CBERIsolagen Therapy (IT)BLA 125348
FDA Clinical Review
Agnes Lim, MD Yao-Yao Zhu, MD, PhD
DCEPT/OCTGT/CBER, FDA
October 9, 2009 Advisory Committee Meeting
CBER
Presentation OutlinePresentation Outline
Overview of Pivotal StudiesOverview of Pivotal StudiesStudies IT-R-005 and IT-R-Studies IT-R-005 and IT-R-006006
Study ResultsStudy ResultsEfficacy Results Efficacy Results Safety ResultsSafety Results
CBER
Overview of Pivotal StudiesOverview of Pivotal StudiesIT-R-005 and IT-R-006IT-R-005 and IT-R-006
Proposed indicationProposed indication Treatment of moderate to severe Treatment of moderate to severe
nasolabial fold wrinkles in adults nasolabial fold wrinkles in adults
Title: A Phase 3, Multicenter, Title: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Double-Blind, Randomized, Placebo-Controlled Trial of the Efficacy and Controlled Trial of the Efficacy and Safety of Isolagen Therapy in the Safety of Isolagen Therapy in the Treatment of Nasolabial Fold Treatment of Nasolabial Fold WrinklesWrinkles
CBER
IT AdministrationIT AdministrationDosage: Dosage: 0.1 mL/linear cm, up to 2 mL/Tx(1.0-2.0 x 107 cells/mL)
Three treatment visits, at intervals of 5 ± 1 week
Control: vehicle-medium onlyControl: vehicle-medium only
CBER
Subject Wrinkle AssessmentSubject Wrinkle Assessment
““How do you feel How do you feel about the wrinkles in about the wrinkles in the lower part of the lower part of your face today”?your face today”?
-2-2 Very Very Dissatisfied Dissatisfied
--11 DissatisfiedDissatisfied 00 Somewhat Somewhat
Satisfied Satisfied +1+1 Satisfied Satisfied +2+2 Very SatisfiedVery Satisfied
CBER
Evaluator Wrinkle Severity Evaluator Wrinkle Severity Assessment Assessment
(Lemperle) with Photoguide(Lemperle) with Photoguide
Grade 0 No wrinkleGrade 0 No wrinkle
Grade 1 Just perceptible Grade 1 Just perceptible
Grade 2 ShallowGrade 2 Shallow
Grade 3 Moderately deep Grade 3 Moderately deep
Grade 4 Deep, well defined edgeGrade 4 Deep, well defined edgeGrade 5 Very deep, redundantGrade 5 Very deep, redundant fold fold
CBERKey Eligibility Criteria Key Eligibility Criteria IT-R-005 and IT-R-006IT-R-005 and IT-R-006
InclusionInclusion M or F ≥M or F ≥ 18 years old 18 years old Pre-specified nasolabial fold wrinkle Pre-specified nasolabial fold wrinkle
gradings of moderate/severe by both gradings of moderate/severe by both subjects and evaluatorssubjects and evaluators
Post-auricular skin acceptable for biopsyPost-auricular skin acceptable for biopsy
ExclusionExclusion Total treatment area > 20 cm in length Total treatment area > 20 cm in length Pre-specified skin conditionsPre-specified skin conditions Pre-specified previous facial cosmetic Pre-specified previous facial cosmetic
procedures, dermal fillers or Rxprocedures, dermal fillers or Rx Basal cell carcinoma Basal cell carcinoma
CBER
Treatment SchemaTreatment Schema
Efficacy evaluation at 6 months following last treatment injection (Visit 6)
Co-primary efficacy endpoints:Subject Wrinkle AssessmentEvaluator Wrinkle Severity Assessment
Safety assessment every visit; Final safety assessment by telephone at 12 month
1. Severity ≥ Grade 3 of bilateral nasolabial fold wrinkles by evaluator 2. Subjects Dissatisfied or Very Dissatisfied with appearance of wrinkles in lower face3. Met entrance criteria
