Carticel

CLINICAL PHARMACOLOGY

Hyaline cartilage forms the articular surface of the femoral condyle. Studies have shown that implantation of autologous chondrocytes into the articular defect can result in the development of hyaline-like cartilage [see Clinical Studies].1,2,3,4,5 Normal 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 hyaline 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. However, because hyaline cartilage is avascular, spontaneous healing of large defects is not believed to occur in humans.

A variety of surgical procedures have been used in attempts to promote repair of articular cartilage, and a few studies have evaluated the histology resulting from these interventions. Generally, procedures such as marrow stimulation techniques (MST) have been shown to produce fibrocartilage or hybrid mixtures of fibrocartilage and hyaline cartilage. Published data show that autologous chondrocyte implantation (ACI) is more likely than MST to result in hyaline-like cartilage at the repair site.1,2,4,5 However, because of differences in study design, lesion size and concomitant patient conditions, these data are not sufficient to draw conclusions concerning the long-term correlation of histology and clinical outcomes.

Animal Pharmacology and/or Toxicology

Pre-approval Studies

Bioactivity of autologous chondrocytes implanted under a periosteal patch was reported in the BLA for three rabbit studies6,7,8 of up to 52 weeks duration post-implant and one dog study9 of up to 18 months duration post-implant.

Rabbit Studies
  • Histologic evaluations were performed at 8, 12 and 52 weeks. Improved healing of experimental defects implanted with autologous chondrocytes was observed compared to periosteal flap alone at 8, 12 and 52 weeks.
Dog Study
  • Histologic evaluations were performed at 6 and 12 weeks and 12 and 18 months. Autologous chondrocytes showed improved healing compared to both empty defects and to defects covered with periosteum alone at 6 and 12 weeks. However, by the 12 and 18 month evaluations, the repair tissue had deteriorated so that no advantage of ACI over periosteum alone controls was demonstrated.

Beyond histologic variability of the defect site, no adverse tissue reaction was identified in any animals in these studies.

Post-approval Studies

Five additional large animal, post-approval studies were performed.

Goat Studies
  • Three of four goat studies were 16 weeks in duration. In the fourth study, the goats were sacrificed immediately after periosteal membrane placement. Despite difficulty in postoperative management of goats and resulting subchondral plate collapse in some animals in the 16-week studies, results from all four studies suggested that chondrocytes may contribute to histological repair of focal cartilage lesions. In the only bilateral joint study, serious subchondral collapse and uniformly poor repair resulted in inconclusive data. No safety issues were identified in any of these studies.
Horse Study
  • The 8-week study included two experimental arms in order to model repair of cartilage lesions with or without subchondral penetration. Both models exhibited destruction/dislodgement of the periosteal flap; however, results suggested that chondrocytes may contribute to histologic repair in cartilage defects with subchondral penetration.

While the defects in all animal models exhibited highly variable repair tissue quality (resulting in only moderate histologic scores) the best repairs with implanted chondrocytes produced hyaline-like cartilage characterized by matrix predominating in type II collagen and saffranin-O or toluidine blue staining proteoglycan. Chondrocyte labeling in one of the rabbit studies8 and in an independent study in goats by Dell'Accio et al10 demonstrated that the hyaline-like matrix in these defects was the product of the implanted autologous chondrocytes.

Clinical Studies

Pre-Approval Studies

Clinical information regarding the use of autologous cultured chondrocytes was obtained from 2 open label, observational studies consisting of a series of patients treated in Sweden and the Cartilage Repair Registry. Patients in the Swedish series received an autologous cultured chondrocyte product similar to Carticel (autologous cultured chondrocytes for implantation) .

Swedish Series

The series consists of 153 patients who received autologous chondrocyte implantation for various defects of the knee. Patients presented with cartilage defects of the femoral condyle, patella, tibia, a combination of these, or osteochondritis dissecans, with or without comorbidity such as anterior cruciate ligament insufficiency requiring reconstruction.

Following autologous chondrocyte implantation, patients were followed for various durations. Clinical follow-up ranged from 1 week to 94 months; 86 patients had at least 18 months of follow-up. Most patients had arthroscopic evaluation; a subset had biopsy and histological evaluations. All patients were retrospectively classified as having one of three clinical outcomes: resumed all activities, some improvement, or no improvement. Clinical outcomes were also reported for patient subgroups including: 1) 40 patients with femoral condyle lesions, 2) 12 patients with osteochondritis dissecans lesions and 3) 22 patients who failed a prior debridement.

