CurrentAetnaPolicy 0777

Novel Injection Methods

Defines Aetna's coverage stance for novel ophthalmic injection methods (suprachoroidal injections, subretinal rtPA, and vessel-wall micro-infusion devices) affecting providers who perform or bill for these procedures and related drugs.

Policy Summary

PayerAetna

PolicyNovel Injection Methods

Policy CodePolicy 0777

Change TypeMinor / administrative

Effective DateFeb 6, 2009

Next Review DateAug 22, 2024

Key ActionObtain prior authorization and submit the listed CPT/HCPCS and ICD-10 codes when billing for suprachoroidal triamcinolone (Xipere) or subretinal rtPA.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

1Medically necessary Xipere

1Medically necessary rtPA

1Device investigational

67516, J3299Key codes discussed

H35.81; H35.60-H35.63ICD-10 listed

Coverage Criteria

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Suprachoroidal triamcinolone (Xipere) for macular edema associated with uveitis

Covered when ALL of the following are met:

Suprachoroidal Xipere coverage: Suprachoroidal injection of triamcinolone acetonide injectable suspension (Xipere) is medically necessary for treatment of macular edema associated with uveitis when criteria are met in CPB 1000 Triamcinolone Acetonide Injectable Suspension (Xipere).

See referenced CPB 1000 for specific selection criteria.

Subretinal injection of rtPA for sub-macular hemorrhage

Covered when ALL of the following are met:

Subretinal rtPA coverage: Subretinal injection of recombinant tissue plasminogen activator (rtPA) is medically necessary for treatment of sub-macular hemorrhage.

Procedure CPT 0810T applies; recombinant rtPA has no specific HCPCS code listed in this policy. Cite appropriate ICD-10 diagnosis codes for retinal hemorrhage (e.g., H35.60–H35.63).

Suprachoroidal delivery of other pharmacologic agents

Not covered / investigational:

Other suprachoroidal agents: Suprachoroidal injection of all other pharmacologic agents (other than triamcinolone acetonide/Xipere) is considered experimental and investigational for all indications because effectiveness has not been established.

Claims for these uses are subject to denial.

Mercator Bullfrog micro-infusion device

Not covered / investigational:

Mercator Bullfrog device: The Mercator Bullfrog micro-infusion device is considered experimental and investigational for direct adventitial delivery of diagnostic or therapeutic agents via blood vessel walls due to lack of evidence regarding safety and effectiveness.

Includes related HCPCS code C9759; use may be denied.

Evidence-summary and investigational stance for novel injection methods

Summarized coverage-relevant conclusions and evidence limits from the document:

Suprachoroidal CLS-TA for NIU and related posterior segment disease: Small preclinical and clinical studies (including AZALEA, PEACHTREE and other trials) demonstrated favorable posterior tissue distribution, prolonged therapeutic levels, and clinically meaningful safety and efficacy signals (notably low rates of IOP elevation and cataract events); however, trials are limited by small sample sizes, some open-label designs, and lack of larger controlled studies.

Further larger controlled trials are needed to establish definitive safety and effectiveness.

Suprachoroidal CLS-TA plus intravitreal aflibercept for DME: A randomized controlled study (Barakat et al) in treatment‑naive DME (n=36 active, n=35 control) showed no statistically significant difference in mean BCVA change at 24 weeks between combination therapy and aflibercept monotherapy, with modestly greater CST improvement in some analyses and fewer total treatments in the active group; authors recommend larger and longer studies to confirm findings.

Study eligibility included BCVA 20–70 letters and CST >300 μm.

Suprachoroidal hyaluronic acid hydrogel for IOP reduction:

This policy notes that Aetna covers suprachoroidal injection of triamcinolone acetonide injectable suspension (Xipere) for macular edema associated with uveitis when the criteria in CPB 1000 are met. For other pharmacologic agents delivered to the suprachoroidal space, coverage is not established and those uses are considered experimental and investigational. Relevant billing guidance identifies CPT 67516 and HCPCS J3299 for Xipere when selection criteria are satisfied; providers should follow the referenced CPB for specific patient selection and documentation requirements.

