Carticel
Carticel® (autologous cultured chondrocytes), marketed in the United States
and Europe by Genzyme Tissue Repair, employs a commercial process to culture a
patient's own (autologous) cartilage cells, known as chondrocytes, for use in
the repair of clinically significant, symptomatic, cartilage 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 arthoscopic or
other surgical procedure. It is not intended as a treatment for people suffering
from arthritis.
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 debilitating osteoarthritis. These
manifestations can severely hinder a person's normal activities and occupation.
Some people undergo arthroscopic surgery to smooth the surface of the damaged
cartilage area. Other surgical procedures, such as microfracture, drilling, and
abrasion, may provide symptomatic relief, but when they do, the benefit usually
lasts 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
cartilage.
More 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. Approximately 200,000 total
knee replacement operations are performed annually at a cost of about $25,000
each. The artificial joint generally lasts only 10 to 15 years and is considered
a poor option for people under the age of 50.
An Option for Patients
Implantation of autologous cultured chondrocytes, the treatment in
which Carticel is used, was initially researched at the Hospital for Joint
Diseases in New York and further developed at the University of Gothenburg and
Sahlgrënska University Hospital, Gothenburg, Sweden, in an effort to provide a
better therapy for people with joint cartilage damage.
The treatment is used in people who have had an inadequate response to a
prior arthroscopic or other surgical repair procedure with cartilage damage to
the part of the knee formed by the end of the thigh bone. Patients with this
type of damage generally display symptoms that include locking, catching,
localized pain, and swelling.
The treatment starts when a trained orthopedic surgeon provides Genzyme
Tissue Repair with a biopsy of healthy knee cartilage, about the size of a
raisin, from the patient during an arthroscopic procedure. Technicians at the
company's cell processing facility in Cambridge, Mass., use proprietary methods
to grow approximately millions of new cells for that patient.
The cells are then delivered in a vial to the surgeon who implants them into
the defect in a surgical procedure. 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, the 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, similar to the original cartilage.
As of March 31, 2000, 3,952 patients had been treated since Genzyme Tissue
Repair began marketing the product in 1995. The number of people covered by
insurance plans that pay for Carticel® (autologous cultured chonodrocytes) as a
matter of policy in the United States is 136 million. The procedure cost ranges
from $17,000 to $38,000, with an average cost of approximately $26,000 per
procedure. Genzyme Tissue Repair charges $10,360 per procedure for the cells.
During the second half of 1996, the company increased its focus on educating
insurance companies about Carticel®. As a result of this program several health
maintenance and utilization review organizations have established protocols for
selecting patients and determining which patients have defects appropriate for
treatment coverage.
In 1996, the FDA created a policy for regulating cellular and tissue based
products. In August 1997, the FDA issued a biologics license to GTR for Carticel®
under the Accelerated Approval process. Carticel® was the first biologic
product to be approved under the FDA's policy for regulating cellular and
tissue-based products.
CARTICEL®
(autologous cultured chondrocytes)
for Implantation
DESCRIPTION
Autologous cultured chondrocytes, the Carticel® product, are derived
from in vitro expansion of autologous chondrocytes harvested from a patient's
normal, femoral articular cartilage. Biopsies from a lesser-weight bearing area
are the source of chondrocytes which are isolated, expanded through cell
culture, and ultimately implanted into articular cartilage defects beneath an
autologous periosteal flap. Each single use container of autologous cultured
chondrocytes has approximately 12 million cells aseptically processed and
suspended in 0.4 mL of sterile, buffered Dulbecco's Modified Eagles Medium (DMEM).
Prior to final packaging, cell viability is assessed to be at least 80%.
CLINICAL PHARMACOLOGY
Studies have shown that implantation of the Carticel®
product into the articular defect can result in the development of hyaline
cartilage (see Clinical Experience). Hyaline cartilage consists 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. Normal hyaline
cartilage also has an extremely low coefficient of friction at the articular
surface. Damage to articular cartilage from acute or repetitive trauma often
results in pain and disability. Partly because hyaline cartilage is avascular,
spontaneous healing of large defects is not believed to occur in humans, though
a variety of surgical procedures have been used in attempts to promote repair of
cartilage. As cartilage heals after these procedures, fibrocartilage rather than
hyaline cartilage is most commonly produced. Fibrocartilage has limited ability
to withstand shock and shearing forces.
