Food and Drug Administration
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` Silver Spring MD 20993
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 203971
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` NDA APPROVAL
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` Bayer HealthCare Pharmaceuticals
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`Attention: Deepika Jalota, Pharm.D.
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` Deputy Director, Global Regulatory Affairs
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` P.O. Box 1000
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` Montville, NJ 07045
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`Dear Dr. Jalota:
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`Please refer to your New Drug Application (NDA) dated December 14, 2012, received
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`December 14, 2012, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for Xofigo® (radium Ra 223 dichloride) Injection, 1000 kBq/mL (0.027
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`microcurie/mL) at reference date.
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`We acknowledge receipt of your amendments dated December 18, 21, 2012, January 9, 10, 16,
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`22, 24, 25, 29, 31, February 4, 5, 7, 8, 13, 19, 25, 26, 28, March 5, 6, 7, 8, 13, 14, 18, 19, 21,
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`22,25, 26, 27, 28, April 1, 2, 5, 23, 26, 30, May 2, 10, 13, 2013.
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`This new drug application provides for the use of Xofigo® (radium Ra 223 dichloride) Injection
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`for the treatment of patients with castration-resistant prostate cancer, symptomatic bone
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`metastases and no known visceral metastatic disease.
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`We have completed our review of this application, as amended. It is approved, effective on the
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`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert). Information
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`on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for
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`Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`Reference ID: 3308326
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`AVENTIS EXHIBIT 2166
`Mylan v. Aventis, IPR2016-00712
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`1
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`NDA 203971
`Page 2
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` CARTON AND IMMEDIATE-CONTAINER LABELS
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` Submit final printed carton and immediate-container labels that are identical to the enclosed
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` carton and immediate-container labels and/or carton, as soon as they are available, but no more
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` than 30 days after they are printed. Please submit these labels electronically according to the
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` guidance for industry Providing Regulatory Submissions in Electronic Format – Human
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` Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
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` (June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually
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` mounted on heavy-weight paper or similar material. For administrative purposes, designate this
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` submission “Final Printed Carton and Container Labels for approved NDA 203971.” Approval
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` of this submission by FDA is not required before the labeling is used.
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`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
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`the product misbranded and an unapproved new drug.
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`EXPIRY DATING AND STORAGE CONDITIONS
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`The drug product is granted a shelf-life of 28 days stored below 40 °C.
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`MARKET PACKAGE
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`Please submit one market package of the drug product when it is available to the following
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`address:
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`Elleni Alebachew, M.S. RAC
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`White Oak Building 22, Room: 2183
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`10903 New Hampshire Avenue
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`Silver Spring, Maryland
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`Use zip code 20903 if shipping via United States Postal Service (USPS).
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`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
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`ADVISORY COMMITTEE
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`Your application for Xofigo® (radium Ra 223 dichloride) Injection was not referred to an FDA
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`advisory committee because the application showed improvement in overall survival and did not
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`raise significant safety or efficacy issues.
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` REQUIRED PEDIATRIC ASSESSMENTS
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` Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
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` active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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` administration are required to contain an assessment of the safety and effectiveness of the
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` product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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` deferred, or inapplicable.
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`Reference ID: 3308326
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`2
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`NDA 203971
`Page 3
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`We are waiving the pediatric study requirement for this application because necessary studies are
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`impossible or highly impracticable as this indication does not occur in children.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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`biological product applications to conduct postmarketing studies and clinical trials for certain
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`purposes, if FDA makes certain findings required by the statute.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
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`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a known serious risk of
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`long-term bone marrow suppression and to identify an unexpected serious risk of developing
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`secondary malignancies.
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` Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following:
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`2041-1 An observational study (N = 1200) to assess the long-term safety of radium Ra
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`223 dichloride 50 kBq/kg every 4 weeks for 6 doses in patients with castration-
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`resistant prostate cancer with bone metastases.
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`The timetable you submitted on April 26, 2013 and on May 2, 2013, states that you will conduct
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`this trial according to the following schedule:
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`09/2013
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`Final Protocol Submission:
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`09/2017
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`First Interim Report Submission:
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`Second Interim Report Submission: 09/2019
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`Study Completion:
`12/2023
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`Final Report Submission:
`09/2024
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
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`study) will be sufficient to assess the known serious risk of bone marrow suppression and
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`identify an unexpected serious risk of developing secondary malignancies.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following:
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`2041-2 A randomized clinical trial to assess the safety of radium Ra 223 dichloride in
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`patients with castration-resistant prostate cancer, symptomatic bone metastases
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`and no known visceral metastatic disease.
