Disposition of Comments
Project ID: CANP0610
The Agency for Healthcare Research and Quality's (AHRQ) Technology
Assessment (TA) Program supports and is committed to the transparency of its review process. Therefore, invited peer review comments and public review comments are publicly posted on the TA Program Web site at http://www.ahrq.gov/clinic/techix.htm within 3 months after the associated final report is posted on this Web site.
This document presents the peer review comments and public review comments
sent in response to the draft report, Outcomes of Sipuleucel-T Therapy:
Technology Assessment Report, posted on the AHRQ Web site from November
17 to December 6, 2010. The final version of the report is available
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1: Invited Peer Reviewer Comments.
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2: Public Review Comments
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1: Invited Peer Reviewer Comments
Appreciate the opportunity to review this report "outcomes
of Sipuleucel T Therapy."
The technology report is timely, comprehensive
and well written.
The 3 questions addressed are very relevant and impact the
practioner's use of the product.
||The summary is very well written and I agree with the conclusions.
||The terminology currently used is CRPC and not HRPC and should
be mentioned in the background Secondary Hormonal treatments are routinely
used prior to chemotherapy in this space and should be mentioned Additional
androgen receptor targeting drugs such as abiraterone/MDV31 in late phase development
in the background would help % of patients who were symptomatic in both SWOG
and TAX 327 trials should be added.
Page 4: Mention must be made that optimum
timing to start chemotherapy after sipuleucel T not known/mentioned. Median
time to docetaxel in IMPACT was 7.2 months.
|We changed terminology. Secondary hormonal treatments are now
mentioned. SWOG symptomatic % was added FDA labeling does not address this,
therefore not mentioned. Docetaxel timing mentioned later in report.
||Define placebo infusion-page 7;Comparator in RCT was non activated
autologous peripheral blood mononuclear cells-
Well defined: and appropriately
|Changed per reviewer suggestion.
||1. 2/3 studies were statistically significant for overall survival in
favor of sipuleucel T. The third had a similar magnitude of benefit; QOL not
2. Insufficient evidence to evaluate outcomes
for off label indications.
3. Infusion reactions common; Infections associated with leucopheresis.
|No comment to address.
||Section is well summarized and concludes well.
||Table 1/2: no change
Table 3: no change
Table 4: very useful
Table 5: no change
Table 6: well described in text; consider deletion
Table 7: would fit better as appendix B3
Table 8: no change
Table 9/10: no
Table 11: no change
Table 12: no change
Table 13: no change
mention no data on late infections
Table 15: no change
Table 6 was kept in.
Table 7 kept in as is.
on late complications.
||Table 1: good summary if I/E criteria of the 3 RCT
Table A3: Not sure if it adds much value
Table A4: Reads well with the
summary of RCT
Table A4: Reads well with the summary of RCT
Table A5: Summarizes
all off label studies; agree with selection of studies
|Table A3 was retained.
||The 38 references are appropriate and span from 2000-2010
|| This report is notable for its clear and unbiased exploration and analysis
of the data on sipuleucel-T. The discussion is complete. I agree completely
with the conclusions.
I would add to the discussion of the immune monitoring data
that the study design (in addition to its other flaws) prevents assessing
the impact of the PA2024 on the results. The authors conclude that three
injections of antigen-presenting cells pulsed with a tumor antigen improves
survival; however, no role for the tumor antigen has been demonstrated. A
better design would have been to administer autologous antigen-presenting
cells stimulated in vitro with GM-CSF alone. Such treatment could well have
resulted in an increase in CD54 expression both in vitro and in vivo and
accounted for the observed effects. A difference between adoptive transfer
of cells treated with GM-CSF alone and cells treated with GM-CSF plus PA2024
would have tested the question of whether the antigen plays any role at all
in the survival increase.
A final point I would like to raise is the unexplainable
nature of the survival effect. Many cancer treatments have been shown to
have effects on the tumor, including partial responses or delay in tumor
progression, but have NOT made an impact on overall survival. In general,
affecting overall survival has always been the more difficult endpoint
to influence with a new intervention. It is extremely unexpected for an
intervention to make an impact on overall survival without any discernible
effect on the tumor itself. Imagine the skepticism that would accompany
a claim that a new antibiotic improved survival in tuberculosis without
affecting the organism in any measureable way.
|Although point interesting, review does not address role of
ingredients of treatment. No comment made to address lack of tumor response.
||In appendix B, all three forest plots should be redrawn using
a log scale. Forest plots depict hazard ratios. One cannot have a ratio of
zero; therefore, a more precise method of depicting the data is to plot it
on a log plot.
||Forest plots were reproduced from other publications. We do
not have actual data points.
|| This is a thorough, well written and complete report discussing the evidence
available supporting the clinical use of sipleucel-T in patients with prostate
cancer. The evidence is summarized and appropriately used to answer the key
|| Exec Summary
||Recommend clarification of the first sentence on the last paragraph
on ES-1: "Three randomized clinical trials ... study design which
includes placebo leukapheresis and infusions for the control group..." In
these studies the leukapheresis procedure was the same for the treatment and
control groups, therefore it cannot be termed "placebo leukapheresis." The
issue of placebo used in this study is complex and addressed well throughout
the document. I would recommend correcting the language here to reflect this.
||Changed per reviewers recommendation.
|| Data describing the three key clinical trials were abstracted
from multiple published reports and described in aggregate for each of the
three trials. As discussed by the authors, this approach may produce inconsistent
results from the same data set due to different data cutoffs, technical differences
in the analyses etc. However, I agree that analyzing the data in aggregate
provides more useful results than analysis of each report separately.
of the nature of the "placebo" used in these studies was accurate.
The fact that the control group received a treatment that is not a true placebo
is an important issue to consider when interpreting these results. Discussion
of the cross-over effect, a common caveat when interpreting the survival
comparison, was thorough.
Appropriately noted was the fact that all three
large prospective studies analyzed were initially designed for a PFS endpoint
and then either amended or subjected to post-hoc analysis for overall survival.
I agree with the rating of data quality as "fair" based on the
studies not meeting their original primary endpoint of PFS, and then being
subsequently analyzed for overall survival.
"Survivor bias" is
appropriately discussed as it pertains to the comparison of patients receiving
frozen salvage product. Regarding receipt of subsequent chemotherapy: As
discussed, the difference in time to administration of chemotherapy between
the treatment and control groups may be explained by delay due to receipt
of frozen salvage product at progression delaying time to chemotherapy in
the control group. I do not believe this bias can be satisfactorily attenuated
with any of the alternative analyses described for the reasons the authors
discuss. The description of the alternative analyses used to
account for the differences in subsequent treatment could be better and more
thoroughly described for a more general readership. The key point is made
that sipuleucel-T is effective in a context in which most patients also receive
chemotherapy, and the interaction between sipuleucel-T and subsequent chemotherapy
should be more closely examined to provide insight into this relationship.
The issue of treatment effect as it relates to baseline characteristics was
appropriately addressed. There are no convincing baseline characteristics
predictive of treatment effect.
The association of product and immune parameters
with patient outcomes was thoughtfully presented. I agree that these analyses,
while scientifically interesting and informative, do not inform the question
of clinical efficacy. Furthermore, potential for the development of any of
these assays for the purposes of patient selection is limited given that
these parameters are only noted after the patient has initiated treatment
The data describing off-label indications for sipuleucel-T
is thoroughly reviewed and accurately presented, and overall does not support
use for off-label indications. Regarding adverse events: The discussion of
adverse events is thorough and inclusive of all reported information to date.
