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

This LCD supplements but does not replace, modify, or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for amniotic and placental-derived product injections and/or applications for musculoskeletal indications, non-wound. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify, or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations, and rules for Medicare payment for amniotic and placental-derived product injections and/or applications for musculoskeletal indications, non-wound and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Pub. 100-02, Medicare Benefit Policy Manual,
  • Chapter 16, Section 10 General Exclusions from Coverage
• CMS IOM Pub. 100-04, Medicare Claims Processing Manual,
  • Chapter 23, Section 30A Physician’s Services
  • Chapter 30, Section 50.3.1 Mandatory ABN Uses

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, §1862(a)(1)(A) states that no Medicare payment may be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.

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 and joint conditions.

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.

NOTE: In accordance with the Internet Only Manual, Chapter 16 of the Medicare Benefit Policy Manual, Section 140, General Exclusions from Coverage, any use of these products for dental conditions is not considered a benefit.

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 is rich in collagen, glycoproteins, proteoglycans, fibroblasts, as well as many cytokines and growth factors thought to promote healing with a lower risk of 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 refers 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 primordial mucous connective tissue of the umbilical cord present between the amniotic epithelium and the umbilical vessels.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 - sits adjacent to the basement membrane and is composed of collagen Types I, III, V, and VI, along with fibronectin.^5,9

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

• 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 basement membrane anchors the epithelial layer¹⁴ 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.⁶

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.^3,5,10

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.⁸

The chorionic membrane is 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 2 layers are easily separated upon blunt dissection at initial harvesting.¹ 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 proprietary 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 devoid 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/Ps”. 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 HCT/P 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:

1. Minimally Manipulated, and
2. Intended for Homologous Use (as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent), and
3. 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, and
4. Either:
1. 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
2. The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
1. Is for autologous use.
2. Is for allogeneic use in a first-degree or second-degree blood relative.
3. 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 to 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.

All amniotic and placental-derived products are considered not reasonable and necessary for the treatment of any musculoskeletal condition.

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 study designs that evaluated efficacy, safety, and quality of life; reported on at least 10 adult participants; evaluated the non-wound treatment of a musculoskeletal disorder that used amniotic/placental derived product injections and/or applications; and documented at least 1 patient-important outcome [e.g., pain, function, quality of life].

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; Intermediate-term: >12 weeks and <12 months; and Long-term: ≥12 months.

The musculoskeletal conditions identified in the above paragraph are the currently identified conditions discussed within the resulting body of evidence. Other musculoskeletal conditions that are not specified in this evidentiary analysis section are those without a substantial amount of reviewable, valid, or relevant literature.

The 36 studies included in the summary of evidence were composed of 7 randomized control trial (RCT) studies, 16 non-randomized studies, 1 prospective observational study, 9 systematic reviews, and 3 meta-analyses. 

EFFICACY

General Musculoskeletal

A single case series (n=40; mean age 51 years) observed participants with various musculoskeletal joint pathologies or tendinopathies after receiving an injection of micronized dehydrated human amnion/chorion membrane.¹⁵ “Overall pain” achieved clinically relevant improvement at all follow-up time points (1, 2, and 3 months). At 3 months assessment, functional outcomes (activities of daily living, and sports and recreation) were clinically improved.

The certainty of the evidence for this case series was determined to be very low as there was the absence of a control or comparator group, a small sample size, a heterogeneous population, and a lack of study participants with similar ages and demographics of the Medicare population. Moreover, the durability of functional outcomes assessed is unknown due to the limited follow-up time.

