CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203441Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`203441
`GATTEX (teduglutide [rDNA origin]) for injection,
`
` 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 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
`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.
`
`
`
`NDA/BLA #
`Product Name:
`
`PMR Description:
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
` 09/30/2013
` 12/30/2029
` 06/30/2031
` MM/DD/YYYY
`
`
`PMR Schedule Milestones:
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`X Unmet need
`X Life-threatening condition
`X Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
`X Theoretical concern
` Other
`
`
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 1 of 4
`
`Reference ID: 3235379
`
`

`

`
`
`
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`Based on the pharmacologic activity and findings in animals, GATTEX has the potential to
`cause hyperplastic changes including neoplasia.
`
`
`Colorectal polyps were identified during the clinical trials.
`
`Based on benign tumor findings in the rat carcinogenicity study, patients should be
`monitored clinically for small bowel neoplasia.
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
`X FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
`X Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 2 of 4
`
`Reference ID: 3235379
`
`

`

`
`
` X
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`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.
`
`
`Required
` Observational pharmacoepidemiologic study
`X Registry studies
`X Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`Y Does the study/clinical trial meet criteria for PMRs or PMCs? Yes
`Y Are the objectives clear from the description of the PMR/PMC? Yes
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 3 of 4
`
`Reference ID: 3235379
`
`

`

`
`
`Y Has the applicant adequately justified the choice of schedule milestone dates? Yes
`Y Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process? Yes
`
`
`PMR/PMC Development Coordinator:
`X This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 4 of 4
`
`Reference ID: 3235379
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RUYI HE
`12/20/2012
`
`Reference ID: 3235379
`
`

`

`SEALD Director Sign-Off Review of the End-of—Cycle Prescribing
`Information: Outstanding Format Deficiencies
`
`
`GATTEX(teduglutlde [rDNAongrn]),formjectronfor
`ProductTitle
`
`
`
`
`subcutaneous use
`
`l
`
`NPS Pharmaceuticals, Inc.
`Applicant
`
`‘ Application/Supplement Number
`NDA 203441
`
`Type of Application
`Original Submission (NME)
`Indication(3)
`For the treatment of adult patients with Short Bowel
`
`Syndrome (SBS) who are dependent on parenteral support
`
`None listed in Highlights
`Established Pharmacologic Classl
`
`
`‘
`
`
`Office/Division
`ODE III/DGIEP
`
`1
`’ Matthew Scherer
`’ Division Project Manager
`
`‘ Date FDA Received Application
`November 30, 2011
`
`
`
`December 30, 2012) Goal Date l——J
`
`
`Date PI Received by SEALD
`December 19, 2012
`l SEALD Review Date
`| December 19, 2012
`I SEALD Labeling Reviewer
` Jeanne M. Delasko
`
`I SEALD Division Director
`Laurie Burke
`P1 = prescribing information
`1 The established pharmacologic class (EPC) that appears in the final draft PI.
`
`l
`’
`
`This Study Endpoints and Labeling Development (SEALD) Director Sign-Off review of the end-of-
`cycle, draft prescribing information (PI) for critical format elements reveals outstanding labeling
`format deficiencies that must be corrected before the final PI is approved. After these outstanding
`labeling format deficiencies are corrected, the SEALD Director will have no objection to the
`approval of this PI.
`
`The critical format elements include labeling regulation (21 CFR 201.56 and 201.57), labeling
`guidance, and best labeling practices (see list below). This review does not include every
`regulation or guidance that pertains to PI format.
`
`Guide to the Selected Requirements of Prescribing Information {SRPI} Checklist: For each SRPI
`item, one of the following 3 response options is selected:
`
`0 NO: The PI does not meet the requirement for this item (deficiency).
`YES: The PI meets the requirement for this item (not a deficiency).
`
`0 N/A (not applicable): This item does not apply to the specific PI under review.
`
`Reference ID: 3234665
`
`Page 1 of 8
`
`

