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

Title 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

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §50.4.1 Approved Use of Drug

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 16, §10 General Exclusions from Coverage, §140 Dental Services Exclusion, and §180 Services Related to and Required as a Result of Services Which Are Not Covered Under Medicare

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations Manual, Chapter 1, Part 2, §110.23 Stem Cell Transplantation

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 the Centers for Medicare & Medicaid Services (CMS) National Coverage Determination (NCD) §110.23 Stem Cell Transplantation.

Introduction

Amniotic and placental-derived products are known to possess certain beneficial characteristics. These products have been identified 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 heavily marketed as allografts that serve as:

• scaffolds for tissue engineering
• membrane covering 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 non-operative 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 to heal injury/trauma and/or slow down degenerative conditions if not effectuate 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 caesarean-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:

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 cord 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 3 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 3 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 (HA), 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 and contains collagen types IV, V and VII, fibronectin, laminin, and HA.^6,10

Adjacent to the basement membrane and in immediate contact with the 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 in turn form the basement membrane.⁵

The amniotic membrane’s purpose is to house and physically protect the fetus, but some 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 identified as sources 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.^8,9 Amniotic fluid also is found to contain amniotic mesenchymal stem cells.⁷

The chorionic membrane connected adjacent to the mother’s endometrium during the 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. From there, 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 transmittable from donor to recipient.

Because the spongy layer loosely connects the amniotic membrane to the chorionic membrane, these 2 layers are easily separated upon initial harvesting by blunt dissection.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 which portions of the placental tissues are utilized, what sterilization processes (if any) are undertaken, and what method of preservation is used. Common methods of preservation include cryopreservation, lyophilization (freeze-drying), glycerol-preservation, γ (gamma)-sterilization, low heat dehydration, and vitrification, to name a few.^5,8,9,10

A 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 ECM components. By removing all cellular components, it is thought that there is less possibility of eliciting an immunogenic response.^3,10 Different decellularization processes are available. Finally, preparation in the form of sheets, cutting into small particulates, processing into a liquid form, along with re-suspension in varying solutions are additional steps that may occur in order to reach the desired final product.

Depending on the methods utilized, the processing of placental and amniotic-based tissues into their final form will affect the viability of cellular components, growth factors, and other valuable properties that these tissues are known for. To date, there are significant differences that exist in the processing of different placental and amniotic-based tissue products.^3,5 Further complicating matters, some manufacturers have their own “proprietary” manufacturing processes, which make it impossible to determine if there is any consistency and standardization in the final product form, characteristics, properties, and components.

Further complicating matters is the fact that there is no standard formulation, dose, or frequency of administration available or considered standard of care in treatment with these types of products.

Despite this lack of standardization in composition, dosing, or administration, numerous amniotic and placental-derived products are flooding the market 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 adjunct in orthopedic surgical treatments. In light of the lack of standardization of composition, the remainder of this Local Coverage Determination (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 only a paucity of accompanying human clinical trials available regarding safety and efficacy.

Literature Inclusion/Exclusion Protocol

A comprehensive literature search of PubMed was performed. Only full text published studies of the musculoskeletal conditions listed below were included. Individual papers within systematic reviews were analyzed. Relevant clinical studies with at least 10 patients per group not included in the systematic reviews were also reviewed. Four level I randomized controlled trial (RCT) studies were identified and analyzed for certainty of evidence and risk of bias. There were 6 systematic reviews and 2 meta-analyses examined. These included studies that were already identified with the search parameters. Eleven non-randomized studies were reviewed. Weakness in the literature included lack of standardization of these products, heterogeneous applications (or intended uses), variations in length of treatment/follow up, lack of comparators/controls, and high risk of bias due to lack of blinding, allocation concealment, publication bias, as well as conflicts of interests by authors. While there was a trend toward a positive benefit for amniotic and placental-derived product injections, the evidence is insufficient to determine efficacy or safety for musculoskeletal indications. While studies did not report adverse effects other than pain with injections, they were not adequately powered or designed to access safety and long-term outcomes.

NOTE: The musculoskeletal conditions listed below were the currently identified conditions discussed within that resulting body of evidence. Other musculoskeletal conditions not singled out in this evidentiary analysis section were those without a critical mass of reviewable literature.

Tendinopathies

This review is notable that the current body of evidence for amniotic and placental-derived products used in the treatment of musculoskeletal applications is heavily based in in-vitro and animal studies, with little to no human clinical data. The level of evidence reviewed was not adequate for a systematic review or meta-analysis.

