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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 203441
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`Food and Drug Administration
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`Silver Spring MD 20993
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`NDA APPROVAL
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`NPS Pharmaceuticals, Inc.
`Attention: Diane C. Fiorenza, BS, RAC
`
`Senior Director, Regulatory Affairs, Product Development
`550 Hills Drive 3rd Floor
`Bedminster, NJ 07921
`
`Dear Ms. Fiorenza:
`
`Please refer to your New Drug Application (NDA), dated and received November 30, 2011,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA), for
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use, 5 mg.
`
`We also refer to our approval letter dated December 21, 2012 which contained the following
`error: the Risk Evaluation and Mitigation Strategy (REMS) appended materials did not reflect
`the final agreed-upon revisions (submitted December 18, 2012).
`
`This replacement approval letter incorporates the correction of the error. In addition, we corrected
`the typographical error in the appended Prescriber Education Slide Deck (on slide 9 “3/32 (9.4%)
`on GATTEX, 0.05 mg/kg/day” was replaced with “3/32 (9.4%) on GATTEX, 0.10 mg/kg/day”).
`The effective approval date will remain December 21, 2012, the date of the original approval
`letter.
`
`We acknowledge receipt of your amendments dated December 22 & 23, 2011; January 12 & 13,
`2012; February 7, 9, 16, 21, 23 & 24, 2012; March 7, 12, 23(2) & 29, 2012; April 11 & 20, 2012;
`May 7, 2012; June 12, 18, 20, 28 & 29, 2012; July 10 & 20, 2012; August 3, 10 & 15, 2012;
`September 5, 6, 10, 12(2) , 18, 19 & 27, 2012; October 2, 18, 24, & 31, 2012; November 8, 9, 20,
`26 & 30, 2012; December 6, 7, 10, 12(3), 13(2), 17, 18(2), 19, & 20(2), 2012.
`
`This new drug application provides for the use of GATTEX (teduglutide [rDNA origin]) for
`injection, for subcutaneous use for the treatment of adult patients with Short Bowel Syndrome
`(SBS) who are dependent on parenteral support.
`
`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 agreed-upon labeling text and with the minor
`editorial revisions listed below.
`
`
`1. In the medication guide, remove the extra bullet point under the list of most common side
`effects.
`
`
`
`Reference ID: 3253828
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`

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`NDA 203441
`Page 2
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`2. On the vial label, revise the storage temperature range to read, “Prior to dispensing, store at
`2°C to 8°C (36°F to 46°F). Do not freeze.”
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`3. For all carton and container labels, revise the room temperature storage conditions to be
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`consistent with those listed in Section 16 HOW SUPPLIED/STORAGE AND HANDLING
`section of the package insert.
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`CONTENT OF LABELING
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`
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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 and Medication
`Guide. Information on submitting SPL files using eLIST may be found in the guidance for
`industry 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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`
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`Submit final printed carton and immediate-container labels that are identical to the submitted
`carton and immediate-container labels, except with the revisions listed above, 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 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 203441.” Approval of this submission by FDA is not required
`before the labeling is used.
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`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
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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
`address:
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`
`
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`Reference ID: 3253828
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`

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`NDA 203441
`Page 3
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`Matthew Scherer
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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: 5139
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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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`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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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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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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`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 possible acceleration of neoplastic growth and enhancement of colon polyp growth,
`gastrointestinal obstruction, and biliary and pancreatic disorders associated with GATTEX
`(teduglutide [rDNA origin]) .
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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.
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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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`1978-1 A prospective, multi-center, long-term, observational, registry study, of short
`bowel syndrome patients treated with teduglutide in a routine clinical setting, to
`assess the long-term safety of teduglutide. Design the study around a testable
`hypothesis to rule out a clinically meaningful increase in colorectal cancer risk
`above an estimated background risk in a suitable comparator. Select and justify
`the choice of appropriate comparator population(s) and corresponding background
`rate(s) relative to teduglutide-exposed patients. Provide sample sizes and effect
`sizes that can be ruled out under various enrollment target scenarios and loss to
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`
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`Reference ID: 3253828
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`