Spine

Two retrospective case series (the first one n=11, ages not provided; the second one n=52, mean age 41 years) that described patients with cervical and lumbar discogenic spine-related disorders.^16,17 Both studies employed injections of amniotic membrane umbilical cord tissue. Pain outcomes (percentage relief, verbal rating of intensity) were described in the short- and intermediate-terms. The results were mixed for patient-reported pain relief rated as a percentage from 0 (no pain relief) to 100 (complete relief): with mean percentages of 38.3%, 45.6%, and 55.8% at 1, 3, and 6 months.¹⁶ Verbal ratings of pain did not reveal clinical improvement at weeks 2, 3-4, 6, and 8; whereas, trivial to moderate improvement in verbal pain rating was recorded at 10.6 weeks follow-up.¹⁷

One randomized control trial was reviewed involving the safety and efficacy of the simultaneous use of umbilical cord products with an injectable parathyroid hormone medication in female patients with osteoporotic vertebral compression fractures.¹⁸ Twenty trial participants met inclusion criteria. Ten patients with an average age of 70.5 years received experimental treatment and only 7 of them completed the 12-month study. Verbal pain assessment ratings significantly decreased from baseline to 12-months among these patients but was not significant in the control group. Both groups saw statistically significant improvements in 2 other patient-reported physical function questionnaires from baseline to 12-months. Bone mass density T-scores also increased over the course of the study for both groups with no significant difference between them.¹⁸

The certainty of the evidence was determined to be very low due to the absence of a or comparator group, small sample size, heterogenous population, lack of male study participants, missing outcome data, uncertainty about the validity of outcome measurements, and lack of generalizability to the Medicare population.

Upper Extremity

Three case series reported on the use of amniotic and placental tissue products for tendinopathies affecting the upper extremity. Ten patients (mean age 56 years) diagnosed with partial rotator cuff tears were prospectively observed following the injection of an amniotic membrane/umbilical cord particulate matrix and a course of physical therapy.¹⁹ At 6 months follow-up, patients reported clinically significant improvement in pain and functional outcome measures. Additionally, there was a 28% relative increase in overall shoulder range of motion. The certainty of the evidence was determined to be very low due to the absence of a control or comparator group, small sample size, uncertainty about the impact of cointervention, uncertainty about the durability of results, and lack of study participants with ages and demographics reflective to that of the Medicare population.

A small (n=10) retrospective case series described pain and function (disability) outcomes following micronized dehydrated human amnion/chorion membrane allograft injection for medial and lateral epicondylosis.²⁰ Intermediate outcomes obtained at 24-36 weeks post-injection showed clinically relevant improvement in pain reduction and functional activities. The mean patient-rated improvement in pain was 77% at intermediate follow-up. The certainty of the evidence was judged to be very low due to the absence of a control or comparator group, small sample size, uncertainty about the impact of cointervention, variable time-points of outcome measurements, selective outcome reporting, and lack of demographic information to compare with the Medicare population.

In a prospective case series, 96 patients (111 digits; mean age 65 years) diagnosed with stenosing tenosynovitis (trigger finger) received and injection of amniotic fluid.²¹ At an average of 11 months follow-up, there was a clinically important mean improvement in pain, while function improved just below the threshold for clinical relevance. Additionally, triggering events improved from a baseline average of 5 to 0 at the end of follow-up. The certainty of the evidence was appraised as very low due to the absence of a control or comparator group, small sample size, variable time-points of outcome measurements, missing outcome data, and uncertainty of participant demographics in comparison to the Medicare population.

Lower Extremity Tendinopathies

Three RCTs (industry sponsored), and 3 observational studies (1 cohort, 1 case-control, 1 case series) specifically assessed the effects of different human amniotic and placental tissue product injections for individuals diagnosed with plantar fasciitis. The three RCTs were industry sponsored.^22-24 Two RCTs employed placebo injections,^22,23 and 1 RCT used an active comparator (corticosteroid injection).²⁴ The cohort study’s comparator group received standard care interventions.²⁵ All 6 studies (n=345) assessed short-term (≤12 weeks) pain outcomes. The case-control study reported on intermediate-term outcomes for pain.²⁶ Two RCTs (n=192) reported on short-term functional outcomes.^22,23 A multicentered RCT (n=147; mean age 51 years) found a modest clinically significant benefit for pain reduction and functional improvement in the intervention group compared to placebo at the primary endpoint (3 months follow-up).²² The certainty of these results was rated as very low, with further concern about study demographics in comparison to the Medicare population. None of the other studies reported significant differences between groups for measures of pain-related outcomes, nor did they assess function.^22-24 The case series observed clinically relevant improvement at all time points (2–12 weeks) compared to baseline in the plantar fasciosis group.²⁷

For individuals diagnosed with plantar fasciitis, the certainty of the evidence regarding human amniotic and placental tissue product injections for pain and functional outcomes was very low and was low for functional outcomes.

