CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022501Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 22-501 (Class 2 Resubmission)
`Priority or Standard Standard
`
`
`Submit Date(s) April 20, 2010
`Received Date(s) April 21, 2010
`PDUFA Goal Date October 21, 2010
`Division / Office Reproductive and Urologic
`Products/Office of New Drugs
`
`
`Reviewer Name(s) Ronald J. Orleans, M.D.
`Review Completion Date October 4, 2010
`
`
`Established Name Norethindrone acetate/ethinyl
`estradiol; ethinyl estradiol; ferrous
`fumarate
`(Proposed) Trade Name Lo Loestrin Fe
`Therapeutic Class Oral Contraceptive
`Applicant Warner Chilcott Company, Inc.
`
`
`Formulation(s) Twenty-four days of norethindrone
`acetate 1 mg/ethinyl estradiol 10
`mcg tablets followed by two days
`of ethinyl estradiol 10 mg tablets
`followed by two days of ferrous
`fumarate tablets
`Dosing Regimen One tablet daily
`Indication(s) Prevention of Pregnancy
`Intended Population(s) Women of reproductive age at risk
`for pregnancy who desire
`contraception
`
`
`October 4, 2010 (Final)
`
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 3
`1.1 Recommendation on Regulatory Action ............................................................. 3
`1.2 Risk Benefit Assessment.................................................................................... 3
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 4
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 4
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 4
`2.1 Product Information ............................................................................................ 4
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 4
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 5
`2.4
`Important Safety Issues With Consideration to Related Drugs........................... 6
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 6
`2.6 Other Relevant Background Information ............................................................ 6
`3 ETHICS AND GOOD CLINICAL PRACTICES......................................................... 6
`
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................... 6
`4.1 Chemistry Manufacturing and Controls .............................................................. 6
`5 SOURCES OF CLINICAL DATA.............................................................................. 8
`5.2 Review Strategy ................................................................................................. 8
`5.3 Discussion of Individual Studies/Clinical Trials................................................... 8
`6 REVIEW OF EFFICACY........................................................................................... 8
`Efficacy Summary........................................................................................................ 8
`6.1
`Indication ............................................................................................................ 8
`7 REVIEW OF SAFETY............................................................................................... 8
`Safety Summary .......................................................................................................... 8
`7.1 Methods.............................................................................................................. 9
`7.7 Additional Submissions / Safety Issues.............................................................. 9
`8 POSTMARKET EXPERIENCE................................................................................. 9
`
`9 APPENDICES ........................................................................................................ 10
`9.2 Labeling Recommendations............................................................................. 10
`
`October 4, 2010 (Final)
`
`2
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`In the original review of NDA 22-501, approval of Lo Loestrin Fe for prevention of
`pregnancy was recommended from the clinical perspective, based on Warner Chilcott
`(the Applicant) having demonstrated an acceptable Pearl Index and an acceptable
`safety profile for this product.
`
`However, from a CMC perspective, this NDA was not recommended for “Approval” until
`the manufacturing facility and the control testing laboratory used to support the
`Application were in full compliance with cGMP requirements to assure the identity,
`strength, purity, and quality of the drug product. Therefore, the Applicant was sent a
`“Complete Response” letter.
`
`This class 2 resubmission documents the Applicant’s response to the complete
`response letter. The present submission contained no new efficacy or safety data.
`Therefore, from the clinical perspective, this Reviewer again recommends approval.
`
`1.2 Risk Benefit Assessment
`
`The Pearl Index for Lo Loestrin Fe was derived from the Pregnancy Intent to Treat
`Population (PITT), which consisted of all women ages 18-35 who completed at least
`one full cycle of therapy (N=1,270). All 28-day cycles in which subjects used additional
`back-up methods of birth control (including condoms) and all incomplete 28-day cycles
`(except those in which conception occurred) were excluded from the denominator used
`in the Pearl Index calculation. A total of 1,270 subjects took the study medication over
`12,482 completed 28-day cycles. Twenty-eight (28) on-drug conceptions occurred
`during this clinical trial.
`
`Based on the 28 pregnancies that occurred over 12,482 completed cycles, the Pearl
`Index was calculated by the FDA Statistician to be 2.92 (95% CI 1.94, 4.21). The life-
`table pregnancy rate was calculated to be 2.71 (95% CI 1.86, 3.95). The Pearl Index
`and the life-table analysis computations are comparable to those of other approved low
`dose oral contraceptive products and support the efficacy of Lo Loestrin Fe in
`preventing pregnancy.
