1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ONCOLOGIC DRUGS ADVISORY COMMITTEE

VOLUME I

Thursday, March 3, 2005

8:05 a.m.

Gaithersberg Hilton

620 Perry Parkway

Gaithersburg, Maryland

PARTICIPANTS

Silvana Martino, D.O., Acting Chair (A.M. Session)

Maha Hussain, M.D., Acting Chair (P.M. Session)

Johanna M. Clifford, M.S., RN, Executive Secretary

COMMITTEE MEMBERS

Otis W. Brawley, M.D.

Ronald M. Bukowski, M.D.

James H. Doroshow, M.D.

Antonio J. Grillo-Lopez, M.D., Industry

Representative

Pamela J. Haylock, RN, Consumer Representative

Maha H.A. Hussain, M.D.

Alexandra M. Levine, M.D.

Joanne E. Mortimer, M.D.

Michael C. Perry, M.D.

Gregory H. Reaman, M.D.

Maria Rodriguez, M.D.

CONSULTANTS (VOTING)

FOR COMBIDEX

Marco Amendola, M.D.

William Bradley, M.D., Ph.D.

Marion Couch, M.D., Ph.D.

Ralph D'Agostino, Ph.D.

Mark Dykewicz, M.D.

Armando Giuliano, M.D.

Dennis Ownby, M.D.

Dana Smetherman, M.D.

PATIENT REPRESENTATIVE (VOTING)

Eugene Kazmierczak - for Combidex and Prostate

Cancer Endpoints

CONSULTANTS

PROSTATE CANCER ENDPOINTS

Victor DeGruttola, Sc.D.

Mario Eisenberger, M.D.

Eric Klein, M.D.

Lisa McShane, Ph.D.

Derek Raghavan, M.D., Ph.D.

Howard Sandler, M.D.

Howard Scher, M.D.

PARTICIPANTS (Continued)

FDA (A.M. Session)

Zili Li, M.D., MPH

Florence Houn, M.D.

George Mills, M.D.

Sally Loewke, M.D.

PARTICIPANTS (Continued)

FDA (P.M. Session)

Peter Bross, M.D.

Patricia Keegan, M.D.

Bhupinder Mann, MBBS

Richard Pazdur, M.D.

Dan Shames, M.D.

Rajeshwari Sridhara, Ph.D.

Robert Temple, M.D.

Grant Williams, M.D.

C O N T E N T S

Page

Call to Order and Introductions

Silvana Martino, D.O. 6

Conflict of Interest Statement

Johanna Clifford, M.S., RN 9

Opening Remarks

George Mills, M.D. 11

Sponsor Presentation

Advanced Magnetics, Inc.

Combidex, Introduction and Indication

Mark C. Roessel 15

Mechanism of Action, Combidex

Appearance on MR Images

Mukesh Harisinghani, M.D. 17

Efficacy Data from Phase III Clinical Studies

William Goeckeler, Ph.D. 29

Safety Data from Clinical Trial

Gerald Faich, M.D. 39

Clinical Utility of Combidex and Various Cancers

Jelle O. Barentsz, M.D. 46

FDA Presentation

Efficacy and Safety of Combidex (NDA 21-115)

Zili Li, M.D., MPH 56

Questions from the Committee 88

Open Public Hearing 146

Committee Discussion 167

C O N T E N T S (Continued)

Page

AFTERNOON SESSION

Call to Order and Introductions

Maha Hussain, M.D. 204

Conflict of Interest Statement

Johanna Clifford, M.S., RN 207

Opening Remarks

Richard Pazdur, M.D. 210

A Regulatory Perspective of Endpoints to

Measure Safety and Efficacy or Drugs:

Hormone Refractory Prostate Cancer

Bhupinder Mann, MBBS 216

Towards a Consensus in Measuring Outcomes

in New Agents for Prostate Cancer

Derek Raghavan, M.D., Ph.D. 227

NCI Prostate Cancer Treatment Trial Portfolio

Alison Martin, M.D. 261

Toward an Endpoint for Accelerated Approval

for Clinical Trials in Castration Resistant/

Hormone Refractory Prostate Cancer

Howard Scher, M.D. 271

Design of Clinical Trials for Select Patients

With a Rising PSA Following Primary Therapy

Anthony D'Amico, M.D., Ph.D. 297

Open Public Hearing 330

Committee Discussion 333

P R O C E E D I N G S

Call to Order and Introductions

DR. MARTINO: Good morning, ladies and

gentlemen. I would like to begin the meeting, if

you would be so kind as to take your seats.

