CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-030
`
`MEDICAL REVIEW! S)
`
`

`

`Financial Disclosure Review
`
`Form FDA 3455 (“Financial Interests and Arrangements of Clinical Investigators”),
`dated Feb. 13th 2006, was submitted and reviewed by this clinical reviewer. In
`accordance with 21 CFR Part 54.4, certification and disclosure requirements, forms of
`clinical investigator certification and financial disclosure were also provided by Schwarz
`BioSciences, Inc.
`'
`
`In this financial disclosure submission all investigators have provided financial disclosure
`information via questionnaires.
`
`No clinical investigator participating in the submitted studies from any of the study sites
`had any disclosures in the categories of compensation potentially affected by the outcome
`of the covered study [21 CFR 54.4(a)(3)(i), 54.2 (a)], significant payments of other sorts
`from the sponsor of the covered study [21 CFR 54.4 (a)(3)(ii), 54.2(i)], proprietary
`interest in the tested product [21 CFR 54.4(a)(3)(iii), 54.2(c)], or significant equity
`interest in the sponsor of the covered study product [21 CFR 54.4(a)(3)(iv), 54.2(b)].
`
`Reviewer ’s Comment:
`
`i There is no reason to suspect that the results ofany ofthe studies submitted in support of
`this NDA were compromised due to financial arrangements between the sponsor and the
`clinical investigators.
`
`Appears This Way
`On Orig/ting,
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Suresh Kaul
`
`10/20/2008 03:39:50 PM
`MEDICAL OFFICER '
`
`

`

`NDA 22-030
`
`Medical Officer’s Review: Complete Response to Approvable
`
`Date Submitted:
`Date Received:
`Date Review Completed:
`PDUFA Goal Date:
`
`May 1, 2008
`. May 1, 2008
`October 9, 2008
`November 3, 2008
`
`-
`Drug Product:
`Dose and Formulation:
`Sponsor:
`
`Toviaz (fesoterodine fumarate)
`4mg and 8mg extended-release tablets
`Pfizer, Inc
`New York, NY.
`Indication: Treatment of overactive bladder with symptoms of urge urinary
`incontinence, urgency and urinary frequency.
`'
`
`1.
`
`Regulatory History
`
`NDA 22—030 was initially submitted by Schwarz Pharma and accepted for filing by the FDA on
`March 17, 2006 for the indication “treatment of symptoms that may occur in subjects with
`overactive bladder syndrome”.
`
`Under terms of an agreement with Pfizer, Inc., effective June 13, 2006, Schwarz Pharma
`transferred all of its rights in fesoterodine to Pfizer on an exclusive world wide basis.
`
`In an Approvable letter to Schwarz Pharma on January 25, 2007, FDA requested: 1) that all
`manufacturing sites be made ready for pre-approval inspection, 2) that revised labeling be
`submitted, and 3) that another Safety Update'be submitted, to include data from all non-clinical
`and clinical fe'soterodine studies since the previous Safety Update.
`
`This review focuses on the requested Safety Update submitted in the Complete Response to
`Approvable action. This final update includes new safety data, obtained since the cutoff date of
`the original NDA (October 14, 2005), from 3 long-term, open-label extension studies completed
`by Schwarz Pharma (Studies SP669, SP73 8, and SP739), and an ongoing 12-week, open-label
`study (A0021007), initiated by Pfizer, with data included as of January 1, 2008.
`'
`
`In addition, this Complete Response to Approvable includes two new Phasel studies completed
`by Schwarz Pharma (Studies SP857 and SP877) and three new Phasel studies conducted by
`Pfizer (Studies A0221004, A0221015 and A0221044) since the NDA. The Clinical Safety
`Update includes summarizes of safety from these 5 new Phase 1 studies.
`
`

