CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204654Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`SEALD Director Sign-
`Information:
`
`Off Review of the End-of—Cycle Prescribing
`Outstanding Format Deficiencies
`
`— L
`
`O MINASTRIN FE (norethindrone acetate and ethinyl
`
`Product Title
`
`estradiol chewable tablets, ethinyl estradiol tablets and
`
`ferrous fumarate tablets
`
`for oral use
`
`Applicant
`A l Ilication/Su I Ilement Number
`
`Warner Chilcott Company, LLC
`NDA 204654
`
`T‘Ie OfAI Ilication
`For use b women to Irevent re u: . IC
`Indication(s)
`
`Established Pharmacologic Class Estrogen/Progestin
`
`Ori - inal NDA
`
`
`
`1-
`
`Office/Division
`
`ODE III/DRUP
`
`Pamela Lucarelli
`
`Division Project Manager
`
`
`Date FDA Received Application
`September 28, 2012
`Goal Date
`July 28, 2013
`
`
`
`Date PI Received by SEALD
`SEALD Review Date
`
`SEALD Labelin- Reviewer
`
`SEALD Division Director
`
`July 22, 2013
`July 23, 2013
`Abimbola Adebowale
`
`P1 = prescribing information
`1 The established pharmacologic class (EPC) that appears in the final draft PI.
`
`This Study Endpoints and Labeling Development (SEALD) Director Sign-Off review of the end-0f-
`cycle, draft prescribing information 01) 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:
`
`NO: The PI does not meet the requirement for this item (deficiency).
`
`YES: The PI meets the requirement for this item (not a deficiency).
`N/A (not applicable): This item does not apply to the specific PI under review.
`
`Reference ID: 3345414
`
`Page 1 of 8
`
`

`

`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:
`(cid:190) For the Filing Period (for RPMs)
`(cid:131) For efficacy supplements: If a waiver was previously granted, select “YES” in the drop-
`down menu because this item meets the requirement.
`(cid:131) 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.
`(cid:190) For the End-of Cycle Period (for SEALD reviewers)
`(cid:131) 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: Insert a white space before the Boxed Warning in Highlights.
`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: The reference (i.e. 12.3) at the end of the information summary of the fifth bullet in
`the Dosage and Administration section in Highlights does not include the identifying number
`(2.1) that corresponds to the location of the information in the Dosage and Administration
`section of the FPI.
`6. Section headings are presented in the following order in HL:
`Section
`Required/Optional
`• Highlights Heading
`Required
`• Highlights Limitation Statement
`Required
`Required
`• Product Title
`
`YES
`
`YES
`
`
`YES
`
`NO
`
`NO
`
`NO
`
`
`
` Page 2 of 8
`
`Reference ID: 3345414
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`• Initial U.S. Approval
`Required
`• Boxed Warning
`Required if a Boxed Warning is in the FPI
`• Recent Major Changes
`Required for only certain changes to PI*
`• Indications and Usage
`Required
`• Dosage and Administration
`Required
`• Dosage Forms and Strengths
`Required
`• Contraindications
`Required (if no contraindications must state “None.”)
`• Warnings and Precautions
`Not required by regulation, but should be present
`• Adverse Reactions
`Required
`• Drug Interactions
`Optional
`• Use in Specific Populations
`Optional
`• Patient Counseling Information Statement Required
`• Revision Date
`Required
`* RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications,
`and Warnings and Precautions sections.
`
`
`Comment: The ninth section heading in Highlights should read as “Dosage Forms and
`Strengths” (as shown above) and not “Dosage Form and Strength” as currently written.
`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: The Highlights Heading is not at the beginning of the HL. Align the heading to the
`left so that it is at the beginning of the HL.
`
`
`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:
`
`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: Initial U.S. Approval in HL is not placed immediately beneath the product title.
`There is a white space between the two. Delete the space.
`
`YES
`
`NO
`
`YES
`
`YES
`
`NO
`
`Boxed Warning
`12. All text must be bolded.
`
`YES
`
`
`
`Reference ID: 3345414
`
`
`
`Page 3 of 8
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`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”).
`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:
`
`YES
`
`YES
`
`YES
`
`YES
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`YES
`
`Dosage Forms and Strengths
`22. For a product that has several dosage forms, bulleted subheadings (e.g., capsules, tablets,
`
`YES
`
`
`
`Reference ID: 3345414
`
`
`
`Page 4 of 8
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`injection, suspension) or tabular presentations of information is used.
`Comment:
`
`Contraindications
`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:
`
`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:
`
`
`YES
`
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`
`
`Reference ID: 3345414
`
`
`
`Page 5 of 8
`
`

