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

Summary Of Evidence

Literature Inclusion/Exclusion Protocol

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

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

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

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

Analysis of Evidence

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.^{16, 17} “Overall pain” achieved clinically relevant improvement at all follow-up time points (1, 2, and 3 months).¹⁶ At three months assessment, functional outcomes (activities of daily living, and sports and recreation) were clinically improved.

The certainty of the evidence was determined to be very low due to the absence of a control or comparator group, small sample size, heterogeneous population, and lack of generalizability to the Medicare population.

Spine

Two retrospective case series (N = 11, 52; mean age 41 years) described patients with cervical and lumbar discogenic spine-related disorders.^15,16 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 percentage of relief, with less than half the patients reporting at least 50% improvement at 1, 3, and 6 months.¹⁵ Verbal ratings of pain did not reveal clinical improvement at weeks 2, 3-4, 6, and 8; whilst, trivial to moderate improvement in verbal pain rating was recorded at 10.6 weeks follow-up.¹⁷

The certainty of the evidence was determined to be very low due to the absence of a control or comparator group, small sample size, heterogeneous population, 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.¹⁸ 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 generalizability to 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.¹⁹ 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 generalizability to the Medicare population.

In a prospective case series, ninety-six patients (111 digits; mean age 65 years) diagnosed with stenosing tenosynovitis (trigger finger) received and injection of amniotic fluid.²⁰ 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 an average of 5 to 0. 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 about generalizability to the Medicare population.

Lower Extremity Tendinopathies

Three RCTs, and three observational studies (1cohort, 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.^21-23 Two RCTs employed placebo injections,^21,22 one RCT used an active comparator (corticosteroid injection),²³ while the cohort study’s comparator group received standard care interventions.²⁴ All six studies (N = 345) assessed short-term (< 12 weeks) pain outcomes. The case-control study reported on intermediate-term outcomes for pain.²⁵ Two RCTs (N = 192) reported on short-term functional outcomes.^21,22 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).²¹ The certainty of these results was rated as moderate, with further concern about generalizability 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.²⁶

Overall, the certainty of the evidence regarding human amniotic and placental tissue product injections for pain and 

functional outcomes was very low and low, respectively, for individuals diagnosed with plantar fasciitis.

Two small (N = 10, 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.^27,28 Both studies reported 100% favorable response in pain reduction over the short-term. A third case series included a mixed population.²⁶ 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. Further, the results were not generalizable to the Medicare population.

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.²⁹

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

Both 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 the more familiar 0-100 mm scale.³¹ The references citing the MCID values (11-13 mm) used by Farr, et al. (2019) and Gomoll, et al. (2021) were specific to the 0-100 VAS.^32,33 The MCID value for the 0-150 mm VAS has not been established. The validation study, however, did calculate its clinical responsiveness as 33.5 mm.³³ 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 was reported as a secondary outcome. 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.

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 concerns the imputation methods failed to correct for bias due to missing outcome data. 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) further comprised the discriminate ability of the studies at 6 and 12 months. 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.

In addition to the two experimentally designed studies, five case series described patient-reported efficacy outcomes.^33-37 Four studies included patients (total N = 169; mean age range = 45-74 years) diagnosed with knee osteoarthritis.^34-37 An industry sponsored study prospectively described outcomes for 10 patients (ages 47-67 years) with hip osteoarthritis.³⁸ 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, certainty in the conclusions of these studies was viewed as very low. All had small sample sizes, and uncertainties relating to generalizability and/or outcome measurement.

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 (N = 11, 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.

Upper Extremity

Three case series reported on the use of amniotic and placental tissue products for tendinopathies affecting the upper extremity.^18-20 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 three 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. 20-25 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).²⁸ 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 assessed adverse events at 12 months.²⁹ 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 were reported for the saline group. Three case series with a total of 87 patients described one patient who developed swelling in the knee within 36 hours of injection.^35-37 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.³⁸ 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

Not reported.