CLINICAL EXPERIENCE
Clinical information regarding the use of autologous cultured
chondrocytes is available from 2 sources: 1) a series of patients treated in
Sweden, and 2) a U.S. patient registry. Patients in the Swedish series received
an autologous cultured chondrocyte product which was produced slightly
differently than Carticel®, the U.S. product.
The series consists of 153 consecutive patients who received autologous
cultured chondrocyte implantations for various defects of the knee. Clinical
follow-up ranged from 1 week to 94 months. Most patients had arthroscopic
evaluation; a subset had biopsy and histological evaluations. Patients presented
with cartilaginous defects of the femoral condyle, patella, tibia, a combination
of these, or osteochondritis dissecans, with or without non-cartilaginous
defects such as anterior cruciate ligament damage requiring repair.
Following autologous cultured chondrocyte implantation, patients were
routinely followed for various durations. All patients were retrospectively
classified as having one of the three clinical outcomes: resumed all activities,
some improvement, or no improvement. Clinical outcomes were also reported for
patient subgroups including: 1) those with femoral condyle lesions who had at
least 18 months of follow-up, and 2) those who failed an earlier procedure. Most
patients were also assessed for arthroscopic outcomes and some patients were
assessed for histological outcomes.
Clinical Outcome - Patients with Femoral Condyle Lesions
A total of 78 of 153 patients in the Swedish series had femoral condyle lesions
with or without concurrent non-cartilaginous knee lesions. Patients had one or
more defects ranging in size from <1-20 cm2. Approximately 90% of
the patients had defects of <10 cm2. Clinical outcomes are shown
below for 40 patients who received autologous cultured chondrocytes and were
evaluable after at least 18 months of follow-up (median = 25; range = 18-94
months). In this evaluation, 70% of the patients demonstrated some clinical
benefit when compared to their pre-operative condition.
Patient Response to Treatment
Clinical Outcome - Failed Earlier Procedures
Debridement of the cartilage defect is often performed along with Carticel® (autologous cultured
chondrocytes) administration. To help differentiate the
effects of the autologous cultured chondrocyte implantation procedure from those
of debridement alone, an analysis was performed on 22 patients who had failed
prior debridement and had a follow-up period after autologous cultured
chondrocyte implantation which was greater than the time period to failure of
their initial debridement. These patients had a range of cartilage defects. At
the end of follow-up, 5 (23%) patients had a functional outcome rating of
"resumed all activities," 8 (36%) patients had a rating of "some
improvement," and 9 (41%) patients had a rating of "no
improvement." Thus, 13/22 (59%) patients who had failed an earlier
debridement had outcomes following autologous cultured chondrocyte implantation
which were more favorable and durable than those following their earlier
therapy.
Histological Outcome
Twenty-two of the initial 23 patients in the Swedish series had histological
evaluation of biopsies from the transplant site. Fifteen of those patients had
defects of the femoral condyle and 7 had defects of the patella. Six of the 15
femoral condyle patients showed only hyaline cartilage on their biopsy, 5 had a
mixture of hyaline and fibrocartilage, and 4 had only fibrocartilage. Of the 6
patients with only hyaline cartilage on biopsy, 2 had minimal to no defects and
4 had more extensive defects (e.g., fissures, fibrillations, etc.).
Arthroscopic Outcome
Most of the 153 patients had arthroscopy. The quality of repair observed at
arthroscopy correlated with the clinical outcomes. A substantial number of
patients were noted at arthroscopy to have tissue hypertrophy (see Adverse
Events).
Data from the US registry included 38 patients with femoral condyle lesions
who received the Carticel® (autologous cultured chondrocytes)
product and had at least 12 months of follow-up. Only functional outcome data
were collected; no arthroscopic or histologic data are available. Although these
patients were rated according to outcome measurements different from those used
in the Swedish series, the results were consistent with the Swedish experience.
Two post-marketing studies are under way to evaluate the long term durability
of the Carticel® repair in patients who have failed a prior surgical
repair procedure. Prior surgical repair procedures are surgical interventions
intended to correct cartilaginous defects such as marrow stimulation techniques,
transplantation of cells or tissues, or debridement followed by an adequate
rehabilitation program. Repair procedures, however, do not include lavage,
biopsy, or diagnostic arthroscopy.
INDICATIONS AND USAGE
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.
WARNINGS
This tissue is intended for autologous use and has not been tested for
biohazards. Health providers should handle this product as if infectious agents
are present.
