| Coverage Policy Manual | |
| Policy #: | 2015014 |
| Category: | Surgery |
| Initiated: | May 2015 |
| Last Review: | April 2024 |
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| Amniotic Membrane and Amniotic Fluid Injections | |
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| Description: |
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 (Parolini, 2009). There is evidence that the tissue has anti-inflammatory, antifibroblastic, and antimicrobial properties. HAM is considered nonimmunogenic and has not been observed to cause substantial immune response. It is believed that these properties are retained in cryopreserved HAM and dehydrated 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 (Koob, 2013).
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 (Parolini, 2009). 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 (Parolini, 2009). 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 (Shimberg, 1938). 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 (Parolini, 2009). 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 policy #2010023.
REGULATORY STATUS
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. 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) (FDA, 2017).
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:
The guidance provides the following specific examples of homologous and non-homologous use for 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 FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104). 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” (FDA, 2003). 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 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.
CODING
There are specific HCPCS codes for some of these products (see codes in CPT/HCPCS section below).
If no specific HCPCS code exists for the product, an unlisted code such as Q4100 would be used.
There are no specific codes for AmnioFix or OrthoFlo. It might be reported using the code for another MiMedx product such as Q4145 – Epifix, injectable, 1 mg, or the not otherwise specified code Q4100.
There is no specific code for this type of injection. It might be reported with one of the musculoskeletal system injection codes (e.g., 20550), the unlisted general musculoskeletal system code (20999), or if subcutaneous or intramuscular, the therapeutic injection code (96372).
There are codes for the placement of amniotic membrane on the ocular surface:
65778: Placement of amniotic membrane on the ocular surface; without sutures
65779: single layer, sutured.
Related Policies:
2012009 Skin and Soft Tissue Substitutes, Bioengineered Products
2010023 Orthopedic Applications of Stem Cell Therapy
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Policy/ Coverage: |
Effective May 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without sutures, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures, are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication.
For members with contracts without primary coverage criteria, injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Placenta Derived Products and Indications
All other placenta derived products including but not limited to amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above as covered including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, all other placenta derived products including but not limited to amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above as covered including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 2023 – April 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without suture, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications is considered investigational.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Placenta Derived Products and Indications
All other placenta derived products including but not limited to amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above as covered including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, all other placenta derived products including but not limited to amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above as covered including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2022 through July 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without suture, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications is considered investigational.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Placenta Derived Products and Indications
All other placenta derived products including but not limited to amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above as covered including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, all other placenta derived products including but not limited to amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above as covered including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective September 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) are limited to 3 applications per eye per condition that meets criteria.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without suture, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc.) for ophthalmic indications is considered investigational.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Human Amniotic Membrane Products and Indications
All other human amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, all other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 2022 through August 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc) are limited to 3 applications per eye per condition that meets criteria.
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (e.g., Prokera, Amnioclip, etc) are limited to 3 applications per eye per condition that meets criteria.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without suture, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (e.g., Prokera, Amnioclip, etc) for ophthalmic indications is considered investigational.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Human Amniotic Membrane Products and Indications
All other human amniotic membrane products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery do not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, all other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to February 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (eg Prokera, Amnioclip, etc) are limited to 3 applications per eye per condition that meets criteria.
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Note: Applications of human amniotic membrane graft (eg Prokera, Amnioclip, etc) are limited to 3 applications per eye per condition that meets criteria.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without suture, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (eg Prokera, Amnioclip, etc) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (eg Prokera, Amnioclip, etc) for ophthalmic indications is considered investigational.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Human Amniotic Membrane Products and Indications
All other human amniotic membrane products (e.g. derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton’s jelly) and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency do not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria all other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency. are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 2019 to February 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Human amniotic membrane grafts, with or without suture, meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Human amniotic membrane grafts with suture or glue may be considered medically necessary for the treatment of the following ophthalmic indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Human Amniotic Membrane Grafts With or Without Suture
