Division of Biostatistics
Office of Biostatistics and Epidemiology
Center for Biologics Evaluation and
Research
Food and Drug Administration
Cellular, Tissue and Gene Therapies
Advisory Committee Meeting
March 29, 2007
Statistical Briefing Document
PROVENGE^{ฎ} (Sipuleucel T)
For the treatment of men with asymptomatic metastatic androgen independent prostate cancer.
Table of Contents
OVERVIEW
.
3
STATISTICAL EVALUSTION
.
4
I.
Study D9901
4
1.0
Statistical Analysis Plan
. 5
3.0 Statistical
Findings and Comments
..22
II.
Study D9902A
29
1.0
Statistical Analysis Plan
29
2.0
Efficacy Evaluation
...30
3.0 Statistical
Findings and Comments
..39
III.
Integrated Summary and
Other findings
42
1.0 Summary of Efficacy
42
2.0 Summary
of Safety
44
3.0 Statistical
Findings and Comments
45
SUMMARY AND CONCLUSIONS
. 47
References
48
INTRODUCTION
Dendreon is seeking licensure of sipuleucelT (Provengeฎ,
APC8015) for the treatment of men with asymptomatic, metastatic androgen
independent prostate cancer (AIPC). The proposed indication is based upon analyses
comparing overall survival between APC8015 treated and placebo groups with the
relative absence of significant toxicity in this patient population.
SipuleucelT is an autologous active cellular
immunotherapy product designed to stimulate an immune response against prostate
cancer. APC8015 consists of autologous peripheral blood mononuclear cells
(PBMCs), including antigen presenting cells (APCs), that have been activated in
vitro with a recombinant fusion protein. The recombinant fusion protein,
PA2024, is composed of prostatic acid phosphatase (PAP), an antigen expressed
in prostate adenocarcinoma, linked to granulocytemacrophage colonystimulating
factor (GMCSF), an immune cell activator.
SipuleucelT falls into the class of therapies
known as active cellular immunotherapies, sometimes termed therapeutic cancer
vaccines. Such immunotherapy products are designed to elicit a specific immune
response to a target antigen. While the precise mechanism of action is unknown,
sipuleucelT is designed to induce a cellular immune response targeted against
a recombinant fusion protein containing prostatic acid phosphatase (PAP), an
antigen expressed in prostate cancer tissue. During ex vivo culture, antigen
presenting cells (APCs) take up and process the recombinant target antigen into
small peptides that are then displayed on the APC surface. In vivo, T cells
bind to and recognize the target antigen peptides on the APC surface, eliciting
a response characterized by the proliferation and activation of T cells. These
activated T cells are the effector cells thought to be responsible for
recognition and destruction of prostate cancer cells in vivo. SipuleucelT has
been shown to stimulate the proliferation of PAPspecific T cell hybridomas in
vitro.
The proposed target indication for sipuleucelT
is for the treatment of men with asymptomatic metastatic androgen independent
prostate cancer (AIPC).
All submissions are under BLA 125197. The electronic
BLA is in CTD format and organized in folders corresponding to BLA structure. Pursuant to the Fast Track Designation
agreement and the agreement to submit portions of the application (rolling
Biologics License Application), the first portion of the BLA including all
clinical and nonclinical sections, draft proposed labeling, and appropriate
administrative documents (e.g., forms, table of contents, certifications) was
submitted on August 21, 2006. The second/final portion which contains all
quality sections along with the final proposed labeling was submitted on
November 9, 2006. In addition, Dendreon intends to submit the 4 Month Safety
Update in February/March 2007.
Study overview
Clinical studies of sipuleucelT have been performed
under BBIND 6933 and include Phase 1, 2, and 3 studies in men with prostate
cancer.
Early Phase 1 and 2 clinical studies in men with
AIPC were conducted to test the safety and preliminary efficacy of sipuleucelT
(Small 2000, Burch 2000, Burch 2004). The results demonstrated the following:
1) Intravenous infusions of sipuleucelT in subjects with prostate cancer were
generally well tolerated with no dose limiting toxicities observed; 2)
Prostatespecific antigen (PSA) reductions of >50% in approximately 10% of
subjects were noted, as well as one striking objective response; 3) Three doses
of sipuleucelT resulted in substantial PAPspecific immune responses. Results of openlabel Phase 2 trials in men
with androgen dependent prostate cancer (ADPC) also demonstrated that
intravenous infusions of sipuleucelT were generally well tolerated with no
dose limiting toxicities observed. Additionally, prolongation of PSA doubling
time was observed in these studies (Rini 2005a, Rini 2005).
The Phase 3 clinical development program for
sipuleucelT was originally designed based on the results of Phase 1 and 2
trials in men with AIPC and guidance received from the Center for Biologics
Evaluation and Research (CBER) and practicing oncologists and urologists. The
program consisted of Protocols D9901 and D9902, two identically designed,
multicenter, randomized, double blind, placebocontrolled studies in men with
asymptomatic, metastatic AIPC. The target number of subjects to be enrolled was
120 in each study, and the primary endpoint for both studies was time to
objective disease progression (TTP). Each of the 2 studies was powered to
independently meet the primary endpoint of TTP; a pooled analysis of the
combined studies was required for sufficient power to meet the secondary
endpoint of time to onset of diseaserelated pain (TDRP). In 1999, no therapy
had been shown to prolong survival in men with asymptomatic metastatic AIPC,
and there were no Phase 1 or 2 survival data specifically for sipuleucelT.
Therefore, survival was not used as the primary endpoint. However, in both
trials, subjects were to be followed until death or until a prespecified
cutoff of 36 months from the time of randomization, whichever occurred first.
The second study (D9902) was initiated shortly
after the first study. The trial design, patient eligibility, objectives and
statistical considerations were the same as those in the study 1 with a planned
sample size of 120 subjects. After the first
study results became available showing no overall significance of TTP in 2002,
the sponsor did a subset analysis of the study 1 and found that there was a difference
of TTP favoring Provenge arm for subjects who had Gleason score ≤ 7. At this point, the study 2 had already enrolled 98 subjects. The sponsor decided to split the second study
into two parts (A and B). Part A (D9902A)
contained the initial 98 subjects with Gleason scores ≤ 7 or ≥ 8,
and part B to enroll subjects only with Gleason score ≤ 7. The BLA contains data from the two pivotal
studies: Studies D9901 and D9902A.
Since
data/results from the two pivotal trials were submitted as the main efficacy
evidence under this BLA to support the licensing application, the
focus of the statistical review is mainly on the two Phase 3 trials (Studies D9901
and D9902A).
Statistical evaluation
I. Study D9901
This was a prospective Phase 3, multicenter,
double blind, placebocontrolled, randomized trial of immunotherapy with
APC8015 for the treatment of subjects with asymptomatic metastatic AIPC. A
total of 127 subjects were randomized
at multiple investigative centers (19
clinical study centers) across the
An independent third party was employed to
generate the randomization schedule for the study. The specifics about the
method of randomization employed (block size and degree of imbalance at each
study site) were not made known to Dendreon until after the study was
unblinded. Subjects were stratified by clinical study center and use of
bisphosphonate therapy (yes or no) prior to being randomized. The allocation of subjects to treatment
utilized multiple blocks, each of size 6, to generate a separate master
randomization schedule for each stratum. A centralized, adaptive randomization
procedure was employed to maintain the overall enrollment in the study at an
approximately 2:1 randomization, while preventing the enrollment at any
clinical study center from departing from the 2:1 randomization ratio by a
large amount.
Following randomization, subjects from both
groups underwent a series of 3 standard leukapheresis procedures (in Weeks 0,
2, and 4), and each procedure was followed 2 days later by infusion of either
autologous antigen loaded APCs (APC8015; active treatment) or autologous
quiescent APCs without antigen (APCPlacebo; control). The treatment phase of
the protocol was complete following the third (Week 4) infusion. For subjects on the control arm, the remaining twothirds of the
quiescent APCs from each leukapheresis that were not used to make APCPlacebo
were cryopreserved for possible later use in the preparation of APC8015F for
the Phase 2 salvage trial D9903.
At the time that subjects developed disease
progression, study treatment could be unblinded. Subjects in the APC8015 group
were then treated at the physicians discretion. Subjects in the APCPlacebo
group had the option to enter a Phase 2, open label, singlearm salvage trial
(Protocol D9903) with a product similar to APC8015. Subjects treated with APC8015
on D9901 were not eligible to participate in the salvage trial.
Regardless of subsequent treatment, subjects
without diseaserelated pain at the time of disease progression were to be
followed with weekly pain logs for 4 additional weeks. After subjects developed
disease progression, followup documentation included treatmentrelated AEs,
first anticancer treatment, and survival for 3 years from the time of
randomization or until death, whichever occurred first. Per the statistical
analysis plan (Appendix 16.1.9.8), the final analysis of survival was performed
36 months following randomization of the last subject.
