CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022501Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`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
`
`October 21, 2010
`Scott Monroe, MD
`Division Director Summary Review
`NDA 022501
`Warner Chilcott Company, LLC
`April 20, 2010 (Class 2 resubmission)
`October 21, 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”
`Approve (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/Denise Toyer PharmD
`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
`DSI=Division of Scientific Investigations
`CDTL=Cross Discipline Team Leader
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Errors Prevention and Analysis
`DRISK=Division of Risk Management
`
`

`

`NDA 022501
`
`
`DIVISION DIRECTOR SUMMARY REVIEW
`
`
`1. INTRODUCTION
`The objective of NDA 022501 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 also 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 that the Applicant currently
`markets in the US. 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 US is
`20 µg of EE. Lo Loestrin is not currently approved for marketing in any country.
`NDA 022501 was originally submitted in March 2009. The Application was not approved
`during the original review cycle because 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 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. On January 26, 2010, a Complete Response letter was issued by the
`Division of Reproductive and Urologic Products (DRUP).
`On April 20, 2010, Warner Chilcott submitted their complete response to the deficiencies
`listed in the Division’s letter of January 2010. The Submission addressed the 2 chemistry,
`manufacturing and control (CMC) deficiencies and included updated product labeling and a
`safety update.
`During the original review of this Application, the only significant issue bearing on the
`approvability of NDA 022501, other than the issues identified by the Office of Compliance,
`was the efficacy of Lo Loestrin based on the Pearl Index. 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 DRUP to date. The highest Pearl Index for a currently approved combination
`oral contraceptive in the US, based on the Phase 3 clinical trial that supported marketing
`approval, is 2.74 pregnancies per 100 women-years of use (Lo Seasonique approved in
`October 2008). No safety issues that would preclude approval of Lo Loestrin were identified
`during the original review of NDA 022501. The Applicant’s complete response did not
`include any new clinical data. All reviewers, including both the primary Clinical Reviewer
`
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`NDA 022501
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`(Dr. Orleans) and the Clinical Team Leader (Dr. Soule), have recommended that
`NDA 022501 for 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).
`2. BACKGROUND
`2.1 Description of the Product
`Lo Loestrin is a low dose combination oral contraceptive consisting of a new lower 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 NA and 10 µg EE for 24 days, followed by a daily tablet containing
`10 µg EE for 2 days, and 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 US. Norethindrone and norethindrone
`acetate, along with levonorgestrel, are considered by some clinicians to be among 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 US in various formulations since 1973
`and (2) more than 20 such products are currently available in the US. Ethinyl estradiol is the
`estrogen in virtually every combination oral contraceptive product currently marketed in
`the US.
`
`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 (thirteen 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
`Original submission: 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.
`Complete Response: The Applicant’s complete response addressed the 2 chemistry,
`manufacturing and control (CMC) deficiencies and included updated product labeling and a
`safety update.
`
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`Page 3
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`NDA 022501
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`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 of the
`original submission that he signed on 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.”
`“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.”
`Dr. Orleans stated the following in his primary Clinical Review, signed on October 12, 2010,
`of the Applicant’s complete response:
`“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.”
`“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.”
`The Cross Disciple Team Leader (CDTL) Lisa Soule MD, who also was the Clinical Team
`Leader, stated the following in her review of the original submission that she signed on
`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.”
`
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`NDA 022501
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`Dr. Soule stated the following in her updated CDTL review, signed on October 20, 2010, of
`the Applicant’s complete response:
`“I recommend approval of this Complete Response submission, because all deficiencies
`have been satisfactorily addressed.”
` Division Director’s Comment
`I concur with the recommendations of both Drs. Orleans and Soule that Lo Loestrin be
`•
`approved for the indication of use by women to prevent pregnancy.
`3. CMC
`Original Submission
`The primary Chemistry Reviewer, Yubing Tang PhD, made the following recommendations
`in her primary CMC 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 of this Review; consequently, Dr. Tang made the
`following recommendation in an Addendum (signed on January 25, 2010) to her primary
`review:
`“… 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.”
`Complete Response
`In their complete response, the Applicant stated that the FDA’s Division of Manufacturing
`and Product Quality had notified the drug substance manufacturer (
`
`) that previously noted deficiencies had been addressed. In addition, the Applicant stated
`that they were withdrawing one of the 2 duplicate analytical laboratories (the laboratory that
`was not prepared for inspection by the FDA during the first review cycle). The Applicant
`further stated in their complete response that “… Warner Chilcott considers all product
`quality deficiencies mentioned in the Division’s Complete Response letter to have been
`completely resolved.”
