1. Abraxane ® (paclitaxel protein-bound particles for injectable suspension). Each 50 mL vial contains 100 mg of paclitaxel and 900 mg of human albumin as a sterile lyophilized powder. Abraxis BioScience, Inc.

2. Approved Indication:
“ABRAXANE® is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.” The application was approved on January 7, 2005.

3. Sponsor’s Proposed Indication:
“ABRAXANE® is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy."

4. Regulatory Pathways to Market a Competitor Drug
NDA
ANDA
505(b)(2)

5. 505(b)(2)
This applies to new formulations of marketed drugs and authorizes the FDA, where appropriate, to base approvals of new drugs entirely or partially on studies not conducted by the applicant and for which the applicant has not obtained a right of use.

6. 505(b)(2) Criteria for Abraxane in Metastatic Breast Cancer
FDA agreed to use the preclinical genetic toxicology studies from the Taxol application to support Abraxane approval
FDA also agreed to use response rate as a comparative measure of Taxol antitumor activity instead of the more stringent standard time to event endpoint.

7. Presentation Outline
Abraxis proposal for approval of Abraxane for the new adjuvant indication
Pharmacokinetics of Abraxane
Abraxane’s basis of approval for metastatic breast cancer
Taxol’s basis of approval for adjuvant breast cancer
FDA concerns with Abraxis proposal
Statistical plan to approve Abraxane in the adjuvant breast cancer setting
Questions to ODAC Committee

8. Abraxis proposal for approval of Abraxane
Results of the randomized Intergroup study that served as the basis for Taxol approval for the adjuvant treatment of node positive early breast cancer.
Preclinical genetic toxicology studies with Taxol.

9. Abraxis proposal for approval of Abraxane (continued)
Comparison of the pharmacokinetics of the Abraxane and Taxol paclitaxel formulations.
Results of the study comparing Abraxane and Taxol that served as the basis for approval of Abraxane for metastatic breast cancer.
Study CA030, a single arm 30 patient study of dose dense AC q 2 weeks x 4 cycles followed by dose dense Abraxane 260 mg/m2 q 2 weeks x 4 cycles.

10. Abraxis proposal for approval of Abraxane (continued)
March 13, 2006: single arm phase II safety study to support the approval of adjuvant breast cancer
July 2006:proposal for a 400 patient randomized safety study comparing Abraxane and Taxol in adjuvant treatment of node positive early breast cancer to be conducted prior to approval.
August 9, 2006: changed to a post approval Phase 4 safety study of unspecified size.

11. Is Abraxis proposal acceptable?
How similar or dissimilar the Abraxane and Taxol formulations are.
Risk/benefit ratio of approving Abraxane w/o an efficacy and safety study.
Taxol prolongs disease free survival and survival in the adjuvant breast cancer setting.
FDA is concerned with the consequences of a potential decrement in DFS and survival in women with node positive early breast cancer.

12. Pharmacokinetics of Abraxane compared to Taxol

13. A Pharmacokinetic Comparison of Abraxane and Taxol
Brian Booth
Division of Clinical Pharmacology 5

14. PK Comparison- Paclitaxel moieties
Albumin P P P P
Total Paclitaxel P P P
In vivo
Abraxane
Paclitaxel P P P P
Total Paclitaxel P P P P P P
In vivo
Taxol

15. PK Comparison- Paclitaxel moieties
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? P P P P

16. PK Comparison-Linearity Total Paclitaxel
Abraxane: 30 min infusion
Linear, predictable PK
Dose
Cmax
AUC CL
(mg/m2)
% δ
(ng/ml)
(ng*hr/ml)
(L/h/m2)
135
----
3071
8604
15.9
175 30
5202 70
15048 75
11.6 25
Taxol: 3 hr infusion
Non-linear,
less-predictable PK