`

`1.0 2. Extent of Exposure to Fesoterodine
`
`2.1
`
`Overview of Extent of Exposure to Fesoterodine
`
`The following table presents the study design, number of subjects who received fesoterodine,
`and duration of treatment in Study SP669, an extension of the Phase 2 study SP668, and one of
`the three open-label, long-term extension studies.
`
`Table 1.
`
`Phase 2 open label studies of fesorerodiue in subjects with overactive bladder
`(Schwarz)
`
`
`
`#5 Subjects
`receiving
`placeboa
`
`Menu treatment
`duration on
`fosoterodine
`
`Study number/study tlesign-‘dosage
`
`.J-F' Subjects
`recein’ng
`fesoterodiue“
`186 (125 new
`exposmesb)
`
`SP6691'Extension of SP668/ 2-phase
`nuxlticenter, double-blind and open—label, long—
`rem: study to assess safety, tolerability, and
`efi‘icacy in OABI' fesotetodine SR 4mg, Sing,
`and 12mg doses once daily in the double-blind
`phase; fecoterodine 4mg and 8mg doses once
`dailyinthe I - vI labelphase
`OAB=ovexactive bladder, SR==sustained release
`1 These subject exposmes are based on the safety set (SS).
`1). New exposures include 20 subjects who previously received placebo in the preceding double-blind study, and
`105 “de novo“ subjects who enrolled directly into SP669 without having participated in SP668.
`
`Table 2 presents the study design, number of subjects who received fesoterodine, and durations
`of treatment in Studies SP738 and SP739, the two, open-label, long-term extension studies to the
`Schwarz Pharma Phase 3 studies SP5 83 and SP5 84, respectively.
`
`Table 2.
`
`Phase 3 open label studies of fesntermline in subjects with overactive bladder
`(Schwarz)
`
`# Sub'ects
`
`
`Stugy imméwr/study
`receding
`Sign, usage
`fesoterodine‘
`
`
`SP738lExtusion of SP583/
`417 (218nm
`nmlticenter, open—label, long-tum
`fesoterodine
`
`
`
`safety and efiicacy in OABI
`exposuos)”
`
`
`
`fssoterodine 4:11; and 8mg doses
`once dail
`
`
`473 (158 new
`
`SP739IExtensiou ofSP584I
`
`fesoterodine
`mnlticenter, open-label, long—tum
`
`
`safety and eficaeyin OAB/
`
`memos)”
`
`
`.fcsctexodine 41113 and 8mg doses
`once daily
`
`
`OAB=ovexactive bladder, NA=not applicable, SR=snstained telease
`a. “race subject exposures are based onthe safetyseKSS) for each study.
`is. New equosuses are defined as those who previously received placebo or tolterodine in the preceding double—blind
`studies.
`
`Mean treatment
`duration
`695 days
`
`584 days
`
`'
`
`
`
`
`‘
`
`# Sub'ects
`receii-ing
`laceho'
`NA
`
`it Subjects
`receiving active
`control'
`
`NA
`
`NA
`
`
`
`
`
`The following table presents the study design, number of subjects receiving fesoterodine, and the
`duration of treatment in the Study A0021007, the new, open-label, Pfizer study in this report.
`
`

`

`
`
`Table 3. Study A0221007: Open-Label Study (Pfizer)
`
`
`
`# Subjects
`receiving
`placebo
`
`# Subjects
`remixing active
`control
`
`Median
`treatment
`duration
`
`Study designidosage
`
`ti Subjects
`receiving
`fesoterodiue
`
`T\V.~'el\‘e-\veek. multicentel: open-
`label study in O.AB- fesotetodiue
`4mg and 8mg (loses once daily
`OAB=o~ceracrive bladder. NA=nol applicable.
`
`2.2
`
`Integrated’Safety Pools in the Final Safety Update
`
`All safety pools are graphically illustrated in the following figure.
`
`Figure 1. Description of safety pools (Schwan Studies)
`
`Phase3Phase2
`
`Open—label
`
`2.3
`
`Overall Extent of Exposure (in Detail)
`
`2,3.1
`
`Schwarz Studies
`
`Table 4 summarizes the overall exposure to fesoterodine in all Schwarz studies, including the
`NDA studies, their open-label extensions, and the 2‘ additional Phase 1 studies since the NDA.
`
`

`

`Table 4.
`
`Schwnrz Studies: Overall fesoterodine exposure
`
`-
`
`
`
`Subj eel-years of
`ex - osure
`
`
`
`~.
`
`.
`
`
`
`
`
`Phase 1 (Pool P1
`‘
`Intravenous formulation
`Immediate-release formulatian
`
`‘//1«PP?
`Sustained-release formulation-:-
`’
`Additional Phase 1 (not acted)
`
`
`Phase Zn (SPSH)
`
`
`Immediate-release formulanen
`
`
`
`
`
`
`
`_ 2sz [1003
`
`
`HE_-——
`
`
`I==IS months
`1606
`.
`
`71-24 months
`145?
`
`
`
`—-—_
`Mean and median duration of exposure
`
`
`
`
`
`
`Population
`
`Mean / median months
`Original NDA
`l-‘SU
`13.51 13.4
`Phase 2/3 ‘ 00182, DB+0L
`21.3 [25.4
`11.71116
`Phase213'00152, 01.0111
`120 I 3.2
`7.6 [3.2
`‘
`Phase 2/3‘00153
`DB=double—blind, FSU=Final Safety Update, NA=not applicable, NDA=New Drug Application; 0L=open—
`label
`
`‘
`
`
`
`a. Percentages based on numbet ofsubjects within each respective pool.
`
`Overall, 2288 subjects received fesoterodine in the Phase 2 and 3 studies and another 525
`received fesoterodine in the Phase 1 studies.
`
`Reviewer ’s Comment: Compared with the original NDA, the mean duration ofexposure
`for Pool S2 increased by 10 months.
`»
`
`2.3.2
`
`Pfizer Studies: Conducted Since the NDA
`
`In the three Pfizer Phase 1 studies (Studies A0221004, A0221015 and A0221044), 106 subjects
`were exposed to fesoterodine. The median duration of exposure for the 53 subjects administered
`fesoterodine 4mg was one day with a range of 1-5 days. The median duration ofexposure for 53
`subjects on fesoterodine 8mg was two days with a range of 2-5 days.
`
`Study A0221007 was a 12-week study with a screening period of 2 weeks in which baseline
`OAB symptoms were assessed prior to baseline. Subjects not satisfied with their previous
`treatment with tolterodine ortolterodine ER and were bothered by OAB symptoms at baseline
`and met all other entry criteria were enrolled. All enrolled subjects were initially treated with
`fesoterodine 4mg QD for the first 4 weeks oftreatment. At Week 4, based upon a discussion
`between the subjects and the investigators of efficacy and tolerability reported by the subjects,
`the investigator either increased the dose to 8mg QD for thoSe who desired greater symptom
`improvement and reported good tolerability, or continued the subjects on 4mg QD dose, for the
`remaining 8 weeks ofthe study.
`
`Five hundred and sixteen subjects with OAB received fesoterodine in Study A0221007. The
`median duration of exposure was 84 days and the range 3 —- 109 days. Four hundred and thirty
`four subjects (434/486; 89.3%) received fesoterodine for > 60 days.
`
`