Skin biopsy/Baseline; biopsy meet acceptance criteria; randomized by site
IT, n= 100Up to 2mL (1-2x107 cells/mL) / Tx
Every 5 ± 1 wkTotal 3 treatments
Vehicle-control, n = 100Every 5 ± 1 wk
Total 3 treatments
CBER
Primary Efficacy Primary Efficacy EndpointsEndpoints
Co-primary Co-primary EndpointsEndpoints
Wrinkle Wrinkle AssessmentAssessment
at at BaselineBaseline
Success Success
at at 6 month6 month
Evaluator Evaluator Wrinkle Wrinkle Severity Severity AssessmentAssessment
Grade Grade >>33 2-point or better 2-point or better improvement improvement for both sidesfor both sides
Subject Subject Wrinkle Wrinkle AssessmentAssessment
-1: dissatisfied-1: dissatisfied
-2: very dissatisfied-2: very dissatisfied2-point or better 2-point or better improvementimprovement
CBER
Secondary EndpointsSecondary Endpoints
Wrinkle Wrinkle AssessmentAssessment
at at BaselineBaseline
Success Success
at at Visits 3,4,5Visits 3,4,5
Evaluator Evaluator Wrinkle Wrinkle Severity Severity AssessmentAssessment
Grade Grade >>33 2-point or better 2-point or better improvement on improvement on both sidesboth sides
Subject Wrinkle Subject Wrinkle AssessmentAssessment
-1: dissatisfied-1: dissatisfied
-2: very dissatisfied-2: very dissatisfied2-point or better 2-point or better improvementimprovement
CBERSecondary Endpoints Secondary Endpoints (cont.)(cont.)
Photos at BaselinePhotos at Baseline
versusversus
Photos at Visits 3,4,5,6Photos at Visits 3,4,5,6Subject Subject ImprovemeImprovement nt AssessmentAssessment
Scale used for rating wrinkle/appearance on photos:-2= much worse than before -1= worse than before 0= the same as before +1= better than before +2= much better than before
Evaluator Evaluator ImprovemeImprovement nt AssessmentAssessment
CBER
Statistical PlanAnalysis populations:Analysis populations: ITT = all randomized ITT = all randomized MITT = MITT = received ≥ one treatment EE (Efficacy Evaluable) = met entrance EE (Efficacy Evaluable) = met entrance
criteria, received all 3 treatments, and no criteria, received all 3 treatments, and no major protocol violationmajor protocol violation
80% power at a two-sided significance level of 0.05 Response rates > 40% of IT; 20% for
vehicle-control Missing data imputed as treatment failures
CBER
IT-R-005 and IT-R-006IT-R-005 and IT-R-006EnrollmentEnrollment
StudyStudyITIT ControlControl # of # of
SitesSitesStudy Study PeriodPeriod
IT-R-005IT-R-005
n=203n=203100100 103103 77 10/06-10/06-
06/0806/08
IT-R-006IT-R-006
n=218n=218110110 108108 66 11/06-11/06-
06/0806/08
CBER
Demographics of ITT Demographics of ITT PopulationPopulation
Population Population CategoriesCategories
IT-R-005IT-R-005 IT-R-006IT-R-006
ITIT
n=100n=100ControContro
ll
n=103n=103
ITIT
n=110n=110ControContro
ll
n=108n=108Ages (Years) Mean (SD)
Median
Range
57.5 (8.3)57.5 (8.3)
5757
38-7538-75
55.9 (7.9)55.9 (7.9)
5656
35-7835-78
53.9 53.9 (10.4)(10.4)
5555
23-7523-75
55.4 (9.9)55.4 (9.9)
5555
26-8126-81
Age Groups n (%)
< 50
> 50, < 65
> 65
19 (19%)19 (19%)
60 (60%)60 (60%)
21 (21%)21 (21%)
25 (24%)25 (24%)
62 (60%)62 (60%)
16 (16%)16 (16%)
39 (35%)39 (35%)
56 (51%)56 (51%)
15 (14%)15 (14%)
34 (31%)34 (31%)
55 (51%)55 (51%)
19 (18%)19 (18%)
Gendern (%)
Female
Male
88 (88%)88 (88%)
12 (12%)12 (12%)94 (91%)94 (91%)