The overall incidence of serious adverse events is relatively low given this
patient population, and comparable between placebo and treatment groups.
The authors appropriately point out that the incidence of adverse events
associated with procedures common between the treatment and control groups
(pheresis and infusion) would be expected to be balanced between the two
groups, and therefore obscuring possible attributions to treatment. The fact
that adverse events associated with frozen salvage product have not been
described is concerning. It should be clarified in the report whether these
events were not reported at all, or reported but not directly attributed
to salvage product. Such events should be both reported and attributed
to better inform the efficacy results of the study. If many patients had
serious adverse events to salvage product, this could help explain why fewer
patients in the control group received salvage chemotherapy. The number of
cardiovascular events is overall small, and attribution is difficult. Further
study of these is ongoing. Infusion reactions were more common in the treatment
group, but seen in the control group as well.
Further sentences regarding alternative analyses were added.
It is not clear from protocol documents regarding the reporting of adverse
events proximate to the time of frozen salvage product. "Late" events
are only reportable if "attributable" to sipuleucel-T.
|| The conclusions are succinct and well founded. Regarding the issue of design
of future trials: While it would be scientifically preferable to dictate
post study treatment, given how fast the landscape of prostate cancer treatment
is changing and the widespread availability of subsequent clinical trial
therapies, it would not be ethical to dictate care up until the survival
||Reworded to emphasize designs which ensure equal quality of
care and avoid potential for systematic bias in subsequent treatments.
||On Table 4, 8015F and 8105F (presumably the second is a typo)
are referenced but not defined.
||Changed to frozen salvage product.
||The figures are clear and helpful.
1. Peer reviewers are not listed in alphabetical order.
2. If listed, page number, line number, or
section refers to the draft report.
3. If listed, page number, line number, or
section refers to the final report.
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Table 2: Public Review Comments
||The major components of this review include a description of
the evidence base for sipuleucel-T use in castrate-resistant metastatic prostate
cancer, including comments on off-label use, safety, and metrics other than
overall survival. Overall, I agree with the committee findings. There is insufficient
evidence to recommend sipuleucel-T immunotherapy for men with non-metastatic
CRPC, hormone-sensitive prostate cancer, and metastatic moderately to severely
symptomatic prostate cancer. I believe there is also limited evidence to support
use in the post-chemotherapy setting, as this was a very small subset of the
IMPACT trial and determining efficacy in this more poor-prognosis group is
difficult with the small evaluable sample size and heterogeneity of this subgroup.
Safety is acceptable, but I agree, certain elements (stroke risk, citrate reactions,
infusion reactions) are difficult to compare to a true control given the presence
of a sham-pheresis control. The overall survival data is robust across several
trials and does not appear explainable by differences in pre or post-treatment
patient differences to the best extent that these can be assessed with the
existing data. Issues that are unresolved include the effect of cross over
to frozen sipuleucel-T and what effect this may have had on immune function
or delayed initiation of docetaxel chemotherapy. Additional important future
analyses should evaluate other metrics of radiographic progression similar
to recently updated immune-response progression guidelines (JNCI 2010), circulating
tumor cell metrics, quality of life, cost-effectiveness, and the appropriate
sequencing of this therapy with chemotherapy and novel hormonal therapies that
may contain modestly immunosuppressive doses of corticosteroids (ie docetaxel
and prednisone, abiraterone acetate and prednisone).
||Comments noted. Thank you.
In the report, under key question 3, the following is stated: "Three
randomized clinical trials of sipuleucel-T are consistent with longer overall
survival in patients meeting the FDA-labeled indication. This conclusion
is tempered by consideration of a trial design with inherent potential for
confounding due to frozen salvage product and post-progression variation
in treatment. The quantity of benefit of sipuleucel-T is less certain because
of these issues."
I would like to specifically address two points with this. The first has
to do with the salvage product and the second has to do with post-progression
variation in treatment.
The main difference in the salvage product (used in the control arm after
cross-over) compared with the experimental arm product is that the salvage
product was frozen. While this may have some impact on the efficacy of the
salvage product (a currently untested hypothesis), that is not relevant to
the point in issue. Generally a cross over design causes an under-estimation
of the true therapeutic effect on overall survival. One would have to argue
that the salvage product actually harmed patients to make the above case
outlined in the Technology Assessment. This is not only very unlikely, but
there is no biologic rationale to support this. First, the salvage product
met the same product release criteria as the product used in the experimental
arm. Second, the median predicted survival of the control arm based on a
validated nomogram was the same (21 months) as the actual overall survival.
If there had been substantial harm caused by the salvage product this should
have negatively impacted the median overall survival for the entire control
arm, something not seen. Third, as reported by Dan George in the MEDCAC meeting,
there is data suggesting improved outcomes for the subset of patients in
the control arm treated with salvage product compared with other patients
even after accounting for clinically relevant variables (to be presented
at the ASCO sponsored Genitourinary Cancers Symposium in 2011). While these
types of subgroup analyses are subject to bias, all the available data suggest
that there is no basis for the argument that the salvage product causes harm.
Furthermore, as mentioned above there is no biologic rationale for harm caused
by the salvage product, indeed available data and biologic rationale suggest
a possible underestimation of the true efficacy impact on overall survival
seen in this trial.
The argument that post-progression treatment led to the improvements seen
in overall survival is also without merit. The data available in this study
is as balanced in post-progression treatment as is likely to be seen in a
trial in patients with advanced cancer. It would not be feasible, and indeed
may be unethical, to prospectively determine post-study cancer therapies
for cancer patients. There are many changes over the course of the disease
course in cancer that may dictate what the appropriate next therapy should
be. In addition, patients may decline or discontinue early some therapies
due to side effects. About half of advanced prostate cancer patients never
get chemotherapy. Fortunately for the interpretation of the results, there
was only one agent shown to impact overall survival in patients with metastatic
castration resistant prostate cancer that was in use during the time period
when this study was conducted. This agent is docetaxel which demonstrated
an improvement in overall survival of 2.4 months (Hazard Ratio 0.76). The
documented post-progression receipt of docetaxel was roughly the same in
the two arms (50 vs. 57%), certainly not enough of a difference to cause
the observed treatment effect (improvement in median overall survival of
4.1 months, Hazard Ratio 0.775). There was also minimal imbalance in the
time to receipt of docetaxel, moreover there is no data to suggest that the
timing (early vs. late) of docetaxel results in improved survival. The extensive
analysis done for docetaxel use post-treatment (prior to FDA approval, some
of which were published in the New England Journal of Medicine) have consistently
demonstrated that the only reasonable explanation for the results is due
to the efficacy of sipuleucel-T. Finally, there are multiple new drugs that
are emerging following docetaxel that may impact survival. Cabazitaxel was
recently approved (June 2010) for use in men with prostate cancer following
docetaxel based on an improvement in overall survival, and abiraterone was
also recently shown to improve overall survival in the same patient population
and is widely expected to be approved soon by the FDA. Both of these drugs
will be used in the post-docetaxel setting (for abiraterone at least initially
this will be the case) and thus after the likely sipuleucel-T use. Another
very promising drug, MDV-3100, is being evaluated in a phase III study in
the post-docetaxel setting. Any overall survival trials done in the future
in the pre-docetaxel setting will thus have many more confounding variables
affecting the primary endpoint. Therefore not only is the available data
from the IMPACT study on post-trial standard therapies relatively well-balanced
(with any slight imbalance not able to explain the improvement in overall
survival), but any trial done in the pre-docetaxel setting in the future
would likely have a greater degree of uncertainty than the IMPACT study due
to multiple (rather than 1) potentially confounding variables.