`

`Formation
`
`Iom Subjects n (0/6)“
`
`E '
`' osure
`S“'°j'~‘“'3““” °f
`
`Table 5.
`Pfizer Studies conducted since the NDA: Overall Fesoterudine Exposure
`
`mm" 1 5M“
`
`
`
`
`
`
`
`
`
` 6.1— 90 days
`
`.
`
`44‘ {86)
`
`Studv A0221007- Median duration of exposure: 84 days; Mean duration of exposure: 19 days;
`
`
`Standard Deviation: 18 days
`Rance: 3 -— 108 dm‘s
`
`a. Percentages based on total number of subjects exposed
`b. Study A0221004: 16 subjects; Study A0221015: 16 subjects; Study A0221044: 36 subjects in a 3-way
`crossover study.
`.
`
`Exposure to Fesoterodine in the Long-Term Studies ~ Pool 82 (Schwarz NDA Open-
`2.4
`Label Studies, All Participants). Pfizer Study A0221007 shown for comparison purposes.
`
`Subjects treated in the open-label periods of the extension studies (Studies SP669, SP73 8, and
`SP73 9) are included in Pool 82. For the first analysis, data from‘prior Double-Blind Treatment *
`Periods are included, while the second analysis included only data from open-label periods.
`
`Safety data from the 12-week, open-label Study A0221007 conducted by Pfizer since the NDA
`are presented alongside to allow comparison.
`
`2.4.1 Treatment duration, maximum daily dose, and daily dose oflongest duration - Pool S2
`
`Pool S2 (SchWarz NDA Open-Label Studies)
`
`In Pool SZ, mean treatment duration was 23 months (range: 1 day to 60 months) for the
`combined DB+OL periods, and 21 months (range: 1 day to 51 months) during OL only. The -
`median maximum daily dose and median dose of longest duration was fesoterodine 8mg/day
`using both analysis approaches in Pool 82.
`'
`
`Study A0221007 (Pfizer)
`
`The median treatment duration in this study was 84 days (range 3 — 108 days). Four hundred and
`forty two subjects were on fesoterodine for 61 — 90 days (442/516 subjects; 86%). The maximum
`daily dose used in this study was fesoterodine 8mg/day and dose of longest duration was
`fesoterodine 4mg/day.
`
`