`

`YES
`
`YES
`
`YES
`
`NO
`
`YES
`
`YES
`
`Selected Requirements of Prescribing Information
`
`
`
`
`Highlights (HL)
`GENERAL FORMAT
`1. Highlights (HL) must be in two-column format, with ½ inch margins on all sides and in a
`minimum of 8-point font.
`Comment:
`2. The length of HL must be less than or equal to one-half page (the HL Boxed Warning does not
`count against the one-half page requirement) unless a waiver has been is granted in a previous
`submission (i.e., the application being reviewed is an efficacy supplement).
`Instructions to complete this item: If the length of the HL is less than or equal to one-half page
`then select “YES” in the drop-down menu because this item meets the requirement. However, if
`HL is longer than one-half page:
` For the Filing Period (for RPMs)
` For efficacy supplements: If a waiver was previously granted, select “YES” in the drop-
`down menu because this item meets the requirement.
` For NDAs/BLAs and PLR conversions: Select “NO” in the drop-down menu because this
`item does not meet the requirement (deficiency). The RPM notifies the Cross-Discipline
`Team Leader (CDTL) of the excessive HL length and the CDTL determines if this
`deficiency is included in the 74-day or advice letter to the applicant.
` For the End-of Cycle Period (for SEALD reviewers)
` The SEALD reviewer documents (based on information received from the RPM) that a
`waiver has been previously granted or will be granted by the review division in the
`approval letter.
`Comment:
`3. All headings in HL must be presented in the center of a horizontal line, in UPPER-CASE letters
`and bolded.
`Comment:
`4. White space must be present before each major heading in HL.
`Comment: There is no white space between each major heading in HL.
`5. Each summarized statement in HL must reference the section(s) or subsection(s) of the Full
`Prescribing Information (FPI) that contains more detailed information. The preferred format is
`the numerical identifier in parenthesis [e.g., (1.1)] at the end of each information summary (e.g.
`end of each bullet).
`Comment:
`6. Section headings are presented in the following order in HL:
`Section
`Required/Optional
`Required
` Highlights Heading
`Required
` Highlights Limitation Statement
`Required
` Product Title
`Required
` Initial U.S. Approval
`Required if a Boxed Warning is in the FPI
` Boxed Warning
`Required for only certain changes to PI*
` Recent Major Changes
`
`
`
` Page 2 of 8
`
`Reference ID: 3234665
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`Required
` Indications and Usage
`Required
` Dosage and Administration
`Required
` Dosage Forms and Strengths
`Required (if no contraindications must state “None.”)
` Contraindications
`Not required by regulation, but should be present
` Warnings and Precautions
`Required
` Adverse Reactions
`Optional
` Drug Interactions
`Optional
` Use in Specific Populations
` Patient Counseling Information Statement Required
`Required
` Revision Date
`* RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications,
`and Warnings and Precautions sections.
`Comment:
`7. A horizontal line must separate HL and Table of Contents (TOC).
`Comment:
`
`
`HIGHLIGHTS DETAILS
`Highlights Heading
`8. At the beginning of HL, the following heading must be bolded and appear in all UPPER CASE
`letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”.
`Comment:
`
`
`Highlights Limitation Statement
`9. The bolded HL Limitation Statement must be on the line immediately beneath the HL heading
`and must state: “These highlights do not include all the information needed to use (insert
`name of drug product in UPPER CASE) safely and effectively. See full prescribing
`information for (insert name of drug product in UPPER CASE).”
`Comment:
`
`Product Title
`10. Product title in HL must be bolded.
`Comment: Product title is not bolded; also, route of administration (i.e., for subcutaneous use)
`is missing and required by regulation.
`
`Initial U.S. Approval
`11. Initial U.S. Approval in HL must be placed immediately beneath the product title, bolded, and
`include the verbatim statement “Initial U.S. Approval:” followed by the 4-digit year.
`Comment:
`
`Boxed Warning
`12. All text must be bolded.
`Comment:
`13. Must have a centered heading in UPPER-CASE, containing the word “WARNING” (even if
`more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and
`other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS
`INFECTIONS”).
`
`YES
`
`YES
`
`YES
`
`NO
`
`YES
`
`N/A
`
`N/A
`
`
`
`Reference ID: 3234665
`
`
`
`Page 3 of 8
`
`

