evekhm/cms_iom_500 huggingface dataset:
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
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 use12
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Due 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.
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
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.
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
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:10.4103/0019-5413.125477Sultan AA, Piuzzi NS, Mont MA. Nonoperative Applications of Placental Tissue Matrix in Orthopaedic Sports Injuries: A Review of Literature. Clin J Sport Med. Jul 2020;30(4):383-389. doi:10.1097/jsm.0000000000000684Gabbe SG, Niebyl JR, Simpson JL, et al. Obstetricsnormal and problem pregnancies. 5th ed. Philadelphia: Churchill Livingstone; 2007.Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM. Properties of the Amniotic Membrane for Potential use in Tissue Engineering. European Cells and Materials. Vol. 15 2008. Pg 88-99.doi:10.22203/ecm.v015a07Huddleston HP, Cohn MR, Haunschild ED, Wong SE, Farr J, Yanke AB. Amniotic Product Treatments: Clinical and Basic Science Evidence. Curr Rev Musculoskelet Med. 2020 Apr;13(2):148-154. PMID: 32076938McIntyre JA, Jones IA, Danilkovich A, Vangsness CT Jr.McIntyre JA, et al. The Placenta: Applications in Orthopaedic Sports Medicine. Am J Sports Med. 2018 Jan;46(1):234-247.
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Riboh JC, Saltzman BM, Yanke AB, Cole BJ. Human Amniotic Membrane-Derived Products in Sports Medicine: Basic Science, Early Results, and Potential Clinical Applications. Am J Sports Med. 2016 Sep;44(9):2425-34.Hannon CP, Yanke AB, Farr J. Amniotic Tissue Modulation of Knee Pain-A Focus on Osteoarthritis. J Knee Surg. 2019 Jan;32(1):26-36. doi:10.1055/s-0038-1676370Leal-Marin S, Kern T, Hofmann N, Pogozhykh O, Framme C, Brgel M, Figueiredo C, Glasmacher B, Gryshkov O. Human Amniotic Membrane: A review on tissue engineering, application, and storage. J Biomed Mater Res. 2021;118. doi.org/10.1002/jbm.b.34782Farr J, Gomoll AH, Yanke AB, Strauss EJ, Mowry KC. A Randomized Controlled Single-Blind Study Demonstrating Superiority of Amniotic Suspension Allograft Injection Over Hyaluronic Acid and Saline Control for Modification of Knee Osteoarthritis Symptoms. J Knee Surg. Nov 2019;32(11):1143-1154. doi:10.1055/s-0039-1696672FDA Guidance for Industry and Food and Drug Administration Staff. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use. 2020 July.Guidance for Industry Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Small Entity Compliance Guide. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. 2007 Aug.Gellhorn A.C., Han A. The use of dehydrated human amnion/chorion membrane allograft injection for the treatment of tendinopathy or arthritis: a case series involving 40 patients.PM&R. 2017;9(12):1236-1243. doi:10.1016/j.pmrj.2017.04.011
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Buck D. Amniotic umbilical cord particulate for discogenic pain.Am. Osteopath. Assoc.2019;119(12):814-819. doi:10.7556/jaoa.2019.138Ross A, Gambrill V, Main C. Clinical outcomes of amniotic membrane/umbilical cord particulate in spinal disorders: a retrospective study.J Pain Res. 2022;15:3971-3979. doi:10.2147/JPR.S375201, 10.2147/JPR.S375201Ackley JF, Kolosky M, Gurin D, Hampton R, Masin R, Krahe D. Cryopreserved amniotic membrane and umbilical cord particulate matrix for partial rotator cuff tears: A case series. Medicine (Baltimore). Jul 2019;98(30):e16569. doi:10.1097/md.0000000000016569Aufiero, D, Sampson, S, Onishi, K, and Bemden, V. Treatment of medial and lateral elbow tendinosis with an injectable amniotic membrane allografta retrospective case series.J Pain Relief. 2016;5(3):242.Quinet MT, Raghavan M, Morris E, et al. Effectiveness of amniotic fluid injection in the treatment of trigger finger: a pilot study.Journal of Hand Surgery Global Online. 2020;2(5):301-305.Cazzell S., Stewart J., Agnew P.S., et al Randomized controlled trial of micronized dehydrated human amnion/chorion membrane (dHACM) injection compared to placebo for the treatment of plantar fasciitis.Foot Ankle Int. 2018;39(10):1151-1161. doi:10.1177/1071100718788549
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Zelen C.M., Poka A., Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis - A feasibility study.Foot Ankle Int. 2013;34(10):1332-1339. doi:10.1177/1071100713502179Hanselman A.E., Tidwell J.E., Santrock R.D. Cryopreserved human amniotic membrane injection for plantar fasciitis: A randomized, controlled, double-blind pilot study.Foot Ankle Int. 2015;36(2):151-158. doi:10.1177/1071100714552824Matthews M, Betrus CJ, Klein EE, et al. Comparison of Regenerative Injection Therapy and Conventional Therapy for Proximal Plantar Fasciitis.J Foot Ankle Surg. 2022;doi:10.1053/j.jfas.2022.11.010, 10.1053/j.jfas.2022.11.010Nakagawa H, Sung K, Ashkani-Esfahani S, et al. Plantar fasciitis: a comparison of ultrasound-guided fasciotomy with or without amniotic membrane allograft injection.Med. 2022;17(12):931-940. doi:10.2217/rme-2022-0094Werber B: Amniotic tissues for the treatment of chronic plantar fasciosis and Achilles tendinosis.J Sports Med(Hindawi Publ Corp) 2015;2015:219896Lullove E. A flowable placental tissue matrix allograft in lower extremity injuries: a pilot study. 2015;7:e275.Spector JE, Hubbs B, Kot K, et al. Micronized dehydrated human amnion/chorion membrane injection in the treatment of chronic Achilles tendinitis.J Am Podiatr Med Assoc. 2021;111(6)doi:10.7547/19-170, 10.7547/19-170