Two small (n=10, n=32) industry-sponsored, retrospective case series provided very-low certainty evidence describing amniotic tissue matrix product injections with individuals having lower extremity tendinopathies other than plantar fasciitis.^28,29 Both studies reported 100% favorable response in pain reduction over the short-term. A third case series included a mixed population.²⁷ Patients diagnosed with Achilles tendinosis showed clinically relevant improvement at all time points (2–12 weeks) compared to baseline. None of these studies described functional outcomes. No confident conclusions about efficacy could be reached from these non-comparative designs.

Lower Extremity Osteoarthritis

Farr et al (2019) conducted a multicentered (n=12), industry sponsored (Organogenesis, Inc.) RCT to evaluate the efficacy of symptom modulation with amniotic suspension allograft (ASA) compared with saline and hyaluronic acid (HA) in participants (55 +10 years) with moderate (Kellgren-Lawrence grade 2 or 3) knee osteoarthritis.¹¹ At baseline, 200 blinded participants were allocated to receive a single intra-articular injection. Follow-up assessments took place at 3 and 6 months. The primary outcomes were patient-reported measures of pain, activity, and quality of life using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the 0-150 mm visual analog scale (VAS). In a subsequently published longitudinal assessment of the participants, the same outcomes were assessed at 12 months.³⁰

The KOOS includes 5 subscales (pain, symptoms, activities of daily living, sports & recreation, and quality of life). A change score of 8 to 10 points, to detect a minimal important difference (MID), was used by the authors of both studies to identify clinically meaningful outcomes in the KOOS subscales. This threshold, however, is not consistent with a recently published literature review that showed the minimal important difference (MID) for the KOOS at 6 months and 12 months follow-up varies by subscale, and clinically significant change is usually greater than 8 points and usually exceeds 10 points.³⁰

A crossover study was performed to assess the efficacy of ASA on patients who self-reported unacceptable pain levels three months post-injection of initial treatment with HA or saline.³¹

The application of these criteria revealed no clinical benefit with ASA compared to saline (placebo injection) at 3, 6, or 12 months for pain, activities of daily living, sports and recreation, and quality of life. Only the ‘symptoms’ subscale marginally achieved minimal clinically important change for those receiving ASA injection vs. sham at 6 and 12 months.

All studies measured pain outcomes (overall pain, pain with strenuous work, pain with sedentary work, and pain with normal daily activity) using a 0-150 mm visual analog scale (VAS) instrument described by McCarthy et al (2005), instead of a more familiar 0-100 mm scale.³² The references citing the MID values (11-13 mm) used by Farr et al (2019) and Gomoll et al (2021, 2023) were specific to the 0-100 VAS.^33,34 The MID value for the 0-150 mm VAS has not been established. The validation study, however, did calculate its clinical responsiveness as 33.5 mm.³⁴ Using this measure as a proxy for clinical significance, ASA compared to placebo injection did not demonstrate clinically relevant improvements for any of the pain-related constructs.

Responder analyses were reported as a secondary outcome in the publication by Farr et al (2019).¹¹ The responder analysis at 6 months showed a significantly greater responder rate for ASA (69.1%) compared with HA (39.1%) and saline (42.6%) groups. These results were durable at 12 months, with 63.2%, 35.9%, and 42.6% of patients in the ASA, HA, and saline treatment groups considered responders, respectively.

Similarly, in the crossover study published by Gomoll et al (2023), those who failed to obtain relief from HA or saline (n=95, mean age=55 years) were evaluated from the point of original baseline to three months (blinded) and then again prior to receiving treatment at 1 week, 6 weeks, 3 months, 6 months, and 12 months post-crossover resulting in 15 months of total study participation.³¹ All outcome measures were based on the same patient-reported outcome (PRO) assessments from the original 3- arm study including the 150-mm VAS scale and KOOS assessment with their respective subcategory scales. Participants, investigators, and study staff were unblinded in the crossover period. KOOS Pain, KOOS ADL, and VAS Overall Pain from baseline to 12 months met or exceeded the MID.

