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

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

NOTE: For information on stem cell transplantation please see the Centers for
Medicare & Medicaid Services (CMS) National Coverage Determination (NCD)
110.23 Stem Cell Transplantation.

**Introduction**

Amniotic and placental-derived products are known to possess certain
beneficial characteristics. These products have been identified as a source of
stem cells. Stem cells, by definition, have the capability to differentiate
into any cell of an organism as well as the capability of self-renewal.1 In
addition, the extracellular matrix (ECM) of placental and amniotic-based
tissues are rich in collagen, glycoproteins, proteoglycans, fibroblasts, as
well as many cytokines and growth factors thought to promote healing with a
lower risk of low immunologic reaction.

Based on these characteristics, amniotic and placental-derived products are
currently being studied and heavily marketed as allografts that serve as:

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

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

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

**_Definitions:_**

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

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

**Amniotic fluid** is the fluid surrounding the fetus within the amnion.  

**Umbilical cord** is the cord connecting the fetus to the placenta comprised
of the umbilical vein, arteries, allantois, and yolk sac embedded in Wharton's
jelly.  

**Wharton 's Jelly** is a gelatinous soft connective tissue derived from
extra-embryonic mesoderm within the umbilical cord.4

The **amniotic membrane** itself is divided into 3 histologic layers:

  * A single **epithelial layer**
  * A thick **basement membrane**
  * An **avascular stromal (mesenchymal) layer** 5,6,7,8 

The avascular stromal layer is further divided into 3 layers:6,7,8

  * The **Compact layer**
  * The middle **Fibroblast layer**
  * The **Spongy layer**

The **Spongy Layer** , loosely connected to the chorionic membrane, is highly
concentrated with proteoglycans and glycoproteins, including hyaluronic acid
(HA), as well as type I, III, and IV collagen.5,6,8,9

**__**

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

**__**

The **Compact layer** that sits adjacent to the basement membrane is composed
of collagen types I, III, V, and VI, along with fibronectin.5,9

**__**

The **basement membrane** anchors the epithelial layer and contains collagen
types IV, V and VII, fibronectin, laminin, and HA.6,10

Adjacent to the basement membrane and in immediate contact with the amniotic
fluid is the single layer of epithelial cells. **Amniotic epithelial cells**
produce type III and IV collagen, glycoproteins such as laminin and
fibronectin, which in turn form the basement membrane.5

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

**__**

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

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

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

Because the spongy layer loosely connects the amniotic membrane to the
chorionic membrane, these 2 layers are easily separated upon initial
harvesting by blunt dissection.10 Other than ease of separation between
amniotic and chorionic membranes, the following steps in processing the
tissues into the desired form vary based on which portions of the placental
tissues are utilized, what sterilization processes (if any) are undertaken,
and what method of preservation is used. Common methods of preservation
include cryopreservation, lyophilization (freeze-drying), glycerol-
preservation,  (gamma)-sterilization, low heat dehydration, and
vitrification, to name a few.5,8,9,10

A process called "Decellularization" may be used in which the layer of
amniotic epithelial cells is removed from the collected amniotic membrane,
leaving behind the valuable ECM components. By removing all cellular
components, it is thought that there is less possibility of eliciting an
immunogenic response.3,10 Different decellularization processes are available.
Finally, preparation in the form of sheets, cutting into small particulates,
processing into a liquid form, along with re-suspension in varying solutions
are additional steps that may occur in order to reach the desired final
product.

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

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

Despite this lack of standardization in composition, dosing, or
administration, numerous amniotic and placental-derived products are flooding
the market for use in treatment of musculoskeletal conditions. These
conditions include, but are not limited to tendon/ligament injuries,
musculoskeletal injuries, cartilage damage, osteoarthritis, (or pain related
of these conditions) as well as an adjunct in orthopedic surgical treatments.
In light of the lack of standardization of composition, the remainder of this
Local Coverage Determination (LCD) will use the term amniotic and placental-
derived products to mean **ANY** product derived from **ANY** combination of
amniotic membrane/chorion/placenta/Wharton's jelly/umbilical cord/amniotic
fluid/umbilical cord blood.

Although amniotic and placental-derived products are marketed to treat certain
musculoskeletal conditions, there is only a paucity of accompanying human
clinical trials available regarding safety and efficacy.

**Literature Inclusion/Exclusion Protocol**

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

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

**Tendinopathies**

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

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

**Plantar Fasciitis**

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

**Osteoarthritis (OA) of the Knee**

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

**Chronic Back Pain**

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

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

**Trigger Finger**

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

**Systematic Reviews**

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

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

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

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

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

**Certainty of Evidence**

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

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

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

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

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

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

The topics of discussion included:

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

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

**Rationale for Determination**

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

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

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

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

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