`Silver Spring MD 20993
`
`
`NDA APPROVAL
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`NDA 202379
`
`
`
`
`
`Ortho Biotech Oncology Research and Development
`
`Unit of Cougar Biotechnology, Inc.
`
`Agent for Centocor Ortho Biotech, Inc.
`
`Attention: Christine Woods
`
`10990 Wilshire Blvd., Suite #1200
`
`Los Angeles, CA 90024-3913
`
`
`Dear Ms. Woods:
`
`
`
`
`Please refer to your New Drug Application (NDA) dated December 18, 2010, received
`December 20, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for Zytiga (abiraterone acetate) Tablets, 250 mg.
`
`We acknowledge receipt of your amendments dated January 6 and 28; February 1, 17, 22 and 23;
`March 7, 14, 21, 25, 28, 30, 31; April 4, 8, 12, 13, 18, 19, 22, 25, 26 and 28 (via electronic mail),
`2011.
`
`This new drug application provides for the use of Zytiga (abiraterone acetate) Tablets in
`
`combination with prednisone for the treatment of patients with metastatic castration-resistant
`prostate cancer who have received prior chemotherapy containing docetaxel.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`A shelf-life of 12 months at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to
`30°C (59°F to 86°F) [USP Controlled Room temperature] is approved.
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling text for the package insert and patient
`package insert. Information on submitting SPL files using eLIST may be found in the guidance
`
`for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
`
`Reference ID: 2939553
`
`AVENTIS EXHIBIT 2158
`Mylan v. Aventis, IPR2016-00712
`
`1
`
`
`
`NDA 202379
`Page 2
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`
`
`
` CONTAINER LABEL
`
`Submit a final printed container label that is identical to the container label submitted on
`April 22, 2011 as soon as it is available, but no more than 30 days after it is printed. Please
`submit this label electronically according to the guidance for industry titled “Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Final Printed
`Container Label for approved NDA 202379.” Approval of this submission by FDA is not
`required before the label is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`
`
`MARKET PACKAGE
`
`
`
`
`Please submit one market package of the drug product when it is available.
`
`If sending via USPS, please send to:
`
`
`Amy Tilley
`Food and Drug Administration
`Center for Drug Evaluation and
`Research
`White Oak Building 22, Room: 2177
`10903 New Hampshire Avenue
`Silver Spring, Maryland 20993
`
`
`
`
`If sending via any carrier other than USPS
`(e.g., UPS, DHL), please send to:
`
`
`Amy Tilley
`Food and Drug Administration
`Center for Drug Evaluation and
`Research
`White Oak Building 22, Room: 2177
`10903 New Hampshire Avenue
`Silver Spring, Maryland 20993
`
`
`
`Reference ID: 2939553
`
`2
`
`
`
`NDA 202379
`Page 3
`
`
`
`Your application for Zytiga was not referred to an FDA advisory committee because outside
`expertise was not necessary; there were no controversial issues that would benefit from advisory
`committee discussion.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`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(s) 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 because the disease does not exist in children.
`
`
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`
`Section 505(o)(3) of the 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.
`
`We have determined 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 an in vivo drug interaction in which abiraterone could increase concentrations of sensitive
`CYP2C8 substrates..
`
`
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA is not yet sufficient to assess this serious risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
` Perform an in vitro screen to determine if abiraterone is an inhibitor of human
`1748-1
`
`CYP2C8. Based on results from the in vitro screen, a clinical drug-drug
`interaction trial may be needed.
`
`
`The timetable you submitted on April 19, 2011, states that you will conduct this study according
`to the following schedule:
`
`
`Study Completion:
`
`Final Report Submission:
`
`January 2012
`
`June 2012
`
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify an unexpected serious risk of: 1) an increase in abiraterone
`exposure in individuals with severe hepatic impairment; 2) a decrease in abiraterone
`concentrations when abiraterone acetate is co-administered with a potent CYP3A inducer, and;
`
`
`Reference ID: 2939553
`
`3
`
`
`
`NDA 202379
`Page 4
`
`3) an increase in abiraterone concentrations when abiraterone acetate is co-administered with a
`potent CYP3A inhibitor.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`
`1748-2
`
`Conduct a trial to determine the pharmacokinetics of abiraterone after an oral dose
`of abiraterone acetate in individuals with severe hepatic impairment. The
`proposed protocol should contain the rationale for dose selection, and must be
`submitted for review prior to trial initiation. In the design of the trial, consider
`development of lower dosage strengths to allow for administration of a safe dose
`in patients with severe hepatic impairment.
`
`
`
`
`The timetable you submitted on April 19, 2011, states that you will conduct this trial according
`to the following schedule:
`
`Final Protocol Submission: October 2011
`
`Trial Completion:
`October 2013
`
`
`
`Final Report Submission: April 2014
`
`
`
`The timetable you submitted on April 19, 2011, states that you will conduct this trial according
`to the following schedule:
`
`
`
`1748-3
`
`
`
`1748-4
`
`Conduct a drug-drug interaction trial to evaluate the effect of a strong CYP3A
`inducer (e.g., rifampin) on the pharmacokinetics of abiraterone after an oral dose
`of abiraterone acetate. The proposed trial protocol must be submitted for review
`prior to trial initiation.
`
`Final Protocol Submission: October 2011
`
`Trial Completion:
`April 2013
`
`
`Final Report Submission: November 2013
`
`
`Conduct a drug-drug interaction trial to evaluate the effect of a strong CYP3A4
`inhibitor (e.g., ketoconazole) on the pharmacokinetics of abiraterone after an oral
`dose of abiraterone acetate. The proposed trial protocol must be submitted for
`review prior to trial initiation.
`
`
`The timetable you submitted on April 19, 2011, states that you will conduct this trial according
`to the following schedule:
`
`
`Final Protocol Submission: October 2011
`
`Trial Completion:
`April 2013
`
`
`Final Report Submission: November 2013
`
`
`
`
`Reference ID: 2939553
`
`4
`
`
`
`NDA 202379
`Page 5
`
`
`
`Submit the protocol to your IND 071023, with a cross-reference letter to this NDA. Submit all
`final report(s) to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence 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 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) 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
`314.81(b)(2)(vii). 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.
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`
`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`METHODS VALIDATION
`
`
`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`Reference ID: 2939553
`
`5
`
`
`
`NDA 202379
`Page 6
`
`
`
`
`
` REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
` MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
` POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, contact Amy Tilley, Regulatory Project Manager, at 301-796-3994.
`
`
`
`Sincerely,
`
`
`
` {See appended electronic signature page}
`
`Richard Pazdur, M.D.
`
` Director
`Office of Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`
`ENCLOSURES:
`Content of Labeling
`Container Label
`
`
`Reference ID: 2939553
`
`
`
`6
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`04/28/2011
`
`Reference ID: 2939553
`
`7