Carticel® should not be used in patients with a known history of
anaphylaxis to gentamicin. The biopsy medium used to transport the cartilage
biopsies and the culture medium used during the first passage of cells contains
DMEM with gentamicin. All subsequent processing is conducted aseptically and
utilizes cell culture medium that does not contain gentamicin; however, trace
quantities of gentamicin may still be present.
Carticel® should not be used in patients with known sensitivities
to materials of bovine origin. The cell culture medium used during the culturing
of the cells contains bovine serum. The medium used to package and transport the
cells does not contain serum; however, trace quantities of bovine-derived
proteins may still be present.
PRECAUTIONS
General
Implantation of the Carticel® product should be restricted to
physicians who have completed Genzyme Tissue Repair's Surgeon Training Program.
Instability of the knee or abnormal weight-distribution within the joint may
adversely affect the success of the procedure and should be corrected prior to
Carticel® implantation. Abnormal varus loading of the medial
compartment may jeopardize the implant. When treating trochlear defects,
abnormal patellar tracking must be corrected, if possible.
Physical activity should be resumed according to the rehabilitation plan
recommended by the physician. Vigorous activity may compromise the durability of
clinical benefit from Carticel® (autologous cultured chondrocytes).
Tissue hypertrophy was an observed adverse event in clinical studies (see
Adverse Reactions). Patients who develop clinical signs of tissue hypertrophy
should be evaluated with arthroscopy.
Both the long-term effect of cartilage harvesting on knee function and the
long term safety of cartilage implantation are unknown.
The safety of the Carticel® product is unknown in patients with
malignancy in the area of cartilage biopsy or implant. The potential exists for
in vitro expansion and subsequent implantation of malignant or dysplastic cells
present in biopsy tissue. In addition, implantation of normal autologous
chondrocytes could potentially stimulate growth of malignant cells in the area
of the implant, although there have been no reported incidents in humans.
The Carticel® product is shipped following a preliminary
sterility test with a 48 hour incubation to determine absence of microbial
growth. Final (14 day incubation) sterility test results are not available at
the time of implantation.
Do Not Refrigerate, Freeze, or Incubate the Carticel® Shipping
Container or its Contents. The Carticel® product consists of viable,
autologous cells packaged and labeled for implantation within specified time
limits. The Carticel® transport box should be held at room
temperature and remain closed until the time of implantation to ensure proper
storage conditions for the cells.
Do Not Sterilize. If the Vial is Damaged or Sterility has been Compromised,
Do Not Use.
Information for Patients
Patients receiving autologous cultured chondrocytes for treatment of an
articular cartilage defect should receive the following information and
instructions. The rehabilitation protocol provided by the physician must be
closely adhered to. Early motion is very important and should start with leg
supported exercises gradually increasing the number of repetitions. If pain
starts to develop as the next level of activity is increased, decrease activity
to the former level until the pain resolves. If exercise causes pain and/or
swelling, reduce the amount of physical activity. Swelling should be controlled
using ice packs. When walking for the first 6 to 7 weeks, the treated knee
should be supported with two crutches. The patient should attempt to walk with a
normal gait, allowing a quarter of the body weight on the treated knee for the
first 3 weeks, then gradually increasing the amount of weight. At anytime during
the rehabilitation process or after, if sharp pain is experienced with locking
or swelling, contact the physician for medical advice.
Pediatric Use
Safety and effectiveness of Carticel® in pediatric populations has
not been established.
ADVERSE EVENTS
General Adverse Events
Any intra-operative and post-operative complication following knee arthrotomy
may occur after autologous cultured chondrocyte implantation. Of 153 patients
treated with autologous cultured chondrocyte implantation in Sweden, 34 (22%)
patients had the following adverse events (other than hypertrophic tissue, see
below): intra-articular adhesions, 8%; superficial wound infection, 3%;
hypertrophic synovitis, 3%; post-operative hematoma, 2%; adhesions of the bursa
suprapatellaris, 2%; and hypertrophic synovium, 1%. About 1% of patients
developed severe adhesions resulting in "frozen knee" and requiring
lysis. Adverse reactions noted at a level of less than 1% included keloid-like
scar, pannus formation, significant swelling of the joint, pain with
post-operative fever, and hematoma following arthroscopy.
