1 abraxane ® (paclitaxel protein-bound particles for injectable suspension). each 50 ml vial...
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Abraxane Abraxane ®®
(paclitaxel protein-bound particles for (paclitaxel protein-bound particles for injectable suspension). Each 50 mL vial injectable suspension). Each 50 mL vial
contains 100 mg of paclitaxel and 900 mg contains 100 mg of paclitaxel and 900 mg of human albumin as a sterile lyophilized of human albumin as a sterile lyophilized
powder.powder.
Abraxis BioScience, Inc.Abraxis BioScience, Inc.
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Approved Indication:Approved Indication:
““ABRAXANE® is indicated for the ABRAXANE® is indicated for the treatment of breast cancer after failure of treatment of breast cancer after failure of combination chemotherapy for metastatic combination chemotherapy for metastatic
disease or relapse within 6 months of disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy adjuvant chemotherapy. Prior therapy should have included an anthracycline should have included an anthracycline unless clinically contraindicated.” The unless clinically contraindicated.” The application was approved on January 7, application was approved on January 7,
2005.2005.
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Sponsor’s Proposed Sponsor’s Proposed Indication:Indication:
““ABRAXANE® is indicated for the ABRAXANE® is indicated for the adjuvant treatment of node-positive adjuvant treatment of node-positive breast cancer administered breast cancer administered sequentially to standard doxorubicin-sequentially to standard doxorubicin-containing combination containing combination chemotherapy."chemotherapy."
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Regulatory Pathways to Regulatory Pathways to Market a Competitor DrugMarket a Competitor Drug
NDA
ANDA
505(b)(2)
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505(b)(2)505(b)(2)
This applies to new formulations of This applies to new formulations of marketed drugs and authorizes the marketed drugs and authorizes the FDA, FDA, where appropriatewhere appropriate, to base , to base approvals of new drugs entirely or approvals of new drugs entirely or partially on studies not conducted by partially on studies not conducted by the applicant and for which the the applicant and for which the applicant has not obtained a right of applicant has not obtained a right of use. use.
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505(b)(2) Criteria505(b)(2) Criteriafor Abraxane in Metastatic for Abraxane in Metastatic
Breast CancerBreast Cancer FDA agreed to use the preclinical FDA agreed to use the preclinical
genetic toxicology studies from the genetic toxicology studies from the Taxol application to support Taxol application to support Abraxane approvalAbraxane approval
FDA also agreed to use response rate FDA also agreed to use response rate as a comparative measure of Taxol as a comparative measure of Taxol antitumor activity instead of the antitumor activity instead of the more stringent standard time to more stringent standard time to event endpoint.event endpoint.
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Presentation OutlinePresentation Outline Abraxis proposal for approval of Abraxane Abraxis proposal for approval of Abraxane
for the new adjuvant indicationfor the new adjuvant indication Pharmacokinetics of AbraxanePharmacokinetics of Abraxane Abraxane’s basis of approval for Abraxane’s basis of approval for
metastatic breast cancermetastatic breast cancer Taxol’s basis of approval for adjuvant Taxol’s basis of approval for adjuvant
breast cancerbreast cancer FDA concerns with Abraxis proposalFDA concerns with Abraxis proposal Statistical plan to approve Abraxane in the Statistical plan to approve Abraxane in the
adjuvant breast cancer setting adjuvant breast cancer setting Questions to ODAC CommitteeQuestions to ODAC Committee
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Abraxis proposal for Abraxis proposal for approval of Abraxaneapproval of Abraxane
Results of the randomized Intergroup Results of the randomized Intergroup study that served as the basis for study that served as the basis for Taxol approval for the adjuvant Taxol approval for the adjuvant treatment of node positive early treatment of node positive early breast cancer.breast cancer.
Preclinical genetic toxicology studies Preclinical genetic toxicology studies with Taxol. with Taxol.
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Abraxis proposal for Abraxis proposal for approval of Abraxane approval of Abraxane
(continued)(continued) Comparison of the pharmacokinetics of the Comparison of the pharmacokinetics of the
Abraxane and Taxol paclitaxel formulations.Abraxane and Taxol paclitaxel formulations.
