP391.16

Change TypeContent removal and coding clarification

Effective DateMar 1, 2026

Next Review Date

Key ActionDocument clinical indication and test validity showing the patient will use results to alter drug selection or dosing when seeking coverage.

SourceLink

POLICY UPDATE CHANGES

Removed content/language addressing HTR2A (5-Hydroxytryptamine Receptor 2A) and HTR2C (5-Hydroxytryptamine Receptor 2C).

Added notation to indicate CPT code 0033U was 'deleted Dec. 31, 2025'.

Updated Clinical Evidence, FDA, and References sections to reflect the most current information.

CPIC A/BActionability standard

TPMTExample covered test

SeveralNamed non-covered panels

1 RCT

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RCTs for urinary biomarker impact

13 RCTsMeta-analysis trials cited

0033UDeleted CPT code

Coverage Criteria and Rationale

Medically Necessary Pharmacogenomics Testing

Covered when ALL of the following are met

Clinical indication and actionability: The patient has a condition for which clinical evaluation determined the need for a medication with a known gene–drug interaction and test results would directly impact drug selection or dosing.

Documentation should demonstrate that results would change management (see Definitions/Instructions).

Evidence standards: The test demonstrates actionability by meeting either: CPIC guideline level A or B for the relevant gene–drug pair OR inclusion in the FDA Table of Pharmacogenomic Biomarkers/Pharmacogenetic Associations supporting therapeutic recommendations or potential impact on safety/response.CPIC level A/B or FDA-listed

Analytical validity, clinical validity, and clinical utility should be established for the test (per Definitions).

Laboratory and validity requirements: The test is performed in an appropriately certified laboratory (e.g., CLIA/CAP) and has demonstrated analytical validity, clinical validity, and clinical utility appropriate to the clinical context.AV/CV/CU demonstrated

See Instructions for Use and related MolDx/LCD guidance for documentation expectations.

Actionable PGx Testing

Covered when test results are expected to inform prescribing based on authoritative sources

Actionable criteria: The test provides genotype information that will lead to selection, avoidance, or dose modification of therapy based on FDA drug labeling or warnings, or CPIC level A or B gene–drug interaction guidance.CPIC level A or B or FDA actionable guidance

An intended therapeutic change not supported by these sources is not considered Actionable Use.

Test validity and utility: The test demonstrates analytic and clinical validity and evidence of clinical utility sufficient to justify changing prescribing decisions in the intended population.AV/CV/CU established

Tests should be evaluated using transparent peer-reviewed processes and follow MolDx/LCD/coding guidance where applicable.

Examples of supported single-gene testing: Single-gene testing with CPIC level A guidance and FDA association (e.g., TPMT prior to thiopurine therapy) is an example of actionable testing that meets criteria.

Coverage decision logic (evidentiary requirements)

Summary of evidence for urinary biomarker testing (including FPI) to change PCP treatment decisions

Evidence requirements for clinical utility: 1) High-quality randomized trials demonstrating that use of the urinary biomarker panel improves patient-centered clinical outcomes (pain, function, quality of life) AND 2) Independent validation of individual biomarkers and the proprietary algorithm with low risk of bias.both conditions required

Current evidence includes one RCT showing physician decision metrics but the GRADE certainty is very low; methodological limitations and COI exist in validation studies.

Coverage logic for PGx and pain biomarker testing

Coverage should align with demonstrated clinical utility and validity; where evidence is limited or inconsistent, testing is informational or not clearly supported.

PGx for MDD with demonstrated benefit: PGx-guided antidepressant selection may be covered when testing focuses on validated actionable genes (primarily CYP2C19 and CYP2D6) and is intended to change medication selection or dosing, supported by randomized trials and meta-analyses showing improved short-term response/remission (typically at 8–12 weeks).evidence of benefit at 8–12 weeks

Benefits vary by panel composition and trial quality; preferential use of targeted panels is recommended.

