Medical Policy

Policy Num:      07.003.012
Policy Name:    Amniotic Membrane and Amniotic Fluid
Policy ID:          [07.003.012]  [Ac / B / M+ / P+]  [7.01.149]

Last Review:      April 19, 2024
Next Review:      April 20, 2025
 

Related Policies:

05.001.006 - Recombinant and Autologous Platelet-Derived Growth Factors for Wound Healing and Other Non-Orthopedic Conditions
07.001.114 - Bioengineered Skin and Soft Tissue Substitutes
08.001.042 - Orthopedic Applications of Stem Cell Therapy (Including Allografts and Bone Substitutes Used With Autologous Bone Marrow)

Amniotic Membrane and Amniotic Fluid

Summary

Description

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.

Summary of Evidence

Diabetic Lower-Extremity Ulcers

For individuals who have non-healing diabetic lower-extremity ulcers who receive a patch formulation of HAM or placental membrane (ie, Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The RCTs evaluating amniotic and placental membrane products for the treatment of non-healing (<20% healing with ≥2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM with standard care or with an established advanced wound care product. These trials 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 (ie, Affinity, AmnioBand Membrane, Biovance, EpiCord, EpiFix, Grafix), results have shown improved outcomes compared with 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 an 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 a patch formulation of HAM, the evidence includes 3 RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The published evidence on HAM for the treatment of venous leg ulcers includes 2 multicenter RCTs with EpiFix and 1 multicenter RCT with Amnioband. One RCT reported a larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure at 4 weeks did not differ between EpiFix and the standard of care. A second RCT evaluated complete wound closure at 12 weeks after weekly application of EpiFix or standard dressings with compression, but interpretation is limited by methodologic concerns. A third RCT demonstrated significantly greater blinded assessor-confirmed rates of complete wound closure at 12 weeks after weekly or twice-weekly application of AmnioBand Membrane with compression bandaging compared with compression bandaging alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Osteoarthritis

For individuals who have knee osteoarthritis who receive an injection of suspension or particulate formulation of HAM 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 assessed the feasibility of a larger RCT evaluating HAM injection. Additional trials, which will have a larger sample size and longer follow-up, are needed to permit conclusions on the effect of this treatment. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Plantar Fasciitis

For individuals who have plantar fasciitis who receive an injection of amniotic membrane, the evidence includes preliminary studies and a larger (N=145) patient-blinded comparison of micronized injectable-HAM and placebo control. Injection of micronized amniotic membrane resulted in greater improvements in the visual analog score for pain and the Foot Functional Index compared to placebo controls. The primary limitation of the study is that this is an interim report with 12-month results pending. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Ophthalmic Conditions

Sutured HAM transplant has been used for many years for the treatment of ophthalmic conditions. Many of these conditions are rare, leading to difficulty in conducting RCTs. The rarity, severity, and variability of the ophthalmic condition was taken into consideration in evaluating the evidence.

Neurotrophic Keratitis with Ocular Surface Damage and Inflammation That Does Not Respond to Conservative Therapy

For individuals who have neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy who receive HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. An RCT of 30 patients showed no benefit of sutured HAM graft compared to tarsorrhaphy or bandage contact lens. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Corneal Ulcers and Melts That Do Not Respond to Initial Medical Therapy

For individuals who have corneal ulcers and melts, that do not respond to initial medical therapy who receive HAM, the evidence includes a systematic review of primarily case series and a non-randomized comparative study. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Corneal ulcers and melts are uncommon and variable and additional RCTs are not expected. The systematic review showed healing in 97% of patients with an improvement of vision in 53% of eyes. One retrospective comparative study with 22 patients found more rapid and complete epithelialization and more patients with a clinically significant improvement in visual acuity following early treatment with self-retained amniotic membrane when compared to historical controls. Corneal ulcers and melts are uncommon and variable and RCTs are not expected. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Corneal Perforation When There is Active Inflammation After Corneal Transplant Requiring Adjunctive Treatment

For individuals who have corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. No comparative evidence was identified for this indication. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Bullous Keratopathy as a Palliative Measure in Patients Who are Not Candidates for a Curative Treatment (eg, Endothelial or Penetrating Keratoplasty)

For individuals who have bullous keratopathy and who are not candidates for curative treatment (eg, endothelial or penetrating keratoplasty) who receive HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. An RCT found no advantage of sutured HAM over the simpler stromal puncture procedure for the treatment of pain from bullous keratopathy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Partial Limbal Stem Cell Deficiency with Extensive Diseased Tissue Where Selective Removal Alone is Not Sufficient

For individuals who have partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. No comparative trials were identified on HAM for limbal stem cell deficiency. Improvement in visual acuity has been reported for some patients who have received HAM in conjunction with removal of the diseased limbus. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Moderate or Severe Stevens-Johnson Syndrome

For individuals who have moderate or severe Stevens-Johnson syndrome who receive HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on HAM for the treatment of Stevens-Johnson syndrome (includes 1 RCT with 25 patients [ 50 eyes]) found improved symptoms and function with HAM compared to medical therapy alone. Large RCTs are unlikely due to the severity and rarity of the disease. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Persistent Epithelial Defects and Ulceration That Do Not Respond to Conservative Therapy

For individuals who have persistent epithelial defects that do not respond to conservative therapy who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. No comparative trials were identified on persistent epithelial defects and ulceration. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Severe Dry Eye with Ocular Surface Damage and Inflammation That Does Not Respond to Conservative Therapy

For individuals who have severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy, who receive HAM, the evidence includes an RCT and a large case series. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on HAM for severe dry eye with ocular surface damage and inflammation includes an RCT with 20 patients and a retrospective series of 84 patients (97 eyes). Placement of self-retained HAM for 2 to 11 days reduced symptoms and restored a smooth corneal surface and corneal nerve density for as long as 3 months. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Moderate or Severe Acute Ocular Chemical Burns

For individuals who have moderate or severe acute ocular chemical burn who receive HAM, the evidence includes 3 RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Evidence includes a total of 197 patients with acute ocular chemical burns who were treated with HAM transplantation plus medical therapy or medical therapy alone. Two of the 3 RCTs did not show a faster rate of epithelial healing, and there was no significant benefit for other outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Corneal Perforation When Corneal Tissue is Not Immediately Available

For individuals who have corneal perforation when corneal tissue is not immediately available who receive sutured HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The standard treatment for corneal perforation is corneal transplantation, however, HAM may provide temporary coverage of the severe defect when corneal tissue is not immediately available. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Pterygium Repair When There is Insufficient Healthy Tissue to Create a Conjunctival Autograft

For individuals who have pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft who receive HAM, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Systematic reviews of RCTs have been published that found that conjunctival or limbal autograft is more effective than HAM graft in reducing the rate of pterygium recurrence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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 amniotic/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 13.67; 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.

Additional Information

2019 Input

Clinical input was sought to help determine whether the use of human amniotic membrane graft either without or with suture fixation for several ophthalmic conditions would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 2 respondents, including 1 specialty society-level response and 1 physician-level response identified through specialty societies including physicians with academic medical center affiliations.

Clinical input supported the use of amniotic membrane in individuals with the following indications:

• Neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy. Non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.

• Corneal ulcers and melts that do not respond to initial medical therapy. Non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.

• Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment.

• Bullous keratopathy and who are not candidates for curative treatment (eg, endothelial or penetrating keratoplasty) as an alternative to stromal puncture.

• Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient.

• Persistent epithelial defects and ulcerations that do not respond to conservative therapy.

• Severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy.

• Moderate or severe acute ocular chemical burn.

• Corneal perforation when corneal tissue is not immediately available.

• Pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft.

Further details from clinical input are included in the Appendix.

Objective

The objective of this evidence review is to evaluate whether various human amniotic membrane products improve the net health outcome for patients with various diabetic and venous ulcers, osteoarthritis, plantar fasciitis, and ophthalmic conditions.

Policy Statements

Treatment of nonhealing diabetic lower-extremity ulcers using the following human amniotic membrane products (ie, Affinity®, AmnioBand® Membrane, AmnioExcel®, Biovance®, EpiCord®, EpiFix®, Grafix™) may be considered medically necessary.

Human amniotic membrane grafts with or without suture may be considered medically necessary for the treatment of the following ophthalmic indications:

• Neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy;

• Corneal ulcers and melts that do not respond to initial conservative therapy;

• Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment;

• Bullous keratopathy as a palliative measure in patients who are not candidates for curative treatment (eg, endothelial or penetrating keratoplasty);

• Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient;

• Moderate or severe Stevens-Johnson syndrome;

• Persistent epithelial defects that do not respond within 2 days to conservative therapy;

• Severe dry eye (DEWS 3 or 4) with ocular surface damage and inflammation that remains symptomatic after Steps 1, 2, and 3 of the dry eye disease management algorithm (see Policy Guidelines); or

• Moderate or severe acute ocular chemical burn.

Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:

• Corneal perforation when corneal tissue is not immediately available; or

• Pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft.

Human amniotic membrane grafts with or without suture are considered investigational for all ophthalmic indications not outlined above.

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

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

All other uses reviewed herein of the human amniotic products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton's jelly) not listed above are considered investigational (see Policy Guidelines).

All other human amniotic products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton's jelly) including but not limited to those in Table PG2 (see Policy Guidelines) for indications not listed above are considered investigational for indications reviewed herein, including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery.

Policy Guidelines

Non-healing of diabetic wounds is defined as less than a 20% decrease in wound area with standard wound care for at least 2 weeks, based on the entry criteria for clinical trials (eg, Zelen et al [2015]).

Non-healing of lower-extremity ulcers due to venous insufficiency is defined as less than a 30% decrease in wound area with standard wound care for at least 2 weeks, based on clinical trial entry criteria (Serena et al [2022]).

This review covers products that do not require FDA approval or clearance. The list of products named in this review is not a complete list of all commercially available products. Table PG1 lists products included in the Policy statements, and Table PG2 lists other amniotic products that have an HCPCS code.

Table PG1. Amniotic Products Listed in the Policy Statements

Table PG2. Other Amniotic Products with HCPCS Codes

HRT: Human Regenerative Technologies; MTF: Musculoskeletal Transplant Foundationa Processed by HRT and marketed under different tradename

Tear Film and Ocular Surface Society staged management for dry eye disease (Jones et al 2017)

Step 1:

• Education regarding the condition, its management, treatment and prognosis

• Modification of local environment

• Education regarding potential dietary modifications (including oral essential fatty acid supplementation)

• Identification and potential modification/elimination of offending systemic and topical medications

• Ocular lubricants of various types (if meibomian gland dysfunction is present, then consider lipid containing supplements)

• Lid hygiene and warm compresses of various types

Step 2:

If above options are inadequate consider:

• Non-preserved ocular lubricants to minimize preservative-induced toxicity

• Tea tree oil treatment for Demodex (if present)

• Tear conservation

• Punctal occlusion

• Moisture chamber spectacles/goggles

• Overnight treatments (such as ointment or moisture chamber devices)

• In-office, physical heating and expression of the meibomian glands

• In-office intense pulsed light therapy for meibomian gland dysfunction

• Prescription drugs to manage dry eye disease

• Topical antibiotic or antibiotic/steroid combination applied to the lid margins for anterior blepharitis (if present)

• Topical corticosteroid (limited-duration)

• Topical secretagogues

• Topical non-glucocorticoid immunomodulatory drugs (such as cyclosporine)

• Topical LFA-1 antagonist drugs (such as lifitegrast)

• Oral macrolide or tetracycline antibiotics

Step 3:

If above options are inadequate consider:

• Oral secretagogues

• Autologous/allogeneic serum eye drops

• Therapeutic contact lens options

• Soft bandage lenses

• Rigid scleral lenses

Step 4:

If above options are inadequate consider:

• Topical corticosteroid for longer duration

• Amniotic membrane grafts

• Surgical punctal occlusion

• Other surgical approaches (eg tarsorrhaphy, salivary gland transplantation)

Dry eye severity level DEWS 3 to 4

Discomfort, severity, and frequency - Severe frequent or constant

Visual symptoms - chronic and/or constant, limiting to disabling

Conjunctival Injection - +/- or +/+

Conjunctive Staining - moderate to marked

Corneal Staining - marked central or severe punctate erosions

Corneal/tear signs - Filamentary keratitis, mucus clumping, increase in tear debris

Lid/meibomian glands - Frequent

Tear film breakup time - < 5

Schirmer score (mm/5 min) - < 5

Coding

See the Codes table for details.

Benefit Application

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BlueCard/National Account Issues

None.

Background

Human Amniotic Membrane

Human amniotic membrane (HAM) consists of 2 conjoined layers, the amnion, and chorion, and forms the innermost lining of the amniotic sac or 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.

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.^1, There is evidence that the tissue has anti-inflammatory, antifibroblastic, and antimicrobial properties. HAM is considered nonimmunogenic and has not been observed to cause a substantial immune response. It is believed that these properties are retained in cryopreserved HAM and HAM products, resulting in a readily available tissue with regenerative potential. In support, 1 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.^2,

Use of a HAM graft, which is fixated by sutures, is an established treatment for disorders of the corneal surface, including neurotrophic keratitis, corneal ulcers and melts, following pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Amniotic membrane products that are inserted like a contact lens have more recently been investigated for the treatment of corneal and ocular surface disorders. Amniotic membrane patches are also being evaluated for the treatment of various other conditions, including skin wounds, burns, leg ulcers, and prevention of tissue adhesion in surgical procedures.^1, Additional indications studied in preclinical models include tendonitis, tendon repair, and nerve repair. The availability of HAM opens the possibility of regenerative medicine for an array 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.^1, The fluid contains proteins, carbohydrates, 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.^3, Amniotic fluid has been compared with synovial fluid, containing hyaluronan, lubricant, cholesterol, and cytokines. Injection of amniotic fluid or amniotic fluid-derived cells is currently being evaluated for the treatment of osteoarthritis and plantar fasciitis.

Amniotic membrane and amniotic fluid are also being investigated as sources of pluripotent stem cells.^1, 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 in evidence review 8.01.52.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. 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).^4,

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:

   1. 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

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

      1. Is for autologous use;

      2. Is for allogeneic use in a first-degree or second-degree blood relative; or

      3. Is for reproductive use."

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

1. "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.

2. 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.

3. 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."

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

In 2003, Prokera was cleared for marketing by the FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104; product code: NQB). The FDA determined that this device was substantially equivalent to the Symblepharon Ring. The Prokera device is intended “for use in eyes in which the ocular surface cells have been damaged, or underlying stroma is inflamed and scarred.”^5, The development of Prokera, a commercially available product, was supported in part by the National Institute of Health and the National Eye Institute.

Rationale

This evidence review was created in April 2015 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through January 3, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (quality of life), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Diabetic Lower-Extremity Ulcers

Amniotic Membrane or Placental Membrane

Clinical Context and Therapy Purpose

The purpose of amniotic membrane or placental membrane in individuals who have diabetic lower-extremity ulcers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with diabetic lower-extremity ulcers that have failed to heal with the standard of care (SOC) therapy.

Interventions

The therapy being considered is an amniotic membrane or placental membrane applied every 1 to 2 weeks. It is applied in addition to the SOC.

Comparators

The following therapies are currently being used to make decisions about the healing of diabetic lower-extremity ulcers: SOC, which involves moist dressing, dry dressing, compression therapy, and offloading.

Outcomes

The primary endpoints of interest for trials of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration (FDA) for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds:

• Incidence of complete wound closure.

• Time to complete wound closure (reflecting accelerated wound closure).

• Incidence of complete wound closure following surgical wound closure.

• Pain control.

• Complete ulcer healing with advanced wound therapies may be measured at 6 to 12 weeks.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

At least 7 RCTs have evaluated rates of healing with amniotic membrane grafts or placental membrane graft compared to SOC or an advanced wound therapy in patients with chronic diabetic foot ulcers (see Table 1). The number of patients in these studies ranged from 25 to 155. Human amniotic membrane (HAM) or placental membrane grafts improved healing compared to SOC by 22% (EpiCord vs. Alginate dressing) to 60% (EpiFix) in the intention-to-treat (ITT) analysis (see Table 2). In a 2018 trial, the cryopreserved placental membrane Grafix was found to be non-inferior to an advanced fibroblast-derived wound therapy (Dermagraft).

Table 1. Summary of Key RCT Characteristics

RCT: randomized controlled trial; SOC: standard of care including debridement, nonadherent dressing, moisture dressing, a compression dressing and offloading.

Table 2. Summary of Key RCT Results

CI: confidence interval; Diff : difference; HR: hazard ratio; ITT: intention-to-treat; NR: not reported; PP: per-protocol; RCT: randomized controlled trial; SOC: standard of care. a. Power analysis indicated that 94 patients per arm would be needed. However, after a prespecified interim analysis at 50% enrollment, the blinded review committee recommended the trial is stopped due to the efficacy of the treatment. 

Limitations in study design and conduct are shown in Table 3. Studies without notable limitations reported power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and ITT analysis. Limitations from the RCT with AmnioExcel (Snyder et al, 2016) ^10, preclude conclusions for this product.

