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

**PUBLIC HEALTH SERVICE**

**FOOD AND DRUG ADMINISTRATION**

> **CENTER FOR DRUG EVALUATION AND RESEARCH**

**FDA CLINICAL BRIEFING DOCUMENT FOR THE ONCOLOGIC DRUGS ADVISORY
COMMITTEE**

NDA NUMBER: **21-386**

DRUG NAME: **Zometa (zoledronic acid for injection)**

INDICATION: **Treatment of Bone Metastases**

SPONSOR: **Novartis**

CLINICAL REVIEWERS: **Amna Ibrahim, M.D**.**( Studies 011 & 039)**

**Grant Williams, M.D. (Study 010)**

**Nancy Scher, M.D. (Safety review)**

1 Executive Summary [4](#executive-summary)

1.1 Recommendations [4](#recommendations)

1.2 Overview of Studies [5](#overview-of-studies)

1.3 Efficacy [5](#efficacy)

1.4 Safety [9](#safety)

2 Introduction and Background [10](#introduction-and-background)

2.1 Drug Information [10](#drug-information)

2.2 Regulatory Background
[11](#regulatory-background-on-approval-of-bisphosphonates-for-treatment-of-patients-with-cancer-metastatic-to-bone)

2.3 Important Milestones in Product Development
[14](#important-milestones-in-product-development)

3 Efficacy Review [15](#efficacy-review)

3.1 Placebo Controlled Trial #039 in Prostate Cancer
[17](#placebo-controlled-trial-039-in-prostate-cancer)

Background [17](#background)

Study Design [18](#study-design)

Planned Study Duration: [19](#planned-study-duration)

Drug administration and formulation:
[19](#drug-administration-and-formulation)

Study Population: [19](#study-population)

Inclusion Criteria: [19](#inclusion-criteria)

Exclusion criteria [20](#exclusion-criteria)

Objectives [20](#objectives)

Primary Objective: [20](#primary-objective)

Definition of SRE: [21](#definition-of-sre)

Follow-up: [21](#follow-up)

Statistical considerations and sample size
[24](#statistical-considerations-and-sample-size)

Protocol Amendments: [25](#protocol-amendments)

Efficacy Results of Study 039 [26](#efficacy-results-of-study-039)

Protocol Violations [29](#protocol-violations)

Efficacy Conclusions of Study 039
[37](#efficacy-conclusions-of-study-039)

3.2 Placebo Controlled Trial #011 in Other Solid Tumors
[39](#placebo-controlled-trial-011-in-other-solid-tumors)

Study Design [39](#study-design-1)

Study Duration [41](#study-duration)

Drug Administration and Formulation
[41](#drug-administration-and-formulation-1)

Inclusion Criteria: [42](#inclusion-criteria-1)

Exclusion Criteria: [42](#exclusion-criteria-1)

Objectives: [42](#objectives-1)

Follow-up: [43](#follow-up-1)

Removal from the study: [44](#removal-from-the-study)

Statistical considerations: [44](#statistical-considerations)

Protocol Amendments: [46](#protocol-amendments-1)

Results: [49](#results)

Protocol Violations [53](#protocol-violations-1)

Efficacy Summary and Conclusions of Study 011
[63](#efficacy-summary-and-conclusions-of-study-011)

3.3 Active Controlled Trial #010 in Breast Cancer and Myeloma
[67](#active-controlled-trial-010-in-breast-cancer-and-myeloma)

Background [67](#background-1)

Study design [67](#study-design-2)

Protocol Amendments [67](#protocol-amendments-2)

Protocol #010 Summary [69](#protocol-010-summary)

Inclusion and exclusion criteria:
[69](#inclusion-and-exclusion-criteria)

Treatment interruption or discontinuation
[70](#__RefHeading___Toc534641874)

Treatment: [70](#treatment)

Randomization [70](#randomization)

Study Schedule [70](#study-schedule)

Planned Efficacy Assessments [73](#planned-efficacy-assessments)

Planned Statistical Analysis [73](#planned-statistical-analysis)

Results of Study #010, Baseline Factors
[74](#results-of-study-010-baseline-factors)

Efficacy Summary and Conclusions from Study #010
[97](#efficacy-summary-and-conclusions-from-study-010)

4 Integrated Safety Review [99](#integrated-safety-review)

4.1 Brief Statement of Reviewer's Conclusions 99

4.2 Description of patient exposure 99

4.3 Methods and specific findings of the safety review 105

4.4 Adequacy of safety testing 107

4.5 Summary of critical safety findings and limitations of data
[108](#__RefHeading___Toc534641887)

**5** **Appendices:**

Appendix 1 Review of Zoledronate Safety in Prostate Cancer, Study 039

Appendix 2 Review of Zoledronate Safety in Solid Tumors, Study 011

Appendix 3 Review of Zoledronate Safety in Breast Cancer and Myeloma,

> Study 010

#  Executive Summary

This briefing document provides the Oncologic Drugs Advisory Committee
(ODAC) with findings from the FDA clinical review of three zoledronate
studies. At the 1/31/02 meeting of ODAC, FDA will seek advice on the
zoledronate efficacy supplement for \"treatment of osteolytic,
osteoblastic, and mixed bone metastases of solid tumors and osteolytic
lesions of multiple myeloma, in conjunction with standard antineoplastic
therapy.\" Because the review process is ongoing (this document was
prepared one month prior to the meeting and four months into a six-month
review cycle), FDA may need to communicate additional findings during
the 1/31/02 meeting.

##  Recommendations

At this point, the clinical team makes no firm recommendations whether
zoledronate should be approved for treatment of patients with bone
metastases. Some issues for the ODAC to consider are listed below.

-   Efficacy in breast cancer and myeloma seems reasonably well
    established by the Applicant\'s large randomized trial (010) that
    compared zoledronate and pamidronate. However, the ODAC should
    discuss whether the zoledronate breast cancer indication should be
    limited to patients with lytic bone metastases. The efficacy of the
    active control, pamidronate, has only been established in patients
    with lytic disease.

```{=html}
<!-- -->
```
-   In Study 039, the statistically significant difference between
    zoledronate 4 mg and placebo in both the primary and secondary
    efficacy analyses suggests that zoledronate is efficacious in
    prostate cancer. However, these same analyses comparing the 8/4 mg
    arm to placebo showed no statistically significant differences. ODAC
    should advise FDA how to reconcile these findings.

```{=html}
<!-- -->
```
-   The *other solid tumors* indication evaluated in Study 011 seems
    problematic. Although the difference between zoledronate 4mg and
    placebo in the primary efficacy analysis was not statistically
    significant, the difference was statistically significant for a
    closely related secondary endpoint (time to first SRE). ODAC should
    consider whether this is sufficient evidence of efficacy. A second
    issue is whether to accept the trial hypothesis that all solid
    tumors metastatic to bone behave in a similar manner when treated
    with a bisphosphonate. About half of the population in Study 011 had
    Non Small Cell Lung Cancer, but the rest had a variety of other
    solid tumors. ODAC should advise FDA whether to approve zoledronate
    for the proposed indication of *other solid tumors*, for a subgroup
    of these tumors, or for none of these tumors.

## Overview of Studies

This document discusses the FDA safety and efficacy findings for three
randomized studies of zoledronate for patients with cancer bone
metastases. In each of the studies the primary endpoint was the
proportion of patients with skeletal-related events (SREs). SRE is an
aggregate endpoint: pathologic fracture, radiation therapy to bone,
surgery to bone, or spinal cord compression. Change in chemotherapy due
to increased pain was an SRE in the prostate cancer study only.

Two placebo-controlled randomized studies compared zoledronate 4 mg (zol
4) to zoledronate 8 mg (zol 8) to placebo in patients with prostate
cancer (Study 039) or patients with solid tumors other than breast
cancer and prostate cancer (Study 011). The third trial was an active
control trial comparing zol 4 to zol 8 to pamidronate 90 mg in patients
with breast cancer and myeloma. Early in the studies, because of renal
toxicity, the zoledronate infusion duration was increased from 5 to 15
minutes. After accrual was complete for all studies, but while many
patients were still on study, the 8mg dose was discontinued from the Zol
8 arm of each study because of continued renal toxicity. Patients on the
zol 8 arms were given 4 mg doses of zoledronate. (This arm is hence
designated as zol 8/4).

Study duration was 15 months for Study 039, 9 months for Study 011, and
13 months for Study 010. When the toxicity of 8 mg zoledronate dose was
established (after accrual was complete), the statistical plan was
amended so that the primary comparisons were between the zol 4 arms and
the control arms (with two-sided testing and alpha of 0.05)

##  Efficacy

**Prostate cancer**

The patients entering Study 039 had prostate cancer with PSA progression
while on first-line hormonal therapy for metastatic disease. 643
patients were randomized to the three arms. Efficacy analyses showed
significantly less skeletal morbidity on the zol 4 arm than on the
placebo arm both by the protocol-specified primary analysis of
proportions of patients with at least one SRE (33% vs. 44%,
respectively, p = 0.021) and by the FDA-preferred analysis of time to
first SRE (p = 0.011). By both analyses, however, the zol 8/4 arm failed
to demonstrate a statistically significant difference from placebo
(Proportions: 38% vs. 44%, respectively, p = 0.222. Time to SRE: p =
0.491). The proportions analysis and a reviewer exploratory analysis of
symptomatic SREs trended in favor of the zol 8/4 mg arm. After
multivariate analyses that included potential prognostic factors
(treatment, prior history of skeletal events, time from initial
diagnosis of cancer to bone metastases, time from first bone metastases
to randomization, log~e~ of baseline PSA, and baseline analgesic
scores), the results overall remained unchanged, although the p value
decreased.

The study was a well-conducted, well controlled trial. Several minor
problems were discussed in this review:

-   Asymptomatic vertebral compression fractures and changes in
    chemotherapy, events of questionable clinical meaning, were included
    as elements of the SRE endpoint. Because there were few such events
    on the study, this was not a significant problem.

-   Unblinding of patients to treatment arm was noted in about 5% of
    patients, but was equally distributed among study arms.

The major problem with this study is the unsupportive evidence provided
by efficacy analyses of the 8/4 mg arm. The FDA and ODAC must consider
the nature of analytical framework for evaluating this dilemma. Do we
consider that the 4 mg/placebo comparison as a positive trial and the
4/8 mg/placebo comparison like a negative (i.e., not positive) trial? Do
the positive and negative results cancel each other out? Since beta
error is 20% when a trial has 80% power, do we attribute the negative
results to beta error? (The latter finding is somewhat credible given
trends in favor of the 8 mg arms in some efficacy analyses.) Do data
from trials of Zometa in other cancers metastatic to bone provide any
support for efficacy in prostate cancer? We look forward to discussing
these issues with ODAC on January 31.

**Other Solid Tumors**

In Study 011, 773 patients with a variety of solid cancers metastatic to
bone were randomized 1:1:1 to treatment with zoledronate 4 mg,
zoledronate 8/4 mg, or placebo to evaluate zoledronate\'s effect on
SREs. Randomization was stratified according to cancer type as either
*NSCLC* or *other tumors*. Stratification was imperfect, with a number
of other tumor types incorrectly included in the *NSCLC* stratum.
However, there was no evidence that the randomization process itself was
compromised.

[Design Problems]{.underline}

The reviewer noted some deficiencies in the study. First, prior
chemotherapy regimens were not documented, so FDA could not determine
whether extent of prior therapy was balanced among the study arms.
Instead, FDA examined data on changes in chemotherapy regimens and
reported tumor response rates during the study, but these data were not
complete. Therefore, response to chemotherapy, which likely would have
affected the incidence of SREs, could not be fully assessed. Second,
there was no central review of the pathology specimens. In the one third
of patients where pathology reports were provided, some of the tumors
were incorrectly classified. Change in this classification could change
the results of the subgroup analyses.

[Efficacy Results]{.underline}

The proportion of patients with an SRE was lower on the 4 mg arm than
placebo, but the difference was not statistically significant (37%
versus 44%, respectively, p = 0.106). The comparison of the 8/4 mg group
to placebo showed a significant difference (35% versus 44% respectively,
p = 0.044).

Time to first SRE was 67 days longer in the 4mg arm than placebo (230
days versus 163 days respectively, p = 0.026) and was also significantly
longer for the 8/4 mg arm. For the 4mg versus placebo comparison,
subgroup analysis demonstrated a marginally statistically significant
difference for the *other tumors* group, but the difference for the
*NSCLC* group was not statistically different. FDA Cox regression
analysis provided estimates for the relative contribution of each
stratum in the overall analysis: the overall hazard ratio for 4 mg
versus placebo was 0.73 while the estimated hazard in the subgroups were
0.79 and 0.66 for *NSCLC* and *other tumors*, respectively.

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 Group         0.785 (0.544, 1.132)     0.194

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

[Conclusions]{.underline}

This study provides some evidence that zoledronate 4 mg provides
clinical benefit to the overall population studied. Although the primary
endpoint was not statistically significantly improved, the FDA-preferred
secondary endpoint was. Positive results from the 8/4 mg arm were
supportive.

However, the study design was based on an assumption that zoledronate
will have a similar effect on bone morbidity, regardless of the tumor
type. For example, cells from breast cancer, small cell lung cancer, or
pancreatic cancer behave quite differently from each other in various
body organs. This study assumes that these cells would behave similar to
each other when acted upon by zoledronate once inside bone. This
hypothesis has not been proven for any biphosphonate. Although an
efficacy trend is suggested for both subgroups in this study, the
stronger evidence for efficacy comes from the subgroup of patients
having a variety of types of cancer.

While it is tempting to fault the design of this study design for
insufficient power to evaluate efficacy in individual tumor subgroups,
it would be difficult to conduct a trial of Zometa separately in each
cancer type. Given the prognosis and survival of patients in Study 011,
the estimated zoledronate benefit, an increase of 67 days in time to
first skeletal event, seems clinically meaningful. At the time of
preparing this briefing document, the FDA review team is uncertain
whether this trial supports a separate zoledronate treatment indication.
The advice of the Oncologic Drugs Advisory Committee will be helpful to
the FDA in making this determination. Issues that should be considered
include:

-   To what extent do the zoledronate NDA trials for prostate cancer,
    breast cancer, and myeloma provide support for efficacy in this
    setting?

-   Would a positive study of this design indicate that efficacy is
    established for all tumor types evaluated?

-   Or, should one evaluate the study population to determine which
    tumor-types were sufficiently represented?

-   Are some tumors sufficiently different that they should be excluded
    from consideration, e.g., small cell lung cancer?

-   Approval of this drug for *all tumors metastatic to bone* would mean
    exposure of a large number of cancer patients to zoledronate along
    with its toxicity and its expense. Is there adequate evidence for
    such a blanket approval?

**Myeloma and Breast Cancer**

Study 010 was an international, multicenter, stratified, double-blind,
study that randomized patients 1:1:1 to zoledronate 4 mg, zoledronate
8mg, or pamidronate 90 mg i.v. every 3-4 weeks for 12 months.
Randomization was stratified by center and 3 disease strata: myeloma,
breast cancer treated with hormones, and breast cancer treated with
chemotherapy. The primary analysis was to be a non-inferiority analysis
of the proportion of patients with at least one SRE, performed after 13
months (12 months of treatment and one month of followup)

The Applicant randomized 1648 patients to the three study arms. Results
suggest that zoledronate 4 mg is effective in decreasing the skeletal
morbidity of myeloma and breast cancer metastatic to bone. As outline
below, conservative non-inferiority methodology using the *two 95%
confidence interval method of estimation* demonstrate that zoledronate
retains at least 49.3% of the pamidronate-versus-placebo effect:

-   The first step in this method is to estimate the size of the
    pamidronate effect based on historical data. The combined data from
    the three pamidronate trials show that 52.0% (293/563) on placebo
    compared to 38.9% (220/565) on pamidronate had an SRE. The treatment
    effect is thus 13.1% (95% ci: 7.3%,18.9%). This method uses the
    conservative limit of the confidence interval to estimate effect
    size (7.3%).

```{=html}
<!-- -->
```
-   The next step is to estimate how much of that pamidronate effect is
    retained (with 95% confidence) by zoledronate. On the zoledronate
    arm of this non-inferiority trial 44% (248/561) of patients had at
    least one SRE compared to 46% (257/555) on the pamidronate arm (95%
    ci: -7.9%, 3.7%). Although the estimate from these data favors
    zoledronate by 2%, again this method uses the conservative limit of
    the confidence interval to estimate the zoledronate effect. The
    confidence interval excludes zoledronate being 3.7% worse than
    pamidronate. The following are the calculations estimating that at
    least 49.3% of the pamidronate-versus-placebo effect has been
    retained: (7.3%-3.7%)/7.3% = 49.3%.

A critical aspect of making conclusions from non-inferiority trials is
the *constant assumption.* This aspect of trial design, discussed in
more depth in the FDA statistical review, requires a determination that
the active control drug (pamidronate) would have shown efficacy in the
new study or current setting, and it also requires an estimation of the
size of the effect that pamidronate would have shown in the current
setting. The FDA reviewers carefully evaluated the historical
pamidronate studies with this assumption in mind. Important differences
were found between the current and historical studies. Compared to the
pamidronate-versus-placebo studies, more patients on Study 010 had:

-   a short time since diagnosis of bone metastases

-   history of a previous SRE

-   no lytic bone lesion

Retrospective analysis of the pamidronate-versus-placebo data showed
that the pamidronate effect appeared even greater in patients with a
short time since diagnosis of bone metastasis and in patients with a
history of a previous SRE. Therefore, enrichment of the study population
with these patients should, if anything, increase the sensitivity of the
study.

The question of whether the active control (pamidronate) is effective in
breast cancer patients with non-lytic lesions, however, cannot be
directly examined in the pamidronate-versus-placebo study because only
patients with lytic lesions were entered. One can examine whether
zoledronate appears to be effective in Study 010 in the subgroup
corresponding to the historical pamidronate study population (patients
with lytic disease). Such a subgroup analysis of Study 010, comparing
zoledronate versus pamidronate in breast cancer patients with lytic bone
lesions, did not suggest a lack of zoledronate efficacy. In fact, the
trend was in favor of zoledronate versus pamidronate.

Whether zoledronate approval in breast cancer should extend to patients
without lytic bone lesions needs further consideration. The results of
Study 039, a study of zoledronate for treating the predominantly blastic
metastases of prostate cancer, may be relevant in making this judgement.

##  Safety

Zoledronate 4 mg i.v. over 15 minutes every 3-4 weeks has an acceptable
safety profile, and is comparable in toxicity to Aredia 90 mg i.v. over
2 hours every 3-4 weeks as an adjuvant to standard anticancer therapy in
patients with bone metastases from breast cancer and lesions of multiple
myeloma. Zoledronate 4 mg i.v. over 15 minutes every 3 weeks has an
acceptable safety profile, but is more toxic than placebo when used as
an adjuvant to standard anticancer therapy in patients with prostate
cancer and other solid tumors.

The major safety concern identified in the randomized trials is
increased risk of renal function deterioration, which is dose-related
and increases with duration of therapy. In the NDA studies, most
incidences were mild and reversible, with rare incidences of acute renal
failure. During the course of the studies, the renal safety of
zoledronate was improved by prolonging the infusion time to 15 minutes
(instead of 5 minutes) and eliminating the 8 mg dose. The safety of the
4 mg dose was improved by requiring assessment of serum creatinine
before each dose and holding zoledronate for renal deterioration, until
the return of creatinine to within 10% of the baseline. When Aredia 90
mg i.v. over 2 hours was compared to zoledronate 4 mg i.v. over 15
minutes every 3-4 weeks in patients with metastatic breast cancer to
bone and multiple myeloma (study #010), the incidence of renal
deterioration was similar (8.8% and 8.2%, respectively). In patients
with prostate cancer (Study #039) and in patients with other solid
tumors (Study #011), the incidence of renal deterioration was increased
relative to placebo, but the differences were not statistically
significant.

Symptoms possibly associated with bisphosphonates as a class, such as
arthralgias, pyrexia, as well as electrolyte disturbances, were noted
for zoledronate and pamidronate, but were not a major concern.

Anemia was slightly more common with zoledronate 4 mg, compared with
placebo. In the Aredia-controlled study, more patients in the
zoledronate 4 mg group had a decrease of \> 25% from baseline
hemoglobin. This is of uncertain significance.

#  Introduction and Background

## Drug Information

[Established Name:]{.underline} zoledronic acid for injection

[Proposed Trade Name:]{.underline} Zometa

[Drug Class:]{.underline} bisphosphonate

[Sponsor's Proposed Indication(s):]{.underline}

The following is the wording of the proposed indication:

**\"**ZOMETA is indicated 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.\"

*[Reviewer\'s comment]{.underline}*

*A more precise description of proven zoledronate benefit should be
considered for labeling. This wording suggests that zoledronate
decreases the morbidity of existing bone lesions. In zoledronate
clinical studies, [patients]{.underline} with bone metastases were
treated, but analyses did not establish whether benefit was from effects
on baseline [metastases]{.underline} or effects on subclinical disease.
Aredia labeling contains similar imprecise wording*.

[Dose, Regimens]{.underline}

The proposed regimen is zoledronate 4 mg diluted in 100 mL of saline
given intravenously over 15 minutes . The following section in dosage
and administration emphasizes a safety concern:

\" *Method of Administration* Due to the Risk of clinically significant
deterioration in renal function, which may progress to renal failure,
single doses of Zometa should not exceed 4 mg and the duration of
infusion should be no less than 15 minutes. (See Warnings)\"

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

*The proposed labeling should be amended to provide a recommended
frequency of treatment.*

## Regulatory Background on Approval of Bisphosphonates for Treatment of Patients with Cancer Metastatic to Bone

Before approaching the review of the zoledonate NDA, we must understand
the historical basis for pamidronate NDA approvals for several reasons:
first, the pamidronate studies provide strong rationale that
biphosphonates can be associated with clinical benefit; second, the NDA
approvals set a regulatory precedent for drugs of this class; and third,
the design, details, and results of the pamidronate trials provide
critical support for Study 010, the Applicant\'s \"non-inferiority\"
trial in breast cancer and myeloma. This latter issue is discussed in
detail in the FDA medical and statistical reviews of Study 010.

Pamidronate (Aredia R) is the only biphosphonate approved to decrease
morbidity in patients with bone metastases. The following is the current
approved indication:

> \"Aredia is indicated, in conjunction with standard antineoplastic
> therapy, for the treatment of osteolytic bone metastases of breast
> cancer and osteolytic lesions of multiple myeloma. The Aredia
> treatment effect appeared to be smaller in the study of breast cancer
> patients receiving hormonal therapy than in the study of those
> receiving chemotherapy, however, overall evidence of clinical benefit
> has been demonstrated.\"

FDA involvement in the design and review of these trials established the
regulatory precedent that an aggregate endpoint, coined a \"skeletal
related event\" (SRE), represented an adequate efficacy measure for new
drug approval and that decreasing the number of SREs would represent
clinical benefit. It was the FDA\'s judgement that each of the elements
composing the endpoint (pathologic fractures, radiation to bone lesions,
surgery to bone, spinal cord compression) represented an adequate
measure of morbidity. The FDA refused to allow episodes of hypercalcemia
to be included as SREs because such events were not local, irreversible
events as were other elements of the endpoint and because physicians
could treat hypercalcemia with biphosphonates if it occurred.

Historically, the first NDA approval for pamidronate was based on a
single nine-month study in multiple myeloma. The second pamidronate
approval was for breast cancer and was based on two twelve-month
studies, one in patients receiving chemotherapy and one in patients
receiving hormonal therapy. Subsequent pamidronate approvals increased
the labeled duration of treatment to two years decreased the infusion
duration from four hours to two hours. The following excerpt from the
drug labeling describes the myeloma study:

> \"In a double-blind, randomized, placebo-controlled trial, 392
> patients with advanced multiple myeloma were enrolled to receive
> Aredia or placebo in addition to their underlying antimyeloma therapy
> to determine the effect of Aredia on the occurrence of
> skeletal-related events (SREs). SREs were defined as episodes of
> pathologic fractures, radiation therapy to bone, surgery to bone, and
> spinal cord compression. Patients received either 90 mg of Aredia or
> placebo as a monthly 4-hour intravenous infusion for 9 months. Of the
> 392 patients, 377 were evaluable for efficacy (196 Aredia, 181
> placebo). The proportion of patients developing any SRE was
> significantly smaller in the Aredia group (24% vs 41%, P\<0.001), and
> the mean skeletal morbidity rate (#SRE/year) was significantly smaller
> for Aredia patients than for placebo patients (mean: 1.1 vs 2.1,
> P\<.02). The times to the first SRE occurrence, pathologic fracture,
> and radiation to bone were significantly longer in the Aredia group
> (P=.001, .006, and .046, respectively). Moreover, fewer Aredia
> patients suffered any pathologic fracture (17% vs 30%, P=.004) or
> needed radiation to bone (14% vs 22%, P=.049).\"

The following excerpt describes the data on treatment beyond 9 months:

> \"After 21 months, the proportion of patients experiencing any
> skeletal event remained significantly smaller in the Aredia group than
> the placebo group (P=.015). In addition, the mean skeletal morbidity
> rate (#SRE/year) was 1.3 vs 2.2 for Aredia patients vs placebo
> patients (P=.008), and time to first SRE was significantly longer in
> the Aredia group compared to placebo (P=.016). Fewer Aredia patients
> suffered vertebral pathologic fractures (16% vs 27%, P=.005).\"

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

*These data show that efficacy of pamidronate is established at two
years in patients taking the drug for two years, however, they do not
establish how long treatment is needed. It is conceivable that the
pamidronate bone-protecting effect is imparted early and that later
benefit is an ongoing manifestation of that early change. Only a study
which randomizes patients to continue or discontinue treatment is likely
to determine the required duration of treatment. Another possible
approach to this questions would to evaluate reliable pharmacodynamic
correlates of bone protection.*

The submission in patients with breast cancer is described in the
following excerpt from labeling:

> \"Two double-blind, randomized, placebo-controlled trials compared the
> safety and efficacy of 90 mg of Aredia infused over 2 hours every 3 to
> 4 weeks for 24 months to that of placebo in preventing SREs in breast
> cancer patients with osteolytic bone metastases who had one or more
> predominantly lytic metastases of at least 1 cm in diameter: one in
> patients being treated with antineoplastic chemotherapy and the second
> in patients being treated with hormonal antineoplastic therapy at
> trial entry.
>
> 382 patients receiving chemotherapy were randomized, 185 to Aredia and
> 197 to placebo. 372 patients receiving hormonal therapy were
> randomized, 182 to Aredia and 190 to placebo. All but three patients
> were evaluable for efficacy. Patients were followed for 24 months of
> therapy or until they went off study. Median duration of follow-up was
> 13 months in patients receiving chemotherapy and 17 months in patients
> receiving hormone therapy. Twenty-five percent of the patients in the
> chemotherapy study and 37% of the patients in the hormone therapy
> study received Aredia for 24 months. The efficacy results are shown in
> the table below:\"

  --------------- --------------------------- ----- ---------------------------------------------------------------------------------- -------------------------------------------------------------------------------- ------------------------- ------ -------------------------------------------------------------------------------- ----- ---------------------------------------------------------------------------------- ------ ------ ------
                  Breast Cancer Patients\                                                                                                                                                                                                                Breast Cancer Patients\                                                                                                                                                                 
                  [Receiving                                                                                                                                                                                                                             [Receiving Hormonal Therapy]{.underline}                                                                                                                                                
                  Chemotherapy]{.underline}                                                                                                                                                                                                                                                                                                                                                                                                      

                  [Any SRE]{.underline}             [Radiation]{.underline}                                                                                                                                             [Fractures]{.underline}                                                                                                                                                                                                  

  N               A\                          P\    A\                                                                                 P\                                                                               A\                        P\     A\                                                                               P\    A\                                                                                 P\     A\     P\
                  185                         195   185                                                                                195                                                                              185                       195    182                                                                              189   182                                                                                189    182    189

  Skeletal\       2.5                         3.7   0.8                                                                                1.3                                                                              1.6                       2.2    2.4                                                                              3.6   0.6                                                                                1.2    1.6    2.2
  Morbidity Rate\                                                                                                                                                                                                                                                                                                                                                                                                                                
  (#SRE/year)                                                                                                                                                                                                                                                                                                                                                                                                                                    
  Mean                                                                                                                                                                                                                                                                                                                                                                                                                                           

  P-Value         \<.001                                                                                                               \<.001                                                                                                            .018                                                                                                                                                                      .021          
                                                                                                                                       [\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F02)                                    [\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F02)                                                                                                          

  Proportion\     46%                         65%   28%                                                                                45%                                                                              36%                       49%    55%                                                                              63%   31%                                                                                40%    45%    55%
  of patients\                                                                                                                                                                                                                                                                                                                                                                                                                                   
  having an SRE                                                                                                                                                                                                                                                                                                                                                                                                                                  

  P-Value         \<.001                                                                                                               \<.001                                                                                                            .014                                                                                                                                                                      .094          
                                                                                                                                       [\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F02)                                    [\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F02)                                                                                                          

  Median Time\    13.9                        7.0   NR                                                                                 14.2                                                                             25.8                      13.3   10.9                                                                             7.4   NR                                                                                 23.4   20.6   12.8
  to SRE\                                           [\*\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F03)                                                                                                                                                                                                            [\*\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F03)                 
  (months)                                                                                                                                                                                                                                                                                                                                                                                                                                       

  P-Value         \<.001                                                                                                               \<.001                                                                                                            .009                                                                                                                                                                      .118          
                                                                                                                                       [\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F02)                                    [\*](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/57300350.htm#F02)                                                                                                          

  \* Fractures                                                                                                                                                                                                                                                                                                                                                                                                                                   
  and radiation                                                                                                                                                                                                                                                                                                                                                                                                                                  
  to bone were                                                                                                                                                                                                                                                                                                                                                                                                                                   
  two of several                                                                                                                                                                                                                                                                                                                                                                                                                                 
  secondary                                                                                                                                                                                                                                                                                                                                                                                                                                      
  endpoints. The                                                                                                                                                                                                                                                                                                                                                                                                                                 
  statistical                                                                                                                                                                                                                                                                                                                                                                                                                                    
  significance of                                                                                                                                                                                                                                                                                                                                                                                                                                
  these analyses                                                                                                                                                                                                                                                                                                                                                                                                                                 
  may be                                                                                                                                                                                                                                                                                                                                                                                                                                         
  overestimated                                                                                                                                                                                                                                                                                                                                                                                                                                  
  since numerous                                                                                                                                                                                                                                                                                                                                                                                                                                 
  analyses were                                                                                                                                                                                                                                                                                                                                                                                                                                  
  performed.                                                                                                                                                                                                                                                                                                                                                                                                                                     

  \*\* NR = Not                                                                                                                                                                                                                                                                                                                                                                                                                                  
  Reached.                                                                                                                                                                                                                                                                                                                                                                                                                                       
  --------------- --------------------------- ----- ---------------------------------------------------------------------------------- -------------------------------------------------------------------------------- ------------------------- ------ -------------------------------------------------------------------------------- ----- ---------------------------------------------------------------------------------- ------ ------ ------

Although FDA accepted the concept that decreasing the number of SREs
represented clinical benefit, there have been many discussions between
sponsors and the FDA regarding the best SRE endpoint for comparing
efficacy in randomized studies. In the pamidronate protocols, the
primary endpoint was skeletal morbidity rate (SMR). This measure used
all events in the denominator and time on study in the numerator to
provide a rate, events per month. After reviewing the pamidronate data,
FDA found SMR not to be an unacceptable measure for primary comparison
of efficacy. Criticisms of the endpoint were that many events within the
same patient were highly correlated and that including time in the
denominator suggested that event rates were constant over time, and the
data suggested otherwise.