`
`The primary clinical trial also demonstrated that the safety profile of Lo Loestrin Fe was
`acceptable. No deaths occurred during the trial. The number of early withdrawals, and
`the frequency and type of adverse events leading to withdrawals, were comparable to
`other low dose combined oral contraceptives and did not raise any new or unexpected
`safety concerns.
`
`In the Medical Reviewer’s opinion, the original Application demonstrated that Lo
`Loestrin Fe was a safe and effective oral contraceptive and approval based on the
`clinical trial data was recommended.
`
`October 4, 2010 (Final)
`
`3
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`No postmarketing risk evaluation and mitigation strategies were recommended.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`Standard post-marketing surveillance was recommended. No specific risk management
`steps were recommended.
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`Lo Loestrin Fe is a low dose oral contraceptive (OC) consisting of a new regimen of the
`combination of norethindrone acetate (NA) and ethinyl estradiol (EE). A tablet
`containing 10 mcg of EE in combination with 1 mg of NA is taken for 24 days, followed
`by a tablet containing 10 mcg of EE taken for 2 days, followed by a tablet containing
`ferrous fumarate 75 mg taken for 2 days. The proposed indication is for the prevention
`of pregnancy in women
`
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Table 1 Combination 28-Day Oral Contraceptives Containing EE/NA
`NDA/ANDA
`Proprietary
`Approval
`EE Strength
`NA
`Name
`Date
`(mg)
`Strength
`(mg)
`1, 1, 1
`
`NDA 20-130
`
`Estrostep 21
`
`1996
`
`0.02, 0.03, 0.035
`
`Marketing
`Status
`
`Discontinued*
`
`NDA 20-130
`
`Estrostep Fe
`
`NDA 17-875
`
`NDA 17-876
`
`NDA 17-355
`
`NDA 17-354
`
`NDA 21-871
`
`NDA 16-749
`
`NDA 16-852
`
`Loestrin 21
`1.5/30
`Loestrin 21
`1/20
`Loestrin Fe
`1.5/30
`Loestrin Fe
`1/20
`Loestrin 24 Fe
`
`Norlestrin 21
`1/50
`Norlestrin 21
`2.5/50
`
`1999
`
`1976
`
`1976
`
`1973
`
`1973
`
`2006
`
`Prior to
`1982
`Prior to
`1982
`
`0.02, 0.03, 0.035
`
`1, 1, 1
`
`Prescription
`
`0.03
`
`0.02
`
`0.03
`
`0.02
`
`0.02
`
`0.05
`
`0.05
`
`1.5
`
`1.0
`
`1.5
`
`1
`
`1.0
`
`1.0
`
`2.5
`
`Prescription
`
`Prescription
`
`Prescription
`
`Prescription
`
`Prescription
`
`Discontinued*
`
`Discontinued*
`
`October 4, 2010 (Final)
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`
`NDA/ANDA
`
`Proprietary
`Name
`
`Approval
`Date
`
`Prior to
`1982
`Prior to
`1982
`Prior to
`1982
`2003
`
`2003
`
`2003
`
`2003
`
`2001
`
`EE Strength
`(mg)
`
`0.05
`
`0.05
`
`0.05
`
`0.30
`
`0.20
`
`0.30
`
`0.20
`
`0.20
`
`NA
`Strength
`(mg)
`1.0
`
`1.0
`
`2.5
`
`1.5
`
`1.0
`
`1.5
`
`1.0
`
`1.0
`
`Marketing
`Status
`
`Discontinued*
`
`Discontinued*
`
`Discontinued*
`
`Prescription
`
`Prescription
`
`Prescription
`
`Prescription
`
`Prescription
`
`2001
`
`0.03
`
`1.5
`
`Prescription
`
`2007
`
`2007
`
`0.02, 0.03, 0.035
`
`0.02, 0.03, 0.035
`
`1, 1, 1
`
`1, 1, 1
`
`Prescription
`
`Prescription
`
`NDA 16-723
`
`NDA 16-766
`
`NDA 16-854
`
`ANDA 76381
`
`Norlestrin 28
`1/50
`Norlestrin Fe
`1/50
`Norlestrin Fe
`2.5/50
`Junel 1.5/30
`
`ANDA 76380
`
`Junel 1/20
`
`ANDA 76064
`
`ANDA 76081
`
`ANDA 75647
`
`ANDA 75548
`
`ANDA 76405
`
`Junel Fe
`1.5/30
`Junel Fe 1/20
`
`Microgestin
`1/20
`Microgestin Fe
`1/20
`Microgestin
`1.5/30
`Microgestin Fe
`1.5/30
`Tri-Legest 21
`
`ANDA 76105
`
`Tri-Legest Fe
`
`ANDA 77075
`
`ANDA 77077
`
`ANDA 78267
`
`NA and EE
`and Fe
`NA and EE
`and Fe
`NA and EE
`and Fe
`Source: Medical Reviewer compilation from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
`*Federal Register determination that product was not discontinued or withdrawn for safety or efficacy
`reasons.