Table 3. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.ITT: intention to treat; SOC: standard of care.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Prospective Single-arm or Registry Studies

Prospective single-arm or registry studies are described in Tables 4 and 5.

Smiell et al (2015) reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types; about a third (n=47) were diabetic foot wounds.^15, Of those treated, 28 ulcers had failed prior treatment with advanced biologic therapies. For all wound types, 41.6% closed within a mean time of 8 weeks and a mean of 2.4 amniotic membrane applications.

In 2016, Frykberg et al reported treatment of complex chronic wounds (exposed tendon or bone) with Grafix. With the cryopreserved placental membrane applied weekly for up to 16 weeks, 59% of wounds closed with a mean time to closure of 9 weeks.^16,

Table 4. Summary of Prospective Single-arm Studies or Registry Characteristics

Table 5. Summary of Prospective Single-arm Studies or Registry Results

Section Summary: Diabetic Lower-Extremity Ulcers

For individuals who have non-healing diabetic lower-extremity ulcers who receive a formulation of HAM or placental membrane (ie, Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix), the evidence includes RCTs. The RCTs evaluating amniotic and placental membrane products for the treatment of non-healing (<20% healing with ≥2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM with standard care or with an established advanced wound care product. These trials used wound closure as the primary outcome measure, and some included power analysis, blinded assessment of wound healing, and ITT analysis. For the HAM products that have been sufficiently evaluated (ie, Affinity, AmnioBand Membrane, Biovance, EpiCord, EpiFix, Grafix), results have shown improved outcomes compared with 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. No studies were identified that compared different amniotic or placental products, and indirect comparison between products is limited by variations in the patient populations.

Summary of Evidence

For individuals who have non-healing diabetic lower-extremity ulcers who receive a patch or flowable formulation of HAM or placental membrane (ie, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The RCTs evaluating amniotic and placental membrane products for the treatment of non-healing (<20% healing with ≥2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM with standard care or with an established advanced wound care product. These trials 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 (ie, AmnioBand Membrane, Biovance, EpiCord, EpiFix, Grafix), results have shown improved outcomes compared with 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.

Population Reference No. 2 

Lower-Extremity Ulcers Due to Venous Insufficiency

Amniotic Membrane

Clinical Context and Therapy Purpose

The purpose of amniotic membrane or placental membrane in individuals who have lower-extremity ulcers due to venous insufficiency is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with lower-extremity venous ulcers that have failed to heal with SOC therapy.

Interventions

The therapy being considered is amniotic membrane or placental membrane applied every 1 to 2 weeks. It is applied in addition to the SOC.

Comparators

The following therapies are currently being used to make decisions about the healing of venous ulcers: SOC, which involves moist dressing, dry dressing, and compression therapy.

Outcomes

The primary endpoints of interest for trials of wound closure are as follows, consistent with guidance from the FDA for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds:

• Incidence of complete wound closure.

• Time to complete wound closure (reflecting accelerated wound closure).

• Incidence of complete wound closure following surgical wound closure.

• Pain control.

• Complete ulcer healing with advanced wound therapies may be measured at 6 to 12 weeks.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Three RCTs, 2 using EpiFix and 1 using AmnioBand, were identified on HAM for venous leg ulcers. Serena et al (2014) reported on an industry-sponsored multicenter open-label RCT that compared EpiFix d-HAM plus compression therapy with compression therapy alone for venous leg ulcers (see Tables 6 and 7).^17, The primary outcome in this trial was the proportion of patients with 40% wound closure at 4 weeks, which was achieved by about twice as many patients in the combined EpiFix group compared with the control group (see Table 8). However, a similar percentage of patients in the combined EpiFix group and the control group achieved complete wound closure during the 4-week study. There was no significant difference in healing for wounds given 1 versus 2 applications of amniotic membrane (62% vs. 63%, respectively). Strengths of this trial included adequate power and ITT analysis with last observation carried forward. Limitations included the lack of blinding for wound evaluation and use of 40% closure rather than complete closure. A 2015 retrospective study of 44 patients from this RCT (31 treated with amniotic membrane) found that wounds with at least 40% closure at 4 weeks (n=20) had a closure rate of 80% by 24 weeks; however, this analysis did not take into account additional treatments after the 4-week randomized trial period.

A second industry-sponsored, multicenter, open-label RCT (Bianchi et al [2018; 2019]) evaluated the time to complete ulcer healing following weekly treatment with EpiFix d-HAM plus compression therapy or compression wound therapy alone (see Tables 6 and 7).^18,19, Patients treated with EpiFix had a higher probability of complete healing by 12 weeks, as adjudicated by blinded outcome assessors (hazard ratio, 2.26; 95% CI, 1.25 to 4.10; p=.01), and improved time to complete healing, as assessed by Kaplan-Meier analysis. In per-protocol analysis, healing within 12 weeks was reported for 60% of patients in the EpiFix group and 35% of patients in the control group (p<.013) (see Table 8). Intent-to-treat analysis found complete healing in 50% of patients in the EpiFix group compared to 31% of patients in the control group (p=.0473). There were several limitations of this trial (see Tables 8 and 9). In the per-protocol analysis, 19 (15%) patients were excluded from the analysis, and the proportion of patients excluded differed between groups (19% from the EpiFix group vs. 11% from the control group). There was also a difference between the groups in how treatment failures at 8 weeks were handled. Patients in the control group who did not have a 40% decrease in wound area at 8 weeks were considered study failures and treated with advanced wound therapies. The ITT analysis used last-observation-carried-forward for these patients and sensitivity analysis was not performed to determine how alternative methods of handling the missing data would affect results. Kaplan-Meier analysis suggested a modest improvement in the time to heal when measured by ITT analysis, but may be subject to the same methodological limitations.

Serena et al (2022) reported an industry-sponsored, multicenter, open-label RCT comparing once- or twice-weekly applications of HAM (AmnioBand Membrane) plus compression bandaging with compression bandaging alone in patients with chronic venous leg ulcers (Tables 6 through 9).^20, This HAM is a dehydrated aseptically processed product without terminal irradiation for sterilization. It is purported to retain the structural properties of the extracellular matrix that enhances wound healing. There were no significant differences in the proportion of wounds with percentage area reduction 40 percent at 4 weeks between all three study groups. A significantly greater proportion of patients assigned to weekly or twice-weekly HAM achieved the primary endpoint of blinded assessor-confirmed complete wound healing after 12 weeks of study treatment (75%) than those assigned to compression bandaging alone (30%; p=.001). Receiving HAM was independently associated with odds of complete healing at 12 weeks after adjusting for baseline wound area (odds ratio, 8.7; 95% CI, 2.2 to 33.6). Median reduction in wound area from baseline was also significantly greater in patients assigned to HAM therapy (100%; interquartile range, 5.3%) than those assigned to compression bandaging alone (75%; interquartile range, 68.7%; p=.012). Adverse events were reported in 55%, 60%, and 75% of the once-weekly HAM, twice-weekly HAM, and standard-of-care groups, respectively. The most commonly reported adverse events were wound-related infections (36.7%) and new ulcer (31.6%). No adverse events were attributed to study treatment.

Table 6. Summary of Key RCT Characteristics

ITT: Intent-to-treat; PP: per-protocol; RCT: randomized controlled trial; SOC: standard of care; VLU: venous leg ulcer.

Table 7. Summary of Key RCT Results

IQR: interquartile range; ITT: Intent-to-treat; PP: per protocol; RCT: randomized controlled trial.

Table 8. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 9. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Biovance

As described above, Smiell et al (2015) reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types; about half (n=89) were venous ulcers.^15, Of the 179 treated, 28 (16%) ulcers had failed prior treatment with advanced biologic therapies. For all wound types, 41.6% closed within a mean time of 8 weeks and a mean of 2.4 amniotic membrane applications. However, without a control group, the percentage of wounds that would have healed with SOC is unknown.