Responder analyses were again examined as secondary outcomes in the study by Gomoll et al (2023).³¹ Patients who were considered responders peaked at 6 months (62.1%) and slightly declined at 12 months (55.8%).

Beyond the failure to achieve clinically significant improvements in most of the primary measures, these studies were judged to have a high risk of bias (RoB) due to the failure to analyze all participants in the group to which they were randomized and because of concerns that the imputation methods failed to correct for bias due to missing outcome data. In the crossover investigation, bias additionally exists in the lack of defining unacceptable pain at 3 months which was the basis for participant selection. Sample size was calculated to detect too low a change value, which likely resulted in underpowered studies.

The substantial withdrawal rate (>75% in the sham group at 6 and 12 months; and 24% in the ASA group at 12 months in the primary and longitudinal studies) further compromised the discriminate ability of the studies at 6 and 12 months. The authors reported prior treatment with HA or saline did not affect subject response from ASA injection when comparing original to crossover responder rates,³¹ however, it is markedly unknown due to the unblinding of participants in the crossover study and the increased risk of a placebo effect. There was uncertainty about the impact of unreported cointerventions on the studies’ results. Standard of care for non-operative OA management, including bracing, physical therapy, weight loss programs, and so on, was used per the physician’s normal practice but was not globally harmonized throughout the study.

The age of most participants (55 + 10 years) fell below that of the typical Medicare beneficiary. Additionally, the study inclusion and exclusion criteria were somewhat restrictive and may not accurately reflect the entire patient population that may receive the product. The overall certainty of the evidence was judged to be very low for pain, function, and quality-of-life outcomes in the short- and intermediate-terms due to very serious study limitations, serious indirectness and serious imprecision. Long-term outcomes (i.e., >1 year) were not reported.

Mautner et al (2023) performed a single-blinded multistate (n=5) RCT comparing 3 types of stem cells, including human umbilical cord tissue (UCT) injectate, to a standard of care treatment, corticosteroid injection (CSI), in participants (n=480, mean age=58 years) with moderate to severe (Kellgren-Lawrence Grade 2, 3, or 4) knee osteoarthritis (OA) and average daily visual analog scale (VAS) ≥3/10.³² Randomization to treatment assignments were propagated by the use of software and were stored in a cloud-based data management system developed by the contracted research organization.³² Investigators were not required to be blinded. Application access to the randomization database was given to unspecified individuals and participant information was placed in the computer by study-employees which likely compromises the assessor-influence and authenticity of reported outcome measures. Patients underwent sham harvesting procedures and subsequently received a single injection respective to their treatment assignment with follow-up exams at 7 days, 1 month, 3 months, 6 months, 9 months, and 1 year. Primary outcome measures were based on patient-reported outcome (PRO) questionnaires, the VAS pain assessment and the Knee Injury and Osteoarthritis Outcome Score (KOOS), for changes from baseline to 12 months. Sample size calculation exceeded the number of actual participants who received treatment. The participants allocated to the UCT arm (n=119), who proceeded with treatment and completed 12 months of the study (n=103) were found to have no significant differences in VAS pain or KOOS from baseline to 12 months.³²

In addition to the failure to achieve clinically significant improvements in the UCT group, statistical analyses refuted any superiority amongst the experimental cohorts and control variable, as none of them proved significant declines in either co-primary outcome measure spanning the study course. This study was deemed to have a high risk of bias due to randomization process concerns, including inadequate allocation sequence concealment of the enrolling investigator and possible selection bias based on differences between participants who elected to start the trial and those who did not.

The mean age of most participants (58 years) fell below that of the typical Medicare beneficiary. Additionally, the heterogenicity of the sample size based on restrictive inclusion and exclusion criteria may not accurately reflect the entire population intended to receive treatment. While patients underwent sham procedures and were blinded to their treatment, it is unclear whether patients who did not respond to cellular or steroid injections were subject to a placebo type effect and thus indicates additional study limitations and outcome uncertainties. Some authors and study contributors reported employment at one of the testing facilities, furthering risk of bias and the validity of subjective data evaluation in facility-specific and comprehensive outcome reporting. The overall certainty of the evidence was deemed to be low due to serious risk of biases and serious indirectness. Long-term outcomes (i.e.,>1 year) were not reported.