PGx for psychiatry without established utility: Multigene or combinatorial panels that include genes without established dosing guidance or use proprietary algorithms lacking independent validation are considered of uncertain clinical utility; coverage requires documentation that the panel contains clinically actionable genes and that results will directly inform treatment decisions.panel must include actionable genes and justification

Heterogeneity across panels and proprietary algorithms limits generalizability of evidence.

Tests for which analytical validity, clinical validity, or clinical utility have not been established are considered not reasonable and necessary. This includes named proprietary panels and urinary biomarker assays identified in the policy as unsupported — for example, the urinary Foundation Pain Index (FPI) and certain commercial psychiatry panels (e.g., Psych HealthPGx Panel, Genomind Professional PGx Express CORE) that the document specifically lists as not reasonable and necessary. These tests should not be used as the basis for clinical management in routine practice unless and until their AV/CV/CU are demonstrated.

Providers should expect that requests for coverage of such tests will be evaluated against demonstrated assay validation and outcomes evidence; absence of these validation domains is a primary rationale for noncoverage. The policy directs clinicians to rely on tests with established analytic and clinical performance and on panels whose results have proven utility to change prescribing decisions and improve patient outcomes.

An intended change in therapy based on genotyping that is not supported by FDA labeling, an FDA warning, or CPIC level A or B is not considered an Actionable Use under this policy. Coverage for pharmacogenomic testing requires that genotype information would lead to selection, avoidance, or dose modification of therapy consistent with these authoritative sources.

In practice this means tests used to inform prescribing must target gene–drug pairs with guidance at CPIC level A or B or be otherwise recognized in FDA pharmacogenomic resources; therapeutic changes proposed outside these standards are not supported for coverage.

Reviewed professional society guidelines do not include urinary biomarkers as part of chronic pain management pathways. The policy cites multiple guideline sources (ASA, American Academy of Pain Medicine, NICE, ICSI, PEER, ACP, HHS task force) and notes there is no role for urine-based biomarker testing in current standard-of-care treatment algorithms for chronic pain.

Because professional guidance does not reference these urinary biomarker tests, their routine use for chronic pain management is not supported by established clinical practice recommendations and is a factor in the policy’s noncoverage determination.

The policy references a Genetic Test Assessment (ECRI) concluding that evidence for the Foundation Pain Index (and similar urine-based biomarker panels) is inconclusive. The assessment highlights very limited outcomes data, small and single-center studies, and methodological limitations that prevent establishing clinical validity or utility for FPI.

Accordingly, urinary biomarker tests such as FPI are characterized in the policy as lacking sufficient independent validation and robust outcomes evidence and therefore are treated as unsupported for routine clinical use.

Systematic reviews and health-technology assessments report inconsistent clinical utility across multi-gene pharmacogenomic tests. The Ontario Health Technology Assessment and meta-analyses cited in the policy note heterogeneity in panel composition, study design, populations, and outcome measures such that the effectiveness demonstrated for one commercial test may not generalize to other panels.

Because panels vary in genes included and often use proprietary algorithms, the policy emphasizes that clinical utility must be demonstrated for the specific test being ordered rather than inferred from results of different products. Targeted panels focusing on established actionable genes (for example, CYP2C19 and CYP2D6 in psychiatry) are favored over large heterogeneous combinatorial assays.

Genetic tests that do not have established analytical validity, clinical validity, or clinical utility — including the specific proprietary/commercial panels and urinary biomarker tests named in the policy — are considered not reasonable and necessary and are therefore not covered.

The policy lists examples of noncovered tests (e.g., Foundation PI, Psych HealthPGx Panel, Genomind Professional PGx Express CORE) to illustrate situations where lack of demonstrated AV/CV/CU drives a noncoverage decision.

The policy concludes that biomarkers proposed for chronic pain (including urinary panels and exploratory serum metabolite assays) have insufficient evidence to support clinical implementation. The cited literature — narrative reviews, systematic reviews, and observational studies — indicates preliminary associations but lacks validated biomarkers and high-quality outcome trials.

Because the available studies are heterogeneous, frequently observational, and often limited in sample size and design, the policy states these biomarkers do not have the required evidence base to inform routine clinical decision-making for chronic pain.

