mp-597
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Amniotic Membrane and Amniotic Fluid

Policy Number: MP-597

Latest Review Date: February 2022

Category: Surgery                                                                  

POLICY:

Effective for dates of service on and after February 23, 2021:

Treatment of nonhealing* diabetic lower extremity ulcers using the following human amniotic membrane products may be considered medically necessary:

  • AmnioBand® Membrane (Effective for dates of service on or after 06/01/17)
  • Biovance®
  • Epifix®
  • Grafix™
  • Affinity®

*Nonhealing is defined as less than 20% decrease in wound area with standard wound care for at least two weeks, based on the entry criteria for clinical trials (e.g., Zelen et al, 2015).

Injection of micronized or particulated human amniotic membrane is considered investigational for all indications, including by not limited to treatment of osteoarthritis and plantar fasciitis.

Injection of human amniotic fluid is considered investigational for all indications.

All other human amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton's jelly; including EpiCord®) and indications not listed above, including but not limited to the treatment of lower extremity ulcers due to venous insufficiency  and repair following Mohs micrographic surgery are considered investigational.

For additional information on specific ocular conditions using amniotic products, refer to medical policy #624 Amniotic Membrane Transplantation for the Ocular Surface.

For bio-engineered skin and soft tissue substitutes other than amniotic products, refer to medical policy #527 Bio-Engineered Skin and Soft Tissue Substitutes.

Effective for dates of service prior to February 23, 2021:

Treatment of nonhealing* diabetic lower extremity ulcers using the following human amniotic membrane products may be considered medically necessary:

  • AmnioBand® Membrane (Effective for dates of service on or after 06/01/17)
  • Biovance®
  • Epifix®
  • Grafix™

*Nonhealing is defined as less than 20% decrease in wound area with standard wound care for at least two weeks, based on the entry criteria for clinical trials (e.g., Zelen et al, 2015).

Injection of micronized or particulated human amniotic membrane is considered investigational for all indications, including by not limited to treatment of osteoarthritis and plantar fasciitis.

Injection of human amniotic fluid is considered investigational for all indications.

All other human amniotic membrane products (including EpiCord®) and indications not listed above, including but not limited to the treatment of lower extremity ulcers due to venous insufficiency are considered investigational.

For additional information on specific ocular conditions using amniotic products, refer to medical policy #624 Amniotic Membrane Transplantation for the Ocular Surface.

For bio-engineered skin and soft tissue substitutes other than amniotic products, refer to medical policy #527 Bio-Engineered Skin and Soft Tissue Substitutes.

DESCRIPTION OF PROCEDURE OR SERVICE:

Several commercially available forms of human amniotic membrane (HAM) and amniotic fluid can be administered by patches, topical application or injection. Amniotic membrane and amniotic fluid are being evaluated for the treatment of a variety of conditions, including chronic full thickness diabetic lower extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions (refer to medical policy #624 Amniotic Membrane Transplantation for the Ocular Surface).

Human Amniotic Membrane

Human amniotic membrane (HAM) consists of two conjoined layers, the amnion and chorion, and forms the amniotic sac and the innermost lining of the placenta. When prepared for use as an allograft, the membrane is harvested immediately after birth, cleaned, sterilized, and either cryopreserved or dehydrated. Many products available using amnion, chorion, amniotic fluid, and umbilical cord are being studied for the treatment of a variety of conditions, including chronic full-thickness diabetic lower-extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions. The products are formulated either as patches, which can be applied as wound covers, or as suspensions or particulates, or connective tissue extractions, which can be injected or applied topically (see Table 1).

Fresh amniotic membrane contains collagen, fibronectin, and hyaluronic acid, along with a combination of growth factors, cytokines, and anti-inflammatory proteins such as interleukin-1 receptor antagonist. There is evidence that the tissue has anti-inflammatory, anti-fibroblastic, and antimicrobial properties. HAM is considered to be non-immunogenic and has not been observed to cause substantial immune response. It is believed that these properties are retained in cryopreserved HAM (c-HAM) and dehydrated HAM (d-HAM) products, resulting in a readily available tissue with regenerative potential. In support, one D-HAM product has been shown to elute growth factors into saline and stimulate the migration of mesenchymal stem cells both in vitro and in vivo.

HAM is an established treatment for corneal reconstruction (refer to medical policy #624 Amniotic Membrane Transplantation for the Ocular Surface) and is being evaluated for the treatment of a variety of conditions, including skin wounds, burns, leg ulcers, and prevention of tissue adhesion in surgical procedures (refer also to medical policy #527, Bio-Engineered Skin and Soft Tissue Substitutes). Additional indications studied in pre-clinical models include tendonitis, tendon repair, and nerve repair. The ready availability of an injectable preparation of amniotic membrane opens the possibility of regenerative medicine for a wide variety of conditions.

Amniotic Fluid

Amniotic fluid surrounds the fetus during pregnancy and provides protection and nourishment. In the second half of gestation, most of the fluid is a result of micturition and secretion from the respiratory tract and gastrointestinal tract of the fetus, along with urea. The fluid contains proteins, carbohydrates, proteins and peptides, fats, amino acids, enzymes, hormones, pigments and fetal cells. Use of human and bovine amniotic fluid for orthopedic conditions was first reported in 1927. Amniotic fluid has been compared with synovial fluid, containing hyalunonan, lubricant, cholesterol, and cytokines. Injection of amniotic fluid is being evaluated for the treatment of pain and stiffness in patients with osteoarthritis and plantar fasciitis.

