Medical Policy: 07.01.64
Original Effective Date: May 2014
Reviewed: February 2021
Revised: February 2021
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Damage to the cartilage that covers the ends of the knee bones is common, especially in active individuals.. The ability of cartilage to repair itself is very limited. The damage may lead to later osteoarthritis and a need for knee replacements. Attempts to repair the damaged cartilage have mostly used a procedure called microfracture (MF), involving drilling small holes into the bone under the damaged area. A clot of blood then covers the damaged area and over time forms scar tissue called fibrocartilage. In the procedure called autologous chondrocyte implantation (ACI), a small piece of healthy cartilage is removed from the knee, and the cartilage-producing cells (chondrocytes) are cultured in the laboratory until there are many millions of them. They are then used to patch the area of damaged cartilage. The hope is that the chondrocytes will form natural cartilage, which will last longer than fibrocartilage. For smaller lesions consideration should be given to marrow-stimulating techniques before autologous chondrocyte implantation (ACI) is performed. The average defect size reported in the literature is about 5 cm2, and the support of ACI over bone stimulating techniques in smaller lesions is not proven at this time. Smaller defects not affecting the subchondral bone are usually treated with microfracturing while lesions with loss of subchondral bone can be managed with osteochondral transfer (OAT). There is no universally accepted algorithm for treatment of cartilage defects at this time.
ACI (Autologous Chondrocyte Implant): ACI is a two-step procedure. New cartilage cells are grown and then implanted in the cartilage defect.
ACI is most useful for younger patients who have single defects larger than 2 cm in diameter. ACI has the advantage of using the patient's own cells, so there is no danger of a patient rejecting the tissue. It does have the disadvantage of being a two-stage procedure that requires an open incision. It also takes several weeks to complete.
The culturing of chondrocytes is considered by the FDA to fall into the category of manipulated autologous structural (MAS) cells, which are subject to a biologic licensing requirement. In 2017, production of Carticel® was phased out and MACI® is the only ACI product that is available in the United States. In this policy: MACI is used both to refer to third-generation autologous chondrocyte implantation (ACI) and as a trade name (MACI®).
MACI®, (Vericel) autologous cultured chondrocytes on porcine collagen membrane), a product that was FDA approved in December 2016, an alternative to autologous cultured chondrocytes and growth with Carticel. MACI is intended for autologous use and must only be administered to the patient for whom it was manufactured.
Per the manufacturer, and FDA indications for use: The use of MACI® in pediatric patients or patients over 65 years of age has not been established or FDA approved. The use in this approved age group is directly from inclusion in the SUMMIT trial, which was used to gain FDA approval for MACI. The indications for use on product insert states "MACI® (autologous cultured chondrocytes on porcine collagen membrane) is an autologous cellularized scaffold product indicated for the repair of single or multiple symptomatic, full-thickness cartilage defects of the knee with or without bone involvement in adults."
The manufacturer plans on studying the pediatric population with further studies. Vericel proposed the following timeline for the completion of the clinical pediatric study: Protocol submission, by June 30, 2017; study initiation, by June 30, 2018; study completion by June 30, 2025; and submission of the final report by December 31, 2025.
The available evidence reports that ACI for the treatment of clinically significant, focal defects of the femoral condyle is associated with improved health outcomes such as diminished pain and improved joint function over the short term. However, the available evidence is not sufficient to determine if the improvements are caused by the use of autologous chondrocytes or how the outcomes compare to the outcomes achievable simply by use of debridement with rehabilitation.
In a 2010 clinical practice guideline on the diagnosis and treatment of osteochondritis dissecans (OCD), the American Academy of Orthopaedic Surgeons (AAOS) was unable to recommend for or against a specific cartilage repair technique in symptomatic skeletally immature or mature patients with an unsalvageable osteochondritis dissecans lesion.
NICE issued an updated Technology Appraisal Guidance (2018). The NICE guidance cited the most accurate cost-effectiveness estimate for ACI compared with microfracture is uncertain. The committee published the consensus of surgeons with specialist knowledge of surgical repair techniques for articular chondrocyte defects of the knee. The following recommendations are based on the consensus of specialist.