The purpose of this morning's meeting is

to consider a new drug application, the agent

Combidex from Advanced Magnetics, Incorporated, a

proposed indication for intravenous administration

as a Magnetic Resonance Imaging contrast agent to

assist in the differentiation of metastatic and

non-metastatic lymph nodes in patients with

confirmed primary cancer who are at risk for lymph

node metastases.

We will start the meeting by having the

members of the panel introduce themselves, and I

would like to begin on my left, please.

DR. LOEWKE: Sally Loewke, FDA. I am the

Deputy Division Director for the Division of

Medical Imaging and Radiopharmaceutical Drug

Products.

DR. MILLS: Good morning. I am George

Mills, FDA. I am the Division Director for Medical

Imaging.

DR. HOUN: Florence Houn, Office Director,

FDA.

DR. LI: Zili Li, Medical Team Leader,

FDA.

MR. KAZMIERCZAK: Eugene Kazmierczak,

Patient Consultant to FDA for prostate cancer.

DR. BUKOWSKI: Ron Bukowski, Medical

Oncologist, Cleveland Clinic Foundation.

DR. BRAWLEY: Otis Brawley, Medical

Oncologist and Epidemiologist, Emory University.

DR. DOROSHOW: Jim Doroshow, Division of

Cancer Treatment and Diagnosis, NCI.

DR. RODRIGUEZ: Maria Rodriguez, Medical

Oncologist, M.D. Anderson Cancer Center.

DR. REAMAN: Gregory Reaman, Pediatric

Oncologist, Children's Hospital, Washington, D.C.,

and George Washington University.

DR. MARTINO: Silvana Martino, Medical

Oncology, Cancer Institute Medical Group in Santa

Monica.

MS. CLIFFORD: Johanna Clifford, Executive

Secretary to the Oncology Drugs Advisory Committee.

DR. HUSSAIN: Maha Hussain, Medical

Oncologist, University of Michigan.

DR. PERRY: Michael Perry, Medical

Oncologist, Ellis Fischel Cancer Center, Columbia,

Missouri.

DR. MORTIMER: Joanne Mortimer, Medical

Oncologist, Moores UCSD Cancer Center.

DR. OWNBY: Dennis Ownby, Pediatric

Allergist at Medical College of Georgia.

DR. D'AGOSTINO: Ralph D'Agostino,

Biostatistician from Boston University.

DR. DYKEWICZ: Mark Dykewicz, Professor of

Internal Medicine, Allergy and Immunology, Training

Program Director, St. Louis University.

DR. GIULIANO: Armando Giuliano, Surgical

Oncologist from Los Angeles.

DR. BRADLEY: Bill Bradley. I am a Neuro

MRI guy. I am the Chairman of Radiology at UCSD.

DR. AMENDOLA: Marco Amendola, Professor

of Radiology, University of Miami.

DR. SMETHERMAN: Dana Smetherman,

Radiologist, Section Head of Breast Imaging,

Oschner Clinic.

DR. COUCH: Marion Couch, Head and Neck

Surgeon from the University of North Carolina.

DR. MARTINO: If you would all turn off

your mikes, and for those of you that are new to

the committee, please recognize that you need to

speak into the microphone, and it only works when

you have pushed it and the red light is on. Once

you are done with its use, please turn it off.

There is a reasonable amount of echo that

I still hear in this room. Can Audiovisual do

anything more to clarify our sound? Okay.

At this point, Ms. Johanna Clifford will

report on the Conflict of Interests.

Conflict of Interest Statement

MS. CLIFFORD: The following announcement

addresses the issue of conflict of interest and is

made a part of the record to preclude even the

appearance of such at this meeting.

Based on the submitted agenda and all

financial interests reported by the committee

participants, it has been determined that all

interests in firms regulated by the Center for Drug

Evaluation and Research present no potential for an

appearance of a conflict of interest.

With respect to the FDA's invited industry

representative, we would like to disclose that Dr.

Antonio Grillo-Lopez is participating in this

meeting as an acting industry representative acting

on behalf of regulated industry. Dr. Grillo-Lopez

is employed by Neoplastic and Autoimmune Disease

Research.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement, and their

exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

upon.