Results of the study comparing Abraxane Results of the study comparing Abraxane and Taxol that served as the basis for and Taxol that served as the basis for approval of Abraxane for metastatic breast approval of Abraxane for metastatic breast cancer.cancer.
Study CA030, a single arm 30 patient study Study CA030, a single arm 30 patient study of dose dense AC q 2 weeks x 4 cycles of dose dense AC q 2 weeks x 4 cycles followed by dose dense Abraxane 260 followed by dose dense Abraxane 260 mg/m2 q 2 weeks x 4 cycles.mg/m2 q 2 weeks x 4 cycles.
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Abraxis proposal for Abraxis proposal for approval of Abraxane approval of Abraxane
(continued)(continued) March 13, 2006: single arm phase II safety March 13, 2006: single arm phase II safety
study to support the approval of adjuvant study to support the approval of adjuvant breast cancerbreast cancer
July 2006:proposal for a 400 patient July 2006:proposal for a 400 patient randomized safety study comparing randomized safety study comparing Abraxane and Taxol in adjuvant treatment Abraxane and Taxol in adjuvant treatment of node positive early breast cancer to be of node positive early breast cancer to be conducted prior to approval. conducted prior to approval.
August 9, 2006: changed to a post approval August 9, 2006: changed to a post approval Phase 4 safety study of unspecified size.Phase 4 safety study of unspecified size.
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Is Abraxis proposal Is Abraxis proposal acceptable?acceptable?
How similar or dissimilar the Abraxane and How similar or dissimilar the Abraxane and Taxol formulations are.Taxol formulations are.
Risk/benefit ratio of approving Abraxane w/o Risk/benefit ratio of approving Abraxane w/o an efficacy and safety study.an efficacy and safety study.
Taxol prolongs disease free survival and Taxol prolongs disease free survival and survival in the adjuvant breast cancer setting.survival in the adjuvant breast cancer setting.
FDA is concerned with the consequences of a FDA is concerned with the consequences of a potential decrement in DFS and survival in potential decrement in DFS and survival in women with node positive early breast cancer.women with node positive early breast cancer.
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Pharmacokinetics of Pharmacokinetics of Abraxane compared to Abraxane compared to
TaxolTaxol
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A Pharmacokinetic Comparison of Abraxane and Taxol
Brian BoothDivision of Clinical Pharmacology 5
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PK Comparison-
Paclitaxel moieties
Albumin
Paclitaxel
PP
P
P
P
P
PP
P
PP P
P
P
P
PP
Abraxane
Taxol
In vivo
In vivo
Total Paclitaxel
Total Paclitaxel
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• Conventional thinking about drug action– Free drug mediates effect
• Abraxane: Total Paclitaxel=
• Taxol: Total Paclitaxel=
• Taxol, Abraxane– How much free paclitaxel is generated by each?
• Unknown
– Comparative biodistribution of paclitaxel from Abraxane and Taxol in patients?