`
`2005
`
`2005
`
`2009
`
`0.3
`
`0.2
`
`0.2
`
`1.5
`
`1.0
`
`1.0
`
`Prescription
`
`Prescription
`
`Prescription
`
`
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`The active ingredients for this drug product, EE and NA, have been used in OC
`products for almost four decades. There is an extensive body of knowledge relating to
`the safety of both active ingredients in the doses proposed.
`
`October 4, 2010 (Final)
`
`5
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`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`2.4
`
`Important Safety Issues with Consideration to Related Drugs
`
`The most significant adverse events are the potential thomboembolic and
`cardiovascular complications. Serious adverse events have decreased with reduction in
`daily doses of EE and progestins.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`See the Medical Officer’s Review, dated 1/9/09, of the original NDA submission.
`
`2.6 Other Relevant Background Information
`
`NDA 22-501 was received by FDA on March 26, 2009. The original PDUFA goal date
`was 1/26/2010. From a clinical perspective, the Application was recommended for
`approval based on the submitted safety and efficacy data from the primary phase 3
`clinical trial, PR-05806.
`
`However, from a CMC perspective, this NDA was not recommended for “Approval” until
`the manufacturing facility and the control testing laboratory used to support the
`Application were in full compliance with cGMP requirements to assure the identity,
`strength, purity, and quality of the drug product. Therefore, the Division determined that
`the Application could not be approved in its present form. On 1/26/10, a “Complete
`Response “letter was sent to the Applicant. For further details, see Section 4.1,
`Chemistry Manufacturing and Controls.
`
`3 Ethics and Good Clinical Practices
`
`Not applicable, as no new clinical or nonclinical data were submitted.
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.1 Chemistry Manufacturing and Controls
`
`The primary Chemistry reviewer, Yubing Tang PhD, made the following
`recommendations in her initial primary review signed on 1/8/2010:
`“This NDA has provided sufficient CMC information to assure the identity,
`strength, purity, and quality of the drug product. Labels have adequate
`information as required. However, the overall “Acceptable” recommendation has
`not been made by the Office of Compliance as of this review.”
`
`
`Therefore, from a CMC perspective, this NDA was not recommended for “Approval”
`until all the facilities involved were fully in compliance with cGMP requirements to
`assure the identity, strength, purity, and quality of the drug product. The NDA could not
`
`October 4, 2010 (Final)
`
`6
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`be approved until the issues cited by the Office of Compliance were resolved and an
`“Acceptable” recommendation was made by the Office of Compliance.
`
`During inspections of a drug substance manufacturing facility and a control testing
`laboratory used to support this application, the Office of Compliance field investigators
`conveyed deficiencies to the representatives of the respective facilities. These
`deficiencies were not resolved. Satisfactory resolution of these deficiencies was
`required before the NDA can be approved.
`
`On 1/19/2010, the Office of Compliance issued an overall rating of “Withhold”
`approval. The recommendation by the Office of Compliance was based on:
`(1) the failure of the contract manufacturer,
`drug substances (NA and EE) to adhere to current GMPs and
`(2) a secondary contract drug substance testing site not being ready to conduct testing
`for the Applicant’s product.
`
`On 1/21/2010, the Applicant submitted by e-mail a proposal to address the deficiencies.
`The proposal included:
` as a supplier of the drug substances and
`(1) Withdrawal of
` as a testing site,
`withdrawal of
` as the sole supplier of the drug substance for Lo Loestrin, and
`(2) Listing only
`(3) Using presently available stability data from a single batch of drug product that had
`been manufactured using
` drug substance.
