6. ADVERSE REACTIONS Information on the safety of implanted autologous chondrocytes is derived from the Study of the Treatment of Articular Repair (STAR) [see Clinical Studies (14) ], the Cartilage Repair Registry, the Swedish Series, and post-marketing adverse event reporting. The most common serious adverse events (> 5% of patients) derived from the STAR study include arthrofibrosis/joint adhesion, graft overgrowth, chondromalacia or chondrosis, cartilage injury, graft complication, meniscal lesion and graft delamination. Only serious adverse events were collected in this study. The most common serious adverse events (> 5% of patients), derived from the STAR study include arthrofibrosis/joint adhesions, graft overgrowth, chondromalacia or chondrosis, cartilage injury, graft complication, meniscal lesion and graft delamination. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Vericel at 1-800-453-6948 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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. Table 1: Interventions during Subsequent Surgical Procedures, Regardless of Relationship, in > 2% of Patients Intervention % of 154 Patients Debridement of Cartilage LesionIncludes debridement of index lesion and other defects 31% (47/154) Lysis of Adhesions 14% (21/154) Synovectomy / Synovial Plica Excision 12% (19/154) Other DebridementIncludes debridement of other joint structures in addition to cartilage (e.g., patellar fat pad) 10% (16/154) Chondroplasty 6% (10/154) Meniscectomy 6% (10/154) Loose Body Removal 5% (7/154) Microfracture – Index Lesion 5% (7/154) Scar Tissue Removal 5% (7/154) Release of Patellar Retinaculum 4% (6/154) Hardware Removal 4% (6/154) Microfracture – New Lesion 4% (6/154) Osteotomy 3% (5/154) 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. Table 2: Most Frequent Serious Adverse Events (in ≥ 5% of Patients), Regardless of Relationship, in the STAR Study Serious Adverse Events % of 154 Patients Arthrofibrosis/Joint Adhesions 16% (25/154) Graft Overgrowth 15% (23/154) Chondromalacia or Chondrosis 12% (18/154) Cartilage InjuryEncompasses cartilage injuries throughout the joint e.g., onset of new defects and tibial plateau fibrillation 11% (17/154) Graft ComplicationIncludes periosteal patch complications, graft fraying or fibrillation 10% (15/154) Meniscal Lesion 8% (12/154) Graft Delamination 6% (9/154) Osteoarthritis 5% (7/154) 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. Table 3: Most Frequent Findings (in ≥ 5% of Patients) at Subsequent Surgical Procedures in the Registry Based Study Symptoms or Surgical Findings (MedDRA preferred term) % of 97 Patients Graft Overgrowth 10% (10/97) Partial Graft Delamination 8% (8/97) Chondromalacia 8% (8/97) Arthrofibrosis/Joint Adhesions 8% (8/97) Arthralgia 7% (7/97) Synovitis 6% (6/97) Meniscal Lesion 5% (5/97) Loose Body 5% (5/97) 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. Table 4: Initial ACI Experience Swedish Series Serious Adverse Reactions (Occurring at a frequency of 1% or more) Serious Adverse Reactions % of 153 Patients Tissue Hypertrophy See below Intra-articular Adhesions 8% Superficial Wound Infection 3% Hypertrophic Synovitis 3% Post-operative Hematoma 2% Adhesions of the Bursa Suprapatellaris 2% 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. 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Carticel®. Most of these reactions are reported voluntarily, and it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Furthermore, the reported frequency of spontaneous reports underestimates the true frequency of adverse reactions. As of July 31, 2006, approximately 12,500 patients have been implanted with Carticel and 559 patients have reported serious adverse reactions after treatment. The most frequently identified operative findings in these patients, in descending order of frequency, were graft overgrowth, graft delamination (partial or complete), arthrofibrosis, joint adhesions, meniscus lesion or tear, graft complications, chondromalacia, loose body in knee joint, and joint malalignment.