MEDICAL POLICY

POLICY
RELATED POLICIES
POLICY GUIDELINES
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
CODING
APPENDIX
HISTORY

Orthopedic Applications of Stem-Cell Therapy (Including Allograft and Bone Substitute Products Used with Autologous Bone Marrow)

Number 8.01.52

Effective Date June 9, 2015

Revision Date(s) 06/09/15; 06/09/14; 06/10/13; 07/10/12

Replaces N/A

Policy

Mesenchymal stemcell therapy is considered investigational for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue.

Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells, are considered investigational for all orthopedic applications.

Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are considered investigational for all orthopedic applications.

Related Policies

2.01.16

Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions

Policy Guidelines

Note: This policy does not address unprocessed allograft bone.

Description

Mesenchymal stem cells (MSCs) have the capability to differentiate into a variety of tissue types, including various musculoskeletal tissues. Potential uses of MSCs for orthopedic applications include treatment of damaged bone, cartilage, ligaments, tendons and intervertebral discs.

Background

MSCs are multipotent cells (also called stromal multipotent cells) that possess the ability to differentiate into various tissues including organs, trabecular bone, tendon, articular cartilage, ligaments, muscle, and fat. MSCs are associated with the blood vessels within bone marrow, synovium, fat, and muscle, where they can be mobilized for endogenous repair as occurs with healing of bone fractures. Bone-marrow aspirate is considered to be the most accessible source and, thus, the most common place to isolate MSCs for treatment of musculoskeletal disease. However, harvesting MSCs from bone marrow requires an additional procedure that may result in donor-site morbidity. In addition, the number of MSCs in bone marrow is low, and the number and differentiation capacity of bone marrowderived MSCs decreases with age, limiting their efficiency when isolated from older patients.

Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous repair. Therefore, tissue engineering techniques are being developed to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. Tissue engineering focuses on the integration of biomaterials with MSCs and/or bioactive molecules such as growth factors. In vivo, the fate of stem cells is regulated by signals in the local 3-dimensional microenvironment from the extracellular matrix and neighboring cells. It is believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold or matrix, culture conditions for tissue-specific induction, and implantation techniques that provide appropriate biomechanical forces and mechanical stimulation. The ability to induce cell division and differentiation without adverse effects, such as the formation of neoplasms, remains a significant concern. Given that each tissue type requires different culture conditions, induction factors (signaling proteins, cytokines, growth factors), and implantation techniques, each preparation must be individually examined.

FDA has stated:

“A major challenge posed by SC [stemcell] therapy is the need to ensure their efficacy and safety. Cells manufactured in large quantities outside their natural environment in the human body can become ineffective or dangerous and produce significant adverse effects, such as tumors, severe immune reactions, or growth of unwanted tissue.”(1)

Regulatory Status

Concentrated autologous MSCs do not require approval by FDA.

DBM, which is processed allograft bone, is considered minimally processed tissue and does not require FDA approval. At least 4 commercially available DBM products are reported to contain viable stem cells:

  • Allostem® (AlloSource): partially demineralized allograft bone seeded with adipose-derived MSCs
  • Map3™ (rti surgical) contains cortical cancellous bone chips, DBM, and multipotent adult progenitor cells
  • Osteocel Plus® (NuVasive): DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
  • Trinity Evolution Matrix™ (Orthofix) DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
  • Whether these products can be considered minimally manipulated tissue is debated. A product would not meet the criteria for FDA regulation part 1271.10 if it is dependent upon the metabolic activity of living cells for its primary function. Otherwise, a product would be considered a biologic product and would need to demonstrate safety and efficacy for the product’s intended use with an investigational new drug and Biologics License Application (BLA).

Other products contain DBM and are designed to be mixed with bone marrow aspirate. Some of the products that are currently available are:

  • Fusion Flex™ (Wright Medical): a dehydrated moldable DBM scaffold that will absorb autologous bone marrow aspirate.
  • Ignite® (Wright Medical): an injectable graft with DBM that can be combined with autologous bone marrow aspirate.