• Unknown
PK Comparison-
Paclitaxel moieties
P P
P P
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PK Comparison-LinearityTotal Paclitaxel
Abraxane: 30 min infusion
Linear, predictable PK
Dose Cmax AUC CL
(mg/m2) % δ (ng/ml) % δ (ng*hr/ml) % δ (L/h/m2) % δ
135 ---- 3071 ---- 8604 ---- 15.9 ----
175 30 5202 70 15048 75 11.6 25
Taxol: 3 hr infusion
Non-linear, less-predictable PK
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Clinical PK Comparison of Abraxane and Taxol- Study C008-0
Total Paclitaxel
• PK study- – Abraxane 14 patients– Taxol 12 patients
• Comparability issues• Different Doses
– Abraxane 260 mg/m2
– Taxol 175 mg/m2
• TOTAL Paclitaxel
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Clinical PK Comparison of Total PaclitaxelStudy C008-0-Unadjusted
Total Paclitaxel
Sparreboom A. et al Clin Cancer Res 2005; 11:4136-4143
Abraxane:
6.5 x higher Cmax
17 % higher AUC40% higher CL50% higher Vd
Than Taxol
Abraxane(260 mg/m2)
Taxol (175 mg/m2)
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Clinical PK Comparison of Total PaclitaxelStudy C008-0
Abraxane(dose-adjusted to 175 mg/m2)
Taxol (175 mg/m2)
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Dose-normalized comparisonof Abraxane and Taxol
Parameter(mean ± %CV)
Abraxane260 mg/m2
(n=14)
Taxol175 mg/m2
(n=12)
Abraxane/taxolRatio
Abraxane*Dose-adjusted
(n=14)
Taxol*Dose-
adjusted(n=12)
Abraxane/taxolRatio
Cmax (ng/ml)
22969 3543 6.5 x 89 20 4.4 X
AUC0-∞
(ng-hr/ml)
14789 12603 1.17 x 57 72 0.80 x
CL (L/hr*m2)
21 15 1.43 x(43%)
21 15 1.43 x(43%)
Vz (L/m2)
664 433 1.53 x(53%)
664 433 1.53 x(53%)
*Dose-normalized. Abraxane is a 30-minute infusion; *Taxol is a 3-hr infusion
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Summary
• Abraxane and Taxol are not pharmacokinetically “the same” (Total paclitaxel)– Need to assess free paclitaxel concentrations
• Different doses• Different CL• Different Vd• Different AUC• Different Cmax• Abraxane linear PK, Taxol non-linear PK
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Basis of Approval for Basis of Approval for Abraxane for Metastatic Abraxane for Metastatic
Breast CancerBreast Cancer
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Study DesignStudy Design Randomized, Phase 3, open labelRandomized, Phase 3, open label Sample size: 460 patientsSample size: 460 patients 70 sites: Russia (77%), UK (15%), Canada 70 sites: Russia (77%), UK (15%), Canada
and US (9%)and US (9%) 2 Arm: Abraxane 260 mg/m2 Arm: Abraxane 260 mg/m22 as a 30- as a 30-
minute infusion and Taxol 175 mg/mminute infusion and Taxol 175 mg/m22 as a as a 3-hour infusion3-hour infusion
59% second line or greater and 77% 59% second line or greater and 77% previous anthracycline exposureprevious anthracycline exposure
Designed to show non inferiority in RRDesigned to show non inferiority in RR
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Study PopulationsStudy Populations
All randomized patientsAll randomized patients SubgroupsSubgroups
Receiving drug as 1Receiving drug as 1stst line only line only Receiving drug as Receiving drug as >> 2 2ndnd line line Taxol approved indication: patients who Taxol approved indication: patients who
have failed combination chemotherapy have failed combination chemotherapy for metastatic disease or relapse within 6 for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior months of adjuvant chemotherapy. Prior therapy should have included an therapy should have included an anthracycline unless clinically anthracycline unless clinically contraindicatedcontraindicated
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EndpointsEndpoints
11° ° Endpoint: Response RateEndpoint: Response Rate 22° ° Endpoints: Endpoints: TTPTTP
SurvivalSurvival
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Response RateResponse Rate (from Abraxane (from Abraxane label)label)
AbraxaneAbraxane
260 mg/m260 mg/m22
TaxolTaxol
175 mg/m175 mg/m22
All randomized patientsAll randomized patients
Response RateResponse Rate
95% CI95% CI50/233 (21.5%)50/233 (21.5%)
(16.19%-(16.19%-26.73%)26.73%)
25/227 (11.1%)25/227 (11.1%)
