CurrentAetnaPolicy 0715

Pharmacogenetic and Pharmacodynamic Testing

Customize your policy alerts

Sign up for Aetna Policy 0715 alerts

Get alerted when Policy 0715 changes without checking for updates manually.

Monitor payer policy activity

Receive email alerts as soon as relevant payer policies are published or updated.

This Aetna clinical policy bulletin defines which pharmacogenetic and pharmacodynamic genetic and molecular tests are considered medically necessary, which are considered experimental/investigational, and related constraints for members being considered for specific drug therapies.

Policy Summary

PayerAetna

PolicyPharmacogenetic and Pharmacodynamic Testing

Policy CodePolicy 0715

Change TypeNo material change

Effective DateSep 16, 2005

Last ReviewFeb 27, 2024

Next Review DateAug 10, 2023

Key ActionOrder and document the specific genetic/molecular test to assess candidacy for the named therapy and ensure the billed code and ICD-10 diagnosis match the policy selection criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

52medically necessary indications

51+not-medically-necessary examples

31experimental panels listed

12related policies

2genes supported for antidepressant selection

Coverage Criteria and Clinical Utility

Therapy-linked molecular/genetic test coverage

Covered when ALL of the following are met for each named test/indication:

Therapy-specific indication: The test is ordered for a member with the specified diagnosis who is being considered for the named therapy (for example: BRAF V600 testing for melanoma when considering vemurafenib; ALK fusion testing for NSCLC when considering crizotinib).

See therapy-linked listings (chunks 3–14) for enumerated test/therapy pairs.

Appropriate test selection: Testing uses the specific gene/test identified in the policy or an FDA-approved companion diagnostic when the drug label or guideline specifies a companion diagnostic (e.g., THxID BRAF, Vysis ALK FISH, Oncomine Dx).positive or actionable result by approved assay

Policy references FDA-approved companion diagnostics and requires documented tumor mutation status when selecting targeted agents (chunks 144–153).

Targeted testing preferred: Targeted single-gene or small targeted panels are preferred for the therapy-specific indication; broad/comprehensive NGS or liquid biopsy panels (e.g., FoundationOne CDx, Guardant360 CDx, FoundationOne Liquid CDx) are not considered to have proven advantage for many listed therapy-selection indications and are considered not medically necessary when targeted testing suffices.

Policy repeatedly states FoundationOne/Guardant360 not medically necessary where targeted testing is available (chunks 3, 4, 8, 12).

Documentation of intent and indication: The order and medical record must document the specific therapy under consideration and the diagnosis/ICD-10 code that meets the policy selection criteria for the test being requested.

Providers should document that testing is being performed to determine candidacy for the named therapy (coverage and ordering requirements in chunks 20, 30, 214–221).

Use of validated/cleared assays when available: When an FDA-cleared or -approved assay/companion diagnostic is available for the drug/indication, that validated/cleared assay should be used and documentation of the specific test and result retained in the medical record.

FDA-cleared assays and companion diagnostics are emphasized (chunks 94, 98, 144–153).

Oncology targeted panels

Covered when selection criteria for the indicated gene/panel and associated diagnosis are met

Panel-diagnosis match: The targeted genomic sequence panel is ordered for a member with a solid organ neoplasm whose ICD-10 diagnosis is listed for that panel in the policy (site-specific mapping required).match between billed ICD-10 and listed covered indications

Extensive ICD-10 site mappings for panels are provided (chunks 30, 34, 38–40).

Panel scope consistent with indication: The panel chosen must interrogate the gene(s) relevant to the therapy decision (use a targeted panel that includes the actionable alteration rather than broad NGS when a focused test suffices).panel includes the actionable gene(s)

Policy states broad panels (e.g., FoundationOne, Guardant360) are not necessary when targeted testing is adequate (chunks 30, 34, 38).

Coding and documentation: Claims must use the appropriate CPT/PLA/H CPT code for the performed panel and document clinical indication and intended therapy selection in the medical record.

Providers must map tests to listed codes and ensure selection criteria met (chunks 30, 33, 38, 56–59).

Pharmacogenetic single-gene testing

Covered when testing informs drug selection or dosing for medications with established pharmacogenetic guidance

Actionable single-gene PGx tests: Genotyping for single genes with established guidance (examples: CYP2C19 81225 for clopidogrel, CYP2D6 81226/associated U-codes for tetrabenazine/eliglustat, DPYD 81232 for 5‑FU contexts, TPMT genotyping/phenotyping for thiopurines) is covered when results will directly inform drug selection or dosing for the patient.presence of planned drug therapy where genotype impacts management

Policy lists covered single-gene tests and maps CPT codes to indications (chunks 20–23, 56–57).

Evidence-based use: Coverage is contingent on clinical situations where genotyping is consistent with product labeling, guideline recommendations, or evidence cited in the policy (e.g., HLA-B*5701 prior to abacavir; CYP2D6 testing prior to tetrabenazine doses >50 mg/day).testing aligned with label/guideline

Policy cites labeling and guideline-based examples (chunks 92, 119–122).

Avoid routine/unsupported uses: Routine use of PGx single-gene testing for indications without established evidence of improved outcomes (e.g., routine CYP2C9/VKORC1 testing to guide warfarin dosing) is not supported by the policy evidence summaries and may be considered not medically necessary.

Large trials and assessments do not support routine warfarin genotype-guided dosing (chunks 98–100).

Oncology site-based coverage

ICD-10 cancer site–linked coverage

Site-specific testing: Genomic tests for oncology are covered when the patient's tumor site (ICD-10 code) matches the site-specific indications listed for the test/panel in the policy (for example: KRAS/NRAS/BRAF testing for colorectal cancer ICD-10 C18.x–C20.x; NSCLC panels for C34.x).ICD-10 diagnosis within listed ranges

Extensive site-to-test code mappings are provided in chunks 30, 34, 38–40.

Companion diagnostic requirement when indicated: When a drug label or guideline requires an FDA-approved companion diagnostic for therapy selection, documented use of that companion diagnostic is required prior to coverage of the associated targeted therapy.positive result by FDA-approved companion diagnostic

Companion diagnostic linkage described (chunks 144–153).

Psychiatric panel noncoverage

Psychiatry pharmacogenetic panels

Named psychiatric multigene panels — not covered for listed psychiatric indications: Specific combinatorial/multigene psychiatry pharmacogenetic panels (examples listed such as GeneSight, RightMed reports, Genecept, GENETWORx Neuropsychiatric Panel) are identified in the policy as CPT codes not covered for the psychiatric ICD-10 diagnoses listed (e.g., depressive disorders, anxiety disorders, ADHD, schizophrenia).N/A

Policy enumerates CPT/PLA codes for psychiatry panels that are not covered for the listed mental health diagnoses (chunks 52–55).

Use in select complex cases: While broad/combinatorial psychiatry panels are generally not covered for listed routine psychiatric indications, testing may be considered in select complex or treatment-resistant cases when documentation supports how results will change management; such requests should be supported by prior authorization and evidence review.documentation of treatment-resistant status or other complex clinical justification

Policy cites limited and inconsistent evidence for clinical utility and suggests payer review/prior authorization in some PGx contexts (chunks 155–156, 236).

Code mapping and evidence context

Coding-based coverage notes and clinical evidence summary

Code-specific coverage mapping: The policy lists many specific PLA/CPT/HCPCS codes and designates some as covered if selection criteria are met and others as not covered for specified indications; providers must bill the code that matches the performed assay and the indication in the medical record.use of correct CPT/PLA/HCPCS code

See coding tables and CPT lists in chunks 20–24, 30–38, 52–60 for exact code mappings.

Evidence informs coverage status: Coverage determinations reflect the evidence summarized in the policy (e.g., routine UGT1A1 genotyping prior to irinotecan lacks sufficient prospective outcome data; warfarin genotype testing not supported by large RCTs/CMS).

Policy background summarizes evidence that underlies code-based coverage and noncoverage (chunks 98–104, 115, 138).

Tetrabenazine (Xenazine) — CYP2D6 genotyping

Drug-specific guidance or recommendations described in the text:

CYP2D6 — tetrabenazine dosing: Prior to prescribing tetrabenazine at planned daily doses greater than 50 mg, perform CYP2D6 genotyping; poor metabolizers should not be given daily doses >50 mg and dosing recommendations in the product label apply.planned tetrabenazine dose >50 mg/day

FDA labeling recommends CYP2D6 genotyping prior to doses >50 mg/day (chunks 92, 7).

Warfarin — CYP2C9 and VKORC1 genotyping — evidence and coverage stance

Warfarin-related statements and evidence:

Warfarin genotype testing stance: Although CYP2C9 and VKORC1 variants explain some warfarin dose variability and several assays are cleared, randomized trials and technology assessments have not demonstrated improved clinical outcomes from routine genotype-guided warfarin dosing; CMS concluded testing to predict warfarin responsiveness is not reasonable and necessary for Medicare beneficiaries.

FDA clearances exist for some assays but RCTs and CMS assessment do not support routine clinical benefit (chunks 94, 98, 99, 100).

Clopidogrel and CYP2C19

Antiplatelet therapy (clopidogrel/prasugrel/ticagrelor):

Clopidogrel/CYP2C19 considerations: Evidence from randomized and observational studies does not consistently demonstrate that routine CYP2C19 genotyping to guide antiplatelet choice improves clinical outcomes; guideline/labeling notes metabolism differences but do not mandate universal testing. Consider genotype information in high-risk settings and document how results will influence therapy (alternative agents such as prasugrel or ticagrelor may be used in poor metabolizers).clinical context where clopidogrel effectiveness is critical

Policy cites NEJM and Lancet analyses and clinical alerts; co-prescription with CYP2C19-inhibiting SSRIs may increase ischemic risk (chunks 90, 91, 244).