Biomarkers for chronic pain are not established as medically necessary due to the absence of robust, high-quality evidence demonstrating that use of these tests improves patient-centered outcomes such as pain, function, or quality of life.

The policy notes the need for well-designed randomized controlled trials with adequate sample sizes and validated biomarker definitions before such tests could be considered medically necessary.

Novel biomarker tests for chronic pain — specifically the Foundation Pain Index (FPI) and similar urine-based multi-analyte panels that rely on proprietary algorithms — lack demonstrated clinical validity and utility according to a Genetic Test Assessment referenced in the policy. ECRI found the evidence inconclusive and highlighted methodological limitations and small-study bias.

Accordingly, these novel biomarker assays are not considered medically necessary for routine management of chronic pain absent independent validation and outcomes data showing improved clinical care.

A Hayes Clinical Utility Evaluation cited in the policy reported insufficient evidence to support use of pharmacogenomic testing for medication or dose selection in ADHD. This assessment (Hayes, 2022; updated 2025) concluded that existing studies do not demonstrate clear clinical utility for ADHD management.

The policy therefore considers PGx-guided ADHD medication dosing as unsupported for routine clinical decision-making until higher-quality evidence demonstrates improved clinical outcomes.

Indications Considered Medically Necessary

Pre-treatment testing when a medication with known gene–drug interaction is planned; TPMT prior to thiopurine supported

Covered when ALL of the following are met

Planned therapy with known gene–drug interaction: Testing is ordered before initiation of a medication for which a known gene–drug interaction exists and where results would change drug selection or dosing.pre-treatment

Documentation must show the medication is being considered and that results would alter management.

Specific supported single-gene example: TPMT genotyping prior to thiopurine initiation (mercaptopurine, azathioprine, thioguanine) when testing will inform initial dosing, consistent with CPIC level A recommendations and FDA pharmacogenomic associations.CPIC level A

See CPT code 81335 for TPMT testing and related diagnostic linkage guidance.

Tests and Uses Not Considered Medically Necessary

The policy explicitly lists urinary biomarker tests for chronic pain (e.g., Foundation PI) and specific commercial PGx panels among procedures that are not covered. The applicable code list includes CPT descriptors for pain-management urinary analyte algorithms and named psychiatry panels, which are marked as noncovered or provisional in the policy’s coding section.

Providers should reference the policy’s code listings when submitting claims; listed codes associated with these noncovered tests indicate the payer’s coverage stance for those services.

Gene–drug pairs classified as CPIC level C or D — or gene–drug relationships for which evidence does not support prescribing recommendations — are not supported for use in guiding therapy. Examples noted in the policy include CYP1A2, CYP3A4, COMT, and TYMS where CPIC guidance does not recommend dosing changes.

The policy therefore excludes clinical actions based on genotypes for these genes and does not consider testing for these gene–drug pairs sufficient to justify changes in medication selection or dosing.

The document reiterates that biomarkers for chronic pain, whether urinary or exploratory serum metabolites, are not supported for clinical use because the evidence base is inadequate. Systematic reviews and narrative reviews conclude that while some metabolomic signals have been reported, few metabolites have been independently validated as clinically useful biomarkers.

Given these persistent evidence gaps, the policy deems such biomarker testing not medically necessary for routine evaluation or management of chronic pain.

Urinary biomarkers for chronic pain are not referenced in the professional society guidelines reviewed by the policy authors. The absence of endorsement from major guideline sources (ASA, AAPM, NICE, ICSI, ACP, HHS task force, and others) is noted as a key reason these tests are not established for routine care.