17. 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

18. Clinical PK Comparison of Total Paclitaxel Study C008-0-Unadjusted Total Paclitaxel
Abraxane:
6.5 x higher Cmax
17 % higher AUC
40% higher CL
50% higher Vd
Than Taxol
Taxol (175 mg/m2)
Abraxane
(260 mg/m2)
Sparreboom A. et al Clin Cancer Res 2005; 11:

19. Clinical PK Comparison of Total Paclitaxel Study C008-0
Abraxane
(dose-adjusted to 175 mg/m2)
Taxol (175 mg/m2)

20. Dose-normalized comparison of Abraxane and Taxol
Parameter
(mean ± %CV)
Abraxane
260 mg/m2
(n=14)
Taxol
175 mg/m2
(n=12)
Abraxane/taxol
Ratio
Abraxane*
Dose-adjusted
Taxol*
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%) Vz
(L/m2)
664
433
1.53 x
(53%)
*Dose-normalized. Abraxane is a 30-minute infusion; *Taxol is a 3-hr infusion

21. 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

22. Basis of Approval for Abraxane for Metastatic Breast Cancer

23. Study Design Randomized, Phase 3, open label Sample size: 460 patients
70 sites: Russia (77%), UK (15%), Canada and US (9%)
2 Arm: Abraxane 260 mg/m2 as a 30-minute infusion and Taxol 175 mg/m2 as a 3-hour infusion
59% second line or greater and 77% previous anthracycline exposure
Designed to show non inferiority in RR

24. Study Populations All randomized patients Subgroups
Receiving drug as 1st line only
Receiving drug as > 2nd line
Taxol approved indication: patients who have failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated

25. Endpoints
1° Endpoint: Response Rate
2° Endpoints: TTP
Survival

26. Response Rate (from Abraxane label)
260 mg/m2
Taxol
175 mg/m2
All randomized patients
Response Rate
95% CI
50/233 (21.5%)
(16.19%-26.73%)
25/227 (11.1%)
(6.94%-15.09%)
P-value
0.003
Taxol Indication: Patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy
20/129 (15.5%)
(9.26%-21.75%)
12/143 (8.4%)
(3.85%-12.94%)

27. TTP
At the time of Abraxane approval TTP results were not included in the label because:
Evaluation of TTP was not rigorous and data were not sufficiently mature to support a comparative efficacy claim in this single non-blinded study

28. Time to progression (TTP) from July 21, 2006 Submission
We have the following concerns:
TTP was not systematically assessed in all patients after cycle 6
Multiple analyses using different criteria without adjustments
TTP results may not be reliable for a labeling claim

29. Overall Survival from July 21, 2006 Submission
We have the following concerns:
There was no difference in overall survival between the Abraxane and Taxol treatment groups. HR (Abraxane/Taxol) was 0.90, p=0.348 (log rank).
No conclusions can be drawn from a subgroup analysis when the main analysis was not statistically significant.
Multiple subgroup analyses using different criteria without p value adjustments
P-values are not interpretable

30. 1st Line Therapy Patients Only 73/98 (74%) (59.4, 87.7) 60/89 (67%)
Abraxane
260 mg/m2
Taxol
175 mg/m2
ITT population
Patients who died
95% CI
172/229 (75%)
(53.4, 76.9)
175/225 (78%)
(48.0, 66.4)
P-value
Hazard Ratio, 95% CI
0.322
0.899 (0.728, 1.110)
1st Line Therapy Patients Only
73/98 (74%)
(59.4, 87.7)
60/89 (67%)
(58.1, 98.0)
0.264
1.215 (0.863, 1.709)
Patients Receiving 2nd or Greater Line Therapy
99/131 (76%)
(45.1, 76.9)
115/136 (85%)
(39.0, 55.3)
0.020
0.726 (0.553, 0.952)

31. Abraxane and Taxol AEs differences (% pts)
260 mg/m2
N=229
Taxol
175 mg/m2
N=225
Neutropenia
<2.0x109/L
<0.5x109/L 80 9 82 22
Febrile Neutropenia 2 1
Infections 24 20
Hypersensitivity Reactions 4 12
Sensory Neuropathy
Any Symptoms
Severe Symptoms 71 10 56

