![](media/image1.png)**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**PUBLIC HEALTH SERVICE**

**FOOD AND DRUG ADMINISTRATION**

**CENTER FOR DRUG EVALUATION AND RESEARCH**

**Medical Division:** Oncology Drug Products (HFD-150)

**Biometrics Division:** Division of Biometrics I (HFD-710)

NDA NUMBER: **21-386**

DRUG NAME: **Zometa (zoledronic acid for injections)**

INDICATION: **Treatment of Bone Metastases**

SPONSOR: **Novartis**

DOCUMENTS REVIEWED: 1, 67, 68, 92, 94, 97, 98, 100, 106, 107, 109, 112,
114, 115

STATISTICAL REVIEWERS: **Rajeshwari Sridhara, Ph.D**. **(HFD‑710)**

**Ning Li, Ph.D. (HFD-710)**

STATISTICAL TEAM LEADER: **Gang Chen, Ph.D**. **(HFD‑710)**

BIOMETRICS DIVISION DIRECTOR: **George Chi, Ph.D**. **(HFD‑710)**

CLINICAL REVIEWERS: **Amna Ibrahim, M.D**. **(HFD‑150)**

**Nancy Scher, M.D. (HFD-150)**

**Grant Williams, M.D. (HFD-150)**

PROJECT MANAGER: **Debra Vause (HFD‑150)**

**Distribution:** NDA 21-386

HFD‑150/Vause

HFD‑150/Ibrahim

HFD-150/Scher

HFD-150/Williams

HFD‑150/Pazdur

HFD‑710/Sridhara

HFD-710/Li

HFD‑710/Chen

HFD‑710/Mahjoob

HFD-710/Chi

HFD‑710/Anello

**File Directory:** C:/nda/novartis/zometa_stat_odac_review.doc

**Table of Contents**

1 Executive Summary and Statistical Findings
[1](#executive-summary-and-statistical-findings)

1.1 Overview of the Studies Reviewed
[1](#overview-of-the-studies-reviewed)

1.2 Some Statistical and Technical Issues
[2](#some-statistical-and-technical-issues)

1.3 Principal Findings [3](#principal-findings)

2 Statistical Review and Evaluation of Evidence
[9](#statistical-review-and-evaluation-of-evidence)

2.1 Introduction [9](#introduction)

2.2 Some Statistical Issues: [10](#some-statistical-issues)

2.3 Study 010 (Breast cancer or multiple myeloma patients with bone
metastasis)
[11](#study-010-breast-cancer-or-multiple-myeloma-patients-with-bone-metastasis)

2.3.1 Background [11](#background)

2.3.2 Data Analyzed and Sources [11](#data-analyzed-and-sources)

2.3.3 Study Objectives [11](#study-objectives)

2.3.4 Efficacy Endpoints [12](#efficacy-endpoints)

2.3.5 Sample Size Considerations [12](#sample-size-considerations)

2.3.6 Stratification [12](#stratification)

2.3.7 Interim Analysis [12](#interim-analysis)

2.3.8 Efficacy Analysis Methods [12](#efficacy-analysis-methods)

2.3.9 Sponsor's Results and Statistical Reviewer's Findings/Comments
[13](#sponsors-results-and-statistical-reviewers-findingscomments)

2.3.10 Sponsor's Conclusion and Reviewer's Conclusion/Comments
[23](#sponsors-conclusion-and-reviewers-conclusioncomments)

2.4 Study 011 (Cancer patients with bone metastasis, other than breast
cancer, multiple myeloma or prostate cancer)
[24](#study-011-cancer-patients-with-bone-metastasis-other-than-breast-cancer-multiple-myeloma-or-prostate-cancer)

2.4.1 Background [24](#background-1)

2.4.2 Data Analyzed and Sources [24](#data-analyzed-and-sources-1)

2.4.3 Study Objectives [24](#study-objectives-1)

2.4.4 Efficacy Endpoints [25](#efficacy-endpoints-1)

2.4.5 Sample Size Considerations [25](#sample-size-considerations-1)

2.4.6 Stratification [26](#stratification-1)

2.4.7 Interim Analysis [26](#interim-analysis-1)

2.4.8 Efficacy Analyses Methods [26](#efficacy-analyses-methods)

2.4.9 Sponsor\'s Results and Reviewer\'s Findings/Comments
[28](#sponsors-results-and-reviewers-findingscomments)

2.4.10 Sponsor\'s Conclusions and Reviewer\'s Conclusions/Comments
[42](#sponsors-conclusions-and-reviewers-conclusionscomments)

2.5 Study 039 (Prostate cancer patients with metastatic bone lesions)
[44](#study-039-prostate-cancer-patients-with-metastatic-bone-lesions)

2.5.1 Background [44](#background-2)

2.5.2 Data Analyzed and Sources [44](#data-analyzed-and-sources-2)

2.5.3 Study Objectives [44](#study-objectives-2)

2.5.4 Efficacy Endpoints [45](#efficacy-endpoints-2)

2.5.5 Sample Size Considerations [45](#sample-size-considerations-2)

2.5.6 Stratification [46](#stratification-2)

2.5.7 Interim Analysis [46](#interim-analysis-2)

2.5.8 Efficacy Analysis Methods [46](#efficacy-analysis-methods-1)

2.5.9 Sponsor\'s Results and Reviewer\'s Findings/Comments
[48](#sponsors-results-and-reviewers-findingscomments-1)

2.5.10 Sponsor's Conclusions and Reviewer's Conclusions/Comments
[61](#sponsors-conclusions-and-reviewers-conclusionscomments-1)

3 Statistical Evaluation of Collective Evidence
[64](#statistical-evaluation-of-collective-evidence)

4 APPENDICES [68](#appendices)

4.1 APPENDIX 1 - STUDY 010 - Zol. 8/4 mg versus Aredia
[68](#appendix-1---study-010---zol.-84-mg-versus-aredia)

4.2 APPENDIX 2 - STUDY 011 - Zol. 8/4 mg versus Placebo
[71](#appendix-2---study-011---zol.-84-mg-versus-placebo)

4.3 APPENDIX 3 - STUDY 039 - Zol. 8/4 mg versus Placebo
[72](#appendix-3---study-039---zol.-84-mg-versus-placebo)

# Executive Summary and Statistical Findings

## Overview of the Studies Reviewed

Zometa or zoledronate (zoledronic acid for injection) is proposed to be
used for the treatment of osteolytic, osteoblastic, and mixed bone
metastases of solid tumors and osteolytic lesions of multiple myeloma,
in conjunction with standard antineoplastic therapy in cancer patients.
Zometa is a member of a class of compounds known as bisphosphonates and
it is a third generation bisphosphonate. Bisphosphonates are effective
inhibitors of osteoclastic bone resorption. Zometa has been approved for
the treatment of hypercalcemia of malignancy. The current NDA
application describes three ranomized clinical trials with Zometa in the
treatment of cancer patients with bone metastases.

Study 010 was a multicenter, double-blind, randomized, controlled, Phase
III parallel comparative trial of i.v. zoledronic acid (Zometa, 4 mg or
8 mg) versus iv. Aredia (90 mg) (pamidronate) as an adjunct to standard
therapies in patients with multiple myeloma and breast cancer with
cancer related bone lesions. The active control agent, intravenous
pamidronate (90 mg) is the current standard of care for the treatment of
patients with predominantly osteolytic bone metastases from breast
cancer and osteolytic lesions associated with multiple myeloma.
Pamidronate (90 mg via 2- to 4-hour infusion every 3 to 4 weeks) has
been shown to significantly prolong the time to first skeletal-related
event (SRE) and to significantly reduce the incidence of SREs for up to
21 months in patients with multiple myeloma and up to 2 years in
patients with breast cancer and osteolytic lesions compared with
placebo. A total of one-thousand-six-hundred-and-forty-eight (1648)
patients were randomized in this trial: 564 patients in the zoledronic
acid 4 mg treatment group, 526 patients in the zoledronic acid 8/4 mg
treatment group and 558 patients in the Aredia 90 mg treatment group.
The study was stratified by three cancer patient groups: Myeloma, Breast
cancer with chemotherapy and breast cancer with hormonal therapy. The
primary objective of study 010 was to show "non-inferiority" of i.v.
Zometa to Aredia in preventing skeletal-related events (SRE) in Stage
III myeloma or Stage IV breast cancer patients with cancer related bone
lesions. The primary efficacy endpoint was the proportion of patients
experiencing at least one SRE up to 13 months, defined as, radiation
therapy to bone, surgery to bone, pathologic bone fracture or spinal
cord compression.

Study 011 was a randomized, double-blind, multicenter, parallel-group,
placebo controlled Phase III study conducted in a total of 773 patients
aged 18 years or over with ECOG performance status 2 and bone metastases
from solid tumors other than breast or prostate cancer. Patients were
randomized in a double-blind fashion to receive either zoledronate 4 mg
intravenously, or zoledronate 8 mg intravenously, or a placebo
intravenous infusion every three weeks for 12 doses in addition to their
antineoplastic therapy. The randomized treatment assignment ratio was to
be 1:1:1 (257 patients were randomized to the 4 mg zoledronic acid
group, 266 patients to the 8 mg zoledronic acid group, and 250 patients
to the placebo group). The randomization was stratified by site of
cancer \'lung cancer\' versus \'other solid tumor\'. Patients were to be
treated for 36 weeks (9 months). In addition, all patients were to
receive 500 mg of calcium orally and a multivitamin tablet (containing
500 I.U. of vitamin D) daily throughout the study. The primary study
objective of this study was to assess the efficacy of zoledronate
therapy (4 or 8 mg) in addition to antineoplastic therapy, compared to
antineoplastic therapy alone, in preventing skeletal-related events in
patients with any cancer with bone metastases other than breast cancer,
multiple meyeloma or prostate cancer. The primary efficacy variable was
the proportion of patients with any SRE exclusive of tumor induced
hypercalcemia (TIH or -HCM)) at 9 months.

Study 039 was an international, multicenter, randomized, double-blind,
placebo-controlled, parallel study conducted in prostate cancer patients
with a history of metastatic bone disease who have a rising serum PSA
concentration despite treatment with first-line hormonal therapy for
meatastatic disease. Patients were randomized in a double-blind fashion
to receive either zoledronate 4 mg intravenously, or zoledronate 8 mg
intravenously, or a placebo intravenous infusion every three weeks in
addition to their antineoplastic therapy. The randomized treatment
assignment ratio was to be 1:1:1 (214 patients were randomized to
zoledronate 4 mg, 221 patients to the zoledronate 8 mg group, and 208
patients to the placebo group). The randomization was stratified by
prostate cancer history (no metastatic disease present at the time of
the initial diagnosis of prostate cancer versus metastatic disease
present at the time of the initial diagnosis). In addition all patients
were to receive 500 mg of calcium orally and multivitamin tablet
(containing 400-500 I.U. of vitamin D) daily throughout the study. The
primary objective of this study was to assess the efficacy of
zoledronate treatments (4 or 8 mg) in addition to antineoplastic
therapy, compared to antineoplastic therapy alone to prevent
skeletal-related events (SREs) in prostate cancer patients with a
history of metastatic bone disease who have developed biochemical
progression of disease. SREs were defined as pathologic bone fracture
events, spinal cord compression events, surgery to bone, and radiation
therapy to bone (including the use of radioisotopes). The primary
efficacy variable in this study was the proportion of patients having at
least one skeletal-related event at 15 months.

## Some Statistical and Technical Issues

-   The protocol stated objective of showing "non-inferiority" of i.v.
    Zometa to Aredia in study 10 is not appropriate according to the
    current understanding of non-inferiority trials. The objective
    should have been stated as demonstrating the ***effectiveness*** of
    i.v. Zometa through a non-inferiority trial with Aredia as the
    active comparator.

-   The protocol defined primary efficacy parameter in all the three
    studies is proportion of skeletal related events. This proportion
    was computed in each treatment arm as the ratio of the number of
    first skeletal related events at 12, 9 and 15 months in studies 010,
    011 and 039, respectively, to the number of patients randomized to
    the treatment arm. These estimates of the skeletal event rates may
    be biased as there is high dropout rate: 27% in study 010 (at 12
    months), 56% in study 011 (at 9 months), and 46% in study 039 (at 15
    months).

-   Time to first occurrence of skeletal-related event is preferred to
    the protocol specified analysis of proportion of skeletal-related
    events and it was recommended by the agency (statistical reviews
    dated 6/18/98 and 8/20/98). Due to high dropout rate in all three
    studies, the analysis of proportion at a fixed time point is
    questionable. The time to skeletal-related event analysis should be
    considered as the primary analysis, which can take into account
    censoring of observations during the course of the study.

-   In all the three studies, the 8 mg Zometa treated arm was not
    included in the efficacy evaluation because of the Amendment 4 of
    the protocols to decrease the dose to 4 mg of every patient in the 8
    mg due to observed renal toxicity. This change occurred after all
    the patients were enrolled in each of the studies and the patients
    in the 8 mg arm had received substantial treatment. However, if the
    efficacy analysis for the 8 mg arm was also performed then type I
    error rate should be adjusted in the comparisons of 4 mg versus
    placebo treated arms.

## Principal Findings

**[Study 010:]{.underline}**

The primary efficacy endpoint was the proportion of patients
experiencing at least one SRE, defined as radiation therapy to bone,
surgery to bone, pathologic bone fracture or spinal cord compression.
The sponsor's analysis result is summarized in Table 1.3.1.

**Table 1.3.1: Proportion of SRE to Month 13 by Stratum (Sponsor's
Analyses)**

+------------+------------+------------+----------------+-------------+
|            | Zometa     | Aredia     | Difference     | Log-rank    |
|            |            |            |                |             |
|            | (4mg)      |            | (95% CI)\*     | p-value     |
+------------+------------+------------+----------------+-------------+
| Myeloma    | 47%        | 49%        | -2%            | 0.694       |
|            |            |            |                |             |
|            | (86/183)   | (82/167)   | (-12.6%, 8.4%) |             |
+------------+------------+------------+----------------+-------------+
| Breast     | 44%        | 43%        | 1%             | 0.806       |
|            |            |            |                |             |
| (Chemo)    | (79/178)   | (78/181)   | (-9%, 11.6%)   |             |
+------------+------------+------------+----------------+-------------+
| Breast     | 42%        | 47%        | -5%            | 0.277       |
|            |            |            |                |             |
| (Hormonal) | (83/200)   | (97/207)   | (-15%, 4.3%)   |             |
+------------+------------+------------+----------------+-------------+
| **Total**  | **44%**    | **46%**    | **-2%**        | **0.461**   |
|            |            |            |                |             |
|            | **(        | **(        | **(-7.9%,      | *           |
|            | 248/561)** | 257/555)** | 3.7%)**        | *OR=0.919** |
+------------+------------+------------+----------------+-------------+

\*=Zometa-Aredia

During design of the non-inferiority study, the sponsor defined a
"non-inferiority" margin of 8% which is based on preserving 60% of the
point estimate of the active control effect (Aredia vs. placebo). By
reviewing the original protocol and the original studies comparing
Aredia with placebo, the active control effect was determined based upon
the following data (Table 1.3.2):

**Table 1.3.2: Active Control (Aredia vs. Placebo) Effect by Studies
(012, 018, 019)**

+-------------+------------+----------+----------------+--------------+
|             | Placebo    | Aredia   | Difference     | Log-rank     |
|             |            |          |                |              |
|             |            |          | (95% CI)\*     | p-value      |
+-------------+------------+----------+----------------+--------------+
| Myeloma     | 44%        | 28%      | 16%            | 0.001        |
|             |            |          |                |              |
|             | (79/179)   | (56/198) | (6.2%, 25.5%)  |              |
+-------------+------------+----------+----------------+--------------+
| Breast      | 56%        | 43%      | 13.7%          | 0.007        |
|             |            |          |                |              |
| (Chemo)     | (110/195)  | (79/185) | (3.8%, 23.7%)  |              |
+-------------+------------+----------+----------------+--------------+
| Breast      | 55%        | 47%      | 8%             | 0.108        |
|             |            |          |                |              |
| (Hormonal)  | (104/189)  | (85/182) | (-1.8%, 18.5   |              |
|             |            |          | %)             |              |
+-------------+------------+----------+----------------+--------------+
| **Total**   | **52.0%**  | *        | **13.1%**      | **\<0.0001** |
|             |            | *38.9%** |                |              |
|             | **(        |          | **(7.3%,       | **OR         |
|             | 293/563)** | **(22    | 18.9%)**       | \*\*=1.702** |
|             |            | 0/565)** |                |              |
+-------------+------------+----------+----------------+--------------+

\*=Placebo-Aredia; \*\*OR= Odds Ratio

From current understanding of active control non-inferiority trial,
margins defined in terms of point estimate of the control effect tends
to be liberal \[1, 2, 3\]. Since there is only one active control
non-inferiority trial and there are only a few historical randomized
studies for the assessment of the control effect, the margin of the
non-inferiority test should be defined based on an Aredia effect
estimated by the lower limit of the 95% CI.

Table 1.3.3 summarizes the results of "Non-inferiority" analysis for
study 010.

**Table 1.3.3: Results of "Non-inferiority" Analysis**

+------------+-----------------+----------------+----------------------+
| Method     | Zole 4mg-Aredia | Placebo-       | "Non-inferiority"    |
|            |                 | Aredia         | Test\*\*             |
|            | (95% CI)        |                |                      |
|            |                 | (95% CI)       |                      |
+------------+-----------------+----------------+----------------------+
| 8%         | -2%             |                | Yes                  |
|            |                 |                |                      |
| Margin     | (-7.9%,3.7%)    |                | (Upper limit 3.7%    |
|            |                 |                | \<8%)                |
+------------+-----------------+----------------+----------------------+
| 3.65%\*    | -2%             | 13.1%          | No                   |
|            |                 |                |                      |
| Margin     | (-7.9%,3.7%)    | (7.3%,18.9%)   | (Upper limit         |
|            |                 |                | 3.7%\>3.65%)         |
+------------+-----------------+----------------+----------------------+

\* 3.65% margin is calculated based on 50% of the lower limit of 95% CI
of the estimator of the Aredia effect.

\*\* Test result is significant at 0.05 level if the upper limit of 95%
CI of Zometa effect (3.7%) is less than the given margin.

Table 1.3.4 summarizes the results of time to first SRE analysis for
study 010.

**Table 1.3.4: Time to First SRE by Stratum and Treatment Arm**

+------------+---------+---------------+----------------+-------------+
|            | N       | Median        | Hazard Ratio   | Log-rank    |
|            |         |               | (95% CI)       |             |
|            |         | (95%CI)       |                | p-value     |
+------------+---------+---------------+----------------+-------------+
| Myeloma    | 167     | 301(191,      | .97(.71, 1.31) | 0.82        |
|            |         | \-\--)        |                |             |
| **Aredia** | 183     |               |                |             |
|            |         | 372(225, 504) |                |             |
| Zol 4 mg   |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| Breast(CT) | 181     | 366(259,      | .96(.70, 1.32) | 0.81        |
|            |         | \-\--)        |                |             |
| **Aredia** | 178     |               |                |             |
|            |         | 364(249,      |                |             |
| Zol 4 mg   |         | \-\--)        |                |             |
+------------+---------+---------------+----------------+-------------+
| Breast(HT) | 207     | 370(258,      | .83(.62, 1.12) | 0.22        |
|            |         | \-\--)        |                |             |
| **Aredia** | 200     |               |                |             |
|            |         | \>380 (\-\--, |                |             |
| Zol 4 mg   |         | \--)          |                |             |
+------------+---------+---------------+----------------+-------------+
| **Total**  | **555** | **363(273,    | **.92(.77,     | **0.31**    |
|            |         | 399)**        | 1.09)**        |             |
| **Aredia** | **561** |               |                |             |
|            |         | **373(350,    |                |             |
| **Zol 4    |         | 504)**        |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+

**[Study 011:]{.underline}**

The primary efficacy variable was the proportion of patients
experiencing at least one SRE (-HCM). Per sponsor analysis by month 9
both the zoledronic acid 4 mg and 8/4 mg groups had a lower proportion
than the placebo group (Table 1.3.5).

Table 1.3.5: Proportion of Patients Having SRE (-HCM) up to Month 9 by
Stratum and Treatment Group (ITT Patients) -- Sponsor's Analysis

  ----------------- ---------------- ------------------ -------------------
                                     **95% C.I. and     
                                     P-value for the    
                                     difference**       

                    **Proportion**   **Zol 4 mg**       **Zol 8/4 mg**

  **Lung Cancer**                                       

  **Placebo**       59/130 (45%)     (-15.6%,8.4%),     (-23.3%,0.1%),
                                     p=0.557            p=0.053

  **Zol 4 mg**      56/134 (42%)     \-                 (-19.5%,3.5%),
                                                        p=0.175

  **Zol 8/4 mg**    47/139(34%)      \-                 \-

  **Other Solid                                         
  Tumors**                                              

  **Placebo**       52/120 (43%)     (22.2%,2.2%),      (-20.1%,4.3%),
                                     p=0.110            p=0.205

  **Zol 4 mg**      41/123 (33%)     \-                 (-9.7%,13.9%),
                                                        p=0.727

  **Zol 8/4 mg**    45/127 (35%)     \-                 \-

  **Total**                                             

  **Placebo**       111/250 (44%)    (-15.2%,1.9%),     (-18.2%,-1.4%),
                                     **p=0.127**        p=0.023

  **Zol 4 mg**      97/257 (38%)     \-                 (-11.4%,5.1%),
                                                        p=0.452

  **Zol 8/4 mg**    92/266 (35%)     \-                 \-
  ----------------- ---------------- ------------------ -------------------

Table 1.3.6 summarizes the results of time to first SRE analysis for
study 011.