1) Clinical Outcome - Patients with Femoral Condyle Lesions

A total of 78 of 153 patients had femoral condyle lesions with or without co-morbidity. Patients had one or more defects ranging in size from < 1-20 cm². Of the patients with femoral condyle lesions, 40 were evaluable after at least 18 months (median = 25; range = 18 to 94 months). Clinical outcomes for the 40 patients are summarized in Table 5.

Table 5: Patient Response to Treatment

Defect Resumed All Activities Some Improvement No Improvement Total Patients
Femoral Condyle 7 (29%) 8 (33%) 9 (38%) 24
Femoral Condyle plus other Non-Cartilage Repair 4 (25%) 9 (56%) 3 (19%) 16
Total 11 (28%) 17 (42%) 12 (30%) 40

2) Clinical Outcome – Patients With Osteochondritis Dissecans Lesions

Of the 12 patients who received autologous cultured chondrocytes for treatment of an osteochondritis lesion, 6 of the 12 had “resumed all activities,” 4 had “some improvement” and 2 had “no improvement” after the 18-month (median = 25; range = 18-94 months) follow-up period.

3) Clinical Outcome – Failed Earlier Procedures

Debridement of the cartilage defect is often performed along with administration of autologous cultured chondrocytes. 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 at least as long as the time period to failure of their initial debridement. At the end of follow-up, 5 of the 22 patients had a functional outcome rating of “resumed all activities,” 8 of the 22 patients had a rating of “some improvement” and 9 of the 22 patients had a rating of “no improvement.” Thus, 13 of the 22 patients (59%) who had failed an earlier debridement had outcomes that were more favorable and durable following autologous cultured chondrocyte implantation than their previous debridement without cells.

Histological Outcome

Twenty-two (22) patients in the Swedish series had histological evaluation of biopsies from the implant site one or more years after their autologous chondrocyte implantation. Fifteen (15) of those patients had defects of the femoral condyle and 7 had defects of the patella. Six (6) of the 15 femoral condyle biopsies showed hyaline-like cartilage, 5 had a mixture of hyaline and fibrocartilage, and 4 had only fibrocartilage. Of the 6 biopsies with hyaline-like cartilage, 2 had minimal to no surface irregularities and 4 had some surface irregularities (e.g., fissures, fibrillations, etc.).

Arthroscopic Outcome

As an objective outcome evaluation, 86 of the 153 patients had a follow-up arthroscopy for investigational purposes at 18 months or more post-implantation. In some cases, the quality of repair observed at arthroscopy was considered to be supportive of the clinical or functional outcomes. A substantial number of patients were noted at arthroscopy to have tissue hypertrophy [see ADVERSE REACTIONS].

Cartilage Repair Registry

The Cartilage Repair Registry (CRR) was established upon the introduction of Carticel (autologous cultured chondrocytes for implantation) into orthopedic practice in March of 1995. The CRR was designed to prospectively collect the clinical outcomes of Carticel (autologous cultured chondrocytes for implantation) and other cartilage repair treatments for chondral lesions in the knee. Clinical data were collected at baseline arthroscopy, implantation, intervals of 6 and 12 months, and annually thereafter; adverse reaction data were collected on an ongoing basis through CRR adverse reaction collection and spontaneous reporting. Inclusion in the CRR was based on a qualifying event that was defined as a knee arthroscopy in which a chondral lesion was identified and a cartilage biopsy was harvested. Participation in the CRR was voluntary, and not all patients biopsied or implanted were included. As of November 21, 1997, 891 patients had been implanted worldwide, and 644 of these patients were included in the CRR. Functional outcomes were based on responses to a modified version of the Cincinnati Knee Rating System.

Data from a subset of 191 US patients in the CRR as of December 31, 1996 who had undergone repair of lesions on the femoral condyle (medial, lateral or trochlea) were assessed to support licensure. Patients were between the ages of 15-57, 66% (126/191) were male, and 34% (64/191) were female and one patient's gender was not reported. Of these 191 patients, 38 had at least 12 months of follow-up. At study baseline, these 38 patients' mean rating of overall condition was 3.2, which is defined as fair to poor: limitations that affect activities of daily living-no sports possible. At 12 month follow-up, these patients reported an overall condition score of 6.4 defined as good: some limitation with sports but can participate if patient compensates. 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.

Post-Approval Studies

Two post-approval studies were conducted and completed as a condition of approval for Carticel (autologous cultured chondrocytes for implantation) : the Registry Based Study (RBS) and the Study of the Treatment of Articular Repair (STAR).