Amniotic membrane and amniotic fluid are also being investigated as a source of pluripotent stem cells. Pluripotent stem cells can be cultured and are capable of differentiation toward any cell type. The use of stem cells in orthopedic applications is addressed separately in medical policy #430 Orthopedic Applications of Stem Cell Therapy.

Table 1. Amniotic Membrane and Amniotic Fluid Preparations: Preparation and Components

Product (Supplier)

Preparation

Components

 

Cryopreserved, Dehydrated, or Extracted

Amnion

Chorion

Amniotic Fluid

Umbilical Cord

Patch

 

 

 

 

 

Affinity™ (NuTech Medical)

C

X

 

 

 

AlloWrap™ (AlloSource)

NS

X

 

 

 

AmnioBand® Membrane (MTF Wound Care)

D

X

X

 

 

AmnioClear™ (Liventa Bioscience)

NS

X

X

 

 

AmnioExcel® (Derma Sciences)

D

X

 

 

 

AmnioFix® (MiMedx)

D

X

 

 

 

AmnioGen™ 45 (US Biologix)a

D

X

 

 

 

AmnioGen™ 200 (US Biologix)a

D

 

X

 

 

AmnioGraft® (BioTissue)

C

X

 

 

 

AmnioPro® 45 (HRT)a

D

X

 

 

X

AmnioPro® 200 (HRT)a

D

 

X

 

X

Artacent® Wound (Tides Medical)

D

X

 

 

 

BioDDryFlex® (BioD)

D

X

 

 

 

BioDfence™ (BioD)

D

X

X

 

 

BioRenew 45 (HRT)a

D

X

 

 

 

BioRenew 200 (HRT)a

D

 

X

 

 

BioSkin 45 (HRT)a

D

X

 

 

 

BioSkin 45 (HRT)a

D

 

X

 

 

Biovance® (Aliqual Biomedical)

D

X

 

 

 

Clarix® (Amniox Medical)

C

X

 

 

X

Cygnus (Vivex Biomedical)

D

X

 

 

 

Cygnus Max (Vivex Biomedical)

D

 

 

 

X

EpiCord™ (MiMedx)

D

 

 

 

X

EpiFix® (MiMedx)

D

X

X

 

 

Dermavest™ (Aedicell)a

C

X

X

 

X

Grafix® (Osiris)

C

X

X

 

 

Guardian/AmnioBand® (MTF Wound Care)

D

X

X

 

 

HydraTek® (Human Regenerative Technologies)

D

X

 

 

 

Neox® 100 (Amniox Medical)

C

X

 

 

X

Neox® Cord (Amniox Medical)

C

X

 

 

X

Neox® Wound Allograft (Amniox Medical)

C

X

 

 

X

NuShield™ (NuTech Medical)

D

X

X

 

 

PalinGen® Membrane (Amnio ReGen Solutions)

C

X

 

 

 

Plurivest™ (Aedicell)a

C

X

X

 

X

Revitalon™ (Medline Industries)

D

X

X

 

 

WoundEx® 45 (Skye Biologics)a

D

X

 

 

 

WoundEx® 200 (Skye Biologics)a

D

 

X

 

 

Suspension, particulate, or extraction

 

 

 

 

 

AmnioBand® Particulate (MTF Wound Care)

D

X

X

 

 

AmnioGen™-A (US Biologix)b

E

X

X

X

X

AmnioGen™-C (US Biologix)b

C

X

X

X

X

AmnioMatrix® (Derma Sciences)

D

X

 

X

 

AmnioPro® Flow (HRT)b

E

X

X

X

X

AmnioVisc™ (Lattice Biologics)

NS

 

 

X

 

BioRenew® Flow (HRT)b

E

X

X

X

X

BioSkin® Flow (HRT)b

E

X

X

X

X

Clarix® Flo (Amniox Medical)

C

X

 

 

X

HydraTek® (Human Regenerative Technologies)

D

X

 

 

 

Interfyl™ (Alliqua Biomedical)

NS

X

X

 

 

Neox® Flo (Amniox Medical)

C

X

 

 

X

OrthoFlo™ (MiMedx)

D

 

 

X

 

PalinGen® Flow (Amnio ReGen Solutions)

C

X

 

X

 

PalinGen® SportFlow (Amnio ReGen Solutions)

C

X

 

X

 

ProMatrX™ ACF (Amnio ReGen Solutions)

C

X

 

X

 

ReNu™ (NuTech Medical)

D

X

 

X

 

WoundEx® Flow (Skye Biologics)b

E

X

X

X

X

C: cryopreserved; D: dehydrated; E: extracted connective tissue; HRT: Human Regenerative Technologies; MTF: Musculoskeletal Transplant Foundation; NS: not specified.

a,b Processed by HRT and marketed by under different tradenames

The preferred outcomes for the healing of lower-extremity ulcers and burn wounds are the percentage of patients with complete wound healing and the time to complete wound healing. The percentage of patients with 50% wound healing and time to 50% wound healing have also been considered appropriate outcomes for these conditions. The percent change in wound area at four weeks is predictive of complete healing at 12 weeks in patients with diabetic foot ulcers. Thus, minimal improvement at 30 days can be considered as an indicator that a wound is unlikely to heal in patients with comorbidities known to affect wound healing, but would not be considered a primary outcome measure.

