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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 203214/S-018
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`PF PRISM C.V.
`C/o Pfizer, Inc.
`Attention: Louis M. Ferrara
`Director, Worldwide Regulatory Strategy
`445 Eastern Point Road
`Groton, CT 06340
`
`
`Dear Mr. Ferrara:
`
`Please refer to your supplemental New Drug Application (sNDA) dated May 4, 2017, received
`May 4, 2017, and your amendments, submitted under section 505(b) of the Federal Food, Drug,
`and Cosmetic Act (FDCA), for XELJANZ (tofacitinib), 5 mg and 10 mg tablets.
`
`We acknowledge receipt of your major amendment dated September 28, 2017, which extended
`the goal date by three months.
`
`This Prior Approval supplemental new drug application provides for the treatment of adult
`patients with moderately to severely active ulcerative colitis (UC).
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of prescribing information.
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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
`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, Medication
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`Reference ID: 4269956
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`

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`NDA 203214/S-018
`Page 2
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`Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
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`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
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`We acknowledge your May 10, 2018, submission containing final printed carton and container
`labels.
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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
`active ingredients (which includes new salts and new fixed combinations), 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 studies requirement for ages less than 2 years because necessary
`studies are impossible or highly impracticable. This is because there is a low incidence of the
`disease in this age group. In addition, difficulties exist in differentiating the subtypes of
`inflammatory bowel disease in infants and very young children.
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`We are deferring submission of your pediatric studies for ages 2 to 17 years for this application
`because this product is ready for approval for use in adults and the pediatric studies have not
`been completed.
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must
`be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(C) of the Federal Food,
`Drug, and Cosmetic Act. These required studies are listed below.
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`Reference ID: 4269956
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`

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`NDA 203214/S-018
`Page 3
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`3400-1 A one-year, multi-center, randomized, controlled trial to evaluate the safety,
`efficacy and pharmacokinetics of XELJANZ (tofacitinib) in pediatric patients 2 to
`17 years of age with moderately to severely active ulcerative colitis.
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`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
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`Draft Protocol Submission: 01/2018
`Final Protocol Submission: 10/2018
`Study/Trial Completion:
`04/2022
`Final Report Submission:
`09/2022
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`3400-2 A multi-center open‐label extension study to evaluate the long-term safety of
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`XELJANZ (tofacitinib) in pediatric patients 2 to 17 years of age with moderately
`to severely active ulcerative colitis who participated in PMR 3400-1.
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`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
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`Draft Protocol Submission: 01/2018
`Final Protocol Submission: 10/2018
`Study/Trial Completion:
`03/2024
`Final Report Submission:
`08/2024
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`
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`Submit the protocol(s) to your IND 111294, with a cross-reference letter to this NDA.
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`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) 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.
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`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 the signal of a serious
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`Reference ID: 4269956
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`

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`NDA 203214/S-018
`Page 4
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`risk of malignancies associated with the long-term use of XELJANZ (tofacitinib) in the
`treatment of adults with moderate to severe ulcerative colitis.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk. Therefore, based on
`appropriate scientific data, you are required to conduct the following:
`
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`3400-3 A long‐term, observational study to assess the long‐term safety of tofacitinib 5mg
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`BID or 10mg BID versus other therapies used in the treatment of adults with
`moderately to severely active ulcerative colitis. The study’s primary outcome is
`malignancy. Secondary outcomes of interest include, but are not limited to,
`opportunistic infections, thromboembolic events, and hepatic injury. Specify
`concise case definitions, and provide outcome validation for both primary and
`secondary outcomes. Describe and justify choice of appropriate comparator
`population(s) and estimated background rates relative to tofacitinib-exposed
`patients; clearly define the primary comparator population for the primary
`objective. Design the study around a testable hypothesis to assess, with sufficient
`sample size and power, a clinically meaningful increase in malignancy risk above
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`the comparator background rate, with a pre‐specified statistical analysis method.
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`For the tofacitinib-exposed and comparator(s), the study drug initiation period
`should be clearly defined, including any exclusion and inclusion criteria. Ensure
`adequate number of patients with at least 18 months of tofacitinib exposure at the
`end of the study. Follow for period of at least 7 years.
`
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`Submit the protocol(s) to your IND 111294, with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing 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)”.
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`Submission of the protocol(s) for required postmarketing observational studies to your IND is for
`purposes of administrative tracking only. These studies do not constitute clinical investigations
`pursuant to 21 CFR 312.3(b) and therefore are not subject to the IND requirements under 21
`CFR part 312 or FDA’s regulations under 21 CFR parts 50 (Protection of Human Subjects) and
`56 (Institutional Review Boards).
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`Reference ID: 4269956
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`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
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`Draft Protocol Submission: 09/2018
`Final Protocol Submission: 01/2019
`Study Completion:
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`01/2026
`Interim Report:
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`01/2023
`Final Report Submission:
`06/2026
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`NDA 203214/S-018
`Page 5
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`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.
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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) 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.
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`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
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`We remind you of your postmarketing commitments:
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`3400-4
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`A double‐blind, randomized, controlled clinical trial to assess the relative efficacy
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`of XELJANZ (tofacitinib) 5mg BID versus 10mg BID for maintaining remission
`in patients with moderate to severe ulcerative colitis who are in stable remission
`for at least 6 months on XELJANZ (tofacitinib) 10mg BID therapy.
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`
`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
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`Draft Protocol Submission: 09/2018
`Final Protocol Submission: 12/2018
`Study/Trial Completion:
`01/2024
`Final Report Submission:
`07/2024
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`A controlled clinical trial to assess both the clinical and immunological responses
`to Shingrix vaccination in adult patients with moderately to severely active
`ulcerative colitis treated with XELJANZ (tofacitinib).
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`3400-5
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`Reference ID: 4269956
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`

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`NDA 203214/S-018
`Page 6
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`The timetable you submitted on May 29, 2018, states that you will conduct this study according
`to the following schedule:
`
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`Draft Protocol Submission: 10/2018
`Final Protocol Submission: 03/2019
`Study/Trial Completion:
`05/2022
`Final Report Submission:
`11/2022
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`Submit clinical protocols to your IND 111294 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“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
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`Reference ID: 4269956
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`NDA 203214/S-018
`Page 7
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`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, contact Kelly Richards, Senior Regulatory Health Project Manager, at
`(240) 402-4276.
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`Sincerely,
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`{See appended electronic signature page}
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`Jessica J. Lee, MD, M.M.Sc.
`Associate Director
`Division of Gastroenterology and Inborn Errors Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
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`Reference ID: 4269956
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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/
`------------------------------------------------------------
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`JESSICA J LEE
`05/30/2018
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`Reference ID: 4269956
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