In addition to the 4 experimentally designed studies, 5 case series described patient-reported efficacy outcomes. ^35-39 Four studies included patients (total n=169; mean age range of 45-74 years) diagnosed with knee osteoarthritis.^37-40 An industry sponsored study prospectively described outcomes for 10 patients (ages 47-67 years) with hip osteoarthritis.⁴¹ Clinically significant improvement in one or more outcomes (pain, function, overall improvement, responder rate) was reported in every study. However, judgments about efficacy could not be made due to the type of study design i.e., lack of a control/comparator group. Additionally, as there were small sample sizes for these publications, certainty in the conclusions of these studies was viewed as very low.

SAFETY

General Musculoskeletal

A single case series (n=40; mean age 51 years) observed participants with various musculoskeletal joint pathologies or tendinopathies after receiving an injection of micronized dehydrated human amnion/chorion membrane.¹⁵ No serious adverse events occurred in any patient at all follow-up time points (1, 2, and 3 months).

Spine

Two retrospective case series (the first one n=11, ages not provided; the second one n=52, mean age 41 years) described patients with cervical and lumbar discogenic spine-related disorders.^16,17 There were no significant complications, repeat procedures, or adverse events reported throughout follow-up periods. One RCT (n=20, average age 70.5 years for experimental group, 100% female) involving the study of osteoporotic vertebral compression fractures noted potentially serious adverse effects including a pulmonary embolism after intravenous (IV) stem cell infusion and an incidental finding of pancreatic cancer during the study in the investigational group.¹⁸ Other self-limiting adverse effects were reported including UTI, nausea, vomiting, dizziness, and post-IV infusion site reaction. Overall, 40% of the experimental group experienced side effects that could not be determined as direct or indirectly related to the trialed regimen. The authors acknowledge that the infusion of mesenchymal stem cells could result in pulmonary emboli and the development of tumor tissue and thus could not entirely exclude the possibility of complications with this treatment.

Upper Extremity

Three case series reported on the use of amniotic and placental tissue products for tendinopathies affecting the upper extremity.^19-21 The authors reported there were no adverse events or complications over short- and intermediate-term follow-up time frames.

Lower Extremity Tendinopathies

Three RCTs, and 3 observational studies (1 cohort, 1 case-control, 1 case series) specifically assessed the safety of different human amniotic and placental tissue product injections for individuals diagnosed with plantar fasciitis.^22-27 Among these studies, there were no serious adverse events reported that were intervention-related. A retrospective case series assessed adverse events described by 32 patients diagnosed with Achilles tendinitis who received an injection of 40 mg of micronized dehydrated human amnion/chorion membrane (mdHACM).²⁹ Two patients reported calf pain or calf and quadricep tightness after injection. No serious or ongoing, unresolved adverse events were observed through 1 month follow-up.

Lower Extremity Osteoarthritis

A multicentered RCT involving 200 participants diagnosed with knee osteoarthritis (OA) assessed adverse events (AEs) at 12 months.³⁰ The number and type of adverse events reported for injection of an amniotic suspension allograft were comparable to the hyaluronic acid injection group, while no treatment-emergent adverse events (TEAEs) were reported for the saline group. In the crossover ASA study of this RCT, there were 5 reported TEAEs including muscle aching, knee swelling/popping, and arthralgia.³³ Additionally, there were statistically significant decreases in immunoglobulin A and in immunoglobulin M from baseline to 6 months and 6 weeks respectively.