Other commercially available products are intended to be mixed with bone marrow aspirate and have received 510(k) clearance, such as:

  • CopiOs sponge or paste (Zimmer): synthetic bone graft material consisting of mineralized, lyophilized collagen.
  • Collage™ Putty (Orthofix): Composed of type-1 bovine collagen and beta tricalcium phosphate.
  • Vitoss® (Stryker, developed by Orthovita): composed of beta tricalcium phosphate.
  • nanOss® Bioactive (rti surgical, developed by Pioneer Surgical): nanostructured hydroxyapatite and an open structured engineered collagen carrier.

FDA product code: MQV

No products using engineered or expanded MSCs have been approved by FDA for orthopedic applications.

In 2008, FDA determined that the mesenchymal stem cells sold by Regenerative Sciences for use in the Regenexx™ procedure would be considered drugs or biological products and thus require submission of a New Drug Application (NDA) or Biologic License Application (BLA) to FDA. (2) In 2014, a federal appellate court upheld FDA’s power to regulate adult stem cells as drugs and biologics and ruled that the Regenexx cell product fell within FDA’s authority to regulate human cells, tissues, and cellular and tissue-based products (HCT/Ps). (3) To date, no NDA or BLA has been approved by FDA for this product. As of 2015, the expanded stemcell procedure is only offered in the Cayman Islands. Regenexx™ network facilities in the United States provide same-day stemcell and blood platelet procedures, which do not require FDA approval (available at http://www.regenexx.com/common-questions/regenexx-fda-clarification\. (Last accessed May 8, 2015.)

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

The Regenexx™ procedure is currently performed in one location (Regenerative Sciences, Centeno Schultz Clinic, Bloomfield, Colorado).

Rationale

This policy was created in 2010 and updated periodically using the MEDLINE database. The most recent literature update was performed through February 25, 2015.

At the time this policy was created, the literature consisted almost entirely of review articles describing the potential of stem-cell therapy for orthopedic applications in humans, along with basic science experiments on sources of mesenchymal stem cells (MSCs), regulation of cell growth and differentiation, and development of scaffolds. (4) Authors of these reviews indicated that the technology was in an early stage of development. In literature searches of the MEDLINE database, use of cultured MSCs in humans was identified in only a few centers in the United States, Europe, and Asia. Since the policy was created, the evidence base has been steadily increasing, although there is a lack of high-quality randomized controlled trials (RCTs), and nearly all of the studies to date have been performed outside of the U.S.

Cartilage Defects

The source of MSCs may have an impact on outcomes, but this is not well understood, and the available literature uses multiple different sources of MSCs. Because of the uncertainty over whether these products are equivalent, the evidence will be grouped by source of MSC.

One systematic review was published in 2013 that included multiple sources of MSC. In 2013, Filardo et al. conducted a systematic review of mesenchymal stem cells for the treatment of cartilage lesions. (5) They identified 72 preclinical papers and 18 clinical reports. Of the 18 clinical reports, none were randomized, 5 were comparative, 6 were case series, and 7 were case reports. The source of MSCs was adipose tissue in 2 clinical studies, bone marrow concentrate in 5, and in 11 studies, the source was bone marrow-derived. Many of these trials had been performed by the same research group in Asia. Following is a summary of the key literature to date, focusing on comparative studies.

MSCs Expanded from Bone Marrow

In December 2013 (after the systematic review by Filardo et al. was published), Wong et al. reported an RCT of cultured MSCs in 56 patients with osteoarthritis who underwent medial opening-wedge high tibial osteotomy and microfracture of a cartilage lesion. (6) Bone marrow was harvested at the time of microfracture and the MSCs were isolated and cultured. After three weeks, the cells were assessed for viability and delivered to the clinic, where patients received an intra-articular injection of MSCs suspended in hyaluronic acid (HA), or for controls, intra-articular injection of HA alone. The primary outcome was the International Knee Documentation Committee (IKDC) score at six months, one year, and two years. Secondary outcomes were the Tegner and Lysholm scores through two years and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system by magnetic resonance imaging (MRI) at one year. All patients completed the two year follow-up. After adjusting for age, baseline scores, and time of evaluation, the group treated with MSCs showed significantly better scores on the IKDC (mean difference, 7.65 on 0-100 scale; p=0.001), Lysholm (mean difference, 7.61 on 0-100 scale; p=0.02), and Tegner (mean difference, 0.64 on a 0 to 10 scale; p=0.02). Blinded analysis of MRI results found higher MOCART scores in the MSC group. The group treated with MSCs had a higher proportion of patients who had complete cartilage coverage of their lesions (32% vs. 0%), greater than 50% cartilage cover (36% vs. 14%) and complete integration of the regenerated cartilage (61% vs. 14%). This study is ongoing and recruiting additional patients.