Thank you.

DR. MARTINO: Dr. Mills, if you would

address the group.

Opening Remarks

DR. MILLS: Thank you, Dr. Martino.

Good morning, Committee. The sponsor of

the application in this morning's session, Advanced

Magnetics, requests marketing approval of Combidex

for the proposed indication of assisting in the

differentiation of metastatic and non-metastatic

lymph nodes, in patients with confirmed primary

cancer, who are at risk for lymph node metastases.

The Agency is asked to consider an

indication specifically for differentiating

metastatic from non-metastatic lymph nodes with

little restriction on the cancer type, clinical

staging, and whether the patients have been

previously treated.

The Agency is in the second review cycle

for this imaging product. The first review cycle

concluded with an approvable action and the sponsor

was asked to conduct additional studies to address

issues related to inconsistent efficacy results

among the differential trials and to provide a

clearer identification for the conditions of use

for Combidex.

In addition, the sponsors were asked to

address safety issues related to Combidex-induced

hypersensitivity reactions.

In today's presentation, the sponsor will

address these deficiency issues by using data that

were originally submitted to the Agency, along with

new information from a published study in the New

England Journal of Medicine.

The Agency's presentation today will focus

on whether the primary analyses that were based on

99 subjects from the U.S. studies and only 48

subjects from the European studies are adequate for

marketing approval based on the sponsor's proposed

indications, which reads as follows:

"Combidex is for the intravenous

administration as a contrast agent for use with

MRI. Combidex can assist in the differentiation of

metastatic and non-metastatic lymph nodes in

patients with confirmed primary cancer who are at

risk for lymph node metastases."

Today, we will be seeking comments on the

issues related to the sample size and the adequacy

of tumor type presentation. We will be presenting

the variable efficacy results by the tumor type and

the size of the lymph nodes.

We are seeking your opinion as to whether

these results suggest that the variations in

efficacy performance of Combidex are related to the

different tumor types and to different lymph node

sizes.

Today, we are seeking your advice on how

to better define the conditions for use for

Combidex, assuming the validity of the efficacy

results, so that use of Combidex can provide

benefits to patients particularly in affecting

patient's treatment decisions. This point is

particularly important given the risks of

hypersensitivity reactions associated with

Combidex.

Lastly, we will be seeking your

recommendations on what additional data are needed

if current data are found to be inadequate for the

marketing approval of Combidex at this time.

This concludes the Agency's introduction

to the morning session.

Thank you, Dr. Martino.

DR. MARTINO: Thank you.

For those of you that are new to the

committee and are consulting to the committee, the

final task that we will bring to you is answers to

certain questions that have been posed to the

committee by the FDA. Those are in a written

format and each of you should have those at your

desk.

They are titled as Discussion and

Questions, so please recognize that it is very

specifically to answer those four questions which

will be the focus of the discussion at the end of

this morning's presentations.

At this point, I would like to ask Dr.

Roessel from the company to introduce their

speakers and proceed with their presentation.

There will be an opportunity for questions

both to the sponsor, as well as to the FDA. I ask

that you hold your questions until their

presentations are completed.

Sponsor Presentation

Advanced Magnetics, Inc.

Combidex, Introduction and Indication

MR. ROESSEL: Good morning. Thank you,

Madam Chairman, members of the Advisory Committee,

FDA.

I am Mark Roessel, Vice President of

Regulatory Affairs, Advanced Magnetics.

Today is an important day for us as we

have been working since 1992 to bring Combidex to

clinicians and cancer patients. We are pleased to

be able to show you today data from controlled

clinical trials demonstrating the safety and

efficacy of Combidex and the great potential it has

for improving imaging in cancer patients.

We have a number of distinguished

consultants and speakers here today including

radiologists, surgeons, oncologists, and they are

available to answer any questions you may have at

the end of the meeting.

I want to bring your attention to the

indication. It has been read twice already. It is

for a differentiation of metastatic and

non-metastatic lymph nodes in cancer patients.

Here is the agenda we are going to have in

our presentation and the key topics. Dr. Mukesh

Harisinghani is going to show you the mechanism of

action of Combidex and how it appears on MR images.

Dr. William Goeckeler from Cytogen

Corporation, Vice President of Cytogen, who is our

marketing partner, is going to present to you data

from Phase III controlled clinical trials that were

designed in cooperation with the FDA for approval

of the agent.