In the multistate RCT involving a 12 month comparison of corticosteroid injections to different cellular injections for knee OA, adverse effects were recorded and analyzed for significance amongst all comparators.³³ Of the participants (n=116) allocated to the umbilical cord tissue-derived (UCT) cohort, disclosed AEs were arthralgia, joint stiffness, and joint swelling in 57% of patients and 1 patient reported post-procedural pain. Three case series with a total of 87 patients described 1 patient who developed swelling in the knee within 36 hours of injection.^36-38 No other adverse events or complications were reported. A small case series (n=10) of participants diagnosed with moderate hip osteoarthritis, who received a single injection of amniotic suspension allograft, observed no immediate complications post-injection.³⁹ No patients developed infection, effusion, or increased stiffness in the injected hip.

QUALITY OF LIFE, WELL-BEING, SATISFACTION

General Musculoskeletal

A small (n=40) case series reported 92.5% of patients with various musculoskeletal joint pathologies or tendinopathies were satisfied after receiving an injection of micronized dehydrated human amnion/chorion membrane.¹⁵

Spine

A small RCT (n=10 experimental group participants) investigated the use of umbilical cord products combined with a parathyroid hormone injectate for the treatment of osteoporotic vertebral compression fractures.¹⁸ The experimental group showed significant improvement from baseline to 12-months based on the patient-reported quality of life questionnaire, Short Form-36 (SF-36) mental component score (MCS).

Upper Extremity

Not reported.

Lower Extremity Tendinopathies

Two RCTs investigating the effects of amniotic membrane tissue product injections for individuals diagnosed with plantar fasciitis found no significant between-group differences for quality-of-life outcomes.^23,24 A case-control study involving the surgical treatment of patients diagnosed with chronic plantar fasciitis found no significant difference in satisfaction at 52 weeks with the injection of a flowable placental tissue matrix immediately following fasciotomy.²⁶

Lower Extremity Osteoarthritis

Three RCT publications describing the same participants diagnosed with knee osteoarthritis (OA) found a clinically significant difference favoring the ASA group between groups that received injections of amniotic suspension allograft (ASA), hyaluronic acid, and saline as well as the crossover ASA study at 12 months.^11,30,31

SYSTEMATIC REVIEWS

The literature search parameters generated 9 eligible systematic reviews. These reviews evaluated some but not all the primary studies that have been included in this evidentiary review.

Guimarães et al (2023) conducted a systematic review and meta-analysis of RCTs encompassing a broad range of therapeutic interventions for plantar fasciitis.⁴² Three RCTs that assessed human amniotic membrane tissue products were included in the review.^22-24 The meta-analysis included only 2 RCTs.^21,23 The authors reported low certainty evidence, in the short-term (1-6 weeks), of a trivial to moderate effect for pain compared to placebo [MD -3.31 (CI: -5.54, -1.08)] The meta-analysis found high heterogeneity (I² = 92%).

Zaffagnini et al (2022) systematically reviewed the safety and efficacy of orthobiologic injections for the treatment of hip osteoarthritis.⁴³ A single case series describing amniotic suspension allograft (ASA) was reported but not sufficient for analysis in this review.³⁹

Aratikatla et al (2022) produced a systematic review aimed at documenting the preclinical and clinical outcomes of various perinatal allogenic tissues and/or derived cells for orthopedic regenerative medicine applications including amniotic suspension allograft, amniotic membrane, amniotic fluid, and umbilical cord product.⁴⁴ The reviewers reported predominantly on preclinical studies and studies in-progress. No formal critical appraisal was performed. The authors concluded, “Further well-designed, multi-center, prospective, clinical studies (both nonrandomized and randomized) should be, and are being, conducted to ultimately justify the clinical use of these biologic agents for musculoskeletal regenerative medicine applications.”

Sultan et al (2019) systematically evaluated the use of placental and amniotic tissue-based products as an adjuvant treatment to the operative management of various types of tendon injuries.⁴⁵ All studies reviewed were low level of evidence and insufficient to determine the efficacy of amniotic and placental-derived products. The reviewers found there were marked differences among the currently available products due to variations in their formulations, tissue source, processing methodology, sterilization method, preservation and storage methods, indications for use, and FDA regulation. The authors concluded “Future clinical trials will need to confirm the safety and establish the extent of efficacy of placental tissue-derived products in the treatment of sports-related injuries.”

