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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`203214Orig1s000
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`APPROVAL LETTER
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 203214/Original 1
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
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`Pfizer Inc.
`445 Eastern Point Road
`Groton, CT 06340
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`Attention: Nickie V. Kilgore, D.V.M.
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`Director
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`Worldwide Regulatory Strategy
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`Dear Dr. Kilgore:
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`Please refer to your New Drug Application (NDA) dated October 21, 2011, received October 21,
`2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Xeljanz (tofacitinib) Tablets, 5 mg.
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`We acknowledge receipt of your amendments dated October 25, and December 16 and 20, 2011,
`and January 13 and 31, February 1, 8, 16, and 20, March 20, 22, 23, 28 (2), and 30, April 3, 10,
`23, and 30, May 21, 22, and 24, June 5, 8, 11, 15 (2), 19, 22, and 25, July 6, 16, and 20, August
`1, 2, 10, 13, and 14, September 5, October 2, 16, 23, and 29 (2), and November 2 and 5 (2),
`2012.
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`NDA 203214 provides for the use of Xeljanz (tofacitinib) Tablets for the treatment of adult
`patients with moderately to severely active rheumatoid arthritis who have had an inadequate
`response or intolerance to methotrexate, to be used as monotherapy or in combination with
`methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). For
`administrative purposes, we have designated this NDA as follows:
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` NDA 203214/Original 1 – 5 mg twice daily
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`The subject of this action letter is NDA 203214/Original 1.
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`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.
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`Reference ID: 3213422
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`(b) (4)
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`(b) (4)
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`NDA 203214/Original 1
`Page 2
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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
`Guide). 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 available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
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`CARTON AND IMMEDIATE-CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels submitted on August 14, 2012, as soon as they are available, but no
`more than 30 days after they are printed. Please submit these labels 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 Carton and Container Labels for approved NDA
`203214/Original 1.” Approval 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
`the product misbranded and an unapproved new it is available.
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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, 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.
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`We are waiving the pediatric study requirement for ages 0 to < 2 years of age because necessary
`studies are impossible or highly impracticable as polyarticular juvenile idiopathic arthritis (JIA)
`is not diagnosed in children < 2 years of age.
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`Reference ID: 3213422
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`NDA 203214/Original 1
`Page 3
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`We are deferring submission of your pediatric study for ages 2 through 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 FDCA 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)(B) of the Federal Food, Drug, and Cosmetic
`Act. These required studies are listed below.
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`1934-1 A multiple-dose pharmacokinetic trial in children from 2 to less than 18 years of
`age with juvenile idiopathic arthritis (JIA)
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`Final Protocol Submission: November 2012
`Trial Completion:
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`March 2014
`Final Report Submission:
`September 2014
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`1934-2 A randomized withdrawal, double-blind, placebo-controlled trial to evaluate the
`efficacy and safety of tofacitinib in children from 2 to less than 18 years of age
`with polyarticular-course juvenile idiopathic arthritis.
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`Final Protocol Submission: March 2014
`Trial Completion:
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`March 2017
`Final Report Submission:
`September 2017
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`Submit the protocols to your IND 070903, 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 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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`The clinical development program showed that treatment with Xeljanz (tofacitinib) is associated
`with an increase in cholesterol levels, which raises the concern of an increase in cardiovascular
`adverse events with Xeljanz (tofacitinib) therapy. An increase in serious infections and
`malignancy was also noted in the Xeljanz (tofacitinib) clinical development program.
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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 signals of the serious
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`Reference ID: 3213422
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`NDA 203214/Original 1
`Page 4
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`risks of cardiovascular adverse events, serious infections, including opportunistic infections, and
`malignancy with Xeljanz (tofacitinib).
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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 these serious risks.
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess signals of the aforementioned risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`1934-3
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`Controlled clinical trial to evaluate the long term safety of tofacitinib in patients
`with rheumatoid arthritis. The trial should include two doses of tofacitinib and an
`active comparator. The trial should be of sufficient size and duration to evaluate
`safety events of interest, including cardiovascular adverse events, opportunistic
`infections, and malignancy.
