The adverse reaction rates as well as the rate and type of subsequent surgical procedures from Carticel® studies of different designs cannot be directly compared amongst each other. Adverse reaction data from these studies do, however, provide a basis for identifying adverse reactions that may be related to product use and for estimating their frequency.

Study of the Treatment of Articular Repair (STAR)

In the STAR study [see Study of the Treatment of Articular Repair (STAR) (14.2.2)], patients who had experienced an inadequate response to a prior cartilage repair procedure underwent Carticel implantation to the index lesion. A total of 154 patients were implanted with Carticel; 28 patients discontinued the study early. The numbers of patients completing the 24 and 48 month follow-up visits are 136 and 115, respectively. Mean patient age was 35 years at consent. The majority of patients were Caucasian (135; 88%) and male (106; 69%).

Seventy-six (76) (49% of 154) patients underwent 113 subsequent surgical procedures (SSPs) on the treated knee, irrespective of relationship to Carticel, during the 4 year follow-up. Of the 76 patients, 52 patients had 1 SSP, 15 patients had 2 SSPs, and 9 patients had 3 or more SSPs. Sixty-one (61) (80%) of the 76 patients who had an SSP underwent a procedure within the first 24 months after implantation. The majority of patients, 83% (63 of the 76), underwent an arthroscopy or manipulation under anesthesia only. Table 1 shows the interventions during SSPs in > 2% of patients.

Lysis of adhesions was the most frequent surgical intervention performed in the first 6 months. After 6 months, cartilage debridement was the most frequently performed intervention. In the STAR study, 61% (46/76) of patients who required an SSP after Carticel did not meet failure criteria by either modified Cincinnati score or surgical criteria (e.g., graft delamination or surgical procedure violating the subchondral bone).

The most clinically significant interventions or findings involving the Carticel graft or periosteal patch are as follows: 3 Carticel grafts were completely removed and 1 was partially removed due to delamination. Partial delamination or fraying of the graft or periosteal patch was reported in 10 additional patients. Four (4) of these patients underwent reattachment/repair of the periosteal patch. Finally, a partially intact graft was found in 1 patient who was re-implanted. Detailed lists of interventions and findings that may have been associated with the graft or periosteal patch are presented in Tables 1 and 2, respectively.

Table 2 shows the serious adverse events (SAEs) that occurred in ≥ 5% of patients, regardless of relationship to study treatment. 

Registry Based Study (RBS)

Data from a cohort of 97 Carticel® treated patients, who were retrospectively evaluated in the Registry Based Study [see Registry-Based Study (RBS) (14.2.1)], showed that 39% (38/97) of patients had a SSP within 3 years of which 63% (24/38) were assessed as related to Carticel. Shaving or trimming (debridement) of overgrown tissue (hypertrophic) commonly relieved patients' symptoms. In the RBS, 67% (16/24) of patients who required arthroscopy after Carticel had a good clinical benefit in terms of improved function and relief of symptoms. Table 3 shows the findings at surgery for the 38 patients who underwent a surgical procedure after Carticel.

Swedish Series

Of 153 patients treated with autologous cultured chondrocyte implantation in the Swedish Series [see Clinical Studies (14)], 22% (34/153) of patients experienced the adverse reactions presented in Table 4 below.

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.

In this series, arthroscopy was scheduled to be undertaken at 18 months of follow-up, regardless of patient symptoms. Of the patients who had arthroscopy, 43% (37/86) had hypertrophic tissue. 

Forty of the 85 patients had femoral condyle defects. Of these, 25% (10/40) of patients had some hypertrophic tissue noted at follow-up arthroscopy. Some patients had clinical symptoms that included painful crepitations or catching, and these symptoms generally resolved after arthroscopic resection of the hypertrophic tissue. Ten percent (10%) of patients with hypertrophy required additional treatment after hypertrophic tissue recurred following initial resection. Not all patients with tissue hypertrophy noted at arthroscopy were symptomatic.