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

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Science
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`Drug Name:
`
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`22-501 / Resubmission
`LO LOESTRIN FE (Norethindrone acetate and Ethinyl Estradiol tablets, and
`Ferrous Fumarate tablets)
`Prevention of Pregnancy
`
`Warner Chilcott Company, Inc.
`
`Submission Date: 4/21/2010
`PDUFA Due Date: 10/21/2010
`Priority
`
`
`
`
`
`Biometrics Division:
`Division of Biometrics III
`Statistical Reviewer:
`Kate Dwyer, Ph.D.
`Concurring Reviewers: Mahboob Sobhan, Ph.D.
`
`
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`
`Keywords: Labeling review
`
`
`
`
`
`
`Division of Reproductive and Urologic Drug Products
`
`Ronald Orleans, M.D., Medical Reviewer
`Lisa Soule, M.D., Team Leader
`Karl Stiller
`
`

`

`
`BACKGROUND
`
`The Applicant has resubmitted this supplement in response to the Complete Response Letter
`issued by the Agency on January 26, 2010 regarding several manufacturing deficiencies. This is
`a labeling review for LO LOESTRIN FE, an oral contraceptive, and no additional clinical trial
`data was included in this submission. The proposed indication is for the prevention of pregnancy
`in women
`.
`
`CONCLUSION
`
`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.
`
`
`
`
`2
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATE L DWYER
`10/18/2010
`re-check in as general review.
`
`MAHBOOB SOBHAN
`10/18/2010
`
`Reference ID: 2851541
`
`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Science
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`Drug Name:
`
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`22-501 / Resubmission
`LO LOESTRIN FE (Norethindrone acetate and Ethinyl Estradiol tablets, and
`Ferrous Fumarate tablets)
`Prevention of Pregnancy
`
`Warner Chilcott Company, Inc.
`
`Submission Date: 4/21/2010
`PDUFA Due Date: 10/21/2010
`Priority
`
`
`
`
`
`Biometrics Division:
`Division of Biometrics III
`Statistical Reviewer:
`Kate Dwyer, Ph.D.
`Concurring Reviewers: Mahboob Sobhan, Ph.D.
`
`
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`
`Keywords: Labeling review
`
`
`
`
`
`
`Division of Reproductive and Urologic Drug Products
`
`Ronald Orleans, M.D., Medical Reviewer
`Lisa Soule, M.D., Team Leader
`Karl Stiller
`
`

`

`
`BACKGROUND
`
`The Applicant has resubmitted this supplement in response to the Complete Response Letter
`issued by the Agency on January 26, 2010 regarding several manufacturing deficiencies. This is
`a labeling review for LO LOESTRIN FE, an oral contraceptive, and no additional clinical trial
`data was included in this submission. The proposed indication is for the prevention of pregnancy
`in women
`.
`
`CONCLUSION
`
`The efficacy (using Pearl Index) result of the labeling based on 28 on-drug pregnancies that had
`occurred over 12,482 completed cycles was calculated by this reviewer in the original statistical
`review of this NDA. Since no additional efficacy data was submitted, no statistical review was
`necessary for this labeling change.
`
`
`
`
`2
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATE L DWYER
`10/15/2010
`
`MAHBOOB SOBHAN
`10/15/2010
`
`Reference ID: 2850627
`
`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Science
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`Drug Name:
`
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`22-501 / N000
`
` [pending] (Norethindrone acetate and Ethinyl Estradiol
`tablets, and Ferrous Fumarate tablets)
`Prevention of Pregnancy
`Warner Chilcott Company, Inc.
`
`Submission Date: 3/26/2009
`PDUFA Date: 1/26/2010
`Standard
`
`
`
`
`
`Biometrics Division:
`Division of Biometrics III
`Statistical Reviewer:
`Kate Dwyer, Ph.D.
`Concurring Reviewers: Mahboob Sobhan, Ph.D.
`
`
`Medical Division:
`Clinical Team:
`
`Division of Reproductive and Urologic Drug Products, HFD-580
`
`Ronald Orleans, M.D., Medical Reviewer
`Lisa Soule, M.D., Team Leader
`Karl Stiller
`
`
`Project Manager:
`
`
`
`Keywords: Clinical studies, NDA review
`
`
`(b) (4)
`
`

