1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ONCOLOGIC DRUGS ADVISORY
COMMITTEE
VOLUME I
Thursday, March 3, 2005
8:05 a.m.
Gaithersberg Hilton
620 Perry Parkway
Gaithersburg, Maryland
2
PARTICIPANTS
Silvana Martino, D.O., Acting Chair (A.M.
Session)
Maha Hussain, M.D., Acting Chair (P.M.
Session)
Johanna M. Clifford, M.S., RN, Executive
Secretary
COMMITTEE MEMBERS
Otis W. Brawley, M.D.
Ronald M. Bukowski, M.D.
James H. Doroshow, M.D.
Antonio J. Grillo-Lopez, M.D., Industry
Representative
Pamela J. Haylock, RN, Consumer
Representative
Maha H.A. Hussain, M.D.
Alexandra M. Levine, M.D.
Joanne E. Mortimer, M.D.
Michael C. Perry, M.D.
Gregory H. Reaman, M.D.
Maria Rodriguez, M.D.
CONSULTANTS (VOTING)
FOR COMBIDEX
Marco Amendola, M.D.
William Bradley, M.D., Ph.D.
Marion Couch, M.D., Ph.D.
Ralph D'Agostino, Ph.D.
Mark Dykewicz, M.D.
Armando Giuliano, M.D.
Dennis Ownby, M.D.
Dana Smetherman, M.D.
PATIENT REPRESENTATIVE (VOTING)
Eugene Kazmierczak - for Combidex and
Prostate
Cancer Endpoints
CONSULTANTS
PROSTATE CANCER ENDPOINTS
Victor DeGruttola, Sc.D.
Mario Eisenberger, M.D.
Eric Klein, M.D.
Lisa McShane, Ph.D.
Derek Raghavan, M.D., Ph.D.
Howard Sandler, M.D.
Howard Scher, M.D.
3
PARTICIPANTS
(Continued)
FDA (A.M. Session)
Zili Li, M.D., MPH
Florence Houn, M.D.
George Mills, M.D.
Sally Loewke, M.D.
PARTICIPANTS (Continued)
FDA (P.M. Session)
Peter Bross, M.D.
Patricia Keegan, M.D.
Bhupinder Mann, MBBS
Richard Pazdur, M.D.
Dan Shames, M.D.
Rajeshwari Sridhara, Ph.D.
Robert Temple, M.D.
Grant Williams, M.D.
4
C O N T E N T S
Page
Call to Order and Introductions
Silvana Martino, D.O. 6
Conflict of Interest Statement
Johanna Clifford, M.S., RN 9
Opening Remarks
George Mills, M.D. 11
Sponsor Presentation
Advanced Magnetics,
Inc.
Combidex, Introduction and Indication
Mark C. Roessel 15
Mechanism of Action, Combidex
Appearance on MR Images
Mukesh Harisinghani, M.D. 17
Efficacy Data from Phase III Clinical
Studies
William Goeckeler, Ph.D. 29
Safety Data from Clinical Trial
Gerald Faich, M.D. 39
Clinical Utility of Combidex and Various
Cancers
Jelle O. Barentsz, M.D. 46
FDA Presentation
Efficacy and Safety of Combidex (NDA
21-115)
Zili Li, M.D., MPH 56
Questions from the Committee 88
Open Public Hearing 146
Committee Discussion 167
5
C O N T E N T S
(Continued)
Page
AFTERNOON SESSION
Call to Order and Introductions
Maha Hussain, M.D. 204
Conflict of Interest Statement
Johanna Clifford, M.S., RN 207
Opening Remarks
Richard Pazdur, M.D. 210
A Regulatory Perspective of Endpoints to
Measure Safety and Efficacy or Drugs:
Hormone Refractory Prostate Cancer
Bhupinder Mann, MBBS 216
Towards a Consensus in Measuring Outcomes
in New Agents for Prostate Cancer
Derek Raghavan, M.D., Ph.D. 227
NCI Prostate Cancer Treatment Trial
Portfolio
Alison Martin, M.D. 261
Toward an Endpoint for Accelerated
Approval
for Clinical Trials in Castration
Resistant/
Hormone Refractory Prostate Cancer
Howard Scher, M.D. 271
Design of Clinical Trials for Select
Patients
With a Rising PSA Following Primary
Therapy
Anthony D'Amico, M.D., Ph.D. 297
Open Public Hearing 330
Committee Discussion 333
6
P R O C E E D I N G S
Call to Order and Introductions
DR. MARTINO: Good morning, ladies and
gentlemen. I would like to begin the
meeting, if
you would be so kind as to take your
seats.
The purpose of this morning's
meeting is
to consider a new drug application, the
agent
Combidex from Advanced Magnetics,
Incorporated, a
proposed indication for intravenous
administration
as a Magnetic Resonance Imaging contrast
agent to
assist in the differentiation of
metastatic and
non-metastatic lymph nodes in patients
with
confirmed primary cancer who are at risk
for lymph
node metastases.
We will start the meeting by
having the
members of the panel introduce
themselves, and I
would like to begin on my left, please.
DR. LOEWKE: Sally Loewke, FDA. I am the
Deputy Division Director for the Division
of
Medical Imaging and Radiopharmaceutical
Drug
Products.
DR. MILLS: Good morning.
I am George
7
Mills, FDA. I am the Division Director for Medical
Imaging.
DR. HOUN: Florence Houn, Office Director,
FDA.
DR. LI: Zili Li, Medical Team Leader,
FDA.
MR. KAZMIERCZAK: Eugene Kazmierczak,
Patient Consultant to FDA for prostate
cancer.
DR. BUKOWSKI: Ron Bukowski, Medical
Oncologist, Cleveland Clinic Foundation.
DR. BRAWLEY: Otis Brawley, Medical
Oncologist and Epidemiologist, Emory
University.
DR. DOROSHOW: Jim Doroshow, Division of
Cancer Treatment and Diagnosis, NCI.
DR. RODRIGUEZ: Maria Rodriguez, Medical
Oncologist, M.D. Anderson Cancer Center.
DR. REAMAN: Gregory Reaman, Pediatric
Oncologist, Children's Hospital,
Washington, D.C.,
and George Washington University.
DR. MARTINO: Silvana Martino, Medical
Oncology, Cancer Institute Medical Group
in Santa
Monica.
8
MS. CLIFFORD: Johanna Clifford, Executive
Secretary to the Oncology Drugs Advisory
Committee.
DR. HUSSAIN: Maha Hussain, Medical
Oncologist, University of Michigan.
DR. PERRY: Michael Perry, Medical
Oncologist, Ellis Fischel Cancer Center,
Columbia,
Missouri.
DR. MORTIMER: Joanne Mortimer, Medical
Oncologist, Moores UCSD Cancer Center.
DR. OWNBY: Dennis Ownby, Pediatric
Allergist at Medical College of Georgia.
DR. D'AGOSTINO: Ralph D'Agostino,
Biostatistician from Boston University.
DR. DYKEWICZ: Mark Dykewicz, Professor of
Internal Medicine, Allergy and
Immunology, Training
Program Director, St. Louis University.
DR. GIULIANO: Armando Giuliano, Surgical
Oncologist from Los Angeles.
DR. BRADLEY: Bill Bradley.
I am a Neuro
MRI guy. I am the Chairman of Radiology
at UCSD.
DR. AMENDOLA: Marco Amendola, Professor
9
of Radiology, University of Miami.
DR. SMETHERMAN: Dana Smetherman,
Radiologist, Section Head of Breast
Imaging,
Oschner Clinic.
DR. COUCH: Marion Couch, Head and Neck
Surgeon from the University of North
Carolina.
DR. MARTINO: If you would all turn off
your mikes, and for those of you that are
new to
the committee, please recognize that you
need to
speak into the microphone, and it only
works when
you have pushed it and the red light is
on. Once
you are done with its use, please turn it
off.
There is a reasonable amount of
echo that
I still hear in this room. Can Audiovisual do
anything more to clarify our sound? Okay.
At this point, Ms. Johanna
Clifford will
report on the Conflict of Interests.
Conflict of Interest
Statement
MS. CLIFFORD: The following announcement
addresses the issue of conflict of
interest and is
made a part of the record to preclude
even the
appearance of such at this meeting.
10
Based on the submitted agenda
and all
financial interests reported by the
committee
participants, it has been determined that
all
interests in firms regulated by the
Center for Drug
Evaluation and Research present no
potential for an
appearance of a conflict of interest.
With respect to the FDA's
invited industry
representative, we would like to disclose
that Dr.
Antonio Grillo-Lopez is participating in
this
meeting as an acting industry
representative acting
on behalf of regulated industry. Dr. Grillo-Lopez
is employed by Neoplastic and Autoimmune
Disease
Research.
In the event that the
discussions involve
any other products or firms not already
on the
agenda for which an FDA participant has a
financial
interest, the participants are aware of
the need to
exclude themselves from such involvement,
and their
exclusion will be noted for the record.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
11
any firm whose products they may wish to
comment
upon.
Thank you.
DR. MARTINO: Dr. Mills, if you would
address the group.
Opening Remarks
DR. MILLS: Thank you, Dr. Martino.
Good morning, Committee. The sponsor of
the application in this morning's
session, Advanced
Magnetics, requests marketing approval of
Combidex
for the proposed indication of assisting
in the
differentiation of metastatic and
non-metastatic
lymph nodes, in patients with confirmed
primary
cancer, who are at risk for lymph node
metastases.
The Agency is asked to consider
an
indication specifically for
differentiating
metastatic from non-metastatic lymph nodes with
little restriction on the cancer type,
clinical
staging, and whether the patients have
been
previously treated.
The Agency is in the second
review cycle
12
for this imaging product. The first review cycle
concluded with an approvable action and
the sponsor
was asked to conduct additional studies
to address
issues related to inconsistent efficacy
results
among the differential trials and to
provide a
clearer identification for the conditions
of use
for Combidex.
In addition, the sponsors were
asked to
address safety issues related to
Combidex-induced
hypersensitivity reactions.
In today's presentation, the
sponsor will
address these deficiency issues by using
data that
were originally submitted to the Agency,
along with
new information from a published study in
the New
England Journal of Medicine.
The Agency's presentation today
will focus
on whether the primary analyses that were
based on
99 subjects from the U.S. studies and
only 48
subjects from the European studies are
adequate for
marketing approval based on the sponsor's
proposed
indications, which reads as follows:
"Combidex is for the
intravenous
13
administration as a contrast agent for
use with
MRI.
Combidex can assist in the differentiation of
metastatic and non-metastatic lymph nodes
in
patients with confirmed primary cancer
who are at
risk for lymph node metastases."
Today, we will be seeking
comments on the
issues related to the sample size and the
adequacy
of tumor type presentation. We will be presenting
the variable efficacy results by the
tumor type and
the size of the lymph nodes.
We are seeking your opinion as
to whether
these results suggest that the variations
in
efficacy performance of Combidex are
related to the
different tumor types and to different
lymph node
sizes.
Today, we are seeking your
advice on how
to better define the conditions for use
for
Combidex, assuming the validity of the
efficacy
results, so that use of Combidex can
provide
benefits to patients particularly in
affecting
patient's treatment decisions. This point is
particularly important given the risks of
14
hypersensitivity reactions associated
with
Combidex.
Lastly, we will be seeking your
recommendations on what additional data
are needed
if current data are found to be
inadequate for the
marketing approval of Combidex at this
time.
This concludes the Agency's
introduction
to the morning session.
Thank you, Dr. Martino.
DR. MARTINO: Thank you.
For those of you that are new
to the
committee and are consulting to the
committee, the
final task that we will bring to you is
answers to
certain questions that have been posed to
the
committee by the FDA. Those are in a written
format and each of you should have those
at your
desk.
They are titled as Discussion
and
Questions, so please recognize that it is
very
specifically to answer those four
questions which
will be the focus of the discussion at
the end of
this morning's presentations.
15
At this point, I would like to
ask Dr.
Roessel from the company to introduce
their
speakers and proceed with their
presentation.
There will be an opportunity
for questions
both to the sponsor, as well as to the
FDA. I ask
that you hold your questions until their
presentations are completed.
Sponsor Presentation
Advanced Magnetics,
Inc.
Combidex, Introduction and
Indication
MR. ROESSEL: Good morning.
Thank you,
Madam Chairman, members of the Advisory
Committee,
FDA.
I am Mark Roessel, Vice
President of
Regulatory Affairs, Advanced Magnetics.
Today is an important day for
us as we
have been working since 1992 to bring
Combidex to
clinicians and cancer patients. We are pleased to
be able to show you today data from
controlled
clinical trials demonstrating the safety
and
efficacy of Combidex and the great
potential it has
for improving imaging in cancer patients.
16
We have a number of
distinguished
consultants and speakers here today
including
radiologists, surgeons, oncologists, and
they are
available to answer any questions you may
have at
the end of the meeting.
I want to bring your attention
to the
indication. It has been read twice
already. It is
for a differentiation of metastatic and
non-metastatic lymph nodes in cancer
patients.
Here is the agenda we are going
to have in
our presentation and the key topics. Dr. Mukesh
Harisinghani is going to show you the
mechanism of
action of Combidex and how it appears on
MR images.
Dr. William Goeckeler from
Cytogen
Corporation, Vice President of Cytogen,
who is our
marketing partner, is going to present to
you data
from Phase III controlled clinical trials
that were
designed in cooperation with the FDA for
approval
of the agent.
Dr. Jerry Faich is going to
review the
safety data available, demonstrating that
Combidex
can be safely administered using dilution
and
17
infusion.
Finally, Dr. Jelle Barentsz, a
clinical
investigator with Combidex, is going to review with
you the clinical utility of Combidex in
various
cancers.
Combidex is a diagnostic tool
that
improves the anatomic imaging that is
done every
day.
Now, I would like to have Mukesh
Harisinghani.
Mechanism of Action,
Combidex
Appearance on MR Images
DR. HARISINGHANI: Good morning, Madam
Chairman, members of the Committee,
ladies and
gentlemen.
What I am going to do in the
next couple
of minutes is to review what are the
current
limitations of lymph node imaging as we
practice
radiology today, also give an overview of
how
Combidex is acting and how it allows us
to
differentiate benign from malignant lymph
node, and
then also show you some examples of how
it improves
18
sensitivity and specificity for nodal
characterization.
So, the question is why do we
need to
image lymph nodes, and I think one needs
to
accurately stage primary cancer, and in
doing so,
it is very important to know what the
nodal status
is.
It is very important to know
this
information to appropriately treat the
patients.
Just to give you an example, in prostate
cancer
patients, if the nodes are found to be
metastatic,
it essentially commits the patients to
non-surgical
modes of therapy.
We also need to get a sense of
prognosis,
and that is another factor why nodal
metastases are
important. Again, to give you an example in
bladder cancer, if the patient is
node-positive,
the five-year survival is way lower than
if the
patient is node-negative.
The risk of death also
increases 20
percent with each additional node being
positive.
The current lymph node staging as is
19
performed today involves non-invasive
imaging
techniques, which essentially
incorporates the
cross-sectional modalities like CT and
MR, and the
other is the invasive modes, which is
essentially
surgery, which are considered to be the
gold
standard today.
When one talks of the
non-invasive
cross-sectional modalities for staging
lymph nodes,
the predominant yardstick by which we
differentiate
benign from malignant lymph nodes is the
size
criterion, and this is what we use.
If the node is oval and less
than 10 mm in
size, or if it is rounded and less than 8
mm in
size, we label the node as benign.
In contrast, if the node is
oval and
greater than 10 mm, or is rounded and
greater than
8 mm, we label the node as malignant.
So, let's apply the size
criterion to
these two individuals. These are two different
patients, both have obtained a CT scan
for staging
purposes.
The example on your left is an
enlarged
20
node in the pelvis, which measures 18 mm
and is
rounded.
No matter which size criterion you use,
you would label this node as malignant.
The example on your right is a
different
patient, again a patient with a primary
pelvic
tumor.
There is a small node in the pelvis, which
measures 5 mm. Again, no matter which size
criterion you use, you would label this
node as
benign.
But at surgery, it was exactly
the
opposite.
Thus, you can see that size criterion is
an inaccurate yardstick by which we
categorize
nodes today.
Morphology has been to a
certain extent
used in conjunction with size criteria
occasionally, and one of the important
morphologic
features we rely on is presence of fatty
hilum, as
you are seeing here.
It is said that if the node has
a central
fatty hilum, that is a sign of benignity,
however,
we
have seen from our experience that even small
nodes, as the case here, with the fatty
hilum in
21
this patient with bladder cancer, was
biopsy proven
to be positive and having malignant
cells.
Thus, morphology, too, has its
drawbacks
and when used with size criterion, can be
a
problem.
Central necrosis is the other
morphologic
feature which has occasionally been said
to be a
very useful way to allow for diagnosing
malignant
nodes, but it is important to realize
that when
nodes become necrotic, they are enlarged
beyond a
cm, and by size criterion, you would
still call
them positive.
Well, what about surgery, which
is
considered to be the gold standard, and I
am going
to use prostate cancer as an example, but
I think
the underlying principle can be applied
or
extrapolated to other tumors, as well.
In prostate cancer, pelvic
lymph node
dissection accompanied by frozen section
path
examination is considered to be the gold
standard.
However, the way lymph nodes are sampled
today, at
the time of surgery in intermediate to
high risk
22
prostate cancer patients, the standard
pelvic
lymphadenectomy is limited. This is because the
surgeon only resects the low external
iliac and the
obturator group of lymph node.
In the recent or not too
recent, in an
April 2000 study published in the Journal
of
Urology, it was shown that if the surgeon
extends
the lymphadenectomy and takes out the
high external
iliac and the internal iliac nodes,
keeping all
other risk factors the same, the
incidence of lymph
node metastases jumps from 10 to 26
percent, so you
can see that a potential of 16 percent
miss rate if
one just follows the standard pelvic
lymphadenectomy.
So, that begs that question why
don't we
do that in all the cases, because there
is a
significant morbidity that comes with
that
procedure. Moreover, it is also important to
realize that the frozen section analysis
can also
have a false negative rate of 30 to 40
percent, so
all these factors show us the limitations
of how
even when surgery is performed and nodes
are
23
sampled, there are some limitations.
Here is an example of a patient
who had
underwent radical prostatectomy, and you
can see
clips where the surgeon has taken out the
lymph
nodes, and as I said earlier, this is
what standard
lymphadenectomy involves, is the low
external iliac
group of lymph nodes.
There was a small nod
posteriorly in the
pelvis that was not sampled, and the
patient was
labeled as cured. Eight months later, the
patient
shows back with that node mushrooming
into a
full-blown metastases, and this is a good
example
of how surgical sampling can sometimes be
limited
by what the surgeon can see and samples.
Thus, there is a current need
for a
non-invasive technique that not only
detects, but
also characterizes lymph nodes with a
high level of
accuracy, not compromising sensitivity
for
specificity.
It also provides a broad
anatomy coverage
which means you not only look at lymph
nodes right
next to the primary cancer, but also can
look at
24
lymph nodes in a broad anatomic area
beyond the
confines of the regional distribution.
That is where I think Combidex,
or the
pharmacologic name ferumoxtran-10, is an
excellent
contrast tool that can be utilized with
MR. This
is an iron oxide based nanoparticle with
a central
iron oxide coat and a surrounding dextran
coating.
This slide shows how the
contrast acts.
After intravenous injection, the contrast
lingers
in
the blood vessels for a long time, has a long
blood half-life. It gradually leaks out and then
is transported to the lymph nodes where
it binds to
the scavenger on macrophages. Thus, the mechanism
of action of uptake in the normal nodes
is via
macrophages. So, if the node is functioning
normally and has its normal complement of
macrophages, the contrast would then
localize to
the nodes and turn the normal area of the
node
dark.
I would like to emphasize at this
point,
two points in the mechanism of
action. One is the
contrast is targeting the normal lymph
node and
25
black is benign, so it is the normal part
of the
node that is turning dark.
If you have an area of tumor
deposited in
the node, then, that area of the node is
devoid of
normal functioning macrophages and that
area would
show lack of uptake and continue to stay
bright.
Another important point to
remember is
that this mechanism of action is
independent of
which primary cancer affects the node,
and, hence,
the lack of uptake would be present no
matter which
tumor deposit is present within the lymph
node.
This slide is just to show the
technique
that we use. Any conventional 1.5 MR system that
exists today in the community,
independent of
vendor platform, can be used for imaging
the MR
with Combidex, and these are the
sequences, again
nothing fancy, just regular bread and
butter
sequences.
We can do post-processing,
which can
provide for elegant ways of communicating
the
information, but these are not essential
for making
the diagnosis.
26
So, let me show you an example
of how the
Combidex acts in real life. This is a patient who
has a known pelvic malignancy. There are two lymph
nodes in the groin. Both are hyper-intense or
bright on the pre-contrast.
Twenty-four hours after
injection of
Combidex, you can see the medial node is
turning
homogeneously dark, and that is the node
that is
benign.
The node to the right shows lack of
uptake, and that means that it's
infiltrated with
cancer and, hence, it is not taking up
the
Combidex.
Let me show you some examples
of how
Combidex scanning improves sensitivity in
detecting
metastases in small lymph nodes.
This is a patient with prostate
cancer
undergoing staging. The yellow arrows point to two
very small nodes next to the external
iliac vein.
Again, by size criterion, you would never
call
these nodes positive.
On the pre-Combidex scan, you
can see
these two nodes are hyper-intense, and 24
hours
27
later after Combidex, the inferior one is
turning
homogeneously dark. It means that that is benign.
The one which is pointed by the red arrow
shows
lack of uptake, and that is the one which is
malignant, which was proven at the time
of surgery.
This is a patient with breast
cancer.
Again, the patient is lying prone. Here is the
lung, the breast of the patient, and we
are looking
at the axilla. Again, there are two very small
nodes in the axilla pointed by the yellow
and the
red arrow, measuring between 3 to 4 mm.
After giving Combidex, the
superior one is
turning dark as outlined by the yellow
arrow, the
inferior one, which is the red arrow,
shows lack of
update, indicating it's malignant and
again proven
with surgery.
So, I have shown you how
Combidex improves
sensitivity in different types of primary
cancers.
It is equally important to have enhanced
specificity, which means if the node is
enlarged,
you need to accurately diagnose it as
benign or
malignant.
28
So, here is a patient with
bladder cancer.
You have an enlarged node measuring 20
mm, and this
was labeled as malignant on the
contrast-enhanced
CT.
On the pre-contrast MR, it is hyper-intense.
Post-Combidex, it turns homogeneously
dark
indicating it's benign and was proven so
on biopsy.
Another example of enhanced
specificity,
again a patient with prostate
cancer. The two
yellow arrows point to enlarged obturator
nodes,
again labeled malignant based on the size
criterion, but post-Combidex, you can see
it is
turning homogeneously dark, and these
turned out to
be reactive enlarged nodes or reactive
benign nodes
in
the pelvis.
As you can see, by improving
the
sensitivity and specificity in these
patients, one
can provide for improved clinical
staging, and then
also provide for better surgical planning
and
better radiation therapy and image-guided
intervention planning. Some of these points will
be highlighted later by my colleague, Dr.
Jelle
Barentsz.
29
Thank you
Efficacy Data from Phase III
Clinical Studies
DR. GOECKELER: Good morning.
I am going
to review in the next few minutes the
efficacy data
in support of the proposed
indication. The studies
I will be discussing were designed to
evaluate the
ability of Combidex to improve the
differentiation
of metastatic from non-metastatic lymph
nodes,
particularly in the post-contrast
setting.
To do this, we compare the
parameters of
sensitivity and specificity in both the
pre- and
post-contrast image sets. The study's design,
which was conducted in cooperation with
the FDA,
provided for multiple primary tumor types
and
independent blinded evaluations of image
sets with
histopathologic confirmation of the
imaging data.
I think it is worth taking just
a step
back to say that all the imaging data
that you will
be presented this morning by the sponsor
involves
histopathologic confirmation at the
individual node
level, which is a significant
undertaking.
So, in reviewing the efficacy
data, I will
30
first go over quickly the blind read
procedures
that were used in conducting the analysis
of this
data, review the data from EU and U.S.
Phase III
studies, talk a little bit about data
from
publication in the New England Journal of
Medicine
that investigated the agent in this
application,
and finally, close by looking at how this
improvement in differentiation at the
nodal level
impacts clinical nodal staging.
So, first, the blinded read
procedure, and
there are a number of blinded reads that
were
carried out in each of the clinical
studies, so I
will try to explain the terminology and
the
sequence in which they were conducted.
All the blinded reads were carried
out
with the readers blinded to clinical,
demographic,
and pathologic information, and the cases
were
presented in random order.
The readers were first
presented with the
pre-contrast images, and based on the
pre-contrast
images alone, made an assessment on size
based.
You will also see that in some
of the
31
slides called an MRI-based diagnosis, and
then the
reader made a second assessment based
solely on the
pre-contrast image, which was based on
the reader's
skill.
In that subjective evaluation, the reader
was allowed to use any criteria they
thought was
appropriate in differentiating metastatic
from
non-metastatic lymph nodes.
Following those readings, the
readers were
presented with the post-contrast images
and carried
out an evaluation of the post-contrast
side by side
with the pre-contrast images. This is a so-called
paired evaluation. The prospective primary
endpoint in each of the Phase III studies
was a
comparison of the paired evaluation with
the
pre-contrast size-based evaluation at the
nodal
level.
Next, a period of about two
weeks to
eliminate a recall bias was allowed, and
then the
readers were presented, again in random
order, with
the post-contrast only images, and then
made an
assessment based only on the
post-contrast image,
which is called the post-contrast
evaluation.
32
Post-contrast images, there
were reading
guidelines developed to assist the reader
in
evaluating the nodal post-contrast
images. They
were prospectively developed and
finalized before
the blinded read. Thus, the Phase III blind read
of images is a valid assessment of nodal
images
across a wide range of cancers.
This is the study population in
the three
studies that I will be talking about -
the U.S.
Phase III, the EU Phase III, and the New
England
Journal.
The number of patients dosed and the
number of patients with histopathology is not
always the same since eventually, not all
patients
go to surgery for things that happen in
the
intervening time between the imaging
session and
the treatment of the patients.
This outlines the number of lymph
nodes
that were evaluated in the various
studies both
pre- and post-contrast and a breakdown of
where
those lymph nodes resided by anatomic
region in the
various cancers.
So, right into the Phase III study, in
the
33
EU Phase III study, what we see is that
in the
pre-contrast evaluations, both the size
and the
subjective base, we see a high
pre-contrast
sensitivity and a low pre-contrast
specificity,
whereas, in the post-contrast evaluation,
the
paired evaluation, what we see is
sensitivity
remains high at 96 percent, but
specificity is
significantly improved, and the
improvement in
specificity was statistically significant
over both
of the pre-contrast reads and for both of
the
blinded readers.
We look at the data from the
U.S. Phase
III study. It's a little bit different
situation.
In the pre-contrast size-based analysis,
in the
pre-contrast analysis, sensitivity was
low and
specificity was high, so sort of just the
opposite
of what was seen in the EU study.
In the subjective evaluation,
we see that
the subjective reader's assessment
resulted in a
very high sensitivity, but the tradeoff
for that
increase in sensitivity was a large
decrease in
specificity.
34
So, the pre-contrast reads had
either high
sensitivity or high specificity, but not
both. In
the post-contrast reads, you will see
that
sensitivity was high and specificity was
high, so
we had a combination of high sensitivity
and high
specificity.
You will also note that in the
post-only
read, in which the only image that was
available
was the post-contrast image, resulted in
the
highest level of imaging performance and the
greatest level of consistency.
If we take a look for just a
minute at
this discrepancy between the two
pre-contrast
reads, where one had high sensitivity and
low
specificity, and the other was the opposite,
if we
look at the false diagnoses that occurred
in these
various blinded readings, and we look at
false
diagnoses as a percentage of the total,
we see that
the percentage of false diagnoses for
both of the
pre-contrast reads is relatively the
same.
What we see is that in the
subjective
readers' diagnosis with the readers
subjectively
35
overreading to try to account for the
known low
sensitivity of the size-based analysis,
we see a
very large percentage of false positive
reads that
occur in the subjective readings,
whereas, in the
post-contrast reads, we see a decreased
percentage
of false reads with the lowest and most
consistent
data again in the post-only read.
This is the data broken out by
body
region, and you can see that in the head
and neck
and breast, we saw large increases in
sensitivity
when we compare the pre- to the
post-contrast read,
maintaining specificity which overall
resulted in
the increase in accuracy.
In the pelvis and abdomen, we
had more
moderate levels of increase in both
sensitivity and
specificity, the net effect of which is
that the
increase in accuracy in the pelvis and
abdomen is
virtually identical to what one sees in
both the
head and neck and the breast.
One region that was a little bit
different
was in the lung. In the lung, we see more
moderate, small increases in both
sensitivity and
36
specificity, and we believe this has to
do with
limitations of anatomic imaging in this
particular
body region, and not differential uptake
or
performance of the contrast agent.
So, turning now to the data
published in
the New England Journal of Medicine, and
I think
this data is important supplemental data
that can
help us understand better some of the
differences
that were seen particularly in the
pre-contrast
reads in the Phase III studies and also can
help us
learn a little bit more about the
performance of
the agent in different size nodes.
So, this is a study carried out
in
prostate cancer patients at two centers,
one in the
U.S., one in the EU, 40 patients from
each site.
There was a centralized independent
blinded read
with histopathologic confirmation of
data.
So, to address some of the
issues that I
just mentioned, I am going to go through
the data
in a little bit of a sequential order.
First, with regard to the issue
of the
discrepancies in the pre-contrast
evaluations and
37
also to look at the issue of the effect
of nodal
size on the performance of the contrast
agent, what
you see is as you move across these three
studies,
the distribution of nodes categorized as
either
greater than or less than 10 mm, and that
is an
appropriate cut point because as Dr.
Harisinghani
said earlier, that is the point at which
we
differentiate a malignant from a
non-malignant
node.
We see that as we move from the
EU to the
U.S. to the New England Journal study,
the
proportion of large nodes are greater
than 10 mm in
the yellow, goes from about
three-quarters to about
a third to only 7 percent in the New
England
Journal study.
We see in the pre-contrast
size-based
sensitivities and specificities, we see
that the
sensitivities and specificities largely
track with
the nodal size. That is, in studies where there
was a high proportion of large nodes, we
see a high
sensitivity in the pre-contrast
evaluation in the
green bars, which decreases as the
proportion of
38
large nodes in the study decreases.
Conversely, as in the purple
bars, we see
that as the percentage of small nodes
increases,
then, the specificity increases also.
So, finally, in the
post-contrast data,
what we see is that we see a lack of
dependence of
the performance of the agent on the size
of
distribution of the nodes in the
study. We have
high sensitivity and specificity
regardless of the
distribution of the lymph node sizes that
were in
those studies.
Finally, just a word about clinical
nodal
staging in the U.S. Phase III study, we
looked at
clinical nodal staging where we could
collapse the
nodal stage in its simplest form to where
patients
were either node positive, node negative,
or
indeterminate.
What we see here is a
comparison of the
clinical nodal stage that was assigned
based on the
images compared to the eventual
pathologic stage,
and we can see as we go from the pre- to
the
post-paired to the post, the percent
where the
39
agreement was correct increases, the
percent where
it's incorrect decreases, and the
percentage that
could not be staged also decreases.
So, to sum up, there are two
prospective
Phase III studies. The pre-contrast evaluations in
these studies show a characteristic
tradeoff of
sensitivity for specificity.
Post-contrast
evaluations show high sensitivity and
high
specificity, which results in an overall
improvement in accuracy.
The improved lymph node
differentiation
improved clinical staging. The supporting data
from the New England Journal publication showed
high sensitivity and specificity in a
population of
largely small lymph nodes.
Finally, these data
collectively
demonstrate the efficacy of Combidex in
differentiating metastatic from
non-metastatic
lymph nodes.
Thank you. Now, Dr. Faich will review the
safety data.
Safety Data from Clinical
Trial
40
DR. FAICH: I am Jerry Faich. Good
morning, members of the panel, Chairman,
and FDA.
What I would like to do rather
briefly is
review the amount of exposure data that
has been
obtained for Combidex, discuss and show
you the
pattern of adverse events that have
occurred, make
a few comparisons with other agents, and
then
discuss the proposed risk management plan
for the
product.
In total, 2,061 subjects have
been dosed
with Combidex. Of these, and I would like to
emphasize this and explain it, 131
received bolus
injection. This was in the process of developing
or exploring the utility of the product
for liver
scanning, which required a bolus
injection. That
indication and mode of administration has
been
dropped.
The remaining patients, the
remaining
1,930 patients were dosed with dilution
and
infusion either in 50 ml or 100 ml
saline, and
within those, there were 1,566 cases at
all doses
who got the 100 ml dilution.
41
For the proposed indication and
mode of
distribution, there were 1,236 patients
in the NDA
receiving 2.6 mg of iron/per kg at the
100 ml
dilution over 30 minutes.
This shows you on the left-hand
side the
rate of adverse events in the bolus
injection 30
percent, in the middle 17 percent for 50
ml
dilution, and 14 percent on the
right-hand side for
100 ml dilution showing a clear
dose-response
relationship in terms of adverse events,
and this
is indeed why the 100 ml dilution has
been focused
on.
It needs to be said that during
the bolus
injection studies, there was one
anaphylactic death
that occurred immediately. That and the need to
use bolus injection for liver scanning is
what led
to dropping the pursuit of that
indication.
This shows you in the 1,236
patients the
pattern and rates of adverse events, you
can see
going from vasodilation at 3.4 percent,
rash, back
pain, pruritus, urticaria, et cetera,
overall
totaling these 15.8 percent.
42
I would simply like to
emphasize that
nearly all of these were mild, transient,
and
self-limited.
Within the 1,236 core patients,
5.6
percent had adverse events from that prior list
that could be called hypersensitivity
events.
Mainly these were vasodilation. It included 24
patients, however, who had more than one
symptom
from that list.
Only 4 of the 1,236 patients, or 3 per
1,000, had a serious adverse event. The serious
adverse event rate is no greater than
that found in
labeling for nonionic iodinated contrast
media,
which ranges from 0.6 to 1.5 percent, and
I will
show you that in a moment.
There were no life-threatening
anaphylactic/anaphylactoid reactions at
the
proposed dose and method of
administration.
In terms of immediate adverse
events,
immediate hypersensitivity adverse events
can, of
course, be controlled in large part by
stopping the
infusion.
The most common reaction, as I noted,
43
was flushing.
Thirty-six patients had
infusion stopped
and restarted, that is, these patients
were
rechallenged. Only two of them could not tolerate
the rechallenge and were
discontinued. The
remaining 36 went on to complete their
procedure.
Put a slightly different way,
94 percent
of all immediate hypersensitivity
reactions
occurred within the first 5 minutes after
dosing.
Most hypersensitivity reactions, as I
indicated,
were mild to moderate in intensity.
At the proposed dose and method
of
administration, out of the 4 serious AEs,
2 were
classified as immediate hypersensitivity
reactions
using the FDA definition. That translates to a
rate of 1.6 per 1,000.
In terms of anaphylactoid
reactions, again
using an FDA definition of affecting two
body
systems, there were 12 such patients at
the
proposed dose and method of
administration. Two of
those were considered serious.
Four of the 12 were in the
group that had
44
infusion stopped and then were
rechallenged without
subsequent problems. The majority of these 12 had
dyspnea and flushing. There were no serious
hypotension or respiratory compromise
seen in those
12 patients.
I don't mean to make much of
this, but I
do show it, and it is always hazardous,
and one has
to interpret data carefully when you
compare one
set of data from one set of studies and
labels to
another, but what I would like to do here
is call
your attention to the Combidex data
across the top.
The overall AE rate was 15.8
percent, the
serious AE rate was 3 per 1,000. That is those 4
cases I mentioned. If you look down in
the
right-hand column just at serious AEs and
compare
it to other iodinated contrast agents,
both from
data in their labels and published
studies, you
will see for Ultravist, that serious AE
rate is 1.1
percent.
For comparators in studies done
with
Ultravist, it was 0.6 percent, for Oxilan
it was
1.5 percent, and for comparators to
Oxilan and
45
studies done with it were 1.1
percent. So, this is
a basis or my basis for concluding there
is not
evidence that there is increased risk of
serious
adverse events comparing this drug to
commonly used
iodinated contrast agents.
There is not much in the
literature about
anaphylaxis in contrast agents. Here are 2 recent
studies that have been published. This is Neugut
in the Archives of Internal
Medicine. His
published anaphylaxis rate done from his
own
studies and across the literature was 2
per 1,000
to 10 per 1,000 or 0.22 to 1
percent. He noted
that it might be lower and most people are
taking a
rate of about half that for low
osmolality contrast
agents.
David Kaufman, at the Center
for
Epidemiology in Boston, published this
paper in
2003, and for contrast agents, this was
an
international study of anaphylaxis, the
observed
rate was 7 per 10,000. For nonionics, again, as I
said, 50 percent of that, about 3.5
percent, and
there was a range as you see here.
46
Combidex falls within or at the
lower end
within that range of values.
In terms of a risk management
plan for
this product, it is largely in keeping
with
existing guidelines and calls for
physician
education, emphasizing the need for
dilution and
slow infusion obviously as a means to be
able to
intervene if a reaction is
occurring. The labeling
will be consistent with that, and the
proposal is
to conduct targeted surveillance to
gather further
data to reinforce the safety data that I
have shown
you.
To summarize, then, there has
been
considerable clinical exposure in the
development
program.
Hypersensitivity is relatively infrequent
and comparable to that of other contrast
agents,
and the risk management program that I
just
described is in accordance with existing
guidelines. Thank you.
Dr. Barentsz, please.
Clinical Utility of Combidex in
Various Centers
DR. BARENTSZ: Madam Chairman, members of
47
the Committee, members of the FDA, I am
an
oncologic radiologist and I have been
using
Combidex MRI in more than 500 patients,
and I am in
frequent contact with investigators in
both the
U.S. and in Europe.
From the previous data, you have
clearly
shown that this contrast agent
works. A black
lymph node is normal, and a white lymph
node is
abnormal.
That is despite the tumors type.
Nonetheless, evaluating its
clinical
utility is a lot more difficult, and for
that you
need personal experience, as well as
post-Phase III
studies.
Based on these two, I am going to try to
show you the clinical utility and some
cancer
types.
The reviewed publications were
all in top
ranking journals. It was blinded post-contrast
image evaluation with gold standard
histopathology,
and all those papers described a
potential impact
on treatment planning.
The areas being defined where
Combidex MRI
provides a significant clinical benefit
were
48
prostate, bladder, head and neck, and
breast, and I
want to address those issues with you in
the next
10 minutes.
As you can see, data were
collected from
almost 200 patients and almost 2,000
lymph nodes.
These are the data on sensitivity and
specificity
and accuracy.
You can see that the data are
highly
consistent, showing a high sensitivity,
specificity, and accuracy for all the
cancers.
Now, let's start with the
clinical utility
in prostate cancer. First of all, you have to
define the current strategies. Current imaging has
an insufficient sensitivity for lymph
node staging,
and therefore, urologists are performing
an
invasive operative surgical lymph node
sampling to
detect the lymph nodes.
These techniques have
limitations, only a
limited area sampled, and therefore, up
to 31
percent of the positive lymph nodes are
outside of
the surgical area, which have been shown
by some
data recently published in the urology
journals.
49
Furthermore, surgical sampling
has a
complication rate reported to be 22
percent for the
open dissection and 5 percent for
laparoscopic
dissection, including lymphocele,
lymphedema, deep
venous thrombosis, pulmonary embolism,
nerve
damage, and blood loss.
Because of the limitations of
current
imaging technique and current staging
techniques
for the lymph node dissection, these
urologists are
advocating at this moment now an extended
lymph
node dissection. They state that they will detect
those lymph nodes, however, this
significantly
increases morbidity. The question is are the less
invasive way techniques to solve this
problem.
As you can see, using the
post-contrast
studies of Combidex, there is a dramatic
decrease
of the number of false positives, as well
as the
number of false negatives, but what is
even more
important is that in our study in the New
England
Journal of Medicine, in 6 percent of all
the
patients, we found a small non-enlarged
lymph node
which we could biopsy, and in all those
patients,
50
we could confirm the diagnosis by
image-guided
biopsy, and these patients did not
undergo any
surgical dissection.
Furthermore, in 11 percent, we
found lymph
nodes which were outside of the surgical
field, so
they will be missed with regular surgery.
All these findings were
confirmed by the
surgery because before the operation, we
told the
urologists where the lymph node was, and
they could
then find them.
I would like to show you two
representative cases. Here, you see a
white lymph
node, metastatic, of only 7 mm in
size. It is very
close to the internal iliac artery, which
is
outside of the normal surgical
field. In this
lymph node, we performed an image-guided
biopsy
which was positive, and in this way a
correct
diagnosis was being evaluated in a less
invasive
manner, and this avoided inappropriate
treatment.
This patient had, instead of a
prostatectomy, an
androgen ablation.
In another patient, you see a
lymph node
51
over there with a tiny white
structure. You can
see it over there. This was also a lymph node
outside of the surgical field. We told our
urologist where this lymph node was
located. It
was found and it was confirmed
histopathologically
that this lymph node had a 1-mm
metastasis.
What about bladder cancer? It is actually
the same story. In 24 percent of positive lymph
nodes, there are positive lymph nodes in
24 percent
despite negative pre-operative imaging
techniques.
The presence of lymph nodes
radically
changes the treatment option especially
if there is
N2 and 3 node, or if there are more than
4 nodes,
so finding these lymph nodes also here is
very
important.
If you perform an extended
lymph node
dissection, you detect more lymph node,
it will
increase survival for minimal disease,
however,
also in this extended lymph node
dissections, not
all lymph nodes have been sampled.
Furthermore,
this increases morbidity.
These are the data in 172 lymph
nodes in
52
58 patients from a Radiology paper, and
it has been
shown that in normal-sized lymph nodes,
10 out of
12 were detected using Combidex MRI, and
this
information was crucial for the surgeon
to find
these lymph nodes, and they were removed.
Most important areas, also head
and neck.
The survival rates depends on whether the
tumor has
metastasis in lymph nodes or not. Therefore, the
status of cervical lymph nodes is vital
for the
choice of therapy.
Twenty-five percent of positive
lymph
nodes are found despite negative
preoperative
imaging techniques like contrast CT or
ultrasound-guided biopsy. Why?
Because these
lymph nodes are below normal size
criteria. They
are only 5 to 10 mm in size.
Because of the fact that these
lymph nodes
do not show up with imaging, head and
neck surgeons
perform commonly a radical neck
dissection, which
causes a very severe cosmetic deformity
and has a
very high complication rate, in
literature reported
up to 54 percent.
53
The data from Mack, et al. in
Radiology
show a very high sensitivity and negative
predictive value, and furthermore, what
is more
important, if you look on a patient
level, they
were able to make an accurate diagnosis
in 26 out
of 27 patients, and what is the most
important
thing is that this information would have
resulted
in reduced extent of surgery in 26
percent of these
patients, so avoiding an aggressive neck
dissection.
One representative image. This was a
patient with, on the CT scan, an enlarged
12 mm
lymph nodes, however, on the
post-Combidex MRI, you
see the lymph nodes are black. This was the 12 mm
one, this was the 10 mm one, and they
were normal.
In this patient, a neck dissection could
have been
avoided.
Finally, breast cancer. The commonly used
staging procedure at this moment is the
sentinel
lymph node staging, which has false
negative
numbers of 3 to 10 percent, and is an
invasive
technique, but what is even more
important is that
54
recent data have shown that the sentinel
lymph node
is the only positive lymph node in 61
percent in
patients with positive lymph nodes.
Nonetheless, these patients all
undergo an
axillary lymph node dissection, and this
has a high
rate of clinically significant
complications.
A technique with a high
negative
predictive value performed in an adjunct
to the
sentinel lymph node procedure in patients
with one
positive sentinel lymph node may reduce
the number
of axillary lymph node dissections.
These are the published data in
almost 300
patients by Michel in Switzerland, and
you can see
that this technique has a high negative
predictive
value.
I would like to show you one
representative case from our
institution. This is
a very, very tiny primary tumor, and this
was the
positive sample on lymph nodes.
This lymph node is
white on Combidex, so that means
metastatic, and
you can see that the second and third
station lymph
nodes, that they are black, so in this
patient, all
55
the other lymph nodes were black, which
in this
case was confirmed by histopathology.
Now, to the final
conclusion. I have
tried to show you some areas of clinical
utility of
this contrast agent, and as soon as we
get more
experience, there will be a lot more
areas.