Dr. Gulley addresses 2 issues that numerous commentors also
commented on. I will title the responses to these concern #1) salvage therapy
response, and #2) bias of subsequent treatments and adequacy of analysis.
In subsequent comments I will simply refer back to #1) salvage therapy response
and/or #2) bias of subsequent treatments.
#1) Salvage therapy response:
Analyses of salvage benefit are either unevaluable (unpublished) or do not
take into account selection and survival biases. Hazard ratios cited of 0.52-0.58
in some comments for salvage therapy is greater than the effect for sipuleucel-T.
An unmeasured benefit of salvage therapy might be assumed if salvage therapy
was identical to sipuleucel-T. In addition to being made from frozen cells,
salvage product is produced from sipuleucel-T naïve cells. In standard
treatment, the 2nd and 3rd treatment products come from sipuleucel-T exposed
The TA does not hypothesize that frozen product is directly harmful to patients.
In the setting of these research studies, it is likely to have caused the
observed delay in subsequent chemotherapy treatment and may have caused the
lower proportion of patient receiving chemotherapy in IMPACT. The interposition
of this treatment after progression in the control group may be responsible
for the complex issues in analyzing this study. In other studies of cancer
treatments where there is overt evidence of treatment response, salvage therapies
will then be administered more frequently to the patients in the group receiving
the less effective primary therapy. Because of the delay in initiating known
effective therapy induced by treatment with salvage product, analysis of
the sipuleucel-T trials was more problematic than other clinical trials of
#2) Analysis of subsequent treatments:
TA reports these analyses, points out limitations, suggests alternative
statistical techniques. Subsequent treatments are problematic to analysis
of clinical trials when there is a systematic difference in application,
as occurred here due to frozen salvage product. Opinions vary as to whether
these methods successfully account for potential confounding.
The technology assessment raises the issue of salvage therapy
on outcome in the sipuleucel-T clinical trials. At the time of progression,
patients were unblinded and control patients were offered therapy with an
autologous cellular immunotherapy, APC8015F, prepared from cells cryopreserved
at the time the placebo was manufactured. APC8015F was otherwise manufactured
like sipuleucel-T, and was required to meet the same release specifications.
To explore the potential effect of this treatment on patient outcomes, we
examined the survival of placebo patients from the time of disease progression
in three randomized controlled trials.
Of 249 control subjects, 165 (66.3%) received APC8015F; the median time from
randomization to first infusion was 5.2 months (range 1.8 to 33.1), median
time from objective disease progression to first APC8015F infusion was 2.2
months (range 0.5 to 14.6), and 145 subjects (87.9%) received all 3 infusions.
APC8015F-treated subjects (n=155) had improved post-progression survival relative
to untreated controls (n=61) (HR=0.52 [95%CI 0.37, 0.73] p=0.0001, log rank
test, unadjusted Cox regression). The beneficial effect of APC8015F was maintained
in additional analyses which adjusted for baseline prognostic features and
for post-randomization docetaxel use.
We recognize that measured and unmeasured factors may confound outcomes
in patients who received APC8015F; nonetheless, these analyses suggest that
post-progression treatment with APC8015F may have extended the survival of
subjects in the control arms of these studies. There is no clinical evidence,
nor biologic rationale, to suggest that APC8015F may have worsened outcomes
in patients. Therefore, the inclusion of treatment with APC8015F following
progression in the sipuleucel-T trials would be expected to lead to an underestimation
of the true overall survival benefit seen. My co-authors and I have submitted
these findings to the 2011 Genitourinary Cancers Symposium.1
1 George D, Nabhan C, Gomella L, Whitmore JB, Frohlich MW. Subsequent Treatment
with APC8015F May Have Prolonged Survival of the Control Arm in Phase 3 Sipuleucel-T
Studies. Submitted to 2011 Genitourinary Cancers Symposium. Orlando, FL Feb
|See #1) Salvage therapy response.
I have been in the field of prostate cancer for 24 years
and have been involved in or led many studies relating to the major therapeutic
advances in this disease area, and was the lead investigator on the IMPACT
trial, published in the NEJM on July 29, 2010. I consider the clinical development
of sipuleucel-T to be a very exciting advance in the treatment of patients
with prostate cancer.
IMPACT was a double blind, randomized, multicenter, placebo-controlled trial
in 512 patients with metastatic castration resistant prostate cancer conducted
under a Special Protocol Assessment with the FDA. Placebo was used as a control
as opposed to chemotherapy with the intent of creating a clinical niche for
the development of treatments which prolonged survival while causing few
treatment-related side effects. Designed to be identical in appearance to
sipuleucel-T, the placebo also maintained the study blind.
Following disease progression, patients were treated at the physician's
discretion, and patients on the placebo arm had the option of crossing over
to treatment. This aspect of the study would be expected to decrease the
observed difference in overall survival; the true benefit would likely have
been greater in the absence of crossover.
The use of docetaxel following study treatment was comparable to what would
be anticipated in clinical practice. Several analyses to investigate the
potential role of docetaxel provided no evidence for an alternative explanation
for the overall survival benefit. Although these analyses have limitations,
the comparable use and time to initiation of docetaxel between the treatment
arms, coupled with the large difference in overall survival observed make
it implausible that differences in subsequent docetaxel use between the arms
could account for the study findings. The Technology Assessment questions
the confounding due to crossover and subsequent interventions. Given that
the true benefit may be greater than that observed in the clinical trials,
the strength of the evidence would if anything be considered to be greater
than that observed.
In conclusion, the IMPACT trial confirms the overall survival findings of
prior randomized trials. I view this trial as definitive proof that sipuleucel-T
provides clinically important benefit to patients. The requirement for additional
trials for the current indication does not seem wise or ethical. The treatment
represents the largest median survival increment of any therapeutic in the
treatment of CRPC patients to date, delivered with modest side effects and
a short duration of therapy. Sipuleucel-T represents a needed advance for
patients with lethal prostate cancer. Trials in the future should be designed
to build upon the success of this treatment.
|See #2) Analysis of subsequent treatments.
Comments on AHRQ Technology Assessment Draft Date of Draft
1) The comments regarding the statistical issues inherent in a 2:1 randomized
trial with a potential crossover are valid. An identical trial design was
employed in IMPACT, D9902A and D9901. These statistical considerations must,
however, be tempered by consideration of patient acceptability and fairness.
In my clinical experience, many patients with metastatic, castrate-resistant
cancer are unwilling to enroll in a 1:1 randomized, placebo controlled trial.
Given the relatively short survival (14 months without treatment) of such
patients, this attitude is understandable. My assumption is that the trial
design was conceived with a fair degree of input from patient advocates.
2) The discussion of the salvage treatment option for the placebo group
is handled somewhat unfairly in the assessment draft. It the agent (and salvage
treatment) are active, then the allowed crossover would be expected lead
to a relative UNDERestimation of treatment benefit. The fact that a consistent
survival benefit was noted in spite of this confounding influence strongly
supports the notion that the agent is active, and further suggests that the
treatment benefit could potentially be greater than that measured.
3) The assessment makes no mention of the rationale underlying the change
in primary endpoint for IMPACT from PFS to overall survival. It is important
to note that this change was based on data gathered as 9901 and 9902A progressed.
Generally, survival is considered to be a more robust endpoint than PFS,
and the trial was thus modified toward a MORE rigorous endpoint. This should
be properly appreciated.