`

`2.4.2 Exposure by maximum daily dose - Pool S2
`
`Pool S2 (Schwarz NDA Open-Label Studies)
`
`In Pool 82 (DB+OL), most subjects (1040/1055: 99%) received a maximum daily fesoterodine
`dose of 8mg. A total of 522/1040 (50%) of these subjects were exposed to fesoterodine 8mg/day
`for more than 24 months, including 101 (10%) subjects exposed to the 8mg dose for more than
`36 months.
`
`During the OL only periods.(Pool $2) a total of 5 12/1054 (49%) subjects were exposed to
`fesoterodine 8mg/day for more than 24 months, including 78 (7%) exposed to the 8mg'dose for
`more than 36 months.
`
`Study A 022100 7 (Pfizer) '
`
`A total of 25 8/516 (50%) subjects were exposed to fesoterodine 8mg. Two hundred forty four
`subjects (95%) received the 8mg/day for > 70 days.
`
`2.4.3. Exposure by daily dose oflongest duration - Pool S2
`
`Pool S2 (Schwarz NDA Open-Label Studies)
`
`The daily fesoterodine dose of longest duration for most subjects (848/1055: 80%) in Pool S2
`(DB+OL) was 8mg/day. A fesoterodine dose of4mg/day was the daily dose of longest duration
`for 204/1055 (19%) subjects, while fesoterodine lng/day was the daily dose of longest duration
`for 3/1055 (<l%) subjects.
`‘
`
`Among subjects in Pool S2 (DB+OL) for whom 8mg/day was the daily dose of longest duration,
`436/848 (51%) subjects were exposed to fesoterodine 8mg/day for more than 24 months,
`including 92 (11%) exposed to the 8mg/day dose for more than 36 months. When double-blind
`data are excluded, 421/894 (47%) subjects were exposed to fesoterodine 8mg/day for more than
`24 months, including 68 (8%) exposed to the 8mg/day dose for more than 36 months.
`
`_
`
`The daily fesoterodine dose of longest duration for most subjects (894/1055: 85%) in Pool S2
`(0L only) was 8mg/day, while fesoterodine 4mg/day was the daily dose of longest duration for
`161/1055 (15%) subjects.
`
`Study A 0221 00 7 (Pfizer)
`
`The daily fesoterodine dose of longest duration for most subjects in Study A0221007 was
`4mg/day (271/516: 53%), while fesoterodine 8mg/day was the daily dose of longest duration for
`245/516 (47%) subjects.
`
`For the subjects in whom 8mg/day was the daily dose of longest duration, 243/245 (99%)
`subjects were exposed to fesoterodine 8mg/day for > 70 days. For the subjects in whom 4mg/day
`
`

`

`was the daily dose of longest duration, 222/271 (82%) subjects were exposed to fesoterodine
`4mg/day for > 70 days.
`
`2.4.4 Fesoterodine dose modifications (luring open-label treatment —— Pool S2
`
`Pool S2 (Schwarz NDA Open-Label Studies)
`All subjects started on afesoterodine dose of 8mg/day, but were allowed to switch to 4mg/day,
`and back to 8mg/day on an annual basis (except for SP669 where a decrease to 4mg/day and a
`subsequent dose increase back to 8mg/day was allowed only once during the study). The
`majority of subjects (825/1055: 78%) remained on the open-label starting dose of fesoterodine
`8mg/day. A total 0f178/ 1055 (17%) subjects reduced their dose to 4mg/day, and remained on
`this dose. Forty—three subjects (4%) re-escalated to fesoterodine 8mg/day.
`‘
`
`Study A0221007 (Pfizer)
`
`In this open-label study all enrolled subjects were initially treated with fesoterodine 4mg/day for
`the first 4 weeks oftreatment. At Week 4, based upon a discussion between the subjects and the
`investigators of efficacy and tolerability reported by the subjects, the investigator either
`increased the dose to 8mg/day for those who desired greater symptom improvement and reported
`good tolerability, or continued the subjects on 4mg/day dose, for the remaining 8 weeks ofthe
`study.
`
`Two hundred and fifiy eight subjects (258/516: 50%) remained on the open-label starting dose of
`fesoterodine 4mg/day. A total of255/516 (49%) subjects increased their dose to 8mg/day, and
`remained on this dose. One other subject who had titrated up to 8mg/day then titrated down to
`4mg/day and subsequently titrated up to 8mg/day again and another subject who had titrated up
`to 8mg/day titrated down to 4mg/day. There was one subject who had received 8mg/day
`through-out the study.
`'
`
`'
`
`Exposure to Fesoterodine in the Long-Term Studies — Pool S3 (All Phase 2/3
`2.5
`Schwarz Studies, Fesoterodine-Treated Subjects Only)
`
`In Pool S3, median treatment duration was 23 months. Most subjects received fesoterodine
`8mg/day.
`‘
`
`2.5.1 Exposure by maximum daily dose — Pool S3
`
`Among subjects treated with any dose of fesoterodine (Pool S3), 1759/2288 (77%) were exposed
`for up to 24 months. An additional 529/2288 (23%) subjects were exposed to fesoterodine for
`more than 24 months, including 105/2288 (5%) subjects who were exposed for more than 36
`months.
`-
`'
`
`The maximum daily dose of fesoterodine received by most subjects (1554/2288: 68%) in Pool S3
`was 8mg. Fesoterodine 4mg/day was the maximum dose for 512/2288 (22%) subjects, while
`fesoterodine 12mg/day was the maximum daily dose for 222/2288 (10%) subjects.
`
`