Human amniotic membrane grafts, with or without suture, for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, human amniotic membrane grafts, with or without sutures are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, bullous keratopathy, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of greater than 3 applications of any human amniotic membrane graft (eg Prokera, Amnioclip, etc) for ophthalmic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, the use of greater than 3 applications of any human amniotic membrane graft (eg Prokera, Amnioclip, etc) for ophthalmic indications is considered investigational.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Human Amniotic Membrane Products and Indications
All other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency do not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria all other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency. are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EFFECTIVE PRIOR TO MARCH 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Sutured human amniotic membrane grafts meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Sutured Human Amniotic Membrane
Sutured human amniotic membrane grafts for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, burns, corneal perforation, bullous keratopathy, limbus stem cell deficiency, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, sutured human amniotic membrane grafts are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, burns, corneal perforation, bullous keratopathy, limbus stem cell deficiency, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Non-sutured Human Amniotic Membrane
Human amniotic membrane without suture (eg, Prokera®, AmbioDisk™) for ophthalmic indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, human amniotic membrane without suture (eg, Prokera®, AmbioDisk™) for ophthalmic indications is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications including but not limited to treatment of osteoarthritis and plantar fasciitis does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Human Amniotic Membrane Products and Indications
All other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency do not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria all other human amniotic membrane products and indications not listed above including but not limited to treatment of lower-extremity ulcers due to venous insufficiency. are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to March 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nonhealing Diabetic Lower-Extremity Ulcers
Treatment of nonhealing diabetic lower-extremity ulcers (less than 20% decrease in wound area with standard wound care for at least 2 weeks) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness using the following human amniotic membrane products:
Ophthalmic Indications
Sutured human amniotic membrane grafts meets member benefit certificate primary coverage criteria and is covered for the treatment of the following ophthalmic indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Sutured Human Amniotic Membrane
Sutured human amniotic membrane grafts for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, burns, corneal perforation, bullous keratopathy, limbus stem cell deficiency, and after photorefractive keratectomy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, sutured human amniotic membrane grafts are considered investigational for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, burns, corneal perforation, bullous keratopathy, limbus stem cell deficiency, and after photorefractive keratectomy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Non-sutured Human Amniotic Membrane
Human amniotic membrane without suture (eg, Prokera®, AmbioDisk™) for ophthalmic indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, human amniotic membrane without suture (eg, Prokera®, AmbioDisk™) for ophthalmic indications is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Micronized or Particulated Human Amniotic Membrane
Injection of micronized or particulated human amniotic membrane for all indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, Injection of micronized or particulated human amniotic membrane is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Injection of Human Amniotic Fluid
Injection of human amniotic fluid does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, Injection of human amniotic fluid is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All Other Human Amniotic Membrane Products and Indications
All other human amniotic membrane products and indications not listed above do not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria all other human amniotic membrane products and indications not listed above are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to August 2017
The injection of amniotic fluid or micronized amniotic membrane for any indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the injection of amniotic fluid or micronized amniotic membrane is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
For conditions in which subjective measures are the primary outcomes, randomized controlled trials (RCTs) are particularly important due to the expected placebo effect and variable natural history. RCTs are also important because there may be numerous confounders of outcomes, and nonrandomized comparisons are prone to selection bias. For these reasons, RCTs are essential to demonstrate the clinical effectiveness of amniotic membrane and amniotic membrane injections compared with alternatives such as continued medical management or other established treatments. Therefore, the products assessed in this review are those that have RCT evidence. For indications where treatment with some amniotic membrane products has been established, nonrandomized studies that include patients with similar characteristics and have similar magnitude of benefit may be considered sufficient evidence.
The primary end points of interest for trials of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration for industry in developing products for treatment of chronic cutaneous ulcer and burn wounds:
1. Incidence of complete wound closure.
2. Time to complete wound closure (reflecting accelerated wound closure).
3. Incidence of complete wound closure following surgical wound closure.
4. Pain control.
DIABETIC LOWER-EXTREMITY ULCERS
Dehydrated Amniotic Membrane or Placental Membrane
AmnioBand vs Standard Care
AmnioBand Membrane was compared with standard of care (SOC) for the treatment of nonhealing (minimum 4 weeks) diabetic foot ulcers in an industry-sponsored, multicenter trial by DiDomenico et al (2016) (DiDomenico, 2016). Forty patients were randomized to SOC or to SOC plus weekly applications of the dehydrated placental allograft for up to 12 weeks. Healing was determined by the principal investigator at each institution and confirmed by an independent and blinded panel of 6 physicians. This study was adequately powered to detect a difference of 45% between groups in the primary outcome (the proportion of wounds healed at 6 weeks). Complete healing by 6 weeks was observed for 70% (14/20) of wounds treated with the dehydrated placental matrix compared with 15% (3/20) of wounds treated by SOC alone (p=0.001). The odds ratio for healing was 17 (95% confidence interval [CI], 3.1 to 93; p=0.001). At 12 weeks, complete healing was observed for 85% (17/20) of wounds in the AmnioBand group compared with 25% (5/20) in the SOC group. Mean time to heal for wounds treated with amniotic membrane was 36 days (95% CI, 27 to 46 days) compared to 70 days (95% CI, 59 to 81 days; p<0.001) with standard care. The number needed to treat to achieve healing at 12 weeks was 1.7 (95% CI, 1.2 to 2.8). Strengths of this study included power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and intention-to-treat (ITT) analysis.