Subsequently, FDA has emphasized the more conservative endpoints of
*proportions of patients having an SRE on study* and *time to first SRE
event*. These endpoints are discussed in greater detail in the FDA
statistical review. The two endpoints are closely related: both utilize
only the first SRE in a patient, ignoring the morbidity of additional
events. FDA statisticians have suggested that the time to first SRE may
provide a more precise estimate because data from patient dropouts are
censored whereas in the proportions analysis these data are effectively
\"carried forward\" to the end of the study. Even the time to SRE
analysis, however, may underestimate morbidity if censoring is not
random but, rather, is \"informative censoring.\" A potential example of
this phenomenon is when more patients drop out on the placebo arm
because of \"inadequate therapeutic response.\" It seems possible that
such patients are having bone pain and are more likely to have a
subsequent SRE, thus violating the assumption of \"informative
censoring.\" So, there seems to be no perfect endpoint. The *proportions
analysis* and *the time to first SRE* are the endpoints emphasized in
FDA reviews.

As the pamidronate labeling excerpts show, the pamidronate treatment
effect was in myeloma and in those breast cancer patients who were
receiving chemotherapy. In breast cancer patients receiving hormones,
the benefit was less, and there were only trends in favor of pamidronate
in the overall analyses. Statistical significance was seen only in the
radiation therapy SRE analysis and only with the time to SRE analysis.
Nevertheless, the FDA approved this indication because of the supporting
data from breast cancer patients receiving chemotherapy. As noted above,
a special notation regarding the lesser apparent benefit in breast
cancer patients receiving hormones was placed in the indication section
of the labeling.

## Important Milestones in Product Development 

The Applicant undertook parallel zoledronate clinical development
programs for treatment of hypercalcemia of malignancy (HCM) and for
treatment of bone metastases. IND 43,240 was submitted to the Division
of Metabolic and Endocrinology Drug Products (DMEDP) for treatment of
HCM while IND 55831 was submitted to the Division of Oncology Drug
Products (DODP) for treatment of bone metastases. An NDA was submitted
to DMEDP for treatment of HCM in December of 1999. Concerns were raised
by DMEDP about renal toxicity. FDA issued an approvable letter in
September 20001, and FDA approval was granted in August 2001 for this
indication.

The current submission to DODP is for a zoledronate efficacy supplement
for treatment of bone metastases. Three phase III studies evaluate
skeletal-related complications in patients with bone metastases in three
classes of tumor types. They are (i) prostate cancer, (ii) breast cancer
and myeloma, and (iii) solid tumors other than breast cancer and
prostate cancer.

The Phase III protocols were submitted in April, May, and September of
1998. After reports of increased incidence of renal failure, all
protocols were amended in June of 1999 to increase the volume of normal
saline infused with zoledronate from 50 to 100 ml to increase infusion
duration from 5 to 15 minutes. Another amendment in June of 2000
eliminated the 8 mg dose of zoledronate from all protocols because of an
increased incidence of renal failure. The studies of zoledronate given
in the adjuvant setting were placed on clinical hold. Trials in
metastatic disease continued at the 4mg dose.

During conduct of the studies, the Applicant informed DODP of violations
of good clinical conduct at a Netherlands site in Study 010 and of
unblinding of an investigator at a site in Study 039. FDA instructed the
Applicant to analyze the trials both including and excluding data from
the involved sites. After review of the data, FDA would decide whether
to include or exclude the data.

FDA met with the Applicant several times during development and conduct
of the studies. The following are selected points discussed with the
Applicant:

[Nov 14, 00]{.underline}:

-   The intent-to-treat analysis should include all randomized patients.

```{=html}
<!-- -->
```
-   Given the toxicity of the 8 mg dose, it is unlikely that the 8 mg
    dose will be approved in any context.

[2-13-01:]{.underline} (Pre-NDA meeting)

-   FDA did not agree with the sponsor that patients without baseline
    radiographs should be excluded from analysis.

-   FDA recommended analyzing efficacy according to the randomized
    treatment group and safety according to treatment actually received.

[7-26-01:]{.underline} (Pre-NDA meeting)

-   FDA suggested analyzing adverse events separately according to
    disease type as well as pooled.

# Efficacy Review

This section presents FDA clinical efficacy review findings from the
Applicant\'s placebo controlled trials in prostate cancer (Study 039)
and in other solid tumors (Study 011) and an active controlled trial in
breast cancer and myeloma (Study 010).

**Placebo Controlled Trial #039 in Prostate Cancer**

## Placebo Controlled Trial #039 in Prostate Cancer

**Protocol Title:**

> \"A randomized, double-blind, placebo-controlled, multicenter,
> comparative, safety and efficacy study of intravenous zoledronate (4
> and 8 mg) in prostate cancer patients with metastatic bone lesions
> receiving antineoplastic therapy\"

First patient enrolled: June 22, 1998

Last patient completed: Jan 26, 2001

Unblinding: April 10, 2001

### Background {#background .unnumbered}

Trial 039 evaluated Zometa's effect on Skeletal Related Events (SREs) in
prostate cancer. Ideally, the focus of a literature review would be to
determine prognostic factors associated with such events. With no
literature available on this topic, however, the following paragraphs
provide a general background on prostate cancer and describe prognostic
factors associated with progression and survival.

Prostate cancer is a major U.S. public health problem. In 1999, more
than 179,000 new cases were diagnosed leading to an estimated 37,000
deaths. Adenocarcinoma is the predominant, found in 95% of patients.
Diagnosed at a median age of 72 years, it is the most common male
malignancy and the second leading cause of cancer-relate death in the
US. Prostate cancer is 1.5 times higher in blacks than in whites. A
higher testosterone level in American blacks than in their caucasian
counterparts is hypothesized to contribute to the increased incidence of
prostate cancer in the former. Asian men have a lower risk related to
reduced 5 α-reductase activity.

Prostate cancer can be cured by surgery or radiation when it is truly
confined to the prostate gland. According to some estimates, 75% of
patients with apparently localized disease develop metastasis within 10
years. Hormonal manipulation by surgical (bilateral orchiectomy) or
medical means is offered as adjuvant therapy or as first line treatment
for advanced prostate cancer but no response is observed in 15-20% of
patients. Even in those who do respond, the tumor becomes refractory to
the hormonal agents in 18 to 36 months. Subsequently, radiation,
radiopharmaceuticals (strontium and samarium), chemotherapy,
corticosteroids and analgesics become mainstays of palliative therapy.
It is in this palliative setting where trial 039 tests the palliative
efficacy of Zometa.

Risk factors for cancer progression are tumor burden, poor performance
status, visceral spread of disease, elevated serum level of alkaline
phosphatase, non-axial bone disease and anemia. Aneuploid primary tumor,
erb and p53 mutation may be risk factors for disease progression.

At the time of diagnosis, the survival is linked to the extent of tumor.
Table 1 demonstrates the according to extent of disease. Other
prognostic factors are histologic grade of tumor (Gleason's score),
patient's age, concurrent illnesses, and level of PSA.

**Survival according to extent of Prostate Cancer**

  ------------------------------------------------------ ----------------
  **Extent of Disease**                                  **Years**

  Confined to prostate gland                             +5

  Locally advanced                                       5

  Metastatic disease                                     1-3
  ------------------------------------------------------ ----------------

Prostate cancer metastasizes to the well-vascularized areas of skeleton
such as the vertebral column, ribs, skull and the proximal ends of long
bones, and bone metastases are a leading cause of morbidity for prostate
cancer patients. Up to 62% of patients have bone metastases at the time
of diagnosis. Prostate cancer presents with bone pain in 10-20% of
patients. About 80-100% of patients who die of prostate cancer have bone
metastases. Clinical stage and Gleason's score correlate with the
long-term development of bone metastases. Patients with T1/T2 disease
and T3/T4 disease develop metastasis at 10 years in 3-41% and 12-55% of
cases respectively. Patients with well-, moderately-, and
poorly-differentiated tumors develop metastases at 10 years in 2.7-10%,
13-57% and 42-80% of the cases respectively.

After prostate cancer metastasizes, survival correlates with tumor
burden. In patients with a solitary metastasis, the median survival is
approximately 50 months, while the median survival for all patients with
bone metastases who receive hormonal therapy is 30-35 months. Severe
bone pain, pathologic fractures and spinal cord compression are the
major 'events' arising from bone metastases.

### Study Design {#study-design .unnumbered}

Study 039 was a double-blind, multi-centered, placebo-controlled
randomized trial in patients with prostate cancer. Patients were
randomized in a ratio of 1:1:1 to treatment with zoledronate 4mg (Zol
4), zoledronate 8mg (Zol 8), or placebo. Zometa or placebo was
administered intravenously once three weeks. After an early amendment,
the randomization was stratified by prostate cancer bone metastases
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). The study duration was to be 15 months.
Patients were not to be removed from the trial for disease progression.

The protocol-specified primary objective was to assess the efficacy of
zoledronate at 4 mg or 8 mg in preventing skeletal-related events (SRE)
in prostate cancer patients with rising PSAs after first-line hormonal
therapy.

The secondary objectives were to evaluate Zoledronate's effect on time
to first SRE, pain scores, analgesic use, performance status, QoL
scores, and survival. Zoledronate's safety and tolerability were also
secondary objectives. Tertiary objectives were evaluation of patient
health care utilization, and productivity loss.

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

*The primary objective as specified in the statistical section was
proportions of patients with at least one SRE and time to first SRE was
a secondary objective along with other secondary objectives noted above.
Although the indication for use in the Applicant's proposed drug label
states Zometa should be used in combination with antineoplastic therapy,
the inclusion criteria for Study 039 did not require continuation of
antineoplastic therapy and was not analyzed in the Applicant\'s study
report.*

### Planned Study Duration: {#planned-study-duration .unnumbered}

Time for enrollment : 12 months

Duration of individual patient participation:

15 months (60 weeks) Phase 1

9 months (36 weeks) Phase 2 (to obtain long-term safety and survival
data).

Total duration of treatment; 24 months (96 weeks)

### Drug administration and formulation: {#drug-administration-and-formulation .unnumbered}

Per Protocol:

"Zolendronate 4 mg or 8 mg or placebo given as a 5 minute infusion every
3 weeks x 24 months. The drug was to be supplied in 4 mg lyophilized
vials; reconstitute in 5 ml of sterile water for injection, then mixed
with NS to a total infusion volume of 50 ml. Solutions must have been
prepared in plastic, as the drug will bind to glass."

### Study Population: {#study-population .unnumbered}

The planned population for Study 039 was prostate cancer patients with a
history of metastatic bone disease who have demonstrated biochemical
progression of disease (e.g. a rising PSA) while on first-line hormonal
therapy for metastatic disease which has resulted during an adequate
state of androgen deprivation (serum testosterone \< 50 ng/ml).

### Inclusion Criteria: {#inclusion-criteria .unnumbered}

-   Aged 18 or older

-   Signed informed consent

-   Histologically confirmed diagnosis of prostate carcinoma

-   Objective evidence of metastatic disease to bone: multiple foci
    (\>3) on bone scan; if [\<]{.underline} 3, additional radiographic
    or biopsy studies are required to confirm metastatic disease.
    Patients with a complete response to first-line hormonal therapy
    were eligible, provided they had prior documentation of disease.
    Hormonal therapy administered in the adjuvant or neoadjuvant setting
    was not be considered to be first-line hormonal therapy.

-   Must have had biochemical progression of disease despite therapy
    with first-line hormonal therapy; defined as 3 consecutively rising
    PSAs, each separated by at least 2 weeks; the 3^rd^ measurement must
    be [\>]{.underline} 0.4 ng/ml.

-   ECOG PS 0, 1, 2

### Exclusion criteria {#exclusion-criteria .unnumbered}

-   Bone pain due to metastatic bone disease that had developed since
    the best response to first-line hormonal therapy

-   Previous or current treatment with cytotoxic chemotherapy (i.e.,
    before Visit 2)

-   Alteration of the first-line hormonal therapy prior to Visit 1

-   Serum testosterone level at Visit 1 elevated above the castrate
    range

-   Radiation therapy to bone (including radioisotopes) within 3 months
    prior to Visit 2

-   Prior therapy with a biphosphonate

-   Treatment with calcitonin, mithramycin, or gallium nitrate within 2
    weeks prior to randomization

-   Use of other investigational drugs within 30 days prior to
    randomization

-   History of noncompliance, unreliability, inability to give informed
    consent

-   Serum creatinine \> 3.0 mg/dL

-   Corrected serum calcium \< 8.0 mg/dL or [\>]{.underline} 11.6 mg/dL

-   History of other neoplasm within 5 years except non-melanomatous
    skin cancer

-   Patients with evidence in the 6 months prior to randomization of
    severe cardiovascular disease, refractory hypertension, or
    symptomatic coronary artery disease

### Objectives {#objectives .unnumbered}

### Primary Objective: {#primary-objective .unnumbered}

The protocol-specified primary endpoint was the proportion of patients
having at least one SRE. SRE are defined in the next section of this
review.

Secondary Objectives:

-   time to first SRE

-   Skeletal Morbidity rate

-   safety

-   Time to disease progression in bone

-   Time to overall disease progression

-   Pain scores

-   Analgesic scores

-   QoL

-   Bone mineral density

-   Bone lesion response from radiological studies

-   Biochemical variables

> Urinary N-telopeptide/creatinine ratio
>
> Urinary pyridinoline/creatininee ratio

Urinary deoxy pyridinoline/creatinine ratio

Serum bone alkaline phosphatase

-   Overall safety

-   Survival

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

*The applicant was advised by the agency to make time to first SRE a
co-primary endpoint, since it is more sensitive and takes into account
the drop outs from the study.*

### Definition of SRE: {#definition-of-sre .unnumbered}

Per protocol:

-   ["Pathologic bone fractures]{.underline}: those bone fractures which
    occur spontaneously or which result from trivial trauma. A new
    compression fracture is defined as a decrease in total vertebral
    height, or anterior vertebral height, or posterior height of
    [\>]{.underline} 25% from baseline. A further reduction in the
    vertebral fracture by [\>]{.underline} 25% during the study is
    classified as a new fracture. Each pathological fracture (vertebral
    and non-vertebral) is to be documented by x-ray and is to be counted
    separately. A central radiologist determine vertebral SRE".

-   ["Spinal cord compression]{.underline}: These will be confirmed by
    an MRI. If spinal cord compression occurs in conjunction with a
    vertebral compression fracture, each will be counted as a separate
    SRE".

-   "[Surgery to bone]{.underline}: This includes the procedures that
    are performed to set or stabilize pathologic fractures or areas of
    spinal cord compression, and surgical procedures which are performed
    to treat or prevent a fracture or a spinal cord compression".

-   ["Radiation therapy to bone]{.underline}: this includes radiation
    administered to bone to palliate painful lesions or to prevent or
    treat fractures or spinal cord compressions. Each port of radiation
    will be considered a separate event. Administration of a
    radioisotope such as Strontium will be included as radiation to
    bone".

-   ["Change of antineoplastic therapy to treat bone pain]{.underline}
    includes any change of anticancer therapy including hormonal
    therapy. Alteration of pain medications will count as an analgesic
    score and will not be recorded as a skeletal event."

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

*At FDA's request, hypercalcemia was not counted as an SRE. As explained
in the introduction to this review, exclusion of hypercalcemia from the
SRE endpoints has been the standard regulatory approach since the design
and analysis of the trials leading to approval of Aredia.*

### Follow-up: {#follow-up .unnumbered}

Schematic representation of the study follow-up is reproduced below from
the original protocol. The following was the planned schedule of
assessment:

-Radionuclide bone scans/Radiographic plain films by central
radiologist: visits 6, 10, 14, 18, 22, 26, 30 and 34.

-SRE: visit 3 through visit 34.

-TTP in bone: visits 6, 10, 14, 18, 22, 26, 30 and 34 by the central
radiologist.

-TTP: 6, 10, 14, 18, 22, 26, 30 and 34.

-Analgesic scores: at visits 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,
24, 26, 28, 30, 32 and 34 according to the analgesic score in appendix
7.

-Pain scores: visits 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,
28, 30, 32 and 34 according to brief Pain Inventory Short form.

-ECOG performance status and QoL: visits 1 (2 for QoL), 6, 10, 14, 18,
22, 26, 30 and 34

Schematic representation of the study follow-up

**Phase 1 (Safety and Efficacy)**

<table>
<colgroup>
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 21%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Period</strong></td>
<td><strong>Screening</strong></td>
<td colspan="20"><strong>Randomized treatment and
evaluation</strong></td>
<td><strong>Final Evaluation Phase 1 and First Randomized Treatment
Phase 2</strong></td>
</tr>
<tr class="even">
<td><strong>Visit</strong></td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>5</td>
<td>6</td>
<td>7</td>
<td>8</td>
<td>9</td>
<td>10</td>
<td>11</td>
<td>12</td>
<td>13</td>
<td>14</td>
<td>15</td>
<td>16</td>
<td>17</td>
<td>18</td>
<td>19</td>
<td>20</td>
<td>21</td>
<td>22</td>
</tr>
<tr class="odd">
<td><strong>Week</strong></td>
<td>-2</td>
<td>0</td>
<td>3</td>
<td>6</td>
<td>9</td>
<td>12</td>
<td>15</td>
<td>18</td>
<td>21</td>
<td>24</td>
<td>27</td>
<td>30</td>
<td>33</td>
<td>36</td>
<td>39</td>
<td>42</td>
<td>45</td>
<td>48</td>
<td>51</td>
<td>54</td>
<td>57</td>
<td>60</td>
</tr>
<tr class="even">
<td><strong>Treatment</strong></td>
<td>none</td>
<td colspan="20"><p>Zoledronate 4 mg q 3 weeks</p>
<p>Zoledronate 8 mg q 3 weeks</p>
<p>Placebo q 3 weeks</p></td>
<td><p>Zoledronate 4 mg q 3 weeks</p>
<p>Zoledronate 8 mg q 3 weeks</p>
<p>Placebo q 3 weeks</p></td>
</tr>
</tbody>
</table>

**Phase 2 (Extension)**

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 24%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Period</strong></td>
<td colspan="11"><strong>Randomized treatment and
evaluation</strong></td>
<td><strong>Evaluation</strong></td>
</tr>
<tr class="even">
<td><strong>Visit</strong></td>
<td>23</td>
<td>24</td>
<td>25</td>
<td>26</td>
<td>27</td>
<td>28</td>
<td>29</td>
<td>31</td>
<td>31</td>
<td>32</td>
<td>33</td>
<td>34</td>
</tr>
<tr class="odd">
<td><strong>Week</strong></td>
<td>63</td>
<td>66</td>
<td>69</td>
<td>72</td>
<td>75</td>
<td>78</td>
<td>81</td>
<td>84</td>
<td>87</td>
<td>90</td>
<td>93</td>
<td>96</td>
</tr>
<tr class="even">
<td><strong>Treatment</strong></td>
<td colspan="11"><p>Zoledronate 4 mg q 3 weeks</p>
<p>Zoledronate 8 mg q 3 weeks</p>
<p>Placebo q 3 weeks</p></td>
<td><p>Zoledronate 4 mg q 3 weeks</p>
<p>Zoledronate 8 mg q 3 weeks</p>
<p>Placebo q 3 weeks</p></td>
</tr>
</tbody>
</table>

Following visit 2, study visits are to be made on the designated study
day with an error of not more than --3 to +7 days.

**Removal from Study**

Patients were NOT to be removed from study for the occurrence of a
skeletal-related event; the study was designed to assess the total
number of events that occur throughout the time period. Patients were
NOT be removed from study for changes in antineoplastic therapy.

Patients were to be removed from study for the following reasons:

-   Adverse events

-   Abnormal laboratory values

-   Abnormal test procedure results

-   Unsatisfactory therapeutic effect

-   Patient's condition no longer requires study drug

-   Protocol violation

-   Patient withdrew consent

-   Lost to follow-up

-   Administrative problems

-   Death

Patients who were removed from study were to be followed every 3 months
for a total of 24 months from the date of randomization.

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

*Some of the reasons for removal from the study are ill-defined, such as
abnormal of laboratory values and abnormal test procedures.*

### Statistical considerations and sample size {#statistical-considerations-and-sample-size .unnumbered}

After an early amendment, 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).

The study 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 between the two dose levels of zoledronate and placebo.).
Bonferroni's adjustment was used to calculate the sample size, assuming
a 40% incidence rate on placebo and a 24% incidence rate on zoledronate,
with an overall Type I error rate of 0.05. Although the calculated
sample size was 519 patients (173 on each arm), and the planned sample
size was 550 patients to account for the noise introduced by the use of
intent-to-treat (ITT) population, 643 patients were actually enrolled.
After the Zol 8 mg arm was dropped from the analysis plan by Amendment
#5, the plan for Bonferroni adjustment of alpha was dropped, and the
primary analysis was specified to compare only the zoledronate 4mg and
placebo study arms. There was no planned interim analysis.

The Applicant's defined the ITT population for efficacy evaluations was
all randomized patients who received trial medication and had at least
one follow-up measurement. Patients receiving a biphosphonate other than
Zometa were to be excluded from analysis.

The primary efficacy analysis was planned for the end of Phase I, 15
months after patient entry, although other analyses were also to be
performed when patients had been on study for 3, 6, 9, and 12 months.
The last observation of each patient was carried forward. According to
the original plan, the test statistic for the primary endpoint was a
Chi-square test, but this was replaced by the Cochran-Mantel-Haenzel
test with amendment 1. Baseline prognostic factors were specified as PS,
renal function, and age.

Additional information about the statistical plan is detailed in the FDA
statistical review.

### Protocol Amendments: {#protocol-amendments .unnumbered}

[Date of Protocol]{.underline}:

March 5, 1998

[Amendment 1]{.underline}:

August 13^th^, 1998:

\- Patients were to be stratified by their prostate cancer history
according to whether they had

1)  No metastatic disease (M0 or Mx) or

2)  metastatic disease present at the time of initial diagnosis (Stage
    D2 or M1)

-   Required last PSA measurement to be obtained within 8 weeks of visit
    1.

-   Specified 2 logistic regression analyses to determine the influence
    of stratum and previous experience of SREs.

[Amendment 2]{.underline}:

April 27, 1999

Prior or current use of estramustine is permitted prior to visit 2.

[Amendment 3]{.underline}

June 24, 1999:

Specified that Zoledronate would be be diluted in 100 ml instead of 50
ml normal saline and was to be administered intravenously over 15
minutes rather than 5 minutes. This amendment was due to 3 reports of
renal failure in 3 patients receiving 8 mg of Zoledronate. One of these
patients died because of sepsis.

[Amendment 4]{.underline}

June 7, 2000:

-   All Patients receiving Zoledronate 8 mg had their dose reduced to 4
    mg based on the suggestions by the Data Safety Monitoring Board
    (DSMB) and the Renal Advisory Board (RAB).

-   As a precaution, serum creatinine was now measured prior to each
    dose of study drug. Drug administration will be delayed as outlined
    in Table

Dose modification according to serum creatinine

+---------------+----------------------------+------------------------+
| **Baseline    | **Creatinine elevation     | **Action**             |
| creatinine**  | above baseline (mg/dl)**   |                        |
|               |                            |                        |
| **(mg/dl)**   |                            |                        |
+---------------+----------------------------+------------------------+
| \<1.4         | 0.5                        | Delay in drug          |
|               |                            | administration until   |
|               |                            | the serum creatinine   |
|               |                            | returns to less than   |
|               |                            | 10% above baseline.    |
+---------------+----------------------------+------------------------+
| [\>           | 1.0                        |                        |
| ]{.underline} |                            |                        |
| 1.4           |                            |                        |
+---------------+----------------------------+------------------------+
| Any           | Doubling                   |                        |
+---------------+----------------------------+------------------------+

[Amendment 5]{.underline}

June 7, 2000:

Patients who completed the two-year protocol, and who in the opinion of
Principal Investigator might benefit from continuation of therapy, could
receive open-label zoledronate.

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

*Out of a total of 8033 infusions, 1688 infusions (21%) were
administered prior to amendment 2 over 5 minutes. Six thousand three
hundred and forty-five infusions (79%) were administered over 10
minutes.*

Number of infusions affected by amendment 2

  ----------------------- ----------------- -------- ------------- ----------
                          **Total           **4 mg** **Placebo**   **8/4 mg**
                          infusions**                              

  Prior to amendment 2    1688 (21%)        552      588           548

  After amendment 2       6345 (79%)        2201     2024          2120
  ----------------------- ----------------- -------- ------------- ----------

Amendment #4, which changed the Zol 8 dose from 4 mg to 8 mg, occurred
after all patients had been accrued and less than six months before the
last patient finished Phase I. Therefore, almost all patients in the 8/4
mg arm received only the 4 mg dose early in their course. Up until the
13^th^ visit only 2 patients in the 8/4 mg arm received 4 mg infusions.
For patients remained on study until the 21^st^ visit, approximately
half the patients were received 4 mg infusions in the 8/4 mg arm.

### Efficacy Results of Study 039 {#efficacy-results-of-study-039 .unnumbered}

#### Populations treated and analyzed {#populations-treated-and-analyzed .unnumbered}

There were 136 study sites, in 17 countries (Argentina, Australia,
Austria, Belgium, Brazil, Canada , Chile, France, Great Britain, Italy,
New Zealand, Peru, Sweden, Switzerland, United Kingdom, Uraguay and
USA). Some of the study sites listed had sub-sites that actually
enrolled and treated patients listed under that site.

643 patients were randomized, but 3 did not receive the study drug.
These three patients were not included in the evaluation for safety.
There was one patient who received the incorrect study drug for the
entire study period. Patient 11002 received 4 mg at all study visits
although he was randomized to the 8/4 mg arm. This patient was included
in the 8/4 mg arm for efficacy analysis. According to the Applicant,
thirty one patients were withdrawn from the study prematurely because
their blind was broken: 9 patients in the 4 mg group, 10 in the 8/4 mg
group, 12 in the placebo group. The number of patients involved in
unblinding according to FDA analysis of the electronic data was slightly
larger the number of patients removed from the study. The violations in
at least 4 patients per FDA review (based on Applicant's e-dataset) are
compiled in the table listed on page 29.

Violations in at least 4 patients

  ------------------------------------------ --------- --------- ---------
                                                                 

                                                                 

                                                                 

                                                                 

                                                                 

                                                                 
  ------------------------------------------ --------- --------- ---------

Although patients could be entered into the study without detectable
metastases (i.e., disease in CR), according to the reviewer\'s analysis,
only seven such patients were entered.

Baseline demographic factors analyzed by the Applicant and selectively
verified by FDA reviewers are listed in the table below.