Clinical and preclinical reports emphasize that not all agents are suitable for suprachoroidal space (SCS) injection because some molecules, particularly highly aqueous-soluble agents, are cleared rapidly from the SCS. Studies to date predominantly used CLS-TA (Xipere) because it demonstrates favorable posterior distribution and slower clearance; additional formulation work or delivery strategies are needed to enable sustained therapeutic levels for other agents. Providers should be aware that rapid SCS clearance and limited targeting to posterior segments are key biologic limitations that affect suitability of alternative drugs for this route.

Aetna considers suprachoroidal injection of all pharmacologic agents other than triamcinolone acetonide (Xipere) to be not medically necessary / experimental and investigational for all indications because effectiveness has not been established. Claims for these uses are subject to denial.

The Mercator Bullfrog micro-infusion device is described as a balloon‑tipped, micro‑needle system intended to deliver agents into adventitial or peri‑vascular tissues. Although it has FDA 510(k) clearance for selected peripheral and coronary vessel uses, Aetna considers use of this device for direct adventitial delivery in the contexts described by this policy to be experimental and investigational due to a lack of evidence demonstrating safety and effectiveness; such uses may be considered not medically necessary and are subject to denial. The related HCPCS code is C9759.

Coding

Covered CPT Codes (suprachoroidal - when selection criteria met)CPTCovered

67516

Suprachoroidal space injection of pharmacologic agent (separate procedure)

Covered HCPCS Codes (Xipere)HCPCSCovered

J3299

Injection, triamcinolone acetonide (Xipere), 1 mg

CPT codes not covered for other suprachoroidal indicationsCPTNot Covered

0699T	Injection, posterior chamber of eye, medication
67516	Suprachoroidal space injection of pharmacologic agent (separate procedure)

ICD-10 codes (covered indications)ICD-10

H35.81	Retinal edema
H35.60	Retinal hemorrhage, unspecified
H35.61	Retinal hemorrhage, preretinal
H35.62	Retinal hemorrhage, subretinal
H35.63	Retinal hemorrhage, intraretinal

No explicit billing codes in this sectionmixed

No codes listed

Central subfield thickness (CST) — > 300 µm (used to define macular edema in cited trial)

Definition> 300 µm — threshold used to define macular edema in cited clinical trials (AZALEA, Henry et al.)

Context of useUsed as an OCT-derived central subfield thickness (CST) threshold to identify study participants with macular edema

Source trial exampleHenry et al. prospective multi-center study: based on CST > 300 µm, 20 of 38 subjects had macular edema at baseline

Central subfield thickness (CST) eligibility used in study — > 300 μm

Eligibility threshold> 300 μm (central subfield thickness) — entry criterion for the Barakat et al. DME study

Measurement modalityOCT-derived central subfield thickness (CST) used to assess retinal edema

Study populationApplied to treatment‑naive DME subjects enrolled in the randomized, double-masked study

Best-corrected visual acuity (BCVA) eligibility used in study — 20 to 70 letters

BCVA eligibility range20 to 70 letters — inclusion criterion in the Barakat et al. DME trial

PurposeDefines visual acuity bounds for enrollment in the randomized CLS-TA plus aflibercept versus aflibercept study

AssessmentBest-corrected visual acuity (BCVA) measured in letter score (ETDRS) format

Provider Actions and Billing Guidance

Prior Authorization

Prior Authorization Required

Prior authorization is expected for covered suprachoroidal injection of triamcinolone acetonide (Xipere) when medical necessity criteria are met. Submit the appropriate CPT/HCPCS along with an ICD-10 diagnosis that supports the indication.

Covered codes when criteria met: CPT 67516; HCPCS J3299 (Xipere, 1 mg); ICD-10 H35.81 (Retinal edema).
Do not submit CPT 67516 or 0699T, or HCPCS C9759, for suprachoroidal delivery of non‑Xipere agents — these are not covered in this CPB.

Documentation Required

Clinical Trial Eligibility Documentation

Document clinical trial eligibility elements when applicable. For studies of suprachoroidal agents combined with intravitreal therapy, include prior treatment history, baseline best-corrected visual acuity (BCVA), central subfield thickness (CST), and pre-specified retreatment criteria (eg, timing and BCVA/CST thresholds).

Trials commonly enrolled treatment‑naive patients with BCVA 20–70 letters and CST >300 μm.
Report retreatment schedule and any as‑needed (PRN) dosing criteria used in the trial (eg, weeks allowed for additional intravitreal therapy).