Four clinical studies were investigating the effect of amniotic and placental-derived products on tendinopathies.^6,8,12,13 Case series were reviewed but omitted from consideration since they lacked sufficient quality to inform the coverage determination. Due to this study design, no causal relationship between the intervention and outcomes can be determined. Additionally, the small heterogeneous patient population severely limits the methodological rigor resulting in significant concerns for systemic bias.^13,14 Furthermore, Quinet, et al. had no control arm, and therefore no comparator.¹⁴ Huddleston, et al. was excluded from the certainty and risk of bias analysis due to lack of patient outcomes.⁶ Riboh, et al. was excluded from analysis because there were too few human studies obtained from a non-systematic search.⁸ Ackley, et al. evaluated the effect of amniotic product on rotator-cuffs¹²; however, this study was excluded from certainty and risk of bias analysis because it was a case series with no control arm and a relatively small patient population. Based on the evidence reviewed, there is no way to conclude with any degree of certainty that amniotic and placental-derived products have a net positive health outcome in patients with tendinopathies.

Plantar Fasciitis

There were 4 clinical studies investigating the effects of amniotic and placental-derived products on plantar fasciitis. Cazzell, et al. demonstrated improvement in Visual Analogue Scores (VAS) for pain at 3-months, and mean VAS scores were significantly (76%) lower in the amniotic product (dehydrated human amnion/chorion membrane (dHACM)) group when compared to controls (45% lower).¹⁵ Though P < 0.0001 is reported, there were no t-statistics, effects sizes, and the confidence intervals for overall effect were not reported. As a result, there is no way to establish whether the treatment was the cause of the observed effect. The mean age for the groups studied was 49 and 53, therefore results reported may not be generalizable to the Medicare population. Zelen, et al. published an industry-sponsored study to investigate the effect of injecting amniotic products at 8 weeks and reported improvement in pain scores, functional health, and well-being in groups receiving amniotic products versus placebo.¹⁶ The median pain score from the 0.5 cc micronized dHACM group was 50% that reported by controls at 1 week (P < 0.001), 40% at 4 weeks (P < 0.001), and 25% at 8 weeks (P < 0.001). The median pain score from the 1.25 cc micronized dHACM group was 50% that reported by controls at 1 week (P = 0.002), 20% at 4 weeks (P < 0.001), and 25% at 8 weeks (P < 0.001). No differences were apparent in pain scores between the micronized dHACM groups. In both micronized dHACM groups, significant improvement was observed at study completion for both physical and mental well-being. The study is challenged by small sample sizes, lack of reporting of major comorbidities, and lack of blinding of the investigator creating a risk of bias. There is insufficient evidence to support the use of amniotic and placental-derived injections for plantar fasciitis.

Osteoarthritis (OA) of the Knee

Seven clinical studies investigating the effects of amniotic products on OA of the knee were identified, but there was only 1 RCT and the literature consisted largely of cases series. Farr, et al. published a patient-blinded multicenter randomized controlled comparative trial.¹¹ They investigated the use of amniotic fluid cells and amniotic membrane particulate (amniotic suspension allograft (ASA)) for the treatment of OA of the knee, comparing outcomes with saline (placebo) and HA. They report statistically significant differences between ASA and HA at 3 months, including EQ-5D-5L pain and anxiety subsets; Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, and activity of daily living (ADL) subsets; and VAS scores for overall pain, pain during strenuous work, and pain during normal daily living. They conclude the treatment with ASA was superior to HA and placebo. In addition, ASA was significantly better than saline at 3 months in the KOOS symptoms subsets. Though significant conflict of interest (COI) was reported, the multicenter trial design and statistical analysis indicated no discernable response by treatment for the different site groups and no significant difference in patients withdrawn at 3 months. This indicates no significant outcome bias by the investigators with COI. Statistical analysis at 6 months could not be performed due to the significant rate of attrition in the placebo group due to withdrawal because of unacceptable pain. Alden, et al., a retrospective case series, reviewed abstracted data from the medical records of 82 OA patients and 100 knees injected with micronized dHACM.¹⁷ An improvement in the KOOS of at least 10 points was considered to represent meaningful positive clinical change. At 3- and 6-months post-injection, 55 and 63% of patients, respectively, reported clinically meaningful improvement in daily living, pain, quality of life, sport/recreation, and symptoms. Castellanos, et al. conducted a non-randomized prospective case series of 20 patients over 24 weeks to evaluate the safety and effectiveness of intra-articular injection of amniotic/umbilical cord (AMUC) particulate in patients presenting with refractory knee OA pain.¹⁸ They showed that the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function, stiffness, and global scores improved with a p-value < 0.01. Though they noted this effect was not sustained in obese patients. Another case series by Vines, et al. demonstrated improvement in knee pain.¹⁹ Despite a trend towards positive findings, the retrospective study design and significant risk of bias among these studies indicates that there is insufficient evidence to be certain there is a clinical efficacy or long-term safety regarding these products for OA.