Tissue Hypertrophy
Of 86 patients with a range of defects and at least 18 months of follow-up, 37
(43%) had hypertrophic tissue noted at follow-up arthroscopy. In those
clinically evaluable patients with femoral condyle defects, 10 of 40 (25%) had
some hypertrophic tissue noted at follow-up arthroscopy. The hypertrophic tissue
ranged from a small amount of diffuse excess tissue at the implantation site, to
a distinct ridge of tissue at the margin of the implant, to widespread excess
tissue throughout the joint space. Some of these patients had clinical symptoms
including painful crepitations or "catching." Symptoms generally
resolved after arthroscopic resection of the hypertrophic tissue. Ten percent of
patients with hypertrophy required additional treatment after hypertrophic
tissue recurred following initial resection.
Registry data on 891 patients who received implantation of autologous
cultured chondrocytes were derived from voluntary reporting by surgeons and do
not include those from routine arthroscopy; 131 patients had a follow up of at
least 18 months. After correcting for differences in follow up time, cumulative
rates of patients requiring additional operative procedures were calculated; 18%
of all patients required an additional procedure within 18 months and 11% of all
patients required (at a minimum) shaving, trimming, debridement, or
chondroplasty.
DOSAGE AND ADMINISTRATION
Patients in the Swedish series received a wide range of cell doses per cm2
of defect. Available data on 70 of 78 patients with femoral condyle defects
showed a median dose of 1.6 million cells/cm2 of defect. The middle 80% of these
patients received from 0.64 million to 3.3 million cells/cm2. Each Carticel® (autologous cultured
chondrocytes) finished product vial contains approximately
12 million cells.
Implantation of the Carticel® product is performed during
arthrotomy and requires both preparation of the defect bed and a periosteal flap
to secure the implant. Complete hemostasis must be achieved prior to periosteal
fixation and cell implantation. See the Carticel® Surgical Manual,
GTR document #65021 for instructions on performance of these procedures.
Cell Aspiration and Implantation
(For complete surgical instructions, see Surgical Manual #65021.)
NOTE:
The exterior of the Carticel® vial containing the cultured cells is
NOT sterile. Follow strict sterile technique protocols.
When treating a defect which requires multiple vials of cells, resuspend,
aspirate and inject one vial at a time.
- Remove red plastic lid from vial. Wipe the vial surface and lid with
alcohol.
- Inspect vial contents for particulates, discoloration or turbidity. The
cellular product appears as a yellowish clump in the bottom of the vial. Do
not administer if contents appear turbid prior to cell suspension.
- While holding vial in a vertical position, insert the needle of the
intraspinal catheter into the vial. The needle must be positioned just above
the fluid level. Slowly remove the inner needle from the catheter, leaving
flexible tip behind. Attach a tuberculin syringe to catheter.
- Lower the catheter tip into the media and position just above the cell
pellet. Aspirate all the medium from the vial leaving only the cell pellet
behind. Slowly expel medium back into the vial. This action will break the
cell pellet and resuspend the cells in the medium.
- Lower the catheter tip to the base of the vial and aspirate all contents
into syringe, leaving the vial empty. Slowly inject the contents into the
vial again. This will assure complete suspension of the cells. Repeat these
steps as needed to ensure all cells are resuspended. Cell resuspension is
complete when cell particles are no longer apparent, and the medium is a
consistent, "cloudy" mixture. Aspirate all contents of vial into
syringe. Always hold syringe vertical to keep an air pocket at the proximal
end of syringe.
- Insert the catheter tip through the superior opening of the periosteal
chamber at the site of the defect. Advance catheter to most inferior aspect
of the defect.
- Slowly inject a cell dose while moving the catheter tip from side to side
and withdrawing the catheter proximally. This will ensure an even
distribution of the cells throughout the defect.
- Complete the implantation by closing the superior opening of the
periosteum as instructed. See Carticel® (autologous cultured chondrocytes) Surgical Manual.
HOW SUPPLIED
Each vial contains approximately 12 million autologous cells for a
single implantation procedure. The vial of cells is placed within secondary
packaging capable of maintaining the appropriate storage temperature and cell
viability for up to 72 hours. The shipping vials containing chondrocytes are
accompanied by a technical data sheet with detailed specifications for the
processed cells. Maintain shipping carton at room temperature.
CAUTION
Federal Law restricts Carticel® to sale and use by or on the
order of a physician.
For more information or to obtain Genzyme Tissue Repair documents or
references, contact:
Genzyme Tissue Repair
64 Sidney Street
Cambridge, MA 02139-4136 USA
Telephone: 800-453-6948 or 617-494-8484
Fax: 617-252-0877
Carticel® is a Registered Trademark of Genzyme Corporation,
Cambridge, MA 65001
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