October 8, 2009
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Senior Regulatory Affairs Associate
500 Kendall Street
Cambridge, MA 02142
Re: Carticel (Autologous Cultured Chondrocytes)
BLA STN# 103661
Dear Ms. Maguire:
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) has reviewed a sales aid (ID# C-00182.A - “Sales Aid”) and patient biopsy letters (ID# C-00160.B - 6 Months Letter, ID# C-00163.B - 12 Months Letter, and ID# C-00164.B - 24 Months Letter) for Carticel (Autologous Cultured Chondrocytes) submitted by Genzyme Corporation (Genzyme) under cover of Form FDA 2253.
These promotional materials are false or misleading because they overstate the efficacy and make unsubstantiated comparative claims for Carticel. Therefore, these materials misbrand Carticel under section 502(a) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. §352(a), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(i) and (x).
According to the FDA-approved prescribing information (PI), Carticel is derived from autologous cultured chondrocytes harvested from the patient’s normal, femoral cartilage. Carticel is indicated for the repair of symptomatic cartilage defects of the femoral condyle (medial, lateral or trochlea), caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure (e.g., debridement, microfracture, drilling/abrasion arthroplasty, or osteochondral allograft/autograft).
Carticel should only be used in conjunction with debridement, placement of periosteal flap and rehabilitation. The independent contributions of the autologous cultured chondrocytes and other components of the therapy to outcome are unknown.
Carticel is not indicated for the treatment of cartilage damage associated with generalized osteoarthritis. Carticel is not recommended for patients with total meniscectomy unless surgically reconstructed prior to or concurrent with Carticel implantation.
Misleading Efficacy Claims
Promotional materials are misleading if they represent or suggest that a drug product is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The patient biopsy letters contain the following misleading statements [bolded for emphasis]:
- “Carticel can provide a long-term solution to your cartilage injury, reduce pain and allow you to enjoy many of your favorite activities for years to come.”
- “Carticel can provide a long-term solution to your cartilage injury, reduce pain and allow you to once again enjoy many of your favorite activities.”
- “Carticel may be able to provide you with a long-term solution to your knee pain ... allows many patients to return to a full or higher level of activity.”
The above cited claims, “long-term” and “for years to come,” are misleading because they imply greater (or longer) benefit for Carticel-treated patients than is suggested by the PI or by substantial evidence or substantial clinical experience. The patient biopsy letters fail to present important contextual information that not all patients may benefit from Carticel implantation and that studies in support of Carticel efficacy were no longer than 4 years.
According to the CLINICAL STUDIES section of the PI, two studies were conducted as a condition of approval for Carticel: the Registry Based Study (RBS) and the Study of the Treatment of Articular Repair (STAR). The RBS was a retrospective analysis of data collected for a cohort of 97 Carticel-treated patients, who were followed up at 1, 2, and 3 years. Subjects in the RBS included patients with a history of failed prior non-Carticel repair procedure who then went on to receive Carticel. This study did not include a control group and only 74% of the patients completed the 3-year follow up. The STAR study was an open-label study to assess the effectiveness of Carticel implantation in 154 patients who failed prior non-Carticel procedures. The patients were assessed every 6 months for up to 4 years (48 months). Only 75% of the patients (n = 115) completed the 4-year follow up. In addition, a total of 28 patients discontinued early and 37 patients failed treatment out of the 154 patients enrolled in the STAR study.
Furthermore, the above cited claims that Carticel “allows many patients to return to a full or higher level of activity” are misleading because they overstate the efficacy of Carticel. Specifically, these claims are inconsistent with the PI and misleadingly imply that the majority of patients will experience complete resumption of a wide-range of physical activities when such benefit has not been demonstrated by substantial evidence or substantial clinical experience. According to the PI, 49% (76 of 154) of Carticel-treated patients in the STAR study underwent a subsequent surgical procedure (SSP). SSPs include debridement of cartilage lesion, lysis of adhesions, synovectomy/synovial plica excision, chondroplasty, menisectomy, loose body removal, microfracture, scar tissue removal, release of patellar retinaculum, hardware removal and osteotomy. In addition, the STAR study demonstrated a mean Overall Modified Cincinnati score of 6.39 with a standard deviation of 2.31 in patients who returned for follow-up at 48 months (n = 101). Given the standard deviation, patient outcomes varied from “moderate limitations affect activities of daily living, no sports” to “only a few limitations with sports.”
Likewise, the taglines in the Sales Aid, “Regenerate a Lifestyle,” “Regenerate Hyaline-Like Cartilage,” and “The Path To Getting Your Patients Back in Action,” that are presented in conjunction with the graphic picture of an active tennis player, overstate the efficacy of Carticel and misleadingly suggest that Carticel has been shown to directly impact outcome in patients treated with Carticel. However, according to the PI, the independent contributions of the autologous cultured chondrocytes and other components of the therapy to outcome are unknown.
Misleading Comparative Claims
The Sales Aid presents a bar graph that misleadingly suggests that Carticel is more effective than non-autologous chondrocyte implantation (ACI) procedures when such has not been demonstrated by substantial evidence or substantial clinical experience. Specifically, under the “Long-Term Durability” tab, the Sales Aid presents a bar graph comparing the time to treatment failure (TTF) for Carticel to prior non-ACI procedures in conjunction with the following claim, based on the STAR study:
“The within-patient difference in the TTF for ACI versus non-ACI procedures was at least 31.7 months (P<0.001).”
The bar graph shows a significant difference between the TTF for Carticel versus the TTF for failed prior non-ACI procedures, >46.1 months vs. 3.4 months, respectively. The totality of this presentation misleadingly suggests that Carticel treatment is more effective than non-ACI procedures with regard to TTF.
The within-patient TTF comparison between Carticel and non-ACI procedures is inappropriate because the study was not adequately designed to make this comparison. Specifically, the direct comparison of TTF for Carticel (or ACI) versus prior non-ACI procedures is statistically flawed because the criteria used to determine treatment failure for each of these treatments are different. According to the PI, treatment failure for Carticel was defined as any of the following: (a) the patient underwent surgical retreatment that violated the subchondral bone or reimplantation with Carticel 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 Modified Cincinnati Knee Rating System failed to improve from the baseline knee score over 3 consecutive 6-month intervals. For prior non-ACI surgical procedures, treatment failure was 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 of <5 using the Modified Cincinnati Knee Rating System. Thus, to suggest that Carticel is more effective than non-ACI procedures with regard to TTF is misleading. In fact, Carticel is considered a second-line treatment and is indicated in patients who have had an inadequate response to prior non-ACI procedures such as debridement, microfracture, drilling/abrasion arthroplasty, or osteochondral allograft/autograft. (See above for Carticel’s full indication).
Conclusion and Requested Actions
For the reasons discussed above, your promotional materials misbrand Carticel under section 502(a) of the Act, 21 U.S.C. §352(a), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(i) and (x).
We request that Genzyme immediately cease the dissemination of these violative promotional materials for Carticel, as well as promotional materials with the same or similar claims and representations. Please submit a written response within ten (10) business days of the date of this letter, stating whether you intend to comply with this request, listing all violative promotional materials for Carticel and explaining your plan for discontinuing use of such materials. Please direct your response to Ms. Ele Ibarra-Pratt, RN, MPH, Branch Chief at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, Division of Case Management, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number. We remind you that only written communications are considered official responses.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Carticel comply with each applicable requirement of the Act and FDA implementing regulations.
If you choose to revise your promotional materials, APLB is willing to assist you in assuring that your revised materials comply with applicable provisions of the Act by reviewing your revisions before you use them in promotion.
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research