CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22—030
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`NDA 22—030
`
`Cross—Discipline Team Leader’s Memorandum
`
`Date Submitted:
`Date Received:
`Date Memo Completed:
`
`May 1, 2008
`May 2, 2008
`October 19, 2008
`
`Toviaz (fesoterodine fumarate)
`Drug:
`4mg and 8mg oral extended-release tablets
`Dose, Route and Formulation:
`'
`Once daily
`Regimen:
`Treatment of overactive bladder (OAB) with
`‘
`Indication:
`symptoms of urge urinary incontinence, urgency and frequency.
`
`1. Executive Summary
`The purpose of this memorandum is to provide the Division Director with my
`recommendation for regulatory action on this new drug application. I recommend
`approval of this application.
`
`On January 25, 2007, this application received an Approvable action. The fundamental
`deficiency that led to the Approvable action was a Chemistry issue; specifically, Pre—
`Approval Inspection (PAI) of the active pharmaceutical ingredient (API) manufacturing
`facility located in Shannon, Ireland could not be conducted because this site was not
`available for PAI prior to the original PDUFA goal date. In the January 25, 2007,
`Approvable letter, the Agency stipulated that a satisfactory inspection of the API
`manufacturing facility was required prior to approval ofthis application. During this
`second cycle, the API site was inspected and Compliance and Chemistry found the site to
`be acceptable.
`
`In addition to the Chemistry issue, the Approvable letter noted that agreement on @2211
`labeling had not been reached. During this cycle, productive labeling discussions
`resulted in successful agreement on the professional package insert (PI), the patient.
`package insert (PPI), and all container/carton labeling.
`
`Finally, the January 25, 2007, Approvable letter stated that another Safety Update would
`need to be submitted with the Complete Response, to include data from all nonclinical
`and clinical fesoterodine studies since the previous Safety Update. The Safety Update
`included new safety data since the cutoff date ofthe original NDA from 3, open-label,
`long-term extension studies completed by Schwar‘z Pharma (Studies SP669, SP73 8, and
`SP739), and a 12-week, open-label study conducted by Pfizer (Study A0021007). In
`addition, new safety data was submitted from 4 new Phase 1 studies. According to the
`medical officer’s review, as well as my secondary Clinical review, the safety profile of
`fesoterodine is acceptable and remains unchanged compared to that described in the
`original NDA and the original lZO-Safety Update. No new risks or safety issues have
`been identified.
`
`

`

`Therefore, all three deficiencies in the Approvable letter have been fully addressed and
`are resolved. Final agreements have been reached with Sponsor on all labeling. There
`are no remaining deficiencies for this application and it may be approved.
`
`The remainder of this memo provides:
`1.
`' Overviews of efficacy and safety results from the original application. For
`additional details, the reader isreferred to my original cross-discipline team
`leader’s memo dated January 25, 2007 as well as Dr. Suresh Kaul’s primary
`medical officer’s review of the original application.
`
`2. An overview of the safety information provided in this most recent Safety
`Update. For additional details the reader is referred to Dr. Harry Handelsman’s
`primary medical officer’s review dated October 7, 2008.
`
`3. An overview of the recommendations and comments from each of the other
`
`disciplines and consultants, as derived from team meetingsand the finalized
`reviews of each discipline and consultant.
`
`2. Overview of Efficacy Results {Original NDAz
`
`As outlined in my previous CDTL memo, the Sponsor conducted two, Phase 3, efficacy
`and safety studies in support of the overactive bladder indication (Study SP5 83 in Europe
`and Study SP5 84 in the United States). These studies were designed in collaboration
`with DRUP reviewers and discussed at. an .End-of-Phase 2 meeting. There were designed
`in the usual standard fashion for the CAB indication; that is, they were both randomized,
`double-blinded, placebo-controlled, fixededose, parallel-arm studies comparing Toviaz
`4mg daily and Toviaz 8mg daily to placebo for a treatment interval of 12 weeks in a well-
`defined OAB population.‘ The co-primary endpoints were:
`
`0
`0
`
`change-from—baseline in the average number of micturitions per 24 hours, and
`change-from-baseline in the average number of urge urinary incontinence
`episodes per 24 hours.
`
`A key secondary endpoint was the average volume voided per micturition as measured
`over 24 hours during the routine periodic dairy period. In both studies, diary-based data
`on micturition frequency per 24 hours, urge incontinence episodes per 24 hours, and
`volume voided with each micturition was collected at baseline and again at Weeks 2, 8
`and 12. Week 12 was the study endpoint. Diaries were recorded for 3 days and data for
`volume voided was collected for 24 hours.
`
`Entry criteria required that patients have symptoms of overactive bladder for Z 6—months
`duration, as demonstrated by at least 8 micturitions per day, and at least 6 urinary
`urgency episodes or 3 urge incontinence episodes per 3-day diary period. Both studies
`enrolled a large number of patients and most of these patients completed the 12-week
`treatment interval.
`
`