9 (9%)9 (9%)103 103 (94%)(94%)
7 (6%)7 (6%)
95 (88%)95 (88%)
13 (12%)13 (12%)
Racen (%)
White
Black or African-American
Asian
American Indian or Alaska
Others
94 (94%)94 (94%)
1 (1%)1 (1%)
2 (2%)2 (2%)
00
3 (3%)3 (3%)
99 (96%)99 (96%)
2 (2%)2 (2%)
00
1 (1%)1 (1%)
1 (1%)1 (1%)
98 (89%)98 (89%)
1 (1%)1 (1%)
00
00
11 (10%)11 (10%)
95 (88%)95 (88%)
1 (1%)1 (1%)
00
00
12 (11%)12 (11%)
Ethnicity n (%)Ethnicity n (%) Hispanic/Latino 10 (10%)10 (10%) 7 (7%)7 (7%) 12 (11%)12 (11%) 12 (11%)12 (11%)
CBER
Key DemographicsKey DemographicsDemographics similar between Demographics similar between studies IT-R-005 and IT-R-006studies IT-R-005 and IT-R-006Age: Age: Median 56 years old; range 23-Median 56 years old; range 23-8181
Gender: Gender: 90% Female90% Female
Race: Race: 92% White92% White 1% Black/African-American1% Black/African-American 1% Asian1% Asian
Ethnicity: Ethnicity: 10% Hispanic/Latino10% Hispanic/Latino
CBER
Disposition of SubjectsDisposition of SubjectsIT-R-005IT-R-005 IT-R-006IT-R-006 TotalTotal
ITIT
n=100n=100ControlControl
n=103n=103ITIT
n=110n=110ControlControl
n=108n=108 n=421n=421
Study Completion Study Completion Status:Status: Completed StudyCompleted Study
Early TerminationEarly Termination
80 (80%)80 (80%)
20 (20%)20 (20%)88 (85%)88 (85%)
15 (15%)15 (15%)93 (85%)93 (85%)
17 (15%)17 (15%)98 (91%)98 (91%)
10 (9%)10 (9%)359 359 (85%)(85%)
62 (15%)62 (15%)
Reasons for Early Reasons for Early Termination:Termination: Subject WithdrawalSubject Withdrawal
Sponsor RequestSponsor Request
Adverse EventAdverse Event
Protocol Non-Protocol Non-ComplianceCompliance
Lost to Follow-UpLost to Follow-Up
OthersOthers
7 (7%)7 (7%)
5 (5%)5 (5%)
1 (<1%)1 (<1%)
3 (3%)3 (3%)
1 (1%)1 (1%)
3 (3%)3 (3%)
6(6%)6(6%)
1 (<1%)1 (<1%)
1 (<1%)1 (<1%)
1 (<1%)1 (<1%)
3 (3%)3 (3%)
3 (3%)3 (3%)
3 (3%)3 (3%)
10 (9%)10 (9%)
1 (<1%)1 (<1%)
2 (2%)2 (2%)
00
1 (<1%)1 (<1%)
4 (4%)4 (4%)
4 (4%)4 (4%)
1 (<1%)1 (<1%)
1 (<1%)1 (<1%)
00
00
20 (5%)20 (5%)
20 (5%)20 (5%)
4 (<1%)4 (<1%)
7 (2%)7 (2%)
4 (<1%)4 (<1%)
7 (2%)7 (2%)
CBER
Manufacturing FailureManufacturing FailureThe total IT manufacturing failure in the two The total IT manufacturing failure in the two pivotal studies was 11% (24/210)pivotal studies was 11% (24/210)
IT/Control pairing to maintain IT/Control pairing to maintain randomization/study blind for re-biopsies due to randomization/study blind for re-biopsies due to manufacturing failuresmanufacturing failures
Type of FailureType of Failure
IT-R-005IT-R-005N=203N=203
IT-R-006IT-R-006N=218N=218
ITITn=100n=100
ControlControln=103n=103
ITITn=110n=110
ControlControln=108n=108
No product No product produced, Totalproduced, Total
5 (5%)5 (5%) 1 (1%)1 (1%) 8 (7%)8 (7%) 4 (4%)4 (4%)
Insufficient product, Insufficient product, Total:Total:
3 (3%)3 (3%) 00 8 (7%)8 (7%) 1 (1%)1 (1%)
1 Tx received1 Tx received 1 (1%)1 (1%) 00 4 (4%)4 (4%) 00 2 Tx received2 Tx received 2 (2%)2 (2%) 00 4 (4%)4 (4%) 1 (1%)1 (1%)
CBER
Primary Endpoints Primary Endpoints Success Rate at 6 MonthSuccess Rate at 6 Month
Co-Primary Co-Primary EndpointsEndpoints
IT-R-005IT-R-005N=203N=203
IT-R-006IT-R-006N=218N=218
ITIT
n=100n=100ControlControl
n=103n=103p-valuep-value ITIT
n=110n=110ControlControl
n=108n=108p-valuep-value
Evaluator Evaluator Wrinkle Wrinkle Severity Severity AssessmenAssessmentt