Registry-Based Study (RBS)

The RBS was a retrospective analysis of data collected for a cohort of 97 U.S. patients treated between March of 1995 and March of 1997. Of the 97 patients enrolled, 95% completed 1-year follow-up, 80% completed 2-year follow-up and 74% completed 3-year follow-up. Of these 97 patients, 44 were part of the subset of 191 US patients in the CRR described above. A limitation of this study is the lack of a control group. Patients included in this study had a prior non-Carticel (autologous cultured chondrocytes for implantation) cartilage repair procedure (e.g., debridement or marrow stimulation procedure) performed at the time of the index arthroscopy, subsequently failed this procedure and went on to receive Carticel (autologous cultured chondrocytes for implantation) . In the 5 years prior to the index arthroscopy for the study, this patient population had received prior knee surgeries to include: 47% (46/97) of patients had at least one debridement/lavage of a cartilage defect, 25% (24/97) of patients had a bone marrow stimulation procedure, 31% (30/97) had at least one diagnostic arthroscopy, 30% (29/97) had at least one meniscus repair/meniscectomy and 10% (10/97) of patients had a ligament repair/reconstruction performed on the treated knee.

Using a modified Cincinnati Knee Rating System at study baseline, this patient population had a mean overall condition score of 3.1 defined as fair to poor: limitations that affect activities of daily living-no sports possible. Patients included were between the ages of 16-56, 69% (67/97) were male and 31% (30/97) were female. For the type of defect, 62% (60/97) of the defects were acute while 37% (36/97) were chronic. Of the treated defects, 75% (73/97) were treated on the medial femoral condyle (MFC), 26% (25/97) on the lateral femoral condyle (LFC) and 19% (18/97) on the trochlea. Adverse reactions collected during this study are provided in Adverse Reactions (6).

Study of the Treatment of Articular Repair (STAR)

The STAR study was an open-label within patient comparison of a prior non-Carticel (autologous cultured chondrocytes for implantation) (index) procedure to implantation of Carticel (autologous cultured chondrocytes for implantation) for articular cartilage defects of the distal femur. All patients had experienced an inadequate response to a prior non-Carticel (autologous cultured chondrocytes for implantation) surgical treatment, defined as both: a) patient and surgeon agreement that the patient's symptoms/function required surgical re-treatment of the defect and b) the patient's rating of the overall condition of the knee was a score ≤ 5 using the Modified Cincinnati Knee Rating System. In this patient population, the median time to meet the failure criteria was 3.4 months for the prior non-Carticel (autologous cultured chondrocytes for implantation) procedure and 90% of patients failed within 10.3 months. Patients who met these criteria were treated with Carticel (autologous cultured chondrocytes for implantation) and assessed every 6 months for up to 4 years.

Treatment failure for Carticel (autologous cultured chondrocytes for implantation) was defined as any of the following: a) the patient underwent surgical retreatment that violated the subchondral bone or reimplantation with Carticel (autologous cultured chondrocytes for implantation) for the same index defect, b) complete delamination or removal of the graft, or c) the patient's rating of the overall condition of the knee using the Modifi ed Cincinnati Knee Rating System failed to improve from the baseline knee score over 3 consecutive 6-month intervals.

A total of 154 patients were treated with Carticel (autologous cultured chondrocytes for implantation) . At the index surgery required for study entry, patients had one or more of the following interventions: 120 patients (78%) had debridement, 44 patients (29%) had microfracture, 18 (12%) had subchondral drilling, 10 (6%) had abrasion arthroplasty, and 7 (5%) had an osteochondral autograft. The mean lesion size was 4.6 (± 3.2, SD) cm². Fifty patients (32%) had multiple lesions in the reference knee and 29 patients had Carticel (autologous cultured chondrocytes for implantation) implanted in more than one lesion. Lesions that were implanted were located on the medial femoral condyle in 109 patients, lateral femoral condyle in 32 patients and trochlea in 46 patients. Forty patients (26%) had lesions which involved osteochondritis dissecans (OCD).

Of the 154 patients treated with Carticel (autologous cultured chondrocytes for implantation) , 28 patients discontinued the study early. The numbers of patients completing the 24 and 48 month follow-up visits are 136 and 115, respectively. The majority of Carticel (autologous cultured chondrocytes for implantation) patients (N= 117) did not meet failure criteria during the study. By the end of the study, a total of 37 patients met the treatment failure criteria. Results for the 40 patients with OCD lesions were comparable to the total study population as 34 (85%) did not meet the failure criteria for the study and 6 (15%) failed treatment with Carticel (autologous cultured chondrocytes for implantation) . Table 6 illustrates, during each year of follow-up, the number of patients who failed Carticel (autologous cultured chondrocytes for implantation) by the surgical criteria along with the number of patients who failed by the Overall Modified Cincinnati scale criteria.

