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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 203441/S-013
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Shire-NPS Pharmaceuticals, Inc.
`Attention: Kailash Jain
` Global Regulatory Project Management Lead
`Global Regulatory Affairs
`650 E. Kendall St.
`Cambridge, MA 02142
`
`
`Dear Mr. Jain:
`
`Please refer to your supplemental New Drug Application (sNDA), dated and received on
`September 11, 2018, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FD&C Act) for GATTEX (teduglutide) for injection, 5 mg.
`
`We additionally acknowledge receipt of your major amendment dated January 11, 2019, which
`extended the goal date by three months.
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`This Prior Approval sNDA provides for the expansion of the indication to pediatric patients 1
`year of age and older with Short Bowel Syndrome (SBS) who are dependent on parenteral
`support, and proposes modifications to the approved GATTEX (teduglutide) Risk Evaluation and
`Mitigation Strategy (REMS).
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`APPROVAL & LABELING
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`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
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`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
`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 Prescribing Information [PI],
`Medication Guide [MG], and Instructions for Use [IFU]), 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. Information on submitting SPL files using eLIST
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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 2
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`may be found in the Guidance for Industry titled, SPL Standard for Content of Labeling
`Technical Qs and As, located at https://www.fda.gov/regulatory-information/search-fda-
`guidance-documents/spl-standard-content-labeling-technical-qs. 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 Microsoft (MS) Word format that
`includes the changes approved in this supplemental application, as well as annual reportable
`changes. To facilitate the review of your submission, provide a highlighted or marked-up copy,
`which shows all changes, as well as a clean MS Word version. The marked-up copy should
`provide appropriate annotations, including supplement number(s) and annual report date(s).
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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 CONTAINER LABELING
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`Submit final printed carton and container labeling that are identical to the enclosed carton and
`container labeling, which was submitted and received on September 11, 2018, as soon as they are
`available, but no more than 30 days after they are printed. Please submit these labeling
`electronically according to the Guidance for Industry titled, Providing Regulatory Submissions in
`Electronic Format –– Certain Human Pharmaceutical Product Applications and Related
`Submissions Using the eCTD Specifications (April 2018, Revision 5), located at
`https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
`333969.pdf. For administrative purposes, designate this submission “Final Printed Carton and
`Container Labeling for approved NDA 203441/S-013.” Approval of this submission by FDA
`is not required before the labeling is used.
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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:
`
`
`Benjamin Vali
`Food and Drug Administration
`Center for Drug Evaluation and Research
`White Oak Building 22, Room 5245
`10903 New Hampshire Avenue
`Silver Spring, Maryland
`Use zip code 20903 if shipping via United States Postal Service (USPS).
`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 3
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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.
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` Because none of these criteria apply to your application, you are exempt from this requirement.
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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`The REMS for GATTEX (teduglutide) was originally approved on December 21, 2012, and the
`most recent REMS modification was approved on December 18, 2018. The REMS consists of
`elements to assure safe use and a timetable for submission of assessments of the REMS. Your
`proposed modifications to the REMS consist of changes to align with this efficacy supplement’s
`approval.
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`In accordance with section 505-1 of the FD&C Act, we have determined that the following
`REMS modifications are necessary to ensure the benefits of the drug outweigh the risks:
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`1.
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`Incorporating information about the new population, which expands usage to include
`pediatric patients 1 year of age and older with SBS who are dependent on parenteral
`support, into the existing REMS.
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`2. Making formatting and editorial changes, typographical corrections, and administrative
`changes throughout the REMS document and all REMS materials.
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`Your proposed modified REMS, submitted and received on May 10, 2019 and appended to this
`letter, is approved. The modified REMS consists of elements to assure safe use and a timetable
`for submission of assessments of the REMS.
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`The timetable for submission of assessments of the REMS remains the same as that approved on
`December 21, 2012. Changes to the assessment plan are included in this modification.