Irinotecan — UGT1A1 testing guidance and evidence

Irinotecan-related UGT1A1 testing:

UGT1A1 testing for irinotecan: UGT1A1*28 homozygosity is associated with increased risk of severe neutropenia on irinotecan; product labeling suggests considering reduced initial dose for homozygotes and FDA-cleared assays are available, but routine pre-treatment genotyping is not mandated and prospective randomized evidence that testing improves outcomes is limited.UGT1A1 7/7 genotype (homozygous)*

Policy summarizes association evidence and notes lack of consensus on dose reduction and limited prospective outcome data (chunks 101, 103, 104, 115).

Extracted coverage guidance and evidence-based stances

Coverage stance and contextual criteria from the evidence and guideline excerpts in this section.

HLA-B*5701 prior to abacavir: Screening for HLA-B*5701 prior to initiating abacavir is supported; HLA-B*5701-positive patients should not receive abacavir and the result should be recorded as an abacavir allergy.one-time prior to first exposure

Randomized trial (Mallal et al) demonstrated prevention of immunologically confirmed hypersensitivity (chunks 121).

HLA-B*5801 / HLA-B*1502 testing: Consider HLA-B*5801 testing prior to allopurinol in specified high-risk ethnic groups (Koreans with stage 3+ CKD; Han Chinese and Thai) and HLA-B*1502 testing prior to carbamazepine in individuals of Asian ancestry per labeling and guidelines.ethnicity and renal function–based

Policy references guideline and FDA labeling recommendations (chunks 119–122).

UGT1A1/UGT1A family testing stance: Although UGT1A1 variants are associated with irinotecan toxicity risk, EGAPP and assessments found insufficient evidence to recommend routine universal UGT1A1 genotyping to modify irinotecan dosing as standard of care.

Policy reflects limited prospective randomized data and lack of consensus (chunks 115, 103–104).

Extracted coverage guidance and evidence-based stances — evidence summaries

Summaries of evidence and implications for clinical utility:

MTHFR testing evidence: Evidence for MTHFR C677T/A1298C predicting antifolate chemotherapy response is inconsistent and does not support routine clinical use to guide therapy selection.

AHRQ assessment and variable study results summarized (chunk 126).

Urinary thromboxane (11-dhTxB2): Urinary 11-dhTxB2 assays (e.g., AspirinWorks) correlate with thromboxane generation and FDA studies defined a cut-off (<1500 pg/mg creatinine) for aspirin effect; however, correlation with platelet aggregation tests is imperfect and routine clinical utility to guide aspirin therapy is not established.<1500 pg 11-dhTxB2/mg creatinine for aspirin effect

FDA device evaluation and cut-off described (chunk 131).

AUC‑targeted 5‑FU and DPYD/TYMS testing: AUC-targeted 5‑FU dosing and DPYD/TYMS genotype testing have limited and mixed evidence; DPYD/TYMS testing has poor predictive value for toxicity and has not been demonstrated to guide dosing to reduce toxicity without affecting tumor response.

TEC assessment and mixed trial results summarized (chunks 138, 140).

BRAF V600 testing and companion diagnostics: BRAF V600 mutations are common in melanoma and actionable for approved targeted therapies; FDA-approved companion diagnostics (e.g., THxID BRAF, cobas 4800, Oncomine Dx) exist and are used to select patients for BRAF-targeted therapy.positive BRAF V600 mutation by approved test

FDA approvals and companion diagnostic linkage described (chunks 141, 144–149).

Oncology companion diagnostic-linked coverage

Coverage for targeted oncology therapy is tied to documented tumor genomic status:

Companion diagnostic requirement for BRAF-targeted therapy: For BRAF-targeted agents (dabrafenib, trametinib, encorafenib/binimetinib, vemurafenib), the tumor must have the specified BRAF V600 mutation as detected by an FDA-approved companion diagnostic prior to initiating the corresponding therapy.positive result by FDA-approved companion diagnostic

FDA approvals and companion diagnostic linkage described (chunks 144–149).

Companion diagnostic requirement for ALK-targeted therapy: For ALK-targeted therapy (e.g., crizotinib), the tumor must be ALK-positive as detected by an FDA-approved test (e.g., Vysis ALK Break Apart FISH) prior to therapy initiation.positive ALK rearrangement by FDA-approved test

Vysis ALK Break Apart FISH kit was approved concurrent with crizotinib (chunk 153).

ALK companion diagnostic-linked coverage

Coverage for ALK-targeted therapy:

children":[],"threshold":"positive ALK rearrangement by FDA-approved test","note":"Crizotinib approval was concurrent with the Vysis ALK Break Apart FISH Probe Kit (chunk 153)."}

Psychiatric pharmacogenomic panels — evidence characterization

Evidence summary for commercial psychotropic pharmacogenomic panels (e.g., GeneSightRx):

Clinical utility evidence: Available studies of commercial psychotropic combinatorial panels show mixed results: small RCTs and open-label studies report variable improvements in symptom scores or remission rates, while other RCTs show non-significant trends; overall evidence is limited, of low strength, and cost-effectiveness remains unclear.evidence not consistently replicated

Policy background synthesizes multiple GeneSight and other PGx studies and systematic reviews (chunks 155–158, 236, 238).

Coverage implication: Because evidence is inconsistent and limited, many named commercial psychotropic multigene panels are listed as CPT codes not covered for the psychiatric indications enumerated; prior authorization or case-by-case review may be required for complex or treatment-resistant cases with documented management plans.documented treatment-resistance or complex justification

Policy lists specific CPT codes not covered and suggests payer review/PA in some contexts (chunks 52–56, 236).

Platelet reactivity/function testing (VerifyNow P2Y12) — coverage stance

Informational and investigational use; clinical utility for routine post-PCI decision-making is not established.

VerifyNow P2Y12 testing stance: Platelet reactivity/function testing (e.g., VerifyNow P2Y12) identifies high on-treatment platelet reactivity associated with increased risk of stent thrombosis in observational studies, but randomized trials (e.g., GRAVITAS) of intensifying antiplatelet therapy in HPR patients did not reduce major cardiovascular events; routine use after PCI to guide therapy changes is not supported by current evidence.

GRAVITAS and related data summarized (chunks 199–200, 207).

ADRB2 genotyping for asthma — coverage stance

ADRB2 genotyping has mixed and inconsistent evidence and is not established for routine use to direct long-term beta-agonist therapy.

ADRB2 evidence summary: Studies of ADRB2 variants (Arg16Gly, Gln27Gly and haplotypes) show inconsistent associations with bronchodilator response and exacerbation risk; randomized trials and meta-analyses generally do not support routine genotype-directed long-term beta-agonist therapy decisions.

Multiple trials and meta-analyses show inconsistent or no effect (chunks 208–215, 216).

MGMT promoter methylation assay for gliomas — coverage stance

MGMT methylation testing is recognized by guidelines to inform chemotherapy decisions in glioblastoma.

MGMT methylation testing for glioblastoma: Assess MGMT promoter methylation in glioblastoma when the result will influence use of temozolomide; NCCN includes MGMT methylation status in recommendations for assessing likelihood of benefit from temozolomide.test ordered when result will affect temozolomide decision

Policy cites NCCN guidance and Hegi et al review supporting use for treatment decisions (chunks 12, 217).

Evidence summaries — no explicit coverage rules in excerpt

Clinical-use summaries and evidence statements (no explicit payer coverage criteria in this excerpt):

Evidence summaries — general: The policy provides multiple clinical-use evidence summaries (e.g., ADRB2, MGMT, TPMT, commercial multi-gene panels) that describe analytical validity, clinical associations, and limitations of outcome data; these summaries inform but do not by themselves constitute detailed payer rules in this excerpt.

See evidence discussion across cited chunks for details on clinical validity, utility, and limitations (chunks 216–217, 222, 224, 229).

TPMT and thiopurines: TPMT genotyping/phenotyping before thiopurine therapy can identify variant carriers for dose reduction to reduce hematologic adverse reactions; randomized prospective data support genotype-directed dosing in selected contexts and cost-effectiveness evidence is mixed.variant carrier identified

Coenen et al prospective TPMT trial summarized (chunks 222, 224).

IFNL3/IL28B context: IFNL3 (IL28B) genotype (rs12979860, rs8099917) predicts higher likelihood of rapid virologic response and sustained virologic response to peginterferon-alpha plus ribavirin in certain HCV genotypes and may inform shared decision-making when Peg-IFNα/RBV is considered.IFNL3 CC or TT genotype

Multiple cohort and regression studies summarized (chunks 249–253).

IFNL3 genotype predictive criteria

IFNL3 genotyping and peginterferon-alpha/ribavirin therapy:

IFNL3 genotype predictive criteria: IFNL3 genotyping (e.g., rs12979860 CC or rs8099917 TT) is associated with higher rates of rapid virologic response and sustained virologic response to Peg-IFNα plus ribavirin and may be used to inform shared decision-making for Peg-IFNα/RBV regimens, particularly in non-RVR patients.genotype == rs12979860 CC or rs8099917 TT

Policy summarizes CPIC and cohort evidence describing predictive associations (chunks 249–253).

Antidepressant pharmacogenomic testing

Pharmacogenomic testing for antidepressant selection:

Antidepressant PGx evidence: Some combinatorial and single-gene pharmacogenomic tests have shown promise in isolated RCTs or observational studies for short-term improvements in remission or tolerability, but overall evidence is limited, inconsistent, and of low strength; cost-effectiveness is unclear and results have not been widely replicated.clinical benefit not consistently replicated

Systematic reviews and RCT summaries cited (chunks 236, 238–241).

Coverage implication: Routine coverage of broad combinatorial pharmacogenomic panels for antidepressant selection is not supported by replicated high-quality evidence; coverage decisions should be based on documented clinical justification, and prior authorization may be required for exceptions (e.g., treatment-resistant depression).documented treatment-resistance or justification

Policy lists many psychiatry panel CPT codes as not covered and recommends case review (chunks 52–56, 236).