3333
(33%)(33%)7 7
(7%)(7%)<0.000<0.000
11
2121
(19%(19%))
8 8
(7%)(7%)0.00750.0075
Subject Subject Wrinkle Wrinkle AssessmenAssessmentt
5757
(57%)(57%)3131
(30%)(30%)0.00010.0001
5050
(45%(45%))
1919
(18%)(18%)<0.000<0.000
11
CBER
Efficacy ConclusionsEfficacy ConclusionsBoth co-primary endpoints at six Both co-primary endpoints at six months were met in each of the months were met in each of the pivotal studies pivotal studies
Results of secondary endpoints Results of secondary endpoints supportive of primary efficacy supportive of primary efficacy resultsresults
Efficacy of IT > 6 months has not Efficacy of IT > 6 months has not been demonstratedbeen demonstrated
No studies conducted for effects of No studies conducted for effects of repeating treatment cyclesrepeating treatment cycles
CBER
Safety OverviewSafety OverviewSafety databaseSafety database
Commercial experienceCommercial experience
Safety PopulationSafety Population ITITVehicle-Vehicle-ControlControl TotalTotal
IT-R-005 & 006IT-R-005 & 006 181181 191191 372372
7 clinical trials 7 clinical trials
(integrated (integrated safety safety
population)population)
508508 354354 862862
CBER
Safety Monitoring Schedule in 005 & Safety Monitoring Schedule in 005 & 006006
5 wks 5 wks 8 wks 8 wks 8 wks 28 wks
Total Safety Observation Period : 62 weeks
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Telephone Call
Treatment Visits
* Acute Study: Visits 1, 2, 3, 4, 5, & 6: 34 weeks
* Long-Term Study: a telephone call at 12 months from Visit 3
CBERAdverse Events in IT-R-005 > Adverse Events in IT-R-005 > 1%1%
Preferred TermsPreferred TermsIT N=83IT N=83 Control N=92Control N=92
SubjectsSubjects EventsEvents SubjectsSubjects EventsEvents
All treatment-emergent AEAll treatment-emergent AE 51 (61%)51 (61%) 193193 57 (62%)57 (62%) 219219
Administration site conditionsAdministration site conditions 31 (37%)31 (37%) 119119 32 (35%)32 (35%) 9494
(Related to Treatment)(Related to Treatment) 28 (33%)28 (33%) 112112 24 (26%)24 (26%) 7676
Injection-site erythemaInjection-site erythema 23 (28%)23 (28%) 5353 17 (19%)17 (19%) 2828
Injection-site swellingInjection-site swelling 18 (22%)18 (22%) 4141 15 (16%)15 (16%) 2727
Injection-site pain Injection-site pain 5 (6%)5 (6%) 66 4 (4%)4 (4%) 55
Injection-site bruisingInjection-site bruising 4 (5%)4 (5%) 55 12 (13%)12 (13%) 1717
Injection-site nodulesInjection-site nodules 2 (2%)2 (2%) 33 2 (2%)2 (2%) 22
Injection-site reactionInjection-site reaction 2 (2%)2 (2%) 22 2 (2%)2 (2%) 22
Injection-site papulesInjection-site papules 2 (2%)2 (2%) 22 1 (1%)1 (1%) 11
CBER
Adverse Events in IT-R-006 > Adverse Events in IT-R-006 > 1%1%
Preferred TermsPreferred TermsIT n=98IT n=98 Control n=99Control n=99
SubjectsSubjects EventEventss
SubjectsSubjects EventEventss
All treatment-emergent All treatment-emergent AEAE 62 (63%)62 (63%) 161161 56 (57%)56 (57%) 172172
Administration site Administration site conditionsconditions 32 (33%)32 (33%) 6969 32 (32%)32 (32%) 8484
(Related to Treatment)(Related to Treatment) 29 (30%)29 (30%) 6363 31 (31%)31 (31%) 8080
Injection-site Injection-site erythemaerythema 14 (14%)14 (14%) 1919 6 (6%)6 (6%) 99
Injection-site Injection-site hemorrhagehemorrhage 10 (10%)10 (10%) 3030 15 (15%)15 (15%) 4545