`

`In Study SP5 83, a total of 1135 patients were randomized and 1132 were treated: 279
`with placebo, 265 with fesoterodine 4mg/day, 276 with fesoterodine 8mg/day, and 283
`with tolterodine 4mg/day. Most patients (>80% in any treatment group) completed the
`fill] 12 weeks of treatment. Most of patients (81%) were female. The mean patient age
`was 57 years, with a range of 19 to 86 years.
`‘
`‘
`
`In Study SP584, a total of 836 patients were randomized and 832 patients were treated:
`266 with placebo, 267 with fesoterodine 4mg/day, and 267 patients with fesoterodine
`4 8mg/day. Most patients (>80% in anytreatment group) completed full 12 weeks of
`treatment. Most of the patients (76%) were female. The mean age was 59 years, with a
`range of 21 to 91 years. A total of 9% of patients were poor metabolizers for CYP2D6 by
`genotyping.
`
`Results for the primary endpoints and for mean change in voided volume per micturition
`from the two 12-week clinical studies of Toviaz are reported in Table 1. Data for the
`tolterodine arm in Study SP583 is not shown.
`
`'
`
`Table 1. Mean baseline and change from baseline to Week 12 for urge urinary
`incontinence episodes, number of micturitions, and volume voided per micturition
`
`— Stud SP583
`_
`‘
`Toviaz
`Placebo
`4mg/day
`N=279
`N=265
`
`Parameter
`
`Toviaz
`8mg/day
`N=276
`
`
`
`Stud SP584
`Toviaz
`4mg/day
`N=267
`
`Toviaz
`8mg/day
`N=267 ~
`
`Placebo
`N=266
`
`Number of urge incontinence episodes per 24 hours“
`Baseline
`3.7
`3.8
`
`3.9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3.9
`—2.42
`
`<0.001
`
`—2.06
`—1.77
`0.001 _ <0.003
`
`Change from baseline
`p—value vs placebo
`Number of micturitions per 24 hours
`Baseline
`12.0
`
`-1.20
`
`
`
`
`
`11.6
`
`12.9
`
`V
`
`-1 .02
`
`—l .74
`Change from baseline
`
`
`<0-001__—_
`p—value vs placebo
`
`
`
`.
`Voided volume per micturition (mL)
`
`
`
`._1
`150
`60
`'
`159
`156
`
`
`10
`_
`<0.001 _ 0.150
`
` Ii\1
`
`<0.001
`
`<0.001
`
`Change from baseline
`p-value vs placebo
`vs=versus
`
`’
`
`a Only those patients who were urge incontinent at baseline wereincluded for the analysis of
`number of urge incontinence episodes per 24 hours: In Study 1, the number of these patients
`was 211, 199, and 223 in the placebo, Toviaz 4 mg/day and Toviaz 8 mg/day groups,
`respectively. In Study 2, the number of these patients was 205, 228, and 218, respectively.
`
`The data presented in Table 1 demonstrates that fesoterodine 4mg and 8mg administered
`once daily for 12 weeks improved the two primary and key secondary efficacy variables
`compared to placebo. All three key variables (change in the average number of
`
`