`
`The Applicant was informed that prior to approval of NDA 22-501, data from 3 batches
`of drug product manufactured with
` drug substance would need to be submitted
`and reviewed by the Agency if
` were to be the sole supplier of drug substance
`for Lo Loestrin Fe.
`
` of the
`
` A
`
` “Complete Response” letter was therefore sent to the Applicant on 1/26/2010. This
`letter detailed several drug substance manufacturing deficiencies.
`
`Warner Chilcott provided a complete response to the deficiencies noted in the Complete
`Response letter and resubmitted NDA 22-501 on 4/20/2010. In the submission, the
`Applicant stated that:
`(1)
` has received correspondence that deficiencies cited in the
`Warning Letter for its
` have been addressed.
` is being withdrawn from NDA 22-501 and that all analytical
`testing of drug substances will be performed by
`
`
`(2)
`
`
`The CMC Reviewer, Yubing Tang, Ph.D. stated in her review of 9/16/2010 that “Now,
`the Office of Compliance has made the overall “Acceptable” recommendation.
`Therefore, from the CMC perspective, this NDA is recommended for approval.”
`
`
`
`October 4, 2010 (Final)
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`5 Sources of Clinical Data
`Not applicable, as the resubmission of NDA 22-501 contained no new clinical data.
`
`5.2 Review Strategy
`
`The complete, class 2 response to the 1/26/2010 action letter was received on
`4/21/2010. This submission was reviewed.
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`No new studies or clinical trials were submitted.
`
`6 Review of Efficacy
`Efficacy Summary
`Based on the 28 pregnancies that occurred over 12,482 completed cycles, the Pearl
`Index was calculated by the FDA Statistician to be 2.92 (95% CI 1.94, 4.21). The life-
`table pregnancy rate was calculated to be 2.71 (95% CI 1.86, 3.95).
`
`6.1
`
`Indication
`
`The indication for Lo Loestrin Fe is for the prevention of pregnancy in women who elect
`to use oral contraceptives as a method of contraception. The Applicant submitted data
`from one primary phase 3 clinical trial report (Report # RR-03108) in support of this
`indication. Details of the medical review of the primary clinical trial can be found in the
`review by Dr. Ronald J. Orleans, dated 1/9/2010. No new studies or clinical trials were
`included in the recent submission.
`
`7 Review of Safety
`Safety Summary
`The published literature concerning OCs clearly identifies the risks associated with the
`use of OCs. The most serious of these risks include arterial and venous thrombosis.
`However, the risk of serious morbidity or mortality is small in healthy women without
`underlying risk factors and is exceeded by the risks of pregnancy.
`
` full safety review of the clinical data submitted in the first review cycle is described in
`the review by Dr. Ronald J. Orleans, dated 1/9/2010. There were no deaths during the
`clinical development of Lo Loestrin Fe. The results of the phase 3 clinical trial did not
`indicate any safety concerns beyond those commonly attributed to OCs. Lo Loestrin Fe
`has been demonstrated to be a safe oral contraceptive when taken over 13 cycles.
`
` A
`
`October 4, 2010 (Final)
`
`8
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`7.1 Methods
`
`A Safety Update was enclosed with the submission. There were no new nonclinical or
`clinical studies conducted or initiated at the time of the submission.
`
`7.7 Additional Submissions / Safety Issues
`
`NDA 22-501 was resubmitted for review on 4/20/2010 (SDN-20). A Safety Update was
`enclosed with the submission. There were no nonclinical or clinical studies conducted
`or initiated at the time of the submission.
`
` A
`
` recent review of the clinical and non clinical literature was conducted by the Applicant
`through January 31, 2010, which did not identify new significant safety information.
`
`There is extensive postmarketing experience with the 28-day combination OC
`formulations containing EE 20 mcg /NA 1mg. No worrisome safety signals have
`emerged from this extensive postmarketing experience.
`
`8 Postmarket Experience
`Lo Loestrin Fe tablets are not marketed outside the United States.
`
`October 4, 2010 (Final)
`
`9
`
`

`

`Clinical Review
`NDA 22-501 (Class 2 Resubmission)
`
`
`9 Appendices
`
`9.2 Labeling Recommendations
`
`Labeling negotiations are currently in progress. Clinical issues under discussion include
`revising the label for consistency with recently approved combination oral contraceptive
`PLR labels, defining and standardizing the terms used to describe the bleeding profile
`and adding some clarification to the DOSAGE AND ADMINISTRATION section.