CYP interaction considerations

CYP-mediated drug interactions and monitoring:

CYP interaction considerations: When prescribing clopidogrel concomitantly with SSRIs that inhibit CYP2C19 (e.g., fluoxetine, fluvoxamine), consider the potential for reduced clopidogrel activation and an associated modestly increased risk of ischemic events; document rationale and consider alternative agents or monitoring as clinically appropriate.co-treatment with clopidogrel + CYP2C19-inhibiting SSRI

Cohort evidence shows increased ischemic event risk with CYP2C19-inhibiting SSRIs (chunk 244).

CYP monitoring for other drug interactions: CYP genotyping or increased therapeutic monitoring may be considered when drug combinations or substrates have known CYP-mediated interactions that alter active metabolite profiles (example: diazepam metabolites with CYP2C19/CYP3A modifiers).co-administration with known strong CYP inhibitors/inducers

Urine metabolite and database analyses discussed (chunks 242–243).

The policy identifies a large set of multi-gene pharmacogenetic panels and related proprietary assays as experimental or investigational (not covered) for the indications listed in this bulletin. Examples explicitly named include Genecept Assay; GeneSight (GeneSight ADHD, GeneSight Analgesic, GeneSight MTHFR, GeneSight Psychotropic, GeneSightRx); INFINITI Neural Response Panel; IDgenetix; Millennium PGT; GENETWORx Neuropsychiatric Panel; OneOme RightMed Pharmacogenomic Test; PersonaGene Genetic Panels; PersonalisedRx; Proove Profiles; RightMed Comprehensive Test, RightMed Gene Report, RightMed PGx16 Test; rxSEEK Epilepsy Drug Metabolism; Aegis Drug-Drug Interaction Test; Amerigene PGT; CQuentia pharmacogenetic comprehensive panel; PGxOnePlus; and other similarly described multi-gene panels. These enumerated panels are listed in the policy scope as examples of multi-gene pharmacogenetics panels considered experimental/investigational and therefore excluded from routine coverage for the CPB-listed clinical indications.

The scope text also lists related assays and monitoring tests that fall under the same ‘experimental/investigational’ designation when used for the CPB indications, including urine thromboxane metabolites (AspirinWorks), ComplyRX urine drug monitoring, OnDose AUC-targeted 5-FU dosing, IFNL3/IL28B genotyping for interferon response, and several other named products. Providers should assume that billing for these multi-gene or proprietary pharmacogenetic panels for the listed psychiatric, chronic pain, adherence-monitoring, or other non-supported indications may be denied per the policy.

The policy explicitly lists multiple CPT/HCPCS/PLA codes and ICD-10 condition groupings as examples of codes and diagnoses that are not covered for the indications listed in this CPB. Examples called out in the coding sections include PLA/CPT entries such as 0029U (broad drug metabolism targeted sequence analysis) and 0030U (warfarin-related targeted sequence analysis), HCPCS G9143 (warfarin responsiveness testing by genetic technique), and BRCA duplication/deletion CPT entries (eg, 81164–81167) appearing in not-covered lists for certain indications. The policy also enumerates psychiatric and behavioral ICD-10 categories (eg, F20–F39, F40–F48, F90.1–F90.9) adjacent to panels that are not covered for those mental health diagnoses.

Additionally, the CPB identifies many specific PLA/CPT entries for psychiatric and multigene PGx panels as not covered (see block of psychiatric panel codes) and lists other CPT codes as not covered for listed CPB indications (for example, tenofovir urine quantification 0025U is shown in the not-covered code list for PrEP/exposure-related ICD-10 codes). Providers should verify coding against the CPB mapping because use of these listed codes for the stated indications may trigger claim denial.

The targeted 324‑gene oncology panel identified as CPT 0037U is explicitly cited in multiple coding sections of the CPB as a CPT code that is not covered for the indications listed. The policy places 0037U in the list of targeted genomic sequence analyses that are not considered medically necessary for the CPB-specified indications and therefore billing this code for those indications may be subject to denial.

Where large comprehensive NGS panels are contemplated, the CPB emphasizes that targeted single-gene or small-panel testing is preferred for many therapy-selection contexts and that use of broad 324‑gene panels (eg, 0037U) for those listed indications is identified as not medically necessary.

The policy names numerous commercial tests/panels and describes their coverage context, frequently listing them as experimental, investigational, or not covered for the CPB indications. Examples called out across the coding and scope sections include RightMed panels (Right Med Comprehensive Test; Right Med PGx16/PGx25/PGx27 reports), OneOme RightMed, GENETWORx Neuropsychiatric Panel, Aegis Drug‑Drug Interaction Test, Proove Profiles (including Proove opioid/response panels and Proove narcotic risk panel), CQ uentia panels, INFINITI Neural Response Panel, PGxOnePlus, and similar proprietary combinatorial PGx products. These tests are repeatedly listed under the multi-gene pharmacogenetic panel examples and within the CPT/PLA code not-covered lists for the relevant psychiatric, chronic pain, adherence-monitoring, or other CPB-specified diagnostic categories.

The CPB therefore frames the coverage context for these named commercial products as not covered/experimental for the listed CPB indications, and it instructs providers to use specific single-gene CPT codes or validated companion diagnostics where coverage criteria are met rather than billing broad proprietary panel codes for the excluded indications.

Indications Where Testing Is Covered

Codes and Billing Guidance

Named example assays referenced as medically necessarymixedCovered

Vysis ALK Break Apart FISH Probe Kit	Example assay for ALK fusion gene testing
Ventana ALK (D5F3) CDx Assay	Example assay for ALK fusion gene testing
BRACAnalysis CDx	Example assay for BRCA testing
cobas 4800 BRAF V600 mutation test	Example assay for BRAF V600 mutation testing

Broad/comprehensive panel assays identified as not medically necessary for specific indicationsmixedNot Covered

FoundationOne CDx	Comprehensive genomic profiling panel — specified as not medically necessary for many therapy-specific indications
FoundationOne Liquid CDx	Liquid biopsy comprehensive genomic panel — specified as not medically necessary for many indications
Guardant360 CDx	Comprehensive liquid biopsy panel — specified as not medically necessary for some indications
Agilent Resolution ctDx FIRST	ctDNA assay — specified as not medically necessary for certain indications

Multi-gene pharmacogenetic panels listed as experimental/investigationalmixedExperimental

GeneSight Psychotropic	Example multi-gene pharmacogenetic panel listed as experimental/investigational
OneOme RightMed Pharmacogenomic Test	Example multi-gene pharmacogenetic panel listed as experimental/investigational

ABCD1 / VLCFA testingCPT

82726

Very long chain fatty acids.

Genotyping for CYP2C19CPTCovered

81225

CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) gene analysis, common variants (eg,*2,*3,*4,*8,*17).

Genotyping for CYP2D6mixedCovered

0028U	CYP2D6 gene analysis, copy number variants, common variants with reflex to targeted sequence analysis.
0070U	CYP2D6 gene analysis, common and select rare variants.
0071U	CYP2D6 full gene sequence (list separately).
0072U	CYP2D6 targeted sequence analysis (CYP2D6-2D7 hybrid).
0073U	CYP2D6 targeted sequence analysis (CYP2D7-2D6 hybrid).
0074U	CYP2D6 targeted sequence analysis (non-duplicated gene when duplication/multiplication is trans).
0075U	CYP2D6 targeted sequence analysis (5' gene duplication/multiplication).
0076U	CYP2D6 targeted sequence analysis (3' gene duplication/multiplication).
81226	CYP2D6 gene analysis, common variants.

Genotyping for cytochrome P450 and related genesmixed

0029U	Drug metabolism targeted sequence analysis (multiple CYP and other genes) - listed as CPT code not covered for indications in the CPB.
0030U	Drug metabolism (warfarin drug response) targeted sequence analysis (CYP2C9, CYP4F2, VKORC1, rs12777823).
0031U	CYP1A2 gene analysis, common variants.
81230	CYP3A4 gene analysis, common variants.
81231	CYP3A5 gene analysis, common variants.
81232	DPYD gene analysis, common variants.
81346	TYMS gene analysis, common variant(s).

Molecular pathology / HCPCSmixed

81400-81408	Molecular pathology.
G9143	Warfarin responsiveness testing by genetic technique - listed as HCPCS not covered for CPB indications.

UGT1A1, VKORC1, HLA testingCPT

81350	UGT1A1 molecular assay - listed as CPT code not covered for indications in the CPB.
81355	VKORC1 gene analysis - listed as CPT code not covered for indications in the CPB.
81381	HLA Class I typing, high resolution; one allele or allele group.

BRCA and large oncology panelsmixed

0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes (e.g., FoundationOne CDx)
0172U	Oncology somatic mutation analysis of BRCA1/BRCA2 and HRD pathways, DNA, FFPE.
81162	BRCA1/BRCA2 full sequence analysis and full duplication/deletion analysis.
81163	BRCA1/BRCA2 full sequence analysis.
81165	BRCA1 full sequence analysis (alternate entry).
81212	BRCA1/BRCA2 specific variant panel (185delAG, 5385insC, 6174delT).
81215	BRCA1 known familial variant.
81216	BRCA2 full sequence analysis.
81217	BRCA2 known familial variant.
81164	BRCA full duplication/deletion analysis - listed as CPT codes not covered for CPB indications.

1–10 of 12

1/2

Oncology actionable mutation codes (BRAF, NRAS, EGFR)CPTCovered

81210	BRAF gene analysis, V600 variants.
81311	NRAS gene analysis, exon 2 and 3 variants.
81235	EGFR gene analysis, common variants (exon 19 deletion, L858R, T790M, etc).