4) The section implying that treatment with Sipuleucel T is associated with
infection is not valid. To make that inference, the authors would need some
data on baseline "infection" rates in this population, as they
correctly emphasize that both the control and placebo groups received I.V.
infusions of processed and shipped cells. Further, the use of the term "infection" is
nebulous in this discussion.
Does table 14 include routine upper respiratory
infections, with an obvious baseline prevalence? In reality, the only infections
that are relevant in such a discussion are those that are clearly product-related
? those data are not shown. Further, the number of infections that are catheter-related
is shown to be in the 3% range, which is more than would be hoped for, but
does not seem to be out of line with general clinical experience.
5) The conclusion that the survival benefit of Sipuleucel-T is observed "only
in the context of a substantial amount of eventual chemotherapeutic treatment" is
not supported by the data or analysis presented. Standard clinical practice
in oncology is to offer additional treatment options to patients who progress
on either standard or experimental therapy. To withhold such treatment is
unethical. So, the trial that the reviewers suggest, assessing the survival
benefit of Sipuleucel-T in the absence of chemotherapy is simply not feasible
One could consider a trial design that makes a greater effort
to control the timing and dosage of additional treatment, but it should be
appreciated that such a sequential trial design would NOT assess the agent
in question, but rather would assess a combination treatment approach. It
is not clear to me that such studies are the responsibility of a drug manufacturer
? instead those kinds of questions are typically posed in the setting of
a cooperative group trial.
The reviewers should also be cognizant of the
fact that the landscape of treatment options available to medical oncologists
is in continual flux. In prostate cancer, for example, a second-line chemotherapy
(cabazitaxel, Sanofi Aventis), was recently approved, and a new hormonal
agent (abiraterone, J&J) will likely be approved in the next several
months. It would seem a nearly impossible task for a drug manufacturer to
control for all such eventualities in a clinical trial design. Instead, the
standard approach has been the randomized controlled trial, which makes the
implicit assumption that post-treatment interventions will be relatively
balanced among the treatment arms. This is the standard that other cancer
treatments have been held to, and it seems unfair to impose additional constraints
on one particular manufacturer or approach.
6) Finally, it is noted that the research upon which the assessment was
based was conducted by the "Blue Cross and Blue Shield Association
Technology Evaluation Center" under contract to the AHRQ. As a large
health insurance provider, Blue Cross and Blue Shield could be assumed to
have a stake in coverage recommendations reached by the AHRQ, and it would
be helpful to know what steps were taken to minimize or eliminate potential
conflict and/or bias.
See #1) Salvage therapy response.
Change in endpoint—survival as a robust end point is recognized in
Infection—"product-related" infections as such are not
known, it would be premature to presume to that certain infections are not
Benefit of sipuleucel-T in "context" of chemotherapy—because
sipuleucel-T does not produce measurable anti-tumor effects, the evidence
of its effectiveness exists in the context of the trials at a time point
beyond secondary treatments. Clinical trials should avoid an explicit
bias in use of subsequent treatments. In the clinical trials salvage
therapy induced a delay in initiation of effective therapies.
Conflict of interest—BCBSA Technology Evaluation Center has been designated
by AHRQ as an evidence-based practice center. This assessment was performed
under the requirements of the Evidence-based Practice Center contract. The
assessment was peer-reviewed by persons with no relationship to Blue
Cross Blue Shield.
I would like to respond to several specific issues raised
by the Technology Assessment. First, the authors raise a question about the
level of evidence provided by the three published Phase III trials of sipuleucel-T,
describing them as "small" and suggesting that they should therefore
carry less weight than a "large" trial.
As the primary author
of the SWOG 9916 trial, one of two trials that supported the approval of
the first agent to show survival benefit in this patient population, I would
like to point out that the number of patients in the arm of the TAX 327 trial
randomized to receive docetaxel at its approved dosing schedule (75mg/Kg)
every three weeks, was 335. In the IMPACT trial of sipuleucel-T, 341 patients
were randomized to the active treatment arm. There was little question as
to our certainty of benefit from docetaxel just as there is little question
of our certainty of benefit from sipuleucel-T.
The Technology Assessment also expresses concern that it is unknown whether
docetaxel use subsequent to treatment with sipuleucel-T could partially explain
the survival benefit in these trials. The issue of confounding of a treatment
effect by subsequent therapies is one that is common to all oncology trials.
To explore the potential effects of post-progression treatment, several sensitivity
analyses have been completed. None of these analyses suggest that earlier
and/or more frequent use of docetaxel in the sipuleucel-T arm can explain
the study result, nor do they suggest that sipuleucel-T was only effective
in those patients who ultimately received docetaxel.
In three randomized
phase III trial of sipuleucel-T, the overall treatment effect remained robust
when adjusting for docetaxel use, and a sipuleucel-T treatment effect was
observed both in patients who did and did not receive subsequent docetaxel.
Taken together, these analyses provide no evidence to suggest that subsequent
docetaxel use explains the observed sipuleucel-T effect. (Petrylak D., ASCO
Further support for the efficacy findings in the IMPACT study is shown in
the consistency of the survival benefit in, in the sipuleucel-T arms of the
three phase III trials, Study D9901, Study D9902A and the IMPACT trial.
In summary the data demonstrating an overall survival benefit of sipuleucel-T
for men with asymptomatic or minimally symptomatic castrate resistant prostate
cancer is based on a robustly sized dataset, cannot be explained by subsequent
use of docetaxel, and is consistent across three Phase 3 studies. The level
of evidence should be characterized as strong rather than moderate
Sample size- robustness of clinical trial results depends
on the size of the smaller group, in this case the control group. In
the GRADE evaluation, the studies are no longer characterized as "small."
See #2) analysis of subsequent treatments.
|| Because of the length of the comments, the comments are
divided into sections to correspond to author comments. Reviewer comments
were not organized by sections of the assessment, order of those comments have
not been changed.
Dr. Mark and colleagues have performed a thorough review
of sipuleucel-T in their Technology Assessment Report entitled "Outcomes
of Sipuleucel-T Therapy." There are several areas that we are concerned
do not accurately reflect the evidence generated by the clinical trials,
and provide below comments and suggestions for changes to the report. The
two areas of particular concern are the grading of the evidence as "moderate" rather
than "strong," and the suggestion that additional clinical trials
in the current label indication may be warranted.
Grading strength of the evidence (ES page 2)
The Technology Assessment (TA) inappropriately grades the strength of the
body of evidence for improved outcomes of sipuleucel-T therapy as "moderate." In
reviewing the Agency for Healthcare Research and Quality (AHRQ) standards
for grading the strength of a body of evidence (Owens 2009), we conclude
that "strong" would be the appropriate grading for the sipuleucel-T
According to the AHRQ standards, evidence is evaluated in four domains:
risk of bias, consistency, directness, and precision. Additional domains
that are relevant to sipuleucel-T include: dose-response association, plausible
confounding that would decrease the observed effect, and strength of association
(magnitude of effect). Each of these categories and the available evidence
is reviewed below.
Risk of bias
Per the AHRQ methods, risk of bias is assessed through two main elements:
study design and aggregate quality of the studies. Randomized study designs
carry the lowest risk of bias. The TA states (Table A4) that "there
are unknown potential confounding effects of frozen salvage product and
post-progression treatments, despite the use of statistical adjustment
In labeling potential effects "unknown, " the
TA fails to characterize the level of uncertainty or the probable directionality,
and fails to provide a score for the "bias " domain. Per the
AHRQ methods the domain of "bias, " scores should be denoted
high, medium, or low. High risk of bias lowers the strength-of-evidence
grade; low risk of bias raises it.
