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.

Backgound    
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 80152.

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). 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.

AmnioClip (FORTECH GmbH) is a ring designed to hold the amniotic membrane in the eye without sutures or glue fixation. A mounting device is used to secure the amniotic membrane within the AmnioClip. The AmnioClip currently has CE approval in Europe.

Policy   
Treatment of nonhealing diabetic lower-extremity ulcers using the following human amniotic membrane products (Affinity^®, AmnioBand^® Membrane, Biovance^®, EpiCord^®, EpiFix^®, Grafix™) may be considered MEDICALLY NECESSARY.

Injection of micronized or particulated human amniotic membrane is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY for all indications, including but not limited to treatment of osteoarthritis and plantar fasciitis.

Injection of human amniotic fluid is investigational and /or unproven therefore NOT MEDICALLY NECESSARY for all indications.

All other human amniotic products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton's jelly) not listed above are investigational and/or unproven therefore NOT MEDICALLY NECESSARY (see policy guidelines).

All other indications not listed above are investigational/unproven therefore is considered NOT MEDICALLY NECESSARY, including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery.

NOTE: See CAM 047 for ophthlamic indications of this technology.

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 (e.g., Zelen et al. [2015]).

Tables PG1 and PG2 list the medically necessary and investigational 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 Foundation
^aProcessed by HRT and marketed under different trade name

Rationale  
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.

Diabetic Lower-Extremity Ulcers
Patch or Flowable Amniotic Membrane or Placental Membrane
Clinical Context and Therapy Purpose
The purpose of patch or flowable amniotic membrane or placental membrane in patients who have diabetic lower-extremity ulcers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does amniotic membrane or placental membrane improve the net health outcome in patients with diabetic lower-extremity ulcers?

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

Populations
The relevant population of interest is patients 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 RCT.
• 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 patch or flowable formulation of HAM or placental membrane (i.e., 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 (i.e., 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.

Lower-Extremity Ulcers Due to Venous Insufficiency
Amniotic Membrane
Clinical Context and Therapy Purpose
The purpose of amniotic membrane or placental membrane in patients 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 question addressed in this evidence review is: Does amniotic membrane or placental membrane improve the net health outcome in patients with venous ulcers?

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

Populations
The relevant population of interest is patients 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
Two RCTs, both with EpiFix, 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.

Two additional studies, one with Amnioband and a second with Artacent, are listed on clinicaltrials.gov as completed in 2018, but results have not been published (see Table 14)

Table 6. Summary of Key RCT Characteristics

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

Table 7. Summary of Key RCT Results

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. 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. Two additional studies with other HAM products have been completed but not published, raising further questions about the efficacy of HAM for lower-extremity ulcers due to venous insufficiency. Therefore, corroboration with well-designed and well-conducted RCTs evaluating wound healing in patients with venous leg ulcers is needed to demonstrate efficacy. The corroborating RCTs should report ITT and sensitivity analysis, with analysis of all patients, including those who were off treatment or had protocol deviations and exclusions.

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.²⁰ 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 after treatment. 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.

Plantar Fasciitis
Clinical Context and Therapy Purpose
The purpose of micronized amniotic membrane in patients who have plantar fasciitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does injectable amniotic membrane improve the net health outcome in patients with plantar fasciitis?

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

Populations
The relevant population of interest is patients 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 = 1,216 patients) compared injection therapies for plantar fasciitis.²¹ 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.²² A subsequent RCT by Cazell et al. (2018) enrolled 145 patients and reported 3-month follow-up (see Table 10).²³ 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

NCT02427191: Micronized dHACM Injection as Compared to the Saline Placebo Injection in the Treatment of Plantar Fasciitis; 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 extended follow-up will be reported in a separate publication.

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.

Repair Following Mohs Microscopic Surgery
Clinical Context and Therapy Purpose
The purpose of repair with human amniotic membrane in patients 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 question addressed in this evidence review is: Does amniotic membrane improve the net health outcome in patients requiring repair following Mohs microsurgery?

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

Populations
The relevant population of interest is patients 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 (e.g., 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).³⁹ 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

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

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 (e.g., 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
Diabetic Lower-Extremity Ulcers
For individuals who have non-healing diabetic lower-extremity ulcers who receive a patch or flowable formulation of HAM or placental membrane (i.e., 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 (i.e., 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 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 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
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 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.

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 (e.g., 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 U.S. professional society, an international society with U.S. 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."⁴⁰

Wound Healing Society
In 2016, the Wound Healing Society updated their guidelines on diabetic foot ulcer treatment.⁴¹ 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

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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Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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