To summarize, the current
techniques to
detect positive lymph nodes in prostate,
bladder,
head and neck, and breast cancer have
significant
limitations.
Combidex MRI shows high
sensitivity and
specificity not only on the nodal basis,
but also
on the patient-to-patient basis, which
for a
clinician is even more important.
Therefore, Combidex MRI may reduce
the
extent of surgery and morbidity, and
finally,
Combidex MRI identifies additional
positive lymph
nodes for biopsy or image-guided extended
lymph
node dissection in this way improving the
staging
of the surgeon.
Thank you.
MR. ROESSEL: Thank you.
That concludes
56
our presentation.
Our clinical data and the
clinicians I
think have shown you that Combidex is an
important
diagnostic imaging tool that improves the
current
practice.
Thank you. We are available for any
questions you have.
DR. MARTINO: Thank you.
At this time, I am going to ask
Dr. Li to
present his view of this data, and once
that is
done, we then will take questions for
both the
sponsor and the FDA.
FDA Presentation
Efficacy and Safety of Combidex
(NDA 21-115)
DR. LI: Dr. Martino, members of panel,
ladies and gentlemen, good morning. My name is
Zili Li.
I am a medical team leader with the
Division of Medical Imaging and
Radiopharmaceutical
Drug Products at FDA. I am a board-certified
physician in preventive medicine with
special
training in epidemiology.
Today, I would like to share
with you our
57
review of findings of NDA Application
21-115
Combidex.
I would like to start off by
noting that
this presentation represents a
collaborative effort
by a group of highly dedicated reviewers
at FDA
whose names are on this list.
Combidex is an MR contrast
agent. The
proposed clinical dose is 2.6 milligram
iron per
kilo of body weight.
Of three methods of administration
which
has been used in the clinical development
program,
the sponsor select the dilution in 100 cc
with the
slow infusion over 30 minutes of a
standard measure
of administration.
The other two methods, particularly
the
direct injection, is no longer being
proposed.
This slide summarized the
indication that
had been proposed by the sponsor--I will
go over
one more time--that Combidex can assist
in the
differentiation of metastatic and
non-metastatic
lymph nodes in patients with confirmed
primary
cancer who are at risk for lymph node
metastases.
58
I would like to draw your
attention to the
fact that this is a broad
indication. If granted,
this agent can be used for almost all
cancers
regardless of type, size, clinical stage,
whether
patient has been previously treated with
drug,
biologic, radiation, or surgery.
One objective of today's
presentation is
to show you why the Agency has concerns
for such a
wide or broad indication given the level
of
efficacy and safety observed from
clinical trials.
To support this indication, the
sponsor
submit one U.S. and three European Phase
III
studies.
In addition, sponsor also ask Agency to
consider data from a published article in
the New
England Journal of Medicine.
For the safety, the sponsor submitted a
safety data adverse event profile in
particular
from approximately 2,000 individuals who
received
Combidex from multiple clinical studies.
I would like to make a remark
on this New
England Journal of Medicine article. This study is
pooled analysis from two ongoing clinical
studies.
59
One is U.S. IND study, is under sponsor's
IND. The
other study is non-IND study and in
Europe.
The clinical investigators
themselves took
initiative to combine 40 cancer patients
from each
original study to form the basis for this
New
England Journal of Medicine study. At this time,
however, it is unclear to us how those 80
patients
were selected, and more important, after
repeat
requests, the sponsor is not able to
provide us the
original source document which included
pre-defined
statistical plan, blind reader evaluation
manual,
and original copy of blind readers'
evaluation of
the medical imaging.
For that reason, the Agency
cannot
conclude this study was conducted in
compliance
with the Federal regulations pertaining
new drug
application. For that reason, we are not able to
consider this study as adequate and
well-controlled
study.
However, the Agency do agree
that the
cases present in this article may
demonstrate some
potential the benefit of the use of
Combidex in a
60
clinical setting.
I also would like to draw your
attention,
say
a few words about this U.S. IND study.
We just
got update from sponsor yesterday. This study is
closed at this time. Roughly, they have
220
patients enrolled including 91 prostate
cancer and
34 bladder cancer patients.
Although the original protocol
require all
the pathology confirmation and MR imaging
for all
the patients, at this time it is not
clear to us
how many patients for this study will
have both
information available for a meaningful
analysis for
efficacy if such analysis is needed.
Now, I would like to first
highlight the
differences between sponsor and the
Agency's final
conclusion regarding efficacy and for
safety.
As far as for the efficacy, the sponsor
believes the non-contrast MR agent only
offer high
sensitivity or high specificity, but not
both. The
advantage of this Combidex is its ability
to offer
both high sensitivity and specificity
consistently
regardless type of cancer or size of the
lymph
61
node.
At this time, the Agency is not
able to
draw such a conclusion because of the
generalizability and validity issues we
are going
to show you in the later presentation,
and also in
the later presentation, we are going to
show some
preliminary evidence which may suggest
the
performance of Combidex may vary by size
or type of
cancer.
For the safety, sponsor
acknowledge that
Combidex is associated with
hypersensitivity
reaction, however, their emphasis is that
no death
or life-threatening AEs are associated
with the
proposed clinical method of
administration. That
is the dilution with the slow infusion.
Also, I just noticed in the
sponsor's
presentation is new to us that they make
a claim
that this agent's safety profile is
equivalent to
the iodinated contrast agent. I believe in your
briefing document, they also made a claim
that
serious adverse event with the Combidex
is only
one-third of that iodinated contrast
agent.
62
Our position is that dilution
and slow
infusion are not entirely free, and also
we
disagree that the Combidex, the safety
profile
resemble that of iodinated contrast
agent.
This slide highlights the
issues we are
going to bring to the panel today. For the
efficacy, we are going to talk about
sample size.
We are going to talk about representation
of
different tumor types in the clinical
study.
We are also going to talk about
impact of
study inclusion/exclusion criteria. Later, the
last one, we are going to talk about
develop use of
Combidex imaging guidance, which was the
major
issue in our briefing documentation to
you.
For safety, we are going to
talk about the
hypersensitivity reaction. We are also going to
make a comparison with iodinated contrast
agent.
Then, we are going to follow up
with the
discussion of risk-benefit ratio,
including the
sponsor's proposed risk management plan
and our
emphasis on the need to understand, to
define the
conditions of use for this product.
63
From the sponsor's
presentation, it was
stated that total 152 U.S. patients and
181
patients from a European study received
Combidex
injection, however, what was not apparent
on their
slide was the number of patients who were
actually
included in the primary analysis. What we are
showing you is, because there are two
different
blind readers, so they may see the
different people
different, so the number may vary
slightly.
For the U.S. study, there is
only 64
percent of original total population were
actually
involved in the final analysis. For the European
studies, the number varies from zero, 16
percent,
roughly 20 percent to 41 percent. It only
represent a small proportion of the
patients who
originally received the Combidex.
I need to make a clarification
for the
study with zero participation. This is a breast
cancer study. You probably read our briefing
document.
The original statistical plan for the
European study is on the patient
basis. It is
totally different from what they did
here. So, for
64
that reason, the individual nodal level
analysis
was never performed, so those people
cannot include
in their primary analysis and consistent
with U.S.
statistical plan.
The small number of patients or small
proportion of patients included in the
primary
analysis create two dilemmas for us. The first, we
need to understand whether the estimate
we got from
this population is applicable to entire
population.
The second one is because of
the small
number of patients, we want to ensure
that the
patients included in the analysis more
represent
the cancer patient distribution in the
United
States.
This is the second issue we would
like to
bring to your attention.
Based on the statistic provided
by
American Cancer Society, it is estimated
this year,
2005, there is going to be 1.4 million
new cancer
diagnosed.
The left two column showed you the rank
of the top 10 cancers and also showed
their
percentage distribution in the United
States. I
65
need to mention that lymphoma or leukemia
are not
included in this table.
On the right two columns show
the number
of patients and their distribution for
each type of
cancer included in the primary
analysis. I would
like to bring your attention to the fact
they have
two readers. In this slide, we pick the highest
number in this table.
You probably noticed that the
majority of
patients come from head and neck, which
is ranked
roughly number 6 in the frequency
distribution, and
also you probably noticed that prostate
cancer
being the number one in the United
States. There
is only 5 patients from the United States
and 5
patients from Europe was included in the
primary
analysis, and the highest number each
category is
only in here is 37.
Also, I need to remind you that
for
European study, the sponsor showed you
the majority
nodes are larger than 10 mm. Actually, in reality,
all 37 patients have a node larger than
10 mm, so
there is no nodes like the 10 mm for the
European
66
study for this population, particularly
this head
and
neck what I referred to.
So, you probably will ask why
that so many
patients are not included in the primary
analysis.
I would like to bring your attention to
the fact
the primary analysis was conduct at the
nodal
level, so the target lymph nodes, which
should be
included in the analysis, is represented
here, the
large circle here, is all the lymph nodes
visualized by site investigators.
When patient enrolled, when
they take MR,
site investigator looked at the MR to
circle the
node they see on those MR images. That should form
the basis for primary analysis. However, not all
the nodes was able to match with
pathology, so you
drop some nodes right over there.
Then, when you present the same
images,
the unmarked images to blinded reader,
the blinded
reader may not pick up the same nodes the
original
investigator picked in the first place,
so you drop
some nodes over there.
Then, for the comparison
purpose, because
67
they want to compare the post-images with
the
pre-images, you can only do analysis on
the nodes
identified on both end, so for that
reason, you
have a few nodes drop again, so by the
end, the
nodes included in the analysis is much
smaller than
the nodes originally seen by site
investigator
initially.
This table actually show you
the
deposition of how the nodes got lost with
each
process.
In the U.S. study, this is the number of
patients.
The first row showed you number of nodes
originally visualized by the site
investigator,
which should form the basis for primary
analysis -
371, 834, 333, and 234.
This row showed you what
percentage of
those nodes have matched pathology, and
this row,
the final one, showed you what number,
how many
nodes were actually included in the
primary
analysis.
You can see it is roughly from 3
percent, 6 percent, to 45 percent of
nodes was
originally seen is included in the
primary
analysis.
68
The fundamental assumption for
this
clinical development program is that the
performance of Combidex should be
independent from
the type of cancer and the size of lymph
nodes.
That was why originally that was allowed
for
different cancer patients included in the
one
study.
However, if you look at this
performance
of Combidex, by different type of cancer,
you will
see, first, this is the sensitivity
slide. You
will see in the U.S. trial, the variation
from 76
to 100 depending on the site of primary
cancer, and
the 95 percent of the lower boundary
could go as
low as 55 percent.
Only if you are willing to accept
assumption that Combidex performance is
independent
of sites, you get 83 percent performance
with the
lower boundary 73. That is exactly the reason why
the Agency was so worried about small
lymph nodes,
small size, because from this table we
really don't
know whether it's a variation because of
the random
event, or if it truly reflects the
different
69
performance of Combidex among the
different type of
cancers.
This is the same table for the
specificity, which again challenge
assumption
whether the Combidex, the performance
should be
considered or accepted independent from
the type of
cancers.
You notice depending on the
different
sites, the specificity vary from 44 to
91, and with
the lower bound, can go as low as 21
percent. The
significance of the two slides is that
with dose
variation we will have a very hard time
to
understand what is appropriate
performance
characteristic of this Combidex-enhanced
MR
contrast agent, and if indeed the
performance are
different, if this drug is approved for
all the
cancers, this information may be misused
by the
clinician to make their clinical
judgment.
The next issue is about study
inclusion/exclusion criteria. I will go very fast.
Basically, for this study, the people who
received
treatment, chemotherapy or radiation
therapy in the
70
past 6 months was excluded.
Actually, in reality, when you look
at the
people included in the primary analysis,
I don't
think any of them had any prior
treatment, so
mainly this database, we believe, if
valid, only
applied to people who are newly diagnosed
patients.
This is issue about development
of a
clinical MR imaging guidance. Why is this imaging
guidance so important? It is because for the
radiation to use this contrast agent, you
need to
have a standard way to interpret
imaging. So, we
work with sponsor to ask them to come
with the
guidance.
So, this actually, the clinical
trial is
actually to validate the guidance for
this validity
and usefulness, however, originally, from
the NDA
submission, it appeared to suggest this
guidance
was developed and validated from the same
database.
That is the U.S. database. That was a big concern
for us because basically, if that is
true, that
destroyed independence of this guidance
themself.
Later on when we spoke to
sponsor, they
71
provided us a revised statement. Basically, the
guidance was developed by use of Phase II
images,
it is not Phase III.
Sponsor's consultant, when she
developed
this guidance, she did look at the 16
cases from
Phase III trials, however, no pathology
was
provided, and also, there was a statement
that
there is no more changes for the guidance
after
review of Phase III data.
To support their statement,
sponsor did
submit original soft document to FDA for
our
verification. We also had extensive discussion
with their consultant to recall what
happening on
that day for the development of a
Combidex imaging
guidance.
All we conclude at this time is
that,
first, we do not have definitive evidence
to
absolutely exclude the probability that
Phase III
data has no impact in this guidance
development,
however, the evidence provided by the
sponsor is
consistent with this revised statement,
therefore,
at this time, we decided not to pursue
this issue
72
any further unless there is new evidence
emerge.
The second issue we are having,
which I
will present was included in our briefing
document,
is in the European study, this guidance,
the core
instrument actually was not used by the
blinded
reader.
The blinded reader was using a different
guidance to make their diagnosis.
At this time, the sponsor is
not able to
provide any documentation for us to
understand
which method or who actually do the
translation
from this guidance and to this one. Actually, the
question we are having for the committee,
especially for people expert in MR
imaging, is
whether the similarity or correlation
between these
two guidance is so great, the Agency
should not
worry about who did it and with all this
documentation.
Now, I would like to switch to
the safety
side of Combidex evaluation. I will focus my
presentation in Combidex-induced
hypersensitivity
reaction.
There is one case
hypersensitivity-related
73
death in a clinical development
program. This is a
70-year-old male with history of allergy
to
contrast, who received undiluted direct
injection
and developed hypersensitivity reaction
immediately
after injection and become unresponsive.
At the clinical site, however,
there were
no appropriate personnel or emergency
response
available, so they have to call 911. When the EMT
arrived, they delivered CPR and
epinephrine. When
the
patient get to the hospital, patient was
pronounced dead approximately 35 minutes
after this
injection. An autopsy revealed no MI or PE, and
they conclude this is a Combidex-related
anaphylactic shock.
I would like to make two points
here.
This injection is no longer being
used. The second
one, we are really concerned about the
lack of
appropriate personnel for emergency
situations
especially if this drug is found to be
valid, safe,
effective, there is many free-standing
clinical
imaging centers around the country, so we
need to
have a way to ensure this drug to be used
74
appropriately. That is with assumption that if
this study is valid and the drug is safe.
This table shows the
distribution of the
safety database or number of patients by
administration and by the dose. There are a total
of 2,061 patients exposed to Combidex,
1,236
patients received proposed clinical dose,
131
patients received bolus injection. Those three
groups will form the comparison for our
next few
slides.
This slide shows the rate and
severe
hypersensitivity reactions by the three
different
subgroups I just mentioned to you. For the
clinical proposed dose, the rate of
hypersensitivity reaction is 5.3. For direct
injection, it is 6.1.
I would like to let you know that in your
briefing document, this number is
slightly higher
because we just discovered some computer
error, so
made correction on this slide.
People may define the severity
differently, so we use few indicators to
give you a
75
range of severity, so you can pick which
one is
appropriate for you. The first one is death. The
second one is serious events, which was
the event
that meet the regulatory definition for
serious
adverse event.
The next one is
hypersensitivity involve
at least two body systems. The next one is the
patient was treated with
antihistamine. The last
one is the patient treated with
steroid. Most of
them are IV steroid.
If you look at this population,
there is
no deaths. There is two cases the sponsor point to
you meet the definition of serious
event. There is
13 cases that involve two body systems,
27, or 2.4
percent, of people treated with
antihistamine, and
1.5 percent of people need IV steroids.
This slide outline the
presenting symptoms
of hypersensitivity reactions. We work extensively
with our internal expert at FDA. We define
hypersensitivity reaction with the
following three
groups of symptoms.
First, is skin reaction. The second group
76
with the respiratory difficulty with
cardiovascular
symptoms together. The third one with the facial,
laryngeal, and general edema. This table show the
distribution of the patient presentation.
You will notice the majority of
patients
present with skin symptoms, however, this
slide
does show that direct injection, they may
associate
with a high percentage of people with
more severe
symptoms.
This is a slide I would like to
bring to
your attention with a comparison with
iodinated
contrast agent. The sponsor told you that
there
were 4 cases serious AE happened in the
clinical
program.
That was an incorrect statement.
In
reality, there was 29 serious events
happened in
the clinical program.
The reason for include there,
because the
25 cases, the Agency do not consider is
drug
related, therefore, we didn't include it in
our
analysis.
In the comparator, iodinated
contrast
agents in their Table 9 safety
presentation, they
77
are
including all SAEs regardless whether drug
related, so that is we believe incorrect
comparison. So, that is why the number of events
in Combidex group is smaller than the
iodinated
group.
This table, we focus on the
hypersensitivity reaction between
Combidex and the
iodinated contrast agent. If you read the labels,
three labels which have clinical data for
iodinated
contrast agents, totaled together there
are 4,545
patients received iodinated contrast
agent. There
is no death happening. For Combidex, there is 1
death of all the people receive
Combidex. There is
zero out of 1,000 who has clinical dose.
For the serious AE, which is associated
with the Combidex, this is zero over
here, and you
have 6 cases out of 2,000 for all doses,
you have 2
cases for the clinical proposed dose.
Also, the last one, the column,
we show
the percent distribution of those
symptoms suggests
hypersensitivity reaction, you can see
the rate is
quite different, the relative risk is
quite
78
different. We do not want to draw definite
conclusion over here because we
understand the
population are different, but at least
this table
do not support this two rate are
comparable.
When you talk about whether the
drug is
appropriate for populations, you
basically talk
about the risk-benefit ratios. From the sponsor's
presentation, they believe the best way
to manage
to get a best ratio is to focus on the
risks. I
will show you their risk management
slides later.
From our end, we believe from the
safety
data we have at this time, this drug is
definitely
associated with hypersensitivity
reaction.
Although we have not observed serious
event, more
serious event including death in the
proposed
clinical dose, our level of assurance is
limited by
the number of patients involved in that
group of
patients who received the clinical dose.
At this time, we are only able
to say that
the death-related hypersensitivity
reaction
probably will now be higher than 1 out of
400 or
500 people based on data. Anything beyond
that,
79
that is purely speculation without any
data.
Sponsor present to you their
risk
management program. I rearranged our slides.
Basically, they say if we provided
dilution and
slow infusion, and educate physicians to
the
labeling and to the targeting academic
center, they
should be able to adequately address the
safety
issue.
We believe this is item we need
to discuss
to implement, and also we believe that
with
uncertainty with those severe events with
this
Combidex administration, when you focus
on the
issues, enhance the benefit of this drug
to the
appropriate population.
We need to better understand
actually the
performance of Combidex by different type
of tumor
and the nodal size, because we have
preliminary
evidence those performance may vary. Also, we need
to define appropriate patient population
or
condition for use, that the use of
Combidex, the
benefit will outweigh the risk, potential
risk.
This is a table to support our
preliminary
80
conclusion that performance of Combidex
may vary by
type, by size of nodes, in addition of
the type of
cancer.
This analysis actually was conducted by
sponsor.
We didn't make any modification to their
slides.
We just presented their slides, their
result to you.
On the top is for the nodes
less than 10
mm, the bottom row is for nodes larger
than 10 mm.
You can see for the nodes less than 10
mm, the
sensitivity from their clinical database
is between
67, 66 percent, and the specificity is 80
to 78
percent.
For the nodes larger than 10, the
sensitivity is 93, 98 for different
readers, and 56
and 71.
This, I would remind you, this is just a
point estimator. We have not put 95 percent lower
boundary yet.
If we put in the boundary, this number
could even be lower. We also don't know whether
there is interaction between size and
type of tumor
because so small nodes that was included
in the
primary analysis would not allow us to do
a further
81
analysis.
This table showed you the
prevalence of
nodes being positive by size of lymph
nodes. Why
this information is important is because
the
sponsor showed you the positive
predictive value
and the negative predictive value in
their
presentation.
To better understand that
positive and
negative predictive value, you not only
need to
understand the performance, that is,
sensitivity
and specificity of agent, you also need
to know the
prior probability that the prevalence of
this node
being positive before you give a drug.
This data collected from their
studies,
and for nodes less than 10, because we
don't have
the MR imaging measurement, so we have to
use the
pathology measurement as a surrogate over
here.
For nodes less than 10, the prevalence
range from
10 to 21 percent, which means if you see
nodes less
than 10 mm, the probability that the
nodes be
cancer-positive range from 10 to 20
percent from
this data.
82
If the nodes are more than 10
mm, then,
the probability from 34 to 60 percent
depending on
different study. We still don't know why there is
variations.
Also, you probably reviewed the
New
England Journal of Medicine. From their study, the
percentage is even higher. They got 75 percent of
people for the nodes larger than 10 has a
cancer.
So, how are we going to put all
this
information together to understand or to
help us to
understand the value of Combidex to help
physicians
in their patient care decisionmaking, or
for any
other benefit that they believe is good
for
patients?
I will present to you the
predictive
values of a positive or negative Combidex
test. I
will go over slowly with you. For the lymph nodes
less than 10 mm, the sensitivity is 68,
the
specificity is 80. We make this assumption. This
has not been demonstrated by data yet, because
the
lymph nodes, the number are too small,
but we
assume if this is what we observed.
83
The prevalence tell you what is
the
probability the nodes is cancer, whether they are
cancer-positive nodes before you give
Combidex.
The positive predictive value really tell
you after
you give Combidex, and if you get a
positive
result, what is the probability that node
is
metastatic at that time.
The negative predictive value
tell you if
you gave Combidex, and the result is
negative, what
is the probability that node is negative.
We look at different
scenarios. If the
prevalence is 1, based on data or based
on your
suspicion, the clinical knowledge, if you
are
thinking the node, the probability of
metastasis is
only 1 percent, based on this
performance, even
Combidex is positive, the probability
that nodes
being positive is only 3 percent, so the
people
should make their own judgment this kind
of
improvement where they have clinical
implication or
values to help you to make decision to
the patient
care.
When the prevalence get into 10, 25
84
percent, you see big changes here in the
probability, and this probably will
getting higher
if sensitivity and specificity get
improved, which
means that after you get a Combidex test,
these
nodes more likely become cancer. You may go ahead
to biopsy that one to confirm your
suspicion.
However, the positive
predictive value is
not
that high enough, so we believe with this
probability or likelihood, you will never
make
final diagnosis based on the Combidex
positive
result only, so most likely you will go
to biopsy
to confirm it.
So, we do believe for nodes
less than 10,
there might be potential values for
Combidex if
performance is constantly demonstrated to
help
physicians to select nodes for further
evaluation,
to help patients to make some decision.
Let's look at nodes more than 10
mm. You
already heard from sponsor for those
nodes, most
physicians will already consider is
metastatic
cancer, so for those nodes more than 10,
most
likely you will proceed with biopsy
anyway without
85
Combidex.
The question you probably can
ask yourself
in that scenario is if I get negative
results from
Combidex, is that going to prevent me
from going to
a biopsy.
Here is the result. As I showed
you,
the answer can vary depending on what is
the
pre-probability, how likely that nodes
being
positive before you give Combidex.
Before Combidex, if the
probabilities are
low, then, you get a pretty high
assurance if you
get an accurate result, it is going to be
a true
and accurate result, however, as you will
see, in
my previous presentation, the probability
already
got up to 75 percent or 60 percent. In that range,
if you get a negative result, you only
get 80
percent assurance that the node is
negative. You
still have 20 percent probability the
nodes become
positive, so maybe in that scenario, most
physicians probably would still go ahead
to do a
biopsy for nodes even Combidex is
negative.
So, for that reason, we are
seeking your
advice to see how we can understand the
values of
86
Combidex for nodes more than 10 mm for
helping
patients.
Also, where you would emphasize
what my
assumption here is based on the
performance and
which we believe has not constantly
demonstrated
from a clinical development program.
So, based on everything I
present today is
we believe or the data seem to suggest
that
Combidex may not have a value for people
with a low
risk, that patients with lymph nodes
larger than
10, the value may be limited, and also
this cannot
be substituted for the confirmation. Also, we
believe there probably is not a good
surveillance
of the recurrence of cancer, because that
population was not studied.
This list and go on and on, and
very long,
so that is why we are really concerned
with the
general indication. So, the key question
we ask
ourself, we are seeking your advice is
how the
Combidex result will really benefit to
patients.
We don't want to leave you a
wrong
impression that FDA do not care about
knowing the
87
nodes, whether positive or not, we care
greatly,
however, there is non-contrast agent
available. We
try to understand what is additional
value with
Combidex to bring it to the table in
addition to
the non-contrast agent.
We also understand this test
cannot be
used as confirmatory test, so we try to
understand
what role this will play to help a
physician help
their patients.
We also understand this drug
may associate
with the potential, the risk, so we want
to make
clear the use of this drug in appropriate
populations, the benefit with risk.
In the later discussion with
the sponsor,
sponsor proposes four types of cancer
which might
benefit, that Combidex may have a
beneficial effect
to the patient, and they also presented
those
cancers in their presentation.
For the prostate cancer first,
I said
earlier the Agency do believe for nodes
less than
10, Combidex may have a potential value,
however,
we are struggling with the fact there is
only 5
88
patients from U.S., 5 patients from the
European
study included in the primary analysis, and
the
estimate is so unstable from the data I
just showed
you, we just have no clear understanding
what is
the true performance of the Combidex for
that
population.
Also, the same concern applied
to bladder
cancer, breast cancer, and in less degree
to head
and neck cancer, because they have more
patients,
but I would like to bring your attention
again for
head and neck cancer, most of nodes in
European
trial, actually, all the nodes in
European trial is
more than 10.
So, with that, I will conclude
my
presentation. Thank you very much for your
attention. We are looking forward for your
guidance to help us to determine the
efficacy and
safety of this product.
DR. MARTINO: Thank you, Dr. Li.
Questions from the
Committee
DR. MARTINO: At this point, I will turn
to the committee and give you the
opportunity to
89
ask questions both of the sponsor, as
well as of
the FDA.
As you do that, please raise your hand.
Your name will be taken down, and I will
call on
you as we go around, so please don't yell
out, we
will acknowledge you in turn.
I would like to ask the first
question. I
would like the sponsor to make it clearer
to me how
they actually looked at the MRIs. I am still not
entirely clear what they did first, what
they did
second, and who, in fact, were the
radiologists,
were they a specific group of
radiologists, were
there any radiologists, please clarify
those issues
for me.
DR. GOECKELER: Let me start by saying the
question with regard to who made the
diagnoses, the
order in which that was done was shown in
the
slides, so that the pre-contrasts were
done first,
and
those diagnoses were committed to. Then,
there
was the paired, and then after some time
there was
the post-only.
In terms of who did that, are
you
referring to the specific specialty of
the
90
radiologist involved?
DR. MARTINO: No, I am trying to figure
out did you have two radiologists that
looked at
all of the films, did you have 100
radiologists? I
am
trying to understand that element.
DR. GOECKELER: I will address that, thank
you.
For the U.S. Phase III trial,
there were
two blinded radiologists each
independently, and
the data has been reported both for each
individual
reader or, as reported today, is the
average of the
two readers.
DR. MARTINO: Can you also clarify to me
what the task of the radiologist
was? I know you
have shown it, but I need it clear in my
own mind
what was the charge given to them at each
of these
interventions?
DR. GOECKELER: I am going to ask Mark
Roessel to speak to that issue a little
bit in
terms of how the radiologists, what they
were
actually asked to do on each of the
blinded reads.
MR. ROESSEL: The blinded readers were
91
given training and given the guidelines
to evaluate
lymph nodes, but they weren't given any
direction.
The nodes were not marked on the images,
so they
saw the pre-contrast images and any nodes
they
identified, they circled, and they made a
diagnosis.
Then, on the paired evaluation,
they did
the same thing. They circled the nodes. But the
nodes were not pre-identified on the
images. The
FDA, when we designed the blind read,
told us that
if we circled the nodes that we had
pathology on,
that that would bias the readers, so the
images
weren't marked, and then they did the
same with the
post alone, they circled the nodes, put
an arrow,
and gave their diagnosis.
Does that answer the question?
DR. MARTINO: It does.
What constituted
the denominator for pathology, then, it
was the
node as seen post-contrast?
DR. GOECKELER: Well, as Dr. Li indicated
on his slide, one of the reasons that these
patients and nodes drop out along the way
is that
92
the two readings were done on unmarked
images, and
then the nodes were also taken out just
according
to standard surgical procedures.
So, then, after all those
readings were
done, and then the readings had to be
matched to
the pathology, so in order to be
evaluable at the
end of all that, the node had to be read
on both
the pre-contrast image and then
identified and read
on the post-contrast image, and then it
had to have
pathology.
So, when you impose those
sequential
conditions for unmarked images, that is
why some of
the
nodes fall out along the way.
DR. MARTINO: So, then, it was, in fact,
the same node. The node had to have been seen on
non-contrast, also seen on contrast, and
pathology
done.
That, then, constituted the denominator.
Am
I clear on that?
DR. GOECKELER: Yes, ma'am.
DR. MARTINO: Dr. D'Agostino.
DR. D'AGOSTINO: I have a couple of
questions, first, of the sponsor, and
then Dr. Li.
93
If you look at Slide 9 on the
sponsor's
presentation, this is page 5 of the
handout.
DR. GOECKELER: Is it possible to get that
slide?
MR. ROESSEL: Yes.
DR. D'AGOSTINO: It was the sponsor's
presentation, I am sorry, the efficacy
analysis.
DR. GOECKELER: Could you help us with the
title, what it says on the slide?
DR. D'AGOSTINO: Slide 9 is Nodal
Analysis, U.S., Phase III.
DR. GOECKELER: Is this the slide you are
referring to?
DR. D'AGOSTINO: Yes. I
guess I was
surprised that there were no confidence
intervals
given as the presentation was made. Later on, the
FDA presentation did have some confidence
intervals.
What I am interested in, in
this here, is
how big were these confidence intervals
if you
looked at, say, the post-contrasts and
compared
them with the pre-contrasts for the
paired, I mean
94
certainly the sensitivity doesn't change
or they
would overlap.
Is there a real differentiation
between
the specificity or are the confidence
intervals so
large that it gets blurred?
DR. GOECKELER: I believe we have a slide
that has the data with the confidence--if
not, I
can obtain it, and if someone could pull
that data
for me, I can provide it to you. I don't have it
sitting right here this minute. I believe it was
in either the briefing book or if someone
could
pull the data.
If you give me just a minute, I
can
provide you the answer to that
question. Perhaps
we could take another one.
DR. D'AGOSTINO: The other question is,
you know, the second question that
follows is, as
you go to the body regions, which is
Slide 11 in
this sheet here, how do you make a
statement or
what kind of statement can be made from
the
statistics point of view, and then
hopefully from a
substantive point of view, that it makes
sense to
95
pool these different body regions,
because it seems
to me in terms of the questions that are
asked
later on, if we go to particular body
regions, it
has to be such a small number of nodes
involved,
and such a small number of subjects, that
the
inferences are really going to be almost
impossible.
So, is there an argument, and I
haven't
heard it, that says you can, in fact,
combine these
body regions?
DR. GOECKELER: I am going to ask a couple
of the clinicians that routinely image
these
patients, but, first of all, you will
recall from
Dr. Harisinghani's talk in the beginning
that the
mechanism of action of the drug depends
on, not a
primary tumor, but a physical process of
displacement of macrophages within a
lymph node.
So, the study was designed with
a variety
of primary tumors based on the way the
imaging
agent acts in terms of imaging lymph
nodes.
Mukesh, would you like to
comment on that
further?
96
Well, with regard to the
specific body
regions, then, the study obviously was
carried out
in a mixed populations of patients, and I
think
that obviously, if you start splitting
out a large
number of subgroups, the confidence
intervals for
any given subgroup increase.
I think that looking at the
study as a
whole, which was designed to evaluate the
premise
of differentiation of lymph nodes,
obviously, that
occurred. With regard to the subgroups, I
think
what is important is that there are
consistent
trends amongst those subgroups based on
the
mechanism of action of the drug.
DR. D'AGOSTINO: Moving on, I have just a
couple more questions, I obviously don't
want to
tie up everything here.
In terms of the post-contrast,
we were
told in the last presentation that not
all the
nodes were actually used because you want
to have a
pre- and a post, but there were nodes that
were
there.
Was any analysis done on the
nodes that
97
didn't enter into the post?
DR. GOECKELER: Yes, there was a separate
analysis that was done called the
"blinded
overread." It is not one of the ones that I
described to you, but it involved a much
higher
percentage of the total nodes.
So, it was again a blinded
reading of the
nodes, and there was histopathologic
correlation of
the data at the nodal level for each of
the
readings, and I can show you--
DR. D'AGOSTINO: Yes, it would be nice to
see what the sensitivity and specificity
was.
DR. GOECKELER: --what happened in those.
Can you first show the data in
terms of
the numbers of patients that were
evaluated both in
the unmarked images and in the blinded
overread?
These are the numbers that were
evaluated
by each reader in the blinded overread,
and you can
see, based on the various reads, the
number of
nodes that were read and for which there
was
histopathologic confirmation for each
reader and in
each diagnosis.
98
DR. D'AGOSTINO: Do you have the
sensitivity and specificity?
DR. GOECKELER: Can you show me the data
on false diagnoses in this, because that
essentially relates to, and we can go
back then?
If you have a slide on sensitivity and
specificity,
I think you do.
This is the data on the false
diagnoses
that occurred in the larger reading
population.
You can see the trends are largely the
same as we
saw before, about 15 percent with the
post-contrast
reads, and 25 percent are slightly
higher.
We did see a higher variability
between
blinded readers and the blinded overread
for the
individual readers.
DR. D'AGOSTINO: It would be nice to see
the sensitivity and the specificity and
the
confidence intervals.
DR. GOECKELER: Do you have the
sensitivity and specificity? Get me the numbers,
so that I can just provide them.
DR. D'AGOSTINO: Again, maybe we can come
99
back to it.
DR. GOECKELER: I can give you the
numbers, and I can tell you that the
trends are
very--
DR. D'AGOSTINO: I think it would be very
helpful, but I don't want to tie it up
here.
My last question is that you
did a lymph
node as the unit of analysis. There is still the
subject, and sometimes in other
activities, I don't
know about the nodes, but in other
activities, when
you are looking at the same subject, and
you are
taking different specimens, and so forth,
they tend
to be correlated.
So, if you did a person
analysis, what
would you do with the person, what would
you say
about the person? Your sample size is greatly
reduced.
Are there still your inferences?
DR. GOECKELER: Yes, the analyses were
also carried out at the patient level, so
we have
the same data for each of the analyses
pre- and
post-contrast at the patient level. I am going to
ask for a slide one more time.
100
DR. D'AGOSTINO: Maybe they can produce it
later on, the confidence intervals around
some of
these things I am talking about.
DR. GOECKELER: No, actually, I think they
have it.
I will tell you and then the slide will
be up here in just a second, that the
trends we saw
in sensitivity and specificity at the
nodal level
translated through to the patient level also.
Here we go. But this is nodes less than
or greater.
DR. D'AGOSTINO: It is really not only the
point estimates, but the confidence
intervals, what
are you actually saying about the
individual, how
much confidence you have.
DR. MARTINO: Dr. Hussain.
DR. HUSSAIN: I have a question to the
sponsor, and it strictly relates to the
study
design, because I am still not clear
about really
what the design was, so starting with the
eligibility criteria, how were the
patients
characterized, were there standardized
surgery, and
was the surgery required each time if it
was
101
prostate or breast or bladder or head and
neck, to
actually do the same template or do
beyond what is
normally needed?
And understanding that my
specialty, and I
am a gyn-oncologist, that there are
certain
prognostic features that will make you
feel or
believe that the patient has a high
probability of
a lymph node positivity, say, in prostate
cancer if
a guy comes in with a T2 disease, PSA of
50, and a
Gleason score, say, of 9, was that
accounted for,
because in this patient you would think,
based on
clinical criteria only, without even
imaging, that
those are very high odds of having this
patient
have lymph node positivity.
So, with all that taken into
account, and
if it's not, why not, and what is wrong
with having
done the appropriate studies, which is
accounting
for the subpopulations as having adequate
head and
neck patients, adequate breast patients,
adequate
lung patients, and so on, to try to make
some
conclusions from that?
And final question, and maybe I
didn't see
102
it, but what actually was the Phase III
trial, what
was compared to what?
DR. GOECKELER: Let me take a couple of
those and then refer some of those to
other people
who are more directly involved.
With regard to the comparison,
the primary
comparator was the paired evaluation as
compared to
the size-based evaluation on
pre-contrast. So,
those were the prospectively designed
endpoints for
the Phase III studies.
With regard to the treatment of
the
patients and how it was decided which
nodes would
be sampled, I am going to ask Mark to
comment on
that.
That varied a little bit as Dr. Barentsz
said between the Phase III studies and
what Dr.
Barentsz presented in the post-Phase III
studies.
So, Mark.
MR. ROESSEL: In the Phase III studies,
the entry criteria were patients who had
a known
primary, who were scheduled for either
surgery or
biopsy, and who had suspicion of
metastatic disease
spread to lymph nodes.
103
There was no direction as to
what the
surgery or biopsy procedures would
be. It was just
based on the clinical investigator.
DR. GOECKELER: The standard of practice
at the institution.
MR. ROESSEL: Does that answer the
question?
DR. HUSSAIN: I guess what I am asking is
was it the sense of the treating
physicians, or
were there guidelines that said if you
had this
size tumor, this kind of risk?
MR. ROESSEL: No, there were no--
DR. HUSSAIN: So, this was left random to
the person enrolling the patient based on
their gut
feeling whether the patient have--
MR. ROESSEL: There were no guidelines
given.
The entry criteria were just that, patients
with a known primary who were scheduled
to have
surgery or biopsy, so that we could get
pathological confirmation of nodal
status.
DR. GOECKELER: Did you have another
question, Dr. Hussain, about risk stratification
104
and predictive of--I am going to ask Dr.
Roach to
speak to that with regard to relative
risk and some
of the models and selection of patients
who might
be
most appropriate for treatment.
DR. ROACH: In the sponsor's indication,
it specified that patients who were at
risk for
nodal involvement, so the clinical use
for this
agent in patients with prostate cancer
would be
patients at intermediate and high risk
disease for
whom we have data from randomized trials
that
demonstrates that treating the nodes is
beneficial,
and that, in fact, it is important to
treat as many
of the nodes as possible.
So, this agent would be useful
for
identifying where the nodes are located
and allow
us to reduce the morbidity of giving
radiotherapy
in patients with prostate cancer.
DR. MARTINO: Dr. Levine.
DR. LEVINE: I have several questions.
First of all, for the sponsor, are you
asking that
the individual, that the patient would
have two
different MRI scans, in other words, your
105
indication is based on the post-read, so
that means
that you are asking that patients are now
going to
have a pre- and a post-MRI? So, that was one
question.
My second question, what was in
those
benign nodes? You know, there are infiltrative
diseases of nodes, TB, MAC, et
cetera. What were
those benign nodes, and what kinds of
benign
conditions, in fact, fulfill your
requirements for
benign?
Number 3. This is kind of a funny one,
but how did you know that the correct
node was
actually taken out? Did you do an MRI
scan after
surgery to know that you really took the
right node
out?
DR. GOECKELER: Let me ask, in terms of
the matching, since Dr. Harisinghani has
been
involved in a number of these studies,
how that is
done.
The first part of the question
dealt
with--I am sorry?
DR. LEVINE: Is the company requesting
106
that the patient have two different--no,
not two
different reads--two different MRI scans?
DR. GOECKELER: Two different images,
yeah.
DR. LEVINE: And who pays for that?
DR. GOECKELER: In the conduct of the
clinical studies, that was required,
because the
primary endpoint was the comparison of a
pre-contrast and a post-contrast read,
and I am
going to let the radiologists comment
upon how they
read these scans and how they match the
nodes in
the clinical studies.
DR. LEVINE: That actually wasn't the
question.
The question is if this compound is
licensed, are you asking that the patient
be sent
to MRI scan twice?
DR. HARISINGHANI: And the answer is yes,
the patient will require two scans pre-
and after
contrast administration, and in terms of
being able
to correlate the nodes specifically to
the areas on
how we know that surgically, we are
right, it is an
arduous and a difficult task, and for
that reason,
107
we have developed exquisite anatomic maps
to which
we map the nodes when we read these out,
and the
surgeons then correlate them to fix the
anatomic
landmarks, which could be the vessels or
bony
landmarks, and that is how they figure
out where
the nodes lie.
DR. LEVINE: All right.
Another question
was the character of the reactive lymph
nodes, what
were they?
DR. HARISINGHANI: The benign enlarged
lymph nodes ranged in etiology. Most of them are
reactive nodes, not pointing to any
specific
etiology for the so-called reactive lymph
nodes,
but we had occasional cases of
sarcoidosis.
I must say there were no
caseating
tuberculosis at least in the trials that
I have
been involved. I am not sure of the general trend,
but the benign nodes mainly were reactive
and
enlarged.
DR. LEVINE: And the sarcoid case
fulfilled your criteria as benign, as
well?
DR. HARISINGHANI: Yes, that was the case
108
I showed earlier in the presentation
where it
behaved like a reactive lymph node.
DR. LEVINE: Have you guys done a cost
analysis of the efficacy of this approach
given the
fact that you are going to do two MRI
scans, is
there a cost analysis perhaps?
DR. HARISINGHANI: We have not formally
studied this in the States, but Dr.
Barentsz's
group in the Netherlands has actually
published
their results on cost saving.
Do you want to comment on that?
DR. GOECKELER: Also, just let me comment
that although two separate imaging
sessions were
required in the clinical trials, because
of the way
that clinical trials were conducted,
different
investigators in the post-Phase III
setting
interpret pre and post different ways, and
Dr.
Barentsz can comment on that also.
DR. BARENTSZ: I would like to comment on
the first question first, about
cost. We recently
published a paper in European Radiology in
which
we, based on the sensitivity and
specificity data,
109
did do a calculation and analysis on the
health
care perspective.
If you are including this
technique, it
will save, in Europe, 2,000 euros per
patient, but
that is I think not the most important
thing. The
most important thing, it saves also
morbidity.
That was not taken in account in that
study.
To reflect on the pre- and
post-contrast,
as among radiologists there are some
discussions
going on, at this moment, with some newer
techniques, you are able to make a
sequence which
is insensitive to iron, so you can tell
the machine
"Iron Off," and you can tell
immediately after
that, "Switch on Iron," and
that will substitute
for the pre-contrast examination.
Nonetheless, to start in the
initial phase
for new readers to get some experience,
it is
advised to use both of those examinations
pre and
post.
I am performing now and studying in the
Netherlands, in foreign patients in
prostate
cancer, a multi-sound study only doing
the post
just by having insensitive and sensitive
sequence.
110
Also, if you have looked at the
data of
the sponsor, you can see that if you do
the
post-read only, it gives a very good
result.
Perhaps you can comment on that also,
Mukesh.
DR. HARISINGHANI: I think, as Dr.
Barentsz alluded to, for initial training
purposes
you need both scans. Once the individual is
trained, then, yes, with the existing
technology,
we can then, as he said, switch on and
switch off.
Then, it would be possible that you could
just do
the post-contrast study.
MR. ROESSEL: If I might add, because we
need to be clear about labeling for this,
as the
sponsor, the proposed labeling, the
proposed
package insert does not specify that you
have to do
a pre-contrast image and a post-contrast
image.
DR. MARTINO: Dr. Mortimer, you are next.
DR. MORTIMER: I wonder if the sponsor
could clarify the management of the lymph
nodes.
Were the lymph nodes just handled in a
routine
fashion?
Were those nodes that were suspicious
handled in any different manner to ensure
micro
111
metastatic disease?
DR. GOECKELER: Let me make sure I
understand. In terms of obtaining them in surgery
or--
DR. MORTIMER: Actually, reviewing them
histologically, so to make an analogy of
sentinel
node mapping, the sentinel node is
immunostained.
DR. GOECKELER: I think I understand. The
histology was reviewed without knowledge
of the
image findings. So, they didn't analyze those
particular nodes any different than they
did any
other nodes that were in the study.
DR. MORTIMER: And it was just H and E
slicing and--
DR. GOECKELER: Right.