`

`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`NO
`
`
`
`
`
`Selected Requirements of Prescribing Information
`
`Comment:
`14. Must always have the verbatim statement “See full prescribing information for complete boxed
`warning.” in italics and centered immediately beneath the heading.
`Comment:
`15. Must be limited in length to 20 lines (this does not include the heading and statement “See full
`prescribing information for complete boxed warning.”)
`Comment:
`16. Use sentence case for summary (combination of uppercase and lowercase letters typical of that
`used in a sentence).
`Comment:
`
`
`Recent Major Changes (RMC)
`17. Pertains to only the following five sections of the FPI: Boxed Warning, Indications and Usage,
`Dosage and Administration, Contraindications, and Warnings and Precautions.
`Comment:
`18. Must be listed in the same order in HL as they appear in FPI.
`Comment:
`19. Includes heading(s) and, if appropriate, subheading(s) of labeling section(s) affected by the
`recent major change, together with each section’s identifying number and date (month/year
`format) on which the change was incorporated in the PI (supplement approval date). For
`example, “Dosage and Administration, Coronary Stenting (2.2) --- 3/2012”.
`Comment:
`20. Must list changes for at least one year after the supplement is approved and must be removed at
`the first printing subsequent to one year (e.g., no listing should be one year older than revision
`date).
`Comment:
`
`Indications and Usage
`21. If a product belongs to an established pharmacologic class, the following statement is required in
`the Indications and Usage section of HL: “(Product) is a (name of established pharmacologic
`class) indicated for (indication)”.
`Comment: This is a new molecular entity. There is no established pharmacological class(PC)
`listed in HL. DGIEP notified and to follow-up with pharm/tox reviewer. If there is an
`established PC, DGIEP must include it in HL.
`
`N/A
`
`Dosage Forms and Strengths
`22. For a product that has several dosage forms, bulleted subheadings (e.g., capsules, tablets,
`injection, suspension) or tabular presentations of information is used.
`Comment:
`
`Contraindications
`
`YES
`
`
`
`Reference ID: 3234665
`
`
`
`Page 4 of 8
`
`

`

`N/A
`
`YES
`
`YES
`
`
`
`Selected Requirements of Prescribing Information
`
`
`23. All contraindications listed in the FPI must also be listed in HL or must include the statement
`“None” if no contraindications are known.
`Comment:
`24. Each contraindication is bulleted when there is more than one contraindication.
`Comment:
`
`Adverse Reactions
`25. For drug products other than vaccines, the verbatim bolded statement must be present: “To
`report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at
`(insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch”.
`Comment:
`
`Patient Counseling Information Statement
`26. Must include one of the following three bolded verbatim statements (without quotation marks):
`
`
`
`
`
`
`If a product does not have FDA-approved patient labeling:
` “See 17 for PATIENT COUNSELING INFORMATION”
`If a product has FDA-approved patient labeling:
` “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.”
` “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.”
` Comment:
`
`
`
`YES
`
`NO
`
`YES
`
`NO
`
`N/A
`
`Revision Date
`27. Bolded revision date (i.e., “Revised: MM/YYYY or Month Year”) must be at the end of HL.
`Comment:
` Contents: Table of Contents (TOC)
`
`
`
`
`GENERAL FORMAT
`28. A horizontal line must separate TOC from the FPI.
`Comment:
`29. The following bolded heading in all UPPER CASE letters must appear at the beginning of TOC:
`“FULL PRESCRIBING INFORMATION: CONTENTS”.
`Comment:
`30. The section headings and subheadings (including title of the Boxed Warning) in the TOC must
`match the headings and subheadings in the FPI.
`Comment: Subsection headings 14.1, 14.2 and 17.1 listed in the TOC do not match the
`subsection headings 14.1, 14.2 and 17.1 listed in the FPI.
`31. The same title for the Boxed Warning that appears in the HL and FPI must also appear at the
`beginning of the TOC in UPPER-CASE letters and bolded.
`
`
`
`Reference ID: 3234665
`
`
`
`Page 5 of 8
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`Comment:
`32. All section headings must be bolded and in UPPER CASE.
`Comment:
`33. All subsection headings must be indented, not bolded, and in title case.
`Comment:
`34. When a section or subsection is omitted, the numbering does not change.
`Comment:
`35. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading
`“FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk
`and the following statement must appear at the end of TOC: “*Sections or subsections omitted
`from the Full Prescribing Information are not listed.”
`Comment:
`
`
`
`Full Prescribing Information (FPI)
`GENERAL FORMAT
`36. The following heading must appear at the beginning of the FPI in UPPER CASE and bolded:
`“FULL PRESCRIBING INFORMATION”.
`Comment:
`37. All section and subsection headings and numbers must be bolded.
`Comment:
`
`38. The bolded section and subsection headings must be named and numbered in accordance with
`21 CFR 201.56(d)(1) as noted below. If a section/subsection is omitted, the numbering does not
`change.
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`Boxed Warning
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`6 ADVERSE REACTIONS
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`
`
`
`
`
`Reference ID: 3234665
`
`
`
`Page 6 of 8
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology (by guidance)
`12.5 Pharmacogenomics (by guidance)
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`Comment:
`
`NO
`
`NO
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`
`39. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for
`Use) must not be included as a subsection under Section 17 (Patient Counseling Information).
`All patient labeling must appear at the end of the PI upon approval.
`Comment: The Medication Guide and Instructions for use do not appear at the end of the PI.
`DGIEP notified and stated that all FDA-approved patient labeling will appear at the end of the
`PI upon approval.
`40. The preferred presentation for cross-references in the FPI is the section heading (not subsection
`heading) followed by the numerical identifier in italics. For example, “[see Warnings and
`Precautions (5.2)]”.
`Comment: In the cross reference, the numerical identifier should appear as (12.1), (13.1)
`respectively, and not “(12-1)” "(13-1)". Delete the “dash” and replace with a “period.” This
`comment applies to Warnings and Precautions, subsection 5.1 and Patient Counseling
`Information, subsection 17.1.
`41. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or
`subsections must be marked with a vertical line on the left edge.
`Comment:
`FULL PRESCRIBING INFORMATION DETAILS
`Boxed Warning
`42. All text is bolded.
`Comment:
`43. Must have a heading in UPPER-CASE, containing the word “WARNING” (even if more than
`one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words
`to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”).
`Comment:
`44. Use sentence case (combination of uppercase and lowercase letters typical of that used in a
`sentence) for the information in the Boxed Warning.
`Comment:
`Contraindications
`
`
`
`
`
`Reference ID: 3234665
`
`
`
`Page 7 of 8
`
`