KEY POINTS:

The most recent literature update was performed through January 3, 2022.

Summary of Evidence

Diabetic Lower-Extremity Ulcers

For individuals who have nonhealing diabetic lower-extremity ulcers who receive patch or flowable formulation of human amniotic membrane (HAM; Affinity, AmnioBand Membrane, Biovance, Epifix, Grafix), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on amniotic and placental membrane products for the treatment of nonhealing (<20% healing with ≥2 weeks of standard care) diabetic lower-extremity ulcers includes several RCTs that compared HAM to standard care or to an established advanced wound care product. These industry-sponsored studies used wound closure as the primary outcome measure, and some used power analysis, blinded assessment of wound healing, and intention-to-treat analysis. For the HAM products that have been sufficiently evaluated (Affinity, AmnioBand Membrane, Biovance, Epifix, Grafix), results have shown improved outcomes compared to standard care, and outcomes that are at least as good as an established advanced wound care product. Improved health outcomes in the RCTs are supported by multicenter registries. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Lower-Extremity Ulcers due to Venous Insufficiency

For individuals who have lower-extremity ulcers due to venous insufficiency who receive patch or flowable formulation of HAM, the evidence includes two RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on HAM for the treatment of lower-extremity venous ulcers includes two multicenter RCTs with EpiFix. One RCT reported larger percent wound closure at four weeks, but the percentage of patients with complete wound closure did not differ between EpiFix and standard of care. A second multicenter RCT reported a significant difference in complete healing at 12 weeks, but the interpretation is limited by methodologic concerns. Well-designed and well-conducted RCTs that compare HAM with the standard of care for venous insufficiency ulcers are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Osteoarthritis

For individuals who have knee osteoarthritis who receive injection of suspension or particulate formulation of human amniotic membrane or amniotic fluid, the evidence includes a feasibility study. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. The pilot study was in preparation for a larger RCT of HAM injection. Additional trials, which will have a larger sample sizes and longer follow-up, are needed to permit conclusions on the effect of this treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

Plantar Fasciitis

For individuals who have plantar fasciitis who receive injection of suspension or particulate formulation of human amniotic membrane or amniotic fluid, the evidence includes two small RCTs. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Literature on HAM injections is at a very early stage. Evidence includes a small (N=23) double-blind comparison with corticosteroid and a patient-blinded (N=45) comparison of two different doses of dehydrated HAM with saline. Additional controlled trials with larger sample sizes and longer follow-up are needed to permit conclusions on the effect of this treatment on plantar fasciitis pain. Also needed are RCTs in humans to evaluate the efficacy of amniotic membrane and amniotic fluid injections for the treatment of other conditions, including but not limited to tendonitis. The evidence is insufficient to determine the effects of the technology on health outcomes.

Repair Following Mohs Micrographic Surgery

For individuals who have undergone Mohs micrographic surgery for skin cancer on the face, head, neck, or dorsal hand who receive  human amnionic/chorionic membrane, the evidence includes a nonrandomized, comparative study and no RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. A retrospective analysis using data from medical records compared a dehydrated human amnionic/chorionic membrane product (dHACM, Epifix) to repair using autologous surgery in 143 propensity-score matched pairs of patients requiring same-day reconstruction after Mohs microsurgery for skin cancer on the head, face, or neck. A greater proportion of patients who received dHACM repair experienced zero complications (97.9% vs 71.3%; P <.0001; relative risk 13.97; 95% CI 4.33 to 43.12). Placental allograft reconstructions developed less infection (P =.004) and were less likely to experience poor scar cosmesis (P <.0001). This study is limited by its retrospective observational design. Well-designed and conducted prospective studies are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

Society for Vascular Surgery

Society for Vascular Surgery et al In 2016, the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine made the following recommendation: "For DFUs [diabetic foot ulcers] that fail to demonstrate improvement (>50% wound area reduction) after a minimum of 4 weeks of standard wound therapy, we recommend adjunctive wound therapy options. These include negative pressure therapy, biologics (platelet-derived growth factor [PDGF], living cellular therapy, extracellular matrix products, amnionic membrane products), and hyperbaric oxygen therapy. Choice of adjuvant therapy is based on clinical findings, availability of therapy, and cost-effectiveness; there is no recommendation on ordering of therapy choice."