DR. MARTINO: Dr. Perry.
DR. PERRY: A comment for Dr. Li. Your
point number 2 about inadequate
representation of
tumor types, I don't think the sponsor
ever
attempted to try to do all sorts of tumor
types.
For many kinds of cancers, this
methodology is not
necessary. For melanoma, as an example, we have
112
other staging systems or imaging systems
that are
quite sufficient.
So, I think it is an unfair
criticism to
say, when they set out to study four
tumor types,
that they didn't do all the tumor
types. I don't
think that is--that is a cheap shot in my
opinion,
and I don't think that is an appropriate
criticism
of the sponsor.
For the sponsor, when it comes
to
education should this product be
approved, I think
you are focusing on the wrong
market. I think if
you put the emphasis on physician
education, you
are really going to miss the mark by a
long shot.
It is really the tech who gives the
medicine, it's
not the physician.
I don't know any physician that
I have
ever seen administer a contrast
agent. Perhaps
it's different in Europe or in other
locations, but
if it is, I would like to know that, but
it seems
to me it is the techs who are going to
need to be
educated and make sure that they give it
the right
way, and if you focus on the physicians,
you are
113
going to have problems.
DR. MARTINO: Dr. Brawley.
DR. BRAWLEY: There are a couple of
statements that were made in the FDA
presentation
that I would like to get the sponsor's
response to
them.
The first is of 152 and 181
patients who
received Combidex in the U.S. and the
European
studies, a third of patients were
censored from the
U.S. study, and two-thirds of patients
were
censored from the European study, and not
included
in the primary analysis.
I would like your response to
that, and
then I have a couple others.
DR. GOECKELER: Yes, sir.
First of all,
with regard to the European studies, as I
think
someone indicated at the beginning, the
European
studies themselves were initially carried
out by
the European sponsor with different
endpoints, so
they were analyzing patients at the
patient and
group and nodal level.
So, in those studies initially,
there was
114
nodal matching predominantly only amongst
the large
nodes because it was felt at the time,
and you have
to recall that these studies were all
done seven or
eight years ago now, it was felt that the
matching
could be better done on those large
nodes, and I
think that is why there is a
disproportionate
number of large nodes in the European
studies.
After the studies were done,
the sponsor
met with the FDA and agreed that they
could take
data that was acquired at the individual
node level
in those studies and analyze it in a
blinded read
through the same sort of matching
procedures, using
the same sort of analyses that were carried
out for
the U.S. study.
So, one of the consequences of
that is
that there were a large number of nodes
removed
from those patients that weren't matched
on a
node-by-node level. So, if you look at the gross
number of nodes, and the numbers that
were
originally--and then the ones that were
eventually
matched up by two blinded readers and
then had
pathology, it's a smaller percentage in
the
115
European studies.
DR. BRAWLEY: A couple more follow-up
questions.
I am told that there are only 5
prostate
cancer patients from the U.S. and 5 from
Europe in
the primary analysis. Is that true?
DR. GOECKELER: Yes, that's true, and one
of the reasons, if you look at both the
U.S. and EU
Phase III studies, the purpose of the
studies was
to investigate the ability of the agent to
differentiate nodes, malignant from
non-malignant.
I think that when you move on
to--and
obviously, you can subset that a lot of
different
ways, either by body region or individual
tumor, or
any number of other ways, and if you do
that,
certain categories will be large or
small, and the
confidence intervals will react
accordingly.
I think that that is why, when
we turn to
the issue--and I think those studies did
show that
Combidex improved the ability to
differentiate
malignant from non-malignant lymph nodes.
I think that as Dr. Li
indicated and as we
116
indicated, when you move on to the
question of
where does that provide a clinical
benefit, the
tumors that we presented on were ones
where not
only we believe there is a clinical
benefit, but
also that there was supplemental data
post-Phase
III, not only on imaging performance, which
you saw
in the slides that Dr. Barentsz provided,
but also
on how that imaging performance impacted
on
clinical utility.
DR. BRAWLEY: So, you are trying to
convince the committee that this drug is
safe,
effective, and efficacious in prostate
cancer with
a series of 10 prostate cancer patients.
DR. GOECKELER: Well, I wouldn't make the
argument about the risk-benefit solely on
those 10.
I think we have to look at some of the
additional
supplemental data that is available from
other
places, such as the publications in the
New England
Journal and other places.
DR. BRAWLEY: I have also heard that
certain source documents, including a
pre-defined
statistical plan, blinded reader manual,
the
117
original copy of the blinded reader
efficacy
evaluation, were not available to the
Food and Drug
Administration.
I would like you to respond to
that
allegation.
DR. GOECKELER: Well, I think that there
have been some questions raised about the
exact
sequences of events in which the nodal
imaging
guidelines were developed and finalized,
and I
addressed that on one of the slides that
I
presented from the sponsor's
perspective. The
guidelines were finalized prior to any
blind
reader, availability of blind read
data. Mark, if
you would like to expand on that.
MR. ROESSEL: I am sorry, I think you are
answering a different question. I think the
question was about the prospective plan
being
available for the New England Journal of
Medicine
article.
Is that correct?
DR. BRAWLEY: That's correct.
MR. ROESSEL: The material that was
published in the New England Journal of
Medicine
118
article, as Dr. Li really nicely showed,
was done
independently of the sponsor. Two
clinical
investigators, one in Europe and one in
the U.S.,
got together and took 40 patients from
trials that
they were conducting and did a blinded
read.
We don't have, as the sponsor,
again, it
was done independent of us, on their own
initiative, I think is the way Dr. Li put
it, we
don't have from them a prospective
statistical plan
or prospective plan for conducting that
blind read.
We do have that for our Phase
III studies,
of course, for our clinical studies.
DR. BRAWLEY: Let me just say
parenthetically that that is an
acceptable answer,
I understand that answer, but I need, and
I don't
want to criticize this company, Advanced
Magnetics
at all, I definitely don't want to impugn
Advanced
Magnetics, and I do want the news media
to listen
to this.
In my last four years here, I
have seen
some companies come before this
committee, and some
companies submit data to the FDA, and
what is done
119
is sort of slight of hand, with selection
biases in
terms of choosing patients, to try to
make one's
point that a particular drug or a
particular agent
works, and we have to be very, very
careful
whenever we look at data to understand
exactly what
the source of the data is and the
validity of the
data, and most importantly, the selection
biases of
the patients going into the data before
we can make
a decision.
That is a point that has been
missed
repeatedly in a number of newspaper
editorials
about drug approval recently, so that is
the basis
for my question. You, sir, you did give me an
acceptable answer, and again I want to
state I
don't want to at all impugn your company.
Last question. I heard that a patient
died getting this contrast agent. I thought I
heard that the patient got the contrast
agent in a
facility that was not able to treat an
allergic
reaction.
Is that true?
DR. GOECKELER: Mark, you can comment on
120
the facility, and I am going to ask Dr.
Bettmann to
comment on sort of the guidelines and
regulations
regarding what those sorts of facilities
are
required to have.
MR. ROESSEL: The facility in question was
a free-standing MRI unit. We made sure in our site
qualifications for doing clinical trials
that
equipment was available to treat any
reactions that
occurred.
They did have emergency equipment, which
I think is what you asked me, they did
have it
available. Apparently, they didn't choose to use
it.
DR. BRAWLEY: That, too, is an acceptable
answer,
I just want to go on the record as saying.
DR. MARTINO: Dr. Houn, did you want to
make a comment?
DR. HOUN: Yes, just to clarify
when a
sponsor obtains right of reference to
studies to
support their application, they have to
be able to
provide to FDA access to underlying data
to provide
the basis of the report of the
investigation.
This did not happen with the
New England
121
Journal study, and also just as a
reference to the
committee, FDA didn't mean to give a cheap
shot in
terms of the numbers of people enrolled,
just in
previous approvals for ProstaScint,
prostate cancer
only imaging drug, there were 152 people
entered
into the analysis only with prostate
cancer, and
there were 183 that were followed for the
open
label efficacy study.
When we did NeoTec, a lung
cancer
detection for non-small cell lung cancer,
there
were 228 entered into the analyses. When we
approved PET-FDG, that got a broad
indication for
all kinds of cancers. There were 1,311 people
entered into the analyses.
DR. MARTINO: Dr. Reaman.
DR. REAMAN: Just a question again about
the eligibility criteria, and I guess to
somewhat
follow up on the issue of selection bias.
You stated that any patient
with cancer
who was at risk for developing lymph node
metastases were eligible for this study,
and they
were eligible based on whether or not
they were
122
going to then have either a biopsy or a
surgical
procedure.
So, how was the decision as to
whether
they were going to have surgery or a
biopsy
procedure made, by equivocal or positive
radiographic studies before they were
entered on
this study, or did they have palpable
adenopathy?
Other than the breast cancer patients in
the
sentinel node biopsy, I am still not
satisfied that
this isn't a selected population.
DR. GOECKELER: I will ask Mark to expand
on that, but I believe it's the case, and
Mark can
verify, that the image findings, the
post-contrast
image findings could not play a role, and
were not
available to the physicians in making
those
assessments.
So, the physicians did not have
any
post-contrast image findings on which to
base that
assessment of whether the patient then
went on to
surgery or biopsy. It was done based on the normal
clinical information that would be
available to
make that decision for every other
patient.
123
DR. REAMAN: So, radiographic studies
weren't part of the clinical information?
DR. GOECKELER: Well, I think that the
pre-contrast, you know, you could have a
CT or an
MRI pre-contrast, but no post-contrast
image
findings.
DR. MARTINO: Dr. Bradley.
DR. BRADLEY: I have a couple of questions
maybe for the authors of the New England
Journal
article, following up on a question by
Dr. Li.
How did you select those 40 and
40
patients from a group that was 3 times
larger? I
mean selection bias kind of comes to
mind, but what
selection criteria did you use?
DR. HARISINGHANI: It is 3 times larger
now, but it wasn't then. The selection was
consecutive patients who were scheduled
to undergo
radical prostatectomy both at the U.S.
and at the
European site.
They were of the intermediate
and
high-risk category, I must admit to that in
terms
of the patient selection.
124
DR. BRADLEY: And then a follow-up
question.
You showed some very nice images of very
small nodes, one of you, or positive
nodes. With
5-mm cuts, and no way of guaranteeing
that you are
in the same place for the second scan,
how do you
know you are comparing the same nodes pre
and post,
particularly not for you, but for the
chest where
you have respiratory artifact?
DR. BARENTSZ: In our New England Journal
paper, we used 3-mm cuts in the obturator
plane,
and we used 5-mm cuts in the axial
plane. We
performed a combination of sequences
which
visualized the anatomy and also a
sequence which
visualizes the iron, and based on also a
3D
sequence which we performed, we were able
to
compare the pre and post and exactly
locate the
lymph nodes where they were, so we could
make a
very accurate match on the 3-mm and 5-mm
images.
Also, we located the nodes in
relation to
the vessels. So, I agree with you that
localization and the location of lymph
nodes is
very important.
125
DR. BRADLEY: So, the slice location of
3-mm slices was accurate, looking at the
other
anatomy?
DR. BARENTSZ: Absolutely.
DR. BRADLEY: A follow-up question. On
the 15 percent--this may not be for you
guys--but
15 percent false positive and false
negative, we
have talked a little bit about what might
cause a
false positive. What about false negative, any
thoughts, did you do an analysis of why
they were
false negative?
DR. HARISINGHANI: I think there are two
issues here at least from our study. I would let
Bill answer for the general part, but the
false
negatives are mainly as we are talking of
nodes
which are smaller than 5 mm, then, the
current
resolution of our scanner only enables us
to be
confident at a certain level, and that could
account for the false negative reads.
DR. BRADLEY: Then, one final question for
the sponsor. Why did you choose a 0.2T Hitachi
when this is clearly a magnetic
susceptibility
126
agent?
Is it so sensitive that a gradient echo at
0.2 shows you what you see at 1.5? Also,
I suspect,
having read all of this, that that was
also where
you had your single death, is that
correct?
DR. GOECKELER: I am going to have to ask
Mark or Paula to comment on the specific
imaging
equipment. Please recall that the death was in a
liver imaging study, not in a lymph node
imaging
study.
DR. BRADLEY: Right.
I saw the physician
of record on that, who happens to own a
bunch of
low-field magnets in Ohio. I am just wondering if
it is the same case. But why include a 0.2 at all?
MR. ROESSEL: We tried to include in the
Phase III clinical studies, we didn't
specify the
imager to be used. There was no
requirement for it
to be a 1.5T or 0.2T. The fact is we provided the
Agency with the information on the types
of imaging
equipment used, and I think most of them were 1.5T,
the vast majority. It was a very, very small, I
think one or two that used 0.2T in the
studies.
DR. BRADLEY: Just to follow up, was the
127
0.2 Hitachi also where the death
occurred?
MR. ROESSEL: That, I don't know.
DR. MARTINO: Ladies and gentlemen, we are
running short of our allotted time, but I
appreciate these questions as important, and
that
is why I am giving you a little more time
in this
part of the meeting.
That being said, I would ask
those of you
asking the subsequent questions, please
be sure
that your questions are necessary to your
thinking
about the efficacy and the approval of
this agent,
and are not just purely for your perhaps
intellectual curiosity.
Dr. Giuliano.
DR. GIULIANO: I am a surgeon, Dr.
Martino.
We have limited intellectual curiosity,
so my--
DR. MARTINO: I know.
[Laughter.]
DR. GIULIANO: Therefore, my questions
will be brief. But I am struggling as a surgeon
through these documents. We say the surgical
128
procedure was not altered, the
post-enhancement
images were not available.
How did you instruct the
surgeon to remove
the Combidex abnormal enhanced lymph
node? He or
she had to know what that node was, where
it was.
It had to be labeled as such. So, on a
node-by-node analysis, I think that
introduces a
surgical bias because as any surgeon
knows, it is
easier to find a positive node than a
negative
node.
In addition, using the
node-by-node
analysis, what happens with nodes not
seen on MR
that are removed? For example, if this agent did
not alter your surgical operation, the
patient with
a prostatectomy may have had a pelvic
lymph node
dissection, and there was one node that
had been
identified on your preoperative images or
an
axillary dissection for breast cancer,
and there
are one or two nodes, and 15 or 20 nodes
were
removed.
If you look at the 1 or 2
nodes, which had
to be seen on the image, had to evaluated
129
histopathologically, and they correlated,
let's say
they were both negative, what if all of
the
remaining nodes were positive or one of
the
remaining nodes was positive, how was
that dealt
with statistically or in your
presentation? I
could not understand that.
DR. GOECKELER: I will ask Dr. Anzai to
talk about the nodal matching and how
those nodes
were identified, and how imaging was or
wasn't used
in the identification of those nodes.
DR. ANZAI: I am the radiologist involved
in Phase II and III clinical trials. Your comment
is absolutely right. This was the hardest trial
that we ever had in Radiology, that I
personally
have to have images going to OR when the
patient is
in operating site, and we have to ask a
surgeon to
make stitches on a certain anatomical
level.
For example, a head and neck
radiology, I
have to ask the surgeon to make stitches on
the
submandibular--this is the jugular vein,
so in
between this lymph node is the lymph node
that I am
seeing in imaging, and it was very labor
intensive.
130
Many of the radiologists have
to be in the
OR with this graph, and the surgeon to
identify,
correctly identify those lymph nodes on
imaging, or
lymph node in a patient, so the pathologist
would
identify this is the exact lymph node
that we saw
in imaging.
That is why the sample size was
so small,
because we have to have a certain
confidence that
the imaging on the lymph node is matched
with final
pathology. That is why the size of the lymph node
that is seen in all the cancer patients
are small,
but this is such a labor intensive study,
but we
did as much as possible to correlate
imaging on a
lymph node with surgical pathology by
being in the
OR.
The second question for
statistics, maybe
Mark can comment.
DR. GOECKELER: I think that the issues
that have just been identified by Dr.
Anzai and
others are the ones that account for the
analysis
that Dr. Li showed, where you start out
with a
large number of nodes and then if you are
going to
131
require evaluation on unmarked images to
avoid bias
in the reading of the data, then, you
lose some
nodes along the way, because the readers
don't all
identify the same nodes every time they
read.
That is why you see some of the
nodes or
the
numbers dropping off at every level. We
tried
to address that in part by looking at
another read
that involved the blinded overread, which
are a
much larger percentage of the nodes.
DR. GIULIANO: Maybe I wasn't very clear
about that. My question is if the labeled node
from the operating room is the one
identified on
the MR, and histologically evaluated, and
is
positive or negative or whatever the
correlation
is, but other nodes that were not seen
are
positive, was that counted as a false
negative or
was that not counted because the other
nodes were
not seen on MR?
DR. GOECKELER: No, the primary analysis
was at the nodal level, so those numbers
that were
presented were at the nodal level. There were
other analyses the data tracked very
closely at the
132
patient level where you can look at the patient
level also.
DR. GIULIANO: Thank you.
DR. MARTINO: Does that answer your
question, Dr. Giuliano, because I am not
sure that
it did.
DR. ANZAI: Let me add one thing. I think
your question that the lymph node that
not
identified on the MRI, how do we handle
that. I
think a nodal level correlation, we
didn't look at
those lymph nodes were pretty not
pre-identified by
imaging, but a patient level analysis,
if, for
example, MRI showed all the normal lymph
node, but
pathology somehow find one positive lymph
node that
not identified MRI, I think that was
considered to
be false negative.
DR. GIULIANO: Perhaps you could share
that patient analysis, would that be
appropriate,
Dr. Martino?
DR. MARTINO: Well, to be honest with you,
I think at this point you are going to
have to make
your decision realizing that the data
that you need
133
perhaps are not presented to you right
now. I
think that may be one of the issues.
Dr. Bukowski.
DR. BUKOWSKI: I am trying to understand
the efficacy and benefits of this
approach, and
there was a statement made that there is
a decrease
in morbidity when you apply this
particular
product.
Can you help me understand what
the
implications are? Are you implying that there will
not be a need for surgery if there is an
identified
positive node, or that there will be then
a
percutaneous biopsy done, and, if so,
what is the
likelihood of being able to biopsy the
small nodes
that you are referring to, less than 10
mm, using
techniques not only at academic centers,
but
centers elsewhere?
DR. BARENTSZ: You raise a very good
point, and I would like to address a
little bit to
our New England Journal paper, which is
different
from the Phase III study in that way,
that in the
New England Journal paper, we were able
to--we were
134
allowed to include data which were
obtained from
the Combidex MRI into clinical practice.
So, that paper shows better the
real
clinical effect of what this contrast
agent can do.
So, if we found an extra node, we were
allowed to
tell to the surgeon, and I again agree
with you,
communication with the surgeon where the
node is,
is very important.
Mukesh and I, we started by
making some
nice schemes, which have been used by the
surgeon,
and sometimes we, well, we went to the
surgery
room.
So, we added the information of the MRI for
the surgeon, and we asked our surgeon how
this
scan, how did this really change his
management,
did that decrease the extent of surgery.
Actually, the black nodes, they
are
normal, and if you have a high
sensitivity and a
high negative predictive value, but if
you have
both very high, as what we obtained in
our paper in
the New England Journal, both on the
patient and as
on the nodal level, that means that the
risk after
an MRI, that the patient has a negative
lymph node
135
is extremely high.
That means the number you are
missing is
extremely low, and that current
threshold, our
urologist advises, but I would like also
to have
one of the urologists to speak on
that. That is
very important clinical information which
may
actually decrease the number of lymph
node
dissections.
If you have a positive lymph
node, it
always must be confirmed
histopathologically. If
it's large, 7 mm, 6 mm, or 10 mm, you can
do that
by image-guided biopsy. If it's smaller, you have
to tell the urologist the node is down
there, and
he can remove it.
Perhaps the urologists can make
also some
clinical remark on that. Comment about the
clinical use, how this technique can be
applied,
what will you do if you have a negative
MR
Combidex, what will you do if I am saying
it's a
positive lymph node.
DR. KALINER: Well, first of all, any
information that I give as a clinician,
first of
136
all, I am a urologist for the last 16
years at
George Washington University, and
recently joined
Cytogen as the Vice President of Medical
Affairs,
so I have a lot of experience in surgery
and
urology.
Any information I can get that
helps me
identify whether there is more extensive
disease or
not is extremely important with these
patients.
So, in the case, if I have a negative
Combidex
scan, first of all, I wouldn't do a
Combidex scan
unless it is somebody that is
intermediate to high
risk, as many of these patients were, so
they are
stratified by risk to begin with.
So, this is somebody that has a
negative
Combidex scan, we still would perform the
lymph
node dissection, but if there was a
reason to look
in an extended area, which we know
pathologically
does occur, then, that scan can help
guide us to do
that.
On the other hand, if we did
find
something ahead of time, we may be able
to
eliminate doing an invasive procedure by
performing
137
a biopsy or perhaps a laparoscopic lymph
node
dissection as opposed to an open
procedure. There
are a variety of ways to look at doing
that.
Any way that I can get more
information to
help prevent an invasive procedure when
it is not
necessary is extremely important.
DR. MARTINO: Dr. Dykewicz.
DR. DYKEWICZ: I have two questions
regarding safety and adverse events. The first is
whether slowing the rate of the infusion
as
proposed will really reduce the risk of
hypersensitivity reactions.
In the sponsor's presentation,
there was
data presented showing that the number of
adverse
events were reduced with the use of that
administration method, but, of course,
adverse
events could include both
hypersensitivity and
non-hypersensitivity events.
Hypersensitivity events are the
ones that
are potentially going to lead to
fatalities, so
that is where I have my greatest concern.
The FDA analysis was that the
overall risk
138
in severity of hypersensitivity reactions
was
actually not reduced, and they presented
one data
on Slide 21, Presenting Symptoms of
Hypersensitivity Reactions, that showed
that at
least in terms of urticaria, the rate
even
increased with slowing the infusion rate
from 63
percent with the bolus to 85 percent.
Some of this I think is
probably just a
result of the signal of having a
relatively smaller
population with the bolus group, but from
the
standpoint of the sponsor, are you of the
belief
that the slower infusion rate will
significantly
reduce the risk of hypersensitivity
reactions?
DR. GOECKELER: I think the issues are
related to risk and management, and I am
going to
ask Dr. Page to speak to that, please.
DR. PAGE: The most telling data about
this are to look, not at all
hypersensitivity
reactions, which again tended to be--this
is an
iron product, so that the notion is that
any
exposure in the bloodstream is likely to
cause some
activation of mediators, so you are going
to see
139
some flush.
So I would contend that the
notion of
hypersensitivity is probably too
broad. That is
what we are looking at, it is a
hypersensitivity
reaction, and in that sense, I agree with
the
statement that it is not clear that
dilution will
reduce rates of hypersensitivity, but I believe the
data show convincingly that they will
reduce severe
both all AEs, as well as hypersensitivity
AEs.
In the case of bolus, there
were 3 serious
adverse events out of 131 patients. That is a rate
of 2.5 percent. In the case of diluted,
there was,
in fact, only 4 out of 1,200, and, of
course, that
is a rate on the order of 0.3, so there
is a log
order difference in the rate of severe
adverse
events.
That is one piece of information.
The other is we know that in
patients who
are having an immediate hypersensitivity
reaction,
you can turn off the infusion, the
reaction goes
away, and you can restart the
infusion. So, it is
not only the accrued rate of all the
reactions.
The real question is severe, and the
reason is can
140
you intervene.
DR. DYKEWICZ: The second question, which
actually dovetails with that, and a
question that
Dr. Brawley had asked about earlier, is
the acute
treatment of the serious hypersensitivity
reactions.
Were any of these patients
given
epinephrine?
DR. PAGE: I believe none were. Mark,
correct me if I am wrong there. Some were given
steroids, of course, some were given
albuterol in
one case.
As far as I recall, there was no
epinephrine given.
DR. DYKEWICZ: Well, this is no indictment
specifically of the sponsor, but for
discussion
later, I would raise the point that the
treatment
of choice for a serious hypersensitivity
reaction
would be epinephrine.
DR. PAGE: And would you say that is true
if there was no hypotension and on
cessation of
infusion, and there is no acute
respiratory
compromise?
141
DR. DYKEWICZ: Potentially, yes. Studies
have shown that in anaphylaxis, delay in
the
administration of emerging anaphylaxis is
associated with an increased fatality
rate.
Obviously, this requires some
clinical
judgment depending upon the clinical
presentation
of the patient, but I would say that, in
general,
if you have patients with serious
hypersensitivity
reactions, that none have received any
epinephrine,
that is sad in my opinion as an
allergist.
But again, this is nothing
specific for
the sponsor of this agent. I think it is
reflective of the standard of care
generally.
DR. GOECKELER: Dr Bettmann.
DR. BETTMANN: I wanted to comment as a
clinical radiologist. I think your point is very
well taken. My recollection of the data are that
the only patient that was given
epinephrine was the
one patient who died, and that patient
was given in
a very delayed fashion, so it was
inappropriate.
Again speaking as a clinical
radiologist,
it gets to the point of who treats these
reactions
142
and how, and how are they trained, and
that gets
back to what Dr. Brawley touched on about
why was
the study done, that one fatality, in a
place where
the reaction couldn't be treated
appropriately.
I think the answer is simply that
there
are, the American College of Radiology
has very
clearly stated that contrast should not
be injected
where there isn't equipment to treat
reactions that
are potentially fatal and where there
aren't people
who are ACLS trained.
So, you started by saying it's
not an
indictment against the sponsor, I think
perhaps
it's an indictment against clinical
radiology.
There is no question that patients should
be
treated appropriately, there is no
question that
the appropriate treatment is known. It is a matter
of linking those two.
I think that is a question that
sort of is
unfortunately way beyond Combidex.
DR. MARTINO: Thank you.
Dr. Rodriguez. For the rest of you, there
is only three of you. Please be brief and
143
succinct.
DR. RODRIGUEZ: I just want to be very
clear about one issue. One of the committee
members previously said that the company
obviously
did not intend this product to be used in
all
malignancies.
As I read the application or in
this
proposed indication, however, it is
worded exactly
the same in both the FDA presentation and
the
sponsor, and it states that it is to
assist in the
differentiation of metastatic and
non-metastatic
lymph nodes in patients with confirmed
primary
cancer who are at risk for lymph node
metastases.
So, to the sponsor, are you, in
fact,
requesting that the FDA approve this
product for
broad application in all malignancies?
DR. MARTINO: I will take a yes or no
answer to that. That is all that is necessary in
my mind.
DR. RODRIGUEZ: That is all I need.
DR. GOECKELER: The indication was based
on
the Phase III clinical trials. I think
the FDA
144
and the sponsor --well, that is the
indication that
is being sought, yes.
DR. MARTINO: Thank you.
DR. D'Agostino. Succinct and brief.
DR. D'AGOSTINO: I will be very brief.
Just to go back to some of the questions
I raised
earlier in here, it seems to me, and the
sponsor
can say yes or no, that what we are
dealing with is
trying to evaluate efficacy based on not
all the
subjects available, not all the nodes
available, if
there is differences between the pre and
post in
terms of sensitivity and specificity, it
is
basically on a per-node basis. It is not based on
per type, body region, and it is not
based on a
per-person basis.
I don't see any justification
for
combining the body regions by statistical
criteria.
I didn't see anything on what happened to
the nodes
that weren't in the paired analysis, and
I think on
the per-patient basis, you have such a
small number
of patients, that we probably don't have
any
significance on sensitivity, specificity,
and
145
disposition of the patient.
A yes or no from the sponsor
would be
interesting.
DR. GOECKELER: There were a lot of
questions. First of all, with regard to
the body
regions, those weren't combined. The data sets
were for the entire populations. They
were
subgrouped out after the fact.
So, the primary analysis was
for
differentiation of metastatic from
non-metastatic
lymph nodes based on the entire
population. That
is why the indication that is being
sought is
written the way it is.
With regard to the question of
where there
is a clinical benefit to that, I think
that is why
we presented additional data from
additional
studies in specific cancers.
DR. MARTINO: Mr. Kazmierczak, the last
question.
MR. KAZMIERCZAK: Thank you.
My one
question on generalization was already asked
and
answered.
In the FDA's presentation, they
146
indicated that certain patients were
excluded on
the basis of pretreatment with radiation
or
androgen ablation.
I would like to have the
sponsor comment
on whether the FDA statement that
Combidex should
be used for newly diagnosed patients as a
restriction is reasonable.
DR. GOECKELER: I think it is the
population that has been studied in
clinical
trials, yes.
DR. MARTINO: Thank you, ladies and
gentlemen. I will give you a five-minute break
only.
I will start without you.
[Break.]
Open Public Hearing
DR. MARTINO: The next portion of this
meeting is the open public hearing. Those of you
who have requested permission to speak at
this
portion of the program, I will remind you
that you
have five minutes only. Please identify
yourselves, and there is a microphone in
the middle
of the room, which is the one that you
will be
147
using.
I need to read a statement, so
that you
all understand the purpose of this
portion.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and
decisionmaking. To
ensure such transparency at the open
public hearing
session of the Advisory Committee
meeting, the FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, FDA encourages
you, the
open public hearing speaker, at the
beginning of
your written or oral statement to advise
the
committee of any financial relationship
that you
may have with the sponsor, its product,
and, if
known, its direct competitors.
For example, this financial
information
may include the sponsor's payment of your
travel,
your lodging, or other expenses in
connection with
your attendance at the meeting.
Likewise, the FDA encourages
you at the
beginning of your statement to advise the
committee
148
if you do not have any such financial
relationship.
If you choose not to address this issue
of
financial relationship at the beginning
of your
statement, it will not preclude you from
speaking.
MS. CLIFFORD: Our first speaker is Mr.
Curtis Holladay.
MR. HOLLADAY: I do not have any financial
affiliation with the sponsor, however, my
travel
and lodging is being paid for.
I am Curtis Holladay, a
73-year-old
prostate cancer survivor of seven years,
here this
morning to tell you about my recent
experience with
the Combidex test. As you will see, this
diagnostic tool was crucial to
understanding the
stage and disposition of my prostate
cancer thereby
allowing the opportunity for experts to
prescribe
the appropriate therapy.
Diagnosed in 1997, I
subsequently
underwent radiation therapy, both
seed-implant and
external beam. After it had become
evident that the
radiation therapy had failed, a hormonal
therapy
was employed, but discontinued after a
year due to
149
liver toxicity.
During this time, four bone
scans and two
computed tomographies revealed no evidence
of
metastasis. In order to determine my eligibility
for local treatment, the question of
metastasis to
the lymph nodes had to be answered.
Internet searches and consultation
with
Dr. Stephen Strum led to the Combidex
technology as
offering the most reliable test. Although one of
the Phase III clinical trials was run in
the U.S.,
it was still not available here, but it
was
available at UMC St. Radboud at Nijmegen
in the
Netherlands. It was under the direction of Dr.
Jelle Barentsz whose work was reported to be
outstanding. The importance of the information to
be gained left me no choice but to travel
to the
Netherlands at my own expense.
Our party arrived at the
Amsterdam Airport
early morning and drove to Nijmegen for
me to
receive the Combidex contrast injection
that
afternoon. The MR scan was performed the next day
allowing the required 24-hour waiting
period.
150
There was no pain or unpleasant effect
from the
Combidex injection.
Dr. Barentsz reviewed with me
the MR scan
images. He pointed out images of lymph
nodes on my
left side were white or illuminated,
indicating
metastasis. Images of the lymph nodes on my right
side were dark or black, indicating that
they were
normal, free of metastasis.
Although I had hoped for a
better outcome,
it was better to know than not to
know. The
Combidex test made it clear that a local
therapy
was no longer an option and that a
chemo-based
therapy would be necessary to check the
metastasis.
I would hope my personal
testimony helps
persuade the FDA to approve the Combidex
test for
use in our country as it becomes more
evident every
day that we need to bring available tools
and
resources to bear on this unrelenting
disease.
Thank you for the opportunity
to make this
statement.
MS. CLIFFORD: Thank you, Mr. Holladay.
Our next speaker is Barbara
Lestage.
151
MS. LESTAGE: Good morning.
I am Barbara
Lestage. I am a 9-year breast cancer
survivor from
Wrentham, Massachusetts. I am currently Chair of
the American College of Radiology Imaging
Network's
Patient Advocacy Committee. I served for
two years
on NCI's Central IRB, and also was Chair
of NCI's
Director's Consumer Liaison Group for
three years.
I was invited to speak today by
Advanced
Magnetics, which is covering my expenses.
I don't know how many of you
have been
personally diagnosed with cancer and
understand,
not only what a frightening time it is or
the
confusing one it is, as well. Living in
the Boston
area, I was fortunate to have three world
renowned
physicians to advise me, but
unfortunately, they
did not agree on what my treatment should
be.
I learned during this very difficult
time
that in spite of all the progress which
has been
made, treating cancer is often as much an
art as it
is a science, because there is still so
much that
we do not know.
Obviously, for each individual
patient,
152
the goal is to gather as much information
as
possible, so that the treatment can be
tailored to
their particular cancer with the goal of
neither
undertreating nor overtreating the
patient, which
can lead to unnecessary side or late
effects and
adversely affect the quality of life.
In my case, two of my
physicians wanted me
to have a nodal dissection, but my
surgeon thought
that because my primary tumor was so
small, it was
non-high grade, and there was no
lymphatic nor
vascular invasion, that the morbidity,
which could
be caused by a nodal dissection, would
outweigh any
information which might be gained by
doing one.
I can't tell you how many
agonizing hours
and days I spent going over, not only the
conflicting opinions, but the literature
before
finally deciding against a nodal
dissection.
Now, nine years later, it seems
pretty
clear that the decision I made was the
correct one.
I spent many years wondering and worrying
if I had
made the right decision.
When I heard about the trial
using MRI and
153
Combidex, I thought to myself how
wonderful it
would have been to have been able to have
such a
scan.
While in my case, it would not have made a
difference in my treatment, it would have
given me
enormous peace of mind.
Obviously, for many patients,
it would
help determine, not only the extent of
their
treatment, but the type of treatment that
they
would have.
I suppose the question could be
asked why
do we need a new way of determining nodal
status
when we already have several, but I think
there are
three reasons why we need one.
First, is that the current method
of
determining that based simply on lymph
node size
alone has an accuracy rate of only 68
percent,
while the stated accuracy rate for MRI
and Combidex
is 85 percent.
Second, is that for many
patients, a nodal
dissection requires a second incision,
which can
sometimes leave the site numb for years
with
prickling, tingling, pain, burning, and
often
154
leaves the muscles weak.
The third is the risk of
lymphedema, which
for breast cancer patients is about 15
percent of
those with a total nodal dissection and
is severe
in 1 to 2 percent of those women. Women who have
had a nodal dissection for the rest of
their lives
have to avoid anything which might cause
lymphedema
to develop.
This means they must constantly
remember
to avoid hot baths or showers, sunburns,
harsh
soaps, insect bites, tight sleeves, or
even playing
with a beloved cat or dog. More importantly, they
must avoid having their blood pressure
tested or
receive any sort of injection or blood
draw in the
arm on the side where they had their nodal
dissection.
A friend of mine was diagnosed
with
cervical cancer in 2001. She was given a radical
hysterectomy and had 35 nodes removed,
all of which
turned out to be negative. She didn't have any
problems at first, but then her left leg
became
infected, which has led to chronic
lymphedema.
155
Each day she must spend an hour
with her
legs in the air, massaging them to try
and get the
fluid out. Then, she must wear
compression hose for
the rest of the day, and she must bandage
her legs
every night before bed.
Flying is possible only if she
can stand
and walk for most of the flight, and she
must
constantly carry antibiotics with her in
case of
infection. She used to wind surf and hike, but now
because of the risk of a scratch or
poison ivy,
those and many other activities are no
longer
possible.
Because of the medical
insurance she has,
the physical therapy and the compression
bandages
often have to be paid for out of pocket.
Because of my two years on
NCI's Central
IRB, I understand the difficulty of
balancing the
risks and benefits of new drugs while
trying to
provide the best possible treatment to
cancer
patients.
We talked this morning about
the value of
physician education and technician
education, and I
156
would suggest to you that equally
important is
patient education. I feel very clearly
that as long
as the risks are explained to a patient,
they
should have the opportunity to have a new
drug if
they feel that the potential benefits
outweigh the
potential risks of doing so.
I understand that Combidex and
MRI is not
risk-free, but I believe the risks to be
reasonable, and that for many patients,
they are
clearly outweighed by the benefits of a
new, more
accurate, non-invasive way of determining
nodal
status.
Thank you.
MS. CLIFFORD: Thank you, Ms. Lestage.
Our next speaker is Mr.
Mendinger.
MR. MENDINGER: My name is Larry
Mendinger. I am a home builder from Ashland,
Oregon, and Combidex paid for me to fly
here,
however, I can tell you that is a
negative
investment for me, because I am missing
three days
of work.
I have prostate cancer. I was diagnosed,
157
oh, three years ago or something like
that. It
should have been four or five, but my
doctor didn't
happen to notice what my PSA was doing.
I went through some treatments,
which
seemed to stave off the growth of the
tumors, and
my PSA kept bouncing around for some
time. In the
last eight or nine months, I have
had--well, I
should say before I had Combidex, myself
and my
insurance company probably spent $18,000
on
everything from ProstaScint to CT scans
and PET
scans, and all that stuff.
It all showed, well, we really
don't think
so, that you really have anything to
worry about,
we can't seem to see it. So, when I finally--I was
feeling very uncomfortable and my PSA was
going up
drastically, last summer my doctor heard
about the
Combidex, and he sent me to Dr.
Barentsz's place in
Nijmegen--did I say that right, Nijmegen,
thank
you--beautiful place, and very enjoyable
trip.
I had the Combidex and I sat down in my
shirt and kind of half-naked, but
afterwards, and
looked at the scanner with the doctor,
and there
158
was absolutely completely, black and
white, exactly
what was wrong with me. I have to say I
can't tell
you as a patient what that means when you
actually
know what is going on in your own
body,when all
these other people, with all this money
spent,
can't tell you.
The other thing I want to say
is I did not
go for a surgical procedure to begin
with, because
my urologist said, well, you need to have
surgery
right away when I first had my diagnosis,
and I
went home and I downloaded--I finally
found a
procedure diagrammed on Johns Hopkins
University
website, and I looked at that and I said,
you know,
I am not a surgeon, but that looks like
brain
surgery to me, no thanks.
So, I have been looking for a way to
remain intact as a man, and this was
really
important. You guys need to approve this.
MS. CLIFFORD: Thank you, Mr. Mendinger.
Our next speaker is Ann
B'rells.
MS. B'RELLS: I am Ann B'rells
from
Schenectady, New York, and I want to
thank you for
159
having me. I have no financial interest in the
company and paid my own way to the
meeting. The
only consideration I am taking is ground
transportation back and forth to the
airport and
maybe lunch.
I come to this hearing as a
breast cancer
survivor for three years. Three years ago, I was
diagnosed with breast cancer during a
routine
mammography, and ultrasound proved it, an
aspiration revealed cancer, which was
small and
fairly well defined, and I was told at
that point
that a lumpectomy was in order.
In order to find out how the
cancer was
spread, it was recommended that I have a
sentinel
node biopsy also at the same time. No other way of
identifying the lymph nodes was suggested
to me
because of the comments that you have
heard earlier
today.
After the surgery, I was lucky
and the
sentinel was clear of cancer. Unfortunately, so
was all the other material they had
taken, and
ultrasound showed that they had missed
the lump,
160
and they had to go back in and get it.
I was recommended for radiation
and
Tamoxifen or Arimidex, and I chose
Arimidex.
The reason I am here talking to you
today
is that at the point of after the second
surgery,
when I had to make a decision about
treatment, it
was quite clear that there was no way, a
non-invasive way--and you have just heard
all about
the problems of taking all the lymph
nodes--available to me even though there
was a
several month delay between the
operations.
There was no way I was going to
have
general chemotherapy as opposed to
Arimidex or
Tamoxifen because of the side effects and
possible
mortality from that.
At this point, the only
diagnostic tools I
have are the usual physical exams,
mammograms,
breast ultrasounds, and uterine ultrasounds. I
have had a couple of scares as everybody
has, and I
can't repeat often enough the emotional
and other
physical effects from just the fear.
To be able to have known after
the second
161
lumpectomy, to have had a test that my
doctor would
have recommended, and I think that he
would have
recommended this one, would have been
wonderful.
I just want the committee to
understand
that even though I was treated only three
years
ago, that there are always complications
that come
up, and that the ability to understand
what is
going on with lymph nodes without
actually taking
them out would be wonderful.
The second comment I have is
that although
sentinel node removal is a much milder
activity
than taking more of them, it still
carries a small
risk, and that risk leads you to the same
preventative activities of only having
one arm to
give blood, et cetera. So, that is another reason
that it would be wonderful if the
sentinel, which
also misses, what is it, 15 percent of
the active
cancers, could be eliminated.
So, I thank you very much for
your
attention.
MS. CLIFFORD: Thank you for your
comments, Ms. B'Rells.
162
Our next speaker is Tom Brady.
DR. BRADY: I am Tom Brady. I am from
Boston.
I am a Patriot, but I am not the
quarterback. It is a problem I have periodically.
I am here with no financial
interactions
with the company. They have never supported my
research.
I am actually the Director of Radiology
Research at the Massachusetts General
Hospital and
Professor of Radiology at Harvard Medical
School.
I came here for the first time
in my life
to address the FDA, because I felt that
this was
important enough to take a day off from
work--I
appreciate the prior speaker saying you
can't pay
for a day off of work--and come here to
say a few
things.
The first is there is no perfect
pharmaceutical or contrast agent. The FDA, in its
wisdom, 40 or 50 years ago, did not
approve a drug
called thalidomide, which saved thousands
of lives
and deformities. That drug is currently I believe
approved for a number of applications
around the
world including leprosy and other
vascular
163
problems.
I was really impressed by the
data that
was generated in Europe and at the MGH
and
presented in the New England Journal of
Medicine
primarily because, as a radiologist,
there is
really no way to evaluate small lymph
nodes,
whether they are benign or malignant.
2-deoxyglucose, which is a PET
agent,
which was not commented on here today, is
extremely
good especially for looking at larger
lesions, but
the ability to identify with high
accuracy disease
in small lymph nodes can significantly
change the
management of patients.
I concur with the studies from
Europe on
the cost efficacy. We will see more of those
studies from the MGH coming out soon, and
we
believe that it will, in fact,
demonstrate that at
a high degree of efficacy.
So, in summary, I thank the
committee for
this opportunity. I don't want to take additional
time, but I think that this agent should
be
approved.
Thank you.
164
MS. CLIFFORD: Thank you, Dr. Brady.
DR. MARTINO: The Committee would like to
thank all the public speakers and all
those of you
who are in the audience who perhaps would
care to
speak, but have chosen not to do so. We do
appreciate your being here.
I will tell you as a clinician,
particularly those of you who are
patients, and who
understand these things from a very personal
perspective, that the Committee welcomes
your being
here and appreciates you putting things
in a
certain perspective for us. So, please know that
we value your contribution.
We are now going to turn to the
discussion
portion of the meeting, and this will end
with
ultimately an actual vote that will be
taken. So,
realize that the vote will be the last
part of what
we are going to do this morning. You will have
opportunities to discuss this before we
actually
request a vote of you.
Dr. Ownby, I have been told
that you had
some burning question that I somehow
ignored. If
165
it is still burning in your heart, I will
allow you
to ask it before we proceed.
DR. OWNBY: It was answered previously.
DR. MARTINO: Thank you.
There are a series of questions
which have
been provided to each of the committee
members. We
are going to focus, however, on truly the
very last
one, because I think the other three are
somewhat
encompassed within the final question.
Before I do that, I just want
to remind
this committee of what it is that is
being sought
here today from the maker of this
agent. It is an
indication for intravenous administration
of this
agent in differentiating metastatic from
non-metastatic lymph nodes in patients
with
confirmed primary cancer who are at risk
for lymph
node metastases.
I do want you to recognize the
nature of
those words. They are not asking for a particular
tumor, nor for any particular size of
lymph node.
We have to deal with the question and the
request
as they have posed it to us. Please keep that in
166
mind as you go through the next
deliberations.
The question that the FDA wants
us to
answer for them, and for those of you
that are
guests to this committee, realize that
this
committee is advisory to the FDA. We give them our
opinion.
They then take that into consideration as
they make final decisions.
Most of the time I think they
take us
quite seriously, however, so there is
weight to
your thoughts and to your vote.
Question No. 5. Do the data demonstrate
that Combidex is safe and effective for
marketing
approval based on the sponsor's proposed
indication?