`

`2.5.2 Exposure by daily dose oflongest duration — Pool S3
`
`Among subjects treated with fesoterodine (Pool S3), the daily fesoterodine dose of longest
`duration for most subjects (1362/2288: 60%) was 8mg/day. Fesoterodine 4mg/day was the daily
`dose of longest duration for 715/2288 (31%) subjects, while fesoterodine 12mg/day was the daily
`dose of longest duration for 21 1/2288 (9%) subjects.
`
`2.6
`
`All Treated Subjects From Phase 2/3 Studies — Pool S4 (Schwarz Studies)
`
`Fesoterodine exposure was greatest in the 8mg/day group at 1638 subject—years. This was
`followed by the fesoterodine 4mg/day group at 433 subject—years, and the fesoterodine 12mg/day
`group at 43 subject-years.
`
`2.7
`
`Summary of Exposure
`
`Overall, 2288 subjects (Pool S3) received fesoterodine SR in Phase 2 or Phase 3 studies during
`the Schwarz development program for fesoterodine. A total of 529 subjects were exposed to
`fesoterodine for over 24 months, including 105 who were exposed for more than 36 months.
`Median treatment duration .for fesoterodine-treated subjects (Pool S3) was 3.2 months, with most
`subjects receiving fesoterodine 8mg/day.
`
`In the long-term pool, including data from the combined DB+OL periods (Pool S2), most
`subjects took fesoterodine 8mg/day for a mean duration of 23 months, ranging from a minimum
`of 1 day to a maximum of 60 months.
`
`In Study A0221007 a total of 5 16subjects received fesoterodine. Four hundred and forty two
`subjects received fesoterodine for. between 61 —‘90 days (442/516 subjects; 86%) and a further
`25 subjects received the drug for Z 91 days. The median treatment duration was 84 days with
`halfthe subjects who initially received 4mg/day were subsequently exposed to 8mg/day
`. (258/516) while the remaining half chose to continue with 4mg/day.
`
`Reviewer ’s Comment: The extent ofexposure to fesoterodine in clinical trials exceeds
`the ICHguidance criteria. There is safety datafiom >500 subjects and >100 subjects
`exposedfor at least 2years andat least 3years, respectively. M‘ [1(4)
`
`

`

`3.
`
`Subject Disposition in the Studies Comprising the NDA and Final Safety Update
`
`Side-by-side comparisons of subject disposition from the original NDA and this Final Safety
`Update are provided in the following table.
`
`Table 6. Schwarz NDA Open Label Studies: Summary of subject disposition (Pool 82)
`Parameter
`Original NDA
`PSI-
`(01. only)
`[01. only)
`.\'=10:'-5
`_\‘=10:‘-:'~
`in ($6)
`11 (*6)
`
`Subject: treated
`Subjects discontinuing treatment period
`Reasons for discontinuation
`
`Protocol violaticu
`Lack of efilcacy
`Adverse even:
`Unsatisfactory compliance of subject
`Subject withdrew consent
`Losttofollow-up
`’
`
`1055 (105‘)
`390 (3'!)
`
`5 (<1)
`
`1.055 (100)
`
`11 x: 1)
`141 (13)
`150 (14)
`22 (2)
`165 (16)
`72 (7) _
`W
`
`F
`
`=Final Safety Update, NDA=New Drug Application. 0L=open~1abel
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In Pool 82 635/1055 60% subjects discontinued treatment prematurely. The most common
`reasons for discontinuation of open-label treatment in Pool 82, as recorded on the study
`termination page of the CRF, were withdrawal of consent (165/1055: 16%), adverse event (AE)
`(150/1055: 14%), and lack of effiCacy (141/1055: 13%). Compared with the original NDA, the
`number of subjects in Pool 82 (CL only) who discontinued treatment prematurely because of
`withdrawal of consent increased by 66 (6%), the number who discontinued because ofABS
`increased by 33 (3%), and the number of subjects who discontinued because of lack of efficacy
`increased by 44 (4%) since the original NDA.
`
`In Comparison, in Study A0221007 a total of 53/5 16 subjects (10%) discontinued from the study
`prematurely. The most common reasons for discontinuing were adverse events and subject
`defaults. Discontinuations from the study were judged to be related to the study drug for 33
`subjects (6%), and a majority ofthem were due to adverse events (29 subjects; 6%). The data are
`summarized in the table below.
`
`Study A0221007: Reasons for Discontinuation from Study
`Table 7.
`Total Number of Sub'ects: 486
`
`Rdatedtosmu- '
`
`I;
`
`Not Related to Stud 1)
`
`, ;
`
`S
`
`'eetdefautted
`
`Number % ofSub'ects
`
`29 '
`4 <1
`
`7(1)
`2 <1
`4 <1
`7(1)
`
`‘
`
`

