ModifiedColorado Rocky Mountain Health PlansPolicy CS149OH.G

Pharmacogenetic Panel Testing (for Ohio Only)

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This policy governs coverage of pharmacogenetic and pharmacogenomic testing for Ohio members, with particular focus on multigene panels used to evaluate drug-metabolizer status. Requests identified as unproven or subject to coverage or quantity limits are evaluated for medical necessity under Ohio Administrative Code 5160-101.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyPharmacogenetic Panel Testing (for Ohio Only)

Policy CodePolicy CS149OH.G

Change TypeModified

Effective DateNovember 1, 2026

Next Review DateN/A

Key ActionFor medical-necessity clinical coverage criteria, providers must refer to InterQual CP: Molecular Diagnostics, Pharmacogenomic Testing for Psychotropic Medication Drug Response.

SourceLink

POLICY UPDATE CHANGES

CPT codes 0650U and 0652U were added to the applicable code set.

CPT codes 0029U and 0423U were removed from the applicable code set.

The clinical evidence and references sections were updated with current information.

The previous policy version CS149OH.F was archived.

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ModifiedColorado Rocky Mountain Health PlansPolicy CS149OH.G

Pharmacogenetic Panel Testing (for Ohio Only)

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Sign up for Colorado Rocky Mountain Health Plans Policy CS149OH.G alerts

Get alerted when Policy CS149OH.G changes without checking for updates manually.

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Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyPharmacogenetic Panel Testing (for Ohio Only)

Policy CodePolicy CS149OH.G

Change TypeModified

Effective DateNovember 1, 2026

Next Review DateN/A

Key ActionFor medical-necessity clinical coverage criteria, providers must refer to InterQual CP: Molecular Diagnostics, Pharmacogenomic Testing for Psychotropic Medication Drug Response.

SourceLink

POLICY UPDATE CHANGES

CPT codes 0650U and 0652U were added to the applicable code set.

CPT codes 0029U and 0423U were removed from the applicable code set.

The clinical evidence and references sections were updated with current information.

The previous policy version CS149OH.F was archived.

Ohio onlyPolicy application

5+ genesMultigene panel threshold

UnprovenDrug-metabolizer panel status

UnprovenPrismRA testing status

2CPT codes added

2CPT codes removed

Coverage Criteria

Psychotropic Medication Pharmacogenomic Testing

For medical-necessity clinical coverage criteria, refer to the InterQual® CP: Molecular Diagnostics, Pharmacogenomic Testing for Psychotropic Medication Drug Response.

Psychotropic medication pharmacogenomic testing is subject to the medical-necessity clinical coverage criteria in InterQual® CP: Molecular Diagnostics, Pharmacogenomic Testing for Psychotropic Medication Drug Response.

Not Medically Necessary Testing

The following testing is excluded as unproven and not medically necessary due to insufficient evidence of efficacy.

ONE of the following

Pharmacogenetic multigene panel testing involving five or more genes for evaluation of drug-metabolizer status, for any indication.
PrismRA® molecular signature testing to evaluate the likelihood of inadequate response to anti-TNF therapies for rheumatoid arthritis.

PrismRA® Molecular Signature Test

The following testing is excluded as unproven and not medically necessary due to insufficient evidence of efficacy.

PrismRA® molecular signature testing for evaluating the likelihood of inadequate response to anti-TNF therapies for rheumatoid arthritis is not medically necessary.

Cardiovascular Disease

The evidence regarding multigene pharmacogenomic testing for cardiac disease is limited, and improved outcomes have not been demonstrated.

Evidence assessment

High-quality studies demonstrating improved outcomes related to pharmacogenomic testing in individuals with cardiac conditions or undergoing cardiac interventions are needed.
Ratner et al. (2022) evaluated individuals undergoing percutaneous coronary intervention (PCI) and bone marrow transplant. In the PCI group of 215 individuals, 66.5% were prescribed at least one medication with actionable pharmacogenomic recommendations; simulation projected 26.5 prescribing opportunities per 100 individuals if multigene testing were available. The authors considered multigene testing potentially beneficial, but additional high-quality studies were needed.
Rouby et al. (2020) studied 211 individuals undergoing PCI. Among the cohort, 77% had at least one actionable phenotype across CYP2C19, CYP2D6, CYP2C9, VKORC1, and SLCO1B1, and 32% had opportunities for genotype-guided prescribing. Simulations projected opportunities in 39% at one year and 52% at five years after PCI. The authors hypothesized that panel testing could influence prescribing beyond CYP2C19 testing alone, but the findings were projections rather than demonstrated clinical outcome improvements.