If yes, are there
post-marketing studies
you would recommend to them? If no, do the data
demonstrate that Combidex is safe and
effective for
marketing approval for any other
indications?
If yes, please describe the
patient
population and clinical setting for which
Combidex
would be indicated, and, if no indication
is
supported by the current data, please
recommend
167
what additional studies or data are
needed.
It is on these questions and
their nuances
that I would now like to invite you to
give us your
thoughts.
As we did before, please raise
your hand.
I will recognize you in turn.
Who wants to start? Dr. Brawley, you are
always a good one to get us going, so I
think I am
going to turn to you.
Committee Discussion
DR. BRAWLEY: I guess I will start out. I
just wrote a couple of things while I was
hearing
some of the public comment. My concern is the guy
with prostate cancer who is told that he
has
positive nodes by the scan, but in
reality, the
nodes are negative, and he does not get a
radical
prostatectomy because the scan was wrong.
If you go through the
mathematics that we
just had, and this incredible
mathematical thing,
talking about epidemiologic terms, such
as
sensitivity, specificity, positive
predictive
value, negative predictive value, and
another thing
168
called accuracy, which is a different
kind of
accuracy from what the lay people talked
about,
that is going to happen.
You are going to have a guy who
has
negative nodes, who gets this test, and
he is told
you have nodal positive prostate
cancer. The guy
does not get a radical prostatectomy
which could
save his life maybe, but it would be the
end of
prostate cancer for this man if he got
that
operation. I can guarantee you if we test 10,000
people, there is actually going to be a
handful,
more than 20 or 30 men, maybe over 100,
who will be
robbed of radical prostatectomy because of
that.
The inverse, I am very worried
about a
woman who gets this test for breast
cancer and is
told you do not have node-positive breast
cancer,
and, in reality, she does, and she ends
up
relapsing and dying from her breast
cancer in 5 or
6 years from now.
With the mathematics that was
presented
here, I can guarantee you that is going
to happen.
I just want to say that and I
want to say,
169
yeah, we definitely need something that
helps us to
discern node positivity from node
negativity. I
like what I have seen here, but I think
we need
like 10 times as many patients as we
currently
have.
The next question I have for
the FDA is am
I allowed to consider the New England
Journal data,
which is not auditable and which the
company has
not turned over to you?
DR. MARTINO: Could we get an answer from
the FDA on that?
DR. HOUN: It was submitted to the
application with the right of reference,
however,
we have not been able to get any source
documents,
so we do not consider it a study that
would support
marketing.
You can give us your opinion of
it, but it
does not meet Federal requirements for a
study.
DR. BRAWLEY: Thank you.
DR. MARTINO: Dr. Smetherman.
DR. SMETHERMAN: With respect to breast
cancer, and Dr. Giuliano can probably
speak to this
170
with even more authority than I, I think
we have
kind of almost moved past this level with
sentinel
lymph node.
We are not really looking at
the sentinel
nodes with just H and E staining, we are
looking at
them with immunohistochemistry. It is certainly
as, you know, the sponsor pointed out, 61
percent
of patients with a sentinel node only
positive will
have additional positive nodes, but I
don't think
they are suggesting that having this
test, even if
it were negative, would obviate the need
for them
to have the sentinel lymph node
dissection anyway.
So, I think at least in what we
are
commonly doing on a day-to-day basis in
breast
imaging and breast surgery, this probably
wouldn't
really be that relevant.
DR. MARTINO: Yes.
DR. BUKOWSKI: I listened to Dr. Brawley
and I must say I agree that the data we
heard today
just there is not enough information on
the various
patient groups to be convincing that, in
prostate
cancer, for example, this will be a
useful test in
171
terms of the auditable data that were
reviewed.
I am concerned that let's say we approve
the application, as this material enters
the use by
individuals, there will not be proof of a
positive
node or a negative node, one will just
accept the
radiologic view of that saying it is
positive or
negative as we have heard.
The specificity and the
accuracy doesn't
sound like that would be supported by
what we have
heard today, so I am somewhat concerned
by the
number of patients that were included in
the small
subset.
I just don't think there are enough
prostate cancer patients, for example, to
support
utility in that particular setting.
DR. MARTINO: The problem that I have
really are many with this. Do I think that this
identifies certain lymph nodes that are
not
appreciated in other ways? I think they have
convinced at least me that yep, that's
true.
Is the value of this in people
who have a
node that is greater than 10 mm, where
others would
already have identified it? I am not sure that
172
that is the right place.
Is it really something that is
of value in
someone whose lymph node measures less
than that,
where other modalities might miss
it? I am not
sure they have convinced me how good they
are in
that setting.
So, I am actually very hopeful
of this
modality.
I have to say that it does have some
value in my mind. I am just struggling with am I
sure enough of what its value is, to what
degree
can I trust the information that comes
from it, and
in whom can I trust it, where does it do
nothing
other than just confirm something I
already knew,
where does it allow me to avoid doing a
surgery,
where does it guide me to a lymph node
that maybe I
should do a surgery on.
There are just so many
questions that I
just, in my mind, cannot answer from the
amount of
data that has been presented, yet, I am
intrigued
that there is something here if only I
could be
sure of what that something was.
So, I am struggling with this whole
173
concept as to how trustworthy is the data
at this
point in time and how do I really use it
clinically, because ultimately, if it
can't be used
clinically, in a manner that I
understand, my guess
is that everyone else will have the same
problem.
The charge that this committee
has is not
just to sort of judge whether something
is
interesting. Lots of things are interesting, lots
of things have some value. What this committee is
charged with is giving an opinion as to
whether,
with the data that exists now, we are
ready to
basically say anyone out there should
have this
test available to them and the results of
it should
be then used for clinical judgment.
I am struggling with that major
leap of
faith, but I can't sort of lose track of
what our
real job is here.
Dr. Amendola, you are up next.
DR. AMENDOLA: Let me tell you I am a
practicing radiologist with a special
interest in
GU radiology. Prostate cancer, as you probably
know, is one of the most controversial
cancers
174
regarding therapy today. One of the key reasons
for this is that we don't have a good
method of
staging this tumor especially one of the
problems
is staging a lymph node, which is a key
element for
management of these patients.
There is another agent which is
being
used, which is another imaging modality
is PET
scanning, which happens to be not as good
in the
pelvis as in other areas of the body
because of
technical reasons.
I agree that the data that was
presented
was not completely convincing from a
statistical
standpoint, but I think that given the
status of
our poor accuracy with the current
imaging methods
that we have to image lymph nodes that
are diseased
in patients with prostate cancer, I think
that
taking the risk-benefit ratio, there is a
group of
patients with prostate cancer would be
highly
beneficial to use this modality.
If we could save some patients
from
unnecessary surgery or radical radiation,
I think
that this would be a very good thing to
do. Thank
175
you.
DR. MARTINO: Dr. Levine.
DR. LEVINE: It seems to me that there is
real potential for the agent, and my
problem is
that the indication that is being requested
is not
really based upon the data that would
allow me to
do that.
So, number one, the indication
says all
tumors, all comers basically, but the
presentation
is not dealing with all tumors, and
somewhere in
your documentation it excludes lymphoma
as an
example, but that is not stated on your
indication,
so the indication is too broad based upon
the data
presented.
Even the issue of newly
diagnosed versus
status post-radiation, you know, I see
that it has
been used in people who have had
radiation before,
and maybe that is valuable, but I don't
know, and
the indication doesn't state that or
doesn't
qualify that, so that would be another
area that
needs to be evaluated more carefully,
studied more
carefully.
176
The other indication, it seems
to me, is
in those tumors or those lymph nodes that
are
small, less than 5 mm, and if you now
break down
the data that exist into that group, you
know,
whatever the specific cancer is, and the
newly
diagnosed, and now less than 5 mm, there
is so
little data here that it is very
frustrating.
I guess I would ask you to
think of that
and come back. Thank you.
DR. MARTINO: Dr. Hussain.
DR. HUSSAIN: So, I had the chance to hear
the scientific presentation previously by
the
doctor from Mass. General who presented,
and I
think he did an excellent presentation
again here
today, and I guess in my mind, this
technology is
quite potentially promising, but I would
underline
potentially.
I don't believe the trials that
have been
shared with us, and the results of them,
and
certainly I think the designs were very
flawed, I
have to tell you that. I came in with more
enthusiasm, and as I sat and listened
more, my
177
enthusiasm went down.
I think the comments that were
made about
sparing people surgery or added treatment
is a
premature statement to be made. Staging gives you
information. You use that information to make a
decision.
I would point out that in
today's
standard, if there is a microscopic lymph
node
positivity, which is what you are talking
about
here, there are patients who are being
operated on
and offered additional therapy, so I
don't think we
need to play on the angle that if you
have one node
by the scan, that means you basically are
to be
doomed to no treatment or some hormone
treatment
that is not going to cure you. I think that is
really the wrong strategy here.
The one thing about this from
my
perspective, I think what I would have
liked to see
is a well-characterized patient
population where
clinical and other predictors of outcome
are
incorporated and how this thing actually
played in.
The other thing that I would
point out is
178
the way you are asking for it would apply
for
people who have seen therapy and failed
for
assessment, so a guy who has had a
radical
prostatectomy or radiation therapy, and
comes back
with a rising PSA, is also covered under this
umbrella, and I don't believe you showed
us any
data to say that this would be a
reasonable thing
to do.
I am not going to comment much
about
breast cancer, but I think the same thing
applies.
I would have loved to see a well done
trial, a well
characterized population, all the
information out
there, and the statistical assumptions to
start
with, what you are looking for, what did
you
expect, and I do reiterate that the
template for
the lymph node dissection is to me--I am
an
oncologist, not a surgeon--but it is
important.
The questions that were asked
from the
surgeon before were very, very relevant,
I think,
and I think not having that information
is a major
flaw.
DR. MARTINO: Dr. Couch.
179
DR. COUCH: I routinely read my own scans
before we decide in the tumor board what
to do with
my patients, and I view this as another
source of
information. I am going to scan all my patients to
decide what their stage is and what the
best
treatment is.
The lack of evidence from that is
always
astounding to all of us. This, to me, seems a
reasonably safe agent that could give you
potentially more information. Would it
determine
alone what I do with our patients? No, it might
make you think you would do a further
testing or
consider a node biopsy or a fine needle
aspiration,
but it is more information.
It is important even when we
have people
with disease to find out what the
radiation reports
will be, whether they are at high risk
and
therefore would qualify for
chemotherapy. To me,
the data was supportive of use in head
and neck
cancer patients.
These studies are difficult to do. I
think they have done a good job, to
understand that
180
the radiologists went to the operating
room and
looked at what nodal basins were being
removed and
analyzed was very reassuring to me.
So, I actually think that this
is quite
promising and the data, to me, is enough
to approve
this broad indication. I am a little confused, and
I asked this of the FDA for the following
reason.
We order tests and we understand it is
part of the
treatment plan for the patient. It is not
going to
determine alone what I do with the
patient.
You are asking this company to
say we will
approve this for a certain patient
subtype that
hadn't had radiation and chemotherapy,
and then you
want the company to come back again and
again for
each sub-subcategory?
DR. MARTINO: The FDA needs to answer
that, please.
DR. HOUN: I think it depends on the drug
and the indication and the disease being
studied.
A disease like ulcers, they get a
treatment
indication for acute ulcers. If you want to say
you can maintain ulcer quiescence, you
have to do
181
another study, a year-long study to
demonstrate
that.
So, there are disease
conditions where to
treat the level, the need for data on
different
stages of the disease, prevention of
ulcers is
totally different with NSAIDs. We do ask for
different studies, and for diagnostic
agents, we do
have different types of indications.
They are seeking an indication
for disease
detection. They are not seeking an indication for
patient management like to help you
better stage.
If that was the case, then, we would
compare
regular staging to this, and that would
be the
clinical trial.
So, they are asking for disease
detection,
and they are looking for cancer
detection.
DR. COUCH: I think that is
extraordinarily difficult. For instance, I am glad
to see they excluded in their studies
patients with
head and neck cancer that had had
previous
radiation and chemotherapy. What happens to those
lymph nodes is unknown, and we are having
trouble
182
even with PET scans, which we think is
probably the
best imaging modality to understand which
patients
have residual disease in their lymph
nodes.
So, I think it is a little bit
different,
and I think that that is decided upon
with the
understanding of the specificity and
sensitivity
and the clinical judgment.
DR. HOUN: If you give us advice that this
is good for primary presentation and that
further
studies are needed for other presentations,
we
would like to hear that, or if like all
comers are
fine, we would like to hear that, as
well.
DR. MARTINO: Dr. Mortimer.
DR. MORTIMER: As I think about
decisionmaking in this process, I think
about
whether this test actually provides us
information
that will make me change therapy, and I
guess I
would reiterate what Dr. Hussain said in
the
prostate cancer setting. Given the sensitivity of
PSA and the value of node dissection, I
am not sure
that it actually fulfills that criterion.
However, I would like to make a
plea that
183
the
more interesting data really isn't the head and
neck population here who are
underrepresented in
the advocacy group for a variety of
obvious
reasons, and I think that data was
actually the
most interesting.
DR. MARTINO: Dr. Ownby.
DR. OWNBY: I have two interrelated
concerns.
One, as I understand the indication, and
the FDA experts can correct me, this
would be
approved for all ages, and not a single
group, and
that would include children, and yet there
is no
child data in this.
My related concern is if you
look at
anaphylaxis and anaphylactoid reactions
in large
populations, young adults and teenagers
seem to be
at particularly higher risk, and the only
age
stratification of this data is the 65 and
over, and
I would certainly like to see some
further
stratification before considering that a
very low
incidence procedure while clinicians are
clearly
going to use it more in an advanced age
population,
I think this is a very broad approval
request.
184
DR. MARTINO: Dr. Reaman.
DR. REAMAN: I would just follow with
that.
I think it is a very broad approval request
and I think some of the comments that I
have heard
here, the real operative word in the
review of this
is promising. I think this is probably one of the
most exciting agents we have had the
opportunity to
actually review in this committee, but
unfortunately, the data presented to us
was
probably some of the least satisfactory
from the
standpoint of study design and conduct.
The FDA was criticized for
making a low
blow because of the mix of patients and
the broad
application. I would like to defend the FDA and I
think including 10 patients or 15 or 20
patients
with the three most common malignancies,
and then
asking for a broad indication is really
inexcusable, whether it is in a primary
diagnosis
setting or in a previously treated
setting.
I am concerned that if this
were to be
approved, that it would be used widely
with no
experience in the previously treated
setting, in
185
the setting of follow-up, and in the
setting of
pediatric cancer.
Most patients or most children
with cancer
are diagnosed with disseminated disease,
and the
question of nodal metastasis is a very
common
issue.
I think the fact that this hasn't been
tested and the likely incidence of
hypersensitivity
reactions is a major concern.
DR. MARTINO: Dr. Brawley.
DR. BRAWLEY: Thank you.
Dr. Reaman, I so
agree with everything you just said. I really
wanted to vote for this drug today,
however, it is
just not proven, it is just not proven
with the
data in front of us.
I don't want to get into a
lecture on
screening and epidemiology for the
clinicians who
don't normally get involved in this, but
I will say
for a diagnostic procedure, you typically
want very
high specificity, 95 percent or
higher. This is
specificity which is much lower than
that, and that
lower specificity means that the
decisions that you
make, you really have very little
confidence in the
186
decisions that you are going to be making
with that
low specificity.
Now, one way that you can
increase
specificity is to enrich the patient
population
that actually has the disease, to use
other
clinical indicators, such that you are
only using
the test on people who are very highly
likely to
have the disease.
They tried to do that, and it is very
fair.
That is what I would call a fair selection
bias.
It would be not appropriate to do this test
on somebody who you didn't know have
cancer
already, for example.
So, using clinical methods to increase
or
enrich the odds that you are going to
find disease
is totally fair, but even when they did
that, the
specificity is less than 90 percent in
most
instances.
I would concur that where we
actually do
have the best evidence of efficacy--and I
actually
split out efficacy versus effectiveness,
they are
different things--is in head and neck
cancer.
187
DR. MARTINO: Dr. Bradley.
DR. BRADLEY: I am a practicing
radiologist that has been doing MRI for
26 years.
We often make decisions based on
imperfect data,
any of the clinicians in the room know
that. What
I have seen, I believe in. If it is approved for
one set of cancers, the clinicians in
this room
will probably use it for all sets of
cancers even
though it is not in the package
insert. We do that
all the time.
But I would like to speak to
the
specificity and specifically to reducing
the false
negative.
If they get a false positive, they get a
biopsy.
If they get a false negative, they die of
their cancer.
There are technologies coming
down the
pike, in fact, many of them are on their
way right
now that are definitely going to increase
the
specificity of this agent. This is a
magnetic
susceptibility agent, turns things dark
in a higher
magnetic field.
I spoke earlier about why did
you include
188
a 0.2T, well, the major market right now
is 3
Tessler.
Standard high field has been 1.5.
We
just ordered eight 3T's at UCSD. There is a larger
market for 3 Tessler MR than there is for
all of
the low-field magnets now. 3 Tessler will be much
more sensitive than 1.5 Tessler using the
same
technique for the same
concentration. So, I would
imagine the false negatives would reduce
on that
basis.
I also mentioned, I asked the
authors of
the New England Journal article how did
they get
exactly the same slice thickness. Well, there is a
technology that is available in the brain
called
auto-align which gives you exactly the
same
position in the brain.
When I spoke to the inventor of
that
technique, could it be applied to the
body, he said
yes, it hasn't been yet, but it could
be. So, now
you have got exactly the same node pre
and post, in
exactly the same position, on a higher
field
scanner, using more sensitive techniques,
I am sure
that the false negative rate will be
reduced and
189
the specificity will increase.
DR. BRAWLEY: Can I just say if I were
presented that data, I would happily vote
for this
drug to be approved, but I haven't been
presented
with that data.
DR. MARTINO: Dr. Perry.
DR. PERRY: First, let me apologize to Dr.
Li.
I think I misinterpreted the sponsor's
indication and I apologize to you and the
FDA if my
comments offended anyone. It was
certainly not
intended.
I intend to rouse some rabble, but not
unnecessarily.
Secondly, I am impressed by the
safety of
the agent. I don't have any particular concerns
about that. I don't think there is anything you
can inject into somebody intravenously
that doesn't
have some problems, and I think with the
appropriate premedication and
precautions, the drug
is safe.
I am not yet convinced that
it's effective
and I am not yet convinced that it's
effective for
all the tumor types that it would
conceivably be
190
used for, and at the moment I am inclined
not to
vote for it.
DR. MARTINO: Mr. Kazmierczak, please.
MR. KAZMIERCZAK: Yes.
As I pointed out,
I am a patient consultant to the FDA for
prostate
cancer.
I was diagnosed back in '98 or '99, and at
the time I had an MRI, which was
negative, and I am
not sure if I had had the
Combidex-enhanced MRI
that it would have changed the fact that
I had a
radical prostatectomy, I am not convinced
it
wouldn't have showed a negative
result. I am not
sure that the accuracy is such that it
would have
changed the therapy that I eventually
elected.
I do agree with some of my
friends up here
that the more information you have on
risk and
benefit, the better the patient feels
about the
decisions that he makes. I found out a
long time
ago that I don't let doctors make
decisions for me
anymore, I try to work with them to make the
decision.
It turns out even after my
radical, my
cancer was not confined to the prostate,
it had
191
seeped into the seminal vesicle, and I am
not sure
that Combidex would have found that
out. So,
essentially, I have had a rising PSA,
went on to
adjuvant treatment with radiation.
I still have a rising PSA, so I
got myself
a Viadur implant, and I am not sure that
any of
these therapies that I went through, and
I probably
have a disease that really attacks me
very badly,
so I am probably going to die of this
disease, and
I am not sure there is anything available
other
than one of these wonderful clinical
trials for me
at this point.
That said, when I read this
information, I
was really hoping I could vote for this,
but the
more I thought about it, the more I
wondered
whether or not it would have made any
difference to
me in terms of the decisions that were
made. That
is my perspective. Thank you.
DR. MARTINO: Dr. Reaman.
DR. REAMAN: It was answered, thanks.
DR. MARTINO: Please.
DR. DYKEWICZ: To address a few issues
192
about safety, I do agree that the safety
of the
agent is within the realm of
consideration for
standard clinical practice. It is a
question, of
course, of always risk versus benefit.
The risk of this agent, I think
is
probably not that significantly greater
than
radiocontrast media, although it may
be. We still
are looking at relatively low numbers of
patients.
I would say looking at it from
an allergy
perspective, although the radiocontrast
media is
certainly a relevant analogous situation,
iron
dextran may be a more direct analogous
comparison,
and there, of course, the reaction rate
is somewhat
higher than with radiocontrast media.
Unfortunately, if we look at
strategies to
reduce iron dextran reactions, nothing
has really
been held to large-scale trials. There are case
reports about medication pretreatment as
used in
radiocontrast media to reduce the risk,
but I am
not clear that that would necessarily
enhance the
safety.
That being said, we do know
from
193
radiocontrast media, which is analogous
in the
sense that this is most likely a
non-IGE-mediated
anaphylactoid reaction, we do know that medication
pretreatment can significantly reduce the
reaction
rate.
Now, this also, though, gets at
the point
about what the type of medication
pretreatment
should be. When you look at radiocontrast
pretreatment regimens that have been
used, the best
data for protection is where
corticosteroids are
given well in advance of the
administration of the
agent, for instance, a regimen that would
give
steroids 13 hours before or 7 hours
before or 1
hour before, and not just, if you will,
on call to
the Radiology suite.
I am kind of really troubled by
the fact
of looking at, if you will, the standard
of care
for treatment of patients in Radiology
administration areas in terms of what is
done to,
number one, pre-treat patients who may be
at
increased risk, and, number two, how to
treat it.
I am not sure if there is good
recognition
194
out there that you need to give steroids
well in
advance of administration in order to
significantly
reduce the risk.
I am pretty sure that there is
a lack of
awareness about when epinephrine should
be
appropriately used. I think this is a situation
where evidence-based medicine and the
standard of
care are not meeting.
We now know that, for instance,
with
epinephrine, it should be given IM rather
that
sub-Q to try to get more rapid
administration, and
to summarize all these musings, if you
will, I
would say that it would be reasonable to
try to
reduce the risk of a reaction by using a
medication
pretreatment regimen that has been
demonstrated to
be effective in radiocontrast media.
Whether the company would be
held to do
that as part of a label indication, I
think depends
on whether you demonstrate good
efficacy. I think
my sense about this is head and neck
cancer has
been demonstrated to be a scenario in
which this
agent would be of value, and if you are
looking at
195
a risk-benefit assessment, you could make
a case
for approving the drug.
But if we are looking at in
general, the
broader area of oncology, and having a
very general
label for all types of cancer, with an agent
that
maybe has a significant reaction rate
risk of 1 to
2 percent, I think that gives me real
pause for
concern.
DR. MARTINO: Dr. Amendola, did you have a
question?
DR. AMENDOLA: Regarding the question of
the value of pre-medication, this is well
recommended in the literature that you
can decrease
the rate of reactions by giving them the
patient
pre-medication with steroids especially
for
iodinated contrasts. I am not aware of any
literature regarding this type of
contrast. I have
another comment.
There is currently an
FDA-approved MR
contrast material which is very similar to
this
one.
It is called Feldex [ph], which is also an
ultra-small, USPI, it is called. To my
knowledge,
196
we use this fairly often, and we have not
had any
serious reaction and, to my knowledge,
there has
been no deaths related to Feldex, but
maybe some
other members of the panel have more
experience
with this.
DR. MARTINO: Dr. Hussain.
DR. HUSSAIN: I have a question to the
FDA, Dr. Li, or any of the team. When the sponsor,
I believe, or yourself mentioned that
they sat down
to talk to you about the design of the
trial, what
was the advice, and what was the spirit
in which
the
trial was designed, was that designed for an
indication approval?
DR. HOUN: I think that it has been a
course over the years that we have worked
with the
sponsor, and I do have to say that their
attempt to
get
the correlation between images and pathology,
as you can tell as Dr. Anzai described
it, is very
difficult, and they did a very good
attempt to try
to do that.
So, we did look at their
proposals, we
provided comments. They revised according to our
197
comments.
I think our goal was to ensure that
pathology was obtained for these nodes.
I think your comment and the
committee's
comments what were other factors that
might
influence the actual surgical field, and
were they
well described, unless the sponsor has
more
information, I don't believe we were
discussing
those specific criteria.
DR. HUSSAIN: Did you tell them, for
example, that you needed to have that
many patients
of that tumor because one of the critique
regarding
their request for the indication, that
this is a
blanket, and they did not address
different tumor
types, was that discussed with them in
advance,
that unless you come in with that number
of
patients with that tumor type, I mean in
all
fairness to them, if they listened to
what you told
them, and now it's not fair to them
because they
did exactly what they were told, and they
come back
and now they are told that is not good
enough.
I guess what I am trying to
find out what
was the advice of the FDA in the first
place.
198
DR. LI: I will try to give my answers.
The interaction has been going on for six
years. A
lot of people give initial comment, may
not be here
anymore, but when we look at the record,
you look
at the original patient population is 181
and 162,
and I don't think the sponsor
anticipated, as we
never anticipated, that so many patients
was
dropped from the study, was not able to
do a
primary analysis.
So, if all the patients was
included, that
may provide some--I mean I couldn't speak
right now
what the data might be, but will probably
provide
more assurance for us. This is one thing I don't
think the sponsor realized at the design
stage that
so many patients--we didn't realize that
either.
Also, I just make a point that
there is
another issue that both sides never
realized is
that pre-contrast MR sensitivity and
specificity is
a moving target. You see from a U.S. trial they
made it from primary analysis, but from
European
trial, they never it. This is an issue that the
sponsor and us never realized at the
beginning, but
199
what I want to say is Agency really
showed the
maximum, at least showed the maximum
flexibility,
say if you really stay on the original
design, the
original design said you have to have two
trials.
Each trial, your sensitivity
post have to
beat pre.
That is basically statistical design.
In the U.S. trial, they meet that design,
they are
able to show improved sensitivity, but in
the
European trial, they failed the
sensitivity.
So, if you just take at face
value, it's a
failed trial, however, when we realized
the reason
they failed the trial, it is because they
only
included large size in the European
trial. That
makes the sensitivity so high, no way
they can beat
it.
So, we say let's go back, let's
come back,
look at more evidence, look at what's
really the
clinical question whether we can take a
look at
data to see whether it's clinical value.
So, that's why you see the
analysis by
subgroup. That was not original plan,
that's true.
The sponsor, what they said that's true,
that's not
200
original plan, but when first primary
analysis
failed by the face value, when we started
looking,
by its group, by those things of value
there, then,
you see that this group is seen by size,
by tumor,
that makes people starting to realize
wait a
minute, what assumption we are having
right now and
whether we should approve it for broad
indication.
That is why we come here, ask
for your
advice, to guide us how to handle the
situation
over here. I hope I answered your question.
DR. MARTINO: Dr. Bradley.
DR. BRADLEY: I have a couple of questions
related to our relative lack of data,
particularly
for the wider indication. As a radiologist, I
assume that all lymph nodes filter lymph
and, in
this case, Combidex, the same way.
Does anybody know that
lymphoma, for
example, would invade a lymph node in a
different
way?
I know that they didn't get lymph node data,
but they said it was because they had
trouble
getting pathology, so that is one
question.
Another question for Gene, they
missed
201
your seminal vesicles. Did you have an optimal MRI
with intrarectal coil and the whole bit?
MR. KAZMIERCZAK: I believe I did.
DR. BRADLEY: You would know.
MR. KAZMIERCZAK: I believe I did, but I
am like the statisticians, I am 85 to 90
percent
sure.
DR. MARTINO: At this point, are there any
final comments? Otherwise, I will bring the
question to a vote.
Seeing no other hands raised, i
will now
call you to a vote, and we will start on
my right
with Dr. Couch, and as you state your
vote, which
is a yes or a no, I need you to state
your name
first for the record, please.
The question is do the data
demonstrate
that Combidex is safe and effective for
marketing
approval based on the sponsor's proposed
indication.
DR. COUCH: Marion Couch.
Yes.
DR. SMETHERMAN: Dana Smetherman. No.
DR. AMENDOLA: Marco Amendola. Yes.
202
DR. BRADLEY: Bill Bradley.
Yes.
DR. GIULIANO: Armando Giuliano. No.
DR. DYKEWICZ: Dykewicz.
No.
DR. OWNBY: Ownby.
No.
DR. MORTIMER: Mortimer.
No.
DR. PERRY: Michael Perry. No.
DR. HUSSAIN:
Hussain. No.
DR. MARTINO: Martino.
No.
DR. REAMAN: Reaman.
No.
DR. RODRIGUEZ: Rodriguez.
No.
DR. LEVINE: Levine.
No.
MS. HAYLOCK: Haylock.
No.
DR. DOROSHOW: Doroshow. Yes.
DR. BRAWLEY: Brawley.
No.
DR. BUKOWSKI: Bukowski.
No.
MR. KAZMIERCZAK: Kazmierczak.
No.
DR. MARTINO: And our tally? There are 15
No's and 4 Yes's.
That is the end of our
meeting. I thank
you all for participating. Are there any
additional questions from the FDA before
I release
the group?
203
Okay. There are no questions for the FDA.
At this point, I will remind you that the
next
meeting begins at exactly 12:45 in this
room.
Thank you.
[Whereupon, at 11:58 a.m., the
proceedings
were recessed, to be resumed at 12:45
p.m.]
204
A F T E R N O O N P R O C E E D I N G S
[1:03 p.m.]
Call to Order and
Introductions
DR. HUSSAIN: Ladies and gentlemen, if you
don't mind taking your seats,
please. We are going
to try to start the afternoon session.
My name is Maha Hussain from
the
University of Michigan. I want to welcome you all
to the afternoon session. The session will
specifically deal with potential
alternative
endpoints to design trials for prostate
cancer
specifically with the intent of
expediting the
approval process of agents in this
particular
disease.
We will start with the
introductions. I
will begin with the FDA on my left. Dr. Williams.
DR. WILLIAMS: Grant Williams, FDA.
DR. KEEGAN: Patricia Keegan, FDA.
DR. SRIDHARA: Rajeshwari Sridhara, FDA.
DR. SHAMES: Dan Shames, FDA.
DR. BROSS: Peter Bross, FDA.
MR. MANN: Bhupinder Mann, FDA.
205
MR. KAZMIERCZAK: Eugene Kazmierczak,
Patient Consultant, Prostate Cancer.
DR. BUKOWSKI: Ron Bukowski, Cleveland
Clinic.
DR. BRAWLEY:
Otis Brawley, Emory
University.
DR. DOROSHOW: Jim Doroshow, NCI.
MS. HAYLOCK: Pam Haylock, Consumer
Representative.
DR. LEVINE: Alexandra Levine, University
of Southern California.
DR. RODRIGUEZ: Maria Rodriguez, M.D.
Anderson Cancer Center.
DR. REAMAN: Gregory Reaman, George
Washington University.
DR. HUSSAIN: Again, Maha Hussain,
University of Michigan.
MS. CLIFFORD: Johanna Clifford, Executive
Secretary to the ODAC.
DR. MARTINO: Silvana Martino, Medical
Oncology, Cancer Institute Medical Group,
Santa
Monica.
206
DR. PERRY: Michael Perry, Ellis Fischel
Cancer Institute, University of Missouri.
DR. MORTIMER: Joanne Mortimer, Moores
UCSD Cancer Center.
DR. GRILLO-LOPEZ: Antonio Grillo-Lopez.
I am a hematologist/oncologist, a
five-year cancer
survivor this month, and the industry
representative.
DR. SCHER: Howard Scher, Memorial
Sloan-Kettering Cancer Center.
DR. D'AGOSTINO: Ralph D'Agostino, Boston
University.
DR. D'AMICO: Anthony D'Amico, Dana Farber
Cancer Institute.
DR. McSHANE: Lisa McShane, NCI.
DR. SANDLER: Howard Sandler, Radiation
Oncology, University of Michigan.
DR. KLEIN: Eric Klein, Cleveland Clinic.
DR. DeGRUTTOLA: Victor DeGruttola,
Harvard School of Public Health.
DR. ANDRIOLE: Jerry Andriole, Washington
University in St. Louis.
207
DR. EISENBERGER: Mario Eisenberger,
Medical Oncology, Johns Hopkins.
DR. RAGHAVAN: Derek Raghavan, Cleveland
Clinic, Taussig Cancer Center.
DR. PAZDUR: Richard Pazdur, FDA.
DR. HUSSAIN: I would like to introduce
Johanna Clifford to read the Conflict of
Interest
statement.
Conflict of Interest
Statement
MS. CLIFFORD: The following announcement
addresses the issue of conflict of
interest with
respect to this meeting and is made part
of the
record to preclude even the appearance of
such.
Based on the agenda it has been determined
that the topics of today's meeting are
issues of
broad applicability and there are no
products being
approved.
Unlike issues before a
committee in which
a particular product is discussed, issues
of
broader applicability involve many
industrial
sponsors and academic institutions.
208
All special government
employees have been
screened for their financial interests as
they may
apply to the general topics at hand to
determine if
any conflict of interest existed. The Agency has
reviewed the agenda and all relevant
financial
interests reported by the meeting
participants.
The Food and Drug
Administration has
granted matters waivers to the special
government
employees participating in this meeting
who require
a waiver under Title 18, United States
Code Section
208.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
Agency's Freedom of Information Office,
Room 12A-30
of the Parklawn Building.
Because general topics may
impact so many
entities, it is all not practical to
recite all
potential conflicts of interest as they
apply to
each member, consultant, and guest
speaker.
The FDA acknowledges that there
may be
potential conflicts of interest, but
because of the
general nature of the discussions before
the
209
committee, these potential conflicts are
mitigated.
With respect to the FDA's
invited industry
representative, we would like to disclose
that Dr.
Antonio Grillo-Lopez is participating in
this
meeting as an acting industry
representative acting
on behalf of regulated industry. Dr. Grillo-Lopez
is employed by Neoplastic and Autoimmune
Disease
Research.
In the event that the
discussions involve
any other products or firms not already
on the
agenda for which FDA participants have a
financial
interest, the participant involvement and
their
exclusion will be noted for the record.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial involvement
with
any firm whose products they may wish to
comment
upon.
Thank you.
DR. HUSSAIN: Thank you, Johanna.
I would like to make a couple
of comments
210
before Dr. Pazdur begins his
presentation. We have
several invited experts to discuss
different
aspects of PSA and other endpoints as it
relates to
prostate cancer.
The intent with this
afternoon's session
is not so much to come up with a specific
endpoint
to address necessarily, but rather a task
list of
what perhaps is needed to begin to
develop
different endpoints for evaluation of
drugs in an
expedited manner in prostate cancer, so I
would
like us to, as much as possible, focus on
that
issue, and not get hung up on little
details that
may not be serving the purpose as a
whole.
Without further delay, I would
like to
introduce Dr. Richard Pazdur, the
Director of
Division of Oncology Drug Products, as
the first
speaker.
Opening Remarks
DR. PAZDUR: Thanks, Maha.
I just have some introductory
comments to
go over the process that we are
addressing here
today.
As you know, part of one of the big
211
initiatives that the Division of Oncology
and
Oncology, in general, at the FDA, has
been to
perform a review of different endpoints
diseases,
and these endpoints are the approval
endpoints that
we would use for approval of new
molecular entities
and also supplemental NDAs.
This is a process that we have
tried to
integrate into the greater oncology
community and,
hence, before we have ODAC meetings on
specific
diseases to discuss endpoints, we usually
have a
workshop, and we had a workshop on
prostate cancer.
It has been almost about a year ago, I
think, where
we had a workshop in Bethesda, held in
conjunction
with ASCO and AECR.
The purpose of this meeting was
really to
explore areas and controversies of
endpoints, and I
think one of the most controversial area
obviously
was the optimal use of PSA, how to use
it, when to
use it, where to use it, and I think a
lot of
discussion that we will have today will
center on
the PSA issue.
As Maha stated, I think one of
our goals
212
is not to achieve direct consensus here,
but to
raise issues. If there is consensus, let us hear
it, and we will be happy to take it into
consideration.
One of the things that I was
most
impressed about as far as attending the
workshop
that we held was the controversial nature
of PSA
and
endpoint for prostate drug development, and I
think we should be aware that there can
be
agreements or disagreements, but
ultimately, at one
time or another we are going to have to
come to
some decision on the use of biomarkers in
prostate
cancer.
So, I am not trying to
discourage
discussion on this or lack of consensus,
but I
think we have to be realistic that there
are many
controversies that exist today in the use
of PSA.
If I take a look at the other
diseases
that we have held workshops on, for
example, colon
cancer and lung cancer, I would have to
say that
this has been the most difficult area to
review,
and the battling of different people and
different
213
ideas regarding PSA has been one that has
necessitated the Division actually to
have separate
meetings and separate discussions with
people in
the academic community after the ODAC
meeting.
Here again, I think the one
thing that was
clear is that this is a controversial
area that we
need to bring some plans on how to
further develop
this.
Hence, therefore, we have the program that
is outlined in your sheet that has been
provided to
you.
The first talk will be by Dr. Bhupinder Mann,
who will go over our past regulatory
approvals for
drugs.
That is what we have done.
Then, we have asked Dr. Derek
Raghavan,
who was one of the Co-Chairs of the
ASCO-AACR
meeting, to basically try to summarize
the
highlights of that ASCO-AACR meeting, and
his
talked is entitled "Towards a
Consensus in
Measuring Outcomes in New Agents for
Prostate
Cancer.
The third talk is one that will
be given
by the NCI, and it is the NCI Prostate
Cancer
214
Treatment Trial Portfolio. I was interested in
bringing this issue up because I think if
we do
discuss endpoints, there has to be a
discussion of
prospective evaluation of these
endpoints, and we
have to have an idea what the NCI is
doing as far
as supporting prostate cancer research
and how we
can utilize those trials to embed
endpoints and to
look at them in a prospective
fashion. Hence, we
have asked the NCI to please provide data,
not
data, but a description of ongoing
research that
they have.
The last two talks, given by
Dr. Howard
Scher and Anthony D'Amico, basically
stemmed out of
our AACR and ASCO symposium, and is
somewhat an
exploration of issues that were explored
during
those workshops.
Howard will give a talk
entitled "Toward
an Endpoint for Accelerated Approval for
Clinical
Trials in Hormone Refractory Prostate
Cancer," and
then Dr. D'Amico, Anthony D'Amico will
end by
discussing clinical trial designs for
selected
patients with a rising PSA following
primary
215
therapy.
I want to emphasize we are not
here to
bury PSA, we are not here to praise
PSA. We are
here basically to have a discussion of
the existing
data that supports its use. Any endpoint that we
have for drug approval has to be credible.
I am not asking for perfection
here with
any endpoint, and as you realize, we have
used many
endpoints that are not true
surrogates. For
example, in our accelerated approval
program, we
ask for surrogates that are reasonably
likely to
predict clinical benefit, but we have to
have some
basic comfort, some basic understanding
of that
endpoint.
That endpoint has to have
credibility and
some acceptance, not only by the FDA, but
by the
greater oncology world, and that includes
you
people as investigators and also
patients.
With that ado, I will turn over
the
program to Dr. Hussain.
DR. HUSSAIN: Thank you, Dr. Pazdur.
Dr. Temple, would you please
for the
216
record state your name.
DR. TEMPLE: Robert Temple. I am the OD-I
Director, Office Director.
DR. HUSSAIN: Thank you.
Our next speaker is Dr.
Bhupinder Mann,
who is a medical officer, Division of
Oncology Drug
Products, and the discussion will be
regarding a
regulatory perspective of endpoints to measure
safety and efficacy of drugs in the
setting of
hormone refractory prostate cancer.
A Regulatory Perspective of
Endpoints to Measure
Safety and Efficacy of
Drugs:
Hormone Refractory Prostate
Cancer
DR. MANN: Good afternoon. I am going to
first present a review of the endpoints
which have
been used during the past few years in
approval of
drugs for treatment of advanced hormone
refractive
prostate cancer.
I have focused specifically on
these
approvals as these are illustrative of
the
underlying regulations. Later, I will also
summarize some of the difficulties which
are
217
encountered in reliably measuring safety
and
efficacy of treatments in prostate
cancer, reviews
of both the traditional and the
innovative
endpoints.
Approval of a new drug requires
substantial evidence of effectiveness
derived from
adequate and well-controlled clinical
investigations.
Before 1992, endpoints used for
drug
approval were required to represent
clinical
benefit.
Some of the endpoints were direct
measures of clinical benefit, for
example,
improvement in survival or improvement of
disease
symptoms.
Others were accepted surrogates for
clinical benefit, for example, durable
complete
responses in acute leukemia.
Since 1992, accelerated
approval
regulations have allowed the use of
surrogate
endpoints that are reasonably likely to
predict
clinical benefit. Accelerated approval may be used
when a new drug would provide benefit
over
available therapy. Accelerated approval also comes
218
with a requirement to do post-approval
studies to
confirm that the drug does provide
clinical
benefit.
During the last 10 years, three
drugs were
approved for treatment of advanced
hormone
refractory prostate cancer. Each of these three
approvals was based on clinical benefit
endpoints.
None of these drugs was approved under
the
accelerated approval regulations.
Most recent of these approvals,
that of
docetaxel in 2004, was based on
demonstration of
improvement in the overall survival. Overall
survival remains one of the most
meaningful
endpoints in controlled clinical trials
in cancer.
It reflects both the safety and efficacy
of a
treatment.
It is an obvious direct measure
of
efficacy and a longer overall survival,
also
provides a reassuring measure of
safety. A therapy
with significant toxicity and possible
mortality of
its own is unlikely to result in a net
survival
benefit.
219
Efficacy of docetaxel, in
combination with
prednisone was demonstrated in a
well-controlled
clinical trial by a significant
prolongation in
overall survival.
In the pivotal trial TAX-327,
two
different schedules of docetaxel
administration, 3
weekly and weekly, were compared to a
control arm
of mitoxantrone. Each of the 3 arms included
prednisone.
Cumulative dose of docetaxel
administration in the 2 study arms was
the same at
750 mg/sqM.
1,006 patients are enrolled in
this trial.
Primary efficacy endpoint was overall
survival.
This was defined as time from
randomization to
death from any cause.
Overall survival was
significantly
superior to the docetaxel given every 3
week arm
compared to the control arm mitoxantrone,
and the
results of every 3 week comparative arms
are
summarized in this table.
Median overall survival was
18.9 months
220
for docetaxel and 16.5 months for
mitoxantrone.
This was statistically significant.
FDA has accepted endpoints based on
measures of patient symptoms and other
non-survival
indices of disease morbidity. Marketing approvals
for mitoxantrone and zoledronic acid were
based on
non-survival endpoints.
Mitoxantrone, in combination with
prednisone, was approved in November of
1996. It
was approved for initial chemotherapy for
treatment
of patients with pain-related to advanced
hormone
refractory prostate cancer.
Its efficacy was shown in an open
label,
Phase III controlled clinical trial, 161
symptomatic patients are enrolled. Endpoint used
was palliative response. This endpoint was
prospectively defined. It consisted of a 2-point
improvement on a 6-point pain intensity
scale,
accompanied by a stable analgesic score
and
duration of improvement lasting at least
6 weeks.
A palliative response was seen
in 29
percent of the patients who received
mitoxantrone
221
compared to 12 percent in the control
arm. Median
duration of this palliative response was
longer for
mitoxantrone at 229 days compared to
53. Median
time to disease progression was
significantly
longer, 301 days compared to 133 days,
however,
this trial of 161 patients did not
demonstrate a
statistically significant difference in
survival
between the two arms. PSA decrease of 75 percent
or greater was seen in a significantly
high number
of patients in the mitoxantrone arm.
Zoledronic acid is a
bisphosphonate. In
2003, it was approved for treatment of
patients
with progressive bone metastases from
prostate
cancer.
Endpoints used in that trial
was a
composite endpoint of several
skeletal-related
events.
A composite endpoint can be useful when
disease manifestations are diverse. It can
increase the power of a study.
Previously, this endpoint had
been used to
measure efficacy of pamidronate for lytic
bone
disease in multiple myeloma and breast
cancer.
222
Several prospectively defined
skeletal
events were included in this composite
endpoint:
pathological bone fractures, spinal cord
compression, and surgery or radiation
therapy to
bones to treat a fracture, to stabilize
an
impending fracture, to prevent or treat a
spinal
cord compression, or for pain relief.
A change in the antineoplastic
therapy due
to increased pain was an added event specifically
for this prostate cancer trial.
Efficacy was demonstrated in a
placebo-controlled, double-blind trial of
643
patients.