Injection-site bruisingInjection-site bruising 5 (5%)5 (5%) 66 13 (13%)13 (13%) 2020
Injection-site papulesInjection-site papules 4 (4%)4 (4%) 44 2 (2%)2 (2%) 22
Injection-site irritationInjection-site irritation 3 (3%)3 (3%) 66 1 (1%)1 (1%) 33
Injection-site swellingInjection-site swelling 3 (3%)3 (3%) 33 00 00
CBER
Related-Adverse Events < 1% in IT-R-005 & Related-Adverse Events < 1% in IT-R-005 & 006006
StudStudyy
GroupGroup Preferred TermsPreferred Terms Onset from Onset from treatmenttreatment DurationDuration SeveritSeverit
y y ActionAction
005005 ITIT Basal cell cancerBasal cell cancer 7 months after 7 months after 11stst
n/an/a moderatmoderatee
excisionexcision
005005 ITIT Herpes simplex of lipHerpes simplex of lip 5 days after 15 days after 1stst 4 days4 days mildmild medsmeds
005005 ITIT Post-procedural Post-procedural headacheheadache
On 2 On 2 rdrd treatmenttreatment
2 days2 days mildmild medsmeds
005005 ControlControl Swelling under left eyeSwelling under left eye 2 days after 12 days after 1stst 5 days5 days mildmild nonenone
005005 ControlControl HeadacheHeadache On 1On 1stst treatmenttreatment
1 day1 day moderatmoderatee
medsmeds
005005 ControlControl Injection site anesthesiaInjection site anesthesia 3.5 months 3.5 months after 3after 3rdrd
5.5 months5.5 months mildmild nonenone
005005 ControlControl Pain in jawPain in jaw On 1On 1stst treatmenttreatment
2 days2 days mildmild nonenone
005005 ControlControl Paraesthesia right Paraesthesia right upper lipupper lip
2 days after 12 days after 1stst 3 days3 days mild mild nonenone
005005 ControlControl Post-procedural Post-procedural discomfortdiscomfort
On 1On 1stst treatmenttreatment
1 day1 day mild mild nonenone
006006 ITIT Bilateral eyelid edemaBilateral eyelid edema 1 day after 1 day after each of 3 each of 3 treatmentstreatments
11stst , 2 , 2rdrd: 1 : 1 weekweek
33rdrd: > 1 year: > 1 year
mildmild nonenone
006006 ITIT Skin hyperpigmentationSkin hyperpigmentation 1 day after 21 day after 2rdrd 3 weeks3 weeks mildmild nonenone
006006 ControlControl Injection site Injection site hypersensitivityhypersensitivity
On 1On 1stst treatmenttreatment
2 days2 days moderatmoderatee
nonenone
CBER
Basal Cell CarcinomaBasal Cell Carcinoma76 y.o. white female with “sun damage”76 y.o. white female with “sun damage”Three IT treatments in IT-R-005Three IT treatments in IT-R-005Detection time: 7 months after first injectionDetection time: 7 months after first injectionRight upper lip near nasolabial fold, tumor: Right upper lip near nasolabial fold, tumor: 0.4 cm x 0.4 cm; solar keratosis was found 0.4 cm x 0.4 cm; solar keratosis was found at bridge of noseat bridge of nosePossibly related per investigatorPossibly related per investigatorIntervention: biopsy and Mohs ExcisionIntervention: biopsy and Mohs ExcisionOther AEs: erythema and swelling for 3 daysOther AEs: erythema and swelling for 3 daysWrinkle outcome: non-responder per Wrinkle outcome: non-responder per investigatorinvestigatorMost recent f/u: no evidence of recurrence Most recent f/u: no evidence of recurrence 18 months after the surgery18 months after the surgery
CBER
Integrated Safety Data in 7 trialsIntegrated Safety Data in 7 trials StudyStudy PhasesPhases
Safety Safety ObservatioObservatio