Demography

+--------------------------------------------+-------+-------+-------+
| **Treatment arm**                          | **4   | *     | **8/4 |
|                                            | mg**  | *Plac | mg**  |
|                                            |       | ebo** |       |
+============================================+=======+=======+=======+
| **No of patients**                         | 214   | 208   | 221   |
+--------------------------------------------+-------+-------+-------+
| **Age range**                              | 45-90 | 37-90 | 43-90 |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 72    | 73    | 72    |
+--------------------------------------------+-------+-------+-------+
| **Age [\<]{.underline} 60 years**          | 19    | 15    | 19    |
+--------------------------------------------+-------+-------+-------+
| **Age \> 60 years**                        | 196   | 193   | 201   |
+--------------------------------------------+-------+-------+-------+
| **Time from initial diagnosis to           | 214   | 208   | 218   |
| randomization N**                          |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Median (months)**                        | 51.8  | 56.9  | 60.6  |
+--------------------------------------------+-------+-------+-------+
| **Range (months)**                         | 3 -   | 1 -   | 8 -   |
|                                            | 283   | 250   | 280   |
+--------------------------------------------+-------+-------+-------+
| **Time from initial diagnosis to diagnosis | 214   | 207   | 217   |
| of bone mets N**                           |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Median (months)**                        | 19.6  | 19.6  | 26.6  |
+--------------------------------------------+-------+-------+-------+
| **Range (months)**                         | 0 -   | 0 -   | 0 -   |
|                                            | 228   | 216   | 215   |
+--------------------------------------------+-------+-------+-------+
| **Time from first bone mets to             | 114   | 115   | 132   |
| randomization N**                          |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Median (months)**                        | 5.8   | 12.3  | 5.4   |
+--------------------------------------------+-------+-------+-------+
| **Range (months)**                         | 0 -   | 0 -   | 0 -   |
|                                            | 121   | 111   | 87    |
+--------------------------------------------+-------+-------+-------+
| **Prior history of bone metastasis**       | 99    | 92    | 87    |
+--------------------------------------------+-------+-------+-------+
| **No prior history of bone metastasis**    | 115   | 116   | 134   |
+--------------------------------------------+-------+-------+-------+
| **No. of bone metastasis per patient**     |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **median**                                 | 4     | 4     | 4     |
+--------------------------------------------+-------+-------+-------+
| **range**                                  | 1-13  | 1-11  | 1-12  |
+--------------------------------------------+-------+-------+-------+
| **Previous SRE N**                         | 214   | 208   | 218   |
+--------------------------------------------+-------+-------+-------+
| **Yes**                                    | 66    | 78    | 70    |
|                                            |       |       |       |
|                                            | 30%   | 37.5% | 32%   |
+--------------------------------------------+-------+-------+-------+
| **No**                                     | 148   | 130   | 148   |
|                                            |       |       |       |
|                                            | 69%   | 62%   | 68%   |
+--------------------------------------------+-------+-------+-------+
| **Number of extraskeletal organs           |       |       |       |
| involved**                                 |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **0**                                      | 2     | 3     | 2     |
+--------------------------------------------+-------+-------+-------+
| **1**                                      | 176   | 182   | 188   |
+--------------------------------------------+-------+-------+-------+
| **2**                                      | 33    | 18    | 24    |
+--------------------------------------------+-------+-------+-------+
| **3**                                      | 3     | 5     | 6     |
+--------------------------------------------+-------+-------+-------+
| **4**                                      | 0     | 0     | 1     |
+--------------------------------------------+-------+-------+-------+
| **Race**                                   |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Caucasian**                              | 178   | 172   | 186   |
+--------------------------------------------+-------+-------+-------+
| **Black**                                  | 24    | 19    | 19    |
+--------------------------------------------+-------+-------+-------+
| **Oriental**                               | 3     | 2     | 1     |
+--------------------------------------------+-------+-------+-------+
| **Other**                                  | 9     | 15    | 15    |
+--------------------------------------------+-------+-------+-------+
| **Performance status**                     |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **0**                                      | 86    | 93    | 98    |
+--------------------------------------------+-------+-------+-------+
| **1**                                      | 112   | 97    | 103   |
+--------------------------------------------+-------+-------+-------+
| **2**                                      | 17    | 18    | 18    |
+--------------------------------------------+-------+-------+-------+
| **Baseline PSA**                           |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Range**                                  | 0.15  | 0.25  | 0.2   |
|                                            | -5963 | -8410 | -9124 |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 79.8  | 57.8  | 88.5  |
+--------------------------------------------+-------+-------+-------+
| Analgesic score (per sponsor)              |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **0**                                      | 93    | 77    | 73    |
+--------------------------------------------+-------+-------+-------+
| **1**                                      | 70    | 77    | 83    |
+--------------------------------------------+-------+-------+-------+
| **2**                                      | 9     | 9     | 11    |
+--------------------------------------------+-------+-------+-------+
| **3**                                      | 40    | 41    | 48    |
+--------------------------------------------+-------+-------+-------+
| **4**                                      | 2     | 3     | 3     |
+--------------------------------------------+-------+-------+-------+
| **BPI composite Pain score (per sponsor)** |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **N**                                      | 193   | 187   | 192   |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 1.8   | 1.8   | 2.3   |
+--------------------------------------------+-------+-------+-------+
| **Fact-G score (per sponsor)**             |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **N**                                      | 193   | 187   | 192   |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 82.5  | 82.8  | 82.1  |
+--------------------------------------------+-------+-------+-------+

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

*The primary reason for examining baseline factors is to consider
whether factors which are prognostic for efficacy outcome are balanced
among the study arms. Because there have been no previous studies using
SRE-based endpoints in prostate cancer, it is difficult to be certain
which factors are predictive for future SREs. In previous studies of
biphosphonates in breast cancer and myeloma, a patient history of a
prior SRE was a strong predictor for future SREs. Other suggested
prognostic factors are based on theoretical considerations or their
prognostic value for other prostate cancer endpoints such as survival.
Factors that seem reasonable to consider also include performance status
and black race. The number of potential SREs could also be expected to
correlate with tumor load. It is unclear whether serum PSA would be
useful in this setting. PSA might not identify more aggressive disease,
since some patients with aggressive disease may have a low PSA. However,
there is a suggestion in a retrospective analysis, that pretreatment PSA
is a predictor of biochemical failure and death due to prostate cancer.
Gleason scores were not collected in this study.*

Performance status, age and number of bone metastases per patient were
equally balanced among the arms. However, there was a slightly increased
number of blacks, and patients with a higher number (2-4) of organs
involved in the 4 mg arm compared to other arms. Baseline serum PSA was
highest in the 8/4 mg arm and lowest for placebo. Baseline pain scores
were highest for 8/4 mg arm and lowest for the 4 mg arm.

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

*As discussed later in this review, the discordant outcomes for the Zol
4 mg and Zol 8mg arm were perplexing. The difference in outcomes was not
changed by the FDA statistical reviewer\'s Cox regression model which
included prior SREs, time from initial diagnosis of cancer to bone
metastases, baseline PSA and baseline analgesic scores. The treatment
effect of 8/4 mg remained not significant although the p value
decreased.*

The baseline metastatic sites were recorded by the investigator only as
number of organs involved and not as number of metastases. The recorded
sites were classified as bone, liver, lymph nodes, lung, pleura, skin,
eye, brain and other. A comparison of extraskeletal sites of metastases
is given in Table 4. Extraskeletal metastases other than distant lymph
nodes were highest in number in the 8/4 mg group (20 in Zol 8/4 mg, 10
in Zol 4mg, and 13 in placebo).

Distribution of the metastases according to treatment arm

  ------------------------------------------------------------------------
  **Site of metastases**           **4 mg**   **Placebo**    **8/4 mg**
  -------------------------------- ---------- -------------- -------------
  Lung                             6          5              4

  Liver, brain, skin, eye          1          1              5

  Pleura                           0          0              1

  Distant lymph nodes              29         15             19

  Other                            3          7              10
  ------------------------------------------------------------------------

### Protocol Violations {#protocol-violations .unnumbered}

The Applicant identified only one major protocol violation. This patient
on the Zol 4mg arm had no history of bone metastases (CAN/2006/15191).
He was removed from the trial after 9 visits and was not followed. Other
violations which occurred frequently (at least in 4 patients) are as
given in Table below.

Violations in at least 4 patients

+------------------------------------------+--------+--------+--------+
| **Violation**                            | **4    | **Pla  | **4/8  |
|                                          | mg**   | cebo** | mg**   |
|                                          |        |        |        |
|                                          | **(#   | **(#   | **(#   |
|                                          | of     | of     | of     |
|                                          | p      | p      | p      |
|                                          | ts.)** | ts.)** | ts.)** |
+==========================================+========+========+========+
| Unblinding                               | 11     | 12     | 14     |
+------------------------------------------+--------+--------+--------+
| No histological diagnosis                | 10     | 14     | 11     |
+------------------------------------------+--------+--------+--------+
| PSA did not comply with Inclusion        | 53     | 40     | 43     |
| criteria of protocol                     |        |        |        |
+------------------------------------------+--------+--------+--------+
| Randomized by incorrect strata           | 19     | 20     | 18     |
+------------------------------------------+--------+--------+--------+
| Chemotherapy less than 2 weeks from      | 1      | 2      | 1      |
| randomization                            |        |        |        |
+------------------------------------------+--------+--------+--------+
| Violation involving hormonal treatment   | 3      | 7      | 5      |
| history or required castration           |        |        |        |
| testosterone levels                      |        |        |        |
+------------------------------------------+--------+--------+--------+

The most serious violations were unblinding and lack of histological
diagnosis. Unblinding occurred mostly at two study sites -- 3123 and
2044. The following table shows the efficacy results of these study
sites (proportions of patients with at least one SRE).

Proportion of patients with SRE at Study Site 3123 and 2044

+----------------+---------+---------+---------+---------------------+
| **Study Site** | **4     | **8/4   | **Pl    | **N at study site** |
|                | mg**    | mg**    | acebo** |                     |
|                |         |         |         | **(# of pts.)**     |
|                | **(# of | **(# of | **(# of |                     |
|                | pts.)** | pts.)** | pts.)** |                     |
+================+=========+=========+=========+=====================+
| 2044 (USA)     | 1/10    | 2/8     | 1/9     | 27                  |
+----------------+---------+---------+---------+---------------------+
| 3123           | 0/2     | 2/2     | 2/3     | 7                   |
| (Argentina)    |         |         |         |                     |
+----------------+---------+---------+---------+---------------------+
| Total          | 1/12    | 4/10    | 3/12    | 34                  |
| (proportion)   |         |         |         |                     |
|                | (8.3%)  | (40%)   | (25%)   |                     |
+----------------+---------+---------+---------+---------------------+

*[Reviewer's comment regarding study violations:]{.underline}*

*Out of the 37 patients that were unblinded, 34 were from study sites
3123 and 2044. The number of patients in these two studies constitute
5.3 % of the total number of patients. The results of these studies are
similar to the overall results of the study. Due to the relatively small
number of patients involved, it is doubtful that unblinding at these
sites would significantly alter the results of the study.*

*Lack of histological diagnosis is reason for concern. However, the
likelihood that these patients did not have prostate cancer is low.
Patients were required to have documentation of three increasing values
of PSA at least 2 weeks apart from each other. There were three patients
who had protocol violations involving inclusion criteria for PSA as well
as lack of histological documentation of Prostate cancer (pt ID 11038,
11232, 11246). These patients were included in the FDA efficacy
analyses.*

*Pt ID 11038 and 11232 were in the placebo arm and did not suffer from
any SRE. Pt ID 11246 was in the 4 mg arm and had SREs. The PSA
measurements of these patients prior to the study were less than 2 weeks
apart. However, prior to these measurement, there is a record of
elevated PSA. In larger numbers, this could alter the target population.
The results of efficacy of Zometa would not be altered.*

#### Discontinuation of Study Drug {#discontinuation-of-study-drug .unnumbered}

As summarized in the following table, most patients either discontinued
study drug or died prior to completing the study.

Early discontinuations and deaths

  ---------- --------- ------------ -------------------------- --------------
  **Arm**    **N**     **Deaths**   **Other Early              **Total D/D**
                                    Discontinuations**         

  4 mg       214       25           108                        133

  Placebo    208       32           111                        143

  8/4 mg     221       40           119                        159
  ---------- --------- ------------ -------------------------- --------------

Table below from the Applicant\'s submission summarizes the reasons for
study discontinuation. Adverse events (AE), unsatisfactory therapeutic
effect and patient withdrawal of consent were the most common reasons
for discontinuation. As would be expected if a drug was effective,
discontinuation due to unsatisfactory therapeutic effect was more common
in the placebo arm compared to the Zol 4 mg and Zol 8 mg arm. There were
more deaths and adverse events in the Zol 8 mg arm.

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

*The increased discontinuation for AEs might have been due to the
increased incidence of renal toxicity found in this arm.*

Reasons for discontinuation

  ---------------------------------------------------------------------------
  **Reason for discontinuation**            **4 mg** **Placebo**   **8/4 mg**
  ----------------------------------------- -------- ------------- ----------
  Adverse Events                            38       29            44

  Abnormal lab values                       3        2             5

  Abnormal test procedures results          1        0             0

  Unsatisfactory therapeutic effect         19       34            17

  Condition no longer requires study drug   1        3             3

  Protocol violation                        1        0             0

  Withdrawal of consent                     40       35            48

  Lost to follow-up                         4        5             0

  Administrative problems                   0        3             0

  Death                                     25       32            40

  Total                                     132      143           157
  ---------------------------------------------------------------------------

#### Primary Efficacy Endpoint:  {#primary-efficacy-endpoint .unnumbered}

#### Proportion of patients with at least one SRE {#proportion-of-patients-with-at-least-one-sre .unnumbered}

The protocol specified primary endpoint was the proportion of patients
with at least one SRE. In reviews prior to NDA analysis, however, FDA
statisticians noted that this analysis could produce biased estimates
because of high dropout rates and recommended using time to first SRE as
a coprimary endpoint. Time to event analyses factor in the time when
dropouts occur and minimize associated bias. The proportion and time to
event analyses were truncated at 15 months, since that was the
pre-specified duration of the study.

According to the Applicant\'s analysis, the proportion of patients
experiencing at least one SRE during the first 15 months was
significantly less in the 4 mg arm compared to placebo (33% vs. 44%; p=
0.021). However, there was no significant difference between the
proportion in the 8 mg arm and placebo (38% vs. 44%, p=0.222). FDA
results were similar.

Proportion of patients with at least one SREs during the first 15 months
of the study

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

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

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

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

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

Proportion = (no. of patients with the event)/total no. in the group) up
to month 15.

C.I. for the difference (treatment labeled in the column minus row) of
percent of patients with events.

P-values are based on stratified Cochran-Mantel-Haenzel test for the
proportion

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

*Two hundred and fifty patients (38.8%) had at least 1 SRE. Since the
8/4 mg arm was too toxic, it is excluded from efficacy analysis as
specified in amendment \# 4. The 4 mg arm is statistically better in
terms of proportions of events over the placebo arm by a difference of
10%. There is no statistically significant difference in the efficacy of
the 8 mg arm over the placebo, although a trend towards improvement is
observed. It is counter intuitive that a lower dose (4 mg) would be
efficacious but not a higher dose (8/4 mg).*

#### Time to first SRE: {#time-to-first-sre .unnumbered}

The median time to first SRE had not been reached for 4 mg arm, but the
25% quartile was about 60 days longer for the 4mg arm than placebo or
the 8/4 mg arm ( p value compared to placebo = 0.009). For 8/4 mg arm
and placebo, the median time to first event are 363 and 321 days (p
value not significant).

Analysis of Time to First Skeletal Related Event Truncated at 15 Months
Using Kaplan-Meier Estimation Procedure (ITT population FDA Analysis)

  ---------- ---- ----------------------- --------------------------------
                                          

                                          

                                          

                                          
  ---------- ---- ----------------------- --------------------------------

Time to first Event per Applicant

  ----------- ----- ---------- --------------------- ------------- -------------
  Treatment   N     25%        Median Time to Event  P-values for  
  Arm               quartile   in days               between Rx    
                                                     comparisons   

                                                     4 mg          8/4 mg

  4 mg        214   182        Not reached                         0.059

  Placebo     208   122        321                   0.011         0.491

  8/4 mg      221   127        363                                 
  ----------- ----- ---------- --------------------- ------------- -------------

Analysis of Time to First Skeletal Related Event Truncated at 15 Months
Using Kaplan-Meier Estimation Procedure (ITT population FDA Statistical
Reviewer's Analysis)

+---------+---+----------------------+-------------------------------+
|         | * | **Median Time to     | **P-value**                   |
|         | * | Event in days (95%   |                               |
|         | N | C.I.)**              | **(Comparison to Placebo      |
|         | * |                      | using Log-rank test)**        |
|         | * |                      |                               |
+---------+---+----------------------+-------------------------------+
| Zol 4   | 2 | \* (383, \*)         | 0.009                         |
| mg      | 1 |                      |                               |
|         | 4 |                      |                               |
+---------+---+----------------------+-------------------------------+
| Placebo | 2 | 321 (252, \*)        |                               |
|         | 0 |                      |                               |
|         | 8 |                      |                               |
+---------+---+----------------------+-------------------------------+
| Zol 8/4 | 2 | 363 (255, \*)        | 0.541                         |
| mg      | 2 |                      |                               |
|         | 1 |                      |                               |
+---------+---+----------------------+-------------------------------+

\* = Not Reached

As shown in table above, FDA analysis was almost identical, with p =
0.009.

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

*Time to first SRE in the 4mg group is statistically longer than in the
placebo group. There is again no difference between the placebo and 8/4
mg groups, and this fails to support the efficacy observed in the 4 mg
arm. A chance imbalance in prognostic factors might explain this
finding. As previously discussed, however, although we know many factors
in prostate cancer that are prognostic for endpoints such survival, we
do not know which factors are prognostic for the occurrence of SREs in
prostate cancer. FDA reviewers evaluated known factors for balance among
treatment arms. As noted above, performance status, age and number of
bone metastases per patient were equally balanced in different arms.
However, there was a slightly increased number of blacks, and patients
with a higher number (2-4) of extraskeletal metastases in the 4 mg arm
as opposed to other arms. Baseline serum PSA was highest in the 8/4 mg
arm and lowest for placebo. Baseline pain scores were highest for 8/4 mg
arm and lowest for the 4 mg arm. When prior SREs, time from initial
diagnosis of cancer to bone metastases, baseline PSA and baseline
analgesic scores were analyzed in a Cox Regression model by the FDA
statistics reviewer, the treatment effect of 8/4 mg remained not
significant although the.*

#### Secondary Efficacy Endpoints {#secondary-efficacy-endpoints .unnumbered}

**Skeletal Morbidity Rate (SMR)**

SMR attempts to capture efficacy in additional SREs occurring after the
first SRE, as FDA has noted in review of prior biphosphonate NDAs.
However, clinical significance of some of these additional events may be
questioned. For instance, some events may be highly correlated or may
occur at the same time. In analyses by the applicant, the SMR for the 4
mg, 8/4 mg and placebo arms are 57%, 44%, and 53% respectively with the
difference between 4 mg and placebo being significant (p=0.011). P value
for the difference between 8/4 mg arm and placebo is 0.059.

#### BPI pain score, analgesic scores, QoL and performance status change: {#bpi-pain-score-analgesic-scores-qol-and-performance-status-change .unnumbered}

In analyses by the Applicant, the BPI pain score increased from baseline
to Month 15 for all treatment groups (p = 0.134). There was no
statistical difference in quality of life scores, analgesic scores,
performance status change from baseline among the treatment arms at
month 15.

**Time to progression of bone metastases and overall disease
progression:**

There was no difference between treatment groups in the distribution of
time to progression of bone metastases or overall disease progression.

##### Survival: {#survival .unnumbered}

As shown in the following table and figure from the FDA statistical
review, although there was a trend in favor of the 4mg arm, there was no
statistical difference survival difference among the three treatment
groups.

Kaplan Meier Curve for analysis of overall survival

![](media/image2.png){width="5.470138888888889in"
height="3.0854166666666667in"}

#### Reviewer exploratory analyses of SREs {#reviewer-exploratory-analyses-of-sres .unnumbered}

Some SREs are of questionable clinical benefit such as asymptomatic
vertebral fractures and change of chemotherapy due to increased pain.
Chemotherapy is changed in USA due to progression of disease and not due
to increased intensity of pain. The next table illustrates the first
SREs by presence or absence of symptoms.

The numbers of patients who had asymptomatic vertebral fractures, or had
change in chemotherapy due to pain are small and favor the 4 mg arm.
There are more patients on the 8/4 mg arm who received chemotherapy due
to pain, than on 4 mg or placebo group.

First SREs by presence of symptoms:

  ----------------------------------------------------------------------------
  **Event**                                      **4    **Placebo**   **8/4
                                                 mg**                 mg**
  ------------------------------- -------------- ------ ------------- --------
  Pathological vertebral fracture Unknown        2      2             0

                                  Asymptomatic   3      6             7

                                  Symptomatic    1      2             0

  Pathological non-vertebral      Unknown        1      1             4
  fracture                                                            

                                  Asymptomatic   12     14            11

                                  Symptomatic    4      6             0

  Spinal cord compression         Asymptomatic   0      0             1

                                  Symptomatic    3      6             2

  Radiation                       Unknown        0      2             4

                                  Asymptomatic   5      6             5

                                  Symptomatic    34     33            34

  Surgery                         Asymptomatic   0      1             0

                                  Symptomatic    1      2             0

  Chemotherapy                    Symptomatic    5      9             15
  ----------------------------------------------------------------------------

**Proportion of patients with at least 1 *symptomatic* SRE**

The reviewer performed an exploratory analysis of proportions of
patients with at least 1 *symptomatic* SREs during the first 15 months.
As shown in Table 12, results on the whole were unchanged, with the
proportion of symptomatic SRE in the 4 mg arm significantly better than
placebo ( 24.7% vs. 35.6%, p = 0.21). Again the comparison between 8/4
mg and placebo shows only a trend towards improvement.

Proportion of patients with at least 1 *symptomatic* SRE during the
first 15 months

+------------------+------------------+---------------+---------------+
| **Treatment      | **Proportion**   | **p value**   |               |
| arm**            |                  |               |               |
+------------------+------------------+---------------+---------------+
|                  |                  | **4 mg**      | **8 mg**      |
+------------------+------------------+---------------+---------------+
| 4 mg             | 53/214           |               |               |
|                  |                  |               |               |
|                  | (24.7%)          |               |               |
+------------------+------------------+---------------+---------------+
| Placebo          | 74/208           | 0.021         | 0.173         |
|                  |                  |               |               |
|                  | (35.6%)          |               |               |
+------------------+------------------+---------------+---------------+
| 8/4 mg           | 64/221           |               |               |
|                  |                  |               |               |
|                  | (28.9%)          |               |               |
+------------------+------------------+---------------+---------------+

P value is 2-sided using Chi square.

The inclusion of change in chemotherapy due to pain and of some
asymptomatic events is of questionable clinical benefit as noted
earlier. Time to SRE excluding chemotherapy was evaluated. The Kaplan
Meier Curve and results are given below. The results in the three arms
were similar and the 4 mg arm remained statistically more effective.

(Note, patient 51129 had a change of antineoplastic treatment that was
listed as due to painful lesions, however he was also noted to be
'asymptomatic'. This was not a first event for this patient.)

**Time to first SRE excluding chemotherapy change as first event for all
patients**

**4 mg
[\_\_\_\_]{.underline}**![](media/image3.wmf){width="3.982638888888889in"
height="2.2743055555555554in"}**[\_]{.underline}**

**8/4 mg \_\_\_\_\_**

**Placebo \_\_\_\_\_**

Time to first SRE excluding change in chemotherapy

  -----------------------------------------------------------------------
  **Treatment arm**                     **Median Time**
  ------------------------------------- ---------------------------------
  4                                     not reached

  8                                     not reached

  Placebo                               324
  -----------------------------------------------------------------------

Log rank p value of 4 mg vs. placebo is 0.02

Log rank p value of 8 mg vs. placebo is 0.25

**Administration of radiation:**

The reason for administration of radiation was not given by the sponsor
in the raw datasets. Due to blinding and randomization, bias in changing
therapy is not expected. However, to evaluate the quality of the data,
the reviewer evaluated the anatomical sites treated by radiation in
asymptomatic patients. This analysis showed that most patients
appropriately received radiation weight-bearing sites. Three patients on
the Zometa arm, listed in table 19, had radiation for lesions that may
not have been clinically significant.

Asymptomatic patients who received XRT

  ---------- ------------------------------------- -----------------------
  **Pt ID**  **Site of Radiation**                 **Treatment arm**

  15051      Skull - bony framework of head        8/4 mg

  25022      Base of skull                         8/4 mg

  26027      Left scapula                          4 mg
  ---------- ------------------------------------- -----------------------

XRT and vertebral fracture were counted as separate SREs, although the
primary bony lesion may have been the same. The next table lists this
occurrence on the treatment arms.

Patients with vertebral fractures who received XRT

  -----------------------------------------------------------------------
  **Treatment arm**  **Number of patients with vertebral \# and XRT**
  ------------------ ----------------------------------------------------
  4                  4

  8                  6

  Placebo            10
  -----------------------------------------------------------------------

**Change in PSA**

The change in PSA of the 8/4 mg arm was the greatest, and that for
placebo arm was the lowest.

Median change in serum PSA

  --------------------- -------------- ----------------------------------
  **Treatment arms**    **Total**      **Median change in PSA**

  4                     214            88

  8                     221            107

  Placebo               208            78
  --------------------- -------------- ----------------------------------

### Efficacy Conclusions of Study 039 {#efficacy-conclusions-of-study-039 .unnumbered}

Patients treated on the 4 mg arm demonstrated significantly less
morbidity than patients on the placebo arm both by the
protocol-specified primary analysis of proportions of patients with at
least one SRE (33% vs. 44%, respectively, p = 0.021) and by the
FDA-preferred analysis of time to first SRE (p = 0.011). By both
analyses, however, the 8/4 mg arm failed to demonstrate a statistically
significant difference from placebo (Proportions: 38% vs. 44%,
respectively, p = 0.222. Time to SRE: p = 0.491). The proportions
analysis and a reviewer exploratory analysis of symptomatic SREs trended
in favor of the 8/4/ mg arm. After multivariate analyses that included
potential prognostic factors (treatment, prior history of skeletal
events, time from initial diagnosis of cancer to bone metastases, time
from first bone metastases to randomization, log~e~ of baseline PSA, and
baseline analgesic scores), the results overall remained unchanged
although the p value decreased.

*[Reviewer\'s comments]{.underline}*

*The study was a well-conducted, well controlled trial. Several minor
problems were discussed in this review:*

-   *Asymptomatic vertebral compression fractures and changes in
    chemotherapy, events of questionable clinical meaning, were included
    as elements of the SRE endpoint. Because there were few such events
    on the study, this was not a signficant problem.*

-   *Unblinding of patients to treatment arm was noted in about 5% of
    patients, but was equally distributed among study arms.*

*The major problem with this study is the unsupportive evidence provided
by efficacy analyses of the 8/4 mg arm. The FDA and ODAC must consider
the nature of analytical framework for evaluating this dilemma. Do we
consider that the 4 mg/placebo comparison as a positive trial and the
4/8 mg/placebo comparison like a negative (i.e., not positive) trial? Do
the positive and negative results cancel each other out? Since beta
error is 20% when a trial has 80% power, do we attribute the negative
results to beta error? Do data from trials of Zometa in other cancers
metastatic to bone provide any support for efficacy in prostate cancer?
We look forward to discussing these issues with ODAC on January 31.*

##  {#section .unnumbered}

##  {#section-1 .unnumbered}

##  {#section-2 .unnumbered}

##  {#section-3 .unnumbered}

##  {#section-4 .unnumbered}

**Placebo Controlled Trial #011 in Other Solid Tumors**

## Placebo Controlled Trial #011 in Other Solid Tumors

The Applicant proposes that Study 011 supports the use of zoledronate 4
mg administered intravenously as an adjuvant to anticancer therapy to
patient with any cancer metastatic to bone other than breast cancer,
multiple myeloma, or prostate cancer.

##### *[Reviewer's Comment:]{.underline}* {#reviewers-comment .unnumbered}

##### *Although patients in Study 011 were not required to receive antineoplastic treatment in this study, over two thirds did so.* {#although-patients-in-study-011-were-not-required-to-receive-antineoplastic-treatment-in-this-study-over-two-thirds-did-so. .unnumbered}

**Protocol Title:**

> \"A randomized, double-blind, placebo-controlled, multicenter trial to
> evaluate the safety and efficacy of zoledronate (4 and 8 mg)
> administered intravenously as an adjuvant to anticancer therapy to
> patients with any cancer with bone metastases other than breast
> cancer, multiple myeloma or prostate cancer**.\"**

First patient accrued: 27 August 1998

Last Patient's 1^st^ visit: 20 April 2000

Last patient completed: 30 January 2001

Date of Unblinding: 30 March 2001

### Study Design {#study-design-1 .unnumbered}

**Rationale**

The following excerpts from the protocol summarize the study rationale:

"Biphosphonates have been approved for the treatment of humoral
hypercalcemia of malignancy (HHM); Aredia (pamidronate) has been
approved to prevent skeletal-related complications of lytic bone lesions
in patients with multiple myeloma and breast cancer. Zoledronate is a
third-generation biphosphonate with greater potency to inhibit
osteoclastic bone resorption, less renal effects, and a wider
therapeutic window (i.e., less inhibition of bone formation). In
addition, zoledronate can be given as a rapid IV infusion over 5
minutes, compared to a 1-2 hour administration of pamidronate".

"Bone metastases frequently occur in patients with advanced cancer.
Although they are rarely directly responsible for mortality, they
frequently cause morbidity with fractures, spinal cord compression, and
pain. The use of daily radiation therapy and/or surgery to alleviate
these problems may decrease quality of life or add to patient morbidity.
Thus, a trial evaluating the effectiveness of zoledronate for these
patients is justified".

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

*A major weakness of this study is its unproven assumption that all
cancer metastatic to bone is affected in a similar manner by
biphosphonates. This study is designed for all solid tumors metastatic
to bone, except for prostate cancer and breast cancer which were
evaluated in trials 011 and 010. There is no evidence to date that any
biphosphonate is effective in decreasing skeletal related events for
these tumors. The design of this study is based on the hypothesis that
even though tumor cells vary greatly in their natural history and in
their response to antineoplastic agents, once they metastasize to bone,
they all react in a similar manner to a biphosphonate. The current study
is not designed to rigorously evaluate zoledronate efficacy in any of
the individual tumor types included. Perhaps a better design would have
powered the study to fully evaluate efficacy in at least the largest
subgroup, i.e., patients with NSCLC.*

**Study Description:**

The following excerpt from the protocol summarizes the study design:

"The trial will be an international multicenter randomized double-blind
placebo-controlled study. Patients Information on prior skeletal-related
events will be collected".

"Patients are to be 18 years or older, with a histologically or
cytologically confirmed diagnosis of cancer, and objective evidence of
at least one site of metastatic disease to bone., diagnosed no longer
than 6 weeks prior to visit 1. Patients with cancer other than breast
cancer, prostate cancer, and multiple myeloma, and must have at least
one site of metastatic bone disease that was detected within 6 weeks of
study entry. Patients must have \> 3 foci of uptake on bone scan
consistent with metastatic disease. If there are \< 3 foci, there must
be either additional radiographic or biopsy confirmation of the presence
of metastases. Patients must enter the trial with a normal calcium and
may not have received prior biphosphonate therapy".