AmnioExcel vs Standard Care
AmnioExcel dehydrated human amniotic membrane (d-HAM) was compared with standard care in an industry-sponsored, open-label multicenter RCT (N=29) by Snyder et al (2016) (Snyder, 2016). Randomization was performed by computer module and stratified by site and wound area. The primary outcome was the percentage of patients with complete wound closure at 6 weeks. The per protocol population included 11 patients in the AmnioExcel group and 10 in the SOC group. For the ITT population, 33% (95% CI, 25.0% to 46.4%) of patients in the AmnioExcel group achieved wound closure by 6 weeks compared to 0% of the SOC group (p=0.017). In the per protocol analysis, 45.5% of patients treated with AmnioExcel achieved wound closure by 6 weeks compared to 0% in the SOC arm (p=0.008) with a 95% confidence interval of the responder ratio of 32.9% to 58.0% (p=0.014). Power analysis was not described and 8 patients withdrew early (4 in each group), raising questions about the reliability of the effect size.
Biovance Registry
In 2015, Smiell et al reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types, including 47 diabetic foot wounds, 20 pressure ulcers, and 89 venous ulcers (Smiell, 2015). This study showed the effectiveness of d-HAM in a real-world setting. The size of the wounds at baseline ranged from less than 2 cm2 (35.4% of wounds) to over 25 cm2 (9.0% of wounds). Ninety-eight percent were on the lower extremities. Twenty-eight ulcers had failed prior treatment with advanced biologic therapies (Apligraf, Dermagraft, or Regranex), including 10 diabetic foot wounds. For all wound types, 41.6% closed, with a mean time to closure of 8 weeks and a mean of 2.4 amniotic membrane applications. In the subgroup of 112 patients who practiced good wound care, including offloading or compression therapy as indicated, 49.6% of wounds closed by a mean of 7.4 weeks. Wounds that had not closed during the observation period decreased in size by a mean of 46.6%.
EpiFix vs Standard Care
In 2013, Zelen et al reported an industry-sponsored, nonblinded, RCT comparing use of EpiFix d-HAM (n=13) with SOC (n=12) for diabetic foot ulcers of at least 4 weeks in duration (Zelen, 2013). EpiFix was applied every 2 weeks if the wound had not healed, with weekly dressing changes comprised of nonadherent dressing, moisture retentive dressing, and a compression dressing. Standard moist wound dressing was changed daily. After 4 weeks of treatment, EpiFix-treated wounds had reduced in size by a mean of 97% compared with 32% for the SOC group. Healing rate, defined as complete epithelialization of the open area of the wound, was 77% for EpiFix compared with 0% for SOC. After 6 weeks of treatment, wound sizes were reduced by 98.4% with EpiFix treatment compared with -1.8% for SOC. The healing rate was 92% with EpiFix compared with 8% with SOC alone. At trial conclusion, unhealed wounds from the control group were treated with EpiFix.9 The mean duration of foot ulcers at the beginning of treatment was 19.4 weeks (range, 6.0-54 weeks) for the combined group. Follow-up was available at 9 to 12 months after primary healing in 18 of 22 eligible patients. Examination of these 18 patients found that 17 (94.4%) wounds remained fully healed.
EpiFix vs Apligraf
EpiFix d-HAM was compared with Apligraf (living cell therapy) in a multicenter RCT published by Zelen et al (2015) (Zelen, 2015). Sixty patients were randomized to treatment with Epifix, Apligraf, or standard wound care. Although patients and site investigators could not be blinded due to differences in products, wound healing was verified by 3 independent physicians who evaluated photographic images. Median wound size was 2.0 cm2 (range, 1.0-9.0 cm2) and median duration of the index ulcer was 11 weeks (range, 5-54 weeks). After 6 weekly treatments, the mean percent wound area healed was 97.1% for EpiFix, 80.9% for Apligraf, and 27.7% for SOC; 95% of wounds had healed completely in the EpiFix group compared with 45% treated with Apligraf and 35% who received standard wound care (p=0.003). The estimated median time to wound closure, based on Kaplan-Meier analysis, was 13 days for EpiFix compared with 49 days for both Apligraf and SOC (p<0.001).