`

`3.1
`
`All Treated Subjects From Phase 2/3 studies — Pool S3 (Schwarz Studies)
`
`Of the 2288 subjects included in Pool S3, 961 (42%) discontinued treatment prematurely.
`
`Consistent with findings in Pool 82, the most common reasons for discontinuation were AE’s ‘
`(266/2288: 12%), withdrawal of consent (238/2288: 10%), and lack of efficacy (156/2288: 7%).
`
`3.2
`
`All Treated Subjects From Phase 2/3 studies —- Pool S4 (Schwarz Studies)
`
`Of the 2964 subjects included in Pool S4, 1098 (37%) discontinued treatment prematurely.
`
`The most common reasons for discontinuation of treatment in Pool S4 were AE (305/2964;
`10%),- withdrawal of consent.(269/2964; 9%), and lack of efficacy (165/2964; 6%).
`
`In Pool S4, 3% to 8% of subjects in double-blind studies (Studies SP582, SP583, SP584, SP668,
`and SP669DB) discontinued due to an AB, compared with 10% to 24% of subjects in open-label
`studies (SP669, SP738, and SP739). The longer period of observation in the open-label studies
`probably contributes to the higher proportions ofAE-related discontinuations.
`
`Reviewer’s Comment: The subject discontinuation rates and reasonsfor discontinuation
`are reasonablefor this indication. Overall, the available datafiom all Phase 2 and
`Phase 3 studies allowsfor a complete overview ofsafety duringfesoterodine exposure.
`
`3.3.
`
`Summary of Subject Disposition
`
`3.3.1 Schwarz Studies
`
`In the pool of subjects treated long—term (Pool 82), 635/1055 (60%) discontinued treatment
`prematurely, mostly due to withdrawal of consent (165/1055; 16%), AEs (150/1055; 14%), and
`lack of efficacy (141/1055; 13%). In the pool of all subjects (Pool S3), 961/2288 (42%)
`discontinued prematurely, the majority due to AEs (12%).
`
`Disposition among all treated subjects (Pool S4) and reasons for discontinuation were also
`similar to those observed in Pool S3: 37% discontinued prematurely, 10% due to AEs.
`
`3.3.2 StudyA0221007 (Pfizer)
`
`In Study A0221007, 53/516 (10%) subjects discontinued prematurely mostly due to AE’s
`(36/516; 7%) and subjects defaulting (7/516; 1%).
`
`Reviewer ’3 Comment: The shorter duration ofthis study (12 weeks as opposed to long-
`term) is presumably the reasonforfewer discontinuations compared to the NDA open—
`label studies.
`'
`
`10
`
`

`

`4.
`
`Demographic and Other Characteristics of Study Population
`
`Schwarz Studies
`
`Demographic tables were not rerun for the NDA studies conducted by Schwarz for the Final
`Safety Update as these data did not change.
`
`Study A 022100 7 (Pfizer)
`
`Demographic characteristics for Study A0221-007 are presented in the following table. A
`majority of the subjects were white females in the age group 45 — 64 years (mean age of 59.4
`years). The demography of subjects in this study are similar to the subjects enrolled in the studies
`in the NDA.
`‘
`'
`
`Table 8.
`
`Study A0221007: Demographic Characteristics
`
`Total
`Female
`Made
`Number (96) ofSubjecls Number (%) of Subjects Number (96) of Subjects
`N=118
`N=398
`
`N=516
`
`
`
`
`“mm-mm:-
`__—a_—m—
`_——-_1_140.0 — 205.7
`
`4.1
`
`Eligibility Criteria for the DAB Program
`
`4.1.1 NDA Studies (Schwarz)
`
`Eligibility criteria were described in the Summary of Clinical Safety in the original NDA. There
`is no new information concerning eligibility criteria.
`
`4.1.2 _ Study A0221007 (Pfizer open-label study)
`
`11
`
` m-“m 39mm
`
`lam—m—
`97 (18.8)
`
`
`
`—_—14(2.7)
`
`.m- 513cm
`
`Im————E_
`
`_———a-
`
`
`
`