Wound Healing Society

In 2016, the Wound Healing Society updated their guidelines on diabetic foot ulcer treatment. The Society concluded that there was level 1 evidence that cellular and acellular skin equivalents improve diabetic foot ulcer healing, noting that, “healthy living skin cells assist in healing DFUs [diabetic foot ulcers] by releasing therapeutic amounts of growth factors, cytokines, and other proteins that stimulate the wound bed.” References from 2 randomized controlled trials on dehydrated amniotic membrane were included with references on living and acellular bioengineered skin substitutes.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Human amniotic membrane, HAM, amniotic fluid injections, AmnioFix® Injectable, Clarix® Flo, Neox® Flo, AmnioMatrix®, AmnioPro™, AmnioGen™, AmnioClear®, AmnioVisc™, OrthoFlow™, PalinGen® Flow, Sport Flow™, ReNu™, Affinity™, AlloWrap™, Amnioband®, AmnioExcel®, AmnioGraft®, Artacent, BioDDryFlex®, BioDfence™, BioRenew, BioSkin, Biovance®, Clarix®, Cygnus, EpiCord™, EpiFix®, Dermavest™, Grafix®, HydraTek®, Interfyl™, NuShield™, Plurivest™, Revitalon™, WoundEx®, Affinity®, VIM, Vendaje, Zenith, Celera™ Dual Layer, Celera™ Dual Membrane, Signature Apatch®, Tag

APPROVED BY GOVERNING BODIES:

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Human amniotic membrane and amniotic fluid are included in these regulations. In 2017, the FDA published clarification of what is considered minimal manipulation and homologous use for human cells, tissues, and cellular and tissue-based products (HCT/Ps).

HCT/Ps are defined as human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. If an HCT/P does not meet the criteria below and does not qualify for any of the stated exceptions, the HCT/P will be regulated as a drug, device, and/or biological product and applicable regulations and premarket review will be required.

An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria:

"1) The HCT/P is minimally manipulated;

2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective

intent;

3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a

sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not

raise new clinical safety concerns with respect to the HCT/P; and

4) Either:

i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or

ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:

a) Is for autologous use;

b) Is for allogeneic use in a first-degree or second-degree blood relative; or

c) Is for reproductive use."

The guidance provides the following specific examples of homologous and non-homologous use for amniotic membrane:

"a. Amniotic membrane is used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects. This is not a homologous use because bone regeneration is not a basic function of amniotic membrane.

b. An amniotic membrane product is used for wound healing and/or to reduce scarring and inflammation. This is not homologous use because wound healing and reduction of scarring and inflammation are not basic functions of amniotic membrane.

c. An amniotic membrane product is applied to the surface of the eye to cover or offer protection from the surrounding environment in ocular repair and reconstruction procedures. This is homologous use because serving as a covering and offering protection from the surrounding environment are basic functions of amniotic membrane."

FDA noted the intention to exercise enforcement discretion for the next 36 months after publication of the guidance.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

There is no specific code for this type of injection. It might be reported with one of the musculoskeletal system injections (e.g., 20550), the unlisted general musculoskeletal system code (20999) or if subcutaneous or intramuscular the therapeutic injection code (96372).

HCPCS Codes:

A2001

Innovamatrix ac, per square centimeter (Effective 01/01/2022)

A2002

Mirragen advanced wound matrix, per square centimeter (Effective 01/01/2022)

A2004

Xcellistem, 1 mg (Effective 01/01/2022)

A2005

Microlyte matrix, per square centimeter (Effective 01/01/2022)

A2006

Novosorb synpath dermal matrix, per square centimeter (Effective 01/01/2022)

A2007

Restrata, per square centimeter (Effective 01/01/2022)

A2008

Theragenesis, per square centimeter (Effective 01/01/2022)

A2009

Symphony, per square centimeter (Effective 01/01/2022)

A2010

Apis, per square centimeter (Effective 01/01/2022)

A2013

Innovamatrix fs, per square centimeter (Effective 04/01/22)

A4100

Skin substitute, fda cleared as a device, not otherwise specified (Effective 04/01/22)

Q4132

Grafix core and grafixpl core, per square centimeter

Q4133

Grafix prime, grafixpl prime, stravix and stravixpl, per square   centimeter

Q4137

Amnioexcel, amnioexcel plus or biodexcel, per square centimeter

Q4138

Biodfence Dryflex, per square centimeter

Q4139

AmnioMAtrix or BioDMatrix, injectable, 1 cc

Q4140

Biodfence, per square centimeter

Q4145

Epifix, injectable, 1mg

Q4148

Neox cord 1k, neox cord rt, or clarix cord 1k, per square centimeter

Q4150

Allowrap DS or dry, per square centimeter

Q4151

AmnioBand or Guardian, per square centimeter

Q4153

Dermavest and Plurivest, per square centimeter

Q4154

Biovance, per square centimeter

Q4155

NeoxFlo or ClarixFlo, 1 mg

Q4156

Neox 100 or clarix 100, per square centimeter

Q4157

Revitalon, per square centimeter

Q4159

Affinity, per square centimeter

Q4160

NuShield, per square centimeter

Q4162

Woundex flow, bioskin flow, 0.5cc

Q4163

Woundex, bioskin, per square centimeter

Q4168

Amnioband, 1 mg

Q4169

Artcent wound, per square centimeter

Q4170

Cygnus, per square centimeter

Q4171

Interfyl, 1mg

Q4173

Palingen or palingen xplus, per square centimeter

Q4174

Palingen or promatrx, 0.36mg per 0.25cc

Q4176

Neopatch or Therion, per square centimeter

Q4177

Floweramnioflo, 0.1cc

Q4178

Floweramniopatch, per square centimeter

Q4180

Revita, per square centimeter

Q4181

Amnio wound, per square centimeter

Q4183

Surgigraft, per square centimeter (Effective 01/01/2019)