1.0 Statistical Analysis Plan
1.1 Efficacy variables
The primary efficacy variable, overall time to
disease progression (TTP), was defined as the time from randomization to the
first observation of disease progression.
Disease progression was defined by any of the following:
Measurable Disease
A greater than 50% increase in the sum of the products of the perpendicular
diameters of all bidimensionally measurable lesions. The change was measured
against the smallest sum observed, or compared with baseline if there was no
response, using the same techniques as baseline.
An appearance of at least 2 new lesions or the reappearance of any lesion that
had disappeared. All lesions had to have a minimum size of at least 2 cm in 1
dimension to be considered measurable.
Evaluable Disease
Unidimensionally measurable disease: at least 50% increase in the sum of the
measurements of all unidimensionally measurable lesions over the smallest sum
observed (over baseline if no response) using the same techniques as baseline.
Nonmeasurable disease: Clear worsening of nonmeasurable, evaluable disease.
Scan only bone disease: The appearance of at least 2 new areas of abnormal
uptake on bone scan. Increased uptake of preexisting lesions on bone scan did
not constitute progression.
Development
of Prostate CancerRelated Events
The development of a prostate cancerrelated event (e.g., spinal cord
compression, a pathologic fracture, the development of a requirement for
radiation therapy, or other clinically significant disease specific event)
constituted progression.
Failure to return for evaluation due to death or deteriorating condition
constituted progression unless the event was clearly unrelated to prostate
cancer.
Development
of Prostate CancerRelated Pain
On the basis of the Investigators opinion, all of the following criteria had
to be met: pain that had the quality and consistency of cancerrelated pain,
pain that occurred since enrollment in the trial, and pain that occurred in a
location that correlated with a site of cancer, as demonstrated by objective
radiographic means.
Secondary efficacy measures included time to development
of diseaserelated pain, objective response rate, and duration of response,
time to clinical progression, time to treatment failure, and incidence of Grade
3 or greater treatmentrelated AEs in all subjects who underwent at least 1
leukapheresis for trial purposes.
Survival as an endpoint was not defined in the
protocol and its amendments though the sponsor stated that all subjects would
be followed for survival for 36 months after their date of randomization or
until death, whichever occurred first. Regarding
survival analysis, the sponsor did state that This study is not powered to show a survival
effect. However, survival data will be summarized descriptively. The definition for a survival endpoint was
later added to the study report in the BLA submission as:
The
survival times for subjects who died during the 3year followup period were
defined as the time span (in months) from the date of randomization to the date
of death. The survival times for subjects who were alive at the end of the
3year followup period were censored and defined as the time span (in months)
from the date of randomization to the censor date of 3 years after the date of
randomization.
1.2 Analysis plan
The statistical analysis plan included 2 interim
analyses and a final analysis. The first analysis was conducted on data from
control subjects only for the purpose of sample size confirmation so no alpha
adjustment was made and the sample size was not adjusted based on the results.
The second interim analysis was performed on data from 79 subjects from both
treatment arms to assess the conditional probability of trial success (i.e.,
futility analysis) and was conducted at the 0.001 level. The final analysis was
conducted at the 0.049 level using an O.BrienFleming adjustment. Both interim
analyses were conducted by an independent third party and Dendreon personnel
remained blinded to treatment assignments.
These data were analyzed using the ITT and
Safety populations. The ITT population included all randomized subjects, and
the Safety population included all subjects who underwent at least 1
leukapheresis. Since all randomized subjects underwent at least 1 leukapheresis
in this trial, both populations are identical.
1.3 Analysis of primary efficacy data
The time to disease progression curves were
constructed with the KaplanMeier technique for the two treatment groups, and
the primary null hypothesis (no difference between treatment groups) was tested
using the log rank test.
The date of data cutoff for the primary
efficacy evaluation was April 30 2002.
Subjects who did not experience disease progression by the time of the efficacy
analysis were censored at the time of their last known radiographic imaging
study. Similarly, if a subject had no disease progression and was lost to
followup prior to the data analysis, the subject was censored at the date of
last radiographic imaging study.
The primary efficacy variable was also
summarized by the following subgroups:
PAP immunohistochemistry expression: 2 subject groupings based on the
proportion of cancer cells staining positive for PAP (25% to 74%, = 75%).
Baseline alkaline phosphatase (within normal limit [WNL] versus above ULN of
local reference range).
Baseline serum PAP levels (WNL of local reference range, > 1 ื ULN to < 3
ื ULN; = 3 ื ULN).
Prior systemic therapy (castration only, combined androgen blockade, combined
androgen blockade plus other; castration plus other was also considered if
there were sufficient numbers in the data).
Inferential tests with appropriate adjustment
for multiplicity were carried out for the above mentioned variables, but such
inferential statistics were only carried out for time to disease progression.
Treatment by subgroup interactions were tested to evaluate if any of them
represented effect modifiers. These interactions were tested before simple
effects and the latter only tested in the event of a significant interaction.
Adjustments were made for the 4 interaction tests using the SidakHolm method.
The tests for simple effects were not considered reportable unless the
corresponding interactions were significant (at the P ≤ 0.10 level).
Subjects were followed for survival for 3 years
following their date of randomization. Subjects who were alive at 3 years
following randomization were censored at 3 years from their date of
randomization. Survival was analyzed using the KaplanMeier technique. Survival
rate estimates at 3, 6, 9, 12, and every 6 months thereafter and median
survival were obtained from the KaplanMeier method. Corresponding confidence
intervals (CIs) were also computed.
Sample size
The most current version of the protocol
(amendment 7, dated 25 JUL 2002) indicates that approximately 120 subjects were
planned, with 80 subjects in the APC8015 group and 40 subjects in the
APCPlacebo group. A 2:1 randomization was used in order to increase the number
of subjects exposed to APC8015. Based on past experience and a review of the
literature, a median time to disease progression for subjects treated with
APCPlacebo was assumed to be 4 months. A delay in the time to disease
progression of 3.7 months (from 4 to 7.7
months) was considered clinically significant for subjects with metastatic
AIPC. This represents a hazard ratio (HR) of 1.925 assuming an exponential
distribution. It was further assumed that accrual into this study would be done
within 16 months and that each subject would be followed for up to 3 years.
With a 2sided 5% level of significance and a 2:1 subjectallocation ratio
between the APC8015 and APCPlacebo groups, a total of 80 events was needed to
achieve 80% power to detect the specified difference of 3.7 months in median
time to disease progression; it was projected that 87 subjects would be
sufficient to attain the 80 events (Lachin 1981). To account for nonuniform
subject entry and 5% loss to followup (Lachin 1986) a total of 96 subjects
(64:32 subjects for APC8015:APCplacebo) was necessary.
It was assumed that the same HR would apply to
time to diseaserelated pain. Therefore, a total of 80 pain progression events
would also be required to power the diseaserelated pain endpoint at 80%.
However, it was further assumed that 60% of the pain events would be censored
when the requisite number of progression events had been recorded. This high
level of censoring would result in 32 pain progression events from Study D9901
alone. Increasing the sample size from 96 to 120 would result in a projection
of approximately 40 events from pain progression. In order to achieve 80% power
and capture 80 pain events for the diseaserelated pain endpoint, enrollment of
240 subjects was required. Therefore, enrollment of 120 subjects in each of the
Phase 3 trials (D9901 and D9902A) was planned with a final pooled analysis for
this endpoint.
2.0 Efficacy Evaluation
2.1 Disposition of subjects
As shown in Figure 1, 127 of the 186 subjects
screened for eligibility were randomized between 04 JAN 2000 and 08 OCT 2001.
Of these, 82 subjects were randomized to receive APC8015 and 45 subjects were
randomized to receive APCPlacebo. All 127 subjects underwent at least 1
leukapheresis procedure and received at least 1 infusion.
Of the 59 subjects who were screened for the
trial but were not randomized, the majority of subjects failed to satisfy the
inclusion criteria (52 of 59 subjects, 88%). Five subjects (8.5%) chose not to
participate in the trial following their registration visit. Two additional
subjects (3.4%) withdrew for other reasons (aortic aneurysm and participation
in a separate clinical trial).
Twelve subjects discontinued the 3year study
before completing the trial, but survival at 36 months following randomization
was available for all 12 subjects. Four subjects treated with APC8015 and 1
subject treated with APCPlacebo withdrew consent prior to meeting the primary
endpoint of disease progression. Rising PSA was not reported as the primary
reason for any subject to discontinue the trial.
Figure 1 Schematic
of Subject Disposition
Major protocol eligibility deviations occurred
for 7.9% of subjects (8 subjects treated with APC8015 and 2 subjects treated
with APCPlacebo) and included the following: no evidence of metastatic disease
at entry, evidence of pleural effusion at study entry, not medically or
surgically castrate at study entry or medical castration therapy discontinued
during trial, PSA values demonstrating or confirming androgen independence
obtained outside the protocolspecified window, and radiation therapy received
during the active period.