`

`Table of Contents
`
`
`
`
`
`
`1. EXECUTIVE SUMMARY .................................................................................................................................4
`1.1
`CONCLUSIONS AND RECOMMENDATIONS .......................................................................................................4
`1.2
`OVERVIEW OF CLINICAL STUDIES ..................................................................................................................4
`1.3
`STATISTICAL ISSUES AND FINDINGS ...............................................................................................................4
`2.
`INTRODUCTION ...............................................................................................................................................5
`2.1
`OVERVIEW......................................................................................................................................................5
`2.2
`DATA SOURCES ..............................................................................................................................................5
`2.3
`INDICATION ....................................................................................................................................................5
`3. STATISTICAL EVALUATION ........................................................................................................................5
`3.1
`EVALUATION OF EFFICACY.............................................................................................................................5
`3.1.1
`Study Design ..........................................................................................................................................5
`3.1.2
`Reviewer’s Comment on Study Design ..................................................................................................6
`3.1.3
`Results....................................................................................................................................................7
`3.2
`EVALUATION OF SAFETY................................................................................................................................8
`4.
` FINDINGS IN SUBGROUP OF POPULATIONS..........................................................................................8
`5. CONCLUSIONS..................................................................................................................................................8
`
`
`
`
`2
`
`

`

`LIST OF TABLES
`
`Table 1: Brief Summary of Clinical Study for WC3016 ..............................................................................................5
`Table 2: Randomization and Disposition of All Treated Patients for Study PR-05806................................................7
`Table 3: Pearl Index Calculation of Treatment Failure Rates: Results of Sponsor and FDA Analysis ........................7
`Table 4: Life Table Analysis of the Cumulative Failure Rates after thirteen-28 Day Cycles of Treatment: Results of
`Sponsor and FDA analysis.............................................................................................................................................8
`Table 5: Pearl Index Calculation of Treatment Failure Rates for PITT Cohort by race ...............................................8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3
`
`

`

`1.
`
`EXECUTIVE SUMMARY
`
`Conclusions and Recommendations
`1.1
`The study results support the efficacy of WC3016, a 28-day low dose combination oral
`contraceptive (COC), in preventing pregnancy as demonstrated by Pearl Index of 2.92 (95%
`Confidence Interval: 1.94% to 4.21%). In this study, the Pearl Index appeared to vary
`substantially by race. However, no conclusion can be drawn due to the small sample sizes in
`subgroups of race.
`
`1.2 Overview of Clinical Studies
`The submission contains data from a single multicenter, open-label, one arm study to
`demonstrate the safety and efficacy of a low-dose, combination oral contraceptive regimen
`WC3016 taken for thirteen-28 day cycles in women desiring pregnancy prevention. This COC
`consists of a regimen of 1 mg norethindrone acetate (NETA) / 10 mcg ethinyl estradiol (EE) oral
`tablets administered for 24 days of a 28-day cycle, followed by EE 10 mcg for 2 days, followed
`by an inactive tablet containing ferrous fumarate for 2 days.
`
`Statistical Issues and Findings
`1.3
`There are two statistical issues indentified with this submission: the Applicant’s definition of
`pregnancy intent-to-treat cohort (PITT) population and “on-drug pregnancies” in study PR-
`05806. The Applicant defined the PITT population as group of women 35 years of age or less
`based on all at risk cycles where no other method of birth control was used, and censored on
`their 36th birthday. The division did not agree that subjects should be censored from the PITT
`population if they were 35 years of age at enrollment but conceived after their 36th birthday.
`
`The Applicant defined an “on-drug pregnancy” as a pregnancy occurring 14 or more days after
`the first date of study medication and up to and including 14 days after the last day of study
`medication. The division believes that an “on-drug pregnancy” should be defined as a conception
`occurring from Day 1 (the initiation of taking study drug) to 7 days after the final tablet was
`taken. The Agency conveyed this information to the Applicant who subsequently revised their
`study report in the July 22, 2009 submission. However, one additional pregnancy was identified
`by the Division after the revision thus making a total of 28 “on drug pregnancies.” Therefore, in
`this review the additional pregnancy was included in the calculation of Pearl Index and Life
`Table analyses.
`
`The efficacy evaluation was based on the calculation of pregnancy rates using Pearl Index in
`women aged 18 to 35 years excluding cycles in which they used other birth control methods. In
`the pivotal study PR-05806, the Pearl Index for WC3016 oral contraceptive for all subjects in the
`PITT population was 2.92 (95% Confidence Interval: 1.94% to 4.21%). The Pearl Index
`appeared to vary substantially by race: 2.07 for Caucasians, 2.96 for Blacks, 8.13 for Hispanics
`and 5.51 for others.
`
`
`
`4
`
`