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.^22,23 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.²⁵

Lower Extremity Osteoarthritis

Two RCT publications describing the same participants diagnosed with knee osteoarthritis, found no significant differences between groups that received injections of amniotic suspension allograft (ASA), hyaluronic acid, and saline at 3 and 6 months follow-up;¹¹ however, there was a clinically significant difference favoring the ASA group at 12 months.²⁹

SYSTEMATIC REVIEWS

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

Guimaraes, et al. (2022) conducted a systematic review and meta-analysis of RCTS encompassing a broad range of therapeutic interventions for plantar fasciitis.³⁹ Three RCTs that assessed human amniotic membrane tissue products were included in the review.^21-23 The meta-analysis included only two 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.⁴⁰ A single case series describing amniotic suspension allograft (ASA) was reported but not sufficient for analysis in this review.³⁸

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.⁴¹ 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.⁴² 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 demonstrate clearer indications and specific guidelines for use in each clinical scenario involving operative management of tendon 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.⁴³ 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.⁴⁴ 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 one small (N=45), single-center, pilot RCT (Zelen, et al.; 2013).²² 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.

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.⁴⁴ Figure 3 summarizes the results of five studies. Two studies were judged to have a low risk of bias.^21,22 Three RCTs were appraised as having a high risk of bias, mainly due to bias arising from deviations from the intended intervention and missing outcome data.^3,23,29

The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was applied to classify the certainty the body of evidence.⁴⁶ 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 four studies, 3 RCTs and 1 cohort (total N=270), assessed short-term pain outcomes for individuals diagnosed with plantar fasciitis.^21-24 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 two RCTs (total N=192).^21,22 The certainty of evidence was judged to be low, owing to serious indirectness and serious imprecision.

Two publications describing a single RCT (N=200) concerning participants diagnosed with knee osteoarthritis assessed short-term and intermediate-term pain and functional outcome measures.^3,29 The certainty of evidence for all outcomes and follow-up periods was rated as very 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 very low for the same reasons.

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 (very low certainty evidence) at the intermediate term for participants diagnosed with knee osteoarthritis.

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, 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. For a treatment to be considered medically reasonable and necessary per 1862(a)(1)(A) of The Act, the treatment must be appropriate, including duration and frequency, and furnished in accordance with accepted standards of medical practice for the condition. Therefore, this contractor concludes that the existing evidence and lack of accepted standardization of preparation, content, administration, safety and effectiveness, precludes standards of medical practice for amniotic and placental-derived product injections and/or applications and, for these reasons do not meet the requirement of Reasonable and Necessary based on Statute 1862 A(1)(a) requirement of Not Experimental or Investigational.

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 nor designated/considered for human systemic or internal administration).

Other musculoskeletal conditions not referenced in this Local Coverage Determination reflect their lack of acknowledgement 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 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.

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

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

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

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

Introduction

Amniotic and placental derived products are reported to possess certain beneficial characteristics. These products have been 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 to serve as:

• scaffolds for tissue engineering
• membrane covering for certain burns, wounds, and ophthalmic corneal injuries
• micronized/particulated products suspended in an aqueous material to be applied topically or injected into joints, tendons, ligaments
• applications or injections performed intra-operatively to promote post-operative healing

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

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

Definitions:

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

The Placenta is a multi-layered circulatory temporary organ that supplies food and oxygen to the fetus during pregnancy.
The multiple layers of the placenta include the:

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

Amniotic fluid is the fluid surrounding the fetus within the amnion.
Umbilical cord is the vascular conduit connecting the fetus to the placenta comprised of the umbilical vein, arteries, allantois and yolk sac embedded in Wharton’s jelly.
Wharton’s Jelly is a gelatinous soft connective tissue derived from extra-embryonic mesoderm within the umbilical cord.⁴

The amniotic membrane itself is divided into 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, 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 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 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 become the basement membrane.⁵

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

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

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

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

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

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

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

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

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

The HCT/P is:

1. Minimally Manipulated
2. Intended for Homologous Use (as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent)
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
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 of these conditions as well as an 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.