DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ONCOLOGIC DRUGS ADVISORY COMMITTEE
Thursday, March 3, 2005
620 Perry Parkway
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
Otis W. Brawley, M.D.
Ronald M. Bukowski, M.D.
James H. Doroshow, M.D.
Antonio J. Grillo-Lopez, M.D., Industry
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.
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
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.
FDA (A.M. Session)
Zili Li, M.D., MPH
Florence Houn, M.D.
George Mills, M.D.
Sally Loewke, M.D.
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.
C O N T E N T S
Call to Order and Introductions
Silvana Martino, D.O. 6
Conflict of Interest Statement
Johanna Clifford, M.S., RN 9
George Mills, M.D. 11
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
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
C O N T E N T S (Continued)
Call to Order and Introductions
Maha Hussain, M.D. 204
Conflict of Interest Statement
Johanna Clifford, M.S., RN 207
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
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
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
DR. MILLS: Good morning.
I am George
Mills, FDA. I am the Division Director for Medical
DR. HOUN: Florence Houn, Office Director,
DR. LI: Zili Li, Medical Team Leader,
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
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,
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
of Radiology, University of Miami.
DR. SMETHERMAN: Dana Smetherman,
Radiologist, Section Head of Breast Imaging,
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.
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
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
any firm whose products they may wish to comment
DR. MARTINO: Dr. Mills, if you would
address the group.
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
The Agency is in the second
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
In addition, the sponsors were asked to
address safety issues related to Combidex-induced
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
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
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
hypersensitivity reactions associated with
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
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.
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.
Advanced Magnetics, Inc.
Combidex, Introduction and Indication
MR. ROESSEL: Good morning. Thank you,
Madam Chairman, members of the Advisory Committee,
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.
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
Finally, Dr. Jelle Barentsz, a clinical
investigator with Combidex, is going to review with
you the clinical utility of Combidex in various
Combidex is a diagnostic tool that
improves the anatomic imaging that is done every
Now, I would like to have Mukesh
Mechanism of Action, Combidex
Appearance on MR Images
DR. HARISINGHANI: Good morning, Madam
Chairman, members of the Committee, ladies and
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
sensitivity and specificity for nodal
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
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
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
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
The example on your left is an
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
But at surgery, it was exactly the
opposite. Thus, you can see that size criterion is
an inaccurate yardstick by which we categorize
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
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
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
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
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
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
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
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
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
I would like to emphasize at this point,
two points in the mechanism of action. One is the
contrast is targeting the normal lymph
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
We can do post-processing, which can
provide for elegant ways of communicating the
information, but these are not essential for making
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
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
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
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
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
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
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
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
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
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
So, right into the Phase III study, in
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
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
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
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
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
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
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
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
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
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
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
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
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
Thank you. Now, Dr. Faich will review the
Safety Data from Clinical
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
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
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.
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
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.
I would simply like to emphasize that
nearly all of these were mild, transient, and
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
The most common reaction, as I noted,
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
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
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
For comparators in studies done with
Ultravist, it was 0.6 percent, for Oxilan it was
1.5 percent, and for comparators to
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
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.
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
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
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
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
prostate, bladder, head and neck, and breast, and I
want to address those issues with you in the next
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
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
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
we could confirm the diagnosis by image-guided
biopsy, and these patients did not undergo any
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
In another patient, you see a
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
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
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.
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
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
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
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
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
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
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.
MR. ROESSEL: Thank you.
Our clinical data and the clinicians I
think have shown you that Combidex is an important
diagnostic imaging tool that improves the current
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.
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
review of findings of NDA Application 21-115
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
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
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
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
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
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
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
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
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.
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
that reason, the individual nodal level analysis
was never performed, so those people cannot include
in their primary analysis and consistent with U.S.
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
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
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
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
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
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
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
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
performance of Combidex among the different type of
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
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
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
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
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
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
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
Now, I would like to switch to the safety
side of Combidex evaluation. I will focus my
presentation in Combidex-induced hypersensitivity
There is one case
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
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
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
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
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
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
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
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
In the comparator, iodinated contrast
agents in their Table 9 safety
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
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
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 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
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
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
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
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
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
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
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
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
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
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.
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
When the prevalence get into 10, 25
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
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
Combidex for nodes more than 10 mm for helping
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
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
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
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
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
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
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
In terms of who did that, are you
referring to the specific specialty of
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
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
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
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
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
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
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
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.
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
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
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
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
certainly the sensitivity doesn't change or they
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
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
So, is there an argument, and I haven't
heard it, that says you can, in fact, combine these
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
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
Was any analysis done on the
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
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
DR. D'AGOSTINO: It would be nice to see
the sensitivity and the specificity and the
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
back to it.
DR. GOECKELER: I can give you the
numbers, and I can tell you that the trends are
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.
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
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
prostate or breast or bladder or head and neck, to
actually do the same template or do beyond what is
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
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.
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.
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
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
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
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
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
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
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
The first part of the question dealt
with--I am sorry?
DR. LEVINE: Is the company requesting
that the patient have two different--no, not two
different reads--two different MRI scans?
DR. GOECKELER: Two different images,
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
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
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
DR. LEVINE: And the sarcoid case
fulfilled your criteria as benign, as well?
DR. HARISINGHANI: Yes, that was the case
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
did do a calculation and analysis on the health
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
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
DR. GOECKELER: Let me make sure I
understand. In terms of obtaining them in surgery
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
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
other staging systems or imaging systems that are
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,
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
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,
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
DR. BRAWLEY: A couple more follow-up
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
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
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,
original copy of the blinded reader efficacy
evaluation, were not available to the Food and Drug
I would like you to respond to that
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
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
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
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
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
Is that true?
DR. GOECKELER: Mark, you can comment on
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
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
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
going to then have either a biopsy or a surgical
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
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
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
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
They were of the intermediate and
high-risk category, I must admit to that in terms
of the patient selection.
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
DR. BRADLEY: So, the slice location of
3-mm slices was accurate, looking at the other
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
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
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
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
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
DR. GIULIANO: I am a surgeon, Dr.
Martino. We have limited intellectual curiosity,
DR. MARTINO: I know.
DR. GIULIANO: Therefore, my questions
will be brief. But I am struggling as a surgeon
through these documents. We say the surgical
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
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
If you look at the 1 or 2 nodes, which had
to be seen on the image, had to evaluated
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
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
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
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
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
patient level where you can look at the patient
DR. GIULIANO: Thank you.
DR. MARTINO: Does that answer your
question, Dr. Giuliano, because I am not sure that
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: 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
perhaps are not presented to you right now. I
think that may be one of the issues.
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
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
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
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
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
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,
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
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
On the other hand, if we did find
something ahead of time, we may be able to
eliminate doing an invasive procedure by
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
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
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
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
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
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
Were any of these patients given
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
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
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
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
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
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
DR. RODRIGUEZ: That is all I need.
DR. GOECKELER: The indication was based
the Phase III clinical trials. I think
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
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,
disposition of the patient.
A yes or no from the sponsor would be
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.