Liquid biopsy and PD-L1 / IHC testingmixed

0242U	Targeted genomic sequence analysis panel, cell-free DNA, analysis of 55-74 genes (Guardant 360 CDx).
0326U	Targeted genomic sequence analysis panel, 83+ genes (listed as CPT code not covered for CPB indications).
88360	Morphometric analysis, tumor IHC, per specimen, each single antibody stain; manual.
88361	Morphometric analysis using computer-assisted technology.

Large panels and high-level molecular proceduresmixed

0239U	Targeted genomic sequence analysis panel, 311+ genes, cell-free DNA - listed as CPT code not covered for some indications.
81404	Molecular pathology procedure, Level 5.

Covered CPT/HCPCS examples (variable by selection criteria)CPT

0239U

Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free DNA, analysis of 311 or more genes

Covered single-gene molecular CPT examplesCPTCovered

81404

Molecular pathology procedure, Level 5

Targeted genomic panels (some covered, some noted not covered in places)CPT

0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes
0154U	FGFR3 gene analysis
0155U	PIK3CA gene analysis

MSI / MMR testing codesCPTCovered

81301	Microsatellite instability analysis
88341	Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain
88342	Immunohistochemistry initial single antibody stain procedure

Psychiatry / multigene pharmacogenetic panels - Not coveredCPTNot Covered

0345U	Psychiatry genomic analysis panel (eg, GeneSight) — listed as not covered for psychiatric indications
0173U	Psychiatry genomic analysis panel — listed as not covered
0175U	Psychiatry genomic analysis panel — listed as not covered
0423U	Psychiatry genomic analysis panel — listed as not covered
0347U	Right Med Comprehensive pharmacogenetic panel — listed as not covered
0348U	Right Med PGx 25 gene report — listed as not covered
0349U	Right Med PGx 27 gene report — listed as not covered
0350U	Right Med PGx 27 gene report variant — listed as not covered
0392U	GENETWORx Neuropsychiatric Panel — listed as not covered
0380U	PersonalisedRx pharmacogenetic panel — listed as not covered

1–10 of 11

1/2

Oncology single-gene / copy number testingCPTCovered

0009U	Oncology (breast cancer), ERBB2 (HER2) copy number by FISH
81236	EZH2 gene analysis, full gene sequence
81237	EZH2 common variant(s) analysis

Cytogenetics / targeted variant codesCPTCovered

88271	Molecular cytogenetics; DNA probe, each (eg, FISH)
88275	Interphase in situ hybridization, analyze 100-300 cells
81120	IDH1 common variants
81121	IDH2 common variants

Other molecular / laboratory assay codesCPTCovered

81222	CFTR gene analysis; duplication/deletion variants
83789	Mass spectrometry and tandem mass spectrometry, non-drug analyte(s)
81287	MGMT methylation analysis

Pharmacogenetic / related diagnostic codesmixed

0347U	Drug metabolism or processing (multiple conditions), DNA analysis, 16 gene report, with variant analysis and reported phenotypes.
0348U	Drug metabolism or processing, 25 gene report, with variant analysis and reported phenotypes.
0349U	Drug metabolism, 27 gene report, with variant analysis, including reported phenotypes and impacted gene-drug interactions.
0350U	Drug metabolism, 27 gene report, with variant analysis and reported phenotypes.
0392U	Drug metabolism (depression, anxiety, ADHD), variant analysis of 16 genes, including CYP2D6 deletion/duplication analysis.
0380U	Drug metabolism, targeted sequence analysis, 20 gene variants and CYP2D6 deletion or duplication analysis with reported genotype and phenotype.
0434U	Genomic analysis panel, variant analysis of 25 genes with reported phenotypes.
0015U	Drug metabolism, DNA, 22 drug metabolism and transporter genes, genotype and metabolizer status for therapeutic decision support.
0078U	Pain management genotyping panel, 16 common variants, algorithm reported as risk.
0093U	Prescription drug monitoring, evaluation of 65 common drugs by LC-MS/MS, urine.

1–10 of 25

1/3

Codes referencedmixed

Not provided

No explicit CPT/HCPCS/ICD codes listed in this document segment.

FDA-approved NGS companion diagnosticmixed

Oncomine Dx

NGS companion diagnostic test detecting BRAF, ROS1, EGFR alterations for NSCLC; FDA-approved

FDA-approved companion diagnostics (named kits)mixed

THxID BRAF / THxID BRAF Kit	FDA-approved companion diagnostic for detection of BRAF V600E and V600K mutations
Vysis ALK Break Apart FISH Probe Kit	FDA-approved companion diagnostic to detect ALK rearrangements

Commercial pharmacogenomic panelsmixed

GeneSightRx

Commercial pharmacogenomic test/panel analyzing multiple pharmacokinetic and pharmacodynamic genes for psychotropic medication management

Commercial test products mentionedmixed

No codes listed

Gene count thresholds for panel coding distinctions

55-74 genes (example code)Mapped to targeted cell-free DNA panel CPT 0242U (55-74 gene panel).

83+ genes (example code)Mapped to targeted genomic sequence analysis CPT 0326U (83 or more genes) — listed as not covered for some CPB indications.

311+ genes (example code)Mapped to targeted genomic sequence analysis CPT 0239U (311 or more genes) — listed as not covered for some indications.

Gene count thresholds in targeted panels

311+ genesCPT 0239U — targeted genomic sequence analysis panel, cell-free DNA, analysis of 311 or more genes (listed as not covered for some indications).

324 genesCPT 0037U — targeted genomic sequence analysis, DNA analysis of 324 genes (listed in places as not covered for some CPB indications).

ContextHigh-complexity oncology panels (e.g., 0037U, 0239U) are variably covered only when selection criteria are met; several such large-panel codes are noted as not covered for listed indications.

Panel gene count examples

6-gene minimum panelCPT 81418 describes a drug metabolism genomic sequence analysis panel that must include at least 6 genes including CYP2C19 and CYP2D6 with duplication/deletion analysis.

16-gene examplesMultiple commercial panels referenced include 16-gene panels (eg, INFINITI Neural Response Panel, PROOVE components) mapped to PLA codes in the CPB listings.

20/22/25/27-gene panelsCommercial PLA/CPT-listed panels in the policy include 20-, 22-, 25-, and 27-gene reports (eg, OneOme 22-gene RightMed; PLA codes 0015U, 0347U–0350U describe 22–27 gene panels).

AspirinWorks (urinary 11-dhTxB2) cutoff

AspirinWorks urinary 11-dhTxB2 cutoffFDA studies established a cutoff for aspirin effect at less than 1500 pg 11-dhTxB2 per mg creatinine (i.e., <1500 pg/mg creatinine indicates aspirin effect).

Non-aspirin users resultIn FDA evaluation, 88.2% of samples from individuals not taking aspirin were above the 1500 pg/mg creatinine cut-off.

Aspirin-user nonresponse ratesIn evaluation, 5.5% of aspirin users overall indicated lack of aspirin effect (>1500 pg/mg creatinine); 4.3% of 81 mg/day users and 10.5% of 325 mg/day users showed lack of effect.

VerifyNow PRU thresholds reported in studies

PRU ≥222Varenhorst et al identified an optimal VerifyNow P2Y12 PRU cut-off for stent thrombosis at PRU ≥222 (sensitivity 70.2%, specificity 67.3%).

PRU ≥240Yu et al used a PRU cut-off of ≥240 to define low-response to clopidogrel in their cohort analyses (reported predictive analyses).

ContextStudies report substantial overlap in PRU distributions between patients with and without events; outcome benefit from PRU-directed therapy not established in randomized trials (eg, GRAVITAS).

Aspirin Reaction Units (ARU) threshold example

Aspirin Reaction Units (ARU) thresholdYu et al reported an ARU cut-off of ≥550 to define aspirin hypo-responsiveness in their cohort analysis.

Clinical predictive valueIn that study, ARU ≥550 did not predict 30-day or 1-year clinical event rates (no significant difference observed).

Assay differencesVerifyNow ARU measures platelet aggregation while AspirinWorks measures urinary thromboxane metabolite; assays capture different biological phenomena.

Hematologic adverse event thresholds

Leukocyte thresholdHematologic adverse event defined as leukocyte count < 3.0 x 10^9/L in TPMT/thiopurine study context.

Platelet thresholdHematologic adverse event defined as platelet count < 100 x 10^9/L in the referenced TPMT study.

ContextThese thresholds were primary safety endpoints used to assess hematologic ADRs in TPMT genotype-guided dosing trials for thiopurines.

Urine tenofovir concentration predictive threshold

Urine tenofovir concentration predictive threshold> 1,000 ng/ml — urine TFV concentration identified as highly predictive of plasma tenofovir > 10 ng/ml (reflecting recent dosing within ~48 hours).

Semi-quantitative ranges>1,000 ng/ml (high adherence within 48 h); 10–1,000 ng/ml (low adherence within 48 h); <10 ng/ml (non-adherence ≥1 week).

Use-case contextUrine TFV assay (UrSure) demonstrated higher sensitivity than plasma and may distinguish recent dosing windows; guideline endorsement not established.

Provider Guidance, Documentation and Authorization

Prior Authorization

Therapy‑linked tests: expect prior‑auth / medical necessity review

Prior authorization/medical-necessity review is implied for pharmacogenetic and pharmacodynamic tests that are ordered to determine candidacy for specific therapies; tests are covered only for the enumerated therapy‑specific indications and providers should follow payer prior‑auth processes when billing those therapy‑linked tests.

Prior Authorization

Ensure panel meets CPB selection criteria

High‑complexity targeted genomic panels and certain companion diagnostic NGS panels are covered only when the CPB selection criteria for that panel and indication are met; confirm that the patient and indication meet the policy’s selection criteria before ordering.