Billing Codes and Status

Non-Covered CPT CodesCPTNot Covered

0031U

CYP1A2 (cytochrome P450 family 1, subfamily A, member 2) gene analysis, common variants (i.e., *1F, *1K, *6, *7)

Non-Covered / Provisional CPT CodesCPTNot Covered

0032U	COMT (catechol-O-methyltransferase) (drug metabolism) gene analysis, c.472G > A (rs4680) variant
0033U	HTR2A (5-hydroxytryptamine receptor 2A), HTR2C (5-hydroxytryptamine receptor 2C) gene analysis, common variants (Deleted 12/31/2025)
0117U	Pain management, analysis of 11 endogenous analytes, LC-MS/MS, urine, algorithm reported as a pain-index score (Foundation PI)
0173U	Psychiatry genomic analysis panel, includes variant analysis of 14 genes (Psych HealthPGx Panel)
0175U	Psychiatry genomic analysis panel, variant analysis of 15 genes (Genomind Professional PGx Express CORE)
81230	CYP3A4 (cytochrome P450 family 3 subfamily A member 4), gene analysis, common variant(s) (e.g., 2, 22)
81346	TYMS (thymidylate synthetase), gene analysis, common variant(s) (e.g., tandem repeat variant)

Covered CPT CodesCPTCovered

81335

TPMT (thiopurine S-methyltransferase) gene analysis, common variants (e.g., *2, *3)

Referenced LCD/LCA/MolDx documents and codesmixed

L39073	Pharmacogenomics Testing (LCD)
A58812	Billing and Coding: Pharmacogenomics Testing (LCA)
L39063	Pharmacogenomics Testing (LCD)
A58801	Billing and Coding: Pharmacogenomics Testing (LCA)
L39995	Pharmacogenomic Testing (LCD)
A59915	Billing and Coding: Pharmacogenomic Testing (LCA)
L39616	Urinary Biomarkers for Chronic Pain Management (LCD)
A59423	Billing and Coding: Urinary Biomarkers for Chronic Pain Management (LCA)
L38394	Pharmacogenomics Testing (MolDX)

Additional MolDx referencesmixed

A58324	Billing and Coding: MolDX: Pharmacogenomics Testing
L38335	MolDX: Pharmacogenomics Testing
A57384	Billing and Coding: MolDX: Pharmacogenomics Testing
L38337	MolDX: Pharmacogenomics Testing
L38337	MolDX: Pharmacogenomics Testing

Applicable CPT Codes NotationCPT

0033U

Deleted Dec. 31, 2025 (formerly a CPT code referenced for PGx testing)

Provider Responsibilities, Documentation, and Prior Authorization

Prior Authorization

Prior authorization: none specified

Prior authorization: None specified in the source text. No explicit prior authorization requirements are stated for the referenced tests in these source chunks. Providers should verify member-specific benefit documents and any delegate requirements for prior authorization.

No explicit PA rules listed in policy text
Follow member-specific benefit plan for coverage/authorization

Billing Rule

Coding and prior authorization note

Coding and prior authorization note: CPT code 0033U was deleted effective 12/31/2025 in the source coding list; providers must follow current coding guidance and any delegate-managed prior authorization processes applicable to the member's plan.

Definitions and Test Characteristics

Actionable Use — definition per FDA/CPIC

DefinitionGenotype information that may lead to selection, avoidance, or dose modification of therapy when the change is supported by FDA drug labeling, an FDA warning/safety communication, or CPIC level A or B gene–drug guidance.

ScopeAn intended therapy change based on genotyping that is NOT supported by FDA labeling, FDA warnings, or CPIC A/B is not considered actionable.

Use requirementActionability requires that results would directly impact drug management (selection, avoidance, or dosing).

Analytical Validity — definition and performance metrics

DefinitionAssessment of a test's technical performance (sensitivity, specificity, accuracy, precision) to determine if the assay detects the intended variant reliably and accurately.

Key metrics

Clinical and Operational Guidance for Providers

Documentation Required

Document pre‑/post‑test counseling for PGx in psychiatry

When PGx testing is used to guide psychiatric medication selection, document pre‑ and/or post‑test counseling about the implications of results and how they will affect treatment decisions, particularly given variable evidence for multigene panels.

Policy requires documentation of pre‑ or post‑test counseling when PGx guides psychiatric medication selection.
Counseling should address limitations of testing and how results will be applied to prescribing decisions.

Documentation Required

Document that PGx results will produce actionable management changes

Ensure documentation demonstrates that PGx test results will lead to an actionable management change (clinician used results to tailor treatment); coverage depends on evidence that results will alter prescribing or dosing decisions.