`

`
`
`Selected Requirements of Prescribing Information
`
`
`45. If no Contraindications are known, this section must state “None”.
`Comment:
`Adverse Reactions
`46. When clinical trials adverse reactions data is included (typically in the “Clinical Trials
`Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate
`modification should precede the presentation of adverse reactions:
`
`“Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`trials of another drug and may not reflect the rates observed in clinical practice.”
`Comment:
`47. When postmarketing adverse reaction data is included (typically in the “Postmarketing
`Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate
`modification should precede the presentation of adverse reactions:
`“The following adverse reactions have been identified during post-approval use of (insert drug
`name). Because these reactions are reported voluntarily from a population of uncertain size, it
`is not always possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.”
`Comment:
`Patient Counseling Information
`48. Must reference any FDA-approved patient labeling, include the type of patient labeling, and use
`one of the following statements at the beginning of Section 17:
` “See FDA-approved patient labeling (Medication Guide)”
` “See FDA-approved patient labeling (Medication Guide and Instructions for Use)”
` “See FDA-approved patient labeling (Patient Information)"
` “See FDA-approved patient labeling (Instructions for Use)"
` “See FDA-approved patient labeling (Patient Information and Instructions for Use)”
`Comment:
`
`
`
`
`
`
`
`
`
`
`
`YES
`
`YES
`
`N/A
`
`YES
`
`
`
`
`
`Reference ID: 3234665
`
`
`
`Page 8 of 8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JEANNE M DELASKO
`12/19/2012
`
`ERIC R BRODSKY
`12/20/2012
`Eric Brodsky, SEALD labeling team leader, signing for Laurie Burke, SEALD Director
`
`Reference ID: 3234665
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`
`Label and Labeling Memorandum
`
`December 17, 2012
`
`Date:
`
`Reviewer:
`Manizheh Siahpoushan, PharmD
`Division of Medication Error Prevention and Analysis
`
`Zachary Oleszczuk, PharmD
`Team Leader:
`
`Division of Medication Error Prevention and Analysis
`Gattex (Teduglutide [rDNA origin]) for Injection
`Drug Name:
`5 mg per vial
`
`Application Type/Number: NDA 203441
`Applicant:
`NPS Pharmaceuticals
`OSE RCM #:
`2011-4410-1
`
`*** This document contains proprietary and confidential information that should
`not be released to the public.***
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3232050
`
`

`

`
`
`Contents
`
`INTRODUCTION ...................................................................................................... 3
`1
`2 MATERIALS REVIEWED........................................................................................ 3
`3 CONCLUSION AND RECOMMENDATIONS ....................................................... 3
`APPENDICES .................................................................................................................... 4
`
`
`
`
`
`Reference ID: 3232050
`
`2
`
`