Anthracyclines and Chemotherapy-Induced Cardiotoxicity

Routine pharmacogenomic panel testing to assess risk of chemotherapy-induced cardiotoxicity is not supported by the evidence at this time.

Evidence assessment

Although initial research suggests potential benefit, additional prospective studies with long-term follow-up are needed to validate the role of pharmacogenomic testing in chemotherapy-induced cardiotoxicity.
Hansson et al. (2025) systematically reviewed pharmacogenomic associations with chemotherapy-induced toxicities in pediatric oncology patients with solid tumors. Of 59 included studies, most were retrospective; 24 articles with low to moderate risk of bias were summarized. Outcomes included myelosuppression, hepatotoxicity, ototoxicity, and cardiotoxicity. Associations were reported for multiple genes, but the review did not establish clinical utility for routine testing.
Wong et al. (2025) reviewed 37 studies involving 26,446 pediatric individuals and identified cardiotoxic and cardioprotective variants associated with anthracycline cardiotoxicity. Models combining genetic and clinical data had area-under-the-curve values of 0.67 to 0.87, compared with 0.57 to 0.81 for clinical data alone. Certainty was very low because of imprecision, inconsistency, potential publication bias, ethnically homogeneous populations, lack of standardized panels, and incomplete coverage of relevant variants by commercially available tests. Robust, ethnically diverse studies are needed before widespread adoption.

Pain Management

The use of multigene pharmacogenomic panel testing for routine pain-management decisions is not established as safe or efficacious in the peer-reviewed literature.

Evidence assessment

Multigene panel testing for predicting response, side effects, or dependence, or for improving overall pain-treatment outcomes, is currently not supported as safe or efficacious.
Jethwa et al. (2025) reviewed six randomized controlled trials of pharmacogenomic-guided opioid prescribing. Testing was associated with reduced opioid use (standardized mean difference -0.38; 95% CI -0.67 to -0.08; p=0.01), but not reduced pain intensity (standardized mean difference 0.31; 95% CI -0.89 to 0.27; p=0.30). Only one trial reported adverse events. Limitations included small samples, heterogeneous populations, opioids and genetic markers, minimal adverse-event data, and mostly short follow-up. Larger trials and standardized protocols are needed.
Kraus et al. (2024) randomized 68 individuals undergoing total knee arthroplasty to pharmacist-guided pharmacogenomic care or standard care. There were no differences in the Overall Benefit of Analgesia Score, total opioids, opioid-prescribing patterns, or tramadol use after adjustment, suggesting no improved pain management or decreased opioid use.

PrismRA® Evidence Limitations in Rheumatoid Arthritis

The body of evidence supporting PrismRA® is limited and does not establish clinical utility.

Evidence assessment

Additional larger, independent studies with better designs are needed before PrismRA® can be considered proven with clinical utility.
Anti-TNF medications are first-tier rheumatoid arthritis treatment for more than 90% of biologic-naive individuals whose disease is not controlled by conventional disease-modifying antirheumatic drugs; approximately 70% do not attain significant clinical improvement. PrismRA® evaluates the likelihood that an individual with rheumatoid arthritis may not respond to traditional anti-TNF therapy before treatment. The test uses 23 assessments, including 19 gene-expression features, anticyclic citrullinated protein, and sex, body mass index, and patient disease-assessment metrics. The manufacturer predicted a 40% increase in response to the first targeted DMARD, but this prediction has not established clinical utility.
A Hayes molecular test assessment (2022b; updated 2025) evaluated the current PrismRA® version for analytic validity, clinical validity, and clinical utility. The test has undergone changes in risk categories and cutoff values; prior analyses that did not evaluate the current version were excluded. The assessment found a very low-quality body of evidence. Larger and more diverse studies are needed, and the 2025 update stated that the D2 rating was unlikely to change despite newly published studies.

Other Pharmacogenetic Multigene Panel Testing

Evidence is insufficient to establish clinical efficacy for pharmacogenomic multigene panels used to guide individualized therapy in the following settings.

Indications with insufficient evidence

Multimorbidity.
Polypharmacy.
Cancer-treatment toxicity.
Medication response.
Inflammatory bowel disease.
General use with medication prescription.

Multigene pharmacogenetic panels involving five or more genes that are used to evaluate drug-metabolizer status are excluded as unproven and not medically necessary for any indication because insufficient evidence demonstrates efficacy.