nn(Months)(Months)
SubjectsSubjectsIT/ControlIT/Control
TreatmenTreatmentt
IntervalInterval(Weeks)(Weeks)
IndicationsIndications
IT-R-001IT-R-001 Phase 2Phase 2 1212 30/1030/10 1-21-2 Rhytids and scars (14 Rhytids and scars (14 facial areas)facial areas)
IT-R-002IT-R-002 Phase 2Phase 2 1212 111/40111/40 1-21-2 Rhytids and scars (14 Rhytids and scars (14 facial areas) facial areas)
IT-R-IT-R-003A003A Phase 3Phase 3 1212 48/5948/59 1-21-2 Nasolabial and Nasolabial and
glabellar (4 areas)glabellar (4 areas)
IT-R-IT-R-003B003B Phase 3Phase 3 1212 52/5452/54 1-21-2 Nasolabial and Nasolabial and
glabellar (4 areas)glabellar (4 areas)
IT-R-005IT-R-005 PivotalPivotal 1515 83/9283/92 4-64-6 Nasolabial (2 areas)Nasolabial (2 areas)
IT-R-006IT-R-006 PivotalPivotal 1515 98/9998/99 4-64-6 Nasolabial (2 areas)Nasolabial (2 areas)
IT-R-007IT-R-007 Phase 2Phase 2 1414 44/044/0 4-64-6Forehead, periorbital, Forehead, periorbital,
cheek, perioral (8 cheek, perioral (8 areas)areas)
TotalTotal 77 12-1512-15821821
(467/354(467/354))
1-61-6 2-14 (injected 2-14 (injected areas)areas)
CBER
Injection-Site Reactions (Injection-Site Reactions (>> 1%) 1%) Preferred TermsPreferred Terms IT IT (N=508)(N=508) Control Control
(N=354)(N=354)
Administration Site ConditionsAdministration Site Conditions 343 (67%)343 (67%) 144 (40%)144 (40%)
(Related to Treatment)(Related to Treatment) 265/508 (52%)265/508 (52%) 119/354 (34%)119/354 (34%)
Injection-site Injection-site erythemaerythema
81 (16%)81 (16%) 33 (9%)33 (9%)
Injection-site bruisingInjection-site bruising 54 (11%)54 (11%) 48 (14%)48 (14%)
Injection-site swellingInjection-site swelling 69 (14%)69 (14%) 15 (4%)15 (4%)
Injection-site painInjection-site pain 31(6%)31(6%) 6 (2%)6 (2%)
Injection-site edemaInjection-site edema 22 (4%)22 (4%) 00
Injection-site nodulesInjection-site nodules 20 (4%)20 (4%) 3 (<1%)3 (<1%)
Injection-site Injection-site hemorrhagehemorrhage
13 (3%)13 (3%) 16 (5%)16 (5%)
Injection-site papulesInjection-site papules 8 (2%)8 (2%) 3(<1%)3(<1%)
Injection-site irritationInjection-site irritation 6 (1%)6 (1%) 1 (<1%)1 (<1%)
Injection-site Injection-site dermatitisdermatitis
5 (1%)5 (1%) 2 (<1%)2 (<1%)
Injection-site pruritusInjection-site pruritus 5 (1%)5 (1%) 3 (<1%)3 (<1%)
Injection-site Injection-site reactionsreactions
5 (1%)5 (1%) 2 (<1%)2 (<1%)
Injection-site Injection-site indurationsindurations
5 (1%)5 (1%) 00
CBER
Total Injection Site Reactions in Pivotal Total Injection Site Reactions in Pivotal Trials and Integrated Safety Trials and Integrated Safety
Population>1%Population>1%
StudyStudy IT-R-005IT-R-005 IT-R-006IT-R-006 Integrated safety Integrated safety populationpopulation
SubjectsSubjectsIT IT
N=83N=83Control Control N=92 N=92
IT IT
N=98N=98Control Control N=99N=99
ITIT
N=508N=508ControlControl
N=354N=354
AdministratioAdministration Site n Site
ConditionsConditions
31 31 (37%)(37%)
32 32 (35%)(35%)
32 32 (33%)(33%)
32 32 (32%)(32%)
343 343 (67%)(67%)
144 144 (40%)(40%)
Higher frequency of injection site adverse events in Higher frequency of injection site adverse events in integrated safety populationintegrated safety populationLower frequency of injection site adverse events in 005 & Lower frequency of injection site adverse events in 005 & 006006Reasons for the decreased injection site adverse eventsReasons for the decreased injection site adverse events
