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April 29, 2010 Approval Letter - Provenge

April 29, 2010

Our STN:  BL 125197/0                                                                                

Dendreon Corporation
Attention:  Elizabeth C. Smith
Vice President of Regulatory Affairs
3005 First Avenue
Seattle, WA 98121

Dear Ms. Smith:

We are issuing Department of Health and Human Services U.S. License No. 1749 to Dendreon Corporation, Seattle, Washington, under the provisions of section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products.  The license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.

Under this license, you are authorized to manufacture the product sipuleucel-T.   Sipuleucel-T is indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

Under this authorization, you are approved to manufacture sipuleucel-T at your facility in Morris Plains, New Jersey.  You may label your product with the proprietary name PROVENGE and will market it in 250 mL infusion bags.

The dating period for sipuleucel-T shall be 18 hours from the date of manufacture when stored at 2-8 °C.  The date of manufacture shall be defined as the time of addition of Lactated Ringer’s Injection, USP to the infusion bag at the end of cell harvest.

You currently are not required to submit samples of future lots of sipuleucel-T to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, under 21 CFR 610.2.  We will continue to monitor compliance with 21 CFR 610.1 requiring completion of tests for conformity with standards applicable to each product prior to release of each lot.

You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing, packaging or labeling of sipuleucel-T, or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14.  You should promptly identify and investigate all manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution.  If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulations, you must submit a report on Form FDA-3486 to the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.

Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert.  We request that the text of information distributed to patients be printed in a minimum of 10-point font.

Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h and FDA Form 2567 as appropriate.  Please provide content of labeling in Structured Product Labeling format.  Please provide three original paper copies for all other labels.

In addition, you may wish to submit two draft copies of the proposed introductory advertising and promotional labeling with an FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. 

All promotional claims must be consistent with and not contrary to approved labeling.  You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).

ADVERSE EVENT REPORTING

You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports as described in 21 CFR 600.81.  You should submit postmarketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology HFM-210, Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448.  Prominently identify all adverse experience reports as described in 21 CFR 600.80.  Per 21 CFR 600.2(f), please refer to http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.

PEDIATRIC REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable. 

We are waiving the pediatric study requirement for this application, because necessary studies are impossible or highly impracticable. This is because the majority of prostate cancer patients are men 65 years of age or older and therefore this condition is unlikely to occur in the pediatric population.

POSTMARKETING REQUIREMENTS UNDER 505(o)

Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)). 

We have concluded that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of cerebrovascular events.

Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious risk.

Therefore, based on appropriate scientific data, we require that you conduct:

  1.  A post-marketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.

We acknowledge the timetable you submitted on March 9, 2010, which states that you will conduct this study according to the following schedule:

Final Protocol Submission: June 30, 2010

Study Completion Date: December 31, 2015

Final Report Submission: September 30, 2016

Interim reports must be submitted to the FDA every six months for the duration of the study. These reports must include the total number of patients treated thus far; the total number of treating sites; the number of treated patients enrolled in the registry (and corresponding number of treating sites); the registry subjects’ survival and stroke experience; the proportion of subjects with each prognostic factor specified in the study protocol, including age and race, categorized by cerebrovascular event status; your assessment of these accumulating data; and your assessment of whether any difficulties in completing the registry study have been encountered.

Please submit the protocol to your IND -b(4)-with a cross-reference letter to this BLA.  Submit all final reports to this BLA, and prominently identify them as appropriate: 

  • Required Postmarketing Protocol under 505(o)
  • Required Postmarketing Final Report under 505(o)
  • Required Postmarketing Correspondence under 505(o)
  • Required Postmarketing Study 6-Month Interim Report under 505(o)

Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any  study or clinical trial required under this section.  This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue.  Section 506B of the FDCA, as well as, 21 CFR 601.70, requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.

We will consider the submission of your annual report under section 506B and 21 CFR 601.70, in addition to the 6-month interim reports described above, to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii), provided that you include the elements listed in 505(o) and 21 CFR 601.70.  We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue.  Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action. Label your annual report an “Annual Status Report of Postmarketing Study Requirements.”

As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our Web site (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm).  Please refer to the July 2009 Draft Guidance for Industry: Postmarketing Studies and Clinical Trials – Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act (see http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM172001.pdf
) for further information.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your letter of April 19, 2010 as outlined below:

  1. -----------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  1. ---------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------
  2. ---------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  3. -----------------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------
  4. -----------b(4)--------------------------------------------------------------------------------------------------------------------------------------------

We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL 125197.

Please use the following designators to prominently label all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Study Correspondence
  • Postmarketing Study Commitment – Final Study Report
  • Supplement Contains Postmarketing Study Commitment – Final Study Report

For each postmarketing commitment not subject to the reporting requirements of 21 CFR 610.70, you may report the status to FDA as a “PMC Submission – Status Update.”  The status report for each commitment should include:

  • The original schedule for the commitment, and
  • The status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted).

When you have fulfilled your commitment, submit your final report as PMC Submission – Final Study Report or Supplement Contains Postmarketing Study Commitment – Final Study Report.

Sincerely yours,

    

Mary A. Malarkey 
Director
Office of Compliance and Biologics Quality
Center for Biologics  Evaluation and Research
Celia M. Witten, Ph.D., M.D. 
Director
Office of Cellular, Tissue and Gene Therapies
Center for Biologics  Evaluation and Research