In 2015, Kirsner et al reported an industry-sponsored observational study comparing the effectiveness of Apligraf and EpiFix in a real-world setting (Kirsner, 2015). Data were obtained from a wound care‒specific database from 3000 wound care facilities. The database included 1458 diabetic ulcers treated for the first time in 2014 with Apligraf (n=994) or EpiFix (n=464). Using the same criteria as the 2015 study by Zelen (described above), data were included on the treatment of 226 diabetic foot ulcers from 99 wound care centers. Selection criteria for foot wounds included size between 1 cm2 and 25 cm2, duration of 1 year or less, and wound reduction of 20% or less in the 14 days prior to treatment. Although wounds for the 2 groups were comparable at baseline, the rationale for using a particular product was not reported. One hundred sixty-three wounds were treated with Apligraf (mean, 2.5 applications) and 63 were treated with EpiFix (mean, 3.5 applications, p=0.003). By week 24, 72% of wounds treated with Apligraf and 47% of wounds treated with EpiFix had closed (p=0.01). Median time to closure was 13.3 weeks for Apligraf and 26.0 weeks for EpiFix (p=0.01). This study is at risk of selection bias in determining treatment assignment.
Cryopreserved Placental Membrane
Grafix vs Standard Care
Grafix cryopreserved placental membrane was compared with standard wound care in a 2014 multicenter RCT (Lavery6, 2014). Strengths of this trial included power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and ITT analysis. Ninety-seven patients with chronic diabetic foot ulcers were randomized to Grafix or to standard wound therapy, both administered once a week for up to 12 weeks. Power analysis indicated that 94 patients per arm would be needed. However, after prespecified interim analysis at 50% enrollment, the blinded review committee recommended that the trial be stopped due to efficacy of the treatment. ITT analysis from the blinded evaluation phase showed a significant increase in the proportion of patients achieving the primary outcome of wound closure by 12 weeks (62.0% vs 21.3%, p<0.001) and a decrease in the median time to complete wound closure (42.0 days vs 69.5 days, p=0.019). Safety evaluation found that fewer Grafix-treated patients experienced at least 1 adverse event (44.0% vs 66.0%, p=0.031) or had wound-related infections (18.0% vs 36.2%, p=0.044), with a trend toward fewer hospitalizations related to infections (6% vs 15%, p=0.15).
Section Summary: Diabetic Lower-Extremity Ulcers
The evidence on amniotic and placental membrane products for the treatment of diabetic lower-extremity ulcers includes several RCTs compared HAM to SOC or to an established advanced wound care product. All of these industry-sponsored studies included evaluation of wound closure as the primary outcome measure, and some included power analysis, blinded assessment of wound healing, and ITT analysis. For the amniotic membrane products evaluated in RCTs (eg, AmnioBand Membrane, EpiFix, Grafix), results indicated improved outcomes compared to SOC, and outcomes that are at least as good as the advanced wound care product Apligraf. In addition, a registry study for Biovance showed improved health outcomes, with a magnitude of benefit similar to that observed in the RCTs for other products.
LOWER-EXTREMITY ULCERS DUE TO VENOUS INSUFFICIENCY
Dehydrated Amniotic Membrane
EpiFix
In 2014, Serena et al reported on an industry-sponsored multicenter open-label RCT that compared EpiFix d-HAM plus compression therapy to compression therapy alone for venous leg ulcers (Serena, 2014). Ulcers were included if they were chronic (>1 month in duration); extended through the full thickness of the skin but not down to muscle, tendon, or bone; and had been treated with compression therapy for at least 14 days. Eighty-four participants were enrolled and assigned to a single EpiFix allograft (n=26), 2 allografts (n=27), or compression therapy alone (n=31). The primary outcome (proportion of patients with 40% wound closure at 4 weeks) was achieved by 62% in the combined EpiFix groups and by 32% in the control group (p=0.005). During the 4-week trial period, 6 (11.3%) patients in the combined EpiFix group and 4 (12.9%) in the control group achieved complete wound closure. Secondary outcomes, which evaluated the use of 1 versus 2 applications of amniotic membrane, showed no significant difference in outcomes (62% vs 63%). Strengths of this study 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 (Serena, 2015).
Biovance
As described above, in 2015, Smiell et al 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 (Smiell, 2015). 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
Given the lack of difference between 1 and 2 applications of EpiFix and the lack of difference between the experimental and control groups in complete wound closure at 4 weeks, and because no HAM products have been shown to improve healing of venous ulcers in comparative trials, additional study is needed to evaluate the effect of this treatment on health outcomes.
OSTEOARTHRITIS
ReNu
A feasibility study (N=6) of cryopreserved human amniotic membrane (c-HAM) suspension with amniotic fluid‒derived cells (ReNu) for the treatment of knee osteoarthritis was reported in 2016 (Vines, 2016). A single intraarticular 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 effects, aside from a transient increase in pain, were noted. An RCT is in progress.
PLANTAR FASCIITIS
One systematic review and 2 randomized pilot studies were identified on the treatment of plantar fasciitis using injection of micronized HAM.
