DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and
1401 Rockville Pike
Rockville, MD 20852-1448
August 3, 2010
Director of Regulatory Affairs
3005 First Avenue
Seattle, WA 98121
Re: PROVENGE® (sipuleucel-T)
BLA STN# 125197
Dear Ms. Kim:
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) has reviewed an In Service Kit (P-A-04.10-007.00) (kit) and PROVENGE Detail Aid (P-A-04.10.009.00) (detail aid) for PROVENGE® (sipuleucel-T). Dendreon Corporation (Dendreon) submitted the kit and detail aid under cover of Form FDA 2253 on May 4 and May 27, 2010, respectively.
These promotional materials are false or misleading because they omit and minimize the risks and overstate the efficacy of PROVENGE. Therefore, this material misbrands PROVENGE under sections 502(a) and 201(n) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. §352(a) and §321(n), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(5)(iii) and (e)(6)(i).
According to the FDA-approved prescribing information (PI), PROVENGE is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.
The Warnings and Precautions section of the PI includes, but is not limited to, the following risks for PROVENGE:
PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.
According to the Clinical Studies section of the PI, the effectiveness of PROVENGE was studied in 512 patients, “randomized in a 2:1 ratio to receive PROVENGE (n=341) or control (n=171).” This study “was a randomized, double-blind, placebo-controlled, multicenter trial in patients with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.” As shown in Table 2, the observed median survival time for patients randomized to the PROVENGE arm was 25.8 months and for patients randomized to placebo was 21.7 months. The Hazard Ratio was 0.775 (95% Confidence Interval: 0.614, 0.979). The study achieved a p-value of 0.032 based on a log-rank test (not pre-specified).
Omission and Minimization of Risk Information
Promotional materials are misleading if they fail to reveal facts that are material in light of representations made with respect to consequences that may result from the use of the product as recommended or suggested by the materials.
Specifically, the kit presents a misleading product timeline on the slide entitled, “Is PROVENGE therapy approved for infusion?” The timeline includes “Test Results Complete” before the product arrives at the office, which is contrary to the Warnings and Precautions section of the PI which states that the final (7-day incubation) sterility test results are not available at the time of infusion. Furthermore, the kit omits the Warning and Precaution that the final sterility test results are not available at the time of infusion.
Overstatement of Efficacy
Promotional materials are misleading if they contain a representation or suggestion, not approved or permitted for use in the labeling, that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience.
Page seven of the professional detail aid includes a chart entitled, “Kaplan-Meier Survival Rate Estimates.” This chart presents the percentage of patients alive at 12, 24, 36 and 48 months. This information is misleading because it does not provide sufficient contextual information for the presented survival rate estimates to convey the limitations of the study. For example, the chart does not include a measure of variability, such as the 95% confidence intervals, when presenting the survival rate estimates.
Conclusion and Requested Actions
For the reasons discussed above, your promotional material misbrands PROVENGE under sections 502(a) and 201(n) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §352(a) and §321(n), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(5)(iii) and (e)(6)(i).
We request that Dendreon immediately cease the dissemination of these violative promotional materials for PROVENGE, as well as promotional materials with the same or similar 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 PROVENGE and explaining your plan for discontinuing use of such materials. Please direct your response to Lisa Stockbridge, PhD, Acting 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 PROVENGE 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