Sultan et al (2020) published a systematic review for the non-operative applications of placental tissue matrix in orthopedic sports injuries.³ The majority of the included studies (3 of 5) lacked a comparative cohort, which translated to a lower level of evidence of the findings observed by these studies. In addition, the 2 studies that were comparative did not fully contrast outcomes with conservative rehabilitation modalities of treatment. The reviewers concluded that despite the progress in the field, the applications are in their infancy, and more research is needed to explore their full potential.

McIntyre et al (2018) performed a systematic review, however, there were only 6 human studies.⁷ The studies had a high degree of variability in placental cell types, placental tissue preparation, routes of administration, and treatment regimens, such that no conclusions could be made regarding efficacy. Safety, however, the authors concluded appeared acceptable.

Tsikopoulos et al (2016) performed a systematic review and network meta-analysis on studies examining injection therapies including amniotic products to treat plantar fasciitis.⁴⁶ The reviewers found indirect comparative evidence that dehydrated amniotic membrane injection was the highest ranked treatment for pain in the short term (0-2 months); however, this data was from only 1 small (n=45), single-center, pilot RCT (Zelen et al; 2013).²³ Investigators reported the paucity of information regarding the long-term efficacy and safety of dehydrated amniotic membrane injection therapy did not permit confident conclusions about the use of this modality in clinical practice.

Lee DH et al (2022) performed a systematic review embedded with a meta-analysis on studies of patients with knee osteoarthritis (OA) or knee articular cartilage defect who underwent arthroscopic and/or open procedure knee repair surgeries with the use of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) as a means of direct primary cartilage lesion treatment.⁴⁷ Seven studies published from 2020 to 2022 were included in the review and 6 were retrospective meta-analyses based on RCT studies. Two centers were responsible for 5 published studies: 3 of the meta-analyses’ were published from a single center which introduces selection biases. Investigators analyzed study characteristics for meta-analyses when the measurement methods were used concurrently in 3 or more studies and mean differences in baseline and final follow-up outcomes were disclosed. Pooled analysis of hUCB-MSCs treatment significantly improved the International Knee Documentation Committee (IKDC) scores in 6 studies, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments in 6 studies, and Visual Analog Scale (VAS) pain scores in 5 studies with an average follow-up duration >15 months. Modified Magnetic Resonance Observation of Cartilage Repair Tissue (M-MOCART) scores were analyzed for studies that notated bone marrow aspiration concentrate (BMAC) treatment versus hUCB-MSCs at 1-year and 2-year intervals: while the M-MOCART scores showed better results in hUCB-MSCs, there was no significant difference. All studies had a high degree of variability in outcome measures, study length, and demographic characteristics of participants affecting the heterogeneity of the study. The authors claimed that use of hUCB-MSCs for knee cartilage regeneration is considered a safe and effective option with lasting results despite. The certainty of evidence was judged to be low due to serious study limitations, inconsistent results, and imprecision.

Lee JS et al (2021) published a systematic review to organize various mesenchymal stem cell (MSC) treatment methods and their associated clinical processes in patients with knee osteoarthritis (OA).⁴⁸ Only clinical trial research papers (n=27) were included in the review with a substantiated randomization process. Primary categories identified cell donor, source, and preparation; delivery methods; lesion preparation; concomitant procedures; and evaluation. Further subcategories were specified for each of the primary divisions. The use of placenta, umbilical cord blood, and umbilical cord MSCs were reported in 3 of the RCTs reviewed. Of the participants (n=135) allocated to this grouping, 34% received the injectable delivery method compared to the transplantation method. Visual analog scale (VAS) pain assessment was the only shared outcome measure amongst the injectable umbilical cord/placental cell sources which were noted as improved in intermediate-term follow-ups. There was a high level of variability in demographics including a large age range (18-80 years old) which is not necessarily reflective of the Medicare population. Demographic information lacked racial and ethnical background, was thought to be too loosely inclusive of patients with chronic co-morbid conditions and had overall small sample sizes. Outcome measures were depicted in multiple formats; however, conclusions were drawn suggesting these treatments provided clinical benefits and deemed umbilical cord/placental MSCs as reasonable regenerative management approaches for knee OA. This review is of prevailing literature and is limited by the studies they identified and the incongruity of those studies. The certainty of evidence is rated low due to serious deviations in imprecision and heterogeneity and high risk of bias due to missing evidence.