`
`
`October 4, 2010 (Final)
`
`10
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RONALD J ORLEANS
`10/12/2010
`
`LISA M SOULE
`10/12/2010
`I concur with Dr. Orleans' recommendation that NDA 22-501 be approved for the prevention of
`pregnancy in women.
`
`Reference ID: 2848335
`
`

`

`Summary Review for Regulatory Action
`
`
`Date
`From
`Subject
`NDA
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name
`Established (USAN) Name
`
`Dosage Forms/Strengths
`
`January 26, 2010
`Scott Monroe, MD
`Division Director Summary Review
`NDA 22-501
`Warner Chilcott Company, Inc
`March 26, 2009
`January 26, 2010
`Lo Loestrin Fe
`Norethindrone acetate (NA) and ethinyl estradiol (EE)
`tablets/EE tablets/ferrous fumarate (Fe) tablets
`Oral Tablet: 1 mg NA+10 µg EE tablet x 24 days,
`10 µg EE tablet x 2 days, 75 mg Fe tablet x 2 days
`Use by women to prevent pregnancy
`See “Dosage Forms/Strengths”
`Complete Response (see Section 13.1)
`
`Proposed Indication(s)
`Proposed Regimen
`Action
`
`
`Material Reviewed/Consulted
`Names of Discipline Reviewers
`OND Action Package, including:
`Medical Officer Review
`Ronald Orleans MD (primary Clinical Reviewer)
`Statistical Review
`Kate Dwyer PhD/Mahboob Sobhan PhD
`Pharmacology Toxicology Review Krishan Raheja DVM/PhD/Lynnda Reid PhD
`CMC Review/OBP Review
`Yubing Tang PhD/Moo-Jhong Rhee PhD
`Microbiology Review
`Vinayak Pawar PhD
`Clinical Pharmacology Review
`Sandhya Apparaju PhD/Myong-Jin Kim PharmD
`DDMAC
`Janice Maniwang PharmD/Carrie Newcomer PharmD
`DSI
`Not requested
`CDTL Review
`Lisa Soule MD (also Clinical Team Leader)
`OSE/DMEPA
`Tara Turner PharmD/Zachary Oleszczuk
`PharmD/Kellie Taylor PharmD/Carol Holquist RPh
`Robin Duer MBA, RN/LaShawn Griffiths, MSHS-
`PH, RN/Mary Willy PhD
`
`OSE/DRISK
`
`OND=Office of New Drugs
`CMC=Chemistry, Manufacturing and Control
`DDMAC=Division of Drug Marketing, Advertising, and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Errors Prevention and Analysis
`DSI=Division of Scientific Investigations
`DRISK=Division of Risk Management
`CDTL=Cross Discipline Team Leader
`
`

`

`NDA 22-501
`
`
`DIVISION DIRECTOR SUMMARY REVIEW
`
`
`1. INTRODUCTION
`The objective of NDA 22-501 is to obtain marketing approval for Lo Loestrin Fe
`(norethindrone acetate [NA] and ethinyl estradiol [EE] tablets/EE tablets/ferrous fumarate
`[Fe] tablets), a combination oral contraceptive. Lo Loestrin Fe (hereafter referred to as Lo
`Loestrin) is a new dosage strength (lower dose of EE) and a new dosing regimen oral
`contraceptive in the “family” of Loestrin oral contraceptives, which the Applicant currently
`markets in the U.S. The dosing regimen for Lo Loestrin is a 24/2/2 28-day regimen in which
`(1) a daily tablet containing 1 mg NA+10 µg EE is taken for 24 days, (2) a daily tablet
`containing 10 µg EE is taken for 2 days, and (3) a daily tablet containing 75 mg Fe is taken
`for 2 days. The lowest dosage combination oral contraceptive currently marketed by the
`Applicant contains 1 mg NA+20 µg EE in each active tablet. The Applicant believes (1) that
`the lower dose of EE in the proposed product (10 µg EE instead of 20 µg EE) might reduce
`the risk of thromboembolic adverse events associated with the use of estrogen-containing
`contraceptive products and (2) that 24 days of active treatment (instead of 21 days) followed
`by 2 days of EE alone might improve the bleeding profile with respect to both withdrawal
`(scheduled) and intracyclic (unscheduled) bleeding. Currently, the lowest dose of EE in the
`estrogen plus progestin tablet of any approved combination oral contraceptive in the U.S. is
`20 µg of EE. Lo Loestrin is not currently approved for marketing in any country.
