Genzyme
Autologous Cultured Chondrocytes – Carticel -Service
Status: approved and marketed in U.S.
Organizations involved:
Genzyme Biosurgery – Manuf.; R&D; Tech.; USA mark.
Genzyme Corp. – Intl. mark.; Parent
Hospital for Joint Diseases – R&D
Sahlgrinska University Hospital – R&D
University of Gothenburg – R&D
Epiontis GmbH – Tech.
Description: Autologous Cultured Chondrocytes or Carticel is both a product and service involving culture of a patient’s own (autologous) cartilage cells (chondrocytes) for implantation back into the knee for the treatment of knee cartilage damage. Biopsies (tissue samples) of femoral articular (knee) cartilage from a lesser-weight bearing area are the source of chondrocytes which are isolated, expanded through cell culture, and ultimately implanted back into the donor’s articular knee cartilage defects beneath a periosteal flap. The cells are implanted for the repair of clinically significant, symptomatic, cartilage defects of the femoral condyle (medial, lateral, or trochlear) of the knee (damage to the part of the knee at the end of the thigh bone) caused by acute or repetitive trauma.
Carticel is supplied in packs of l-4 single-use vials depending upon the size of the defect. Each single use vial of autologous cultured chondrocytes for implantation after resuspension contains approximately 12 million cells aseptically processed and suspended in 0.4 mL of sterile, buffered Dulbecco’s Modified Eagles Medium (DMEM), and labeled for implantation within specified time limits. The product contains no preservatives. Prior to final packaging, cell viability is assessed to be at least 80%. The cultured chondrocytes have a dating period of 72 hours. The Carticel product is shipped following a preliminary sterility test with a 48 hour incubation to determine absence of microbial growth. The Carticel transport box is held at room temperature and remains closed until the time of implantation to ensure proper storage conditions for the cells. Final sterility test results (after 14 days incubation) are not available at the time of implantation into the patient. A new sterility testing method was approved in Feb. 2004, allowing use of BacT/Alert automated microbial detection system for the release of product based on interim negative results at day 3 of a 14-day assay.
Nomenclature: Chondrocytes, autologous [BIO]; Carticel [TR]; Autologous Cultured Chondrocytes [FDA]; cartilage cells, autologous [SY]
Biological.: Once damaged, joint cartilage does not normally regenerate in the body. In addition to causing pain and restricted mobility, chronic injuries to joint cartilage over time may lead to debili-tating osteoarthritis. Partly because hyaline cartilage is avas-cular (no blood supply, capillaries), spontaneous healing of large defects is not believed to occur in humans. A variety of surgical procedures have been attempted to promote repair of cartilage. However, as cartilage heals after these procedures, fibrocartilage rather than hyaline cartilage is most commonly produced, with fibrocartilage having limited ability to withstand shock and shearing forces. Hyaline cartilage also has an extremely low coefficient of friction at the articular surface.
Studies have shown that implantation of the Carticel product into articular defects can result in the development of hyaline cartilage, consisting of chondrocytes (< 5% total volume) and extracellular matrix (> 95% total volume). The matrix contains a variety of macromolecules, including type II collagen and proteoglycan. The structure of the matrix allows the cartilage to absorb shock and withstand shearing and compression forces (like undamaged cartilage).
Companies.: Carticel was developed, and is manufactured by and marketed in the U.S. and Europe by Genzyme Biosurgery, CBER/FDA est. no. 1659 (formerly Genzyme Tissue Repair, est. 1233), a subsidiary of Genzyme Corp.
Implantation of autologous cultured chondrocytes was initially performed at the Hospital for Joint Diseases (New York, NY) and further developed at the University of Gothenburg and Sahlgrinska University Hospital (Gothen-burg, Sweden).
In Nov. 2005, Genzyme announced its will use DNA methylation technology from Epiontis GmbH (Berlin, Germany) to develop quality control tests for Carticel. Epiontis also will provide cell purity and identity assays and tissue-specific biomarkers. Epiontis will receive R&D funding, milestones and technology license payments
Manufacture: The procedure for Carticel is similar to that used by Brittberg et al., in Guttenburg, Sweden (New Eng. J. Med. 331:889, 1994). Biopsy specimens of cartilage obtained during arthroscopic surgery are shipped to Genzyme Biosur-gery using transport kits supplied by the company. The biopsies are enzymatically digested, and freed cells are expanded (cultured) in culture flasks at 37˚C. Cells obtained from biopsies from different patients are physically separated within the incubator. After limited expansion, cells are cryopreserved until a request is received for implantation. Thawed cells are then further expanded/cultured. The time period for expansion is determined by the interval required for producing the required numbers of cells to be used for implantation. This number of cells may vary from 12 million (one vial) to 48 million (four vials), depending upon the number of cells required to fill the patient’s articular cartilage defect. Cells are processed for assembly in a dedicated room within a laminar flow biological safety cabinet used only for product assembly. The cells in the tissue culture flasks are treated with trypsin to remove them from the plastic culture substrate followed by washing. The product is sampled for testing, filled into glass vials, and shipped to the surgeon for implantation.