"Treatment of SRE present prior to visit 1 is permitted as long as
therapy did not include the use of a biphosphonate. Likewise TIH may be
treated with agents other than biphosphonates. Patients must have a
corrrected serum calcium between 8 and 12 mg/dl at visit 1. Prior
therapy with a biphosphonate will exclude a patient from the study. The
patient will be discontinued if hypercalcemia occurs".

"Patients will be stratified by type of cancer: lung cancer or other
cancer. Patients will then be randomized in a double-blind fashion to
receive zoledronate 4 mg, zoledronate 8 mg, or placebo in a 1:1:1 ratio.
All drug assignments will be given as a rapid 5 minute IV infusion every
3 weeks for 12 doses in addition to antineoplastic therapy. Patients
will receive treatment for 9 months. They will also receive 500 mg of
oral calcium supplementation and a multivitamin containing 400-500 IU of
vitamin D daily in order to blunt the compensatory rise in serum PTH
levels caused by the administration of biphosphonates. Supplementation
may also help prevent SRE because PTH is an osteoclast activating
factor".

"Data on the occurrence of SRE, inclusive and exclusive of TIH, will be
collected for each patient. The proportion of patients experiencing at
least one SRE, the time to the first SRE, and the skeletal morbidity
rate will be calculated. Time to progression of bone metastases and
objective bone lesion response will be assessed by a central
radiologist. Time to overall progression of disease will be determined
in several ways: by the treating physician, by the central radiologic
assessments of bony sites of involvement, by central review of
appropriate serial radiographic studies of non-skeletal sites. Quality
of life, performance status, pain, and analgesic scores will be
determined serially throughout the study. Survival data will be
collected on each patient. Adverse event information and serial
biochemical marker data will be collected".

"Patients will not be taken off study solely for the occurrence of a SRE
or progressive disease, because the study is designed to evaluate the
total number of skeletal events that occur over the entire duration of
the study. A change in antineoplastic therapy will not cause the patient
to be discontinued from the study. The development of TIH will be an
off-study criteria. The need for use of other drugs that affect
osteoclast function, such as gallium nitrate, calcitonin, mithramycin,
or other biphosphonate, will also cause patients to be removed from
study. Other reasons for withdrawal from study are listed in the
protocol and are standard factors. Patients who are removed from study
for any reason should still be followed".

"The sample size is planned to be 600 in order to obtain 570 patients
(190 patients per arm) who meet entry criteria. No interim analyses will
be performed".

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

*This protocol required histological confirmation for every patient, as
opposed to study 039, where patients could have be enrolled on the basis
of serially escalating serum PSA. Another difference is that all
patients must have documents bone metastases within 6 weeks of
randomization.*

### Study Duration {#study-duration .unnumbered}

Time permitted for patient enrollment: 12 months

Duration of individual participation: 9 months (36 weeks)

Total duration of treatment : 9 months (36 weeks)

Total duration of study: 21 months

### Drug Administration and Formulation {#drug-administration-and-formulation-1 .unnumbered}

-   The following are details of drug adminiatration for the study arms:

-   Zoledronate 4 mg in 50 ml normal saline IV infusion over 5 minutes q
    3 weeks plus calcium 500 mg taken by mouth with food (daily) and one
    MVI tablet by mouth daily.

-   Zoledronate 8 mg in 50 ml normal saline IV infusion over 5 minutes q
    3 weeks plus calcium 500 mg taken by mouth with food (daily) and one
    MVI tablet by mouth daily.

-   Placebo in 50 ml normal saline IV infusion over 5 minutes q 3 weeks
    plus calcium 500 mg taken by mouth with food (daily) and one MVI
    tablet by mouth daily .

As zoledronate may bind to glass, the solution was to be prepared in
plastic syringes, bags, and tubes. If not used immediately, the solution
was to be stored at temperatures between 36-46^o^ F and can be used for
up to 8 hours.\
\
*[Reviewer\'s comment:]{.underline}*

*With Amendment #3, infusion duration was increased to 15 minutes and
infusion volume to 100 ml of normal saline.*

### Inclusion Criteria: {#inclusion-criteria-1 .unnumbered}

-   Signed Informed Consent

-   Age 18 years or older

-   A histologically or cytologically confirmed diagnosis of cancer
    other than breast cancer, multiple myeloma or prostate cancer.

-   Objective evidence (at least 3 foci of increased activity on bone
    scan) of disease to bone within 6 weeks of study entry. If there are
    less than 3 foci, other radiologic or biopsy studies are required to
    confirm the presence of osteoblastic or osteolytic malignant
    lesions.

-   Performance status of 0, 1 or 2 at Visit 1.

### Exclusion Criteria: {#exclusion-criteria-1 .unnumbered}

-   Previous treatment with a biphosphonate.

-   Other investigational agent.

-   History of non-compliance.

-   Liver metastases with bilirubin higher than 2.5 mg/dl at visit 1.

-   Abnormal corrected serum calcium.

-   Severe cardiovascular disease.

-   Pregnancy or lactation.

### Objectives: {#objectives-1 .unnumbered}

#### Primary efficacy endpoint {#primary-efficacy-endpoint-1 .unnumbered}

The primary efficacy variable was the proportion of patients having at
least one skeletal-related event (SRE). Events were the same as those
defined in study 039 (see FDA review of Study 039 for detailed
description):

-   Radiation therapy to bone

-   Change of antineoplastic therapy to treat bone pain includes any
    change in anticancer agents to palliate pain. This was later
    excluded in an amendment.

```{=html}
<!-- -->
```
-   Surgery to bone

-   Spinal cord compression

```{=html}
<!-- -->
```
-   Pathologic fractures

> **Secondary efficacy parameters**

-   Skeletal-related event rate inclusive of tumor induced hypercalcemia

-   Time to first skeletal-related event or TIH

-   Skeletal morbidity rate

-   Time to progression of bone metastases

-   Time to overall progression of disease

-   Quality of life (FACT-G)

-   Performance status

-   Pain scores

-   Analgesic scores

-   Biochemical markers

-   Objective bone lesion response

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

*After FDA reviewed the protocol and analysis plans, the Applicant was
informed that:*

-   *The FDA would not consider hypercalcemia as an SRE in the primary
    analysis of efficacy. FDA maintained that zoledronate effects on
    bone should be separate from its calcium-lowering effects.*

-   *Events in separate radiation ports could be considered separate
    skeletal-related events if separated in time.*

-   *Multiple events occurring in as the result of a single local
    problem should not be counted as multiple events, e.g., a spinal
    cord compression occurring because of vertebral collapse in 2
    adjacent vertebral bodies should not count as 3 events.*

-   *FDA questioned including worsening of an existing vertebral
    compression fracture as an SRE.*

-   *FDA questioned including a change in antineoplastic therapy to
    treat bone pain as an SRE . Chemotherapy is usually changed because
    of progressive disease, and distinguishing between a change in
    therapy because of progression versus pain would be difficult.*

Note:

-   In amendment 2, *change in antineoplastic therapy* was removed from
    the definition of SRE.

-   *Inclusion of worsening of a compression fracture* as an SRE had
    minimal impact. According to the Applicant, there was only one
    patient (randomized to the 4 mg arm) who had a worsening compression
    fracture counted as a new SRE.

### Follow-up: {#follow-up-1 .unnumbered}

The schedule for follow-up is reproduced from the protocol:

Schematic Design diagram

<table>
<colgroup>
<col style="width: 12%" />
<col style="width: 11%" />
<col style="width: 5%" />
<col style="width: 3%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Period</strong></td>
<td><strong>Screening</strong></td>
<td colspan="12"><strong>Randomized treatment and
evaluation</strong></td>
<td><strong>Final evaluation</strong></td>
</tr>
<tr class="even">
<td><strong>Visit</strong></td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>5</td>
<td>6</td>
<td>7</td>
<td>8</td>
<td>9</td>
<td>10</td>
<td>11</td>
<td>12</td>
<td>13</td>
<td>14</td>
</tr>
<tr class="odd">
<td><strong>Week</strong></td>
<td>-2 weeks</td>
<td>0</td>
<td>3</td>
<td>6</td>
<td>9</td>
<td>12</td>
<td>15</td>
<td>18</td>
<td>21</td>
<td>24</td>
<td>27</td>
<td>30</td>
<td>33</td>
<td>36</td>
</tr>
<tr class="even">
<td><strong>Treatment</strong></td>
<td>none</td>
<td colspan="12"><p>Zoledronate 4 mg q 3 weeks</p>
<p>Zoledronate 8 mg q 3 weeks</p>
<p>Placebo q 3 weeks</p></td>
<td></td>
</tr>
</tbody>
</table>

A radionuclide bone scan was performed at visit 1. Follow-up bone scans
and bone surveys were to be performed every three months at visit 6, 10,
and 14. Supplement radiographs of areas not covered by a routine survey
were to be performed in the following circumstances if clinically
indicated. All films are to be reviewed by the central radiologist.

FACT-G and performance status scores were assessed initially and then at
visits 6, 10, and 14

Analgesic and pain scores were assessed at visits 2, 3, 4, 6, 8, 10, 12
and 14.

### Removal from the study: {#removal-from-the-study .unnumbered}

Patients were not to be discontinued from study due to progression of
disease. If a patient discontinued therapy, every effort was to be made
to continue visits on an every 3 month schedule through 9 months from
date of randomization. Survival data will be collected for all
randomized patients.

-   Adverse events

-   Abnormal laboratory values

-   Abnormal test procedure results

-   Unsatisfactory therapeutic results

-   Patients condition no longer requires study drug

-   Protocol violation

-   Lost to follow up

-   Administrative problems

-   Death

### Statistical considerations: {#statistical-considerations .unnumbered}

[General]{.underline}

The following are important excerpts from the protocol\'s statistical
plan:

"An intent-to-treat analysis of all randomized patients who receive
trial medication and from whom at least one measurement is obtained will
be performed for all efficacy analyses. For patients who withdraw from
the study and begin treatment with a biphosphonate, all data after the
new treatment point will be excluded".

"Background and demographic data will be evaluated by summary
statistics. If the treatment groups are not comparable, additional
analyses will be performed to adjust for the influence, if any, of the
variable on the efficacy outcome. Concomitant therapy will be
summarized".

"All evaluations will be performed using stratified analysis for the two
cancer populations, lung cancer versus other. Two comparisons will be
performed: 4 mg zoledronate versus placebo and 8 mg zoledronate versus
placebo, and 4 mg zoledronate versus 8 mg zoledronate. The Bonferroni
criteria will be used to adjust for multiple comparisons, and will use a
significance level of 0.05".

[Primary efficacy evaluation]{.underline}

"The primary efficacy variable is the *proportion of patients with any
SRE exclusive of tumor-induced hypercalcemia.* Treatment groups will be
compared using a Cochran-Mantel-Haenszel test statistic. The 95% CI by
treatment group within each stratum will be presented".

"A comparison of the proportion of patients reporting any SRE exclusive
of TIH during the first 3, 6, and 9 months of the study will be
presented. Summary statistics for the primary efficacy variables will be
tabulated by country. Effects of country or treatment-by-country
interactions will not be examined unless enrollment in each country is
sufficient".

"The primary efficacy variable will be summarized by the baseline
prognostic factors of PS (0-1 versus \> 1), renal function (creatinine
\< 2.0 mg/dl versus [\>]{.underline} 2.0 mg/dl) and age
([\<]{.underline} 60 versus \>60).

Zoledronate will 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 of \< 0.025".

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

-   *Amendment 7 changed the primary efficacy analysis. Due to safety
    concerns, all patients in the 8 mg arm received 4 mg. According to
    the amended analysis plan, 8 mg would not be evaluated for efficacy,
    and that zoledronic acid 4 mg would be considered more efficacious
    than placebo if the comparison for the primary efficacy outcome was
    statistically significant at 0.05 level (2-sided).*

```{=html}
<!-- -->
```
-   *At the time of the amendment discontinuing the 8 mg dose, all
    patients had already been enrolled in the study and had completed at
    least visit #3.*

Patient enrollment at the time of amendment 7

+----------------+---------------+-------------------------------------+
| **Treatment    | **No of       | **Range of visit numbers**          |
| arm**          | patients**    |                                     |
|                |               | **at time of amendment change**     |
+----------------+---------------+-------------------------------------+
| 4              | 68            | 4 -14                               |
+----------------+---------------+-------------------------------------+
| 8              | 67            | 4 -14                               |
+----------------+---------------+-------------------------------------+
| 60             | 65            | 4 -14                               |
+----------------+---------------+-------------------------------------+

[Secondary efficacy variables]{.underline}

-   Statistical plans were also provided for secondary endpoints (See
    FDA statistical review for details) :

-   Proportion of patients with any SRE inclusive of TIH

-   Time to the first occurrence of a SRE

-   Multiple events analysis

• Skeletal morbidity rate

-   Time to progression of bone metastases.

-   Time to overall progression of disease.

-   QoL, PS, pain, and analgesic scores.

-   The FACT-G score is defined as the sum of 4 subscales (physical,
    functional, social, and emotional). Change from baseline of the
    total score will be the primary end point.

-   The BPI pain composite score will be the primary efficacy variable
    for QoL, including pain, analgesic use, PS, and QoL index. The mean
    of the two BPI composite scores and two analgesic use scores for
    each 3 month interval will be used for the analysis of BPI pain
    composite score and analgesic use respectively.

-   Biochemical markers

-   Objective bone lesion response.

[Sample size and power calculations]{.underline}

"The trial is 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 of zoledronate and placebo.
Bonferroni's adjustment was used, and it was assumed that the SRE
incidence rate will be 48% on placebo and 32% on either dose of
zoledronate. An alpha of 0.05 (two-sided) was used. With these
assumptions, the sample size was determined to be 570 patients, 190 per
arm. Six hundred patients will be enrolled in order to allow 5% for an
intent-to-treat analysis".

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

*The study was probably underpowered due to an overly optimist estimate
of the zoledronate effect. Results from this trial for the 8mg versus
placebo comparison showed a difference between arms of only 7%.*

### Protocol Amendments: {#protocol-amendments-1 .unnumbered}

There were 6 amendments to the protocol, with two addressing renal
safety issues.

Date of Protocol:March 5, 1998

[Amendment 1:]{.underline}

June 26, 1998:

-   Modification to match the Tumor Response Criteria to match other
    Zoledronic acid bone metastases trials.

[Amendment 2:]{.underline}

November 24, 1998

-   Change in antineoplastic therapy was removed from the definition of
    SRE.

-   Patients with asymptomatic brain metastases could be included.

-   With an ECOG PS of 2, the bone metastases should have been diagnosed
    within 6 weeks of visit 1. There were no restrictions concerning
    diagnosis of bone metastases for patients with a PS of 0 or 1 at
    visit 1.

[Amendment 3]{.underline}

June 24, 1999:

-   Zoledronate for all study patients is to be diluted in 100 ml. of
    normal saline and is to be administered intravenously as a 15 minute
    infusion. This amendment was due to 3 SAE reports of renal failure.
    All 3 patients were receiving 8 mg of Zoledronate. One of these
    patients died because of sepsis, and creatinine returned to base for
    another. The outcome for the third patient was not known at that
    time because of inadequate follow up.

[Amendment 4]{.underline}:

February 16, 2000

-   Sample size increased to 700 patients to procure 663 evaluable
    patients.

-   Indicated that the modified Bonferroni criteria would be used in
    efficacy analysis.

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

*773 patients were enrolled in to this study.*

[Amendment 5]{.underline}

June 7, 2000:

-   All Patients receiving Zoledronate 8 mg should have their dose
    reduced to 4 mg, effective immediately. This was based on the
    suggestions by the Data Safety Monitoring Board (DSMB) and the Renal
    Advisory Board (RAB). The blind was to continue.

-   Serum creatinine should be measured prior to each dose of study
    drug. Drug administration will be delayed as outlined in the next
    table.

Dose modification according to serum creatinine

+---------------+----------------------------+------------------------+
| **Baseline    | Creatinine elevation above | **Action**             |
| creatinine**  | baseline prior to drug     |                        |
|               | administration (mg/dl)     |                        |
| **(mg/dl)**   |                            |                        |
+---------------+----------------------------+------------------------+
| \<1.4         | 0.5                        | Delay in drug          |
|               |                            | administration until   |
|               |                            | the serum creatinine   |
|               |                            | returns to less than   |
|               |                            | 10% of baseline.       |
+---------------+----------------------------+------------------------+
| \> 1.4        | 1.0                        |                        |
+---------------+----------------------------+------------------------+
| Any           | doubling                   |                        |
+---------------+----------------------------+------------------------+

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

*Due to first part of amendment 5, 70 of 266 patients received 8 and
then 4 mg doses in the 8mg arm. The change in dosage occurred some time
after visit \# 3. No patient in this arm received 4 mg dosage from the
first treatment visit. Approximately 27% of infusions in the 8/4 mg arm
were administered at a 4 mg dosage.*

No. of infusions per actual dose administered

  ---------------- -------------------------------- -------- -------- -------------
  **Dose           **\# of infusions administering  **4 mg** **8/4    **Placebo**
  administered**   actual dose**                             mg**     

  0                1600                             0        0        1600

  4                2083                             1755     328      0

  8                1384                             0        1384     0
  ---------------- -------------------------------- -------- -------- -------------

No. of patients per actual dose administered

+-------------+-------------------------------+-------+-------+-------+
| **Dose      | **\# of patients receiving    | **4   | **8/4 | *     |
| adm         | actual dose**                 | mg**  | mg**  | *Plac |
| inistered** |                               |       |       | ebo** |
|             |                               | **N=  | **N=  |       |
|             |                               | 257** | 266** | **N=  |
|             |                               |       |       | 250** |
+-------------+-------------------------------+-------+-------+-------+
| 0           | 247                           | 0     | 0     | 247   |
+-------------+-------------------------------+-------+-------+-------+
| 4           | 321                           | 254   | 67    | 0     |
+-------------+-------------------------------+-------+-------+-------+
| 8           | 265                           | 0     | 265   | 0     |
+-------------+-------------------------------+-------+-------+-------+

There is a lack of concordance between the total number of patients
randomized to an arm and the number of patients receiving drug because 7
randomized patients did not receive study drug.

The dose modification for serum creatinine abnormalities as amended is
in the table below.

[Amendment 6]{.underline}

Oct 13, 2000

-   ITT population will be all randomized patients who had evidence of
    bone metastases at study entry.

```{=html}
<!-- -->
```
-   Modified all efficacy evaluation section to explain the efficacy
    analyses as follows:\
    \-- For all efficacy variables analyzed, zoledronic acid 4 mg vs.
    placebo would be used to assess the effectiveness of the zoledronic
    acid treatment. Comparisons between zoledronic acid 8/4 mg and 4 mg
    acid would be available to assess whether an initial treatment of
    Zoledronic acid 8 mg would prove greater efficacy than the initial
    treatment with 4 mg.\
    -- Explained that zoledronic acid 4 mg would be considered more
    efficacious than placebo if the comparison for the primary efficacy
    outcome was statistically significant at 0.05 level (2-sided),
    favoring the zoledronic acid 4 mg group.

*[Reviewer's comments on the original protocol and
amendments]{.underline}:*

-   *The study was based on an assumption that all osteolytic tumors in
    bone behave in a similar fashion to Zometa or by bone osteoclast.
    Generally cells from breast cancer, small cell lung cancer, or
    pancreatic cancer behave quite differently from each other in the
    human body. This study assumes that these cells would behave similar
    to each other when acted upon by Zometa once inside bone. This
    hypothesis has not been proven for any biphosphonate.*

-   *Amendment 6 made changes to the way statistical plan after all
    patients had already been enrolled in to the study. The alpha value
    in the original protocol would have been 0.025 because of the two
    planned comparisons to avoid obtaining significance by chance.
    Amendment 6 was made after enrollment was completed. In it, alpha
    was increased to 0.05. Since all patients had been enrolled by the
    time the amendment was submitted, it is this reviewer\'s opinion
    that the level of significance should remain at 0.025.*

-   *Patients with any number of prior chemotherapeutic regimens could
    have been enrolled and they could receive more chemotherapy during
    the study. Response to chemotherapy administered could affect
    progression of bone metastases and consequent occurrence of SREs.
    Data documenting the number of prior chemotherapy regimens and
    response prior to prior chemotherapy should have been noted and
    perhaps served as stratification factor since it would be expected
    to impact the study results.*

-   *According to the protocol, the randomization was stratified lung
    cancer vs. other. However, it is not specified whether both Non
    Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC)
    patients would be included in this category. This apparently led to
    confusion so that many patients with small cell cancer were
    incorrectly stratified with the NSCLC group.*

-   *Inclusion or exclusion criteria did not specify whether a patient
    should have been on treatment for the cancer or not, although the
    proposed zoledronate indication is for use in conjunction with
    antineoplastic therapy.*

-   *Clinical relevance of asymptomatic SREs is not clear. For example
    if there are asymptomatic vertebral fractures, delay in these events
    is of no obvious clinical benefit.*

-   *The reason for administration of radiation is not captured well in
    the protocol, or the electronic dataset.*

-   *The protocol was improved by an FDA-suggested amendment that change
    of chemotherapy secondary to pain as SRE not be included in this
    protocol. In US, chemotherapy is usually not changed prior to
    disease progression.*

-   *The secondary endpoint skeletal morbidity rate (SMR) is based on a
    value calculated using arbitrary time points, its utility is
    questionable. Several major events in a time period in one patient
    would have the same significance as a single event in another
    patient. This endpoint is an attempt to capture efficacy beyond the
    first event.*

-   *Specific criteria for removal from study for based on \"abnormal\"
    lab values and test results are not given.*

```{=html}
<!-- -->
```
-   *According to the protocol, the central radiologist was to assess
    the time to progression of bone metastasis and objective lesions. It
    is expected that the radiologist will determine only the presence
    rather than time to progression of bone metastasis.*

### Results: {#results .unnumbered}

#### Patient Disposition: {#patient-disposition .unnumbered}

Seven hundred and seventy three patients were randomized, but 7 did not
receive the study drug (10410, 10816, 12452, 12811, 20642, 22707, and
22708). All patients were included in the efficacy analysis, but were
excluded from the safety analysis.

According to the sponsor, 35 patients with small cell lung cancer were
randomized in the incorrect group, with the NSCLC patients. Three
patients were randomized with the 'other solid tumor' stratum. The
sponsor analyzed the patients in the incorrect stratum.

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

*Although the randomization to the incorrect stratum may affect the
individual strata's results, it does not change the overall result of
the protocol.*

#### Patients discontinuing the study drug prior to study completion: {#patients-discontinuing-the-study-drug-prior-to-study-completion .unnumbered}

Only about a quarter of patients completed the study. According to the
Applicant, percentage of patients who did not complete the study was
similar for all treatment groups: 73.2% in the 4 mg arm, 75.5% in the
8/4 mg arm, and 74.4% in the placebo arm. (The reviewer obtained similar
results using the electronic data).

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

*Table below shows dropouts in study 039 and 011. Whereas dropout rates
varied among study arm in study 039, in study 011 the rates were higher,
and were more similar among study arms.*

> Number of patients discontinuing Zometa prior to end of study for
> protocols 039 and 011.

  ------------------- ---------------- ------------------ -----------------
  **Protocol**        **4 mg**         **Placebo**        **8/4 mg**

  039                 61.7%            68.7%              71%

  011                 73.2%            73.2%              75.5%
  ------------------- ---------------- ------------------ -----------------

The number of deaths (counted from study phase completion or within 28
days of study drug discontinuation) were similar across treatment arms.
(35%, 33.6% and 33.6% in the 4 mg, 8/4 mg and placebo arms
respectively).

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

*Death was the primary reason for discontinuation from study. Reasons
for withdrawal were similar between the 4 mg arm and Placebo. The top
three reasons are the same as in study 039, although the order is
different. Withdrawal of consent followed by adverse events, and then
deaths were the primary reasons for discontinuation from protocol.
Deaths are less in study 039 probably due to the often prolonged course
of prostate cancer.*

*Death and adverse events were more in the 8/4 mg arm. Interestingly,
unsatisfactory therapeutic result as a reason was similar across 4 mg
and placebo arm for study 011.*

Reason for discontinuation from protocol

  ----------------------------------------------------------------------------------------------------
  **Reason for discontinuation   **Protocol                         **Protocol                 
  from protocol**                011**                              039**                      
  ------------------------------ ------------ ------------- ------- ------------ ------------- -------
                                 **4 mg**     **Placebo**   **8/4   **4 mg**     **Placebo**   **8/4
                                                            mg**                               mg**

  **Death**                      72           74            81      25           32            40

  **Adverse events**             50           53            66      38           29            44

  **Consent withdrawal**         46           44            36      40           35            48

  **Unsatisfactory therapeutic   17           19            13      19           34            17
  result**                                                                                     

  **Abnormal labs**              1            2             4       3            2             5

  **Condition does not require   2            3             2       1            3             3
  study drug**                                                                                 

  **Lost to follow up**          2            1             4       4            5             0

  **Administrative problem**     2            1             1       0            3             0

  **Protocol violation**         3            0             0       1            0             0

  **Abnormal Test Results**      1            0             1       1            0             0
  ----------------------------------------------------------------------------------------------------

#### Population {#population .unnumbered}

The study population is described in the table titled Demography.

Table 1: Demography

+--------------------------------------------+-------+-------+-------+
| **Treatment arm**                          | **4   | *     | **8   |
|                                            | mg**  | *Plac | mg**  |
|                                            |       | ebo** |       |
+============================================+=======+=======+=======+
| **No of patients per FDA**                 | 257   | 250   | 266   |
+--------------------------------------------+-------+-------+-------+
| **No. of patients per sponsor**            | 257   | 250   | 266   |
+--------------------------------------------+-------+-------+-------+
| **Age range**                              | 25-88 | 25-86 | 28-84 |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 63    | 63.5  | 62    |
+--------------------------------------------+-------+-------+-------+
| **Age [\<]{.underline} 60 years**          | 109   | 99    | 125   |
+--------------------------------------------+-------+-------+-------+
| **Age \> 60 years**                        | 148   | 151   | 141   |
+--------------------------------------------+-------+-------+-------+
| **Race (per sponsor)**                     |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Caucasian**                              | 226   | 223   | 237   |
|                                            |       |       |       |
|                                            | 89%   | 90.3% | 89.4% |
+--------------------------------------------+-------+-------+-------+
| **Black**                                  | 15    | 12    | 15    |
|                                            |       |       |       |
|                                            | 5.9%  | 4.0%  | 5.7%  |
+--------------------------------------------+-------+-------+-------+
| **Other**                                  | 13    | 12    | 13    |
|                                            |       |       |       |
|                                            | 5.1%  | 4.9%  | 4.9%  |
+--------------------------------------------+-------+-------+-------+
| **Time from initial diagnosis to           | 120   | 117   | 130   |
| randomization (per sponsor) N**            |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Median (months)**                        | 4.1   | 5.6   | 4.6   |
+--------------------------------------------+-------+-------+-------+
| **Range (months)**                         | 0-282 | 0-97  | 0-124 |
+--------------------------------------------+-------+-------+-------+
| **Time from initial diagnosis to diagnosis | 254   | 247   | 265   |
| of bone mets N**                           |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Median (months)**                        | 3.8   | 2.5   | 2.4   |
+--------------------------------------------+-------+-------+-------+
| **Range (months)**                         | 0-520 | 0-211 | 0-371 |
+--------------------------------------------+-------+-------+-------+
| **Time from first bone mets to             | 254   | 247   | 265   |
| randomization (per sponsor) N**            |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Median (months)**                        | 1.6   | 1.8   | 1.8   |
+--------------------------------------------+-------+-------+-------+
| **Range (months)**                         | 0-46  | 0-102 | 0-63  |
+--------------------------------------------+-------+-------+-------+
| **Prior history of bone metastasis (per    |       |       |       |
| sponsor)**                                 |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **No prior history of bone metastasis (per |       |       |       |
| sponsor)**                                 |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **No of bone metastasis per patient**      | 247   | 235   | 250   |
+--------------------------------------------+-------+-------+-------+
| **median**                                 | 2     | 3     | 2     |
+--------------------------------------------+-------+-------+-------+
| **range**                                  | 1-10  | 1-9   | 1-12  |
+--------------------------------------------+-------+-------+-------+
| **Previous SRE**                           |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **Yes**                                    | 80    | 88    | 89    |
|                                            |       |       |       |
|                                            | 66.7% | 75.2% | 68.5% |
+--------------------------------------------+-------+-------+-------+
| **No**                                     | 40    | 29    | 41    |
|                                            |       |       |       |
|                                            | 33.3% | 24.8% | 31.5% |
+--------------------------------------------+-------+-------+-------+
| **Performance status**                     |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **0**                                      | 50    | 50    | 60    |
+--------------------------------------------+-------+-------+-------+
| **1**                                      | 162   | 168   | 158   |
+--------------------------------------------+-------+-------+-------+
| **2**                                      | 42    | 30    | 44    |
+--------------------------------------------+-------+-------+-------+
| **3**                                      | 1     | 1     | 1     |
+--------------------------------------------+-------+-------+-------+
| **4**                                      | 0     | 1     | 0     |
+--------------------------------------------+-------+-------+-------+
| **Analgesic score (per sponsor)**          |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **0**                                      | 13    | 8     | 13    |
|                                            |       |       |       |
|                                            | 10.8% | 6.8%  | 10%   |
+--------------------------------------------+-------+-------+-------+
| **1**                                      | 17    | 15    | 27    |
|                                            |       |       |       |
|                                            | 14.2% | 12.8% | 20.8% |
+--------------------------------------------+-------+-------+-------+
| **2**                                      | 3     | 3     | 4     |
|                                            |       |       |       |
|                                            | 2.5%  | 2.6%  | 3.1%  |
+--------------------------------------------+-------+-------+-------+
| **3**                                      | 44    | 41    | 38    |
|                                            |       |       |       |
|                                            | 36.7% | 35%   | 29.2% |
+--------------------------------------------+-------+-------+-------+
| **4**                                      | 43    | 50    | 48    |
|                                            |       |       |       |
|                                            | 35.8% | 42.7% | 36.9% |
+--------------------------------------------+-------+-------+-------+
| **BPI composite Pain score (per sponsor)** |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **N**                                      | 234   | 227   | 245   |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 3.5   | 3.3   | 3.3   |
+--------------------------------------------+-------+-------+-------+
| **Fact-G score (per sponsor)**             |       |       |       |
+--------------------------------------------+-------+-------+-------+
| **N**                                      | 230   | 227   | 241   |
+--------------------------------------------+-------+-------+-------+
| **Median**                                 | 71    | 71.2  | 69    |
+--------------------------------------------+-------+-------+-------+

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

*The Applicant analyzed time from initial diagnosis to diagnosis of bone
metastases and time from first bone metastases to randomization
according to the safety evaluation groups. The results would likely be
similar if the same calculations were performed according to the
'efficacy' group of patients. Note that the ranges of these evaluations
are quite, therefore, there will be extensive variability from patient
to patient. This is expected with such a diverse treatment group.*

*The patients are fairly well matched across treatment arms for the
prognostic factors listed in the table above, except whether the patient
had any SRE prior to entering the study. This favors the 4 mg treatment
arm (67% on 4mg versus 75% on placebo). Presence or absence of prior
SREs has emerged as the strongest prognostic factor for study 011 as
well as the study 039. The FDA statistician included this factor in a
multivariate analysis (see discussion of results).*

The distribution of patients by tumor type according to the Applicant
and according to FDA analysis of the data are given in tables below. The
number of patients in this table is different from that provided by the
sponsor. The reason for this is given in the section on protocol
violations.