`

`The eligibility criteria for inclusion in this study were subjects 2 18 years of age who had been
`treated with tolterodine for their OAB symptoms and had reported dissatisfaction with it. Their
`dissatisfaction with tolterodine treatment was documented in a Treatment Satisfaction Question
`prior to inclusion. The severity of urinary symptoms was also documented prior to inclusion and
`subjects with a mean urinary frequency ofZ 8 micturitions per 24 hours and mean number of
`urgency episodes 2 3 per 24 hours, as verified by a screening micturition diary, were considered
`eligible. The primary objective of the study was to evaluate the effect of fesoterodine on patient
`satisfaction and DAB symptom relief in this group of subjects.
`
`4.1.3 Phase 1 Studies .
`
`Schwarz Phase 1 studies
`
`Two Phase 1 studies have been completed since the original NDA by Schwarz: Study SP857, a
`randomized, double-blind, placebo-controlled, dose-escalation study to investigate safety and
`tolerability of fesoterodine in healthy Japanese males, and Study SP877, a randomized, open-
`label, crossover study to investigate dose proportionality of the 4mg and 8mg tablets.
`
`Pfizer Phase 1 studies
`
`An additional three Phase 1 studies have been cOmpleted by Pfizer since the NDA: Studies
`A0221004, A0221015, and A0221044. Study A0221004 was a double—blind, placebo-controlled,
`multiple dose, randomized study to evaluate the safety and pharmacokinetics of fesoterodine
`sustained release tablets in healthy male subjects. Study A0221015 was another double-blind,
`placebo-controlled, multiple dose, randomized study to evaluate the safety and pharmacokinetics
`of fesoterodine sustained release tablets in healthy male subjects. Study A0221044 was an open-
`label, randomized, single-dose, 3-way crossover study to determine bioequivalence oftwo newly
`developed 4 mg and 8 mg dose-normalized formulations E1 of fesoterodine sustained release
`tablets as well as to determine bioequivalence of 8 mg formulation E1 and 8 mg formulation F of
`fesoterodine sustained release tablets in healthy subjects.
`
`Reviewer’s Comment: For complete review ofthese Phase 1 studies, the reader is
`referred to the Clinical Pharmacologist ’s review.
`
`4.2
`
`Summary of Demographics and Baseline Characteristics ’
`
`As no new subjects were exposed to fesoterodine for this Safety Update in the NDA studies,
`there areno overall changes to the demographics and baseline characteristics. Concomitant
`medication use during long-term studies was similar to that observed in the original NDA.
`The demographic characteristics ofthe subjects in Study A0221007 were broadly comparable to
`the subjects enrolled in the NDA studies. Majority of the subjects were white females with a
`mean age of 59 years. This was similar to that seen in the NDA.
`
`12
`
`

`

`5.0
`
`Adverse Events in the Safety Update
`
`The following AB results represent the cumulative data until finalization for Pools $2 and S3...
`Results for Pool 81 and Pool SS are not presented here as these data did not change since the
`original NDA. Data were analyzed in 2 ways for Pool 82. In one analysis, data from Double-
`Blind Treatment Periods and Open-Label Treatment Periods were combined (DB+OL). In the
`' other analysis, only data from Open-Label Treatment Periods were used (0L only).
`
`Common Adverse Events From Long-Term Studies — Pool SZ (Schwarz NDA Open-
`5.1 '
`Label Studies). Study A0221007 (Pfizer) shown for comparison purposes.
`
`Pool 52' (Schwarz NDA Open—Label Studies)
`Table 9.
`Treatment-emergent adverse events reported by 22% of subjects (Pool 32:
`Schwarz NDA Open—Label Studies)
`
`
`
`Preferred term
`
`.
`
`‘
`
`_
`
`
`
`Original NDA (0L only)
`N=1055
`3
`n
`29w»
`90(9)
`
`
`
`l-‘SU (0L only)
`N=1055
`n %
`3226»
`
`w
`
`m w mm i
`
`s (2)
`33(3)
`W)
`
`m
`m3)
`m2)
`
`_ m
`25(2)
`
`m 20 (2)
`25(2)
`22(2)
`13(2)
`21 (2)
`m
`
`D C
`
`_ 15(1)
`
`m m
`
`13(1)
`13(1)
`
`15m
`FSU==Fmal Safety Update, NDA=New Drug Application, OL=open—1abd
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'
`
`
`
`
`
`-
`we
`
`.
`
`13
`
`

`

`Study A0221007 (Pfizer)
`
`There were 230 subjects who suffered an adverse event in Study A0221007.
`
`Adverse events reported in at least 2% of subjects treated with fesoterodine in Study A0221007
`are presented in the following table and compared with the incidences seen in the NDA open-
`label studies presented above.
`
`Table 10. Study AOZZIOO?: Treatment—emergent adverse events reported by 22% of
`subjects
`
`
`
`
`
`
`PSU (NDA 01. only)
`N=1055
`n 96)
`
`Preferred term
`
`'
`
`
`
`
`
`
`
`
`
`
`
`
`
`FSU=Final Safety Update, NDA=New Drug Application, OIFopen-label ’ = includes the terms abdominal
`pain, abdominal pain lower, abdominal pain upper and abdominal discomfort
`
`The pattern of adverse events seen in Study A0221007 was similar to that seen in the NDA open-
`label studies. The most common AE’s were dry mouth, constipation and headache.
`
`Appears This Way
`' On Original
`
`14
`
`