Studies emphasize clinicians used PGx results to tailor treatments; PREPARE and meta‑analyses focus on actionable phenotypes (CYP2C19/CYP2D6).

Background and Evidence Summary

Pharmacogenomic variation can alter drug response through effects on drug receptors, transport/uptake mechanisms, and drug metabolism pathways, potentially changing therapeutic effectiveness or risk of adverse events. The policy frames pharmacogenomic testing (single-gene, multi-gene panel, and combinatorial tests) as tools intended to inform medication selection or dosing when results are expected to change clinical management.

When used appropriately — that is, for gene–drug pairs with established clinical guidance and in tests with demonstrated analytic and clinical validity — PGx testing can be incorporated into treatment decisions to optimize efficacy and safety.

Policy Revision History

2026-03-01policy_revisionLatest

Removed policy language referencing HTR2A and HTR2C from the Coverage Rationale and updated supporting sections (Clinical Evidence, FDA, References); archived prior version MMP391.15.

2025-12-31code_update

Noted deletion of CPT code 0033U (formerly referenced for pharmacogenomic testing) effective Dec. 31, 2025.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyPharmacogenomics Testing

Policy CodePolicy MMP391.16

Change TypeContent removal and coding clarification

Effective DateMar 1, 2026

Next Review Date

Key ActionDocument clinical indication and test validity showing the patient will use results to alter drug selection or dosing when seeking coverage.

SourceLink

On This Page

See CPT code listings for specific covered single-gene codes.

Genetic tests for chronic pain biomarkers (e.g., FPI): Urinary biomarker panels such as the Foundation Pain Index lack established clinical validity and clinical utility per independent assessment; these tests are not supported for routine management of chronic pain absent robust clinical outcomes data and independent validation.absence of demonstrated outcomes utility

ECRI and systematic reviews judged evidence inconclusive with very low certainty for impact on PCP treatment decisions.

PGx testing to guide drug selection/dosing when results are actionable per FDA labeling/warnings or CPIC A/B and test has AV/CV/CU

Covered when ALL of the following are met

Actionability standard: Pharmacogenomic testing to guide drug selection or dosing is covered when the genotype information is actionable per FDA labeling/warnings or CPIC level A or B gene–drug interactions.CPIC A/B or FDA actionable

Actionability requires that analytic validity, clinical validity, and clinical utility are established for the test.

Test validity and documentation: The test used must have demonstrated analytical validity, clinical validity, and clinical utility and documentation must be provided showing how results will be used to change treatment.AV/CV/CU established

Follow MolDx/LCD coding and documentation guidance when applicable.

MDD — PGx testing focusing on actionable genes (CYP2C19/CYP2D6) used to guide medication selection/dosing when it will change management

Covered when ALL of the following are met

Clinical context: MDD: Patient has a diagnosis of major depressive disorder and testing is intended to guide antidepressant selection or dosing.MDD diagnosis

Ordering clinician should document indication and planned management changes.

Gene focus and panel composition: Testing focuses on clinically actionable pharmacogenes with established prescribing guidance (primarily CYP2C19 and CYP2D6); panels should emphasize these genes rather than large heterogeneous panels that include unvalidated variants.CYP2C19/CYP2D6 prioritized

Evidence and subgroup analyses in trials often used CYP2C19/CYP2D6-based recommendations.

Expectation of management change: Results are expected to change medication selection or dosing and the treating clinician will act on results.will change management

Studies demonstrate modest short-term improvements (8–12 weeks) in response/remission when PGx-guided therapy is used.

Major depressive disorder (MDD) — RCTs and meta-analyses show modest improvements when testing focuses on key genes

Covered when ALL of the following are met

Evidence of improved short-term outcomes: Randomized controlled trials and meta-analyses demonstrate modest but statistically significant improvements in response and/or remission at approximately 8–12 weeks when pharmacogenomic-guided treatment is used compared with treatment as usual.improvement at 8–12 weeks

Meta-analyses report increased likelihood of remission and response in PGx-guided groups, though heterogeneity and risk of bias exist.

