ModifiedUnitedHealthcarePolicy CS149TN.W

Pharmacogenetic Panel Testing (for Tennessee Only)

Policy governing coverage of multi-gene pharmacogenetic (PGx) panel testing and related molecular signature tests for Tennessee Medicaid and CoverKids members.

Policy Summary

PayerUnitedHealthcare

PolicyPharmacogenetic Panel Testing (for Tennessee Only)

Policy CodePolicy CS149TN.W

Change TypeDefinition updatedsupporting info refreshed

Effective DateJan 1, 2026

Next Review Date

Key ActionInclude the referenced procedure/PLA/CPT codes on claims and follow prior authorization guidance when submitting requests for PGx or MSRC/PrismRA testing.

SourceLink

POLICY UPDATE CHANGES

Updated definition of 'Multi - Gene Panel'.

Supporting Information sections (Description of Services, Clinical Evidence, FDA, References) were updated to reflect the most current information.

>=5 genespanels considered in policy

PrismRAnamed molecular signature test evaluated

Medicaid & CoverKidsprograms governed

Numerousapplicable procedure codes referenced

11 RCTs / 5,347

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Wang et al. meta-analysis

75.6%MSRC alignment with prescribed b/tsDMARD

Coverage Criteria and Evidence Summary

Not Medically Necessary Criteria

Covered when ALL of the following are met:

Not medically necessary - multi-gene panels: The use of pharmacogenetic Multi-Gene Panels (five or more genes) for evaluation of drug-metabolizer status is unproven and not medically necessary for any indication due to insufficient evidence of efficacy.

Policy states blanket non-coverage for multigene panels (≥5 genes).

Not medically necessary - PrismRA: The use of the PrismRA molecular signature test is unproven and not medically necessary for evaluating likelihood of inadequate response to anti‑TNF therapies for rheumatoid arthritis due to insufficient evidence of efficacy.

Named molecular signature test explicitly considered not medically necessary.

Psychiatric — Evidence and limitations

Evidence summary for psychiatric indications (major depressive disorder, schizophrenia, anxiety):

Psychiatric PGx evidence summary: Randomized trials and meta-analyses report modest, early improvements in response or remission and reductions in adverse drug reactions or prescriptions with PGx-guided care. Most trials include CYP2C19 and CYP2D6; some proprietary multigene panels report incremental benefits in select populations, but risk of bias, heterogeneity, limited generalizability (e.g., ethnicity, inpatient vs outpatient populations), and proprietary algorithms limit certainty.

Examples include PREPARE (12-gene ADR reduction), GUIDED, Oslin et al., Wang et al. meta-analysis; many studies had industry involvement or high risk of bias.

Cardiovascular — Evidence and limitations

Evidence summary for cardiovascular indications:

Cardiovascular PGx evidence: Observational studies and simulation analyses identify many post-PCI patients with actionable genotypes and potential genotype-guided prescribing opportunities, but retrospective claims analyses have not demonstrated improved clinical outcomes and in one large claims study the tested group had higher rates of thromboembolic events; high-quality outcome trials are needed.

Rouby et al. and Ratner et al. show potential prescribing opportunities; Billings et al. retrospective claims analysis found no improved outcomes and possible increased thromboembolic events.

Anthracycline cardiotoxicity — Evidence and limitations

Evidence summary for anthracycline-induced cardiotoxicity (ACT):

Pediatric ACT PGx evidence: Systematic reviews and meta-analyses identified genetic variants associated with increased or decreased risk of anthracycline cardiotoxicity and predictive models combining genetic and clinical data achieved higher AUCs (approximately 0.67–0.87) than clinical data alone; however, certainty is very low due to imprecision, heterogeneity, ethnic homogeneity, lack of standardized panels, and limited prospective validation.AUC 0.67-0.87 for combined models

Wong et al. 2025 systematic review (37 studies, 26,446 pediatric individuals) found candidate variants but concluded routine testing is not supported without robust prospective validation.

Coverage stance summaries

Summary coverage stance statements from the document:

Anthracycline PGx testing: Routine use of PGx panel testing to assess risk of chemotherapy-induced cardiotoxicity (CIC) is not supported by current evidence; additional prospective, ethnically diverse studies with standardized panels are needed before recommending widespread clinical adoption.