Autologous chondrocyte implantation (ACI) is recommended as an option for treating symptomatic articular cartilage defects of the knee, only if:
In a 2016 guideline by the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma entitled "Autologous chondrocyte implantation (ACI) for cartilage defects of the Knee" indications for ACI include:
The British Association for Surgery of the Knee (BASK) UK Consensus recommends that all patients being considered for ACI should have had physical therapy first, as that may relieve symptoms.
A recently published evidence report on MACI® (2018) Conclusions: Available evidence is too limited in quantity and quality to determine whether MACI works as well as or better than other ACIs for improving pain and functional status. Larger, blinded randomized controlled trials (RCTs) comparing MACI with microfracture and other ACIs and reporting longer-term outcomes (e.g., quality of life, pain) are needed to assess MACI's comparative safety and effectiveness; however, the only ongoing trial (addressing pediatric patients) will not address the evidence gaps.
A published report on Combined Autologous Chondrocyte Implantation and Osteochondral Autograft for Repairing Osteochondral Knee Defects (2019) found the following conclusions: Evidence from 2 very small case series and 3 case reports at very high risk of bias is insufficient to determine hybrid ACI-OAT’s safety and efficacy. Randomized controlled trials (RCTs) that compare hybrid ACI-OAT to ACI alone and OAT alone, as well as to other cartilage defect treatments, are needed.
The MACI package insert is noted below:
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Warnings and Precautions
The FDA approval was supported by the results of SUMMIT trial (Superiority of MACI implant versus Microfracture Treatment in patients with symptomatic articular cartilage defects in the knee), a Phase 3 two-year, prospective, multicenter, randomized, open-label, parallel-group study that enrolled a total of 144 patients, ages 18 to 54 years, with at least one symptomatic Outerbridge Grade III or IV focal cartilage defect on the medial femoral condyle, lateral femoral condyle, and/or the trochlea co-primary efficacy endpoint was change from baseline to Week 104 for the subject's Knee injury and Osteoarthritis Outcome Score (KOOS) in 2 subscales: Pain and Function (Sports and Recreational Activities [SRA]). At Week 104, KOOS pain and function (SRA) had improved from baseline in both treatment groups, but the improvement was statistically significantly (p<0.001) greater in the MACI group compared with the microfracture group. In a responder analysis, the proportion of subjects with at least a 10-point improvement in both KOOS pain and function (SRA) was greater in the MACI group (63/72 = 87.5%; 95% CI [77.6%, 94.6%]) compared with the microfracture group (49/72 = 68.1%; 95% CI [56.0%, 78.6%]). Patients from the two-year SUMMIT study had the option to enroll in a three-year follow-up study (extension study). A majority of the patients who completed the SUMMIT study also participated in a three-year extension study. The FDA concluded that the overall efficacy data support a long-term clinical benefit from the use of the Maci implant in patients with cartilage defects of the knee. There is a paucity in recent evidence in superiority of autologous chondrocyte implantation versus microfracture or osteochondral transplant. The gaps in data is not being addressed in current clinical trials.
A number of second-generation methods for implanting autologous chondrocytes in a biodegradable matrix are currently in development/testing. These include Atelocollagen (collagen gel, Koken), BioCart II (ProChon Biotech, Phase II trial), Bioseed C (polymer scaffold, BioTissue Technologies) CaReS (collagen gel, Ars Arthro), Cartilix (polymer hydrogel, Cartilix), Cartipatch (solid scaffold with an agarose-alginate matrix, TBF Tissue Engineering, Phase III trial), Chondron (fibrin gel, Sewon Cellontech), Hyalograft C (hyaluronic acid-based scaffold, Fidia Advanced Polymers), NeoCart (ACI with a 3-dimensional chondromatrix, Histogenics. Phase III trial), and Novocart (collagen-chondroitin sulfate scaffold, B. Braun-Tetec). ChondroCelect (characterized chondrocyte implantation, TiGenex, Phase III trial completed) uses a gene marker profile to determine in vivo cartilage-forming potential and thereby optimizes the phenotype (e.g., hyaline cartilage vs. fibrocartilage) of the tissue produced with each ACI implantation cell batch. Each batch of chondrocytes is graded based on the quantitative gene expression of a selection of positive and negative markers for hyaline cartilage formation. Although clinical use of these second-generation ACI products has been reported in Europe and Asia (Chondrosphere (Spherox), only MACI is approved for use in the U.S. at this time.