2.2 Demographics and other baseline characteristics
A summary of demographics and baseline
characteristics is provided in Table 1. The demographic characteristics were
similar between the 2 treatment groups. All
subjects enrolled in this trial were male, and the majority of subjects were
Caucasian (90.6%). The median age in this population was 73.0 years; ages
ranged from 47 years to 86 years. The majority of subjects from both treatment
groups had a baseline ECOG performance status of 0 (75.6% of subjects treated
with APC8015 and 82.2% of subjects treated with APCPlacebo).
Baseline laboratory evaluations were well
matched between the treatment groups and are provided in Table 1.
The estimated median time from diagnosis to
randomization for subjects treated with APC8015 was 397.6 weeks (approximately
7.6 years) compared to 356.9 weeks (approximately 6.9 years) for subjects
treated with APCPlacebo.
Table 1
Summary of Subject Demographics and Baseline Characteristics, ITT
The protocol required subjects to have a tumor
specimen (tissue block, core biopsy, or precut unstained slides) submitted to
a central pathology facility for immunohistochemistry testing of PAP.
Eligibility required a positive PAP immunohistochemistry reaction in ≥ 25%
of cells. The PAP immunohistochemistry results are summarized in Table 2. A
higher percentage of subjects in the APC8015 group than in the APCPlacebo
group had tumor specimens with at least 75% PAPpositive cells.
Table 2 Summary of PAP Immunohistochemistry, ITT
For this study, 116 of 127 subjects (91.3%) had
a Gleason score assigned by a central pathology laboratory prior to
randomization. The Gleason scores obtained by local pathology facilities were
used for those subjects not given Gleason scores by the central pathology
facility. Gleason score and tumor status at baseline is presented in Table 3.
Overall, a majority of the subjects had a Gleason score ≤ 7 (75 subjects
[59.1%] versus a Gleason score ≥ 8 (52 subjects [40.9%]). Differences
between the treatment groups were not statistically significant.
Table 3 Summary of Gleason Score and Tumor
Status at Baseline, ITT
It should be noted that pvalues provided by the
sponsor in the above tables should not be considered as those from a hypothesis
test for the difference between the two arms.
They just reflect the chance of obtaining the observed difference (and
more extreme) between the two arms in these demographic and baseline
characteristics factors when in fact the two samples were randomly drawn from the
same population.
2.3 Efficacy results
The protocol prospectively designated time to
disease progression as the primary endpoint and specified that complete
survival data (up to 36 months) would be collected. Survival is the focus of
this study report. Survival is objectively ascertained, represents the standard
for establishing clinical benefit in oncology clinical trials, and best represents
the therapeutic effect of APC8015. To be consistent with the prospectively
defined protocol, time to disease progression and the secondary endpoints are
presented first in this study report, but the most extensive information and
critical analyses are focused on survival.
The
efficacy review focuses on the survival endpoint.
2.3.1 The primary endpoint
The sponsor states in this BLA that the primary
efficacy endpoint was the overall time to disease progression. The following analyses for the primary
endpoint presented in the study report by the sponsor were based on the
unblinded review data. The terminology
change for the primary endpoint and the adequacy of using unblinded review data
will be discussed later in the section Statistical Findings and Comments.
Out of 127 subjects randomized on this study,
115 subjects (90.6%) contributed a progression event. Ninetyeight subjects
(77.2%) had progression documented by imaging (as determined by independent,
blinded, radiology review). Of the 98 subjects who progressed based on imaging
studies, 48 subjects treated with APC8015 and 24 subjects treated with
APCPlacebo progressed based on bone disease, while 15 subjects treated with
APC8015 and 11 subjects treated with APCPlacebo progressed based on soft
tissue disease. Ten subjects (7.9%) had progression based on clinical events
other than radiographic events, as defined in the protocol, and 7 subjects
(5.5%) had progression based on the onset of cancerrelated pain. Additionally,
6 subjects (4.7%) were censored prior to meeting the disease progression
endpoint and 6 subjects (4.7%; all in the APC8015 group) were censored without
disease progression at the primary efficacy evaluation cutoff date (30 APR
2002).
When the KaplanMeier curves for time to disease
progression were compared, there was a delay from randomization to disease
progression in the APC8015 group compared with the APCPlacebo group (P =
0.052, log rank; unadjusted HR = 1.45 [95% CI: 0.99, 2.11]; Figure 2). After Week 8 the KaplanMeier curves showed a
marked separation that persisted throughout the remainder of followup. The estimated median time to disease
progression was 11.7 weeks in the APC8015 group compared with 10.0 weeks in the
APCPlacebo group.
Figure 2 Primary Efficacy Endpoint, Time to Disease
Progression (KaplanMeier Method), ITT
The sponsor also reported time to objective
disease progression confirmed by imaging studies as follow (p74 of the Study
Reports for D9901): During the trial, available imaging studies were evaluated
for all subjects by a central, independent radiology facility. A supplementary
analysis was conducted on the time from randomization to objective disease
progression confirmed by imaging studies. Results of this analysis indicated
that statistical significance was not reached in the ITT population (P = 0.183,
log rank; unadjusted HR = 1.32 [95% CI: 0.87, 2.00]).
2.3.2 The secondary endpoints
There was no statistically significant difference
between the treatment groups with respect to time to onset of diseaserelated
pain progression (P = 0.210 log rank; unadjusted HR = 1.47 [95% CI: 0.80,
2.68]). The median time to onset of diseaserelated pain in subjects treated
with APCPlacebo was estimated to be 24.0 weeks, while the median time to onset
of diseaserelated pain in subjects treated with APC8015 was not estimable. The
painfree rate estimate at 12 weeks, 71.5% of the subjects treated with APC8015
and 69.7% of the subjects treated with APCPlacebo had not experienced onset of
diseaserelated pain progression.
Since no subjects experienced a tumor response
based on review by the central radiology facility, there is no evaluation on tumor
response rate and duration of response.
Time to clinical progression was analyzed to
determine the difference in the primary endpoint in cases where both subjective
evidence and independently confirmable evidence of disease progression were
present. For the time to clinical progression analysis, the first evidence of
disease progression for each subject was used, whether based on subjective or
independently confirmable evidence. (For the primary endpoint of time to
disease progression, the date of independently confirmable disease progression
was used when available.) Twentytwo subjects treated with APC8015 and 18
subjects treated with APCPlacebo had a clinical progression date that differed
from their time to disease progression date. There was a trend toward a prolonged time from
randomization to clinical progression in the APC8015 group compared with the
APCPlacebo group, which approached but did not reach statistical significance
(P = 0.061, log rank; unadjusted HR = 1.44 [95% CI: 0.98, 2.10]).
Time to treatment failure was defined as the
time from randomization until any of the following occurred: disease
progression, death, or withdrawal for any reason except withdrawal of consent.
(Withdrawal of consent caused the subject to be censored at the time of the
last visit.) Initiation of other primary anticancer therapy, including
radiation therapy, in the absence of study withdrawal was considered treatment
failure for the purpose of this endpoint, as of the date the therapy was
initiated. The difference between APC8015 and APCPlacebo in time to treatment
failure was not statistically significant (P = 0.124, log rank; unadjusted HR =
1.34 [95% CI: 0.92, 1.94]).
2.3.3 Overall survival
The primary comparison between two arms in overall
survival WAS NOT prespecified in the protocol and the statistical analysis
plan before unblinding the data.
The analysis of the 3year survival data was
based on the ITT population of all 127 randomized subjects. Every subject was followed until death or the
prespecified cutoff of 36 months(i.e.: the cutoff date should be in October
2004 since the last patient was enrolled in October 2001); there were no
censored events prior to the 36th month of followup. Although there was one subject who lost to
followup as shown in Figure 1, this is just specific for the time to
disease progression endpoint.
The first analysis of the survival data were
based on the KaplanMeier technique and the log rank test. Subjects treated
with APC8015 demonstrated an improvement in overall survival, compared to those
treated with APCPlacebo (P = 0.010, log rank; Figure 3). The unadjusted HR was
1.71 (95% CI: 1.13, 2.58), indicating a 41% reduction in the death rate for
subjects treated with APC8015 compared to APCPlacebo. The median survival time
for subjects treated with APC8015 was 4.5 months longer than that for subjects
treated with APCPlacebo (median survival times of 25.9 months and 21.4 months,
respectively). Table 4 and Table 5
present key summary statistics that characterize the differences between the 2
treatment arms.
