LCD L39139: Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound

This is a NON-coverage policy for all amniotic membrane, amniotic fluid or other placental-derived product injections and/or applications as a means of managing musculoskeletal injuries, joint conditions, and all other conditions not stated below.

This guidance does NOT include discussion on burns, wounds or ophthalmic conditions.

NOTE: For information on stem cell transplantation please see CMS National Coverage Determination 110.23 Stem Cell Transplantation

Introduction

Amniotic and placental-derived products are reported to possess certain beneficial characteristics. These products have been proposed as a source of stem cells. Stem cells, by definition, have the capability to differentiate into any cell of an organism as well as the capability of self-renewal. 1 In addition, the extracellular matrix (ECM) of placental and amniotic-based tissues are rich in collagen, glycoproteins, proteoglycans, fibroblasts, as well as many cytokines and growth factors thought to promote healing with a lower risk of low immunologic reaction.

Based on these characteristics, amniotic and placental-derived products are currently being studied and marketed as allografts to serve as:

• scaffolds for tissue engineering

• membrane covering for certain burns, wounds, and ophthalmic corneal injuries

• micronized/particulate products suspended in an aqueous material to be applied topically or injected into joints, tendons, ligaments

• applications or injections performed intra-operatively to promote post-operative healing

These amniotic and placental-derived products are further being investigated for a multitude of indications, including but not limited to musculoskeletal conditions involving joint pain and back pain, chronic pain in general, dental conditions, alopecia, wounds, burns, and a plethora of others. In the quest to find alternative treatments for certain musculoskeletal conditions, the emergence of a class of substances being marketed as “orthobiologics” has become more prevalent in the pharmaceutical market. “Orthobiologics” are biological products aimed at treating musculoskeletal conditions purported to heal injury/trauma, slow degenerative processes and affect regeneration of tissues. 2 The result ideally would be decreased pain and increased function. One such category of orthobiologics involves the incorporation of human amniotic and placental-derived products.

The amniotic and placental-derived products are obtained from the placenta of donors, usually, immediately post C-section at full term and screened for transmittable diseases. These products are made up of varying combinations of amniotic membrane, amniotic fluid, chorionic membrane, umbilical cord, umbilical cord blood, and what is known as Wharton’s jelly. 3

Definitions:

Musculoskeletal- Refer to the connective tissues including bones, muscles, and their associated tissues such as tendons and ligaments.

The Placenta is a multi-layered circulatory temporary organ that supplies food and oxygen to the fetus during pregnancy.

The multiple layers of the placenta include the:

• Amnion - the innermost membrane that surrounds the fetus during gestation

• Chorion - outermost membrane that surrounds the fetus during gestation

Amniotic fluid is the fluid surrounding the fetus within the amnion.

Umbilical cord is the vascular conduit connecting the fetus to the placenta comprised of the umbilical vein, arteries, allantois and yolk sac embedded in Wharton’s jelly.

Wharton’s Jelly is a gelatinous soft connective tissue derived from extra-embryonic mesoderm within the umbilical cord. 4

The amniotic membrane itself is divided into three histologic layers:

• A single epithelial layer

• A thick basement membrane

• An avascular stromal (mesenchymal) layer 5.6,7,8

The avascular stromal layer is further divided into three layers: 6,7,8

• The Compact layer

• The middle Fibroblast layer

• The Spongy layer

The Spongy Layer , loosely connected to the chorionic membrane, is highly concentrated with proteoglycans and glycoproteins including hyaluronic acid, as well as type I, III, and IV collagen. 5,6,8,9

The middle Fibroblast layer is made up of type I, III, V, and VI collagen. 6,8,9

The Compact layer that sits adjacent to the basement membrane is composed of collagen Types I, III, V, and VI, along with fibronectin. 5,9

The basement membrane anchors the epithelial layer 14 and contains collagen Types IV, V and VII, fibronectin, laminin, and hyaluronic acid. 6,10

Adjacent to the basement membrane and in immediate contact with amniotic fluid is the single layer of epithelial cells. Amniotic epithelial cells produce type III and IV collagen, glycoproteins such as laminin and fibronectin, which become the basement membrane. 5

The amniotic membrane’s purpose is to house and physically protect the fetus, but additional functions include regulation of the pH of the amniotic fluid, transportation of water and soluble material between the mother and fetus, and the synthesis of numerous growth factors and cytokines. The amniotic membrane also secretes anti-inflammatory proteins. All of this results in these tissues having anti-inflammatory, anti-microbial, anti-fibroblastic, and non-immunogenic properties.

Amniotic products have been asserted to be a source of stem cells. Both the amniotic epithelial layer (fetal derived cells) and mesenchymal (avascular stromal) layer derived from the embryonic mesoderm contain their respective stem cells that can differentiate into multiple cell lines, including myocytes, osteocytes, and chondrocytes. 8,9 Amniotic fluid also is found to contain amniotic mesenchymal stem cells. 7

The chorionic membrane adjacent to the mother’s endometrium during development of the fetus. Umbilical cord, Wharton’s jelly, and umbilical cord blood have also been found to contain mesenchymal stem cells. 7,11

Under normal conditions, placental tissues are collected via aseptic technique during cesarean section. Protocols vary as to how the tissues are harvested, prepared, preserved and stored. Testing is also required to ensure these tissues do not carry any communicable diseases transmissible from donor to recipient.