Section Summary: Lower-Extremity Ulcers Due to Venous Insufficiency

The evidence on HAM for the treatment of venous leg ulcers includes 2 multicenter RCTs with EpiFix and 1 multicenter RCT with AmnioBand Membrane. One RCT reported a larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure at 4 weeks did not differ between EpiFix and the SOC. A second RCT evaluated complete wound closure at 12 weeks after weekly application of EpiFix or standard dressings with compression. Although a significant difference in complete healing was reported, interpretation is limited by the differential loss to follow-up and exclusions between groups. Although a subsequent publication reported ITT analysis, the handling of missing data differed between the groups and sensitivity analysis was not performed. The methodological flaws in the design, execution, and reporting of both of these RCTs limit inference that can be drawn from the results. An additional RCT evaluated outcomes using AmnioBand Membrane, a dehydrated aseptically processed product without terminal irradiation for sterilization that s purported to retain the structural properties of the extracellular matrix that enhances wound healing. The application of HAM plus SOC resulted in significantly higher rates of complete wound closure at 12 weeks compared with SOC alone. This endpoint was confirmed by a blinded assessor panel in the ITT population. All 60 subjects received the allocated intervention, and none were lost to follow-up or exited because of protocol deviation. Adverse event rates were numerically greater in the biweekly HAM group but no adverse events were attributed to appeared to be similar between groups.

Summary of Evidence

For individuals who have lower-extremity ulcers due to venous insufficiency who receive a patch or flowable formulation of HAM, the evidence includes 2 RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The published evidence on HAM for the treatment of venous leg ulcers includes 2 multicenter RCTs with EpiFix. One RCT reported a larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure at 4 weeks did not differ between EpiFix and the standard of care. A second RCT evaluated complete wound closure at 12 weeks after weekly application of EpiFix or standard dressings with compression, but interpretation is limited by methodologic concerns. Two additional studies with other HAM products have been completed but not published, raising further questions about the efficacy of HAM for venous insufficiency ulcers. Therefore, corroboration with well-designed and well-conducted RCTs evaluating wound healing is needed to demonstrate efficacy for this indication. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 3 

Osteoarthritis

ReNu™ Knee Injection in Patients with Osteoarthritis

In 2016, a feasibility study (N=6) was reported of cryopreserved human amniotic membrane (c-HAM) suspension with amniotic fluid-derived cells for the treatment of knee osteoarthritis.^21, A single intra-articular injection of the suspension was used, with follow-up at 1 and 2 weeks and at 3, 6, and 12 months posttreatment. Outcomes included the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scale, and a numeric pain scale. Statistical analyses were not performed for this small sample. No adverse events, aside from a transient increase in pain, were noted. RCTs are in progress.

A trial with 200 participants was completed in February 2019 (see Table 14). No publications from this trial have been identified.

Section Summary: Osteoarthritis

Current evidence is insufficient to support definitive conclusions on the utility of c-HAM in the treatment of knee osteoarthritis.

Summary of Evidence

For individuals who have knee osteoarthritis who receive an injection of suspension or particulate formulation of HAM 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 assessed the feasibility of a larger RCT evaluating HAM injection. Additional trials, which will have a larger sample size 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.

Population Reference No. 4

Plantar Fasciitis

Clinical Context and Therapy Purpose

The purpose of micronized amniotic membrane in individuals who have plantar fasciitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with plantar fasciitis that has failed to heal with SOC therapy.

Interventions

The therapy being considered is micronized amniotic membrane. It is applied in addition to the SOC.

Comparators

The following therapies are currently being used to make decisions about the healing of plantar fasciitis: corticosteroid injections and SOC, which involves offloading, night-splinting, stretching, and orthotics.

Outcomes

The primary endpoints of interest for trials of plantar fasciitis are as follows: Visual Analog Score (VAS) for pain and function measured by the Foot Functional Index.

Acute effects of HAM injection may be measured at 2 to 4 weeks. The durability of treatment would be assessed at 6 to 12 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

One systematic review and 2 randomized pilot studies were identified on the treatment of plantar fasciitis using an injection of micronized HAM.

Systematic Review

A 2016 network meta-analysis of 22 RCTs (total N=1216 patients) compared injection therapies for plantar fasciitis.^22, In addition to c-HAM and micronized d-HAM/chorionic membrane, treatments included corticosteroids, botulinum toxin type A, autologous whole blood, platelet-rich plasma, nonsteroidal anti-inflammatory drugs, dry needling, dextrose prolotherapy, and polydeoxyribonucleotide. Placebo arms included normal saline, local anesthetic, sham dry needling, and tibial nerve block. Analysis indicated d-HAM had the highest probability for improvement in pain and composite outcomes in the short-term, however, this finding was based only on a single RCT. Outcomes at 2 to 6 months (7 RCTs) favored botulinum toxin for pain and patient recovery plan for composite outcomes.

Randomized Controlled Trials

Zelen et al (2013) reported a preliminary study with 15 patients per group (placebo, 0.5 cc, and 1.25 cc) and 8-week follow-up.^23, A subsequent RCT by Cazell et al (2018) enrolled 145 patients and reported 3-month follow-up (see Table 10).^24, In Cazzell et al (2018) amniotic membrane injection led to greater improvements in the VAS for pain and the Foot Functional Index between baseline and 3 months (see Table 11) compared to controls. VAS at 3 months had decreased to 17.1 in the AmnioFix group compared to 38.8 in the placebo control group, which would be considered a clinically significant difference.

Table 10. Summary of Key RCT Characteristics

 RCT: randomized controlled trial; VAS: visual analog score.

Table 11. Summary of Key RCT Results

CI: confidence interval; FFI-R: Foot Function Index; RCT: randomized controlled trial; VAS: visual analog score.

Limitations in relevance and design and conduct of this publication are described in Tables 12 and 13. The major limitation of the study is the short-term follow-up, which the authors note is continuing to 12 months. The authors stated that extended follow-up would be reported in a subsequent publication; no subsequent publications have been identified for this trial.

Table 12. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 13. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Plantar Fasciitis

The evidence on injection of amniotic membrane for the treatment of plantar fasciitis includes preliminary studies and a larger (N =145) patient-blinded comparison of micronized injectable-HAM and placebo control. Injection of micronized amniotic membrane resulted in greater improvements in VAS for pain and the Foot Functional Index compared to placebo controls. The primary limitation of the study is this is an interim report of 3 months' results. The authors noted that 12-month follow-up will be reported in a subsequent publication. No additional publications have been identified as of the latest update.

Summary of Evidence

The evidence on injection of amniotic membrane for the treatment of plantar fasciitis includes preliminary studies and a larger (n=145) patient-blinded comparison of micronized injectable-HAM and placebo control. Injection of micronized amniotic membrane resulted in greater improvements in the visual analog score for pain and the Foot Functional Index compared to placebo controls. The primary limitation of the study is that this is an interim report with 12-month results pending. The evidence is insufficient to determine the effects of the technology on health outcomes.

Human Amniotic Membrane for Ophthalmologic Conditions

Sutured and self-retained HAM has been evaluated for a variety of ophthalmologic conditions. Traditionally, the amniotic membrane has been fixed onto the eye with sutures or glue or placed under a bandage contact lens for a variety of ocular surface disorders. Several devices have been reported that use a ring around a HAM allograft that allows it to be inserted under topical anesthesia similar to insertion of a contact lens. Sutured HAM transplant has been used for many years for the treatment of ophthalmic conditions. Many of these conditions are rare, leading to difficulty in conducting RCTs. The rarity, severity, and variability of the ophthalmic condition was taken into consideration in evaluating the evidence. The following indications apply to both sutured and self-retained HAM unless specifically noted.

Population Reference No. 5 

Neurotrophic Keratitis with Ocular Surface Damage or Inflammation That Does Not Respond to Conservative Treatment

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have neurotrophic keratitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have neurotrophic keratitis with ocular surface damage or inflammation that does not respond to conservative treatment.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: tarsorrhaphy or bandage contact lens.

Outcomes

The general outcomes of interest are eye pain and epithelial healing.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Khokhar et al (2005) reported on an RCT of 30 patients (30 eyes) with refractory neurotrophic corneal ulcers who were randomized to HAM transplantation (n=15) or conventional treatment with tarsorrhaphy or bandage contact lens. At the 3-month follow-up, 11 (73%) of 15 patients in the HAM group showed complete epithelialization compared with 10 (67%) of 15 patients in the conventional group. This difference was not significantly significant.

Suri et al (2013) reported on 11 eyes of 11 patients with neurotrophic keratopathy that had not responded to conventional treatment.^25, The mean duration of treatment prior to ProKera insertion was 51 days. Five of the 11 patients (45.5%) were considered to have had a successful outcome.

Section Summary: Neurotrophic Keratitis with Ocular Surface Damage and Inflammation that Does Not Respond to Conservative Therapy

An RCT of 30 patients showed no benefit of sutured HAM graft compared to tarsorrhaphy or bandage contact lens.

Summary of Evidence

For individuals who have neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy who receive HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. An RCT of 30 patients showed no benefit of sutured HAM graft compared to tarsorrhaphy or bandage contact lens. Based on clinical input, HAM might be considered for patients who did not respond to conservative therapy. Clinical input indicated that non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 6 

Corneal Ulcers and Melts That Do Not Respond to Initial Medical Therapy

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have corneal ulcers and melts is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have corneal ulcers and melts that do not respond to initial medical therapy.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: tarsorrhaphy and bandage soft contact lens.