Systematic Review
A 2016 network meta-analysis of 22 RCTs (total N=1216 patients) compared injection therapies for plantar fasciitis (Tsikopoulos, 2016). In addition to c-HAM and micronized d-HAM/chorionic membrane, treatments included corticosteroids, botulinum toxin type A, autologous whole blood, platelet-rich plasma (PRP), nonsteroidal anti-inflammatory drugs, dry needling, dextrose prolotherapy, and polydeoxyribonucleotide. Placebo arms included normal saline, local anesthetic, sham dry needling, and tibial nerve block. The minimum clinically important difference (MCID) was defined as -9 mm on a visual analog scale (VAS), which is substantially lower than the 30% or 20-mm decrease in VAS score for pain more typically used. Secondary outcomes included total and subscores for the Foot Health Status Questionnaire (FHSQ), with an MCID defined as 7 on the FHSQ function and 9 on the FHSQ general foot health subscales. Overall, risk of bias was low for randomization and blinding of participants, high for blinding of personnel, and uncertain for allocation concealment and outcome reporting. Analysis found d-HAM had the highest probability for improvement in pain and composite outcomes in the short term. However, this finding was based only on 1 RCT. When the efficacy of d-HAM was compared to corticosteroid injections, the mean difference in VAS score was a modest at -7.32 out of 100 (95% CI, -11.2 to -3.38) and the mean difference in the FHSQ score was 31.2 (95% CI, 13.9 to 48.6). Outcomes at 2-to-6 months (7 RCTs) favored botulinum toxin for pain and PRP for composite outcomes.
Clarix Flo
One small (N=23), industry-sponsored, double-blind study (2015) found similar improvements with injection of c-HAM (Clarix Flo) compared with corticosteroid injection (Hanselman, 2015). Another industry-sponsored, patient-blinded study (2013) by Zelen et al (N=45) compared injection of saline to d-HAM (AmnioFix) 0.5 mL or 1.25 mL in patients with symptoms recalcitrant to conservative treatment (Zelen, 2013). In the 2 d-HAM groups, scores on the American Orthopaedic Foot and Ankle Society hindfoot scale improved by about 50 points over the 8 weeks of the study compared with 10 points for controls (p<0.001). FACES pain scores decreased from 8.7 out of 10 at baseline to 0.8 at 8 weeks with d-HAM, compared with a decrease from 8.0 to 4.6 for controls (p<0.001). Longer follow-up is ongoing.
Section Summary: Plantar Fasciitis
The evidence on injection of particulated amniotic membrane and amniotic fluid for the treatment of plantar fasciitis is limited. Evidence includes a small (N=23) double-blind comparison with corticosteroid and a patient-blinded (N=45) comparison of 2 different doses of d-HAM with saline. Power analyses were not reported. A network meta-analysis, which identified only the Zelen et al trial, concluded that d-HAM was more effective than corticosteroid. However, these 2 small trials are not sufficient to demonstrate an improvement in health outcomes for this common condition. Additional study in a larger number of patients is needed to demonstrate consistency in results.
SUTURED HAM GRAFT FOR OPHTHALMOLOGIC CONDITIONS
Sutured HAM graft has been evaluated for a variety of ophthalmologic conditions.
Neurotrophic Keratitis
In 2005, Khokhar and Natung reported on an RCT of 30 patients (30 eyes) with refractory neurotrophic corneal ulcers who were randomized to HAM transplantation (n=15) or to conventional treatment with tarsorrhaphy or bandage contact lens (Khokhar, 2005). At the 3-month follow-up, 11 (73.3%) of 15 patients in the HAM group showed complete epithelialization compared to 10 (66.7%) of 15 in the conventional group. This difference was not significantly significant.
Following Pterygium Repair
A number of RCTs have been reported on 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 (Kaufman, 2013). 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.
Stevens-Johnson Syndrome
One RCT from India (2016) assigned 25 patients (50 eyes) with acute ocular Stevens-Johnson syndrome to c-HAM plus medical therapy (antibiotics, steroids, or lubricants) or to medical therapy alone (Sharma, 2016). The c-HAM was prepared locally and applied with fibrin glue rather than sutures. Application of c-HAM in the early stages of Stevens-Johnson syndrome resulted in improved visual acuity (p=0.042), tear breakup time (p=0.015), Schirmer test results (p<0.001), and less conjunctival congestion (p=0.03). 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 compared dramatically with the medical therapy alone group, which had 11 (44%) of 25 cases with corneal haze (p=0.001), 6 (24%) cases of corneal vascularization and conjunctivalization (p=0.03), and 6 (24%) cases of trichiasis and metaplastic lashes.
Persistent Epithelial Defects and Ulceration
In 2004, Bouchard and John wrote a review of amniotic membrane transplantation in the management of severe ocular surface disease (Bouchard, 2004). 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 rarity of the diseases and the absence of a 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.