Distribution of patients by cancer type and treatment arm per Applicant

  -------------------- ----------------------- ------- ------------- ---------
  **Cancer type**      **Number of patients**  **4     **Placebo**   **8/4
                                               mg**                  mg**

  **NSCLC**            386                     126     126           134

  **Thyroid**          11                      2       4             5

  **Head and Neck**    17                      6       4             7

  **Renal**            74                      27      19            28

  **Unknown primary**  43                      15      14            14

  **Other**            242                     81      83            78
  -------------------- ----------------------- ------- ------------- ---------

Distribution of patients by cancer type and treatment arm per FDA Review

  ------------------------------------------------------------------------------------
  **Cancer type**                **Number of       **4 mg**   **placebo**   **8/4 mg**
                                 patients**                                 
  ------------------------------ ----------------- ---------- ------------- ----------
  **NSCLC**                      375               124        121           130

  **Renal**                      73                26         19            28

  **Small cell lung cancer**     66                19         22            21

  **Colorectal**                 52                19         16            17

  **Unknown**                    47                17         14            16

  **Bladder**                    33                11         16            6

  **GI (other)**                 29                10         12            7

  **Head and neck**              16                6          4             6

  **Genitourinary**              15                6          6             3

  **Malignant melanoma**         15                5          4             6

  **Hepatobiliary**              11                3          4             4

  **Thyroid**                    11                2          4             5

  **Other**                      9                 3          2             4

  **Sarcoma**                    9                 3          3             3

  **Neuroendocrine/carcinoid**   7                 2          3             2

  **NHL**                        3                 0          0             3

  **Mesothelioma**               2                 1          0             1
  ------------------------------------------------------------------------------------

There was a difference of 10% between the 4 mg and the placebo group for
the renal cancer patients. This difference was less for the rest of the
cancer types in the non-NSCLC stratum. All NHL patients (they should not
have been included per inclusion criteria) were in the 8 mg arm.

**Study Treatment**

The number of infusions delivered on each study arm is given in the
following table. The highest number of infusions were administered in
the 4 mg followed by 8/4 mg and placebo. Patients in the placebo arm
received 91% of the number infusions as those in the 4 mg arm. Sixteen
per cent of infusions in the 8/4 mg arm were 4 mg infusions.

Doses and Infusions administered

+----------------+------------+-----------+---------+-----------------+
| **Actual       | **Total    | **        |         |                 |
| Dose**         | I          | Treatment |         |                 |
|                | nfusions** | arms**    |         |                 |
| **             |            |           |         |                 |
| Administered** |            |           |         |                 |
|                |            |           |         |                 |
| **mg**         |            |           |         |                 |
+----------------+------------+-----------+---------+-----------------+
|                |            | **4 mg**  | **8/4   | **Placebo**     |
|                |            |           | mg**    |                 |
+----------------+------------+-----------+---------+-----------------+
| 0              | 1600       | 0         | 0       | 1600            |
+----------------+------------+-----------+---------+-----------------+
| 4              | 2083       | 1755      | 328     | 0               |
+----------------+------------+-----------+---------+-----------------+
| 8              | 1384       | 0         | 1384    | 0               |
+----------------+------------+-----------+---------+-----------------+

### Protocol Violations {#protocol-violations-1 .unnumbered}

The most common protocol violations are listed in the next table. This
table was prepared from the electronic dataset provided by the sponsor

Protocol Violations per sponsor in at least 5 patients

+-------------------------------------------+--------+--------+--------+
| **Protocol Violations**                   | **4    | **Pla  | **4/8  |
|                                           | mg**   | cebo** | mg**   |
|                                           |        |        |        |
|                                           | **(#   | **(#   | **(#   |
|                                           | of     | of     | of     |
|                                           | p      | p      | p      |
|                                           | ts.)** | ts.)** | ts.)** |
+===========================================+========+========+========+
| Patient randomized to incorrect stratum   | 18     | 18     | 15     |
+-------------------------------------------+--------+--------+--------+
| Treatment with bisphosphonate during the  | 1      | 4      | 12     |
| 12 months prior to visit1                 |        |        |        |
+-------------------------------------------+--------+--------+--------+
| Patients ECOG status of 2 not diagnosed   | 4      | 2      | 8      |
| within 6 weeks of visit 1                 |        |        |        |
+-------------------------------------------+--------+--------+--------+
| No objective evidence of metastatic bone  | 3      | 1      | 7      |
| disease                                   |        |        |        |
+-------------------------------------------+--------+--------+--------+
| No bone metastases on bone lesion survey  | 3      | 2      | 4      |
| at visit1                                 |        |        |        |
+-------------------------------------------+--------+--------+--------+
| Consent form not signed prior to study    | 1      | 5      | 1      |
| procedure                                 |        |        |        |
+-------------------------------------------+--------+--------+--------+
| Corrected serum calcium out of range at   | 2      | 1      | 1      |
| visit 1                                   |        |        |        |
+-------------------------------------------+--------+--------+--------+
| Unblinding                                | 2      | 5      | 1      |
+-------------------------------------------+--------+--------+--------+
| Treatment with bisphosphonate 12 months   | 1      | 3      | 1      |
| after start of study drug                 |        |        |        |
+-------------------------------------------+--------+--------+--------+
| treatment with other investigational      | 3      | 0      | 0      |
| drugs                                     |        |        |        |
+-------------------------------------------+--------+--------+--------+

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

*According to the sponsor, there are 403 patients with NSCLC, whereas on
FDA review, there were 375 patients with NSLC in the study. The
discrepancy is partly due to the incorrect stratification, in which 51
patients with SCLC were assigned to the NSCLC stratum.*

*There were also discrepancies in the diagnosis. Of 773 patients, only
262 (34%) patients had a brief histology report submitted, allowing FDA
to verify the diagnosis. By FDA review of these reports, eleven patients
who were classified by the Applicant as having NSCLC had either SCLC
(n=10) or mesothelioma (n=1). Other patients incorrectly labeled as
having NSCLC are listed in the following table. Although these
discrepancies may effect the relative numbers in the two strata, they
should not affect the overall comparison of the study arms.*

Patients stratified as NSCLC per Applicant, not consistent with
documented histology

  -----------------------------------------------------------------------
  **Patient   **Histology**                            **Treatment arm**
  no.**                                                
  ----------- ---------------------------------------- ------------------
  10459       Mesothelioma                             4

  12705       Carcinoid typical                        4

  20699       Carcinoid (atypical)                     4

  10601       Neuroendocrine carcinoma                 8

  11573       Neuro endocrine                          8

  21081       Carcinoid                                8

  10181       Neuroendrocrine carcinoma                Placebo

  10783       Carcinoid with neuroendocrine            Placebo
              differentiation                          

  20810       Carcinoid tumor of lung                  Placebo

  22413       Small cell lung cancer                   Placebo

  22714       Microutoma (SCLC)                        Placebo
  -----------------------------------------------------------------------

Another serious violation could be lack of evidence of bone metastases.
According to the Applicant, all but two patients had documented bone
metastases. Several patients did not have the specific protocol-required
evidence on bone scans or survey. For these patients, however, a CT
scan, MRI, or pathological evidence was available.

There were 3 patients with a hematological malignancy included (NHL),
though only patients with solid tumors were to be included in this
study. All 3 patients were in the 8/4 mg arm.

#### Primary Efficacy Analysis {#primary-efficacy-analysis .unnumbered}

The primary efficacy endpoint was the proportion of patients
experiencing at least one SRE. Hypercalcemia is excluded from this
analysis. The cut-off for all analyses except for survival is end of
phase 1, at 14 visits (9 months). Table 26 provides results by the
Applicant and FDA (based on evaluation of the electronic data sets). By
both the FDA and Applicant analyses the proportion of patients with an
SRE is about 9% less on the 8/4 mg arm than placebo, a statistically
significant difference. However, the proportion is only 6-5% less on the
4 mg arm than placebo, and this difference is not statistically
significant.

Proportion of patients having any SRE up to Month 9 by Treatment group
(ITT)

+-------------------+--------------+-----------------+---------------+
|                   | **           | **95% C.I. and  |               |
|                   | Proportion** | P-value for the |               |
|                   |              | difference**    |               |
+===================+==============+=================+===============+
|                   |              | **Zol 4 mg**    | **Zol 8/4     |
|                   |              |                 | mg**          |
+-------------------+--------------+-----------------+---------------+
| **Lung Cancer**   |              |                 |               |
+-------------------+--------------+-----------------+---------------+
| Placebo           | 59/130       | (-15.6%,8.4%),  | (             |
|                   |              |                 | -23.3%,0.1%), |
|                   | (45%)        | p=0.557         |               |
|                   |              |                 | p=0.053       |
+-------------------+--------------+-----------------+---------------+
| Zol 4 mg          | 56/134       | \-              | (             |
|                   |              |                 | -19.5%,3.5%), |
|                   | (42%)        |                 |               |
|                   |              |                 | p=0.175       |
+-------------------+--------------+-----------------+---------------+
| Zol 8/4 mg        | 47/139       | \-              | \-            |
|                   |              |                 |               |
|                   | (34%)        |                 |               |
+-------------------+--------------+-----------------+---------------+
| **Other Solid     |              |                 |               |
| Tumors**          |              |                 |               |
+-------------------+--------------+-----------------+---------------+
| Placebo           | 52/120       | (22.2%,2.2%),   | (-20.1%,4.3%) |
|                   |              |                 |               |
|                   | (43%)        | p=0.110         | p=0.205       |
+-------------------+--------------+-----------------+---------------+
| Zol 4 mg          | 41/123       | \-              | (-9.7%,13.9%) |
|                   |              |                 |               |
|                   | (33%)        |                 | p=0.727       |
+-------------------+--------------+-----------------+---------------+
| Zol 8/4 mg        | 45/127       | \-              | \-            |
|                   |              |                 |               |
|                   | (35%)        |                 |               |
+-------------------+--------------+-----------------+---------------+
| **Total**         |              |                 |               |
+-------------------+--------------+-----------------+---------------+
| Placebo           | 111/250      | (-15.2%,1.9%)   | (-            |
|                   |              |                 | 18.2%,-1.4%), |
|                   | (44%)        | p=0.127         |               |
|                   |              |                 | p=0.023       |
+-------------------+--------------+-----------------+---------------+
| Zol 4 mg          | 97/257       | \-              | (             |
|                   |              |                 | -11.4%,5.1%), |
|                   | (38%)        |                 |               |
|                   |              |                 | p=0.452       |
+-------------------+--------------+-----------------+---------------+
| Zol 8/4 mg        | 92/266       | \-              | \-            |
|                   |              |                 |               |
|                   | (35%)        |                 |               |
+-------------------+--------------+-----------------+---------------+

The following table lists the proportion of patients having at least one
SRE by the FDA analyzed strata vs. the Applicant's ITT strata up to 9
months.

Comparison of proportion of patients in each stratum having any SRE up
to 9 months according to treatment group

+------------------+--------------+-----------------+------------------+
|                  | **Treatment  | **Proportion**  |                  |
|                  | Arm**        |                 |                  |
+==================+==============+=================+==================+
|                  |              | **FDA**         | **Applicant**    |
+------------------+--------------+-----------------+------------------+
| Lung Cancer      | 4            | 51/124          | 56/134           |
|                  |              |                 |                  |
|                  |              | 41%             | 42%              |
+------------------+--------------+-----------------+------------------+
|                  | Placebo      | 54/121          | 59/130           |
|                  |              |                 |                  |
|                  |              | 45%             | 45%              |
+------------------+--------------+-----------------+------------------+
|                  | 8/4          | 43/130          | 47/139           |
|                  |              |                 |                  |
|                  |              | 33%             | 34%              |
+------------------+--------------+-----------------+------------------+
| Other            | 4            | 43/133          | 41/123           |
|                  |              |                 |                  |
|                  |              | 32%             | 33%              |
+------------------+--------------+-----------------+------------------+
|                  | Placebo      | 56/145          | 52/120           |
|                  |              |                 |                  |
|                  |              | 39%             | 43%              |
+------------------+--------------+-----------------+------------------+
|                  | 8/4          | 50/136          | 45/127           |
|                  |              |                 |                  |
|                  |              | 37%             | 35%              |
+------------------+--------------+-----------------+------------------+

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

*There were some differences in numbers of patients included for
individual tumor types due to reasons noted earlier in the review.
However, the proportions with SREs in FDA and Sponsor analyses are
similar for the NSCLC strata.*

*Proportions of patients by tumor type are shown in the next table.
Please note that the percentages shown in this table are based on number
of patients in arm/ total number of patients in tumor type. This is not
the proportion percentage. These are given in table on the previous
page.*

Proportion of patients with at least one SRE, by tumor type, FDA
analysis

+-----------+--------------------+----------+------------+-----------+
| **Cancer  | **Pts. with        | **       |            |           |
| type**    | SRE/Total \# of    | Patients |            |           |
|           | patients in Ca     | with SRE |            |           |
| **Per     | type**             | in       |            |           |
| FDA**     |                    | t        |            |           |
|           | **%**              | reatment |            |           |
|           |                    | arm/     |            |           |
|           |                    | total \# |            |           |
|           |                    | of       |            |           |
|           |                    | patient  |            |           |
|           |                    | in       |            |           |
|           |                    | t        |            |           |
|           |                    | reatment |            |           |
|           |                    | arm of   |            |           |
|           |                    | Cancer   |            |           |
|           |                    | type**   |            |           |
+===========+====================+==========+============+===========+
|           |                    | **4 mg** | *          | **8/4     |
|           |                    |          | *Placebo** | mg**      |
|           |                    | **% of   |            |           |
|           |                    | total    | **% of     | **% of    |
|           |                    | tumor    | total      | total     |
|           |                    | type**   | tumor      | tumor     |
|           |                    |          | type**     | type**    |
+-----------+--------------------+----------+------------+-----------+
| NSCLS     | 148/375            | 51/124   | 54/121     | 43/130    |
|           |                    |          |            |           |
|           | 39.47%             | 13.60%   | 14.40%     | 11.47%    |
+-----------+--------------------+----------+------------+-----------+
| Renal     | 36/73              | 8/26     | 14/19      | 14/28     |
|           |                    |          |            |           |
|           | 49.32%             | 10.96%   | 19.18%     | 19.18%    |
+-----------+--------------------+----------+------------+-----------+
| SCLC      | 25/66              | 7/19     | 9/22       | 9/25      |
|           |                    |          |            |           |
|           | 37.88%             | 10.61%   | 13.64      | 13.64%    |
+-----------+--------------------+----------+------------+-----------+
| C         | 17/52              | 7/19     | 5/16       | 5/17      |
| olorectal |                    |          |            |           |
|           | 32.69%             | 13.46%   | 9.62%      | 9.62%     |
+-----------+--------------------+----------+------------+-----------+
| Unknown   | 16/47              | 3/17     | 7/14%      | 6/16      |
|           |                    |          |            |           |
|           | 34.04%             | 6.38%    | 14.89      | 12.77%    |
+-----------+--------------------+----------+------------+-----------+
| Bladder   | 9/33               | 4/11     | 5/16       | 0/6       |
|           |                    |          |            |           |
|           | 27.27%             | 12.12%   | 15.15%     | 0%        |
+-----------+--------------------+----------+------------+-----------+
| GI other  | 12/29              | 3/10     | 6/12       | 3/7       |
|           |                    |          |            |           |
|           | 41.38%             | 10.34%   | 20.69%     | 10.34%    |
+-----------+--------------------+----------+------------+-----------+
| Head and  | 9/16               | 4/6      | 2/4        | 3/6       |
| neck      |                    |          |            |           |
|           | 56.25%             | 25.00%   | 12.50%     | 18.75%    |
+-----------+--------------------+----------+------------+-----------+
| GU        | 4/15               | 1/6      | 1/6        | 2/3       |
|           |                    |          |            |           |
|           | 26.67%             | 6.67%    | 6.67%      | 13.33%    |
+-----------+--------------------+----------+------------+-----------+
| Malignant | 3/15               | 3/5      | 0/4        | 0/6       |
| melanoma  |                    |          |            |           |
|           | 20%                | 20%      | 0%         | 0%        |
+-----------+--------------------+----------+------------+-----------+
| Hepa      | 3/11               | 0/3      | 2/4        | ¼         |
| tobiliary |                    |          |            |           |
|           | 27.27%             | 0%       | 18.18%     | 9.09%     |
+-----------+--------------------+----------+------------+-----------+
| Thyroid   | 4/11               | 0/2      | 2/4        | 2/5       |
|           |                    |          |            |           |
|           | 36.36%             | 0%       | 18.18%     | 18.18%    |
+-----------+--------------------+----------+------------+-----------+
| Other     | 4/9                | 0/3      | 1/2        | 3/4       |
|           |                    |          |            |           |
|           | 44.44%             | 0%       | 11.11%     | 33.33%    |
+-----------+--------------------+----------+------------+-----------+
| Sarcoma   | 4/9                | 1/3      | 1/3        | 1/3       |
|           |                    |          |            |           |
|           | 44.44%             | 22.22%   | 11.11%     | 11.11%    |
+-----------+--------------------+----------+------------+-----------+
| Neuroe    | 2/7                | 0/2      | 1/3        | 1/2       |
| ndocrine/ |                    |          |            |           |
| carcinoid | 28.57%             | 0%       | 14.29%     | 14.29%    |
+-----------+--------------------+----------+------------+-----------+
| NHL       | 0/3                | 0/0      | 0/0        | 0/3       |
|           |                    |          |            |           |
|           | 0%                 | 0%       | 0%         | 0%        |
+-----------+--------------------+----------+------------+-----------+
| Mes       | 1/2                | 1/1      | 0/0        | 0/1       |
| othelioma |                    |          |            |           |
|           | 50%                | 50%      | 0%         | 0%        |
+-----------+--------------------+----------+------------+-----------+

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

*The improvement in proportions of patients suffering from at least one
SRE in the 4 mg arm does not reach statistical significance over placebo
in the analysis for the primary objective.*

*(p= 0.127)*

#### Secondary Objectives: {#secondary-objectives .unnumbered}

##### Time to First SRE {#time-to-first-sre-1 .unnumbered}

Time to first SRE was a secondary end point. Time to first SRE was 67
days longer in the 4mg arm than placebo (230 days versus 163 days, p =
0.026 by log rank test).

Time to First SRE up to 9 months (-HCM)

+-----------+----------------+---------+------------------------------+
|           | **Treatment    | **M     | **p value compared to        |
|           | arm**          | edian** | placebo and 95% confidence   |
|           |                |         | limits**                     |
+-----------+----------------+---------+------------------------------+
| **Per     | 4 mg           | 230     | 0.023                        |
| Sponsor** |                |         |                              |
+-----------+----------------+---------+------------------------------+
|           | Placebo        | 163     |                              |
+-----------+----------------+---------+------------------------------+
|           | 8/4 mg         | 219     | 0.034                        |
+-----------+----------------+---------+------------------------------+
| **Per**   | 4 mg           | 230     | 0.026                        |
|           |                |         |                              |
| **FDA**   |                |         | 168-\* days                  |
+-----------+----------------+---------+------------------------------+
|           | Placebo        | 163     | 106-188 days                 |
+-----------+----------------+---------+------------------------------+
|           | 8/4 mg         | 219     | 0.035                        |
|           |                |         |                              |
|           |                |         | 172-\* days                  |
+-----------+----------------+---------+------------------------------+

\* not reached

P values were calculated using Cox-regression by the sponsor

P values were calculated using Log-rank method by the FDA

The relative efficacy of the subgroups was also addressed in the FDA
statistical reviewer\'s Cox regression analysis:

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

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

The overall hazard is 0.73 while the estimated hazard in the subgroups
are 0.79 and 0.66 for *NSCLC* and *other tumors*, respectively.

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

*'Time to First Event' although a secondary endpoint, is more sensitive
than 'proportions of patients'. This is because it accounts and adjusts
for the timing of dropouts. Median time to first event was increased by
a median of 67 days in the 4 mg arm over placebo.*

*Although the difference in time to first event is statistically
significant for all patients, this difference is lost when evaluating
each stratum separately.*

##### Proportion of patients with each type of SREs {#proportion-of-patients-with-each-type-of-sres .unnumbered}

According to Applicant analyses (Volume 1.92), the proportion of
patients having each type of SRE (fracture, radiation, etc.) was lower
in the zoledronic acid groups than in placebo except surgery to bone.
However, statistical significance was not reached.

#####  {#section-5 .unnumbered}

##### Time to first SRE for each type of SRE {#time-to-first-sre-for-each-type-of-sre .unnumbered}

According to Applicant analyses (volume 1.92), the median time to the
first event was generally not reached due to low event rates. The
distribution of time to first event was statistically significant in
favor of the 4 mg arm versus placebo in the case of fractures.

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

*Pathologic vertebral fractures are of questionable clinical
significance if they include asymptomatic events.*

**Evaluation of symptomatic events**

Using the electronic data, the reviewer evaluated whether SREs were
listed as being symptomatic. These data are given below in the table. As
can be observed, about half (20/41) of vertebral fractures were
asymptomatic.

First events, whether symptomatic or otherwise by treatment arm

  ---------------------------------------------------------------------------------
  **Event**             **Symptomatic**   **Total**   **4     **8     **Placebo**
                                                      mg**    mg**    
  --------------------- ----------------- ----------- ------- ------- -------------
  radiation             unknown           3           1       2       0

  radiation             No                26          5       12      9

  radiation             Yes               155         53      45      57

  nonvertebral fracture unknown           7           3       1       3

  nonvertebral fracture No                19          7       7       5

  nonvertebral fracture Yes               22          7       5       10

  Vertebral fracture    unknown           4           2       0       2

  Vertebral fracture    No                20          5       6       9

  Vertebral fracture    Yes               17          4       3       10

  surgery               No                2           1       1       0

  surgery               Yes               13          3       7       3

  cord compression      unknown           1           1       0       0

  cord compression      Yes               13          5       5       3
  ---------------------------------------------------------------------------------

The reviewer performed an exploratory analysis evaluating the proportion
of patients with SREs excluding asymptomatic vertebral fractures. As
shown in the table below, the relative differences between study arms
are little affected by exclusion of these data.

Proportions of patients with at least 1 SRE excluding patients with
asymptomatic vertebral fractures.

+--------------------+-------------------------------------------------+
| **Treatment arm**  | **Number of patients with at least 1 SRE**      |
+--------------------+-------------------------------------------------+
| 4                  | 90/257                                          |
|                    |                                                 |
|                    | 35%                                             |
+--------------------+-------------------------------------------------+
| 8                  | 90/266                                          |
|                    |                                                 |
|                    | 34%                                             |
+--------------------+-------------------------------------------------+
| Placebo            | 103/250                                         |
|                    |                                                 |
|                    | 41%                                             |
+--------------------+-------------------------------------------------+

Skeletal Morbidity Rate (SMR):

Skeletal morbidity rate captures all events as one in an evaluation
period of 28 days. It sums all occurrences and divides by time on study.
It attempts to capture events occurring beyond the first event. However,
it does not distinguish between the severity or number of events in one
evaluation period. The Applicant analysis of the skeletal morbidity
rates for the 4, 8/4mg arms and placebo for all patients together is not
given in the study report (p 56). Compared to placebo, SMR was
significantly lower on the 8/4 arm (p = 0.005) but not the 4 mg arm (p =
0.069) and not in subgroups of the 4 mg arm.

##### Brief Pain Inventory (BPI) composite pain score: {#brief-pain-inventory-bpi-composite-pain-score .unnumbered}

A higher composite pain score indicates more pain. In the Applicant
analysis, the mean BPI score increased slightly from baseline to Month 9
for all 3 treatment groups. There was no statistically significant
difference between any of the treatment groups. This lack of
significance was also observed in protocol 039.

##### Analgesic scores: {#analgesic-scores .unnumbered}

In this analysis, analgesic scores ranged from 0 to 4, higher scores
indicating stronger analgesic used. In Applicant analyses, there were no
statistical differences in analgesic score changes from baseline among
the treatment arms at Month 9.

##### Performance Status: {#performance-status .unnumbered}

In Applicant analyses, there were no statistical differences in the ECOG
performance status from baseline among the treatment arms at Month 9.

##### Quality of Life (FACT-G): {#quality-of-life-fact-g .unnumbered}

In applicant analyses, there were no statistical differences in change
from baseline among the treatment arms at Month 9.

##### Progression of bone metastases and disease: {#progression-of-bone-metastases-and-disease .unnumbered}

There was no difference between treatment groups in the distribution of
time to progression of bone metastases or overall disease progression.

##### Survival: {#survival-1 .unnumbered}

The median survival of patients was similar in the three treatment arms.
The Kaplan-Meier curve is shown in the next Figure.

Kaplan-Meier Curve for survival

![](media/image4.png){width="5.492361111111111in"
height="3.189583333333333in"}

Survival according to subgroups is described in the following tables.
The first presents survival according to subgroups reclassified by the
medical reviewer, and the second provides subgroups as analyzed by the
Applicant.

FDA's analysis of median survival by stratum

+--------------+-----------------+-----------------+-----------------+
| **Tumor      | **Median        |                 |                 |
| type**       | survival**      |                 |                 |
|              |                 |                 |                 |
|              | **Days**        |                 |                 |
+--------------+-----------------+-----------------+-----------------+
|              | **4 mg**        | **Placebo**     | **8 mg**        |
+--------------+-----------------+-----------------+-----------------+
| NSCLC        | 202             | 157             | 174             |
+--------------+-----------------+-----------------+-----------------+
| Other        | 208             | 192             | 214             |
+--------------+-----------------+-----------------+-----------------+
| Total        | 203             | 183             | 189             |
+--------------+-----------------+-----------------+-----------------+

Applicant's analysis of median survival by stratum

+--------------+-----------------+-----------------+-----------------+
| **Tumor      | **Median        |                 |                 |
| type**       | survival**      |                 |                 |
|              |                 |                 |                 |
|              | **days**        |                 |                 |
+==============+=================+=================+=================+
|              | **4 mg**        | **Placebo**     | **8 mg**        |
+--------------+-----------------+-----------------+-----------------+
| NSCLC        | 199             | 155             | 181             |
+--------------+-----------------+-----------------+-----------------+
| Other        | 215             | 192             | 213             |
+--------------+-----------------+-----------------+-----------------+
| Total        | 203             | 183             | 189             |
+--------------+-----------------+-----------------+-----------------+

##### *[Reviewer's Comment:]{.underline}*  {#reviewers-comment-1 .unnumbered}

##### *The purpose of analyzing overall survival is to provide assurance that Zometa does not affect survival adversely. It is not expected to improve survival*. {#the-purpose-of-analyzing-overall-survival-is-to-provide-assurance-that-zometa-does-not-affect-survival-adversely.-it-is-not-expected-to-improve-survival. .unnumbered}

#### Reviewer's Exploratory Analysis of Chemotherapy on study {#reviewers-exploratory-analysis-of-chemotherapy-on-study .unnumbered}

The chemotherapy received by the patients could have impacted the SRE by
its effect on bone metastases. An expoloratory analysis of
antineoplastic therapy was performed by the reviewer to evaluate
potential imbalances. In the data set, any change in treatment, such as
addition or deletion of an agent,was recorded as a new regimen by the
sponsor. No data was available on the number of regimens prior to coming
on study and can not be analyzed. One might assume that randomization
would provide balance for this baseline factor. The following table
describes the number of regimens given while on study.

Number of on-study antineoplastic regimens

  -------------------------------------------------------------------------
  **Number of           **Total**   **4 mg**   **Placebo**    **8/4 mg**
  regimens**                                                  
  --------------------- ----------- ---------- -------------- -------------
  0                     213         64         67             82

  1-2                   495         166        166            166

  3-6 regimens          61          25         15             21
  -------------------------------------------------------------------------

Number of on-study antineoplastic regimens in NSCLC patients

  --------------------- ----------- ---------- -------------- -------------
  **\# of regimens**    **Total**   **4 mg**   **Placebo**    **8/4 mg**

  0                     79          23         27             29

  1-2                   255         84         84             87

  3-6                   83          16         8              14
  --------------------- ----------- ---------- -------------- -------------

The number of patients receiving chemotherapy on study was similar
across arms.