Q4184

Cellesta, per square centimeter (Effective 01/01/2019)

Q4185

Cellesta flowable amnion (25 mg per cc); per 0.5 cc (Effective 01/01/2019)

Q4186

Epifix, per square centimeter (Effective 01/01/2019)

Q4187

Epicord, per square centimeter (Effective 01/01/2019)

Q4188

Amnioarmor, per square centimeter (Effective 01/01/2019)

Q4189

Artacent ac, 1 mg (Effective 01/01/2019)

Q4190

Artacent ac, per square centimeter (Effective 01/01/2019)

Q4191

Restorigin, per square centimeter (Effective 01/01/2019)

Q4192

Restorigin, 1 cc (Effective 01/01/2019)

Q4194

Novachor, per square centimeter (Effective 01/01/2019)

Q4198

Genesis amniotic membrane, per square centimeter (Effective 01/01/2019)

Q4199

Cygnus matrix, per square centimeter (Effective 01/01/2022)

Q4201

Matrion, per square centimeter (Effective 01/01/2019)

Q4204

Xwrap, per square centimeter (Effective 01/01/2019)

Q4205

Membrane graft or membrane wrap, per square centimeter (Effective 10/01/19)

Q4206

Fluid flow or fluid GF, 1 cc (Effective 10/01/19)

Q4208

Novafix, per square centimeter (Effective 10/01/19)

Q4209

Surgraft, per square centimeter (Effective 10/01/19)

Q4210

Axolotl graft or axolotl dualgraft, per square centimeter (Effective 10/01/19

Q4211

Amnion bio or Axobiomembrane, per square centimeter (Effective 10/01/19)

Q4212

Allogen, per cc (Effective 10/01/19)

Q4213

Ascent, 0.5 mg (Effective 10/01/19)

Q4214

Cellesta cord, per square centimeter (Effective 10/01/19)

Q4215

Axolotl ambient or axolotl cryo, 0.1 mg (Effective 10/01/19)

Q4216

Artacent cord, per square centimeter (Effective 10/01/19)

Q4217

Woundfix, BioWound, Woundfix Plus, BioWound Plus, Woundfix Xplus or BioWound Xplus, per square centimeter (Effective 10/01/19)

Q4218

Surgicord, per square centimeter (Effective 10/01/19)

Q4219

Surgigraft-dual, per square centimeter (Effective 10/01/19)

Q4220

BellaCell HD or Surederm, per square centimeter (Effective 10/01/19)

Q4221

Amniowrap2, per square centimeter (Effective 7/1/20)

Q4224

Human health factor 10 amniotic patch (hhf10-p), per square centimeter (Effective 04/01/22)

Q4225

Amniobind, per square centimeter (Effective 04/01/22)

Q4227

Amniocore, per square centimeter (Effective 7/1/20)

Q4229

Cogenex amniotic membrane, per square centimeter (Effective 7/1/20)

Q4230

Cogenex flowable amnion, per 0.5 cc (Effective 7/1/20)

Q4231

Corplex p, per cc (Effective 7/1/20)

Q4232

Corplex, per square centimeter (Effective 7/1/20)

Q4233

Surfactor or nudyn, per 0.5 cc (Effective 7/1/20)

Q4234

Xcellerate, per square centimeter (Effective 7/1/20)

Q4235

Amniorepair or altiply, per square centimeter (Effective 7/1/20)

Q4237

Cryo-cord, per square centimeter (Effective 7/1/20)

Q4238

Derm-maxx, per square centimeter (Effective 7/1/20)

Q4239

Amnio-maxx or amnio-maxx lite, per square centimeter (Effective 7/1/20)

Q4240

Corecyte, for topical use only, per 0.5 cc (Effective 7/1/20)

Q4241

Polycyte, for topical use only, per 0.5 cc (Effective 7/1/20)

Q4242

Amniocyte plus, per 0.5 cc (Effective 7/1/20)

Q4244

Procenta, per 200 mg (Effective 7/1/20)

Q4245

Amniotext, per cc (Effective 7/1/20)

Q4246

Coretext or protext, per cc (Effective 7/1/20)

Q4247

Amniotext patch, per square centimeter (Effective 7/1/20)

Q4248

Dermacyte amniotic membrane allograft, per square centimeter (Effective 7/1/20)

Q4249

Amniply, for topical use only, per square centimeter (Effective 10/1/20)

Q4250

Amnioamp-mp, per square centimeter (Effective 10/1/20)

Q4251

Vim, per square centimeter (Effective 10/1/21)

Q4252

Vendaje, per square centimeter (Effective 10/1/21)

Q4253

Zenith amniotic membrane, per square centimeter (Effective 10/1/21)

Q4254

Novafix dl, per square centimeter (Effective 10/1/20)

Q4255

Reguard, for topical use only, per square centimeter (Effective 10/1/20)

Q4256

Mlg-complete, per square centimeter (Effective 04/01/22)

Q4257

Relese, per square centimeter (Effective 04/01/22)