PrismRA® testing to predict the likelihood of inadequate response to anti-TNF therapy in rheumatoid arthritis is excluded as unproven and not medically necessary because insufficient evidence demonstrates efficacy.

FDA approval or clearance alone is not a basis for coverage. FDA information is provided for informational purposes only. Laboratories performing genetic tests are regulated under the Clinical Laboratory Improvement Amendments Act of 1988. FDA resources include the lists of cleared or approved in vitro diagnostic tests, companion diagnostics, and pharmacogenetic associations.

Pharmacogenetic multigene panels involving five or more genes for evaluation of drug-metabolizer status are not medically necessary for any indication.

PrismRA® testing for predicting inadequate response to anti-TNF therapy in rheumatoid arthritis is not medically necessary.

Applicable Codes and Coding Rules

Applicable CodesHCPCS

0173U	Psychiatry (i.e., depression, anxiety), genomic analysis panel, includes variant analysis of 14 genes.
0175U	Psychiatry (e.g., depression, anxiety), genomic analysis panel, variant analysis of 15 genes.
0345U	Psychiatry (e.g., depression, anxiety, attention deficit hyperactivity disorder [ADHD]), genomic analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6.
0347U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 16 gene report, with variant analysis and reported phenotypes.
0348U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 25 gene report, with variant analysis and reported phenotypes.
0349U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis, including reported phenotypes and impacted gene-drug interactions.
0350U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis and reported phenotypes.
0392U	Drug metabolism (depression, anxiety, attention deficit hyperactivity disorder [ADHD]), gene-drug interactions, variant analysis of 16 genes, including deletion/duplication analysis of CYP2D6, reported as impact of gene-drug interaction for each drug.
0411U	Psychiatry (e.g., depression, anxiety, attention deficit hyperactivity disorder [ADHD]), genomic analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6.
0419U	Neuropsychiatry (e.g., depression, anxiety), genomic sequence analysis panel, variant analysis of 13 genes, saliva or buccal swab, report of each gene phenotype.

1–10 of 11

1/2

Applicable CodesHCPCS

0438U	Drug metabolism (adverse drug reactions and drug response), buccal specimen, gene-drug interactions, variant analysis of 33 genes, including deletion/duplication analysis of CYP2D6, including reported phenotypes and impacted gene-drug interactions.
0460U	Oncology, whole blood or buccal, DNA single-nucleotide polymorphism (SNP) genotyping by real-time PCR of 24 genes, with variant analysis and reported phenotypes.
0461U	Oncology, pharmacogenomic analysis of single-nucleotide polymorphism (SNP) genotyping by real-time PCR of 24 genes, whole blood or buccal swab, with variant analysis, including impacted gene-drug interactions and reported phenotypes.
0476U	Drug metabolism, psychiatry (e.g., major depressive disorder, general anxiety disorder, attention deficit hyperactivity disorder [ADHD], schizophrenia), whole blood, buccal swab, and pharmacogenomic genotyping of 14 genes and CYP2D6 copy number variant analysis and reported phenotypes.
0477U	Drug metabolism, psychiatry (e.g., major depressive disorder, general anxiety disorder, attention deficit hyperactivity disorder [ADHD], schizophrenia), whole blood, buccal swab, and pharmacogenomic genotyping of 14 genes and CYP2D6 copy number variant analysis, including impacted gene-drug interactions and reported phenotypes.
0516U	Drug metabolism, whole blood, pharmacogenomic genotyping of 40 genes and CYP2D6 copy number variant analysis, reported as metabolizer status, impacted gene-drug interactions and reported phenotypes.
0533U	Drug metabolism (adverse drug reactions and drug response), genotyping of 16 genes (i.e., ABCG2, CYP2B6, CYP2C9, CYP2C19, CYP2C, CYP2D6, CYP3A5, CYP4F2, DPYD, G6PD, GGCX, NUDT15, SLCO1B1, TPMT, UGT1A1, VKORC1), reported as metabolizer status.
0650U	Drug metabolism (adverse drug reactions and drug response), genotyping of 9 genes (i.e., CYP2D6, CYP2C19, G6PD, SLCO1B1, HLA-B*58:01, NAT2, CYP2C9, VKORC1, ABCG2), reported as metabolizer status and transporter function.
0652U	Drug metabolism (adverse drug reactions), DNA analysis of 13 genes by targeted genotyping, using saliva or buccal swab, reported as diplotype and metabolizer status.
81418	Drug metabolism (e.g., pharmacogenomics) genomic sequence analysis panel, must include testing of at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis.