`

`2.
`
`INTRODUCTION
`
`2.1 Overview
`The Applicant, Warner Chilcott Company, Inc., is seeking approval of a new drug application for
` is a low dose oral contraceptive consisting of a new dose
`and new regimen of the combination of norethindrone acetate (NA) and ethinyl estradiol (EE).
`The dosing regimen consists of norethindrone acetate 1 mg/ethinyl estradiol 10 mcg (NA 1/EE
`10) oral tablets administered for 24 days followed by 2 days of ethinyl estradiol 10 mcg (EE 10)
`and 2 days of a placebo tablet. This regimen is referred to as WC3016.
`
`The Applicant has submitted one multicenter, open-label, single arm study with thirteen-28 day
`cycles of use to support the safety and efficacy of WC3016 oral contraceptive in sexually active
`women aged 18 to 45 years who desire pregnancy prevention. Table 1 shows a brief summary of
`the study.
`
`Table 1: Brief Summary of Clinical Study for WC3016
`Sample Size
`Duration of
`(MITT1)
`Treatment
`
`Subject Population
`
`Treatments
`
`WC3016
`
`1660 (1582)
`
`thirteen-28 Day
`cycles of WC3016
`
`Design2
`
`OL,
`MC,
`U
`
`
`
`Study Number
`(No. of Sites / Country)
`Dates of Study Conduct
`PR-05806
`(68 / U.S.)
`11-01-06 to 08-27-08
`
`Heterosexually active
`females who were at risk of
`pregnancy with 18-45 years
`of age and BMI ≤ 35
`1 all treated patients who were evaluated for pregnancy at least once after beginning the study medication
` 2 OL = Open Label, MC = Multicenter, U = Uncontrolled
`
`2.2
`Data Sources
`The study reports and additional information for this submission are available in paper format.
`The SAS data sets for the study were complete and well documented. These items are located in
`the Electronic Document Room at \\Fdswa150\nonectd\N22501\N_000 under submission date
`3/26/2009.
`
`2.3
`
`Indication
` is indicated for the prevention of pregnancy.
`
`
`
`3.
`
`STATISTICAL EVALUATION
`
`Evaluation of Efficacy
`3.1
`3.1.1 Study Design
`Study PR-05806 was a multi-center, open label, single arm study of a 28-day oral contraceptive
`tablet containing NA 1 mg and EE 10 mcg oral tablets administered for 24 days followed by 2
`days of EE 10 mcg and 2 days of a placebo tablet. The objective of the study was to demonstrate
`the safety and efficacy of WC3016 in the prevention of pregnancy.
`
`
`5
`
`(b) (4)
`
`(b) (4)
`
`

`

`Heterosexually active women aged 18 to 45 years and at risk of becoming pregnant were
`enrolled into the study and assigned to take WC3016 daily for thirteen-28 day cycles of
`treatment. After completion of the treatment phase of the study, all subjects were followed to
`determine if any pregnancy had occurred in the immediate post-treatment period. All
`pregnancies occurring during the study and within 30 days after the end of treatment were
`assessed to determine their relationship to the use of the products in this study. Pregnancies
`found to have an estimated date of conception more than 14 days after the initiation of study
`medication and up to and including 14 days after the last day of study medication were counted
`by the Applicant as being “on drug.”
`During the study, all patients completed a daily paper diary to record study drug use, incidence
`of bleeding or spotting, any additional forms of contraception used, and any concomitant
`medications.
`The Modified intent-to-treat cohort (MITT) consists of all treated patients who were evaluated
`for pregnancy, either positive or negative, at least once after beginning the study medication. The
`Completed population was defined as the subset of MITT subjects who completed at least 360
`days of treatment based on the diary reports.
`Efficacy was evaluated based on Pearl Index in the group of women 35 years of age or less based
`on all at risk cycles where no other method of birth control was used. A pregnancy was counted
`in the Applicant’s initial efficacy analysis if the EDC occurred 14 or more days after the first
`date of study medication and up to and including 14 days after the last day of study medication.
`The Pearl Index for all subjects, regardless of age, based on all risk cycles where no other
`method of birth control was used was also presented. The 95% confidence intervals for the Pearl
`Indices and life table estimates of a subject becoming pregnant were also presented. The Pearl
`Index was calculated as follows:
`Pearl Index = 1300 × (number of pregnancies) / (number of woman-cycles of treatment)
`No formal statistical testing was planned.
`
`3.1.2 Reviewer’s Comment on Study Design
`At the protocol stage, we did not agree with the Applicant’s definition of the pregnancy intent-to-
`treat cohort (PITT) and “on-drug pregnancies” analysis population. The Division notified the
`Applicant in the 74-Day letter of the following definitions:
`The PITT should be defined as women aged 18 to less than 36 years at the time of enrollment in
`the clinical trial. The PITT cohort should be the principal analysis cohort for pregnancy
`evaluation. Subjects in this group should not be censored in the pregnancy assessment if their
`36th birthday occurred after study enrollment.
`“On-drug pregnancies” was defined as all conceptions that occur from Day 1 (the initiation of
`taking study drug) to 7 days after the final tablet (i.e., the second Fe tablet) in the pill pack is
`taken. If the pills were stopped prior to completing a 28-day pack, then “on-drug pregnancies”
`should be defined as all conceptions from Day 1 (the initiation of taking study drug) to 7 days
`after the final tablet was taken.
`Based on the above definitions of the PITT population and “on-drug pregnancies,” we requested
`the Applicant to resubmit results of the Pearl Indices and life table pregnancy rates.
`
`
`6
`
`