Ocular Burns
A 2012 Cochrane review evaluated the evidence on HAM graft for acute ocular burns (Clare, 2012). Included in the review was a single RCT from India of 68 patients with acute ocular burns who were randomized to c-HAM plus medical therapy or to medical therapy alone. In the subset of 36 patients with moderate ocular burns treated within 7 days, 13 (65.0%) of 20 control eyes and 14 (87.5%) of 16 AMT-treated eyes had complete epithelialization by 21 days. There was a trend (p=0.09) toward a reduced relative risk of failure of epithelization in the treatment group. Mean logarithm of the minimum angle of resolution (logMAR) final visual acuities were 0.06 in the treatment group and 0.38 in the control group. In the subset of patients with severe ocular burns treated within 7 days, 1 (5.9%) of 17 AMT-treated eyes and 1 (6.7%) of 15 control eyes were epithelialized by day 21. There was no significant difference in final visual acuity, which was 1.77 logMAR in the treated eyes and 1.64 in the control group (p=NS). The risk of bias was considered high because of differences between the groups at baseline and because outcome assessors could not be masked to treatment. Reviewers determined that conclusive evidence supporting the treatment of acute ocular surface burns with AMT is lacking.
Bullous Keratopathy
Bullous keratopathy is characterized by stromal edema and epithelial and subepithelial bulla formation. In 2013, Dos Santos Paris et al published an RCT that compared fresh HAM to stromal puncture for the management of pain in patients with bullous keratopathy (Paris, 2013). 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 pain did not resolve.
Dry Eye Syndrome, Corneal Perforation, and Limbus Stem Cell Deficiency
No RCTs were identified on these other ophthalmic indications.
Section Summary: Sutured HAM Graft for Ophthalmic Conditions
The most widely studied condition with a technology assessment evaluating RCT evidence is use of HAM following pterygium repair. The assessment concluded, based on 4 RCTs, that conjunctival or limbal autograft was more effective than HAM. An RCT on HAM for refractory neurotrophic corneal ulcers found that outcomes following HAM graft were similar to those for conventional therapy. One RCT has shown that application of c-HAM in the early stages of Stevens-Johnson syndrome leads to clinically significant improvement compared to medical therapy alone. A 2012 Cochrane review found 1 RCT evaluating HAM graft for acute ocular burns. The trial suggested a benefit for HAM in the healing rate for ocular burns, but it was considered at high or uncertain risk of bias due to unequal baseline scores and lack of masking to treatment condition. A trial on HAM for the treatment of bullous keratopathy reported that there was no
difference in clinical outcomes between HAM and stromal puncture. Other indications have been studied only in case series.
HAM WITHOUT SUTURE FOR OPHTHALMIC CONDITIONS
Traditionally, 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 c-HAM allograft that allows it to be inserted under topical anesthesia similar to insertion of a contact lens. The easier insertion may lead to more widespread use, such as dry eye disease and for healing after photorefractive keratectomy (PRK).
Dry Eye Disease
The Prokera c-HAM device was evaluated in a 2016 series by Cheng et al (Cheng, 2106). The senior author of the study (S.C.G. Tseng) holds the patent on Prokera. This retrospective review assessed 10 patients treated with the self-retained device for moderate-to-severe dry eye disease. In this study, these 10 patients had moderate-to-severe dry eye syndrome despite conventional medical treatment. The c-HAM device was placed in 15 eyes (1 eye at a time) for a mean of 4.9 days (range, 2-8 days), after which the c-HAM was either dissolved or cloudy. Treatment resulted in symptomatic relief for a mean of 4.2 months (range, 0.3 to 6.8 months) after a single treatment. Symptomatic improvement was accompanied by statistically significant reductions of Ocular Surface Disease Index scores, use of topical medications, conjunctival hyperemia, corneal staining (all p<0.001), and a trend toward improved visual acuity (p=0.06).
Photorefractive Keratectomy
In 2016, Vlasov et al reported on a prospective, nonrandomized controlled trial evaluating the effect of sutureless amniotic membrane (Prokera) on corneal wound healing after PRK (Vlasov, 2016). Forty patients (80 eyes) had PRK for myopia. After surgery, a high-oxygen-transmissible bandage contact lens was applied on the dominant eye and cryopreserved amniotic membrane on the nondominant eye. Patients were assessed daily until complete corneal re-epithelialization occurred in both eyes and then at 2 weeks and 1, 3, 6, and 12 months thereafter. The primary outcome was re-epithelialization, which was assessed daily with slitlamp examination, fluorescein staining, and photography. The time to complete reepithelization was faster in eyes treated with a bandage contact lens (3.7 days; range, 3-7 days) than with the amniotic membrane product (4.6 days; range, 3-16 days). Initially, patients reported greater discomfort and dryness with amniotic membrane. Visual and clarity and optical quality of the cornea were similar between the amniotic membrane graft eyes and bandage contact lens eyes.