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` Revised Assessment Plan
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` The effectiveness of the GATTEX REMS will be evaluated through healthcare professional
` training metrics and knowledge, attitude, and behavior (KAB) surveys of GATTEX prescribers,
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` patients, and caregivers’ understanding of the potential risks associated with GATTEX. The
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`REMS assessment will include an evaluation of the effectiveness of the REMS and
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`recommendations on any areas for program improvements or modifications, as appropriate. The
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`frequency of the KAB surveys changed from annually to every two years at the FDA’s request
`on May 20, 2015.
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` Surveys will be conducted with a random sample of prescribers, patients, and caregivers,
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`identified through dispensing data from specialty pharmacies, in order to assess their
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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 4
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` awareness and understanding of the potential risks associated with GATTEX.
` Assessment protocols and survey instruments will be submitted to the FDA at least 90
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`days before the assessments are conducted.
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` Protocols will include the rationale for and description of methodologies and
`questionnaires to be used to evaluate prescribers’, patients’, and caregivers’
`understanding about the safe use of GATTEX. Shire-NPS Pharmaceuticals, Inc. will
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`initiate the prescriber, patient, and caregivers’ KAB surveys so that survey results can be
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`included in the REMS Assessment Report to be submitted to FDA 12 months after
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`REMS approval and annually thereafter. The protocol will include:
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`o Expected sample size and confidence intervals associated with that sample size
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`o Description of the methodology for recruitment and selection of the prescribers’
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`sample
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`o Selection criteria for inclusion into the survey
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`o Description of how and when the survey will be administered
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`o Explanation of the design features and controls that will be included to minimize
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`bias and compensate for any limitations in the methodology
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`The proposed REMS assessment plan includes the following:
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`1. Communication Activities:
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`a. Date(s) the Dear Healthcare Professional letter mailing(s) were sent and number of
`healthcare professionals that were sent this letter
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`i. Number of mailings returned
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`ii. Sources of the recipient lists
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`2. Healthcare Professional (HCP) Training (each reporting period and cumulatively):
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`a. Number of HCPs who have prescribed GATTEX
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`b. Number of HCPs who completed the Post-Training Knowledge Assessment
`Questions
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`c. Number of HCPs who have completed training and prescribed GATTEX
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`d. Demographics of HCPs (by specialty type) that completed the Post-Training
`Knowledge Assessment Questions, to the extent possible
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`e. Number and percent of HCP who completed the Post-Training Knowledge
`Assessment Questions by method of completion (on-line, fax/mail)
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`f. Number of HCPs who completed each knowledge assessment question correctly and
`the number of HCPs who did not complete each post-training knowledge assessment
`question correctly
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`g. Number of HCPs who were retrained
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`h. Number of HCPs identified through specialty pharmacy dispensing data to have
`dispensed a patient prescription who did not complete the Post-Training Knowledge
`Assessment Questions (during the reporting period and cumulatively)
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`Reference ID: 4434570
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` NDA 203441/S-013
` Page 5
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`i. Number of HCPs who did not complete the Post-Training Knowledge Assessment
`Questions who were contacted by Shire-NPS Pharmaceuticals, Inc., and then who
`completed the Post-Training Knowledge Assessment Questions
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`3. KAB surveys (to be conducted every two years beginning in 2018):
`KAB surveys of prescribers’, patients’, and caregivers’ understanding of the potential
`risks associated with use of GATTEX for SBS and their understanding of the
`recommended monitoring during treatment with GATTEX.
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`4. Narrative summary of adverse events of interest including the risks of acceleration of
`neoplastic growth and enhancement of colon polyp growth, gastrointestinal obstruction,
`and biliary and pancreatic disorders, reporting from spontaneous sources, published
`literature, regulatory agencies, clinical studies and trials (clinical serious adverse
`events/SAEs), and solicited sources for entry into the Shire-NPS Pharmaceuticals, Inc.
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`drug safety database.
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`5. Utilization (each reporting period and cumulatively):
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`a. A report of the number of GATTEX prescriptions
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`b. A report of the number of patients who were dispensed GATTEX
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`6. 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 REMS assessments submitted according to the timetable in
`the approved REMS, you must include an adequate rationale to support a proposed REMS
`modification for the addition, modification, or removal of any goal or element of the REMS, as
`described in section 505-1(g)(4) of the FD&C Act.