Limitations and generalizability: Benefits vary by study design, panel composition, population, and trial quality; some trials used panels assessing additional genes beyond CYP2C19/CYP2D6 and many panels use proprietary algorithms which may limit generalizability.acknowledge heterogeneity

Larger panels show diminishing clinical returns; targeted testing is preferred when possible.

This lack of guideline support contributes to the policy’s determination that urinary biomarker testing for chronic pain is not an accepted component of chronic pain management.

The policy summarizes the Genetic Test Assessment and related literature as finding the Foundation Pain Index evidence inconclusive, with clinical validity and clinical utility not established. The assessment points to small, heterogeneous studies and insufficient outcomes data to justify clinical implementation.

Consequently, the Foundation Pain Index is listed among tests with unestablished validity and utility and is treated as not covered for routine clinical management of pain.

Multiple reviews cited in the policy highlight panel heterogeneity and the inclusion of unvalidated variants across commercially available pharmacogenomic assays. This heterogeneity, combined with proprietary algorithms, complicates interpretation and reduces confidence that findings from one panel apply to another.

Therefore, large combinatorial or multi-gene panels that include many genes without established dosing guidance may not be supported unless the specific test demonstrates analytic and clinical validity and a clear impact on management.

The policy emphasizes that multi-gene PGx tests with heterogeneous content and proprietary decision algorithms have inconsistent evidence of effectiveness and may not generalize across tests. Health-technology assessments and meta-analyses found variable results among evaluated products, underscoring that utility should be proven for each specific test.

As a result, coverage decisions depend on demonstration of validated performance and clinical benefit for the particular multi-gene panel rather than assumptions based on other tests.

CPT 0033U deleted 12/31/2025 (was listed in applicable codes)
Follow current CPT/HCPCS coding and payer/delegate PA rules

Denial Risk

Insufficient validity/utility

Insufficient validity/utility: Tests lacking established Analytical Validity (AV), Clinical Validity (CV), or Clinical Utility (CU) are considered not reasonable and necessary and may be denied. Examples in the source include certain pharmacogenomic panels and the Foundation Pain Index where AV/CV/CU were not established.

Non-covered when AV, CV, or CU not established
Psych HealthPGx and Genomind Professional PGx Express CORE cited as not reasonable/necessary

Note

No direct statements of authorization

No direct statements of authorization: The source documents do not include explicit blanket authorization statements for the referenced tests; coverage decisions should be based on member benefit documents, applicable Medicare guidance (NCD/LCD/LCA), MolDx directives, and the Coverage Rationale in this policy.

If no applicable NCD/LCD/LCA, refer to Coverage Rationale
Medicare source materials supersede internal policy where conflicts exist

Documentation Required

Clinical indication and test validity documentation

Clinical indication and test validity documentation: Providers must document the clinical indication showing that a medication with a known gene–drug interaction is being considered and that the test results would directly impact drug management. Documentation should also demonstrate test validity (AV/CV) and clinical utility (CU), and reference CPIC level A/B guidance or FDA gene–drug interaction tables when applicable.

Document condition and how test would alter management for medications with known gene–drug interactions
Reference CPIC level A/B or FDA pharmacogenomic biomarkers where applicable
Maintain availability of supporting documentation for coverage review

Note

Studies reported urine or serum biomarke

Studies reported urine or serum biomarker linkage to patient-reported outcomes: The source includes observational studies and one RCT evaluating urine-based biomarker panels (Foundation Pain Index) showing associations with PROMIS-29 or SF-36 scores and some provider behavior changes in simulated cases, but evidence quality was graded very low or inconclusive for clinical validity and utility.

Peabody et al. (2020) RCT: provider decision changes in simulated patients using FPI (one RCT)
Pope et al. (2021) and Amirdelfan et al. (2020): associations between FPI biomarkers and PROMIS-29/SF-36
ECRI concluded evidence inconclusive; clinical validity and utility not established

Billing Rule

Diagnosis linkage for certain CPT codes

Diagnosis linkage for certain CPT codes: Specific diagnosis codes are associated with some CPT codes (for example, CPT 81335 is linked to leukemia, transplant, autoimmune diagnoses, and certain transplant status codes). Ensure correct ICD-10 linkage when submitting claims.