Outcomes

The general outcomes of interest are eye discomfort and epithelial healing.

Changes in symptoms may be measured in days, while changes in ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Liu et al (2019) conducted a systematic review of 17 studies (390 eyes) of amniotic membrane for corneal ulcers.^26, All but 1 of the studies was conducted outside of the U.S. There was 1 RCT with 30 patients, the remainder of the studies were prospective or retrospective case series. Corneal healing was obtained in 97% (95% CI: 0.94 to 0.99, p=.089) of patients evaluated. In the 12 studies (222 eyes) that reported on vision, the vision improvement rate was improved in 113 eyes (53%, 95% CI: 0.42 to 0.65, p<.001).

Yin et al (2020) compared epithelialization and visual outcomes of 24 patients with corneal infectious ulcers and visual acuity of less than 20/200 who were treated with (n=11) or without (n=13) self-retained amniotic membrane.^27, Utilization of amniotic membrane was initiated in their institution in 2018, allowing a retrospective comparison of the 2 treatment groups. Complete epithelialization occurred more rapidly (3.56± 1.78 weeks vs. 5.87 ± 2.20 weeks, p=.01) and was reached in significantly more patients (72.7% vs. 23.1%, p=.04). The group treated with amniotic membrane plus the standard therapy had more patients with clinically significant (> 3 lines) improvement in visual acuity (81.8% vs 38.4%, p=.047) and greater total improvement in visual acuity (log MAR 0.7 ± 0.6 vs 1.6 ± 0.9, p=.016).

Suri et al (2013) reported on a series of 35 eyes of 33 patients who were treated with the self-retained ProKera HAM for a variety of ocular surface disorders.^25, Nine of the eyes had non-healing corneal ulcers. Complete or partial success was seen in 2 of 9 (22%) patients with this indication.

Section Summary: Corneal Ulcers and Melts That Do Not Respond to Initial Medical Therapy

Corneal ulcers and melts are uncommon and variable and additional RCTs are not expected. A systematic review of 1 RCT and case series showed healing in 97% of patients with an improvement of vision in 53% of eyes. One retrospective comparative study with 22 patients found more rapid and complete epithelialization and more patients with a clinically significant improvement in visual acuity following early treatment with self-retained amniotic membrane when compared to historical controls. These results support the use of non-sutured amniotic membrane for corneal ulcers and melts that do not respond to initial medical therapy.

Summary of Evidence

For individuals who have corneal ulcers and melts, that does not respond to initial medical therapy who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Corneal ulcers and melts are uncommon and variable and RCTs are not expected. Based on clinical input, HAM might be considered for patients who did not respond to conservative therapy. Clinical input indicated that non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 7

Corneal Perforation When There is Active Inflammation After Corneal Transplant Requiring Adjunctive Treatment

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have active inflammation after a corneal transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have corneal perforation when there is active inflammation after a corneal transplant.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical therapy.

Outcomes

The general outcomes of interest are eye discomfort and reduction in inflammation.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

No evidence was identified for this indication.

Section Summary: Corneal Perforation When There is Active Inflammation After Corneal Transplant Requiring Adjunctive Treatment

No evidence was identified for this indication.

Summary of Evidence

For individuals who have corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. No comparative evidence was identified for this indication. Clinical input supported the use of HAM to reduce inflammation and promote epithelial healing with active inflammation following corneal transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 8

Bullous Keratopathy in Patients Who are Not Candidates for a Curative Treatment (eg, Endothelial or Penetrating Keratoplasty)

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have bullous keratopathy is to provide a treatment option that is an alternative to or an improvement on existing therapies. Bullous keratopathy is characterized by stromal edema and epithelial and subepithelial bulla formation.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have bullous keratopathy who are not candidates for curative treatment.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: stromal puncture.

Outcomes

The general outcomes of interest are eye discomfort and epithelial healing.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Dos Santos Paris et al (2013) published an RCT that compared fresh HAM with stromal puncture for the management of pain in patients with bullous keratopathy.^28, Forty patients with pain from bullous keratopathy who were either waiting for a corneal transplant or had no potential for sight in the affected eye were randomized to the 2 treatments. Symptoms had been present for approximately 2 years. HAM resulted in a more regular epithelial surface at up to 180 days follow-up, but there was no difference between the treatments related to the presence of bullae or the severity or duration of pain. Because of the similar effects on pain, the authors recommended initial use of the simpler stromal puncture procedure, with use of HAM only if the pain did not resolve.

Section Summary: Bullous Keratopathy in Patients Who are Not Candidates for a Curative Treatment and Who are Unable to Remain Still for Stromal Puncture

An RCT found no advantage of sutured HAM over the simpler stromal puncture procedure for the treatment of pain from bullous keratopathy.

Summary of Evidence

For individuals who have bullous keratopathy and who are not candidates for curative treatment (eg, endothelial or penetrating keratoplasty) who receive HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. An RCT found no advantage of sutured HAM over the simpler stromal puncture procedure for the treatment of pain from bullous keratopathy. Based on clinical input, non-sutured HAM could be used as an alternative to stromal puncture. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 9 

Partial Limbal Stem Cell Deficiency with Extensive Diseased Tissue Where Selective Removal Alone is Not Sufficient

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have partial limbal stem cell deficiency is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: limbal stem cell transplants.

Outcomes

The general outcomes of interest are visual acuity and corneal epithelial healing.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

No RCTs were identified on HAM for limbal stem cell deficiency.

Keirkhah et al (2008) reported on the use of HAM in 11 eyes of 9 patients who had limbal stem cell deficiency.^29, Patients underwent superficial keratectomy to remove the conjunctivalized pannus followed by HAM transplantation using fibrin glue. An additional ProKera patch was used in 7 patients. An improvement in visual acuity was observed in all but 2 patients. Pachigolla et al (2009) reported a series of 20 patients who received a ProKera implant for ocular surface disorders; 6 of the patients had limbal stem cell deficiency with a history of chemical burn.^30, Following treatment with ProKera, 3 of the 6 patients had a smooth corneal surface and improved vision to 20/40.^30, The other 3 patients had final visual acuity of 20/400, counting fingers, or light perception.

Section Summary: Partial Limbal Stem Cell Deficiency with Extensive Diseased Tissue Where Selective Removal Alone is Not Sufficient

No RCTs were identified on HAM for partial limbal stem cell deficiency. Improvement in visual acuity has been reported for some patients who have received HAM in conjunction with removal of the diseased limbus.

Summary of Evidence

For individuals who have partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. No RCTs were identified on HAM for limbal stem cell deficiency. Improvement in visual acuity has been reported for some patients who have received HAM in conjunction with removal of the diseased limbus. Clinical input noted the limitations of performing an RCT and supported the use of HAM for this indication. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 10 

Moderate or Severe Stevens-Johnson Syndrome

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have Stevens-Johnson syndrome is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have moderate or severe Stevens-Johnson syndrome.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical therapy alone (antibiotics, steroids, or lubricants).

Outcomes

The general outcomes of interest are visual acuity, tear function, and corneal clarity.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

One RCT from India by Sharma et al (2016) assigned 25 patients (50 eyes) with acute ocular Stevens-Johnson syndrome to c-HAM plus medical therapy (antibiotics, steroids, or lubricants) or medical therapy alone.^31, The c-HAM was prepared locally and applied with fibrin glue rather than sutures. Application of c-HAM in the early stages of SJS resulted in improved visual acuity (p=.042), better tear breakup time (p=.015), improved Schirmer test results (p<.001), and less conjunctival congestion (p=.03). In the c-HAM group at 180 days, there were no cases of corneal haze, limbal stem cell deficiency, symblepharon, ankyloblepharon, or lid-related complications. These outcomes are dramatically better than those in the medical therapy alone group, which had 11 (44%) cases with corneal haze (p=.001), 6 (24%) cases of corneal vascularization and conjunctivalization (p=.03), and 6 (24%) cases of trichiasis and metaplastic lashes.

Section Summary: Moderate or Severe Stevens-Johnson Syndrome

The evidence on HAM for the treatment of SJ Syndrome includes 1 RCT with 25 patients (50 eyes) that found improved symptoms and function with HAM compared to medical therapy alone.