Wakitani et al. first reported use of expanded MSCs for repair of cartilage defects in 2002. (7) Cells from bone marrow aspirate of 12 patients with osteoarthritic knees were culture expanded, embedded in collagen gel, transplanted into the articular cartilage defect, and covered with autologous periosteum at the time of high tibial osteotomy. Clinical improvement was not found to be different between the experimental group and a group of 12 control patients who underwent high tibial osteotomy alone. Wakitani et al. have since published several cases of patients treated for isolated cartilage defects, with clinical improvement reported at up to 27 months. (8) However, most of the defects appear to have been filled with fibrocartilage. A 2011 report from Wakitani et al. was a follow-up safety study of 31 of the 41 patients (3 patients had died, 5 had undergone total knee arthroplasty) who had received MSCs for articular cartilage repair in their clinics between 1998 and 2008. (8) At a mean of 75 months (range, 5-137) since the index procedure, no tumors or infections were identified. Function was not reported.

Another study from Asia evaluated the efficacy of bone marrow-derived MSCs compared with autologous chondrocyte implantation (ACI) in 36 matched patient pairs. (10) Thirty-six consecutive patients with at least 1 symptomatic chondral lesion on the femoral condyle, trochlea, or patella were matched with 36 cases of ACI performed earlier, based on lesion sites and 10-year age intervals. Autologous MSCs were cultured from 30 mL of bone marrow from the iliac crest, tested to confirm that the cultured cells were MSCs, and implanted beneath a periosteal patch. Concomitant procedures included patella realignment, high -tibial osteotomy, partial meniscectomy, and anterior cruciate ligament reconstruction. Clinical outcomes, measured pre-operatively and at 3, 6, 12, 18, and 24 months after operation using the International Cartilage Repair Society Cartilage Injury Evaluation Package, showed improvement in patients’ scores over the 2-year follow-up in both groups, with no significant difference between groups for any of the outcome measures except for Physical Role Functioning on the 36-Item Short-Form Health Survey, which showed a greater improvement over time in the MSC group.

A 2010 publication from Centeno et al. of Regenerative Sciences describes the use of percutaneously injected culture-expanded MSCs from the iliac spine in 226 patients. (11) Following harvesting, cells were cultured with autologous platelet lysate and re-injected under fluoroscopic guidance into peripheral joints (n=213) or intervertebral discs (n=13). Follow-up for adverse events at a mean of 10.6 months showed 10 cases of probable procedure-related complications (injections or stem-cell related), all of which were considered to be self-limited or treated with simple therapeutic measures. Serial MRIs from a subset of patients showed no evidence of tumor formation at a median follow-up of 15 months. The efficacy of these procedures was not reported. This procedure is no longer offered in the United States.

MSCs Concentrated from Bone Marrow

In 2009, Giannini et al. reported a one-step procedure for transplanting bone marrow-derived cells for Type II (>1.5 cm2, <5 mm deep) osteochondral lesions of the talus in 48 patients. (12) A total of 60 -mL-bone marrow aspirate was collected from the iliac crest. The bone marrow-derived cells were concentrated in the operating room and implanted with a scaffold (collagen powder or HA membrane) and platelet gel. In a 2010 publication, Giannini et al. reported results of a retrospective analysis based on the evolution of the investigator’s technique at the time of treatment. Outcomes following arthroscopic application of the MSC concentrate (n=25) were similar to open (n=10) or arthroscopic (n=46) ACI. (13) ACI with a biodegradable scaffold is not commercially available in the United States (see Related Policies).

Adipose-Derived MSCs

The literature on adipose-derived MSCs for articular cartilage repair comes from 2 different research groups in Korea. One of the groups appears to have been providing this treatment as an option for patients for a number of years. They compare outcomes of this new add-on treatment with those of patients who only received other cartilage repair procedures.