`

`
`
`Selected Requirements of Prescribing Information
`
`
`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 heading 2.1 in the TOC reads as “How to Take Lo Minastrin FE” but
`subsection heading 2.1 in the FPI reads as “How to Lo Minastrin FE.” The subsection heading
`in the TOC must match the FPI subsection heading.
`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.
`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.
`
`NO
`
`
`
`YES
`
`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
`
`
`
`
`
`Reference ID: 3345414
`
`
`
`Page 6 of 8
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`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
`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:
`
`YES
`
`YES
`
`N/A
`
`YES
`
`YES
`
`
`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:
`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:
`
`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:
`
`
`
`
`
`Reference ID: 3345414
`
`
`
`Page 7 of 8
`
`

`

`
`
`Selected Requirements of Prescribing Information
`
`
`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
`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
`
`N/A
`
`YES
`
`
`
`YES
`
`YES
`
`
`
`
`
`Reference ID: 3345414
`
`
`
`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/
`----------------------------------------------------
`
`ABIMBOLA O ADEBOWALE
`07/23/2013
`
`LAURIE B BURKE
`07/23/2013
`
`Reference ID: 3345414
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date: July 19, 2013
`
`
`To: Pam Lucarelli
`Project Manager
`Division of Bone, Reproductive, and Urologic Products (DBRUP)
`
`
`
`From: Carrie Newcomer, PharmD
`
` Regulatory Review Officer
`
` Office of Prescription Drug Promotion (OPDP)
`
`Subject: NDA: 204654
`Norethindrone acetate and ethinyl estradiol chewable tablets,
`ethinyl estradiol tablets and ferrous fumarate tablets
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`As requested in DBRUP’s consult dated October 9, 2012, OPDP has reviewed
`the draft labeling (package insert [PI], patient package insert [PPI], and
`carton/container labeling) for the original NDA submission for norethindrone
`acetate and ethinyl estradiol chewable tablets, ethinyl estradiol tablets and
`ferrous fumarate tablets. OPDP’s comments are based on the proposed,
`substantially complete, marked-up version of the draft PI and PPI provided to
`OPDP on July 15, 2013, via access to the DBRUP eRoom. OPDP’s comments
`on the draft carton/container labeling are based on the draft labeling submitted by
`the applicant on July 16, 2013, and provided to OPDP on July 16, 2013, via
`email.
`
`OPDP’s comments on the PI and PPI are provided directly in the attached copy
`of the labeling.
`
`OPDP does not have any comments on the carton/container labels.
`
`Thank you for your consult. If you have any questions, please contact Carrie
`Newcomer at 6-1233, or carrie.newcomer@fda.hhs.gov.
`
`
`
`Reference ID: 3343891
`
`1
`
`33 Pages 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/
`----------------------------------------------------
`
`CARRIE A NEWCOMER
`07/19/2013
`
`Reference ID: 3343891
`
`