Risk of Bias and Certainty of Evidence

The Cochrane risk-of-bias 2 tool was employed to assess the risk of systematic error influencing the internal validity of individual RCTs.⁴⁹ Two studies were judged to have a low risk of bias.^22,23 Five RCTs were appraised as having a high risk of bias, mainly due to bias arising from deviations from the intended intervention and randomization process as well as missing outcome data.^{3,24,30,31,32}

The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was applied to classify the certainty of the body of evidence.⁵⁰ Overall, the certainty of the evidence was low to very low. Confidence in the effect estimates is limited to very limited; the true effect may be or is likely to be substantially different from the estimates of the effect.

A total of 4 studies, 3 RCTs and 1 cohort (total n=270), assessed short-term pain outcomes for individuals diagnosed with plantar fasciitis.^22-25 The certainty of evidence was rated as very low, due to serious study limitations (high risk of bias), inconsistent results (heterogeneity), indirectness (uncertain applicability), and imprecision (uncertainty about clinical decision making).

Functional outcomes were evaluated over the short-term for participants with plantar fasciitis in 2 RCTs (total n=192).^{22, 23} The certainty of evidence was judged to be low, owing to serious indirectness and serious imprecision.

Three publications describing a single RCT (n=200) and subsequent crossover study (n=95) concerning participants diagnosed with knee osteoarthritis (OA), assessed short-term and intermediate-term pain and functional outcome measures.^3,30,31 The certainty of evidence for all outcomes and follow-up periods was rated as low. There were very serious study limitations, serious indirectness, and serious imprecision. Quality-of-life was also assessed in the intermediate term. The certainty of the evidence was judged to be low for the same reasons. One 4-arm parallel RCT (n=480) compared experimental and control treatments for knee OA assessed baseline and intermediate-term pain measures.³² The certainty of evidence for co-primary outcomes at 12-month study completion were rated low. There was serious risk of biases and serious indirectness.

Clinical Significance

Preliminary, noncomparative studies (case series) generally reported clinically meaningful effects for pain and functional patient-important outcomes. Higher quality experimental designs (RCTs) did not substantiate observational research. The absolute between-group effects were not clinically significant for virtually any diagnosis, outcome, or time frame. Short-term function in participants treated with human amniotic membrane injection achieved a clinically relevant benefit. However, this result was based on low certainty evidence from 2 RCTs. A minimally clinically significant benefit was reported (low certainty evidence) at the intermediate term for participants diagnosed with knee osteoarthritis.

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

First Coast participated in 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, wound 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
• Osteoarthritis 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 randomized controlled trials, 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 efficacy of any amniotic and placental-derived product in the treatment of specific musculoskeletal conditions, whether injected or applied intra-operatively. There is 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.

Finally, depending on the combination of individual product components and the variable way in which these products are processed into their final product form, amniotic and placental-derived products currently marketed may not meet section 361 FDA regulatory requirements as an HCT/P. Instead, these products may require formal Premarket Approval (PMA) or other appropriate device Premarket Clearance such as 510(k), or a (BLA) Biologics License Approval. Moreover, it is likely that these products are used in "off-label" treatments or methods which have not been established as safe and effective for the prescribed condition (e.g., injection of product not FDA approved designated/considered for human systemic or internal administration).

In conclusion, there is insufficient evidence-based literature to support coverage of amniotic and placental-derived products injected or applied, both non-operatively and intra-operatively in the treatment of musculoskeletal conditions or pain related to such. Therefore, this policy is a non-coverage policy as Medicare Reasonable and Necessary requirements have not been met.

Please refer to the related Local Coverage Article: Billing and Coding: Billing and Coding: Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound (A59764) for documentation requirements, utilization parameters and all coding information as applicable.

N/A

This bibliography presents those sources that were obtained during the development of this policy. The Contractor is not responsible for the continuing viability of Website addresses listed below.

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