Prior Authorization

Confirm indication and diagnosis match policy selection criteria

Verify that the specific selection criteria in the policy are satisfied for high‑complexity genomic panels and single‑gene tests — including matching ICD‑10 cancer site/diagnosis ranges and the named therapy consideration — prior to ordering or billing.

Confirm the billed ICD‑10 maps to the CPB‑listed covered diagnosis for the test.
Document the intended therapy or therapeutic decision the result will inform.

Billing Rule

Use correct CPT/PLA/HCPCS codes and verify coverage before testing

Bill using the specific CPT/PLA/HCPCS code that corresponds to the performed assay and check payer coverage rules — several PLA/CPT codes for multigene panels are listed as not covered for CPB indications and may trigger claim denial if used inappropriately.

Map the assay performed to the gene‑specific CPT/PLA code (e.g., 81225 for CYP2C19).
Verify whether the code is listed as covered or not covered for the requested indication.

Note

Genetic testing is not universally required — use clinical judgment

The policy does not mandate genetic testing; clinician judgment directs whether testing is performed — labeling and clinical alerts make testing optional and do not require pre‑therapy genotyping in all cases.

Documentation Required

Use FDA‑cleared/validated assays and document the assay

When available and relevant, use FDA‑cleared or validated assays and document which cleared/validated assay was used and the clinical indication when reporting results.

Examples of cleared assays cited include Verigene (warfarin) and Invader UGT1A1.

Prior Authorization

Perform indicated HLA genotyping before high‑risk therapies

For therapies with known HLA risk associations, order HLA genotyping in the specified high‑risk groups prior to initiating therapy (e.g., HLA‑B*5801 or HLA‑B*1502 where indicated) and document results in the record.

Consider HLA‑B*5801 testing before allopurinol in defined high‑risk ethnic subgroups.
Consider HLA‑B*1502 testing in individuals of Asian ancestry prior to carbamazepine.

Documentation Required

Document companion diagnostic results when requesting targeted therapy

When requesting coverage for targeted oncology drugs, include documentation of tumor mutation testing performed with an FDA‑approved companion diagnostic and retain the companion diagnostic result in the medical record.

Companion diagnostics cited include THxID BRAF, cobas 4800 BRAF V600 test, Oncomine Dx, and Vysis ALK FISH.

Prior Authorization

Include documented tumor mutation testing in prior‑auth for targeted oncology drugs

Prior authorization requests for targeted oncology agents should include documented tumor mutation testing using an FDA‑approved companion diagnostic to support eligibility for the requested agent.

Prior Authorization

Expect payer review/prior‑auth for multi‑gene PGx panels

Because clinical utility varies across multi‑gene pharmacogenetic tests, payer review or prior authorization may be required to establish medical necessity before coverage is granted for multi‑gene PGx panels.

Documentation Required

Order MGMT methylation testing only if it will change temozolomide use

Order MGMT promoter methylation testing only when the result will directly affect the decision to use temozolomide in glioblastoma patients and document how the result will influence management.

Prior Authorization

Follow payer‑specific prior‑auth processes (not specified in this excerpt)

The excerpt does not specify a universal prior‑authorization workflow for pharmacogenetic tests; providers must follow payer‑specific prior authorization policies for genetic testing requests.

Prior Authorization

Obtain prior‑auth for PGx‑guided antidepressant testing where required

Given inconsistent RCT evidence and unclear cost‑effectiveness for many combinatorial pharmacogenomic tests used to guide antidepressant therapy, obtain prior authorization when required to document medical necessity.

Documentation Required

Use validated/central assays when therapy eligibility depends on the result

When eligibility for a targeted therapy depends on a test result, use a validated or central assay and provide the assay method and provenance (e.g., cobas EZH2 Mutation Test) when requesting therapy authorization.

Document the specific validated assay used and that it produced the actionable result.

Step Therapy

Step‑therapy: none specified in excerpt

No explicit step‑therapy rules are stated in this document excerpt; there are no operational step‑therapy requirements specified here.

Documentation Required

Order tests to assess candidacy for named therapy and document intent

Order tests to determine candidacy for a named therapy and document in the record that the test was ordered specifically to assess eligibility for the indicated treatment.

Include the intended therapy or treatment decision in the order and clinical notes.

Step Therapy

If CYP2C19 poor metabolizer identified, consider alternative antiplatelet therapy

If testing identifies a CYP2C19 poor‑metabolizer status, clinicians may consider alternative antiplatelet therapy (for example, prasugrel) or other treatment strategies; document the genotype consideration and rationale for any change.

Balance ischemic benefit against bleeding risk when selecting alternatives.
Document the decision and genotype result in the medical record.

Step Therapy

Do not prescribe abacavir to HLA‑B*5701‑positive patients; document as allergy

Do not prescribe abacavir to patients who test positive for HLA‑B*5701; record a positive result as an abacavir allergy and select an alternative regimen.

Document HLA‑B*5701 positive status in the medical record and allergy list.

Step Therapy

No operational step‑therapy rules provided in background

The background sections do not specify operational step‑therapy rules for medication sequencing or mandated trials of alternative agents prior to targeted therapies.

Denial Risk

Do not base step changes solely on VerifyNow results — outcome benefit unproven

Randomized trials (e.g., GRAVITAS) showed that intensifying clopidogrel based on VerifyNow platelet reactivity lowered PRU but did not improve 6‑month clinical endpoints; do not rely solely on VerifyNow‑based step changes to alter therapy without documented clinical rationale.

Note

Avoid initiating CYP2C19‑inhibiting SSRIs in patients on clopidogrel; document rationale

When patients are taking clopidogrel, avoid initiating SSRIs that inhibit CYP2C19 (for example, fluoxetine or fluvoxamine) when possible, or document the clinical rationale and monitoring plan if such co‑prescription is necessary.

Consider alternative SSRIs with less CYP2C19 inhibition.
Document risk/benefit discussion and monitoring strategy.

Documentation Required

Document that test was ordered to assess candidacy for the named therapy

Document in the medical record that the genetic or molecular test was ordered to assess candidacy for the named therapy and include the indication and how the result will affect therapeutic selection.

Record the intended therapy, relevant diagnosis/ICD‑10 code, and clinical rationale.

Documentation Required

Include matching ICD‑10 and clinical rationale to support medical necessity

Support medical‑necessity with diagnosis and indication: include the matching ICD‑10 code and clinical rationale for how the test result will influence treatment when submitting orders or claims.

Ensure billed CPT/HCPCS code corresponds to the covered indication listed in the policy.

Billing Rule

Use appropriate pathology/IHC CPT codes for MSI/MMR testing

When billing MSI or MMR testing, capture the appropriate pathology and IHC CPT codes (for example, 81301 for MSI analysis and 88342/88341 for IHC staining) as listed in the policy.

Use 81301 for MSI analysis and 88342/88341 for mismatch‑repair IHC procedures where applicable.

Billing Rule

Use gene‑specific CPT/PLA codes matching the performed assay

Bill using gene‑specific CPT/PLA codes that correspond to the actual assay performed (for example, 81225 for CYP2C19, 81226 for CYP2D6, 81418 for genomic sequence analysis panels) and ensure code selection reflects the test methodology (copy‑number analysis, sequencing, etc.).

Select codes that match whether the assay includes duplication/deletion analysis or targeted sequencing.

Documentation Required

Document CYP2C19 genotype consideration when selecting antiplatelet therapy

Document consideration of CYP2C19 genotype when making antiplatelet therapy decisions and record any alternative antiplatelet selection or monitoring rationale in the chart.

Record genotype result, discussion of alternatives, and chosen management plan in the medical record.

Documentation Required

Document assay provenance and labeling (which assay was used)

Record the provenance and labeling of the assay used (e.g., FDA‑cleared or central laboratory) when eligibility for therapy depends on the test result; include the assay name and whether it is FDA‑cleared/validated.

Documentation Required

Record HLA‑B*5701 result and mark positive results as abacavir allergy

For HLA‑B*5701 screening prior to abacavir, record the test result in the medical record and mark a positive result as an abacavir allergy.

Documentation Required

Include companion diagnostic result in record before targeted therapy

Provide the documented result from an FDA‑approved companion diagnostic (for example, THxID BRAF, Oncomine Dx, or Vysis ALK FISH) in the medical record prior to prescribing the corresponding targeted therapy.

Documentation Required

Document baseline assessments, prior treatments, and the specific PGx test used

When using PGx to guide medication changes, document baseline assessments, prior treatment history, the specific PGx test used (genes included), and how the test informed the prescribing decision.

Retain the test report and note which genes and variants were used in decision‑support.

Documentation Required

Document platelet reactivity results and any management changes

If platelet function testing (e.g., VerifyNow P2Y12) is used to guide post‑PCI therapy, document the on‑treatment reactivity measurement and any subsequent therapeutic changes, noting that platelet‑guided intensification did not improve 6‑month clinical endpoints in GRAVITAS.

Denial Risk

Avoid broad/comprehensive panels when targeted testing is available (denial risk)

Do not order broad/comprehensive NGS or liquid biopsy panels for therapy selection when a validated targeted single‑gene or small‑panel test is available for that indication; use of broad panels in such cases is identified as not medically necessary and may lead to noncoverage.

Examples of broad panels cited as not medically necessary include FoundationOne CDx, FoundationOne Liquid CDx, and Guardant360 CDx.

Denial Risk

Using not‑covered codes for listed indications may trigger denial

Billing a CPT/HCPCS code that the policy lists as 'not covered for indications listed in the CPB' may trigger claim denial; verify the code‑indication pairing before submitting claims.

Confirm that the CPT/PLA/HCPCS code is appropriate for the indication and is not listed as not covered.

Denial Risk

Psychiatric multigene panels and named PGx panels may be not covered for listed indications

Specific multigene pharmacogenetic and psychiatric panels (for example, GeneSight and several RightMed panels) are identified as not covered for listed psychiatric and other non‑oncology indications; billing these panels for the excluded diagnoses may result in denial.