`

`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, Labeling, and Packaging Memorandum
`
`Date:
`
`Reviewer:
`
`
`
`Team Leader:
`
`
`
`
`Drug Name and Strength:
`
`
`
`
`
`
`
`
`
`
`July 12, 2013
`
`Manizheh Siahpoushan, PharmD
`Division of Medication Error Prevention and Analysis
`
`
`James Schlick, RPh
`Division of Medication Error Prevention and Analysis
`Lo Minastrin Fe
`(Norethindrone Acetate and Ethinyl Estradiol Acetate
`Chewable Tablets, Ethinyl Estradiol Tablets and Ferrous
`Fumarate Tablets)
`1 mg/10 mcg and 10 mcg
`NDA 204654
`Warner Chilcott, LLC
`2013-1-1
`
`
`
`
`
`Application Type/Number:
`Applicant:
`OSE RCM #:
`
`*** This document contains proprietary and confidential information that should
`not be released to the public.***
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3340118
`
`

`

`
`
`
`
`
`
`Contents
`
`INTRODUCTION ...................................................................................................... 3
`1
`2 MATERIALS REVIEWED........................................................................................ 3
`3 CONCLUSIONS AND RECOMMENDATIONS ..................................................... 3
`APPENDICES .................................................................................................................... 4
`
`
`
`
`
`Reference ID: 3340118
`
`2
`
`

`

`
`
`1
`INTRODUCTION
`This memorandum evaluates the revised container labels and carton labeling for Lo
`Minastrin Fe (Norethindrone Acetate and Ethinyl Estradiol Chewable Tablets, Ethinyl
`Estradiol Tablets and Ferrous Fumarate Tablets) submitted on June 27, 2013 (see
`Appendix A). The Division of Medication Error Prevention and Analysis (DMEPA)
`initially reviewed the container labels and carton labeling in OSE Review 2013-1, dated
`May 21, 2013.
`
`2 MATERIALS REVIEWED
`DMEPA evaluated the revised container labels and carton labeling submitted on
`June 27, 2013. We compared the revised labels and labeling against our
`recommendations in OSE Review 2013-1, dated may 21, 2013, to assess whether the
`revised labels and labeling address our concerns from a medication error perspective.
`
`3
`CONCLUSIONS AND RECOMMENDATIONS
`Our review of the revised container labels and carton labeling determined the Applicant
`has implemented all of our recommendations and we find the revisions acceptable.
`Therefore, we have no further recommendations.
`If you have further questions or need clarifications, please contact OSE Project Manager,
`Marcus Cato, at 301-796-3903.
`
`Reference ID: 3340118
`
`3
`
`3 Pages 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
`07/12/2013
`
`JAMES H SCHLICK
`07/12/2013
`
`Reference ID: 3340118
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`M E M O R A N D U M
`
`
`PUBLIC HEALTH SERVICE
`
`
`
`
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`_______________________________________________________________
`
`DATE:
`
`TO:
`
`January 18, 2013
`
`Director, Investigation Branch
`Florida District Office
`555 Winderley Place, Suite 200
`Maitland, FL 32751
`
`
`
`
`
`
`
`
`
`
`FROM:
`
`
`
`
`
`Chief, Medical Products and Tobacco Trip Planning
`Branch
`Division of Medical Products and Tobacco Inspections
`Office of Medical Products and Tobacco Operations
`
`Sam H. Haidar, Ph.D., R.Ph.
`Chief, Bioequivalence Branch
`Division of Bioequivalence and GLP Compliance
`Office of Scientific Investigations
`
`
`SUBJECT: FY 2013, CDER High Priority User Fee NDA, Pre-Approval
`Data Validation Inspection, Bioresearch Monitoring,
`Human Drugs, CP 7348.001
`
`
` RE: NDA 204-654
` DRUG: Norethindrone Acetate and Ethinyl Estradiol
`Chewable Tablets, Ethinyl Estradiol Tablets,
`and Ferrous Fumarate Tablets
` SPONSOR: Warner Chilcott Company, LLC, USA
`
`This memo requests that you arrange for inspections of the
`clinical and analytical portions of the following bioequivalence
`study. Following identification of the FDA investigator,
`background materials will be forwarded directly. Please contact
`the DBGLPC point of contact (POC) for background materials.
`Please complete the inspections prior to April 12, 2013.
`
`Do not identify the application, sponsor, study to be inspected,
`drug names, or the study investigator prior to the start of the
`inspections. The information will be provided to the sites at
`the inspection opening meetings. Please note that these
`inspections will be conducted under Bioresearch Monitoring
`Compliance Program CP 7348.001, and not under CP 7348.811
`(Clinical Investigators).
`
`
`
`Reference ID: 3247885
`
`