Q4258

Enverse, per square centimeter (Effective 04/01/22)

Q4259 Celera dual layer or celera dual membrane, per square centimeter (Effective 07/01/22)
Q4260 Signature apatch, per square centimeter (Effective 07/01/22)
Q4261 Tag, per square centimeter (Effective 07/01/22)

PREVIOUS CODING:

Q4131

EpiFix or Epicord, per square centimeter (Deleted 12/31/18)

Q4228

Bionextpatch, per square centimeter (Deleted 9/30/21)

Q4236

Carepatch, per square centimeter (Deleted 9/30/21)

There are no specific codes for Amniofix or OrthoFlo. It is possible that it might be reported using the code for another MiMedx product such as, Q4145- Epifix, injectable, 1 mg, or the not otherwise specified code Q4100.

REFERENCES:

  1. Abdo, RJ. Treatment of diabetic foot ulcers with dehydrated amniotic membrane allograft: a prospective case series. J Wound Care 2016; 25(Suppl7):S4-S9.
  2. Ananian, CC, Dhillon, YY, Van Gils, CC, Lindsey, DD, Otto, RR, Dove, CC, Pierce, JJ, Saunders, MM. A multicenter, randomized, singleblind trial comparing the efficacy of viable cryopreserved placental membrane to human fibroblast-derived dermal substitute for the treatment of chronic diabetic foot ulcers. Wound Repair Regen, 2018 Aug 12;26(3).
  3. Barr SM. Dehydrated amniotic membrane allograft for treatment of chronic leg ulcers in patients with multiple co-morbidities: a case series. J Am Coll Clin Wound Spec 2016; 6(3):38-45.
  4. Bianchi C, Cazzell S, Vayser D, et al. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix(R)) allograft for the treatment of venous leg ulcers. Int Wound J. Oct 11 2017.
  5. Bianchi C, Tettelbach W, Istwan N, et al. Variations in study outcomes relative to intention-to-treat and per-protocol data analysis techniques in the evaluation of efficacy for treatment of venous leg ulcers with dehydrated human amnion/chorion membrane allograft. Int Wound J. Jun 2019; 16(3): 761-767.
  6. Bouchard, CC, John, TT. Amniotic membrane transplantation in the management of severe ocular surface disease: indications and outcomes.. Ocul Surf, 2007 Jan 12;2(3).
  7. Boyer V, Galiczewski C.  Efficacy of dehydrated human amniotic membrane allograft for the treatment of severe extravasation injuries in preterm neonates. Wounds Research 2018; 30(8):224-228.
  8. Cazzell, SS, Stewart, JJ, Agnew, PP, Senatore, JJ, Walters, JJ, Murdoch, DD, Reyzelman, AA, Miller, SS. Randomized Controlled Trial of Micronized Dehydrated Human Amnion/Chorion Membrane (dHACM) Injection Compared to Placebo for the Treatment of Plantar Fasciitis.
  9. Clearfield, EE, Muthappan, VV, Wang, XX, Kuo, II. Conjunctival autograft for pterygium. Cochrane Database Syst Rev, 2016 Feb 13;2:CD011349.
  10. DiDomenico LA, Orgill DP, Galiano RD, et al. Aseptically processed placental membrane improves healing of diabetic foot ulcerations: prospective, randomized clinical trial. Plast Reconstr Surg Glob Open. Oct 2016; 4(10):e1095.
  11. Eslani M, Baradaran-Rafii A, Cheung AY et al. Amniotic Membrane Transplantation in Acute Severe Ocular Chemical Injury: A Randomized Clinical Trial. Am. J. Ophthalmol. 2019 Mar;199:209-215.
  12. Food and Drug Administration. 510(k) Summary: ProKeraTM Bio-Tissue Inc. (K032104). 2003; https://www.accessdata.fda.gov/cdrh_docs/pdf3/K032104.pdf. Accessed January 26, 2018.
  13. Food and Drug Administration. 510(k) Summary: ProKeraTM Bio-Tissue Inc. (K032104). 2003; https://www.accessdata.fda.gov/cdrh_docs/pdf3/K032104.pdf. Accessed January 10, 2022.
  14. Frykberg, RR, Gibbons, GG, Walters, JJ, Wukich, DD, Milstein, FF. A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane.. Int Wound J, 2016 Aug 5;14(3).
  15. Gottrup F, Apelqvist J, Price P, et al. Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care. Jun 2010; 19(6):237-268.
  16. Hanselman AE, Tidwell JE, Santrock RD. Cryopreserved human amniotic membrane injection for plantar fasciitis: a randomized, controlled, double-blind pilot study. Foot Ankle Int. Feb 2015; 36(2):151-158.
  17. Hingorani, AA, LaMuraglia, GG, Henke, PP, Meissner, MM, Loretz, LL, Zinszer, KK, Driver, VV, Frykberg, RR, Carman, TT, Marston, WW, Mills, JJ, Murad, MM. The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine.
  18. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  19. Kaufman SC, Jacobs DS, Lee WB, et al. Options and adjuvants in surgery for pterygium: a report by the American Academy of Ophthalmology. Ophthalmology. Jan 2013;120(1):201-208.
  20. Kirsner RS, Sabolinski ML, Parsons NB, et al. Comparative effectiveness of a bioengineered living cellular construct vs. a dehydrated human amniotic membrane allograft for the treatment of diabetic foot ulcers in a real world setting. Wound Repair Regen. Sep 2015; 23(5):737-744.
  21. Koob TJ, Rennert R, Zabek N, et al. Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. Oct 2013; 10(5):493-500.
  22. Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. Oct 2014; 11(5):554-560.
  23. Lintzeris D, Yarrow K, Johnson L, White A, Hampton A, Strickland A, Albert K, Cook, A. Use of a dehydrated amniotic membrane allograft on lower extremity ulcers in patients with challenging wounds: a retrospective case series. Ostomy Wound Manage. 2015; 61(10):30-36.