**Table 1.3.6: Analysis of Time to First Skeletal Related Event
Truncated at 9 Months Using Kaplan-Meier Estimation Procedure (ITT
Population FDA Analysis)**

+------------+---------+----+------------+---------------+------------+
|            | **Event | *  | **Median   | **Hazard      | **P-value  |
|            | Rate at | *N | Time to    | Ratio**       | (          |
|            | 9       | ** | Event in   |               | Comparison |
|            | M       |    | days (95%  | **(95%        | to Placebo |
|            | onths** |    | C.I.)**    | C.I.)**       | using      |
|            |         |    |            |               | Log-rank   |
|            |         |    |            |               | test)**    |
+------------+---------+----+------------+---------------+------------+
| **Lung     |         |    |            |               |            |
| Cancer**   |         |    |            |               |            |
+------------+---------+----+------------+---------------+------------+
| *          | 67.9%   | 1  | 151 (90,   |               |            |
| *Placebo** |         | 30 | 202)       |               |            |
+------------+---------+----+------------+---------------+------------+
| **Zol 4    | 60.7%   | 1  | 168 (154,  | 0.785 (0.544, | 0.19       |
| mg**       |         | 33 | \*)        | 1.132)        |            |
+------------+---------+----+------------+---------------+------------+
| **Zol 8/4  | 53.6%   | 1  | 249 (175,  | 0.673 (0.459, | 0.04       |
| mg**       |         | 39 | \*)        | 0.987)        |            |
+------------+---------+----+------------+---------------+------------+
| **Other    |         |    |            |               |            |
| Solid      |         |    |            |               |            |
| Tumors**   |         |    |            |               |            |
+------------+---------+----+------------+---------------+------------+
| *          | 58.2%   | 1  | 168 (106,  |               |            |
| *Placebo** |         | 20 | \*)        |               |            |
+------------+---------+----+------------+---------------+------------+
| **Zol 4    | 43.9%   | 1  | \* (174,   | 0.664 (       | 0.05       |
| mg**       |         | 23 | \*)        | 0.438, 1.009) |            |
+------------+---------+----+------------+---------------+------------+
| **Zol 8/4  | 52.4%   | 1  | 198 (156,  | 0.826 (0.553, | 0.35       |
| mg**       |         | 27 | \*)        | 1.234)        |            |
+------------+---------+----+------------+---------------+------------+
| **Total**  |         |    |            |               |            |
+------------+---------+----+------------+---------------+------------+
| *          | 63.2%   | 2  | 163 (106,  |               |            |
| *Placebo** |         | 50 | 188)       |               |            |
+------------+---------+----+------------+---------------+------------+
| **Zol 4    | 52.8%   | 2  | 230 (168,  | 0.733 (0.557, | 0.026      |
| mg**       |         | 56 | \*)        | 0.965)        |            |
+------------+---------+----+------------+---------------+------------+
| **Zol 8/4  | 53.0%   | 2  | 219 (172,  | 0.743 (0.563, | 0.035      |
| mg**       |         | 66 | \*)        | 0.980)        |            |
+------------+---------+----+------------+---------------+------------+

\* = Not Reached

**[Study 039:]{.underline}**

The primary efficacy variable was the proportion of patients
experiencing at least one SRE (-HCM). Per sponsor analysis by month 15
both the zoledronic acid 4 mg and 8/4 mg groups had a lower proportion
than the placebo group (Table 1.3.7).

Table 1.3.7: Proportion of Patients Having SRE (-HCM) up to Month 15 by
Stratum and Treatment Group (ITT Patients) -- Sponsor's Analysis

  ----------------- ---------------- ------------------ -------------------
                                     **95% C.I. and     
                                     P-value for the    
                                     difference**       

                    **Proportion**   **Zol 4 mg**       **Zol 8/4 mg**

  **No Initial                                          
  Metastases**                                          

  **Placebo**       54/116 (47%)     (-24.4%,0.9%),     (-21.5%,3.0%),
                                     p=0.069            p=0.140

  **Zol 4 mg**      40/115 (35%)     \-                 (-9.4%,14.5%),
                                                        p=0.679

  **Zol 8/4 mg**    50/134 (37%)     \-                 \-

  **With Initial                                        
  Metastases**                                          

  **Placebo**       38/92 (41%)      (-23.6%,3.6%),     (-15.5%,13.3%),
                                     p=0.152            p=0.884

  **Zol 4 mg**      31/99 (31%)      \-                 (-4.9%,22.7%),
                                                        p=0.206

  **Zol 8/4 mg**    35/87 (40%)      \-                 \-

  **Total**                                             

  **Placebo**       92/208 (44%)     (-20.3%,-1.8%),    (-15.1%,3.6%),
                                     **p=0.021**        p=0.222

  **Zol 4 mg**      71/214 (33%)     \-                 (-3.7%, 14.3%),
                                                        p=0.255

  **Zol 8/4 mg**    85/221 (38%)     \-                 \-
  ----------------- ---------------- ------------------ -------------------

Table 1.3.8 summarizes the results of time to first SRE analysis for
study 039.

**Table 1.3.8: Analysis of Time to First Skeletal Related Event
Truncated at 15 Months Using Kaplan-Meier Estimation Procedure (ITT
Population FDA Analysis)**

+---------------+--------+----+-----------+--------------+-----------+
|               | *      | *  | **Median  | **Hazard     | **P-value |
|               | *Event | *N | Time to   | Ratio**      | (C        |
|               | Rate   | ** | Event in  |              | omparison |
|               | at 9   |    | days (95% | **(95%       | to        |
|               | Mo     |    | C.I.)**   | C.I.)**      | Placebo   |
|               | nths** |    |           |              | using     |
|               |        |    |           |              | Log-rank  |
|               |        |    |           |              | test)**   |
+---------------+--------+----+-----------+--------------+-----------+
| **No Initial  |        |    |           |              |           |
| Metastases**  |        |    |           |              |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Placebo**   | 59.6%  | 1  | 304 (198, |              |           |
|               |        | 16 | \*)       |              |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Zol 4 mg**  | 45.6%  | 1  | \* (291,  | 0.673        | 0.058     |
|               |        | 15 | \*)       | (0.446,      |           |
|               |        |    |           | 1.016)       |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Zol 8/4     | 50.7%  | 1  | 419 (251, | 0.805        | 0.270     |
| mg**          |        | 34 | \*)       | (0.547,      |           |
|               |        |    |           | 1.185)       |           |
+---------------+--------+----+-----------+--------------+-----------+
| **With        |        |    |           |              |           |
| Initial       |        |    |           |              |           |
| Metastases**  |        |    |           |              |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Placebo**   | 54.0%  | 92 | 335 (244, |              |           |
|               |        |    | \*)       |              |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Zol 4 mg**  | 44.4%  | 99 | \* (364,  | 0.673        | 0.085     |
|               |        |    | \*)       | (0.446,      |           |
|               |        |    |           | 1.016)       |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Zol 8/4     | 57.0%  | 87 | 346 (209, | 1.091        | 0.709     |
| mg**          |        |    | \*)       | (0.689,      |           |
|               |        |    |           | 1.728)       |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Total**     |        |    |           |              |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Placebo**   | 57.2%  | 2  | 321 (252, |              |           |
|               |        | 08 | \*)       |              |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Zol 4 mg**  | 44.9%  | 2  | \* (383,  | 0.661        | 0.009     |
|               |        | 14 | \*)       | (0.484,      |           |
|               |        |    |           | 0.903)       |           |
+---------------+--------+----+-----------+--------------+-----------+
| **Zol 8/4     | 53.2%  | 2  | 363 (255, | 0.912        | 0.541     |
| mg**          |        | 21 | \*)       | (0.679,      |           |
|               |        |    |           | 1.226)       |           |
+---------------+--------+----+-----------+--------------+-----------+

\* = Not Reached

1.  **Conclusions**

The "non-inferiority" test in Study 010 demonstrates marginal
effectiveness (p=0.052) with respect to proportion of SREs at 12 months
of zoledronate 4mg arm, using a margin of 3.65% which is defined as
preserving 50% of the lower limit of the 95% CI of the point estimate of
the Aredia effect. The original selection of 8% margin is not acceptable
based on the current understanding because it tends to be liberal.

Study 011 has failed to demonstrate efficacy of 4 mg zoledronate over
placebo treated group in reducing the proportion of SREs at 9 months per
protocol specified analysis (P-value=0.127). The protocol specified
estimates of the proportion of SREs may be biased estimates because of
high dropout rate. The sponsor was advised by the agency during the
protocol development stage to consider time to first SRE as the primary
efficacy parameter, which can take into account censoring of
observations during the course of the study. Therefore, in order to
account for the early censoring of the observations, this reviewer
conducted time to first SRE analysis using Kaplan-Meier estimation
procedure, which was recommended by the agency as the primary analysis,
truncating the maximum follow up time at 9 months. There appears to be a
statistically significant difference between the Zoledronate 4 mg group
and placebo group (p=0.026, 2-sided log-rank test) by this analysis.

In study 039, there is a statistically significant difference between
zoledronate 4 mg and placebo groups (p=0.021) with respect to the
proportion of SREs at 15 months as defined in the protocol. However, the
per protocol estimates of the proportion of SREs may be biased estimates
because of high dropout rate. The sponsor was advised by the agency
during the protocol development stage to consider time to first SRE as
the primary efficacy parameter, which can take into account censoring of
observations during the course of the study. Therefore, in order to
account for the early censoring of the observations, this reviewer
conducted time to first SRE analysis using Kaplan-Meier estimation
procedure, truncating the maximum follow up time at 15 months. There is
a statistically significant difference between the zoledronate 4 mg
group and placebo group (p=0.009, 2-sidered log-rank test).

In these reviewers\' opinion the results of Studies 11 and 39 support
efficacy of zoledronate 4 mg given intravenously versus placebo given
intravenously in patients with bone metastases from solid tumors other
than breast cancer, and the results of Study 10 suggest marginal
effectiveness of zoledronate 4 mg given intravenously in patients with
bone metastases from breast cancer and multiple myeloma based on a
"non-inferiority" test using Aredia as the active control .

# Statistical Review and Evaluation of Evidence

## Introduction

Zometa or zoledronate (zoledronic acid for injection) is proposed to be
used for the treatment of osteolytic, osteoblastic, and mixed bone
metastases of solid tumors and osteolytic lesions of multiple myeloma,
in conjunction with standard antineoplastic therapy in cancer patients.
Zometa is a member of a class of compounds known as bisphosphonates and
it is a third generation bisphosphonate. Bisphosphonates are effective
inhibitors of osteoclastic bone resorption. Zometa has been approved for
the treatment of hypercalcemia of malignancy.

The current NDA application describes clinical trials with Zometa in the
treatment of cancer patients with bone metastases. Pivotal efficacy data
in the treatment of bone metastases are provided by three double-blind
studies (010, 011 and 039), two of which (011, 039) were
placebo-controlled, and the other (010) active-controlled, the active
control being pamidronate (Aredia). Study 010 was conducted in patients
with bone metastases breast cancer or multiple myeloma. Study 011 was
conducted in patients with any cancer with bone metastases other than
breast cancer, multiple myeloma or prostate cancer. Study 039 was
conducted in prostate cancer patients with bone lesions.

Statistical review and evaluation of evidence of each of the studies
010, 011 and 039 are presented, respectively, in sections 2.3, 2.4 and
2.5 of this review. An overall statistical evaluation of collective
evidence and conclusions are presented in section 3 of this review.

## Some Statistical Issues:

-   The protocol stated objective of showing "non-inferiority" of i.v.
    Zometa to Aredia in study 10 is not appropriate according to the
    current understanding of non-inferiority trials. The objective
    should have been stated as demonstrating the ***effectiveness*** of
    i.v. Zometa through a non-inferiority trial with Aredia as the
    active comparator.

-   The protocol defined primary efficacy parameter in all the three
    studies is proportion of skeletal related events. This proportion
    was computed in each treatment arm as the ratio of the number of
    first skeletal related events at 12, 9 and 15 months in studies 010,
    011 and 039, respectively, to the number of patients randomized to
    the treatment arm. These estimates of the skeletal event rates may
    be biased as there is high dropout rate: 27% in study 010 (at 12
    months), 56% in study 011 (at 9 months), and 46% in study 039 (at 15
    months).

-   Time to first occurrence of skeletal-related event is preferred to
    the protocol specified analysis of proportion of skeletal-related
    events and it was recommended by the agency (statistical reviews
    dated 6/18/98 and 8/20/98). Due to high dropout rate in all three
    studies, the analysis of proportion at a time point is questionable.
    The time to skeletal-related event analysis should be considered as
    the primary analysis, which can take into account censoring of
    observations during the course of the study.

-   In all the three studies, the 8 mg Zometa treated arm was not
    included in the efficacy evaluation because of the Amendment 4 of
    the protocols to decrease the dose to 4 mg of every patient in the 8
    mg due to observed renal toxicity. This change occurred after all
    the patients were enrolled in each of the studies and the patients
    in the 8 mg arm had received substantial treatment. However, if the
    efficacy analysis for the 8 mg arm was also performed then type I
    error rate should be adjusted in the comparisons of 4 mg versus
    placebo treated arms.

## Study 010 (Breast cancer or multiple myeloma patients with bone metastasis)

### Background 

Study 010 was a multicenter, double-blind, randomized, controlled, phase
III parallel comparative trial of i.v. zoledronic acid (Zometa, 4 mg or
8 mg) versus iv. Aredia (90 mg) (pamidronate) as an adjunct to standard
therapies in patients with multiple myeloma and breast cancer with
cancer related bone lesions.

The active control agent, intravenous pamidronate (90 mg), is the
current standard of care for the treatment of patients with
predominantly osteolytic bone metastases from breast cancer and
osteolytic lesions associated with multiple myeloma. Pamidronate (90 mg
via 2- to 4-hour infusion every 3 to 4 weeks) has been shown to
significantly prolong the time to first skeletal-related event (SRE) and
to significantly reduce the incidence of SREs for up to 21 months in
patients with multiple myeloma and up to 2 years in patients with breast
cancer and osteolytic lesions compared with placebo.

Study 010 was conducted in 21 countries including United States, Europe,
Canada, South Africa and Australia. A total of
one-thousand-six-hundred-and-forty-eight (1648) patients were randomized
in this trial: 564 patients in the zoledronic acid 4 mg treatment group,
526 patients in the zoledronic acid 8/4 mg treatment group and 558
patients in the Aredia 90 mg treatment group. One site did not meet the
GCP standards and 8 patients from this site were excluded from the
efficacy analysis. The resulting intention-to-treat population has 1640
patients.

### Data Analyzed and Sources

Data used for review is from the electronic submission received on
9/28/01. The network path is "
cdsesub1\\N21386\\N_000\\2001-10-02\\\\datasets\\CRT\\010 " in the EDR.
The following volumes were reviewed: 1, 67, and 68.

### Study Objectives

The primary objective of study 010 was to show non-inferiority of i.v.
Zometa to Aredia in preventing skeletal-related events (SRE) in Stage
III myeloma or Stage IV breast cancer patients with cancer related bone
lesions. The study was completed as planned in the protocol and its
amendments. Due to reports of renal SAEs for zoledronic acid 8 mg,
patients randomized to zoledronic acid 8 mg were later switched to
zoledronic acid 4 mg (Amendment 5; dated 07-Jun-2000); and their data
would not be used to support any efficacy claim.

### Efficacy Endpoints

The primary efficacy endpoint was the proportion of patients
experiencing at least one SRE, defined as radiation therapy to bone,
surgery to bone, pathologic bone fracture or spinal cord compression.

The secondary objectives were to compare the effects of i.v. zoledronic
acid 4 mg and/or 8 mg to i.v. Aredia 90 mg with respect to safety and
tolerability and the assessment of SRE with or without HCM; time to
first SRE; time to progression of bone metastases; time to overall
progression of disease; quality of life scores, and BMD.

### Sample Size Considerations

For the purposes of sample size calculation, the non-inferiority margin
was set at 8%, which is approximately 60% of the difference that was
observed in the percentage of patients experiencing SREs during the
trials with Aredia and placebo (active vs. placebo).

To power for maximal variance, the percentage of patients with SREs was
assumed to be 50% for each treatment group. To test a 50% retention of
Aredia effect with the type I error rate of 0.025 and 80% power using a
two-group large-sample normal approximation, the required number of
patients is 484 per arm. The actual number of patients was sufficient
enough for the assumed effect size.

### Stratification

The study was stratified by three cancer patient groups: Myeloma, Breast
cancer with chemotherapy and breast cancer with hormonal therapy.

### Interim Analysis

No interim analysis for efficacy was planned for this study. However, at
an interim time point the 8 mg zoledronate arm was dropped due to renal
toxicity concerns. The sponsor claimed there was no efficacy interim
look.

### Efficacy Analysis Methods

The analysis for the primary efficacy variable, the proportion of
patients who experience at least one SRE, exclusive of tumor induced
hypercalcemia (TIH), during the complete core phase participation up to
Month 13, is based upon the 95% CI of the rate difference. Either
zoledronate dose (4 or 8 mg) will be declared non-inferior to Aredia 90
mg if the upper limit of the 95% confidence interval (2-sided) for the
difference in the percentage of patients having SREs after
administration of zoledronate and Aredia is below 8%. In terms of
testing, this means that the statistical null hypothesis to be tested is
8% with the alternative hypothesis \< 8%, where is the above mentioned
difference in percentages. The confidence interval will be based on the
large-sample normal approximation of the distribution of the difference
in the proportions.

Time to event analysis was performed using log-rank test, Cox regression
models and Anderson-Gill approach for multiple events.

### Sponsor's Results and Statistical Reviewer's Findings/Comments

This section will summarize the results of intention to treat analysis
for study 010. The intention to treat patient population includes all
patients as randomized (but one site did not meet GCP and was excluded
from the analysis). All tests used in this review are two-sided unless
otherwise stated.

#### Baseline Characteristics

The baseline demographic characteristics including age, sex, races,
weight, and performance status were balanced between the two treatment
groups (Zometa 4 mg and Aredia 90 mg). The baseline disease
characteristics for both myeloma and breast cancer, including primary
site of mets, time to diagnoses, baseline serum creatinine, previous
SRE, and baseline quality of life scale scores were examined (Table
2.3.1). A slightly greater proportion of patients in the Aredia 90 mg
group had a performance status of 2. Patients with multiple myeloma were
slightly older and a greater proportion were male than in the overall
population. ECOG status was also worse in this group compared with the
overall population, although time since initial diagnosis of cancer was
much shorter. Characteristics within this stratum were similar across
treatment groups, except that abnormal renal function was present in a
lower proportion of patients in the Aredia 90 mg group. Within each
breast cancer stratum, characteristics were generally similar across
treatment groups, except that in the stratum of patients with hormonal
therapy, a lower proportion of patients in the zoledronic acid 4 mg
group than in the Aredia group were on first line anti-neoplastic
therapy or had brain metastases. (Table 2.3.1).

![](media/image3.png){width="5.666666666666667in" height="6.35in"}
**Table 2.3.1: Baseline Characteristics of Study 010 (Sponsor's
Analysis)**

#### Primary Efficacy Analyses: Skeletal Related Event (SRE) Rate

The primary efficacy endpoint was the proportion of patients
experiencing at least one SRE, defined as radiation therapy to bone,
surgery to bone, pathologic bone fracture or spinal cord compression.
The sponsor's analysis result is summarized in Table 2.3.2.

Table 2.3.2: Proportion of SRE to Month 13 by Stratum (Sponsor's
Analyses)

+------------+------------+------------+----------------+-------------+
|            | Zometa     | Aredia     | Difference     | p-value\*   |
|            |            |            |                |             |
|            | (4mg)      |            | (95% CI)\*     |             |
+------------+------------+------------+----------------+-------------+
| Myeloma    | 47%        | 49%        | -2%            | 0.694       |
|            |            |            |                |             |
|            | (86/183)   | (82/167)   | (-12.6%, 8.4%) |             |
+------------+------------+------------+----------------+-------------+
| Breast     | 44%        | 43%        | 1%             | 0.806       |
|            |            |            |                |             |
| (Chemo)    | (79/178)   | (78/181)   | (-9%, 11.6%)   |             |
+------------+------------+------------+----------------+-------------+
| Breast     | 42%        | 47%        | -5%            | 0.277       |
|            |            |            |                |             |
| (Hormonal) | (83/200)   | (97/207)   | (-15%, 4.3%)   |             |
+------------+------------+------------+----------------+-------------+
| **Total**  | **44%**    | **46%**    | **-2%**        | **0.461**   |
|            |            |            |                |             |
|            | **(        | **(        | **(-7.9%,      | *           |
|            | 248/561)** | 257/555)** | 3.7%)**        | *OR=0.919** |
+------------+------------+------------+----------------+-------------+

\*=Zometa-Aredia

*[Reviewer's Comments:]{.underline}*

1.  The sponsor's analysis shows that the proportions were 44% and 46%
    for the zoledronic acid 4 mg group and the Aredia 90 mg group,
    respectively. The upper limit of the 95% confidence interval of the
    difference was 3.7%, which was less than the non-inferiority margin
    of 8% specified in the protocol. In the stratum of breast cancer
    patients receiving hormonal therapy, the difference in the
    proportions between the zoledronic acid 4 mg group and the Aredia 90
    mg group was --5%, which was the largest difference of the three
    strata in this study. While In the stratum of breast cancer patients
    receiving chemotherapy, the difference in the proportions between
    the zoledronic acid 4 mg group and the Aredia 90 mg group was +1%
    with an upper bound of 11.6%, implying 11.8% worse than Aredia.

2.  The protocol stated objective of showing "non-inferiority" of i.v.
    Zometa to Aredia in study 10 is not appropriate according to the
    current understanding of non-inferiority trials. The objective
    should have been stated as demonstrating the effectiveness of i.v.
    Zometa through a non-inferiority trial with Aredia as the active
    comparetor. During design of the non-inferiority study, the sponsor
    intended to preserve 60% of the point estimator of the active
    control effect (Aredia vs. placebo), which resulted in an 8%
    non-inferiority margin. By reviewing the original protocol and the
    original study comparing Aredia with placebo, the active control
    effect was determined based upon the following data (Table 2.3.3):

    **Table 2.3.3: Active Control (Aredia vs. Placebo) Effect by
    Stratum**

+------------+------------+------------+-----------------+-----------+
|            | Placebo    | Aredia     | Difference      | Log-rank  |
|            |            |            |                 |           |
|            |            |            | (95% CI)\*      | p-value   |
+------------+------------+------------+-----------------+-----------+
| Myeloma    | 44%        | 28%        | 16%             | 0.001     |
|            |            |            |                 |           |
|            | (79/179)   | (56/198)   | (6.2%, 25.5%)   |           |
+------------+------------+------------+-----------------+-----------+
| Breast     | 56%        | 43%        | 13.7%           | 0.007     |
|            |            |            |                 |           |
| (Chemo)    | (110/195)  | (79/185)   | (3.8%, 23.7%)   |           |
+------------+------------+------------+-----------------+-----------+
| Breast     | 55%        | 47%        | 8%              | 0.108     |
|            |            |            |                 |           |
| (Hormonal) | (104/189)  | (85/182)   | (-1.8%, 18.5 %) |           |
+------------+------------+------------+-----------------+-----------+
| **Total**  | **52.0%**  | **38.9%**  | **13.1%**       | **\       |
|            |            |            |                 | <0.0001** |
|            | **(        | **(        | **(7.3%,        |           |
|            | 293/563)** | 220/565)** | 18.9%)**        | **O       |
|            |            |            |                 | R=1.702** |
+------------+------------+------------+-----------------+-----------+

\*=Placebo-Aredia

3.  The overall SRE difference between placebo and Aredia was 13.1% with
    95% CI lower bound of 7.3%, which means that the Aredia was at least
    **7.3%** better than a placebo in the Aredia trials for previous
    approval. Thus, we may conclude that the active control effect using
    these trials is 7.3% if we believe that the patient populations and
    other conditions and parameters are similar in the historical trial
    and the current trial (Constant Assumption).