`

`micturitions per 24 hours, change in the average number of urge incontinence episodes
`per 24 hours, and volume voided) improved in a dose-responsive manner compared to
`placebo treatment. Comparisons to placebo for both doses for each endpoint were
`statistically significant except for volume voided per micturition in Study SP5 84.
`
`The Biometrics review of the original NDA corroborated these results. Dr. Sobhan’s
`final review of January 10, 2007, concluded:
`
`”Based on the efiicacy data submittedfrom the two Phase 3 studies, our analysis
`showed that at Week 12, compared with placebo, both doses of163%(4 and
`8mg) significantly (P<. 05) reduced the average number ofmicturitions and urge
`incontinence episodes. ”
`
`b(4)
`
`A reduction in the number of urge urinary incontinence episodes per 24 hours was
`observed for both Toviaz doses as compared to placebo as early as two weeks after
`starting blinded study medication.
`
`Finally, it is important to point out that the recommended dosing regimen for Toviaz will
`be a starting dose of 4mg in all patients. If tolerability allows, and efficacy necessitates,
`patients may be titrated up to the 8mg daily dose. The two Phase 3, plaCebo-controlled,
`efficacy studies were fixed-dose, parallel-arm studies. The 9-month, open-label
`extensions of these fixed-dose studies allowed for dose-titration based upon tolerability
`and efficacy. Despite the lack of a placebo-controlled, dose-titration efficacy study, the
`review team strongly supports the recommended dose-titration regimen primarily because
`safety will be enhanced and efficacy will not be compromised. Many patients will be
`well-managed at the low dose and some may require the higher dose.
`
`3. Overview of Safety Results (Original NDA)
`
`In the medical officer’s review for the original NDA, the Clinical review team drew the
`following conclusions about the safety of Toviaz:
`
`0 The reported adverse clinical events for Toviaz are similar to the known side
`effects of other approved anti—muscarinic drugs, including dry mouth,
`constipation, dry eyes and urinary retention.
`0 Most reported clinical adverse events were mild to moderate in severity and
`resolved without significant medical intervention.
`0 The anti-muscarinic adverse eVents observed in the pivotal trials (i.e., dry mouth,
`constipation and urinary retention) appeared to be dose-related.
`'
`0 A thorough clinical review of a small number of serious adverse events (SAEs) in
`Studies SP583 and SP5 84 revealed no probable association with the use of
`fesoterodine.
`‘
`
`0 The thorough QT safety assessment from Study SP686 demonstrated no signal of
`any effect of fesoterodine on the QT interval at the clinical dose of 4mg once a
`day and at a supra-therapeutic dose of 28mg once a day.”
`
`

`

`0 No (frank) hepatotoxicity was reported in any trials of fesoterodine, although
`there were a few patients with mild increase in serum transaminase levels, but
`<3X ULN. There was no determination of a direct association between these
`increases in transaminase levels and fesoterodine.
`
`0
`
`In the Phase 3 studies, a slight dose—dependent increase in mean pulse rate from
`baseline to end of treatment occurred in all the fesoterodine treatment groups. In
`the thorough QT study, there was a mild-moderate increase in heart rate following
`treatment in the high dose group (the supratherapeutic dose of 28mg daily).
`
`The effect of Toviaz on heart rate is shown in the Electrophysiology section of the
`label, as follows: “Toviaz is associated with an increase in heart rate that
`correlates with increasing dose. In the study described above (the TQT study),
`when compared to placebo, the mean increase in heart rate associated with a dose
`of 4 mg/day and 28 mg/day of fesoterodine was 3 beats/minute and 11
`beats/minute respectively. In the two, phase 3, placebo-controlled studies in
`patients with overactive bladder, the mean increase in heart rate compared to
`placebo was approximately 3-4 beats/minute in the 4 mg/day group and 3-5
`beats/minute in the 8 mg/day group.”
`
`According to the original NDA, the safety of fesoterodine was evaluated in Phase 2 and 3
`trials in a total of 2859 patients with overactive bladder. Safety data was primarily drawn
`from the 2288 patients who received Toviaz. Of these, 782 received Toviaz 4 mg per
`day, and 785 received Toviaz 8 mg per day in treatment periods of 8. or 12 weeks. Other
`patients in the clinical development program received Toviaz at higher and lower doses,
`including a dose of 12mg per day, and approximately 80% of those patients had at least
`10 weeks exposure to Toviaz.
`'
`
`A total of 1964 patients participated in the two, Phase 3, 12-week, placebo-controlled
`studies and their subsequent 9-month, open-label extensions. In the two “pivotal” Phase 3
`studies combined, 554 patients received Toviaz 4 mg per day and 566 patients received
`Toviaz 8 mg per day.
`
`Patients also received Toviaz for longer durations in the 9-month, open—label extension
`phases ofthe two, Phase 3, “pivotal” studies. In the original NDA, in all trials combined,
`857, 691, and 354 patients received Toviaz for at least 6 months, 1 year, and 18‘months
`respectively.
`
`~
`
`In the original NDA, a total of 6 deaths were reported. Of these, one patient died from
`cerebrovascular accident, the second patient died from M1, the third patient died due to
`metastastases to liver, the fourth patient died due to “sudden death”, the fifth patient died
`due to “unknown causes” several months after completing treatment, and the sixth patient
`died due to “natural causes”. Five of the six deaths were considered by the investigators
`to be unrelated to festerodine. The “sudden death” case was considered “unlikely
`related”.
`
`