  24. McDonald, MM, Sheha, HH, Tighe, SS, Janik, SS, Bowden, FF, Chokshi, AA, Singer, MM, Nanda, SS, Qazi, MM, Dierker, DD, Shupe, AA, McMurren, BB. Treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study.. Clin Ophthalmol, 2018 Apr 20;12:677-681.
  25. Paris Fdos S, Goncalves ED, Campos MS, et al. Amniotic membrane transplantation versus anterior stromal puncture in bullous keratopathy: a comparative study. Br J Ophthalmol. Aug 2013;97(8):980-984.
  26. Rosenblum BI. A retrospective case series of a dehydrated amniotic membrane allograft for treatment of unresolved diabetic foot ulcers. J Am Podiatr Med Assn 2016; 106(5):328-337
  27. Serena TE, Carter MJ, Le LT, et al. A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. Nov-Dec 2014; 22(6):688-693.
  28. Serena TE, Yaakov R, DiMarco D, et al. Dehydrated human amnion/chorion membrane treatment of venous leg ulcers: correlation between 4-week and 24-week outcomes. J Wound Care. Nov 2015; 24(11):530-534.
  29. Serena TE, Yaakov R, Moore S, et al. A randomized controlled clinical trial of a hypothermically stored amniotic membrane for use in diabetic foot ulcers. J Comp Eff Res. Jan 2020; 9(1): 23-34.
  30. Sharma N, Thenarasun SA, Kaur M, et al. Adjuvant role of amniotic membrane transplantation in acute ocular stevens-johnson syndrome: a randomized control trial. Ophthalmology. Mar 2016;123(3):484-491.
  31. Smiell JM, Treadwell T, Hahn HD, et al. Real-world experience with a decellularized dehydrated human amniotic membrane allograft. Wounds. Jun 2015; 27(6):158-169.
  32. Snyder RJ, Shimozaki K, Tallis A, et al. A prospective, randomized, multicenter, controlled evaluation of the use of dehydrated amniotic membrane allograft compared to standard of care for the closure of chronic diabetic foot ulcer. Wounds. Mar 2016; 28(3):70-77.
  33. Suri, KK, Kosker, MM, Raber, II, Hammersmith, KK, Nagra, PP, Ayres, BB, Halfpenny, CC, Rapuano, CC. Sutureless amniotic membrane ProKera for ocular surface disorders: short-term results. Eye Contact Lens, 2013 Aug 16;39(5).
  34. Tandon, RR, Gupta, NN, Kalaivani, MM, Sharma, NN, Titiyal, JJ, Vajpayee, RR. Amniotic membrane transplantation as an adjunct to medical therapy in acute ocular burns.. Br J Ophthalmol, 2010 Aug 3;95(2).
  35. Tettelbach W, Cazzell S, Reyzelman AM et al. A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: A prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics.. Int Wound J, 2018 Aug 24;16(1).
  36. Tettelbach W, Cazzell S, Reyzelman AM, et al. A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: A prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics. Int Wound J. Feb 2019; 16(1): 19-29.
  37. Tettelbach, WW, Cazzell, SS, Sigal, FF, Caporusso, JJ, Agnew, PP, Hanft, JJ, Dove, CC. A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers. 2019 Feb; 16(1): 122 -130.
  38. Toman J, Michael GM, Wisco OJ, et al. Mohs Defect Repair with Dehydrated Human Amnion/Chorion Membrane. Facial Plast Surg Aesthet Med. Jan-Feb 2022; 24(1): 48-53.
  39. Tsikopoulos K, Vasiliadis HS, Mavridis D. Injection therapies for plantar fasciopathy ('plantar fasciitis'): a systematic review and network meta-analysis of 22 randomised controlled trials. Br J Sports Med. Nov 2016; 50(22):1367-1375.
  40. U.S. Food and Drug Administration. Guidance for industry: Chronic cutaneous ulcer and burn wounds. 2006; www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071324.pdf. Accessed December 22, 2016.
  41. U.S. Food and Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff. 2017 https://www.regulations.gov/document?D=FDA-2017-D-6146-0003 Accessed January 13, 2020
  42. U.S. Food and Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff. 2017 https://www.regulations.gov/document?D=FDA-2017-D-6146-0003 Accessed January 13, 2020
  43. U.S. Food and Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff. 2017 https://www.regulations.gov/document?D=FDA-2017-D-6146-0003 Accessed January 10, 2022
  44. Vines JB, Aliprantis AO, Gorroll AH, et al. Cryopreserved Amniotic Suspension for the Treatment of Knee Osteoarthritis. J Knee Surg. J Knee Surg. Aug 2016;29(6):443-450.
  45. Zelen CM, Gould L, Serena TE, et al. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. Dec 2015; 12(6):724-732.
  46. Zelen CM, Gould L, Serena TE, et al. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. Dec 2015;12(6):724-732.
  47. Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis--a feasibility study. Foot Ankle Int. Oct 2013; 34(10):1332-1339.
  48. Zelen CM, Serena TE, Denoziere G et al. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J 2013; 10(5):502-507.
  49. Zelen CM, Serena TE, Fetterolf DE. Dehydrated human amnion/chorion membrane allografts in patients with chronic diabetic foot ulcers: a long term follow-up study. Wound Medicine 2014; 4:1-4.
  50. Zelen CM, Serena TE, Gould L, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. Int Wound J. Apr 2016;13(2):272-282.
  51. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly vs biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. Apr 2014;11(2):122-128.