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`We also remind you that you must submit a REMS assessment when you submit a supplemental
`application for a new indication for use, as described in section 505-1(g)(2)(A) of the FD&C
`Act. This assessment should include:
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`c.
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`a. An evaluation of how the benefit-risk profile will or will not change with the new
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`indication.
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`b. A determination of the implications of a change in the benefit-risk profile for the current
`REMS.
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`If the new indication for use introduces unexpected risks: A description of those risks and
`an evaluation of whether those risks can be appropriately managed with the currently
`approved REMS.
`If a REMS assessment was submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: A statement about whether the
`REMS was meeting its goals at the time of that last assessment and if any modifications
`of the REMS have been proposed since that assessment.
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`d.
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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 6
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`e.
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`f.
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`If a REMS assessment has not been submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: Provision of as many of the
`currently listed assessment plan items as is feasible.
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`If you propose a REMS modification based on a change in the benefit-risk profile or
`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS modification
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`is necessary, the potential effect on the serious risk(s) for which the REMS was required,
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`on patient access to the drug, and/or on the burden on the health care delivery system;
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`and other appropriate evidence or data to support the proposed change. Additionally,
`include any changes to the assessment plan necessary to assess the proposed modified
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`REMS. If you are not proposing REMS modifications, provide a rationale for why the
`REMS does not need to be modified.
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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 203441 REMS 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,
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`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`We remind you that section 505-1(f)(8) of FD&C Act 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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`Prominently identify any submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of the
`first page of the submission as appropriate:
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`NDA 203441 REMS ASSESSMENT
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`or
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`NEW SUPPLEMENT FOR NDA 203441/S-XXX
`CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 7
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`or
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`NEW SUPPLEMENT FOR NDA 203441/S-XXX
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` PRIOR APPROVAL SUPPLEMENT
`PROPOSED MAJOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 203441/S-XXX
`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
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`SUBMITTED IN SUPPLEMENT YYY
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 203441/S-XXX
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
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`REMS REVISIONS FOR NDA 203441
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`Should you choose to submit a REMS revision, prominently identify the submission containing
`the REMS revisions with the following wording in bold capital letters at the top of the first page
`of the submission:
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`
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`To facilitate review of your submission, we request that you submit your proposed modified
`REMS and other REMS-related materials in MS Word format. If certain documents, such as
`enrollment forms, or website screenshots are only in PDF format, they may be submitted as such,
`but MS Word format is preferred.
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`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
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`FDA can accept the REMS document in SPL format. If you intend to submit the REMS
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`document in SPL format, as soon as possible, but no later than 14 days from the date of this
`letter, submit the REMS document in SPL format using the FDA automated eLIST.
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`For more information on submitting REMS in SPL format, please email
`FDAREMSwebsite@fda.hhs.gov.
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`PROMOTIONAL MATERIALS
`
`
`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
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`(3) the PI to:
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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 8
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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
`
`
`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 titled, Providing Regulatory Submissions in Electronic and Non-
`Electronic Format –– Promotional Labeling and Advertising Materials for Human Prescription
`Drugs, located at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf.
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`You must submit final promotional materials and the PI, accompanied by a Form FDA 2253, at
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`the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is
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`available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`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 https://www.fda.gov/about-fda/center-drug-evaluation-and-
`research/office-prescription-drug-promotion-opdp.
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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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`Reference ID: 4434570
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`

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` NDA 203441/S-013
` Page 9
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`If you have any questions, contact Benjamin Vali, Regulatory Project Manager, at (301) 796-
`4261 or benjamin.vali@fda.hhs.gov.
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Jessica J. Lee, M.D., 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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`Enclosures:
`Content of Labeling:
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`PI
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`MG
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`IFU
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`Carton and Container Labeling
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`REMS
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`Reference ID: 4434570
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`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JESSICA J LEE
`05/16/2019 03:39:19 PM
`
`Reference ID: 4434570
`
`