4.  Concerns about the constant assumption: To design and analyze a
    non-inferiority study such as Study 010, requires a determination
    that the active control drug (Aredia) would have shown efficacy in
    the new study or current setting, and it also requires an estimation
    of the size of the effect that Aredia would have shown relative to a
    placebo in the current setting. A comparison of the previous
    Aredia/Placebo studies with the current Zometa/Aredia study has been
    conducted. The comparison was performed as a comprehensive analysis
    on the issue and consider such factors as the nature and stage of
    disease/previous treatment; concomitant treatment; timing of events,
    duration of follow-up, dropout rate, etc. According to the FDA
    reviewer's request, the sponsor provided a report regarding the
    comparability of the historical and current studies. Detailed review
    of this issue can be found in Medical Officer's NDA review. The
    conclusion is summarized as follows. The comparison was made using
    current study 010, historical trials 012, 018 and 019.

In the multiple myeloma population, the protocol 010 (current study)
patients had a higher proportion of SREs at three months than did the
protocol 012 (historical study) patients (25% compared to 10%), but the
increase from 3 to 6 months in the proportion of patients with any SRE
was similar (15% and 10%). The major differences between the study 010
and study 012 are that time since diagnosis was longer and previous
history of an SRE was much less in the Aredia/placebo trial. Medical
reviewer reviewed the data showed in tables below. These data
demonstrated that the Aredia effect would be numerically larger in
subgroup of patients with short time to diagnosis (\<6 mo) as in the
current trial (Table 2.3.4), and the Aredia treatment effect for patient
with previous SRE is also larger than in patients had no SRE history
(Table 2.3.5).

**Table 2.3.4**: **Proportion of Myeloma Patients with SRE versus Time
Since Diagnosis in Study 012**

  ------------------ ----------------------- ----------------------------
                     **Time since            
                     diagnosis**             

                     **\> 6mo**              **\<6mo**

  **Aredia           36/150 (24%)            11/55 (20%)
  Proportion with                            
  SRE**                                      

  **Placebo          50/127 (39%)            26/60 (43%)
  Proportion with                            
  SRE**                                      

  **Placebo -        15%                     23%
  Aredia**                                   
  ------------------ ----------------------- ----------------------------

**Table 2.3.5: Proportion of Myeloma Patients with SRE versus History of
Previous SRE**

  ------------------ ----------------------- ----------------------------
                     **History of SRE in     
                     previous 3 months**     

                     **Yes**                 **No**

  **Aredia           35% (23/65)             17% (24/240)
  Proportion with                            
  SRE**                                      

  **Placebo          58% (33/57)             33% (43/130)
  Proportion with                            
  SRE**                                      

  **Placebo -        23%                     16%
  Aredia**                                   
  ------------------ ----------------------- ----------------------------

In conclusion, to use the effect of Aredia in study 012 in the testing
of non-inferiority is a reasonable approach. In the population of breast
cancer patients receiving hormonal treatment the proportions of patients
with any SRE at 3 months were similar for the historical controls and
the current population (32% and 28%). The increases in pathological
fractures were identical, 6%, and were similar for radiation to bone, 5%
and 8%. In the population of breast cancer patients receiving
chemotherapy the proportion of patients with any SRE at 3 months was
identical, and the increases in proportion of patients having any SRE, a
pathological fracture or radiotherapy to bone were similar, indicating
the consistent effect of Aredia inn the historical and current studies.
In conclusion, when the known demographic and prognostic differences
between the historical and current studies are taken into account the
descriptive analyses reveal that Aredia had a similar effect in the
previous and the current trials.

> **Preservation of active control effect**: The preservation of active
> treatment effect using the SRE rates can be determined by
> (7.3%-3.7%)/7.3%=49.3%. Hence, the current trial demonstrated an at
> least 49.3% retention of Aredia vs. a placebo effect if we believe
> that the constant assumption holds. This result demonstrates marginal
> effectiveness (p=0.052) with respect to proportion of SREs at 12
> months of zoledronate 4mg arm using a margin defined based on 50%
> retention of the lower limit of 95% CI of the Aredia effect.

5.  The SRE event rates over the study period (the longitudinal
    follow-up) are presented in Tables 2.3.6 (the protocol defined event
    rate analysis) and 2.3.7. (K-M estimated event rate). Numerically,
    the Zole 4mg arm shows similar effect pattern to the Aredia arm.

    **Table 2.3.6: SRE Event Rate (Intent-to-Treat Patients) over study
    period**

+-----------------+-----+----------+-----------+-----------+-----------+
| **Treatment**   | **  | **3      | **6       | **9       | **12      |
|                 | N** | month**  | month**   | month**   | month**   |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Myeoloma:**   | 167 | 42 (25%) | 66 (40%)  | 75 (45%)  | 82 (49%)  |
|                 |     |          |           |           |           |
| Aredia 90 mg    |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| Zometa 4 mg     | 183 | 56 (31%) | 70 (38%)  | 74 (40%)  | 86 (47%)  |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Breast        |     |          |           |           |           |
| (Chemo):**      |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Aredia 90 mg  | 181 | 49 (27%) | 64 (35%)  | 72 (40%)  | 78 (43%)  |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Zometa 4 mg   | 178 | 39 (22%) | 60 (34%)  | 68 (38%)  | 79 (44%)  |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Brea          |     |          |           |           |           |
| set(Hormonal)** |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Aredia 90 mg  | 207 | 58 (28%) | 79 (38%)  | 86 (42%)  | 97 (47%)  |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Zometa 4 mg   | 200 | 50 (25%) | 58 (29%)  | 70 (35%)  | 83 (42%)  |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Overall:**    |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| Aredia 90 mg    | 555 | 149(27%) | 209(38%)  | 233(42%)  | 257 (46%) |
+-----------------+-----+----------+-----------+-----------+-----------+
| Zometa 4 mg     | 561 | 145(26%) | 188(34%)  | 212(38%)  | 248 (44%) |
+-----------------+-----+----------+-----------+-----------+-----------+

**Table 2.3.7: K-M Estimated Event Rate (Intent-to-Treat Patients) Over
Study Period**

+-----------------+-----+----------+-----------+-----------+-----------+
| **Treatment**   | **  | **9      | **D       | **12      | **        |
|                 | N** | month**  | ifference | month**   | p-value** |
|                 |     |          | in Event  |           |           |
|                 |     |          | Rate**    |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Myeoloma:**   | 167 | 44.9%    | 4.9%      | 47.3%     | 0.75      |
|                 |     |          |           |           |           |
| Aredia 90 mg    |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| Zometa 4 mg     | 183 | 40.4%    |           | 42.6%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Breast        |     |          | 1.5%      |           | 0.68      |
| (Chemo):**      |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Aredia 90 mg  | 181 | 39.2%    |           | 42.5%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Zometa 4 mg   | 178 | 38.7%    |           | 42.1%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Brea          |     |          | 6.6%      |           | 0.35      |
| set(Hormonal)** |     |          |           |           |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Aredia 90 mg  | 207 | 40.6%    |           | 43.5%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| > Zometa 4 mg   | 200 | 34.0%    |           | 40.0%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| **Overall:**    |     |          | 4.0%      |           | 0.30      |
+-----------------+-----+----------+-----------+-----------+-----------+
| Aredia 90 mg    | 555 | 41.4%    |           | 44.3%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+
| Zometa 4 mg     | 561 | 37.4%    |           | 41.5%     |           |
+-----------------+-----+----------+-----------+-----------+-----------+

####  Secondary Efficacy Analyses

The secondary efficacy endpoints for the study include time to first
SRE, skeletal morbidity rate (SMR), and the overall survival. The time
to event "Time" defined in the protocol is the time period from the date
of randomization to the first date of event or censoring date.

**(1) Time to first SRE**

Time to first SRE is one of the secondary efficacy endpoints. Table
2.3.8 summarizes the results for study 010.

**Table 2.3.8: Time to first SRE by Stratum and Treatment Arm**

+------------+---------+---------------+----------------+-------------+
|            | N       | Median        | Hazard Ratio   | Log-rank    |
|            |         |               | (95% CI)       |             |
|            |         | (95%CI)       |                | p-value     |
+------------+---------+---------------+----------------+-------------+
| Myeloma    | 167     | 301(191,      | .97(.71, 1.31) | 0.82        |
|            |         | \-\--)        |                |             |
| Aredia     | 183     |               |                |             |
|            |         | 372(225, 504) |                |             |
| **Zol 4    |         |               |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| Breast(CT) | 181     | 366(259,      | .96(.70, 1.32) | 0.81        |
|            |         | \-\--)        |                |             |
| Aredia     | 178     |               |                |             |
|            |         | 364(249,      |                |             |
| **Zol 4    |         | \-\--)        |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| Breast(HT) | 207     | 370(258,      | .83(.62, 1.12) | 0.22        |
|            |         | \-\--)        |                |             |
| Aredia     | 200     |               |                |             |
|            |         | \>380 (\-\--, |                |             |
| **Zol 4    |         | \--)          |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| **Total**  | **555** | **363(273,    | **.92(.77,     | **0.31**    |
|            |         | 399)**        | 1.09)**        |             |
| **Aredia** | **561** |               |                |             |
|            |         | **373(350,    |                |             |
| **Zol 4    |         | 504)**        |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+

Figure 2.3.1 is the K-M curve for the time to first SRE comparing
overall Aredia with Zol 4 mg arm.

**Figure 2.3.1**

![](media/image4.wmf){width="6.707638888888889in"
height="3.7881944444444446in"}

**(2) Time to Multiple Events:**

Because the patients could continue on the study after the occurrence of
a skeletal-related-event, multiple events might be observed. Analysis
for the time to multiple events (SRE) was conducted by the sponsor. The
sponsor used the Anderson-Gill approaches for the analysis. The analysis
results of multiple events analysis of all SRE (-HCM) showed that there
was no difference between the two treatment arms (p=0.076), though
favoring zoledronic acid 4 mg over Aredia 90 mg. Most of the
contribution of this trend was derived from the breast cancer patients
with hormonal therapy at study entry.

*[Reviewer's Comment:]{.underline}*

The Anderson-Gill approach requires the assumption of independent
events. This assumption may not hold in this study because skeletal
related events for each patient might be highly correlated. The meaning
of this analysis result should be cautiously interpreted.

#### Safety Analyses

**(1) Overall Survival Time**

One of the safety endpoints in this study was overall survival. Table
2.3.9 summarizes the survival result using the most updated safety
database.

**Table 2.3.9:** **Sponsor's Analysis for Overall Survival (Safety
Population)**

+-------------+----------------+------------+-------------+----------+
| ITT         | Median (95%CI) | Hazard     | 95% CI for  | Log-rank |
| Population  |                | Ratio      | Hazard      | P-value  |
|             | (Days)         |            | Ratio       |          |
| N=1119      |                |            |             |          |
+-------------+----------------+------------+-------------+----------+
| Aredia      | 802(684-802)   |            |             |          |
|             |                |            |             |          |
| (179/556)   |                |            |             |          |
+-------------+----------------+------------+-------------+----------+
| Zole 4mg    | Not reached    | 0.958      | 0.776-1.182 | 0.55     |
|             |                |            |             |          |
| (171/563)   |                |            |             |          |
+-------------+----------------+------------+-------------+----------+

Figure 2.3.2.

![](media/image5.wmf){width="6.6in" height="4.39375in"}

*[Reviewer's Comments:]{.underline}*

1.  The survival curves are presented in Figure 2.3.2.

2.  The median survival time for Aredia arm is 802 days, but the median
    was not reached for the Zole 4mg arm. There is no statistically
    significant difference between the two treatment arms.

### Sponsor's Conclusion and Reviewer's Conclusion/Comments

The primary objective of study 010 was to show non-inferiority in SRE in
patients with myeloma and breast cancer with cancer related bone
lesions. SRE, the primary objective for study 010, was not statistically
significant between the arm and the control arm. Regarding the
non-inferiority test, the upper limit of 95% CI for the difference of
SRE event rate between the two treatment arms was 3.7%. A 49% retention
of Aredia effect can be demonstrated.

Study 010 demonstrated marginal efficacy with respect to proportion of
SREs of zoledronate 4mg arm relative to the active control Aredia 30mg
arm. The SRE rate in zoledronate 4mg retained at least 49% of the active
control Aredia effect in the similar patient population as demonstrated
in a previous registration trial under the condition that the current
medical practice is similar to the historical trial.

## Study 011 (Cancer patients with bone metastasis, other than breast cancer, multiple myeloma or prostate cancer)

### Background

Bone metastases are frequently one of the first signs of disseminated
disease in cancer patients. Skeletal complications due to metastatic
disease include bone pain, spinal cord compromise, and pathological
fractures. The purpose of this clinical study was to determine if
therapy with zoledronate is an effective treatment to decrease the
occurrence of skeletal-related complications associated with metastatic
bone disease in patients with cancer other than breast cancer, multiple
myeloma or prostate cancer. Skeletal-related events included radiation
therapy to bone (including the use of radioisotopes), surgery to bone,
spinal cord compression, and pathological fracture events. In this
study, zoledronate treatment in addition to antineoplastic therapy
versus antineoplastic therapy alone was administered to the cancer
patients with metastatic bone lesions.

Study 011 was a randomized, double-blind, multicenter, parallel-group,
placebo controlled Phase III study conducted in a total of 773 patients
aged 18 years or over with ECOG performance status 2 and bone metastases
from solid tumors other than breast or prostate cancer. Patients were
randomized in a double-blind fashion to receive either zoledronate 4 mg
intravenously, or zoledronate 8 mg intravenously, or a placebo
intravenous infusion every three weeks for 12 doses in addition to their
antineoplastic therapy. The randomized treatment assignment ratio was to
be 1:1:1. Patients were to be treated for 36 weeks (9 months). In
addition, all patients were to receive 500 mg of calcium orally and a
multivitamin tablet (containing 500 I.U. of vitamin D) daily throughout
the study.

### Data Analyzed and Sources

Data used for this review was obtained from the electronic submission
dated 8/21/2001. The network path is
\"\\\\Cdsesub1\\n21386\\N_000\\2001_08_21\\CRT\\datatsets\\011\" in the
EDR. The following volumes were reviewed: 1, 92, 94, 97, 98, and 100.

### Study Objectives

The primary study objective of this study was to assess the efficacy of
zoledronate therapy (4 or 8 mg) in addition to antineoplastic therapy,
compared to antineoplastic therapy alone, in preventing skeletal-related
events in patients with any cancer with bone metastases other than
breast cancer, multiple meyeloma or prostate cancer. Originally
skeletal-related events (SREs) were defined as radiation therapy to
bone, a change in antineoplastic therapy to treat bone pain, surgery to
bone, spinal cord compression, and pathologic fracture events. This
definition of SRE was amended in Amendment 2 (Volume 98 Page 8-18) and
excluded the change in antineoplastic therapy to treat bone pain as a
SRE.

### Efficacy Endpoints

The primary efficacy variable was the proportion of patients with any
SRE exclusive of tumor induced hypercalcemia (TIH or -HCM)).

The secondary efficacy variables were: (a) proportion of patients with
any SRE inclusive of TIH; (b) time to first occurrence of a SRE; (c)
skeletal morbidity rate, defined as the ratio of the number of
occurrences of any SRE, allowing one event per assessing period (3
weeks), divided by the time at risk for each patient. Time at risk for
each assessing period is defined as the duration from the start of the
assessing period to the first SRE. If there is no SRE for an assessing
period, the whole duration of the assessing period was considered at
risk. Time at risk during the study was the sum of time at risk of each
assessing period of the study. (d) Time to progression to bone
metastases; (e) time to overall progression of disease; (f) quality of
life index (FACT-G), performance status (ECOG), Pain (BPI pain composite
score), and analgesic scores; (g) biochemical markers; and (h) objective
bone lesion response.

*[Reviewer's Comments:]{.underline}*

FDA reviewer of the IND protocol had conveyed to the sponsor that the if
the drop-out rate is relatively high, then the primary endpoint, SRE
proportion estimate may be biased and had also suggested that the time
to the first SRE be used as the co-primary endpoint.

### Sample Size Considerations

This trial was designed to have 80% power to detect a 16% difference in
the proportion of patients reporting any SRE during the first 9 months
of the trial between the two dose levels (4 mg and 8 mg) of zoledronate
and placebo. Based on the Bonferroni's adjustment, the samples size was
calculated, assuming a 48% incidence rate on placebo; a 32% incidence
rate on either dose level of zoledronate, with an overall type I error
rate of 0.05 (two-sided). The total sample size was determined to be 570
patients (190 on each arm). It was recommended that 600 patients be
enrolled allowing for a 5% noise included in the intent-to-treat
population. However, the sample size was increased (Amendment 4, Volume
98, Page 8-33) that at least 700 patients would be enrolled in order to
obtain 663 patients (221 patients per treatment arm). It was stated that
the amendment was based on the higher than expected overall drop-out
rate of 40% and the lower than expected SRE rate of less than 30%. The
sample size was modified assuming to have 80% power to detect a 14%
difference in the proportion of SREs during the first 9 months of the
trial between the two dose levels of zoledronate and placebo (Bonferroni
adjustment for multiple comparisons, overall type I error rate=0.05).

*[Reviewer's Comments:]{.underline}*

1.  The sample size calculations were based on that zoledronate would be
    considered more efficacious than placebo if either of the two
    comparisons (4 mg versus placebo or 8 mg versus placebo) was
    statistically significant at a 2-sided p-value \< 0.025.

2.  During the study, the design was amended (Amendment 5) to treat all
    patients on study in the 8 mg group at 4 mg dose level because of
    the observed renal toxicity with 8 mg group. In lieu of this, in the
    Amendment 6 (Volume 98, Page 8-54), it was stated that zoledronate 4
    mg will be considered more efficacious than placebo if the
    comparison for the primary efficacy outcome is statistically
    significant at 0.05 level (2-sided) favoring zoledronate 4 mg. It
    should be noted that the original design and calculation of sample
    size was based on comparing 4 mg versus placebo group at 0.025
    level. Dropping a treatment arm (in this case 8 mg group) could
    potentially inflate the overall type I error rate. (Reference:
    Tsong, Y, Hung HMJ, Wang SJ, et. al.. Dropping a treatment arm in
    clinical trial with multiple arms, JSM Proceedings, 1997).

### Stratification

The randomization was stratified by site of cancer \'lung cancer\'
versus \'other solid tumor\' (Appendix 5, Volume 100, page 8-319).

### Interim Analysis

There was no planned interim analysis for this study. However, at an
interim time point the 8 mg zoledronate arm was dropped due to renal
toxicity concerns. The sponsor claimed there was no efficacy analyses
conducted at the interim look.

### Efficacy Analyses Methods

The primary efficacy endpoint of proportion of patients with SREs per
protocol would be compared between treatment groups using a
Cochran-Mantel-Haenszel (CMH) test statistic. 95% confidence intervals
by treatment group within each stratum for the proportion of patients
reporting SRE exclusive of TIH would be presented. Zoledronate would be
considered more efficacious than placebo if either of the two
comparisons of the primary efficacy outcome is statistically superior at
a two-sided p-value \< 0.025. In Amendment 2 (Volume 98, page 8-20) the
primary analysis was modified to state that the analysis of the primary
endpoint at 9 months would be the primary analysis and that the last
observation of each patient before the time point would be carried
forward to the respective time points.

The secondary efficacy endpoint of proportion of patients with any SRE
inclusive of TIH would be compared between the treatment groups using
CMH statistic and 95% confidence intervals by treatment group within
each stratum for the proportion of patients reporting any SRE inclusive
of TIH would be presented.

Time from randomization to the first occurrence of any SRE, inclusive
and exclusive of TIH would be compared between the treatment groups,
using stratified survival analysis methods, including Kaplan-Meier
product-limit estimates of the survival functions, and the log-rank
test. Death not related to SRE would be considered as censored
observation. Multiple events analysis, allowing one event every
assessing period would be explored using Anderson-Gill approach.

Skeletal morbidity rate (SMR) will be compared between the treatment
groups using CMH test statistic with modified ridit scores.

Time to the progression of bone metastases would be compared between the
treatment groups using log-rank test. Time to overall progression of
disease would be compared between the treatment groups using stratified
log-rank test statistic.

FACT-G-total score is defined as the sum of the 4 subscales (physical,
functional, social, and emotional). Change from baseline FACT-G-total
scores and the 4 subscales would be compared between the treatment
groups using analysis of coavariance with baseline value as covariate
and treatment group and disease population as factors, at 3, 6, and 9
months. The mean of the two BPI pain composite scores and two analgesic
use for each 3 month interval would be used for the analysis of BPI pain
score and analgesic use, respectively. Change from baseline in mean BPI
composite score would be compared between the treatment groups using
analysis of covariance with baseline value as a covariate and treatment
group and disease population as factors at 3, 6, and 9 months. Change
from baseline in mean analgesic use and performance status would be
compared between the treatment groups using CMH test statistic with the
modified ridit scores at 3, 6, and 9 months.

*[Reviewer's Comments:]{.underline}*

1.  Early dropouts and missing assessments were not considered in the
    above planned analyses.

```{=html}
<!-- -->
```
2.  The infusion time was amended (Amendment 3) from 5 minutes to 15
    minutes during the study.

3.  After the enrollment was completed in all the three treatment arms,
    the dose was reduced in the 8 mg arm to 4 mg (Amendment 5) because
    of renal toxicity. In this Amendment it was also stated that the 8/4
    mg arm would not be evaluated for efficacy. However, it should be
    noted that by the time of this Amendment, majority of the patients
    had completed the study treatment phase (9 months) or had dropped
    out of the study.

### Sponsor\'s Results and Reviewer\'s Findings/Comments

#### Baseline Characteristics

A total of 773 patients were randomized as follows: 257 patients were
randomized to the 4 mg zoledronic acid group, 266 patients to the 8 mg
zoledronic acid group, and 250 patients to the placebo group. Eligible
patients were randomized into two groups: patients with non-small cell
lung cancer (NSCLC) and patients with all other types of solid tumor
cancers except breast and prostate. Several patients in each treatment
group were randomized to the incorrect stratum as follows: 35 patients
with small cell lung cancer were randomized into the NSCLC stratum,
instead of other solid tumor stratum (12 in the 4 mg group, 10 in the
8/4 mg group, and 13 in the placebo group); 3 patients with NSCLC were
randomized into the other solid tumors stratum (one patient in each
treatment group). It is reported that 7 patients did not receive
treatment with the study medication, one of these 7 patients died prior
to receiving any study medication. One patient in the 4 mg group was
found to have no evidence of skeletal metastases on the radiographic
evaluations performed at study entry and the films for another patient
on 8/4 mg group were lost in transit and therefore had no confirmed
radiographic evidence of bone metastases. Ten patients, 2 in 4 mg group,
1 in 8/4 mg group, and 7 in the placebo group were unblinded at the
study sites. All were discontinued from the study. The following Table
2.4.1a describes the baseline characteristics as presented by the
sponsor in the per protocol or safety population (Sponsor's Table 7-3,
page 8-52, Volume 92).