1–10 of 11

1/2

Added CPT CodesCPT

0650U	CPT code added
0652U	CPT code added

Removed CPT CodesCPT

0029U	CPT code removed
0423U	CPT code removed

Multigene panel threshold

Panel sizeFive or more genes

Use addressed by the policyEvaluation of drug-metabolizer status

Coverage statusUnproven and not medically necessary for any indication due to insufficient evidence of efficacy

CPT 81418 requirements

Minimum panel sizeAt least 6 genes

Required genesCYP2C19 and CYP2D6

Provider Guidance

Note

Use InterQual® Pharmacogenomic Criteria

For medical-necessity clinical coverage criteria, refer to InterQual® CP: Molecular Diagnostics, Pharmacogenomic Testing for Psychotropic Medication Drug Response.

Documentation Required

Verify Governing Benefit Requirements

Before determining coverage, verify the applicable federal, Ohio Administrative Code (OAC), and contractual benefit requirements. These governing requirements control if they conflict with this policy.

Denial Risk

Five-or-More-Gene Panels Not Medically Necessary

Clinical Background

Pharmacogenetics, also called pharmacogenomics, evaluates how genetic variation may affect an individual’s response to medications, including treatment benefit and adverse effects. Testing directed at a specific drug typically evaluates one gene, while warfarin testing generally evaluates two to three genes. This policy addresses multigene panels containing five or more genes that assess possible responses to multiple drugs; evidence of clinical utility for many combinatorial panels remains uncertain or inconsistent.

Definitions

Multigene Panel

DefinitionA genetic test that typically uses next-generation sequencing to test multiple genes simultaneously

Alternative termMultigene test

Other alternative termsMultiple-gene panel test; multiple-gene test

Pharmacogenetic test

DefinitionTesting intended to guide treatment strategies, clinical evaluations, and decisions

Basis for useIts ability to predict response to treatment in particular clinical contexts

Typical application

Not Covered Services

Not covered: pharmacogenetic multigene panels containing five or more genes for evaluation of drug-metabolizer status, for any indication, and PrismRA molecular signature testing used to evaluate the likelihood of inadequate response to anti-TNF therapies for rheumatoid arthritis. Both are considered unproven and not medically necessary because evidence of efficacy is insufficient.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyPharmacogenetic Panel Testing (for Ohio Only)

Policy CodePolicy CS149OH.G

Change TypeModified

Effective DateNovember 1, 2026

Next Review DateN/A

Key ActionFor medical-necessity clinical coverage criteria, providers must refer to InterQual CP: Molecular Diagnostics, Pharmacogenomic Testing for Psychotropic Medication Drug Response.

SourceLink

On This Page

Billings et al. (2018) retrospectively compared 11,060 individuals who received testing including CYP2C19, CYP2C9, VKORC1, F5, F2, and MTHFR with 178,096 matched controls using claims data. The tested group appeared significantly more likely to experience stroke, pulmonary embolism, deep-vein thrombosis, or a composite event. Real-world testing did not appear to improve outcomes in the claims analysis.

Yang et al. (2021) reviewed 41 studies involving 88 genes and 154 single-nucleotide polymorphisms. Six variants were associated with increased risk of chemotherapy-induced cardiotoxicity, including CYBA rs4673, RAC2 rs13058338, CYP3A5 rs776746, ABCC1 rs45511401, ABCC2 rs8187710, and HER2-Ile655Val rs1136201. The authors described potential benefit but stated that further studies are required to validate prognostic and diagnostic roles.

Sági et al. (2018) genotyped 26 genes and 70 single-nucleotide polymorphisms in 622 children with acute lymphoblastic leukemia and 39 children with osteosarcoma treated in Hungarian pediatric oncology centers. Variants in ABCC2, NQO1, SLC22A6, and SLC28A3 were associated with decreased fractional shortening and ejection fraction, particularly five to ten years after diagnosis; NQO1 rs1043470 T and CYP3A5 rs4646450 TT were also associated with cardiac findings. Additional prospective, long-term studies are needed.

Agulló et al. (2023) conducted a double-blinded randomized trial of 60 individuals with chronic noncancer pain; 50 completed three months. The genotype-guided group had reported improvements in pain intensity, pain relief, quality of life, adverse effects, and opioid dose. However, the study was small, conducted at a single pain unit during the COVID-19 pandemic, and had limited generalizability.