Document cites systematic reviews and cohort studies but concludes evidence certainty very low.

PGx panel testing for pain management: Multigene PGx panel testing to predict response, side effects, dependence, or to improve overall pain outcomes is not currently supported as safe or efficacious by published literature.

Policy notes evolving but insufficient evidence for routine use in pain management.

PrismRA / MSRC for RA treatment selection: Evidence supporting PrismRA is limited and very low quality; additional larger, independent studies are necessary before considering it proven with clinical utility. Observational data indicate MSRC results have influenced prescribing but are subject to bias and insurer step‑therapy confounding.

Hayes assessment rated evidence very low; Curtis et al. shows physician alignment but limitations include manufacturer funding and limited diversity.

MSRC/PrismRA — coverage evidence summary

Summary of evidence-based coverage considerations for MSRC/PrismRA in rheumatoid arthritis:

Evidence requirements for coverage consideration: Coverage consideration could require high-quality, generalizable evidence demonstrating clinical validity and clinical utility (improved clinical outcomes) for the current version of the test in representative RA populations; independent randomized or well-controlled studies that address confounding and insurer step-therapy impacts are needed.

Hayes assessment rated the evidence very low quality and noted version changes in PrismRA; larger, diverse studies are needed.

Supportive performance metrics: Existing observational cohorts and decision analyses report PPV in the high 80s and sensitivity around the mid-50s to 60% for predicting anti-TNF nonresponse in selected populations, and MSRC-aligned treatment was associated with higher response rates in nonrandomized analyses.PPV ~87-89%, sensitivity ~54-60%

Reported metrics derive from Curtis et al. cohort analyses and other nonrandomized studies; interpretation limited by study design and potential bias.

PGx multigene panels — coverage evidence summary

Summary of PGx multigene panel coverage considerations:

PGx panels with demonstrated benefit: A 12-gene panel (PREPARE) and other RCTs have shown reductions in clinically significant adverse drug reactions and increased medication changes consistent with PGx guidance in diverse outpatient settings, supporting gene-drug–specific clinical utility for certain drug classes when high-quality evidence exists.

PREPARE (Swen et al.) found reduced ADRs; other trials and meta-analyses provide proof-of-concept for selected gene-drug pairs rather than blanket panel efficacy.

Current limitations: Evidence for broad, routine use of PGx multigene panels for multimorbidity, polypharmacy, or generalized prescribing remains heterogeneous and insufficient for generalized coverage; more robust, diverse trials with longer follow-up and standardized panels are required.

Systematic reviews and meta-analyses (David et al., other reviews) found increased medication changes and reduced hospitalizations in some studies but highlight evidence gaps.

This policy defines the coverage stance for certain pharmacogenetic tests. Specifically, the use of pharmacogenetic Multi-Gene Panels (five or more genes) is considered not medically necessary for any indication due to insufficient evidence of efficacy. The policy also deems the PrismRA molecular signature test as not medically necessary for predicting inadequate response to anti‑TNF therapies in rheumatoid arthritis.

Routine use of multigene PGx panel testing to assess risk of chemotherapy‑induced cardiotoxicity (CIC) is not supported by current evidence. Although preliminary studies identify candidate variants and modeling suggests potential predictive value, the document concludes additional prospective, validated, and ethnically diverse research is required before routine clinical adoption.

Multigene PGx panel testing used routinely to guide general pain management decisions is not supported by the published literature and therefore is not recommended as standard practice. Similarly, routine multigene PGx panel testing to predict anthracycline‑induced cardiotoxicity is not supported and should not be used as a routine predictive tool outside of research or well‑justified clinical contexts.

While targeted, gene‑specific pharmacogenetic testing can inform individual drug selection or dosing when strong gene‑drug evidence exists, the policy does not support blanket coverage of multigene PGx panels to guide individualized therapies across many indications (for example, multimorbidity, polypharmacy, cancer toxicity prevention, or IBD) because clinical efficacy has not been established for broad panel use.

Professional guidance from the American Academy of Child and Adolescent Psychiatry advises clinicians to avoid using pharmacogenetic testing to select psychotropic medications in children and adolescents, reflecting concerns about limited pediatric evidence, conflicts of interest in some studies, and challenges when multiple concurrent medications are used.