`On May 26, 2010, an overall “Acceptable” recommendation was issued by the Office of
`Compliance for all facilities involved in the manufacturing and testing of Lo Loestrin.
`Dr. Tang subsequently made the following recommendation in her Review signed on
`September 16, 2010:
`“This NDA provided adequate information on the raw material controls, manufacturing
`process, specifications, and container/closure system. It also provided sufficient stability
`data to assure identity, strength, purity and quality of the drug product during the
`
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`Page 5
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`(b) (4)
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`NDA 022501
`
`
`expiration dating period. Labels have required information. The Office of Compliance
`has issued the overall “Acceptable” recommendation for all manufacturing and testing
`facilities.”
`“Therefore, from the CMC perspective, this NDA is recommended for approval.”
`
`Division Director’s Comment
`I concur with Dr. Tang’s overall assessments and recommendation.
`•
`4. NONCLINICAL PHARMACOLOGY/TOXICOLOGY
`Original Submission
`The active ingredients of this product, NA and EE, have been marketed in a number of
`products for more than 35 years. The Applicant did not provide any new nonclinical
`pharmacology/toxicology data in the current NDA, but did reference their approved
`NDA (21-871) for Loestrin 24. The primary Toxicology Reviewer, Krishan Raheja
`DVM/PhD, made the following recommendations in his review signed on June 16, 2009:
`Recommendations on approvability: Pharmacology/toxicology data support approval
`of NDA 22-501 for
` [Lo Loestrin] for contraception.
`Recommendations for nonclinical studies: All pharmacology/toxicology data were
`reviewed under the sponsor’s approved NDA 21-871 for Loestrin® 24 Fe (norethindrone
`acetate and ethinyl estradiol tablets, USP, and ferrous fumarate tablets) for the
`contraception indication.
`Recommendations on labeling: As required, the Labeling is in accordance with PLR and
`provided in SPL format.
`Complete Response
`Dr. Raheja made the following statement in his Review signed on September 20, 2010:
`“The new resubmitted label for Lo Loestrin Fe is acceptable from the P/T perspective.”
`
`Division Director’s Comment
`I concur with the recommendations of Dr. Raheja that the pharmacology/toxicology data
`•
`support approval.
`5. CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS
`Original Submission
`Three clinical pharmacology Phase 1 studies were conducted in support of this NDA. These
`studies were conducted to assess (1) the pharmacokinetics of NA and EE after a single dose
`and at steady state after once daily administration of Lo Loestrin for 24 days, (2) the relative
`bioavailability of NA and EE when dosed as Lo Loestrin tablets or as a hydroalcoholic
`solution of NA and EE, and (3) the effect of food on the bioavailability of NA and EE
`following administration of Lo Loestrin tablets.
`Norethindrone acetate is deacetylated to norethindrone (NE) after oral administration.
`Norethindrone acetate and EE are absorbed from Lo Loestrin Fe, with maximum plasma
`concentrations of NE and EE generally occurring 1 to 2 hours postdose. Both are subject to
`
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`NDA 022501
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`first-pass metabolism after oral dosing, resulting in an absolute bioavailability of
`approximately 64% for NA and 55% for EE.
`The studies evaluating food effect showed that dosing under fed conditions reduced the Cmax
`for EE by about 23%, while Cmax for NA was unchanged. There was no effect of food on
`the AUC for EE, while the AUC for NA increased by about 24%. Because the clinical trial
`permitted dosing without regard to meals, instructions in labeling will also permit dosing
`without regard to meals.
`Dr. Apparaju stated the following in her review signed on November 20, 2009:
`“NDA 22-501 is acceptable from a Clinical Pharmacology perspective, provided an
`agreement can be reached with the sponsor pertaining to labeling language.”
`Complete Response
`During the current review cycle, additional labeling changes were conveyed to the Applicant.
`All were accepted by the Applicant. In her Clinical Pharmacology Review that she signed on
`October 7, 2010, Dr. Apparaju made the following recommendation:
`“NDA 22-501 is acceptable from a Clinical Pharmacology perspective.”
`Dr. Apparaju did not recommend any Phase 4 commitments.
`
`Division Director’s Comment
`I concur with Dr. Apparaju’s conclusion that the Clinical Pharmacology data and related
`•
`labeling support approval.
`6. CLINICAL MICROBIOLOGY
`The Applicant originally did not propose any microbial limits testing for the final tablets.
