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`Approved Products > April 29, 2010 Approval Letter - Provenge
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`April 29, 2010 Approval Letter Provenge
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`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.
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`AVENTIS EXHIBIT 2156
`Mylan v. Aventis, IPR2016-00712
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`11/16/2016
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`Approved Products > April 29, 2010 Approval Letter - Provenge
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`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
`(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:
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`Approved Products > April 29, 2010 Approval Letter - Provenge
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`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
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`Study Completion Date: December 31, 2015
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`Final Report Submission: September 30, 2016
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`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
`(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/
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`Guidances/UCM172001.pdf
`(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:
`2. -----------b(4)-------------------------------------------------------------------------------------------------------------------------------
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`a. ---------------b(4)---------------------------------------------------------------------------------------------------------------------
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`b. ---------b(4)---------------------------------------------------------------------------------------------------------------------------
`---------------------------------------------------------------------------------
`c. -----------------b(4)-------------------------------------------------------------------------------------------------------------------
`--------------------------------------------------
`d. -----------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
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