This document fragment does not list every possible test or scenario that may be excluded. Final coverage determinations must comply with the applicable federal, state, or contractual benefit plan terms, which govern in the event of any conflict with the policy text.

The policy specifically addresses the use of Multi‑Gene Panels (five or more genes) and evaluates the PrismRA / MSRC molecular signature test. Both topics are explicitly discussed in the policy and the current stance—based on available evidence—is that routine use of these tests is unproven and not medically necessary.

Panel‑based pharmacogenetic testing has not demonstrated reliable routine prediction of cardiovascular outcomes or of anthracycline cardiotoxicity. Real‑world retrospective analyses did not show improved cardiovascular outcomes and, for CIC, systematic reviews report promising candidate variants but emphasize very low certainty and the need for validation before routine use.

The policy does not support use of multigene PGx panels as a routine clinical tool to predict anthracycline‑induced cardiotoxicity nor for broad application in general pain management. Current evidence is insufficient to demonstrate validated clinical utility for these routine uses.

Assessments of the PrismRA / MSRC test conclude the current evidence base is limited and of very low quality (Hayes rating D2). Available studies show potential impact on physician prescribing but are nonrandomized, subject to bias, and require larger, independent validations before clinical utility can be established.

The VA/DoD guideline (2022) concluded that evidence was insufficient to recommend either for or against use of pharmacogenetic testing to guide antidepressant selection in major depressive disorder, indicating that routine adoption for this purpose remains unsupported.

Indications Where Testing May Be Considered

Pharmacogenomic-guided treatment for psychiatric disorders

Consider pharmacogenomic-guided treatment for psychiatric disorders (MDD, schizophrenia, anxiety) when used as part of clinical decision-making and documentation supports likely benefit:

Clinical indication: Individual has a diagnosis of major depressive disorder, schizophrenia, or anxiety disorder for which pharmacologic treatment is being initiated or changed.

Trials often enrolled individuals starting or switching therapy or with prior inadequate response; documentation should reflect indication.

Prior treatment context: There is documentation of prior inadequate response or intolerance to one or more standard medications, or the clinician justifies the need for PGx guidance to inform selection/dosing.

Many RCTs enrolled participants with prior failed medications; prior therapy history is relevant to interpretation.

Test scope and genes: Testing focuses on actionable pharmacogenes with demonstrated guidance (at minimum CYP2C19 and CYP2D6 for many psychiatric medications); proprietary multi-gene algorithm outputs should be interpreted cautiously and documented.

Procedure and PLA/CPT Codes

Applicable PLA Codes (sample)CPT

0029U

Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (i.e., CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823)

Applicable CPT/PLA Codesmixed

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, 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.

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Panel gene count threshold

Policy panel definitionMulti-gene pharmacogenetic panels are addressed in the policy as tests that include five or more genes and are considered as a panel category subject to the policy's coverage stance.

CPT 81418 requirementCPT 81418 describes a genomic sequence analysis panel for drug metabolism that must include testing of at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis.

Scope noteThe policy distinguishes its panel definition (>=5 genes) from coding definitions; some billing codes (e.g., 81418) require ≥6 genes for that specific code.

Provider Actions, Prior Authorization, and Documentation

Billing Rule

Coding and claim submission

Use the procedure, PLA, and CPT/HCPCS codes listed in the policy when submitting claims. Include all procedure codes reported by the testing laboratory (e.g., listed U-codes and 81418/81479) on the claim. Listing of a code in this policy does not guarantee coverage; verify benefit plan terms.

Include procedure and PLA/CPT codes from the Applicable Codes section on claims (e.g., 0029U, 0173U, 0175U, 0345U, 0347U, 0348U, 0349U, 0350U, 0392U, 0411U, 0419U, 0423U, 0434U, 0438U, 0460U, 0461U, 0476U, 0477U, 0516U, 0533U, 81418, 81479).
Provide supporting clinical documentation (see documentation callout).

Denial Risk

Multi-gene panels — denial risk

Multi-gene pharmacogenetic panels (panels including five or more genes) are considered unproven and not medically necessary for any indication based on insufficient evidence. Claims for routine use of multi-gene panels may be denied.

Not Covered Tests and Indications

The policy explicitly states that Multi‑Gene Panel pharmacogenetic tests (five or more genes) and the PrismRA molecular signature test for predicting inadequate anti‑TNF response in rheumatoid arthritis are considered not covered / not medically necessary based on insufficient evidence.