For information on Osteochondral Transplants see policy 07.01.65
In this policy: (*MACI is used both to refer to third-generation autologous chondrocyte implantation (ACI) and as a trade name (MACI®).
Autologous chondrocyte implantation (also referred to as autologous chondrocyte transplant/ACT), or matrix induced chondrocyte implantation (MACI) with the MACI® product, may be considered medically necessary for the treatment of articular cartilage defects of single joints of the femoral condyle (medial, lateral, or trochlear) or patella caused by acute or repetitive trauma, in the following patients:
If ALL of the above criteria are met, the additional surgical considerations are as follows:
As a first line surgical treatment: For surgical repair of the defect greater than 4 cm²
As a second line surgical treatment: Previous inadequate response to arthroscopic or other surgical repair of the defect (microfracture, drilling) for all defects 2 cm2-4 cm2
The use of MACI for individuals less than 18 years of age without closure of growth plates has not been proven, per FDA product indications “The safety and effectiveness of MACI in pediatric patients have not been established”. The use in pediatric individuals will be considered investigational.
Repeat autologous chondrocyte implantation is considered not medically necessary.
If the procedure does not meet all the medical criteria above, the culturing of chondrocytes will not meet medical criteria.
Autologous chondrocyte implantation for treatment of, but not limited to the following conditions/scenarios is considered investigational:
Autologous chondrocyte implants are investigational for talar lesions or lesions of other joints (e.g., hip and shoulder) because the effectiveness of autologous chondrocyte implants for these lesions has not been established or FDA approved.
The use of non-FDA approved second-generation methods for implanting autologous chondrocytes in a biodegradable matrix and additional non-FDA approved products are investigational for the treatment of osteochondral defects/lesions and all other indications because their effectiveness has not been established. This includes products: Atelocollagen (Koken); Bioseed® C (BioTissue Technologies); CaReS (Ars Arthro); Cartilix (Biomet); Chondron (Sewon Cellontech); Hyalograft C (Fidia Advanced Polymers); NeoCart (Isogonics); Novocart®3D (Aesculap Biologics); ChondroCelect® (TiGenix).and Chondrosphere (Spherox). The main deficiency of the existing evidence is that there are no published controlled studies that compare the outcomes of autologous chondrocyte implant with any other treatments or with the natural progression of the disease. The available studies do report the proportions of patients treated with ACT who achieved various levels of outcomes, but there is no way to determine if those outcomes are better than, the same as, or worse than, the outcomes that would have occurred with other treatments.
The use of autologous chondrocyte implantation and the MACI® (autologous cultured chondrocytes on porcine collagen membrane) procedure as a first line treatment is considered investigational for smaller defects (<4 cm2). Although the studies show promise that the procedures may be more beneficial than microfracture, only short-term outcomes are available, longer term outcomes fail to show superiority of autologous chondrocyte transplant currently. Additional well-designed studies involving larger study populations and long-term follow-up are needed to determine the role of ACI/MACI relative to microfracture or other surgical interventions (microfracture, drilling, osteochondral transplant, allograft transplantation) for the treatment of isolated cartilage defects of the knee in adults. The evidence is considered of very low quality with high or unclear risk of bias.
Softening and swelling
Fragmentation and fissures in area less than 0.5 inch in diameter
Fragmentation and fissures in area larger than 0.5 inch in diameter
Exposed subchondral bone
|MRI Results||Arthroscopy Results|
|GRADE 0||Normal Cartilage||Normal Cartilage|
|GRADE I||focal areas of hyperintensity with normal contour||cartilabe with softening and swelling|
|GRADE II||blister-like swelling/fraying of articular cartilage extending to surface||fragmentation and fissuring within soft areas of articular cartilage|
|GRADE III||partial thickness cartilage loss with focal ulceration||partial thickness cartilage loss with fibrillation|
|GRADE IV||full thickness cartilage loss with underlying bone reactive changes||cartilage destruction with exposed subchondral bone*|
To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
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