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Gomoll A.H., Farr J., Cole B.J., et al. Safety and efficacy of an amniotic suspension allograft injection over 12 months in a single-blinded, randomized controlled trial for symptomatic osteoarthritis of the knee.J. Arthrosc. Relat. Surg.2021;37:22462257. doi: 10.1016/j.arthro.2021.02.044.elik D, oban , Kilioglu . Minimal clinically important difference of commonly used hip-, knee-, foot-, and ankle-specific questionnaires: a systematic review.J Clin Epidemiol. 2019;113:44-57. doi:10.1016/j.jclinepi.2019.04.017McCarthy M Jr, Chang CH, Pickard AS, et al. Visual analog scales for assessing surgical pain.J Am Coll Surg. 2005;201(2):245-252. doi:10.1016/j.jamcollsurg.2005.03.034Landorf KB, Radford JA, Hudson S. Minimal important difference (MID) of two commonly used outcome measures for foot problems.J Foot Ankle Res2010;3(1):7.Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale.Ann Emerg Med2001;38(6):633-638.Alden KJ, Harris S, Hubbs B, et al. Micronized dehydrated human amnion chorion membrane injection in the treatment of knee osteoarthritis  a large retrospective case series.J Knee Surg. 2021;34(8):841-845. doi:10.1055/s-0039-3400951, 10.1055/s-0039-3400951Castellanos R, Tighe S. Injectable amniotic membrane/umbilical cord particulate for knee osteoarthritis: a prospective, single-center pilot study.Pain Med. 2019;20(11):2283-2291. doi:10.1093/pm/pnz143
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Mead OG, Mead LP. Intra-articular injection of amniotic membrane and umbilical cord particulate for the management of moderate to severe knee osteoarthritis.Res. Rev.2020;12:161170. doi: 10.2147/ORR.S272980.Natali S, Farinelli L, Screpis D, et al. Human amniotic suspension allograft improves pain and function in knee osteoarthritis: a prospective not randomized clinical pilot study.Clin. Med. 2022;11(12)doi:10.3390/jcm11123295,10.3390/jcm11123295Meadows MC, Elisman K, Nho SJ, et al. A single injection of amniotic suspension allograft is safe and effective for treatment of mild to moderate hip osteoarthritis: a prospective study. 2022;38:325331. doi: 10.1016/j.arthro.2021.04.034.Guimaraes JDS, Arcanjo FL, Leporace G, et al Effects of therapeutic interventions on pain due to plantar fasciitis: A systematic review and meta-analysis.Rehabil. 2022;no pagination. doi:10.1177/02692155221143865Zaffagnini M, Boffa A, Andriolo L, et al. Orthobiologic injections for the treatment of hip osteoarthritis: a systematic review.J Clin Med. 2022;11(22):6663. Published 2022 Nov 10. doi:10.3390/jcm11226663Aratikatla A, Maffulli N, Rodriguez HC, et al. Allogenic perinatal tissue for musculoskeletal regenerative medicine applications: a systematic review protocol. J. Orthop. Surg.2022;17(1):307. doi:10.1186/s13018-022-03197-z,10.1186/s13018-022-03197-z
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39116)
Sultan AA, Samuel LT, Roth A, et al. Operative Applications of Placental Tissue Matrix in Orthopaedic Sports Injuries: A Review of the Literature.Surg Technol Int.2019;34:397-402.McIntyre JA, Jones IA, Danilkovich A, Vangsness CT. The placenta: applications in orthopaedic sports medicine.J. Sports Med. 2018;46(1):234-247. doi:10.1177/0363546517697682Tsikopoulos K, Vasiliadis HS, Mavridis D. Injection therapies for plantar fasciopathy ('plantar fasciitis'): A systematic review and network meta-analysis of 22 randomised controlled trials.J. Sports Med. 2016;50(22):1367-1375. doi:10.1136/bjsports-2015-095437Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials.BMJ. 2019;366:l4898. Published 2019 Aug 28. doi:10.1136/bmj.l4898Schnemann H, Brozek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013.The GRADE Working Group, 2013. Available fromguidelinedevelopment.org/handbook.
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39118)
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 that serve as:
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39118)
scaffolds for tissue engineeringmembrane covering 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 end result ideally would be decreased pain and increased function. One such category of orthobiologics involves 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 gestation
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39118)
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 3 histologic layers:A singleepithelial layerA thickbasement membraneAnavascular stromal (mesenchymal) layer5.6,7,8The avascular stromal layer is further divided into 3 layers:6,7,8TheCompact layerThe middleFibroblast layerTheSpongy layer
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39118)
TheSpongy 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 connected 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.7,11
Proposed LCD - Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (DL39118)
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.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.