Figure 3 Overall
Survival (KaplanMeier Method), ITT
Table 4
Summary Statistics, ITT
Table 5
KaplanMeier Survival Rate Estimates, Percent ITT
Following study closure, Dendreon attempted to
obtain death certificates and other source documents to confirm the cause of
death. Based on a review of these additional documents as well as data obtained
from the death summary CRF, all causes of death were ascertained. Given the
importance of the death date, Dendreon also compared the death date recorded by
the clinical study center (on the Death Summary CRF) to the date listed on the
Social Security Death Index (SSDI) for 93 of the 94 subjects who died during
the 36 month followup (An SSDI death date was not available for 1 subject). In
the majority of these cases (86 of 93 cases) the death dates from the 2 sources
were identical. Discrepancies were noted
for 4 subjects treated with APC8015 and for 3 subjects treated with
APCPlacebo. The observed differences are minor and would not substantively
change the survival difference observed between APC8015 and APCPlacebo (Detailed
results of these findings are contained in Section 12.3.3.1).
Several other sensitivity analyses were
performed to test the robustness of the survival results. Specifically, these
sensitivity analyses included the following:
Removal of influential subjects
Removal of investigational study centers
Reversing the treatment assignment of subjects
with randomization errors
Removal of subjects with protocol deviations
Assessing the influence of cell processing
centers (CPCs) on survival
Comparison of use of chemotherapy during
longterm followup
Assessing the influence of prognostic factors
on the observed survival effect
Six of the longest surviving subjects in the
APC8015 group had to be removed before the pvalue exceeded 0.05.
The exclusion of study center 69 was the only
one that resulted in a nonsignificant pvalue (P = 0.062, log rank). This was
the largest study center with a total of 20 subjects (15.8% of all subjects). Each of the other study center exclusions
yielded a significant survival finding.
2.3.4 Proportional model for survival analysis
The sponsor evaluated the individual effect of
the 21 potential prognostic factors as listed in Appendix 16.1.9.11 and found
that eight of these prognostic factors (age, alkaline phosphatase, hemoglobin, lactate
dehydrogenase [LDH], localization of disease, number of bone metastases, PSA,
and weight) could be independently identified as predictors of survival at the
0.05 level. The sponsor also stated that each one of these 8 variables has
previously been identified in the literature as a significant prognostic factor
of survival. Additional prognostic
factor, serum PAP, was also identified as a significant prognostic factor by
the sponsor, but the sponsor excluded it from the model since they believed
that it had substantially more missing data.
In order to build a model that was predictive of
survival, the 9 prognostic factors (including serum PAP) identified in the
univariate analyses were considered as candidates and included in a
multivariate PHR model.
The backwards stepwise selection method (P =
0.05 for entry and P = 0.10 for removal, likelihood ratio test) was then used
to identify the prognostic factors that added significantly to the fit of the
model. Serum PAP was found not to be significant following the backwards
elimination procedure. This analysis was repeated without serum PAP as a
covariate since there was a relatively large number of missing PAP values. The
results of this analysis reduced the number of prognostic factors remaining in
the model to 5. The 5 baseline prognostic factors that remained in the final
model were LDH (ln), PSA (ln), localization of disease, number of bone
metastases, and body weight (lbs). It should further be noted that the
treatment effect continued to be significant at every step of the backward
elimination procedure and was a predictor of survival in the final model.
Following identification of these 5 prognostic factors and in order to utilize
all of the data available, the PHR analyses were conducted with just these 5
variables and the treatment effect in the model because the 3 eliminated
variables had missing data. The results of these analyses are presented in
Table 6. Note that the pvalue for localization was greater than 0.05 but less
than 0.10. The treatment effect was significant (P = 0.002, Wald.s test;
adjusted HR = 2.16).
Table 6
Proportional Hazards Regression Model of Survival Cox model (I)
2.3.5 Cell dose and product potency
While the design of the study was not one in
which the cell dose was specified, the analysis of cell dose and product
potency was requested as a means of examining the relationship between survival
and cell dose. To this end, survival data for subjects treated with APC8015
were assessed in the context of the key release specification parameters of the
product, notably, the TNC, CD54 cell count, and the upregulation of CD54. CD54
cell count and CD54 upregulation were chosen as biologically relevant release
specifications because of CD54s uniform expression on APCs, its role in the
immunologic synapse between APCs and T cells, and its role as a marker of APC
activation. Specifically, experiments have demonstrated that the CD54+
population of mononuclear cells possesses the ability to take up the PA2024
antigen and present epitopes of PAP to hybridoma cell lines recognizing PAP
epitopes.
In the simple Cox PHR model, subjects who had a
CD54 cell count at or above the median of 2.5 x 10^{9} cells, or CD54
upregulation ratio at or above the median of 23.3, had an improved survival
compared to those subjects below the median (HR = 0.63 and HR = 0.79,
respectively). A significant effect on survival was observed between subjects
above and below the median TNC count of 10.8 x 10^{9} cells (HR = 0.52;
P = 0.018; Table 7). A multivariate Cox
PHR model was used to determine whether cell counts correlated with survival
when correcting for the 5 key prognostic variables of baseline PSA, lesion
count, localization of disease, baseline LDH, and weight. A similar trend was
observed when TNC was included in the multivariate Cox PHR model (P = 0.054; HR
= 0.56). As in the simple Cox model,
there was no statistically significant correlation for total CD54 cell count (P
= 0.233; HR = 0.70) or CD54 upregulation (P = 0.274, HR = 0.72) in the
multivariate Cox PHR model.
It should be noted that there was no information
on the cell dose and characteristics from the placebo group and the study was
not designed to provide confirmative evidence for relationship between survival
and cell dose. The significant result
below may just indicate that TNC count is another patient factor predicting prognosis.
Table 7 Analyses
of Survival and Cell Dose
2.3.6 Comparison of Use of Chemotherapy during
LongTerm FollowUp
In order to assess whether the use of
chemotherapy, in particular the use of docetaxel, influenced the survival
results, the two treatment groups were compared with respect to the
administration of chemotherapy use following protocol treatment. This analysis
revealed that there was not a statistically significant imbalance in the
administration of chemotherapies between treatment groups. Based on data from
122 of 127 randomized subjects, 54.4%
of subjects who received APC8015 and 62.8%
of subjects who received APCPlacebo were treated with any chemotherapy following
disease progression (Table 8). (Only the type of chemotherapy and the date of
initiation were collected for this trial. No data on the dose or duration of
chemotherapy are available.)
Table 8 Chemotherapy Use Following Therapy
3.0 Statistical Findings and Comments
3.1 Overall Survival Endpoint
The statistical review focuses mainly on overall
survival since the key efficacy evidence is based on findings of the difference
between APC8015 treated patients and placebo patients in overall survival.
3.1.1 Inflation of Type I error rate
Study D9901 was unblinded in June 2002. In the study protocol and its amendments
including Amendment #6 (9/27/2001) and Amendment #7 (7/25/2002, last amendment),
overall survival as an endpoint was NOT defined. The definition for a survival
endpoint was later added to the study report under this BLA submission as:
The
survival times for subjects who died during the 3year followup period were
defined as the time span (in months) from the date of randomization to the date
of death. The survival times for subjects who were alive at the end of the
3year followup period were censored and defined as the time span (in months)
from the date of randomization to the censor date of 3 years after the date of
randomization.
As described in
Section 9.3 of the protocol below, the sponsor did not plan any hypothesis test
for an effect for overall survival or any other survival endpoints. This
indicates that the sponsor did not prespecify a statistical analysis method
for the primary comparison between the two arms in overall survivalthe
comparison resulted in key efficacy evidence in support of the licensing
application.
9.3 Analysis endpoints
..
This study is not powered to show a survival
effect. However, survival data will be summarized descriptively.
Thus, one would face
the challenge of estimating type I error rate and statistical correction for
multiplicity (multiple endpoints and multiple analysis methods) due to the
unprespecified nature in survival analysis.
The following are the summaries for survival analysis:
a.
Overall survival as
an endpoint was not defined in the protocols;
b.
A statistical analysis
method for the primary comparison of overall survival between the two arms was
not prespecified;
c.
It
is difficult to estimate Type I error rate (false positive rate) for the
difference between two arms in overall
survival
due to multiplicity issues, though it is certain that the type I error rate is
inflated.
3.1.2 Additional sensitivity analyses using Cox
model
The logrank test for treatment effect resulted in a pvalue of
0.01 and the pvalue was reduced to 0.002 when adjusting for a set of
covariates using Cox proportional hazards regression (PHR) model as reported by
the sponsor [Cox model (I) in Table 9].
The results were verified by the statistical reviewer.
It should be noted that there are so
many ways to incorporate covariates in Cox PHR model. These ways include, but
are not limited to: 1) criteria of selecting candidate covariates; 2) covariate
selection procedure in the model (forward, backward, stepwise, etc.); 3) type
of scale used for nonbinary candidate covariates using original scale, using
log scale, using median as cutoff point, using other cutoff point, etc. Therefore, it is very difficult to judge
which model should be treated as the primary when an analysis was not
prespecified because anyone would tend to select the one for his/her own favor
intentionally or unintentionally.