`Dr. Pawar, Microbiology Reviewer, expressed concern that the manufacturing process did not
`address the possibility of contamination by adventitious pathogens during manufacturing.
`The Applicant subsequently agreed to the product testing requested by Dr. Pawar. In a second
`review, signed on December 23, 2009, Dr. Pawar stated that the Applicant’s response was
`acceptable, and he made the following recommendation on approvability:
`“The amended original NDA is recommended for approval.”
`Division Director’s Comment
`• The Applicant’s complete response was not re-reviewed by Microbiology because there
`were no microbiology deficiencies at the completion of the first review cycle.
`I concur with Dr. Pawar’s recommendation of approval.
`•
`7. CLINICAL/STATISTICAL-EFFICACY
`The following efficacy data summarized in Section 7 is based primarily on the information
`contained in the Applicant’s original NDA submission of March 2009.
`
`7.1 Overview of Primary Phase 3 Clinical Trial and Subject Demographics
`The Applicant conducted a single, multicenter, open-label, non-comparative, 12 month
`(thirteen 28-day treatment cycles), Phase 3 clinical trial (PR-05806) in which 1,660 women
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`NDA 022501
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`received at least one dose of Lo Loestrin. Subjects were enrolled at 68 US sites. The
`modified intent-to-treat (MITT) population consisted of 1,582 women who received at least
`one dose of Lo Loestrin and who were evaluated for pregnancy at least once after beginning
`study medication. Subjects in the MITT were 18.0-45.9 years of age (mean [SD]
`age = 28.6 [6.9] years), and 1,270 of the subjects were ≤ 35 years of age. The inclusion and
`exclusion criteria were, in general, consistent with those of other clinical trials for oral
`contraceptives. As in many trials, women with a body mass index (BMI) > 35 kg/m2 were to
`be excluded. The mean (SD) weight of the MITT subjects was 150.1 (29.3) pounds
`(range: 89-260). The racial distribution of the subjects who received at least one dose of
`study drug was 74.9% Caucasian, 11.8% African-American, 9.8% Hispanic, 1.3% Asian, and
`2.2% other.
`
`Division Director’s Comments
`• The racial distribution of the population appears fairly representative of the general US
`population.
`• Although the Protocol for Study PR-05806 excluded women with a BMI of >35 kg/m2, the
`mean weight of subjects in the MITT population (150.1 pounds) was only 9 pounds less
`than that (i.e., 159 pounds) in the primary efficacy and safety study for another approved
`combination oral contraceptive that did not have any weight limit or BMI restrictions.
`Nevertheless, because women with a BMI >35 kg/m2 were not studied in the Phase 3
`clinical trial, this should be reflected in product labeling for Lo Loestrin.
`
`7.2 Study Populations and Subject Disposition
`A total of 1,683 subjects were enrolled in Study PR-05806. Of these, 1,660 women took at
`least one dose of study drug. This constituted the safety population. A total of 692 women
`(42%) from the population who took at least one dose of Lo Loestrin discontinued
`prematurely for the reasons listed in Table 1.
`
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`NDA 022501
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`Table 1 Study Populations, Subject Disposition, and Reasons for
`Premature Discontinuation (Study PR-05806)
`Total
`Population/Disposition/Reason
`1,683
`Total subjects enrolled
`Total subjects treated A
`1,660 (100%)
`MITT population B
`1,582 (95.3%)
`PITT population C
`1,270 (76.2%)
`968 (58.3%)
`Completed the study
`692 (41.7%)
`Prematurely discontinued from the study
`227 (13.7)
`• Lost to follow-up
`177 (10.7%)D
`• Adverse event
`147 (8.9%)
`• Withdrawal of consent
`96 (5.8%)
`• Other
`25 (1.5%)
`• Lack of efficacy (pregnancy)
`20 (1.2%)
`• Protocol violation
`0
`• Death
`A Defined as all subjects who received at least one dose of study drug. This is the safety population.
`B Modified Intent to Treat population. Defined as all subjects who received at least one dose of study drug
`and were evaluated for pregnancy at least once after beginning study medication.
`C Pregnancy Intent to Treat population. Defined as the subgroup of the MITT population who were
`18-35 years of age at enrollment.
`D Includes 5 subjects in which the adverse event occurred prior to starting treatment with study drug.
`Source: Table 6 from the primary Clinical Review signed on January 8, 2010.
`
`Division Director's Comments
`• A premature discontinuation rate of 41.7% for a one year Phase 3 contraceptive clinical
`trial is similar to that reported for other recently reviewed one year Phase 3 contraceptive
`clinical trials.