`The only significant issues that could affect the approvability of NDA 22-501, which were
`identified during the review of the Application, were (1) the Office of Compliance issuing on
`January 19, 2010, an overall rating of “Withhold” approval and (2) the demonstrated efficacy
`of Lo Loestrin based on the Pearl Index. The recommendation by the Office of Compliance
`
`was based on (1) the failure of the manufacturer (
`) of the drug substances (NA and EE) to adhere to current Good Manufacturing Practices
`(cGMPs) and (2) a secondary contract drug substance testing site not being ready to conduct
`testing for the Applicant’s product.
`The Pearl Index for Lo Loestrin was 2.92 pregnancies per 100 women-years of use in the
`single Phase 3 trial conducted by the Applicant. This value is slightly higher than that of any
`combination oral contraceptive approved by the Division of Reproductive and Urologic
`Products (DRUP) to date. The highest Pearl Index for a currently approved combination oral
`contraceptive in the U.S., based on the Phase 3 clinical trial that supported marketing
`approval, is 2.74 pregnancies per 100 women-years of use (Lo Seasonique, which was
`approved in October 2008). No safety issues that would preclude approval of Lo Loestrin
`were identified during the review of NDA 22-501. Both the primary Clinical Reviewer
`(Dr. Orleans) and the Clinical Team Leader (Dr. Soule) recommended that, from a clinical
`perspective, Lo Loestrin be approved. I concur with their recommendations. The basis for
`my concurrence is provided later in this Memorandum (see Section 7.4 and Section 13.2).
`Because of the overall rating of “Withhold” from the Office of Compliance, however, a
`Complete Response letter will be issued for NDA 22-501 during the present review cycle.
`
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`NDA 22-501
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`2. BACKGROUND
`2.1 Description of the Product
`Lo Loestrin is a low dose combination oral contraceptive consisting of a new dosage of EE
`(i.e., 10 µg) and a new dosing regimen (i.e., 24/2/2) for the “family” of Loestrin combination
`oral contraceptives. A 28-day dosing cycle of Lo Loestrin consists of a daily tablet containing
`1 mg of NA and 10 µg EE for 24 days, followed by a daily tablet containing 10 µg of EE for
`2 days, followed by a daily tablet containing 75 mg ferrous fumarate for 2 days.
`Norethindrone is one of the 2 progestins that were used in the first combination oral
`contraceptives to be approved for marketing in the U.S. Norethindrone and norethindrone
`acetate, along with levonorgestrel, are considered by some clinicians to be the progestins that
`are associated with the lowest risk of venous thromboembolic adverse events. According to
`the primary Clinical Review, combination oral contraceptive products containing EE and NA
`(1) have been marketed in the U.S. in various formulations since 1973 and (2) more than
`20 such products are currently available in the U.S. Ethinyl estradiol is the estrogen in
`virtually every combination oral contraceptive product currently marketed in the U.S.
`
`2.2 Regulatory History
`The development program for Lo Loestrin was conducted under IND 73,510 that was opened
`in 2006. The Applicant was advised by DRUP that a single clinical study would be adequate
`to support an NDA as long as the trial (1) provided at least 10,000 x 28-day evaluable
`treatment cycles and (2) included data from at least 200 women, aged 18-35 years, who took
`the study drug for at least one year (13 x 28-day treatment cycles). The Applicant’s single
`Phase 3 clinical trial provided the requested number of treatment cycles.
`
`2.3 Clinical Content of NDA
`The primary support for the efficacy and safety of Lo Loestrin is based on the Applicant’s
`single, multicenter, open-label, non-comparative Phase 3 clinical trial (Study PR-05806) that
`treated 1,660 women for up to one year. The Applicant’s NDA submission also included
`Final Study Reports from three Phase 1 pharmacokinetic studies. Summary data from a Phase
`1 pharmacodynamic study to assess the capacity of (1 mg NA plus 5 µg EE) tablets to inhibit
`ovulation also were provided.
`
`2.4 Recommendations of Primary Clinical Reviewer and Cross-Discipline
`Team Leader regarding Approvability
`The primary Clinical Reviewer, Ronald Orleans MD, stated the following in his review that
`was signed January 8, 2010:
`“Approval of WC3016 [Lo Loestrin] for prevention of pregnancy is recommended based
`on Warner Chilcott (the Applicant) having demonstrated an acceptable Pearl Index and
`an acceptable safety profile for this product.”