Dr. Jerry Faich is going to review the

safety data available, demonstrating that Combidex

can be safely administered using dilution and

infusion.

Finally, Dr. Jelle Barentsz, a clinical

investigator with Combidex, is going to review with

you the clinical utility of Combidex in various

cancers.

Combidex is a diagnostic tool that

improves the anatomic imaging that is done every

day.

Now, I would like to have Mukesh

Harisinghani.

Mechanism of Action, Combidex

Appearance on MR Images

DR. HARISINGHANI: Good morning, Madam

Chairman, members of the Committee, ladies and

gentlemen.

What I am going to do in the next couple

of minutes is to review what are the current

limitations of lymph node imaging as we practice

radiology today, also give an overview of how

Combidex is acting and how it allows us to

differentiate benign from malignant lymph node, and

then also show you some examples of how it improves

sensitivity and specificity for nodal

characterization.

So, the question is why do we need to

image lymph nodes, and I think one needs to

accurately stage primary cancer, and in doing so,

it is very important to know what the nodal status

is.

It is very important to know this

information to appropriately treat the patients.

Just to give you an example, in prostate cancer

patients, if the nodes are found to be metastatic,

it essentially commits the patients to non-surgical

modes of therapy.

We also need to get a sense of prognosis,

and that is another factor why nodal metastases are

important. Again, to give you an example in

bladder cancer, if the patient is node-positive,

the five-year survival is way lower than if the

patient is node-negative.

The risk of death also increases 20

percent with each additional node being positive.

The current lymph node staging as is

performed today involves non-invasive imaging

techniques, which essentially incorporates the

cross-sectional modalities like CT and MR, and the

other is the invasive modes, which is essentially

surgery, which are considered to be the gold

standard today.

When one talks of the non-invasive

cross-sectional modalities for staging lymph nodes,

the predominant yardstick by which we differentiate

benign from malignant lymph nodes is the size

criterion, and this is what we use.

If the node is oval and less than 10 mm in

size, or if it is rounded and less than 8 mm in

size, we label the node as benign.

In contrast, if the node is oval and

greater than 10 mm, or is rounded and greater than

8 mm, we label the node as malignant.

So, let's apply the size criterion to

these two individuals. These are two different

patients, both have obtained a CT scan for staging

purposes.

The example on your left is an enlarged

node in the pelvis, which measures 18 mm and is

rounded. No matter which size criterion you use,

you would label this node as malignant.

The example on your right is a different

patient, again a patient with a primary pelvic

tumor. There is a small node in the pelvis, which

measures 5 mm. Again, no matter which size

criterion you use, you would label this node as

benign.

But at surgery, it was exactly the

opposite. Thus, you can see that size criterion is

an inaccurate yardstick by which we categorize

nodes today.

Morphology has been to a certain extent

used in conjunction with size criteria

occasionally, and one of the important morphologic

features we rely on is presence of fatty hilum, as

you are seeing here.

It is said that if the node has a central

fatty hilum, that is a sign of benignity, however,

we have seen from our experience that even small

nodes, as the case here, with the fatty hilum in

this patient with bladder cancer, was biopsy proven

to be positive and having malignant cells.

Thus, morphology, too, has its drawbacks

and when used with size criterion, can be a

problem.

Central necrosis is the other morphologic

feature which has occasionally been said to be a

very useful way to allow for diagnosing malignant

nodes, but it is important to realize that when

nodes become necrotic, they are enlarged beyond a

cm, and by size criterion, you would still call

them positive.

Well, what about surgery, which is

considered to be the gold standard, and I am going

to use prostate cancer as an example, but I think

the underlying principle can be applied or

extrapolated to other tumors, as well.

In prostate cancer, pelvic lymph node

dissection accompanied by frozen section path

examination is considered to be the gold standard.

However, the way lymph nodes are sampled today, at

the time of surgery in intermediate to high risk

prostate cancer patients, the standard pelvic

lymphadenectomy is limited. This is because the

surgeon only resects the low external iliac and the

obturator group of lymph node.

In the recent or not too recent, in an

April 2000 study published in the Journal of

Urology, it was shown that if the surgeon extends

the lymphadenectomy and takes out the high external

iliac and the internal iliac nodes, keeping all

other risk factors the same, the incidence of lymph

node metastases jumps from 10 to 26 percent, so you

can see that a potential of 16 percent miss rate if

one just follows the standard pelvic

lymphadenectomy.

