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 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 are rich in collagen, glycoproteins, proteoglycans, fibroblasts, as
well as many cytokines and growth factors thought to promote healing with a
lower risk of low immunologic reaction.

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

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 three 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 three 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 layer (ref 13) 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.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 (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 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, 
(gamma)-sterilization, low heat dehydration, and vitrification.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 extracellular matrix components. 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.

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 products are harvested, their
process 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 (NDA) New Drug application, an (IND)
Investigational New Drug application, or a (BLA) Biologics License
Approval.8,9,12,13

If a human cells or tissue product should meet 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 article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/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; or
      3. Is for reproductive use12

Due to the ongoing development of new products and clinical trials, the field
of FDA regulatory requirements is fluid and evolving. It is the expectation
that the respective Medicare Administrative Contractor will continue to follow
any guidance and insight as it is brought forward by the FDA.

Lack of standard formulation, dose, frequency of administration, and standard
of care in treatment with these products further complicates regulation and
guidance determinations.

Despite this lack of standardization, numerous amniotic and placental-derived
products have been released for use in treatment of musculoskeletal
conditions. These conditions include, but are not limited to tendon/ligament
injuries, musculoskeletal injuries, cartilage damage, osteoarthritis, (or pain
related of these conditions) as well as an adjunctive to orthopedic surgical
treatments. Due to the lack of component standardization, the remainder of
this LCD will use the term amniotic and placental-derived products to mean ANY
product derived from ANY combination of amniotic
membrane/chorion/placenta/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 support for safety and efficacy
from human clinical trials available.

All injectable amniotic and/or placental-derived products fall under FDA
section 551 of the Federal Food, Drug, and Cosmetic Act. Promotion relating to
novel indication or evidence of new intended use may constitute labeling,
adulteration, or misbranding of the drug or device if such dissemination fails
to comply with section 551 of the Federal Food, Drug, and Cosmetic Act (the
act) (21 U.S.C. 360aaa) and the requirements of this part. A manufacturer's
failure to exercise due diligence in submitting the clinical studies necessary
for the approval of a new use as subject of information disseminated under
this part or in beginning or completing such clinical studies shall be deemed
a failure to comply with section 551 of the act and the requirement of this
part. Use of any amniotic and/or placental-derived products that have not met
the requirements of section 551 of the Federal Food, Drug, and Cosmetic Act
will be denied per Medicare Benefit Policy Manual 100-2 Chapter 15 Section
50.4.1 and associated services will also be denied per Medicare Benefit Policy
Manual 100-2 Chapter 16 Section 180.

**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 were:
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)
reported 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 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.



**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.14 "Overall
pain" achieved clinically relevant improvement at all follow-up time points
(1, 2, and 3 months). 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.16

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.17 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.18
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.19 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.20-22 Two RCTs employed
placebo injections,20,21 one RCT used an active comparator (corticosteroid
injection),22 while the cohort study's comparator group received standard care
interventions.23 All six studies (N = 345) assessed short-term ( _<_ 12 weeks)
pain outcomes. The case-control study reported on intermediate-term outcomes
for pain.24 Two RCTs (N = 192) reported on short-term functional
outcomes.20,21 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).20 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.21-23 The case series observed clinically relevant improvement at all
time points (2-12 weeks) compared to baseline in the plantar fasciosis
group.25

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.26,27 Both studies reported 100% favorable response in pain
reduction over the short-term. A third case series included a mixed
population.25 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.28

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.29 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.30 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.31,32 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.32 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.33-36 An industry sponsored study prospectively described
outcomes for 10 patients (ages 47-67 years) with hip osteoarthritis.37
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.14 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.15,16
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.17-19 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).27 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.28 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.34-36 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.37 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.14

_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.21,22 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.24

_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.28

**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.38 Three RCTs that assessed human amniotic membrane tissue products
were included in the review.20-22 The meta-analysis included only two
RCTs.20,22 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.39 A single
case series describing amniotic suspension allograft (ASA) was reported but
not sufficient for analysis in this review.37

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.40 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.41 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.42 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.43 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).21
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.20,21 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.3,22,28

The GRADE (Grading of Recommendations, Assessment, Development, and
Evaluation) approach was applied to classify the certainty the body of
evidence.45 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.20-23 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).20,21 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.3,28 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 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 such reasons
do not meet the requirement of Medically 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, along with their final
product form, several of the current amniotic and placental-derived products
on the market, whether injected or applied intra-operatively, may not meet the
section 361 FDA regulatory requirements for HCT/P. Moreover, it is more likely
than not that these products are used in "off-label" treatments and in methods
which have not been established as safe and effective for the prescribed
condition (e.g., injection of product not FDA approved designated or
considered for human systemic or internal administration).

Other musculoskeletal conditions that are not referenced in this Local
Coverage Determination are due to 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 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 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.