Routine multigene PGx panel testing to predict anthracycline‑related cardiotoxicity in pediatric patients is not covered as standard care. Although systematic reviews identify associated variants and improved predictive models when genetics are combined with clinical data, the overall certainty of evidence is very low and further validation is required.

Routine PGx panel testing to predict anthracycline‑induced cardiotoxicity and routine multigene PGx panel testing for general pain management are considered not covered for routine use because peer‑reviewed evidence does not yet demonstrate safety and efficacy for these indications.

Broad, routine application of multigene PGx panels for patients with multimorbidity, polypharmacy, or for general medication prescribing is not supported and therefore not covered under standard practice; the literature shows heterogeneity and insufficient high‑quality outcome data to justify generalized coverage.

AACAP's 2020 statement advises against PGx testing to select psychotropic medications in children and adolescents. CPIC guidance supports specific gene‑drug pairs (for example, CYP2D6 and CYP2C19 for some antidepressants) but does not provide recommendations endorsing use of multigene panels that include five or more genes for pediatric psychotropic selection.

This fragment does not enumerate every test as explicitly not covered. Coverage determinations must align with the applicable benefit plan terms; in the event of a conflict, federal, state, or contractual requirements govern.

Definitions and Background

Pharmacogenetics examines how genetic variation affects drug response. Tests range from single‑gene assays to multigene panels; this policy focuses on multigene panels and molecular signature tests and the evidence supporting or refuting their routine clinical use.

Multi-Gene Panel (definition)

DefinitionMulti-Gene Panel: genetic tests that typically use next-generation sequencing to test multiple genes simultaneously; also called multigene test, multiple-gene panel test and multiple-gene test.

Policy focusThis policy is designed to address Multi-Gene Panel testing, specifically panels that include five or more genes used to proactively evaluate drug response across many medications.

Common technologiesPanels frequently employ next-generation sequencing and can include targeted gene sets for pharmacogenomics rather than single-gene assays.

Actionable phenotype

Definition

Eligibility and Test Ordering Requirements

No eligibility criteria are specified in the extracted fragment.

Operational Notes for Providers

Note

Documentation Required

Provide clinician interpretation and genetic counseling as appropriate

Provide clinician interpretation and pre‑/post‑test counseling when PGx testing will inform therapy decisions; testing programs in cited studies implied the need for provider interpretation and counseling.

Document that clinicians will interpret and act on PGx results and that pre/post-test counseling was provided as appropriate.
Counseling is recommended especially when test results influence treatment or when pediatric cancer risk is involved.

Documentation Required

Document genetic counseling for cardiotoxicity‑related PGx testing

Document genetic counseling when PGx testing is performed for cardiotoxicity risk or when results may have familial implications; include counseling notes in the medical record.

Policy Revision History

2026-01-01definition_updateLatest

Updated definition of 'Multi - Gene Panel' and refreshed supporting sections (Description of Services, Clinical Evidence, FDA, and References); previous policy version CS149TN.V archived.

As noted elsewhere in this policy, the document fragment does not list specific tests as universally excluded; therefore, when applying coverage determinations ensure alignment with federal, state, or contractual benefit plan terms that govern the member’s coverage.

Policy Summary

PayerUnitedHealthcare

PolicyPharmacogenetic Panel Testing (for Tennessee Only)

Policy CodePolicy CS149TN.W

Change TypeDefinition updatedsupporting info refreshed

Effective DateJan 1, 2026

Next Review Date

Key ActionInclude the referenced procedure/PLA/CPT codes on claims and follow prior authorization guidance when submitting requests for PGx or MSRC/PrismRA testing.

SourceLink

On This Page

Most psychiatric evidence centers on CYP2C19/CYP2D6; other genes in panels have unclear additive utility.

Intended use and actionability: Clinician documents how PGx results will be used to influence medication choice or dosing and agrees to record treatment decisions and follow-up outcomes.

Documentation supports appropriate clinical use and aligns with prior authorization expectations where applicable.

Use of MSRC/PrismRA to inform biologic selection in RA

Use MSRC/PrismRA to inform selection of biologic/targeted DMARDs in RA only when test results will directly influence treatment selection and supporting evidence/documentation is provided:

Appropriate clinical context: Individual has active rheumatoid arthritis for whom b/tsDMARD selection is being considered and the treating rheumatologist intends to use MSRC results to guide selection between anti‑TNF and non‑TNF therapies.