`

`In the controlled clinical trials combined, serious adverse events (SAE's) were reported in _
`patients treated with placebo, fesoterodine 4 mg/day and fesoterodine 8mg/day in 2%, 4%
`and 3% of patients, respectively. Serious AE's in all treatment groups occurred across
`multiple body systems with no obvious trends. Serious AEs reported by more than 1
`patient in any fesoterodine-treated group included: chest pain/angina (in 3 patients),
`pneumonia, electrocardiocardiogram QTc interval prolongation, appendicitis, and I
`salpingitis (in 2 patients each). All other SAE types were reported in 1 patient each.
`
`In the original NDA, commonly reported AE’s that occurred more often in patients
`treated with fesoterodine than placebo included: dry mouth, constipation, urinary tract
`infection, dyspepsia, lacrimal disorder (dryeyes), dry throat, dysuria, and abdominal
`pain.
`
`Table 2 lists adverse events, regardless of causality, that were reported in the combined
`Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in
`1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.
`
`

`

`Table 2. Adverse events with an incidence exceeding the placebo rate and reported by 21% of
`natients from double-blind, nlacebo-controlled Phase 3 trials of 12 weeks treatment duration
`
`System organ class/Preferred term
`
`
`
`
`
`Placebo
`
`
`N=554
`
`
`%
`
`
`
`Gastrointestinal disorders
`
`Dry mouth
`
`
`Constipation
`
`
`Dyspepsia
`
`
`Nausea
`
`
`Abdominal ain u .er
`
`
`Infections
`
`LAN'-‘
`
`
`
`tract infection
`Urin
`U - er res a irato
`tract infection
`
`Eye disorders
`D e es
`
`Renal and urinary disorders
`Dysuria
`Urin
`
`retention
`
`Psychiatric disorders
`Insomnia
`
`
`
`
`
`
`
`H
`
`NW
`
`....
`
`Nh—ifi0wk»#-
`
`o \r
`
`._. b)
`
`0.5
`0.4
`
` 0.\1
`
`7‘?“.0.comU!
`
`DJ \l
`
`1""N91"!“.Nwxo4:-O\
`
`O 4;
`
`1.2
`1.2
`
`..Q 1..
`
`
`
`
`
`
`
`O \l....09PP599’.0.'Lu:NuNum
`
`O U1
`
`99.0oU!JRKO#
`
`Respiratory disorders
`1.6
`Cough
`0.9
`D Throat
`
`General disorders
`
`Edema Heriheral
`Musculoskeletal disorders
`
`Back ain
`
`
`Investigations
`ALT increased
`GGT increased
`
`Skin disorders
`
`Rash
`
`
`
`
`
`
`ALT=alanine aminotransferase, GGT=gamma glutamyltransferase
`
`Most AE’s were mild or moderate in intensity. Severe AE’s were reported for 4%, 5%,
`and 8% of patients in the placebo, Toviaz 4 mg/day, and Toviaz 8 mg/day groups,
`respectively. Dry mouth was the AE most often rated as severe in intensity. Adverse
`events led to discontinuation in 3%, 5%, and 6% of patients in the placebo, Toviaz 4
`mg/day and Toviaz 8 mg/day groups respectively. The most common adverse event
`leading to discontinuation was dry mouth.
`
`