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`The timetable you submitted on August 2, 2012, states that you will conduct this
`trial according to the following schedule:
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`Final Protocol Submission: March 2013
`Trial Completion:
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`December 2019
`Final Report Submission:
`June 2020
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`Submit the protocol(s) to your IND 070903, with a cross-reference letter to this NDA. Submit
`all final reports 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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`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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`Reference ID: 3213422
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`NDA 203214/Original 1
`Page 5
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS), if FDA determines that such a strategy is necessary to ensure that
`the benefits of the drug outweigh the risks [section 505-1(a)].
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`In accordance with section 505-1 of FDCA, we have determined that a REMS is necessary for
`Xeljanz (tofacitinib) to ensure the benefits of the drug outweigh the risks of serious infections,
`including opportunistic infections, tuberculosis, malignancy, increase in cholesterol, and
`decrease in blood counts.
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`In accordance with section 505-1 of FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR part 208. Pursuant to 21 CFR
`part 208, FDA has determined that Xeljanz (tofacitinib) poses a serious and significant public
`health concern requiring the distribution of a Medication Guide. The Medication Guide is
`necessary for patients’ safe and effective use of tofacitinib. FDA has determined that Xeljanz
`(tofacitinib) is a product that has serious risks (relative to benefits) of which patients should be
`made aware because information concerning the risks could affect patients’ decisions to use, or
`continue to use Xeljanz (tofacitinib). Under 21 CFR part 208, you are responsible for ensuring
`that the Medication Guide is available for distribution to patients who are dispensed Xeljanz
`(tofacitinib).
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`We have also determined that a communication plan is necessary to support implementation of
`the REMS.
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`Your proposed REMS, submitted on November 5, 2012, and appended to this letter, is approved.
`The REMS consists of a Medication Guide, communication plan, and a timetable for submission
`of assessments of the REMS.
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`Your REMS must be fully operational before you introduce Xeljanz (tofacitinib) into interstate
`commerce.
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`The REMS assessment plan should include, but is not limited to, the following:
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`1. A survey of the patients’ knowledge and understanding of the serious risks of tofacitinib.
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`2. A survey of the prescribers’ knowledge and understanding of the serious risks of
`tofacitinib.
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`3. A survey of the pharmacists’ knowledge and understanding of the serious risks of
`tofacitinib.
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`4. An assessment and conclusions regarding the success of the REMS in meeting the stated
`goals.
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`5. An assessment of the communication plan including:
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`Reference ID: 3213422
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`NDA 203214/Original 1
`Page 6
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`a. The source(s) of the list of healthcare professionals to whom the DHCPL and Dear
`Pharmacist Letter are distributed
`b. Journal information pieces published, including date and journal name, volume, and
`issue.
`c. The date of launch of the communication plan (DHCPL, Dear Pharmacist Letter,
`website, and journal information pieces
`d. The number of recipients of the DCHP and Dear Pharmacist letters
`e. Date(s) of distribution of the DHCP and Dear Pharmacist letters
`f. The number of returned and refused letters
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`The requirements for assessments of an approved REMS under section 505-1(g)(3) include, with
`respect to each goal included in the strategy, an assessment of the extent to which the approved
`strategy, including each element of the strategy, is meeting the goal or whether one or more such
`goals or such elements should be modified.
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`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of the FDCA.
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`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
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`NDA 203214 REMS CORRESPONDENCE
`(insert concise description of content in bold capital letters, e.g.,
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`METHODOLOGY)
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
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`Reference ID: 3213422
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`

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`NDA 203214/Original 1
`Page 7
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`NDA 203214 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 203214
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 203214
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send five copies of REMS-related submissions.
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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, 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:
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`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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`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 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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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`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.
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`Reference ID: 3213422
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`NDA 203214/Original 1
`Page 8
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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
`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.
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`If you have any questions, call Philantha Montgomery Bowen, Senior Regulatory Project
`Management Officer, at (301) 796-2466.
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`Sincerely,
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`{See appended electronic signature page}
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`Curtis J. Rosebraugh, M.D., M.P.H.
`Director
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Enclosures:
`Content of Labeling
`Carton and Immediate-Container Labeling
`REMS
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`Reference ID: 3213422
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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/
`----------------------------------------------------
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`CURTIS J ROSEBRAUGH
`11/06/2012
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`Reference ID: 3213422
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