POLICY HISTORY:

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3): New policy adopted for this injection procedure – products already considered investigational (Q4139, Q4155, Q4145)

Medical Policy Administration Committee, June 2015

Available for comment June 1 through July 15, 2015

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added new HCPCS code Q4162 andQ4163 to current coding

Medical Policy Panel, February 2016

Medical Policy Group, February 2016 (3): 2016 Updates to Description, Key Points, Key Words & References; no change in policy statement.

Medical Policy Panel, January 2017

Medical Policy Group, May 2017 (3): 2017 Updates to Title, Description, Key Points, Key Words, Governing Bodies, Current Coding & Reference sections. No change to policy statements other than clarifications; all amniotic information related to indications of diabetic lower extremity ulcers moved from medical policy #527 to this policy; refer to #527 for history prior to April 2015.

Medical Policy Administration Committee, June 2017

Available for comment May 31 through July 14, 2017

Medical Policy Group, July 2017 (3):  added clarification to investigational policy statement to include EpiCord® as investigational at this time; no other changes; no change in comment period

Medical Policy Group, December 2017: Annual Coding Update 2018.  Added new HCPCS codes Q4177 – Q4181 to the Current Coding section. Updated verbiage for revised HCPCS codes Q4132, Q4133, Q4148, Q4156, Q4158, Q4162, and Q4163.

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (3):  2018 Updates to Key Points & References; clarifying statements added to Policy section – no change in intent.

Medical Policy Group, December 2018:  2019 Annual Coding Update.  Added HCPC codes Q4183-Q4192, Q4194, Q4198, Q4201 and Q4204, to the Current coding section. Moved HCPC code from Current coding section to Previous coding.  Created Previous coding section to include code Q4131.

Medical Policy Panel, February 2019

Medical Policy Group, April 2019 (7):  2019 Updates to Key Points & References. No change in Policy Statement.

Medical Policy Panel, February 2020

Medical Policy Group, February 2020 (5): Updates to Key Points, Practice Guidelines and Position Statements, Approved By Governing Bodies, and References. No change to Policy Statement.

Medical Policy Group, June 2020: Quarterly coding update.  Added new HCPCS codes from 10/1/19 and 7/1/20 to Current Coding.  Codes include: Q4205-Q4219, Q4221, Q4227 – Q4248.

Medical Policy Group, September 2020: Quarterly coding update.  Added new HCPCS codes Q4249, Q4250, Q4254, Q4255 to Current Coding.

Medical Policy Panel, February 2021

Medical Policy Group, February 2021 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, Key Words, and References. Policy statement updated to include Affinity®  for treatment of nonhealing* diabetic lower extremity ulcers; edits made to investigational statement on human amniotic products. Available for comment: February 22, 2021 through April 8, 2021.       

Medical Policy Group, September 2121: Quarterly coding update: Added new HCPCS codes Q4251, Q4252, Q4253 to Current Coding. Removed HCPCS codes Q4228, and Q4236 from Current Coding and added to Previous Coding. Update to Key Words.

Medical Policy Group, December 2021: 2022 Annual Coding Update. Added HCPCS codes A2001, A2002, A2004, A2005, A2006, A2007, A2008, A2009, A2010, Q4199 to the Current coding section.

Medical Policy Panel, February 2022

Medical Policy Group, February 2022 (5): Updates to Description, Key Points, and References. Policy Statement related to non-coverage updated to include ‘repair following Mohs micrographic surgery’ for clarification. This indication was previously investigational per this policy. Current Coding section updated to include HCPCS codes Q4176 and Q4220. Codes Q4176 and Q4220 removed from MP#527- Bio-Engineered Skin and Soft Tissue Substitutes.

Medical Policy Group, March 2022 (5): Quarterly Coding Update: Added HCPCS codes A2013, A4100, Q4224, Q4225, Q4256, Q4257, Q4258 to Current Coding Section.

Medical Policy Group, June 2022: Quarterly Coding Update. Added new HCPCS codes to current Coding Section. Codes include: Q4259, Q4260, Q4261. Description revised for A2004. Key Words section updated.

                                                                                                                       

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

 

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.