In 2014, Koh et al. reported results of an RCT that evaluated cartilage healing after high tibial osteotomy (HTO) in 52 patients with osteoarthritis of the medial compartment. (14) Patients were randomly assigned via sealed envelopes to HTO with application of platelet-rich plasma (PRP) or HTO with application of PRP plus MSCs. (Use of PRP is considered investigational, see Related Policies for further information.) MSCs from adipose tissue were obtained through liposuction from the buttocks. The tissue was centrifuged and the stromal vascular fraction mixed with PRP for injection. A total of 44 patients completed second look arthroscopy and 1- and 2-year clinical follow-up. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS; 5 subscales with 0-100 scale), the Lysholm score (0-100 scale), and a VAS pain scale (0-100 scale). There were statistically significant differences for PRP only versus PRP+MSC on 2/5 KOOS subscales; pain (74±5.7 vs. 81.2±6.9, p<0.001) and symptoms (75.4±8.5 vs. 82.8±7.2, p=0.006). There were also statistically significant differences on the final pain score for the PRP only versus PRP+MSC groups (16.2±4.6 vs. 10.2±5.7, p<0.001), but the final Lysholm score was not significantly different between the PRP only and PRP+MSC groups (80.6±13.5 vs. 84.7±16.2, all respectively, p=0.36). Articular cartilage healing was rated as improved with MSCs following video review of second-look arthroscopy; blinding of this measure is unclear. There are a number of limitations of this study, including the small sample size, short duration of follow-up, and significant improvements on only some of the outcomes. All of the significant differences in outcomes were modest in magnitude, and as a result, there is uncertainty regarding the clinical significance of the findings.

A 2013 publication from this group reported a retrospective comparison of outcomes from 35 patients (37 ankles), who were older than 50 years of age, had focal osteochondral lesions of the talus, and were treated with microfracture alone between May 2008 and September 2010. (15) The comparison group was 30 patients (31 ankles) who received MSC injection along with marrow stimulation between October 2010 and December 2011. MSCs were harvested from the fat pad of the buttock of the patients 1 day before surgery, concentrated, and injected after the arthroscopic procedure. With an average 22 month follow-up (range, 12-44 months), patients treated with MSCs showed greater improvements in VAS score, American Orthopaedic Foot and Ankle Society Ankle‒Hindfoot Scale, Tegner Activity Scale, and the Roles and Maudsley score. A 2014 retrospective review from this group reported clinical outcomes and MRI results from 49 patients who had undergone marrow stimulation with or without MSCs at their institution. (16) The use of MSCs in addition to microfracture was determined by patient choice, and there was an overlap of 26 patients between this report and their 2013 previously discussed publication.15 This analysis also found modest but statistically significant improvements in clinical outcomes for the MSC group compared with microfracture alone. Blinded ratings with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scale resulted in a score of 49.4 for the conventional group and 62.1 for the MSC group (p=0.037).

Koh et al. also reported a retrospective analysis of the injection of adipose-derived MSCs from the infrapatellar fat pad and PRP into arthroscopically-débrided knees of 25 patients with osteoarthritis of the knee. (17) Results were compared with a randomly selected group of patients who had previously undergone arthroscopic débridement and PRP injections without stem cells. Although there was a trend for greater improvement in the MSC group, at final follow-up, there was no significant difference between the MSC and control groups in clinical outcomes (Lysholm, Tegner, VAS).

Another group reported a Phase I/II trial of intra-articular injection of adipose-derived MSCs for the treatment of osteoarthritis of the knee. (18) Phase I was a dose escalation study in 9 patients, and Phase II assessed efficacy of the highest dose in 9 patients. The study of 18 patients was approved by the Korean Food and Drug Administration. Procedures included liposuction, arthroscopy of the knee 1 week later with MSC injection through the portal, MRI at 3 and 6 months, and second-look arthroscopy with punch biopsy at 6 months. Intent-to-treat analysis showed a 39% improvement in Western Ontario and McMaster Universities Arthritis Index at 6 months after injection and a 45% improvement in VAS. Arthroscopy showed a decrease in size of the cartilage defect and an increase in the volume of cartilage. Histology showed thick, hyaline-like cartilage regeneration. Additional study is needed with a larger sample size, sham-treated controls, and longer follow-up.