**Table 2.4.1a: Baseline Characteristics (Sponsor's Analysis -- Safety
Population)**

+------------------+---------------+-----------------+----------------+
|                  | **Total**     |                 |                |
+==================+===============+=================+================+
|                  | **Zol 4 mg**  | **Zol 8/4 mg**  | **Placebo**    |
|                  |               |                 |                |
|                  | **N=254**     | **N=265**       | **N=247**      |
+------------------+---------------+-----------------+----------------+
| **Age (years)**  |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 254           | 265             | 247            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 62.310.60     | 60.810.46       | 62.310.87      |
+------------------+---------------+-----------------+----------------+
| Median           | 63.5          | 62.0            | 64.0           |
+------------------+---------------+-----------------+----------------+
| Age n (%)        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| 60               | 106 (41.7%)   | 124 (46.8%)     | 98 (39.7%)     |
+------------------+---------------+-----------------+----------------+
| \> 60            | 148 (58.3%)   | 141 (53.2%)     | 149 (60.3%)    |
+------------------+---------------+-----------------+----------------+
| **Sex n (%)**    |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Male             | 158 (62.2%)   | 186 (70.2%)     | 159 (64.4%)    |
+------------------+---------------+-----------------+----------------+
| Female           | 96 (37.8%)    | 79 (29.8%)      | 88 (35.6%)     |
+------------------+---------------+-----------------+----------------+
| **Race n (%)**   |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Caucasian        | 226 (89.0%)   | 237 (89.4%)     | 223 (90.3%)    |
+------------------+---------------+-----------------+----------------+
| Black            | 15 (5.9%)     | 15 (5.7%)       | 12 (4.9%)      |
+------------------+---------------+-----------------+----------------+
| Other            | 13 (5.1%)     | 13 (4.9%)       | 12 (4.9%)      |
+------------------+---------------+-----------------+----------------+
| **Weight (kg)**  |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 252           | 262             | 245            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 72.815.23     | 74.316.91       | 71.616.04      |
+------------------+---------------+-----------------+----------------+
| Median           | 72.0          | 73.0            | 69.8           |
+------------------+---------------+-----------------+----------------+
| **Primary site   |               |                 |                |
| of cancer n      |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Lung             | 124 (48.8%)   | 134 (50.6%)     | 123 (49.8%)    |
+------------------+---------------+-----------------+----------------+
| Other            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Renal cell       | 27 (10.6%)    | 28 (10.6%)      | 19 (7.7%)      |
| carcinoma        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Cancer unknown   | 15 (5.9%)     | 14 (5.3%)       | 14 (5.7%)      |
| primary          |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Thyroid          | 2 (0.8%)      | 5 (1.9%)        | 4 (1.6%0       |
+------------------+---------------+-----------------+----------------+
| Head and neck    | 6 (2.4%)      | 7 (2.6%)        | 4 (1.6%)       |
+------------------+---------------+-----------------+----------------+
| Other            | 80 (31.5%)    | 77 (29.1%)      | 83 (33.6%)     |
+------------------+---------------+-----------------+----------------+
| **Prior type of  |               |                 |                |
| therapy**        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Chemotherapy     | 207 (81.5%)   | 212 (80.0%)     | 197 (79.8%)    |
+------------------+---------------+-----------------+----------------+
| Hormonal         | 3 (1.2%)      | 1 (0.4%)        | 2 (0.8%)       |
+------------------+---------------+-----------------+----------------+
| Missing          | 44 (17.3%)    | 52 (19.6%)      | 48 (19.4%)     |
+------------------+---------------+-----------------+----------------+
| **Previous SRE n |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Yes              | 166 (65.4%)   | 180 (67.9%)     | 179 (72.5%)    |
+------------------+---------------+-----------------+----------------+
| No               | 88 (34.6%)    | 85 (32.1%)      | 68 (27.5%)     |
+------------------+---------------+-----------------+----------------+
| **Serum          |               |                 |                |
| creatinine n     |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Normal (\< 1.4   | 233 (91.7%)   | 232 (87.5%)     | 220 (89.1%)    |
| mg/dL)           |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Abnormal ( 1.4   | 18 (7.1%)     | 33 (12.5%)      | 25 (10.1%)     |
| mg/dL)           |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Missing          | 3 (1.2%)      | 0 (0.0%)        | 2 (0.8%)       |
+------------------+---------------+-----------------+----------------+
| **Time from      |               |                 |                |
| initial          |               |                 |                |
| diagnosis of     |               |                 |                |
| cancer to bone   |               |                 |                |
| metastases       |               |                 |                |
| (month)**        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 254           | 265             | 247            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 20.346.58     | 15.539.50       | 17.233.24      |
+------------------+---------------+-----------------+----------------+
| Median           | 3.8           | 2.4             | 2.5            |
+------------------+---------------+-----------------+----------------+
| **Time from bone |               |                 |                |
| metastases to    |               |                 |                |
| Visit 2          |               |                 |                |
| (month)**        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 254           | 265             | 247            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 4.77.69       | 4.97.90         | 5.19.52        |
+------------------+---------------+-----------------+----------------+
| Median           | 1.6           | 1.8             | 1.8            |
+------------------+---------------+-----------------+----------------+
| **ECOG status n  |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| ECOG 0-1         | 211 (83.1%)   | 218 (82.3%)     | 215 (87.0%)    |
+------------------+---------------+-----------------+----------------+
| ECOG 2           | 42 (16.5%)    | 45 (17.0%)      | 32 (13.0%)     |
+------------------+---------------+-----------------+----------------+
| Missing          | 1 (0.4%)      | 2 (0.8%)        | 0 (0.0%)       |
+------------------+---------------+-----------------+----------------+
| **Analgesic      |               |                 |                |
| score n (%)**    |               |                 |                |
+------------------+---------------+-----------------+----------------+
| 0                | 30 (11.8%)    | 27 (10.2%)      | 24 (9.7%)      |
+------------------+---------------+-----------------+----------------+
| 1                | 39 (15.4%)    | 44 (16.6%)      | 38 (15.4%)     |
+------------------+---------------+-----------------+----------------+
| 2                | 6 (2.4%)      | 8 (3.0%)        | 5 (2.0%)       |
+------------------+---------------+-----------------+----------------+
| 3                | 93 (36.6%)    | 86 (32.5%)      | 76 (30.8%)     |
+------------------+---------------+-----------------+----------------+
| 4                | 86 (33.9%)    | 100 (37.7%)     | 103 (41.7%)    |
+------------------+---------------+-----------------+----------------+
| Missing          | 0 (0.0%)      | 0 (0.0%)        | 1 (0.4%)       |
+------------------+---------------+-----------------+----------------+
| **BPI composite  |               |                 |                |
| pain score**     |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 234           | 245             | 227            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 3.62.20       | 3.31.94         | 3.41.99        |
+------------------+---------------+-----------------+----------------+
| Median           | 3.5           | 3.3             | 3.3            |
+------------------+---------------+-----------------+----------------+
| **FACT-G total   |               |                 |                |
| score**          |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 230           | 241             | 227            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 70.115.21     | 69.316.85       | 70.817.73      |
+------------------+---------------+-----------------+----------------+
| Median           | 71.0          | 69.0            | 71.2           |
+------------------+---------------+-----------------+----------------+

**Table 2.4.1b: Baseline Characteristics (FDA Analysis -- ITT
population)**

<table style="width:100%;">
<colgroup>
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 10%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="3"><strong>NSCLC</strong></th>
<th colspan="3"><strong>All Others Tumors</strong></th>
<th colspan="3"><strong>Total</strong></th>
</tr>
<tr class="odd">
<th></th>
<th><p><strong>Zol 4 mg</strong></p>
<p><strong>N=134</strong></p></th>
<th><p><strong>Zol 8/4 mg</strong></p>
<p><strong>N=139</strong></p></th>
<th><p><strong>Placebo</strong></p>
<p><strong>N=130</strong></p></th>
<th><p><strong>Zol 4 mg</strong></p>
<p><strong>N=123</strong></p></th>
<th><p><strong>Zol 8/4 mg</strong></p>
<p><strong>N=127</strong></p></th>
<th><p><strong>Placebo</strong></p>
<p><strong>N=120</strong></p></th>
<th><p><strong>Zol 4 mg</strong></p>
<p><strong>N=257</strong></p></th>
<th><p><strong>Zol 8/4 mg</strong></p>
<p><strong>N=266</strong></p></th>
<th><p><strong>Placebo</strong></p>
<p><strong>N=250</strong></p></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><strong>Age (years)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>134</td>
<td>139</td>
<td>130</td>
<td>123</td>
<td>127</td>
<td>120</td>
<td>257</td>
<td>266</td>
<td>250</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>63.20.8</td>
<td>61.90.9</td>
<td>62.50.9</td>
<td>61.01.1</td>
<td>59.60.9</td>
<td>62.51.1</td>
<td>62.00.7</td>
<td>60.80.6</td>
<td>62.30.7</td>
</tr>
<tr class="even">
<td>Median</td>
<td>64.0</td>
<td>63.0</td>
<td>64.0</td>
<td>62.0</td>
<td>60.0</td>
<td>63.0</td>
<td>63.0</td>
<td>62.0</td>
<td>63.5</td>
</tr>
<tr class="odd">
<td><strong>Age n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>60</td>
<td>54 (40.3%)</td>
<td>60 (43.2%)</td>
<td>51 (39.2%)</td>
<td>55 (44.7%)</td>
<td>65 (51.1%)</td>
<td>48 (40.0%)</td>
<td>109 (42.4%)</td>
<td>125 (47.0%)</td>
<td>99 (39.6%)</td>
</tr>
<tr class="odd">
<td>&gt; 60</td>
<td>80 (59.7%)</td>
<td>79 (56.8%)</td>
<td>79 (60.8%)</td>
<td>68 (55.3%)</td>
<td>62 (48.9%)</td>
<td>72 (60.0%)</td>
<td>148 (57.6%)</td>
<td>141 (53.0%)</td>
<td>151 (60.4%)</td>
</tr>
<tr class="even">
<td><strong>Sex n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Male</td>
<td>89 (66.4%)</td>
<td>99 (71.2%)</td>
<td>82 (63.1%)</td>
<td>71 (57.7%)</td>
<td>87 (68.5%)</td>
<td>80 (66.7%)</td>
<td>160 (62.3%)</td>
<td>186 (69.9%)</td>
<td>162 (64.8%)</td>
</tr>
<tr class="even">
<td>Female</td>
<td>45 (33.6%)</td>
<td>40 (28.8%)</td>
<td>48 (36.9%)</td>
<td>52 (42.3%)</td>
<td>40 (31.5%)</td>
<td>40 (33.3%)</td>
<td>97 (37.7%)</td>
<td>80 (30.1%)</td>
<td>88 (35.2%)</td>
</tr>
<tr class="odd">
<td><strong>Race n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Caucasian</td>
<td>121 (90.3%)</td>
<td>123 (88.5%)</td>
<td>119 (91.5%)</td>
<td>108 (87.8%)</td>
<td>115 (90.6%)</td>
<td>107 (89.2%)</td>
<td>229 (90.2%)</td>
<td>238 (89.5%)</td>
<td>226 (90.4%)</td>
</tr>
<tr class="odd">
<td>Black</td>
<td><p>3</p>
<p>(2.2%)</p></td>
<td><p>8</p>
<p>(5.8%)</p></td>
<td><p>5</p>
<p>(3.6%)</p></td>
<td>12 (9.8%)</td>
<td><p>7</p>
<p>(5.5%)</p></td>
<td><p>7</p>
<p>(5.8%)</p></td>
<td>12 (4.7%)</td>
<td>15 (5.6%)</td>
<td><p>12</p>
<p>(4.8%)</p></td>
</tr>
<tr class="even">
<td>Other</td>
<td>10 (6.5%)</td>
<td><p>8</p>
<p>(5.8%)</p></td>
<td><p>6</p>
<p>(4.6%)</p></td>
<td><p>3</p>
<p>(2.4%)</p></td>
<td><p>5</p>
<p>(3.9%)</p></td>
<td><p>6</p>
<p>(5.0%)</p></td>
<td>13 (5.1%)</td>
<td>13 (4.9%)</td>
<td><p>12</p>
<p>(4.8%)</p></td>
</tr>
<tr class="odd">
<td><strong>Weight (kg)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>133</td>
<td>137</td>
<td>128</td>
<td>121</td>
<td>125</td>
<td>119</td>
<td>254</td>
<td>262</td>
<td>247</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>72.81.3</td>
<td>74.01.5</td>
<td>70.01.3</td>
<td>72.71.5</td>
<td>74.71.5</td>
<td>73.31.6</td>
<td>72.71.0</td>
<td>74.31.0</td>
<td>71.61.0</td>
</tr>
<tr class="even">
<td>Median</td>
<td>72.2</td>
<td>73.0</td>
<td>68.8</td>
<td>71.4</td>
<td>73.0</td>
<td>72.0</td>
<td>72.0</td>
<td>73.0</td>
<td>69.8</td>
</tr>
<tr class="odd">
<td><strong>Previous SRE</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Yes</td>
<td>44 (33.1)</td>
<td>47 (33.8)</td>
<td>32 (24.8)</td>
<td>44 (36.1)</td>
<td>38 (30.3)</td>
<td>36 (30.3)</td>
<td>88 (34.5)</td>
<td>85 (32.1)</td>
<td>68 (27.4)</td>
</tr>
<tr class="odd">
<td>No</td>
<td>89 (66.9)</td>
<td>92 (66.2)</td>
<td>97 (75.2)</td>
<td>78 (63.9)</td>
<td>88 (69.7)</td>
<td>83 (69.7)</td>
<td>167 (65.5)</td>
<td>180 (67.9)</td>
<td>180 (72.6)</td>
</tr>
<tr class="even">
<td><strong>Serum creatinine</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Normal (&lt; 1.4 mg/dL)</td>
<td>129 (96.3%)</td>
<td>125 (89.9%)</td>
<td>125 (96.1%)</td>
<td>110 (89.4%)</td>
<td>108 (85.0%)</td>
<td>100 (83.3%)</td>
<td>239 (93.0%)</td>
<td>233 (87.6%)</td>
<td>225 (90.0%)</td>
</tr>
<tr class="even">
<td>Abnormal ( 1.4 mg/dL)</td>
<td><p>5</p>
<p>(3.7%)</p></td>
<td>14 (10.1%)</td>
<td><p>5</p>
<p>(3.9%)</p></td>
<td>13 (10.6%)</td>
<td>19 (10.6%)</td>
<td>20 (16.7%)</td>
<td>18 (7.0%)</td>
<td>33 (12.4%)</td>
<td>25 (10.0%)</td>
</tr>
<tr class="odd">
<td><strong>Time from initial diagnosis of cancer to bone metastases
(month)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>134</td>
<td>139</td>
<td>130</td>
<td>123</td>
<td>127</td>
<td>120</td>
<td>257</td>
<td>266</td>
<td>250</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>10.22.4</td>
<td>6.51.3</td>
<td>8.31.4</td>
<td>31.05.3</td>
<td>25.54.7</td>
<td>26.53.9</td>
<td>20.12.9</td>
<td>15.62.4</td>
<td>17.02.1</td>
</tr>
<tr class="even">
<td>Median</td>
<td>1.1</td>
<td>0.6</td>
<td>0.6</td>
<td>12.3</td>
<td>4.9</td>
<td>11.3</td>
<td>3.8</td>
<td>2.4</td>
<td>2.6</td>
</tr>
<tr class="odd">
<td><strong>Time from bone metastases to Visit 2 (month)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>134</td>
<td>139</td>
<td>130</td>
<td>123</td>
<td>127</td>
<td>120</td>
<td>257</td>
<td>266</td>
<td>250</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>3.60.5</td>
<td>3.40.4</td>
<td>3.90.5</td>
<td>5.90.8</td>
<td>6.50.9</td>
<td>6.21.1</td>
<td>4.70.5</td>
<td>4.90.5</td>
<td>5.00.6</td>
</tr>
<tr class="even">
<td>Median</td>
<td>1.3</td>
<td>1.5</td>
<td>1.8</td>
<td>1.9</td>
<td>2.1</td>
<td>2.0</td>
<td>1.6</td>
<td>1.8</td>
<td>1.8</td>
</tr>
<tr class="odd">
<td><strong>ECOG status n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>ECOG 0-1</td>
<td>110 (82.1%)</td>
<td>118 (85.5%)</td>
<td>116 (89.2%)</td>
<td>102 (84.2%)</td>
<td>100 (80.0%)</td>
<td>102 (90.0%)</td>
<td>212 (83.1%)</td>
<td>218 (82.9%)</td>
<td>218 (87.2%)</td>
</tr>
<tr class="odd">
<td>ECOG 2</td>
<td>24 (17.9%)</td>
<td>20 (14.5%)</td>
<td>14 (10.2%)</td>
<td>19 (15.7%)</td>
<td>25 (20.0%)</td>
<td>18 (10.0%)</td>
<td>43 (16.9%)</td>
<td>45 (17.1%)</td>
<td>32 (12.8%)</td>
</tr>
<tr class="even">
<td><strong>Analgesic score n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>0</td>
<td>15 (11.4)</td>
<td>14 (10.1)</td>
<td>10 (7.8)</td>
<td>15 (12.3)</td>
<td>13 (10.2)</td>
<td>14 (11.9)</td>
<td>30 (11.8)</td>
<td>27 (10.2)</td>
<td>24 (9.8)</td>
</tr>
<tr class="even">
<td>1</td>
<td>20 (15.2)</td>
<td>30 (21.6)</td>
<td>14 (10.9)</td>
<td>19 (15.6)</td>
<td>14 (11.0)</td>
<td>24 (20.3)</td>
<td>39 (15.4)</td>
<td>44 (16.5)</td>
<td>38 (15.5)</td>
</tr>
<tr class="odd">
<td>2</td>
<td>3 (2.3)</td>
<td>4 (2.9)</td>
<td>4 (3.1)</td>
<td>3 (2.5)</td>
<td>4 (3.2)</td>
<td>1 (0.9)</td>
<td>6 (2.4)</td>
<td>8 (3.0)</td>
<td>5 (2.0)</td>
</tr>
<tr class="even">
<td>3</td>
<td>49 (37.1)</td>
<td>39 (28.1)</td>
<td>42 (32.8)</td>
<td>44 (36.1)</td>
<td>47 (37.0)</td>
<td>34 (28.8)</td>
<td>93 (36.6)</td>
<td>86 (32.3)</td>
<td>76 (30.9)</td>
</tr>
<tr class="odd">
<td>4</td>
<td>45 (34.1)</td>
<td>52 (37.4)</td>
<td>58 (45.3)</td>
<td>41 (33.6)</td>
<td>49 (38.6)</td>
<td>45 (38.1)</td>
<td>86 (33.9)</td>
<td>101 (38)</td>
<td>103 (41.9)</td>
</tr>
<tr class="even">
<td><strong>BPI composite pain score</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>N</td>
<td>109</td>
<td>120</td>
<td>106</td>
<td>125</td>
<td>125</td>
<td>121</td>
<td>234</td>
<td>245</td>
<td>227</td>
</tr>
<tr class="even">
<td>Mean SD</td>
<td>3.60.2</td>
<td>3.50.2</td>
<td>3.40.2</td>
<td>3.60.2</td>
<td>3.20.2</td>
<td>3.40.2</td>
<td>3.60.1</td>
<td>3.30.1</td>
<td>3.40.1</td>
</tr>
<tr class="odd">
<td>Median</td>
<td>3.5</td>
<td>3.5</td>
<td>3.3</td>
<td>3.5</td>
<td>3.0</td>
<td>3.3</td>
<td>3.5</td>
<td>3.3</td>
<td>3.3</td>
</tr>
<tr class="even">
<td><strong>FACT-G total score</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>N</td>
<td>108</td>
<td>120</td>
<td>106</td>
<td>122</td>
<td>121</td>
<td>121</td>
<td>230</td>
<td>241</td>
<td>227</td>
</tr>
<tr class="even">
<td>Mean SD</td>
<td>69.41.3</td>
<td>68.41.5</td>
<td>69.81.7</td>
<td>70.71.5</td>
<td>70.21.6</td>
<td>71.71.7</td>
<td>70.11.0</td>
<td>69.31.1</td>
<td>70.81.2</td>
</tr>
<tr class="odd">
<td>Median</td>
<td>70.0</td>
<td>67.1</td>
<td>70.0</td>
<td>71.1</td>
<td>69.0</td>
<td>74.0</td>
<td>71.0</td>
<td>69.0</td>
<td>71.2</td>
</tr>
</tbody>
</table>

*[Reviewer's Comments]{.underline}*:

1.  Table 2.4.1b describes the baseline characteristics of the ITT
    population as analyzed by the reviewer.

2.  Although there appears to be no imbalance between the treatment
    arms, there are significant differences between the two stratum
    (lung versus other solid tumors) with respect time from initial
    diagnosis of cancer to bone metastases, and time from first bone
    metastases to Visit 2 of the study (study start day). It is not
    clear as to how this difference in time between the two strata
    translates to differences or lack of differences with respect to
    skeletal related events. These patients were also receiving
    concomitantly anticancer therapy and this may be a confounding
    factor with the study drug in estimating the reduction in skeletal
    related events attributable to the study drug in each stratum and
    treatment group.

#### Primary Efficacy Analyses

The primary efficacy variable was the proportion of patients
experiencing at least one SRE (-HCM). Per sponsor analysis by month 9
both the zoledronic acid 4 mg and 8/4 mg groups had a lower proportion
than the placebo group. However, there was **no statistically
significant difference between 4 mg and placebo groups (p=0.13)** as
presented below in Table 2.4.2 (Sponsor Table 9-1, Volume 92, page
8-58).