`• A discontinuation rate of 10.7% due to adverse events also is similar to that for other
`recently reviewed one year Phase 3 contraceptive clinical trials.
`
`7.3 Efficacy Findings
`
`7.3.1 Primary Assessment of Efficacy (On-Treatment Pregnancies)
`The primary efficacy analysis in this and other contraceptive trials is the Pearl Index, which is
`computed as:
`
`Pearl Index =
`
`(number of “on-treatment” pregnancies) x 13 cycles/year
`(total number of completed 28-day treatment cycles)*
`* Only cycles in which no back-up contraceptive methods were used are included
`
`x 100
`
`The primary analysis population was the pregnancy intent-to-treat (PITT) population, defined
`as all subjects who received at least one dose of study drug, were evaluated for pregnancy at
`least once after beginning study drug, and were between the ages of 18-35 years at entry. All
`treatment cycles during which any backup method of birth control was used, including
`condoms, were excluded from the efficacy analysis unless the subject conceived during the
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`cycle. All pregnancies conceived after the onset of treatment with study drug or within 7 days
`after a subject’s last tablet of study drug were included in the calculation of the Pearl Index.
`
`Division Director’s Comment
`• The Division’s recent thinking on the window in which conceptions are counted as
`treatment failures is that pregnancies conceived within 7 days after the last pill taken
`(whether active or placebo pill) are to be counted. This allows for inaccuracy in
`ultrasound dating of pregnancies, but acknowledges that contraceptive protection is not
`expected to be maintained beyond the last tablet in a 28-day treatment cycle.
`
`7.3.2 Primary Efficacy Findings
`The PITT population, comprised of 1,270 women aged 18-35 years, contributed a total of
`12,482 treatment cycles during which no backup contraception was used. The Applicant
`initially identified 24 pregnancies for which the conception date was considered to be
`on-treatment. The primary Clinical Reviewer, however, identified 4 additional pregnancies
`that he believed were on-treatment pregnancies, for a total of 28 on-treatment pregnancies.
`These pregnancies included (1) 2 pregnancies in subjects who were 35 years of age at study
`entry but 36 years of age at the time of conception, (2) one pregnancy for which the estimated
`day of conception was 9 days after the onset of treatment, and (3) one pregnancy for which
`the documentation consisted solely of the subject’s reporting to the Principle Investigator at
`her study site that she had had a positive urine pregnancy test 6 days after her last dose of
`study drug.
`Division Director's Comment
`Inclusion in the efficacy analysis of the single pregnancy that was based solely upon the
`•
`subject’s report of a positive pregnancy test without any further documentation could be
`questioned. Exclusion of this one subject would not have a significant effect on the
`assessment of the efficacy of Lo Loestrin as it would only reduce the Pearl Index from
`2.92 to 2.81.
`
`7.3.3 Primary Efficacy Analysis
`The Pearl Index values (and associated 95% confidence intervals) based on 28 on-treatment
`pregnancies in both the MITT (subjects of all ages) and the PITT population (subjects
`≤ 35 years of age at enrollment) are listed in Table 2. Based on 28 on-treatment pregnancies
`and a total of 12,484 completed 28-day cycles of treatment for subjects ≤ 35 years of age
`during which no backup contraception was used (PITT population), the Pearl Index was
`calculated by the FDA statistician to be 2.92 (95% Confidence Interval [CI]: 1.94, 4.21).
`
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`Table 2 Pearl Index Values Based on Completed Treatment Cycles in which No Back-Up
`Contraception Was Used in the MITT and PITT Populations (Study PR-05806) *
`Pearl
`Population
`Total
`Number of Cycles
`Number of
`95%
`Index
`Number of
`Without Use of
`On-treatment
`Confidence
`Subjects
`Back-up Birth
`Pregnancies
`Interval
`Control
`2.33
`(1.55, 3.37)
`28
`15,591
`1,555
`MITT **
`2.92
`(1.94, 4.21)
`28
`12,482
`1,270
`PITT ***
`* Analyses performed by FDA statistician and based on DRUP’s determination of 28 on-treatment
`pregnancies.
`** MITT: subjects of all ages
`*** PITT: subjects ≤ 35 years of age at enrollment
`Source: Table 3 of the FDA Statistical Review signed on December 28, 2009.
`
`Division Director’s Comment
`• No pregnancies were reported in the population of women who were > 35 years of age at
`enrollment. The Pearl Index was 2.33 (95% CI: 1.55, 3.37) in the MITT population,
`which included women of all ages (and is more representative of the population that is
`likely to use Lo Loestrin should the product be approved).