MSCs from Peripheral Blood

A 2013 report from Asia described a small RCT with autologous peripheral blood MSCs for focal articular cartilage lesions. (19) Fifty patients with grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling followed by 5 weekly injections of HA. Half of the patients were randomly allocated to receive injections of peripheral blood stem cells or no further treatment. There were baseline differences in age between the groups, with a mean age of 38 years for the treatment group compared with 42 for the control group. The peripheral blood stem cells were harvested after stimulation with recombinant human granulocyte colony-stimulating factor, divided in vials, and cryopreserved. At 6 months after surgery, HA and MSCs were re-administered over 3 weekly injections. At 18 months after surgery, second look arthroscopy on 16 patients in each group showed significantly higher histologic scores (about 10%) for the MSC group (1,066 vs. 957 by independent observers) while blinded evaluation of MRI showed a higher morphologic score (9.9 vs. 8.5). There was no difference in IKDC scores between the two groups at 24 months after surgery. It is uncertain how differences in patient age at baseline may have affected the response to subchondral drilling.

MSCs from Synovial Tissue

Akgun et al. reported a small (N=14), though without major bias, investigator-blinded RCT that compared matrix-induced autologous MSCs from synovial tissue versus matrix-induced autologous chondrocyte implantation (MACI). (20) Both chondrocytes from cartilage and MSCs from synovia were harvested in an arthroscopic procedure, expanded in culture, and then cultured on a collagen membrane for 2 days. Implantation was performed with the construct trimmed to the size and shape of the defect and placed with the cells facing the subchondral bone. Rehabilitation was the same for the 2 groups, with continuous passive motion for at least 1 hour daily and nonweight bearing for the first 6 weeks. The 2 groups were similar at baseline, and all patients completed the evaluations through 24 months. Outcomes on the KOOS subscales and Tegner activity score were statistically better in the MSC group, although it is not clear if the difference observed would be considered clinically significant, with differences of around 6 on the 100-point KOOS subscales and 0.6 on the 10-point Tegner. The results of this small pilot study do suggest that cartilage repair with matrix-induced MSCs from synovial tissue may result in outcomes that are at least as good as MACI, warranting additional study in a larger sample. It should also be noted that neither of these procedures is approved for use in the United States.

Section Summary

The evidence base on MSCs for cartilage repair is increasing, although nearly all studies to date have been performed in Asia with a variety of methods of MSC preparation. Four randomized studies reported an improvement in histological and morphologic outcomes. Three of these studies also reported an improvement in functional outcomes. The method of preparation used in one positive study was to obtain MSCs from bone marrow at the time of microfracture, culture (expand) over a period of 3 weeks, and inject in the knee in a carrier of HA. Another randomized trial, using MSCs from peripheral blood, found improvement in histologic and morphologic outcomes, but not functional outcomes, following stimulation with recombinant human granulocyte colony-stimulating factor. A third small RCT found that MSCs from synovial tissue and cultured on collagen resulted in outcomes that were at least as good as those following MACI.

The literature on adipose-derived MSCs includes a Phase I/II study with cultured MSCs and an RCT from a separate group in Asia that has been using uncultured MSCs as an adjunctive procedure in clinical practice. Comparisons between patients who have and have not received uncultured adipose-derived MSCs shows modest improvement in health outcomes that are of uncertain clinical significance. Potential for bias from non-blinded use of a novel procedure on subjective outcome measures is also a limitation of these studies. The phase I/II study of cultured MSCs from adipose tissue shows promising results for this technology. Additional study in a larger sample of patients with longer follow-up is needed to evaluate the long-term efficacy and safety of the procedure. U.S. Food and Drug Administration (FDA) approval for this method has also not been obtained.