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`Page 2 - BIMO Assignment, NDA 204-654 Norethindrone Acetate and
`Ethinyl Estradiol Chewable Tablets, Ethinyl Estradiol
`Chewable Tablets, and Ferrous Fumarate Tablets
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`
`At the completion of the inspections, please send a scanned copy
`of the completed sections B & C of this memo to Dr. Sam Haidar,
`and the DBGLPC POC listed at the end of this memo.
`
`Study Number: PR-12111
`Study Title: “A study to assess the comparative
`bioavailability of norethindrone acetate and
`ethinyl estradiol from WC3016 tablets and WC3064
`tablets and to assess the effect of food on
`bioavailability from WC3064 tablets in healthy
`female volunteers, Study PR-12111”
`
`
`Clinical Site:
`
`Comprehensive Clinical Development
`3400 Enterprise Way
`Miramar, FL 33025
`Tel: 954-266-1000, Ext 1100
`Fax: 954-266-1012
`Maria Gutierrez, MD
`
`Investigator:
`
`Please confirm documented informed consent for 100% of subjects
`enrolled at all the sites. Please audit the reports for at least
`50% of the total subjects included for the conduct of study by
`site. The subject records in the NDA submission should be
`compared to the original documents at the sites. Include a
`description of your findings in the EIR.
`
`
`SECTION B
`
`
`RESERVE SAMPLES: Because this bioequivalence study is subject to
`21 CFR 320.38 and 320.63, the site conducting the study (i.e.,
`each investigator site) is responsible for randomly selecting and
`retaining reserve samples from the shipments of drug product
`provided by the sponsor for subject dosing.
`
` Please note that the final rule for "Retention of Bioavailability
` and Bioequivalence Testing Samples" (Federal Register, Vol. 58,
` No. 80, pp. 25918-25928, April 28, 1993) specifically addresses
` the requirements for bioequivalence studies
`(http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm120265.htm).
` Please refer to CDER's "Guidance for Industry, Handling and
` Retention of BA and BE Testing Samples" (May 2004), which
` clarifies the requirements for reserve samples
`(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126836.pdf).
`
`Please follow the instructions below:
`
`
`
`Reference ID: 3247885
`
`

`

`Page 3 - BIMO Assignment, NDA 204-654 Norethindrone Acetate and
`Ethinyl Estradiol Chewable Tablets, Ethinyl Estradiol
`Chewable Tablets, and Ferrous Fumarate Tablets
`
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`
`
`
`
`
`
` Verify if reserve samples were retained according to
`regulations.
` If the reserve samples were stored at a third party site,
` please verify and collect an affidavit to confirm that the
` third party is independent from the sponsor, manufacturer,
` and packager, and that the sponsor was notified in writing
` of the location. In an event the reserve samples were not
` retained or are not adequate in quantity, please notify the
` POC immediately.
` Please obtain a written assurance from the clinical
` investigator or the responsible person at the clinical
`site that the reserve samples are representative of those
`used in the specific bioequivalence study, and that they
`were stored under conditions specified in accompanying
`records. Document the signed and dated assurance [21 CFR
`320.38(d, e, g)] on the facility's letterhead, or Form FDA
`463a, Affidavit.
` Samples of the test and reference products in their
` original containers should be collected and shipped to the
` Division of Pharmaceutical Analysis, St. Louis, MO, for
` screening, at the following address:
`
`Benjamin Westenberger, Ph.D.
` Center for Drug Evaluation and Research
` Division of Pharmaceutical Analysis (DPA)
` Center for Drug Analysis (HFH-300)
` US Courthouse and Customhouse Bldg
` 1114 Market Street, Room 1002
` St. Louis, MO 63101
`TEL: (314) 539-2135
`
`
`
`SECTION C
`
`
`Data Audit Checklist:
`
`
`• Primary pharmacodynamic endpoint data verifiable? ______
`• Evidence of under-reporting of AEs identified? ______
`• Other endpoint data verifiable? ______
`• Evidence of inaccuracy in electronic data capture? ______
`• Presence of 100% of signed and dated informed consent
`forms:______
`• Reports for the subjects audited:_____
`• Number of subjects screened at the site:______
`
`
`
`Reference ID: 3247885
`
`