`“In this Reviewer’s opinion, the Applicant has clearly demonstrated that WC3016 is a
`safe and effective oral contraceptive and approval is recommended with labeling that
`clearly shows the pregnancy rates reported in the primary clinical trial.”
`
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`NDA 22-501
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`
`“Epidemiologic evaluations of oral contraceptives and vascular disease have indicated
`that minimizing exposure to estrogen and progestin reduces the risk for both arterial and
`venous thrombotic events. WC3016, with its reduced ethinyl estradiol dosage, may be
`especially useful in subsets of woman who are at increased risk for these thrombotic
`complications (e.g., women over 40, obese women, smokers), yet who still desire
`combined oral contraception.”
`The Cross Disciple Team Leader (CDTL, who was also the Clinical Team Leader), Lisa
`Soule MD, stated the following in her review signed January 25, 2010:
`“I agree with Dr. Orleans that the submitted clinical trial demonstrates an acceptable
`safety profile for Lo Loestrin Fe, and the pregnancy rate is clearly lower than what would
`be expected in the absence of contraception. There may be a population of women who
`desire the lowest possible dose of EE, and are willing to accept the risk of a higher
`pregnancy rate. For these reasons, from a clinical perspective, I concur with Dr.
`Orleans’ recommendation for approval. However, it will be critical that labeling clearly
`describe the Pearl Index and the population studied so that prescribers and potential
`users will be aware of the risk of pregnancy when using this product, and the fact that the
`product was not studied in a population broadly representative of the target population
`with respect to weight.”
`“Although the clinical evidence of safety and efficacy is acceptable to support approval,
`the NDA is not approvable from a CMC perspective. At the present time, based on the
`Withhold recommendation by the Office of Compliance with respect to facilities
`inspections, I recommend that a Complete Response action be taken.”
` Division Director’s Comment
`I concur with the overall recommendations of both Drs. Orleans and Soule and believe
`•
`that Lo Loestrin should be approved after (1) resolution of the CMC issues identified by
`the Office of Compliance and (2) agreement on acceptable labeling is reached.
`3. CMC
`The primary Chemistry reviewer, Yubing Tang PhD, made the following recommendations in
`her primary review signed on January 8, 2010:
`“This NDA has provided sufficient CMC information to assure the identity, strength,
`purity, and quality of the drug product. Labels have adequate information as required.
`However, the overall “Acceptable” recommendation has not been made by the Office of
`Compliance as of this review.”
`“Therefore, from a CMC perspective, this NDA is not recommended for “Approval” until
`the final “Acceptable” recommendation is made by the Office of Compliance.”
`On January 19, 2010, the Office of Compliance issued an overall rating of “Withhold”
`approval. As described earlier in Section 1, the recommendation by the Office of Compliance
`was based on (1) the failure of the contract manufacturer (
`
` of the drug substances (NA and EE) to adhere to current GMPs and (2) a
`secondary contract drug substance testing site not being ready to conduct testing for the
`Applicant’s product.
`
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`NDA 22-501
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`In an Addendum (signed on January 25, 2010) to her primary review, Dr. Tang made the
`following recommendation:
`“Therefore, from a CMC perspective, this NDA is recommended not to approve in its
`present form until all the facilities involved are fully in compliance with cGMP
`requirements to assure the identity, strength, purity, and quality of the drug product.”
`Dr. Tang did not recommend any Phase 4 commitments.
`
`Division Director’s Comments
`I concur with the assessment/recommendation made by Dr. Tang that from a CMC
`•
`perspective, this NDA should not be approved until the issues cited by the Office of
`Compliance are satisfactorily resolved.
`• On January 20, 2010, the Applicant was notified in a teleconference that the Office of
`Compliance had issued an overall rating of “Withhold” approval because of deficiencies
`that were identified during an inspection of the
` drug substance
`manufacturing facility and a control testing laboratory. Later on January 20, 2010, the
`Applicant submitted by e-mail a proposal to address the deficiencies. The proposal
`included
` as a supplier of the drug substances and
`1. Withdrawal of
` as a testing site,
`withdrawal of
` as the sole supplier of the drug substance for Lo Loestrin, and
`2. Listing only
`3. Using presently available stability data from a single batch of drug product that had
`been manufactu