So, that begs that question why don't we

do that in all the cases, because there is a

significant morbidity that comes with that

procedure. Moreover, it is also important to

realize that the frozen section analysis can also

have a false negative rate of 30 to 40 percent, so

all these factors show us the limitations of how

even when surgery is performed and nodes are

sampled, there are some limitations.

Here is an example of a patient who had

underwent radical prostatectomy, and you can see

clips where the surgeon has taken out the lymph

nodes, and as I said earlier, this is what standard

lymphadenectomy involves, is the low external iliac

group of lymph nodes.

There was a small nod posteriorly in the

pelvis that was not sampled, and the patient was

labeled as cured. Eight months later, the patient

shows back with that node mushrooming into a

full-blown metastases, and this is a good example

of how surgical sampling can sometimes be limited

by what the surgeon can see and samples.

Thus, there is a current need for a

non-invasive technique that not only detects, but

also characterizes lymph nodes with a high level of

accuracy, not compromising sensitivity for

specificity.

It also provides a broad anatomy coverage

which means you not only look at lymph nodes right

next to the primary cancer, but also can look at

lymph nodes in a broad anatomic area beyond the

confines of the regional distribution.

That is where I think Combidex, or the

pharmacologic name ferumoxtran-10, is an excellent

contrast tool that can be utilized with MR. This

is an iron oxide based nanoparticle with a central

iron oxide coat and a surrounding dextran coating.

This slide shows how the contrast acts.

After intravenous injection, the contrast lingers

in the blood vessels for a long time, has a long

blood half-life. It gradually leaks out and then

is transported to the lymph nodes where it binds to

the scavenger on macrophages. Thus, the mechanism

of action of uptake in the normal nodes is via

macrophages. So, if the node is functioning

normally and has its normal complement of

macrophages, the contrast would then localize to

the nodes and turn the normal area of the node

dark.

I would like to emphasize at this point,

two points in the mechanism of action. One is the

contrast is targeting the normal lymph node and

black is benign, so it is the normal part of the

node that is turning dark.

If you have an area of tumor deposited in

the node, then, that area of the node is devoid of

normal functioning macrophages and that area would

show lack of uptake and continue to stay bright.

Another important point to remember is

that this mechanism of action is independent of

which primary cancer affects the node, and, hence,

the lack of uptake would be present no matter which

tumor deposit is present within the lymph node.

This slide is just to show the technique

that we use. Any conventional 1.5 MR system that

exists today in the community, independent of

vendor platform, can be used for imaging the MR

with Combidex, and these are the sequences, again

nothing fancy, just regular bread and butter

sequences.

We can do post-processing, which can

provide for elegant ways of communicating the

information, but these are not essential for making

the diagnosis.

So, let me show you an example of how the

Combidex acts in real life. This is a patient who

has a known pelvic malignancy. There are two lymph

nodes in the groin. Both are hyper-intense or

bright on the pre-contrast.

Twenty-four hours after injection of

Combidex, you can see the medial node is turning

homogeneously dark, and that is the node that is

benign. The node to the right shows lack of

uptake, and that means that it's infiltrated with

cancer and, hence, it is not taking up the

Combidex.

Let me show you some examples of how

Combidex scanning improves sensitivity in detecting

metastases in small lymph nodes.

This is a patient with prostate cancer

undergoing staging. The yellow arrows point to two

very small nodes next to the external iliac vein.

Again, by size criterion, you would never call

these nodes positive.

On the pre-Combidex scan, you can see

these two nodes are hyper-intense, and 24 hours

later after Combidex, the inferior one is turning

homogeneously dark. It means that that is benign.

The one which is pointed by the red arrow shows

lack of uptake, and that is the one which is

malignant, which was proven at the time of surgery.

This is a patient with breast cancer.

Again, the patient is lying prone. Here is the

lung, the breast of the patient, and we are looking

at the axilla. Again, there are two very small

nodes in the axilla pointed by the yellow and the

red arrow, measuring between 3 to 4 mm.

After giving Combidex, the superior one is

turning dark as outlined by the yellow arrow, the

inferior one, which is the red arrow, shows lack of

update, indicating it's malignant and again proven

with surgery.