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`NDA 203441
`Page 4
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`follow-up assumptions. The study’s primary outcome should be colorectal cancer,
`and secondary outcomes should include other malignancies, colorectal polyps,
`bowel obstruction, pancreatic and biliary disease, heart failure, and long-term
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`effectiveness. Patients should be enrolled over an initial 5-year period and then
`followed for a period of at least 10 years from the time of enrollment. Progress
`updates of registry patient accrual and a demographic summary should be
`provided annually. Registry safety data should be provided in periodic safety
`reports.
`
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`The timetable you submitted on December 10, 2012, states that you will conduct this study
`according to the following schedule:
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`Final Protocol Submission: 09/13
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`Study Completion:
`12/29
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`Final Report Submission:
`06/31
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`Submit the protocol to your IND 058213 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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`POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
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`We remind you of your postmarketing commitments:
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`1978-2
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`Elemental impurities specifications will be expanded to include limits and testing
`for all metals, as recommended in USP <232>.
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`Reference ID: 3253828
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`

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`NDA 203441
`Page 5
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`The timetable you submitted on December 18, 2012, states that you will implement these
`specifications by March 31, 2013; submitted as a CBE-30 supplement.
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`Submit clinical protocols to your IND 058213 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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`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
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`the benefits of the drug outweigh the risks [section 505-1(a)].
`
`
`In accordance with section 505-1 of FDCA, we have determined that a REMS is necessary for
`GATTEX (teduglutide [rDNA origin]) to ensure the benefits of the drug outweigh the risks of
`possible acceleration of neoplastic growth and enhancement of colon polyp growth,
`gastrointestinal obstruction, and biliary and pancreatic disorders associated with GATTEX
`(teduglutide [rDNA origin]).
`
`We have also determined that a communication plan is necessary to support implementation of
`the REMS.
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`Pursuant to 505-1(f)(1), we have also determined that GATTEX can be approved only if
`elements necessary to assure safe use are required as part of a REMS to mitigate the risk of
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`possible acceleration of neoplastic growth and enhancement of colon polyp growth,
`gastrointestinal obstruction, and biliary and pancreatic disorders associated with GATTEX
`(teduglutide [rDNA origin]) that are listed in the labeling. The elements to assure safe use will
`include training for health care providers who prescribe GATTEX (teduglutide [rDNA origin])
`and appropriate risk information for patient education.
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
`
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`Your proposed REMS, submitted on December 18, 2012, and appended to this letter, is
`approved. The REMS consists of a communication plan, elements to assure safe use, and a
`timetable for submission of assessments of the REMS.
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`Reference ID: 3253828
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`

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`NDA 203441
`Page 6
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`Your REMS must be fully operational before you introduce GATTEX (teduglutide [rDNA
`origin]) into interstate commerce.
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`The REMS assessment plan should include, but is not limited to, the following:
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`
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` 1. An evaluation of healthcare providers’ understanding of the serious risks of possible
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`acceleration of neoplastic growth and enhancement of colon polyp growth,
`gastrointestinal obstruction, and biliary and pancreatic disorders associated with
`GATTEX (teduglutide [rDNA origin].
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`
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`2. An evaluation of patients’ understanding of the serious risks of possible acceleration of
`neoplastic growth and enhancement of colon polyp growth, gastrointestinal obstruction,
`and biliary and pancreatic disorders associated with GATTEX (teduglutide [rDNA
`origin].
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`
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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 1 or more such
`goals or such elements should be modified.
`
`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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`Reference ID: 3253828
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`

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`NDA 203441
`Page 7
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`NDA 203441 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`
`METHODOLOGY)
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`
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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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`NDA 203441 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 203441
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 203441
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
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`If you do not submit electronically, please send 5 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:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`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
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`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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`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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`Reference ID: 3253828
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`

`

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`NDA 203441
`Page 8
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` 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.
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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 Matthew Scherer, Regulatory Project Manager, at
`(301) 796-2307.
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`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Victoria Kusiak, MD
`Deputy Director
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`
`Enclosures:
`Content of Labeling
`REMS
`
`
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`Reference ID: 3253828
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`VICTORIA KUSIAK
`12/21/2012
`
`Reference ID: 3253828
`
`