`

`Finally, with long-term fesoterodine treatment in the open-label extension studies, in the
`original NDA, the profile of common AE’s was similar to that listed in Table 2 above.
`Similar to the controlled studies, most adverse events of dry mouth and constipation were
`mild to moderate in intensity, with only a few cases reported as severe. Specifically, with
`long-term treatment, severe AEs were reported for 14% of patients. Severe dry mouth
`(4%) and severe constipation (1%) were the only AEs reported as severe by 21% of
`patients during longer-term treatment. Serious adverse events reported by more than 2
`patients each during the open-label extension studies included: myocardial infarction,
`bronchitis, cholecystectomy, knee arthroplasty, and breast cancer,
`
`V
`
`There are several additional special safety issues and these are delineated individually in
`the original CDTL memo. One notable finding was a modestly increased incidence of
`anticholinergic adverse effects in patients aged 75 years and greater compared to patients
`younger than 75 years. Of 1120 patients who received Toviaz in the two Phase 3, 12-
`week, placebo-controlled, efficacy and safety studies, 373 (33%) were 65 years of age or
`older, and 123 (11%) were 75 years of age or older. No overall differences in safety or
`effectiveness were observed between patients younger than 65 years of age and those 65
`years of age or older in these studies; however, the incidence of commonly reported
`anticholinergic adverse events (constipation, urinary tract infection and dizziness) was
`higher in patients 75 years of age and older as compared to younger patients. This
`information has been added to the label. In addition, the label recommends starting all
`patients on 4mg daily and titrating up as tolerability allows and efficacy necessitates.
`This is acceptable for all patients, including geriatric patients.
`
`4. Overview of Sareg Results from the Final Safeg Update
`
`The Complete Response included a substantive Final Safety Update, which was reviewed
`in detail by the primary medical officer, Dr. Harry Handelsman. The reader is referred to
`Dr. Handelsman’s review for additional details. An overview of results from the Safety
`Update is provided here.
`
`Contents ofthe Safety Update
`4.]
`The final update included 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, SP738, and. SP739), and from an ongoing 12-week,
`open—label study (A0021007), initiated by Pfizer, with data included as of January 1,
`2008. In addition, the Complete Response included summaries of safety from one new
`Phase 1 study completed by Schwarz Pharma (Studies SP857) and three new Phase]
`studies conducted by Pfizer (Studies A0221004, A0221015 and A0221044) since the
`NDA.
`
`4.2
`
`Extent ofExposure in the Safety Update and Disposition ofSubjects
`
`The extent of exposure to fesoterodine in the original NDA and final Safety Update is
`substantial. Overall, 2288 subjects received fesoterodine in the Phase 2 and 3 studies,
`and another 525 received'fesoterodine in the Phase 1 studies. In all fesoterodine studies
`
`

`

`conducted by Schwarz Pharma combined, including the original NDA studies, their open-
`label extensions, and the additional Phase 1 study since the NDA, a total of 857 patients,
`701 patients, 615 patients, 529 patients, and 105 patients received at least 6 months, 12
`months, 18 months, 24 months and 36 months of fesoterodine, respectively. The median
`durations of exposure to fesoterodine in the original NDA and Final Safety Update were
`13.4 months and 26.3 months, respectively.
`
`In addition, Pfizer conducted 3 new Phase 1 studies (Studies A0221004, A0221015 and
`A0221044) in which 106 subjects were exposed to fesoterodine. Finally, an additional 516
`subjects with OAB received fesoterodine in the 12-week, Pfizer Study A0221007. The median
`duration of exposure in that study Was 84 days.
`
`Of all 2288 fesoterodine-treated subjects from Schwarz Pharma Phase 2/3 studies (Safety
`Pool S3), 961 subjects (42%) discontinued treatment prematurely. In this group, 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%).
`'
`
`Demographics in the Safety Update
`4.3
`Demographic tables were not rerun for the NDA studies conducted by Schwarz Pharma for the
`Final Safety Update as the Sponsor stated that these data did not change from the original NDA
`. The demographics fi'om the original NDA Were comparable to those for the new Pfizer Study
`A0221007. A majority ofthe subjects were white females in the age group 45 — 64 years (mean
`age of 59.4 years).
`.
`
`Commonly Reported Adverse Events in the Safety Update
`4.4
`The following table (Table 3 of this memo ~ same as Table 11 from the Final Safety Update)
`describes the AE’s seen in 2 2 % of subjects in all fesoterodine-treated subjects in Schwarz
`Pharma Phase 2/3 studies (Schwarz Safety Pool S3). The table shows a comparison of the
`reported incidences of these AE terms from the original NDA and from the Final Safety Update.
`
`Appears This Way
`On Original
`
`