Table 2.4.2: Proportion of Patients Having SRE (-HCM) up to Month 9 by
Stratum and Treatment Group (ITT patients) -- Sponsor's Analysis

  ----------------- ---------------- ------------------ -------------------
                                     **95% C.I. and     
                                     P-value for the    
                                     difference**       

                    **Proportion**   **Zol 4 mg**       **Zol 8/4 mg**

  **Lung Cancer**                                       

  **Placebo**       59/130 (45%)     (-15.6%,8.4%),     (-23.3%,0.1%),
                                     p=0.557            p=0.053

  **Zol 4 mg**      56/134 (42%)     \-                 (-19.5%,3.5%),
                                                        p=0.175

  **Zol 8/4 mg**    47/139(34%)      \-                 \-

  **Other Solid                                         
  Tumors**                                              

  **Placebo**       52/120 (43%)     (22.2%,2.2%),      (-20.1%,4.3%),
                                     p=0.110            p=0.205

  **Zol 4 mg**      41/123 (33%)     \-                 (-9.7%,13.9%),
                                                        p=0.727

  **Zol 8/4 mg**    45/127 (35%)     \-                 \-

  **Total**                                             

  **Placebo**       111/250 (44%)    (-15.2%,1.9%),     (-18.2%,-1.4%),
                                     **p=0.127**        p=0.023

  **Zol 4 mg**      97/257 (38%)     \-                 (-11.4%,5.1%),
                                                        p=0.452

  **Zol 8/4 mg**    92/266 (35%)     \-                 \-
  ----------------- ---------------- ------------------ -------------------

*[Reviewer\'s Comments:]{.underline}*

1.  The study has failed to demonstrate efficacy of 4 mg zoledronate
    over placebo treated group in reducing the proportion of SREs at 9
    months. Since the decision of dropping 8/4 mg zoledronate arm for
    toxicity was made, the efficacy comparison between 8/4 mg arm and
    placebo arm is not appropriate and may result in type I error
    adjustment.

2.  The estimates of the proportion of SREs presented in Table 2.4.2 may
    be biased estimates because of high dropout rate (approximately only
    27% were treated at 9 months) as presented below in Table 2.4.3. In
    the least conservative approach, if the total number of events at 9
    months in each of the treatment groups are subtracted from the total
    number of patients that were randomized, then 71/160 patients
    (44.3%) in zoledronate 4 mg group, 69/173 patients (39.9%) in
    zoledronate 8/4 mg group, and 69/133 patients (50.4%) in the placebo
    group received treatment at 9 months. Therefore the dropout rate was
    at least 56%.

    **Table 2.4.3: Number of Patients Treated up to 9 Months (FDA
    Analysis)**

<table style="width:100%;">
<colgroup>
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"></td>
<td colspan="3"><strong>Lung Cancer</strong></td>
<td colspan="3"><strong>Other Solid Tumors</strong></td>
<td colspan="3"><strong>Total</strong></td>
</tr>
<tr class="even">
<td><strong>Zol 4 mg</strong></td>
<td><strong>Zol 8/4 mg</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Zol 4 mg</strong></td>
<td><strong>Zol 8/4 mg</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Zol 4 mg</strong></td>
<td><strong>Zol 8/4 mg</strong></td>
<td><strong>Placebo</strong></td>
</tr>
<tr class="odd">
<td><strong>Study Start (Visit 2)</strong></td>
<td>134</td>
<td>139</td>
<td>130</td>
<td>123</td>
<td>127</td>
<td>120</td>
<td>257</td>
<td>266</td>
<td>250</td>
</tr>
<tr class="even">
<td><strong>3 months</strong></td>
<td>98</td>
<td>96</td>
<td>84</td>
<td>89</td>
<td>80</td>
<td>84</td>
<td>187</td>
<td>176</td>
<td>168</td>
</tr>
<tr class="odd">
<td><strong>6 months</strong></td>
<td>59</td>
<td>50</td>
<td>48</td>
<td>53</td>
<td>56</td>
<td>48</td>
<td>112</td>
<td>106</td>
<td>96</td>
</tr>
<tr class="even">
<td><strong>9 months</strong></td>
<td><strong>38 (28.4%)</strong></td>
<td><p><strong>30</strong></p>
<p><strong>(21.6%)</strong></p></td>
<td><strong>35 (26.9%)</strong></td>
<td><strong>33 (26.8%)</strong></td>
<td><p><strong>39</strong></p>
<p><strong>(30.7%)</strong></p></td>
<td><strong>32 (26.7%)</strong></td>
<td><strong>71 (27.6%)</strong></td>
<td><p><strong>69</strong></p>
<p><strong>(25.9%)</strong></p></td>
<td><strong>67 (26.8%)</strong></td>
</tr>
</tbody>
</table>

3.  The sponsor was advised by the agency during the protocol
    development stage to consider time to first SRE as the primary
    efficacy parameter, which can take into account censoring of
    observations during the course of the study. Therefore, in order to
    account for the early censoring of the observations, this reviewer
    conducted time to first SRE analysis using Kaplan-Meier estimation
    procedure, truncating the maximum follow up time at 9 months (Table
    2.4.4). Data beyond 9 months was confounded because of cross over of
    patients to zoledronate treatment group from placebo group. The
    Kaplan-Meier estimates of the proportion of skeletal event rate at 9
    months are higher than those presented in Table 2.4.2 using simple
    proportion method. This is because the censoring information was
    incorporated in the Kaplan-Meier estimates. There appears to be a
    statistically significant difference between the Zoledronate 4 mg
    group and placebo group (p=0.026) by this analysis. In this analysis
    death before SRE was censored for SRE. Patient with subject ID 12452
    the visit 2 date (start date) was after the date of death and
    therefore this patient was deleted from the analysis. Patients with
    subject IDs 12451, 12485, 13108, 21719 and 22515 was recorded with
    time to first SRE greater than survival time and therefore in these
    patients time to first SRE was replaced with survival time and
    censored for the SRE. Kaplan-Meier estimates of proportion of SREs
    at 3, 6, and 9 months respectively are presented in Table 2.4.4b.

Table 2.4.4a: Analysis of Time to First Skeletal Related Event Truncated
at 9 Months Using Kaplan-Meier Estimation Procedure (ITT Population FDA
Analysis)

  -------------- -------------- ------- --------------------- ---------------
                 **Event Rate   **N**   **Median Time to      **P-value
                 at 9 Months**          Event in days (95%    (Comparison to
                                        C.I.)**               Placebo using
                                                              Log-rank
                                                              test)**

  **Lung                                                      
  Cancer**                                                    

  **Placebo**    67.9%          130     151 (90, 202)         

  **Zol 4 mg**   60.7%          133     168 (154, \*)         0.19

  **Zol 8/4 mg** 53.6%          139     249 (175, \*)         0.04

  **Other Solid                                               
  Tumors**                                                    

  **Placebo**    58.2%          120     168 (106, \*)         

  **Zol 4 mg**   43.9%          123     \* (174, \*)          0.05

  **Zol 8/4 mg** 52.4%          127     198 (156, \*)         0.35

  **Total**                                                   

  **Placebo**    63.2%          250     163 (106, 188)        

  **Zol 4 mg**   52.8%          256     230 (168, \*)         0.026

  **Zol 8/4 mg** 53.0%          266     219 (172, \*)         0.035
  -------------- -------------- ------- --------------------- ---------------

\* = Not Reached

**Table 2.4.4b:** **Analysis of Time to First Skeletal Related Event
Truncated at 3, 6, and 9 Months Using Kaplan-Meier Estimation Procedure
(ITT Population FDA Analysis)**

  ------------- ---------- -------------- ---------- -------------- ---------- --------------
  **Total**     **At 3                    **At 6                    **At 9     
                Months**                  Months**                  Months**   

                **Event    **\*Event Rate **Event    **\*Event Rate **Event    **\*Event Rate
                Rate**     difference**   Rate**     difference**   Rate**     difference**

  **Placebo**   33.2%                     53.7%                     63.2%      

  **Zol 4 mg**  25.4%      7.8%           43.6%      10.1%          52.8%      10.4%

  **Zol 8/4     26.7%      6.5%           42.1%      11.6%          53.0%      10.2%
  mg**                                                                         
  ------------- ---------- -------------- ---------- -------------- ---------- --------------

\* Difference between Placebo and Treatment, not for comparison

4.  The penalty for dropping a treatment group (8/4 group) with respect
    to type I error rate is debatable because although the treatment
    group was dropped for safety reasons, the decision to drop the
    treatment arm from efficacy analysis was made after all the patients
    were enrolled into the 8 mg group and had received a significant
    amount of treatment. Table 2.4.5 lists the occurrence of events
    during the 9 months study period. More than 75% of the SREs had
    occurred by 3 months evaluation, at which time majority of the
    patients in the 8 mg treatment group had received the treatment per
    original protocol at 8 mg dose level (Table 2.4.6).

**Table 2.4.5: Number of SREs by Stratum, Treatment, and Evaluation
Times (FDA Analysis)**

  ------------------- ---------- ---------- ---------- --------------------
                      **3        **6        **9        **Total up to 9
                      months**   months**   months**   months**

  **Lung Cancer**                                      

  **Placebo**         48         9          5          62

  **Zol 4 mg**        39         13         4          56

  **Zol 8/4 mg**      36         8          4          48

  **Other Solid                                        
  Tumors**                                             

  **Placebo**         43         10         2          55

  **Zol 4 mg**        30         7          4          41

  **Zol 8/4 mg**      35         8          2          45

  **Total**                                            

  **Placebo**         91         19         7          117

  **Zol 4 mg**        69         20         8          97

  **Zol 8/4 mg**      71         16         6          93
  ------------------- ---------- ---------- ---------- --------------------

**Table 2.4.6: Number of Patients in the Zoledronate 8 mg group Who Were
Treated at Reduced Dose of Zoledronate 4 mg up to 3 Months**

  ------------------- ----------- ------- ---------- ---------- --------------
  **Visit #:**        **2         **3**   **4**      **5**      **6 (3
                      (start)**                                 months)**

  **\# of patients    0/265       0/234   2/206      12/173     29/151
  treated at Zol 4                                              
  mg**                                                          
  ------------------- ----------- ------- ---------- ---------- --------------

5.  It should also be noted that according to this reviewer\'s analysis
    (Table 2.4.5) there were 6 more events in the placebo group and one
    more event in the zoledronate 8/4 mg group than the number of events
    reported by the sponsor (Table 2.4.2). Furthermore, these events
    were based on evaluation of 239 patients (instead of 250 patients as
    randomized) in the placebo group, 247 patients (instead of 257
    patients as randomized) in the zoledronate 4 mg group, and 253
    patients (instead of 266 patients as randomized) in the zoledronate
    4/8 mg group. The sponsor has clarified that 7 of the 34 patients on
    whom event data were not available, did not receive any treatment on
    the study and were not evaluable. The sponsor has also clarified
    that the remaining 27 patients had dropped out of the study before
    the 3 month radiological evaluation of skeletal related events. This
    furthermore indicates that the estimate of proportion as defined in
    the protocol would be biased because, 34 patients who were not even
    evaluated for the primary efficacy endpoint were in fact counted as
    having no events in the sponsor analysis.

#### Secondary Efficacy Analyses

The sponsor evaluated several parameters as secondary efficacy
variables. The results of the parameters: (1) the proportion of patients
experiencing a SRE, including hypercacemia of mailignancy (HCM) or also
known as tumor-induced hypercalcemia (TIH); (2) the proportion of
patients experiencing individual SREs, including HCM; (3) change in ECOG
performance status; (4) change in FACT-G score; (5) change in analgesic
scores; and (6) change in pain scores, evaluated by the sponsor will not
be further presented or discussed in this review (see comment 2 below).

Time to first occurrence of an SRE was evaluated by the sponsor as a
secondary efficacy parameter as specified in the protocol (Table 2.4.7)
(Sponsor's Table 9-3, page 8-61, Volume 92).

Table 2.4.7: Summary of Time to the First SRE (-HCM) up to Month 9, by
Stratum and Treatment Group (Sponsor Analysis)

  ------------- ---------- ---------- ---------- ---------- -------------- ----------
                                                            **P-values\*   
                                                            for the        
                                                            between        
                                                            treatment      
                                                            comparison**   

                **N**      **Event    **25%      **Median   **Zol 4 mg**   **Zol 8/4
                           rate at    Quartile   (days)**                  mg**
                           day 252**  (days)**                             

  **Lung                                                                   
  Cancer**                                                                 

  **Placebo**   130        67.9%      74         151        0.188          0.041

  **Zol 4 mg**  134        60.5%      84         171                       0.406

  **Zol 8/4     139        53.6%      82         249                       
  mg**                                                                     

  **Other Solid                                                            
  Tumors**                                                                 

  **Placebo**   120        58.2%      69         168        0.051          0.342

  **Zol 4 mg**  123        43.9%      89         314                       0.328

  **Zol 8/4     127        52.4%      83         198                       
  mg**                                                                     

  **Total**                                                                

  **Placebo**   250        63.2%      70         163        0.023          0.034

  **Zol 4 mg**  257        52.7%      84         230                       0.969

  **Zol 8/4     266        52.9%      82         219                       
  mg**                                                                     
  ------------- ---------- ---------- ---------- ---------- -------------- ----------

\* P-values from Cox-regression with factor treatment stratified by the
strata

Skeletal morbidity rate defined as the number of SREs divided by the
time at risk in years was analyzed by the sponsor as presented below in
Table 2.4.8. (Sponsor's Table 9-5, page 8-62, Volume 92).

Table 2.4.8: Summary of Skeletal Morbidity Rate (risk set definition) of
any SRE (-HCM) up to Month 9, by Stratum and Treatment Group (Sponsor
Analysis)

  ------------- ----------- ------------ ------------ -------------- -----------
                **N**       **Skeletal                **P-values\*   
                            morbidity                 for the        
                            rate (no. of              between        
                            events per                treatment      
                            year)**                   comparison**   

                            **Mean SD**  **Median**   **Zol 4 mg**   **Zol 8/4
                                                                     mg**

  **Lung                                                             
  Cancer**                                                           

  **Placebo**   130         2.37 4.102   0            0.307          0.012

  **Zol 4 mg**  134         2.62 11.815  0                           0.117

  **Zol 8/4     139         1.36 3.279   0                           
  mg**                                                               

  **Other Solid                                                      
  Tumors**                                                           

  **Placebo**   120         2.67 6.039   0            0.116          0.147

  **Zol 4 mg**  123         1.82 4.707   0                           0.849

  **Zol 8/4     127         1.75 4.300   0                           
  mg**                                                               

  **Total**                                                          

  **Placebo**   250         2.52 5.115   0            0.069          0.005

  **Zol 4 mg**  257         2.24 9.124   0                           0.309

  **Zol 8/4     266         1.55 3.798   0                           
  mg**                                                               
  ------------- ----------- ------------ ------------ -------------- -----------

The time to multiple occurrences of SREs was also analyzed by the
sponsor using Anderson-Gill approach. In this analysis every counted
occurrence of an SRE was followed by a 20-day period during which no
other occurrence of an SRE was counted. Time to each counted occurrence
of an SRE was counted from the 22^nd^ day of the last counted occurrence
of an SRE to the onset day. Per sponsor analysis the difference between
placebo and zoledronate 4 mg group was statistically significant.

*[Reviewer's Comments]{.underline}*:

1.  All secondary efficacy analyses can only be considered as
    exploratory and supportive of a positive primary efficacy analysis.
    In this study per sponsor and protocol specified primary efficacy
    analysis the treatment (zoledronate 4 mg) is not statistically
    significantly different from placebo.

2.  The agency had recommended that the time to first occurrence of an
    SRE to be evaluated as a primary efficacy variable. The results of
    this analysis have already been discussed in the previous section
    (section 2.3.8.2, Reviewer's comment 3).

3.  As stated before (section 2.3.8.2, Reviewer\'s comments), the
    estimates of the treatment effect may be biased due to high drop out
    rate and less than optimum method used for evaluation of missing
    data (last observation carried forward).

4.  Per sponsor analysis there is no statistically significant
    difference between the placebo and zoledronate 4 mg with respect to
    skeletal morbidity rate (Table 2.4.8).

5.  The sponsor's multiple event analysis has not been verified by the
    reviewer at this time.

6.  This reviewer conducted exploratory multivariable Cox regression
    analyses of the time to first SRE data with treatment (placebo=0,
    zoledronate=1), prior history of skeletal events (no=0, yes=1), time
    from initial diagnosis of cancer to bone metastases (in months), and
    time from first bone metastases to Visit 2 of the study (in months).
    The results of these analyses are presented in Tables 2.4.9a -
    2.4.9c. In all of the models treatment effect was statistically
    significant. The point estimate of hazard ratio for placebo versus
    treatment was consistent among all the models and the upper 95%
    confidence limit of the hazard ratio was less than 1. Exploratory
    models comparing placebo with zoledronate 8/4 mg groups are
    presented in Appendix (Appendix 4.2).

**Table 2.4.9a: Cox Regression Model with Treatment (Placebo vs. Zol 4
mg) as Co-variate**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment Overall**   0.733 (0.557, 0.965)         0.027

  **Treatment Lung Cancer 0.785 (0.544, 1.132)         0.194
  Group**                                              

  **Treatment Other Solid 0.664 (0.438, 1.009)         0.055
  Tumors Group**                                       
  ----------------------- ---------------------------- -------------------

**Table 2.4.9b: Cox Regression Model with Treatment (Placebo vs. Zol 4
mg) and prior history of SRE (Yes or No) as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.741 (0.563, 0.976)         0.033

  **Prior SRE**           1.437 (1.050, 1.965)         0.023
  ----------------------- ---------------------------- -------------------

**Table 2.4.9c: Cox Regression Model with Treatment (Placebo vs. Zol 4
mg ) and Prior History of SRE (Yes or No), Time from Initial Diagnosis
of Cancer to Bone Metastases, and Time from First Bone Metastases to
Visit 2 of the Study as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.722 (0.548, 0.952)         0.021

  **Prior SRE**           1.535 (1.116, 2.110)         0.008

  **Time from Initial Dx. 0.994 (0.989, 0.999)         0.015
  of Ca. To Bone Met.**                                

  **Time from First Bone  0.986 (0.969, 1.003)         0.102
  Met. to Study Entry**                                
  ----------------------- ---------------------------- -------------------

#### Safety Analyses

##### Survival Analysis

Because the zoledronate treatment was not expected to improve survival,
it was evaluated as part of safety analysis. The following is the
survival analysis results of FDA analysis using the ITT population
(instead of safety population used by sponsor). There were no
statistically significant differences in survival between zoledronate 4
mg and placebo groups, or between zoledronate 8 mg and placebo groups as
presented in Figures 2.4.1-2.4.3 and Table 2.4.10. All other safety
analyses are presented in the clinical review of the application.

**Figure 2.4.1: Kaplan-Meier Survival Analysis of Over All Survival in
ITT Population (FDA Analysis)**

![](media/image6.png){width="5.492361111111111in"
height="3.189583333333333in"}

**Figure 2.4.2: Kaplan-Meier Survival Analysis of Zoledronate 4 mg
versus Placebo groups in ITT Population (FDA Analysis)**

![](media/image7.png){width="5.495138888888889in"
height="3.3319444444444444in"}

**Figure 2.4.3: Kaplan-Meier Survival Analysis of Zoledronate 8/4 mg
versus Placebo Groups in ITT Population (FDA Analysis)**

![](media/image8.png){width="5.495138888888889in"
height="3.3319444444444444in"}

**Table 2.4.10: Summary of Survival Analyses Results (FDA Analysis)**

+------------+----+---------+-----------+--------------+--------------+
|            | *  | *       | **Median  | **Hazard     | **P-values** |
|            | *N | *Number | (95%      | Ratio**      |              |
|            | ** | of      | C.I.) in  |              | **(Treatment |
|            |    | E       | days**    | **( 95%      | versus       |
|            |    | vents** |           | C.I.)**      | Placebo,     |
|            |    |         |           |              | Log-rank     |
|            |    |         |           |              | test)**      |
+------------+----+---------+-----------+--------------+--------------+
| *          | 2  | 188     | 183 (155, |              |              |
| *Placebo** | 50 |         | 205)      |              |              |
+------------+----+---------+-----------+--------------+--------------+
| **Zol 4    | 2  | 199     | 203 (175, | 0.632        | 0.63         |
| mg**       | 56 |         | 228)      | (0.780,      |              |
|            |    |         |           | 1.163)       |              |
+------------+----+---------+-----------+--------------+--------------+
| **Zol 8/4  | 2  | 191     | 189 (154, | 0.923        | 0.44         |
| mg**       | 66 |         | 237)      | (0.755,      |              |
|            |    |         |           | 1.129)       |              |
+------------+----+---------+-----------+--------------+--------------+

### Sponsor\'s Conclusions and Reviewer\'s Conclusions/Comments

Study 011 was a randomized, double-blind, multicenter, parallel-group,
placebo controlled Phase III study conducted in a total of 773 patients
aged 18 years or over with ECOG performance status 2 and bone metastases
from solid tumors other than breast or prostate cancer. The primary
objective of this study was to assess the efficacy of zoledronate
therapy (4 or 8 mg) in addition to antineoplastic therapy, compared to
antineoplastic therapy alone, in preventing skeletal-related events in
patients with any cancer with bone metastases other than breast cancer,
multiple meyeloma or prostate cancer. Skeletal-related events (SREs)
were defined as radiation therapy to bone, surgery to bone, spinal cord
compression, and pathologic fracture events. The primary efficacy
endpoint was the proportion of patients with any SRE exclusive of tumor
induced hypercalcemia by month 9.

1.  The sample size calculations were based on that zoledronate would be
    considered more efficacious than placebo if either of the two
    comparisons (4 mg versus placebo or 8 mg versus placebo) was
    statistically significant at a 2-sided p-value \< 0.025. During the
    study, the design was amended to treat all patients on study in the
    8 mg group at 4 mg dose level because of the observed renal toxicity
    with 8 mg group. In lieu of this, the protocol was amended
    (Amendment 6) which stated that zoledronate 4 mg will be considered
    more efficacious than placebo if the comparison for the primary
    efficacy outcome is statistically significant at 0.05 level
    (2-sided) favoring zoledronate 4 mg. It should be noted that the
    original design and calculation of sample size was based on
    comparing 4 mg versus placebo group at 0.025 level. Dropping a
    treatment arm (in this case 8 mg group) could potentially inflate
    the overall type I error rate.

2.  Although there appears to be no imbalance between the treatment arms
    there are significant differences between the two stratum (lung
    versus other solid tumors) with respect time from initial diagnosis
    of cancer to bone metastases, and time from first bone metastases to
    Visit 2 of the study (study start day). It is not clear as to how
    this difference in time between the two strata translates to
    differences or lack of differences with respect to skeletal related
    events. These patients were also receiving concomitantly anticancer
    therapy and this is a confounding factor with the study drug in
    estimating the reduction in skeletal related events attributable to
    the study drug in each stratum and treatment group.

3.  The study has failed to demonstrate efficacy of 4 mg zoledronate
    over placebo treated group in reducing the proportion of SREs at 9
    months per protocol specified analysis (P-value=0.127). The protocol
    specified estimates of the proportion of SREs (Table 2.4.2) may be
    biased estimates because of high dropout rate. The sponsor was
    advised by the agency during the protocol development stage to
    consider time to first SRE as the primary efficacy parameter, which
    can take into account censoring of observations during the course of
    the study. Therefore, in order to account for the early censoring of
    the observations, this reviewer conducted time to first SRE analysis
    using Kaplan-Meier estimation procedure, truncating the maximum
    follow up time at 9 months (Table 2.4.4). There appears to be a
    statistically significant difference between the Zoledronate 4 mg
    group and placebo group (p=0.026, 2-sided log-rank test) by this
    analysis.