CPT 81335 associated with diagnoses including acute/chronic leukemias, transplant status (e.g., Z94.0, Z94.84), and selected autoimmune codes
Verify effective/deleted code dates and use current diagnosis codes

Step Therapy

No step therapy rules are specified

Step therapy: No step therapy rules are specified in the source chunks for these tests. Management emphasis in the evidence sections notes lifestyle, nutritional, and standard nonopioid therapies as current approaches where applicable.

No plan-level step therapy requirements listed in policy text
Clinical management may emphasize nonpharmacologic and nutritional approaches in pain contexts

Note

Follow plan and delegate requirements

Follow plan and delegate requirements: Medicare Advantage policies may be used to support coverage decisions; however, providers must follow member-specific benefit documents and any delegate-managed utilization management and prior authorization requirements.

If a delegate manages prior authorization for a member's plan, follow the delegate's requirements
Retain supporting documentation and follow member plan and administrative guides for coverage verification

Includes sensitivity, specificity, accuracy, and precision as measures of acceptable technical performance.

FocusAnalytical validation evaluates whether the test measures what it was designed to measure, not its clinical usefulness.

Clinical Utility — definition

DefinitionThe ability of a test to provide information that informs patient care and management such that use of the results leads to treatment that improves health outcomes.

Coverage relevanceCMS places primary emphasis on Clinical Utility when assessing whether a test guides patient management and improves outcomes.

Evidence requirementDemonstration that test-guided management changes lead to improved patient-centered outcomes is needed to establish CU.

Clinical Validity — definition

DefinitionThe ability of a test to accurately classify a patient's circumstance into diagnostic, prognostic, or predictive categories in the defined population.

CharacteristicsClinical Validity is not fixed; it includes the test's ability to detect the disease/variant and reliably predict clinical condition or outcome.

DistinctionDifferent from analytical validity (technical performance) and clinical utility (impact on outcomes).

Combinatorial PGx Test — definition and use of proprietary algorithms

DefinitionA multi-gene pharmacogenomic panel that uses a proprietary algorithm to evaluate pharmacokinetic or pharmacodynamic relationships and produce drug recommendations or warnings.

CharacteristicRelies on algorithmic synthesis of multiple gene results rather than single-gene guidance.

Coverage noteProprietary algorithms can limit generalizability and may require evidence that the algorithm-driven recommendations improve outcomes.

Multi-Gene Panel — definition

DefinitionA laboratory test detecting genetic variants in at least two genes where the clinician orders a defined panel rather than individual single-gene tests.

Ordering distinctionOrdering two or more single-gene tests individually is not considered a panel; panels are predefined multi-gene lists.

Coverage implicationPanel composition should include clinically actionable genes to support coverage for management decisions.

Single-Gene Test — definition

DefinitionA laboratory test detecting relevant genetic variants of a single gene; simultaneous individual orders of multiple single-gene tests do not constitute a panel.

Use caseSingle-gene tests (e.g., TPMT) can be covered when there is an established CPIC level A recommendation and intended to change management.

Ordering noteClinicians should order single-gene tests when only one gene is needed to inform therapy rather than a broader panel.

Actionable Use — genotype info leading to selection/avoidance or dose modification

DefinitionGenotype information that leads to selection or avoidance of a therapy, or to dose modification, when supported by FDA labeling, FDA warnings, or CPIC level A/B guidance.

Clinical implicationActionable genotype results must be expected to directly inform prescribing decisions (selection, avoidance, dosing).

Non-actionable exampleTherapy changes based on genotyping not supported by FDA or CPIC A/B are not considered actionable and are excluded from this definition.

Analytical Validity (AV) — technical performance assessment

DefinitionAnalytical Validity (AV) — the assessment of technical performance (sensitivity, specificity, accuracy, precision) to confirm the test measures the intended variant reliably.