Table 6: Category and Timing of Treatment Failure for Patients who Met Treatment Failure Criteria (N=37)

  1 Year 2 Years 3 Years 4 Years Total
Patients Who Failed During the Interval 14 11 11 1 37
  Surgery criteria 0 5 5 1 11
  Overall Modified Cincinnati Scale criteria 14 6 6 0 26

The Overall Modifi ed Cincinnati mean baseline score for the patient population as a whole was 3.26, poor: significant limitations that affect activities of daily living, to fair: moderate limitations that affect activities of daily living, no sports possible. At 48 months, the mean score was 6.39, good: some limitations with sports but can participate/compensate. The improvement was statistically significant. Table 7 shows the improvement in the Overall Modified Cincinnati score over time.

Table 7: Mean Overall Modifi ed Cincinnati Score at Baseline and Follow-up Visits

Visit Baseline
N=154
Month 12
N=146
Month 24
N=131
Month 36
N=104
Month 48
N=101
Overall Modified Cincinnati Score1 Mean (SD) 3.26 (1.02) 5.58 (1.99) 5.92 (2.08) 5.87 (2.19) 6.39 (2.31)
1 Scores are for patients who returned for follow-up. Patients who failed by score criteria are included and patients who failed by surgical criteria are excluded from the scores for timepoints after the failure criteria were met.

In addition to the change over time in activity level as measured with the Overall Modified Cincinnati Scale, there were similar and consistent changes in knee symptoms and function as measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS), a measure of knee-specific symptoms and function consisting of the following five subscales: pain, symptoms, sports and recreation, knee-related quality of life, and activities of daily living. At 12 months post-Carticel (autologous cultured chondrocytes for implantation) implant, the mean improvement from baseline for the patient population as a whole in each subscale was as follows: pain 19 (N = 146), symptoms 15 (N = 147), sports and recreation 17 (N = 129), knee-related quality of life 18 (N = 147), and activities of daily living 18 (N = 145). At 48 months post-Carticel (autologous cultured chondrocytes for implantation) implant, the mean improvement from baseline was as follows: pain 24 (N = 100), symptoms 19 (N = 101), sports and recreation 31 (N = 86), knee-related quality of life 32 (N = 101), and activities of daily living 23 (N = 99).

Adverse reactions collected during this study are provided in Adverse Reactions (6).

REFERENCES

1. Knutsen G, Engebretsen L, Ludvigsen T, et al. Autologous chondrocyte implantation compared with microfracture in the knee. J Bone Joint Surg, 2004; 86A:455-464.

2. Bentley G, Biant LC, Carrington RWJ, et al. A prospective, randomized comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br. 2003;85-B:223-230.

3. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889-895.

4. Peterson L, Minas T, Brittberg M, et al. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop. 2000;1(374):212-234.

5. Peterson L, Brittberg M, Kiviranta I, et al. Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med. 2002;30:2-12.

6. Peterson L, Menche D, Grande D, et al. Chondrocyte transplantation-an experimental model in the rabbit. Transactions from the 30th Annual Orthopedic Research Society, Atlanta, February 7-9, 1984. Palatine, III.:Orthopedic Resarch Society, 1984:218. bstract.

7. Grande DA, Pitman MI, Peterson L, et al. The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. J Orthop Res. 1989;7(2):208-18.

8. Brittberg M, Nilsson A, Lindahl A, et al. Rabbit articular cartilage defects treated with autologous cultured chondrocytes. Clin Orthop Relat Res. 1996 May;(326):270-83.

9. Breinan H, Minas T, Barone L, et al. Histological evaluation of the course of healing of canine articular cartilage defects treated with cultured autologous chondrocytes. Tiss Engin 1998; 4(1):101-14.

10. Dell'Accio F, Vanlauwe J, Bellemans, et al. Expanded phenotypically stable chondrocytes persist in the repair tissue and contribute to cartilage matrix formation and structural integration in a goat model of autologous chondrocyte implantation. Journal of Orthopaedic Research 21 2003; 21: 123–131.

Last reviewed on RxList: 12/22/2010
This monograph has been modified to include the generic and brand name in many instances.

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