4.  Multivariate analyses of time to first occurrence suggest that the
    results are consistent and the zoledronate 4 mg treatment appears to
    have efficacy.

5.  Patients on the study were receiving varying anticancer therapy,
    which could potentially be confounding efficacy of the study drug in
    estimating the reduction in skeletal related events in each stratum
    and treatment group.

## Study 039 (Prostate cancer patients with metastatic bone lesions)

### Background

Prostate cancer is one of the most common cancers among men. The vast
majority of patients with advanced prostate cancer have skeletal
metastases. Skeletal complications due to metastatic disease include,
bone pain, spinal cord compromise, and pathological fractures. The
purpose of this clinical study was to determine if zoledronate would be
an effective treatment to decrease the occurrence of skeletal-related
complications associated with metastatic bone disease in prostate cancer
patients. In this study, zoledronate treatment in addition to
antineoplastic therapy versus antineoplastic therapy alone, was to be
administered to prostate cancer patients who have developed biochemical
progression of disease (a rising serum prostate-specific antigen (PSA)
level) while on first-line hormonal therapy for metastatic bone disease.
Skeletal-related events were to include pathologic bone fracture event,
spinal cord compression events, surgery to bone, radiation therapy to
bone (including the use of radioisotopes) and a change of antineoplastic
therapy to treat bone pain.

Study 039 was a international, multicenter, randomized, double-blind,
placebo-controlled, parallel study conducted in prostate cancer patients
with a history of metastatic bone disease who have a rising serum PSA
concentration despite treatment with first-line hormonal therapy for
meatastatic disease. Patients were randomized in a double-blind fashion
to receive either zoledronate 4 mg intravenously, or zoledronate 8 mg
intravenously, or a placebo intravenous infusion every three weeks in
addition to their antineoplastic therapy. The randomized treatment
assignment ratio was to be 1:1:1. In addition all patients were to
receive 500 mg of calcium orally and multivitamin tablet (containing
400-500 I.U. of vitamin D) daily throughout the study.

### Data Analyzed and Sources

Data used for this review was obtained from the electronic submission
dated 8/21/2001. The network path is
\"\\\\Cdsesub1\\n21386\\N_000\\2001_08_21\\CRT\\datatsets\\039\" in the
EDR. The following volumes were reviewed: 1, 106, 107, 109, 112, 114,
and 115.

### Study Objectives

The primary objective of this study was to assess the efficacy of
zoledronate treatments (4 or 8 mg) in addition to antineoplastic
therapy, compared to antineoplastic therapy alone to prevent
skeletal-related events (SREs) in prostate cancer patients with a
history of metastatic bone disease who have developed biochemical
progression of disease. SREs were defined as pathologic bone fracture
events, spinal cord compression events, surgery to bone, and radiation
therapy to bone (including the use of radioisotopes).

### Efficacy Endpoints

The primary efficacy variable in this study was the proportion of
patients having at least one skeletal-related event.

The secondary efficacy variables included: (1) skeletal morbidity rate
(SMR), (2) time to the first occurrence of a SRE, (3) time to disease
progression in bone, (4) time to disease progression, (5) pain scores
(BPI), (6) analgesic scores, (7) performance status (ECOG), (8) quality
of life (FACT-G and EURO QOL EQ-5D), (9) objective bone lesion response
from radiological studies, and (10) biochemical variables.

*[Reviewer's Comments:]{.underline}*

FDA reviewer of the IND protocol had conveyed to the sponsor that the if
the drop-out rate is relatively high, then the primary endpoint, SRE
proportion estimate may be biased and had also suggested that the time
to the first SRE be used as the co-primary endpoint.

### Sample Size Considerations

This trial was designed to have 80% power to detect a 16% difference in
the proportion of patients reporting any SRE during the first 15 months
of the trial (Phase I) between the two dose level (4 mg and 8 mg) of
zoledronate and placebo. Based on the bonferroni\'s adjustment, the
sample size was calculated, assuming a 40% incidence rate on placebo; a
24% incidence rate on either dose level of zoledronate, with an overall
Type I error rate of 0.05 (two-sided). The total sample size was
determined to be 519 patients (173 on each arm). It was recommended that
550 patients be enrolled to account for the noise introduced by the use
of intent-to-treat (ITT) population.

*[Reviewer's Comments:]{.underline}*

1.  A total of 643 patients were enrolled into the study (208 in placebo
    group, 214 in the zoledronate 4 mg group and 221 in the zoledronate
    8/4 mg group) instead of the planned total of 550 patients.

2.  The sample size calculations were based on that zoledronate would be
    considered more efficacious than placebo if either of the two
    comparisons (4 mg versus placebo or 8 mg versus placebo) was
    statistically significant at a 2-sided p-value \< 0.025.

3.  During the study, the design was amended (Amendment 4) to treat all
    patients on study in the 8 mg group at 4 mg dose level because of
    the observed renal toxicity with 8 mg group. In lieu of this, in the
    Amendment 6 (Volume 112, Page 8-181), it was stated that zoledronate
    4 mg will be considered more efficacious than placebo if the
    comparison for the primary efficacy outcome is statistically
    significant at 0.05 level (2-sided) favoring zoledronate 4 mg. It
    should be noted that the original design and calculation of sample
    size was based on comparing 4 mg versus placebo group at 0.025
    level. Dropping a treatment arm (in this case 8 mg group) could
    potentially inflate the overall type I error rate. (Reference:
    Tsong, Y, Hung HMJ, Wang SJ, et. al.. Dropping a treatment arm in
    clinical trial with multiple arms, JSM Proceedings, 1997).

### Stratification

The randomization was stratified by prostate cancer history (no
metastatic disease present at the time of the initial diagnosis of
prostate cancer versus metastatic disease present at the time of the
initial diagnosis), after Amendment 1 of the protocol (Volume 112, page
8-99).

### Interim Analysis

No interim analysis was planned for this study. However, at an interim
time point the 8 mg zoledronate arm was dropped due to renal toxicity
concerns. The sponsor claimed there was no efficacy analyses conducted
at the interim look.

### Efficacy Analysis Methods

The primary efficacy endpoint of proportion of patients with any SRE
during the first 15 months of the study, was originally planned to be
compared between treatment and placebo groups using chi-squared test.
This plan was amended after Amendment 1 of the protocol (Volume 112,
page 8-119) to compare the treatment and placebo groups using the
Cochran-Mantel-Haenzel test statistic. 95% CI for the proportion of
patients reporting any SRE by treatment group was also to be presented.
In the Amendment 1 the analysis also included evaluation of the
influence of stratum and previous experience of SREs using logistic
regression analyses.

One of the secondary efficacy variables, skeletal morbidity rate (SMR)
defined as the ratio of the number of occurrences of any SRE, allowing
one event per assessing period (3 weeks), divided by the time at risk,
was originally planned to be compared between treatment groups using
Wilcoxon rank sum test, which was later amended (Amendment 1, Volume
112, page 8-120) to analyze using Cochran-Mantel-Haenzel test statistic
with modified ridit scores.

Time to first occurrence of a SRE was planned to be compared between the
treatment groups using survival analysis methods, including Kaplan-Meier
product limit estimates and the log-rank test. Death not related to SRE
would be considered as censored observation. Multiple events analysis,
allowing one event every assessing period would be explored using
Anderson-Gill approach.

For each particular type of SRE, the proportion of patients with the
SRE, the SMR of the SRE, at month 3, 6, 9, 12 and 15 and the time to
first occurrence of the SRE was planned to be similarly analyzed using
the method for the respective variable with any SRE.

Change from baseline in BPI composite score was planned to compared
between the treatment groups using analysis of covariance with baseline
value as a covariate and the treatment group as a factor at 3, 6, 9, 12,
and 15 months. Change from baseline in mean analgesic use and
performance status were planned to be compared between the treatment
groups using the Cochran-Mantel-Haenzel (CMH) test statistic with
modified ridit scores (originally planned to use Wilcoxon rank sum test)
at 3, 6, 9, 12, and 15 months. Change from baseline in FACT-G total
scores and the 4 subscales were planned to be compared between the
treatment groups using analysis of covariance with baseline value as a
covariate and treatment groups as a factor, at 3, 6, 9, 12, and 15
months. Change from baseline in EURO QOL-5D was planned to be analyzed
similarly.

Time to progression of disease and time to progression of bone lesions
were planned to be compared between treatment groups using Kaplan-Meier
product limit estimates and log-rank test.

Percent change from baseline of biochemical variables were planned to be
compared between the treatment groups using the CMH test statistics with
modified ridit scores.

*[Reviewer's Comments:]{.underline}*

1.  Early dropouts and missing assessments were not considered in the
    above planned analyses.

2.  The infusion time was amended (Amendment 3) from 5 minutes to 15
    minutes during the study.

3.  After the enrollment was completed in all the three treatment arms,
    the dose was reduced in the 8 mg arm to 4 mg (Amendment 4) because
    of renal toxicity. In this Amendment it was also stated that the 8/4
    mg arm would not be evaluated for efficacy. However, it should be
    noted that by the time of this Amendment, majority of the patients
    had completed the phase I (15 months) or had dropped out of the
    study.

4.  The definition of ITT population was modified (Amendment 6) to
    include all randomized patients who had evidence of bone metastases
    at study entry.

### Sponsor\'s Results and Reviewer\'s Findings/Comments

#### Baseline Characteristics

A total of 643 patients were randomized as follows: 214 patients were
randomized to zoledronate 4 mg, 221 patients to the zoledronate 8 mg
group, and 208 patients to the placebo group. At the time of
randomization, patients were stratified by the their history of prostate
cancer (presence or absence of metastatic disease at the time of their
initial diagnosis of prostate cancer). Several patients in each stratum
were randomized to the incorrect stratum as follows: 30 patients were
incorrectly assigned to the stratum of patients with no metastases at
the time of initial diagnosis, and 27 patients were incorrectly assigned
to the stratum of patients with metastases at the time of initial
diagnosis. Thirty one patients were withdrawn from the study
prematurely. One patient in the zoledronate 4 mg group was discovered to
never have had bone lesions. Table 2.5.1a describes the baseline
characteristics as presented by the sponsor in the safety population
(Sponsor\'s Table 7-3, 7-4, 7-5, Volume 106, pages 8-56 to 8-58).

**Table 2.5.1a: Baseline Characteristics (Sponsor's Analysis -- Safety
Population)**

+------------------+---------------+-----------------+----------------+
|                  | **Total**     |                 |                |
+==================+===============+=================+================+
|                  | **Zol 4 mg**  | **Zol 8/4 mg**  | **Placebo**    |
|                  |               |                 |                |
|                  | **N=214**     | **N=218**       | **N=208**      |
+------------------+---------------+-----------------+----------------+
| **Age (years)**  |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 214           | 218             | 208            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 71.87.91      | 71.28.04        | 72.27.89       |
+------------------+---------------+-----------------+----------------+
| Median           | 72.0          | 72.0            | 73.0           |
+------------------+---------------+-----------------+----------------+
| **Age n (%)**    |               |                 |                |
+------------------+---------------+-----------------+----------------+
| 60               | 19 (8.9%)     | 19 (8.7%)       | 98 (7.2%)      |
+------------------+---------------+-----------------+----------------+
| \> 60            | 195 (91.9%)   | 199 (91.3%)     | 149 (92.8%)    |
+------------------+---------------+-----------------+----------------+
| **Race n (%)**   |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Caucasian        | 178 (83.2%)   | 184 (84.4%)     | 172 (82.7%)    |
+------------------+---------------+-----------------+----------------+
| Black            | 24 (11.2%)    | 18 (8.3%)       | 19 (9.1%)      |
+------------------+---------------+-----------------+----------------+
| Other            | 12 (5.6%)     | 16 (7.3%)       | 17 (8.2%)      |
+------------------+---------------+-----------------+----------------+
| **Weight (kg)**  |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 212           | 217             | 207            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 82.714.15     | 82.214.50       | 83.416.08      |
+------------------+---------------+-----------------+----------------+
| Median           | 81.9          | 81.0            | 80.2           |
+------------------+---------------+-----------------+----------------+
| **Metastases     |               |                 |                |
| other than bone  |               |                 |                |
| at initial       |               |                 |                |
| diagnosis n      |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Lung             | 4 (.9%)       | 1 (0.5%0        | 1 (0.5%0       |
+------------------+---------------+-----------------+----------------+
| Liver, Brain,    | 0 (0.0%)      | 0 (0.0%)        | 0 (0.0%)       |
| Skin, and Eye    |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Pleura           | 0 (0.0%)      | 1 (0.5%)        | 0 (0.0%)       |
+------------------+---------------+-----------------+----------------+
| Distant lymph    | 19 (8.9%)     | 9 (4.1%)        | 9 (4.3%)       |
| nodes            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Other            | 2 (0.9%)      | 4 (1.8%)        | 4 (1.9%)       |
+------------------+---------------+-----------------+----------------+
| **Serum          |               |                 |                |
| creatinine n     |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Normal (\< 1.4   | 173 (80.8%)   | 168 (77.1%)     | 170 (81.7%)    |
| mg/dL)           |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Abnormal ( 1.4   | 41 (19.2%)    | 47 (21.6%)      | 33 (15.9%)     |
| mg/dL)           |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Missing          | 0 (0.0%)      | 3 (1.4%)        | 5 (2.4%)       |
+------------------+---------------+-----------------+----------------+
| **Previous SRE n |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Yes              | 66 (30.8%)    | 70 (32.1%)      | 78 (37.5%)     |
+------------------+---------------+-----------------+----------------+
| No               | 148 (69.2%)   | 148 (67.9%)     | 130 (62.5%)    |
+------------------+---------------+-----------------+----------------+
| **Prostate       |               |                 |                |
| Specific         |               |                 |                |
| Antigen**        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 276.5 737.10  | 354.0 1156.54   | 211.1 464.89   |
+------------------+---------------+-----------------+----------------+
| Median           | 81.7          | 88.5            | 61.0           |
+------------------+---------------+-----------------+----------------+
| **Time from      |               |                 |                |
| initial          |               |                 |                |
| diagnosis of     |               |                 |                |
| cancer to bone   |               |                 |                |
| metastases       |               |                 |                |
| (month)**        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 214           | 217             | 207            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 39.147.98     | 41.746.00       | 38.447.72      |
+------------------+---------------+-----------------+----------------+
| Median           | 19.6          | 26.6            | 19.6           |
+------------------+---------------+-----------------+----------------+
| **Time from bone |               |                 |                |
| metastases to    |               |                 |                |
| Visit 2          |               |                 |                |
| (month)**        |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 214           | 217             | 207            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 23.525.77     | 25.531.33       | 28.430.70      |
+------------------+---------------+-----------------+----------------+
| Median           | 16.1          | 15.5            | 17.8           |
+------------------+---------------+-----------------+----------------+
| **ECOG status n  |               |                 |                |
| (%)**            |               |                 |                |
+------------------+---------------+-----------------+----------------+
| ECOG 0-1         | 197 (92.1%)   | 199 (91.3%)     | 190 (91.3%)    |
+------------------+---------------+-----------------+----------------+
| ECOG 2           | 17 (7.9%)     | 18 (8.3%)       | 18 (8.7%)      |
+------------------+---------------+-----------------+----------------+
| **Analgesic      |               |                 |                |
| score n (%)**    |               |                 |                |
+------------------+---------------+-----------------+----------------+
| 0                | 93 (43.5%)    | 73 (33.5%)      | 77 (37.0%)     |
+------------------+---------------+-----------------+----------------+
| 1                | 70 (32.7%)    | 83 (38.1%)      | 77 (37.0%)     |
+------------------+---------------+-----------------+----------------+
| 2                | 9 (4.2%)      | 11 (5.0%)       | 9 (4.3%)       |
+------------------+---------------+-----------------+----------------+
| 3                | 40 (18.7%)    | 48 (22.0%)      | 41 (19.7%)     |
+------------------+---------------+-----------------+----------------+
| 4                | 2 (0.9%)      | 3 (1.4%)        | 3 (1.4%)       |
+------------------+---------------+-----------------+----------------+
| **BPI composite  |               |                 |                |
| pain score**     |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 193           | 198             | 191            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 2.01.98       | 2.52.10         | 2.12.04        |
+------------------+---------------+-----------------+----------------+
| Median           | 1.8           | 2.3             | 1.8            |
+------------------+---------------+-----------------+----------------+
| **FACT-G total   |               |                 |                |
| score**          |               |                 |                |
+------------------+---------------+-----------------+----------------+
| N                | 193           | 192             | 187            |
+------------------+---------------+-----------------+----------------+
| Mean SD          | 81.015.36     | 81.213.69       | 82.214.57      |
+------------------+---------------+-----------------+----------------+
| Median           | 82.5          | 82.1            | 82.8           |
+------------------+---------------+-----------------+----------------+