GeneSight and RightMed panel CPT/PLA codes are listed as not covered for specified psychiatric ICD‑10 codes.

Denial Risk

Code‑based denial risk for listed multigene/PLA codes

Certain CPT and PLA codes for multigene pharmacogenetic panels and specialty tests are explicitly listed as 'CPT codes not covered for indications listed in the CPB' — using those codes for the listed indications is a code‑based denial risk.

Denial Risk

Warfarin genotype testing has limited demonstrated utility — potential denial risk

Routine warfarin genotype testing (CYP2C9/VKORC1) to guide initial dosing has not demonstrated improved clinical outcomes in large randomized trials and may not be supported for routine coverage.

Denial Risk

UGT1A1 testing prior to irinotecan: limited utility; document rationale

Routine UGT1A1 genotyping prior to irinotecan to guide dosing is of uncertain clinical value; evidence does not establish routine genotyping to prevent severe neutropenia and may affect coverage decisions.

Denial Risk

Confirm BRAF V600E by FDA‑approved companion diagnostic before BRAF‑targeted therapy

Confirm BRAF V600E mutation by an FDA‑approved companion diagnostic before initiating BRAF‑targeted therapy (e.g., dabrafenib + trametinib); absence of a documented FDA‑approved companion diagnostic result may trigger denial.

Denial Risk

Document FDA‑approved ALK companion diagnostic results for ALK inhibitors

Document ALK testing using an FDA‑approved companion diagnostic (e.g., Vysis ALK Break Apart FISH Probe Kit) when requesting coverage for ALK inhibitors; absence of documented ALK test results may affect coverage.

Tests and Panels Considered Not Medically Necessary

Aetna considers the enumerated multi-gene pharmacogenetic panels (see policy list) to be experimental/investigational and not medically necessary for the clinical indications listed in this CPB because the evidence does not demonstrate consistent clinical utility for routine decision-making.

Named examples include psychiatric and pain-focused panels (eg, GeneSight, Genecept, GENETWORx, OneOme RightMed, Millennium PGT, Proove Profiles) among others; these are presented in the policy as illustrative—not exhaustive—lists of tests treated as not covered for the specified CPB indications.

Broad/comprehensive genomic profiling panels and liquid biopsy NGS assays (for example FoundationOne CDx, FoundationOne Liquid CDx, Guardant360 CDx, Agilent Resolution ctDx FIRST) are identified in the policy as not medically necessary for many therapy-specific indications where targeted single-gene or small-panel testing is available and appropriate.

The policy emphasizes that use of these comprehensive panels for assessing candidacy for specific targeted therapies offers no proven advantage over validated targeted testing for those indications and therefore may be denied when used in place of indicated targeted assays.

The policy enumerates numerous tests and CPT/HCPCS examples that are identified as not covered for CPB-listed indications. Specific CPT/PLA codes cited in not-covered contexts include 0029U, 0030U, 0037U, 0239U, 0326U, and other high-gene-count targeted panel codes noted in the CPT tables.

These code-level listings are tied to particular indications or diagnosis code ranges in the CPB; billing the listed codes for the CPB-specified indications without meeting the documented selection criteria risks denial.

Multiple named pharmacogenetic panels used in psychiatry and related behavioral indications are explicitly listed as CPT codes not covered for the psychiatric ICD-10 diagnoses called out in the CPB. Examples include GeneSight family panels (no specific CPT listed), RightMed panels (0347U–0350U), GENETWORx Neuropsychiatric Panel (0392U), PersonalisedRx (0380U, 0434U) and others.

The policy states that use of these psychiatry-focused multigene PGx panels for the listed psychiatric diagnoses may be denied because evidence of consistent clinical utility and cost-effectiveness across these indications is limited and inconsistent.

The CPT code 0037U (targeted genomic sequence analysis of 324 genes) is repeatedly cited in the policy's CPT tables as a code not covered for the listed indications. It appears across oncology panel and MSI/MMR testing sections among codes not covered for CPB-listed uses.

Because 0037U is listed in multiple not-covered rows, the policy flags this specific high-gene-count panel as noncovered for the CPB indications unless a covered, therapy-specific selection criterion is met and a different covered code applies.

The policy lists numerous commercial PGx panels and PLA/CPT entries as experimental/investigational or not covered for CPB indications. Examples called out include Proove Profiles (multiple Proove panels), rxSEEK Epilepsy Drug Metabolism, PGxOnePlus, INFINITI Neural Response Panel, Aegis Drug-Drug Interaction Test, OnDose AUC testing, and many RightMed/OneOme variants.

These proprietary panels and many PLA codes are enumerated in the CPT tables as not covered for the specified psychiatric, chronic pain, adherence-monitoring, or other CPB-indicated diagnoses where evidence of clinical utility is insufficient.

The policy indicates that CYP2D6 genotyping to direct tamoxifen selection or for routine SSRI initiation/prevention is not supported by sufficient evidence to improve clinical outcomes and thus is not recommended in the preventive setting.

Assessments cited (eg, BCBS TEC, ASCO updates, AHRQ/EGAPP) conclude that current data do not support use of CYP2D6 testing to guide endocrine therapy selection or routine SSRI prescribing decisions until prospective trials demonstrate clinical benefit.

Randomized trials and technology assessments cited in the policy conclude that routine pharmacogenomic testing of CYP2C9 and VKORC1 (to guide initial warfarin dosing) has not demonstrated improved anticoagulation control or clinical outcomes. The Centers for Medicare & Medicaid Services (CMS) determined such testing to predict warfarin responsiveness is not reasonable and necessary for Medicare beneficiaries.

Consequently, routine genotype-guided warfarin dosing using these variants lacks supporting outcome evidence and is not supported for broad adoption per the CPB discussion.

Routine genotyping for UGT1A1, ApoE, and MTHFR to guide chemotherapy, statin therapy, or antifolate chemotherapy selection is not supported by sufficient evidence of clinical effectiveness. The policy summarizes TEC/EGAPP/AHRQ findings that these tests have limited predictive value and inconsistent associations with treatment outcomes.

For UGT1A1 specifically, although UGT1A1*28 homozygosity is associated with increased irinotecan neutropenia risk, prospective randomized data demonstrating that pre-treatment genotyping improves health outcomes are lacking, and routine preemptive testing is not established as standard of care.

Testing for DPYD and TYMS variants to guide 5‑FU dosing is described as having poor predictive value and no demonstrated utility to safely guide dose alterations that reduce toxicity without adversely affecting tumor response. TEC assessments found evidence insufficient to support routine DPYD/TYMS-based dosing adjustments.

Therefore, genetic testing of DPYD/TYMS for routine 5‑FU dose selection is not supported by the document’s evidence summaries.

The policy states that evidence for commercial psychiatry pharmacogenetic panels (for example GeneSight, OneOme RightMed, CNSDose and similar tests) is mixed and overall limited in strength. Randomized trials are few, often underpowered, and results are inconsistent, and economic evaluations provide unclear conclusions on cost-effectiveness.

As a result, combinatorial psychiatry PGx panels lack established clinical utility and broad cost-effectiveness evidence to warrant routine coverage across the listed psychiatric indications.

The policy emphasizes that multi-gene PGx tests should not be assumed interchangeable; effectiveness demonstrated for one proprietary test does not imply the same clinical utility for other tests. Differences in gene content, algorithms, and decision-support outputs create heterogeneity in potential clinical impact.

Because of this heterogeneity and the variable evidence base, multi-gene PGx panels without direct evidence of clinical utility for a specific assay or indication should not be presumed covered.

The policy finds insufficient evidence to support routine platelet reactivity/function testing (eg, VerifyNow P2Y12) after percutaneous coronary intervention for the purpose of changing antiplatelet therapy. Observational data link high on‑treatment platelet reactivity with stent thrombosis, but randomized trials (eg, GRAVITAS) that intensified therapy based on reactivity did not demonstrate improved clinical endpoints.

Therefore, routine use of platelet function testing to guide post‑PCI therapy changes is not supported and remains investigational pending outcome-driven trial results.

The policy flags commercial tests for which peer‑reviewed clinical utility is not established (for example Millennium PGT and PROOVE narcotic risk panels): these products have limited or no peer‑reviewed evidence supporting their clinical use for the CPB-indicated purposes.

As such, these named assays are presented as lacking sufficient evidence to support routine coverage for the listed indications.

The CPB states that routine coverage of combinatorial pharmacogenomic panels used to guide antidepressant selection is not supported because the available evidence is limited, inconsistent, and of low-to-moderate strength. While some individual studies show possible short-term symptom improvement, findings are not yet sufficiently replicated to support broad coverage.

Consequently, broad routine coverage of combinatorial antidepressant PGx panels is not endorsed in the policy absent stronger, replicated RCT and health‑outcome evidence.

The policy notes that current pre‑exposure prophylaxis (PrEP) guidelines do not recommend routine urine tenofovir monitoring and that available urine TFV assays (eg, UrSure) require additional studies to establish clinical utility and guideline endorsement.

Therefore, urine tenofovir monitoring for adherence assessment is not established as a recommended or covered routine test in the CPB context.

Testing Frequency and Repeat Testing

Repeat genotyping — CYP2C19 and CYP2D6

Repeat CYP2C19/CYP2D6 genotypingRepeat genotyping for CYP2C19 and CYP2D6 has no proven value; routine repeat genotyping is not indicated.

ScopeApplies to members prescribed clopidogrel and other listed CYP2C19/CYP2D6-linked therapies where repeat testing was considered in the policy scope.

RationalePolicy notes lack of benefit from repeat genotyping and treats initial genotype as the relevant information unless clinical circumstances change.