Several additional sensitivity analyses with different set of
covariates in Cox model were conducted by the statistical reviewer and the
results are displayed in Table 9. In one
of the analyses [Cox model (II)] when using localization of disease (bone and
soft tissue vs. bone only or soft tissue only), PSA (<20, 20<100, ≥100),
and Gleason score (≤6, 7, ≥8) as covariates, pvalue=0.0778
(confirmed by the sponsor). As shown in
this table, analysis using different set of covariates resulted in different
pvalue.
Table 9 Treatment effect on overall survival using
Cox model with different set of covariates (total subjects: 127)
Testing Method 
Hazard Ratio 
Pvalue 
Covariate Adjustment 
#Patients Missing 
Logrank
test* Cox Model
(I)* Cox Model
(II)^{~} Cox Model
(III)^{~} Cox Model
(IV)^{~} Cox Model
(V)^{~} 
1.71 2.16 1.47 1.51 1.53 1.52 
0.01 0.002 0.078 0.060 0.053 0.048 
None Localization
of disease, PSA(ln), LDH(ln), Weight, #Bone metastases Localization
of disease, Gleason Score (≤6, 7, ≥8), PSA (<20, 20  <100,
≥100) Localization
of disease, PSA (<20,
20  <100, ≥100) Localization
of disease, Gleason Score (≤6, 7, ≥8) Gleason Score
(≤6, 7, ≥8), PSA (<20,
20  <100, ≥100) 
0 10 5 5 4 1 
*: The sponsors
analyses and confirmed by the reviewer
^{~}: Reviewers analysis
Although 36month survival data are complete for all randomized
subjects, there are some subjects with missing covariate data mainly due to the
nature of unprespecification in overall survival analysis. It should be noted that 10 subjects were
excluded from the analysis due to missing covariate data when Cox model (I) was
used by the sponsor (resulting in a reduction of pvalue from 0.01 to
0.002).
Therefore, the statistical reviewer further analyzed the survival
data by breaking subjects into two groups: 1) subjects with any missing
covariate data and were excluded from the analysis in Cox model (I) by the
sponsor; 2) subjects with complete covariates data for Cox model (I). As presented in Table 10, one can see that patients
without complete covariate data had poor median survival in APC8015 treated
group, compared to the rest of the APC0805 treated patients. In contrast, placebo patients with missing
covariate data had longer median survival relative to the rest of the placebo patients. The randomization principle may be seriously
compromised when using Cox model (I) and exclusion of subjects can lead to
biased estimates of treatment effects. Thus, the results from any analyses with
exclusion of subjects should be interpreted cautiously.
Table 10 Impact of missing covariate
data in Cox Model (I)
Complete Covariate Data 
APC8015 Median N #
Deaths Survival (mons) 
Placebo Median N # Deaths
Survival (mons) 
No Yes 
4
4 19.7 78 50 28.7 
6 5 22.1
39
35 19.0 
In order to include all randomized
patients in the analysis using Cox Model (I), one may want to impute missing
covariate data using different imputation approaches. It is certain that different approaches will
result in different answers. For
example, one may want to assign a median value estimated from those who have
PSA or LDH data to those with missing PSA or LDH values, respectively. If further assume that the 4 patients without
Localization of disease information had bone and soft tissue disease, the
hazards ratio for treatment effect was 1.52 (p=0.054) using Cox Model (I). If assume that the 4 patients without
Localization of disease information had bone only or soft tissue only disease,
the hazards ratio for treatment effect was 1.57 (p=0.036). These two imputation approaches did not low
down the pvalue compared to the logrank test (no covariate adjustment). Again, since no imputation approaches was
prespecified, anyone would tend to select her/his favorite one as
the primary intentional or unintentionally.
The reviewer also evaluated all demographics and baseline
characteristics parameters presented in the study report for their impacts on
overall survival. Column Cov. Effect only in Table 11 shows the
individual effect of each covariate on survival. From this column, one can see that age,
weight, baseline PSA, baseline PAP, baseline hemoglobin, localization of
disease, baseline LDH, and number of bone metastases had statistically
significant (without adjustment for multiplicity) impacts on overall
survival. The third column in this table
shows the treatment effect while adjusting each of the covariates. Pvalues for treatment effect ranged from
0.003 to 0.041 depending on which covariate was adjusted in the model.
It should also be noted that the proportional hazards assumption
as required for Cox PHR model may be violated.
From Figure 4 below, one can see that there was a minimal difference in
the two curves within the first ten months and the hazards between the two arms
may not be proportional over time. This
may indicate that Cox PHR model may not be the optimal analysis tool for this
type of survival data.
Table 11 Single
covariate effect and treatment effect on overall
survival
in Cox model
Selection of Covariate 
Cov. Effect only HR Pvalue 
Treatment Effect HR Pvalue 
#Patients Missing 
Baseline PSA (ln)
Baseline PSA <20 vs. 20  <100 <20 vs.=100
#Bone metastases 05 vs. 610 05 vs. > 10
Baseline LDH (ln)
Localization of disease
Weight
Gleason Score
Gleason Score =6 vs. 7 =6 vs. =8
Age
Baseline alkaline phosphatase (ln)
Baseline hemoglobin (ln)
Baseline serum PAP (ln)
PAP positive reaction Immunohistochemistry (< 75% vs. = 75%)
ECOG (0 vs. 1)
Race (Caucasian vs. other)
Time from diagnosis (yr)

• <.0001 0.0006 1.58 3.06
0.0017 1.66 2.31
3.09 0.0030
1.86 0.0047
0.99 0.0167
1.11 0.2064
0.3037 1.34 1.55
• 0.0243
1.49 0.0225
0.07 0.0079
1.30 0.0038
0.87 0.5464
1.30 0.2766
0.75 0.4601
0.99 0.7275 
1.67 0.015
1.59 0.028
1.89 0.003
1.64 0.022
1.56 0.041
1.75 0.008 1.67 0.016
1.64 0.021
1.86 0.003
1.81 0.005
1.75 0.008
1.83 0.007
1.70 0.012
1.74 0.008
1.68 0.015
1.70 0.011

1
1
0
4
4
1
0
0
0
0
0
13
0
0
1
0 
Thus, three challenges are faced when using Cox PHR model for this
study:
a. The treatment effect was not always
statistically significant since it depended on the set of covariates chosen and
the number of patients excluded from the model;
b. Exclusion of patients from the analysis
due to missing covariate data could lead to biased estimates of the treatment
effect;
c. Proportion hazards assumption for Cox
PHR model may be violated.
Although the difference between the two arms in overall survival was
not statistically significant at the level of 0.05 in a few sensitivity
analyses, many other sensitivity analyses using Cox PHR model reached statistically
significant conclusion at this level. In
summary, it appears that the sensitivity analyses support the statistically
significant finding in overall survival.
3.1.3 Using all available survival data
The protocol was not designed to collect survival data beyond
36 months. Survival data beyond 36
months were not systematically collected; any additional survival data that
Dendreon received from the clinical study centers were not disregarded but
included in the D9901 listing entitled Deaths Known to have Occurred After the
36 Month Followup Period (refer to
Item 8, D9901 CSR, Appendix 16.2.7.7).
Eight patients died after 36 months
were included in the analysis as event (all in APC8015 treated group) and
the survival curves are presented in the following figure (p =0.011 from
logrank test for comparing the two curves).
However, one should interpret the curves after 36month with caution
because of lack of followup data for those who are still alive after 36month.
Figure 4
KaplanMeier Plot of Survival Time
3.2 The Primary Efficacy Endpoint
3.2.1 Change of terminology
In the study protocol and its amendments, the
primary endpoint was described as overall
time to objective disease progression.
However, the primary efficacy variable in the study report under the BLA
submission was presented as overall time
to disease progression. The reviewers
have checked the primary endpoint definitions in protocols against the one in
the study report and found that they were the same except using different
terminology so it appears that the sponsor did not really change the primary
endpoint after completing the study.
3.2.2 Pvalue change for the primary efficacy endpoint
As reported by the sponsor in Appendix 16.1.9.10
in Study CSRD9901 of the BLA submission, Study D9901 was
unblinded in JUN 2002. At that time, the pvalue for time to disease
progression in the ITT population was P = 0.088 (logrank test) when comparing
the two arms. The pvalue changed to P = 0.085 due to a correction by the
independent radiology facility reviewing the scans. A complete clinical audit
was performed comparing source documentation at the clinical study centers to
the clinical database. Based upon this intensive review of the unblinded data,
additional corrections and/or adjustments to the data were warranted, and the
pvalue changed to P = 0.061 for time to disease progression. A radiographic
error was subsequently discovered by the third party CRO responsible for
confirmation of objective disease progression, resulting in a pvalue change to
P = 0.052 for time to disease progression.