**Table 2.5.1b: Baseline Characteristics (FDA Analysis -- ITT
population)**

<table style="width:100%;">
<colgroup>
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 10%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="3"><strong>No Metastasis at Initial Diagnosis</strong></th>
<th colspan="3"><strong>Metastases at Initial Diagnosis</strong></th>
<th colspan="3"><strong>Total</strong></th>
</tr>
<tr class="odd">
<th></th>
<th><p><strong>Zol 4 mg</strong></p>
<p><strong>N=115</strong></p></th>
<th><p><strong>Zol 8/4 mg</strong></p>
<p><strong>N=134</strong></p></th>
<th><p><strong>Placebo</strong></p>
<p><strong>N=116</strong></p></th>
<th><p><strong>Zol 4 mg</strong></p>
<p><strong>N=99</strong></p></th>
<th><p><strong>Zol 8/4 mg</strong></p>
<p><strong>N=87</strong></p></th>
<th><p><strong>Placebo</strong></p>
<p><strong>N=92</strong></p></th>
<th><p><strong>Zol 4 mg</strong></p>
<p><strong>N=214</strong></p></th>
<th><p><strong>Zol 8/4 mg</strong></p>
<p><strong>N=221</strong></p></th>
<th><p><strong>Placebo</strong></p>
<p><strong>N=208</strong></p></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><strong>Age (years)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>115</td>
<td>134</td>
<td>116</td>
<td>99</td>
<td>87</td>
<td>92</td>
<td>214</td>
<td>221</td>
<td>208</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>72.60.8</td>
<td>70.80.7</td>
<td>73.00.7</td>
<td>70.90.8</td>
<td>71.70.9</td>
<td>71.30.9</td>
<td>71.80.5</td>
<td>71.20.5</td>
<td>72.20.5</td>
</tr>
<tr class="even">
<td>Median</td>
<td>73</td>
<td>71</td>
<td>74</td>
<td>71</td>
<td>72</td>
<td>73</td>
<td>72</td>
<td>72</td>
<td>73</td>
</tr>
<tr class="odd">
<td><strong>Age</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>60</td>
<td>9 (7.8%)</td>
<td>11 (8.2%)</td>
<td>6 (5.2%)</td>
<td>10 (10.1%)</td>
<td>8 (9.2%)</td>
<td>9 (9.8%)</td>
<td>19 (8.9%)</td>
<td>19 (8.6%)</td>
<td>15 (7.2%)</td>
</tr>
<tr class="odd">
<td>&gt; 60</td>
<td>106 (92.2%)</td>
<td>123 (91.8%)</td>
<td>110 (94.8%)</td>
<td>89 (89.9%)</td>
<td>79 (90.8%)</td>
<td>83 (90.2%)</td>
<td>195 (81.2%)</td>
<td>202 (91.4%)</td>
<td>193 (92.8%)</td>
</tr>
<tr class="even">
<td><strong>Race n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Caucasian</td>
<td>102 (88.7%)</td>
<td>116 (86.6%)</td>
<td>93 (80.2%)</td>
<td>76 (76.8%)</td>
<td>70 (80.5%)</td>
<td>79 (85.9%)</td>
<td>178 (83.2%)</td>
<td>186 (84.2%)</td>
<td>172 (82.7%)</td>
</tr>
<tr class="even">
<td>Black</td>
<td>8 (7.0%)</td>
<td>10 (7.5%)</td>
<td>11 (9.5%)</td>
<td>16 (16.2%)</td>
<td>9 (10.3%)</td>
<td>8 (8.7%)</td>
<td>24 (11.2%)</td>
<td>19 (8.6%)</td>
<td>19 (9.1%)</td>
</tr>
<tr class="odd">
<td>Other</td>
<td>5 (4.3%)</td>
<td>8 (5.9%)</td>
<td>12 (10.3%)</td>
<td>8 (7.0%)</td>
<td>8 (9.2%)</td>
<td>5 (5.4%)</td>
<td>12 (5.6%)</td>
<td>16 (7.2%)</td>
<td>17 (8.2%)</td>
</tr>
<tr class="even">
<td><strong>Weight (kg)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>N</td>
<td>114</td>
<td>133</td>
<td>116</td>
<td>98</td>
<td>87</td>
<td>91</td>
<td>212</td>
<td>220</td>
<td>207</td>
</tr>
<tr class="even">
<td>Mean SD</td>
<td>83.81.3</td>
<td>82.31.3</td>
<td>83.91.5</td>
<td>81.51.5</td>
<td>81.91.6</td>
<td>82.81.7</td>
<td>82.81.0</td>
<td>82.11.0</td>
<td>83.41.1</td>
</tr>
<tr class="odd">
<td>Median</td>
<td>82.3</td>
<td>81.0</td>
<td>79.7</td>
<td>81.4</td>
<td>79.8</td>
<td>82.0</td>
<td>82.0</td>
<td>81.0</td>
<td>80.2</td>
</tr>
<tr class="even">
<td><strong>Serum creatinine</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Normal (&lt; 1.4 mg/dL)</td>
<td>92 (80.0%)</td>
<td>101 (75.4%)</td>
<td>96 (82.8%)</td>
<td>81 (81.8%)</td>
<td>72 (82.8%)</td>
<td>79 (85.9%)</td>
<td>173 (80.8%)</td>
<td>173 (78.3%)</td>
<td>175 (84.1%)</td>
</tr>
<tr class="even">
<td>Abnormal ( 1.4 mg/dL)</td>
<td>23 (20.0%)</td>
<td>33 (24.6%)</td>
<td>20 (17.2%)</td>
<td>18 (18.2%)</td>
<td>15 (17.2%)</td>
<td>13 (14.1%)</td>
<td>41 (19.2%)</td>
<td>48 (21.7%)</td>
<td>33 (15.9%)</td>
</tr>
<tr class="odd">
<td><strong>Previous SRE</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Yes</td>
<td>30 (26.1%)</td>
<td>42 (31.6%)</td>
<td>44 (37.9%)</td>
<td>36 (36.7%)</td>
<td>29 (33.3%)</td>
<td>34 (37.0%)</td>
<td>66 (31.0%)</td>
<td>71 (32.3%)</td>
<td>78 (37.5%)</td>
</tr>
<tr class="odd">
<td>No</td>
<td>85 (73.9%)</td>
<td>91 (68.4%)</td>
<td>72 (62.1%)</td>
<td>62 (63.3%)</td>
<td>58 (66.7%)</td>
<td>58 (63.0%)</td>
<td>147 (69.0%)</td>
<td>149 (67.7%)</td>
<td>130 (62.5%)</td>
</tr>
<tr class="even">
<td><strong>Prostate Specific Antigen</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>N</td>
<td>115</td>
<td>132</td>
<td>113</td>
<td>97</td>
<td>86</td>
<td>87</td>
<td>212</td>
<td>218</td>
<td>200</td>
</tr>
<tr class="even">
<td>Mean SD</td>
<td>261.263.4</td>
<td>382.3109.4</td>
<td>164.138.8</td>
<td>294.782.6</td>
<td>302.8104.1</td>
<td>272.255.9</td>
<td>276.550.6</td>
<td>350.977.8</td>
<td>211.132.9</td>
</tr>
<tr class="odd">
<td>Median</td>
<td>89.4</td>
<td>90.9</td>
<td>56.0</td>
<td>76.7</td>
<td>87.2</td>
<td>69.7</td>
<td>81.7</td>
<td>88.2</td>
<td>61.0</td>
</tr>
<tr class="even">
<td><strong>Time from initial diagnosis of cancer to bone metastases
(month)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>N</td>
<td>115</td>
<td>133</td>
<td>115</td>
<td>99</td>
<td>87</td>
<td>92</td>
<td>214</td>
<td>220</td>
<td>207</td>
</tr>
<tr class="even">
<td>Mean SD</td>
<td>64.74.5</td>
<td>64.43.7</td>
<td>63.84.6</td>
<td>8.12.2</td>
<td>7.92.7</td>
<td>6.61.8</td>
<td>38.53.3</td>
<td>42.03.1</td>
<td>38.43.3</td>
</tr>
<tr class="odd">
<td>Median</td>
<td>60.8</td>
<td>58.3</td>
<td>53.0</td>
<td>0.2</td>
<td>0.3</td>
<td>0.2</td>
<td>19.2</td>
<td>28.6</td>
<td>19.6</td>
</tr>
<tr class="even">
<td><strong>Time from bone metastases to Visit 2 (month)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>N</td>
<td>115</td>
<td>133</td>
<td>115</td>
<td>99</td>
<td>87</td>
<td>92</td>
<td>214</td>
<td>220</td>
<td>207</td>
</tr>
<tr class="even">
<td>Mean SD</td>
<td>15.02.1</td>
<td>13.61.4</td>
<td>20.02.4</td>
<td>33.92.6</td>
<td>44.54.2</td>
<td>39.03.5</td>
<td>23.81.8</td>
<td>25.82.1</td>
<td>28.42.1</td>
</tr>
<tr class="odd">
<td>Median</td>
<td>6.5</td>
<td>6.5</td>
<td>12.3</td>
<td>26.2</td>
<td>31.3</td>
<td>32.3</td>
<td>16.1</td>
<td>16.1</td>
<td>17.8</td>
</tr>
<tr class="even">
<td><strong>ECOG status n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>ECOG 0-1</td>
<td>106 (92.2%)</td>
<td>124 (92.5%)</td>
<td>104 (89.7%)</td>
<td>91 (91.9%)</td>
<td>78 (90.7%)</td>
<td>86 (93.5%)</td>
<td>197 (92.1%)</td>
<td>202 (91.8%)</td>
<td>190 (91.3%)</td>
</tr>
<tr class="even">
<td>ECOG 2</td>
<td>9 (7.8%)</td>
<td>10 (7.5%)</td>
<td>12 (10.3%)</td>
<td>8 (8.1%)</td>
<td>8 (9.3%)</td>
<td>6 (6.5%)</td>
<td>17 (7.9%)</td>
<td>18 (8.2%)</td>
<td>18 (8.7%)</td>
</tr>
<tr class="odd">
<td><strong>Analgesic score n (%)</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>0</td>
<td>56 (48.7%)</td>
<td>46 (34.6%)</td>
<td>44 (38.3%)</td>
<td>38 (38.4%)</td>
<td>27 (31.4%)</td>
<td>33 (35.9%)</td>
<td>94 (43.9%)</td>
<td>73 (33.3%)</td>
<td>77 (37.2%)</td>
</tr>
<tr class="odd">
<td>1</td>
<td>32 (27.8%)</td>
<td>49 (36.8%)</td>
<td>39 (33.9%)</td>
<td>37 (37.4%)</td>
<td>35 (40.7%)</td>
<td>38 (41.3%)</td>
<td>69 (32.2%)</td>
<td>84 (38.4%)</td>
<td>77 (37.2%)</td>
</tr>
<tr class="even">
<td>2</td>
<td>4 (3.5%)</td>
<td>6 (4.5%)</td>
<td>6 (5.2%)</td>
<td>5 (5.0%)</td>
<td>5 (5.8%)</td>
<td>3 (3.3%)</td>
<td>9 (4.2%)</td>
<td>11 (5.0%)</td>
<td>9 (4.4%)</td>
</tr>
<tr class="odd">
<td>3</td>
<td>23 (20.0%)</td>
<td>31 (23.3%)</td>
<td>25 (21.7%)</td>
<td>17 (17.2%)</td>
<td>17 (19.8%)</td>
<td>16 (17.4%)</td>
<td>40 (18.7%)</td>
<td>48 (21.9%)</td>
<td>41 (19.8%)</td>
</tr>
<tr class="even">
<td>4</td>
<td>0 (0.0%)</td>
<td>1 (0.8%)</td>
<td>1 (0.9%)</td>
<td>2 (2.0%)</td>
<td>2 (2.3%)</td>
<td>2 (2.2%)</td>
<td>2 (0.9%)</td>
<td>3 (1.4%)</td>
<td>3 (1.5%)</td>
</tr>
<tr class="odd">
<td><strong>BPI composite pain score</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>107</td>
<td>124</td>
<td>110</td>
<td>86</td>
<td>75</td>
<td>81</td>
<td>193</td>
<td>199</td>
<td>191</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>2.20.2</td>
<td>2.30.2</td>
<td>2.20.2</td>
<td>1.90.2</td>
<td>2.80.3</td>
<td>2.00.2</td>
<td>2.00.1</td>
<td>2.50.1</td>
<td>2.10.1</td>
</tr>
<tr class="even">
<td>Median</td>
<td>1.8</td>
<td>2.0</td>
<td>1.9</td>
<td>2.0</td>
<td>2.8</td>
<td>1.8</td>
<td>1.8</td>
<td>2.3</td>
<td>1.8</td>
</tr>
<tr class="odd">
<td><strong>FACT-G total score</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>N</td>
<td>107</td>
<td>120</td>
<td>107</td>
<td>86</td>
<td>73</td>
<td>80</td>
<td>193</td>
<td>193</td>
<td>187</td>
</tr>
<tr class="odd">
<td>Mean SD</td>
<td>80.71.5</td>
<td>81.11.2</td>
<td>81.21.4</td>
<td>81.31.6</td>
<td>81.91.7</td>
<td>83.61.6</td>
<td>81.01.1</td>
<td>81.41.0</td>
<td>82.21.1</td>
</tr>
<tr class="even">
<td>Median</td>
<td>80.2</td>
<td>80.0</td>
<td>82.0</td>
<td>83.0</td>
<td>83.0</td>
<td>83.4</td>
<td>82.5</td>
<td>82.2</td>
<td>82.8</td>
</tr>
</tbody>
</table>

*[Reviewer's Comments]{.underline}*:

1.  Table 2.5.1b above describes the baseline characteristics of the ITT
    population as analyzed by this reviewer.

2.  Both by the Sponsor's description (Table 2.5.1a) and FDA description
    (Table 2.5.1b) there appears to be imbalance between treatment
    groups favoring zoledronate 4 mg group with respect to age group,
    serum creatinine, previous SRE, time from initial diagnosis of
    cancer to bone metastases, performance status, analgesic score and
    BPI composite pain score.

```{=html}
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```
3.  There are significant differences between the two stratum (no
    metastases at initial diagnosis of prostate cancer versus metastases
    at initial diagnosis of prostate cancer) with respect to time from
    initial diagnosis of cancer to bone metastases, and time from first
    bone metastases to Visit 2 of the study (study start day). As in
    Study 011, in this study also, it is not clear as to how this
    difference in time between the two strata translates to differences
    or lack of differences with respect to skeletal related events.
    These patients were also receiving concomitantly anticancer therapy
    and this is a confounding factor with the study drug in estimating
    the reduction in skeletal related events attributable to the study
    drug in each stratum and treatment group.

#### Primary Efficacy Analyses

The primary efficacy variable was the proportion of patients
experiencing at least one SRE (-HCM). Per sponsor analysis by month 15
both the zoledronic acid 4 mg and 8/4 mg groups had a lower proportion
than the placebo group. There was statistically significant difference
between 4 mg and placebo groups (p=0.021), where as there was no
statistically significant difference between 8/4 mg and placebo groups
(p=0.222), as presented below in Table 2.5.2 (Sponsor Table 9-1, Volume
106, page 8-61).

Table 2.5.2: Proportion of Patients Having SRE (-HCM) up to Month 15 by
Stratum and Treatment Group (ITT patients) -- Sponsor's Analysis

  ----------------- ---------------- ------------------ -------------------
                                     **95% C.I. and     
                                     P-value for the    
                                     difference**       

                    **Proportion**   **Zol 4 mg**       **Zol 8/4 mg**

  **No Initial                                          
  Metastases**                                          

  **Placebo**       54/116 (47%)     (-24.4%,0.9%),     (-21.5%,3.0%),
                                     p=0.069            p=0.140

  **Zol 4 mg**      40/115 (35%)     \-                 (-9.4%,14.5%),
                                                        p=0.679

  **Zol 8/4 mg**    50/134 (37%)     \-                 \-

  **With Initial                                        
  Metastases**                                          

  **Placebo**       38/92 (41%)      (-23.6%,3.6%),     (-15.5%,13.3%),
                                     p=0.152            p=0.884

  **Zol 4 mg**      31/99 (31%)      \-                 (-4.9%,22.7%),
                                                        p=0.206

  **Zol 8/4 mg**    35/87 (40%)      \-                 \-

  **Total**                                             

  **Placebo**       92/208 (44%)     (-20.3%,-1.8%),    (-15.1%,3.6%),
                                     **p=0.021**        p=0.222

  **Zol 4 mg**      71/214 (33%)     \-                 (-3.7%, 14.3%),
                                                        p=0.255

  **Zol 8/4 mg**    85/221 (38%)     \-                 \-
  ----------------- ---------------- ------------------ -------------------

*[Reviewer's Comments]{.underline}*:

1.  Since the decision was made to drop 8/4 mg zoledronate arm for
    toxicity, the efficacy comparison between 8/4 mg arm and placebo arm
    is not appropriate and may result in type I error adjustment.

2.  The estimates of the proportion of SREs presented in Table 2.5.2 may
    be biased estimates because of high dropout rate (approximately only
    35% were treated at 15 months) as presented below in Table 2.5.3. In
    the least conservative approach, if the total number of events at 15
    months in each of the treatment groups are subtracted from the total
    number of patients that were randomized, then 84/143 patients
    (58.7%) in zoledronate 4 mg group, 63/136 patients (46.3%) in
    zoledronate 8/4 mg group, and 66/116 patients (56.9%) in the placebo
    group received treatment at 15 months. Therefore the dropout rate
    was at least 46%.

    **Table 2.5.3: Number of Patients Treated up to 15 Months (FDA
    Analysis)**

  ---------- -------------- ----------- ------------- -------------- ----------- ------------- ----------- ----------- -------------
             **No Initial                             **With Initial                           **Total**               
             Metastases**                             Metastases**                                                     

             **Zol 4 mg**   **Zol 8/4   **Placebo**   **Zol 4 mg**   **Zol 8/4   **Placebo**   **Zol 4     **Zol 8/4   **Placebo**
                            mg**                                     mg**                      mg**        mg**        

  **Study    115            134         116           99             87          92            214         221         208
  Start                                                                                                                
  (Visit                                                                                                               
  2)**                                                                                                                 

  **3        99             117         108           80             69          79            179         186         187
  months**                                                                                                             

  **6        75             94          84            67             57          64            142         151         148
  months**                                                                                                             

  **9        65             69          62            54             51          48            119         120         110
  months**                                                                                                             

  **12       54             50          43            50             36          41            104         86          84
  months**                                                                                                             

  **15       **42 (36.5%)** **36        **35          **42 (42.4%)** **27        **31          **84        **63        **66
  months**                  (26.9%)**   (30.2%)**                    (31.0%)**   (33.7%)**     (39.3%)**   (28.5%)**   (31.7%)**
  ---------- -------------- ----------- ------------- -------------- ----------- ------------- ----------- ----------- -------------

3.  The sponsor was advised by the agency during the protocol
    development stage to consider time to first SRE as the primary
    efficacy parameter, which can take into account censoring of
    observations during the course of the study. Therefore, in order to
    account for the early censoring of the observations, this reviewer
    conducted time to first SRE analysis using Kaplan-Meier estimation
    procedure, truncating the maximum follow up time at 15 months (Table
    2.5.4). Data beyond 15 months was confounded because of cross over
    of patients to zoledronate treatment group from placebo group. The
    Kaplan-Meier estimates of the proportion of skeletal event rate at
    15 months are larger than the estimates presented in Table 2.5.2
    (protocol specified analysis). There is significant difference
    between the zoledronate 4 mg group and placebo group (p=0.009,
    2-sided log rank test). Kaplan-Meier estimates of proportion of SREs
    at 3, 6, and 9 months respectively are presented in Table 2.5.4b.

**Table 2.5.4a: Analysis of Time to First Skeletal Related Event
Truncated at 15 Months Using Kaplan-Meier Estimation Procedure (ITT
Population FDA Analysis)**

  ------------------ ------------- ------- ------------------ ---------------
                     **Event Rate  **N**   **Median Time to   **P-value
                     at 9 Months**         Event in days (95% (Comparison to
                                           C.I.)**            Placebo using
                                                              Log-rank
                                                              test)**

  **No Initial                                                
  Metastases**                                                

  **Placebo**        59.6%         116     304 (198, \*)      

  **Zol 4 mg**       45.6%         115     \* (291, \*)       0.058

  **Zol 8/4 mg**     50.7%         134     419 (251, \*)      0.270

  **With Initial                                              
  Metastases**                                                

  **Placebo**        54.0%         92      335 (244, \*)      

  **Zol 4 mg**       44.4%         99      \* (364, \*)       0.085

  **Zol 8/4 mg**     57.0%         87      346 (209, \*)      0.709

  **Total**                                                   

  **Placebo**        57.2%         208     321 (252, \*)      

  **Zol 4 mg**       44.9%         214     \* (383, \*)       0.009

  **Zol 8/4 mg**     53.2%         221     363 (255, \*)      0.541
  ------------------ ------------- ------- ------------------ ---------------

\* = Not Reached

**Table 2.5.4b:** **Analysis of Time to First Skeletal Related Event
Truncated at 3, 6, 9, 12 and 15 Months Using Kaplan-Meier Estimation
Procedure (ITT population FDA Analysis)**

  ------------- ---------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ---------- -----------
  **Total**     **At 3                 **At 6                 **At 9                 **At 12                **At 15    
                Months**               Months**               Months**               Months**               Months**   

                **Event    **\*Diff.   **Event    **\*Diff.   **Event    **\*Diff.   **Event    **\*Diff.   **Event    **\*Diff.
                Rate**     in Event    Rate**     in Event    Rate**     in Event    Rate**     in Event    Rate**     in Event
                           Rate**                 Rate**                 Rate**                 Rate**                 Rate**

  **Placebo**   16.5%                  31.6%                  42.7%                  52.8%                  57.2%      

  **Zol 4 mg**  9.1%       7.4%        21.8%      9.8%        30.0%      12.7%       36.9%      15.9%       43.7%      13.5%

  **Zol 8/4     16.7%      -0.2%       29.6%      2.0%        42.0%      0.7%        46.5%      6.3%        53.2%      4.0%
  mg**                                                                                                                 
  ------------- ---------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ---------- -----------

\* Difference in event rates between placebo and treatment groups - not
for comparison.

4.  The penalty for dropping a treatment group (8/4 group) with respect
    to type I error rate is debatable because although the treatment
    group was dropped for safety reasons, the decision to drop the
    treatment arm from efficacy analysis was made after all the patients
    were enrolled into the 8 mg group and had received a significant
    amount of treatment. Table 2.5.5 lists the occurrence of events
    during the 15 months study period. More than 50% of the SREs had
    occurred by 3 months evaluation in the two zoledronate treatment
    groups, at which time majority (99%) of the patients in the 8 mg
    treatment group had received the treatment per original protocol at
    8 mg dose level (Table 2.5.6).

**Table 2.5.5: Number of SREs by Stratum, Treatment, and Evaluation
Times (FDA Analysis)**

  ---------------- ---------- ---------- ---------- ---------- ---------- ----------
                   **3        **6        **9        **12       **15       **Total up
                   months**   months**   months**   months**   months**   to 15
                                                                          months**

  **No Initial                                                            
  Metastases**                                                            

  **Placebo**      29         11         8          3          3          54

  **Zol 4 mg**     15         13         6          5          1          40

  **Zol 8/4 mg**   28         9          9          3          1          50

  **With Initial                                                          
  Metastases**                                                            

  **Placebo**      18         7          7          5          1          38

  **Zol 4 mg**     10         8          3          6          4          31

  **Zol 8/4 mg**   20         6          3          5          1          35

  **Total**                                                               

  **Placebo**      47         18         15         8          4          92

  **Zol 4 mg**     25         21         9          11         5          71

  **Zol 8/4 mg**   48         15         12         8          2          85
  ---------------- ---------- ---------- ---------- ---------- ---------- ----------

**Table 2.5.6: Number of Patients in the Zoledronate 8 mg Group Who Were
Treated at Reduced Dose of Zoledronate 4 mg up to 3 Months**

  ------------------- ----------- ------- ---------- ---------- --------------
  **Visit #:**        **2         **3**   **4**      **5**      **6 (3
                      (start)**                                 months)**

  **\# of patients    1/219       1/208   1/199      2/188      1/178
  treated at Zol 4                                              
  mg**                                                          
  ------------------- ----------- ------- ---------- ---------- --------------

#### Secondary Efficacy Analyses

The sponsor evaluated several parameters (as listed in section 2.5.3) as
secondary efficacy variables. Here we will present analyses of only two
of the secondary efficacy variables.

Time to first occurrence of an SRE was evaluated by the sponsor as a
secondary efficacy parameter as specified in the protocol (Table 2.5.7)
(Table 9-2, page 8-62, Volume 106). By this analysis zoledronate 4 mg
group was significantly different from placebo group (p=0.011) and there
was no difference between the zoledronate 8/4 mg and placebo groups
(p=0.491). However, there appears to border line significant difference
between zoledronate 4 mg and 8/4 mg groups (p=0.059).

Table 2.5.7: Summary of Time to the First SRE (-HCM) up to Month 15, by
Stratum and Treatment Group (Sponsor Analysis)

  -------------- ---------- ---------- ---------- ---------- -------------- ----------
                                                             **P-values\*   
                                                             for the        
                                                             between        
                                                             treatment      
                                                             comparison**   

                 **N**      **Event    **25%      **Median   **Zol 4 mg**   **Zol 8/4
                            rate at    Quartile   (days)**                  mg**
                            day 252**  (days)**                             

  **No Initial                                                              
  Metastases**                                                              

  **Placebo**    116        59.6%      109        304        0.045          0.225

  **Zol 4 mg**   115        45.6%      175        Not        \-             0.398
                                                  Reached                   

  **Zol 8/4 mg** 134        50.7%      133        419        \-             \-

  **With Initial                                                            
  Metastases**                                                              

  **Placebo**    92         54.0%      140        335        0.110          0.709

  **Zol 4 mg**   99         44.4%      222        Not        \-             0.052
                                                  Reached                   

  **Zol 8/4 mg** 87         57.0%      105        346        \-             \-

  **Total**                                                                 

  **Placebo**    208        57.2%      122        321        0.011          0.491

  **Zol 4 mg**   214        44.9%      182        Not        \-             0.059
                                                  Reached                   

  **Zol 8/4 mg** 221        53.2%      127        363        \-             \-
  -------------- ---------- ---------- ---------- ---------- -------------- ----------

\* P-values from Cox-regression with factor treatment stratified by the
strata

Skeletal morbidity rate defined as the number of SREs divided by the
time at risk in years was analyzed by the sponsor as presented below in
Table 2.5.8. (Sponsor's Table 9-3, page 8-63, Volume 106).

Table 2.5.8: Summary of Skeletal Morbidity Rate (risk set definition) of
any SRE (-HCM) up to Month 15, by Stratum and Treatment Group (Sponsor
Analysis)

  -------------- ----------- ------------ ------------ -------------- -----------
                 **N**       **Skeletal                **P-values\*   
                             morbidity                 for the        
                             rate (no. of              between        
                             events per                treatment      
                             year)**                   comparison**   

                             **Mean SD**  **Median**   **Zol 4 mg**   **Zol 8/4
                                                                      mg**

  **No Initial                                                        
  Metastases**                                                        

  **Placebo**    116         1.32 2.19    0.00         0.068          0.132

  **Zol 4 mg**   115         0.91 1.70    0.00         \-             0.730

  **Zol 8/4 mg** 134         0.95 1.86    0.00         \-             \-

  **With Initial                                                      
  Metastases**                                                        

  **Placebo**    92          1.70 4.38    0.00         0.040          0.627

  **Zol 4 mg**   99          0.67 1.70    0.00         \-             0.109

  **Zol 8/4 mg** 87          1.23 2.62    0.00         \-             \-

  **Total**                                                           

  **Placebo**    208         1.49 3.33    0.00         0.006          0.143

  **Zol 4 mg**   214         0.80 1.70    0.00         \-             0.191

  **Zol 8/4 mg** 221         1.06 2.19    0.00         \-             \-
  -------------- ----------- ------------ ------------ -------------- -----------

The time to multiple occurrences of SREs was also analyzed by the
sponsor using Anderson-Gill approach. In this analysis every counted
occurrence of an SRE was followed by a 20-day period during which no
other occurrence of an SRE was counted. Time to each counted occurrence
of an SRE was counted from the 22^nd^ day of the last counted occurrence
of an SRE to the onset day. Per sponsor analysis the difference between
placebo and zoledronate 4 mg group was statistically significant.

*[Reviewer's Comments]{.underline}*:

1.  The agency had recommended that the time to first occurrence of an
    SRE to be evaluated as a primary efficacy variable. The results of
    this analysis have already been discussed in the previous section
    (section 2.5.8.2, Reviewer's comment 1).

2.  Per sponsor analysis there is statistically significant difference
    between the placebo and zoledronate 4 mg groups with respect to
    skeletal morbidity rate (Table 2.5.8). However these estimates of
    the treatment effect may be biased because of high drop out rate.

3.  The sponsor's multiple event analysis has not been verified by the
    reviewer at this time. It should be noted that the Anderson-Gill
    approach assumes the multiple events are independent of each other.
    However the skeletal related events being considered here are likely
    to be highly correlated.

4.  This reviewer conducted exploratory multivariable Cox regression
    analyses of the time to first SRE data with treatment (placebo=0,
    zoledronate=1), prior history of skeletal events (no=0, yes=1), time
    from initial diagnosis of cancer to bone metastases (in months),
    time from first bone metastases to Visit 2 of the study (in months),
    log~e~ of baseline PSA and baseline analgesic scores. The results of
    these analyses are presented in Tables 2.5.9a - 2.5.9c. Although in
    all of the models considered here zoledronate 4 mg treatment effect
    was statistically significant, when the factors identified with
    imbalance in section 2.5.8.1, Reviewer comment, the p-value
    increased. The point estimate of hazard ratio for placebo versus
    zoledronate 4 mg treatment was consistent among all the models and
    the upper 95% confidence limit of the hazard ratio was less than 1.
    Exploratory models comparint placebo with zoledronate 8/4 mg groups
    are presented in Appendix (Appendix 4.3).

**Table 2.5.9a: Cox Regression Model with Treatment (Placebo vs. Zol 4
mg) as Co-variate**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment Overall**   0.661 (0.484, 0.903)         0.009

  **Treatment No          0.673 (0.446, 1.016)         0.06
  Metastases at Initial                                
  Dx.**                                                

  **Treatment With        0.658 (0.408, 1.063)         0.088
  Metastases at Initial                                
  Dx.**                                                
  ----------------------- ---------------------------- -------------------

**Table 2.5.9b: Cox Regression Model with Treatment (Placebo vs. Zol 4
mg) and prior history of SRE (Yes or No) as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.670 (0.490, 0.916)         0.012

  **Prior SRE**           1.450 (1.055, 1.992)         0.022
  ----------------------- ---------------------------- -------------------

**Table 2.5.9c: Cox Regression Model with Treatment (Placebo vs. Zol 4
mg ) and prior history of SRE (Yes or No), time from initial diagnosis
of cancer to bone metastases, and time from first bone metastases to
Visit 2 of the study as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.680 ( 0.491, 0.941)        0.020

  **Prior SRE**           1.374 (0.984, 1.919)         0.063

  **Time from Initial Dx. 0.999 (0.996, 1.003)         0.725
  of Ca. To Bone Met.**                                

  **Time from First Bone  0.993 (0.986, 1.000)         0.042
  Met. to Study Entry**                                

  **Log~e~ (baseline      1.154 (1.047, 1.272)         0.004
  PSA)**                                               

  **Baseline Analgesic    1.214 (1.056, 1.396)         0.007
  Score**                                              
  ----------------------- ---------------------------- -------------------

#### Safety Analyses

##### Survival Analyses

Because the zoledronate treatment was not expected to improve survival,
it was evaluated as part of safety analysis. The following is the
survival analysis results of FDA analysis using the ITT population
(instead of safety population used by sponsor). There were no
statistically significant differences in survival between zoledronate 4
mg and placebo groups, or between zoledronate 8 mg and placebo groups as
presented in Figures 2.5.1-2.5.3 and Table 2.5.10. All other safety
analyses are presented in the clinical review of the application.

Figure 2.5.1: Kaplan-Meier Survival Analysis of Over All Survival in ITT
Population (FDA Analysis)

![](media/image9.png){width="5.495138888888889in" height="3.1in"}

Figure 2.5.2: Kaplan-Meier Survival Analysis of Zoledronate 4 mg versus
Placebo in ITT Population (FDA Analysis)

![](media/image10.png){width="5.495138888888889in"
height="3.3319444444444444in"}

Figure 2.5.3: Kaplan-Meier Survival Analysis of Zoledronate 8/4 mg
versus Placebo in ITT Population (FDA Analysis)

![](media/image11.png){width="5.495138888888889in"
height="3.3319444444444444in"}

**Table 2.5.10: Summary of Survival Analyses Results (FDA Analysis)**

+-----------+----+-------+-----------+----------------+---------------+
|           | *  | **N   | **Median  | **Hazard Ratio | **P-values**  |
|           | *N | umber | (95%      | (95% C.I.)**   |               |
|           | ** | of    | C.I.) in  |                | **(Treatment  |
|           |    | Eve   | days**    |                | versus        |
|           |    | nts** |           |                | Placebo,      |
|           |    |       |           |                | Log-rank      |
|           |    |       |           |                | test)**       |
+-----------+----+-------+-----------+----------------+---------------+
| **        | 2  | 122   | 464 (379, |                |               |
| Placebo** | 08 |       | 521)      |                |               |
+-----------+----+-------+-----------+----------------+---------------+
| **Zol 4   | 2  | 107   | 546 (461, | 0.792 (0.611,  | 0.078         |
| mg**      | 14 |       | \*)       | 1.027)         |               |
+-----------+----+-------+-----------+----------------+---------------+
| **Zol 8/4 | 2  | 138   | 419 (363, | 1.083 (0.849,  | 0.521         |
| mg**      | 21 |       | 478)      | 1.382)         |               |
+-----------+----+-------+-----------+----------------+---------------+

*[Reviewer's Comments]{.underline}*:

It appears from the survival analysis of the time to death that the
zoledronate 8/4 mg was slightly worse than the placebo group. It is not
clear if this is because of inherent not apparent differences in
baseline prognostic factors, or because of chance mechanism.

### Sponsor's Conclusions and Reviewer's Conclusions/Comments

Study 039 was a international, multicenter, randomized, double-blind,
placebo-controlled, parallel study conducted in prostate cancer patients
with a history of metastatic bone disease who have a rising serum PSA
concentration despite treatment with first-line hormonal therapy for
meatastatic disease. A total of 643 patients were enrolled into the
study (208 in placebo group, 214 in the zoledronate 4 mg group and 221
in the zoledronate 8/4 mg group). The primary objective of this study
was to assess the efficacy of zoledronate treatments (4 or 8 mg) in
addition to antineoplastic therapy, compared to antineoplastic therapy
alone to prevent skeletal-related events (SREs) in prostate cancer
patients with a history of metastatic bone disease who have developed
biochemical progression of disease. SREs were defined as pathologic bone
fracture events, spinal cord compression events, surgery to bone, and
radiation therapy to bone (including the use of radioisotopes). The
primary efficacy endpoint of this study was the proportion of patients
having at least one skeletal-related event by month 15.

1.  A total of 643 patients were enrolled into the study instead of the
    planned total of 550 patients. No explanation is provided for the
    increase in sample size.

2.  The sample size calculations were based on that zoledronate would be
    considered more efficacious than placebo if either of the two
    comparisons (4 mg versus placebo or 8 mg versus placebo) was
    statistically significant at a 2-sided p-value \< 0.025. During the
    study, the design was amended (Amendment 4) to treat all patients on
    study in the 8 mg group at 4 mg dose level because of the observed
    renal toxicity with 8 mg group. In lieu of this, it was stated that
    zoledronate 4 mg will be considered more efficacious than placebo if
    the comparison for the primary efficacy outcome is statistically
    significant at 0.05 level (2-sided) favoring zoledronate 4 mg
    (Amendment 6). It should be noted that the original design and
    calculation of sample size was based on comparing 4 mg versus
    placebo group at 0.025 level. Dropping a treatment arm (in this case
    8 mg group) could potentially inflate the overall type I error rate.
    It should also be noted that by the time of this Amendment, majority
    of the patients had completed the phase I (15 months) or had dropped
    out of the study.

3.  There appears to be imbalance between treatment groups favoring
    zoledronate 4 mg group with respect to age group, serum creatinine,
    previous SRE, time from initial diagnosis of cancer to bone
    metastases, performance status, analgesic score and BPI composite
    pain score.

4.  There are significant differences between the two stratum (no
    metastases at initial diagnosis of prostate cancer versus metastases
    at initial diagnosis of prostate cancer) with respect to time from
    initial diagnosis of cancer to bone metastases, and time from first
    bone metastases to Visit 2 of the study (study start day).

5.  There is statistically significant difference between zoledronate 4
    mg and placebo groups (p=0.021). The per protocol estimates of the
    proportion of SREs may be biased estimates because of high dropout
    rate. The sponsor was advised by the agency during the protocol
    development stage to consider time to first SRE as the primary
    efficacy parameter, which can take into account censoring of
    observations during the course of the study. Therefore, in order to
    account for the early censoring of the observations, this reviewer
    conducted time to first SRE analysis using Kaplan-Meier estimation
    procedure, truncating the maximum follow up time at 15 months. There
    is statistically significant difference between the zoledronate 4 mg
    group and placebo group (p=0.009, 2-sided log-rank test).

6.  Multivariate analyses of time to first occurrence adjusting for some
    of the covariates which appear to be imbalanced among the treatment
    groups suggest that the results are consistent and the zoledronate 4
    mg treatment appears to have efficacy, although the strength of
    evidence is not as significant.

7.  It appears from the survival analysis of the time to death that the
    zoledronate 8/4 mg was slightly worse than the placebo group. It is
    not clear if this is because of inherent differences in baseline
    prognostic factors, or because of chance mechanism.

# Statistical Evaluation of Collective Evidence

Zometa or zoledronate (zoledronic acid for injection) is proposed to be
used for the treatment of osteolytic, osteoblastic, and mixed bone
metastases of solid tumors and osteolytic lesions of multiple myeloma,
in conjunction with standard antineoplastic therapy in cancer patients.
Sponsor has submitted efficacy data and results from three double-blind
studies (Studies 010, 011, and 039). In all the three studies patients
were randomized in a double-blind fashion to receive either zoledronate
4 mg intravenously, or zoledronate 8 mg intravenously, or an active
control/placebo intravenous infusion every three weeks in addition to
their antineoplastic therapy. The randomized treatment assignment ratio
was to be 1:1:1. The primary efficacy endpoint in all the three studies
was the proportion of patients experiencing at least one SRE, defined as
radiation therapy to bone, surgery to bone, pathologic bone fracture or
spinal cord compression.

Study 010 was a multicenter, double-blind, randomized, controlled, Phase
III parallel comparative trial of i.v. zoledronic acid (Zometa, 4 mg or
8 mg) versus iv. Aredia (90 mg) (pamidronate) as an adjunct to standard
therapies in a total of 1640 patients with multiple myeloma and breast
cancer with cancer related bone lesions. The "non-inferiority" test in
Study 010 demonstrates marginal effectiveness (p=0.052) with respect to
proportion of SREs at 12 months of zoledronate 4mg arm, using a margin
of 3.65% which is defined as preserving 50% of the lower limit of the
95% CI of the point estimate of the Aredia effect. The original
selection of 8% margin is not acceptable based on the current
understanding because it tends to be liberal.

Study 011 was a randomized, double-blind, multicenter, parallel-group,
placebo controlled Phase III study conducted in a total of 773 patients
with bone metastases from solid tumors other than breast or prostate
cancer. The study has failed to demonstrate efficacy of 4 mg zoledronate
over placebo treated group in reducing the proportion of SREs at 9
months per protocol specified analysis (p=0.127). The protocol specified
estimates of the proportion of SREs (Table 2.4.2) may be biased
estimates because of high dropout rate. The sponsor was advised by the
agency during the protocol development stage to consider time to first
SRE as the primary efficacy parameter, which can take into account
censoring of observations during the course of the study. Therefore, in
order to account for the early censoring of the observations, this
reviewer conducted time to first SRE analysis using Kaplan-Meier
estimation procedure, truncating the maximum follow up time at 9 months
(Table 2.4.4). There appears to be a statistically significant
difference between the Zoledronate 4 mg group and placebo group
(p=0.026, 2-sided log-rank test) by this analysis.

Study 039 was an international, multicenter, randomized, double-blind,
placebo-controlled, parallel study conducted in 643 prostate cancer
patients with a history of metastatic bone disease who have a rising
serum PSA concentration despite treatment with first-line hormonal
therapy for meatastatic disease. There was statistically significant
difference between zoledronate 4 mg and placebo groups (p=0.021) with
respect to the proportion of SREs at 15 months as defined in the
protocol. However, the per protocol estimates of the proportion of SREs
may be biased estimates because of high dropout rate. The sponsor was
advised by the agency during the protocol development stage to consider
time to first SRE as the primary efficacy parameter, which can take into
account censoring of observations during the course of the study.
Therefore, in order to account for the early censoring of the
observations, this reviewer conducted time to first SRE analysis using
Kaplan-Meier estimation procedure, truncating the maximum follow up time
at 15 months. There is statistically significant difference between the
zoledronate 4 mg group and placebo group (p=0.009, 2-sided log-rank
test).

In these reviewers\' opinion the results of Studies 11 and 39 support
efficacy of zoledronate 4 mg given intravenously versus placebo given
intravenously in patients with bone metastases from solid tumors other
than breast cancer, and the study results of Study 10 suggest marginal
effectiveness of zoledronate 4 mg given intravenously in patients with
bone metastases from breast cancer and multiple myeloma based on a
"non-inferiority" test using Aredia as the active control .

**References:**

1.  Gang Chen, George Chi, Mark Rothmann, Ning Li (2001), Active Control
    Trials - Hypotheses and Issues. ASA Proceedings.

2.  Mark Rothmann, Ning Li, Gang Chen, George Chi and Hsiao-Hui Tsou
    (2001), Non-inferiority Methods for Mortality Trials, ASA
    Proceedings.

3.  Ning Li, Mark Rothmann, Gang Chen, George Chi, (2001), Application
    of non-infweriority analysis methods in oncology NDA, ASA
    Proceedings.

Ning Li, M.D. Ph.D. Rajeshwari Sridhara, Ph.D. Mathematical Statistician
Mathematical Statistician

Date: Date:

Concur: Dr. Chen

Team Leader

> Dr. Chi

Division Director, DBI

Cc:

HFD-150/ Ms. Vause

HFD-150/ Dr. Ibrahim

HFD-150/ Dr. Scher

HFD-150/ Dr. Williams

HFD-710/ Dr. Sridhara

HFD-710/ Dr. Li

HFD-710/ Dr. Chen

HFD-710/ Dr. Mahjoob

HFD-710/ Dr. Chi

HFD-700/ Dr. Anello

This review consists of 72 pages of text

C:\\NDA\\Novartis\\zometa_stat_odac_review.doc

# APPENDICES

## APPENDIX 1 - STUDY 010 - Zol. 8/4 mg versus Aredia

**Skeletal related Event (SRE) rate**

The sponsor provided data for SRE for Zole 8/4 mg arm. The Zole 8/4 mg
arm was the original 8 mg arm but changed the dosage due to renal
toxicity. The exploratory analysis result is summarized in Table 4.1.1.

**Table 4.1.1: Proportion of SRE to Month 13 by Stratum**

+------------+------------+----------+------------------+------------+
|            | Zometa     | Aredia   | Difference       | p-value\*  |
|            |            |          |                  |            |
|            | (8/4mg)    |          | (95% CI)\*       |            |
+------------+------------+----------+------------------+------------+
| Myeloma    | 49%        | 49%      | 0%               | 0.961      |
|            |            |          |                  |            |
|            | (79/160)   | (82/167) | (-10.6%,11.1%)   |            |
+------------+------------+----------+------------------+------------+
| Breast     | 47%        | 43%      | 4%               | 0.519      |
|            |            |          |                  |            |
| (Chemo)    | (80/172)   | (78/181) | (-7%, 13.8%)     |            |
+------------+------------+----------+------------------+------------+
| Breast     | 43%        | 47%      | -4%              | 0.467      |
|            |            |          |                  |            |
| (Hormonal) | (83/192)   | (97/207) | (-13.4%, 6.1%)   |            |
+------------+------------+----------+------------------+------------+
| **Total**  | **46%**    | **46%**  | **0%**           | **0.963**  |
|            |            |          |                  |            |
|            | **(        | **(25    | **(-6.1%,        |            |
|            | 242/524)** | 7/555)** | 5.8%)**          |            |
+------------+------------+----------+------------------+------------+

\*=Zometa-Aredia

*[Reviewer's Comments:]{.underline}*

1.  The analysis shows that the proportions were 46% and 46% for the
    zoledronic acid 8/4 mg group and the Aredia 90 mg group,
    respectively. The upper limit of the 95% confidence interval of the
    difference was 5.8%, which was less than the non-inferiority margin
    of 8% specified in the protocol before dose amendment. In the
    stratum of breast cancer patients receiving hormonal therapy, the
    difference in the proportions between the zoledronic acid 8/4 mg
    group and the Aredia 90 mg group was --4%, while in the stratum of
    breast cancer patients receiving chemotherapy, the difference in the
    proportions between the zoledronic acid 8/4 mg group and the Aredia
    90 mg group was +4% with an upper bound of 13.8%, implying 13.8%
    worse than Aredia is possible.

> **Preservation of active control effect**: The preservation of active
> treatment effect using the SRE rates can be determined by
> (7.3%-5.8%)/7.3%=20.5%. Hence, the current trial arm 8/4 mg arm
> demonstrated a 20.5% retention of Aredia vs. a placebo effect if we
> believe that the constant assumption holds.

**Time to First SRE**

Table 4.1.2 summarizes the results for study 010 by comparing Zole 8/4
mg with Aredia.

**Table 4.2.2.: Time to First SRE by Stratum and Treatment Arm**

+------------+---------+---------------+----------------+-------------+
|            | N       | Median        | Hazard Ratio   | p-value\*   |
|            |         |               | (95% CI)       |             |
|            |         | (95%CI)       |                |             |
+------------+---------+---------------+----------------+-------------+
| Myeloma    | 167     | 301(191,      | 1.09(.80,      | 0.58        |
|            |         | \-\--)        | 1.49)          |             |
| Aredia     | 160     |               |                |             |
|            |         | 283(196,      |                |             |
| **Zol 8/4  |         | \-\--)        |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| Breast(CT) | 181     | 366(259,      | 1.03(0.75,     | 0.87        |
|            |         | \-\--)        | 1.4)           |             |
| Aredia     | 172     |               |                |             |
|            |         | 351(262,      |                |             |
| **Zol 8/4  |         | \-\--)        |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| Breast(HT) | 207     | 370(258,      | .89(.67, 1.20) | 0.44        |
|            |         | \-\--)        |                |             |
| Aredia     | 192     |               |                |             |
|            |         | 381 (275,     |                |             |
| **Zol 8/4  |         | \--)          |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+
| **Total**  | **555** | **363(273,    | **.99(.83,     | **0.90**    |
|            |         | 399)**        | 1.18)**        |             |
| **Aredia** | **524** |               |                |             |
|            |         | **353(283,    |                |             |
| **Zol 8/4  |         | \-\--))**     |                |             |
| mg**       |         |               |                |             |
+------------+---------+---------------+----------------+-------------+

\*Log-rank test

Figure 4.1.1 is the K-M curve for the time to first SRE comparing
overall Aredia with Zol 8/4 mg arm.

**Figure 4.1.1**

![](media/image12.wmf){width="5.951388888888889in"
height="4.100694444444445in"}

## APPENDIX 2 - STUDY 011 - Zol. 8/4 mg versus Placebo

**Table 4.2.1: Cox Regression Model with Treatment (Placebo vs. Zol 8/4
mg) as Co-variate**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment Overall**   0.743 (0.563, 0.980)         0.036

  **Treatment Lung Cancer 0.673 (0.459, 0.987)         0.043
  Group**                                              

  **Treatment Other Solid 0.826 (0.553, 1.234)         0.351
  Tumors Group**                                       
  ----------------------- ---------------------------- -------------------

**Table 4.2.2: Cox Regression Model with Treatment (Placebo vs. Zol 8/4
mg) and prior history of SRE (Yes or No) as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.745 (0.565, 0.983)         0.038

  **Prior SRE**           1.359 (0.991, 1.864)         0.057
  ----------------------- ---------------------------- -------------------

**Table 4.2.3: Cox Regression Model with Treatment (Placebo vs. Zol 8/4
mg) and prior history of SRE (Yes or No), time from initial diagnosis of
cancer to bone metastases, and time from first bone metastases to Visit
2 of the study as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.722 (0.547, 0.954)         0.022

  **Prior SRE**           1.486 (1.077, 2.051)         0.016

  **Time from Initial Dx. 0.996 (0.991, 1.000)         0.062
  of Ca. To Bone Met.**                                

  **Time from First Bone  0.981 (0.963, 1.000)         0.047
  Met. to Study Entry**                                
  ----------------------- ---------------------------- -------------------

## APPENDIX 3 - STUDY 039 - Zol. 8/4 mg versus Placebo

**Table 4.3.1: Cox Regression Model with Treatment (Placebo vs. Zol 8/4
mg) as Co-variate**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment Overall**   0.912 (0.679, 1.226)         0.541

  **Treatment No          0.805 (0.547, 1.185)         0.272
  Metastases at Initial                                
  Dx.**                                                

  **Treatment With        1.091 (0.689, 1.728)         0.709
  Metastases at Initial                                
  Dx.**                                                
  ----------------------- ---------------------------- -------------------

**Table 4.3.2: Cox Regression Model with Treatment (Placebo vs. Zol 8/4
mg) and prior history of SRE (Yes or No) as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.926 (0.689, 1.245)         0.611

  **Prior SRE**           1.534 (1.135, 2.073)         0.005
  ----------------------- ---------------------------- -------------------

**Table 4.3.3: Cox Regression Model with Treatment (Placebo vs. Zol 8/4
mg) and prior history of SRE (Yes or No), time from initial diagnosis of
cancer to bone metastases, and time from first bone metastases to Visit
2 of the study as Co-variates**

  ----------------------- ---------------------------- -------------------
  **Co-variate**          **Hazard Ratio (95% C.I.)**  **P-value**

  **Treatment**           0.868 (0.638, 1.182)         0.368

  **Prior SRE**           1.468 (1.059, 2.036)         0.021

  **Time from Initial Dx. 1.000 (0.996, 1.003)         0.901
  of Ca. To Bone Met.**                                

  **Time from First Bone  0.995 (0.989, 1.000)         0.073
  Met. to Study Entry**                                

  **Log~e~ (baseline      1.175 (1.070, 1.290)         0.0007
  PSA)**                                               

  **Baseline Analgesic    1.020 (0.888, 1.172)         0.777
  Score**                                              
  ----------------------- ---------------------------- -------------------