`

`Table 3. Adverse events reported in 2 2 % of subjects in all fesoterodine—treated subjects in
`Schwarz Pharma Phase 2/3 studies (same as Table 11 from the Final Safety Update)
`
`Table 11. Treatment-emergent adverse events reported by 22% of subjects (Pool SS)
`
`Preferred term
`
`Original .\'D.-\.
`1:31?
`
`
`
`.\'=2288
`.\'=3388
`
`
`.
`N (9'6)
`u (%y
`
`
`
`Dry: men-‘11
`
`
`Urinar; Iracr mfeenon
`21319 [9:-
`
`Headache
`
`C'onsripmion
`
`93 (4)
`
`
`
`kwsopharfgngitis
`
`
`
`
`
`
`
`
`
`
`
`
`81m
`78m
`
`75c»
`m,
`
`m 6
`
`36)
`
`we)
`
`m m
`
`'
`
`-
`
`
`
`m w
`w
`- W
`W)
`W)
`
`FSU=Final Safety Update, NDA=Ncw Drug Application
`
`In this group of patients, most AEs were mild or moderate in intensity. Adverse events with a
`maximum intensity of severe were reported by 15% of subjects overall. As in the original NDA
`severe dry mouth, reported by 4% of subjects, was the only severe AE that occurred in 21% of
`subjects in this Safety Pool.
`
`’
`
`Adverse events reported by at least 2% of fesoterodine-treated subjects in the new, 12-week,
`Pfizer Study A0221007 were: dry mouth (23%), constipation (5%), headache (4%), abdominal
`pain — inclusive ofthe terms abdominal pain, abdominal pain lower, abdominal pain upper and
`abdominal discomfort (3%), and diarrhea (2%).
`
`In the new Phase 1 study conducted by Schwarz Pharma (Study SP857), where subjects
`were exposed to single doses of fesoterodine 4, 8, or 16mg or placebo, dry mouth was the
`most commonly reported AE. There were no SAEs or AEs leading to discontinuation in
`this study._
`
`10
`
`

`

`In the three new Phase 1 studies conducted by Pfizer, there were no new safety signals.
`In Study A0221004, a study of fesoterodine 4mg and 8mg and placebo administered once
`daily for five days, the most frequent adverse event was somnolence. In Study
`A0221015, also of fesoterodine 4mg and 8mg and placebo administered for five days, the
`most frequent adverse event was headache.
`In Study A0221044, a randomized, open-
`label, three-way crossover, single dose study of 4mg and 8mg dosage strengths of
`different formulations, the most common AE was headache. There were no SAEs or
`AEs leading to discontinuation in these studies and all AEs reported in the three studies ‘
`were mild or moderate in intensity.
`-
`
`Deaths, Serious Adverse Events, and Discontinuations Due to Adverse Events in
`4.5
`the Final Safety Update
`
`4. 5. 1
`
`Deaths
`
`In all Schwarz studied combined, there were reports of 6 deaths. Table 4 of this memo (same as
`Table 13 from the Final Safety Update), is a list of these deaths, including the preferred and
`reported AE terms, and causality as assessed by the investigator. The medical officer’s review
`contains narratives for these events.
`
`Table 4. Reports of death - Schwarz Pharma Safety Pool S3
`
`Table 13. Subjects who had adverse events with fatal outcomes
`
`Dose and duration of
`study medication at onset
`of AF.
`choterodine 8mg/day for
`827 days
`Fesoterodine 8mg/day for
`949 days
`NA’
`
`Study unmher/
`subject number
`
`513738111047
`
`SP739/13686
`
`SP738/l 1035
`
`SP669/12221
`
`
`
`Preferred term/
`reported term
`
`Cerebral infarction/sight middle
`cerebral ..
`6‘
`infarct
`Death/Death
`
`Hemorrhage intracranial/lefi
`parietoocdpital hemorrhage
`(intracranial hemorrhage)
`Pancreatic carcinoma! pancreatic
`mncer
`
`V
`
`
`
`
`
`
`
`Causality (per
`investigator)
`
`Not related
`
`Not assessable (as
`per reporter)
`Unlikely
`
`No: related
`
`Unlikely
`
`
`
`
`
`NA
`__ Wm‘w‘m
`AMl'Facute .. eloid leukemia
`NA
`SP739/14862
`Pancreatic caminoma/ pancreatic
`carcinoma (metastatic)
`
`
`
`’
`AEadvetse event, NA=not applicable
`
`1 Brent occuxred during the Safety Follow-Up Period.
`
`b. Event accrued afler the Safety Follow—Up Period (ie. AE was non-teammt—emergmt).
`
`Of note, the report of death of Subject 13686 was from an obituary in a local newspaper
`and additional attempts to contact family members for information were not successful.
`Therefore, causality was not assessable by the investigator. There were no deaths
`reported in the new Pfizer study A0221007, nor in the new Phase 1 studies.
`
`4. 5. 2
`
`Serious Adverse Events
`
`11
`
`