The
reviewer was unable to duplicate the pvalues using the data provided in the
submission. After talking to the
sponsor, they pointed out that there were a couple typos in the report:
a)
Date
of last contact for patient 9122082 should be 30MAR2001 instead of
20MAR2001 as shown in the study report.
b)
1.1 Pvalue change from p=0.088 to 0.085 as shown
in Appendix 16.1.9.10 should be rewritten as 1.1 Pvalue change from p=0.085 to 0.088.
After
correcting the typos, the pvalues become:
p
=0.085 using blinded review data in June 2002
p =0.088 after the first
unblinded review
p
=0.061 after the second unblinded review in 2004
p =0.052 after the last
unblinded review
It
should be noted that the last three pvalues (0.088, 0.061, and 0.052) for
comparing the curves in time to disease progression (the primary endpoint) were
based on unblinded review of selected data.
The corrections for errors may or may not be plausible. However, the
process of selected corrections in an unblinded fashion could lead to biased
estimates of treatment effect. Therefore,
the pvalue using blinded review data (p=0.085) should be considered as the
primary result for the time to disease progression primary endpoint. Others are just exploratory.
3.3 Randomization errors
There were 15 randomization errors. The majority
of errors consisted of subjects not being assigned to the randomization slots
expected based on the sequence of enrollment. Since Dendreon was blinded to the
randomization, the errors were made by the independent third party that did not
have access to subject profiles at the time of randomization, and the errors
occurred in similar proportions in both treatment arms. An analysis of the
potential impact of these randomization errors on overall survival was addressed
in a sensitivity analysis by the sponsor in which the treatment assignment of
subjects with randomization errors was reversed.
To further evaluate the errors, this reviewer
excluded the 15 subjects with randomization errors and repeated the
KaplanMeier and logrank analyses, the difference between the two groups in
survival endpoint was still statistically significant (p=0.0155). The impact of randomization errors on
survival outcome seems to be minimal.
3.4 Overall comments
The major efficacy results presented in the
efficacy evaluation of the study report for the primary endpoint and overall
survival were not analyzed and presented based on a well prespecified
plan. Additional sensitivity analyses conducted
by the sponsor and presented in this section showed survival efficacy results
ranging from statistically significant difference to nonstatistical
significant. Due
to the nature of the posthoc analysis, anyone would tend to select any
endpoint and/or result as the primary intentional or unintentionally. Therefore, it is difficult to estimate the type I error rate for this
trial.
II. Study D9902
This trial design, patient eligibility,
objectives and statistical considerations were the same as those in Study D9901. This was a prospective
Phase 3, multicenter, double blind, placebocontrolled, randomized trial of
immunotherapy with APC8015 for the treatment of subjects with asymptomatic
metastatic AIPC. Approximately 120 subjects were planned for enrollment at
multiple investigative centers (27 clinical study centers) across the
This study was initiated shortly after the first
study (D9901). After the first study results became available showing no
overall significance of TTP, the sponsor did a subset analysis of the first study
and found that there was a difference of TTP favoring Provenge arm for subjects
who had Gleason score ≤ 7 (p=0.0014).
At this point, this study had already enrolled 98 subjects. The
sponsor decided to split the second study into two parts (A and B). Part A (D9902A) contained 98 subjects with all
Gleason scores, and part B to enroll subjects only with Gleason score ≤
7. This BLA contains data from the first
part of Study D9902, i.e.: Study D9902A.
1.0 Statistical Analysis Plan
See analysis plan for Study D9901 since the
trial design, patient eligibility, objectives and statistical considerations
were the same as those in Study D9901.
The original primary and secondary objectives of
the study were to compare time to disease progression and time to onset of
diseaserelated pain for subjects treated with APC8015 versus APCPlacebo.
Following discussions with the FDA and prior to performing any analyses, the
statistical analysis plan was revised to elevate overall survival to a
secondary endpoint.
Subjects were followed for survival for 3 years
following their date of randomization. Subjects who were alive at 3 years
following randomization were censored at 3 years from their date of
randomization. Per the statistical analysis plan, survival was evaluated after
the 96th subject had been followed for 3 years following randomization, at
which point 2 additional subjects were censored for survival and included in
the 36month statistic. The sponsor stated that Cox PHR model with
covariates were using the same from Study D9901 before they looked at the data.
These data were analyzed using the ITT and
Safety populations. The ITT population included all randomized subjects (n =
98), and the Safety population included all subjects who underwent at least 1
leukapheresis (n = 96).
2.0 Efficacy Evaluation
2.1 Disposition of subjects
Of the 182 subjects screened for eligibility, 98
subjects were randomized between 12 MAY
2000 and 21 MAR 2003. Of these, 65 subjects were randomized to receive
APC8015 and 33 subjects were randomized to receive APCPlacebo. A total of 96
subjects underwent at least one leukapheresis procedure and a total of 95
subjects received at least one infusion. Figure 6 presents a schematic of the
subject disposition summary for this trial.
Figure
6 Schematic of Subject Disposition
For all randomized subjects, 28 of 98 (28.6%)
subjects had protocol deviations with similar percentages of subjects in both
treatment groups reporting these deviations (17 of 65 [26.2%] subjects treated
with APC8015 compared with 11 of 33 [33.3%] subjects treated with APCPlacebo).
Major protocol eligibility deviations were issued for 2 subjects (1 subject
treated with APC8015 and 1 subject treated with APCPlacebo). The subject
treated with APC8015 had no evidence of metastatic disease at entry and entered
the study with a baseline testosterone value of > 50 ng/mL. The subject
treated with APCPlacebo was not medically or surgically castrate at study
entry. The remainders of the deviations were either minor eligibility
deviations or noneligibility related.
Based on a review of the randomized treatment
assignments performed by Dendreon after the study was unblinded, it was
determined that 18
randomization errors occurred. The
majority of errors consisted of subjects not being assigned to the randomization
slots expected based on the sequence of enrollment. Since Dendreon was blinded
to the randomization, the errors were made by the independent third party that
did not have access to subject profiles at the time of randomization, and the
errors occurred in similar proportions in both treatment arms.
2.2 Demographics and other baseline characteristics
A summary of demographics and baseline
characteristics is provided in Table 12. The demographic characteristics were
similar between the 2 treatment groups. All subjects enrolled in this trial
were male, and the majority of subjects were Caucasian (91.8%). The median age
in this population was 71.0 years; ages ranged from 51 years to 87 years. The
majority of subjects from both treatment groups had a baseline ECOG performance
status of 0 (78.5% of subjects treated with APC8015 and 69.7% of subjects
treated with APCPlacebo).
Table 12 Summary of Subject Demographics and
Baseline Characteristics, ITT
The PAP immunohistochemistry results are summarized
in Table 13. A higher percentage of subjects in the APC8015 group than in the
APCPlacebo group had tumor specimens with at least 75% PAPpositive cells
Table 13 Summary of PAP Immunohistochemistry, ITT
For this study, 85 of 98 subjects (86.7%) had a
Gleason score assigned by a central pathology laboratory prior to randomization.
The Gleason scores obtained by local pathology facilities were used for those
subjects not given Gleason scores by the central pathology facility. A Gleason
score was unattainable for 1 subject (randomized to APC8015). A summary of
subjects Gleason score and tumor status at baseline is presented in Table 14.
Overall, a majority of the subjects had a Gleason score ≤ 7 (61 subjects
[62.9%] versus a Gleason score ≥ 8 (36 subjects [37.1%]).
Table 14 Summary of Gleason Score and Tumor Status at
Baseline, ITT
It should be noted that pvalues provided by the
sponsor in the above tables should not be considered as those from a hypothesis
test for the difference between the two arms.
They just reflect the chance of obtaining the observed difference (and
more extreme) between the two arms in these demographic and baseline
characteristics factors when in fact the two samples were randomly drawn from
the same population.
2.3 Efficacy Results
2.3.1 The primary endpoint
Out of 98 subjects randomized on this study, 89
subjects (90.8%) contributed a progression event. Seventythree subjects
(74.5%) had progression documented by serial imaging (as determined by
independent blinded radiology review) and 16 subjects (16.3%) had progression
based on clinical events other than radiographic events, as defined in the
protocol. Of the 73 subjects who progressed based on imaging studies, 36
subjects treated with APC8015 and 17 subjects treated with APCPlacebo
progressed based on bone disease, while 11 subjects treated with APC8015 and 9
subjects treated with APCPlacebo progressed based on softtissue disease.
When the KaplanMeier curves for overall time to
disease progression were compared, there was no significant difference between
the 2 arms (P = 0.719, log rank; unadjusted HR = 1.09 [95% CI: 0.69, 1.70];
Figure 7). The estimated median time to disease progression was 10.9 weeks in
the APC8015 group compared with 9.9 weeks in the APCPlacebo group.