Lacking any score, the TA does not provide insight to the reviewers‘ thinking
regarding these potential sources of bias. Other aspects of the TA suggest
that the reviewers concluded that these risks were not only theoretical,
but were also unlikely to reduce the strength of the evidence. To clarify,
the potential bias introduced by salvage product and variations in post-progression
treatment could have only acted in one of 3 ways " the two extremes
of which are outlined on pages 12 and 13 of the TA.
Namely, the bias could
have reduced the observed benefit relative to the "true" benefit
(i.e., conservative bias), had no impact, or could have created an artificially
large observed benefit relative to the "true" benefit (i.e.,
optimistic bias). Nowhere in the TA is there any suggestion that the latter
of the 3 effects was at play in these studies, and the concern is considered
mainly theoretical. In fact, there is no mention of any evidence within the
TA suggesting that either the frozen salvage product or variations in post-progression
treatment caused the observed effect to be larger than the "true" effect.
Such a phenomenon is the only type of bias that should concern reviewers
that the evidence of benefit is weaker than it appears. Yet, the multiple
sub-group analyses conducted by the FDA as well as data presented at the
MEDCAC meeting provide no evidence of a bias in the direction that would
weaken the strength of evidence.
Several prostate cancer experts at the MedCAC
meeting noted that the crossover design of the study was likely to lead to
a more conservative estimate of the overall survival benefit, and that post-progression
chemotherapy could not explain the observed survival benefit. The TA itself
notes on page 23 that whether such a bias is present in these studies is "difficult
Moreover, the TA notes that all of the analyses that
adjusted (using multiple methods) for post-progression treatments failed
to show any evidence of a bias that favored sipleucel-T. Potential confounding
by the salvage product and post-progression variation in treatment are discussed
Disagree that potential bias of post-treatment chemotherapy
is "theoretical," as IMPACT study showed earlier and more frequent
use of known effective treatment. This would cause an over-estimation
of treatment effect. See also #1) Salvage therapy response. Given
the differences between salvage therapy and sipuleucel-T, we do not assume
an unmeasurable benefit of cross-over therapy. GRADE table has been
revised to be more clear regarding the presence of bias.
See also #2) analysis of subsequent treatments
The TA suggests the possibility that the salvage product could have had
a negative impact on the survival of control-group patients. The TA should
acknowledge that while this is a theoretical possibility, the available facts
make it unlikely.
First, there is no biologic rationale to suggest this. The salvage product,
APC8015F, is prepared from cells cryopreserved at the time of placebo generation.
Once the cells are thawed, washed and placed into culture, the manufacturing
process is exactly the same as for sipuleucel-T and the final salvage product
must meet the same release specifications as sipuleucel-T (Kantoff 2010).
There is a long history of the safe use of cryopreserved blood products,
including red cells, platelets, plasma and stem cells (Sputtek 2007, Watt
Second, the overall outcome of the placebo arm is very favorable compared
to the control arms of contemporaneous trials of men with asymptomatic or
minimally symptomatic metastatic castrate resistant prostate cancer (Berthold
2008, Higano 2009, James 2009, Kantoff 2009), suggesting that it is unlikely
that the observed survival benefit in the sipuleucel-T group is due to poor
outcome of the placebo group.
Finally, survival of men on the placebo arm who specifically received APC8015F
is very favorable and comparable to men who received sipuleucel-T. In the
IMPACT trial, median survival for sipuleucel-T patients was 25.8 months vs.
23.8 months for those receiving placebo and APC8015F and 11.6 months for
those receiving placebo only (Kantoff 2010). Interpretation of these outcomes
is confounded by potential selection bias, but a significant effect of APC8015F
on overall survival in placebo subjects persists after adjustment for potential
confounding differences in baseline characteristics (HR=0.576; 95% CI: 0.380,
Additional exploratory analyses have examined overall survival from
the time of disease progression for placebo patients who received APC8015F
compared to those who did not. A positive treatment effect was observed for
placebo patients who received APC8015F, relative to those who did not. This
result held both in an unadjusted analysis, and analyses which adjusted for
baseline prognostic factors and subsequent docetaxel use (George 2011).
In summary, multiple analyses provide no indication that salvage treatment
was harmful to patients, and in fact suggest if anything, the contrary. The
observed overall survival benefit observed in the randomized trials of sipuleucel-T
is therefore likely to be an underestimate of the true treatment effect.
See #1) Salvage therapy response. The studies
of frozen salvage product-associated survival are unpublished and unevaluable. If
the analyses do not take into account "immortal time bias," the
fact that patients who receive frozen salvage product have 100% survival
up to the time of receiving it, then the analyses are not valid.
Potential confounding from subsequent therapies is a feature which is common
to all survival trials in oncology (Center for Drug Evaluation and Research,
Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints
for the Approval of Cancer Drugs and Biologics. May 2007). Sensitivity
analyses to explore the potential influence of docetaxel have included adjustment
for docetaxel as a time dependent covariate in a Cox model, and an analysis
censoring subjects at the time of docetaxel initiation.
These, and additional
analyses performed by FDA and reviewed by external consultants (FDA Center
for Biologics Evaluation and Research, statistical review of sipuleucel-T)
failed to provide evidence that subsequent chemotherapy could explain the
survival benefit. Furthermore, future survival trials of agents like
sipuleucel-T that are used in the pre-chemotherapy space in metastatic castrate
resistant prostate cancer will involve a much greater degree of confounding
from subsequent therapies, given that in addition to docetaxel, two new agents,
cabazitaxel and abiraterone, have already been demonstrated to prolong overall
The final TA should grade the strength of evidence regarding potential bias
from salvage and subsequent therapy on outcomes observed with sipleucel-T. Attempts
should be made to quantify the directionality of hypothetical concerns, taking
into consideration the biology, as well as the available clinical data and
sensitivity analyses. If after reviewing these data the TA grades this bias
as "high risk," it should provide what observations in the empiric
data, and/or what biologic data, supports the contention that either cross-over
or post-progression treatment variation biased findings towards an over-estimation
of the survival benefit.
If the revised TA grades the risk of bias as "ow",
as would be in keeping with the available data, this would lead to the overall
strength of evidence being graded higher as specified in the AHRQ manual.
|See #2) analysis of subsequent treatments
As noted in the TA, "The survival findings of the studies are consistent
in direction and magnitude. Disease progression outcomes showed no
As noted in the TA, "The outcome of overall survival is the most direct
and least subject to bias."
The TA concludes that "the result is not precise due to the small
overall sample size and unknown direction and magnitude of potential confounding
In reaching this conclusion, the TA did not take the steps strongly encouraged
in the AHRQ methods to generate an accurate estimate of precision. Moreover,
the TA confounds issues of "bias" with issues of "precision," and
it also employs a descriptor for the sample size (i.e., "small")
which has neither statistical nor clinical meaning. It also fails to
provide a grade for precision. Specifically:
methods suggest that meta-analytic techniques should be used when "appropriate," which
should be when multiple potentially combinable studies are available (page
3), and proposes that precision be assessed in "pooled analyses" (page
5). The standards for "precision" involve whether the estimate
and the boundaries of confidence around it are relevant to clinical decision
makers. The manual requires that: "EPCs [Evidence-based Practice
Centers] should assess the boundaries of the pooled confidence interval for
that effect estimate in relation to a threshold that would allow CER [Comparative
Effectiveness Reviews] users to make judgments about the treatments being compared."
the case of sipleucel-T, integration of the results from the three studies
in metastatic castrate resistant prostate cancer is justified by the very
similar patient populations and trial designs. This integrated analysis,
based on 737 patients, demonstrated a HR of 0.734 (95% CI, 0.612, 0.881;
P=0.0009) (Finn, FDA Summary Basis for Regulatory Action, 2010). The upper bound estimate
of 0.881 is not close to 1.0, and even the 12% reduction in the risk of death
is clinically meaningful to patients when the outcome is overall survival.