Zobdeh et al. (2022) systematically reviewed 25 studies of pharmacogenomics involving NSAIDs and antidepressants in pain treatment. Ten drug-gene combinations were identified, including ibuprofen/CYP2C9, celecoxib/CYP2C, piroxicam/CYP2C8 and CYP2C9, diclofenac/CYP2C9, UGT2B7, CYP2C8 and ABCC2, meloxicam/CYP2C9, aspirin/CYP2C9, SLCO1B1 and CHST2, amitriptyline/CYP2D6 and CYP2C19, imipramine/CYP2C19, nortriptyline/CYP2C19, CYP2D6 and ABCB1, and escitalopram/HTR2C, CYP2C19 and CYP1A2. Effects on pain relief were limited, and well-powered in vivo studies are lacking. Larger studies are needed to establish efficacy.

CYP2D6 duplication/deletion analysis

CDAI minimal important difference

Moderate baseline disease activityImprovement of ≥ 6 in CDAI at 24 weeks

High baseline disease activityImprovement of ≥ 12 in CDAI at 24 weeks

Assessment point24 weeks

PrismRA poor-response score

PrismRA thresholdScore of ≥ 11.8

InterpretationHigh or very-high likelihood of poor response or nonresponse to anti-TNF treatment

Clinical contextRheumatoid arthritis treatment response assessment

Pharmacogenetic multigene panels containing five or more genes for evaluating drug-metabolizer status are unproven and not medically necessary for any indication because evidence of efficacy is insufficient.

Denial Risk

PrismRA® Testing Not Medically Necessary

PrismRA® molecular signature testing for evaluating the likelihood of inadequate response to anti-TNF therapies for rheumatoid arthritis is unproven and not medically necessary because evidence of efficacy is insufficient.

Denial Risk

Pain-Management PGx Panels Unsupported

Routine multigene pharmacogenetic panel testing for pain management is not supported as safe or efficacious in the peer-reviewed literature for predicting treatment response, side effects, or dependence, or for improving overall treatment outcomes.

Denial Risk

Anthracycline Cardiotoxicity Testing Not Validated

Routine pharmacogenetic panel testing to assess risk of anthracycline-related chemotherapy-induced cardiotoxicity is not supported by current evidence. Additional prospective studies with long-term follow-up are needed to validate its clinical role; the certainty of available evidence remains very low.

Available studies have limitations including imprecision, inconsistency, potential publication bias, limited ethnic diversity, lack of standardized testing panels, and incomplete variant coverage in commercial tests.

Denial Risk

Cardiovascular Outcome Evidence Insufficient

Evidence is insufficient to establish that multigene pharmacogenetic testing improves cardiovascular outcomes or outcomes related to cardiac interventions. Coverage may be denied when high-quality evidence demonstrating improved outcomes is lacking.

Additional high-quality studies are needed to establish clinical benefit for individuals with cardiac conditions or those undergoing cardiac interventions.
A real-world claims analysis found that PGx testing did not appear to improve outcomes and that the tested group appeared more likely to experience certain thromboembolic events than matched controls.

Note

FDA Status Alone Does Not Establish Coverage

FDA approval or clearance alone is not a basis for coverage. Evaluate the test under the applicable medical-necessity criteria and governing benefit requirements.

Treatment planning based on an individual's predicted medication response

Pharmacogenetics / pharmacogenomics

DefinitionThe study of how variation in genes impacts the way an individual may respond to certain medications

Treatment benefitGenetic differences may influence whether an individual benefits from a specific medication

Medication safetyGenetic differences may influence medication side effects

PrismRA

DefinitionA molecular signature response classifier

AssessmentsEvaluates 23 different assessments, including 19 gene-expression features

Additional featuresAnticyclic citrullinated protein and three clinical metrics: sex, body mass index, and patient disease assessment

MSRC

DefinitionA molecular signature response classifier

Treatment selectionGuides selection of TNF inhibitor versus non-TNF biologic or targeted synthetic DMARD therapy

Clinical contextRheumatoid arthritis

Pharmacogenetic multigene panel testing

DefinitionTesting of multiple pharmacogenetic genes intended to guide individualized therapy

Clinical applicationsMultimorbidity, polypharmacy, cancer-treatment toxicity, medication response, and inflammatory bowel disease

Additional useGeneral medication prescribing