##### Best tumor Response {#best-tumor-response .unnumbered}

The next table shows results of the reviewer\'s analysis of the best
tumor responses (created from the electronic dataset 'tumoresp'). Only
607 patients were listed in the dataset. For 99 patients, the best tumor
response was listed as unknown. Response was given for 513 of 773 (66%)
patients in the electric dataset provided by the Applicant, and are
given below:

Best tumor response/patient /arm

  --------------------- -------------------- -------- ------------- ---------
  **Maximum response**  **Total \# of        **4 mg** **Placebo**   **8/4
                        patients**                                  mg**

  **CR**                4                    1        2             1

  **PR**                55                   12       15            28

  **SD**                170                  66       51            53

  **PD**                278                  95       92            91
  --------------------- -------------------- -------- ------------- ---------

#####  {#section-6 .unnumbered}

##### *[Reviewer's Comments:]{.underline}* {#reviewers-comments .unnumbered}

*The responses across the arms are similar. However, a third of patients
had no response outcome recorded. Furthermore, the study was not
designed to evaluate the impact of chemotherapy and prior history of
treatment with chemotherapy was not known. For these reasons, it is
difficult to draw any conclusions regarding the effect of chemotherapy
on bone metastases and its impact on results obtained for Zometa.*

##### Distribution of First Events by Treatment Arm {#distribution-of-first-events-by-treatment-arm .unnumbered}

The frequency of the individual types of SREs occuring first in patients
(and hence composing events in the SRE proportions analysis and time to
first SRE analysis) are given in the following table.

Distribution of first events for patients according to treatment arm

  ---------------------------- ----------- --------- ------------- -----------
  **Event**                    **Total**   **4 mg**  **Placebo**   **8/4 mg**

  Radiation                    177         57        63            57

  Non-vertebral fracture       46          16        16            14

  Vertebral fracture           41          11        21            9

  Surgery                      16          4         4             8

  Cord compression             16          6         5             5
  ---------------------------- ----------- --------- ------------- -----------

Radiation treatment to bone was the most common SRE, followed by
non-vertebral and vertebral fractures. There were relatively few
surgeries to bone or spinal cord compressions. More vertebral fractures
occurred on the placebo arm. Consequently, there are more symptomatic
and asymptomatic patients with vertebral fractures in the placebo arm
Otherwise, the first events were similar across the treatment arms.

**Administration of radiation:**

The reason for administration of radiation was not given by the sponsor
in the raw datasets. Using the electronic data, the reviewer determined
the anatomical sites treated by radiation therapy in asymptomatic
patients. This analysis showed that most of these patients received
radiation to weight bearing sites that seemed to justify radiation
therapy in the absence of symptoms. There were four patients who were
exceptions. The number of these patients who received radiation for
unclear reasons is small and similar across treatment arms.

### Efficacy Summary and Conclusions of Study 011 {#efficacy-summary-and-conclusions-of-study-011 .unnumbered}

[Study design]{.underline}

In this study, 773 patients with a variety of solid cancers metastatic
to bone were randomized 1:1:1 to treatment with zoledronate 4 mg,
zoledronate 8/4 mg, or placebo to evaluate zoledronate\'s effect on
SREs. Randomization was stratified according to cancer type as either
*NSCLC* or *other tumors*. Stratification was imperfect, with a number
other tumor types incorrectly included in the *NSCLC* stratum. However,
there was no evidence that the randomization process itself was
compromised. The primary objective was to compare *the proportion of
patients with at least one SRE* on the zoledronate 4 mg arm versus
placebo, although FDA statisticians, because of design concerns, had
suggested making *time to first SRE* a co-primary endpoint.

[Design Problems]{.underline}

The reviewer noted some deficiencies in the study. First, prior
chemotherapy regimens were not documented, so FDA could not determine
whether extent of prior therapy was balanced among the study arms.
Instead, FDA examined data on changes in chemotherapy regimens and
reported tumor response rates during the study, but these data were not
complete. Therefore, response to chemotherapy, which likely would have
affected the incidence of SREs, could not be fully assessed. Second,
there was no central review of the pathology specimens. In the one third
of patients where pathology reports were provided, some of the tumors
were incorrectly classified. Change in this classification could change
the results of the subgroup analyses.

[Efficacy Results]{.underline}

The proportion of patients with an SRE was lower on the 4 mg arm than
placebo, but the difference was not statistically significant (37%
versus 44%, respectively, p = 0.106). The comparison of the 8/4 mg group
to placebo showed a significant difference (35% versus 44% respectively,
p = 0.044).

Time to first SRE was 67 days longer in the 4mg arm than placebo (230
days versus 163 days respectively, p = 0.026) and was also significantly
longer for the 8/4 mg arm. For the 4mg versus placebo comparison,
subgroup analysis demonstrated a marginally statistically significant
difference for the *other tumors* group, but the difference for the
*NSCLC* group was not statistically different. FDA Cox regression
analysis provided estimates for the relative contribution of each
stratum in the overall analysis: the overall hazard ratio for 4 mg
versus placebo was 0.73 while the estimated hazard in the subgroups were
0.79 and 0.66 for *NSCLC* and *other tumors*, respectively.

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

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

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

  **Lung Cancer Stratum**     0.785 (0.544, 1.132)     0.194

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

[Conclusions]{.underline}

This study provides some evidence that zoledronate 4 mg provides
clinical benefit to the overall population studied. Although the primary
endpoint was not statistically significantly improved, the FDA-preferred
secondary endpoint was. Positive results from the 8/4 mg arm were
supportive.

However, the study design was based on an assumption that zoledronate
will have a similar effect on bone morbidity, regardless of the tumor
type. Generally cells from breast cancer, small cell lung cancer, or
pancreatic cancer behave quite differently from each other in the body.
This study assumes that these cells would behave similar to each other
when acted upon by Zometa once inside bone. This hypothesis has not been
proven for any biphosphonate. Although an efficacy trend is suggested
for both subgroups in this study, the stronger evidence for efficacy
comes from the subgroup of patients having a variety of types of cancer.

At the time of preparing this briefing document, the FDA review team is
uncertain to what extent this trial supports a separate zoledronate
treatment indication. The advice of the Oncologic Drugs Advisory
Committee will be helpful to the FDA in making this determination.
Issues that should be considered include:

-   To what extent do the zoledronate NDA trials for prostate cancer,
    breast cancer, and myeloma provide support for efficacy in this
    setting?

-   Would a positive study of this design indicate that efficacy is
    established for all tumor types evaluated?

-   Or, should one evaluate the study population to determine which
    tumor-types were sufficiently represented?

-   Are some tumors sufficiently different that they should be excluded
    from consideration, e.g., small cell lung cancer? Approval of this
    drug for *all tumors metastatic to bone* would mean exposure of a
    large number of cancer patients to zoledronate along with its
    toxicity and its expense. Is there adequate evidence for such a
    blanket approval?

```{=html}
<!-- -->
```
-   On the other hand, it would be difficult to conduct a trial of
    Zometa in each type of cancer individually. If overall prognosis and
    survival for the cancer types included are considered, should one
    consider an increase of 67 days in time to first skeletal event,
    marked enough to reach overall statistical significance, as
    meaningful clinical benefit?

**Active Controlled Trial #010 in Breast Cancer and Myeloma**

## Active Controlled Trial #010 in Breast Cancer and Myeloma 

**Protocol Title:**

\"A randomized, double-blind multicenter, comparative trial of i.v.
zoledronate (4 or 8 mg) versus i.v. Aredia (90 mg), as an adjunct to
standard therapies, in the treatment of multiple myeloma and breast
cancer patients with cancer-related bone lesions\"

First patient randomized: October 16, 1998

Last patient randomized: December 13, 1999

Last data for Phase 1 analysis: December 20, 2000

Data cutoff: July 3, 2001

### Background {#background-1 .unnumbered}

By comparing zoledronate 4 mg to pamidronate 90 mg in Study 10, the
Applicant claims that zoledronate 4 mg is effective for treating myeloma
and breast cancer metastatic to bone. This conclusion is from
demonstrating not *superiority* but rather *non-inferiority* of
zoledronate compared to pamidronate and involves not only direct
evidence from the trial, but also inference and assumptions about the
historical pamidronate placebo-controlled trial. To reach the conclusion
that zoledronate is effective, one must examine the historical evidence
that pamidronate is effective compared to placebo, estimate the size of
that pamidronate effect versus placebo, assume that that same effect is
manifest in the conditions of the new study of zoledronate versus
pamidronate, and, using statistical methods, estimate what fraction of
that pamidronate effect must have been retained by zoledronate if the
trial assumptions are valid.

The critical historical information describing the results of the
pamidronate trials is discussed in section 2.2 of this review and is
summarized again in section 4.3.4 of this review.

### Study design {#study-design-2 .unnumbered}

The following is a brief overview of protocol 010 emphasizing important
differences from the other pivotal studies in this NDA.

### Protocol Amendments {#protocol-amendments-2 .unnumbered}

Below are important protocol amendments with the dates and number of
patients accrued at the time of the amendment. The two most critical
amendments were because of renal toxicity. Amendment #2, which occurred
after about half of the patients had been randomized, increased the
infusion time to 15 minutes, and amendment #5, which occurred after all
patients had been randomized, decreased the dose of zoledronate from 8mg
to 4mg for patients randomized to the 8mg arm. The following are details
of the amendments:

#1 February 19, 1999

This early amendment affected virtually all patients entering the study:

-   Clarified that breast cancer patients should be receiving first or
    second line treatment and that all myeloma patients should be
    receiving anti-cancer therapy at the time of study entry.

```{=html}
<!-- -->
```
-   Specified that patients should be followed for SRE\'s even after
    study medication was discontinued.

```{=html}
<!-- -->
```
-   Specified that skeletal surveys would be performed in both breast
    cancer and myeloma patients every 3 months but that bone scans would
    only be done in breast cancer patients (every 6 months).

-   The statistical section clarified that the time to event secondary
    endpoints will use the Cox regression model with creatinine (\<2 vs
    \>=2), ECOG PS (0-1 vs \>1), age (\<=60 vs \>60), previous SRE
    experience (yes/no), and treatment group, with stratum as the
    stratified variable.

-   Sample size calculations adjust goal to 1509 patients (503 per arm)

#2 June 25, 1999

This amendment was activated when about half (815) of the patients had
been entered.

-   Because of renal toxicity, the infusion volume was increased from 50
    ml to 100 ml and the infusion time was increased from 5 minutes to
    15 minutes.

#3 September 30, 1999

This amendment was activated after 83% (1374) of the patients had been
accrued. Less than 10% (158) patients had reached their last visit in
Phase I.

-   An interim analysis plan was provided for a single analysis when 40%
    of patients had been evaluated for 13 months. A Lans-Demets plan was
    specified.

#4 February 21, 2000 This was a minor amendment.

#5 June 7, 2000

This amendment was activated about 6 months after the last patient was
randomized (December 13, 1999).

-   Because of renal toxicity noted with 8 mg zoledronate, patients on
    the 8mg arm were to receive 4mg. This amendment occurred when about
    60% (304) of the patients on the 8mg arm had already reached their
    last visit in Phase I.

#6 October 13, 2000

This amendment presented statistical amendments to the protocol. Most
patients (1446) had reached their last efficacy visit for phase I prior
to this amendment.

-   4 mg is specified as the primary arm for analysis.

-   Two logistic regression analyses are proposed analysis of
    SRE\'s: (1) stratum, previous SREs, treatment, and interaction
    terms, and (2) stratum, previous SREs.

-   The previous interim analysis plan is deleted.

### Protocol #010 Summary {#protocol-010-summary .unnumbered}

The primary objective was to demonstrate non-inferiority of i.v.
zoledronate 4mg and/or 8 mg to Aredia in preventing SREs in myeloma or
breast cancer. If non-inferiority was demonstrated, the possibility of
superiority would be tested. (The definition of SRE is the same as that
in the prostate cancer Protocol 039). Secondary objectives were also
similar to those stated in Protocol 039.

This was in international, multicenter, stratified, double-blind, study
that randomized patients 1:1:1 to zoledronate 4 mg, zoledronate 8mg, or
pamidronate 90 mg i.v. every 3-4 weeks for 12 months. Randomization was
stratified by center and 3 disease strata: myeloma, breast cancer
treated with hormones, and breast cancer treated with chemotherapy. The
primary analysis was to be a non-inferiority analysis of the proportion
of patients with at least one SRE, performed after 13 months (12 months
of treatment and one month of followup), comparing each of the
zoledronate arms to the active pamidronate active control arm with
confidence intervals of the difference excluding a 8% difference.
However, with Amendment #5 on June 7, 2000, the 8mg zoledronate arm was
dropped from the primary analysis because of nephrotoxicity.

All patients received treatment in the same volume of normal saline over
the same time, initially in 50 ml over 5 minutes, and after amendment
#2, in 100 ml over 15 minutes. Only the local pharmacist was unblinded
to treatment. Drugs were given every 3-4 weeks, depending upon the
chemotherapy administration schedule.

### Inclusion and exclusion criteria:  {#inclusion-and-exclusion-criteria .unnumbered}

Entry criteria were similar to those in Trial 039, with the following
exceptions:

-   Patients with myeloma were to have Durie-Salmon Stage III disease,
    at least one lytic lesion, and were to be receiving chemotherapy
    (per amendment 1).

-   Breast cancer patients were to have at least one bone lesion visible
    on conventional radiographs. According to amendment #1, all patients
    were required to be receiving first or second line chemotherapy.

```{=html}
<!-- -->
```
-   Includes ECOG PS 0-2.

*[Reviewer\'s comment.]{.underline}*

*These entry criteria select patients reasonably similar to those
entered in the pamidronate breast cancer and myeloma trials. One
difference, however, is the inclusion of patients with osteoblastic
disease in the breast cancer patients.*[]{#__RefHeading___Toc534641874
.anchor}

### Treatment interruption or discontinuation {#treatment-interruption-or-discontinuation .unnumbered}

Patients were to remain on study for efficacy and safety evaluations
despite progression of disease, change in antineoplastic therapy, or the
occurrence of an SRE.

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

*As discussed later in this review, few data were actually captured
after discontinuation of study drug.*

### Treatment: {#treatment .unnumbered}

A double dummy system was used. The initial infusion was either
Zoledronate or placebo, and this was followed by a 2-hour infusion of
placebo or pamidronate. 500 mg calcium tables were taken daily to
suppress parathyroid hormone response to biphosphonate treatment. Most
concomitant antineoplastic medications were allowed, except for drugs
known to affect calcium metabolism, such as biphosphonates.

### Randomization {#randomization .unnumbered}

Lists of numbers randomized numbers in blocks of 3 were provided to the
centers for each of the 3 treatment strata leading to stratification by
the 3 disease groups and center. In an emergency, the investigator could
determine the blinded treatment assignment by removing a scratch-off
cover on a \"code break card.\"

### Study Schedule {#study-schedule .unnumbered}

Randomization occurred on visit 2, day 0. Skeletal related events and
blood work were evaluated at every visit, every 3-4 weeks. Skeletal
surveys were done every 3 months in all patients and bone scans every 6
months in only the breast cancer patients. Other details are outlined in
the attached excerpts from the protocol schedule. Visits were planned
for every 3 weeks. Patients receiving treatments every 4 weeks would not
have visits at V5, 9, 13, and 17. If patients went off study medication,
they were to be followed for SREs every 3 months.

*[Reviewer's comments]{.underline}*

*The Applicant notes that data were collected differently in these
Zometa trials than in the pamidronate trials becausedata were to be
collected even after patients discontinued study medication (albeit only
at 3-month intervals). One might expect that the quality of these data
collected after stopping study medication would be poor because of less
frequent and potentially erratic follow-up in these patients. FDA asked
Novartis to evaluate the effect of these data on efficacy. Review of the
Novartis 12/10/01 showed that only 9 additional patients had an SRE
affecting the primary analysis when these data were included, six
patients on Zom 4, two on Zom 8, and four on placebo. Therefore,
efficacy results differed little whether they were included or
excluded.*

**Excerpts from the Protocol Schedule of Assessments:**

### ![](media/image5.png){width="5.45in" height="6.308333333333334in"}  {#section-7 .unnumbered}

### Planned Efficacy Assessments

**Primary Endpoint**

The proportion of patients with SRE (-HCM) at 13 months was the primary
endpoint. As noted earlier, these events included pathologic bone
fractures, vertebral compression fractures (a 25% decrease in anterioror
or posterior vertebral height), spinal cord compression, surgery to
bone, and radiation therapy to bone (including strontium-89). Fractures
were determined by a central radiologist who had access to serial films.

**Secondary Endpoints**

Tumor assessment was to be done every 3 months according to SWOG
criteria. The definitions of tumor progression according to these
criteria were:

-   In myeloma, a 50% increase of M protein on two occasions constituted
    progression.

-   In breast cancer, a new bone lesion or a 25% increase in the product
    of bidimensionally measurable tumor measurements

Pain and analgesic data were collected every two visits. Pain scores
used the Brief Pain Inventory (BPI). This consists of questions rating
each specific pain (1-10) and how pain interfers with activity, mood,
walking, normal work, relationships, sleep, and enjoyment of life. A
composite score was specified as the main variable, but derivation of
the composite was not explained in the protocol or study report.
Analgesic use was scored as none, 1 = minor analgesics, 2 =
tranquilizers, 3 = mild narcotics (oxycodone, meperidine, codeine) and 4
= strong narcotics (morphine, hydromorphone).

### Planned Statistical Analysis {#planned-statistical-analysis .unnumbered}

The original protocol specified that the analysis of the proportion of
patients with at least one SRE would be a non-inferiority test between
8mg zoledronate arm and placebo. If the 8 mg arm was non-inferior to
placebo, then the 4mg arm would also be compared to placebo. If a
Zoledronate arm was non-inferior to placebo, then tests for superiority
were allowed. Originally, the protocol specified one-sided confidence
intervals of the difference in proportions between study arms were to
show that Z arms were no more than 8% inferior to placebo. After
amendment 5, the 8mg arm was dropped from the analysis plan.
Furthermore, the final study report uses two-sided 95% confidence
intervals upon advice of the FDA at Pre-NDA meetings.

The target \"delta\" of 8% for the non-inferiority analysis was derived
from the pamidronate registration studies for myeloma and breast cancer.
The Applicant calculated that a difference of 8% represented 60% of the
treatment effect that would be expected in +this study. The expected
effect of 13% was averaged from the results from the 3 registration
studies listed below:

[Disease]{.underline} [Study duration]{.underline} [Placebo
SRE]{.underline} [Pamid. SRE]{.underline} [Placebo - Pam]{.underline}

Myeloma 9 mos 40.9% 24.0% 16.9%

Breast-chemo. 12 mos 56.4% 42.7% 13.7%

Breast-horm. 12 mos 55.0% 46.7% 8.3%

The original protocol designated a sample size of 1470 (490 per arm) to
have 80% power to determine the non-inferiority boudary of 8% using
2-sided 95% confidence intervals with alpha of 0.05. The final sample
size of 1648 exceeded this goal due to rapid accrual.

### Results of Study #010, Baseline Factors {#results-of-study-010-baseline-factors .unnumbered}

**Patient Disposition and Grouping for Analysis**

Novartis randomized 1648 patients to the 3 study arms. The following
table summarizes patient randomization and grouping for Novartis
analyses:

**Number (%) of patients in analysis populations by treatment group (All
randomized patients)**

**Zol 4 mg Zol 8/4 mg Aredia 90 mg Total**

**Populations**

**Randomized** 564 526 558 1648

**Safety evaluable population** 563 (99.8%) 524 (99.6%) 556 (99.6%) 1643

**ITT population** 561 (99.5%) 524 (99.6%) 555 (99.5%) 1640

**Per Protocol population** 453 (80.3%) 435 (82.7%) 446 (79.9%) 1334

For the safety population the Applicant included all patients that
received study drug, excluding 5 patients. The eight patients accrued
from one center (2711) were excluded from the Applicant\'s efficacy
analyses because the center did not meet Good Clinical Practices (GCP)
standards. Problems included inadequate reporting of trial related
issues to the ethics committee, improper informed consent process, and
inadequate procedures to maintain the blind. Efficacy was also analyzed
in a per protocol analysis that included all patients that met entry
criteria and had a 3-month evaluation and did not have a major protocol
deviation (use of bone-active agent, missed cycle of study drug during
first three months, or missed more than 50% of cycles after the first
three months). This excluded about 100 patients per arm.

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

*The 8 patients excluded in the ITT analysis included only 1 patient
with an event on the Zom 4 arm and only one patient with an event on the
Pam arm. Excluding these 8 patients is unlikely to alter the outcome.FDA
efficacy assessment usually emphasizes the ITT analysis. However, for
non-inferiority assessments, the per protocol (PP) analysis is also
important. Missing data from patients in the ITT analysis may obscure
differences in non-inferiority trials, and PP analyses may help to
lessen the \"noise\" caused by the incomplete data. This secondary PP
analysis is more credible in Study 010 because the criteria for
inclusion in the PP analysis were carefully specified in the protocol.
As noted in the table above, 20% of the patients in each arm are not
included in the PP analysis.*

The following Applicant table describes patient disposition during the
study:

  ------------------------------- ----------- ------------ ---------------
  **Patient disposition for each                           
  treatment group (Safety                                  
  evaluable patients)**                                    

                                  **Zol 4     **Zol 8/4    **Aredia 90
                                  mg**        mg**         mg**

                                  **n (%)**   **n (%)**    **n (%)**

  **Total no. of patients** -                              
  n(%)                                                     

  randomized                      564         526          558

  safety evaluable                563         524          556

  completed                       353 (62.7)  313 (59.7)   338 (60.8)

  **Discontinuations of study                              
  medication**                                             

  total                           210 (37.3)  211 (40.3)   218 (39.2)

  adverse event(s)                57 (10.1)   71 (13.5)    51 (9.2)

  abnormal lab value(s)           6 (1.1)     3 (0.6)      4 (0.7)

  abnormal procedure              0 (0.0)     2 (0.4)      2 (0.4)

  unsat. therap. effect           18 (3.2)    18 (3.4)     22 (4.0)

  cond. no longer required study  6 (1.1)     7 (1.3)      8 (1.4)
  drug                                                     

  protocol violation              6 (1.1)     4 (0.8)      4 (0.7)

  patient withdrew consent        46 (8.2)    44 (8.4)     54 (9.7)

  lost to follow-up               3 (0.5)     4 (0.8)      3 (0.5)

  administrative problems         7 (1.2)     2 (0.4)      6 (1.1)

  death                           61 (10.8)   56 (10.7)    64 (11.5)

  Source: Post-text tables 7.1-1                           
  and 7.1-3.                                               
  ------------------------------- ----------- ------------ ---------------

Reasons for discontinuation were balanced among the study arms, with
three categories (adverse events, patient withdrawal of consent, and
death) each accounting for about 10% of the discontinuations in each
arm. Further reviewer examination of distribution of these reasons by
study arm and according to stratum (mylema, breast-chemo,
breast-hormone) did not find marked imbalances between study arms (NDA
volume 69, p 723). The Zol 8 arm showed a higher rate of discontinuation
for adverse events in the myeloma stratum (12.5% for Zol8 versus about
5% in the other arms).

**Protocol Violations**

Assessment of study conduct is especially important for a
non-inferiority trial. The following presents the reviewer analysis of
electronic data on protocol violations. 825 protocol violations are
listed, with about the same number of violations for the zoledronate 4mg
and placebo arms (298 and 287 respectively).

[Zol 4 mg]{.underline} [Zol 8 mg]{.underline} [Pam]{.underline}

Breast Chemo 96 86 95

Breast Hormonal 122 94 109

Myelma 80 60 83

The median number of violations per study site was 0.44 per patient
entered and the median number of patients with a violation per site was
0.5 per patient entered.

In the breast cancer chemotherapy stratum, about 30 patients in each arm
were not receiving chemotherapy at the time of study entry. About 30
patients in each arm missed one dose of biphosphonate during the first 3
months. About 10 patients in each arm were randomized in the wrong
stratum. There were a variety of other infrequent deviations from
protocol.

In the breast cancer hormone treatment stratum, about 35 patients on the
Zom 4 arm and 21 patients on the placebo arm were not receiving hormone
therapy at study entry. The other frequent violation, missing a dose in
the first 3 months, was noted in 23 patients on Zom 4 and 22 on placebo.

In the myeloma stratum 31 patients were not on chemotherapy in the Zom 4
arm compared to 28 patients on placebo. 23 patients missed a
biphosphonate dose in the first 3 months in the Zom 4 arm compared to 23
on placebo.

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

*The nature and frequency of these protocol violations seem unlikely to
significantly affect analyses of efficacy or safety.*

**Baseline Demographic and Disease Factors**

When evaluating the validity of any randomized trial, one should compare
baseline prognostic factors among study arms. An equally important
question in non-inferiority studies is whether the current study
population is sufficiently similar to the historical population in whom
the efficacy of the active control (pamidronate) was established. This
latter issue will be addressed in later sections of the review.

The following tables from the study report describe the demographic
factors common to all three strata:

![](media/image6.png)Additional tables in the NDA submission evaluated
these factors by stratum. The median age in each stratum was 54 y for
Breast-Chemo, 59 y for Breast -Horm, and 62 y for Myeloma.

Baseline disease characteristics for the myeloma patients are outlined
in the following table from the application:

**Baseline Disease Characteristics in Myeloma**

![](media/image7.png){width="5.658333333333333in" height="2.25in"}

As noted above, most patients were recently diagnosed; the median time
from diagnosis to randomization was less than 3 months.

The following table summarizes the Applicant\'s evaluation of baseline
disease characteristics of patients in the two breast cancer strata
combined:

The Applicant evaluated together the disease characteristics of patients
in the two breast cancer strata as documented in the following table
from the submission:

**Baseline Disease Characteristics in Breast Cancer**

![](media/image8.png)

In addition to these Applicant analyses of baseline factors according to
the combined breast cancer strata, the following are reviewer analyses
of important factors by stratum:

**Percent patients with a prior SRE:**

[STRATUM]{.underline} [Zol 4]{.underline} [Pam]{.underline}

Breast-Chemo 85% 81%

Breast-Horm 61% 64%

**Percent patients receiving first-line chemotherapy:**

[STRATUM]{.underline} [Zol 4]{.underline} [Pam]{.underline}

Breast-Chemo 50% 47%

Breast-Horm 37% 47%

**Time since initial diagnosis of breast cancer:**

[STRATUM]{.underline} [Zol 4]{.underline} [Pam]{.underline}

Breast-Chemo 51 mo 51 mo

Breast-Horm 64 mo 62 mo

Finally, symptom findings combined from all three strata
(breast-chemotherapy, breast-hormonal, myeloma) at baseline are
summarized in the following table from the application:

  ---------------------- ----------------- ---------------- --------------
  **Baseline quality of                                     
  life variables by                                         
  treatment group**                                         

                                                            

                         **Zol 4 mg**      **Zol 8/4 mg**   **Aredia 90
                                                            mg**

                         **N=563**         **N=524**        **N=556**

  **ECOG status - n                                         
  (%)**                                                     

  **ECOG 0-1**           476 (84.5)        429 (81.9)       437 (78.6)

  **ECOG  2**           86 (15.3)         94 (17.9)        116 (20.9)

  **Missing**            1 (0.2)           1 (0.2)          3 (0.5)

  **Analgesic score -- n                                    
  (%)**                                                     

  **0**                  133 (23.6)        107 (20.4)       133 (23.9)

  **1**                  125 (22.2)        124 (23.7)       120 (21.6)

  **2**                  31 (5.5)          29 (5.5)         31 (5.6)

  **3**                  161 (28.6)        159 (30.3)       146 (26.3)

  **4**                  113 (20.1)        105 (20.0)       125 (22.5)

  **Missing**            0 (0.0)           0 (0.0)          1 (0.2)

  **BPI composite pain                                      
  score**                                                   

  **n**                  506               479              506

  **Median**             3.0               3.0              2.8

  **FACT-G total score**                                    

  **n**                  496               467              499

  **Median**             76.0              75.0             77.2

  **Source: Post-text                                       
  table 7.4-1.**                                            
  ---------------------- ----------------- ---------------- --------------

The reviewer evaluated several factors by disease (stratum):

**Percent patients with ECOG \>=2:**

[Zol 4]{.underline} [Pam]{.underline}

Myeloma Stratum 20% 27%

Breast-Chemo Stratum 14% 19%

Breast-Horm Stratum 11% 17%

**Median Analgesia Score:**

[STRATUM]{.underline} [Zol 4]{.underline} [Pam]{.underline}

Myeloma 25 29

Breast-Chemo 20 21

Breast-Horm 25 22

**Median BPI composite pain score:**

[STRATUM]{.underline} [Zol 4]{.underline} [Pam]{.underline}

Myeloma 3 2.8

Breast-Chemo 2.9 3.1

Breast-Horm 3.0 3.0

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

*In each of the strata, there 3 to7% more poor performance status
patients in the Pam arm than in the Zol 4 mg arm. Other than this, the
sponsor\'s evaluation of a large number of potential prognostic factors
according to arm and stratum did not reveal any major imbalance of
apparent relevance to efficacy analysis.*

Novartis did not present an analysis of the extent of bone disease at
baseline, a potential prognostic factor for the occurrence of an SRE.
The following tables present results from reviewer analyses of bone scan
and skeletal survey data. Again, the factors appear balanced in the most
relevant study arms (Pam and Zom 4) for each stratum.