(6.94%-15.09%)(6.94%-15.09%)
PP-value-value 0.0030.003
Taxol Indication: Patients who failed combination Taxol Indication: Patients who failed combination chemotherapy or relapsed within 6 months of chemotherapy or relapsed within 6 months of adjuvant chemotherapy adjuvant chemotherapy
Response RateResponse Rate
95% CI95% CI20/129 (15.5%)20/129 (15.5%)
(9.26%-21.75%)(9.26%-21.75%)12/143 (8.4%)12/143 (8.4%)
(3.85%-12.94%)(3.85%-12.94%)
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TTPTTP
At the time of Abraxane approval TTP At the time of Abraxane approval TTP results were not included in the label results were not included in the label because:because:
Evaluation of TTP was not rigorous Evaluation of TTP was not rigorous and data were not sufficiently mature and data were not sufficiently mature to support a comparative efficacy to support a comparative efficacy claim in this single non-blinded studyclaim in this single non-blinded study
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Time to progression (TTP) Time to progression (TTP) from July 21, 2006 Submissionfrom July 21, 2006 Submission
We have the following concerns:We have the following concerns: TTP was not systematically assessed TTP was not systematically assessed
in all patients after cycle 6in all patients after cycle 6 Multiple analyses using different Multiple analyses using different
criteria without adjustmentscriteria without adjustments TTP results may not be reliable for a TTP results may not be reliable for a
labeling claimlabeling claim
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Overall Survival Overall Survival from July 21, from July 21, 2006 Submission2006 Submission
We have the following concerns:We have the following concerns: There was no difference in overall survival There was no difference in overall survival
between the Abraxane and Taxol between the Abraxane and Taxol treatment groups. treatment groups. HR (Abraxane/Taxol) HR (Abraxane/Taxol) was 0.90, p=0.348 (log rank).was 0.90, p=0.348 (log rank).
No conclusions can be drawn from a No conclusions can be drawn from a subgroup analysis when the main analysis subgroup analysis when the main analysis was not statistically significant. was not statistically significant.
Multiple subgroup analyses using different Multiple subgroup analyses using different criteria without p value adjustmentscriteria without p value adjustments
P-values are not interpretable P-values are not interpretable
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AbraxaneAbraxane
260 mg/m260 mg/m22
TaxolTaxol
175 mg/m175 mg/m22
ITT populationITT population
Patients who diedPatients who died
95% CI95% CI172/229 (75%)172/229 (75%)
(53.4, 76.9)(53.4, 76.9)175/225 (78%)175/225 (78%)
(48.0, 66.4)(48.0, 66.4)
PP-value-value
Hazard Ratio, 95% Hazard Ratio, 95% CICI
0.3220.322
0.8990.899 (0.728, 1.110) (0.728, 1.110)
11stst Line Therapy Patients Only Line Therapy Patients Only
Patients who diedPatients who died
95% CI95% CI73/98 (74%)73/98 (74%)
(59.4, 87.7)(59.4, 87.7)60/89 (67%)60/89 (67%)
(58.1, 98.0)(58.1, 98.0)
PP-value-value
Hazard Ratio, 95% Hazard Ratio, 95% CICI
0.2640.264
1.2151.215 (0.863, 1.709) (0.863, 1.709)
Patients Receiving 2Patients Receiving 2ndnd or Greater Line Therapy or Greater Line Therapy
Patients who diedPatients who died
95% CI95% CI99/131 (76%)99/131 (76%)
(45.1, 76.9)(45.1, 76.9)115/136 (85%)115/136 (85%)
(39.0, 55.3)(39.0, 55.3)
PP-value-value
Hazard Ratio, 95% Hazard Ratio, 95% CICI
0.0200.020
0.7260.726 (0.553, 0.952) (0.553, 0.952)
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Abraxane and Taxol AEs Abraxane and Taxol AEs differences (% pts)differences (% pts)
AbraxaneAbraxane
260 mg/m260 mg/m22
N=229N=229
TaxolTaxol
175 mg/m175 mg/m22
N=225N=225
NeutropeniaNeutropenia
<2.0x10<2.0x1099/L/L
<0.5x10<0.5x1099/L/L8080
998282
2222
Febrile Febrile NeutropeniaNeutropenia
22 11
InfectionsInfections 2424 2020
Hypersensitivity Hypersensitivity ReactionsReactions
44 1212
Sensory Sensory NeuropathyNeuropathy
Any SymptomsAny Symptoms
Severe SymptomsSevere Symptoms
7171
10105656