So, I have shown you how Combidex improves

sensitivity in different types of primary cancers.

It is equally important to have enhanced

specificity, which means if the node is enlarged,

you need to accurately diagnose it as benign or

malignant.

So, here is a patient with bladder cancer.

You have an enlarged node measuring 20 mm, and this

was labeled as malignant on the contrast-enhanced

CT. On the pre-contrast MR, it is hyper-intense.

Post-Combidex, it turns homogeneously dark

indicating it's benign and was proven so on biopsy.

Another example of enhanced specificity,

again a patient with prostate cancer. The two

yellow arrows point to enlarged obturator nodes,

again labeled malignant based on the size

criterion, but post-Combidex, you can see it is

turning homogeneously dark, and these turned out to

be reactive enlarged nodes or reactive benign nodes

in the pelvis.

As you can see, by improving the

sensitivity and specificity in these patients, one

can provide for improved clinical staging, and then

also provide for better surgical planning and

better radiation therapy and image-guided

intervention planning. Some of these points will

be highlighted later by my colleague, Dr. Jelle

Barentsz.

Thank you

Efficacy Data from Phase III Clinical Studies

DR. GOECKELER: Good morning. I am going

to review in the next few minutes the efficacy data

in support of the proposed indication. The studies

I will be discussing were designed to evaluate the

ability of Combidex to improve the differentiation

of metastatic from non-metastatic lymph nodes,

particularly in the post-contrast setting.

To do this, we compare the parameters of

sensitivity and specificity in both the pre- and

post-contrast image sets. The study's design,

which was conducted in cooperation with the FDA,

provided for multiple primary tumor types and

independent blinded evaluations of image sets with

histopathologic confirmation of the imaging data.

I think it is worth taking just a step

back to say that all the imaging data that you will

be presented this morning by the sponsor involves

histopathologic confirmation at the individual node

level, which is a significant undertaking.

So, in reviewing the efficacy data, I will

first go over quickly the blind read procedures

that were used in conducting the analysis of this

data, review the data from EU and U.S. Phase III

studies, talk a little bit about data from

publication in the New England Journal of Medicine

that investigated the agent in this application,

and finally, close by looking at how this

improvement in differentiation at the nodal level

impacts clinical nodal staging.

So, first, the blinded read procedure, and

there are a number of blinded reads that were

carried out in each of the clinical studies, so I

will try to explain the terminology and the

sequence in which they were conducted.

All the blinded reads were carried out

with the readers blinded to clinical, demographic,

and pathologic information, and the cases were

presented in random order.

The readers were first presented with the

pre-contrast images, and based on the pre-contrast

images alone, made an assessment on size based.

You will also see that in some of the

slides called an MRI-based diagnosis, and then the

reader made a second assessment based solely on the

pre-contrast image, which was based on the reader's

skill. In that subjective evaluation, the reader

was allowed to use any criteria they thought was

appropriate in differentiating metastatic from

non-metastatic lymph nodes.

Following those readings, the readers were

presented with the post-contrast images and carried

out an evaluation of the post-contrast side by side

with the pre-contrast images. This is a so-called

paired evaluation. The prospective primary

endpoint in each of the Phase III studies was a

comparison of the paired evaluation with the

pre-contrast size-based evaluation at the nodal

level.

Next, a period of about two weeks to

eliminate a recall bias was allowed, and then the

readers were presented, again in random order, with

the post-contrast only images, and then made an

assessment based only on the post-contrast image,

which is called the post-contrast evaluation.

Post-contrast images, there were reading

guidelines developed to assist the reader in

evaluating the nodal post-contrast images. They

were prospectively developed and finalized before

the blinded read. Thus, the Phase III blind read

of images is a valid assessment of nodal images

across a wide range of cancers.

This is the study population in the three

studies that I will be talking about - the U.S.

Phase III, the EU Phase III, and the New England

Journal. The number of patients dosed and the

number of patients with histopathology is not

always the same since eventually, not all patients

go to surgery for things that happen in the

intervening time between the imaging session and

the treatment of the patients.

This outlines the number of lymph nodes

that were evaluated in the various studies both

pre- and post-contrast and a breakdown of where

those lymph nodes resided by anatomic region in the

various cancers.