**\# Lesions on bone scan per patient (median, mean)**

**Stratum Zol 4 Pam**

Breast-Chemo 5, 5.36 5, 5.24

Breast-Hormone 5., 5.08 5, 5.04

**\# Lesions on plain film per patient**

**Stratum Zom 4 Pam**

Breast-Chemo 4, 4.31 4, 4.39

Breast-Hormones Median 4, 4.10 4, 4.26

Myeloma 5, 4.92 4, 4.75

\% Patients with 1 or less lesions on skeletal survey

  --------------------------------------- --------------- ----------------
  **Stratum**                             **Zom 4**       **Pam**

  **Breast cancer with chemotherapy**     13% (23/179)    12% (30/183)

  **Breast cancer with hormonal therapy** 11% (22/201)    14% (30/208)

  **Multiple myeloma**                    11% (20/184)    7% (12/167)
  --------------------------------------- --------------- ----------------

  --------------------------------------- --------------- ----------------
  **% Patients with 2 or less lesions on                  
  skeletal survey**                                       

  **STRATUM**                             **Zom 4**       **Pam**

  Breast cancer with chemotherapy         27% (49/179)    27% (49/183)

  Breast cancer with hormonal therapy     30% (60/201)    28% (58/208)

  Multiple myeloma                        20% (36/184)    20% (33/167)
  --------------------------------------- --------------- ----------------

A potentially important factor not evaluated in the Novartis study
report was whether patients had lytic bone lesions at baseline. Entry
criteria for the historical Aredia breast cancer studies (which
established the efficacy of Aredia versus placebo) required at least one
lytic bone lesion. The following table presents the results of the
reviewer analysis how many patiens in each stratum had at least one
baseline lytic lesion in Study #010

**Number of patients with at least one lytic lesion at baseline**

  ------------------------------------- ---------------- -----------------
  **Stratum**                           **Patients with  
                                        lytic lesions    
                                        (N,%)**          

  Treatment Arm                         Zometa 4mg       Aredia

  Breast Cancer (Chemo)                 89/179 (50%)     74/183 (40%)

  Breast Cancer (Hormone)               101/201 (50%)    90/208 (43%)

  Myeloma                               174/184 (95%)    149/167 (89%)
  ------------------------------------- ---------------- -----------------

\*Analysis used dataset BONE2, element TYPCODE where 1= lytic

There does seem to be a slight imbalance with 7 to 10% more patients
with at least one baseline lytic bone lesion on Zom 4 than on Aredia.
The presence of a baseline lytic lesion also appears to be an adverse
prognostic factor in this trial, as the following analysis shows that
52% of patients with a lytic lesion subsequently had an SRE compared to
37% without.

Proportion of Patients with SRE according to presence or absence of
baseline lytic bone lesion

  ------------------- ---------------------------------------------------
  **Baseline Lytic    **Proportion of Breast Cancer Patients with SRE
  event?**            During Study**

  NO                  226/605 (37%)

  YES                 275/531 (52%)
  ------------------- ---------------------------------------------------

Another potential prognostic factor is antineoplastic treatment
received. FDA asked Novartis to evaluate the starting therapy on the two
arms. The following are the most common baseline antineoplastic agents
on each arm at baseline:

+----------------------------+-----------------------+--------+-------+
| **STRATUM**                | **ANTINEOPLASTIC      | **Zol  | **Pam |
|                            | AGENT**               | 4      | (%)** |
|                            |                       | (%)**  |       |
+============================+=======================+========+=======+
| Multiple myeloma           | MELPHALAN             | 34     | 40    |
+----------------------------+-----------------------+--------+-------+
|                            | DEXAMETHASONE         | 33     | 23    |
+----------------------------+-----------------------+--------+-------+
|                            | DOXORUBICIN           | 29     | 26    |
+----------------------------+-----------------------+--------+-------+
|                            | PREDNISONE            | 28     | 37    |
+----------------------------+-----------------------+--------+-------+
|                            | VINCRISTINE           | 24     | 23    |
+----------------------------+-----------------------+--------+-------+
|                            |                       |        |       |
+----------------------------+-----------------------+--------+-------+
| Breast cancer with         | PACLITAXEL            | 37     | 35    |
| chemotherapy               |                       |        |       |
+----------------------------+-----------------------+--------+-------+
|                            | DOCETAXEL             | 31     | 39    |
+----------------------------+-----------------------+--------+-------+
|                            | CYCLOPHOSPHAMIDE      | 30     | 31    |
+----------------------------+-----------------------+--------+-------+
|                            | DOXORUBICIN           | 28     | 27    |
+----------------------------+-----------------------+--------+-------+
|                            | FLUOROURACIL          | 25     | 25    |
+----------------------------+-----------------------+--------+-------+
|                            | TRASTUZUMAB           | 22     | 17    |
+----------------------------+-----------------------+--------+-------+
|                            |                       |        |       |
+----------------------------+-----------------------+--------+-------+
| Breast cancer with         | ANASTROZOLE           | 37     | 27    |
|                            |                       |        |       |
| hormonal therapy           |                       |        |       |
+----------------------------+-----------------------+--------+-------+
|                            |                       |        |       |
+----------------------------+-----------------------+--------+-------+
|                            | TAMOXIFEN             | 30     | 36    |
+----------------------------+-----------------------+--------+-------+
|                            | LETROZOLE             | 10     | 14    |
+----------------------------+-----------------------+--------+-------+

**Medication Received**

The mean duration of treatment was about 10 months for patients in all
three strata and was similar in the study arms.

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

*Multiple comparisons of the study arms for baseline demographic and
disease factors demonstrate no critical imbalances. A few more patients
with poor performance status and a few more breast cancer patients with
lytic lesions were entered on the Zol 4mg arm than on pamidronate.*

Results of Study #010, Primary Efficacy Analysis: Non-inferiority
Comparison of Proportions of Patients with an SRE, Zoledronate 4mg
versus Pamidronate

The goal of Study 010 was to demonstrate that Zoledronate is effective
by comparing the proportion of zoledronate-treated patients to the
proportion of pamidronate-treated patients suffering an SRE during the
study. This non-inferiority comparison depends upon historical knowledge
of the treatment effect of pamidronate, i.e., the historical value of
the event rate of placebo minus pamidronate. One must show that
conditions and study populations of the historical trial, which
demonstrated pamidronate efficacy, are similar to the current trial,
which is comparing efficacy outcomes of zoledronate and pamidronate.
Statistical tests are then performed to assure us that the new drug,
zoledronate, retains, with confidence, an acceptable amount of the
pamidronate treatment effect.

The ideal methodology for performing non-inferiority analyses is a topic
of statistical research and is widely discussed in academic and
regulatory settings. The Applicant and FDA present different analyses,
but they both conclude that the zoledronate 4mg arm is effective in
decreasing the proportion of patients suffering an SRE. The Applicant\'s
prospective analysis uses methodology that is no longer accepted by FDA.
In that analysis, the historical pamidronate effect size is calculated
using \"point estimates.\" Current FDA thinking considers also the
probability that the effect size is correctly estimated, and the FDA
analysis uses 95% confidence intervals to estimate the original effect
size.

> The review sections below present the Applicant\'s results, the FDA
> results, and a comprehensive comparison of the historical
> pamidronate-versus-placebo study and the current
> zoledronate-versus-pamidronate study.
>
> **Applicant\'s Primary Analysis of Efficacy**

The following table displays the Applicant\'s findings for the
proportion of patients having at least one SRE, the primary endpoint of
the study:

![](media/image9.png){width="6.3in" height="4.485416666666667in"}

The Applicant notes that in the overall analysis comparing Zol 4 to
Aredia, 46% of the Aredia patients had an SRE compared to 44% on Zol 4,
and that the 95% confidence interval of the difference excluded Zol 4
being 3.7% worse (more patients with events) than Aredia. Because the
goal was to exclude being 8% worse, the Applicant claims that
non-inferiority of Zol 4 with respect to Aredia has been demonstrated.
Further, the Applicant notes that results were similar in the per
protocol (PP) analysis (48% on Aredia, 47% on Zol 4, with upper 95% ci =
5%).

The Applicant also performed an analysis stratified by performance
status (ECOG = 0-1 vs. \>1) which gave upper 95% ci = 5%. By all
analyses, the Applicant notes that the non-inferiority goal of 8% was
met.

**FDA\'s Primary Analysis of Efficacy**

FDA analyses also demonstrate non-inferiority of Zometa to Aredia in the
proportion of patients with an SRE during Study 010 and are described in
more detail in the FDA statistical review. The following table describes
the treatment effect estimated from the historical trials of pamidronate
versus placebo.

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

+-------------+-----------+-----------+-----------------+------------+
|             | **        | *         | **Difference    | **p        |
|             | Placebo** | *Aredia** | ∆**             | -value\*** |
|             |           |           |                 |            |
|             |           |           | **(95% CI)\***  |            |
+-------------+-----------+-----------+-----------------+------------+
| 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 %) |            |
+-------------+-----------+-----------+-----------------+------------+
| ##### Tota  | 52.0%     | 38.9%     | 13.1%           | \<0.0001   |
| l {#total . |           |           |                 |            |
| unnumbered} | (293/563) | (220/565) | (7.3%, 18.9%)   | OR=1.702   |
+-------------+-----------+-----------+-----------------+------------+

Combining the data from the historical trials, the point estimate of
effect is 13.1%, but the 95% confidence intervals allow us to determine
with confidence that the effect size is at least **7.3%.**

Recall the results of the proportions analysis of the combined strata of
Study 010 comparing zoledronate 4mg and pamidronate:

+--------+----------------+-------------+------------------+----------+
|        | **             | **Aredia**  | **Difference ∆** | **p      |
|        | Zoledtronate** |             |                  | -value** |
|        |                |             | **(95% CI)**     |          |
|        | **(4mg)**      |             |                  |          |
+--------+----------------+-------------+------------------+----------+
| ####   | 44%            | 46%         | -2%              | 0.461    |
| # Tota |                |             |                  |          |
| l {#to | (248/561)      | (257/555)   | (-7.9%, 3.7%)    |          |
| tal-1  |                |             |                  |          |
| .unnum |                |             |                  |          |
| bered} |                |             |                  |          |
+--------+----------------+-------------+------------------+----------+

95% confidence intervals of the difference of the difference between the
zoledronate and pamidronate exclude a difference of **3.7%** or greater.
The preservation of active treatment effect using the SRE rates can be
determined by (7.3%-3.7%)/7.3%=49.3%. Hence, using conservative
methodology (the \"two-95% confidence limit method\") the current trial
demonstrated a 49.3% retention of Aredia vs. placebo effect .

Results of Study #010, Primary Efficacy Analysis: FDA Evaluation of
Design Assumptions for Analysis of the Primary Efficacy Endpoint

When designing a non-inferiority study, we make a critical assumption,
*the constant assumption*, a determination that the active control drug
(pamidronate) would have shown efficacy in the new study or current
setting. While we cannot directly test this assumption, we can compare
the historical and current study populations, study design, and study
conduct. The Applicant\'s initial submission did not provide sufficient
information or analyses to support the *constant assumption*. During the
course of the NDA review, at the reviewer\'s request, the Applicant
submitted a thorough analysis that compared the designs and populations
of the historical Aredia trials and the Zometa trials (submission dated
November 27, 2001) and provided electronic data sets from the Aredia
trials. This section describes results from analyses requested or
performed by the reviewer to evaluate the constant assumption.

**Reviewer Approach to Comparing Historical and NDA Trials:**

The reviewer\'s goal was to determine that the NDA Zometa clinical trial
setting was sufficiently similar to the historical pamidronate clinical
trial setting so that, were placebo substituted for Zometa, the
pamidronate treatment effect versus placebo would be fully apparent.
Considerations include:

-   Evaluating whether historical and NDA populations were similarly
    responsive to pamidronate.

-   Determing whether trial design and conduct would allow detection of
    the pamidronate effect. One difference between a \"superiority
    trial\" and a \"non-inferiority trial\" are the potential
    ramifications of poor study conduct. Sloppiness, which hides
    differences between treatment arms, generally makes superiority more
    difficult to detect, but sloppiness assist a claim of
    non-inferiority. Evaluation of the design and conduct of the study
    is one approach to addressing this issue. A second is to perform a
    per protocol (PP) analysis as the Applicant has done. The PP
    analysis excludes data of questionable utility which could obscure
    differences between study arms.

**Comparison of baseline factors in historical trials of Aredia versus
placebo and NDA trials of Zometa versus Aredia**

The following are three Applicant tables comparing baseline factors in
historical Aredia trials with the corresponding strata of the Zometa NDA
trials (from the submission of 11/27/01). \"Protocol 12\" was the Aredia
myeloma trial, \"Protocol 18\" was the Aredia breast cancer trial in
patients receiving hormonal therapy, and \"Protocol 19\" was the Aredia
breast cancer trial in patients receiving chemotherapy. I have added
bold type to factors showing a major difference between the Aredia NDA
trials and the Zometa NDA trials.

###### Summary of demographic and prognostic variables for multiple myeloma patients from Aredia 12 and Zometa 010 {#summary-of-demographic-and-prognostic-variables-for-multiple-myeloma-patients-from-aredia-12-and-zometa-010 .unnumbered}

  ------------------ ----------- ----------- ----------- ----------- -----------
                     **Aredia                **Zometa                
                     study 12**              study 010**             

  **Demographic/\    **Aredia\   **\         **Aredia\   **Zometa\   **Zometa\
  Prog.variables**   90 mg**     Placebo**   90 mg**     4 mg**      8/4 mg**

  Number of patients 198 (100%)  179 (100%)  167 (100%)  183 (100%)  160 (100%)

  Sex                                                                

  Male               110 (55.6%) 107 (59.8%) 91 (54.5%)  103 (56.3%) 92 (57.5%)

  Female             88 (44.4%)  72 (40.2%)  76 (45.5%)  80 (43.7%)  68 (42.5%)

  Age (yrs)                                                          

  Mean ± s.d.        64.1 ± 9.4  62.7 ± 10.1 62.6 ±      63.1 ±      62.2 ±
                                             11.41       10.52       11.37

  Median             66.0        63.0        62.0        62.0        63.0

  ECOG                                                               

  0 - 1              141 (71.2%) 126 (70.4%) 120 (71.9%) 146 (79.8%) 117 (73.1%)

  ≥ 2                57 (28.8%)  53 (29.6%)  46 (27.5%)  37 (20.2%)  43 (26.9%)

  Missing            N/C         N/C         1 (0.6%)    0 (0.0%)    0 (0.0%)

  Myeloma Subtype                                                    

  IgA                28 (14.1%)  43 (24.0%)  31 (18.6%)  25 (13.7%)  41 (25.6%)

  IgG                113 (57.1%) 83 (46.4%)  100 (59.9%) 115 (62.8%) 83 (51.9%)

  Light Chain        42 (21.2%)  46 (25.7%)  28 (16.7%)  32 (17.5%)  27 (16.9%)

  Other              15 (7.6%)   7 (3.9%)    7 (4.2%)    10 (5.5%)   5 (3.1%)

  Time from Init                                                     
  Diag of Cancer to                                                  
  Visit 2                                                            

  Mean ± s.d.        30.5 ± 32.2 27.7 ± 33.5 17.3 ±      18.0 ±      13.5 ±
                                             28.62       32.24       21.75

  Median (mo.)       19.3        14.4        2.7         2.8         2.6

  Prior type of                                                      
  therapy                                                            

  Chemo              152 (76.8%) 139 (77.7%) 156 (93.4%) 169 (92.3%) 147 (91.9%)

  Other              46 (23.2%)  40 (22.4%)  11 (6.6%)   14 (7.7%)   13 (8.1%)

  Previous SRE\*                                                     

  Yes                63 (31.8%)  54 (30.2%)  135 (80.8%) 149 (81.4%) 128 (80.0%)

  No                 135 (68.2%) 125 (69.8%) 31 (18.6%)  34 (18.6%)  31 (19.4%)

  Missing            N/C         N/C         1 (0.6%)    0 (0.0%)    1 (0.6%)
  ------------------ ----------- ----------- ----------- ----------- -----------

N/C: Not collected

Summary of demographic and prognostic variables for breast cancer
patients with hormonal therapy from Aredia 18 and Zometa 010

  ----------------- ----------- ----------- ----------- ----------- -----------
                    **Aredia                **Zometa                
                    study 18**              study 010**             

  **Demographic/\   **Aredia\   **\         **Aredia\   **Zometa\   **Zometa\
  Prog. variables** 90 mg**     Placebo**   90 mg**     4 mg**      8/4 mg**

                                                                    

  Number of         182 (100%)  189 (100%)  207 (100%)  200 (100%)  192 (100%)
  patients                                                          

  Sex                                                               

  Male              N/C         N/C         0 (0.0%)    0 (0.0%)    0 (0.0%)

  Female            N/C         N/C         207 (100%)  200 (100%)  192 (100%)

  Age (yrs)                                                         

  Mean ± s.d.       60 ± 12.0   62 ± 11.0   58.9 ±      59.9 ±      59.0 ±
                                            13.11       12.63       12.96

  Median            62          64          60.0        59.0        59.0

  ECOG                                                              

  0 -- 1            144 (79.1%) 139 (73.5%) 169 (81.6%) 177 (88.5%) 171 (89.1%)

  ≥ 2               38 (20.9%)  50 (26.5%)  36 (17.4%)  23 (11.5%)  21 (10.9%)

  Missing           N/C         N/C         2 (1.0%)    0 (0.0%)    0 (0.0%)

  Time from Init                                                    
  Diag of Cancer to                                                 
  Visit 2                                                           

  Mean ± s.d.       90.6 ± 73.1 82.1 ± 61.4 75.5 ±      82.3 ±      82.6 ±
                                            65.14       64.62       81.16

  Median (mo.)      75.3        71.9        62.6        63.5        62.6

  Time from bone                                                    
  mets to Visit 2                                                   

  Mean ± s.d.       25.6 ± 34.2 24.2 ± 26.7 11.2 ± 22.3 16.1 ± 26.3 13.7 ± 25.0

  Median (mo.)      13.0        14.9        3.2         4.4         4.1

  Prior type of                                                     
  therapy                                                           

  Chemo             93 (51.1%)  95 (50.3%)  127 (61.4%) 115 (57.5%) 100 (52.1%)

  Other             89 (48.9%)  94 (49.7%)  80 (38.6%)  85 (42.5%)  92 (47.9%)

  Previous SRE\*                                                    

  Yes               46 (25.3%)  57 (30.2%)  132 (63.8%) 123 (61.5%) 110 (57.3%)

  No                136 (74.7%) 132 (69.8%) 75 (36.2%)  77 (38.5%)  81 (42.2%)

  Missing           N/C         N/C         0 (0.0%)    0 (0.0%)    1 (0.5%)
  ----------------- ----------- ----------- ----------- ----------- -----------

N/C: Not collected

###### Summary of demographic and prognostic variables for breast cancer patients with chemotherapy therapy from Aredia 19 and Zometa 010 {#summary-of-demographic-and-prognostic-variables-for-breast-cancer-patients-with-chemotherapy-therapy-from-aredia-19-and-zometa-010 .unnumbered}

+--------------+----------+----------+----------+----------+----------+
|              | **Aredia |          | **Zometa |          |          |
|              | study    |          | study    |          |          |
|              | 19**     |          | 010**    |          |          |
+--------------+----------+----------+----------+----------+----------+
| **D          | *        | **\      | *        | *        | *        |
| emographic/\ | *Aredia\ | P        | *Aredia\ | *Zometa\ | *Zometa\ |
| Prog.        | 90 mg**  | lacebo** | 90 mg**  | 4 mg**   | 8/4 mg** |
| variables**  |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Number of    | 185      | 195      | 181      | 178      | 172      |
| patients     | (100%)   | (100%)   | (100%)   | (100%)   | (100%)   |
+--------------+----------+----------+----------+----------+----------+
| Sex          |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Male         | N/C      | N/C      | 1 (0.6%) | 1 (0.6%) | 4 (2.3%) |
+--------------+----------+----------+----------+----------+----------+
| Female       | N/C      | N/C      | 180      | 177      | 168      |
|              |          |          | (99.4%)  | (99.4%)  | (97.7%)  |
+--------------+----------+----------+----------+----------+----------+
| Age (yrs)    |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Mean ± s.d.  | 57 ± 12  | 56 ± 12  | 54.9 ±   | 56.0 ±   | 55.8 ±   |
|              |          |          | 12.15    | 11.68    | 11.70    |
+--------------+----------+----------+----------+----------+----------+
| Median       | 58       | 56       | 54.0     | 54.5     | 57.0     |
+--------------+----------+----------+----------+----------+----------+
| ECOG         |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| 0 - 1        | 121      | 128      | 147      | 151      | 140      |
|              | (65.4%)  | (65.6%)  | (81.2%)  | (84.8%)  | (81.4%)  |
+--------------+----------+----------+----------+----------+----------+
| ≥ 2          | 64       | 67       | 34       | 26       | 31       |
|              | (34.6%)  | (34.4%)  | (18.8%)  | (14.6%)  | (18.0%)  |
+--------------+----------+----------+----------+----------+----------+
| Missing      | N/C      | N/C      | 0 (0.0%) | 1 (0.6%) | 1 (0.6%) |
+--------------+----------+----------+----------+----------+----------+
| Time from    |          |          |          |          |          |
| Init Diag of |          |          |          |          |          |
| Cancer to    |          |          |          |          |          |
| Visit 2      |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Mean ± s.d.  | 80.9 ±   | 71.0 ±   | 65.9 ±   | 73.8 ±   | 73.7 ±   |
|              | 71.6     | 66.3     | 57.73    | 69.72    | 67.31    |
+--------------+----------+----------+----------+----------+----------+
| Median (mo.) | 60.6     | 53.0     | 49.7     | 51.3     | 51.0     |
+--------------+----------+----------+----------+----------+----------+
| Time from    |          |          |          |          |          |
| bone mets to |          |          |          |          |          |
| Visit 2      |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Mean ± s.d.  | 24.8 ±   | 21.1 ±   | 13.8 ±   | 18.8 ±   | 14.4 ±   |
|              | 32.6     | 22.4     | 20.0     | 40.7     | 20.5     |
+--------------+----------+----------+----------+----------+----------+
| Median (mo.) | 12.3     | 14.6     | 4.2      | 3.6      | 4.5      |
+--------------+----------+----------+----------+----------+----------+
| Prior type   |          |          |          |          |          |
| of therapy   |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Chemo        | 175      | 189      | 174      | 173      | 166      |
|              | (94.6%)  | (96.9%)  | (96.1%)  | (97.2%)  | (96.5%)  |
+--------------+----------+----------+----------+----------+----------+
| Hormonal     | 10       | 6 (3.1%) | 7 (3.9%) | 5 (2.8%) | 6 (3.5%) |
|              | (5.4%)   |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Previous     |          |          |          |          |          |
| SRE\*        |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Yes          | 61       | 80       | 112      | 109      | 96       |
|              | (32.9%)  | (41.0%)  | (61.9%)  | (61.2%)  | (55.8%)  |
+--------------+----------+----------+----------+----------+----------+
| No           | 124      | 115      | 68       | 68       | 76       |
|              | (67.0%)  | (58.9%)  | (37.6%)  | (38.2%)  | (44.2%)  |
+--------------+----------+----------+----------+----------+----------+
| > Missing    | N/C      | N/C      | 1 (0.6%) | 1 (0.6%) | 0 (0.0%) |
+--------------+----------+----------+----------+----------+----------+

N/C: Not collected

The reviewer notes three major differences between the populations in
the historical Aredia trials and the Zometa NDA trials. These are listed
below and then discussed in subsequent sections:

-   Time since diagnosis of bone metastases (or time since diagnosis of
    myeloma which usually would include a bone lesion) was shorter for
    the Zometa NDA trial.

-   More patients gave a history of a previous SRE in the Zometa NDA
    trial.

-   Lytic bone lesions were present in all breast cancer patients in the
    Aredia trials compared to only about half of the breast cancer
    patients in Zometa trial.

The concern raised by these differences is whether biphosphonates have
demonstrable efficacy in the subpopulations over-represented in the
Zometa NDA trial. If the Applicant demonstrates that Zometa is no
different from Aredia in a setting where Aredia does not work , this
proves nothing about the efficacy of Zometa. To evaluate the
appropriateness of including these subpopulations in the Zometa trials,
the reviewer performed the following exploratory subgroup analyses of
efficacy with data from Aredia NDA. The purpose was to evaluate whether
the Aredia effect (versus placebo) in these subgroups was at least
similar to that in the overall study population where Aredia efficacy
was established.

**Time Since Diagnosis of Bone Metastases**

The striking difference between the Aredia trials and the Zometa trial
in time since diagnosis of myeloma (and hence time since diagnosis of
bone metastasis) was evaluated in the following subgroup analysis of
patients diagnosed within 6 months of study entry (similar to the Zometa
trial population). Although numbers were small, benefit of Aredia is
suggested in this subgroup with 23% more placebo patients than Aredia
patients having an SRE.

  -------------------- ----------------------- ---------------------------
  **Proportion of                              
  Myeloma Patients                             
  with SRE versus Time                         
  Since Diagnosis**                            

                       **Time since            
                       diagnosis**             

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

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

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

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

**History of Previous SRE**

The number of patients with a history of a previous SRE at baseline was
also different between the Aredia and Zometa NDA studies. However, as
the Applicant notes, the findings were counterintuitive...time since
diagnosis was longer in the Aredia trials yet history of an SRE was much
less common. This apparent difference may stem from differences in the
way data was collected. In the Aredia trials as history of SREs was
solicited only for the three months prior to entry whereas in the Zometa
trial a history of SRE was solicited for the prior year. Nevertheless,
the Aredia data were evaluated to determine whether patients with a
prior history of an SRE appeared to derive benefit from Aredia.

  -------------------- ----------------------- ---------------------------
  **Proportion of                              
  Myeloma Patients                             
  with SRE versus                              
  History of Previous                          
  SRE**                                        

                       **History of SRE in     
                       previous 3 months**     

                       **Yes**                 **No**

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

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

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

This analysis suggests that patients in the Aredia myeloma trial with a
history of a recent SRE were more likely to have a subsequent SRE and
were also at least as likely to derive benefit from Aredia.

**Lytic bone lesions at baseline**

In the studies comparing Aredia to placebo, inclusion criteria required
at least one lytic bone lesion whereas the Zometa 010 trial allowed
lytic or blastic lesions. As noted in a prior section of this review,
about half of the breast cancer patient in Study 010 had no baseline
lytic bone lesions. Is it possible that biphosphonates are effective
only in patients with lytic lesions? If so, the breast cancer strata of
Study 010 are grossly underpowered for comparing Zometa 4 mg and Aredia.

Two lines of evidence suggest that inclusion of breast cancer patients
with non-lytic (blastic and \"mixed\") lesions is appropriate.

First, in subsets of Study 010 patients with baseline lytic bone
lesions, the Zom 4 event rate is similar to the Aredia event rate:

-   As discussed above, in the myeloma stratum of Study 010, where 95%
    of patients had lytic lesions, 49% of the Aredia arm had an event
    compared to 47% in the Zom 4 arm.

-   The following reviewer exploratory subset analysis of the breast
    cancer strata of Study 010 shows no trend toward more SRE events
    occuring with Zom 4 relative to Aredia in patients with baseline
    lytic lesions; in fact, a trend in the opposite direction is
    suggested. (bolded):

**Proportion of Patients in Zometa study 010 with an event, according to
whether lytic bone lesion was present at baseline\***

  -------------------- ------------- ------- ------------ ----------- ----------
                                             **#(%) of                
                                             Patients                 
                                             with SRE**               

  **Stratum**          **Lytic       **\#    **Aredia**   **Zom 4**   **Zom 8**
                       Lesion at     pts**                            
                       baseline?**                                    

  Breast cancer with   No            284     37/109 (34%) 35/90 (39%) 34/85
  chemotherapy                                                        (40%)

                       Yes           251     **42/74      **44/89     46/88
                                             (57%)**      (49%)**     (52%)

  Breast cancer with   No            321     44/118 (37%) 36/100      40/103
  hormonal therapy                                        (36%)       (39%)

                       Yes           280     **53/90      **47/101    43/89
                                             (59%)**      (47%)**     (48%)
  -------------------- ------------- ------- ------------ ----------- ----------

**\***(Analysis used dataset BONE2, element TYPCODE where 1= lytic)

Other data supports the claim that Zometa can be effective in blastic
cancer metastases. Zometa Study 039 in prostate cancer, a different
disease setting where essentially all patients have blastic disease,
demonstrates that Zometa can be effective in decreasing SREs in patients
with blastic metastases.

**Comparison of type of SREs Between Aredia Trials and the Zometa
Trial**

Because the primary endpoint of the 010 trial is a composite endpoint
(SRE), thorough comparison of the Zometa NDA Study 010 and the Aredia
NDA studies includes comparison of the specific events observed. The
reviewer\'s concern may be expressed by the following worst-case
theoretical scenario:

> Imagine that a composite endpoint (EP) consists of elements A and B.
> An event consists of an occurrence of either A or B. Aredia efficacy
> is shown by a decrease of EP on Aredia relative to placebo, and this
> is predominantly due to an advantage in decreasing type A events.
> Zometa is then compared to Aredia, and shows non-inferiority for the
> EP composite endpoint. However, in the Zometa trial, there are mostly
> B events. With this scenario, although the Zometa EP rate is identical
> to that of Aredia, Zometa has not been proven to be effective...
> without inclusion of \"A\" events, we cannot assume that the efficacy
> of Zometa with respect to Aredia has been tested.

In the Aredia NDA trials and the Zometa Study 010, the most frequent SRE
events were *radiotherapy to bone* and *pathological fractures*. The
following displays the effect of Aredia on these events and compares the
frequency of these events in the corresponding trials/strata.