PrismRA intended for use by rheumatologists to predict anti‑TNF nonresponse; clinical context should match intended test purpose.

Evidence and documentation: Documentation includes MSRC/PrismRA test result, the specific version of the test used, rationale why the result changes treatment choice, prior conventional DMARD/biologic history, and acknowledgement of insurer step‑therapy implications.

Hayes assessment noted test versioning and limited evidence; prior therapy and insurer constraints are relevant to coverage decisions.

Conditional coverage considerations: Consideration for coverage may be given when (a) high‑quality, independent evidence demonstrates clinical utility in representative populations, or (b) prior authorization demonstrates that MSRC interpretation will directly alter the medically necessary treatment plan and insurer step‑therapy requirements have been addressed.

Observational studies show provider alignment with MSRC but are nonrandomized and potentially biased; prior authorization may be required.

Selected PGx-guided therapy to reduce severe adverse drug reactions

Use PGx-guided therapy to reduce severe adverse drug reactions for specific high‑risk gene–drug pairs when supported by high-quality evidence:

High-quality evidence requirement: Coverage consideration applies only for gene–drug pairs with demonstrated high‑quality evidence (e.g., randomized trials such as PREPARE for fluoropyrimidines or other trials showing reduced serious ADRs) or established guideline/CPIC recommendations linking genotype to management.

PREPARE (12‑gene) and other trials demonstrate ADR reduction for specific drug sets; coverage should be gene–drug specific rather than blanket panel coverage.

Clinical relevance to therapy: The patient is scheduled to receive or is receiving a medication for which actionable pharmacogenetic guidance exists (e.g., fluoropyrimidines, certain oncology agents) and test results would directly guide dosing or avoidance to reduce risk of severe toxicity.

Documented indication and planned therapy aligning with tested gene–drug guidance required.

PGx testing for cancer-related pain (NCCN guidance)

PGx testing may be considered for cancer-related pain management in accordance with guideline recommendations when toxicity or inadequate analgesia is present:

NCCN-aligned consideration: Consider targeted PGx testing to inform analgesic selection or dosing for cancer-related pain when the treating clinician documents toxicity, lack of analgesic response, or other rationale consistent with NCCN adult cancer pain guidance.

NCCN adult cancer pain guidance indicates PGx may be considered before or during treatment when toxicity or lack of response is present; panel testing is not specifically addressed.

Test scope: Testing should focus on genes with established analgesic relevance (e.g., CYP2D6, CYP2C9, others supported in guidance) rather than routine multigene panel screening.

Policy emphasizes targeted, guideline-based use rather than routine multigene panel use for pain.

Pharmacogenomic testing across specialties — conditional considerations

Pharmacogenomic testing to guide drug selection and dosing across specialties — apply the following considerations:

Evidence-based application: Use PGx testing when high-quality evidence or authoritative guidance (CPIC, guideline, randomized trial) supports a specific gene–drug management decision in the patient’s clinical context (psychiatry, cardiology, oncology, rheumatology, pain management).

Randomized trials and meta-analyses provide support for selected gene–drug pairs; broad panel testing without gene–drug justification is discouraged.

Documentation and follow-up: Document indication, prior therapy, the specific genes tested and test version, how results informed medication selection or dosing, and planned follow-up to assess clinical outcomes.

Records support prior authorization and coverage determinations and align with implementation study practices.

Avoid routine multigene panel use: Routine use of multigene pharmacogenetic panels (five or more genes) for generalized prescribing, multimorbidity, or polypharmacy without specific, evidence-based gene–drug intent is not supported by current evidence and is considered not medically necessary per policy.

Policy defines multigene panels (≥5 genes) as not medically necessary unless specific high-quality evidence and indication exist.

Denial risk applies to multigene panels (≥5 genes) for evaluation of drug-metabolizer status.
Coverage determinations remain subject to federal, state, and contractual benefit plan requirements.

Denial Risk

PrismRA / MSRC — denial risk

The PrismRA molecular signature test and similar MSRC tests have very-low-quality or insufficient evidence to support use for predicting inadequate anti‑TNF response in rheumatoid arthritis. PrismRA is considered unproven and not medically necessary for this purpose; claims for PrismRA may be denied.