22
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Abraxane and Taxol AEs differences (% Abraxane and Taxol AEs differences (% pts)pts)
AbraxaneAbraxane
260 mg/m260 mg/m22
N=229N=229
TaxolTaxol
175 mg/m175 mg/m22
N=225N=225
NauseaNausea
Any SymptomsAny Symptoms
Severe SymptomsSevere Symptoms3030
332121
<1<1
VomitingVomiting
Any SymptomsAny Symptoms
Severe SymptomsSevere Symptoms1818
4499
11
DiarrheaDiarrhea
Any SymptomsAny Symptoms
Severe SymptomsSevere Symptoms2626
<1<11515
11
AstheniaAsthenia
Any SymptomsAny Symptoms
Severe SymptomsSevere Symptoms4747
883838
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Basis of Approval for Taxol Basis of Approval for Taxol for Adjuvant Breast Cancerfor Adjuvant Breast Cancer
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Study DesignStudy Design
3170 Node-positive breast cancerStratified by # lymph nodes
AC x 4 cy→Taxol 175 mg/m2
x 4cyAC x 4 cy alone
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Disease Free Survival: AC vs AC+TDisease Free Survival: AC vs AC+T
(HR=0.78, 95% CI 0.67-0.91, (HR=0.78, 95% CI 0.67-0.91, pp=0.0022)=0.0022)
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Survival: AC versus AC+T Survival: AC versus AC+T (HR=0.74, 95% CI 0.60-0.92, (HR=0.74, 95% CI 0.60-0.92, pp=0.0065)=0.0065)
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Disease Free Survival: AC vs AC+TDisease Free Survival: AC vs AC+T
Receptor Neg/Unknown Receptor Neg/Unknown(HR=0.68, 95% CI 0.55-0.85)(HR=0.68, 95% CI 0.55-0.85)
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Should Abraxane be Should Abraxane be approved for the adjuvant approved for the adjuvant treatment of node positive treatment of node positive early breast cancer without early breast cancer without an adequate RCT powered an adequate RCT powered
for DFS, OS and safety?for DFS, OS and safety?
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Abraxane and Taxol are Abraxane and Taxol are differentdifferent
Formulations are differentFormulations are different Pharmacokinetics are differentPharmacokinetics are different Not bioequivalentNot bioequivalent Free paclitaxel not measuredFree paclitaxel not measured Abraxane does not contain Abraxane does not contain
cremophor, given by 30 minute cremophor, given by 30 minute infusion w/o premedicationinfusion w/o premedication
Taxol is given by 3 hour infusion and Taxol is given by 3 hour infusion and requires premedicationrequires premedication
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Abraxane and Taxol toxicity Abraxane and Taxol toxicity profiles are differentprofiles are different
Taxol has a higher incidence of Taxol has a higher incidence of neutropenia and hypersensitivity neutropenia and hypersensitivity reactionsreactions
Abraxane has a higher incidence of Abraxane has a higher incidence of peripheral neuropathy, nausea, peripheral neuropathy, nausea, vomiting, diarrhea and astheniavomiting, diarrhea and asthenia
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FDA Agrees that in the FDA Agrees that in the metastatic breast cancer metastatic breast cancer
studystudyAbraxane had a higher Abraxane had a higher
tumor response rate than tumor response rate than TaxolTaxol
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FDA believes that in the MBC FDA believes that in the MBC study TTP improvement has study TTP improvement has
not been adequately not been adequately demonstrateddemonstrated
There was no type 1 error allocated for TTP There was no type 1 error allocated for TTP analysis.analysis.
TTP claims could not be confirmed since no TTP claims could not be confirmed since no IRL review was conducted beyond cycle 6. IRL review was conducted beyond cycle 6. Patients were not systematically evaluated Patients were not systematically evaluated after cycle 6. In an open label study, there is after cycle 6. In an open label study, there is a potential for bias in progression a potential for bias in progression assessments.assessments.
PP-values for TTP analyses are not -values for TTP analyses are not interpretable.interpretable.