Neither the patient nor the patient’s expanded cell culture is tested for infectious viral agents. Therefore, all products are subjected to biohazard precautions and labeling. All biopsy samples and cell cultures are handled separately within biological safety cabinets, which are decontaminated between each use. Raw materials and packaging components to be used in the production of Carticel are subjected to appropriate quality control evaluations before use in manufacture.
Genzyme Biosurgery has instituted a number of process controls during the production process to ensure integrity of the final product. Cell cultures are sampled at various points during the manufacturing process and tested for bacterial and fungal contamination. The cells are closely monitored throughout the cell expansion process for morphological characteristics. The manufacturing process is periodically monitored for mycoplasma contamination. Final product must pass internal lot release specifications. Each patient’s cellular product is an independent lot.
The requirement for lot identity and purity is met by cellular morphological assessment, and potency is assessed by cell count and viability. Requirements include microbiologic sterility (direct inoculation, 72 hr prior to assembly); endotoxin (LAL); viability; morphology (> 80% typical chondrocyte); general safety; and trypan blue (> 80% dye-excluding cells). Product not passing lot release specifications may be, depending on the release criterion, retested according to applicable SOP.
FDA class: Biologic BLA
Approvals: Date = 19970822; first approval, BLA, accelerated approval [Note, Carticel had previously been on the market since 1995 as an unregulated autologous cell culturing service]; Indication = for the repair of symptomatic, cartilaginous defects of the femoral condyle (medial, lateral or trochlear)
Date = 20000302; BLA supplement; Indication = narrowing of the indication to second line therapy, for use in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure.
Date =20040217; BLA supplement; Indication = BacT/Alert automated microbial detection system for the release of product based on interim negative results at approximately day 3 of a 14-day assay, as an alternative to prior bacterial contamination detection method (14 day sterility testing), with side-by-side testing using both methods for one year
Date = 20070621; BLA supplement; Indication = addition of new safety and efficacy data from the STAR study (see the Trials section below); and formatting and content changes in compliance with the Physician’s Labeling Rule
Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling]:
Carticel is indicated for the repair of symptomatic, cartilaginous defects of the femoral condyle (medial, lateral or trochlear), caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure.
Carticel is not indicated for the treatment of cartilage damage associated with osteoarthritis. Carticel should only be used in conjunction with debridement, placement of a periosteal flap and rehabilitation. The independent contributions of the autologous cultured chondrocytes and other components of the therapy to outcome are unknown. Data regarding functional outcomes beyond 3 years of autologous cultured chondrocyte treatment are limited.
Status: Historically, a variety of mechanisms have been used in the U.S. to regulate somatic cell products. Depending on the makeup and the intended use of the product, some were regulated as biologics, others as medical devices, and others not at all. Genzyme Tissue Repair (GTR; now Genzyme Biosurgery) began marketing Carticel in 1995 based upon indications: from CBER, FDA that, Carticel, was an autologous cell therapy not subject to regulation. Later that year, CBER notified GTR that Carticel was considered to be a somatic cell therapy product as defined in a Oct. 14, 1993 Federal Register notice concerning human somatic cell and gene therapy products, and advised GTR that marketing approval would be required. GTR submitted a request for product designation to clarify agency jurisdiction, and the agency notified GTR it could continue to market Carticel while jurisdiction was under consideration and policy under development. On May 28, 1996, CBER issued “Guidance on Applications for Products Comprised of Living Autologous Cells Manipulated Ex Vivo and Intended for Structural Repair or Reconstitution,” (these cells are collectively referred to as MAS cells). This notified GTR and other sponsors of MAS cell products that they were manufacturing biological products and that, effective Nov. 1997, those products could be used only under an approved license or IND exemption.
The BLA was filed on March 28, 1996 and granted on Aug. 22, 1997; review time of ~16.9 months (~1.4 years). Carticel was granted accelerated approval based on available Phase II trial data, with continued approval contingent on Genzyme completing confirmatory trials. Carticel was the first biologics license issued for a manipulated autologous structural cell therapy. Because the live cells must be implanted within 72 hours of final harvest, the product has been exempted from the requirements of sterility testing as specified in 21 CFR 610.12 (see below).