Summary of Evidence

For individuals who have moderate or severe Stevens-Johnson syndrome (SJS) who receive HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on HAM for the treatment of SJS includes 1 RCT with 25 patients (50 eyes) that found improved symptoms and function with HAM compared to medical therapy alone. Clinical input indicated that large RCTs are unlikely due to the severity and rarity of the disease, supported the use of HAM for moderate or severe SJS. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 11 

Persistent Epithelial Defects and Ulcerations That Do Not Respond to Conservative Therapy

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have persistent epithelial defects and ulcerations is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have persistent epithelial defects that do not respond to conservative therapy.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used for persistent epithelial defects and ulceration: medical therapy alone (eg, topical lubricants, topical antibiotics, therapeutic contact lens, or patching).

Outcomes

The general outcomes of interest are epithelial closure.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Bouchard and John (2004) reviewed the use of amniotic membrane transplantation in the management of severe ocular surface disease.^32, They noted that c-HAM has been available since 1995, and has become an established treatment for persistent epithelial defects and ulceration refractory to conventional therapy. However, there was a lack of controlled studies due to the rarity of the diseases and the absence of standard therapy. They identified 661 reported cases in the peer-reviewed literature. Most cases reported assessed the conjunctival indications of pterygium, scars and symblepharon, and corneal indications of acute chemical injury and postinfectious keratitis.

Section Summary: Persistent Epithelial Defects and Ulceration that Do Not Respond to Conservative Therapy

No RCTs were identified on persistent epithelial defects and ulceration.

Summary of Evidence

For individuals who have persistent epithelial defects that do not respond to conservative therapy who receive HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. No RCTs were identified on persistent epithelial defects and ulceration. Clinical input noted the difficulty in conducting RCTs for this indication and supported the use of amniotic membrane for persistent epithelial defects and ulcerations that do not respond to conservative therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 12

Severe Dry Eye Disease with Ocular Surface Damage and Inflammation that Does Not Respond to Conservative Therapy

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have severe dry eye is to provide a treatment option that is an alternative to or an improvement on existing therapies. Dry eye disease involves tear film insufficiency with the involvement of the corneal epithelium. Inflammation is common in dry eye disease, which causes additional damage to the corneal epithelium.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have severe dry eye with ocular surface damage and inflammation.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical management consisting of artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and nonsteroidal anti-inflammatory medications.

Outcomes

The general outcomes of interest are the pain, corneal surface regularity, and vision, which may be measured by the Report of the International Dry Eye WorkShop score (DEWS). The DEWS assess 9 domains with a score of 1 to 4 including discomfort, visual symptoms, tear breakup time, corneal signs and corneal staining. Corneal staining with fluorescein or Rose Bengal indicates damaged cell membranes or gaps in the epithelial cell surface. A DEWS of 2 to 4 indicates moderate-to-severe dry eye disease.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

John et al (2017) reported on an RCT with 20 patients with moderate-to-severe dry eye disease who were treated with Prokera c-HAM or maximal conventional treatment.^33, The c-HAM was applied for an average of 3.4 days (range, 3-5 days), while the control group continued treatment with artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and nonsteroidal anti-inflammatory medications. The primary outcome was an increase in corneal nerve density. Signs and symptoms of dry eye disease improved at both 1-month and 3-month follow-ups in the c-HAM group but not in the conventional treatment group. For example, pain scores decreased from 7.1 at baseline to 2.2 at 1 month and 1.0 at 3 months in the c-HAM group. In vivo confocal microscopy, reviewed by masked readers, showed a significant increase in corneal nerve density in the study group at 3 months, with no change in nerve density in the controls. Corneal sensitivity was similarly increased in the c-HAM group but not in controls.

The treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study (McDonald et al [2018]) was a retrospective series of 84 patients (97 eyes) with severe dry eye despite maximal medical therapy who were treated with Prokera self-retained c-HAM.^34, A majority of patients (86%) had superficial punctate keratitis. Other patients had filamentary keratitis (13%), exposure keratitis (19%), neurotrophic keratitis (2%), and corneal epithelial defect (7%). Treatment with Prokera for a mean of 5.4 days (range, 2 to 11) resulted in an improved ocular surface and reduction in the DEWS score from 3.25 at baseline to 1.44 at 1 week, 1.45 at 1 month and 1.47 at 3 months (p=.001). Ten percent of eyes required repeated treatment. There was no significant difference in the number of topical medications following c-HAM treatment.

Section Summary: Severe Dry Eye with Ocular Surface Damage and Inflammation that Does Not Respond to Conservative Therapy

The evidence on HAM for severe dry eye with ocular surface damage and inflammation includes an RCT with 20 patients and a retrospective series of 84 patients (97 eyes). Placement of self-retained HAM for 2 to 11 days reduced symptoms and restored a smooth corneal surface and corneal nerve density for as long as 3 months.

Summary of Evidence

For individuals who have severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy, who receive HAM, the evidence includes an RCT and a large case series. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on HAM for severe dry eye with ocular surface damage and inflammation includes an RCT with 20 patients and a retrospective series of 84 patients (97 eyes). Placement of self-retained HAM for 2 to 11 days reduced symptoms and restored a smooth corneal surface and corneal nerve density for as long as 3 months. Clinical input supported HAM in cases of severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 13

Moderate or Severe Acute Ocular Chemical Burns

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have acute ocular burns is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have moderate or severe acute ocular chemical burn.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical therapy (eg, topical antibiotics, lubricants, steroids and cycloplegics, oral vitamin C, doxycycline).

Outcomes

The general outcomes of interest are visual acuity, corneal epithelialization, corneal clarity, and corneal vascularization.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

An RCT of 100 patients with chemical or thermal ocular burns was published by Tandon et al (2011).^35, Half of the patients (n=50) had moderate ocular burns and the remainder (n=50) had severe ocular burns. All but 8 of the patients had alkali or acid burns. Patients were randomized to HAM transplantation plus medical therapy or medical therapy alone. Epithelial healing, which was the primary outcome, was improved in the group treated with HAM, but there was no significant difference between the 2 groups for final visual outcome, symblepharon formation, corneal clarity or vascularization.

A second RCT that compared amniotic membrane plus medical therapy (30 eyes) to medical therapy alone (30 eyes) for grade IV ocular burn was reported by Eslani et al (2018).^36, Medical therapy at this tertiary referral hospital included topical preservative-free lubricating gel and drops, chloramphenicol, betamethasone, homatropine, oral vitamin C, and doxycycline. There was no significant difference in the time to epithelial healing (amniotic membrane: 75.8 vs. 72.6 days) or in visual acuity between the 2 groups (2.06 logMAR for both groups). There was a trend for a decrease in corneal neovascularization (p=.108); the study was not powered for this outcome.

A third RCT by Tamhane et al (2005) found no difference between amniotic membrane and medical therapy groups in an RCT of 37 patients with severe ocular burns.^37,

Section Summary: Moderate or Severe Acute Ocular Chemical Burns

Evidence includes 3 RCTs with a total of 197 patients with acute ocular chemical burns who were treated with HAM transplantation plus medical therapy or medical therapy alone. Patients in the HAM group had a faster rate of epithelial healing in 1 of the 3 trials, without a significant benefit for other outcomes. The other 2 trials did not find an increase in the rate of epithelial healing in patients with severe burns.

Summary of Evidence

For individuals who have moderate or severe acute ocular chemical burn who receive HAM, the evidence includes 3 RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Evidence includes a total of 197 patients with acute ocular chemical burns who were treated with HAM transplantation plus medical therapy or medical therapy alone. Two of the 3 RCTs did not show a faster rate of epithelial healing, and there was no significant benefit for other outcomes. Clinical input was in support of HAM for acute ocular chemical burn. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 14

Corneal Perforation When Corneal Tissue is Not Immediately Available

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have corneal perforation when corneal tissue is not immediately available is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have corneal perforation when corneal tissue is not immediately available.

Interventions

The therapy being considered is sutured HAM.

Comparators

The following therapies are currently being used: conservative management.

Outcomes

The general outcomes of interest are eye pain.

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

No RCTs were identified on corneal perforation.

Section Summary: Corneal Perforation When Corneal Tissue is Not Immediately Available

The standard treatment for corneal perforation is corneal transplantation, however, sutured HAM may be used as a temporary covering for this severe defect when corneal tissue is not immediately available.

Summary of Evidence

For individuals who have corneal perforation when corneal tissue is not immediately available who receive sutured HAM, the evidence is limited. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The standard treatment for corneal perforation is corneal transplantation. Based on clinical input, sutured HAM may be used as a temporary measure when corneal tissue is not immediately available. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 15

Following Pterygium Repair When There is Insufficient Healthy Tissue to Create a Conjunctival Autograft

Clinical Context and Therapy Purpose

The purpose of HAM in individuals who have pterygium repair is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft.