Meniscectomy

In 2014, Vangsness et al. reported an industry-sponsored Phase I/II randomized, double-blind, multicenter study (NCT00225095, NCT00702741) of cultured allogeneic MSCs (Chondrogen™, Osiris Therapeutics) injected into the knee after partial meniscectomy. (21) The 55 patients in this U.S. study were randomized to intra-articular injection of either 50x106 allogeneic MSCs, 150x106 allogeneic MSCs in HA, or HA vehicle control at seven to ten days after meniscectomy. The cultured MSCs were derived from bone-marrow aspirates from unrelated donors. At two year follow-up, 3 patients in the low-dose MSC group had significantly increased meniscal volume measured by MRI (with an a priori determined threshold of at least 15%) compared with none in the control group and none in the high-dose MSC group. There was no significant difference between the groups in the Lysholm Knee Scale. On subgroup analysis, patients with osteoarthritis who received MSCs had a significantly greater reduction in pain at two years compared with patients who received HA alone. This appears to be a post hoc analysis and should be considered preliminary. No serious adverse events were thought to be related to the investigational treatment.

Spinal Fusion

There is limited evidence on the use of allografts with stem cells for fusion of the extremities or spine or for the treatment of nonunion, although several large observational studies are ongoing (see Table 1). In 2014, Eastlack et al. reported outcomes from a series of 182 patients who were treated with anterior cervical discectomy and fusion using Osteocel Plus in a PEEK cage and anterior plating. (22) At 24 months, 74% of patients (180/249 levels treated) were available for follow-up. These patients had significant improvements in clinical outcomes; 87% of levels achieved solid bridging and 92% of levels had range of motion less than 3º. With 26% loss to follow-up at 24 months and lack of a standard of care control group, interpretation of these results is limited.

Osteonecrosis

Two randomized comparative trials from Asia have been identified that evaluated the use of MSCs for osteonecrosis of the femoral head.

MSCs Expanded from Bone Marrow

In 2012, Zhao et al. reported a randomized trial that included 100 patients (104 hips) with early stage femoral head osteonecrosis treated with core decompression and expanded bone marrow MSCs versus core decompression alone. (23) At 60 months after surgery, 2 of the 53 hips (3.7%) treated with MSCs progressed and underwent vascularized bone grafting, compared with 10 of 44 hips (23%) in the decompression group who progressed and underwent either vascularized bone grafting (n=5) or total hip replacement (n=5). The MSC group also had improved Harris Hip Scores compared with the control group on independent evaluation (data presented graphically). The volume of the lesion was also reduced by treatment with MSCs.

MSCs Concentrated from Bone Marrow

Another small trial randomized 40 patients (51 hips) with early stage femoral head osteonecrosis to core decompression plus concentrated bone marrow MSCs or core decompression alone. (24) Blinding of assessments in this small trial was not described. Harris Hip Score was significantly improved in the MSC group (scores of 83.65 and 82.42) compared with core decompression (scores of 76.68 and 77.39). Kaplan-Meier analysis showed improved hip survival in the MSC group (mean, 51.9 weeks) compared with the core decompression group (mean, 46.7 weeks). There were no significant differences between the groups in the radiographic assessment or MRI results.

Section Summary

Two small studies from Asia have compared core decompression alone versus core decompression with MSCs in patients with osteonecrosis of the femoral head. Both studies reported improvement in the Harris Hip Score in patients treated with MSCs, although it was not reported whether the patients or investigators were blinded to the treatment group. Hip survival was significantly improved following treatment with either expanded or concentrated MSCs. The effect appears to be larger with expanded MSCs compared with concentrated MSCs. Additional studies with a larger number of patients are needed to permit greater certainty regarding the effect of this treatment on health outcomes.

Ongoing and Unpublished Clinical Trials

  • A 2014 review on FDA regulations of adult stem cell therapies for sports medicine identified over 45 ongoing clinical trials on this topic. (3) Some of the currently ongoing and unpublished trials that might influence this policy are listed in Table 1. Many are observational studies with commercially available products (Cartistem®, AlloStem®, Trinity Evolution™, and Osteocel® Plus).