PrismRA (Scipher Medicine) is specifically identified as not proven for predicting inadequate anti‑TNF response.
Hayes assessment rates evidence as very low quality; additional larger, independent studies are needed.

Prior Authorization

Insurance coverage, step‑therapy, and MSRC adherence

MSRC/PrismRA results have influenced physician prescribing in observational studies, but deviations from test recommendations were frequently attributed to insurance coverage limitations and potential step-therapy requirements. Prior authorization or lack of coverage may prevent adherence to test-guided treatment choices.

In Curtis et al. (2024), when providers did not follow MSRC recommendations, insurance coverage concerns were the most common reason.
Decision-analytic modeling (Bergman et al.) assumed full provider adherence to MSRC recommendations — real-world adherence may be limited by benefit coverage and step-therapy.

Prior Authorization

Prior authorization and step‑therapy considerations for PrismRA-guided care

For PrismRA/MSRC-guided treatment, insurers may require evidence that standard first‑line therapies (e.g., anti‑TNF for biologic‑naive RA) were considered or tried. When submitting authorization requests, document prior medication trials and rationale for deviating from standard sequencing.

Document trials of conventional DMARDs and rationale for biologic selection.
If requesting coverage of an alternative to an anti‑TNF based on MSRC results, include prior treatment history and why step‑therapy requirements (if any) are not appropriate.

Documentation Required

RA treatment sequencing and documentation

When MSRC or PrismRA is used to guide RA treatment selection, document RA disease activity measures and treatment sequencing decisions. Guidelines emphasize objective disease activity measures and escalation to biologics when appropriate.

Include baseline and follow‑up disease activity scores (e.g., DAS, CDAI, SDAI, RAPID3) and ACR response metrics where available.
Document why treatment was selected (alignment or deviation from MSRC result) and any insurer or step‑therapy constraints.

Documentation Required

Required clinical documentation for psychiatric PGx prior authorization

For psychiatric PGx testing prior authorization requests, include the clinical indication and detailed prior medication history demonstrating inadequate response or intolerance. Indicate number and names of antidepressants/antipsychotics tried and duration of therapy where available.

Specify diagnosis (e.g., major depressive disorder, anxiety, ADHD, schizophrenia).
List prior medication trials, reasons for discontinuation (inefficacy or intolerance), and relevant timelines.

Documentation Required

Document test results and treatment alignment

Document the specific test results, interpreted phenotype/metabolizer status, and how results informed treatment decisions (medication chosen, dose change, or monitoring plan). Include any modeled or expected treatment alignment used in economic/decision analyses.

Attach laboratory report with genotype/phenotype calls and interpretive comments.
Explain clinical actions taken as a result of the test (e.g., drug selection, dosage adjustment, monitoring).

Note

Laboratory and regulatory information

Laboratories performing genetic testing must follow CLIA regulations. FDA resources (lists of cleared/approved tests, companion diagnostics, and pharmacogenetic associations) are informational; FDA clearance is not by itself a basis for coverage. Provide CLIA certification and any available analytic validity documentation when requested.

Provide laboratory CLIA accreditation information on request.
FDA informational resources: list of cleared/approved genetic tests, companion diagnostics, and PGx associations (see FDA links in policy).

Note

Reference benefit plan requirements and adjudication tools

When making coverage decisions, reference the applicable federal, state, or contractual benefit plan requirements; these govern and may override the policy. UnitedHealthcare may also use third‑party tools (e.g., InterQual) to assist in administering benefits.

Benefit plan terms take precedence over this policy in the event of conflict.
UnitedHealthcare may use InterQual or other third‑party clinical tools to adjudicate coverage.

Note

Pediatric psychotropic PGx — AACAP recommendation

In pediatric patients, clinicians should avoid using combinatorial PGx testing to select psychotropic medications. High‑quality pediatric evidence is lacking; follow AACAP recommendations and provide strong clinical justification if testing is requested for children or adolescents.

AACAP (2020) recommends against PGx testing to select psychotropic medications in children and adolescents.
If pursued, include justification and supporting evidence that testing is necessary and cannot be deferred.