Because the spongy layer loosely connects the amniotic membrane to the chorionic membrane, these two layers are easily separated upon blunt dissection at initial harvesting. 10 Other than ease of separation between amniotic and chorionic membranes, the following steps in processing the tissues into the desired form vary, based on the portions of the placental tissues extracted, sterilization processes (if any) undertaken, and method of preservation utilized. Common methods of preservation include cryopreservation, lyophilization (freeze-drying), glycerol-preservation, γ (gamma)-sterilization, low heat dehydration, and vitrification. 5,8,9,10

A process called “Decellularization” using physical, biological, chemical or combination of methods may be used to remove all cellular and nuclear materials while preserving the extracellular matrix components. 12 Removal of all cellular components is thought to lessen the possibility of eliciting an immune response. 3,10 Different decellularization processes are available. Eventual preparation of sheets, particulate suspensions, liquids, or gels allows the final marketed product.

Depending on the methods utilized, the processing of placental and amniotic-based tissues will affect the viability of cellular components, growth factors, and other valuable properties for which these tissues are promoted. To date, there are significant differences that exist in the processing of different placental and amniotic-based tissue products. 3,5 Lack of consistency and standardization within propriety manufacturing (preparation) processes precludes determination and comparison of the final product form, characteristics, properties, and components. Placental-Based Products are not analogous to stem cells as many placental-based products are void of stem cell or living cells after processing.

The Food and Drug Administration (FDA), under Sect. 361 of the Public Health Service Act (regulated by the Centers for Biologics Evaluation and Research CBER, an arm of the FDA) oversees the therapeutic use of "Human cells or tissue products" or “HCT/P”s. Once these types of products are harvested, their processing and handling will determine whether the products fall under Section 361 guidance or default to the more regulated section 351 of the Public Health Service Act and/or the Federal Food, Drug, and Cosmetic Act. The regulatory pathway for pre-market FDA approval of new drugs, devices and/or biological products, requires registration as a New Drug application (NDA), a Premarket Approval (PMA) or other appropriate device premarket clearance such as 510(k), or a (BLA) Biologics License Approval. 8,9,13,14

If a human cells or tissue product meets Section 361 FDA requirements, the product will not require FDA pre-market review and approval. To meet “Section 361” FDA regulatory requirements, the placental/amniotic-based tissue product must meet the following 4 criteria:

The HCT/P is:

• Minimally Manipulated

• Intended for Homologous Use (as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent)

• The manufacture of the HCT/P does not involve the combination of the cells or tissues with another agent, 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

• Either:

• 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

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

• Is for autologous use.

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

• Is for reproductive use. 13

Due to the ongoing development of new products and clinical trials, the field of FDA regulatory requirements is evolving. It is the expectation that the respective Medicare Administrative Contractor will continue to follow any guidance as it is issued by the FDA.

Lack of standard formulation, dose, frequency of administration, and standard of care in treatment with these products further complicates regulation and guidance determinations.

Despite this lack of standardization, numerous amniotic and placental-derived products have been released for use in treatment of musculoskeletal conditions. These conditions include, but are not limited to tendon/ligament injuries, musculoskeletal injuries, cartilage damage, osteoarthritis, or pain related of these conditions as well as adjunctive orthopedic surgical treatments. Due to the lack of component standardization, the remainder of this LCD will use the term amniotic and placental-derived products to mean ANY product derived from ANY combination of amniotic membrane/chorion/placenta/Wharton’s jelly/umbilical cord/amniotic fluid/umbilical cord blood.

Although amniotic and placental-derived products are marketed to treat certain musculoskeletal conditions, there is limited available support for safety and efficacy from human clinical trials.

Literature Inclusion/Exclusion Protocol

A comprehensive literature search of PubMed was performed. Only full text published studies of musculoskeletal conditions were included. Individual papers within systematic reviews were analyzed. Included in this review are (1) study designs that evaluated the efficacy, safety, quality of life, and reported on at least 10 adult participants, (2) that evaluated the non-wound treatment of a musculoskeletal disorder, (3) with the use of any type of amniotic/placental derived product injections and/or applications, and (4) those reporting at least one patient-important outcome [e.g., pain, function, quality of life].

A total of 25 studies were included in the summary of the evidence. More than 90% of the included studies were industry sponsored, disclosed potential conflicts of interest, or the funding source was not disclosed. Five level I (RCT) studies were identified and analyzed for risk of bias and certainty of evidence. Sixteen non-randomized studies were reviewed. There were seven systematic reviews, two included meta-analyses. These included primary studies that were already identified within the search parameters.

Studies were classified into the following regional musculoskeletal categories: general musculoskeletal, spine, upper extremity, lower extremity tendinopathies, and lower extremity osteoarthritis. Outcome groups were designated as efficacy, safety, and self-reported measures of quality of life, well-being, or satisfaction. Follow-up periods were classified as short-term: 12 weeks and 12 months.