Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)

CMS National Coverage PolicyTitle XVIII of the Social Security Act, 1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.Title XVIII of the Social Security Act, 1862(a)(1)(D) addresses services that are determined to be investigational or experimental.CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 16, 10 General Exclusions from CoverageCMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 23, 30A Physicians ServicesCMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 30, 50.3.1 Mandatory ABN UsesCoverage Indications, Limitations, and/or Medical NecessityThis is a NON-coverage policy for allamniotic membrane, amniotic fluid or other placental-derived productinjections 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 TransplantationIntroductionAmniotic 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.1In 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 engineeringmembrane covering for certain burns, wounds, and ophthalmic corneal injuriesmicronized/particulate products suspended in an aqueous material to be applied topically or injected into joints, tendons, ligamentsapplications or injections performed intra-operatively to promote post-operative healingThese 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.2The 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 Whartons jelly.3Definitions:ThePlacentais 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 gestationChorion- outermost membrane that surrounds the fetus during gestationAmniotic fluidis the fluid surrounding the fetus within the amnion.Umbilical cordis the vascular conduit connecting the fetus to the placenta comprised of the umbilical vein, arteries, allantois and yolk sac embedded in Whartons jelly.Whartons Jellyis a gelatinous soft connective tissue derived from extra-embryonic mesoderm within the umbilical cord.4Theamniotic membraneitself is divided into three histologic layers:A singleepithelial layerA thickbasement membraneAnavascular stromal (mesenchymal) layer5.6,7,8The avascular stromal layer is further divided into three layers:6,7,8TheCompact layerThe middleFibroblast layerTheSpongy layerTheSpongy 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.5,6,8,9Themiddle Fibroblast layeris made up of type I, III, V, and VI collagen.6,8,9TheCompact layerthat sits adjacent to the basement membrane is composed of collagen Types I, III, V, and VI, along with fibronectin.5,9Thebasement membraneanchors the epithelial layer (ref 13) and contains collagen Types IV, V and VII, fibronectin, laminin, and hyaluronic acid.6,10Adjacent to the basement membrane and in immediate contact with amniotic fluid is the single layer of epithelial cells.Amniotic epithelial cellsproduce type III and IV collagen, glycoproteins such as laminin and fibronectin, which become the basement membrane.5The amniotic membranes 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 (maternal 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.8,9Amniotic fluid also is found to contain amniotic mesenchymal stem cells.7The chorionic membrane adjacent to the mothers endometrium during development of the fetus. Umbilical cord, Whartons jelly, and umbilical cord blood have also been found to contain mesenchymal stem cells.7,11Under 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.10Other 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,  (gamma)-sterilization, low heat dehydration, and vitrification.5,8,9,10A process called Decellularization may be used in which the layer of amniotic epithelial cells is removed from the collected amniotic membrane, leaving behind the valuable extracellular matrix components. Removal of all cellular components is thought to lessen the possibility of eliciting an immune response.3,10Different 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.3,5Lack of consistency and standardization within propriety manufacturing (preparation) processes precludes determination and comparison of the final product form, characteristics, properties, and components.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/Ps. Once these types products are harvested, their process 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 (NDA) New Drug application, an (IND) Investigational New Drug application, or a (BLA) Biologics License Approval.8,9,12,13If a human cells or tissue product should meet 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 ManipulatedIntended for Homologous Use (as reflected by the labeling, advertising, or other indications of the manufacturers objective intent)The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/PEither:The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; orThe 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; orIs for reproductive use12Due to the ongoing development of new products and clinical trials, the field of FDA regulatory requirements is fluid and evolving. It is the expectation that the respective Medicare Administrative Contractor will continue to follow any guidance and insight as it is brought forward 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 an adjunctive to 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/Whartons jelly/umbilical cord/amniotic fluid/umbilical cord blood.Although amniotic and placental-derived products are marketed to treat certain musculoskeletal conditions, there is limited support for safety and efficacy from human clinical trials available.All injectable amniotic and/or placental-derived products fall under FDA section 551 of the Federal Food, Drug, and Cosmetic Act. Promotion relating to novel indication or evidence of new intended use may constitute labeling, adulteration, or misbranding of the drug or device if such dissemination fails to comply with section 551 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa) and the requirements of this part. A manufacturers failure to exercise due diligence in submitting the clinical studies necessary for the approval of a new use as subject of information disseminated under this part or in beginning or completing such clinical studies shall be deemed a failure to comply with section 551 of the act and the requirement of this part. Use of any amniotic and/or placental-derived products that have not met the requirements of section 551 of the Federal Food, Drug, and Cosmetic Act will be denied per Medicare Benefit Policy Manual 100-2 Chapter 15 Section 50.4.1 and associated services will also be denied per Medicare Benefit Policy Manual 100-2 Chapter 16 Section 180.General InformationAssociated InformationN/ASources of InformationN/ABibliographyZakrzewski W, Dobrzynski M, Szymonowicz M, and Rybak Z. Stem Cells: Past, Present, and Future. Stem Cell Research & Therapy 2019 10:68.doi:10.1186/s13287-019-1165-5Dhillon MS, Behera P, Patel S, and Shetty V. Orthobiologics and Platelet Rich Plasma. Indian J of Orthop. 2014 Jan-Feb; 48(1):1-9.doi:10.4103/0019-5413.125477