Figure 7 Primary Efficacy Endpoint, Overall Time to
Disease Progression (Kaplan Meier Method), ITT
2.3.2 Overall survival
The analysis of the 3year survival data was based
on the ITT population of all 98 randomized subjects. As described in the
protocol and statistical analysis plan, every subject was followed until death
or the prespecified cutoff of 36 months. Per the statistical analysis plan,
survival was evaluated after the 96th subject had been followed for 3 years
following randomization, at which point 2 additional subjects were censored for
survival and included in the 36month analysis.
As shown in Figure 8, the unadjusted HR was 1.27
([95% CI: 0.78, 2.07]; P = 0.331, log rank). The median survival time for
subjects treated with APC8015 was 3.3 months longer than that for subjects
treated with APCPlacebo (median survival times of 19.0 months [95% CI: 13.6,
31.9] and 15.7 months [95% CI: 12.8, 25.4], respectively). Table
15 and Table 16 present key summary statistics that characterize the
differences between the two treatment arms. Overall, 28 subjects were alive at
the 36month followup visit and had survival times that were censored at that
time (21 subjects treated with APC8015 and 7 subjects treated with APCPlacebo).
At the end of the study, the proportion of subjects in the APC8015 group who
were alive was 50% higher than that of the APCPlacebo group (31.6% versus
21.2%, respectively).
Figure 8
Overall Survival (KaplanMeier
Method), ITT
Table 15
Overall Survival Summary
Statistics, ITT
Table 16
KaplanMeier Survival Rate Estimates, Percent ITT
A PHR model was
developed to test the robustness of the survival results in the randomized,
placebo controlled companion study, D9901. The 5 baseline prognostic factors
described in this model were LDH (natural log [ln]), PSA (ln), localization of
disease, number of bone metastases, and body weight (lbs). When the model with
these prognostic factors identified in D9901 was applied to D9902A,
localization of disease, LDH, and weight were no longer significant, but PSA
and lesion count continued to be strong predictors of survival. In this multivariate analysis, the treatment
effect was significant (adjusted HR = 1.92; P = 0.023, Table 17). In the model
below, the HR for treatment with APC8015 indicates that the death rate of
subjects randomized to receive APCPlacebo is 1.92fold higher than that for
subjects randomized to receive APC8015.
Table 17 Proportional Hazards Regression Model of
Survival
In order to assess
whether the use of chemotherapy, in particular the use of docetaxel, influenced
the survival results, the two treatment groups were compared with respect to
the administration of chemotherapy following protocol treatment. This analysis
revealed that there was not a statistically significant imbalance in the
administration of chemotherapies between treatment groups. Based on data from
93 of 98 randomized subjects, 66.7% of subjects who received APC8015 and 54.5%
of subjects who received APCPlacebo went on to be treated with any
chemotherapy. More specifically, 56.1% of subjects who received APC8015 and
40.6% of subjects who received APCPlacebo were subsequently treated with
taxanebased chemotherapy; 38.6% of APC8015treated subjects and 34.4% of
APCPlacebotreated subjects received docetaxel. No statistically significant
differences at the 0.05 level in chemotherapy use were found. (Only the type of
chemotherapy and the date of initiation were collected for this trial. No data
on the dose or duration of chemotherapy are available.)
3.0 Statistical Findings and Comments
Similar issues identified in Study 9901 will be
not discussed again in this section. These issues include the inflation of type I
error rate, change of terminology for the primary endpoint, and randomization
errors. However, results from the sensitivity
analyses for overall survival in Study D9902A are quite different from those
for Study D9901. There are some other
unique issues for D9902A and they are discussed together with overall survival in
the following.
3.1 Additional sensitivity analyses for
overall survival using Cox model
The logrank test for treatment effect on overall survival resulted
in a pvalue of 0.331 and the pvalue was reduced to 0.023 when adjusting for a
set of covariates using Cox proportional hazards model as reported by the
sponsor [Cox model (I) in Table 18]. The
results were verified by the statistical reviewer.
When conducting additional sensitivity analyses with different set
of covariates in Cox model, most of them did not reach statistical significance
for the difference between the two groups.
The reviewer also evaluated all demographics and baseline characteristics
parameters and their impacts on overall survival. The treatment effect was NOT statistically
significant when adjusting for any individual covariate in Cox PHR model.
Table 18 Treatment effect on overall survival using Cox model with
different set of covariates (total subjects: 98)
Testing
Method 
Hazard
Ratio 
Pvalue 
Covariate
Adjustment 
Missing 
Logrank test* Cox Model (I)* Cox Model (II)^{~} Cox Model (III)^{~} 
1.27 1.92 1.49 1.12 
0.331 0.023 0.122 0.642 
None Localization of disease, PSA(ln), LDH(ln),
Weight, #Bone metastases (strata: bisphosphonate) Localization of disease, Gleason Score (≤6,
7, ≥8), PSA (<20, 20  <100, ≥100) Age, LDH(ln) 
0 10 2 2 
*: The sponsors analyses and
confirmed by the reviewer
^{~}:
Reviewers analysis
Similar to Study 9901, 10 subjects
were excluded from the analysis due to missing data in some of the covariates
when Cox model (I) was used by the sponsor (resulting in a reduction of pvalue
from 0.33 to 0.023). Therefore, the
statistical reviewer further analyzed the survival data by breaking subjects
into two groups: 1) subjects with any missing covariate data and were excluded
from the analysis in Cox model (I) by the sponsor; 2) subjects with complete
covariates data for Cox model (I). As
presented in Table 19, one can see that patients without complete covariate
data had poor median survival in APC8015 treated group, compared to the rest of
the APC0805 treated patients. In
contrast, placebo patients with missing covariate data had longer median
survival relative to the rest of the placebo patients. The randomization principle may be seriously
compromised when using Cox model (I) and exclusion of subjects can lead to
biased estimates of treatment effects. Thus, the results from any analyses with
exclusion of subjects should be interpreted cautiously. Similar to Study D9901, if imputing missing
covariate data in order to include all randomized patients in the analysis
using Cox Model (I), the difference between the two arms in overall survival
could be statistically significant or nonstatistically significant depending
on what imputation approach was used.
Table 19 Impact of missing
covariate data in Cox Model (I)
Complete Covariate Data 
APC8015 Median N #
Deaths Survival (mons) 
Placebo Median N #
Deaths Survival (mons) 
No Yes 
8
6 13.2 57 38 19.6 
2 2 20.9 31
24 15.3 
In summary, there is not enough evidence in support of the
sponsors finding of statistically significant difference between the two arms
in overall survival using Cox model (I) though there was a trend of difference
in overall survival in Study D9902A.
3.2 Discrepancy between D9901 and D9902A in
Cox model (I)
The sponsor stated that they planned to use the
same set of covariates in Cox model (I) from Study D9901 for Study D9902A before
they looked at the data in order to support their statement that the analysis
using Cox model was prespecified in Study D9902A. However, there is a discrepancy between the
two studies in terms of using Cox PHR model.
As shown in the randomization plan in both Phase
III studies, subjects were stratified by clinical study center and use of
bisphosphonate therapy (yes or no) prior to being randomized. The Cox PHR model the sponsor used for Study
D9901 did not incorporate use of bisphosphonate therapy as strata in the model
while the Cox model for Study D9902A did.
Therefore, the two models are different.
When analyzing data from Study D9902A using the exact same Cox model in
Study D9901 (without use of bisphosphonate therapy as strata in the model), hazards
ratio changed from 1.92 to 1.79 and pvalue for comparing the two treatment
groups changed from 0.023 to 0.036.
Given the fact that data were available at the
time when the sponsor developed an analysis plan for survival for Study D9902A,
there was a chance that the analysis plan might be developed under the
influence with the knowledge of the survival data intentionally or
unintentionally.
3.3 Inappropriate presentation of data
The sponsor presented overall survival data for
Study D9902A as below (Table 15 in this review memo). Reporting 21 subjects (APC8015 treated) alive
in Column Subjects alive at 36month
visit is misleading. Two subjects
who censored before 36month (alive at the end of followup before 36month)
were treated as alive at 36month. In fact, there were only 19 subjects in
APC8015 group who were known to be alive at 36month. Thus, number of subjects
alive a 36month in APC8015 group should be estimated in the range of 1921
(29.2%32.3%).


III. Integrated Summary and Other Findings
1.0 Summary of Efficacy
The
The Phase 3 clinical development program was
initiated in 2000 and was designed to evaluate the safety and effectiveness of
APC8015 to address the unmet medical need of treating men with asymptomatic
metastatic AIPC. At the time the Phase 3 program was designed, there were no
approved therapies for men with asymptomatic or minimally symptomatic AIPC.
Standard and experimental chemotherapies available at the time were palliative
and associated with significant toxicity. It was not until May 2004 that docetaxel
was approved and shown to prolong survival in AIPC. However, there remains a
clear need for less toxic therapies that benefit patients with AIPC,
particularly those without cancerrelated pain, many of whom elect not to
pursue chemotherapy.