`

`5.2
`
`Common AEs in Subjects Exposed to Fesoterodine — Pool S3 (Schwarz Studies)
`
`The following table describes the AE’s seen in 2 2 % of subjects in Pool S3 (fesoterodine—treated
`subjects only).
`
`Table 11. Treatment—emergent adverse events reported by 22% of subjects (Pool 53)
`EST:
`
`Preferred term
`Original .\'D.—\
`
`
`
`.\'=2288
`.\'=2288
`
`
`
`11 (cm .
`.\‘ (2’0)
`
`
`
`Dry mouth
`
`
`
`923 (36)
`85.4 (37)
`148(7)
`
`
`
`we
`
`mm
`
`m w
`
`e
`
`’
`
`' m
`,
`m»
`
`we
`
`65(3)
`
`w m m 5
`
`76)
`
`35 (2)
`
`m w w 4
`
`40»
`
`
`
`75(3)
`
`60(3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`30w _
`44(2)
`
`
`35 (2)
`47 (2)
`
`Urinary tract infection
`Headache
`
`Constipation
`
`Nasopharyngitis
`Nausea
`
`Back pain
`Diarrhea
`Influenza
`
`Dyspeps’a
`
`Upper respiratory tract infection
`Cough
`
`d
`g
`
`Hynettmsion
`Dizziness
`
`Dry throat
`Sinusitis
`
`Uxinary retention
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_
`Bronchitis
`Abdominal pain upper
`Gastroesophagml reflux disease
`
`
`
`FSU=Final Safety Update, NDA=N€W Drug Applic'ation
`
`Agogecars this ‘sz
`On Original
`
`15
`
`

`

`5.3
`
`Adverse Events in Phase 1 Studies
`
`Schwarz Phase 1 studies
`
`Since the original NDA, two Phase 1 studies have been completed. In Study SP877, a study of
`single doses of fesoterodine 4mg or 8mg, the most frequent AE was headache. In Study SP857,
`subjects were exposed to single doses of fesoterodine 4, 8, or 16mg or placebo. In this study, dry
`mouth was the most commonly reported AE. There were no SAEs or ABS leading to
`discontinuation in either of these studies. With the exception of 1 event of headache of moderate
`intensity in Study SP877, all AEs reported in these 2 studies were mild in intensity.
`V
`
`Pfizer Phase 1 studies
`
`Pfizer conducted three Phase 1 studies since the NDA. In Study A0221004, a study of
`fesoterodine 4mg and 8mg and placebo administered for five days, the most frequent adverse
`event was somnoience. In Study A0221015, also of fesoterodine 4mg and 8mg and placebo
`administered for five days, the Mist fiequent adverse event was headache. Study AO221044 was
`a randomized, open-label, three—way crossover, single dose study in which the subjects received
`a single fesoterodine 4 mg Formulation El tablet (Treatment A), a single fesoterodine 8 mg
`Formulation E1 tablet (Treatment B) or a single fesoterodine 8 mg Formulation F tablet
`(Treatment C) at the start of each ofthree. periods of the study. The most common AB in this
`study was headache.
`
`There were no SAEs or AEs leading to discontinuation in any of these studies and all AEs
`reported in these three studies were mild or moderate in intensity.
`
`5.4 Time to First Onset of an Adverse Event in Long-term Studies — Pool 82 (Schwarz
`NDA Open-Label Studies). Study A0221007 (Pfizer) shown for comparison purposes.
`
`Pool SZ (Schwarz NDA Open-Label Studies)
`
`The number of subjects reporting first onset of an AB from any system organ class during 0L
`only treatment declined over time. A total of 667/1055 (63%) subjects reported first onset of any
`AE during the first 6 months of open-label treatment, 81/793 (10%) subjects reported first onset
`of any AE during months 7 to 12, 63/680 (9%) subjects reported first onset of an AB during
`months 13 to 24, and 19/512 (4%) subjects reported first onset of any AE during months 25 to
`36. None ofthe 78 subjects with more than 36 months of fesoterodine treatment reported their
`first AE starting after 36 months.
`
`16
`
`

`

`Table 12. Adverse events by period of first onset reported by 25% of subjects overall
`(Pool SZ 0]. only)
`
`Drj: moudi
`
`first onset
`First onset
`first onset
`first onset
` first onset
`
`
`
`
`
`1-6 months
`7—12 months
`13-24 months
`25-36 months
`' >36 months
`
`
`
`
`
`
`
`
`.\"=1055
`N=793
`N=680
`_\'=78
`N=Sll
`
`
`
`
`
`n (%)
`n (94»)
`
`
`
`
`Urinary trace infection
`
`
`NOTE: ’f-i’a refers to percentage of subjects among total (N).
`
`Constipation
`
`
`
`First onset of dry mouth and constipation almost always occurred during the first 6 months of
`treatment. There was no clear trend for onset of first urinary tract infection (UTI).
`
`Study A0221007 (Pfizer) .
`
`Study A0221007 was a 12-week open-label study. During this 12-week trial, the first onset of
`dry mouth and constipation occurred in 23% and 5% of all subjects respectively. This w