Chronic Back Pain

There was only 1 clinical study based on the literature search parameters published to evaluate the effects of amniotic and placental-derived products for back pain. In a case series, Buck, et al. studied 11 patients with discogenic pain, treating them with 50 mg and 100 mg of amniotic membrane and umbilical cord particulate solution.²⁰ Before treatment, all patients reported severe pain, and 10 patients took opioids daily. After treatment, the median reported pain relief was 40%, 50%, and 75% at 1-month (n=6), 3 months (n=8), and 6 months (n=5), respectively. Complete pain relief was noted in 1 patient; however, 2 patients (18%) reported no pain relief at 1 and 3 months. No adverse events, repeated procedures, or complications occurred. There is a high degree of uncertainty regarding the treatment effect due to severe selection bias (6 out of 11 patients were without results reported at 6 months, and only 2 patients had data reported for all time periods studied) and the extremely small sample size.

Due to the high degree of uncertainty, meaningful conclusions regarding the efficacy of amniotic and placental-derived injections for back pain remain elusive.

Trigger Finger

In a single case series, Quinet, et al. hypothesized that amniotic fluid injections could serve as a conservative treatment for trigger finger resulting in pain reduction and triggering frequency in patients with mild (able to be actively extended) to moderate (able to be passively extended) trigger finger.¹⁴ Participants were injected with 1 mL amniotic fluid into the sheath of the affected tendon. Before administering the initial amniotic fluid therapy (AFT) injection, baseline triggering frequency, numerical pain rating scale scores (0-10), and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores (1-100) were recorded. The DASH score served as an indication of the patient’s upper-extremity function. Triggering frequency was determined by asking about the frequency of triggering based on the number of times per day or per hour the subject experienced locking or catching. Ninety-six patients (48 men and 48 women, average age 65 ± 11 years) participated in the study. A total of 111 digits received amniotic fluid injections. Pain scores, triggering per day, and DASH scores decreased significantly from baseline to 5 or more months (P < 0.001). There were no episodes of locking or catching reported after injections. While these outcomes may seem promising, the absence of controls and high risk of bias requires further investigation to determine clinical significance.

Systematic Reviews

The literature search parameters generated 6 systematic reviews evaluating amniotic or a combination of amniotic and additional placental-derived products.

Tsikopoulos, et al. performed a meta-analysis on studies examining various injection therapies, including amniotic products for the treatment of plantar fasciitis.²¹ They found that the dehydrated amniotic membrane had the highest probability of being among the best injection treatments for pain in the short term (0-2 months). This was the data from only 1 RCT performed in the United States (U.S.), which we reviewed.¹⁶ Investigators concluded that the dehydrated amniotic membrane was the injection therapy with the highest probability of being superior to placebo injection over 8 weeks; however, additional randomized trials with longer follow-up are necessary to get more precise estimates about the relative efficacy of this intervention.

Riboh, et al. reported that most of the evidence studying these products was heavily biased toward in vitro and animal studies with little to no human clinical data.⁸ In fact, they determined that the level of evidence obtained from their literature search was inadequate for a systematic review or metanalysis. The authors concluded that little to no research has been done on the effect of amniotic membrane-derived products on intended clinical use and caution against any assumptions regarding the equivalency of the different formulations studied. The most recent systematic review echoed these findings, concluding that clinical trials remain extremely limited, and the current evidence should be interpreted with caution.⁶

McIntyre, et al. performed a systematic review of both animal and human studies reporting the use of placental-derived therapeutics for musculoskeletal conditions. However, there were only 6 human studies. The studies had a high degree of variability in placental cell types-amniotic and non-amniotic components, placental tissue preparation, routes of administration, and treatment regimens such that no conclusions could be made regarding efficacy.⁷ Safety, however, they concluded appeared acceptable. However, long-term follow-up data was not available.

Sultan, et al. published 2 systematic reviews, 1 for non-operative applications and another for operative ones.^3,22 For non-operative applications, the majority of the reviewed studies (3 of 5) lacked a comparative cohort, resulting in lower confidence in the reported effect size observed by these studies.^13,23,24 In addition, the 2 studies that were comparative did not fully compare outcomes to conservative rehabilitation modalities of treatment.^16,25 The authors concluded that despite the progress in the field, the applications are in their infancy, and more research is needed to explore their full potential. For operative applications, all studies reviewed were low level of evidence and insufficient to determine the efficacy of amniotic and placental-derived products.