The AHRQ methods also provide some insight into what should be classified
as "imprecise," giving as an example, "A truly imprecise
estimate is one with a confidence interval so wide that it does not rule
out the superiority or inferiority of either treatment being compared"that
is, an estimate whose confidence interval includes two incompatible possibilities:
one treatment is clinically significantly better than the other, and the
difference is in the opposite direction? (page 5). There are no data
in the TA that even approach being internally contradictory.
mistakenly incorporates issue of "bias" into its consideration
of "precision," essentially double-counting the concerns reviewers
had about bias (even though those are purely speculative). Per the
AHRQ methods definition, "Precision is the degree of certainty
surrounding an estimate of effect with respect to a specific outcome (page
5)," and the AHRQ methods specifications explains that the dimensions
of effect estimates have to do with specific statistical issues of confidence
boundaries and how those boundaries interact with clinically important endpoints. There
is no suggestion in the AHRQ methods that issues of "bias" are
to be included in the assessment of "precision" " a logical
division given that the domain of "bias" is separately considered.
invokes the term "small" to describe the available sample size. There
are three problems with this term. First is its imprecision. The
TA does not define what sample size would be considered "adequate" or "sufficient," so
the subjective term "small" cannot be assessed for its validity
or credibility. Next, in characterizing the studied sample size as "small," the
TA seems to be suggesting that the sample size is small with respect to some
other study type or design. If so, then the size of other clinical
studies in similar populations should be contemplated for comparison.
such an approach, the reviewers would have found that the size of the sample
is consistent with that of other studies that led to treatment paradigm shifts
in prostate cancer (details of such comparisons are provided below). Last
is the problem that in labeling the studies as small, the reviewers ignore
the ethical requirement of clinical research to not over-enroll studies that
could potentially place patients at risk when adequate answers can be gleaned
from studies involving fewer patients. It is axiomatic in clinical
research that studies be appropriately sized, but not overpowered, particularly
when the treatments being assessed could be toxic and the subjects being
studied have life threatening conditions.
For instance, the "Common
Rule" includes, under ?46.111 Criteria for IRB approval of research: (a)
In order to approve research covered by this policy the IRB shall determine
that all of the following requirements are satisfied: (1) Risks to subjects
are minimized: (i) By using procedures which are consistent with sound research
design and which do not unnecessarily expose subjects to risk. Calling
the studies "small" implies that the reviewers consider ethical
requirements including the minimization of risk for volunteer subjects unimportant.
fails to provide a score for the level of precision. The AHRQ methods
require a dichotomous choice between "precise" and "imprecise",
explaining that a "precise estimate is an estimate that would allow
a clinically useful conclusion. An imprecise estimate is one for which the
confidence interval is wide enough to include clinically distinct conclusions.
For example, results may be statistically compatible with both clinically
important superiority and inferiority (i.e., the direction of effect is unknown),
a circumstance that will preclude a valid conclusion.?
It is inconceivable
that the highly consistent data on sipleucel-T could be judged to be ?imprecise," because
the confidence intervals are simply not wide enough to accommodate clinically
distinct conclusions. Moreover, it seems clear that the upper bound
of the pooled confidence interval of 0.88 is sufficiently below 1.0 to conclude
that the benefit is clinically meaningful.
The TA should be revised so that the level of precision of the overall survival
benefit is evaluated in an integrated analysis of the three randomized studies
in metastatic castrate resistant prostate cancer and that the standards for
what constitutes a clinically important upper bound of the confidence limit
be specified so it can be evaluated in a transparent manner. Moreover,
the theoretical issues of "bias" should be removed from the assessment
of "precision" as they are already incorporated into the evaluation
of "bias". This will avoid the current double counting of
these theoretical concerns.
Lastly, the TA should include specific statements
about sample size that clarify how the reviewers arrived at the judgment
that the sample size was "small", and the reviewers should offer sample
sizes that they would have deemed "adequate" and "excessive" (or
whatever terms are appropriate). They should also explain the rationale
for considering the sample size small given the importance of protecting human
subjects and the reality that the study’s power was adequate and appropriate
in the eyes of the IRB’s that reviewed it and the FDA at the time of
approval. A score for the precision as either "precise" or "imprecise" should
In a narrow interpretation of precision, which relates to
the confidence interval of the estimate of treatment benefit, we now state
that the point estimate of benefit across all 3 trials is precise.
The studies are no longer characterized as "small" for GRADE evaluation.
Three of these AHRQ methods defined domains are relevant to the sipuleucel-T
Per the AHRQ methods, "this association, either across or within studies,
refers to a pattern of a larger effect with greater exposure (dose, duration,
adherence)." Associations between overall survival and the total nucleated
cell count, the absolute number of CD54 positive large cells, and the CD54
upregulation ratio have been observed in the sipuleucel-T trials. In an integrated
analysis of the three randomized metastatic castrate resistant trials, there
was a significant correlation between overall survival and each of these
3 product parameters, in analyses both unadjusted and adjusted for baseline
parameters (Stewart 2010).
Per the TA, "The results between the two
studies show a consistent positive direction of associations, but apparently
the strength of the association of a particular parameter varies between
studies." Based on these facts, the TA should score this domain as "Present".
Plausible confounding that would decrease the observed effect
Per the AHRQ methods, "Occasionally, in an observational study,
plausible confounding factors would work in the direction opposite that of
the observed effect. Had these confounders not been present, the observed
effect would have been even larger than the one observed. In such a case,
an EPC may wish to upgrade the level of evidence."
This is a case which is particularly relevant to the sipuleucel-T data,
with the trial designs including cross-over to salvage (see above). The appropriate
grading for this domain would therefore be "present," i.e., "confounding
factors that would decrease the observed effect may be present."
Strength of the association (magnitude of the effect)
Per the AHRQ methods, "Strength of association refers to the likelihood
that the observed effect is large enough that it cannot have occurred solely
as a result of bias from potential confounding factors." The median
survival benefit observed in the sipuleucel-T trials (4.5 and 4.1 months)
is larger than any other FDA approved agent for metastatic castrate resistant
In conclusion, the TA should score each of the four domains and the additional
domains relevant to sipuleucel-T. The TA should also provide an explanation
of how these scores are integrated to provide a grading of the level of evidence,
given the AHRQ methods statement that "in arriving at an overall strength-of-evidence
grade, the crucial requirement is transparency. " The level of evidence
should be graded as strong based on the results being consistent, direct
and precise, and there being a low risk of bias.
The level of evidence warrants
upgrading based on the presence of a dose-response association, plausible
confounding that would decrease observed effect, and a strong magnitude of
the effect. Failing a change in the evidence designation to strong, the TA
should clarify for readers that it appears impossible for oncologic survival
trials to reach a rating of "strong," and therefore, sipuleucel-T
has reached the highest level of evidence that the grading system allows
Dose-response: the analyses of product characteristics
and outcomes does not constitute evidence of dose-reponse.