`

`Serious AE’s were reported by 213/2288 (9%) subjects in all fesoterodine-treated patients in
`Phase 2/3 Schwarz Pharma studies (Safety Pool S3). This number includes an additional 55
`subjects (2%) reporting SAEs after the cutoff date for the original NDA. Table 5 of this memo
`(same as Table 15 from the Final Safety Update) shows the incidence of all serious adverse
`events reported by more than 2 subjects per AE term. The table provides comparisons of SAE
`incidences from the original NDA and from the Final safety Update.
`-
`
`Table 5. Serious AE’s in Phase 2/3 Schwarz Pharma Studie‘s (Safety Pool S3) reported by at
`least 2 subject (per AE term.
`'
`
`Table 15. Serious treatlnent-elnergent adverse events reported by >2 subjects (Pool SS)
`
`
`
`
`Preferred term
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Myocardial infarction
`
`Stress urinary incontmence
`
`Knee arthroplasty
`
`Inververtebral disc protrusion
`
`Appendrcitis
`
`
` prolonged
`
`Original NDA
`(F950 [DB-FOLD
`.\'=2288
`1!
`
`
`
`
`
`
`FSU
`(F950 [DB+OL])
`N=2288
`
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Abdominal pain‘
`
`DB=double~blincL FSU=Final Safety Update, Feso=fesoterodine, NDA=New Drug Application,
`OL=opcn~1abeL n=subjects
`
`Note: This table is sorted in descending order by the FSU column.
`
`a Atthe time ofthe originalNDA, serious “abdominal pain”hadbeenreportedfot 3 subjects in
`Pool S3. The seriousness of the event in l of these subjects was subsequently revised and
`categorized as nonserious.
`
`In this group of patients, 1% of subjects had SAEs considered by the investigator to be at least
`possibly treatment related. Most SAEs assessed as at least possibly-related to treatment by the
`
`12
`
`

`

`investigator occurred in 1 subject only, with the exception of urinary retention, which was
`considered at least possibly related to treatment in 3 cases, and angina pectoris, diverticulitis,
`constipation, irritable bovVel syndrome, and electrocardiogram QT corrected interval prolonged,
`each of which was also considered at least possibly related to treatment in 2 cases. Narratives for
`several of these SAEs appear in Dr. Handelsman’s medical officer’s review.
`In addition, the 2
`cases described as “electrocardiogram QT corrected interval prolonged” are further discussed in
`Section 4.6 below.
`
`4.5.3
`
`Discontinuations Due to Adverse Events
`
`In Schwarz Pharma Phase 2/3 studies (Safety Pool S3), AEs led to discontinuation of 250/2288
`(11%) subjects, and were often those associated with antimuscarinic treatment. This was an
`increase of 27 subjects since the original NDA. The incidence of individual AEs leading to .
`discontinuation in this group of patients is shown in Table 5 below (which is the same as Table
`16 of the Final safety Update).
`
`Table 5. AEs leading to discontinuation in more than 3 fesoterodine—treated subjects in
`the Phase 2/§ Schwarz Pharma studies (Safety Pool S3)
`
`Table 16. Treatment-emergent adverse events leading to discontinuation of treatment by
`>3 subjects (Pool 83)
`
`Original NDA
`FSU
`
`
`
`(Feso [DB+OL])
`(Feso [DB+OL])
`
`
`
`
`N=2288
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“<0
`-
`4
`
`
`
`DB=doub1e-blind, ECCFelectromrdiogram, Feso=fesotetodine, FSU=Fina1 Safety Update,
`NDA=New Drug Application, OIFopen-label
`
`a. In the original NBA, 8 subjects had events of“residual urine volume” reported; one ofthese
`events was subsequently revised bythe investigator and no longer considered an adverse event
`for the subject.
`
`13
`
`