Carticel was the first product to be approved under FDA’s, “Guidance in Applications for Products Comprised of Living Autologous Cell Manipulated Ex-Vivo and Intended for Structural Repair or Reconstruction.” A new component of this guidance and Carticel’s approval allowed Genzyme to release Carticel based on its own sampling and testing (i.e., the company is exempt from CBER lot release requirements requiring samples from each lot be approved by FDA prior to release).
As part of the accelerated approval, Genzyme committed to conduct two randomized trials – a double-blinded, placebo-controlled trial of the periosteal flap procedure with and without Carticel treatment in patients with femoral cartilage defects; and an open-label, controlled study of Carticel vs. conventional treatments. Both trials must show superiority of Carticel (for it to retain approval for its original indications:). Genzyme also committed to maintain a patient registry to follow long-term outcomes.
The BLA included information on the biopsy transport kit used to transport cartilage biopsies from the clinical treatment site to company facilities. This kit, regulated as a medical device, was reviewed in Carticel’s BLA and found appropriate for its intended use.
In March 2000, the approved indications: for Carticel were changed, with the product use restricted to second-line use after surgery, i.e., for repair of cartilaginous defects of the femoral condyle in patients with inadequate response to prior surgical repair procedures. The company had been unable to complete enrollment of post-approval studies to confirm the benefit of first-line use (for which it had originally received accelerated approval in 1997). The company issued a “Dear Doctor” letter to U.S. physicians informing them of the change. The company will conduct further studies to confirm the benefits of second-line therapy, comparing long-term outcomes with Carticel to prior surgical repair procedures.
Because the live cells of Carticel must be implanted within 72 hours of final harvest, the product has been exempted from requirements of sterility testing as specified in 21 CFR 610.12. To provide assurance of sterility, Genzyme removes a sample of culture supernatant 72 hours prior to harvest to test for microbial contamination. Product is released for shipment based upon a negative reading of this test. A second sterility test is performed on a sample taken at the conclusion of harvest, cell washing, and resuspension. Both samples are cultured for 14 days in conformance with 21 CFR 610.12 (with this changed in Feb. 2004 to allow release on day three of a 14-day assay with the BaT/Alert automated microbial detection system).
Any positive contamination result from the final product sample is immediately reported to the physician. In addition, because of the time constraints associated with shipment of viable cells, an alternative method for the General Safety test described in 21 CFR 610 was developed, which consists of a combination of three assays accepted as equivalent methods.
No centralized or other European approvals.
Tech. transfer: Genzyme has received chondrocyte culture-related patents including U.S. 6,150,163, “Chondrocyte media formulations and culture procedures,” with claims including use serum-free chondrocyte culture media and enhancement of the differentiation of chondrocytes by supplementation with growth factors – tumor growth factor-beta (TGF-beta) and insulin growth factor (IGF). U.S. 5,786,217, assigned to Genzyme, claims methods and compositions for the repair of articular cartilage defects using chondrogenic cells cultured as multilayered sheets (not fluid-suspended cells as in Carticel).
Trials: Results from a post-marketing study of 41 Carticel recipients with large cartilage lesions were published in the Oct. 26, 1998 issue of the Journal of Orthopedic and Sports Physical Therapy. Average knee function scores improved from a baseline of 3.3 (on a scale of 10) to 6.8 one year after surgery (p < 0.001) and increased to 8.8 two years after surgery (p < 0.001). Significant improvements in pain and swelling were also reported. A second study of the cost-effectiveness of Carticel was published in the November 13, 1998 issue of the American Journal of Orthopedics. Genzyme Biosurgery periodically reports and publishes data from its Cartilage Repair Registry.
In July 2007, Genzyme reported results from the 4-year, open label, prospective Study of the Treatment of Articular Repair (STAR) of Carticel in patients who had an inadequate response to a previous knee cartilage repair procedure. Aautologous chondrocyte implantation provided sustained and meaningful improvements in knee function and reductions in knee pain in this patient population with significant limitations and knee pain at baseline. This study achieved its endpoints and fulfilled Genzyme’s final post-approval commitments to FDA. Carticel's labeling includes the safety and efficacy data from the STAR study.
Medical: Patients with knee cartilage damage generally display symptoms that include knee locking, catching, localized pain, and swelling. Carticel is not a first-line treatment, and is not intended as a treatment for arthritis.