ImportanceRequired evidence domain to support that reported variants are correctly detected before considering clinical validity or utility.

DocumentationClinical documentation should reference the test's analytical validation when seeking coverage for genotype-guided management.

Clinical Utility (CU) — definition

DefinitionClinical Utility (CU) — the ability of a test to provide information that informs patient care and where using results leads to treatment changes that improve health outcomes.

Assessment focusEvidence should show that test-guided management improves patient-centered outcomes (e.g., symptom relief, function, quality of life).

Coverage relevanceCMS emphasizes clinical utility when determining whether a test should guide management and be covered.

Clinical Validity (CV) — definition

DefinitionClinical Validity (CV) — extent to which a test result accurately classifies or predicts a clinical condition, and reliably detects the variant/disease in the defined population.

RoleNecessary to demonstrate that the genotype meaningfully correlates with the clinical state before asserting clinical utility.

Not fixedClinical validity can vary by population, indication, and study design; validation in the intended-use population is required.

Multi-Gene Panel (duplicate)

DefinitionA laboratory test detecting variants of at least two genes ordered as a defined panel rather than separate single-gene orders.

Ordering distinctionPanels are predefined lists of genes selected and ordered as a unit by the clinician.

Coverage considerationPanel heterogeneity and inclusion of non-actionable genes may limit generalizability of evidence across panels.

Single-Gene Test (duplicate)

DefinitionTest detecting relevant variants of a single gene; multiple single-gene tests ordered individually are not considered a panel.

Coverage exampleTPMT single-gene testing (CPT 81335) is an example of a covered single-gene test when used pre-treatment to guide thiopurine dosing.

Practical noteUse single-gene testing when only one gene will inform management to avoid unnecessary panel testing.

FPI definition — multi-analyte urine-based biomarker panel and proprietary algorithm

DefinitionFoundation Pain Index (FPI) — a multi-analyte urine-based biomarker panel plus a proprietary algorithm intended to identify biochemical abnormalities (e.g., micronutrient deficiencies, metabolic abnormalities, oxidative stress markers) purportedly associated with chronic pain.

Intended useDesigned to inform lifestyle, nutritional, or supplement-based treatment approaches targeting underlying biochemical abnormalities.

Evidence concernMechanistic rationale exists but interventions based on these findings lack high-quality evidence for improved clinical outcomes.

Actionable phenotype — genotype-derived phenotype with recommended medication changes

DefinitionA genotype-derived phenotype (e.g., non-normal CYP2C19 or CYP2D6 metabolizer status) that has a recommended change in medication selection or dose based on authoritative guidance.

ExampleCYP2C19 and CYP2D6 metabolizer phenotypes used to guide antidepressant selection/dosing in PGx-guided psychiatry trials.

RelevanceActionable phenotypes are the analytic focus in studies demonstrating reduced adverse drug reactions or improved remission rates when therapy is adjusted.

Clinical validity — extent to which a test result predicts a clinical condition; not established for FPI

DefinitionClinical validity — the extent to which a test result predicts a clinical condition or outcome; for the Foundation Pain Index, clinical validity has not been established per the Genetic Test Assessment.

Assessment findingECRI concluded evidence is inconclusive with very low-quality data and that clinical validity outcomes have not been established for FPI.

ImplicationAbsence of established clinical validity undermines the ability to demonstrate clinical utility for routine management of chronic pain.

Pharmacogenomic (PGx)-guided treatment — definition

DefinitionPharmacogenomic (PGx)-guided treatment — medication selection or dosing recommendations informed by a patient’s genotype (commonly CYP2C19 and CYP2D6) to improve outcomes such as antidepressant response or reduce adverse drug reactions.

Clinical contextPGx-guided psychiatry trials often base prescribing recommendations on CYP2C19 and CYP2D6 genotypes; studies report faster response/remission or fewer adverse drug reactions in some trials.

Coverage noteCoverage is considered when PGx results are actionable per FDA or CPIC A/B guidance and when evidence supports that using results changes management and improves outcomes.

Ordering clinicians should document how results will change medication selection or dosing.