`

`3.1.3 Results
`Patient Disposition: Table 2 summarizes the number of randomized subjects and the disposition
`of all treated subjects. The primary reason for study discontinuation in study PR-05806 was “lost
`to follow-up” (13.7%), “Adverse Events” (10.7%) and “Withdrew Consent” (8.9%). Also, the
`mean age was 28.6 years, 51% of the patients were new start and the majority (75%) of subjects
`was Caucasian.
`Table 2: Randomization and Disposition of All Treated Patients for Study PR-05806
`
`
`
`(Source: Clinical Study Report RR-03108.0; Table 4, page 44)
`
`Pregnancy Rates: The sponsor’s results were from the resubmission received on July 23, 2009 in
`response to the 74-Day Letter sent to the sponsor. The original submission for PITT was based
`on 24 pregnancies instead of 27 pregnancies. One additional pregnancy was identified thereafter
`by the FDA clinical reviewer.
`Table 3 presents the Pearl Index results for WC3016 in MITT and PITT population. For the PITT
`cohort, the Sponsor included 27 pregnancies with a Pearl Index of 2.81; while our review
`included one additional pregnancy for a total of 28 pregnancies with a Pearl Index of 2.92. Our
`calculation excluded all cycles (28-day) in which back-up contraception was used, including
`condom. However, it counted the cycles in which a pregnancy occurred.
`
`Table 3: Pearl Index Calculation of Treatment Failure Rates: Results of Sponsor and FDA
`Analysis
`
`Number of On-Treatment
`Pregnancies
`27
`27
`28
`28
`
`Number of
`Cycles
`15,595
`12,486
`15,591
`12,482
`
`Pearl Index 95% Confidence
`Interval
`2.25
`(1.48, 3.27)
`2.81
`(1.85, 4.09)
`2.33
`(1.55, 3.37)
`2.92
`(1.94, 4.21)
`
`Sponsor
`
`Reviewer
`
`Population
`MITT
`PITT
`MITT
`PITT
`
`N
`1,555
`1,270
`1,555
`1,270
`
`
`
`
`
`
`
`
`7
`
`

`

`Table 4 summaries the results of life table analysis of cumulative pregnancy rate. For the PITT
`cohort, the cumulative failure rate after 13 cycles of treatment was 2.71%, as reported by the
`Applicant based on 27 “on drug” pregnancies. The Applicant did not provide a confidence
`interval. Our analysis showed a rate of 2.71% (95% C.I.: 1.86% - 3.95%) which was based on 28
`“on drug” pregnancies.
`Table 4: Life Table Analysis of the Cumulative Failure Rates after thirteen-28 Day Cycles of
`Treatment: Results of Sponsor and FDA analysis.
`Population Number of On-Treatment
`Pregnancies
`27
`27
`28
`28
`
`Sponsor
`
`Reviewer
`
`MITT
`PITT
`MITT
`PITT
`
`Cumulative
`Pregnancy Rate
`2.17%
`2.71%
`2.17%
`2.71%
`
`95% Confidence
`Interval
`
`( 1.49%, 3.17%)
`( 1.86%, 3.95%)
`
`
`
`
`
`
`Evaluation of Safety
`3.2
`There was no statistical evaluation of safety data necessary for this review. Detailed safety
`information can be found in the clinical reviewer’s review.
`
`
`
` FINDINGS IN SUBGROUP OF POPULATIONS
`
`4.
`
`We performed additional analysis by the subgroup of race. As shown in Table 5, the Pearl Index
`appeared to vary substantially by race: 2.07 for Caucasians, 2.96 for Blacks, 8.13 for Hispanics
`and 5.51 for others. However, no conclusion can be drawn due to the small sample sizes across
`subgroups of race.
`
`Table 5: Pearl Index Calculation of Treatment Failure Rates for PITT Cohort by race
`95% Confidence
`Number of On-Treatment
`Number of
`Race
`Pearl Index
`N
`Interval
`Pregnancies
`Cycles
`Caucasian
`948
`15
`9,414
`2.07
`(1.16, 3.41)
`Black
`139
`3
`1,316
`2.96
`(0.61, 8.64)
`Hispanic
`137
`8
`1,280
`8.13
`(3.51, 15.96)
`Others
`46
`2
`472
`5.51
`(0.67, 19.79)
`Total
`1,270
`28
`12,482
`2.92
`(1.94, 4.21)
`(Source: Reviewer’s results)
`
`
`
`5.
`
`CONCLUSIONS
`
`
`
`From a statistical perspective, the study results support the efficacy of WC3016, 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.
`
`
`8
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22501
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`WARNER
`CHILCOTT CO INC
`
`------------------------------------------
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATE L DWYER
`12/28/2009
`
`MAHBOOB SOBHAN
`12/28/2009
`
`(b) (4)
`
`