Note

Cardiovascular outcomes uncertainty

Evidence from real‑world claims analyses raises concerns about cardiovascular outcomes after PGx testing in some populations; testing did not clearly improve outcomes and was associated with higher rates of thromboembolic events in one retrospective cohort. Exercise caution when considering PGx for cardiovascular management and include supporting rationale.

Billings et al. (2018) found higher rates of stroke, pulmonary embolism, and DVT in a tested cohort versus controls; claims‑based analyses did not show improved outcomes.
Routine PGx panel testing for cardiovascular indications should be justified with specific clinical rationale.

Documentation Required

Consider prior medication trials

Consider prior medication trials when evaluating requests for PGx testing: many psychiatric RCTs of PGx-guided care enrolled participants who were starting or switching antidepressants or who had failed prior therapies. Prior trials and treatment context are relevant to determining medical necessity.

For psychiatric indications, note whether testing is being used to guide initial therapy vs to address inadequate response after trials of medications.
Provide objective evidence of prior treatment attempts (medication names, doses, durations).

Step Therapy

Step‑therapy and plan requirements

Step‑therapy requirements may apply; documentation should state whether step‑therapy was attempted or why it is not clinically appropriate. No specific plan‑level step‑therapy rules are provided in this policy; check member contract for applicable requirements.

If step‑therapy prevented alignment with MSRC recommendations, document the insurer requirement and attempts to obtain exceptions.
Refer to the member's benefit plan for any specific step‑therapy or quantity‑limit rules.

Actionable phenotype: a genotype-predicted metabolic phenotype (for example, CYP2C19 or CYP2D6 poor, intermediate, or rapid metabolizer) that would prompt a change in medication selection or dosing based on PGx guidance.

Clinical contextIn psychiatric studies (e.g., PREPARE), actionable phenotypes were those that related to CYP2C19/CYP2D6 and were associated with fewer adverse drug reactions when acted upon.

ImplicationThe proportion of individuals with an actionable phenotype may be modest and can affect statistical significance of study outcomes.

Proprietary combinatorial PGx algorithm (definition and examples)

DefinitionProprietary combinatorial PGx algorithm: a laboratory-specific algorithm that combines results from multiple genes into treatment recommendations or risk categorizations; examples include the proprietary algorithm used by Assurex Health in the GUIDED trial (GeneSight/NeuroIDgenetix) and other marketed combinatorial tests evaluated in RCTs.

Clinical noteProprietary algorithms were used in trials such as GUIDED and may produce differing recommendations across commercial tests, contributing to heterogeneity and interpretation challenges.

Evidence considerationMany studies using proprietary algorithms are industry-funded and at risk of bias, affecting certainty of clinical utility conclusions.

CIC (chemotherapy-induced cardiotoxicity)

DefinitionChemotherapy-induced cardiotoxicity (CIC): cardiotoxicity associated with chemotherapeutic agents (notably anthracyclines) that can result in acute or late-onset cardiac dysfunction and heart failure.

Evidence contextSystematic reviews and cohort studies have identified multiple genomic variants associated with increased or decreased risk of anthracycline-related cardiotoxicity, but evidence certainty remains very low and routine PGx panel testing is not currently supported.

Clinical implicationPGx models combining genetic and clinical data showed higher predictive accuracy (AUC 0.67–0.87) than clinical data alone (AUC 0.57–0.81), yet generalizability and standardized panels are lacking.

PrismRA / MSRC (Scipher Medicine) — concise definition

DefinitionPrismRA / MSRC: a molecular signature response classifier developed by Scipher Medicine that evaluates multiple biomarkers (19 gene expression features), anti-cyclic citrullinated protein, and clinical metrics (sex, BMI, patient disease assessment) to stratify likelihood of inadequate response to anti-TNF therapies in rheumatoid arthritis.

Intended useDesigned to predict nonresponse to anti-TNF treatments prior to prescription and to inform selection of targeted DMARDs to improve first-line response rates.

Test componentsThe PrismRA biomarker panel combines gene expression features, a serologic marker (anti-CCP), and clinical measures to produce a nonresponse signature.

PrismRA / MSRC — additional details

Performance detailsPublished cohort data report a nonresponse signature in ~59% of tested individuals; in MSRC-tested cohorts, MSRC-aligned treatment occurred in ~70% and PPV for anti-TNF nonresponse was reported as high (approximately 87–88%) with sensitivity around 54–60%.