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FDA believes that in the MBC FDA believes that in the MBC study survival improvement has study survival improvement has
not been adequately not been adequately demonstrateddemonstrated
There was no type 1 error allocated for OS There was no type 1 error allocated for OS analysis.analysis.
There is no significant OS effect in the all There is no significant OS effect in the all randomized populationrandomized population
Subgroup analysis is not appropriate when Subgroup analysis is not appropriate when the study failed to demonstrate an effect the study failed to demonstrate an effect in the overall population.in the overall population.
Multiple analyses in multiple subgroups Multiple analyses in multiple subgroups with no adjustmentwith no adjustment
PP-values for OS analyses is not -values for OS analyses is not interpretable.interpretable.
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11stst line patients, survival trended line patients, survival trended against Abraxane HR (A/T)= 1.215against Abraxane HR (A/T)= 1.215
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There is a need for a RCT in the There is a need for a RCT in the adjuvant population to properly adjuvant population to properly estimate the risk:benefit ratio of estimate the risk:benefit ratio of AbraxaneAbraxane
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Data on toxicity comparisons Data on toxicity comparisons from the metastatic study may from the metastatic study may not be appropriate to the not be appropriate to the adjuvant setting were Abraxane adjuvant setting were Abraxane would be given following AC.would be given following AC.
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Taxol increases DFS and OS in the Taxol increases DFS and OS in the adjuvant treatment of women with adjuvant treatment of women with
node positive early breast cancer.node positive early breast cancer. 22% reduction in the risk of disease 22% reduction in the risk of disease
recurrencerecurrence 26% reduction in the risk of death26% reduction in the risk of death
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FDA is concerned with the FDA is concerned with the consequences of a potential consequences of a potential
decrement in DFS and survival in decrement in DFS and survival in women with node positive early women with node positive early
breast cancerbreast cancer
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Trial Design ConsiderationsTrial Design Considerations
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Trial Design Considerations
R. Sridhara, Ph.D.
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Randomized Clinical Trial to Demonstrate DFS Efficacy of Abraxane
Is it required?Is it feasible?
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Size of Trials in Prior Approvals in Adjuvant Breast Cancer – All Based on RCTsNOTE: All were approved in metastatic disease prior to adjuvant disease
Taxol: 624 events; N = 3170 patients Taxotere: 400 events; N = 1491 patients Adriamycin: (1745 recurrences, 1348 deaths) N =
3510 (meta analysis) Tamoxifen: 372 events; N = 1285 patients Anastrozole:1056 events; N = 9500 patients (3
arms) Letrozole: 665 events; N = 8000 patients (4 arms) Exemestane: 520 events; N = 4724 patients Herceptin*: 394 events; N = 3351 patients
* As reported in literature; Under review at FDA
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Example: Other Adjuvant Setting
Xeloda approved for the treatment of metastatic colorectal cancer based on 2 randomized studies with N = 605 and 603 patients
Later approved for the treatment of adjuvant colon cancer based on DFS in a non-inferiority hypothesis RCT with N = 1987 patients
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Available data on paclitaxel
Registration study, ITT population, DFS HR(AC/AC+Taxol) = HR(AC/ACT) = 0.78 (0.67 – 0.91) based on 3170 patients (624 events) with node positive breast cancer
95% Upper Confidence Limit (UCL) = 0.91 70% UCL = 0.83
Subset of ER/PR negative population N = 1055; events) DFS HR (AC/ACT) = 0.68 (0.55 – 0.85)
95% UCL = 0.85 70% UCL = 0.74
Demonstrated OS superiority in both populations
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Non-inferiority or Superiority
Risks with Non-inferiority Trial How well we know the effect of the control How much of the control effect can we
afford to give up At least 50% - 75% retention of the control
effect necessary to rule out that the new treatment is significantly better than placebo
Sponsor claims Abraxane could be superior to Paclitaxel