+---------+------------+---+--------+-----------+-----------+-----------+
| **Type  |            |   |        |           |           |           |
| of SRE  |            |   |        |           |           |           |
| in      |            |   |        |           |           |           |
| Trials  |            |   |        |           |           |           |
| of      |            |   |        |           |           |           |
| Aredia  |            |   |        |           |           |           |
| versus  |            |   |        |           |           |           |
| Placebo |            |   |        |           |           |           |
| and     |            |   |        |           |           |           |
| Zometa  |            |   |        |           |           |           |
| versus  |            |   |        |           |           |           |
| Are     |            |   |        |           |           |           |
| dia\*** |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
| *       | **Type of  | * |        |           | **D       |           |
| *Cancer | Event**    | * |        |           | ifference |           |
| Type**  |            | P |        |           | in        |           |
|         |            | r |        |           | Pr        |           |
|         |            | o |        |           | oportions |           |
|         |            | p |        |           | Compared  |           |
|         |            | o |        |           | to        |           |
|         |            | r |        |           | Control   |           |
|         |            | t |        |           | Arm**     |           |
|         |            | i |        |           |           |           |
|         |            | o |        |           |           |           |
|         |            | n |        |           |           |           |
|         |            | w |        |           |           |           |
|         |            | i |        |           |           |           |
|         |            | t |        |           |           |           |
|         |            | h |        |           |           |           |
|         |            | E |        |           |           |           |
|         |            | v |        |           |           |           |
|         |            | e |        |           |           |           |
|         |            | n |        |           |           |           |
|         |            | t |        |           |           |           |
|         |            | i |        |           |           |           |
|         |            | n |        |           |           |           |
|         |            | A |        |           |           |           |
|         |            | r |        |           |           |           |
|         |            | e |        |           |           |           |
|         |            | d |        |           |           |           |
|         |            | i |        |           |           |           |
|         |            | a |        |           |           |           |
|         |            | A |        |           |           |           |
|         |            | r |        |           |           |           |
|         |            | m |        |           |           |           |
|         |            | o |        |           |           |           |
|         |            | f |        |           |           |           |
|         |            | s |        |           |           |           |
|         |            | t |        |           |           |           |
|         |            | u |        |           |           |           |
|         |            | d |        |           |           |           |
|         |            | y |        |           |           |           |
|         |            | * |        |           |           |           |
|         |            | * |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         |            | * |        | **Zometa  | **Aredia  | **Zometa  |
|         |            | * |        | Study     | NDA       | Study     |
|         |            | A |        | 010**     | St        | 01        |
|         |            | r |        |           | udy\*\*** | 0\*\*\*** |
|         |            | e |        |           |           |           |
|         |            | d |        |           |           |           |
|         |            | i |        |           |           |           |
|         |            | a |        |           |           |           |
|         |            | N |        |           |           |           |
|         |            | D |        |           |           |           |
|         |            | A |        |           |           |           |
|         |            | S |        |           |           |           |
|         |            | t |        |           |           |           |
|         |            | u |        |           |           |           |
|         |            | d |        |           |           |           |
|         |            | y |        |           |           |           |
|         |            | * |        |           |           |           |
|         |            | * |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
| **My    | **Any      | 2 |        | 49%       | 16%       | 2%        |
| eloma** | SRE**      | 8 |        |           |           |           |
|         |            | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         | **-        | 2 |        | 42%       | 10%       | 2%        |
|         | F          | 2 |        |           |           |           |
|         | ractures** | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         | **- RT to  | 1 |        | 14%       | 12%       | -1%       |
|         | bone**     | 6 |        |           |           |           |
|         |            | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
| *       | **Any      | 4 |        | 47%       | 8%        | 5%        |
| *Breast | SRE**      | 7 |        |           |           |           |
| Cancer  |            | % |        |           |           |           |
| (Hor    |            |   |        |           |           |           |
| mone)** |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         | **-        | 3 |        | 34%       | 8%        | 3%        |
|         | F          | 6 |        |           |           |           |
|         | ractures** | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         | **- RT to  | 2 |        | 25%       | 12%       | 9%        |
|         | bone**     | 1 |        |           |           |           |
|         |            | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
| **B     | **Any      | 4 |        | 43%       | 13%       | -1%       |
| reast** | SRE**      | 3 |        |           |           |           |
|         |            | % |        |           |           |           |
| **C     |            |   |        |           |           |           |
| ancer** |            |   |        |           |           |           |
|         |            |   |        |           |           |           |
| **(C    |            |   |        |           |           |           |
| hemo)** |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         | **-        | 3 |        | 34%       | 5%        | -3%       |
|         | F          | 4 |        |           |           |           |
|         | ractures** | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
|         | **- RT to  | 1 |        | 20%       | 14%       | 5%        |
|         | bone**     | 9 |        |           |           |           |
|         |            | % |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
| \*      |            |   |        |           |           |           |
| Derived |            |   |        |           |           |           |
| pr      |            |   |        |           |           |           |
| imarily |            |   |        |           |           |           |
| from    |            |   |        |           |           |           |
| tables  |            |   |        |           |           |           |
| in the  |            |   |        |           |           |           |
| 1       |            |   |        |           |           |           |
| 1/27/01 |            |   |        |           |           |           |
| sub     |            |   |        |           |           |           |
| mission |            |   |        |           |           |           |
|         |            |   |        |           |           |           |
| \*\*    |            |   |        |           |           |           |
| Placebo |            |   |        |           |           |           |
| minus   |            |   |        |           |           |           |
| Aredia  |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+
| \*\*\*  |            |   |        |           |           |           |
| Aredia  |            |   |        |           |           |           |
| minus   |            |   |        |           |           |           |
| Zol 4   |            |   |        |           |           |           |
+---------+------------+---+--------+-----------+-----------+-----------+

Examination of this table demonstrates that reviewer worst-case scenario
described above does not apply to these trials. The Aredia benefit
versus placebo was apparent in both major types of SREs (RT to bone and
fractures) and both types of events were well represented in the Zometa
NDA Study 010.

**Results of Study #010, Secondary Efficacy Analyses**

**Time to occurrence of an SRE**

Time to first SRE was similar on Zom 4 and Aredia arms by both the
Applicant\'s analysis and the FDA\'s analysis. Results from the FDA
statistical review are displayed in the following table and Figure.

Time to first SRE by stratum and treatment arm

+-----------+-----+--------------+--------------------------+---------+
|           | **  | **Median**   | **Hazard Ratio (95%      | **p-va  |
|           | N** |              | CI)**                    | lue\*** |
|           |     | **(95%CI)**  |                          |         |
+-----------+-----+--------------+--------------------------+---------+
| Myeloma   | 167 | 301(191,     | .97(.71, 1.31)           | 0.82    |
|           |     | \-\--)       |                          |         |
| ##### A   | 183 |              |                          |         |
| redia {#a |     | 372(225,     |                          |         |
| redia .un |     | 504)         |                          |         |
| numbered} |     |              |                          |         |
|           |     |              |                          |         |
| Zol 4 mg  |     |              |                          |         |
+-----------+-----+--------------+--------------------------+---------+
| B         | 181 | 366(259,     | .96(0.70, 1.32)          | 0.81    |
| reast(CT) |     | \-\--)       |                          |         |
|           | 178 |              |                          |         |
| ##### Are |     | 364(249,     |                          |         |
| dia {#are |     | \-\--)       |                          |         |
| dia-1 .un |     |              |                          |         |
| numbered} |     |              |                          |         |
|           |     |              |                          |         |
| Zol 4 mg  |     |              |                          |         |
+-----------+-----+--------------+--------------------------+---------+
| B         | 207 | 370(258,     | .83(.62, 1.12)           | 0.22    |
| reast(HT) |     | \-\--)       |                          |         |
|           | 200 |              |                          |         |
| ##### Are |     | \>380        |                          |         |
| dia {#are |     | (\-\--, \--) |                          |         |
| dia-2 .un |     |              |                          |         |
| numbered} |     |              |                          |         |
|           |     |              |                          |         |
| Zol 4 mg  |     |              |                          |         |
+-----------+-----+--------------+--------------------------+---------+
| ##### T   | 555 | 363(273,     | .92(.77, 1.09)           | 0.31    |
| otal {#to |     | 399)         |                          |         |
| tal-2 .un | 561 |              |                          |         |
| numbered} |     | 373(350,     |                          |         |
|           |     | 504)         |                          |         |
| ##### Are |     |              |                          |         |
| dia {#are |     |              |                          |         |
| dia-3 .un |     |              |                          |         |
| numbered} |     |              |                          |         |
|           |     |              |                          |         |
| ######    |     |              |                          |         |
| ### Zol 4 |     |              |                          |         |
|  mg {#zol |     |              |                          |         |
| -4-mg .un |     |              |                          |         |
| numbered} |     |              |                          |         |
+-----------+-----+--------------+--------------------------+---------+

\*Log-rank test

#  {#section-8 .unnumbered}

![](media/image10.wmf){width="6.707638888888889in"
height="3.7881944444444446in"}

**Other Secondary Efficacy Analyses**

In any trial, secondary analyses and exploratory analyses are usually of
marginal value for making a firm conclusion about efficacy. In a
non-inferiority trial such as Study 010, one also must consider whether
a non-inferiority conclusion is even remotely possible for that
secondary or exploratory analysis. Since non-inferiority conclusions
depend on careful documentation of historical evidence that control
(Aredia) produces the effect of interest, these secondary analyses must
also have been done with the historical data. It seems unlikely that
historical data on the effect of the active control will be sufficient
to serve as the basis for a non-inferiority analysis. Secondary analyses
will be useful only if:

-   They demonstrate superiority.

-   Strong evidence of benefit is substantiated by evidence from other
    trials or strata.

-   The findings are sufficiently robust to overcome the doubt
    (inflation of type one error) associated with performing multiple
    analyses.

[Skeletal Morbidity Rate(SMR)]{.underline}

The SMR is the \# events divided by time onstudy. The Applicant found no
statistical difference between the study arms.

[Proportion of Events by Type of Event]{.underline}

The following Applicant displays the proportion of events according to
the event type:

  ------------------------------ ------------ ------------ --------------
  **Proportion of patients                                 
  having a SRE, for each type of                           
  SRE, up to Month 13**                                    

  **by treatment group**                                   

                                 **Zol 4 mg** **Zol 8/4    **Aredia 90
                                              mg**         mg**

                                 **N=561**    **N=524**    **N=555**

  Proportion of pathological     200/561      179/524      203/555 (37%)
  fracture                       (36%)        (34%)        

  Proportion of vertebral        109/561      84/524 (16%) 108/555 (19%)
  fracture                       (19%)                     

  Proportion of non-vertebral    145/561      135/524      148/555 (27%)
  fracture                       (26%)        (26%)        

  Proportion of spinal cord      11/561 (2%)  12/524 (2%)  16/555 (3%)
  compression                                              

  Proportion of radiation        85/561 (15%) 112/524      112/555 (20%)
  therapy to bone                             (21%)        

  Proportion of surgery to bone  21/561 (4%)  15/524 (3%)  31/555 (6%)

  Proportion of hypercalcemia    7/561 (1%)   5/524 (1%)   12/555 (2%)

  P-values are based on                                    
  stratified                                               
  Cochran-Mantel-Haenszel test                             
  for the proportion.                                      

  Source: Post-text tables                                 
  9.2-9, 9.2-12, 9.2-15, and                               
  9.2-18.                                                  
  ------------------------------ ------------ ------------ --------------

The proportions are similar beteween Zol 4mg and Aredia for each of the
major event subtypes.

[Brief Pain Inventory (BPI) composite endpoint]{.underline}

A higher composite score was meant to indicate more pain. According to
the Applicant\'s analyis, the mean change from baseline was similar in
each arm (-.5 on Zol 4 and -.4 on Aredia).

[Analgesic score]{.underline}

Analgesic scores ranged from 0-4 with higher score indicating stronger
analgesics. According to Applicant analyses, mean scores changes from
baseline were similar for the Zol 4 and Aredia arms (-0.1 for each 3
month visit for each arm).

[Performance status (PS)]{.underline}

In Applicant analyses, mean changes from baseline in ECOG PS were
similar on the Zol 4 mg and Aredia arms at each 3-month comparison.
Within each arm, mean PS increased from 0.1 at 3 months to 0.3 at 13
months.

[Quality of Life (QoL)]{.underline}

QoL was evaluated by FACT-G. As shown in the following table from the
Applicant\'s submission, results were statistically inferior in the Zol
4mg arm than Aredia, but also were worse on Zol 4mg than Zol 8mg. These
results cannot be easily explained, and are probably due to chance and
the inflation of alpha due the large number of secondary efficacy
analyses.

![](media/image11.png){width="5.516666666666667in" height="4.5in"}

[Time to Progression (TTP)]{.underline}

In the Applicant\'s analysis of overall time to progression (Volume 69,
post text table 9.2-56), median TTP was 134 days on Zol 4mg (p = 0.174
versus placebo) 125 days on Zol 8mg, and 111 days on placebo.
Examination of the KM curves (post text figures 9.2-25) within each
stratum shows the study arms to be nearly identical for myeloma and
breast cancer treated with chemotherapy. In the stratum of patients with
hormone-treated breast cancer, placebo appeared worse, with a median of
94 days compared to 104 days on Zol 4 mg (p =0.063) and 107 days on Zol
8 mg (p = 0.035). (The low p values reflect differences in the curves
beyond the median.) These TTP trends are not supported by Applicant
analyses of time to bone event (NDA post text table 9.2-55 and figure
9.2-24).

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

*Collection of data on tumor progression was not a primary goal of this
study. Again, isolated subgroup findings which are of marginal
statistical significance are questionable, especially when they
represent only one of many secondary analyses performed.*

[Bone resporption markers]{.underline}

As documented in the Applicant\'s study report, markers of bone
resporption (N-telopeptide, Pyridinoline, and Deoxypyridinoline) were
decreased in all study arms relative to baseline and parathyroid hormone
was increased 10 to 23%.

[Survival]{.underline}

Median survival had not been reached in the study at the time of NDA
submission. The following table presents the Applicant\'s analysis of
survival. There were no significant differences or trends between the
study arms.

+-------------+----------------+------------+-------------+----------+
| 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)   |                |            |             |          |
+-------------+----------------+------------+-------------+----------+

### Efficacy Summary and Conclusions from Study #010 {#efficacy-summary-and-conclusions-from-study-010 .unnumbered}

This well-designed well-controlled clinical study demonstrates that
zoledronate 4 mg is effective in decreasing the skeletal morbidity of
myeloma and breast cancer metastatic to bone. As outline below,
conservative non-inferiority methodology using the *two 95% confidence
interval method of estimation* demonstrate that zoledronate retains at
least 49.3% of the pamidronate-versus-placebo effect:

-   The combined data from the three pamidronate trials show that 52.0%
    (293/563) on placebo compared to 38.9% (220/565) on pamidronate. The
    treatment effect is thus 13.1% (95% ci: 7.3%,18.9%). This method
    uses the conservative limit of the confidence interval to estimate
    effect size (7.3%).

```{=html}
<!-- -->
```
-   On the zoledronate arm of this non-inferiority trial 44%(248/561) of
    patients had at least one SRE compared to 46% (257/555) on the
    pamidronate arm (95% ci: -7.9%, 3.7%). Although the estimate from
    these data favors zoledronate by 2%, again this method uses the
    conservative limit of the confidence interval to estimate the
    zoledronate effect which exclude zoledronate being 3.7% worse than
    pamidronate. The following are the calculations estimating that at
    least 49.3% of the pamidronate-versus-placebo effect have been
    retained: (7.3%-3.7%)/7.3% = 49.3%.

A critical aspect of making conclusions from non-inferiority trials is
the *constant assumption.* This aspect of trial design, discussed in
more depth in the FDA statistical review, requires a determination that
the active control drug (pamidronate) 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. The FDA reviewers carefully compared the historical
pamidronate study with this assumption in mind. Important differences
were found between the studies. Compared to the
pamidronate-versus-placebo studies, more patients on Study 010 had:

-   a short time since diagnosis of bone metastases

-   history of a previous SRE

-   no lytic bone lesion

Retrospective analysis of the pamidronate-versus-placebo data showed
that the pamidronate effect appeared even greater in patients with a
short time since diagnosis of bone metastasis and in patients with a
history of a previous SRE. Therefore, enrichment of the study population
with these patients should, if anything, increase the sensitivity of the
study.

The question of whether the active control (pamidronate) is effective in
breast cancer patients with non-lytic lesions, however, cannot be
directly examined in the pamidronate-versus-placebo study because only
patients with lytic lesions were entered. One can examine whether
zoledronate appears to be effective in Study 010 in the subgroup
corresponding to the pamidronate study. Such a subgroup analysis of
Study 010, comparing zoledronate versus pamidronate in breast cancer
patients with lytic bone lesions, did not suggest a lack of zoledronate
efficacy. In fact, the trend was in favor of zoledronate.

Whether zoledronate approval in breast cancer should extend to patients
without lytic bone lesions needs further consideration. The results of
Study 039, a study of zoledronate for treating the predominantly blastic
metastases of prostate cancer, should also be considered in making this
determination.

# Integrated Safety Review

This integrated safety review discusses safety findings from all
submitted zoledronate studies. Detailed FDA safety reviews of the
studies in breast cancer and myeloma (010), prostate cancer (039), and
other solid tumors (011) can be found in the appendices to this briefing
document.

## Brief Statement of Reviewer's Conclusions

Zoledronate 4 mg i.v. over 15 minutes every 3-4 weeks has an acceptable
safety profile, and is comparable in toxicity to Aredia 90 mg i.v. over
2 hours every 3-4 weeks as an adjuvant to standard anticancer therapy in
patients with bone metastases from breast cancer and lesions of multiple
myeloma. Zoledronate 4 mg i.v. over 15 minutes every 3 weeks has an
acceptable safety profile, but is more toxic than placebo when used as
an adjuvant to standard anticancer therapy in patients with prostate
cancer and other solid tumors.

The major safety concern identified in the randomized trials is
increased risk of renal function deterioration, which is dose-related
and increases with duration of therapy. Most incidences were mild and
reversible, with rare incidences of acute renal failure. During the
course of the studies, the renal safety of zoledronate was improved by
prolonging the infusion time to 15 minutes (instead of 5 minutes) and
eliminating the 8 mg dose. The safety of the 4 mg dose was improved by
requiring assessment of serum creatinine before each dose and holding
zoledronate for renal deterioration, until the return of creatinine to
within 10% of the baseline. When compared with Aredia 90 mg i.v. over 2
hours, zoledronate 4 mg i.v. over 15 minutes every 3-4 weeks in patients
with metastatic breast cancer to bone and multiple myeloma (study #010),
the incidence of renal deterioration was similar (8.8% and 8.2%,
respectively. The incidence of renal deterioration for patients with
prostate cancer (study #039) and solid tumor malignancies other than
prostate and breast (#011) was higher than placebo, but the difference
was not statistically significant.

Symptoms felt possibly to be associated with bisphosphonates as a class,
such as arthralgias, pyrexia, as well as electrolyte disturbances, were
noted for zoledronate and Aredia, but were not a major concern.

Anemia was slightly more common with zoledronate 4 mg, compared with
placebo. In the Aredia-controlled study, more patients in the
zoledronate 4 mg group had a decrease of \> 25% from baseline
hemoglobin. This is of uncertain significance.

## Description of patient exposure

Zoledronate was approved in August 2001 for treatment of hypercalcemia
of malignancy. This was based on 2 identical randomized trials in which
a total of 86 patients received zoledronate 4 mg i.v. over 5 minutes,
with Aredia 90 mg i.v. infusion over 2 hours as the control. The
approved dose of zoledronate was 4 mg by 15-minute i.v. infusion. The
infusion duration was prolonged because of the increased risk of renal
deterioration associated with shorter infusions.

The primary safety population for the current NDA includes 3,337 safety
evaluable patients (2,251 treated with zoledronate) in phase 2 and phase
3 randomized trials for cancer patients with metastatic disease to bone.
Zoledronate was given i.v. every 3 or 4 weeks, usually to correspond
with the schedule of concomitant anti-cancer therapy. The planned
treatment duration for these studies was 9 months for protocol 011, 10
months for protocol 007, 12 months for protocol 10 and 15 months for
protocol 039. Applicant table 1-1 provides a summary of the studies.

Applicant table 1-1

![](media/image12.png){width="5.677083333333333in" height="2.6875in"}

For the primary safety population, the applicant provided all data
available until the data base lock on 2/28/01 for the time to death and
renal function deterioration analyses.

The applicant provided safety data for an additional 493 patients from 8
studies and study extensions as the "supportive safety population." For
this supportive population, only 27 patients received zoledronate 4 mg;
61 received \< 4 mg; 197 received zoledronate 8/4 mg; 22 received
zoledronate 8 mg, and 186 received Aredia 90 mg i.v.

Study 506 is a clinical pharmacology study in 19 cancer patients with
varying renal function, to provide information on dosing for this
special population.

The cut-off date of February 28, 2001, was used for reporting data on
deaths and serious adverse events (SAEs) in trials for other
indications. Applicant's table 1-3 summarizes ongoing trials and trials
in other indications.

Applicant table 1-3

![](media/image13.png){width="5.997916666666667in"
height="6.822916666666667in"}

Applicant table 2-1 summarizes the duration of exposure of the primary
safety population to zoledronate and controls.

Applicant table 2-1

![](media/image14.png){width="5.999305555555556in"
height="1.6645833333333333in"}

The mean and median duration of exposure were shortest for the placebo
group, in part because placebo served as the control for the study
(#011) with the shortest duration of treatment, 9 months. The mean and
median exposure for zoledronate 4 mg was 8.5 and 9.07 months,
respectively, similar to zoledronate 8/4 mg, and slightly shorter than
for Aredia.

Applicant table 2-2 summarizes additional information about duration of
exposure for the primary safety population.

Applicant table 2-2

![](media/image15.png){width="5.996527777777778in"
height="2.254861111111111in"}

The duration of exposure was at least 12 months for 38.9% of zoledronate
4 mg patients, 35.6% for zoledronate 8/4 mg, and 49.3% for Aredia
patients.

For the three phase 3 trials, patients were to be randomized to
zoledronate treatment arms of 4mg and 8 mg. After it was determined that
8 mg was associated with excess renal toxicity, no patient received more
than 4 mg per dose and the 8 mg arm was renamed "8/4 mg". This occurred
June 2000. The percentage of infusions in the 8/4 mg groups that was
actually 4 mg was 10% for #039 (prostate cancer), 20% for #010 (multiple
myeloma and breast cancer, and 22% for #11 (miscellaneous solid tumors).

In June 1999, amendments to studies 039, 010, and 011 increased the
infusion time from 5 to 15 minutes, which was shown to decrease the
renal toxicity of zoledronate. See individual study safety reviews,
which are contained in the Appendix, for details of the separate renal
safety analyses done for patients according to whether they were
randomized pre or post the 15-minute infusion amendment. Applicant table
2-4 demonstrates the total number of patients and infusions and the
total number of 15-minute infusions by study.

Applicant table 2-4

![](media/image16.png){width="6.0in" height="1.9791666666666667in"}

In studies 010, 011, and 039, 69.4%, 26.3% and 53.6% of patients,
respectively, received at least twelve 15-minute infusions (from
applicant table 2-5).

Detailed reviews of the individual studies, 010, 011, 039 (see Appendix
for details), show a balance among treatment arms of age and baseline
renal function. Applicant table 3-1 shows a summary of demographic
information for the pooled primary safety population

Applicant table 3-1

![](media/image17.png){width="5.999305555555556in"
height="6.267361111111111in"}

The imbalance in gender for the pooled population of patients treated
with placebo and Aredia relates to the design of the studies, with
placebo controlling the prostate study and Aredia controlling the breast
cancer (and myeloma) study.

Prior to the start of the study drug, 90% or more of patients were
taking antineoplastic therapies. After the start of the study drug, the
percentage of patients receiving antineoplastic therapy was 42.6% for
the placebo group, 74.3% for zoledronate 4 mg, 69.7% for zoledronate 8/4
mg. 94.8% for the Aredia group. The percentage of patients in these
groups receiving cisplatin was 9%, 4.4%, 5.1%, and 0.6%, respectively.

## Methods and specific findings of the safety review

Adverse events (AEs), serious adverse events (SAEs), laboratory studies
and survival data were the main safety variables. Safety analysis was
based on the type and frequency of adverse events and laboratory values
outside of pre-determined ranges. Results were tabulated. Data was cut
at the end of the study drug period, which was the end of the core study
phase or 28 days following the last study medication. However, any
available data was included up to the date of the data base lock for
time to death or time to renal deterioration analyses.

Clinical study reports for the three phase 3 trials used the IMN
dictionary to code adverse events. AEs are reported using MedDRA
preferred terms. AEs were mapped from

the IMN preferred terms to the corresponding MedDRA terms.

Following the occurrence of 3 renal failure SAEs in patients receiving
zoledronate 8 mg, a Renal Advisory Board (RAB) was formed and amendments
were made to the protocol. The effect on renal function was analyzed
according to the number of patients who experienced renal adverse events
using selected terms suggested by the RAB and the number of patients who
met pre-defined criteria of renal deterioration. Kaplan-Meier curves
were used to describe the time course to first renal function
deterioration.

The "all terms criteria" from the RAB used to describe renal AEs and
SAEs are as follows:

![](media/image18.png){width="4.8125in"
height="2.5208333333333335in"}Baseline serum creatinine was considered
normal if \<1.4 mg/dL and abnormal if [\>]{.underline} 1.4mg/dL. Renal
function deterioration was defined as any of the following:

-   Normal baseline with change from baseline [\>]{.underline} 0.5 mg/dL

-   Abnormal baseline with change from baseline [\>]{.underline} 1.0
    mg/dL

-   Post-baseline value [\>]{.underline} 2 time the baseline value.

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

*The Applicant has provided an Integrated Summary of Safety with data
pooled for the three randomized phase 3 trials (039, 10, 11) plus study
007. Study 007 is a phase 2 study in breast cancer and multiple myeloma
patients comparing zoledronate 0.4 mg, 2 mg, and 4 mg i.v. over 5
minutes with Aredia as control. This last study adds little to the
safety analysis since only 67 patients received the recommended 4 mg
zoledronate dose and all zoledronate infusions were 5 minutes, rather
than the recommended 15-minute infusion. Comparison of the major
findings of each of the phase 3 studies with each other seems more
useful than pooling the data for 4 studies without reference to the
specific control in each case and the type of malignant disease.
Furthermore, pooling the safety data without reference to duration of
infusion significantly obscures the fact that the safety of zoledronate
was improved when infused over 15 minutes rather than over 5 minutes.*

For detailed safety information pertaining to each of the phase 3
randomized trials analyzed separately, refer to the Appendix. Some of
the major points will be reviewed here, as well.

The major safety concern identified in the randomized trials is
increased risk of renal function deterioration, which is dose-related
and increases with duration of therapy. Most incidences were mild and
reversible, with rare incidences of acute renal failure. During the
course of the studies, the renal safety of zoledronate was improved by
prolonging the infusion time to 15 minutes (instead of 5 minutes) and
eliminating the 8 mg dose. The safety of the 4 mg dose was improved
further by requiring assessment of serum creatinine before each dose and
holding zoledronate for renal deterioration, until the return of
creatinine to within 10% of the baseline.

When compared with Aredia 90 mg i.v. over 2 hours, zoledronate 4 mg i.v.
over 15 minutes every 3-4 weeks in patients with breast cancer or
multiple myeloma (study #010), the incidence of renal deterioration was
similar (8.8% and 8.2%, respectively). It was 18.6% for zoledronate 8/4
mg. The incidence of and time to first renal deterioration for patients
with prostate cancer (study #039) and solid tumor malignancies other
than prostate and breast (#011) was higher than placebo, but the
difference was not statistically significant. For prostate cancer
patients treated with zoledronate 4 mg infused over 15 minutes, the
incidence of renal deterioration was 15.2% compared with zoledronate 8/4
mg (20.7%) and placebo (11.5%). For patients with solid tumor
malignancies other than prostate and breast cancer (#11), the incidence
of renal deterioration was 10.9% for zoledronate 4 mg, 11.6% for
zoledronate 8/4 mg and 6.7% for placebo. In all studies, deterioration
of renal function was observed in patients with normal baseline
creatinine and in patients with abnormal creatinine ([\>]{.underline}
1.4-3.0). The prostate cancer patients (#39) with abnormal creatinine
had a higher incidence of deterioration when treated with zoledronate or
placebo, but there were only a small number of patients in this group,
so the significance is uncertain. There were *fewer* patients with
abnormal baseline creatinine in study #010 (breast/myeloma) who showed
deterioration with zoledronate 4mg, compared with those with normal
baseline creatinine. For study #011, the deterioration of renal function
with zoledronate 4mg was similar for both baseline creatinine groups.

Symptoms felt possibly to be associated with bisphosphonates as a class,
such as arthralgias, pyrexia, as well as electrolyte disturbances, were
noted for zoledronate and Aredia, but were not clinically problematic.
The incidence of eye-related AEs and injection site problems is less for
zoledronate than Aredia.

Anemia was slightly more common with zoledronate 4 mg, compared with
placebo. In the prostate study (#039), the incidence of anemia in the
zoledronate groups was approximately 27% compared with 17.8% for
placebo. In the miscellaneous solid tumor study (#011), anemia was
present in 7.9% of the zoledronate 4 mg group and 3.6% of the placebo
group. In the Aredia-controlled study (#010, breast/myeloma), more
patients in the zoledronate 4 mg group had a decrease of \> 25% from
baseline hemoglobin. This is of uncertain significance

## Adequacy of safety testing

Zoledronate has been tested adequately for safety for the population
studied. The randomized trials have established safety in a broad
spectrum of malignancies for long-term therapy.

## Summary of critical safety findings and limitations of data

Zoledronate 4 mg i.v. over 15 minutes every 3-4 weeks has an acceptable
safety profile, and is comparable in toxicity to Aredia 90 mg i.v. over
2 hours every 3-4 weeks as an adjuvant to standard anticancer therapy in
patients with bone metastases from breast cancer and lesions of multiple
myeloma. Zoledronate 4 mg i.v. over 15 minutes every 3 weeks has an
acceptable safety profile, but is more toxic than placebo when used as
an adjuvant to standard anticancer therapy in patients with prostate
cancer and other solid tumors.

The risk of renal deterioration with zoledronate is greater than
placebo, but similar to Aredia. It must be infused over not less than 15
minutes in a volume of 100ml, and clinical monitoring of serum
creatinine should be done before each dose to minimize renal risk. The
risk of renal toxicity increases with duration of therapy (# of
infusions). Caution is indicated for patients with elevated baseline
creatinine, particularly since the study population excluded patients
with creatinine \> 3.0 and the drug is excreted unchanged by the
kidneys. The study population did not have extensive concomitant
exposure to other potentially nephrotoxic drugs. As the treatment
population is expanded, it will be necessary to monitor for possible
synergistic nephrotoxic drug effects.