Increased treatment intervals, decreased treatment areas, Increased treatment intervals, decreased treatment areas, enhanced physician training for injectionenhanced physician training for injectionIncreased spacing for clinical safety observation intervalsIncreased spacing for clinical safety observation intervals
CBER Related-Adverse Events < 1%Related-Adverse Events < 1% (ISP)(ISP)Preferred TermsPreferred Terms IT N=508IT N=508 Control Control
N=354N=354
AcneAcne 44 00
RashRash 22 00
Eye edemaEye edema 22 11
Face edemaFace edema 33 11
Herpes labialisHerpes labialis 33 00
Injection site vesiclesInjection site vesicles 11 00
HypoaesthesiaHypoaesthesia 22 00
Injection site hypersensitivityInjection site hypersensitivity 00 11
Lip paraesthesia Lip paraesthesia 00 11
Basal cell carcinomaBasal cell carcinoma 11 00
Injection site fibrosis Injection site fibrosis 11 00
Injection site ischemiaInjection site ischemia 22 00
ParapsoriasisParapsoriasis 11 00
Alopecia areataAlopecia areata 11 00
HyperpigmentationHyperpigmentation 11 00
Pain in jawPain in jaw 00 11
HeadacheHeadache 55 22
Post-procedural discomfortPost-procedural discomfort 00 11
ToothacheToothache 00 11
Chapped lipsChapped lips 11 00
DizzinessDizziness 22 00
TotalTotal 32 32 9 9
CBER
Severity of Injection-Site Severity of Injection-Site Adverse Events >1%Adverse Events >1%
Administration-Administration-site conditionssite conditions IT N=343IT N=343 Control N=144Control N=144
MildMild 283 (82.5 %)283 (82.5 %) 131 (91%)131 (91%)
ModerateModerate 55 (16%)55 (16%) 12 (8%)12 (8%)
SevereSevere 5 (1.5%)5 (1.5%) 1 (<1%)1 (<1%)
N=subjects reporting injection site adverse eventsN=subjects reporting injection site adverse events
Severity grading: CTCAE V3 (NCI/NIH)Severity grading: CTCAE V3 (NCI/NIH)6 cases of severe injection-site adverse events6 cases of severe injection-site adverse events
5 IT subjects: erythema (1), ischemia (1), 5 IT subjects: erythema (1), ischemia (1), swelling (2), pain (1)swelling (2), pain (1)1 control subject: bruising1 control subject: bruisingResolved within 10 days, no withdrawalResolved within 10 days, no withdrawal
CBERDuration of Related-Adverse Duration of Related-Adverse Reaction>1%Reaction>1%
AE Duration AE Duration
in Daysin DaysIT: related IT: related
events = 444events = 444Control: related Control: related
events = 207events = 207
<1 to 7<1 to 7 380 (85.5%)380 (85.5%) 187(90%)187(90%)
8 to 148 to 14 23 (5%)23 (5%) 13 (6%)13 (6%)
15 to 3015 to 30 16 (3.6%)16 (3.6%) 1 (0.5%)1 (0.5%)
31 to 6031 to 60 9 (2%)9 (2%) 2 (1%)2 (1%)
61 to 9061 to 90 8 (1.8%)8 (1.8%) 2 (1%)2 (1%)
91 to 12091 to 120 2 (0.4%)2 (0.4%) 00
OngoingOngoing 5 (1%)5 (1%) 00
CBER
Unresolved Adverse Events Unresolved Adverse Events (All Subjects in IT Group)(All Subjects in IT Group)
StudyStudy Adverse Adverse EventsEvents
Treatment Treatment AreasAreas Onset DayOnset Day Duration Duration
in Dayin Day Severity Severity ActionAction
IT-R-IT-R-001001
Red,swelling Red,swelling in glabellarin glabellar
Glabellar,peGlabellar,perioralrioral
2nd2nd
treatmenttreatment357+357+ mildmild BenadrBenadr
ylAleveylAleve
IT-R-IT-R-002002
Flare of Flare of alopecia alopecia areataareata