There was an 11 person absolute decrease
in the proportion of the patients with at
least 1
SRE favoring zoledronic acid. Another measure of
efficacy was an increase in the median
time to
first skeletally-related event. This was 321 days
for the control and this had not been
reached for
the zoledronic acid arm.
Now, I will briefly present the
difficulties encountered in evaluating
treatments
of prostate cancer. These issues will be
covered in
223
depth by Dr. Raghavan.
In general, difficulties
encountered in
evaluating treatments of prostate cancer
stem from
several factors. These relate to the
characteristics of the disease itself,
characteristics of the patient
population, and the
prevalent clinical practices.
One disease factor that makes
it difficult
to evaluate treatment is the
heterogeneous natural
history of both the advanced and the
early stage
prostate cancer. Disease course is highly
variable
with diverse clinical manifestations.
At least until recently, that
is to say
until docetaxel approval, use of
traditional
endpoints, for example, overall survival
in
evaluation of treatment efficacy had been
of very
limited utility.
In this disease, on one extreme
in many
patients a rising PSA may be the only
sign of the
advanced disease. These patients do not
have any
disease-related symptoms, their bone
scans are
negative, performance status and quality
of life
224
are well preserved. Although the survival
experience of these patients can vary,
the vast
majority have a relatively long survival.
On the other extreme, there are
patients
who have rapidly progressive disease,
they have
disease-related symptoms, their
performance status
is affected by their disease, quality of
life is
impaired, and their survival is
shortened.
Clinical benefit of treatment
is now well
established for these patients.
Two characteristics of the
patient
population which make it difficult to
evaluate
treatments for advanced prostate cancer
are the
advanced patient age and comorbid
conditions.
Whenever you measure survival, and a
large number
of trial participants have a disease with
a long
natural history, the observed results are
confounded by competing causes of
mortality, and
interpretation of the observed results
can become
difficult.
Thus, the advanced age of the
vast
majority of the patients with prostate
cancer and
225
comorbid conditions they may have at that
age, they
can make conduct of a clinical trial and
interpretation of the results difficult.
These patient characteristics
are often
cited as an explanation for the inability
to show
clinical benefit in terms of overall
survival
prolongation both in prostate cancer and
other
advanced cancers.
However, in 2004, investigators were
able
to show overall survival advantage for
docetaxel in
two different clinical trials even though
they used
slightly different regimens. One can argue that it
was the lack of drugs with enough
activity that it
was difficult to demonstrate clinical
benefit in
terms of an improvement in overall
survival.
Finally, prevalent clinical
practices are
a factor which lead to difficulties in
evaluation
of
treatments for prostate cancer.
Currently, in
clinical practice, as well as during the
conduct of
clinical trials, treatment changes are
frequently
driven by changes in the PSA level, thus,
many
patients can go off study before any
clinical
226
endpoint of disease progression is
reached.
Subsequently, data on other
endpoints of
interest may not be collected at
all. Collection
of such data is necessary to eventually
define
clinical benefit from a treatment as well
as to
confirm the validity of a surrogate
endpoint.
PSA-based endpoint may be
acceptable
surrogates for anti-tumor activity of a
drug, for
example, in a Phase II clinical
trial. However,
reliable use of PSA-based endpoints as
surrogates
for clinical benefit in Phase III
controlled
clinical trials when two treatments are
being
compared, it remains to be defined.
This needs to be explored
further. A
surrogate endpoint that is reasonably
likely to
predict a clinical benefit can be the
basis of an
accelerated approval. However, the new
drug should
provide an advantage over available
therapy, and
the clinical benefit needs to be
confirmed
subsequently.
Thanks for your attention and I
would like
to acknowledge the contribution of all
these
227
individuals for this.
DR. HUSSAIN: Thank you, Dr. Mann. We
will hold all questions until the final
speaker,
Dr. D'Amico, and then we will open up the
floor for
discussion.
Our next speaker is Dr. Derek
Raghavan,
who is Chairman of the Department of
Hematology and
Medical Oncology at the Cleveland Clinic
Taussig
Cancer Center. He will discuss Towards a Consensus
in Measuring Outcomes in New Agents for
Prostate
Cancer.
Towards a Consensus in Measuring
Outcomes in
New Agents for Prostate
Cancer
DR. RAGHAVAN: It is always a pleasure to
follow Dr. Pazdur's introduction because,
as you
know, the FDA is characterized by
scholars of
Shakespeare, and I personally was
relieved that he
chose to quote from Julius Caesar rather
than from
Hamlet, because I thought he would have
probably
gone for the cheap shot of asking the
question to
pee or not to pee, but fortunately, he
didn't.
So, my task is to discuss some
of the
228
complexities that came out of the meeting
in which
our original plan was to try to achieve a
consensus
about what should be the new era of
evaluating
prostate cancer studies, and as Dr. Mann
has said
very elegantly, there are a number of
confounding
variables that make it difficult.
Probably the hardest thing is
that
prostate cancer spans such a broad
spectrum, and it
goes from a disease that unfortunately
can kill
people in less than a year to a disease
that can be
metastatic and which can co-exist in a
patient for
more than 10 years, and the key is to try
to
identify which variant of the disease one
is
dealing with.
As Dr. Mann mentioned, there
are the
additional confounding variables of the
advanced
age of the patients and the many symptoms
of aging
that go with them, and Dr. Eisenberger
and I were
just commiserating with each other that
having
worked together in this field for 30
years, we now
have most of the symptoms that our
patients have
acquired, and it's a sad thing, and the
point that
229
I make is to the best of my knowledge,
both of us
have normal PSAs, and yet we have aches
and pains
and sometimes failure to thrive and
fatigue, so it
can be really quite difficult to identify
the
specifics of the disease against the
background of
a well older patient.
Then, there is the phenomenon
of death
from competing risk, which happens in any
of the
studies that are relatively long.
Howard Scher made I think an
important
contribution and spent some time talking
about this
at our series of meetings of what he
terms the
states model and what many of us would
simply
identify as the staging approach to
prostate
cancer, and I think correctly Howard has
made the
point that there are many different
scenarios that
the FDA will need to address in
quantifying drugs
that are presented here.
There is the sort of
conventional testing
ground for new medications in prostate
cancer, the
patient with advanced conventional
metastatic
disease.
When some of us started practicing the
230
management of prostate cancer, the
typical patient
would have a large volume of disease with
narcotic-dependent pain, potentially
pathological
fractures, and that has changed over a
period of
time.
There is the question of
whether one has
had effective hormonal therapy, and with
some of
the newer regimens that are around, there
are data
that suggest that some of the newer drugs
don't as
effectively suppress hormones as some of
the
standards of care, and there are
compliance issues
and issues that relate to drug uptake.
Then, we are looking at earlier
stage of
disease when we are faced with using more
advanced
treatments. With the increasing microscope that is
focused on prostate cancer and pressure
from the
community to deliver the goods, patients
are
looking to find relapse at an earlier
stage, and
physicians are being faced with the
problem of
sometimes treating disease that they can
only
measure biochemically, which certainly
will have
changed the situation, and that leads us
to the
231
phenomenon of stage migration, which I
will return
to through this presentation - in brief,
changes in
imaging, changes in the use of PSA and
other
markers, and even a functional migration
in that we
are now tending to use quality of life
parameters
as another measure of outcome, so that
the
goalposts in a way have widened.
Normally, when I steal Howard
Scher's
slides, I apologize and act embarrassed,
but my
role is, in fact, to summarize
discussions that we
were involved in, so I steal these slides
with
absolutely no apology at all. There are only two,
Howard, of yours, so I am not actually
giving your
talk for you, although I will do it
perhaps a
little more elegantly and with larger
words.
So, I think an important point
that Howard
has demonstrated here is the concept of a
continuum
of disease from the initial prostatic
evaluation
through to advanced disease, and the
reality is
that a particular product can be used at
multiple
points through the course of the disease,
and thus
one would anticipate different types of
outcome.
232
One has even the situation for
the
asymptomatic patient where one may decide
to do
nothing and simply watch the patient in
the context
of a slowly evolving disease, and that
brings in
the biggest problem.
At the moment, there is a
vogue, an
affection for stable disease as a
rediscovered
category.
There are now a series of static drugs
where the claim is that these drugs
somehow
influence the natural history of the
disease by
making it more stable than it was before
the drugs
are used, and that may be a very
reasonable
concept, but it is a concept that is
somewhat alien
to the standard practice of oncology, and
what, in
fact, is a cause of concern is that there
may be
the potential for misinterpretation of
data when
one has the phenomenon of stage
migration, such
that one is looking at stability of
disease at an
earlier phase in the natural history of
the
disease.
So, that is where the question
of PSA as
an initial endpoint and quality of life
measurement
233
will come in.
Just to remind us all of the
scenario and
remembering that we have the world's
expert on AIDS
here, Dr. Alexandra Levine, who shared
prostate
cancer patients with me at USC, but just
to remind
her of the history that antedated her
involvement
into oncology, I would just like to
remind you that
the Nobel Prize for Medicine was awarded
to Charles
Huggins and Clarence Hodges, I think
Hodges being
the only urologist ever to win a Nobel
Prize, and
that was given for the demonstration of
an ability
to suppress the growth of prostate cancer
in dogs.
The models that we used in the
pre-1960s
era were essentially much cruder, but
were still a
good reflection of the disease as we know
it today.
They just reflected a more advanced
variant of the
disease going to Howard's states model,
the more
advanced end game part of management.
Human studies at that time, as
I
mentioned, were characterized by patients
with
large tumor cell volumes and symptoms to
go with
them.
Unfortunately, at the time, although they
234
were the best available, the endpoints
that were
measured were imprecise, they weren't
structured
ways of measuring the degree of
improvement of
pain.
We maybe correctly or maybe
incorrectly
said pain, yes or no. There was the acid
phosphatase measurement, which was
clearly an
imprecise one that correlated
occasionally, usually
Monday, Wednesday, and Friday with
disease
outcomes, but Tuesdays, Thursdays, and
Saturdays
didn't, and Sunday was in the eyes of the
Lord.
So, the reality of the
situation was that
we had markers that were unreliable and
didn't
correlate directly with tumor
volume. So,
ultimately, the one quantifiable endpoint
came to
be survival, and that stood the test of
time.
Now, as physicians spent more
time dealing
with patients with varying stages of
prostate
cancer, they started to look for
different
surrogates of outcome, and it was in that
period
that the National Prostatic Cancer
Project, one of
probably the most underappreciated useful
entities
235
that we have had in the U.S., actually
did a lot of
very important work, were able to start
to model
the concept of the variability of the
different
states, they just didn't call it that.
So, they identified the category of stable
disease within prostate cancer,
identified that
there was a variant that evolved slowly,
and then
set about trying to structure what
constituted
stability and were there different levels
of
stability and could you influence
stability in a
meaningful way.
In other words, if a patient
had absence
of progression for 6 months, was that
less good
than absence of progression for 12 months,
and the
logical answer to that would be sure,
provided the
progression was being measured in an
accurate way.
The whole situation became a
little more
complex with the very, very important
identification by Ming Chu and his
colleagues at
Roswell Park of the entity prostate
specific
antigen, which has totally revolutionized
the way
we think about prostate cancer. The truth of the
236
matter is that it has allowed us to start
to look
at this disease in a subclinical way.
The problem is that this has
had its own
complexities, and as we have used PSA
more and
more, we have come to understand that
there is the
phenomenon of release, so sometimes PSA
going up is
good, and sometimes PSA going up is bad,
and the
problem has been that with the passage of
time, our
ability to quantify outcomes has been
obfuscated by
a lack of understanding of this molecule
and its
production.
Once again, in the 1970s to the
1990s, the
availability of PSA led to stage
migration and
because it was being used for screening
purposes,
resulted in functional terms in a much
higher level
of awareness of the public of the entity
of
prostate cancer which heretofore had not
really
been a very well-known entity at all.
Bhupinder Mann has shown you
this snapshot
of the approvals, and this is simply to
remind us
of the parameters that we used for
approval in the
past.
237
Now, currently, there are a number
of
situations that bring pressure on all of
us to try
to come up with the goods, and which
certainly led
to some extent to the development of a
series of
meetings to try to structure our
assessment of
outcome of novel products, be they
cytotoxic or
cytostatic.
There is question that the
microscope is
on the community of patients and
physicians who are
involved with prostate cancer. There is a
requirement for us to do better than we
have done.
This is a common entity, it is being
diagnosed more
frequently. It may even be developing into
epidemic proportions.
It is not absolutely clear
whether that is
reservoir effect or a real finding, but
what is
absolutely clear is that in contrast to
the United
States, if we look at the Far East, in
Singapore,
in Hong Kong, in China, there is clearly
an
epidemic of prostate cancer and no one
knows why.
It is clearly more than just doing PSA
screening. It may have to do with
lifestyle and
238
diet, it could be a whole bunch of
things, but it
is quite clear that prostate cancer
incidence rates
are increasing rapidly, so we are going
to be faced
worldwide with an epidemic of this
disease and need
to be ready for it.
Currently, there is a new era
of stage
migration. We now have the PET scan,
which is being
rationalized as useful for the diagnosis
and
management of advanced prostate cancer.
At the symposium that we held
some months
ago, Dr. Steve Larson from Memorial
Sloan-Kettering
gave a very erudite discussion of the new
strategies of quantifying response using
radionuclide bone scans, tomography, and
the new
tools, so this is again allowing us to
look at both
outcome migration and stage migration in
a
completely different way.
As you have heard mentioned, as
I am going
to talk about, and I am sure Howard will,
as well,
there is a refinement in the
understanding of PSA
response.
So, at the present time, new endpoints
are being presented.
239
Clearly, there is an increased
refinement
of measurement of quality of life, and I
would like
to talk about that, because I, in fact,
am not a
great believer at least in using the
refinements of
quality of life measurement as an index
of
acceptance today. I don't think we are ready for
that.
The issue of absence of
progression for
some of the cytostatic agents I think is
going to
be perhaps the most controversial item
that we will
need to face today, and then the issue of
having
PSA, prostate specific membrane antigen,
PSMA, and
the whole concept of time-dependent
fluxes.
There was a time when we simply
said if it
goes down, that's good, now we are
starting to look
at time points and trying to interpret
what is a
significant time point - is a 50 percent
reduction
at 3 months better than a 50 percent
reduction at 2
months, and, if so, how much better and
what does
it mean.
So, ultimately, we have a whole
series of
different endpoints, and the key question
I think
240
that we need to address today is should
survival
still be regarded as the standard, and if
it isn't
the ultimate test, because it is
confounded by
death from other causes, because it may
be
confounded by a series of salvage
therapies, in
other words, a new drug may work for a
time and
then depending on the pathway that the
patient
follows, again going back to the state's
model, you
may
end up having different follow-on pathways of
treatment.
If survival isn't an ultimate
test, and we
decide to bring in quality of life with
some of the
surrogates, will they lead us to new
treatments
that actually alter outcome.
The big concern about the
screening debate
today has been we are not still sure
after many
years of PSA screening, are we actually
saving
lives or are we just moving the
diagnostic point.
So, one of the things that I think
is a
concept that most people who treat
prostate cancer,
be they surgeons, radiation oncologists,
medical
oncologists, or palliative care
physicians,
241
whatever point in the disease, I think we
would all
recognize that for the different states
of the
disease, the aims are going to be
different, and
this is essentially taken again from
Howard's
presentation although it is not his slide,
just
identifying the different aims and
outcomes that
relate to each of the stages of the
disease.
Clearly, the focus will change
from when
there is very little disease, trying to
stop it
from evolving into something that is
life-threatening versus when there is
advance to
hormone refractory disease, then,
actually feeling
that you are playing what might be an end
game and
trying to prolong that for as long as
possible.
So, clearly, acceptance of drug
X for the
patient who has PSA-only disease with no
bone scan,
no physical findings, no symptoms, the
nature of
what will influence the acceptance of
that entity,
the force must be different from what
will
influence the acceptance of an entity on
your
right, in other words, advanced hormone
refractory
disease that is symptomatic and which has
the
242
potential to kill a patient in three to
six months.
Again, for those of you who
aren't
familiar with prostate cancer, this gives
you a
sense of what a protein disease it is,
and even
today, in a high end clinical practice
such as at
Memorial Sloan-Kettering or M.D. Anderson
or the
Cleveland Clinic, or any of the places,
Hopkins,
that have major prostate cancer programs,
people
every day of the week will see patients
who happen
to come in, not knowing about prostate
cancer and
therefore having allowed the disease to
get totally
out of control with a whole series of
constitutional features that can cause
hemorrhage,
that can cause pruritus, it can cause
weight loss,
it can cause symptoms related to the
sites of
metastatic involvement, back down to the
patient
who will come up after a radical
prostatectomy or
radical radiotherapy with a PSA that has
gone from
0.05 to 0.1, so it is very difficult for
the FDA to
look at this, in my opinion, as a unit
entity.
So, one of our tasks will be to
try to
give advice to ODAC about how to
structure the way
243
of presenting a framing reference.
This is some work from Don
Newling from
the United Kingdom, and it is just
illustrative of
just how big an impact stage of presentation
can
have, so this was looking at a series of
his Phase
II trials where he looked at simple
parameters that
resulted in the presentation of patients,
and as
you can see, the median time from
progression to
death, for example, for just a PSA
increase was
dramatically different from the time
frame for a
patient who presented with a liver
metastases.
Now, today, there is a new
nuance that we
understand, and that is that many patients
who
present with liver metastases don't
actually have
classical adenocarcinoma of the prostate.
Today, if you summarize the
folks around
this table who see prostate cancer and
treat it,
and ask the question what do you think
about when a
patient presents with liver metastases in
isolation, everyone will tell you I think
about
neuroendocrine small cell variant
carcinoma.
It may not be that, but it is
almost
244
certain that many of the cases over the
last 20
years, that have shown response in the
liver with
prostate cancer, have probably been of
that
variant.
So, that is a novel entity and again
relates to a histological migration with
time.
So, one of the things that we
need to deal
with is the impact of earlier
intervention and what
it does to survival curves, so, for
example, we
have heard mention briefly of two pivotal
studies
that were reported in the New England
Journal of
Medicine earlier this year, one led by
Dr.
Eisenberger, who is here, and one from
the
Southwest Oncology Group and its friends,
and the
principal investigator of that was Daniel
Petrylak,
and I was involved in that publication
myself.
So, this was a survival curve
that was
yawned at by the press. They looked at the
figures.
They said p value of 0.01, Taxotere
better than mitoxantrone, big deal, and
if you look
at that survival curve, I think you have
to accept
that this is not a home run. It was the first or
one of the first two trials that showed a
survival
245
benefit for one drug over another, and
that is
important.
It was very similar if we go
back 15 years
in the history of breast cancer to the
sort of
figures that we saw in advanced breast
cancer, that
went on to help us develop therapeutic
strategies
of adjuvant care.
In fact, this type of study has
led to the
development, for example, of SWOG-9921, a
randomized trial that looks at hormones
plus or
minus chemotherapy for patients with
locally
advanced prostate cancer, but accepting
that it's
an interesting paradigm, those curves are
not very
impressive to look at.
Just note that the number of total cases
is 670 and keep that in mind.
Now, if you want to consider
the surrogate
outcomes, that is way more attractive,
and this
relates to the 50 percent PSA reduction
that was
identified, and blind Freddie could
identify the
difference on the left of docetaxel
versus, on the
right, mitoxantrone, and that is the
stuff that
246
headlines are made of.
So, we decided that we would do
some
modeling in the Southwest Oncology Group,
and this
is work that was done by Catherine Tangen
[ph], who
is a lead biostatistician in the GU
Committee,
Genitourinary Cancer Committee, and she
did some
very interesting modeling where she
looked at
survival by a surrogate, which was 50
percent PSA
reduction at 3 months, and that actually
is quite
impressive.
If you had treatment A versus
treatment B,
you would say home run, that's a really
big
difference. So, here, what we are identifying is
that a surrogate outcome is actually
reflective of
an important endpoint, and if we make it
a little
more interesting, and we then put in the
responses
broken down for the type of treatment,
you will see
that again the key difference relates to
surrogacy,
but here is the problem.
Let's go back for a minute and
add the
numbers of risk, and what you will notice
is that
the number is 520 patients would had
serial PSA
247
values, 520 out of nearly 700 cases, so
what that
means is that we have lost from the
denominator a
large number of cases.
The reason that is important,
if you go
back to here, is look at the number of
deaths in
that study, and the number of deaths,
while clearly
important, in absolute terms is not all
that
dramatic.
So, the point that I wanted to
make in
taking you through this circuitous
argument is that
we need to be extraordinarily careful
when we leap
to a new surrogate, if we don't set the
framing
reference of did we lose patients by
using that
surrogate and what happened to the
patients that we
lost that might have influenced the
outcome, in
that situation we need to be very careful
before we
set new standards.
So, my plea today is that we
shouldn't be
setting new standards. I think we should be
identifying endpoints that require
further study
and that the FDA might be able to require
in the
trials that are presented to them. I think the FDA
248
has the potential to influence medical
history here
by making certain demands.
So, my view is we are not ready
for prime
time changes to outcome, but I think we
are ready
to look for new indicators of outcome.
Now, measurement of quality of
life has
been particular popular, and
unfortunately, somehow
one is cast in the role of being
anti-patient if
one says that one doesn't like quality of
life
measures as a finite indicator.
I hope that my clinical career
hasn't
suggested that I am anti-patient, because
I see
myself as a substantial patient
advocate. I just
don't happen to think that this set of
measurement
tools is ready for interpretation yet,
and the
reason, I have summarized here. There is
difficulty
of assessing response.
Within the stable category, we have a
widening of the goalposts and the problem
is that
measures of quality of life, as I
mentioned, as Dr.
Eisenberger and I creak through our
coffee and
biscuits that he was kind enough to bring
to my end
249
of the table, those measures of quality
of life are
confounded by the age and intercurrent
problems of
the patients.
They can relate to age, they
can relate to
therapy, they can relate to a whole bunch
of
things, and as we look at the data that
are
available to us, there is clearly a
dichotomy
between objective measurement, subjective
measurement, and whatever in that frame
of
reference PSA constitutes, which is
somewhere I
guess in the middle, but closer to
objective. I
think the key problem is that the optimal
technology has not yet been defined.
Now, what is good is that we
have, in
fact, begun to rationalize our approach
to this.
So, again, I want to be very clear that I
am not
opposed to developing the
methodology. I just see
it as still work in progress.
These are some of the patient
reporting
domains that will come up again and again
in the
different quality of life assessment
schemes, and I
am not going to read them, they are all
provided in
250
the handouts that are available, but they
relate to
different ways of looking at a patient
and asking
the question how do you feel.
There are structured scores
like the
McGill Melzack, which involves looking at
present
pain intensity, and there it is an
attempt to
mathematize the assessment of
outcome. The problem
is it is not yet clear what is the best
way of
using this tool.
It allows for a 2-point
reduction, which
is the best type of reduction. Ideally, if you
have a 2-point reduction on the McGill
Melzack
scale from 2 down to zero, that is a big
win. But
what is the impact if you happen to have
a tough
Anglo Saxon dockworker who has a high
pain
threshold and claims only to have one
level of pain
at the beginning and he goes to
zero. Is that
somehow less important, and the answer is
we don't
know.
What if there is no pain, but
there are a
whole series of bone metastases that are
present,
what is the impact of having no change in
pain?
251
So, my point is simply that all the models
that I
have summarized up there address that
dichotomy
very poorly.
The problems include the impact
of
baseline variables, as I have said, we
don't really
know how to score them, we have got no
good model
for
dealing with missing data, in other words, the
patient who doesn't fill in one of these
scales, is
he too sick to fill it in, is he so well
that he
couldn't be bothered, is he not bright
enough to,
is he too busy? In other words, we don't know how
to integrate that into our assessment of
this
endpoint.
The statistical analysis is
another
problem, do we look at absolutes, do we
try to
construct an area under the curve for the
number of
days spent in agony versus the number of
days spent
doing wonderful things.
We don't have a good mechanism,
we don't
even have a model, such as looking at
receiver
operating characteristic curves, which we
use
sometimes when we are not quite sure
where a cut
252
point appears because we don't know how
to define
the cut points properly.
So, our confounding variables,
to add up
to that, is what the patient knows. We have
tremendously educated patients, so you
can
have--and I am sure the physicians on the
panel
have seen this--a patient who comes in
and you say
how are you feeling, and he says great,
and you
say, well, I am glad because I have some
bad news,
your PSA just went up 50 points, and they
walk out
feeling horrible.
It is not that there is
anything foolish
in that, it's that knowledge of PSA is
integrated
into the model, and so it confounds our
ability to
assess it.
There are clearly differences
in the way
different racial groups and different
societal
groups address pain, death, dying,
cancer, and our
models don't allow for those differences
of
perception.
So, then the question is what
does that
leave us with, and I thought I would use
an
253
illustration which was the one that Dr.
Mann
mentioned, of how mitoxantrone was
approved.
Studies of mitoxantrone in the
Phase II
fashion dated back to about 1982-83. I think in
Australia we did one of the very early
ones where
the assessment of quality of life was
whether you
could drink a beer. That didn't translate to the
USA, but it was a pretty good endpoint as
far as I
was concerned.
More recently, Ian Tannock, who
has one of
the leaders in assessment of quality of
life with
the Canadians, did a randomized trial
comparing
mitoxantrone plus prednisone versus
prednisone
alone, a small number of patients, and
the primary
endpoint was palliation with a secondary
endpoint
being survival.
Now, this survival curve has
been
interpreted universally to show that
mitoxantrone
doesn't improve survival, and that is a
fundamental
misunderstanding of the design of the
study,
because in truth, this was a relatively
small
study, the p value, in fact, reflected a
trend in
254
favor of mitoxantrone for survival, and
the key
issue was this study allowed crossover,
and so it
allowed a patient who was on prednisone,
if he
progressed, to cross over to
mitoxantrone.
My interpretation of this study
is
that--and it has influenced my practice
heavily--is
there isn't necessarily a rush to run to
chemotherapy in a patient if you have a
relatively
indolent pace of disease.
But what influenced the FDA, I
think
correctly, was this chart, which was an
attempt to
look at area under the curve for quality
of life,
and what it showed is that despite the
toxicity and
cost of mitoxantrone, the patients who
received
mitoxantrone front line had a better quality
of
life.
They did a series of other
assessments
that related to cost economics and
identified that
it was cheaper for the Canadian
community, that
there were patients going back to paying
taxes
sooner, they were spending less time
dying in
hospital, so this was a drug that
actually did
255
influence outcome.
Dowling and colleagues in the
Annals of
Oncology, looked in a little more detail
at the
whole issue of studying that trial, so
this was a
retrospective analysis, and what it
showed very
clearly was that while mitoxantrone had
been quite
useful, palliative response did not
predict for
survival, and there were major
discontinuities
between quality of life measures, PSA
response, and
ultimate survival.
So, that should make us very,
very
cautious about interpreting or overinterpreting
data.
I always think it is a good thing to suck up
to the Chair, so I did want to show this
slide that
I stole without apology from Dr. Maha
Hussain at a
previous time. Maha, thank you for providing the
slide.
I have jazzed it up a little bit.
The point of this slide is to
demonstrate
simply that the issue of variability of
quality of
life is not an inherent characteristic of
the agent
mitoxantrone. These are a series of drugs that
hold up a cell cycle in a fashion
analogous to
256
Taxol or Taxotere, and what it simply
shows, as you
look down at the columns on the right, is
that
there is a variability of survival, there
is a
variability of pain improvement, and
there is a
variability of PSA response.
So, it simply says the Venn
diagrams of
assessment of outcome do not overlap very
well
irrespective of which agent is being
used.
Dr. Eisenberger, at our
symposium,
presented data from TAX-327, one of the
two pivotal
trials that seems to have been
responsible for the
approval of Taxotere for prostate cancer,
and this
is important work.
I am showing this just to show
that both
studies give us the same message. If we look at
the different indicators of outcome,
again looking
at the denominator of cases for which data
are
available, you can see that there is a
really quite
dramatic heterogeneity of interpretation,
and
depending on what you want to draw from
this set of
data, you can draw pretty much whatever
you wish.
I think there is a general
consensus that
257
in each of the parameters, docetaxel won
and that
the difference wasn't all that great.
This may be a good time to quote
Benjamin
Disraeli, one of the former prime
ministers of the
United Kingdom, who was quoted to say,
"There are
lies, damn lies, and statistics,"
and that may well
relate to the way the confounding
difficulties we
have in interpreting data from the
prostate cancer
environment.
I think this is an important
study to show
because it shows how the community can
make serious
mistakes.
Now, this was an important study
published by Tom Beer and his colleagues
from the
University of Oregon, and they looked at
the
combination of Taxotere and a vitamin D
analogue,
and this hit the headlines in virtually
every major
publication in the USA.
I was puzzled because this was
a Phase I
study, and it was a Phase I study in
which there
were indices that I have summarized
there. They
identified the ability to achieve PSA
response,
survival was not an endpoint, because the
numbers
258
which are small, and it was a Phase I
study, and
what was puzzling was that there was a
complete
discontinuity between the different
indicators of
patient-driven outcome, and yet the press
heralded
this as a major breakthrough.
So, I think what it shows us is
that we
have to be very careful in interpreting
quality of
life data.
Finally, Tannock and his team
have also
addressed in specific ways the impact of
placebos
in oncology, and I think it is always
good to
remind ourselves something that we know,
but that
we sometimes forget in dealing with
prostate
cancer, which is that the placebo effect
can
certainly have an impact on quality on
life.
It generally doesn't improve
performance
status and it generally doesn't improve
survival,
but it does alter quality of life, so
that means
that we need to be looking at the quality of life
assessments very carefully and assessing
them in
the context of the interpretation of the
placebo
effect.
259
So, my take on patient reporting
of
symptoms is that if we incorporate them
into the
evaluation of new agents, it will lead to
an
additional stage response migration. These will
one day be very useful tools in the assessment
of
prostate cancer, but I think that the
tools that
are extant at the moment are not ready
for prime
time. We certainly need to be
incorporating them
into our assessments, but they shouldn't
be the
drivers of decisionmaking.
PSA response versus symptom
response
versus toxicity lead to a disconnect, and
that may
sometimes be because big trials don't
allow for a
detailed structured assessment of what
are the
factors causing that disconnect.
So, it leads me to feel that
this area
should be regarded as work in progress by
the FDA
in its formal and structured evaluations
of new
products.
Survival has been the standard.
It is
my personal belief, supported by some
data that are
not yet incontrovertible that time
dependent PSA
kinetics will ultimately be a very useful
surrogate
260
of outcome, but we will need to apply
Howie Scher's
states model such that we acquire data
for time
dependent PSA kinetics in a series of
different
clinical contexts.
One size fits all simply won't
work in
giving us a meaningful evaluation of new
products
that come into the marketplace, and most
particularly those that are cytostatic in
their
type.
We will still need to do
well-powered,
large, carefully designed, structured
randomized
trials, and those trials should require
surrogates
to be evaluated including quality of life
and
patient reporting, PSA response, PSA time
dependent
kinetics, perhaps markers of bone
turnover, and we
shouldn't throw out survival just because
it may be
a confounded variable.
Ultimately, we haven't figured
out an
optimal way of assessing the cytostatic
drugs. We
spent a lot of time at the symposium
discussing
those, and I am figuring Howard will
probably talk
a little about that. I feel personally that this
261
is work in progress, so I have stayed
away from
putting up the assessment of cytostatic
drugs in a
structured fashion, because I think we
are still
learning how to do that.
Ultimately, I think we are not
ready for
definition of a new era, but I think the
FDA is
very well positioned to demand certain
things of
the companies and the agencies that
produce new
medications to allow us to finally define
what is
the new era in prostate cancer treatment.
Thank you.
DR. HUSSAIN: Thank you, Dr. Raghavan.
Our next speaker is Dr. Alison
Martin from
the NCI.
She will be addressing the NCI's
Portfolio of Prostate Cancer Treatment
Trials.
NCI Prostate Cancer Treatment
Trial Portfolio
DR. MARTIN: Good afternoon, Madam
Chairman, members of the panel, Dr.
Pazdur. Thank
you for the invitation to present.
I was considering how to be
useful to
these proceedings since many of the
investigators
that my program, the Cancer Therapy
Evaluation
262
program, funds through the cooperative
groups are
here, have reported their trials in
prostate
cancer, including with surrogate
endpoints and
including today.
So, I decided to step back and
focus on
our program as a capacity to further
address the
questions that come up in these
proceedings and at
other times. I have talked myself into the
possibility that our program is at a
crossroads in
the sense that we have approved more
concepts this
year for prostate cancer treatment than
any other
year in the past decade, and that we have
seen more
hypothesis generating for surrogates than
at any
other time.
So, I would like to encourage
us all to
think about how we can maximize the
capacity across
all of these trials.
Currently, I think we are
standing from a
position of strength and weaknesses. With regard
to some of the strengths, there are a
number of
randomized treatment trials that are
mature, which
provide us with well-defined cohorts,
high quality
263
and long term follow-up and defined
treatments.
We heard about some of them a
year ago at
the PSA Workshop RTOG 92-02, which Dr.
Sandler has
reported on, and we will hear again from
Dr.
D'Amico, which looks at PSA doubling time
as a
surrogate for survival in high-risk,
early stage
patients.
You have already heard and will
hear again
later this afternoon about the two
trials, SWOG's
9916 and Aventis-sponsored TAX trial that
led to
the approval for docetaxel, and by
finally
identifying a treatment which had an
impact on
survival in the randomized setting, it
provided an
opportunity to look at surrogates across
arms and
across trials.
Separate from the randomized
trials, there
are significant longitudinal databases
from certain
cancer centers with large cohorts and
CaPSURE/CPDR.
There are limitations
also. You have
heard from Dr. Raghavan quite eloquently
about the
population issues and the heterogeneity,
coupled
with stage and assay migration. There are also
264
design issues, which is that most of the
randomized
trials weren't prospectively designed to
ask a
surrogate question or consider the power
associated
with that.
Furthermore, the schedules for
the
collection of PSA or other intermediate
markers,
such as bone, may not have been
sufficiently
specific.
Even if it were within one trial, it may
have differed across the trials.
There have been treatment
issues limiting
us in our questions and answers. One, the fact
that some treatments, for instance,
hormones can
interact with the surrogate of interest,
or that
there has been a lack of effective
treatments to
allow validation of the surrogate's
association
with survival.
Now, I would like to move from
separate
from limitations of individual
databases. Once we
have identified a database that may be
contributory, there are difficulties we
have
experienced in terms of analyzing those
databases
in a timely fashion using the same
surrogates of
265
interest.
It is rare that people turn
over their
databases to someone else of whom it is a
priority,
so it requires a collaboration which is
sometimes
difficult to arrange and perhaps best
thought of
prospectively.
Other trial design issues,
whether we are
looking at data mining existing databases
or
looking forward to how we should consider
the
designs that are coming up this next
year, or
whether we want to ask questions about
PSA as a
prognostic factor, as an eligibility criterion
to
make our cohort more homogeneous, or to
choose a
high-risk cohort to allow us to arrive at
an answer
sooner.
Do we want to use PSA as an
outcome
measure, and, if so, which outcome? Do we want to
use
it as an indicator itself of cure, for
instance, in an initially diagnosed
patient treated
with a radical prostatectomy who either
did not
nadir or has a return of the PSA to a
certain
level, is that sufficient to tell us that
the
266
physician prescribed treatment, which was
intended
to be curative, had failed, or do we want
to ask
whether even though they were not cured,
we need to
know how this correlates to survival, does
that
depend on the adjuvant or neoadjuvant
treatment
given, and the risk classification.
Are we interested in PSA as it
correlates
to some other measure of clinical relevance,
such
as those listed on the slide, and then
which PSA
parameter are we to use? Once we choose, what is
the magnitude of change that we think
will be
relevant and the strength of association
with the
outcome of real interest.
Potential opportunities in the
near
future.
We have approved 6 and there perhaps will
be a 7th later this year, treatment
concepts, and
we expect actually they may open in the
same year
that they are approved due to a number of
new
processes, one, the collaboration with
the FDA at
the time of concept approval, and also
our
collaboration with investigators and the
generation
of the protocol. Rather than holding our review to
267
the end of the process, we are integrated
into the
process.
Of these approved concepts,
they will be
accruing in each of the clinical states
that the
previous speakers have mentioned. I have taken the
liberty of borrowing the clinical state
slide from
both Drs. Raghavan and Scher, and
inserted the
pending trial next to it for ease of
reference.
The goals are as previously
listed with
some of the goals added for the cohorts
that have
clinical metastases, either non-castrate
or
castrate.
Although I didn't list survival
of
prostate cancer, specific mortality is a
goal in
the first two boxes, and they weren't
previously
either, it should be stated that, of
course,
survival is important when any
intervention is
given.
It is just that there are also
comorbidities and competing causes of
death and
nearer term outcomes that may be relevant
also.
In localized disease, there
will be a
trial with hormone therapy coupled with
268
docetaxel-based regimen in two
cooperative groups.
In hormone-resistant rising PSA state,
there will
be a vaccine trial, and as currently
planned, while
survival will be collected as a secondary
endpoint,
the primary endpoint is the incidence of
clinical
metastasis.
The other trials are androgen
deprivation
therapy with a backbone of docetaxel, and
lastly,
in the population that showed the
docetaxel had a
survival benefit, the addition of either
bevacizumab or Atrasentan.
In conclusion, these are some
of the
strategies we have thought of and we
would welcome
other comments and suggestions on how to
maximize
the return from these trials.
Number one, of course, nesting a surrogate
question into the therapeutic
trials. There are
probably still databases, well, I know
there are
databases that could be mined for
hypothesis
generation of surrogate endpoints, but at
any rate,
can we prioritize the most important, if
it's PSA
response by 50 percent at 3 months, so be
it.
269
Are there others, how many can
we
incorporate prospectively without
suffering from
multiple comparisons, one, two, three?
Can we, while we are looking at
surrogacy,
compare it to survival, but, as well,
some other
intermediate endpoints of interest?
Separate from embedding a surrogate,
can
we systematically create a comprehensive
database
for subsequent interrogation, so that if
our PSA
definitions change or we are interested
in some
other question, we can interrogate the
database
across trials, not just within trials?
To the extent possible, can we
harmonize
the amount of PSA data collected prior to
treatment
to look at new risk classifiers? Can we
standardize when they are collected, when
bone
scans are collected, so that we know when
there is
time to clinical metastases in a more
rigorous way?
Do we want to know when a
patient becomes
castrated, if they have been treated with
hormones?
There will no doubt be, in the
future,
more informative markers, although we may
not know
270
exactly which ones they are now, and to
the extent
possible, we would like to encourage
specimen
banking depending on the stage of
disease, blood or
tumor.
Lastly, two other partners that
would be
helpful to our efforts right now are to
prospectively identify what industry
trials are
relevant to the clinical states, and try
to
harmonize our schedule of collection of
data.
We are opening six or seven
trials this
year.
That certainly does not represent very many
in each clinical state, and we would like
to work
with our industry partners and the FDA to
encourage
industry.
Lastly, the Cancer Diagnosis
Program has
an initiative PACCT, the Program for
Assessment of
Clinical Cancer Tests. They have worked with
breast cancer field and color cancer to
identify
new risk classifiers, and they have made
a
commitment this year to convene a
strategy working
group to further identify trial designs
and
questions with PSAs and other markers.
271
With that, I will
conclude. Thank you.
DR. HUSSAIN: Thank you, Dr. Alison.
Our next speaker is Dr. Howard
Scher from
Memorial Sloan-Kettering. He will discuss similar
endpoints dealing with accelerated
approval for
clinical trials in castration
resistant/hormone
refractory prostate cancer.
Toward an Endpoint for
Accelerated Approval
for Clinical Trials in Castration
Resistant/
Hormone Refractory Prostate
Cancer
DR. SCHER: Thank you very much.
I won't try to mimic Derek's
accent, but I
will echo some of the same themes.
What I think is becoming
apparent from the
previous presentations is that we are, in
fact, in
a position to ask the questions which
will allow us
to better understand different intermediate
endpoints, because for the first time, we
are
actually conducting trials that are large
enough
and enroll a sufficient number of
patients to
address meaningful questions.
So, just briefly to summarize where
we
272
have been in terms of outcomes
assessment, we all
recognize that the manifestations of
prostate
cancer are very, very difficult to
assess. The
clinical realities are that PSA levels
guide what
we do in clinical practice.
We are now faced with the
challenges, PSA
response outcome or progression measure
which is
reasonably likely to predict clinical
benefit and
form the basis of an accelerated approval.
I would like to argue that
these trials
can be designed, but before we can
actually say
anything about the rule of PSA in outcome
assessment, we actually need to
prospectively
design the trial, as you have heard from
previous
speakers, in which the endpoint, based on
the
marker, is embedded.
So, I would like to think a
little bit
more in terms of the disconnect that has
been
discussed earlier in terms of PSA response,
symptom
assessment, and effects on survival.
All of these can be important
clinical
endpoints, and if we start thinking about
treatment
273
objectives across clinical states, we can
really
divide them into two categories, which I
will call
eliminate/relieve versus prevent or
inhibit
progression.
If we start thinking about the
patients
who have progressed post-hormonal
therapy,
so-called castration resistant or
hormonal
refractory state, we are really now
dealing with
two discrete populations, and they
represent
patients who have received hormonal
therapy without
any evidence of clinical metastasis on
physical
examination or on an imaging study, the
so-called
rising PSA castrate state, and those
patients who
first received hormonal therapy at the
time of
objective detectable disease on an
imaging study or
physical signs or symptoms of disease,
which we
have called the clinical metastasis
castrate group.
I will be focusing most of the
discussions
on those patients who have overt
metastasis at the
time hormonal therapy was initiated,
although
certainly the discussions will hold for
patients
with a rising PSA.
274
What we are dealing with again
is the
battle or race between death from other
causes,
which is inevitable, versus death from
disease,
which is what we are trying to prevent.
So, if we think about patients
really in
two categories, if there are
manifestations
present, we will use those manifestations
to assess
a response measure designed to either
eliminate a
symptom, relieve or control it.
If it is not present, we can
think in
terms of how do we prevent it from occurring
in the
future, and here the risk assessment
models are
very important in terms of how do we know
that the
patient is likely to need therapy for a
specific
event, and we have a very unique
opportunity to
data mine some existing databases with
regards to
eligibility for trials.
If we think about what the
outcomes are as
you are sitting with the patient or
explaining a
trial to your colleagues, you would like
to be able
to say that what you have assessed is
clinically
relevant and of tangible and concrete
benefit, and
275
obviously, we will factor in the risk/reward
ratio
before we think about therapy.
Looking back at the approved
drugs, you
can see how this eliminate/relieve or
prevent
objectives has been played out. The
bisphosphonates, radiopharmaceuticals,
chemotherapy, the original approval of
mitoxantrone
and prednisone were based on response
measures that
showed the elimination or relief of
symptoms.
We can think of delaying
symptoms or
change in therapy, skeletal-related
events in terms
of a progression endpoint, and even death
from
disease is a progression endpoint because
you are
preventing death from cancer, but none of
these
approvals were based on measure of tumor
progression, and none of them were based
on a
post-therapy change in PSA.
So, we think back now in terms
of
eliminate/relieve. We are thinking about the
manifestations of disease that are
present, how we
relieve those manifestations, a response
algorithm,
and figure out what they mean.
276
It was interesting looking
across our own
series of patients at MSKCC treated with
chemotherapy versus the two recently reported
SWOG-9916 and TAX-327 in terms of the
frequency of
the different manifestations of prostate
cancer.
As you can see, the frequency
of
measurable disease is on the order of 20
percent.
There is a component of patients with
visceral
metastases. Arguably, these have a worst
prognosis. Many of the so-called nodal sites we
are looking at are actually very small,
and one can
argue what their clinical significance
is,
particularly when you are looking at the
changes in
size.
The dominating theme in this
patient
population is osseous metastasis and a
rising PSA,
and symptoms are variably reported, and Dr.
Raghavan gave a very elegant discussion
of the
issues surrounding quality of life, but
about 35 to
40 percent of patients will have some
symptoms
which are recorded as significant, but
again the
dominating symptom complex that we are
treating,
277
trying to relieve or prevent from
recurring relate
to complications of bone disease.
What are the outcome
measures? If you are
looking at disease in the primary site,
there are
no defined criteria. For soft tissue disease, we
have been mandated to use RECIST, which
has
problems because it relates only to your
relatively
unique proportion of the symptoms of
prostate
cancer.
It does not address issues related to bone
metastasis or PSA.
