NDA 20-449 SE-011 Docetaxel FDA Review. FDA Review Team Biostatistics –Clara Chu, PhD. –Gang...
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Transcript of NDA 20-449 SE-011 Docetaxel FDA Review. FDA Review Team Biostatistics –Clara Chu, PhD. –Gang...
![Page 1: NDA 20-449 SE-011 Docetaxel FDA Review. FDA Review Team Biostatistics –Clara Chu, PhD. –Gang Chen, PhD. Biopharmaceutics –Safaa Ibrahim PhD –Atiq Rahman,](https://reader036.fdocuments.in/reader036/viewer/2022082711/56649f315503460f94c4c4a3/html5/thumbnails/1.jpg)
NDA 20-449 SE-011Docetaxel
FDA Review
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FDA Review Team
• Biostatistics– Clara Chu, PhD.
– Gang Chen, PhD.
• Biopharmaceutics– Safaa Ibrahim PhD
– Atiq Rahman, PhD.
• Project Manager– Ann Staten, RD
• Medical– Julie Beitz, MD
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Proposed Indication
“for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior
chemotherapy”
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The Randomized, Controlled Trials
• TAX 317– Docetaxel 100 mg
(N= 49)
– Best Supportive Care (N=51)
– Docetaxel 75 mg(N=55)
– Best Supportive Care (N=49)
• TAX 320– Docetaxel 100 mg
(N=125)
– Docetaxel 75 mg(N=125)
– Vinorelbine OR Ifosfamide(N=123)
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Trials’ Shared Features
• Eligibility/Exclusion Criteria– prior platinum-based chemotherapy required in
both studies– prior taxane exposure excluded in TAX 317
only
• Primary Endpoint = Survival
• Secondary Endpoints
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Major Efficacy Issues
• Pre-specified vs. Other Analyses
• Consistency across studies
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Survival - Prespecified Analyses
TAX 317 TAX 320Tax
(100+75)N=103
BSC
N=99
Tax(75mg)N=125
V/I
N=123
MedianSurvival
7.2 mo 4.7 mo 5.7 mo 5.6 mo
95% CI (5.5, 9.2)p=0.14
(3.7, 6.0) (5.1, 7.9)p=0.14
(4.3, 7.9)
Sept. 99Update
7.0 mo 4.6 mo 5.7 mo 5.6 mo
95% CI (5.5, 9.0)P=0.047
(3.7, 6.0) (5.1, 7.1)P=0.13
(4.4, 7.9)
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Survival - Retrospective Analyses
TAX 317 TAX 320Tax
75mgN=55
BSC(75mg)
N=49
Tax75mgN=125
V/I
N=123
MedianSurvival
9.0 mo 4.6 mo 5.7 mo 5.6 mo
95% CI (5.5,13.1)p=0.016*
(3.7, 6.1) (5.1, 7.9)p=0.14
(4.3, 7.9)
Sept 99Update
7.5 mo 4.6 mo 5.7 mo 5.6 mo
95% CI (5.5,12.8)P=0.010*
(3.7, 6.1) (5.1, 7.1)P=0.13
(4.4, 7.9)
* Unadjusted
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K-M Survival Curves - 75 mg vs. Control
TAX 317 TAX 320
Product-Limit Survival Estimates
Time Variable: Survival Time (Days)
Censoring Variable: Survival Censoring Y/N
Survival Plot
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 200 300 400 500 600
Survival Time (Days)
1.2
55.2
Tests Between Groups
Test
Log-Rank
Wilcoxon
Chi-Square
5.7584
4.9894
DF
1
1
Prob>ChiSq
0.0164
0.0255
1.2
55.2
Combined
Product-Limit Survival Estimates
Time Variable: Survival Time (Days)
Censoring Variable: Survival Censoring Y/N
Survival Plot
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 300 500 700
Survival Time (Days)
1.2
813
Tests Between Groups
Test
Log-Rank
Wilcoxon
Chi-Square
2.1719
0.3318
DF
1
1
Prob>ChiSq
0.1406
0.5646
1.2
813
Combined
SurvIvIng
SurvIvIng
Tax
BSC
Tax
Control
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Rate of Survival at One Year - Retrospective Analyses
TAX 317 TAX 320Tax
75mgN=55
BSC(75mg)
N=49
Tax75mgN=125
V/I
N=123
1-yearSurvival
40%* 16% 32%* 19%
95% CI (26, 54) (3, 30) (23,40) (12, 26)
Sept 99Update
37%* 12% 30% 20%
95% CI (24, 50) (2, 23) (22, 39) (13, 27)
* Unadjusted p<0.05
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Historical Perspective
Lack of phase 3 data in the second line setting First line rates of survival at one year are
reported in the range of 18 - 43% for combination regimens (in randomized controlled trials)Gemcitabine + Cisplatin = 39%Pactilaxel + Cisplatin = 36%Vinorelbine + Cisplatin = 35%
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Survival: Summary of Review Issues
• A significant difference between arms was demonstrated in a pre-specified survival analysis in only one study (TAX317, pooled), in an updated analysis
• The analysis of overall survival at the 75 mg dose level favored docetaxel in a retrospective analysis of a single study (TAX317)
• Exploratory analyses of rates of one year survival favor docetaxel in both studies
• Rates of one year survival are comparable to those reported in the first line setting
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Clinical Benefit Parameters
TAX 317 TAX 320
PerformanceStatus
MorphinicAnalgesic
Use
Weight Loss LCSS QoL
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Safety
TAX 317 TAX 320 BreastCancer
100 mg 75 mg 100 mg 75 mg 100 mg
FebrileNeutropenia
22.4% 1.8% 11.6% 8.3% 11.8%
Grade 3/4Infection
14.3% 5.5% 15.7% 12.4% 7.1%
TRM 14.3% 1.8 % 5.0% 3.3% 1.5%
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Summary
• Safety • QoL • Survival