Other
Use of Prokera has also been reported for refractory ulcerative keratitis, neurotrophic keratitis, recurrent epithelial erosion, high-risk corneal grafts, acute chemical and thermal burns, acute Stevens-Johnson syndrome, necrotizing scleritis, and limbal stem cell deficiency (Cheng, 2016).
Section Summary: HAM Without Suture for Ophthalmic Conditions
Current evidence on use of the Prokera device includes 1 within-subject comparative study and case series. While the case series reported generally positive effects, RCTs are needed to determine the effect of sutureless self-contained HAM on corneal healing. The single prospective comparative trial identified found no benefit of HAM compared to a bandage contact lens when used for wound healing after PRK. RCTs are needed to determine whether HAM improves healing for these various disorders.
SUMMARY OF EVIDENCE
Diabetic Lower-Extremity Ulcers
For individuals who have nonhealing diabetic lower-extremity ulcers who receive patch or flowable formulation of human amniotic membrane (HAM; (AmnioBand Membrane, Biovance, Epifix, Grafix), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The RCTs evaluating amniotic and placental membrane products for the treatment of nonhealing (<20% healing with ≥2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM to standard care or to 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 (AmnioBand Membrane, Biovance, Epifix, Grafix), results have shown improved outcomes compared to standard care, and outcomes that are at least as good as an established advanced wound care product. Improved health outcomes in the RCTs are supported by multicenter registries. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Lower-Extremity Ulcers due to Venous Insufficiency
For individuals who have lower-extremity ulcers due to venous insufficiency who receive patch or flowable formulation of HAM, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. In a randomized comparison of a cryopreserved HAM product to standard of care, there was no difference between the experimental and controls groups in complete wound closure at 4 weeks. Because HAM has not been shown to improve healing of venous ulcers in controlled studies, comparative studies on other HAM products are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.
Osteoarthritis
For individuals who have knee osteoarthritis who receive injection of suspension or particulate formulation of 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 was for a precursor to a larger RCT of HAM injection. Additional trials, which will have a larger sample sizes and longer followup, are needed to permit conclusions on the effect of this treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.
Plantar Fasciitis
For individuals who have plantar fasciitis who receive injection of suspension or particulate formulation of HAM or amniotic fluid, the evidence includes 2 small RCTs. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Research on HAM injections for plantar fasciitis is at an early stage. The evidence includes a small (N=23) double-blind comparison with corticosteroid and a patient-blinded (N=45) comparison of 2 different doses of dehydrated HAM with saline. Additional controlled trials with larger sample sizes and longer follow-up are needed to permit conclusions on the effect of HAM and amniotic fluid injections on plantar fasciitis pain. The evidence is insufficient to determine the effects of the technology on health outcomes.
Ophthalmic Conditions
For individuals who have neurotrophic keratitis, corneal ulcers and melts, pterygium repair, Stevens-Johnson syndrome, or persistent epithelial defects who receive sutured HAM graft, the evidence incudes several RCTs and a technology assessment. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The most widely studied condition with a technology assessment of RCT evidence is the use of HAM following pterygium repair. The technology assessment concluded, based on 4 RCTs, that conjunctival or limbal autograft was more effective than HAM. An RCT evaluating HAM for refractory neurotrophic corneal ulcers found that outcomes following HAM graft were similar to conventional therapy. The evidence is insufficient to determine the effects of the technology on health
outcomes.
For individuals who have ophthalmic disorders other than neurotrophic keratitis, corneal ulcers and melts, pterygium repair, Stevens-Johnson syndrome, or persistent epithelial defects who receive sutured HAM graft, the evidence includes 2 RCTs and a systematic review that included 1 RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. A 2012 Cochrane review found a single RCT on HAM graft for acute ocular burns. The trial suggested a benefit in the healing rate for ocular burns, but it was considered at high or uncertain risk of bias due to unequal baseline scores and the lack of masking of the treatment condition. A trial assessing HAM for the treatment of bullous keratopathy reported no difference in clinical outcomes between HAM and stromal puncture. RCTs are needed to evaluate the benefit of HAM for these other indications. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have ophthalmic conditions who receive HAM without suture, the evidence includes 1 within-subject comparative study and case series. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Traditionally, amniotic membrane has been sutured onto the eye for a variety of severe ocular surface disorders. The Prokera device is novel because it has a ring around the cryopreserved HAM allograft that permits it to be inserted under topical anesthesia, similar to insertion of a contact lens, allowing for more widespread use. Use of Prokera has been reported for refractory ulcerative keratitis, neurotrophic keratitis, recurrent epithelial erosion, high-risk corneal grafts, acute chemical and thermal burns, acute Stevens-Johnson syndrome, necrotizing scleritis, and limbal stem cell
deficiency. Current evidence on use of the Prokera device is limited. While the case series reported generally positive effects, the prospective comparative trial found no benefit of HAM compared to a bandage contact lens for healing a wound after photorefractive keratectomy. RCTs are needed to determine whether HAM improves healing for the various ophthalmic disorders. The evidence is insufficient to determine the effects of the technology on health outcomes.