`

`
`
`1
`INTRODUCTION
`This memorandum evaluates the revised packaging configuration, container labels, carton
`labeling, package insert, Medication Guide, and Instructions for Use for Gattex
`(Teduglutide [rDNA origin]) Injection submitted on November 9, 2012 (see Appendix A)
`and December 12, 2012. The Division of Medication Error Prevention and Analysis
`(DMEPA) previously reviewed the packaging configuration, container labels, carton
`labeling, package insert, Medication Guide, and Instructions for Use under OSE Review
`2011-4410, dated February 16, 2012.
`
`2 MATERIALS REVIEWED
`DMEPA evaluated the following labels and labeling.
` Revised container labels and carton labeling submitted on November 9, 2012
` Revised package insert, Medication Guide, and Instructions for Use submitted
`on December 12, 2012
`Additionally, our recommendations in OSE Review 2011-4410, dated
`February 16, 2012 were reviewed to assess whether the revised labels and labeling
`adequately address our concerns from a medication error perspective.
`
`3
`CONCLUSION AND RECOMMENDATIONS
`Review of the revised documents show that the Applicant has implemented all of
`DMEPA’s recommendations under OSE Review 2011-4410, dated
`February 16, 2012 and we find them acceptable. Therefore, we have no further
`recommendations.
`If you have further questions or need clarifications, please contact, Franklin Stephenson
`OSE Project Manager, at 301-796-3872.
`
`
`
`
`
`Reference ID: 3232050
`
`3
`
`7 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MANIZHEH SIAHPOUSHAN
`12/17/2012
`
`ZACHARY A OLESZCZUK
`12/17/2012
`
`Reference ID: 3232050
`
`

`

`
`
`M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`____________________________________________________________________________
`
`
`
`CLINICAL INSPECTION SUMMARY
`
`
`DATE: December 6, 2012
`
`TO:
`
`
`
`Matthew Scherer, Regulatory Project Manager
`John Troiani, Clinical Reviewer
`
`
`
`
`Khairy Malek, M.D., Ph.D.
`
`FROM:
` Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`
`
`
`
`
`
`THROUGH:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Susan Leibenhaut, M.D.
`
`Acting Team Leader
`
`Good Clinical Practice Assessment Branch
`
`Division of Good Clinical Practice Compliance
`
`Office of Scientific Investigations
`
`Susan D. Thompson, M.D.
`Acting Branch Chief
`Good Clinical Practice Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`Evaluation of Clinical Inspections
`
`
`
`
`
`
`
`
`SUBJECT:
`
`NDA: 203-441
`
`APPLICANT: NPS Pharmaceuticals, Inc.
`DRUG:
` GattexTM (teduglutide)
`NME:
` Yes
`THERAPEUTIC CLASSIFICATION: Standard
`
`INDICATIONS:
`
`CONSULTATION REQUEST DATE: January 30, 2012
`PDUFA DATE: December 20, 2012
`
`
`
`
`
`
`Treatment of adults with short bowel syndrome
`
`
`
`
`Reference ID: 3227585
`
`

`

`
`
`
`
`
`
`
`
`
`Clinical Inspection Summary
`NDA #203-441 (Gattex)
`
`Page 2
`
`
`
`I. BACKGROUND:
`
`Short Bowel Syndrome (SBS) results from inadequate anatomical or functional length of
`residual small intestine following surgical resection. As a consequence, there is significant
`reduction in the absorptive capacity of the intestine. Patients with SBS are highly prone to
`malnutrition, diarrhea, and dehydration due to reduced intestinal capacity to absorb
`macronutrients, water and electrolytes. Despite the adaptation that occurs generally two years
`after resection, a large proportion of SBS patients require the use of supplemental PN
`(parenteral nutrition). PN is associated with:
`• High cost
`• Potential life threatening complications including sepsis and liver damage
`• Reduced quality of life.
`Consequently, increasing the absorptive capacity of the remaining intestine is a rational
`therapeutic objective.
`
`Teduglutide is a recombinant analog of human glucagon-like Peptide-2 (GLP-2). Clinical
`experience has shown that teduglutide is able to reduce PN volumes substantially; so that
`patients can be weaned off PN completely.
`
`Anticipated adverse reactions are: injection site reactions; gastrointestinal pain and distention;
`constipation, nausea and vomiting; headache and increase in CRP (C reactive protein). The
`most frequent adverse events were headache and abdominal pain in up to 30% of subjects.
`
`The following protocols were studied at the two sites inspected:
`
`1. Protocol CL0600-004 “A Study of the Efficacy and Safety of Teduglutide in Subjects with
`Parenteral Nutrition-Dependent Short Bowel Syndrome”.