32. Abraxane and Taxol AEs differences (% pts)
260 mg/m2
N=229
Taxol
175 mg/m2
N=225
Nausea
Any Symptoms
Severe Symptoms 30 3 21
<1
Vomiting 18 4 9 1
Diarrhea 26 15
Asthenia 47 8 38

33. Basis of Approval for Taxol for Adjuvant Breast Cancer

34. Study Design

35. Disease Free Survival: AC vs AC+T (HR=0. 78, 95% CI 0. 67-0. 91, p=0

36. Survival: AC versus AC+T (HR=0.74, 95% CI 0.60-0.92, p=0.0065)

37. Disease Free Survival: AC vs AC+T Receptor Neg/Unknown (HR=0
Disease Free Survival: AC vs AC+T Receptor Neg/Unknown (HR=0.68, 95% CI )

38. Should Abraxane be approved for the adjuvant treatment of node positive early breast cancer without an adequate RCT powered for DFS, OS and safety?

39. Abraxane and Taxol are different
Formulations are different
Pharmacokinetics are different
Not bioequivalent
Free paclitaxel not measured
Abraxane does not contain cremophor, given by 30 minute infusion w/o premedication
Taxol is given by 3 hour infusion and requires premedication

40. Abraxane and Taxol toxicity profiles are different
Taxol has a higher incidence of neutropenia and hypersensitivity reactions
Abraxane has a higher incidence of peripheral neuropathy, nausea, vomiting, diarrhea and asthenia

41. FDA Agrees that in the metastatic breast cancer study Abraxane had a higher tumor response rate than Taxol

42. FDA believes that in the MBC study TTP improvement has not been adequately demonstrated
There was no type 1 error allocated for TTP analysis.
TTP claims could not be confirmed since no IRL review was conducted beyond cycle 6. Patients were not systematically evaluated after cycle 6. In an open label study, there is a potential for bias in progression assessments.
P-values for TTP analyses are not interpretable.

43. FDA believes that in the MBC study survival improvement has not been adequately demonstrated
There was no type 1 error allocated for OS analysis.
There is no significant OS effect in the all randomized population
Subgroup analysis is not appropriate when the study failed to demonstrate an effect in the overall population.
Multiple analyses in multiple subgroups with no adjustment
P-values for OS analyses is not interpretable.

44. 1st line patients, survival trended against Abraxane HR (A/T)= 1.215

45. There is a need for a RCT in the adjuvant population to properly estimate the risk:benefit ratio of Abraxane

46. Data on toxicity comparisons from the metastatic study may not be appropriate to the adjuvant setting were Abraxane would be given following AC.

47. Taxol increases DFS and OS in the adjuvant treatment of women with node positive early breast cancer.
22% reduction in the risk of disease recurrence
26% reduction in the risk of death

48. FDA is concerned with the consequences of a potential decrement in DFS and survival in women with node positive early breast cancer

49. Trial Design Considerations

50. Trial Design Considerations
R. Sridhara, Ph.D.

51. Randomized Clinical Trial to Demonstrate DFS Efficacy of Abraxane
Is it required?
Is it feasible?

52. Size of Trials in Prior Approvals in Adjuvant Breast Cancer – All Based on RCTs NOTE: 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

53. 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

54. 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

55. 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

56. 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 better
M 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

57. 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

58. 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

59. 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)

60. 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)

61. 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)

62. 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

63. Important Issues to Consider
Pharmacokinetics of Abraxane and Taxol are different
Free paclitaxel was not measured
Differences in Abraxane and Taxol tumor response rate and toxicity profiles in the MBC study indicates they are different drugs

64. Important Issues to Consider
Treatment of MBC has different risk:benefit
Treatment of adjuvant breast cancer is given with curative intent therefore risk: benefit should be well established in a RCT adequately powered for efficacy and safety
FDA is concerned that the gains with Taxol therapy may not be maintained with Abraxane