Frequency — CYP2D6 genotyping for tetrabenazine

CYP2D6 genotyping for tetrabenazine frequencyOne-time per patient unless clinical circumstances change — genotype recommended prior to tetrabenazine when daily dose exceeds 50 mg.

RationaleFDA labeling recommends genotyping prior to dosing >50 mg/day and indicates dosing limits for poor metabolizers.

RetestingNo routine repeat genotyping indicated unless clinical circumstances (eg, new therapies or changes) warrant reassessment.

Frequency — HLA-B*5701 screening

HLA-B*5701 testing frequencyOne-time per patient prior to first exposure to abacavir (screening before initiation).

Action on positive resultHLA-B*5701-positive status should preclude abacavir use and be recorded as an allergy in the medical record.

RationaleRandomized trial (Mallal et al) demonstrated elimination of immunologically confirmed hypersensitivity with prospective screening.

Frequency — Preemptive pharmacogenomic genotyping

Preemptive PGx genotyping frequencyOne-time — preemptive pharmacogenomic genotyping is generally described as a one-time test to be stored and used for future prescribing decisions.

Use-caseResults can be integrated into electronic health records and clinical decision support for later medication decisions.

RetestingNo routine repeat testing indicated; retesting only as clinically required or when new gene-variant assays are introduced.

Frequency — FGFR2 fusion and EZH2 mutation testing

FGFR2 fusion testing frequencyTypically one-time at diagnosis or prior to therapy initiation when used to determine eligibility for FGFR-targeted therapy (eg, pemigatinib).

EZH2 mutation testing frequencyTypically one-time at diagnosis or prior to therapy initiation when used to determine eligibility for EZH2 inhibitor therapy (eg, tazemetostat).

RationaleClinical trials and approvals used central validated assays performed at diagnosis or pre-therapy to select patients for targeted agents.

Frequency — VerifyNow P2Y12 / platelet function assays

VerifyNow / platelet function assays frequencyNot specified in the excerpt — no routine periodicity provided for VerifyNow P2Y12 testing.

ContextPolicy notes limited evidence for routine post-PCI platelet reactivity testing to guide therapy; studies (eg, GRAVITAS) did not show outcome benefit from assay-guided intensification.

RecommendationIf used, document results and management decisions; follow institution/payer rules for repeat testing.

Frequency — AspirinWorks / urinary 11-dhTxB2

AspirinWorks frequencyNot specified in the excerpt — no routine testing interval provided for AspirinWorks urinary 11-dhTxB2 assay.

ContextFDA studies established assay cut-off and performance characteristics but did not define recommended periodic retesting intervals in the policy excerpt.

DocumentationWhen used, document creatinine-normalized results and clinical rationale per device evaluation guidance.

Frequency — Commercial multi-gene panels (OneOme etc.)

OneOme / commercial panel retesting frequencyNo frequency limits specified in this excerpt for OneOme RightMed or other commercial multi-gene panels.

ContextOneOme RightMed is described as a 22-gene panel whose results cover many medications; policy does not specify periodic retesting intervals.

RecommendationRetesting only as clinically indicated (eg, if new actionable variants are identified or assay content changes).

General note where frequency limits absent

General absence of frequency specificationsNot specified in this section — where the policy excerpt does not provide frequency limits, no routine retesting interval is defined.

ImplicationProviders should follow test-specific labeling, clinical context, and payer rules when considering repeat testing.

ExceptionsSome tests (eg, HLA-B*5701, CYP2D6 for tetrabenazine) have explicit one-time recommendations; otherwise frequency is as clinically indicated.

No explicit retesting frequency provided

No explicit retesting frequency providedNot specified in this section — the policy does not provide an explicit retesting frequency or periodicity for many assays in the excerpt.

Clinical approachRetesting should be considered only when clinical circumstances change or when a new assay/therapeutic decision requires re-evaluation.

DocumentationRecord rationale for retesting in the medical record to support medical necessity where applicable.

How to Order and Document Tests

Note

Background and Evidence Summary

Pharmacogenetic and pharmacodynamic testing aims to identify genetic variants that influence drug metabolism, response, or risk of adverse drug reactions. The policy frames PGx testing as a tool to potentially guide medication selection or dosing when there is evidence that test results will meaningfully alter management.

However, the document stresses that clinical utility is gene-, drug-, and indication‑specific; some single‑gene tests (eg, HLA‑B*5701 prior to abacavir, certain FDA‑cleared companion diagnostics) have clear, evidence‑supported roles, whereas many multi‑gene panels lack consistent outcome data to support routine use.

Evidence summaries in the policy draw on randomized controlled trials, observational cohorts, systematic reviews, and technology assessments to assess clinical validity and utility. Where robust RCT data exist (for example, warfarin genotype trials or GRAVITAS for platelet testing), the CPB incorporates those trial results into coverage stance and denial‑risk discussion.

For many PGx applications the CPB finds evidence inconsistent, underpowered, or not replicated — leading to conservative coverage positions for broad multi‑gene panels and to targeted coverage where therapy‑linked testing or FDA‑approved companion diagnostics demonstrate validated benefit.

The policy highlights key utility considerations: single‑gene tests with established drug‑label guidance or strong trial/guideline support (eg, HLA‑B*5701 screening, MGMT methylation when it will inform temozolomide use) can be medically necessary when selection criteria are met, whereas many multi‑gene PGx panels and certain pharmacogenomic applications (eg, routine UGT1A1 screening to alter irinotecan dosing; MTHFR for chemotherapy selection; combinatorial PGx for antidepressant choice) lack high‑quality replicated evidence of improved clinical outcomes.

Therefore, the CPB supports a selective, evidence‑linked coverage approach: cover validated, therapy‑specific tests and companion diagnostics; consider single‑gene PGx where labeling or guidelines recommend testing; and treat broad/commercial multi‑gene panels as experimental/investigational absent demonstrated clinical utility.

For oncology, the policy ties coverage to actionable tumor genomic alterations demonstrated to select for FDA‑approved targeted therapies. Examples include BRAF V600 mutations in melanoma and NSCLC and companion diagnostic–linked approvals (eg, THxID BRAF, cobas 4800 BRAF, Oncomine Dx Target Test; Vysis ALK Break Apart FISH for ALK rearrangements).

When an FDA‑approved companion diagnostic exists and the tumor genomic status is required to determine eligibility for a targeted agent, documented testing with the approved companion diagnostic is required to support therapy selection and coverage.

Definitions and Key Terms

Definition — Multi-gene pharmacogenetics panels

Definition — Multi-gene pharmacogenetics panelsDiagnostic tests that identify genetic variations linked to drug metabolism or side effects across multiple drug classes; examples listed include GeneSight, OneOme RightMed, Millennium PGT, GENETWORx, and others.

Intended useDesigned to inform medication selection or dosing by reporting multiple gene variants and predicted phenotypes across drug classes.

Coverage status noteMany named multi-gene PGx panels are listed in the policy as experimental/investigational or not covered for certain indications in the CPB.

Definition — Pharmacogenetic testing

Definition — Pharmacogenetic testingGenetic testing of drug-metabolizing enzymes and related genes (eg, CYP2C19, CYP2D6, DPYD) to predict drug response or adverse reactions and guide therapy selection/dosing.

Biologic basisCYP enzymes account for ~75% of drug metabolism; polymorphisms can alter drug blood levels and response.

Clinical intentAim is to reduce ADRs and improve therapeutic response by tailoring medication choices or doses to genotype.

Definition — Targeted genomic sequence analysis panel

Definition — Targeted genomic sequence analysis panelMulti-gene sequencing panels for solid organ neoplasms used to detect sequence variants, copy number changes, rearrangements, MSI, and tumor mutational burden (examples: 0037U for 324 genes, 0242U for 55-74 genes).

Use-caseEmployed to identify actionable somatic alterations to guide targeted oncology therapy when selection criteria and ICD-10 mappings are met.

Coding examplesPolicy lists multiple CPT/PLA codes for panels of varying gene counts (eg, 0037U, 0242U, 0239U) with coverage conditional on indication.

Definition — MSI/MMR testing

Definition — MSI/MMR testingMolecular and immunohistochemical analyses to detect microsatellite instability and mismatch repair deficiency; relevant CPT codes include 81301 (MSI) and IHC codes 88341/88342 for MMR proteins.

Clinical useUsed for Lynch syndrome evaluation and to identify tumors that may respond to certain immunotherapies.

Coding notePolicy cites CPT 81301, 88341, and 88342 when selection criteria are met for coverage.

Definition — Cytochrome P450 (CYP) enzymes

Definition — Cytochrome P450 (CYP) enzymesA family of liver enzymes (eg, CYP2C9, CYP2C19, CYP2D6, CYP3A4) responsible for approximately 75% of drug metabolism; genetic polymorphisms can alter drug levels and response.

Clinical relevanceVariants can produce poor, intermediate, normal, rapid, or ultra-rapid metabolizer phenotypes affecting dosing and adverse event risk.

Testing examplesGenotyping for CYP2C19 (81225), CYP2D6 (81226/PLA codes) and others are discussed across the policy.

Definition — Pharmacogenomic testing

Definition — Pharmacogenomic testingLaboratory testing to determine how an individual's genetic factors may affect medication safety and effectiveness, to reduce ADRs and improve response.

GoalInform drug selection and dosing based on gene-drug relationships with established guidance (eg, CPIC).

IntegrationOften combined with clinical decision support systems for prescribing workflows.

Definition — CYP2D6 / CYP2C19 poor metabolizer

Definition — CYP2D6/CYP2C19 poor metabolizerIndividuals with loss-of-function alleles (eg, CYP2D6 *4/*4 or CYP2C19 *2/*2) leading to reduced enzyme activity and altered drug metabolism; may require dosing changes or alternative therapy.