For bone metastasis, there is
no standard
criteria for response, and I will go
through some
of the post-therapy PSA change
metrics. In terms
of assessing quality of life, we always
feel better
if there is pain relief, but we also like
to see
what are corroborating domains, that is,
the
patient was more mobile, more active,
slept better,
less constipated because of analgesic
uses, and we
have all pretty much agreed in the
community, if
you will, that the group categorizations
of CR, PR,
and stable disease are really of little
value when
it relates to clinical trials.
278
So, thinking about the
post-therapy PSA
endpoints, one can look at decline, no rise or
fall, undetectable, normalization. Some of these
are relatively infrequent occurrences
unfortunately
with our available therapies, so most of
our
reports have focused on either a decline
by a fixed
degree, most reporting 50 percent, or
more
recently, no rise or no fall at a fixed time
point,
but whatever decision rule one is looking
at in the
Phase II setting will vary depending on
what type
of drug you are studying.
The differentiating agent, for
example,
may make the PSA go up before it goes
down. The
cytotoxic drug may arguably make the PSA
go down.
Otherwise, it is likely to be
ineffective, but
whatever response measure is used in most
criteria,
the change that you see is required to be
detected
over a period of time.
There was a consensus meeting
in the late
1990s.
A consensus was described for a PSA
response, which required a 50 percent
decline from
baseline, and as you have seen here, in
this
279
particular illustration, the decline was
confirmed
on multiple occasions.
The reporting standard has
become 50
percent or greater decline as a "PSA
partial
response," which is confirmed by a
second value
four weeks or more apart, but even within
these
criteria, there was recognition that
there are
other issues of relevance, as stated,
different
endpoints can also be reported.
Time to PSA progression and index of
the
durability of the response was of
interest, and in
order to be considered in a response
category,
there could be no evidence of clinical or
radiographic progression, again arguing
that other
manifestations of disease must still be
monitored.
Looking for associations of PSA
decline
and survival, again, a 50 percent decline
versus no
50 percent decline. These particular analyses were
done using a landmark method, that is,
the patients
had to live a period of time before
survival
distributions were analyzed, and these
results were
analyzed on an independent data set, but
in both
280
situations, where there was a 50 percent
decline or
no 50 percent decline, no rise versus
rise, again
at 12 weeks, there did appear to be a
survival
benefit for the patients who achieved
this
endpoint, and, as illustrated, several groups
have
shown this.
More recently, other measures
are being
considered, a variety of metrics. In this case, as
I am sure Dr. D'Amico will discuss
further, the
ratio of the post- versus pre-therapy PSA
slope,
but with the consistent theme that one
sees that
regardless of the metric used, these
trials are
reporting a difference in survival based
on the
outcome measure.
So, clearly, we are at the
point now where
the associations between a PSA decline
have been
demonstrated. This makes sense. If you are
studying a cytotoxic drug, you kill
cells, PSA
should go down.
This may not apply, as Dr.
Raghavan
mentioned earlier, to non-cytotoxic
agents or, for
example, a drug directed at a component
of the
281
metastatic process, for example, an
angiogenesis
inhibitor or a specific bone targeting
agent that
may not necessarily kill cells.
But missing in all these
analyses were
positive randomized trials to explore the
surrogacy
questions.
I won't detail these trials,
these have
been reported before, and we are all
familiar with
them.
Suffice as to say that in 2004, there were
two trials reported which did show a
survival
benefit, which allowed the exploration of
whether a
specific PSA outcome measure was
associated with
survival.
Again using various criteria
for
surrogacy, in this case the Prentice
criteria, Dr.
Petrylak and his colleagues asked the
question
whether achieving any PSA value--it could
be a
single value--below 50 percent of
baseline was
associated with survival, this performed
in the
context of the SWOG-9916 trial.
Again, as shown earlier by Dr.
Raghavan,
there was a first qualification required
that there
282
be a survival benefit for therapy. Looking again
at the association between the 50 percent
decline
and no 50 percent decline, a significant
difference
of 50 percent improvement if one is
looking at the
survival distributions.
When one accounts for the 50
percent
decline, the treatment effect
disappears. So, this
would appear to satisfy the Prentice
criteria, but
what has been misinterpreted is whether
or not
these results can, in fact, be
extrapolated to
other trials, and the answer is no, this
would
apply only to this trial, and it may not
necessarily be applicable to other
therapies.
But it did suggest at least for
this
specific treatment that a 50 percent
decline from
baseline could be used as a surrogate for
survival,
but again, we do not have multiple trials
in which
to address this particular question, and
at this
point it could only be listed as a
hypothesis.
So, TAX-327 was like was
reported, showing
a similar PSA response rate as we
discussed, and in
this particular trial, although the PSA
response
283
rate as reported was identical, there was
only a
survival benefit demonstrated for the Q3
week arm.
For patients who received weekly therapy,
there was
no difference in overall survival. So,
this raises
the question as how much survival is
explained by a
post-therapy PSA change. In order to be a true
surrogate, you like all of the survival
to be
explained by the post-therapy PSA change.
This led us to look at what is
the
association between time dependent
changes in PSA
and relative risk of death. This was again a
retrospective analysis of patients treated
in Phase
II trials.
You see the risk of death for a
very low
PSA appears to be higher than patients
with a
moderate level PSA, as illustrated by the
dip in
the curve, and as the PSA levels go up,
associated
with much higher tumor burdens, the risk
of death
increases, but the amount of survival
that was
explained in this analysis was only about
17
percent, and as my statistical colleague,
Dr.
Halabi reminds me repeatedly this is not
enough to
284
base treatment decisions.
So, looking back at some of the
other
trials that have been reported, it was of
interest
in Dr. Crawford's presentation, looking
at the
construct of a 50 percent decline in the
context of
SWOG-9916, association with survival was
about 22
percent.
Using a metric of change in PSA
velocity,
16 percent, Dr. D'Amico's slope changed
22 percent,
similar to ours, so again there is a
significant
amount of survival which does not appear
to be
explained on the basis of PSA decline.
What about palliative
response? Again, to
show how Dr. Raghavan and I are thinking
in a
similar fashion, which is scary to some
degree,
there has clearly been a disconnect
between the
observation of a palliative response and
a PSA
response.
This was the work of Dr.
Tannock cited
earlier, of looking at
mitoxantrone/prednisone
trial, which did lead to the approval of
mitoxantrone and prednisone, and to my
view
285
established a very important principle
that
systemic chemotherapy could provide
palliation of
symptoms of the disease.
Looking at the PSA response
rates, the
palliative response rates appear to be
similar, but
in the proportion of patients who
achieved, looking
at PSA response relative to palliative
response,
only 60 percent of patients who achieved
a
palliative response had a decline in PSA.
This was very dramatic in terms
of the
prednisone arm where only one patient
showed a
significant decline in PSA, although a
proportion
did show a palliative response.
So, where does this leave us in
terms of
PSA change and survival? Trial 9916 showed that
there was an association of PSA decline
and the
treatment effect was eliminated when
adjusting for
the intermediate, did not see the same
effect in
both arms of the TAX-327 study. The Q3 week arm
was the only arm to show a survival
difference.
Although we have used different
metrics in
the construct, and looking at
retrospective Phase
286
II data, and post-trial analyses of
randomized
comparisons, the amount of survival that
is
explained appears to be very similar,
about 20
percent.
Does this make sense? Yes, it does make
sense, because if you think about what
does PSA do
in
terms of prostate cancer progression, it is
really not known. There has been some speculation
as to its modulation of growth factor
effects, but
one could understand that PSA alone does
not
necessarily drive a prostate cancer cell.
We still have to remember in
terms of
clinical benefit that there is this
association of
a PSA response and a palliative response,
which
reminds us that we must continue to
monitor the
other manifestations of the disease, and
we all
know based on pathologic studies that not
all cells
within a tumor in fact express PSA, so we
may be
dealing with a component of clonal
selections.
But a limitation of all of
these analyses
is that they were retrospective and they
were not
the results of prospectively designed
trials
287
looking at a question around the marker.
So, maybe if we have so much
difficulty
with response, maybe we should think
about the
failure to progress or looking at a
non-progression
endpoint.
If one considers the importance
of
following patients using different
measures, both
physical assessments, symptom assessment,
PSA, and
imaging studies, perhaps we can start
getting a
better index of whether or not we are
changing the
disease particularly if we are enriching
the
population that we are treating for high
risk of a
clinical event.
If you are thinking exclusively
about
overall progression of disease, you don't
really
have to worry about surrogate, you have
defined it
on a clinical endpoint, and it is really
going to
be a measure that will be drug mechanism
independent depending on the question
that you are
asking.
So, if we think about
preventing
progression of disease, we do have
criteria for
288
some of the manifestations. For
measurable disease,
we do have RECIST. We do have a problem in that we
do not have scan criteria which have been
standardized to assess serial changes in
bone scan.
We do know that in about 70 to
80 percent
of cases, however, that PSA elevations do
precede
other measures of progression, so this
may be
sufficient and certainly a point of
discussion of
whether this type of endpoint could be
considered
in the context of a prospective study.
For quality of life measures,
again, there
are validated instruments. These are not 100
percent concordant with PSA, and death
from disease
is clearly an endpoint that will not be
debated.
There has likewise been as a
result of
collaborations in the academic community,
standardization of reporting and
definitions of
progressions that we accept.
This is an illustration from
the JCO
publication in 1999 showing a definition
of
progression by PSA, which includes a 25
percent
rise from the nadir as the time point,
but again
289
keep in mind, as shown earlier, that we
can see
benefits which are clinically significant
or at
least lead to drug approval without an
effective
PSA, which is clearly illustrated by the
endpoint
used for the approval of zoledronic acid,
which was
a reduction in skeletal-related events at
15 months
in a patient population at risk.
So, we have been asked to put
up a bar,
and I have been debating with many people
what this
bar actually means, because what we have
been
challenged to do is to come up with a
measure that
is reasonably likely to predict clinical
benefit.
The regulations for accelerated
approval
are very clear. They require substantial evidence
from well-controlled trials regarding a
surrogate
endpoint.
The problem that we have had in prostate
cancer clinical trials, too few studies,
too little
participation by both patients,
physicians, and
overall community at large in these
studies.
Until recently, the trials were
underpowered and undersized. As shown by Dr.
Raghavan earlier, the response observed
with
290
estramustine and vinblastine in the early
1990s was
not dissimilar to what we are seeing now,
yet the
Phase III trials that were designed were
not of
sufficient size to actually address the
survival
question.
Although we have looked at
various
associations between PSA outcome measures
and
survival, these are all retrospective
analyses.
They were not derived from trials prospectively
designed to test the value of the
surrogate
measure.
So, as we look forward, we do
have several
challenges. We have to balance the clinical
realities of practice, that treatment is
rarely
continued if the PSA is going up, and
this is one
of the problems I have in terms of slope
modulation.
The patients comes in with a
graph, it is
going up, they are not happy. If the treatment is
going down, it is very hard to stop
treatment.
That is reasonable, although in many
cases, there
may be other measures suggesting that the
treatment
291
is no longer working.
We have seen in clinical trials that
there
are specific protocol-mandated
definitions of
progression. That can lead to premature
discontinuation of a drug. This will relate
primarily to some of the definitions that
have been
applied to the use of bone scanning
agents.
One or two new lesions dictates
progression, and I will illustrate a
couple of
situations where that, in fact, may not
be the
case.
What we really need is clear evidence of
progression before treatment is
continued.
It is not as if we are
withholding
tremendous options, so an approach, when
I am
discussing treatment with a patient is
trying to
really make sure it is either working or
not
working before you abandon it, because
you don't
necessarily know what will be next, and
you don't
want to abandon a treatment that may, in
fact, be
helping an individual.
So, here is an example of a
patient.
Actually, this data was generated
yesterday, so
292
it's contemporary. Here is a patient who
is
progressing after previous microtubular
targeting
therapy.
His PSA went up to the low
300s. The
date, which you may not be able to see,
is early
October of 2004. His PSA after this next
chemotherapy has been going down. He is
asymptomatic, his pain is resolved. His bone scans
are stable.
He would not meet the criteria
for a PSA
response, and arguably, this is a patient
who is
benefiting, and even though he has shown
a degree
of myelosuppression, he religiously comes
in for
his treatment. So, this patient would be missed as
a responder or a patient who is
benefiting from
therapy if we were stuck with a 50
percent decline.
Here is another
illustration. If you look
at the patient's baseline bone scan on
the upper
left, there are some lesions visible in
the
skeleton and in the manubrium.
At the three-month scan, there
were two
lesions that appeared, one in the rib and
one in
293
the vertebra. By some protocol criteria, this
would be considered progression. The patient was
asymptomatic. His PSA kinetic curve is on the
right.
You can see the PSA is going down.
Treatment was continued. A bone scan was
done a six months. It remained stable. Patient
remained asymptomatic and subsequently,
there was
an improvement in these lesions.
So, this mandates very cautious
interpretation of bone scans, something
we have to
consider as we are designing trials going
forward.
So, what might a prospective
trial look
like which is powered on survival, which
has an
intermediate endpoint embedded, which might
be
considered for interim approval?
The first question one might
ask, and this
is an example of powering a trial on
survival, does
Treatment A prolong life relative to Treatment
B?
In the first line setting, this could be
patients
with no prior chemotherapy, obviously,
this would
be going against a standard of Taxotere,
or in the
second line setting with one prior
therapy, one
294
could power on trial on survival, for
example, a 25
percent improvement, and secondary
endpoints might
include a PSA response definition using
the
consensus criteria, for example, a 50
percent
decline, a PSA progression criteria. Again, there
are consensus criteria for same, or a
composite
endpoint that includes PSA.
It is obviously in yellow,
which is where
my bias happens to be. One could certainly
consider an accelerated approval based on
an
interim evaluation assuming the trial
endpoint was
met, with the proviso that the trial
accrual and
monitoring continue until accrual was
complete, the
analysis complete, to assess the primary
endpoint,
which in this case would be survival.
As mentioned earlier, it
becomes critical
in these trials not to stop following
patients at
the first sign of progression. They need to be
followed and monitored at fixed intervals
after
treatment in order to better define the
clinical
course if we are going to validate some
of these
endpoints.
295
The CLGB has designed one such
study, and
Dr. Halabi was kind enough to allow me to
present
this.
The PI will be Dr. Kelly at our institution.
They are studying whether the addition of
an
anti-androgenesis agent Avastin will
improve the
outcomes to standard first line
chemotherapy.
The primary endpoint is looking
for
prolongation of life. The secondary endpoint will
look at a progression-free survival
endpoint
comparatively between the two regimens.
Eligibility is risk based, based on
nomograms and
risk of mortality with stratifications
based on a
nomogram that was developed by Dr.
Halabi, and all
symptoms of disease and manifestations
will be
recorded.
The primary endpoint is to look
for a
reduction in the hazard ratio of death of
25
percent using a two-sided analysis, and
they will
explore associations between
progression-free
survival.
This is not intended as an approval
study.
Another example might be in the
second
296
line setting for a cytotoxic drug - does
this new
cytotoxic drug (a) prolong life relative
to
mitoxantrone and prednisone, for example,
we can
discuss what the comparator might be, in
patients
who have received one prior chemotherapy.
The secondary endpoint might be
to compare
the PSA or overall progression-free
survival of the
two regimens. Again, the trial would be
powered on
survival, and consider PSA progression or
a
composite that includes PSA for a
potential for
accelerated improvement as enrollment on
the trial
continues to reach the primary endpoint.
So, where we are now? Clearly, we still
recognize that this is not a
straightforward
disease to manage. There are clear difficulties in
assessing response and outcomes. We must
address
within our trials the clinical realities
that PSA
levels and changes in those levels do
drive
treatment, and the question remains for
us to prove
prospectively whether there is a PSA response
or
progression construct that can predict
for true
clinical benefit and form the basis for
an
297
accelerated approval.
But I clearly believe we are in
a position
to do those trials, and there has been a
demonstrated commitment to complete the
trials of
adequate size and power, so that we can
actually
address these questions going forward.
Thank you very much.
DR. HUSSAIN: Thank you, Dr. Scher.
Our final speaker is Dr.
Anthony D'Amico
from the Harvard Medical School, who will
discuss
the design of clinical trials for select
patients
with a rising PSA following primary
therapy.
Design of Clinical Trials for
Select Patients
With a Rising PSA Following
Primary Therapy
DR. D'AMICO: While we get the screen up,
I want to thank Dr. Pazdur for letting me
part of
this experience. Actually, it has been a
wonderful
thing to put this set of data together,
and it has
been a lot of fun.
I also want to thank Johanna
Clifford and
Diane Spielman for all the logistical
support that
you helped me with during the course of
getting
298
here.
I never used to put humor into
my talks
until I met Dr. Raghavan. There was a talk that he
was giving once at the course we have in
Boston
every other year, and I was very
impressed with his
delivery, in addition to the information
that he
gave.
He said to me, though, today on
the way in
that you are not supposed to have a joke
prepared,
you are supposed to do it on the
fly. I was
thinking to myself, well, maybe when I
reach his
age, I will be able to do that, or maybe
if I reach
his age, I will be able to do that.
What I would like to talk about
here is a
very specific disease state, the rising
PSA after
surgery and radiation in a very
well-defined
population, people who have, in some
people's data
sets, achieved "surrogate for cancer
death," with a
very specific endpoint that involves the
standard
endpoints - death due to prostate cancer
and
metastatic disease predates that, and
then also
consider some questions that we could
raise about a
299
PSA construct.
Now, I am a believer that it is
more
important that the information that you
give is
concise and important more than it being
excess
volume, so contrary to Dr. Raghavan's
suggestion, I
am going to tell you a little thing I had
planned,
because it sets the stage for this talk.
I enjoy martial arts, it is
something I
have been doing since I am a child, and
this is a
story that I heard once that I really
found very
interesting.
There is a young gentleman who
wants to
enter a Buddhist monastery, and he is
told at the
age of 12, "Well, listen, you know,
this is a
strict place, there is vows you have to
take,
something called chastity, poverty,
silence." He
says, "In fact you only get to speak
two words
every five years." He says, "I want to do it." So
he goes into the monastery and does his
first five
years, and when he comes out, okay,
"You have got
two words, you're 17 now, what are they,
and he
says, "Bed hard."
300
Okay, fine.
Go back on in. Comes out at
the age of 22 after 10 years, he gets two
more
words, and he says, "Food
cold." They look at him,
sort of a seniors look back and forth and
shake
their head. "We will give him one more try."
After the 15-year stint at the age of 27,
he comes
out, and he says, "I
quit." They said, "Fine, you
have done nothing but complain since you
got here."
So, in terms of this particular
construct,
I am going to start designing a clinical
trial from
the first slide, and the first thing we
need to
design in a clinical trial setting is
patient
selection. Let me focus you again on the disease
state that we will be talking about, is
the rising
PSA following surgery or following
radiation.
In my mind, and there may be
some dispute
about this, if one really wants to have a
"alternative" endpoint to the
standard endpoints,
the place where it is needed most in my
mind is the
earlier states of bad disease to come,
and not the
endpoint of the disease where they have
only got an
average 18 months to live.
301
I think that, you know, the
TAX-327 and
the SWOG-9916 study from accrual to
publication was
four years, which isn't bad. I mean that
survival-based studies in hormone
refractory
metastatic disease are not unreasonable,
but in
locally advanced prostate cancer, the
bolus study,
the ORTC, the RTOG studies, 92-02, a
study we ran
in localized high-risk prostate cancer,
radiation
plus or minus hormones from start of
accrual to
publication was 10 years.
This is where, if anything, we
need help
in defining endpoints that are clinically
meaningful and earlier. So, with that said, we
have a huge amount of information, and as
I go
through each of the centers or
cooperative groups
that have contributed, I will recognize
them.
There has really been a
national effort
that has been designed at exploring PSA
doubling
time following radiation or following
surgery, and
I will take you through all the
information that
has been published to date or soon to be
presented,
and I have gotten permission from the
investigators
302
in
ASCO where some of this will be presented to
show some summary slides.
But what we have learned is
that the
doubling time following radiation or
surgery is
significantly associated with time to
cancer-specific death following the
institution of
PSA failure on which the doubling time
calculation
is based.
This data comes from a series
of
multi-institutional and single
institutional
studies, and I am going to highlight four
of them
because each one has a unique
characteristic.
The first one is RTOG 92-02
where patients
managed with radiation were randomized to
short- or
long-term hormones. The next one is a
multi-institutional database, 44
institutions
around the country, CaPSURE, which is run
through
Peter Kal [ph] on the West Coast, and
CPDR, which
is run through Jud Mool [ph] and Dave
McCloud here
at Walter Reed, and then two single
institution
studies of importance, Johns Hopkins and
Barnes
Jewish, Johns Hopkins because this was a
place
303
where no one got hormonal therapy for a
rising PSA
until the bone scan was positive.
That is a unique data set,
which tells us
something about the natural history of a
rising PSA
patient following failure after surgery;
and then
the Barnes Jewish, Bill Catalona's
database, which
I will show you some results from, and
will be
published later in the year, from a group
of men
who were prospectively screened.
Everybody had serial PSAs, so
this is the
stage migration issue that Derek Raghavan
was
talking about. We will look to see what doubling
time does in that particular group, and
how
significant or lack of significance is
it, so let's
go through it.
This is from Dr. Valacenti and
Dr. Howard
Sandler. This is the schema for RTOG
92-02, and
this study has been published in the
Journal of
Clinical Oncology, but what is soon to
come is the
slide that follows.
The two arms are shown, locally
advanced
prostate cancer T2c-T4, Pretreatment PSA is
under
304
150, 1,500 patients or so randomized to
radiation
with 4 months of hormonal therapy or 2
years and 4
months.
This is what they found. They applied the
full Prentice criteria to the model. I am not
going to present that and I will get to
why later.
But the one point I am going to bring out
is that
when they looked at PSA doubling time,
and
specifically this is for a break point at
1 year,
they found a 6-fold increase in
cancer-specific
death.
The confidence interval is pretty tight, 4
to 9, as shown.
For this particular parameter,
for the
first time really in a group of men
managed with
radiation and hormonal therapy, it hasn't
been done
before.
It has been done for radiation, it has
been done for surgery. These are guys getting
radiation and short- or long-term
hormonal therapy,
so this is new information.
There is the cancer-specific
survival plot
or 1 minus the cumulative incidence of
cancer
death, stratified by the doubling time, a
305
significant difference.
Of note, I will just point out
that if you
look at the guys with the doubling times
less than
12 months, which is the dotted curve at
the bottom,
by the time you get out about 5 years,
already
about 25 percent of these people have
died of
prostate cancer, and it is a doubling
time less
than 12 months. That story is going to evolve.
Here is the study that was
written up by
CaPSURE and CPDR databases, that
multi-institutional database several
years ago now
in JNCI, and what was shown here is that
in a
select group of people with a doubling
time less
than 3 months, which are the green and
black curves
at the bottom for radiation and
surgically managed
patients respectively, that the median
survival was
only 6 years.
This stood in contradistinction
to the
Pound's paper from Hopkins, which said
the median
survival for guys with a rising PSA is 13
years,
until you put the things together and
realize that
the Pound data incorporated everybody on
the plot,
306
and we get to the very important point
that this
makes, which is in the rising PSA cohort,
all
patients are different, it's not one
group.
In that one state of disease,
you have got
a multitude of biology, from the very
worst to the
very best, and the very worst can be
characterized
by the short doubling times, the very
best by the
longer ones, and there is the basis for
patient
selection for a clinical trial.
Let's go to the rest of the data. The
hazard ratio from that data set was 20, a
20-fold
increased risk of cancer-specific death
if your
doubling time was less than three months
as opposed
to three months or more in contrast to
the value of
6 when the doubling time break point was
12.
Now, here is an interesting
slide that
hasn't been shown yet. This is Dr. Catalona's
screened database, all these men, 8,000
or so of
them have had a screened PSA each
year. Their
median PSA of diagnosis is 4.2, so they
are very
early, but the fascinating thing to me is
that that
red and blue curve at the top, red is
overall
307
death, Kaplan-Meier incidence of death,
and blue is
cumulative incidence.
If your doubling time is less
than 3
months, even though you were screened,
you still
got a very high death rate, and the point
I want to
make is if you look out five years, where
the
numbers at risk are still reasonable,
overall death
and cancer death are the same.
That goes right along with this
doubling
time less than 3 months being very highly
correlated, if you will, a surrogate for
cancer
death, even in a screened population.
In the population of them at
longer
doubling times, cancer death and overall
death are
about 50 percent of one another. You can see if
you work it out, half of death is due to
other
causes, half of death is due to cancer in
the
orange and the green curves below.
But the striking thing that I
find here,
as you look at the numbers at risk at
time zero,
the percent of patients who have a
doubling time
less than 3 months in a screened cohort
is 7
308
percent, and in the CaPSURE or CPDR, what
happens
in the community where some people get
screened and
some people don't, it is 20 percent.
So, it is very interesting to
me that the
proportion of men with bad biology at the
time of
recurrence in the screened group is much
less as
you would probably expect than it is in a
relatively normal community population.
It gives us some estimate, here
is 0.2, at
the size of the population we could
enroll into a
study where the patient selection is
based on
doubling time, and I will tell you what
the study
is in a moment. Those are treated patients with
surgery.
Now, this is the slide from Dr.
Parton,
Dr. Eisenberger, and Dr. Friedland at
Johns
Hopkins, and this, too, is to come, but
it is a
fascinating description in my mind where
they have
broken out surgically managed patients,
doubling
time now not as a categorical, but as a
continuous
variable, and the adjusted hazard ratio of
0.86
with tight confidence intervals basically
says that
309
as your doubling time goes up, your risk
of cancer
death goes down by about 14 percent per
unit
increase in doubling time.
But look at the plot here of
cancer-specific survival, the largest
doubling time
is at the top, the less than 3 months at
the
bottom.
Again, you are getting that 5- or 6-year
median survival in that doubling time
less than
3-month group. The same number we are seeing it
over and over again, multiple databases
showing
that that doubling time less than 3 month
group has
got
about 5 or 6 years to go.
But it is nice to see that
there is a
stratification in survival that goes from
the worst
doubling times to the best or the longest
illustrated in this particular database.
The other thing that is interesting here
in this well-selected group of patients
is they
have exactly 7 percent of men on this
plot with a
doubling time less than 3 months exactly
the same
as Bill Catalona's.
It sort of shows you that as you go from a
310
community database, where all comers come
in to a
very select institutional database, the
proportion
of the most unfavorable go down, but
nonetheless,
to my mind, it is validation that that
group does
poorly, whether they were screened and
they end up
there, or that they weren't and they end
up there.
So, in summary, in terms of
patient
selection, what we have here are data
from
cooperative groups, the RTOG,
multi-institutional
databases, CaPSURE/CPDR, and Centers of
Excellence
- Hopkins and the Barnes Jewish where the
screening
studies were started, showing that
doubling time is
significantly associated with
cancer-specific
mortality.
I am staying away purposely
from surrogate
for the following reason that I will now
state. I
have discussed surrogacy with many
different
statisticians. Dr. Rubin is the one who is closest
to me who runs statistics at Harvard
University.
He has pointed out all of the issues, the
difference between a clinical surrogate
and a
statistical surrogate.
311
I would submit that even if you
run a
randomized study and you apply Prentice's
criteria,
and you show it works, it still may not
work
clinically, and the way that one would
get around
that is by having multiple measures of
surrogacy,
things like proportion of treatment
effect
explained, the PTE model, and multiple
studies all
showing the same thing, like I just
showed for
doubling time, that would get us to the
point where
we need to be.
So, I am staying away from
surrogacy, I am
saying with associations or prognostic
factors for
the time being, and the conclusion I
would make
from the data I just showed you is that
the
doubling time itself is significantly
associated
with cancer death whether you have had
surgery,
radiation, radiation and short-term
hormones, or
radiation and long-term hormones, and
that is just
about every treatment you can offer to a
man who
presents upfront.
So, it covers all the treatment
domains,
and doubling time less than 3-month group
is a
312
particularly poor prognostic group and
represents
about 20 percent of men who come from the
community
where screening is not practiced
necessarily, and
about 6 to 7 percent of men who come from
a
screened group.
But the point I am going to
make is it
doesn't matter how you get there, once
you are
there, you do poorly whether you were
screened or
not, because I think that that very short
doubling
time is reflecting biologic behavior.
So, now we have identified some
patients
for study. Now, we need some issues from clinical
practice and what has been done in this
country to
decide what the arms of this study are going
to be.
So, in the United States for
patients with
a rising PSA, as Dr. Scher and everybody
has said,
PSA dictates management, the rate of rise
of PSA
has been shown to influence when hormonal
therapy
is used.
Peter Carroll from the CaPSURE
database
has shown this quite nicely the PSA
doubling time
or velocity or how quickly the PSA rises
is
313
directly associated with the timing of
hormonal
therapy.
The doctor looks at the PSA going up
quickly, the patient looks at it,
something is
done, and in the community, that
something is
hormonal therapy.
In academic centers, it can be
anything
from vaccines to Celebrex, et cetera, on
studies,
but in the community, which is where we
are aiming
this, the big picture of what we do in
this
country, it's hormonal therapy.
Then, a very important piece of
information from the Hopkins database
where men
didn't get hormonal therapy until their
bone scan
was positive. What is the median time to a
positive bone scan following PSA failure
in a guy
with a very short doubling time - 18
months from
the one database that could actually
measure it,
where hormonal therapy was withheld until
the bone
scan was positive.
So, there is your next piece of
information, and that is what sort of
drives
people's thinking in the community to
start
314
hormonal therapy. So, the bottom line is that
patients with a doubling time less than 3
months
are offered hormonal therapy. Whether it has been
proven to improve survival or not is not
the case
here, it is what is done, so I would
submit that
that is a reasonable control arm.
So, here is the study. The treatment arms
would be hormonal therapy plus or minus
some
systemic therapy in the setting of a
doubling time
less than 3 months.
Now, what systemic therapy are
we going to
choose, or even more importantly said,
what class
of agents are we going to choose? This is where
the talk takes another twist.
I would say that Taxotere is
the leading
contender because it is the drug that has
been
shown to prolong survival in men with
hormone
refractory metastatic disease, and the
thinking is,
well, we will backstep it into earlier
states and
maybe we will even see more of a benefit.
Maybe we won't see any at all,
but that is
what studies are for. So, that would be my number
315
one choice would be docetaxel or
Taxotere, but
there could be a number of other agents
used, but
let's be careful here.
I would not recommend an agent
that isn't
cytocidal for the reasoning I am about to
go
through with the last part of the talk,
which has a
whole host of data addressing this issue.
We don't know in the cytostatic
agents, or
agents that modulate PSA, whether
anything I am
about to say holds, but in the cytocidal,
the ones
that kill cancer, as Dr. Scher was sort
of alluding
to, you kill prostate cancer, the PSA
tends to go
down in the hormone refractory state, well,
that is
why I would stick to cytotoxics. I put Taxotere as
number one, there could be other agents,
but I
think they have to be in that class.
So, now the last part which gets
to the
endpoint of this clinical trial. So, you have a
rising PSA patient. You have given me
hormonal
therapy plus or minus some new cytotoxic,
Taxotere
or other.
The primary endpoint, the
conventional one
316
would be time to bone metastases. It's the next
clinically relevant event that comes
along the
path, and your secondary endpoints would
be time to
cancer death and overall death, all-cause
death.
I think that is your standard
approach,
and no one I don't think would argue with
that, and
it is very reasonable, and this study is
being
done.
Dr. Scher and I have been talking about it.
I think Dr. Scher has already got it
underway. So,
this study is already happening or about
to happen.
But PSA, and this is where I am
going to
sort of focus my last part, you know,
what is the
evidence, is there any evidence to
suggest an
association between the nadir level of
PSA--and I
use 0.2, more than 0.2 as a detectable
level,
because that is a fairly good consensus
across the
country--what is the relationship between
someone
who goes on hormonal therapy, rising PSA,
and
doesn't get below 0.2?
Is there a relationship between
that
person and time to cancer-specific death
in that
setting?
317
Now, I am going to show you a
series of
studies that I will argue that there is a
significant relationship statistically,
and then
the last point, clinically.
Here are the databases from
which these
arguments will be made or evidence will
be
presented. First, the last one I will show you is
the multi-institutional database, the
CaPSURE or
CPDR contingent. I will start with the single
institution databases from New York. Peter
Scardino, Bianco, and Howard Scher
actually worked
on this project. Then, I will show the Harvard and
Barnes Jewish single institution
experience.
So, here is the New York experience. We
had 346 men who underwent surgery. Now, this is
interesting because not all of them are
bone scan
negative at the time of entry, 81
percent. I will
address that later. The endpoint they used was
time to cancer-specific death, prostate
cancer
specific mortality following 8 months of
hormonal
therapy, very bright, because it takes at
least--the median is 3 months, which we
found and
318
others, but it can take up to 8 months
before your
PSA nadirs.
So, you set your time zero at 8
months
following the institution of hormonal
therapy, so
you are not biased. Everybody has had a
chance to
experience a nadir or not by that
point. So, your
categorical variable or continuous,
however you
want to look at it, continuous or
categorical, has
happened by that point.
The covariates that they looked
at in the
model was PSA level at the start of
hormonal
therapy, the pre-hormonal therapy PSA
doubling
time, the PSA nadir that actually
occurred within 8
months of hormonal therapy, and then
prostatectomy,
T-category Gleason score, and bone scan
status
positive or negative, and the results are
shown
here.
The PSA nadir level being
undetectable was
very significant, as was the PSA level at
the time
of hormonal therapy, and if they had a
pre-treatment PSA doubling time greater
than 3
months, they did much better than if they
had one
319
less or equal to 3.
The other factors, factors
related to the
prostatectomy specimen, bone scan status
didn't
matter.
There were 63 cancer deaths out of the 360
or so patients, and the median survival
for
patients who never nadired on hormonal
therapy was
about 5 years, which is again consistent
with that
6-year number I gave you before, you are
just a
little bit further into the picture now,
it's
short.
This is the data that they
have, the slide
that Dr. Bianco sent me. That dotted line at the
top, this is cancer-specific death, the
dotted line
at the top is the guys who never nadired
and who
had a pre-treatment PSA doubling time
less than 3
months.
Now, they didn't put numbers at
risk on
here, but you have essentially got 100
percent
deaths in the first decade estimated, but
if you go
out 5 years, you have got 80 percent of
the people
gone estimated, okay, because it is
always subject
to follow up, it's a pretty bad group.
320
Whereas, the people who died of
disease,
if they did nadir, is the other dotted
line where,
when you go out about 5 years, you have
got about
15 percent deaths. So, there are still some people
dying even if they nadired, and I want to
make an
important biological or clinical point
here.
This is the twist in my
mind. If you
nadir on hormonal therapy, it doesn't
mean you
don't have hormone refractory disease,
because
there are still some people who go on to
die even
if you nadir on hormonal therapy, 20
percent at 5
years, and double that by the time you
get out to
10 years.
But if you don't nadir on
hormonal
therapy, you damn well have hormone
refractory
disease because almost everybody is dead
within the
first decade, and I think that is an
important
point because it is saying it's like, you
know,
when we biopsy the prostate, if the
biopsy is
negative, it doesn't mean they don't have
prostate
cancer, but if you find it, they do.
The same concept here. I think that the
321
nadir is an important construct because
when it
doesn't happen, it is very bad; when it
does
happen, it is not as bad, but it still
can be bad.
Now, let's go on a little.
This is the data from Harvard
and from
Bill Catalona, the Barnes Jewish
group. This is
doubling time less than 3 months, did
they get
below 0.2 or not, the same picture as Dr.
Bianco,
Dr. Scardino, Dr. Scher's data set, same
picture.
A lot of death if you didn't nadir,
almost 100
percent in this case by 7 years, but
still some,
but not nearly as much if you do nadir.
Then, going ahead, the final
study. This
is the multi-institutional study from
CaPSURE and
CPDR, which included 486 men who had
surgery, 261
who had radiation. At the time of hormonal
therapy, everybody who had a bone scan
which was
negative.
The endpoint here is the same endpoint
that the New York group used, time to
cancer-specific mortality following 8
months of
hormonal therapy. The covariates are all the same
322
covariates I just mentioned, and the
results are
exactly the same with the only exception
being that
Gleason 8 to 10 came in, but everything
else in
terms of PSA nadir, pre-treatment PSA
doubling
time, and the PSA level at the start of
hormonal
therapy are all significant.
In this study, there were 53
deaths, a
little over half of them from prostate
cancer, and
the hazard ratio adjusted for all of
these factors,
when you didn't nadir, there was a
20-fold increase
in cancer death.
Now, let's look at the actual
plots, the
graph first. This table is important from a
statistical standpoint and a power issue
if you
were going to design a study in this
group. I want
you to look at where the events occur.
If you look at doubling time
less than 3
months, and you look at the column that
says Number
of Patients, Number of Prostate Cancer
Deaths, you
will see that 21 of the cancer deaths
occurred in
the guys who didn't nadir and had a
doubling time
less than 3 months; 3 occurred in guys
who did
323
nadir and had a doubling time less than 3
months.
Now, you go across the table
and you go
from 21 to 23 to 24, you pick up two more
events
and then one more event, and at the
bottom, 3 to 4
to 4, you pick up one more event. What I am saying
is that the vast majority of the 28
deaths are in
that upper left-hand corner box, the
doubling time
less than 3, and the PSA nadir greater
than 0.2.
The reason why this is
important is that
if you take a trial and you select people
with
doubling time less than 9 months or 6
months, you
will still see a difference, as I am
about to show
you, but the difference will be dampened
by the
fact that almost all of your events are
occurring
in that enriched population with the
shortest
doubling times.
My point is just that for a
power purpose,
as I will show in the next three slides,
the
selection should be very strict if you
really want
to get an endpoint quickly.
So, here is the plot now, the
one I have
been showing you all along from the New
York group,
324
the Harvard, Barnes Jewish group, and
here is now
the multi-institutional group. This is doubling
time less than 3 months, did they nadir
or not, the
same story, same picture. If they don't nadir,
they do terribly, almost everybody is
estimated to
die within 7 years. If they do nadir, some still
die, but not all, not nearly as much.
The number at the bottom, 68
over 224 just
tells you the percent of patients, which
is 30
percent of men whose doubling time is
less than 3
months, going on to hormonal therapy
don't get
below 0.2, almost a third.
Now, that's in
contradistinction to what
we think, we put people on hormonal
therapy, the
PSAs go right down. Well, that is because
most of
them are not doubling time less than 3
months
coming in. Most of them are 6 months or 9 months
or 12 months.
So, you will see as you go to
the next set
of slides, here is doubling time less
than 6
months, 25 percent of them don't go down
to
undetectable levels, and the survival
difference
325
here is still significant, but I want you
to
remember that the only thing that is
driving this
big difference is the group of men with a
doubling
time less than 3 months.
Almost all of the events in
this doubling
time less than 6 months are coming from
that very
poor group. The same thing with doubling time less
than 9 months. Now, you have got 22 percent of
people who don't nadir, all being driven
again by
that worst cohort.
I don't want you to get fooled
here by
looking at these big differences in 6-
and 9-month
plots.
You have to know where the numbers are
really coming from.
So, we are almost done, 2
slides to go.
So, the summary of what I said. In a group of men
who come in with a rising PSA that is
rapid, a
short doubling time, less than 3 months,
a third of
them, 30 percent of them don't nadir at
least in
this multi-institutional database and the
other
ones I showed you, despite hormonal therapy,
and in
my mind, given how quickly and how vastly
they all
326
die of cancer when you look at those
cumulative
incidence plots, they have to have some
component
of
hormone-resistant prostate cancer in them.
I
can't imagine that they don't. So, that is Point
1.
Now we come to the study
hormones plus or
minus Taxotere, and the question is if a
guy
doesn't nadir to less than 0.2 on
hormonal therapy
and docetaxel, what does that say? We know that
docetaxel doesn't decrease testosterone
levels.
That has been shown by William Ohe and
others in
studies of neoadjuvant Taxotere Phase II
studies
prior to surgery.
So, it doesn't go through that
mechanism,
and when PSA does go down, it has been
suggested
from the hormone refractory state that at
least
there is some association with that in
cancer
killing or cancer death. That led to a survival
benefit, but there was a disconnect
between a PSA
reduction of 50 percent and
survival. Why? Well,
perhaps you don't have the ability here
of zero,
the nadir.
327
See, in the hormone refractory
state, you
get down to 4 or 10, you are happy, but
here, you
are going to either be undetectable or
not. So, if
you don't go to undetectable levels on
hormonal
therapy and docetaxel, I would
submit--and this is
a hypothesis, but I think it's a darn
good
one--that you are hormone resistant and
you are
Taxotere resistant, and in my mind, that
means you
are dead from prostate cancer because
there is
nothing else that we know works, so I
think that is
a good endpoint.
That is my opinion, but that is
a
discussion that we can have. So, the trial that I
would then project to you is that if you
nadir
above 0.2, 30 percent of the time on
hormonal
therapy, and you could show that that
goes down to
10 percent or less on hormones and
docetaxel, would
that be likely to delay your time to
distant
metastasis, would that be likely to delay your time
to cancer death?
That is a question, I can't
answer it. I
could guess. I think the answer probably is yes,
328
but I don't have that. That is the first question
here.
Then, the second question is in the setting
of a Phase III randomized trial, if the
proportion
of men who didn't nadir went from 30
percent to
less than 10 percent, would this produce
a clinical
benefit, and the clinical benefits I put
below, the
time to bone metastases, the time to
cancer death.
Those are the accepted endpoints in this
setting.
The question is, is there a
connection
between this nadir construct in that
trial that I
described, not all trials, not all
agents, this
very specific trial, is there a
connection or not?
The only way to answer that
scientifically
is to do the study powered for a distant
metastasis
and/or survival, and see. But are we at a point
where we already can see?
DR. HUSSAIN: Thank you, Dr. D'Amico.
I want to thank all the
speakers for very
informative presentations and for sticking
to time.
I am going to be slightly more lenient
than Dr.
Martino earlier, and give you a 10-minute
break. I
would like us to assemble at 3:10 if you
don't
329
mind, so we can begin to dissect all of
the
information that we heard.
Hopefully, we will have a
robust, lively,
but most importantly, productive
conversation where
we would come out with some plans. Thank you.
[Break.]
DR. HUSSAIN: Before the committee
discusses some of the issues that came
up, I would
like to begin this session of open public
hearing.
Prior to inviting members of the public
to make
their statements, I would like to read
this
statement.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and decisionmaking. To
ensure such transparency at the open
public hearing
session of the Advisory Committee
meeting, the FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, FDA encourages
you, the
open public hearing speaker, at the
beginning of
your written or oral statement to advise
the
330
committee of any financial relationship
that you
may have with any company or any group
that is
likely to be impacted by the topic of
this meeting.
For example, the financial
information may
include a company's or group's payment of
your
travel, lodging, or other expenses in
connection
with your attendance at the meeting.
Likewise, the FDA encourages
you at the
beginning of your statement to advise the
committee
if you do not have any such financial
relationships. If you choose not to address this
issue of financial relationships at the
beginning
of your statement, it will not preclude
you from
speaking.
Also, those of you from the
public who
have not signed up to speak, you will be
allowed to
speak after the registered members have
already
done that. Thank you.
Open Public Hearing
MS. CLIFFORD: Our first speaker is John
Willey.
MR. WILLEY: My name is John Willey. I am
331
the treasurer and board member of the
National
Prostate Cancer Coalition, which is
America's most
active group in the fight against
prostate cancer.
I speak on behalf of many other
prostate
cancer survivors, and let me back up for
a second.
No one paid my way here. I have no financial
interest in any drug company unless they
are owned
by
a mutual fund that I am not really going to the
second layer of, but I have no
financial--I did get
a free lunch today, though.
When I was diagnosed with
prostate cancer
at age 47, there was a lot of problems, and
one of
the problems, as a baseball fan, was how
many more
seasons was I going to see. One of the people that
I have gotten to know as I have done a
lot of work
for prostate cancer was Larry Lucano, and
as some
of you may know, he took over the Boston
Red Sox in
2002, and they came on to win the World
Series
after years of frustration this last
year.
I would submit to you that
three years
would be a real good time for drug
approval, that
that is something that we should really
shoot for.
332
To get there, surrogate endpoints is the
only way
to go.
We are dragging our heels on
this. I look
back on the June meeting and I am
wondering what
has happened from June to here. We really need
desperately to get something moving on
surrogate
endpoints.
As you know, there are over 2
million men
who are now suffering from prostate
cancer, and
about 1 in 6 men will be diagnosed with
prostate
cancer.