So, right into the Phase III study, in the

EU Phase III study, what we see is that in the

pre-contrast evaluations, both the size and the

subjective base, we see a high pre-contrast

sensitivity and a low pre-contrast specificity,

whereas, in the post-contrast evaluation, the

paired evaluation, what we see is sensitivity

remains high at 96 percent, but specificity is

significantly improved, and the improvement in

specificity was statistically significant over both

of the pre-contrast reads and for both of the

blinded readers.

We look at the data from the U.S. Phase

III study. It's a little bit different situation.

In the pre-contrast size-based analysis, in the

pre-contrast analysis, sensitivity was low and

specificity was high, so sort of just the opposite

of what was seen in the EU study.

In the subjective evaluation, we see that

the subjective reader's assessment resulted in a

very high sensitivity, but the tradeoff for that

increase in sensitivity was a large decrease in

specificity.

So, the pre-contrast reads had either high

sensitivity or high specificity, but not both. In

the post-contrast reads, you will see that

sensitivity was high and specificity was high, so

we had a combination of high sensitivity and high

specificity.

You will also note that in the post-only

read, in which the only image that was available

was the post-contrast image, resulted in the

highest level of imaging performance and the

greatest level of consistency.

If we take a look for just a minute at

this discrepancy between the two pre-contrast

reads, where one had high sensitivity and low

specificity, and the other was the opposite, if we

look at the false diagnoses that occurred in these

various blinded readings, and we look at false

diagnoses as a percentage of the total, we see that

the percentage of false diagnoses for both of the

pre-contrast reads is relatively the same.

What we see is that in the subjective

readers' diagnosis with the readers subjectively

overreading to try to account for the known low

sensitivity of the size-based analysis, we see a

very large percentage of false positive reads that

occur in the subjective readings, whereas, in the

post-contrast reads, we see a decreased percentage

of false reads with the lowest and most consistent

data again in the post-only read.

This is the data broken out by body

region, and you can see that in the head and neck

and breast, we saw large increases in sensitivity

when we compare the pre- to the post-contrast read,

maintaining specificity which overall resulted in

the increase in accuracy.

In the pelvis and abdomen, we had more

moderate levels of increase in both sensitivity and

specificity, the net effect of which is that the

increase in accuracy in the pelvis and abdomen is

virtually identical to what one sees in both the

head and neck and the breast.

One region that was a little bit different

was in the lung. In the lung, we see more

moderate, small increases in both sensitivity and

specificity, and we believe this has to do with

limitations of anatomic imaging in this particular

body region, and not differential uptake or

performance of the contrast agent.

So, turning now to the data published in

the New England Journal of Medicine, and I think

this data is important supplemental data that can

help us understand better some of the differences

that were seen particularly in the pre-contrast

reads in the Phase III studies and also can help us

learn a little bit more about the performance of

the agent in different size nodes.

So, this is a study carried out in

prostate cancer patients at two centers, one in the

U.S., one in the EU, 40 patients from each site.

There was a centralized independent blinded read

with histopathologic confirmation of data.

So, to address some of the issues that I

just mentioned, I am going to go through the data

in a little bit of a sequential order.

First, with regard to the issue of the

discrepancies in the pre-contrast evaluations and

also to look at the issue of the effect of nodal

size on the performance of the contrast agent, what

you see is as you move across these three studies,

the distribution of nodes categorized as either

greater than or less than 10 mm, and that is an

appropriate cut point because as Dr. Harisinghani

said earlier, that is the point at which we

differentiate a malignant from a non-malignant

node.

We see that as we move from the EU to the

U.S. to the New England Journal study, the

proportion of large nodes are greater than 10 mm in

the yellow, goes from about three-quarters to about

a third to only 7 percent in the New England

Journal study.

We see in the pre-contrast size-based

sensitivities and specificities, we see that the

sensitivities and specificities largely track with

the nodal size. That is, in studies where there

was a high proportion of large nodes, we see a high

sensitivity in the pre-contrast evaluation in the

green bars, which decreases as the proportion of

large nodes in the study decreases.

Conversely, as in the purple bars, we see

that as the percentage of small nodes increases,

then, the specificity increases also.

So, finally, in the post-contrast data,

what we see is that we see a lack of dependence of

the performance of the agent on the size of

distribution of the nodes in the study. We have

high sensitivity and specificity regardless of the

distribution of the lymph node sizes that were in

those studies.