The pooled survival data are derived from all 225
randomized subjects in D9901 and D9902A. A total of 223 subjects were followed
until death or until a cutoff of 36 months after their date of randomization.
Two additional subjects in D9902A were censored at 25.6 months and 26.7
months as a result of a predefined data cutoff point.
The summary of posthoc analyses on the overall
survival endpoint is presented in Figure 9 and Table 20 (P = 0.011, log rank,
stratified by study). The HR for treatment, based on the Cox PHR model with no
covariates, was 1.50, indicating a 33% reduction in the death rate for subjects
treated with APC8015 compared to APCPlacebo. The median survival time for
subjects treated with APC8015 was 4.3 months longer than that for subjects
treated with APCPlacebo (median survival times of 23.2 months and 18.9 months,
respectively).
Figure 9 Integrated D9901 and D9902A Overall Survival
(KaplanMeier Method), ITT
Table 20
Summary of Overall Survival in Studies D9901 and D9902A
When the KaplanMeier curves for overall time to
disease progression were compared, there was no significant difference between
the 2 treatment arms in the integrated D9901 and D9902A ITT population (P =
0.111, log rank; HR = 1.26 [95% CI: 0.95, 1.68]; Figure 10). The estimated
median time to disease progression was 11.1 weeks in the APC8015 group compared
with 10.0 weeks in the APCPlacebo group.
Figure 10 Integrated D9901 and D9902A Overall Time to
Disease Progression (Kaplan Meier Method), ITT
2.0 Summary of Safety
Subjects who underwent at least 1 leukapheresis
procedure were included in the safety population. The safety population
consists of 669 subjects who
underwent at least 1 leukapheresis procedure and were to be treated with
APC8015, APCPlacebo, APCPlacebo followed by APC8015F, or APC8026 (a product
similar to APC8015 but with a different method of manufacture and cell
composition).
Detailed review on safety can be seen in the clinical
briefing document.
3.0 Statistical Findings and Comments
3.1 Inconsistent efficacy results between the
two trials
The study design was identical in
the two studies and the outcome for the primary endpoint, time to disease
progression, was quite similar between the two studies. As shown in the following table, the median
time to disease progression for placebo patients were 9.1 weeks and 9.9 weeks
for Studies D9901 and D9902A, respectively; the median time to disease
progression for APC8015 treated patients were 11.0 weeks and 10.9 weeks for
Studies D9901 and D9902A, respectively.
However, the baseline survival
experience was quite different for the two studies. As shown in Table 21, the median survival for
placebos was 15.7 months in Study D9902A, but 21.4 months in Study D9901. The median survival for APC8015 treated
patients in Study D9902A was 19 month which is shorter than that for the
placebo patients in Study D9901. More
discussion on this discrepancy should be seen in the clinical briefing document.
Table 21 Comparisons of TTP and overall survival between the two Phase III
studies
Study 
Median Time to Progression (wks) APC8015 Placebo 
Median Survival Time (Months) APC8015 Placebo 
D9901* D9902A 
11.0 9.1
10.9 9.9 
25.9 21.4 19.0 15.7 
* using the blinded review
data
3.2 Strength of overall efficacy evidence
The Guidance for
IndustryProviding Clinical Evidence of Effectiveness for Human Drugs and
Biological Products (see ref: [1]) explicitly says With regard to quantity, it has been FDAs position that Congress
generally intended to require at least two adequate and wellcontrolled
studies, each convincing on its own, to establish effectiveness. It implies that positive results from at
least two adequate and wellcontrolled trials are, in general, required for
licensure application. Two positive
trials not only substantially reduce the chance of making a false claim, but
also assure that a result could be more robust, replicated in different
settings, and more representative to the targeted population.
In each adequate, wellcontrolled
(pivotal) trial, the probability of erroneously rejecting the null hypothesis
(significance level) needs to be prespecified. Conventionally, this level is
set at 0.05 (twosided). If two trials are required to show statistically
significant on the primary endpoint, the operational type I error rate for approving an
ineffective product should be controlled under a level of 1/1600 (=1/40 ื 1/40),
from a statistical perspecitve. This is because taking the operational view,
we simply regard a twosided test at the 0.05 level as being a onesided test
at the 0.025 level (1/40). (see refs:
Senn[2], Fisher[3])
The key efficacy
evidence in this BLA is the difference between the two arms in overall
survival. The logrank tests for
comparing the two arms in overall survival resulted in a pvalue
of 0.01 and 0.331 for Studies D9901
and D9902A, respectively. As shown in the integrated analyses, analyzing the
pooled survival data derived from all 225 randomized subjects in D9901 and
D9902A showed a statistically significant difference between the two arms in
overall survival (pvalue= 0.011). Although
analyzing the pooled data from the two studies supported the statistically
significant finding in overall survival, it did not enhance the strength of efficacy
evidence in support of the efficacy claim, from a statistical perspecitve.
Additional analysis using Cox PHR adjusting some
sets of covariates could lower pvalues for the comparisons. However, the results could be biased mainly due
to the exclusion of randomized patients and should be used just as supportive. Therefore, 0.01 is likely the pvalue for comparing
the two arms in overall survival.
As shown in this
review, overall survival was not defined as the primary or secodary endpoint in
the protocols. The primary statistical analysis
for comparing the two arms in overall survival was not prespecified. Because of these unprespecified nature, it is
impossible to precisely estimate the operational type I error rate for
approving an ineffective product.
However, with the adjustment for multiple endpoints and multiple
analyses, one may still want to judge that the type I error is controlled under
the level of 0.05 or close to this level.
This implies that the type I error rate for approving this product may
be close to the level of 1/40.
Therefore, even if the statistically significant judgment is considered
reasonable, it
is certain that the level of falsely claiming effectiveness for this product is
substantially higher than the one in a conventional setting (1/1600).
Although none of
the prespecified endpoints reach statistical significance when comparing the
two arms in both trials, all comparisons show a trend in favor of APC8015
arm. Study 9902A did not provide convincing
evidence to show statistically significant result in overall survival, but
numerically it showed a trend toward improvement in overall survival.
The
key efficacy evidence (difference between the two arms in overall survival) for
this BLA is based on posthoc analyses and the efficacy evidence is not
substantial from a statistical perspective.
However, the following points should be weighed while considering the unfavorable
strength of statistical evidence: 1) showing statistically significant difference in overall survival in Study D9901 and
showing a trend toward improvement
in overall survival
in the second study; 2) showing a
trend in favor of APC8015 arm in all comparisons for other important
endpoints; 3) the safety profile
of the product; 4) other existing effective treatments for the targeting
patient population.
Summary and Conclusions
Study Summary
BLA
125197.0 is an original submission on Provenge (SipuleucelT, APC8015) for the treatment of men with asymptomatic
metastatic androgen independent prostate cancer. Data from two randomized, double blind,
placebocontrolled studies were submitted as the main efficacy evidence under
this BLA to support the licensing application.
Both
studies failed to meet their primary endpoints.
However, In Study D9901 with 127 patients, the median overall survival
in subjects treated with APC8015 was 25.9 months, compared to 21.4 months among
placebo subjects. The difference between the two arms in overall survival
reached statistical significance (p = 0.01) by the log rank test. Study D9902A,
an identically designed study with 98 patients, only showed a trend toward
improvement in overall survival. It
should be noted that overall survival as an endpoint was not defined in both
study protocols and the primary
statistical analysis for comparing the two arms in overall survival was not prespecified. Although none of the prespecified endpoints reached statistical
significance when comparing the two arms in both trials, all comparisons showed
a trend in favor of APC8015 arm.
Conclusions
ท
Based
on the results of the statistical analyses of the efficacy data presented by
the sponsor and the results of analysis performed by this reviewer, it appears
that the two studies provide some evidence in support of using Provenge for the
treatment of men with asymptomatic metastatic androgen
independent prostate cancer.
ท
However,
the key efficacy evidence (difference between the two arms in overall survival)
is based on posthoc analyses. Although
it is impossible to precisely estimate the false positive rate due to the
nature of the analyses, it is certain that the level of falsely claiming
effectiveness for this product is substantially higher than the one in a
conventional setting.
ท
It
may be important to weigh the following points while considering the unfavorable
strength of statistical evidence: 1) showing statistically significant difference in overall survival in Study 9901
and showing a trend toward
improvement in overall survival in the second study; 2) showing a trend in favor of APC8015 arm in all comparisons for other important
endpoints; 3) the safety profile
of the product; 4) other existing effective treatments for the targeting
patient population.
References
1.
2.
Senn S. Statistical Issues in Drug Development, Section 12.2.7: The twotrials rule.
3.
Fisher
LD. One large, welldesigned,
multicenter study as an alternative to the usual FDA paradigm. Drug information Journal. 1999; 33: 265271.