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Non-inferiority trial designs with DFS as the primary endpoint
H0: HR(Abraxane/Taxol) ≥ M vs. H1: HR (ACab/ACT) = 1 if the two are
expected to be similar, Or H1: HR(ACab/ACT) = 0.95, for example, if
abraxane is expected to be slightly betterM is the margin determined based on the taxol
effect size estimated from historical trials and percentage of the effect to be retained
HR > 1 implies, Abraxane is worse than Taxol
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Percent Retention and Estimated Active Control Effect Size
Non-inferiority ≈ “not much less effective” ‘X’ is the effect size of the active control; example:
Point estimate of HR (AC+Taxol/AC) = 0.78 implies an estimate of taxol effect size (over the control) was a 22% reduction in the risk of DFS event
Percent retention is a percentage of ‘X’ that is retained; example: a 50% retention of the 22% effect size is 11% effect size, i.e., the putative HR(AC+Abraxane/AC) = 0.89; similarly a 25% retention implies putative HR(ACab/AC) = 0.945; a 75% retention implies putative HR(ACab/AC) = 0.835
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Methods for estimating active control effect size: No method is ideal and no particular method is endorsed by the Agency
All methods assume that the control effect has not changed over time
Some methods do not consider the variation between and within studies
Other methods incorporate variation between and within studies
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Sample size required for a NI trial with DFS as primary endpoint and using, for example, 70% UCL of Taxol effect, HR(ACT/AC) = 0.83, for ITT population
Hypothetical Example # of Patients (# of Events)
% Retention 75% 50%
H1: HR(ACab/ACT) = 0.95
11,276(3,834)
6,831(1,682)
H1: HR(ACab/ACT) = 1.0
34,523(20,410)
12,099(4,227)
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Sample size required for a NI trial with DFS as primary endpoint and using, for example, 70% UCL of Taxol effect, HR(ACT/AC) = 0.74 for receptor negative population (enriched population)
Hypothetical Example # of Patients (# of Events)
% Retention 75% 50%
H1: HR(ACab/ACT) = 0.95
8,099(2,220)
4,687(861)
H1: HR(ACab/ACT) = 1.0 16,442(6,858)
6,772(1,607)
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Examples of Superiority trial designs with DFS as the primary endpoint
Assumptions: 1500 pts/yr accrual, 2- sided = 0.05, 1 – β = 0.8, % DFS rate at 5 years
in the control arm = 83%,
H0: HR (control/abraxane) = HR(C/ab) = 1
H1: HR =
(5 yr % DFS)
# of Patients
(# of Events)
0.81(86%)
4446 (709)
0.87(85%)
7200(1685)
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Summary All prior approvals in adjuvant breast cancer are based on
controlled, randomized studies, and all had prior approvals for treatment in metastatic disease. A large study is feasible.
Prior approvals in adjuvant studies have been based on approx. 400 – 1,000 events or 1,500 – 6,000 patients
Sample sizes for a superiority trial range approx. 700 to 1,600 events, or 4,000 to 7,000 patients
Sample sizes for a NI trial is dependent on the estimate of control effect, population, % retention and H1
A randomized study will provide information on retained effect and safety, unlike the proposed single arm study with 30 patients
Any potential benefit with respect to toxicity/convenience must be weighed against potential loss of efficacy
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Important Issues to Important Issues to ConsiderConsider
Pharmacokinetics of Abraxane and Pharmacokinetics of Abraxane and Taxol are differentTaxol are different
Free paclitaxel was not measuredFree paclitaxel was not measured Differences in Abraxane and Taxol Differences in Abraxane and Taxol
tumor response rate and toxicity tumor response rate and toxicity profiles in the MBC study indicates profiles in the MBC study indicates they are different drugsthey are different drugs
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Important Issues to Important Issues to ConsiderConsider
Treatment of MBC has different Treatment of MBC has different risk:benefitrisk:benefit
Treatment of adjuvant breast cancer is Treatment of adjuvant breast cancer is given with curative intent therefore risk: given with curative intent therefore risk: benefit should be well established in a benefit should be well established in a RCT adequately powered for efficacy and RCT adequately powered for efficacy and safetysafety
FDA is concerned that the gains with FDA is concerned that the gains with Taxol therapy may not be maintained Taxol therapy may not be maintained with Abraxanewith Abraxane