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`Reference ID: 3308326
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`3
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`NDA 203971
`Page 4
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`The timetable you submitted on April 26, 2013 and on May 2, 2013, states that you will conduct
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`this trial according to the following schedule:
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`08/2013
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`09/2016
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`03/2017
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`01/2024
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`Final Protocol Submission:
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`Trial Completion:
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`Interim Report
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`Final Report Submission:
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`, with a cross-reference letter to this NDA. Submit all
`Submit the protocol(s) to your
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`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
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`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
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`study or clinical trial required under this section. This section also requires you to periodically
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`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
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`report annually on the status of any postmarketing commitments or required studies or clinical
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`trials.
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`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)
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`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
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`remind you that to comply with 505(o), your annual report must also include a report on the
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`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
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`submit an annual report for studies or clinical trials required under 505(o) on the date required
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`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
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`action.
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`Reference ID: 3308326
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` The timetable you submitted on April 26, 2013 and on May 2, 2013, states that you will conduct
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` this trial according to the following schedule:
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`Final Protocol Submission:
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`Trial Completion:
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`Interim Report Submission:
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`Final Report Submission:
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`2041-3 A trial of the short and long-term safety of re-treatment of patients with
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`castration-resistant prostate cancer with bone metastases with radium Ra 223
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`dichloride.
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`12/2013
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`12/2017
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`09/2018
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`03/2025
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`(b) (4)
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`4
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`NDA 203971
`Page 5
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` POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
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` UNDER SECTION 506B
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` We remind you of your postmarketing commitments:
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` 2041-4 Optimize the dosing regimen of Xofigo by conducting a randomized Phase 2 clinical
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` trial to evaluate the efficacy and safety of Xofigo at a dose higher than 50 kBq/kg in
` patients with castration-resistant prostate cancer with bone metastases.
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`Depending on the results of the Phase 2 trial, a randomized Phase 3 trial may be
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`needed to further confirm the appropriateness of the dosing regimen determined in the
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`Phase 2 trial.
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`The timetable you submitted on May 2, 2013, states that you will conduct this trial according to
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`the following schedule:
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`Submit clinical protocols to your IND 067521 for this product. Submit nonclinical and
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`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
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`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
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`status summary of each commitment in your annual report to this NDA. The status summary
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`should include expected summary completion and final report submission dates, any changes in
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`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
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`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
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`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
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`proposed materials in draft or mock-up form with annotated references, and the package insert
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`to:
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
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`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
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`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
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`Reference ID: 3308326
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`Final Protocol Submission:
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`Trial Completion:
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`Final Report Submission:
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`09/2013
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`09/2018
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`03/2019
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`5
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`NDA 203971
`Page 6
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` information about submission of promotional materials to the Office of Prescription Drug
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` Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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` METHODS VALIDATION
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` We have not completed validation of the regulatory methods. However, we expect your
` continued cooperation to resolve any problems that may be identified.
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`REPORTING REQUIREMENTS
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` We remind you that you must comply with reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
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`event reports that are received directly by the FDA. New molecular entities and important new
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`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
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`copies of reports for this product. To participate in the program, please see the enrollment
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`instructions and program description details at
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`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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`POST-ACTION FEEDBACK MEETING
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`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
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`meetings are used to discuss the quality of the application and to evaluate the communication
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`process during drug development and marketing application review. The purpose is to learn
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`from successful aspects of the review process and to identify areas that could benefit from
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`improvement. If you would like to have such a meeting with us, call the Regulatory Project
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`Manager for this application.
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`PDUFA V APPLICANT INTERVIEW
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`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
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`and final assessment of the Program for Enhanced Review Transparency and Communication for
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`NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
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`Letter states that these assessments will include interviews with applicants following FDA action
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`on applications reviewed in the Program. The purpose of the interview is to better understand
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`applicant experiences with the Program and its ability to improve transparency and
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`communication during FDA review.
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`You will be contacted by ERG to schedule the interview following this action on your
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`application; ERG will provide specifics about the interview process at that time. Your responses
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`during the interview will be confidential with respect to the FDA review team. ERG has signed a
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`non-disclosure agreement and will not disclose any identifying information to anyone outside
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`their project team. They will report only anonymized results and findings in the interim and final
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`assessments. Members of the FDA review team will be interviewed by ERG separately. While
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`Reference ID: 3308326
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`6
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`NDA 203971
`Page 7
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`Sincerely,
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` {See appended electronic signature page}
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`Richard Pazdur, M.D.
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`Director
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`Office of Hematology and Oncology Products
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`Center for Drug Evaluation and Research
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` Enclosure(s):
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`Content of Labeling
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`Carton and Container Labeling
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`Reference ID: 3308326
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` your participation in the interview is voluntary, your feedback will be helpful to these
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` assessments.
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`If you have any questions, call Elleni Alebachew, Regulatory Health Project Manager, at
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`(301) 796-5225.
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`7
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`

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`---------------------------------------------------------------------------------------------------------
`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
`05/15/2013
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`Reference ID: 3308326
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`8