Nasolabial, Nasolabial, perioralperioral
Third day Third day from 2nd from 2nd treatmenttreatment
354+354+ mildmildAldara, Aldara, KenaloKenalo
gg
IT-R-IT-R-003A003A
Plumpness in Plumpness in upper lipupper lip
Nasolabial, Nasolabial, glabellarglabellar
A month A month from 3rd from 3rd
treatmenttreatment287+287+ mildmild nono
IT-R-IT-R-005005
Ridge in right Ridge in right nasolabial foldnasolabial fold nasolabialnasolabial
A week A week from 2from 2nd nd
treatmenttreatment409+409+ mildmild nono
IT-R-IT-R-006006
Swelling on Swelling on both upper both upper
eye lidseye lidsnasolabialnasolabial Third Third
treatmenttreatment 396+396+ mildmild nono
CBER
SubgroupsSubgroupsUnder-represented subgroups in integrated Under-represented subgroups in integrated safety populationsafety population
Safety profilesSafety profiles– Similar common injection-site reactionsSimilar common injection-site reactions– No keloid formation reportedNo keloid formation reported– Limited information due to small sample Limited information due to small sample
sizessizes
Sub-groupsSub-groupsIT IT
N=467*N=467*Control Control N=354N=354
TotalTotal
N=821N=821
>65 yo>65 yo 44 (9%)44 (9%) 41 (12%)41 (12%) 85 (10%)85 (10%)
MaleMale 42 (9%)42 (9%) 34 (10%)34 (10%) 76 (9%)76 (9%)
Non-whiteNon-white 43 (9%)43 (9%) 35 (10%)35 (10%) 78 (10%)78 (10%)
* 41 cross-over subjects not included* 41 cross-over subjects not included
CBER
Commercial ExperienceCommercial ExperienceUS: 1,200 + subjects (1995-1999) US: 1,200 + subjects (1995-1999)
UK: 7,800 + subjects (2002-2007)UK: 7,800 + subjects (2002-2007)
Retrospective chart reviews, limited Retrospective chart reviews, limited registryregistry
Common AEs: red, swelling, rash, lumpCommon AEs: red, swelling, rash, lump
Three serious adverse event reportsThree serious adverse event reports– AngioedemaAngioedema– Severe systemic allergic reactionSevere systemic allergic reaction– Lump on the eyelid, requiring surgeryLump on the eyelid, requiring surgery
CBERSafety SummarySafety SummaryAdverse events in >1%Adverse events in >1%
injection site redness, bruising, swelling, pain, injection site redness, bruising, swelling, pain, nodules, hemorrhage, papules, irritation, nodules, hemorrhage, papules, irritation, dermatitis, pruritusdermatitis, pruritus
Adverse events in <1%Adverse events in <1%Probable facial allergic reactions, flare of herpes Probable facial allergic reactions, flare of herpes labialis, change of skin sensation, post-procedural labialis, change of skin sensation, post-procedural discomfortdiscomfort
Severity and duration of adverse reactionsSeverity and duration of adverse reactionsMild/moderate in severityMild/moderate in severity5% injection-site events lasting beyond 30 days5% injection-site events lasting beyond 30 days
Five cases unresolved beyond one yearFive cases unresolved beyond one yearOne case of injection-site basal cell cancerOne case of injection-site basal cell cancerTwo cases of serious allergic reactions in UKTwo cases of serious allergic reactions in UKSmall sample sizes for male, elderly, and non-whiteSmall sample sizes for male, elderly, and non-whiteSafety observation limited to 12 to 15 monthsSafety observation limited to 12 to 15 months
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