Denial Risk

Experimental Suprachoroidal Agents

Suprachoroidal delivery of pharmacologic agents other than triamcinolone acetonide injectable suspension (Xipere) is considered experimental and investigational for all indications due to insufficient evidence of safety and effectiveness. Do not bill covered suprachoroidal codes for these agents.

Experimental suprachoroidal agents: any pharmacologic agent delivered suprachoroidally other than Xipere.
Do not use CPT/HCPCS listed as covered for Xipere when the agent is not Xipere; such use may be denied as experimental.

Step Therapy

Comparative Step Considerations

Comparative step considerations: when suprachoroidal CLS‑TA has been studied in combination with intravitreal aflibercept, studies showed similar mean BCVA gains versus aflibercept monotherapy but greater CST reduction and fewer total treatments in the combination arm. Consider that combination therapy may reduce number of intravitreal treatments but has not shown superior BCVA in the referenced trial.

Active group (CLS‑TA + aflibercept) vs aflibercept monotherapy: similar BCVA change at 24 weeks; greater CST reduction in active group; fewer scheduled plus as‑needed treatments (average 2.6 vs 4.6).
No treatment‑related serious adverse events observed in the referenced study.

Denial Risk

Investigational Device Risk

Investigational device risk: the Mercator Bullfrog micro‑infusion device is considered experimental and investigational for adventitial delivery via blood vessel walls due to lack of evidence on safety and effectiveness; claims for its use (eg, HCPCS C9759) may be denied.

Bullfrog device: experimental/investigational for direct adventitial delivery — lack of clinical evidence.
Billing note: HCPCS C9759 (transcatheter intraoperative blood vessel microinfusion) is listed as not covered for indications in this CPB and may be denied.

Definitions

Suprachoroidal space (SCS) — definition and purpose

DefinitionThe suprachoroidal space (SCS) is the potential anatomic space between the sclera and the choroid used as a route for targeted drug delivery to posterior segment tissues.

Access techniqueCan be accessed via hollow micro-needles or microcannulae fitted to scleral thickness and visualized with OCT

Therapeutic rationaleProvides a route from anterior to posterior eye enabling higher drug concentrations in chorio-retinal tissues with potentially reduced anterior segment exposure

CLS-TA / Xipere — definition and intended use

ProductTriamcinolone acetonide injectable suspension (CLS-TA; marketed as Xipere) — proprietary formulation for suprachoroidal administration

Intended useDeveloped for treatment of macular edema associated with non-infectious uveitis and investigated for other posterior segment diseases

Clinical contextStudied in phase I/II and other trials (e.g., AZALEA, PEACHTREE) showing favorable posterior tissue distribution and preliminary safety/efficacy signals

Subretinal rtPA — definition

DefinitionSubretinal rtPA — recombinant tissue plasminogen activator delivered via subretinal injection to treat sub-macular hemorrhage

Procedure coding noteProcedure CPT 0810T applies for subretinal injection of a pharmacologic agent including vitrectomy and retinotomies

Clinical guidanceAAO and referenced literature list subretinal rtPA as a therapeutic option for submacular hemorrhage

Suprachoroidal space (SCS) — alternate mention/definition

Alternate definitionThe SCS is the potential space between the sclera and choroid that can be used to deliver therapeutics to the back of the eye

Visualization and accessSCS can be visualized with advanced OCT techniques and accessed safely via microneedles or microcannulae

Pharmacokinetic noteSCS injections may achieve higher target-tissue concentrations but highly aqueous soluble molecules clear more rapidly from the SCS

CLS-TA — formulation and investigational contexts

FormulationCLS-TA is a triamcinolone acetonide injectable suspension formulated for suprachoroidal administration (examples: 4 mg in 100 μl used in early trials)

Investigational contextsStudied in phase I/II open-label and multi-center trials for non-infectious uveitis and macular edema (e.g., Goldstein 2016, Henry et al. 2022, AZALEA/PEACHTREE)

Safety signalsTrials reported predominantly mild-to-moderate adverse events, low steroid-related IOP increases in some studies, and preliminary efficacy in reducing macular edema

OpenPayer

Novel Injection Methods

Coverage Criteria

Coding

Provider Actions and Billing Guidance

Background

Definitions