Plausible confounding: the systematic bias of post-treatment chemotherapy
caused by delay due to administration of frozen salvage product in
IMPACT is a plausible source of confounding.
Strength of association: The direction of plausible confounding we
believe is in the direction of the studies over-estimating the effectiveness
of sipuleucel-T. This leads to moderating the calculated magnitude
We did not include the additional domains in an additional table because they
are covered adequately in the principal table.
Risk of infection (ES page 3)
The TA currently states: "Sipuleucel-T also is associated with infections." This
implies that sipuleucel-T treatment increases the general risk of infection,
which is not the case. It should be clarified that there is a risk of infection
associated with central lines which may be required for the leukapheresis
procedure. (As the TA does correctly state, infections that appeared to be
due to catheter related infections occurred in approximately 3 percent of
subjects.) The results section of the TA (page 31), states, "However,
15.3 percent and 14.5 percent of subjects in each group developed infections
within one week of their final infusion.
These infections are more likely
related to leukapheresis and/or infusion." Most of these infections
are in fact not related to leukapheresis or infusion. First, it is important
to understand that the period of data collection was from registration until
1 week after the last leukapheresis or infusion, whichever came later. Since
treatment typically occurs over a 4-6 week period, the duration of adverse
event collection would be approximately 5-7 weeks for the typical patient.
review of the adverse events in this period reveals events which might be
anticipated in an elderly population followed for a 1-2 month period: pharyngitis,
bronchitis, sinusitis, urinary tract infection, etc. As a cross-reference,
the FDA review of an endothelin-A receptor antagonist, atrasentan, documents
the frequency of adverse events related to infection in the advanced prostate
cancer population (FDA clinical review, accessed Nov 24, 2010, http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4174B1_02_01-FDA-Clinical-Xinlay.pdf).
duration of adverse event collection was longer than for the above sipuleucel-T
analysis and likely roughly the duration of treatment, which was 16.5 weeks
in the placebo arm. A comparison of specific adverse event terms from the
FDA review is provided in the table below. The frequency of these events
is higher in the atrasentan trials consistent with the longer duration of
follow-up for that analysis, but serves to substantiate the fact that these
infectious adverse events are not uncommon in this patient population.
|Urinary tract infection
||With a new therapy, we should presume to know which infections
should or should not be attributed to treatment. Infections section was
changed to be more circumspect regarding the causality of infections, even
those proximate in time to infusion.
Considerations for future trials (ES page 3)
The TA states that "Consideration should be given for conducting unblinded
trials without placebo infusions or salvage product, and for more thorough
treatment protocols out to the survival end point." The TA should make
statements that are consistent with the standards in oncologic research and
the practices of FDA, study groups and IRB boards reviewing oncology clinical
trials. We therefore have several concerns with this statement and suggest
revising it to: "For future trials in other indications, consideration
should be given to designs without cross-over, and with overall survival
as the primary endpoint." The rationale for these changes is below:
The current sentence in the TA suggests that an unblinded, non-placebo controlled
trial would lead to higher confidence of the trial outcome. This is not the
case. Blinded placebo controlled trials may not be necessary in future trials
for other indications where overall survival is again the primary endpoint,
but the blinded, placebo controlled design of the studies under review considerably
strengthens rather than diminishes the robustness of their findings.
placebo controlled trials remain the gold standard design in oncology trials,
given they are the least susceptible to bias. There is no biologic rationale
that the placebo product used here could be harmful to patients; the product
consists simply of the patients own peripheral blood mononuclear cells held
at 2-8?C without addition of antigen. While there are adverse events associated
with the leukapheresis and infusion procedures for both the sipuleucel-T
and control groups, these risks can be readily quantified by the temporal
association of these adverse events with leukapheresis and infusion (see "Risk
of infection" section above).
The presence of the observed adverse
events associated with the control arm is not sufficient grounds for the
TA to claim that a non-placebo controlled trial design would actually be
superior to a placebo-controlled trial.
The current sentence in the TA suggests that additional clinical trials
in the current label indication would be important. As noted in the FDA review
of sipuleucel-T, "Study D9902B is an adequate and well-controlled investigation
in which sipuleucel-T demonstrates a clinically meaningful effect on survival
in patients with metastatic prostate cancer. Because of the effect on survival,
a second trial would not be ethical or feasible" (Bryan 2010).
Dr. Mark presented the TA at the Nov. 17th Medicare Evidence Development
and Coverage Advisory Committee (MedCAC) meeting, he did clarify that this
statement regarding additional trials referred to additional indications,
and not the current label indication. This should be clarified in the TA.
The current TA statement suggests that more thorough treatment protocols
out to the survival endpoint need to be included in future clinical trials.
While this would address the TA’s concern regarding variability of
post-progression cancer care, it is neither feasible nor ethical. The standard
design for oncology clinical trials is to specify treatment up until the
time of disease progression. Mandating that all patients be required to receive,
for example, docetaxel chemotherapy following disease progression would not
be ethical or permissible by institutional review boards (IRBs).
if and when to institute chemotherapy or other care must be individualized
to each patient coping with metastatic cancer, and will depend on a variety
of factors, including their degree of symptomatology, the rate of disease
progression, and patient preferences at the time of treatment. Decisions
about the long-term future medical therapy of ill patients cannot be dictated
in a clinical protocol at the time of randomization.
TA was adjusted to emphasize that trials should avoid potential
for systematic biases of application of subsequent treatments and equal quality
of care across treatment arms.
TA does not suggest studies prior to coverage.
Description of sipuleucel-T (page 3)
While sipuleucel-T contains dendritic cells, and early publications described
the biological as a dendritic cell product, a more appropriate description
of the product would be (additions in capital letters):
" The collected cells, which are mixture of PERIPHERAL BLOOD MONONUCLEAR
CELLS (remove 'dendritic cells'), INCLUDING ANTIGEN PRESENTING CELLS, T-cells,
(remove 'monocytes'), and B-cells, are then cultured with a protein called
PA2024. PA2024 is a recombinant protein consisting of human prostatic acid
phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor
(GM-CSF). The interaction of the ANTIGEN PRESENTING CELLS (remove 'dendritic
cells') with PA2024 is considered the essential process that stimulates the
immune system. ANTIGEN PRESENTING CELLS(remove 'Dendritic cells') take in
antigens and then "present" them to T-cells throughout the body,
which should then react to cells with PAP such as prostate cancer cells as
The following paragraph on page 4 should also be modified as follows:
During the manufacture of sipuleucel-T, the number of CD54 molecules expressed
on the(remove'dendritic') antigen PRESENTING CELLS increases. The amount
of this increase can be quantified using specific assays. The quantity of
this increase varies between patients, and varies depending on prior exposure
to sipuleucel-T. Greater CD54 upregulation is observed after the first dose
of treatment, indicating that (remove 'dendritic') antigen PRESENTING CELLS
respond differently to culture in PA2024 after an initial systemic exposure
Gleason score (page 13)
"IMPACT enrolled a higher proportion of subjects with Gleason scores
of 7 or less" should be a lower proportion, not a higher proportion,
as demonstrated by the previous sentence: "The entry criteria Gleason
score for IMPACT was changed during the trial from 7 or less to any Gleason
Progression endpoint (page 13)
The TA currently states: "However, studies D9901 and D9902A were designed
for an end point of progression-free survival, and the primary end point
of IMPACT was changed from progression-free survival to overall survival." Both
occurrences of "progression-free survival" in this sentence should
be changed to "time to disease progression," since "time
to disease progression" was the pre-specified endpoint in these trials,
not "progression-free survival." These endpoints are similar,
but have distinct definitions.