`

`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
`
`Stamp Date: 3/26/2009
`Applicant: Warner Chilcott Company, Inc.
`45 day Meeting Date: 4/30/2009
`
`Project Manager: Karl Stiller
`
`
`
`NDA: 22-501
`Drug Name:
`
`Indication: Prevention of Pregnancy
`Medical Officer: Ronald Orleans, M.D.
`
`A: Summary
`The sponsor submitted one pivotal Phase III efficacy study in support of WC3016 for pregnancy prevention.
`Brief summary of the study is shown below. Based on the data from the study, sponsor’s analysis
`demonstrated that Combination Oral Control (COC) therapy WC3016 provides comparable efficacy and
`safety results for currently marketed COC therapy.
`
`
`Subject Population
`
`Treatments
`
`Duration of
`Treatment
`
`WC3016
`
`1660 (1582)
`
`thirteen of 28-day
`cycles of WC3016
`
`Design2
`
`OL,
`MC,
`U
`
`
`
`Brief Summary of Pivotal Phase III Clinical Study for WC3016
`Study Number
`Sample Size
`(No. of Sites / Country)
`(MITT1)
`Dates of Study Conduct
`Sexually active females who
`WC3016
`were at risk of pregnancy
`(68 / U.S.)
`with 18-45 years of age and
`11-01-06 to 08-27-08
`BMI ≤ 35
`1 MITT = subset of all treated population who were evaluated for at least once after beginning the study medication
`2 OL = Open Label, MC = Multicenter, U = Uncontrolled
`
`On initial overview of the NDA/BLA application for RTF:
`
`
`
`1
`
`2
`
`3
`
`Content Parameter
`Index is sufficient to locate necessary reports, tables, data,
`etc.
`ISS, ISE, and complete study reports are available
`(including original protocols, subsequent amendments, etc.)
`Safety and efficacy were investigated for gender, racial,
`and geriatric subgroups investigated (if applicable).
`4 Data sets in EDR are accessible and do they conform to
`applicable guidances (e.g., existence of define.pdf file for
`data sets).
`
`Yes No NA Comments
`
`
`X
`
`
`X
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`B: Conclusion
`After preliminary review of the submission of the following checklist items, this submission is fileable from
`statistical point of view.
`
`Potential review issues to be forwarded to the Applicant for the 74-day letter:
`
`Content Parameter (possible review concerns for 74-
`day letter)
`Designs utilized are appropriate for the indications requested. X
`
`
`
`
`
`
`
`Yes No
`
`NA Comment
`
`(b) (4)
`
`

`

`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
`
`
`Endpoints and methods of analysis are specified in the
`protocols/statistical analysis plans.
`Interim analyses (if present) were pre-specified in the protocol
`and appropriate adjustments in significance level made.
`DSMB meeting minutes and data are available.
`Appropriate references for novel statistical methodology (if
`present) are included.
`Safety data organized to permit analyses across clinical trials
`in the NDA/BLA.
`Investigation of effect of dropouts on statistical analyses as
`described by applicant appears adequate.
`
`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`X
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Kate Dwyer, Ph. D.
`Reviewing Statistician
`
`Mahboob Sobhan, Ph. D.
`Supervisor/Team Leader
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`4/30/09
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`4/30/09
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`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Kate L Dwyer
`4/30/2009 02:03:29 PM
`BIOMETRICS
`
`Mahboob Sobhan
`5/5/2009 09:37:59 AM
`BIOMETRICS
`
`