Interventions

The therapy being considered is sutured or glued HAM.

Comparators

The following therapies are currently being used: conjunctival autograft.

Outcomes

The general outcomes of interest are a recurrence of pterygium.

Pterygium recurrence would be measured at 1 to 3 months.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

RCTs have been reported on the use of amniotic membrane following pterygium repair. In 2013, the American Academy of Ophthalmology published a technology assessment on options and adjuvants for pterygium surgery.^38, Reviewers identified 4 RCTs comparing conjunctival or limbal autograft procedure with amniotic membrane graft, finding that conjunctival or limbal autograft was more effective than HAM graft in reducing the rate of pterygium recurrence. A 2016 Cochrane review of 20 RCTs (total N=1866 patients) arrived at the same conclusion.^39,

Section Summary: Following Pterygium Repair When There is Insufficient Healthy Tissue to Create a Conjunctival Autograft

Systematic reviews of RCTs have been published that found that conjunctival or limbal autograft is more effective than HAM graft in reducing the rate of pterygium recurrence.

Summary of Evidence

For individuals who have pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft who receive HAM, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Systematic reviews of RCTs have been published that found that conjunctival or limbal autograft is more effective than HAM graft in reducing the rate of pterygium recurrence. Based on clinical input, sutured or glued HAM may be considered when there is insufficient healthy tissue to create a conjunctival autograft (eg, extensive, double, or recurrent pterygium). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 16

Repair Following Mohs Microscopic Surgery

Clinical Context and Therapy Purpose

The purpose of repair with human amniotic membrane in individuals who have undergone Mohs microsurgery for skin cancer is to provide a treatment option that is an alternative to or an improvement on existing procedures.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who require reconstruction following Mohs microsurgery for skin cancer on the head, neck, face, or dorsal hand.

Interventions

The therapy being considered is repair following Mohs microsurgery with human amniotic membrane. It is proposed as a nonsurgical alternative to cutaneous repair in cosmetically sensitive areas such as the head, neck, face, or dorsal hand.

Comparators

Comparators of interest include surgical repair using autologous tissue (eg, local flaps and full-thickness skin grafts) and healing without surgery. Second intention healing (i.e., the wound is left open to heal by granulation, contraction, and epithelialization) is a nonsurgical option for certain defects.

Outcomes

The primary endpoints of interest for trials of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration (FDA) for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds:

• Incidence of complete wound closure.

• Time to complete wound closure (reflecting accelerated wound closure).

• Incidence of complete wound closure following surgical wound closure.

• Pain control.

• Complete ulcer healing with advanced wound therapies may be measured at 6 to 12 weeks.

In trials comparing human amniotic membrane to surgical repair in patients post-Mohs microscopic surgery, other important outcomes are postprocedure morbidity and mortality, surgical complications, development of a non-healing wound, and quality of life.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

No RCTs were identified for this indication.

Nonrandomized Studies

Toman et al (2022) conducted an observational study that compared repair using a dehydrated human amnion/chorion membrane product (Epifix) with surgical repair using autologous tissue in patients who underwent same-day repair following Mohs microsurgery for removal of skin cancer on the face, head, or neck (Table 14).^40, Propensity-score matching using retrospective data from medical records was used to identify 143 matched pairs. The primary endpoint was the incidence of postoperative morbidity, including the rate of infection, bleeding/hematoma, dehiscence, surgical reintervention, or development of a nonhealing wound. Postoperative cosmetic outcomes were assessed at 9 months or later and included documentation of suboptimal scarring, scar revision treatment, and patient satisfaction.

Results are summarized in Table 15, and study limitations in Tables 16 and 17. A greater proportion of patients who received dHACM repair experienced zero complications (97.9% vs. 71.3%; p<.0001; relative risk 13.67; 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). Confidence in these findings is limited, however, by the study's retrospective design and potential for bias due to missing data. Additionally, the study's relevance is limited due to a lack of diversity in the study population and no comparison to non-surgical treatment options.

Table 14. Nonrandomized Study of Dehydrated Human Amnion/Chorion Membrane for Repair Following Mohs Microsurgery - Characteristics

dHACM: dehydrated human amnionic/chorionic membrane.

Table 15. Nonrandomized Study of Dehydrated Human Amnion/Chorion Membrane for Repair Following Mohs Microsurgery- Results

 dHACM: dehydrated human amnionic/chorionic membrane; SD: standard deviation.

Table 16. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (eg, proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 17. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Repair Following Mohs Microscopic Surgery

A retrospective observational study found a higher complication-free rate in 143 propensity score-matched pairs of patients who had received autologous tissue or dHACM repair following Mohs microsurgery for skin cancer on the face, head, or neck. This study was limited by its retrospective design. Additional evidence from well-designed and conducted prospective studies is needed.

Summary of Evidence

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 amniotic/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 13.67; 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.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2019 Input

Clinical input was sought to help determine whether the use of human amniotic membrane graft either without or with suture fixation for several ophthalmic conditions would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 2 respondents, including 1 specialty society-level response and 1 physician-level response identified through specialty societies including physicians with academic medical center affiliations.

Clinical input supported the use of amniotic membrane in individuals with the following indications:

• Neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy. Non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.

• Corneal ulcers and melts that do not respond to initial medical therapy. Non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.

• Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment.

• Bullous keratopathy and who are not candidates for curative treatment (eg, endothelial or penetrating keratoplasty) as an alternative to stromal puncture.

• Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient.

• Persistent epithelial defects and ulcerations that do not respond to conservative therapy.

• Severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy.

• Moderate or severe acute ocular chemical burn.

• Corneal perforation when corneal tissue is not immediately available.

• Pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft.

Further details from clinical input are included in the Appendix.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

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."^41,

Tear Film and Ocular Surface Society

In 2017, the Tear Film and Ocular Surface Society published the Dry Eye Workshop II (DEWS) management and therapy report.^24, The report evaluated the evidence on treatments for dry eye and provided the following treatment algorithm for dry eye disease management:

Step 1:

• Education regarding the condition, its management, treatment, and prognosis

• Modification of local environment

• Education regarding potential dietary modifications (including oral essential fatty acid supplementation)

• Identification and potential modification/elimination of offending systemic and topical medications

• Ocular lubricants of various types (if meibomian gland dysfunction is present, then consider lipid containing supplements)

• Lid hygiene and warm compresses of various types

Step 2:

If above options are inadequate consider:

• Non-preserved ocular lubricants to minimize preservative-induced toxicity

• Tea tree oil treatment for Demodex (if present)

• Tear conservation

• Punctal occlusion

• Moisture chamber spectacles/goggles

• Overnight treatments (such as ointment or moisture chamber devices)

• In-office, physical heating and expression of the meibomian glands

• In-office intense pulsed light therapy for meibomian gland dysfunction

• Prescription drugs to manage dry eye disease

• Topical antibiotic or antibiotic/steroid combination applied to the lid margins for anterior blepharitis (if present)

• Topical corticosteroid (limited-duration)

• Topical secretagogues

• Topical non-glucocorticoid immunomodulatory drugs (such as cyclosporine)

• Topical LFA-1 antagonist drugs (such as lifitegrast)

• Oral macrolide or tetracycline antibiotics

Step 3:

If above options are inadequate consider:

• Oral secretagogues

• Autologous/allogeneic serum eye drops

• Therapeutic contact lens options

• Soft bandage lenses

• Rigid scleral lenses

Step 4:

If above options are inadequate consider:

• Topical corticosteroid for longer duration

• Amniotic membrane grafts

• Surgical punctal occlusion

• Other surgical approaches (eg tarsorrhaphy, salivary gland transplantation)

Wound Healing Society

In 2016, the Wound Healing Society updated their guidelines on diabetic foot ulcer treatment.^42, 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 amniotic membrane were included with references on living and acellular bioengineered skin substitutes.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 18.