Severe and chronic forms of knee cartilage damage can lead to greater deterioration of the joint cartilage and may eventually lead to some of the many total knee joint replacements performed each year. Artificial joints generally last only 10 to 15 years, and are considered a poor option for people under the age of 50. Some people undergo arthroscopic surgery to smooth the surface of the damaged cartilage area. Other surgical options, such as microfracture, drilling, and abrasion, may provide symptomatic relief, but the benefits often last only a few years, especially if the person’s pre-injury activity level is maintained. These procedures are performed with the intent of allowing bone marrow cells to infiltrate the defect, resulting in the formation of a fibrous cartilage tissue, which is less durable and resilient than normal articular hyaline cartilage.
Treatment starts when a trained orthopedic surgeon provides Genzyme Biosurgery with a biopsy of healthy cartilage from the patient. The company’s cell processing facility in Cambridge, MA, uses proprietary methods to grow millions of new cells from the sample. The cells are then delivered to the surgeon who implants them into the defect in a surgical procedure. Implantation of Carticel product is performed during arthrotomy, and requires both preparation of the defect bed and placement of a periosteal flap to secure the implant. Complete hemostasis must be achieved prior to periosteal fixation and cell implantation. During surgery, the physician carefully removes damaged tissue and prepares the defect for the introduction of the cultured cells. A small piece of the periosteum (tissue covering a bone) is taken from the patient’s lower leg and sutured over the defect to hold the cells in place. The cultured cells are then implanted under the periosteum in the defect where they continue to multiply and integrate with surrounding cartilage to produce durable repair cartilage.
Market: Genzyme reported in late 2009 that "There have been approximately 12,000 Carticel implants
since the product’s introduction in 1995, at the rate of 1,000 to 1,500 procedures a year. It works well for
many patients, with durable results, but has several drawbacks, including its expense—an average of $26,000 per procedure (depending upon how large the defect is and how many vials of cells are required), the difficulty ofhe surgical implantation procedure,
and the inconvenience of a two-stage procedure, in addition to its uncertain efficacy for a large number of patients.
In Jun 2007, Genzyme reported that “More than 13,000 patients in the United States have had Carticel implant,: reported (4/2006) that “since 1995, it has been used in more than 10,000 knees;” and that as of March 31, 2000, 3,952 patients had been treated. Thus, an average of 1,000-1,500/year have received Carticel. For comparison, ~200,000 total knee replacement operations are performed annually in the U.S. at a cost of about $25,000 each.
Carticel sales were $21 million in 2002, $18.5 million in 2001, $20.5 million (est.) in 2000, $15.1 million in 1999, $11.0 million in 1998, and $6.6 million in 1997. Genzyme has not reported annual sales in recent years' releases. The author’s rough guess (with no additional information available) for 2006/2007 sales is in the range of $25-$35 million (est. 1,500 pateints/year each paying $20,000 or more).
The Average Wholesale Price (AWP) is $23,844.00/0.4 mL, 12 million cell vial, with a Direct Price (Manufacturer’s discount) of $19,870.00 (Red Book, 2007).
Carticel is marketed to orthopedic surgeons. Gen-zyme’s marketing strategy is to aggressively develop high-volume usage of Carticel by surgeons in regions where reimbursement for Carticel is easiest to obtain. Marketing programs are designed to increase patient flow to key surgeons in these high focus markets. Non-coverage of Carticel and other therapeutics having received accelerated approval, considered “investigational” treatments by some insurance carriers, had been an issue with Carticel, but this subsided as insurers have come to (or were forced to) recognize that these products have legally received full FDA approval and/or that these products are cost-effective.
Ongoing: In Feb. 2005, Genzyme acquired Verigen AG for up to $50 million. This German company markets matrix-induced autologous chondrocyte implantation in Europe and Australia that has been used in more than 3,200 patients since 1998. Both Verigen’s product/process and Carticel involve culture of autologous chrondocytes for knee repair, but Verigen’s product/process is quicker and easier to use than Carticel. Genzyme plans to develop and seek approval for Verigen technology-based products, and is conducting U.S. clinical studies.
Companies involvement:
Full monograph
650 Chondrocytes, autologous/
Nomenclature:
Chondrocytes, autologous [BIO]
Carticel [TR]
Autologous Cultured Chondrocytes [FDA]
cartilage cells, autologous [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19970822
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
human materials used<!-- humansource -->
autologous cells, human
cartilage, femoral articular (human)
cells, human
chondrocytes, human
Dulbecco's Modified Eagles Medium (DMEM)
human cells, chondrocytes
mammalian cell culture
periosteum
accelerated approval (based on surrogate endpoints) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
exempt from CBER lot release requirements
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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