Evidence limitationsAvailable evidence is limited, largely observational, and subject to potential confounding; Hayes rated the evidence very low quality and additional larger, independent studies are needed.

Implementation noteScipher Medicine reported plans for CLIA/CAP laboratory offering and ongoing validation; observed alignment with test recommendations in practice may be influenced by insurer coverage and step-therapy policies.

PGx multigene panel — example (12-gene PREPARE panel)

Example panelPREPARE trial used a 12-gene pharmacogenetic panel (multicenter, pragmatic trial) to evaluate prevention of clinically significant adverse drug reactions across multiple drugs and conditions.

Clinical outcomeIn PREPARE, participants with actionable results experienced fewer clinically significant ADRs compared with usual care in the trial population.

Panel focusAlthough PREPARE genotyped 12 genes across many conditions, analyses for some indications (e.g., psychiatry) focused primarily on CYP2C19/CYP2D6 as the most relevant pharmacogenes.

Pharmacogenomic panel / multigene test — general definition and CPIC context

DefinitionPharmacogenomic (PGx) panel / multigene test: a laboratory test that assesses multiple gene variants (often five or more) that may influence drug metabolism, efficacy, or toxicity; panels can include genes such as CYP2C19, CYP2D6, CYP2C9, DPYD, TPMT, SLCO1B1 and others depending on purpose.

Guideline contextCPIC provides gene-specific dosing guidelines (e.g., CYP2D6, CYP2C19) but does not provide recommendations specific to multigene panels that include five or more genes; STRIPE and other reviews identify clinically actionable gene-drug pairs but note variability across CPGs.

Clinical usePGx panels range from single-gene targeted tests to broader panels used proactively for multimorbidity or polypharmacy; evidence for panel-based utility varies by gene-drug pair and indication.

Multi-Gene Panel — policy history (updated definition)

Policy updateThe policy history notes an updated definition of 'Multi - Gene Panel' effective 01/01/2026; supporting sections (Description of Services, Clinical Evidence, FDA, References) were refreshed and the prior policy version was archived.

Material changeThe definition revision is recorded as a material change in the policy history and should be referenced when applying coverage decisions.

Implementation noteProviders should reference the current policy effective date for the revised definition when submitting claims or prior authorization requests.

Record that genetic counseling was offered or provided and summarize counseling content relevant to cardiotoxicity risk.
Include counseling documentation in PA submissions when relevant.

Documentation Required

Document result reporting and integration into care

Ensure timely return of PGx or MSRC results to treating clinicians and integrate results into clinical workflows; studies emphasize appropriate result return and suggest tools/systems to support clinician use.

Document how results were communicated to treating clinicians and any EHR tools or decision support used.
Provide evidence of processes that ensure clinicians received and acted on test results when requesting coverage.

Note

No explicit ordering restrictions; treating clinicians usually order tests

No explicit ordering provider restrictions are stated in the policy excerpt; ordering is typically performed by treating clinicians who will use results to guide care.

Treating clinicians (psychiatrists, oncologists, rheumatologists, primary care) commonly order PGx testing in cited programs.
If a plan imposes specialist ordering requirements, follow that plan's contractual rules.

Documentation Required

Treating clinician should order tests and document intended use

Ordering is typically performed by the treating clinician responsible for acting on PGx or MSRC results (e.g., psychiatrists for psychiatric PGx, rheumatologists for PrismRA), and the order should document intended clinical use.

Document who will use the results to inform treatment decisions.
Include the clinical question the test is intended to address in the order.

Documentation Required

Order PrismRA for rheumatology decision‑making with documented intended use

PrismRA/MSRC was developed to inform rheumatologists' b/tsDMARD treatment decisions; when ordering for RA, document that a rheumatologist will interpret results and how results will change management.

State that PrismRA results will be used by a rheumatologist to guide biologic/targeted therapy selection.
Provide rationale linking PrismRA score to planned treatment changes.

Note

Use centralized review or clinical triage processes for test appropriateness

Centralized implementation programs have used review units and clinical categories to determine appropriateness of PGx testing; consider similar pre‑test review workflows to support utilization management.

A centralized testing unit evaluated requests and triaged tests into categories (preemptive actionable, disease-specific, or poorly defined) to approve testing.
Consider including a brief clinical justification and category when submitting PA requests.