Certainty of Evidence

The best evidence available has serious limitations due to an absence of blinding, control or sham arms, randomization, and allocation concealment methods. Additionally, there are concerns for publication bias, as there are multiple large multicenter trials that were registered to Clinicaltrials.gov but without results posted or published to date. Due to study design, lack of standardization of human amniotic fluid/membrane and placental-derived product injections used (including processing, content, and storage), and small patient population studied to date; there is little certainty that these products have a net positive health outcome in patient populations with similar demographics as Medicare beneficiaries. As a result of ongoing clinical trials, we will continue to monitor the evidence for further developments.

Contractor Advisory Committee (CAC) Evidentiary Review- 5/12/2021

Noridian Healthcare Solutions hosted a multi-jurisdictional CAC meeting to review the evidence on amniotic and placental-based tissue products injections/application for the treatment of musculoskeletal conditions for both non-operative and operative clinical situations. There was a paucity of peer-reviewed literature found on other uses outside of musculoskeletal, burns, wounds, or ophthalmic use, indicating the highly investigational status of such uses. However, those identified references were provided for evidentiary review.

Subject matter experts (SMEs) from hematology/oncology specializing in stem cell transplant, podiatry, orthopedic, physical medicine & rehabilitation, anesthesiology, and rheumatology were represented. All literature submitted by the SMEs to supplement the reference list was also reviewed.

Initial discussion involved the subject of FDA labeling and concerns for erroneous interpretation of FDA regulations surrounding HCT/Ps. SME concerns included the lack of FDA oversight of those amniotic and placental-derived products that have been exempt of pre-market FDA review and approval, as well as the lack of standardization of product content, various processing methods, and paucity of human clinical trials that demonstrated safety and efficacy in general.

The discussions were separated by general conditions or groupings of conditions. These groupings were also based on the actual clinical literature on specific musculoskeletal conditions available for review in which placental/amniotic-based tissue products were utilized as treatment options.

The topics of discussion included:

• General concepts
• FDA labeling/product safety
• OA of the knee, hip, and other joints
• Plantar Fasciitis/Achilles tendinopathies/tendinitis
• Rotator Cuff tears, patellar tendinopathies/tendinitis, lateral epicondylitis, carpal tunnel syndrome, and trigger finger
• Low back pain (including intradiscal and facet joint-related back pain) and cervical facet joint pain

Overall, the panel of SMEs determined that while confidence in short term safety of the discussed musculoskeletal conditions was higher compared to long-term safety, short/intermediate/long-term efficacy, and short/intermediate/long-term post-operative outcomes; all areas were rated low in confidence of the evidence currently available for amniotic and placental-derived injections/applications to treat musculoskeletal conditions.

Rationale for Determination

Due to the paucity of RCTs, poor study designs, small sample sizes, lack of comparators, lack of long-term efficacy and safety data, and high risk of bias in the current body of literature, there is insufficient evidence to demonstrate the efficacy of any amniotic and placental-derived product in the treatment of specific musculoskeletal conditions, whether injected or applied intra-operatively. There is a lack of knowledge of intermediate or long-term safety data derived from human clinical trials.

In addition, based on the available human clinical trials reviewed, there is no consistent formulation, method of delivery, or administration studied to allow for a determination of a standard dosing schedule nor frequency, nor efficacy that can translate across different products. This applies to both non-operative and operative injections/applications used for the treatment of musculoskeletal conditions. For a treatment to be considered medically reasonable and necessary per §1862(a)(1)(A) of the Social Security Act (SSA), the treatment must be appropriate, including duration and frequency furnished in accordance with accepted standards of medical practice for the condition. Therefore, this contractor concludes that the existing evidence and lack of accepted standards of medical practice for amniotic and placental-derived product injections and/or applications do not meet the requirement of medically reasonable and necessary.

Other musculoskeletal conditions that are not referenced in this LCD are due to their lack of acknowledgment in any peer-reviewed literature and are therefore considered investigational and not covered by Medicare.

In conclusion, there is insufficient evidence-based literature to support coverage of amniotic and NON-amniotic placental-derived products injected or applied both non-operatively and intra-operatively to treat musculoskeletal conditions or pain related to said conditions as any other condition that is not burn, wound, or ophthalmologic treatment.

NOTE: In accordance with the CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 16, §140 Dental Services Exclusion, any use of these products for dental conditions is not considered a benefit.

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15. Cazzell S, Stewart J, Agnew PS, 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.
16. Zelen CM, 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.
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• Amniotic
• Placental-Derived
• Musculoskeletal Indications