`Life table calculations also are commonly used as supportive assessments of contraceptive
`efficacy; these methods provide cumulative rates of pregnancy. The FDA statistician
`provided a life table estimate based on the 28 on-treatment pregnancies. The statistician
`excluded from the analyses only those cycles in which back-up contraception was used, rather
`than censoring a subject as soon as she used back-up contraception. The results of these
`analyses in the MITT and PITT populations are provided in Table 3.
`
`Table 3 Life Table Analysis of the Cumulative Failure Rates after Thirteen 28-Day Cycles
`of Treatment *
`
`Population
`
`95% Confidence
`Cumulative
`Number of On-treatment
`Interval
`Pregnancy Rate
`Pregnancies
`(1.49%, 3.17%)
`2.17%
`28
`MITT **
`(1.86%, 3.95%)
`2.71%
`28
`PITT ***
`* Analyses performed by FDA statistician and based on DRUP’s determination of 28 on-treatment
`pregnancies.
`** MITT: subjects of all ages
`*** PITT: subjects ≤ 35 years of age at enrollment
`Source: Table 4 of the FDA Statistical Review signed on December 28, 2009.
`
`Division Director's Comment
`• Results from the life table analysis showed a cumulative one year pregnancy rate of
`2.71% (95% CI: 1.86%, 3.95%) in the PITT population and were supportive of the
`estimate of the risk of pregnancy based on the Pearl Index (2.92).
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`7.3.4 Statistician’s Conclusion regarding Primary Efficacy Findings
`The primary statistical reviewer, Kate Dwyer PhD, made the following statement in the
`conclusion of her original statistical review signed on December 28, 2009:
`“From a statistical perspective, the study results support the efficacy of WC3016
`[Lo Loestrin], a low dose oral contraceptive consisting of a new dose and new regimen of
`the combination of norethindrone acetate (NA) and ethinyl estradiol (EE), in the
`prevention of pregnancy.”
`In her review, signed on October 18, 2010, of the Applicant’s complete response, Dr. Dwyer
`stated:
`“The efficacy (using Pearl Index) result in the label was evaluated and verified by this
`reviewer in the original statistical review of this NDA. Since no additional efficacy data
`was included in this resubmission, this reviewer agrees with the final version of the label.”
`
`7.4 Overall Assessment of Efficacy
`The Pearl Index for Lo Loestrin, calculated by the FDA statistician, was 2.92 pregnancies per
`100 women-years of use (95% CI: 1.94, 4.21), based on 28 on-treatment pregnancies in
`subjects ≤ 35 years of age. This Pearl Index value is slightly higher than that of any
`combination oral contraceptive approved by DRUP to date. The highest Pearl Index for a
`currently approved combination oral contraceptive in the US, 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).
`The primary Clinical Review (Dr. Orleans) did not express any concern in his original review
`or his review of the Applicant’s complete response regarding the demonstrated efficacy of Lo
`Loestrin. He stated the following in his original review signed on January 8, 2010:
`“The PI of 2.916 (1.938, 4.213) per 100 women-years of use for this product is slightly
`higher than previously approved combination OCs. However, it is problematic to make
`valid, cross-study, comparisons of Pearl Indices. The Pearl Indices for clinical trials vary
`considerably, even for the same formulation, depending on the studies from which data
`are obtained. … Nevertheless, in my opinion, a PI of 2.92 is acceptable to support the
`efficacy of WC3016 [Lo Loestrin].”
`The issue of what constitutes an acceptable upper limit for the Pearl Index for oral
`contraceptives was discussed by a group of contraceptive experts at a meeting of the Advisory
`Committee for Reproductive Health Drugs (ACRHD) in January 2007. The Committee
`Members were asked if there was a specific Pearl Index above which they believed an oral
`contraceptive should not be approved. The Committee Members declined to recommend a
`specific value. In the Final Summary Minutes of the 2-day meeting, Dr. Charles Lockwood,
`who was the acting Chairperson of the meeting, made the following statement:
`“However, the committee was unanimous in its desire to make clear that arbitrary limits
`be avoided in order to promote the widest range of new contraceptive products being
`developed and brought to the market. … Most abstained from giving an exact point
`estimate or upper confidence interval. The key point to emphasize is that you have to
`provide all the information to the clinician and the patient in an easily understood format
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`•
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`in labeling and then let them make the final decision on which product is most
`appropriate for the patient (i.e., caveat emptor).”
`Division Director's Summary Comments
`• The App