Wording changes adopted.
Reviewer erred regarding Gleason score, or misunderstood. IMPACT differed
from the other 2 smaller trials in the proportion of patients with Gleason
score 7 or less.
We think the progression end points are analytically identical.
Time to development of cancer related pain (page 16)
The TA reports the lack of difference in the median time to development
of cancer related pain in Studies D9901 and D9902A. While not statistically
significant, Studies D9901 and IMPACT both showed a trend towards a delay
in the time to development of cancer related pain (Small 2010, Petrylak
2010). In each of these studies there was a marked delayed separation of
the Kaplan-Meier curves, accounting for the similar median time to development
cancer related pain between the treatment arms in these studies. In the
IMPACT trial, for example, the estimated percentage of patients free of
cancer-related pain at 12 months was 32.7% in the sipuleucel-T arm compared
to 14.5% in the control arm.
Time to docetaxel initiation (page 16)
The TA currently states, "In IMPACT, a greater proportion of sipuleucel-T-treated
patients received docetaxel chemotherapy (57.2 percent versus 50.3 percent),
and they also received it earlier (median 7.2 months versus 9.6 months)." The
stated time to receipt of docetaxel is based on the median of those subjects
who actually received docetaxel. While these numbers provide the time to
docetaxel in those who actually received it, they ignore the large number
of patients who did not receive docetaxel at all.
The Kaplan Meier method is the standard method for time to event analyses
for endpoints such as time to disease progression or overall survival,
and was therefore the method used to describe the median time to docetaxel
initiation in the published manuscript in the New England Journal of Medicine: "The
Kaplan?Meier estimate of the median time to docetaxel use was 12.3 months
in the sipuleucel-T group and 13.9 months in the placebo group" (Kantoff
2010). It would therefore be more appropriate to cite these estimates in
the TA, given the statement in the TA, "We used the peer-reviewed
publication value whenever there was a discordance."
The longer time to initiation of docetaxel in the control arm, while small,
depended on an event that would occur only in the study and not in the
real-world setting, namely the interposition of salvage treatment with
APC8015F for many patients on the control arm. A sensitivity analysis was
performed using Kaplan-Meier estimates of time to initiation of docetaxel
or salvage treatment with APC8015F, whichever came first. In the IMPACT
trial, the median time to intervention was 12.3 months for sipuleucel-T
compared with 6.5 months for control and for the integrated analysis of
the 3 randomized trials in metastatic castrate resistant prostate cancer,
16.8 months for sipuleucel-T as compared to 6.3 months for control (Dendreon,
data on file).
It is also noteworthy that the exploratory analyses undertaken to examine
the potential effect of subsequent docetaxel use also adjusted for any
potential differences in the timing of docetaxel initiation. These analyses
include the adjustment for docetaxel use as a time dependent covariate
in a Cox regression model, and the analysis censoring patients at the time
of docetaxel initiation.
Sample size (page 19)
The TA states: "Although the findings of the studies are mostly
consistent in showing a similar magnitude hazard ratio, estimates of the
effectiveness of sipuleucel-T are imprecise due to the relatively small
total sample size of the clinical trials"?
The overall sample size for the randomized studies of sipuleucel-T in
castrate resistant prostate cancer was not small. The overall survival
result for the IMPACT trial was based on 512 patients, and revealed a HR
of 0.775 (95% CI, 0.614, 0.979; P=0.032). An integrated analysis of the
3 randomized trials in metastatic castrate resistant prostate cancer based
on 737 patients demonstrated a HR of 0.734 (95% CI,0.612, 0.881; P=0.0009)
(Finn, FDA Summary Basis for Regulatory Action, 2010). The registration
trial for docetaxel, was based on 672 patients between the docetaxel every
3 week arm and the control arm (Tannock 2004).
The trial demonstrated a HR of 0.76 (95% CI, 0.62 to 0.94; P=0.009). Based
on the 95% CI of the HRs, the estimate of the sipuleucel-T treatment effect
based on the IMPACT trial was therefore comparably precise to that in the
Tax327 trial, and more precise than the Tax327 trial based on the integrated
analysis of the 3 randomized trials of sipuleucel-T in metastatic castrate
resistant prostate cancer.
The pain data cited is unpublished.
Time to chemotherapy is not an outcome, therefore not critical to use Kaplan
Meier. Kaplan Meier estimate does not take into account competing risk
of mortality, simply censors patients at death.
Reviewer cites unavailable data.
Studies not characterized as "small" or "imprecise" in
GRADE evaluation any more.
Biologic mechanism of action (page 23)
It is important to clarify that while the biologic mechanism of action of
sipuleucel-T is not fully understood, as is the case for most agents in oncology,
the available data support the proposed mechanism of action. Sipuleucel-T
is designed to generate an immune response against the tumor antigen, prostatic
acid phosphatase (PAP). Studies labeling the recombinant PAP-GMCSF fusion
protein have demonstrated that the antigen is taken up into antigen presenting
cells, defined as large CD54 expressing cells.
These cells have been demonstrated to present PAP peptides as assessed by
the proliferation of T cell hybridomas recognizing PAP peptides (Sheikh 2008).
We have documented evidence of both cellular and humoral immune response
to PAP-GMCSF and to PAP (Frohlich 2010, Kantoff 2010). Furthermore, the demonstrated
correlations between these measures and overall survival, as well as between
measures of product potency and overall survival (Higano 2009, Kantoff 2010,
Frohlich 2010), support the biologic importance of these biomarkers.
|TA stated that these correlates with survival do not provide
evidence of the efficacy of sipuleucel-T, as these were not measured or are
not measurable in the control group.
Nonfatal Serious Adverse Events (page 28)
This section and Table 12 on page 29 should be titled, simply, "Serious
Adverse Events," as serious adverse events included fatal events.
Risk of cerebrovascular events (page 30)
Table 13 lists the incidence of cerebrovascular events at 4.0% and 2.9%
in the sipuleucel-T and control groups, respectively. It should be clarified
that these figures include transient ischemic attacks (TIAs). The figures
of 3.5% and 2.6% in the sipuleucel-T and control groups, respectively, as
stated in the FDA label exclude TIAs, since these events do not have the
same clinical consequence for patients as the other cerebrovascular events,
e,g., ischemic or hemorrhagic stroke.
Risk of infection (page 31)
See "Executive Summary" section.
Infusion Reaction Adverse Events (page 32)
The incidence of any infusion reaction adverse event in the sipuleucel-T
group should be 71.2 percent rather than 71.4 percent, which is a typographical
error within the CBER Clinical Review, Table 38. Please see the Package Insert/Prescribing
Information, Section 5.1.
FDA document is in fact unclear, section heading of text
differs from table title.
We note a minor decimal point difference in infusion rate calculation.
||Rest of Dr. Frolich’s comments are either minor decimal
point changes or repeated comments.
1. Names are alphabetized by last name.
Those who did not disclose name are labeled "Anonymous Reviewer 1," "Anonymous
Reviewer 2," etc.
2. Affiliation is labeled "NA" for
those who did not disclose affiliation.
3. If listed, page number, line number, or
section refers to the draft report.
4. If listed, page number, line number, or
section refers to the final report.
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Current as of April 2011
Outcomes of Sipuleucel-T Therapy: Disposition of Comments.
April 2011. Rockville, MD: Agency for Healthcare Research and Quality.