Table 1. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

     

NCT01626677/ NCT01041001a

Randomized, Open-Label, Multi-Center and Phase 3 Clinical Trial to Compare the Efficacy and Safety of Cartistem® and Microfracture in Patients With Knee Articular Cartilage Injury or Defect/ Long Term Follow-Up Study of CARTISTEM® Versus Microfracture

104

May 2015

NCT00885729

Mesenchymal Stem Cells in a Clinical Trial to Heal Articular Cartilage Defects

50

2018

NCT01413061a

Study of Subtalar Arthrodesis Using AlloStem® Versus Autologous Bone Graft

140

Feb 2017

Unpublished

     

NCT00965380a

A Radiographic and Clinical Study Evaluating a Novel Allogeneic, Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity Evolution™ Viable Cryopreserved Cellular Bone Matrix) in Posterior Lumbar or Transforaminal Lumbar Interbody Fusion (PLIF or TLIF)

200

Jun 2014

NCT00988338a

A Radiographic and Clinical Study Evaluating a Novel Allogeneic, Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity Evolution™ Matrix) in Subjects Undergoing Foot and Ankle Fusion

106

Jan 2013

NCT00951938a

A Radiographic and Clinical Study Evaluating a Novel Allogeneic, Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity Evolution™ Viable Cryopreserved Cellular Bone Matrix) in Patients Undergoing Anterior Cervical Discectomy and Fusion

200

Aug 2012

NCT00948532a

Osteocel® Plus in eXtreme Lateral Interbody Fusion (XLIF®): Evaluation of Radiographic and Patient Outcomes

104

Oct 2012

NCT00948831a

Osteocel® Plus in Anterior Lumbar Interbody Fusion (ALIF): Evaluation of Radiographic and Patient Outcomes

51

Oct 2012

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Summary of Evidence

Use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method. Current available evidence on procedures using autologous uncultured MSCs for orthopedic indications in humans consists of a few small randomized and non-randomized comparative trials with insufficient data to evaluate health outcomes. Expanded MSCs for orthopedic applications are not U.S. Food and Drug Administration (FDA) approved (concentrated autologous MSCs do not require FDA approval). Due the lack of evidence that clinical outcomes are improved and the lack of regulatory approval, use of stem cells for orthopedic applications is considered investigational.

Practice Guidelines and Position Statements

The American Association of Orthopaedic Surgeons states that stem-cell procedures in orthopedics are still at an experimental stage; most musculoskeletal treatments using stem cells are performed at research centers as part of controlled, clinical trials, and results of studies in animal models provide proof-of-concept that in the future, similar methods could be used to treat osteoarthritis, nonunion of fractures, and bone defects in humans.(25)

In 2006, the Mesenchymal and Tissue Stem-Cell Committee of the International Society for Cellular Therapy proposed a minimal set of criteria to standardize the characterization of multipotent mesenchymal stem cells. (26) The proposed criteria for human MSCs included plastic-adherence when maintained in standard culture conditions; a phenotype of expression of CD105, CD73, and CD90 with a lack surface expression of CD45, CD34, CD14 or CD11b, CD79 alpha or CD19, and HLA-DR surface molecules; and the capability of differentiating into osteoblasts, adipocytes, and chondrocytes using standard in vitro tissue culture-differentiating conditions.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References