Table 18. Summary of Key Trials

NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

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2. 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. PMID 23902526
3. Shimberg M, Wadsworth K. The use of amniotic-fluid concentrate in orthopaedic conditions. J Bone Joint Surg. 1938;20(I):167-177.
4. 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 3, 2024
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6. 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. PMID 31691579
7. Ananian CE, Dhillon YS, Van Gils CC, et al. A multicenter, randomized, single-blind 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. May 2018; 26(3): 274-283. PMID 30098272
8. Tettelbach W, Cazzell S, Sigal F, et al. A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers. Int Wound J. Feb 2019; 16(1): 122-130. PMID 30246926
9. DiDomenico LA, Orgill DP, Galiano RD, et al. Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective, randomised, multi-centre clinical trial in 80 patients. Int Wound J. Dec 2018; 15(6): 950-957. PMID 30019528
10. 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): 70-7. PMID 26978860
11. 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): 724-32. PMID 25424146
12. 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): 272-82. PMID 26695998
13. 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. PMID 30136445
14. Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix(®) 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): 554-60. PMID 25048468
15. Smiell JM, Treadwell T, Hahn HD, et al. Real-world Experience With a Decellularized Dehydrated Human Amniotic Membrane Allograft. Wounds. Jun 2015; 27(6): 158-69. PMID 26061491
16. Frykberg RG, Gibbons GW, Walters JL, et al. 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. Jun 2017; 14(3): 569-577. PMID 27489115
17. 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. 2014; 22(6): 688-93. PMID 25224019
18. Bianchi C, Cazzell S, Vayser D, et al. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix ® ) allograft for the treatment of venous leg ulcers. Int Wound J. Feb 2018; 15(1): 114-122. PMID 29024419
19. 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. PMID 30864259
20. Serena TE, Orgill DP, Armstrong DG, et al. A Multicenter, Randomized, Controlled, Clinical Trial Evaluating Dehydrated Human Amniotic Membrane in the Treatment of Venous Leg Ulcers. Plast Reconstr Surg. Nov 01 2022; 150(5): 1128-1136. PMID 36067479
21. Vines JB, Aliprantis AO, Gomoll AH, et al. Cryopreserved Amniotic Suspension for the Treatment of Knee Osteoarthritis. J Knee Surg. Aug 2016; 29(6): 443-50. PMID 26683979
22. 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. PMID 27143138
23. 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): 1332-9. PMID 23945520
24. Cazzell S, Stewart J, Agnew PS, et al. Randomized Controlled Trial of Micronized Dehydrated Human Amnion/Chorion Membrane (dHACM) Injection Compared to Placebo for the Treatment of Plantar Fasciitis. Foot Ankle Int. Oct 2018; 39(10): 1151-1161. PMID 30058377
25. Suri K, Kosker M, Raber IM, et al. Sutureless amniotic membrane ProKera for ocular surface disorders: short-term results. Eye Contact Lens. Sep 2013; 39(5): 341-7. PMID 23945524
26. Liu J, Li L, Li X. Effectiveness of Cryopreserved Amniotic Membrane Transplantation in Corneal Ulceration: A Meta-Analysis. Cornea. Apr 2019; 38(4): 454-462. PMID 30702468
27. Yin HY, Cheng AMS, Tighe S, et al. Self-retained cryopreserved amniotic membrane for treating severe corneal ulcers: a comparative, retrospective control study. Sci Rep. Oct 12 2020; 10(1): 17008. PMID 33046729
28. Paris Fdos S, Gonçalves 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): 980-4. PMID 23723410
29. Kheirkhah A, Casas V, Raju VK, et al. Sutureless amniotic membrane transplantation for partial limbal stem cell deficiency. Am J Ophthalmol. May 2008; 145(5): 787-94. PMID 18329626
30. Pachigolla G, Prasher P, Di Pascuale MA, et al. Evaluation of the role of ProKera in the management of ocular surface and orbital disorders. Eye Contact Lens. Jul 2009; 35(4): 172-5. PMID 19474753
31. 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): 484-91. PMID 26686968
32. Bouchard CS, John T. Amniotic membrane transplantation in the management of severe ocular surface disease: indications and outcomes. Ocul Surf. Jul 2004; 2(3): 201-11. PMID 17216092
33. John T, Tighe S, Sheha H, et al. Corneal Nerve Regeneration after Self-Retained Cryopreserved Amniotic Membrane in Dry Eye Disease. J Ophthalmol. 2017; 2017: 6404918. PMID 28894606
34. McDonald MB, Sheha H, Tighe S, et al. Treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol. 2018; 12: 677-681. PMID 29670328
35. Tandon R, Gupta N, Kalaivani M, et al. Amniotic membrane transplantation as an adjunct to medical therapy in acute ocular burns. Br J Ophthalmol. Feb 2011; 95(2): 199-204. PMID 20675729
36. 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. Mar 2019; 199: 209-215. PMID 30419194
37. Tamhane A, Vajpayee RB, Biswas NR, et al. Evaluation of amniotic membrane transplantation as an adjunct to medical therapy as compared with medical therapy alone in acute ocular burns. Ophthalmology. Nov 2005; 112(11): 1963-9. PMID 16198422
38. 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): 201-8. PMID 23062647
39. Clearfield E, Muthappan V, Wang X, et al. Conjunctival autograft for pterygium. Cochrane Database Syst Rev. Feb 11 2016; 2(2): CD011349. PMID 26867004
40. Toman J, Michael GM, Wisco OJ, et al. Mohs Defect Repair with Dehydrated Human Amnion/Chorion Membrane. Facial Plast Surg Aesthet Med. 2022; 24(1): 48-53. PMID 34714143
41. Hingorani A, LaMuraglia GM, Henke P, et al. 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. J Vasc Surg. Feb 2016; 63(2 Suppl): 3S-21S. PMID 26804367
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Codes

Policy History

APPENDIX

2019 Clinical Input

Clinical input was sought to help determine whether the use of human amniotic membrane graft either without or with suture fixation for several ophthalmic conditions would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 2 respondents, including 1 specialty society-level response and 1 physician-level response identified through specialty societies including physicians with academic medical center affiliations.

Respondents

Clinical input was provided by the following specialty societies and physician members identified by a specialty society or clinical health system:

• American Academy of Ophthalmology (AAO)

• Mark Latina, MD, Ophthalmology, Tufts University School of Medicine, identified by Massachusetts Society of Eye Physicians and Surgeons

Clinical input provided by the specialty society at an aggregate level is attributed to the specialty society. Clinical input provided by a physician member designated by a specialty society or health system is attributed to the individual physician and is not a statement from the specialty society or health system. Specialty society and physician respondents participating in the Evidence Street® clinical input process provide a review, input, and feedback on topics being evaluated by Evidence Street. However, participation in the clinical input process by a specialty society and/or physician member designated by a specialty society or health system does not imply an endorsement or explicit agreement with the Evidence Opinion published by BCBSA nor any Blue Plan.

Clinical Input Ratings

Respondent Profile

Respondent Conflict of Interest Disclosure

Individual physician respondents answered at individual level. Specialty Society respondents provided aggregate information that may be relevant to the group of clinicians who provided input to the Society-level response. NR = not reported

Responses

• We are seeking your opinion on whether using human amniotic membrane graft either without or with suture fixation for the below indications provide a clinically meaningful improvement in net health outcome. Please respond based on the evidence and your clinical experience. Please address these points in your response:

  • Relevant clinical scenarios (e.g., a chain of evidence) where the technology is expected to provide a clinically meaningful improvement in net health outcome;

  • Any relevant patient inclusion/exclusion criteria or clinical context important to consider in identifying individuals who may be appropriate for human amniotic membrane graft with versus without suture fixation for this indication;

  • Supporting evidence from the authoritative scientific literature (please include PMID).

NR = not reported

• Based on the evidence and your clinical experience for using human amniotic membrane with suture fixation for the clinical indications described below:

  • Respond YES or NO for each clinical indication whether the intervention would be expected to provide a clinically meaningful improvement in net health outcome; AND

  • Rate your level of confidence in your YES or NO response using the 1 to 5 scale outlined below.

NR = not reported

• Based on the evidence and your clinical experience for using human amniotic membrane with suture fixation for the clinical indications described below:

  • Respond YES or NO for each clinical indication whether this intervention is consistent with generally accepted medical practice; AND

  • Rate your level of confidence in your YES or NO response using the 1 to 5 scale outlined below.

NR = not reported

• Based on the evidence and your clinical experience for using human amniotic membrane without suture fixation for the clinical indications described below:

  • Respond YES or NO for each clinical indication whether the intervention would be expected to provide a clinically meaningful improvement in net health outcome; AND

  • Rate your level of confidence in your YES or NO response using the 1 to 5 scale outlined below.

NR = not reported

• Based on the evidence and your clinical experience for using human amniotic membrane without suture fixation for the clinical indications described below:

  • Respond YES or NO for each clinical indication whether this intervention is consistent with generally accepted medical practice; AND

  • Rate your level of confidence in your YES or NO response using the 1 to 5 scale outlined below.

NR = not reported

• Additional narrative rationale or comments regarding clinical pathway and/or any relevant scientific citations (including the PMID) supporting your clinical input on this topic.

NR = not reported

• Is there any evidence missing from the attached draft review of evidence that demonstrates clinically meaningful improvement in net health outcome?