`

`The 8 discontinuations described as “electrocardiogram QT corrected interval prolonged” (6
`from the original NDA and 2 from the Final Safety Update) are further discussed in Section 4.6
`below.
`
`4.6
`
`Notable Issuesfrom the Final Safely Update
`
`4. 6. I
`
`Electrocardiographic QTc prolongation
`
`During the Schwarz Pharma studies, including the open~label extensions, EKGs were
`conducted at periodic intervals and the QT interval was assessed with each EKG. The
`QT interval was measured without correction and with correction using Bazett’s and
`Fridericia’s correction methods. It is known that fesoterodine has an effect on increasing
`the heart rate, therefore, the Fridericia’s method is most suitable for correction.
`However, during the trials, Bazett’s correction was used for the discontinuation criteria.
`For example, the patient was to be discontinued if the QTcBazett was > 60 milliseconds
`above baseline or >500 millisecond on any given EKG assessment.
`
`. According to the Final Safety Update, 8 subjects (6 in the original NDA and 2 more in
`the Final safety Update) were discontinued based upon one or both QTc Bazett criteria.
`However, during the review of the Complete Response, information from the Sponsor
`showed that an overall total of 13 patients were discontinued based upon changes in the
`corrected QT. Of these, a total of 7 patients had only mild prolongation of the Bazett
`corrected QT interval (23-54 ms above baseline) that did not meet either per-protocol
`criterion for discontinuation. Two (2) patients were discontinued based upon
`prolongation of the Bazett corrected QT from‘baseline by 67 and 70 milliseconds,
`respectively, just slightly above the cutpoint for discontinuation. Three (3) patients were
`discontinued due to absolute Bazett corrected QT 500 msec (ranging from 509 to 518
`msec). Finally, 1 patient was discontinued after meeting both discontinuation criteria:
`this 75 year old man taking 8 mg of drug for 118 days had a QTcB reported as 527 ms,
`up from 459 ms at baseline. In at least 2 of the 6 patients who were discontinued as a
`consequence of meeting at least one of the Bazett corrected QT interval discontinuation
`criteria, the heart rate was notably increased, implying an undercorrection when using the
`Bazett method.
`I
`
`The results of a prospectively designed and well-conducted thorough QT study using
`multiple doses of 4mg and 28mg revealed no evidence of QTcFridericia prolongation.
`
`Each individual AE of QTc prolongation was reviewed by the medical officers (Dr.
`Suresh Kaul for the original NDA and Dr. Harry Handelsman in the Final Safety Update)
`and this medical team leader. Dr. Handelsman’s conclusion agreed with that ofthe
`medical reviewer of the original NDA submission (Dr. Kaul) that the reported QTc
`prolongations were mild in intensity, somewhat exaggerated by undercorrection when
`using the Bazett method, frequently associated with co-morbidities and/or concomitant
`medications, and unlikely associated with fesoterodine.
`
`i4
`
`

`

`4.6.2
`
`Adverse Events in Patients Aged 75 years and Older
`
`Analysis of adverse events in previous applications for antimuscurinics for overactive
`bladder showed that elderly patients experienced antimuscurinic adverse events more
`frequently than did younger patients. Therefore, the Sponsor carried out such an analysis
`for fesoterodine and the results again demonstrated the increased AE incidence1n those
`aged 75 years and older Specifically, analysis of data from the Schwarz Pharma
`placebo-controlled Phase 2/3 studies revealed that dry mouth constipation, dyspepsia,
`increase in residual urine, dizziness (at 8mg only), and urinary tract infection were more
`commonly reported1n subjects 2 75 years of age as compared to subjects <75 years.
`These differences are described in the Geriatric Use section of the package insert.
`
`5. Relevant Items from Other Disciplines
`
`All major disciplines conducted reviews of the original NDA as well as this Complete
`Response. Consultative reviews were requested for several items. These are
`summ