Vietnam veterans, such as myself, have an
added higher incidence, about twice the
national
average.
Prostate cancer gets about 17 percent of
the diagnosis of non-skin cancers, and
yet has only
about 7 percent of the funding for
research. We
desperately need surrogate markers in
place to get
new drugs in place. Without the new
drugs, we are
not going to have any sort of pushing
back of this
disease, so that it is a chronic,
treatable
disease.
I have been on a vaccine GVAX,
and that is
333
only in a clinical trial and I received
it twice,
in '98 and '99, but that alone has kept
me going.
We need multiple of these types of drugs
that can
push back prostate cancer and put it into
a chronic
state, so that men can live with this and
die of
other causes.
Thank you for your time.
DR. HUSSAIN: Thank you, Mr. Willey.
Are there any other members of
the public
that wish to speak?
[No response.]
DR. HUSSAIN: I think that concludes our
open public session.
Committee Discussion
DR. HUSSAIN: In preparation for the
discussion, I wanted to sort of summarize
some of
the points that were made by the
speakers. Then, I
would like to ask the FDA for points of
clarification on some issues of approval,
and then
we will go into the questions. The speakers can
correct me if my summary is not in spirit
with what
they have said.
334
The first thing I think what I
heard from
everyone, that survival certainly is the
gold
standard, whether it is practical or not
practical
to reach, but clearly that is the key.
In the era of active agents, at
least in
the advanced setting, it is not an
impossible goal
to get, so unlike previously, where we
didn't have
good drugs, the problem is not so much
the disease,
it is really not having active agents.
What you also heard that there
are
multiple states of the disease to address
different
endpoints for drug approvals, and that
each state
would need to be addressed in a separate
way.
There are some potential PSA
kinetics that
might be promising, and I underline
promising,
because they clearly have not been shown
and
validated prospectively, but that they
are
promising and, in fact, will need or may
need to be
prospectively validated, and that each of
these
points should be defined in light of the
therapy
that has been utilized, that one cannot
use a
one-size-fits-all for these endpoints.
335
That integrations of other
disease-related
outcomes are important and should not be
excluded,
and it should be perhaps included as part
of a
composite benefit endpoint.
Is that pretty much within the
spirit of
what you all said? Okay.
Now, I want to just address a
few points
to the FDA, Drs. Pazdur or Temple, or any
of the
group.
Does an accelerated approval require a
Phase III trial? In my experience over the last
year, there have been presentations of
drugs where
they have been approved based on some
good results
in a large Phase II trial. I just want a
clarification on that, so that will help
us in our
discussion.
DR. PAZDUR: Here again, let's distinguish
what accelerated approval is. It's an effect on a
surrogate endpoint reasonably likely to
predict
clinical benefit, and it has to be an
improvement
over existing therapy or available
therapy I should
say.
Now, there has been a lot of I
think
336
confusion in the oncology community
between
accelerated approval and using a
single-arm trial
for accelerated approval. When you are using a
single-arm trial generally, you have to
perform the
trial in a very refractory disease
population,
because the comparison is usually to a
situation
where we are saying that there is no
existing
therapy, hence, you could use a
single-arm trial
since the control is recognized as having--there
is
no control basically, there is no
available
therapy, so any improvement would be
considered an
improvement, or "any" in
quotations.
The issue here is yes, we would
be happy
to look at other stages of disease and
have a
randomized trial. We have advocated doing
randomized trials and doing interim
analysis
looking at surrogate endpoints of
response rate of
time to progression, and granting
accelerated
approval on that, and continuing the
study on to
demonstrate clinical benefit of survival.
That was one of the initial
trials that we
did was the initial approval of
oxaliplatin, 5-FU
337
and oxaliplatin in colon cancer was a
randomized
trial initially approved on response rate
and time
to progression in a randomized trial, but
here
again, you have to be better on that
surrogate
endpoint than the control arm.
So, there is various ways of
doing it.
The major issue is the surrogate has to
be in a
clinical estimation reasonably likely to
predict
clinical benefit, and you have to
demonstrate to us
convincingly that it is an improvement
over
available therapy.
We have even in some
discussions looked at
improvements in terms of toxicity or
safety being a
benefit rather than efficacy.
DR. HUSSAIN: Just so that I understand,
so in a third line setting, for example,
if you
argue that Taxotere is first line, and
mitoxantrone
for the sake of discussion is second
line, someone
comes up with a 100-patient trial that
shows some
composite benefit of palliation, what
looks like in
the PSA activity, may be measurable to
these
activities, stabilization and maybe some
quality of
338
life, would that, in fact, make it for
the
possibility of an accelerated approval in
third
line setting pending appropriate trials
to be done?
DR. TEMPLE: The trouble is you have
quoted a lot of different kinds of
endpoints. The
principal endpoint that we have relied on
in
single-arm studies has been tumor
response, the
contention being that tumor responses are
unusual,
to say the least, in the absence of
therapy, so if
you see a tumor response, it probably can
be
attributed to the drug.
We would not say the same thing
about
palliative responses or improvements in
pain. You
really do, we would say, need a control
group
there.
So, that is not as satisfactory.
Whether
PSA convinces you, that is what you are
going to
talk about.
DR. PAZDUR: The point also is that those
endpoints that you specified are truly
clinical
benefit endpoints of pain benefit, so they
would be
looked at potentially as full clinical
benefit.
DR. EISENBERGER: I do believe that, in
339
general, for cytotoxics, a clinical trial
that
would set the bar at survival is still a
reasonable
thing, but I would suggest also that as
we progress
with our targeted approaches, that we
actually
consider paradigms that would have a
clinical
meaning, such as a bone-targeted
approach, for
instance.
If you delay the onset or
progression of a
composite, similar to the Zometa, so that
these
paradigms be considered, and these are
disease-specific, but also
treatment-specific,
then, they perhaps have a different
consideration.
DR. PAZDUR: I think, generally speaking,
we would not have a problem with
that. Again, we
are looking always at a risk-benefit
relationship
here, and if there is a more favorable
toxicity
profile, I think there could be an
argument made
for a delay in a certain event
happening. We did
this, for example, with the
bisphosphonates.
DR. EISENBERGER: For instance, an example
is a trial that would build on the
efficacy or the
primers that were used for the approval
of the
340
bisphosphonate, one would use a
radiopharmaceutical
and add it to a bisphosphonate, and
develop a trial
in that fashion, that would have nothing
to do with
survival, certainly not with PSA, but
with the
interference with progression of bone
target
approach.
DR. TEMPLE: But one of the things that
would certainly be discussed was whether
you have
made a change in the person's symptoms of
some
kind, or whether you have changed a
radiologic
thing.
I am not taking a position, but that would
be something that you would have to
discuss.
DR. EISENBERGER: Obviously, the trials--
DR. HUSSAIN: Excuse me, Dr. Eisenberger,
can I please define just some of the
ground rules.
That way, we don't end up with in a duel
and miss
the overall discussion here.
So, the ground rules will be
that you
raise your hand. We will call on you in order to
make the point. In order to accommodate as many
people to participate, it would be very
good to
have very brief and clear points, and I
would like
341
us to, those who want to rebuttal a
point, again to
raise their hand, and in that way we will
call on
them in order.
The topics that were put for
discussion,
they are listed in front of you, and the
first
question, I am going to read it in
general, but I
am going to try to take the Chair's
prerogative and
maybe improvise the way we look at it.
The question reads or the point
of
discussion reads: Regulations allow granting
regular or accelerated approval to a drug
after
demonstration of safety and
efficacy. Considering
these two situations, discuss the
clinical states
in which PSA-based endpoints should be
evaluated
for use in clinical trials to provide
evidence to
support either type of drug approval.
Based on what we heard today,
there is
clearly I think two general distinct
states that we
probably should focus on, and not get
into too many
breakdowns.
There is the early stage
disease which Dr.
D'Amico was pointing to. I would like to reserve
342
that for the second part of the
discussion. But
the first part would be metastatic
conventional
hormone refractory state of disease i
would like us
to focus the questions on.
In your comments, please phrase
whether
you believe PSA by itself or some other
composite
endpoint is what you think is needed.
Anybody wants to begin? Dr. Brawley, we
will call on you.
DR. BRAWLEY: Thank you.
I was very
impressed with all the speakers this
afternoon. I
will tell you my prejudice right now is
Howard
Scher had a slide that said that PSA plus
other
endpoints is one point. That might be a reasonable
thing to look at as an endpoint.
PSA by itself clearly is not a
good
surrogate endpoint except for the one
state of PSA
rising is a bad thing clearly.
DR. HUSSAIN: Dr. Klein.
DR. KLEIN: I would like to disagree a
little bit with Otis. I think there is substantial
evidence in the urologic literature,
although not
343
all of it is as rigorous as defined by
the Prentice
criteria, that PSA doubling time or
another form or
another derivative of PSA kinetics really
reflects
the biology of the disease, and Anthony
showed a
lot of it, but there is more.
There is evidence in the
pre-diagnosis,
pre-prostatectomy model that a rapid PSA
doubling
time is associated with poor survival
despite
aggressive therapy.
There is evidence that Anthony
has fleshed
out that after treatment, that it is
associated
after radiation or surgery, there is
evidence in
the older literature and in the JAMA
article that
was published multi-institutional study
last year
by Andrew Stevenson, that in response to
predicting
a response to radiation therapy, that it
is
predictive, and all of those things are
based on
PSA doubling time or some derivative of
PSA
kinetics.
When you see a predictor like
that, that
crosses the boundaries of all the
different
clinical states, it says to me that it is
capturing
344
the essence of the biology of the
disease, and we
ought not ignore that.
I would agree with Dr. Scher's
point that
he showed with those two cases, that PSA
doubling
time is not going to be the perfect
surrogate for
every case. You will always find exceptions. But
we are in a situation now where we have a
clear
need for new drugs in the management of
all these
different states in prostate cancer.
Neither pharma nor big academic
centers
are going to put a lot of time, effort,
and money
into looking at survival when the
survival
endpoints are so far off, and it really
is time now
to design the clinical trials as has been
suggested
with a PSA kinetic-based endpoint to try
and
validate it, and whether that will be
sufficient
for accelerated approval or not, I don't
know.
But if we don't do that, we are
going to
be stuck, and I would just sort of add
that we may
not as a group today agree on what the
appropriate
PSA endpoint is, but we should go where
the bulk of
the data is, which I think supports PSA
doubling
345
time as an appropriate surrogate to test
in
clinical trials, and then we can have some
data and
say yes or no, this was the right thing
to do.
DR. HUSSAIN: I just want to point out and
remind you, please, we are talking
strictly right
now about metastatic hormone refractory
disease, so
if you don't mind limiting your comments
to that,
and then we will get to the early stage
disease.
Dr. Andriole, did you have your
hand up?
DR. ANDRIOLE: Yes, I did.
We are talking
about the later stage of patients with
hormone
response disease, and my question or
thought to the
medical oncologists, which I am not, is
it feasible
to do a study in which men with this
stage of
disease are blinded to their PSA, and
just treat
them and make your treatment decisions on
the basis
of symptoms?
Number 1. The first question, is it
ethical, and number 2, were it to be
considered
ethical, would it be doable, because if
you could,
that would I think give us a lot to talk
about.
DR. HUSSAIN: I would probably respond
346
simply by saying no, I don't think it's
doable.
Ethical, we can debate it later, but I
think doable
is more important than ethical.
Dr. Scher.
DR. SCHER: I think what we have seen
about PSA doubling time is that it
becomes an
important prognostic factor as to who is
at high
risk for a significant event, and that
has to be
distinguished from a treatment predictive
factor,
which is a post-intervention outcome.
What we have seen across the
states is
that this has become critical to identify
patients
for enrollment, but that does not tell
you anything
about its role as a potential outcome
measure.
DR. HUSSAIN: Dr. Martino.
DR. MARTINO: At the risk of being simple,
ladies and gentlemen, I need to ask a
question, and
I would like a simple answer from
somebody, because
you are all rattling on, as best as I can
judge
right now. I want to focus the group on people
with metastatic disease, not early
disease,
metastatic disease. I think that was the point
347
that you were taking us to.
Is a change in PSA alone, is a
change in
PSA
alone adequate for any of you to change
therapy?
To me, that is really the question.
That's the question, and I would like an
answer to
that.
Is PSA alone adequate?
DR. HUSSAIN: Dr. Brawley, do you want to
take that?
DR. BRAWLEY: Yes.
First off, Eric, I
agree with everything you said for
localized
disease, but in the case of metastatic
disease, I
do believe--well, first off, if you give
Taxotere
and measure PSA several days later, you
will have
an increase in PSA because of tumor dying
out and
releasing PSA.
But a sustained increase in
PSA, while one
is getting cytotoxic chemotherapy, to me
does mean
progression of disease. A decline in PSA is not
nearly as much information to me as a
rise in PSA.
DR. HUSSAIN: Dr. Scher, you wanted to
respond to that?
DR. SCHER: If the PSA is going up, and is
348
not affected in any way by a cytotoxic
agent, that
is a indication that it does not work.
I would add that there are, for
example,
using weekly Taxotere, you can see delays
in the
decline of PSA for upwards of 6 weeks, so
that is
important information to explain to a
patient.
What?
We agree.
DR. BRAWLEY: We are saying the same
thing.
DR. SCHER: We agree, yes. Going down,
it's helpful, but it's not the whole
story.
DR. HUSSAIN: Dr. Eisenberger.
DR. EISENBERGER: I just want to also,
just for the sake of keeping in the
record, when
you treat patients with Taxotere, and the
PSA goes
up, it doesn't mean that it has anything
to do with
Taxotere.
It is the disease that is progressing.
We actually looked into that in TAX-327.
So, these are patients who are
rapidly
progressing, who will take a little
longer for
their PSA to go down, but that doesn't
happen very
frequently. Most of the time, early rises in PSA
349
equal progression.
DR. HUSSAIN: Dr. D'Agostino.
DR. D'AGOSTINO: I am not sure I digested
all the material on the accelerated
approval. If
some sponsor gets an accelerated approval
based on
PSA, they still have to do a clinical
study, right?
So, in terms of moving the discussion, it
seems to
me like the PSA analyses that we have
seen have
more been like baseline as opposed to if
you have
this, you are in trouble.
The progression, I haven't
heard that
really said that that leads to
anything. But
studies that talk about the progression
as the
Phase III in an accelerated approval, and
then
followed in the Phase IV with a harder
endpoint,
and the confirmation of the PSA rising, I
think
would be a sort of a scenario that one
could
possibly implement without running into
some big
ethical problems.
But I haven't seen, just to
iterate, I
haven't seen the increase, the doubling
of the PSA
as being an indicator of mortality in the
data that
350
I have seen presented.
DR. HUSSAIN: Dr. Raghavan.
DR. RAGHAVAN: I would like to come back
to answer Dr. Martino's question. So, the answer I
think, Silvana, is it depends on the
context. I
don't think you can predicate management
solely on
PSA because prostate cancer is a heterogeneous
disease.
Now, if you want to do it on
averages,
that is, on average will I be accurate
most of the
time, then, you can do it. If a PSA drops 75
percent, most of the time that correlates
with a
good outcome. If the PSA consistently rises over a
period of 3 months, most of the time that
correlates with a bad outcome.
But there are some phenomena
that
interfere with the answers that we have
heard
before.
For example, there are quite clear data
that show that for a number of
cytotoxics, if you
are silly enough to do daily PSAs, which
very few
people do, you will identify a flare-up
reaction
with release of PSA in response to a
cytotoxic,
351
much as you occasionally do in breast
cancer with
one of the breast markers.
Many of the clinical trials
that we talk
about sample PSA values at weekly or
3-weekly
intervals, so they don't actually have
the data to
answer the question.
The second phenomenon is a
clinical one,
which is you will see patients who have a
clone
that produces PSA that disappears during
chemotherapy with a resistant clone that
is silent,
sometimes neuroendocrine, sometimes not,
where you
will have a patient who is actually
deteriorating,
losing weight, losing performance status,
increasing pain. So, this is the
disconnect between
symptoms and PSA when the PSA goes down.
So, the answer to your question
is it
depends on what proportion of the time
you are
prepared to accept being right or wrong.
DR. HUSSAIN: Dr. Martino.
DR. MARTINO: So, can I then conclude that
PSA alone would not be an adequate way to
power a
trial, that something beyond that must be
added?
352
If that is correct, then, can we move on
a little?
What would be the other things that would
need to
be added?
DR. HUSSAIN: Dr. Klein.
DR. KLEIN: You are correct, you are
correct.
I mean I would point out again that we
are looking for a surrogate that
describes or
predicts the behavior of a population,
not the
individual exceptions. No surrogate is going to
perfectly predict the outcome for an
individual
patient, and we need not to perseverate
on that
issue.
I think we need to move beyond that.
I think what you have heard
today from
everybody is that there is a substantial
amount of
evidence that suggests that a PSA
derivative may be
a useful surrogate, but it needs to be
tested in a
prospective clinical trial, using a
standard
clinical endpoint, before we will accept
that.
DR. HUSSAIN: Dr. Temple.
DR. TEMPLE: It just seems we are saying
that PSA isn't an absolute thing, there
are a
variety of measurements that have already
been
353
discussed, like doubling time or percent
reduction,
or something, so that you might not be
convinced
that any change means something, but you
might be
convinced that some kind of change, a
nadir less
than 0.2 or something means something.
Can I just say something about possible
study designs? It is always tempting to take a
look at the people who have a response,
like whose
PSA goes to something very low, and then
see how
they do compared to people who don't get
that
response.
This has been done for years,
and it
always gets the same criticism that maybe
this is
true true unrelated, you might have
picked out the
people with a good prognosis because they
are the
ones who responded.
There is a study design that I
want to
throw out, so you can tell me it's
impossible, that
avoids that problem. If I understood the slides I
saw, you can expect a reasonable
percentage of
whatever PSA response you are going to get
in about
6 weeks.
It would therefore be possible to take a
354
population, treat them all, look at what
happened
at 6 weeks, and then stratify according
to
response, you know, 50 percent, 40
percent,
whatever people thought was meaningful,
stratify
and randomize to treatment and no
treatment.
You do that, and you see a
better
response, you see a better outcome on
whatever it
is you are measuring, associated with a
bigger PSA
response, and then you don't have to
worry about
Prentice anymore, because if you saw
that, that
would make it a credible surrogate for
outcome, I
think.
Now, the obvious question is
would anybody
let you do that trial. Everybody would be on
whatever hormonal therapy there be, but
you would
have to take people who had a response
that at
least some people believe in and not give them the
drug.
So, it would be nicer if you could do some
scan at one day or something, and people
would be
more comfortable with that, but I would
be
interested in what people think about
that as a
possible design.
355
It really does avoid the true
true
unrelated problem.
DR. HUSSAIN: Dr. D'Agostino.
DR. D'AGOSTINO: Maybe I am not following,
but doesn't that sort of stratify by what
you think
might be severity as opposed to saying
PSA is
progression after you have taken the drug
is going
to be useful?
DR. TEMPLE: Well, you are going to look
and see, I mean you may also stratify by
the
pre-treatment doubling time or something
like that,
but, no, you are taking--let's make it
up.
Let's say you want people who
fall to less
than 0.2, that is one stratum. Less than 0.4 is
another, no response is another. We will have 3
strata.
Then, you randomize to the treatment or no
treatment, and you show presumably that
people who
had no response don't get any benefit on
whatever
it is you are measuring, but the people
who were
knocked down to 0.2 by the treatment have
a
dramatic improvement in outcome.
DR. D'AGOSTINO: I am missing.
When do
356
you stratify, do you put them on
treatment, wait
until they respond?
DR. TEMPLE: Everybody goes on treatment.
You look at the response and then you
stratify.
You stratify by response.
DR. D'AGOSTINO: But you have the
individuals. I thought you said you looked at
doubling and then you categorized
individuals, then
randomized within those categories.
DR. TEMPLE: That's right.
DR. D'AGOSTINO: Well, they don't have
treatment before you randomize.
DR. TEMPLE: They have all been treated
for 6 weeks.
DR. D'AGOSTINO: They have all been
treated for 6 weeks.
DR. TEMPLE: For 6 weeks or 4 weeks, or
whatever you think is long enough to know
what
their PSA response is. You then randomize them to
treatment and no treatment. So, you have got to
hope the 4 weeks of treatment doesn't
make too big
a difference. If it did, that would undermine this
357
design.
You then have groups who are
stratified by
response, and you then randomize to the
two
treatments. So, it is multiple randomized trials
in people with different responses. Now, whether
you can do that or not, I don't know, but
I think
it does have the potential for answering
the
question whether the PSA response, in
fact,
predicts an effect of therapy on some
other kind of
outcome, like death.
DR. D'AGOSTINO: But your outcome would be
death?
DR. TEMPLE: Well, you choose the outcome.
Time to progression, I mean I am not
trying to
choose the outcome, one that you feel is
a
comfortable outcome. Could be time to bone mets or
whatever you want really.
DR. HUSSAIN: Dr. Raghavan.
DR. RAGHAVAN: So, this is a composite
answer to a composite endpoint. This is Dr.
Eisenberger and myself muttering
together. So, if
we understood you correctly, and the
randomization
358
comes in patients who have had a PSA
response, it
goes back to what Dr. Hussain said. It is not
doable in the world today, because
patients are so
PSA dependent, irrespective of what
oncologists
think.
Most urologists, as you heard earlier,
believe in PSA, and get excited about the
concept
that it correlates with the disease.
So, if you have a patient with
metastatic
disease, in the early part of their
PSA-associated
lives, PSA is very important as a
parameter of what
is going on. It becomes less important later, but
they have been trained to be PSA
responsive.
So, to say to a patient whose
PSA has
disappeared, well, we are going to flip a coin, and
on the toss of a coin, you might not get
that
treatment that is about to save your
life, has no
chance of working. So, you will get an accrual of
zero.
DR. TEMPLE: Well, not if they can't get
the drug any other way, they won't.
DR. HUSSAIN: Dr. Perry.
DR. PERRY: I apologize.
I feel like a
359
nickel among dimes here, listening to all
the
experts on prostate cancer. Perhaps you could
answer a simple question for me. Everyone
wants to
compare PSA against a hard endpoint, and
I don't
know what that hard endpoint is.
I hear you say that survival
doesn't work
because too many people die of comorbid
diseases,
and it takes too long. it is the ultimate great
endpoint, but for practical purposes it
isn't going
to work.
Time to progression is complicated, and
bone scans don't work.
So, what are we going to
compare PSA
against in these trials?
DR. HUSSAIN: Dr. Perry, I think that in
the hormone refractory setting, I think
patients, 9
out of 10, of they were going to die,
they are
going to die from their cancer, so that
is not a
problem there.
DR. PERRY: It's going to take a long
time.
DR. HUSSAIN: Dr. Perry, the median
survival in a hormone refractory
patient--and
360
perhaps that is where this whole thing
seems to be
sort of, if I want to say, oxymoronish in
some
ways--in the late stage disease, I don't
think we
have too much of a problem of time way
and beyond
any other solid tumor.
The median survival of your
best patient
population that go into chemotherapy
trials is a
year and a half, that is how good we are,
this is
it, a year and a half. So, I guess in my mind, the
hormone refractory setting in front line,
if I may
just put my two cents in there, to me,
the answer
is clear.
It's survival endpoints, get drugs up
there and randomize and get it done with.
Where I think--and perhaps if
we can maybe
just to get focused a little bit--if we
can agree,
for example, that in a front line
setting, survival
should still be front line for brand-new
metastatic
hormone refractory disease, that survival
is the
endpoint because these trials are not
difficult to
do from time points.
It is more in terms of patient
accrual
into the trial, and I think we have
demonstrated in
361
the last 5 to 10 years that we have
really
maximized per year our ability to get
these
patients in to do trials in a short
period of time.
Where I think there may be room
to get
drugs more into these patients is in the
second and
third line setting where now that we have
Taxotere
front line, but it is not exactly curing
patients,
so
the question is can we envision trial designs
that are short of being randomized
700-patient
trials, that would allow us to test some
promising
agents in that setting and give us some
expedited
drugs into the market while we prove the
principle.
If I may ask that we focus on
that point
perhaps, because as I am speaking, I see
everyone
shaking their head that they are agreeing
that,
without even a vote, that survival for
front line
hormone refractory is a done deal, so let's
just
move on.
The question is we have a
second line or
third line setting, whatever you want to
argue it,
can anyone make a recommendation for what
they view
as a trial design that would be of
value? Since
362
there are people who have raised their
hand prior
to that, Dr. McShane, I am going to allow
her to go
first.
DR. McSHANE: Some of the points I was
going to raise have already been raised,
but I
would like to emphasize that to really
establish
something as a surrogate, no matter what
setting we
are talking about, it takes more than a
single
trial.
You have to demonstrate that
repeatedly,
over multiple trials, that the answer you
get on
the definitive endpoint is the same as
the answer
you get on the surrogate, so I think we
need to
keep that in mind.
DR. HUSSAIN: So, is what you are saying
that from everything you heard, that PSA,
as it
stands right now, with all the
suggestions about
its correlation to outcome, is not yet a
valid
endpoint to be trusted 100 percent until
we
validate it?
DR. McSHANE: That would be my opinion.
DR. HUSSAIN: Just so that people know,
363
the two randomized Phase III trials that
Dr. Alison
point out to, the CLGB and the SWOG trial
that is
going to look at Taxotere, Atrasentan
versus
Taxotere, there are built into it
prospectively
criteria to validate the observations that
were
made in the TAX-3 trial, and then the
SWOG-9916
trial, so some validation on percent
decline of PSA
is being built into these trials
prospectively, and
this may, in fact, serve as a model for
cytotoxic
chemotherapy for screening.
Dr. Eisenberger had his hand
first.
DR. EISENBERGER: I just wanted to go back
on the PSA. I think we are trashing too much the
PSA.
The PSA, in fact, is used in clinical
practice extensively. If a PSA is going down, we
know the patients are being helped, if
the PSA is
going up, it's actually most likely not
being
effective, and that is what we use.
We effectively use PSA to
define whether a
therapeutic regimen in the Phase II setting
is
going to be effective or not, and
regardless of
whether we agree exactly on how much and
for how
364
long the PSA declines, this was done in
the
docetaxel regimens, and this is how we
eventually
defined in two, Phase III trials that
there is a
survival advantage.
So, I don't think there is a
question that
the changes in PSA sort of tell us
whether a
therapy is working or not, and here is
the
difficulties. When we are actually trying to pin
this down and look at a surrogacy for any
survival
or any other outcome, this is where there
is a
problem.
Part of the problem is that you
can't do a
trial when the PSA is going down, and
then stop
therapy in a substantial proportion of
these men,
and you cannot continue a trial if your
PSA is
going up, if this is what you design,
just to test
the PSA, I think it would be a waste or
it would be
very difficult to do, and that is why I
think it
would be a waste of resources.
But one of the things that I
wanted to
refocus here, what we are trying to do
here, is we
are trying to come up with a reasonable
hypothesis
365
that need to be incorporated into Phase
III trials
from now on. I don't think it's enough for us to
just do a Phase III trial and find out
whether
there is a survival advantage.
I think what we need to do is
we need to
come up with trials that will look at
survival as
the main endpoint, but also test a
certain
hypothesis, which is reasonable, and I
think we
ought to focus on that here today, and
provide you
with something which is clinically
relevant and
testable in the context of Phase III
trials. This
is what Anthony tried to do and this is
what Howard
tried to do, and maybe we ought to focus
on that.
DR. HUSSAIN: I will get back with you as
the first person to make a hypothesis
once I get
the other individuals to speak, so get
prepared.
Dr. D'Amico.
DR. D'AMICO: I just wanted to
just
highlight a point that has been made, and
that has
been made by several people. In the two, Phase III
randomized studies in hormone refractory
metastatic
disease that we have heard about today,
the SWOG
366
and the TAX-327 study, they accrued
somewhere
between 700 and 1,000 patients in a year
and a
half, and then they had follow-up, and
they were
published four years after accrual
started.
So, I want you to think about
if we had a
surrogate in that setting that was based
on PSA,
that you could figure out within 3 months
after
treatment ended, you have a year and a
half to
accrue, and then after that, another 6
months,
let's say, to do your analysis, 6 months
to have it
peer reviewed and published, when you add
all that
up, that's 2 1/2 years, so you will buy a
year and
a half perhaps at best if everything goes
exactly
perfectly in this setting with the
surrogate.
That doesn't mean we shouldn't
explore
that, a year and a half could be very
valuable, but
I want people to understand exactly what
are we
talking about when we are talking about
end-stage
prostate cancer in a surrogate, we are
talking
perhaps a year, year and a half sooner to
report.
But maybe more importantly, with the
studies that have been designed and have
this PSA
367
constructs built into it, we will learn
something
about the biology. It is conceivable in terms of
study design that if these PSA constructs
aren't
proven to be important, that you can
start somebody
in a randomized study, they achieve a
certain PSA
endpoint which you now know is important,
and you
take them and put them, randomize them
onto the
next study based on that construct, it is
possible
that you might then be able to figure out
something
sooner in the game.
But I just think that the point
I want to
make is a surrogate in this setting could
be of
some value, but if you are looking at the
most
value for a surrogate, clearly, we will
talk about
it later, in earlier disease would be
where that
biggest impact could be made.
DR. HUSSAIN: Dr. Grillo-Lopez.
DR. GRILLO-LOPEZ: Thank you.
I wanted to
make two comments. First, I certainly don't agree
that overall survival should be the gold
standard
even for front line in the setting that
we are
discussing, and if you look at one of the
studies
368
that has been discussed, presented a
couple of
times today, the docetaxel versus mitoxantrone
study, and you see that the median
survival was
reached in 16 to 18 months, that means
that half of
the patients had progressed and died
before that,
so they probably had received some other
therapies.
So, not only the median, but the rest of
that Kaplan-Meier curve was affected
depending on
what other therapies plus a number of
other
confounding factors those patients
had. Overall
survival is not a good endpoint even in this
setting.
The second point I wanted to
make is that,
again, searching for focus in this
meeting, from
what I hear the FDA saying, and from the
content of
the agenda, I think that the FDA is
really looking
for
recommendations for surrogate endpoints that
could be helpful to the FDA in getting
their job
done, and certainly helpful to
pharmaceutical
industry in getting these products
approved faster.
I also hear that some of the
studies, the
large randomized trials that are
necessary to
369
validate the endpoints may take 4 to 10
years.
That was the comment from one of the
speakers.
So, if we were to say that
today, we
cannot recommend to the FDA a surrogate
endpoint,
and that we have to wait 4 to 10 years,
that means
that pharmaceutical companies can really
not
negotiate with the FDA for another 10
years or 4
years to start a trial, which would then
take
another 4 years to complete.
So, we are saying that at the
earliest, if
that happens, we would not be doing
trials based on
or we would not be completing trials
based on
surrogate endpoints for another 8 to 20
years.
So, we need to take some
risk. We around
the table today need to take some risk
and say with
what we know today, which may not be
perfect, which
may not be 100 percent validated, is
there some
surrogate endpoint, PSA, PSADT, whatever,
that can
be used today while we take those 10
years to
validate all of this with 100 percent
certainty.
DR. HUSSAIN: Dr. Temple.
DR. TEMPLE: A point you have made several
370
times now is that if you take people who
are
hormone refractory, we are talking about
much
shorter periods of time, so don't make it
10 years
right away.
The other thing is that I think
Dr.
D'Amico's data on initial therapy show
unequivocally that if you put the right
people into
the trials, namely, people with short
doubling
times, you can do a study very rapidly,
and if you
put the wrong people into the trial, you
have no
chance of ever finding anything, because
there are
not going to be any deaths.
So, that was too discouraging,
I think.
There are ways to do these even if
mortality is the
endpoint, but we have never said that
mortality is
the only endpoint, and if you look at the
approvals
there have been, they used other
endpoints which
occur earlier than mortality.
Can I ask Dr. D'Amico a
question? Even
though people are critical of studies
that show the
relationship between outcome and the
results on a
test, a potential surrogate because it
might be
371
confounded, that is the thing you start
with. I
mean there has to be a relationship
between outcome
and the putative surrogate in an
after-the-fact
way, or you don't have a chance.
So, my question for you is,
have you
looked at nadir, say, as a good candidate
endpoint,
corrected for baseline doubling time,
because in a
lot of the data you showed, the two were
going
together, but one of those is a
characteristic of
the tumor, has nothing to do with
treatment, but
the nadir does have to do with treatment,
so can
you tease out the nadir effect and relate
that to
outcome?
Maybe you have already done that,
because
you would expect that at a minimum, even
if you
weren't entirely satisfied with that
approach, it
is still what you would expect.
DR. D'AMICO: I will say it quickly
because it really doesn't apply to
metastatic
disease as far as I know, because I
haven't looked
at it in metastatic disease.
DR. HUSSAIN: Thank you, Dr. D'Amico.
372
DR. D'AMICO: The answer is they are
independent, because they are both
significant in a
multivariable analysis.
DR. HUSSAIN: Dr. DeGruttola.
DR. DeGRUTTOLA: I wanted to return a
little bit to the topic of validating
surrogates,
and I think an important point here is
that the
goal of the surrogate is to know that the
effect of
treatment on the surrogate predicts the
effect of
treatment on the clinical endpoint, and
there is a
number of ways to do that, as Dr. Temple
mentioned.
The design that he proposed is an elegant
one, but
obviously is only workable when there is
uncertainty about the surrogate, so that
people
will accept the idea of being randomized
even if
they had a surrogate response.
The other approach is just to
collect
information from a number of trials and
show that
you can actually predict the extent of
treatment
benefit from the effect on the surrogate.
A number of people have
commented on the
Prentice condition, and I think the
Prentice
373
condition is conceptually very useful,
the idea
that if you have a test on the surrogate,
it's a
valid test of the clinical endpoint, but
I think
that operationally, it may not be the
best way to
try and approach the issue of surrogacy.
First of all, meeting the Prentice
condition, which is that the hazard of
the clinical
endpoint, given the surrogate, is not
impacted by
the treatment, in other words, once you
know the
surrogate, the treatment gives no
additional
information about the risk of the
endpoint.
That isn't really necessary to
show that
something is a good surrogate. I mean in a case of
using HIV viral load in AIDS, no one has
ever
demonstrated, in fact, that the Prentice
conditions
are met.
Michael Hughes and colleagues work showed
that, in fact, only a relatively modest
proportion
of treatment effect was explained by HIV,
but it
still has turned out to be a very good
surrogate,
as everyone knows from the declining
death rates,
and so on.
The other thing is that it is
not
374
necessary. It may also not really be sufficient.
The problem is that a lot of the analyses
that are
used, are the so-called showing the
proportion of
treatment effect explained is close to 1,
but those
estimates tend to be highly unstable both
in terms
of large confidence intervals, unless you
have
really big treatment effects, and also,
they are
very subject to fluctuations when you
include or
don't include certain covariates, and so
on.
I think that they are useful
analyses to
do, I think you can learn from them, but
I am not
sure that that should be the primary way
of
addressing surrogacy.
The other point that Tom
Fleming has made
a number of times in print with a number
of
colleagues is that there is an
identifiability
issue that if the treatment can have
negative
effects on the outcome of interest by a
different
mechanism from the positive effects, you
can show
that a proportion of treatment effect is
quite
large, when, in fact, the surrogate isn't
explaining most of the benefit.
375
So, I think that while the
Prentice
condition is a useful way to think about
things,
and the proportion of treatment effect
explained,
are useful analyses, other approaches may
be
preferable for establishing surrogacy.
DR. HUSSAIN: Dr. Scher.
DR. SCHER: I would just like to try to
refocus the discussion a little bit. For the
patients who progress on hormones, there
are two
populations, the first line setting where
the
median survival is 18 months, maybe a
little longer
with the stage migration, and the second
line
setting when you are in the order of 12
to 16
months depending on what you look at.
The response in patients after
second line
therapy, using PSA criteria, is less than
15
percent.
So, it is highly unlikely you are going
to see a significant impact on survival.
So, the question I would like
to pose is,
if you are designing a trial based on
survival for
the sake of argument, in which you will
embed some
PSA construct with or without other
measures, would
376
the Agency accept a trial which includes
more than
one intermediate on which to base an accelerated
approval, or are you restricted to
declaring one,
looking at others?
So, for example, if you put in
a trial
which has one metric, which is PSA
response, a
second which is based on a PSA
progression, and a
third which is based on PSA progression
plus
clinical progression, if all of those
three were
proposed in a trial powered on survival,
could you
do an analysis and not be penalized
because you
happen to select number one, number two,
or number
three, as your hypothesis?
DR. PAZDUR: You would probably have to
have some decision tree here. The answer is yes,
but you would have to prospectively
adjust here.
There are many trials that have multiple
secondary
endpoints.
DR. SCHER: But the question is if you are
using one of those secondary endpoints as
the
embedded indication for reasonably likely
to
predict, while the trial goes on to
completion, do
377
you have to declare one, or conceivably
could more
than one be looked at?
DR. TEMPLE: You have to preserve your
alpha, there would be a debate about it,
since
those are obviously not completely
independent, you
have to argue about what the correction
would need
to be, and just--ask Ralph, he will tell
you.
DR. D'AGOSTINO: You are powering it on
mortality, you said, right, survival, so
I think
you could very comfortably run a study
like this.
It may be overpowered on the surrogates,
if
anything, and that's okay, but that might
be what
will happen, and you can protect yourself
in terms
of alphas, and what have you, because you
are going
to have such a powerful study on the
surrogates, it
is the question of do you list the
surrogates, do
you know the surrogates, are we
comfortable enough
with the surrogate that we are proposing.
I had another question I wanted
to ask,
and it goes back to Lisa's in terms of
pushing for
the surrogate. As a statistician, I would be the
last one to say that surrogate variable
don't need
378
careful validation, and what have you,
but
sometimes the hell with that, and when
you have the
accelerated approval, the surrogate is
reasonably
likely to predict a clinical benefit.
If we are talking about
situations, second
line, and what have you, where you might
be able to
put together a reasonable study with the
surrogate,
the proposed surrogate, and then move on
to a Phase
IV that really has an endpoint--
DR. PAZDUR: Or continuation.
DR. D'AGOSTINO: Phase III, it depends on
how long the accrual is. If the accrual is fast,
and the mortality, you know, it is going
to be a
solid one, then, why talk about it at
all.
But you don't want to have the
study based
on the survival as, you know, sort of
losing track
of the fact that if you can run it fast
enough on
the survival, then, you can look at the
surrogate,
and I presume everybody would say that
would be a
fine study.
I am concerned with the
situation when you
are talking about the survival is going
to take too
379
long, trying to get these hard endpoints
is going
to take too long, so can you do something
with a
reasonably likely surrogate, and then put
a more
careful study together where you can
confirm that
surrogate variable.
DR. SCHER: The median time to progression
in the TAX-327 and 9916, was on the order
of 6
months, and if you are looking at median
survival
of 18 to 20 months, that is not--
DR. D'AGOSTINO: If you can do it.
DR. SCHER: A progression-based trial,
whether it is PSA or PSA response, you
would still
be saving 18 months to a year, so that is
significant.
DR. HUSSAIN: Only because we have a lot
of area to cover, I want to ask you to
please be
brief and make the point.
Dr. Klein, you had your hand
up.
DR. KLEIN: I just wanted to add something
to what Dr. D'Amico observed about a
benefit in
terms of defining a surrogate and getting
the
answer 18 months early. That is one benefit for an
380
individual agent, but there is another
benefit. If
we can define that surrogate, we can
screen other
agents a lot more rapidly, and that 18
months is
very meaningful in that setting in
assessing
alternative or new agents. So, there is both
benefits.
DR. HUSSAIN: Dr. Raghavan.
DR. RAGHAVAN: I wanted to just respond to
Tony Grillo-Lopez's comment, because I
think one of
the things we haven't stated today, but
is
implicit, is that there is an awful lot
of work
going on at the moment with the data that
we have
already acquired.
So, I know the TAX-327 team are
busily
playing with numbers, as are the SWOG
team and many
other people around the world. There is the tool
of meta-analysis. So, I think it's a little facile
to suggest that if we don't come up with
the answer
today, we are somehow committing a crime
against
mankind.
I think the reality of the
situation is if
I bring a new product to the FDA
tomorrow, and we
381
set up a series of parameters that I
embed in my
trial, those parameters will have better
data
available to help evaluate them by the
time the
study is done.
So, it is not as if, as has
been implied
now a couple of time, that it is a bad
thing to do
this in a scientifically rational
way. There will
be data.
Nothing that anybody has said today is
going to come out of left field as a
surprise.
We know what the current
potential
surrogates are, and that is why I was
making the
plea to embed them. I still think, Mike Perry,
survival is a good place to anchor
this. That was
the point I was making.
Where it becomes blunted is if
you don't
take the state's model into
consideration, in other
words, survival for someone with early
stage
disease becomes much more hard to
interpret.
DR. HUSSAIN: Dr. Sridhara.
DR. SRIDHARA: I just wanted to go back to
Dr. Scher's question of having three sort
of
PSA-based endpoints and how do we deal
with it if
382
we want to keep all three of them as
primary
endpoints, and in this case, you are
powering the
study for overall survival.
I think if you can prioritize which one of
them is the first one that you are going
to look
at, then, probably you don't have to pay
a penalty,
in other words, if you can go, okay, this
is the
first one, this is the second one, and
this is the
third one.
But I think you have to
carefully examine
the data that is already available, what
would be
these three, and how would you
prioritize. If you
think of PSA response and PSA progression,
obviously, you will be seeing PSA
response before
you see the PSA progression.
So, there will be some kind of
time effect
in your prioritization of how you want to
look at
it, and whether you want to give higher
priority
for progression, that may be something
that you
want to look at, and then we can deal
with it
statistically. That is not an issue.
DR. HUSSAIN: Dr. D'Agostino.
383
DR. D'AGOSTINO: If we are talking about
the setting where you can do a mortality
trial and
get it done in a reasonable amount of
time, then,
putting forth different variations of the
surrogate
can I think easily be put in, and they
probably
will have a lot of power.
You can put them in a sequence,
as you
said, but probably if we are clever
enough, we
could probably have a reasonably good
power on all
three of them, three or four, so I think
that would
be a very sensible type of design.
DR. HUSSAIN: Can we then use that
criteria for first line?
DR. SCHER: Yes.
DR. HUSSAIN: Powered for survival and use
other endpoints. Howard?
DR. SCHER: Yes. I
mean I obviously have
a bias toward progression, because I
think that PSA
response doesn't capture all the
information that
you can learn, and there is a time
factor, but I
think if people can start developing
trials, and
not pay a penalty for selecting one,
then, we have
384
really made significant progress.
DR. SRIDHARA: I think if you can
elaborate on how you are going to define
this
progression, that would be important,
like how
often are you going to measure this, and
how are
you going to deal with missing values if
it comes.
I think these are the issues
that we come
up with progression in other solid
tumors, when we
are trying to measure progression, it is
a question
of how often you measure, and if you have
missing
values, how are you going to deal with these
missing issues, and those have to be very
specific.
DR. HUSSAIN: Let me ask you then a
question.
Supposing you have drug A you are
testing against Taxotere, and drug A wins
against
Taxotere for a primary endpoint of time
to
progression by, say, 4 months, and the
survival is
no different, is that drug not worth it?
DR. PAZDUR: Why?
Why isn't the survival,
why aren't you winning that survival?
DR. HUSSAIN: If I am God, I will answer
it, but I am not.
385
DR. PAZDUR: I guess the question that I
am asking, is it crossover effect, is it
inadequate
powering of the trial--
DR. SCHER: Or is it a bisphosphonate that
doesn't affect survival and affects
clinical
events.
DR. HUSSAIN: If the drug is brought here,
and
it has a phenomenal time to progression or
progression-free survival benefit, and
not a
survival advantage, I guess that ties
into my
question that I was going to ask you,
have there
been drugs approved based on a progression-free
survival?
DR. PAZDUR: Oh, of course.
DR. HUSSAIN: Even though there is no
survival advantage?
DR. PAZDUR: Of course, correct.
DR. HUSSAIN: So, a setting like this
would not basically kill the drug.
DR. PAZDUR: As long as there is not a
decrement in survival.
DR. TEMPLE: We have brought this question
386
to the committee. There are at least two major
reasons why you don't see an effect on
survival.
One is that people cross over when they
progress.
That has got to go in the direction of
not showing
an effect even though you don't know how
big it is.
The second is just as a hazard
ratio
matter, going from 10 to 8 is as bigger
effect than
going from 20 to 18, so survival is more
difficult.
It is clearly more difficult especially
if it's at
some distance from progression.