A review of the literature has shown that amniotic membrane has been used for nearly 2 decades for ophthalmic disorders, although RCT evidence is limited. Therefore, clinical input was requested on the specific disorders for which amniotic membrane would be expected to improve health outcomes and use is consistent with generally accepted medical practice. Input supported the use of sutured or glued amniotic membrane for neurotrophic keratitis, corneal ulcers and melts, pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Those providing input had low confidence that sutureless amniotic membrane performed as well or better than sutured amniotic membrane.
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed as follows:
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2018. Injection of micronized or particulated human amniotic membrane for treatment of osteoarthritis and plantar fasciitis and injection of human amniotic fluid added to policy non-coverage statement. The key identified literature is summarized below.
EpiFix vs Standard of Care
In a subsequent report by Zelen et al, weekly application of EpiFix resulted in significantly faster healing (n=20; mean, 2.4 weeks) compared with biweekly application (n=20; mean, 4.1 weeks; p=0.039) (Zelen, 2014). All wounds treated weekly had healed by week 8 compared with 75% of wounds treated biweekly (p=0.047).
EpiFix vs Apligraf
EpiFix d-HAM was compared with Apligraf (living cell therapy) in a multicenter RCT published by Zelen et al (Zelen, 2015; Zelen 2016). Sixty patients with less than 20% wound reduction during a 2-week run-in period were randomized to treatment with EpiFix, Apligraf, or standard wound care. Although patients and site investigators could not be blinded due to differences in products, wound healing was verified by 3 independent physicians who evaluated photographic images. Median wound size was 2.0 cm2 (range, 1.0-9.0 cm2) and median duration of the index ulcer was 11 weeks (range, 5-54 weeks). After 6 weekly treatments, the mean percent wound area healed was 97.1% for EpiFix, 80.9% for Apligraf, and 27.7% for SOC; 95% of wounds had healed completely in the EpiFix group compared with 45% treated with Apligraf and 35% who received standard wound care (p=0.003). The estimated median time to wound closure, based on Kaplan-Meier analysis, was 13 days for EpiFix compared with 49 days for both Apligraf and SOC (p<0.001). This study was extended to 12 weeks with 100 patients who were treated with either Epifix (n=32), Apligraf (n=33), or standard wound care (n=35) (Zelen, 2016). Patients whose wound failed to heal by at least 50% by 6 weeks exited the study; this included 4 patients in the Apligraf group and 13 in the SOC group. An additional 5 SOC patients withdrew from the study. Patients treated with EpiFix had a higher probability of wound healing (hazard ratio, 5.66; 95% CI, 3.03 to 10.57; p<0.001) compared with SOC and required fewer weekly treatments (3.4) compared with wounds treated with Apligraf (5.9; p=0.003).
LOWER-EXTREMITY ULCERS DUE TO VENOUS INSUFFICIENCY
Dehydrated Amniotic Membrane
EpiFix
A second industry-sponsored multicenter open-label RCT evaluated the time to complete ulcer healing following weekly treatment with EpiFix d-HAM and compression therapy or compression therapy with standard dressing (Bianchi, 2017). 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=0.01), and improved time to complete healing, as assessed by Kaplan-Meier analysis. Healing within 12 weeks was reported for 60% of patients in the EpiFix group and 35% of patients in the control group (see Table 3). There were several limitations of this trial. Nineteen (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). Also, the trial did not use ITT analysis. Had all excluded patients been considered treatment failures, the difference between groups would have been 17% (48% wound healing for EpiFix vs 31% for controls). 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. Although the trialists noted that only 1 patient from this group had healed by weeks 12 and 16, reporting is unclear about how many patients from the d-HAM group would have been considered treatment failures at 8 weeks using the same cutoff.
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Food and Drug Administration. 510Ik) Summary: ProKera™ Bio-Tissue Inc. Int Wound J. Apr 2014;11(2):122-128. PMID 24618401 https://www.accessdata.fda.gov/cdrh_docs/pdf3/K032104.pdf. Accessed May 19, 2017. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association. |
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