Clinical implicationPoor metabolizer status can increase exposure to parent drugs or active metabolites depending on the pathway, influencing toxicity or reduced efficacy.

Testing impactGenotype results can inform selection of alternative agents (eg, consider prasugrel instead of clopidogrel for CYP2C19 poor metabolizers in high-risk contexts).

Definition — VKORC1

Definition — VKORC1Vitamin K epoxide reductase complex 1 — the molecular target of warfarin; genetic variants influence warfarin dose requirements and contribute to inter-individual dose variability.

Testing contextCombined CYP2C9 and VKORC1 genotyping can explain part of warfarin dose variability, but randomized trials have not shown routine genotype-guided dosing improves clinical outcomes.

Assay examplesFDA-cleared assays (eg, Verigene warfarin test) detect CYP2C9 and VKORC1 variants relevant to dosing calculations.

Definition — UGT1A1*28

Definition — UGT1A1*28A promoter dinucleotide repeat polymorphism in UGT1A1 associated with reduced glucuronidation of SN-38 and increased irinotecan-related toxicity (UGT1A1*28 homozygosity linked to higher neutropenia risk).

Clinical implicationProduct labeling suggests considering reduced initial irinotecan dose for UGT1A1*28 homozygotes though routine pre-treatment testing is not mandated by labeling.

Assay examplesInvader UGT1A1 molecular assay was FDA-cleared to detect UGT1A1 variants prior to irinotecan therapy.

Definition — CYP2D6 genotyping for tetrabenazine

Definition — CYP2D6 genotyping for tetrabenazineFDA recommends CYP2D6 genotyping prior to tetrabenazine treatment when planned daily doses exceed 50 mg to guide maximum dosing and limit exposure in poor metabolizers.

Actionable resultPoor metabolizers should not be given daily doses >50 mg; dosing adjustments are based on genotype.

Testing frequencyTypically a one-time test unless clinical circumstances warrant repeat genotyping.

Definition — HLA-B*5701

Definition — HLA-B*5701An HLA class I allele associated with abacavir hypersensitivity; screening prior to abacavir initiation reduces immunologically confirmed hypersensitivity reactions.

Clinical actionPositive HLA-B*5701 should preclude abacavir prescribing and be recorded as an abacavir allergy in the medical record.

EvidenceMallal et al randomized trial demonstrated elimination of immunologically confirmed hypersensitivity with prospective HLA-B*5701 screening.

Definition — rs3798220 (LPA)

Definition — rs3798220 (LPA)A non-synonymous SNP (I4399M) in the LPA gene associated with elevated Lp(a); observational studies suggest carriers may derive greater aspirin benefit for CV event reduction, but prospective utility is unproven.

Population frequencyMinor allele carriers were ~3.6% in the Women's Health Study cohort.

Clinical implicationTesting not established for routine aspirin selection; further prospective trials needed.

Definition — BRAF V600

Definition — BRAF V600Hotspot somatic mutation (commonly V600E) in exon 15 of BRAF associated with multiple solid tumors, notably melanoma (~50-60%); predictive for response to BRAF/MEK inhibitors.

Companion diagnosticsFDA-approved companion diagnostics (eg, THxID BRAF, cobas 4800 BRAF, Oncomine Dx) are used to identify patients for BRAF-targeted therapies.

Therapeutic relevanceBRAF V600 status used to select dabrafenib + trametinib and other BRAF-targeted therapies in melanoma and NSCLC per approvals cited.

Definition — Companion diagnostic

Definition — Companion diagnosticA genetic test approved by the FDA to detect specific mutations (eg, BRAF V600E/K, ALK rearrangements) used to determine patient eligibility for a corresponding targeted therapy.

ExamplesTHxID BRAF, cobas 4800 BRAF, Oncomine Dx, Vysis ALK Break Apart FISH Probe Kit are cited as companion diagnostics in the policy.

Documentation requirementDocumented result from an FDA-approved companion diagnostic is required prior to prescribing the corresponding targeted agent per policy guidance.

Definition — Combinatorial pharmacogenomic tests

Definition — Combinatorial pharmacogenomic testsMulti-gene PGx tests that integrate variants across multiple pharmacokinetic and pharmacodynamic genes to generate medication recommendations (eg, GeneSight, NeuroIDgenetix).

Clinical intentIntended to provide actionable prescribing recommendations by combining gene variants and drug interaction data.

Evidence notePolicy summarizes mixed and limited evidence for clinical utility and cost-effectiveness of such tests in psychiatry.

Definition — Actionable gene-drug pairs

Definition — Actionable gene-drug pairsGene-drug relationships with established dosing or selection guidance (eg, CPIC level A/B, PharmGKB level 1) that can influence prescribing decisions (eg, CYP2D6, CYP2C19).

Clinical useThese pairs form the basis for single-gene pharmacogenetic testing where evidence supports dosing or selection changes.

ExamplesCYP2D6/CYP2C19 recommended for certain antidepressant/antipsychotic dosing per expert consensus cited in policy.

Definition — High on-treatment platelet reactivity (HPR)

Definition — High on-treatment platelet reactivity (HPR)Elevated platelet reactivity measured while on antiplatelet therapy (eg, VerifyNow P2Y12 PRU above study-specific cut-offs such as ≥222 or ≥240) associated with higher stent thrombosis risk in observational analyses.

Study thresholdsVarenhorst et al reported PRU ≥222 associated with stent thrombosis; Yu et al used PRU ≥240 as a low-response cut-off in cohort analysis.

Clinical cautionRandomized trials of PRU-directed therapy (eg, GRAVITAS) did not demonstrate improved clinical outcomes, limiting routine use.

Definition — MGMT promoter methylation

Definition — MGMT promoter methylationEpigenetic silencing of the MGMT gene promoter in tumor tissue associated with increased sensitivity to alkylating chemotherapy (eg, temozolomide) in glioblastoma; NCCN supports testing when it will influence therapy.

Clinical actionOrder when test result will affect temozolomide use; results should be documented in medical record.

LimitationsNot all methylated patients respond and strategies to overcome MGMT-mediated resistance remain investigational.

Definition — TPMT genotyping/phenotyping

Definition — TPMT genotyping/phenotypingTests to detect TPMT genetic variants or enzyme activity to guide thiopurine dosing and reduce hematologic toxicity risk; variant carriers may require dose reductions.

EvidenceProspective trial showed variant carriers identified and dose-reduced had fewer hematologic ADRs compared with unidentified carriers; overall group-level ADR rates were similar.

Clinical useUsed to guide thiopurine dosing in IBD to mitigate hematologic toxicity when variants are present.

Definition — Pharmacogenomic clinical decision support system (CDSS)

Definition — Pharmacogenomic CDSSSoftware tools that provide genotype-informed prescribing recommendations, alerts, and interfaces (eg, inbox messages, patient portals) to integrate PGx data into clinical workflows.

FunctionMay store test results, provide alerts, and support preemptive genotyping use; careful design needed to avoid alert fatigue.

Evidence noteMost published PGx CDSS reports describe prototypes; further evaluation is needed to support routine deployment.

Definition — IFNL3 (IL28B) genotype

Definition — IFNL3 genotypeSNPs near IFNL3 (eg, rs12979860, rs8099917) predictive of response to peginterferon-alpha plus ribavirin therapy for HCV; CC (rs12979860) and TT (rs8099917) associated with higher SVR rates.

Clinical useCan inform shared decision-making about Peg-IFNα/RBV regimens where these agents are considered.

CodingCPT 81283 represents IFNL3 (rs12979860) genotyping, which is noted in CPT listings.

Definition — Urine tenofovir threshold predictive of recent dosing

Definition — Urine tenofovir threshold>1,000 ng/ml — urine TFV concentration identified as predictive of plasma TFV >10 ng/ml and recent dosing; distinguishes high versus low adherence windows.

Semi-quantitative interpretation>1,000 ng/ml: high adherence within 48 h; 10–1,000 ng/ml: low adherence within 48 h; <10 ng/ml: non-adherence ≥1 week.

Clinical statusProof-of-concept data exist; guidelines do not yet endorse routine urine TFV monitoring for PrEP adherence per policy excerpt.

Definition — Molecular alterations used to select targeted therapies

Definition — FGFR2 fusion and EZH2 mutation testingMolecular alterations used to select targeted therapies: FGFR2 fusions/rearrangements for pemigatinib; EZH2 hotspot mutations (eg, Y646X variants, A682G, A692V) for tazemetostat.

TimingTypically one-time testing at diagnosis or prior to therapy initiation to determine eligibility for the corresponding targeted agent.

Assay examplesClinical trials used central validated assays (eg, cobas EZH2 Mutation Test) for patient selection per policy documentation.

Policy Revision History

2005-09-16original_effective_date

Policy originally effective.

2023-08-10next_review_date

Scheduled next review date recorded in policy metadata.

2024-02-27last_review_dateLatest

Most recent policy review date recorded in policy metadata.

Policy Summary

PayerAetna

PolicyPharmacogenetic and Pharmacodynamic Testing

Policy CodePolicy 0715

Change TypeNo material change

Effective DateSep 16, 2005

Last ReviewFeb 27, 2024

Next Review DateAug 10, 2023

Key ActionOrder and document the specific genetic/molecular test to assess candidacy for the named therapy and ensure the billed code and ICD-10 diagnosis match the policy selection criteria.

SourceLink

On This Page

OpenPayer is powered by Trek Health's payer performance platform. Trek continuously ingests, validates, and normalizes Transparency in Coverage data alongside payer policies and other commercial payer data to create a structured payer intelligence foundation. OpenPayer uses this foundation to deliver personalized search results, dynamically generated policy pages, and tailored policy monitoring based on each user's payers, specialties, billing codes, and areas of interest. The same intelligence powers broader payer performance workflows, including reimbursement benchmarking, contract evaluation, payer negotiations, and financial decision-making.