So, yeah, there are a lot of
drugs that
have been approved based on progression.
DR. HUSSAIN: Dr. Grillo-Lopez.
DR. GRILLO-LOPEZ: There is two points I
would like to make. My friend at the end of the
table here, I don't know that anything
has been
approved on the basis of a meta-analysis
as a
primary pivotal trial although it is
useful in
support of certain data.
But more importantly, the word
"accelerated" means to be
faster than something, in
this case, regular approvals, and the
more we make
387
the accelerated approval mechanism
similar to the
regular approval mechanism, the slower it
gets.
So, we tend to discuss
randomized trials a
lot, and, yes, those are more elegant,
perhaps they
give you greater security that you are
doing the
right thing, but the faster way to
develop a new
agent is with a single-arm trial with the
appropriate endpoints, and that is where
this
committee has to take some risk today and
come up
with suggestions to the FDA on some
appropriate
endpoints for those kinds of trials.
I like the situation where Dr.
Temple is
the optimist and I am the pessimist,
because it
allows me to make my points more strongly
and gives
me hope that you are going to act faster
in
approving drugs.
So, I look at prostate cancer
drug
approvals, and in the past 24 years,
there has been
three.
It is better than nothing, but it is a
dismal record for prostate cancer
patients that
only three new agents have been approved
in 24
years, ladies and gentlemen.
388
The other thing that I want you
to
consider is that as you look at the
audience here,
this is a relatively small audience this
afternoon,
and if you discount the analysts, the
media people,
and if you count only the company people,
the
pharmaceutical company people who are
here because
they have under development a prostate
cancer
agent, there are very few of them.
We need to ask ourselves why,
why is there
not more interest in developing new
agents for
prostate cancer, and, in part, it may be
the
hurdles that they have to overcome in
getting these
agents approved.
DR. TEMPLE: I really must respond. There
is no evidence that supports what you are
saying.
There may just not be any drugs around. We don't
know whether it is the difficulty. I really don't
think that is fair, and I don't think you
should
say it.
DR. HUSSAIN: I have to agree with Dr.
Temple.
DR. GRILLO-LOPEZ: But he didn't raise his
389
hand.
I need to rebut him, he did not raise his
hand.
He jumped in and he had interrupted me once
before also in the same manner without
raising his
hand and asking you for a turn.
DR. HUSSAIN: Dr. Temple, please raise
your hand.
DR. TEMPLE: Shall I repeat it?
DR. HUSSAIN: You have the floor.
DR. TEMPLE: I just don't think you can
say what the reason for the lack of
interest in
prostate cancer is. I certainly don't know what it
is.
In fact, if you look at the approvals that
there have been, they are not
particularly
burdensome, they have not required
survival for the
most part, so I just don't think you can
say what
you said and know that it's true.
DR. HUSSAIN: Dr. Williams.
DR. WILLIAMS: Your question about time to
progression, I think it was a bit
abstract in this
setting. Yes, we have used time to
progression in
other settings with solid tumors you can
measure.
One of the biggest problems in
prostate
390
cancer is that we don't have time to
progression,
we have time to PSA mostly because people
change
therapies, and therefore, we don't, in
general,
have time to progression, and I think the
point
could we use time to progression is a bit
abstract
unless we really develop an endpoint that
we can
call time to progression, believe there
is time to
progression, believe it represents what
time to
progression represents in other settings,
and also
can measure without 40 to 60 percent
missing data.
So, yes, we have done it in
other
settings, but one of the biggest problems
in
prostate cancer is we don't have a time
to
progression endpoint.
DR. HUSSAIN: So, for this part, I am
going to take one more response from Dr.
Brawley,
and then I would like us to go to the
next session,
and those of you, while Dr. Brawley is
speaking,
think about what you would like to be
hypothesizing
to test in the context of a Phase III
trial or a
Phase II trial for that matter.
Otis.
391
DR. GRILLO-LOPEZ: Can I ask for a turn,
because he has made a statement that I
have no
basis for what I have said. I have to rebut that.
DR. HUSSAIN: Then, I will give you a
moment after Dr. Brawley has done his
presentation.
Yes, sir.
DR. BRAWLEY: You actually may want to
rebut me, too. I have had the opportunity to do
compare and contrast between prostate
cancer and
breast cancer. Why is it that a number of the very
basic fundamental questions in breast
cancer, such
as does mastectomy or lumpectomy save
lives? Why
do we have the answer to that, yet, in
2005, we
still have an open question is radical
prostatectomy better than watchful waiting?
Part of the answer--and it
relates
directly to this validation of a
surrogate endpoint
issue--so frequently over the last 30
years, men
with gray hair have just wanted to jump
to a
conclusion, and not be very scientific
and not
validate surrogate endpoints, and that is
why it is
really important that we finally get
around in this
392
disease to finally being scientific in
doing it.
One of the reasons why no drugs
have been
developed, and we have studied this
issue, as well,
is actually the doctor community that
treated
urologic diseases in the 1970s and 1980s,
or
especially early '80s, were not very
friendly
toward randomized clinical trials. They and your
patients already knew all the answers, so
why do
the science.
One of the wonderful things
over the last
15 or 20 years is you now start having a
number of
very sophisticated urologists, some of
whom are in
this room, like Dr. Klein, who are
designing
clinical trials.
Now, some of those clinical
trials, even
today, we are having trouble getting men
to go into
those clinical trials, so we can finally
get the
answers.
All you have to do is look at all the
cooperative group clinical trials in
prostate
cancer that are not filling up with
patients,
unfortunately, because so many men know
what the
answers are now and don't care about
their sons
393
actually getting real answers applied to
them as
opposed to fake answers.
DR. HUSSAIN: I am going to give you, Dr.
Grillo-Lopez, some time to respond, but
if you
don't mind being brief, so that we can
get into the
second part, which is what you had been
advocating
for, is to hypothesize something that we
ought to
test, so if you don't mind, go ahead.
DR. GRILLO-LOPEZ: Very briefly.
I am
glad to see the FDA jumping in and
commenting every
time I say anything, which means that
what I am
saying is important enough and/or
controversial
enough to merit a response from them even
if they
don't raise their hands and ask for a
turn.
Secondly, I am on like seven or
eight
scientific advisory boards. All of them are small
companies, but they do have three to five
or more
new agents that are in clinical trials.
Of all of those, there is only
one agent
that is going to be studied in prostate
cancer,
because for a variety of reasons, these
companies
have been dissuaded from studying their
promising
394
agents in prostate cancer, and that is
why they are
not here today. Only one of those companies is
represented here today.
DR. HUSSAIN: Thank you.
The second point that I think
we need to
discuss before we go to early stage
disease is the
issue of the fact that there are several
PSA-based
endpoints that are possible. We are to discuss the
approach to select the endpoints for
further study
in a prospective clinical trial.
While you are thinking about
that, I
thought I will summarize what I heard from
the
first part of the discussion, which was
very lively
and I think very informative, in that we
are all
agreeing that survival is good for
metastatic
hormone refractory disease front line,
but we are
also willing to entertain the possibility
of
designing trials with some composite,
albeit
clinically meaningful, endpoints in
trials that are
powered for survival--is that a fair
estimate--and
that whatever PSA exploratory analyses
that there
are will need to be validated in the
planned
395
prospective Phase III trials.
So, those who are from industry
out there,
you have your work cut out for you. We need those
trials.
I had promised that I was going to call on
Mario first and then Derek next for the
issue of
what PSA endpoint to look at or whatever
other
composite endpoint we want to look at for
surrogacy. Mario.
DR. EISENBERGER: I just want to again
point out that only recently we had two
prospective
randomized Phase III trials showing a
survival
advantage. I think all of us now are very busy
looking at the databases and come up with
models
that represent reasonable hypotheses.
I was gratified to hear that
the Agency
may be considering approving drugs if you
look at
different models and different paradigms
as long as
they are clinically relevant or clinically
meaningful.
The question is if you
hypothesize
something where there isn't agreement
that this
could be clinically relevant, and the
trial is
396
approved for survival and possible
survival and is
accrued, if you reach that endpoint early
on, even
though
you don't have survival data, could that
constitute reason for an accelerated approval
without demonstrating that there is a
survival
advantage at this point?
DR. PAZDUR: Yes, that is the while
purpose of accelerated approval.
DR. HUSSAIN: Yes, that is what we just
said.
DR. EISENBERGER: What I did not hear, at
this point we don't have a validated
model that has
shown to correlate with survival, so I am
talking
about--
DR. PAZDUR: But I think, you know, that
would have to be discussed and it is
something that
we would have to agree with, with the
Advisory
Committee, et cetera, and this is one of
the
reasons why we are holding this is, is
there an
endpoint that is reasonably likely to
predict
clinical benefit.
Remember, we are not asking for
surrogacy
397
via the Prentice criteria here. Remember our past
accelerated approvals, they have been on
response
rates that are 15 percent, 10 percent, 20
percent,
and I think in the oncology world, people
could
question whether these are true
surrogates, but we
have accepted these as reasonably likely
surrogates.
The other point, we are talking
about
these endpoints as if they existed in a
vacuum, and
not having any magnitude to them. For example, if
we took an endpoint that was a PSA nadir
of a
certain value that was predefined, there
is a
tremendous difference between a drug that
produced
a 5 percent PSA nadir versus something
that had a
90 percent PSA nadir in the population.
So, I think we have to think
about that
also in making regulatory decisions and
also
looking at these endpoints that are still
yet to be
proven.
There is a magnitude here that has to be
looked at also.
DR. HUSSAIN: Just remember this is your
chance to recommend whatever your wish
list is of
398
potential PSA endpoints or other
potential
endpoints that are to be put forward for
the test,
so that is exactly what we are talking
about here,
and I would like us to not go back to
what we
discussed about approvals and otherwise.
Dr. Raghavan, you are next.
DR. EISENBERGER: Can I just say on
TAX-327 at this point we are defining a
progression
model, you know, censoring was initial,
and we are
reformatting the database, coming up with
a
definition of a progression composite
that
correlates in a multivariate analysis
with
survival, and that will then be a
testable
hypothesis for a subsequent Phase III
trial, which
will be powered for survival.
So, if you reach a reasonable
test of that
hypothesis, as I understand that could be
as long
as it's reasonable, the reason for
accelerated
approval.
DR. PAZDUR: A lot of it depends on the
magnitude of change here that we are
seeing in that
endpoint.
One thing that is dangerous about these
399
composite endpoints that we are talking
about, that
have PSA as one of the composites, is the
whole
endpoint may be driven by the PSAs.
You know, if you are taking a
look at bone
scanning plus PSA, let's face it, that
whole
endpoint is going to be driven by PSA
changes, and
we are kind of fooling ourselves by
calling it a
composite.
DR. HUSSAIN: Dr. Raghavan.
DR. RAGHAVAN: So, I am going to
hypothesize and run. I would suggest that we begin
to explore strategically for accelerated
approval
the use of the 3-month PSA 50 percent
reduction,
and I like Howard Scher's idea of
multiple
endpoints, so I would add to that a 75
percent
absolute PSA reduction.
I would put in the caveat, just
to remind
everyone of history, Dr. Temple and Dr.
Justice
were troopers here when I was on ODAC,
and we had a
very controversial drug that came to us
that was
fated on two bases, wonderful PSA
responses,
wonderfully high level of toxicity, and a
400
pharmaceutical company that had one
pivotal trial,
and were outraged when we turned them
down.
The reality of the situation
was that the
turndown was based on inferior survival
in the test
arm, so the divorce of survival from
surrogate
endpoints shouldn't be allowed to happen,
because
it is a trap.
I am totally sympathetic to Dr.
Grillo-Lopez that companies can go
belly-up with
new products, but the flip side of that
is
companies can make a lot of money from
good
products.
I personally don't lose any sleep over
the fact that all the drugs that don't
work in
prostate cancer haven't been
approved. I totally
agree with Bob Temple, why would we prove
ineffective drugs.
So, I would hypothesize that
PSA time
dependent kinetics are worth exploring,
but that
that exploration should not be divorced
from a
standard that we know in hormone
refractory
disease, which is survival.
DR. HUSSAIN: Just to modify what
you
401
said, or to ask you the question, is it
important
to bring your PSA down or is it important
to bring
it down and keep it down?
DR. RAGHAVAN: I would say we need to do
both.
That is why I like Howard's idea of being
flexible.
I would bring it down and keep it down,
and we have some data from SWOG,
preliminary, that
suggests a 3-month time point, and I have
proposed
a 75 percent reduction, and I am not
going to fight
anyone, if they want to make it 50
percent
absolute, that's fine. I just think 75 percent is
setting the bar a little higher as we
understand
it, and I figure that is a good place to
start the
discussion. But I am going to leave now, so thank
you.
DR. HUSSAIN: Dr. D'Agostino, and then Dr.
Scher.
DR. D'AGOSTINO: I may be asking out of
turn, because I want to go back to the
accelerated
approval.
If it was a mortality study, you have
the surrogate, a likely surrogate, you
give
approval, then, you tell them to continue
this
402
mortality trial. You don't stop and start all over
again.
DR. TEMPLE: But, Ralph, that is if the
accelerated approval is based on the
early phase of
a trial that is ongoing.
DR. D'AGOSTINO: Exactly.
DR. TEMPLE: As you know, because they
were presented to the Oncology Committee,
we have
not always done that. Sometimes you have to start
a new trial, and that doesn't always
happen, et
cetera, et cetera.
DR. D'AGOSTINO: No, but this fits in
nicely with the way we are talking about
a
mortality trial with surrogate endpoints
built in,
and then you can move on.
DR. PAZDUR: And that accelerated approval
paradigm is commonly used in AIDS with
6-month
viral load reductions going on to 12
months.
DR. HUSSAIN: Dr. Scher.
DR. SCHER: I was just, you know--
DR. HUSSAIN: Oh, you are
deferring to
someone else? Dr. Temple, sir.
403
DR. TEMPLE: No, I had a fundamental
question.
There are now enough data, I would have
thought, so that one could start looking
among the
trials that exist already and look at
various
candidate surrogates and see, you know,
with all
the flaws that this after-the-fact stuff
has, and
see at least whether they predict, so you
would be
able to say a 50 percent reduction, no,
that
doesn't tell you anything, 90 percent
reduction,
that is pretty good, that does predict.
So, there ought to be some way
to look at
those right now and see which ones are
promising
candidates. You can tell me I am wrong, but that
is where you would usually start.
DR. HUSSAIN: In fact, this is what I was
making a comment about. In the SWOG-9916 trial,
there is PSA data that has been
analyzed. It may
turn out that different cutoffs are more
in line
with the Prentice prediction of a
surrogate than
others, and that is what is going to go
into the
prospective validation.
As we speak, the paper has been
written,
404
so the information will be scrutinized
and come to
publication, but after Dr. Scher speaks,
I have a
question to the FDA.
When was a response ever
validated as a
surrogate by all the harsh criteria that
we were
asked to comply with? Has any disease where you
accept response as a measure to approve a
drug
where a response actually was rigidly,
you know,
scrutinized for the Prentice criteria or
any other
criteria?
DR. PAZDUR: Here again, you know the data
in prostate cancer, breast cancer, colon
cancer.
There is a great deal of debate regarding
response
rates and their even correlation to
survival, let
alone true surrogacy.
That is why we have used those
generally
as reasonably likely, and here again, I
think when
one
takes a look at a response rate, you know, you
have a number of complete responses,
duration,
where they occur, are they associated
with
symptoms.
You know, it is a very complicated
issue, and it is not just in a vacuum here.
405
It is a complicated thing and
there isn't
a lot of data here. You know, they are still
arguing about response rate correlation
in colon
cancer with survival, the area that I am
familiar
with, and a lot of this has to do with
our
therapies in the 5-FU era were so meager.
DR. HUSSAIN: Howard.
DR. SCHER: I don't know how specific you
would like to be, but I would like to
make the
argument that there is a durability
component that
is important to the response
duration. Again,
looking at the median, I would put the
bar at 6
months for the response, whether it's a
50 percent
decline.
I would also add the no rise
versus rise,
because you do see patients who do
achieve their
nadirs beyond 6 months and some patients
who
benefit who never achieve a 50 percent
nadir.
Those patients would be, I would argue,
devastated
if they were taken off treatment when
their PSAs
were going down with no other signs of
progression.
I was very encouraged by Dr.
Sridhara's
406
comments that we could look at multiple
endpoints
at the same time and just power the trial
based on
the one that might occur most distally
using a 6-
or 9-month time frame.
DR. HUSSAIN: Just for the sake of my
summary here, and I don't mean to
interrupt you,
what was your first proposal?
DR. SCHER: I would add no rise versus
rise in PSA.
DR. HUSSAIN: And that is the only
proposal that you made?
DR. SCHER: And I would add one that would
include as progression, objective
measures
obviously to be discussed, you know,
either
clinical deterioration or change in
therapy. When
we looked at our patients on first line
microtubular targeting agents, 120-odd
patients
were treated, about 85 went on to second
line
therapy.
The median time to administration of a
second chemotherapy was 6 months.
So, that is essentially where that is
coming from and arguably, the decision to
change
407
chemotherapy would suggest that the
patients needed
a change in treatment. This wasn't a soft
endpoint.
DR. HUSSAIN: Just so that we don't stay
all night--unless you want to, and I am
happy to
stay because I am here until
tomorrow--what I
wanted to do is not miss the discussion
on early
stage.
I have here Dr. DeGruttola who had his hand
up and then Dr. Sandler and then Dr.
D'Agostino,
and then we will move to the early stage
disease.
DR. DeGRUTTOLA: I just want to say
briefly in response to the question about
are there
other diseases in which there was
extensive
analyses of surrogate that led to changes
in FDA
policy, and I think AIDS is an example of
that with
the viral load measure, surrogacy
analyses were
done.
In addition, it was found that
with more
potent drugs, you could drive virus below
levels of
suppression, at which point immunological
decline
was very much slowed down, in fact,
immunologic
function definitely improved, and I would
think if
408
it were possible in the prostate setting
that some
people could be driven to PSA levels
where
progression is really quite rare, I don't
know if
that is possible, but that would be sort
of
comparable to the AIDS setting.
Even if that weren't possible
in most
patients, but it were possible in some,
and in
those patients, they didn't progress,
progression
rates are really low, then, I would think
that that
would be the kind of evidence that might
be
developed without needing a whole large
range of
studies.
DR. HUSSAIN: Dr. Sandler.
DR. SANDLER: My question is were you
going to save some time to talk about
localized
disease, and you answered it, thank you.
DR. HUSSAIN: And I just said yes.
Dr. D'Agostino.
DR. D'AGOSTINO: I just want to make sure
that because we are saying you can do
three or four
endpoints, the surrogate endpoints, that
that makes
it an easy task. I mean one has to be
very careful
409
about how you do spend your alpha through
them.
You don't necessarily just
power against
the one you think is least likely, so you
want to
keep us statisticians in business and
make sure you
visit one.
The other is that when you move
to these
surrogate endpoints, then, the visit
scheduling,
and so forth, that we were talking about,
becomes
very, very important. I mean you are not just
asking did the person live or die, you
are asking
within a month, within a week, and so
forth, what
is happening, and so it is a whole
different level
in following these endpoints, and that
has to be
built into the studies.
DR. HUSSAIN: Thank you.
So, if I were to
summarize as to what hypotheses on the
table to be
tested, it is a percent decline of PSA,
and it is
your wish 50, 75 less or more, at some
finite
period, percent decline of PSA at 3
months. Dr.
Scher suggested no rise versus rise plus
some other
objective criteria for progression.
Are there any other suggestions
or ideas
410
or thoughts or hypotheses? Okay.
Then, I would like us to spend
the rest of
the time--and I would want to point out
there is
one population that we have not gotten to
speak
about, which I think is very important
because
there may be a clear answer in it, and
that is the
non-metastatic androgen-independent
patients where
potentially time to development of
metastases would
be a good endpoint in randomized trials,
and it
will not take a million years to get.
So, if I may sneak this in and
put that as
a conclusion statement and move into the
early
stage disease, and open the floor for
that. Mario.
DR. EISENBERGER: We don't have enough
data to give you a more solid, concrete
model, so I
would like to ask you the opportunity for
maybe in
the next three months to provide the data
from
TAX-327.
DR. PAZDUR: Yes, that would be fine, and
here again I want to emphasize one of the
reasons
why we are having this workshop is an
exploration
of ideas.
This is not the last time that we will
411
be discussing this whole issue, believe
me, and we
will be bringing this back and hearing
from you and
doing other discussions with you before
our next
ODAC.
DR. HUSSAIN: So, who wants to start the
discussion? Dr. Sandler.
DR. SANDLER: Thank you.
I think I would
first just like to congratulate Anthony
D'Amico
because I though this presentation was
terrific,
and the idea of the PSA nadir of 0.2 as
being a
sign of treatment progression or the
hormone
refractory state, I think is fascinating.
In terms of localized disease,
something
relatively uncontroversial, I hope, and
that is
that for a novel local ablative
technique, such as
radiation, surgery, cryotherapy, who
knows, some
new novel local technique, I think that
simple
biochemical failure is an adequate
endpoint for a
clinical trial.
I think that has wide
acceptance in the
community, something that Rick Pazdur
mentioned in
his introductory remarks, so in my mind,
if I am
412
thinking of a new machine or a new
radiation
technique, and I define a Phase III
study, while I
would love to collect data for survival,
I think
that primary PSA failure is an adequate
assessment
of the efficacy of the novel technique.
I don't know whether that is
worth
discussing or not, but I think since some
of it may
be outside of CDER, but I think it is an
important
issue nonetheless, especially since it
affects how
CTEP deals with a lot of prostate cancer
clinical
trials.
DR. HUSSAIN: Just so that I understand
it, and clarify it, that would be
applicable to an
intervention at the prostate level
modality, you
are not suggesting that, for example, for
radiation
and Taxotere, to have a PSA endpoint.
DR. SANDLER: Right.
I am thinking of
radiation A versus radiation B. Although I think
there is data to support the ability to
use
short-term hormone therapy concurrent
with the
novel therapy, and still have an adequate
PSA
endpoint, for example, in the radical
prostatectomy
413
trials where neoadjuvant hormone therapy
was used,
there is wide acceptance that there is no
difference in biochemical failure, and
that has
affected the way therapy is done in the
U.S.
So, I think that a biochemical
endpoint,
even with short-term hormone therapy, is
adequate.
DR. HUSSAIN: Dr. Klein.
DR. KLEIN: Just a follow-up question for
Dr. Sandler. There is a lot of controversy over
how you define PSA failure for therapies
that leave
the prostate in situ and I am wondering
if you
could suggest to us some consensus
definition that
would be appropriate.
DR. SANDLER: I think that there is a lot
of controversy, as you mentioned, in
terms of the
radiation community as to when you
declare someone
a failure. If someone really has cancer, they will
express it by having an elevated PSA, so
the
question is not whether they failed or
not, but
maybe how quickly you can call the
failure and how
important the failure is.
In the radiation community, we
are moving
414
from the well-used ASTRO definition of
three
consecutive rises in PSA to a discrete
rise of 2
nanograms above the post-therapy
nadir. The
advantage of that definition is that it
probably
works for both patients who received
hormone
therapy and radiation and those who
received
radiation therapy alone.
I think in the surgery
community, there is
even some controversy as to when
biochemical
failure occurs, but if you really have
cancer, it
doesn't really matter whether you call it
a 0.3 or
0.4 or 0.5, it will show up.
DR. HUSSAIN: Dr. Bross.
DR. BROSS: Yes, I am from the Center for
Biologics. I would like to thank the gentleman
from the open public hearing. He is the only one
who has mentioned vaccines so far, and I
will say
in contrast to the metastatic indication,
there are
a lot of vaccine studies, and we
desperately would
appreciate advice from the Advisory
Committee in
terms of what is the appropriate trial
design.
At the moment, we have a number
of study
415
proposals that propose to include
patients with a
rising PSA, usually PSA doubling time of
less than
six months, say, and the question is, is
this an
appropriate endpoint.
Dr. D'Amico suggested less than three
months was more associated, and also what
is the
appropriate trial population, is there a
population
of patients with rising PSAs and no
metastatic
disease.
That would be the easiest to
study because
then you just study the time to
development of
metastatic disease, and also, what is the
appropriate measurement of metastatic
disease. We
don't usually accept bone scans, but in
this case
it may be appropriate.
So, we would very much
appreciate any
advice you can give us with respect to
this
population.
DR. HUSSAIN: Dr. D'Amico.
DR. D'AMICO: I think it is important that
we
stay to the topic because we have gone
completely away from the rising PSA state
just
416
following surgery or radiation, and,
Maha, maybe it
would be good for you to phrase the
questions that
you want us to answer in that particular
disease
state. Maybe they are the same questions
we just
did.
DR. HUSSAIN: It's the same question as to
the PSA endpoints, but dealing with early
stage
disease.
In early stage disease, I think there are
two settings. There is the brand-new patient where
you are trying to maximize and/or improve
local
therapy for with or without systemic
treatment or
some other modality, and then there is
the setting
of rising PSA post-local therapy.
Howard began making comments
about the
first part, and then, of course, there is
the
rising PSA. If I may make a suggestion, because
the
bulk of the population that we struggle with is
the rising PSA post-local therapy, if you
don't
mind that we focus on that population,
and Dr.
Bross raised the question regarding, for
example,
vaccines in that setting and what kind of
trial
design, if, Anthony, you want to take
that.
417
DR. D'AMICO: I think in the talk that I
gave, I really tried to focus very
carefully,
because I don't think you can explore all
types of
drug classes with one study design, and
so that the
design that I put forth was one in which
you take a
very unfavorable population, short
doubling time.
You can justify hormonal
therapy as the
conventional treatment, and then you
randomize them
to the plus or minus a cytocidal agent in
which the
endpoint and progression is not nadiring.
So, I think that with vaccine
therapy,
this trial design would not apply
necessarily,
because--again I am not an expert in
vaccines, but
my understanding is that whether it's
cytocidal or
cytostatic is a question.
If it's cytostatic, I don't
think you
should apply such a design with a nadir construct.
If it's cytocidal, you might be able to.
DR. HUSSAIN: If I may just take the
Chair's prerogative to make a comment, I
am not so
sure that the rising PSA population--and
I am going
to go out on a limb to make that
statement--is the
418
appropriate population for drug
discovery, so that
if you have vaccines that have not shown
evidence
of activity in advanced disease, to me it
is wrong
to bring them into the minimal disease
setting
trying to prove a point.
So, to me, this population as
Anthony
suggested, is perhaps a population where
we would
have some drugs that have shown some
evidence of
activity in advanced disease in some form
of
setting, that we know they will have a
chance of
working, and then bring them into the
early
setting.
Howard.
DR. SCHER: I will respectfully disagree.
I think there are patients within this
cohort who
have a relatively favorable prognosis,
yet, who are
extremely concerned about their doubling
times and
rising PSAs, who do not want to undergo
medical or
surgical castration, in whom there is an
opportunity to explore vaccines.
This is actually in some cases
ideal
because you have a biomarker. In designing the
419
trial, I mean I think you can do
exploratory
studies in patients with modest doubling
times, we
have selected a year or two as that
window.
If you are looking for a patient
with a
rapid doubling time, that is not the
group I would
use an experimental untested vaccine, but
if you
did see some efficacy or some effect on
PSA,
recognizing it has problems, a design
that could be
used is a discontinuation design with
hormones plus
or minus the vaccine.
So, we have actually looked at
effects of
hormones, and looking at long-term
survival, as
suggested, there are patients with
minimal tumor
burdens who may, in fact, be cured with
hormones
alone, and if you want to integrate
cytotoxics, you
would have to build on those results.
So, you could then look at what
proportion
of patients reach a nadir that is
undetectable and
stay there as one readout depending on
the level of
effect that you see.
So, I think to try to do this
study
looking at what is a reasonable endpoint
of
420
objective metastatic regression would be
very, very
difficult as the PSAs are going up. So, you would
have to show some treatment effect first.
DR. HUSSAIN: Dr. Williams.
DR. WILLIAMS: Anthony, I think to clarify
your endpoint, because I think I
understand it from
our earlier discussions, it is a
dichotomous
endpoint which is measured at a certain
length of
time after a patient is treated, perhaps
8 months,
so
at 8 months, the percentage of patients who will
have not nadired, that is the endpoint
you are
suggesting, is that correct?
DR. D'AMICO: That's correct, and the 8
months is important because multiple
studies have
shown that it can take up to that long
for that to
occur, and the way the study would be
exactly
powered is you would use from the data
available
with hormonal therapy alone, you would
know the
percent of patients who would achieve
progression,
that endpoint, not nadiring, and then you
would say
I would like to see a 10 percent or 15
percent
difference.
421
I think having said that, it
would be
important that that study looked at that
as an
endpoint, but that it be powered for time
to
distant disease, which is your clinically
significant endpoint, you know, beyond
the rising
PSA.
DR. HUSSAIN: Dr. Sandler.
DR. SANDLER: I just wanted to comment
about the rising PSA situation after
local therapy.
Usually, we are talking about rising PSA
after
surgery.
Now, those patients could have
distant
disease, but there is a certain subset of
patients
with a rising PSA after surgery who only
have
localized disease, so in the design of
clinical
trials testing new systemic therapy, I
think we
should be careful to either mandate or
allow local
therapy, such as radiation, prior to
enrollment.
I mean I think that it is
potentially
unethical to treat a localized prostate
cancer
patient only with an untested novel
systemic
therapy.
422
DR. HUSSAIN: Dr. Martino.
DR. MARTINO: Just a basic question to
those of you who deal with this
disease. Given a
patient who has had local therapy only, a
newly-diagnosed patient, be it surgery or
radiation
plus or minus whatever hormonal therapy
you folks
like to use, and then you are watching
them and
their PSA rises, do we actually know that
you
intervening at a time before there is
clinical
symptomatology actually alters anything,
and what
is that something that is altered, is it
survival
or is it time to clinical event?
DR. HUSSAIN: If I may answer that, and
that is, there is no prospective data
that has
demonstrated an impact of an intervention
in a
randomized manner, so that is a fact of
life.
The history of hormonal therapy
in this
setting is that over and over again, not
necessarily in the rising PSA, but if you
look at
all the hormonal trials historically,
there is an
indication potentially that hormone
therapy may
delay progression.
423
If you give it adjuvantly, you
can prolong
life, but no one knows whether you
intervene today,
when the PSA is 5, versus when the PSA is
100, or
when you have metastatic disease, that
survival is
impacted.
So, that is an unknown, and
that is the
biggest shame of our community, is that
that simple
question has not been answered.
DR. MARTINO: Whether it has altered time
to
clinical symptomatology.
DR. HUSSAIN: Well, clinical
symptomatology is a bit late in the
process. I
think we know it delays metastases. There have
been trials looking at early versus
delayed
hormonal therapy for patients who have
either
upfront metastatic disease or locally
advanced
disease, indicating that those who have
been
treated with hormones have less odds of
developing
symptomatic disease, that there is more
cord
compression, bladder outlet obstruction,
things of
that sort.
Understanding that this is not
the case in
424
this country, patients get treated early
when they
have metastatic disease, and as you heard
from Dr.
D'Amico, a fair number of people in the
community
are treating simply by a rising PSA.
Dr. Scher.
DR. SCHER: We don't have sufficient data
in terms of overall survival, but again
looking at
long-term outcomes, the difference in
survival
appears to be similar to what you see in
breast
cancer populations.
So, we have actually looked at
the
proportion of patients who achieve a
nadir of zero
post-prostatectomy, and, yes, we included
radiation
patients, in relation to whether they had
minimum
metastatic disease and their PSA levels,
and not
surprisingly, there is an association.
So, why not, with the
availability of
cytotoxic drugs, why can't we just shift
the
paradigm to try to make an undetectable
PSA as our
endpoint, and ideally, if you have an
undetectable
PSA, and the patient is off hormones, and
their
testosterone levels are normal or back to
their
425
baseline, arguably, those patients may,
in fact, be
cured, and I think that is where we should
be
setting the bar for the patients who have
aggressive disease.
DR. HUSSAIN: Dr. Eisenberger.
DR. EISENBERGER: I hear all of the
discussions, and I think what we need is
to come up
with a reasonable set of endpoints other
than
survival.
Survival is not possible. That is
ultimately an endpoint where we can
validate some
of our hypotheses.
I just want to point out that
today, we
don't know what the long-term effects
other than
toxicity of early antigen deprivation is
for
patients with non-metastatic prostate
cancer.
The fact is, is that we
probably estimated
somewhere around 7 out of 10 men today
get treated
with hormonal therapy before they develop
metastatic disease, and that is a measure
issue
when we talk about designing our clinical
trials,
unless you blind PSA and do it.
At Hopkins, as you know, there
is a
426
generation difference. In the past, very few
patients would actually receive hormonal
therapy
until the development of studies, there
is a
current database, about 11 percent of our
patients,
and 5,000, that Anthony demonstrated, and
900 with
high PSA relapsed. Eleven percent received antigen
deprivation treatment.
As we update these data, now,
about
30-some percent of these patients are now
receiving
antigen deprivation treatment, so there
is at an
institution where there is a conservatism
in terms
of initiating hormonal therapy, and that
is
changing.
So, I don't know what the endpoint
should
be, but I think that that is the critical
first
step before we talk about anything is
what, in an
adjuvant trial, is bone scan metastasis
what we
need to use as an endpoint, is it any
form of
metastasis, is it initiation of therapy
using
certain parameters? I don't know.
I think this is
where we need to focus a lot of our
discussion.
DR. HUSSAIN: Dr. Brawley and then Dr.
427
D'Amico.
DR. BRAWLEY: I just want to make a couple
of brief comments. These are all related, yet
unrelated, as we talk about PSA rise
after
treatment.
Dr. Catalano recently published
a paper
that suggests that 30 percent or more of
his
patients, does a radical prostatectomy on
have a
rising PSA within five years of the
radical.
In the prostate cancer outcome
study done
by the NCI, for all comers in a large
community, a
large city, it was nearly 40 percent of
people who
undergo a radical prostatectomy have a
rising PSA
afterwards, so the number of individuals
who have a
rising PSA afterward is a considerable
number of
individuals.
Many of them do get hormones,
which cause
osteoporosis, and I have seen patients
who have
died, not of their prostate cancer, which
they were
technically cured of, but of a broken hip
due to
their hormonal therapy.
Also, the prostate cancer
prevention trial
428
data, which Dr. Klein knows probably
better than
anyone, that study screened a large
number of men
in their 60s for 7 years and diagnosed 12
percent
of those men with prostate cancer due to
screening
and then said the hell with screening and
biopsied
everybody who had a normal PSA for 7
years and
found that 15 percent of those men had
prostate
cancer.
So, of this 26, 27 percent of
all men in
their 60s who have been diagnosed with
cancer, the
NCI, through Rocky Foyer's [ph] data,
indicates
that 3 percent of them will die from
prostate
cancer.
So, with screening, we can
diagnose 12
percent of men with prostate cancer, only
1 out of
every 4 for whom will ultimately die from
the
disease, but I worry about the guys who
get
radicals and have a rising PSA, and that
rising PSA
is actually not a threat to their life.
So, a survival study using that
group of
people actually might be fraught with
some dangers.
The last thing I want to note
is I talked
429
about the new breed of academic
urologists and I
forgot to mention Dr. Andriole who is
over there.
DR. HUSSAIN: Dr. D'Amico.
DR. D'AMICO: Mario's point that even at
Johns Hopkins where hormonal therapy was
withheld
before a positive bone scan, now went
from 11 to 30
percent of people having that, sort of
documenting
what I said, and that is, even in now
academic
centers, fastly rising PSAs, people go on
hormonal
therapy, so I think it justifies that in
a control
arm of patients with very rapid rises in
PSA, i.e.,
short doubling times.
To Dr. Scher's point, this is an important
one.
An undetectable PSA, this is really important
that you get this, an undetectable PSA,
after
hormonal therapy following surgery or
radiation,
does not mean you are in the clear. You
can still
recur and die of prostate cancer. That is what
those curves showed you. Guys who nadired, 15, 20
percent of them still died of prostate
cancer, but
a detectable PSA is always bad.
So, I am arguing that the
endpoint should
430
not be undetectable, but detectable. It is just
the reverse. It talks about the endpoint being a
progression endpoint. A statistician would say
this is an event, not a non-event, this
is an
event, don't get undetectable PSA, it's
an event,
and that is always bad, so I think that
that is an
important distinction.
To Otis' point, I think your
point about
people getting hormonal therapy and dying
of the
side effects of treatment is an important
one,
osteoporosis, neurocognitive issues, QT,
and so on.
That is why the long doubling time
patients should
go on studies with vaccines and things
that are not
involving a treatment that might impact
their
longevity, and the short ones, though,
don't die of
side effects, they die of prostate
cancer.
But I have one more thing,
Otis, that you
will find interesting. The 3 percent number,
one-third of people sustain PSA failure,
a fifth in
the community have a short doubling
time. That is
one-third times one-fifth is
one-fifteenth. That
is 6 percent.
431
I showed you that of the guys
with the
short doubling time, a third of them
don't nadir.
One-fifteenth times one-third is
one-45th. That is
2 percent, 2 1/2 percent. There is your 3 percent.
So, the people who die from
prostate
cancer, the 3 percent number can come
from PSA
failure, short doubling time, don't
nadir, that is
3 percent, and I think that's it, and I
think it's
that simple.
DR. BRAWLEY: I am agreeing with that.
DR. HUSSAIN: Okay, and I am glad we are
one big happy family.
Dr. Klein. I am going to probably ask
afterwards do we want to wrap it up, or
do you have
any other burning questions, the
FDA? No.
Then, I
will summarize and then people can object
to my
summary or agree with it, and we will go
from
there.
Dr. Klein.
DR. KLEIN: So, to focus on the
post-treatment rising PSA population due
to Dr.
D'Amico's work and all the people who
collaborated
with him, we have more data on PSA as a
predictor,
432
as a surrogate loosely used, than in any
other
disease state in prostate cancer, and we
ought not
ignore that.
I would put my vote with the
suggestion
that PSA doubling time be used as a
stratification
or selection criteria in this population,
and that
nadir versus not be used as the response
criteria,
and at least as an initial pass, and we
should move
on that quickly. We don't need more preliminary
data on this, it has all been done.
DR. HUSSAIN: Dr. Pazdur.
DR. PAZDUR: Here again, you are using it
as a prognostic factor. The question that I have,
one of the areas that we have looked at
is
basically in order to verify a surrogate
or even a
correlate, you have to have an effective
therapy in
the disease, and that is what enables us
now to
take a look at hormone refractory
disease, because
we could look at the Taxotere studies,
for example,
and
we could develop new drugs in that area.
But in this PSA rising
situation where you
have no therapies that have demonstrated
an impact
433
on a clinical endpoint--
DR. HUSSAIN: Because they have never been
tested.
DR. PAZDUR: Okay, but you don't have
them, so how can you then verify any
surrogate
endpoint here, and I guess that is a
question for
Dr.
D'Agostino, can you, in the absence of an
effective therapy, really--I am using the
word
verify loosely, because I don't want to
use the
word verify a surrogate, but even look at
a
correlation even.
DR. D'AGOSTINO: Are we talking about
where we are going to do a mortality
study or some
endpoint?
DR. PAZDUR: There is no tie to what you
are doing to a clinical endpoint here in
this PSA
rising, is that what you said--validate
it, to
validate it.
DR. HUSSAIN: This is the rising PSA, Dr.
D'Agostino, where those patients, if you
take them
as a lump sum, a good number of them are
not likely
to die from their disease, but as Dr.
D'Amico
434
pointed out, there is a subset based on
sort of
retrospective PSA data analysis, that you
might be
able to predict that this is the subset
that has a
shorter survival.
But I think what Dr. Pazdur is
asking,
since all of that is retrospective, how
are you
going to then design a trial with an
endpoint that
can be reached before we all retire, and
validate
at
the same time whatever hypothesis you have about
a doubling time, or a nadir PSA, or any
other
criteria.
DR. D'AGOSTINO: I think you would have to
go back to something like Bob was
suggesting
earlier, that you try to get a reading on
the
increase and then randomize things of
that nature
that you have to be able to sort of set a
baseline
and then move on.
DR. KLEIN: In this population, I think
you would have to use a time to
progression
endpoint, recognizing the imperfect
definition. No
one will ever stay on a study long enough
or, as
Dr. Scher pointed out, detectable versus
435
undetectable PSA. That triggers additional therapy
in the community, and the clinical
benefit is no
additional therapy.
DR. HUSSAIN: Dr. Scher, you had your hand
up a moment ago.
DR. SCHER: I reiterate that I think the
undetectable PSA with a normal
testosterone is a
good start to suggest efficacy. In the minimal
disease settings and other tumor types,
there is a
cure rate, so we can ask the question
appropriately
using the prognostic models that have
been so well
described now, and use them in trials.
DR. HUSSAIN: So, let me ask you this,
though.
That would not apply if the patients have
gotten hormone treatment, and that you
have to set
your clock for looking at a PSA relapse
point or
undetectable point from the point in time
where the
patient's testosterone recovered. That, by itself,
adds another magnitude of weight.
DR. SCHER: We have designed the study
which will enroll patients with doubling
times of 6
months or less using the endpoint of an
436
undetectable PSA at 3 years, accounting
for the
fact that about 20 percent of the
patients will not
recover their testosterone levels, and
the total
duration of hormonal exposure will be 18
months.
So, it is a 3-year endpoint for
the trial,
and we will hopefully be opening shortly.
DR. HUSSAIN: The last comment is Dr.
Eisenberger.
DR. EISENBERGER: Again, I do feel that
there are data to suggest that certain
PSA changes
may, in fact, be a reasonable endpoint at
some
point in the future.
What we don't have at this
point is any
correlation between any of these PSA data
in a
prospective fashion with more
conventional
endpoints, such as time to progression,
for
instance.
This what we need.
I think what we need is a focus
here
today, is what does that constitute at
this point
in time, and not what a 6-month PSA or
nadir PSA is
following therapy. What are we going to validate
that against? That is what you want to know at
437
this point in time.
DR. HUSSAIN: Just because I said that,
ladies go, so that's fine, please.
DR. McSHANE: I think you raise an
excellent point and just so that we are
not all
here again in five years still debating
these
issues, what can we do now to get the
data that we
need, so that we won't continue to
debate.
I think Dr. Martin from the NCI
suggested
some very good possibilities. We have several NCI
trials.
They are ripe for putting in these
surrogate endpoints now or these
potential
surrogate endpoints now, but if we don't
decide on
what kind of schedule we are going to
measure the
PSA or at least collect the specimens, so
that PSA
or something else could be measured, we
are going
to end up with data that we can't compare
across
studies and we will still be scratching
our heads
in five years.
So, I think it would be very
beneficial if
this committee could--and I know we are
running
short on time--could spend just a few moments
438
discussing, you know, if we could have
whatever we
wanted, what would we do in the way of
measuring
PSA or collecting specimens, should we
collect it
on every trial, only in certain kinds of
patient
groups, should we collect it every 3
months, should
we collect it every week, you know, what
can se do,
so that we are not still debating this
issue.
DR. HUSSAIN: Do you want to go a little
bit more or you want to wrap it up and
this would
be the subject of future
discussions? Dr. Pazdur,
it is 5:05.
DR. PAZDUR: I guess what I would ask is
the committee's opinion, would they rather
go on
with further discussions or wrap things
up, because
I know we are losing some people because
of
flights.
DR. HUSSAIN: If I may suggest, I think we
have accomplished a fair amount. I do think it's a
good idea to have us all digest
everything that got
said.
If I may wrap up this session
dealing with
a rising PSA population and the local
disease, I
439
would say the local disease, there is
really no
consensus or plans at this moment. The rising PSA,
what has been put for discussion is
perhaps one of
two possibilities, as was suggested,
begin looking
at some validation of certain surrogacy
endpoints
and the ongoing trials or the planned
trials for
the rising PSA population.
The other alternative is to
bite the
bullet and say we have enough data on
from
retrospective series showing that certain
doubling
time or some PSA kinetic is likely to
predict for
poor prognosis patients and begin then
targeting
those patients for clinical trials. Is that a fair
assessment?
Mario, I am going to have to
cut the
discussion.
I want to thank the Committee
members for
a wonderful discussion. Before I end, I want to
thank especially the public, particularly
patients,
patient advocates, patients' families,
those who
are interested and concerned about
prostate cancer.
I want to thank you all. Please know that
440
we are all here because we have patients'
interests
at heart, no other real issues, and thank
you very
much.
[Whereupon, at 5:11 p.m., the
meeting was
adjourned.]
- - -