  1. U.S. Food and Drug Administration. Assuring safety and efficacy of stem-cell based products. Available online at: http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127182.htm. Last accessed May, 2015.
  2. U.S. Food and Drug Administration. Untitled letter. Guidance, compliance, and regulatory information (Biologics) 2008; . Available online at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/UntitledLetters/ucm091991.htm. Last accessed May, 2015.
  3. Chirba MA, Sweetapple B, Hannon CP, et al. FDA regulation of adult stem cell therapies as used in sports medicine. J Knee Surg. Feb 2015;28(1):55-62. PMID 25603042
  4. Deans TL, Elisseeff JH. Stem cells in musculoskeletal engineered tissue. Curr Opin Biotechnol. Oct 2009; 20(5):537-544. PMID 19879127
  5. Filardo G, Madry H, Jelic M, et al. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. Aug 2013; 21(8):1717-1729. PMID 23306713
  6. Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy. Dec 2013; 29(12):2020-2028. PMID 24286801
  7. Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. Mar 2002; 10(3):199-206. PMID 11869080
  8. Wakitani S, Nawata M, Tensho K, et al. Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med. Jan-Feb 2007; 1(1):74-79. PMID 18038395
  9. Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. Feb 2011; 5(2):146-150. PMID 20603892
  10. Nejadnik H, Hui JH, Feng Choong EP, et al. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. Jun 2010; 38(6):1110-1116. PMID 20392971
  11. Centeno CJ, Schultz JR, Cheever M, et al. Safety and Complications Reporting on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique. Curr Stem Cell Res Ther. Dec 2 2010;5(1):81-93. PMID 19951252
  12. Giannini S, Buda R, Vannini F, et al. One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop Relat Res. Dec 2009; 467(12):3307-3320. PMID 19449082
  13. Giannini S, Buda R, Cavallo M, et al. Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury. Nov 2010; 41(11):1196-1203. PMID 20934692
  14. Koh YG, Kwon OR, Kim YS, et al. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy. Nov 2014;30(11):1453-1460. PMID 25108907
  15. Kim YS, Park EH, Kim YC, et al. Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. May 2013; 41(5):1090-1099. PMID 23460335
  16. Kim YS, Lee HJ, Choi YJ, et al. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. Oct 2014;42(10):2424-2434. PMID 25106781
  17. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. Dec 2012; 19(6):902-907. PMID 22583627
  18. Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. May 2014;32(5):1254-1266. PMID 24449146
  19. Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular Cartilage Regeneration With Autologous Peripheral Blood Stem Cells Versus Hyaluronic Acid: A Randomized Controlled Trial. Arthroscopy. Apr 2013; 29(4):684-694. PMID 23380230
  20. Akgun I, Unlu MC, Erdal OA, et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. Feb 2015;135(2):251-263. PMID 25548122
  21. Vangsness CT, Jr., Farr J, 2nd, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. Jan 15 2014; 96(2):90-98. PMID 24430407
  22. Eastlack RK, Garfin SR, Brown CR, et al. Osteocel plus cellular allograft in anterior cervical discectomy and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine (Phila Pa 1976). Oct 15 2014;39(22):E1331-1337. PMID 25188591
  23. Zhao D, Cui D, Wang B, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. Jan 2012; 50(1):325-330. PMID 22094904
  24. Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty. May 2012; 27(5):679-686. PMID 22000577
  25. American Academy of Orthopaedic Surgeons. Stem cells and orthopaedics. Your Orthopaedic Connection 2007. Available online at: http://orthoinfo.aaos.org/topic.cfm?topic=A00501. Accessed May 2, 2015
  26. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8(4):315-317. PMID 16923606

Coding

Codes

Number

Description

CPT

20999

Unlisted procedure, musculoskeletal system, general

 

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous

 

38230

Bone marrow harvesting for transplantation

 

38241

Bone marrow or blood-derived peripheral stem cell transplantation; autologous

Appendix

N/A

History

Date

Reason

08/09/11

New policy; add to Therapy section.Policy created with literature review through January 2011; considered investigational. ICD-10 codes included in policy.

07/20/12

Replace policy. Policy updated with literature review through February 2012; reference 6 added and references reordered; policy statement unchanged.

08/15/12

Update Related Policies: remove 7.01.48, it was archived.

08/20/12

Update Related Policies – add 2.02.18.

10/09/12

Update Coding Section – ICD-10 codes are now effective 10/01/2014.

04/26/13

Clarification only. Statement within the Benefit Application section stating, “Therefore, requests may be made for an out-of-network facility” was removed, as this conflicts with the FDA statements in the rest of the policy. No other changes.

06/10/13

Replace policy. New policy statement added that allograft bone containing viable stem cells is considered investigational. New policy guideline added that policy does not address unprocessed allograft bone. Regulatory status section updated regarding allograft bone. Rationale updated based on a literature review through March 2013. References 4, and 11-15 added; others renumbered or removed. Policy statement changed as noted.

08/20/13

Update Related Policies. Change title to 2.02.18.

06/19/14

Annual Review. Policy updated with literature review through March 3, 2014; references 5, 13, and 17 added; policy statements unchanged. ICD-10 codes removed in line with code mapping project and implementation delay.

06/09/15

Annual Review. Policy updated with literature review through February 26, 2015; references 3, 14, 16, 18, 20, and 22 added; investigational statement added on bone graft substitutes that must be used with autologous blood or bone marrow aspirate; title changed to “Orthopedic applications of stem cell therapy (including allograft and bone substitute products used with autologous bone marrow)”. Related policies removed: 2.02.18, 7.01.15 and 8.01.55. CPT code 20999 added to policy.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
©2015 Premera All Rights Reserved.