`

`Page 4 - BIMO Assignment, NDA 204-654 Norethindrone Acetate and
`Ethinyl Estradiol Chewable Tablets, Ethinyl Estradiol
`Chewable Tablets, and Ferrous Fumarate Tablets
`
`
`
`
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`• Number of subjects enrolled at the site:______
`• Number of subjects completing the study:______
`• Verify from source documents that evaluations related to the
`primary endpoint were accurately reported in case report
`forms:______
`• Confirm that clinical assessments were conducted in a
`consistent manner and in accordance with the protocol:______
`• Number of subject records reviewed during the
`inspection:______
`• SOPs were followed during study conduct:_____
`• Examine correspondence files for any sponsor- or monitor-
`requested changes to study data or reports:______
`• Include a brief statement summarizing your findings (IRB
`approvals, study protocol and SOPs, protocol deviations,
`adverse events, concomitant medications, inclusion/exclusion
`criteria, adequacy of records, drug accountability documents
`and case report forms for dosing, whether the randomization
`schedule was followed for dosing of subjects, etc.)
`
`• Other Comments:
`______________________________________________________________
`______________________________________________________________
`
`
`Collect relevant exhibits for all findings, including discussion
`items at closeout, as evidence of the findings.
`
`Analytical Site:
`
`
`
`Contact:
`
`
`
`
`
`
`
`
`
`
`Methodology: Gas Chromatography - Mass Spectrometry
`
`
`
`
`
`Please confirm the following during the inspection:
`• All pertinent items related to the analytical method used for
`the measurement of ethinyl estradiol and norethindrone acetate
`concentrations in human plasma should be examined.
`• The accuracy of the analytical data provided in the NDA
`submission by the applicant should be compared with the
`original documents at the site.
`
`
`
`Reference ID: 3247885
`
`(b) (4)
`
`

`

`Page 5 - BIMO Assignment, NDA 204-654 Norethindrone Acetate and
`Ethinyl Estradiol Chewable Tablets, Ethinyl Estradiol
`Chewable Tablets, and Ferrous Fumarate Tablets
`
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`• The method validation and the actual assay of the subject
`plasma samples, the variability between and within runs, QC,
`demonstration of accuracy and precision in matrix using
`standards and QCs prepared from separate stocks, stability of
`subject samples covered by validated stability period.
`• Use of freshly made calibrators and/or freshly made QCs for
`stability evaluations during pre-study method validation.
`• At least one demonstration of precision and accuracy from QCs
`and calibrators prepared from separate stock solutions.
`• Scrutinize the number of repeat assays of the subject plasma
`samples, and the reason for such repetitions, the SOP(s) for
`repeat assays and if relevant stability criteria like freeze
`thaw cycles sufficiently covered the stability of reanalyzed
`subject samples.
`
`
`Additional instructions to ORA Investigator:
`
`In addition to the compliance program elements, other study
`specific instructions may be provided by the DBGLPC POC prior to
`the inspection. Therefore, we request that the DBGLPC POC be
`contacted for further instructions before the inspection, and
`also regarding data anomalies or questions noted during review of
`study records. The ORA investigator should contact the DB