Finally, just a word about clinical nodal

staging in the U.S. Phase III study, we looked at

clinical nodal staging where we could collapse the

nodal stage in its simplest form to where patients

were either node positive, node negative, or

indeterminate.

What we see here is a comparison of the

clinical nodal stage that was assigned based on the

images compared to the eventual pathologic stage,

and we can see as we go from the pre- to the

post-paired to the post, the percent where the

agreement was correct increases, the percent where

it's incorrect decreases, and the percentage that

could not be staged also decreases.

So, to sum up, there are two prospective

Phase III studies. The pre-contrast evaluations in

these studies show a characteristic tradeoff of

sensitivity for specificity. Post-contrast

evaluations show high sensitivity and high

specificity, which results in an overall

improvement in accuracy.

The improved lymph node differentiation

improved clinical staging. The supporting data

from the New England Journal publication showed

high sensitivity and specificity in a population of

largely small lymph nodes.

Finally, these data collectively

demonstrate the efficacy of Combidex in

differentiating metastatic from non-metastatic

lymph nodes.

Thank you. Now, Dr. Faich will review the

safety data.

Safety Data from Clinical Trial

DR. FAICH: I am Jerry Faich. Good

morning, members of the panel, Chairman, and FDA.

What I would like to do rather briefly is

review the amount of exposure data that has been

obtained for Combidex, discuss and show you the

pattern of adverse events that have occurred, make

a few comparisons with other agents, and then

discuss the proposed risk management plan for the

product.

In total, 2,061 subjects have been dosed

with Combidex. Of these, and I would like to

emphasize this and explain it, 131 received bolus

injection. This was in the process of developing

or exploring the utility of the product for liver

scanning, which required a bolus injection. That

indication and mode of administration has been

dropped.

The remaining patients, the remaining

1,930 patients were dosed with dilution and

infusion either in 50 ml or 100 ml saline, and

within those, there were 1,566 cases at all doses

who got the 100 ml dilution.

For the proposed indication and mode of

distribution, there were 1,236 patients in the NDA

receiving 2.6 mg of iron/per kg at the 100 ml

dilution over 30 minutes.

This shows you on the left-hand side the

rate of adverse events in the bolus injection 30

percent, in the middle 17 percent for 50 ml

dilution, and 14 percent on the right-hand side for

100 ml dilution showing a clear dose-response

relationship in terms of adverse events, and this

is indeed why the 100 ml dilution has been focused

on.

It needs to be said that during the bolus

injection studies, there was one anaphylactic death

that occurred immediately. That and the need to

use bolus injection for liver scanning is what led

to dropping the pursuit of that indication.

This shows you in the 1,236 patients the

pattern and rates of adverse events, you can see

going from vasodilation at 3.4 percent, rash, back

pain, pruritus, urticaria, et cetera, overall

totaling these 15.8 percent.

I would simply like to emphasize that

nearly all of these were mild, transient, and

self-limited.

Within the 1,236 core patients, 5.6

percent had adverse events from that prior list

that could be called hypersensitivity events.

Mainly these were vasodilation. It included 24

patients, however, who had more than one symptom

from that list.

Only 4 of the 1,236 patients, or 3 per

1,000, had a serious adverse event. The serious

adverse event rate is no greater than that found in

labeling for nonionic iodinated contrast media,

which ranges from 0.6 to 1.5 percent, and I will

show you that in a moment.

There were no life-threatening

anaphylactic/anaphylactoid reactions at the

proposed dose and method of administration.

In terms of immediate adverse events,

immediate hypersensitivity adverse events can, of

course, be controlled in large part by stopping the

infusion. The most common reaction, as I noted,

was flushing.

Thirty-six patients had infusion stopped

and restarted, that is, these patients were

rechallenged. Only two of them could not tolerate

the rechallenge and were discontinued. The

remaining 36 went on to complete their procedure.

Put a slightly different way, 94 percent

of all immediate hypersensitivity reactions

occurred within the first 5 minutes after dosing.

Most hypersensitivity reactions, as I indicated,

were mild to moderate in intensity.

At the proposed dose and method of

administration, out of the 4 serious AEs, 2 were

classified as immediate hypersensitivity reactions

using the FDA definition. That translates to a

rate of 1.6 per 1,000.

In terms of anaphylactoid reactions, again

using an FDA definition of affecting two body

systems, there were 12 such patients at the

proposed dose and method of administration. Two of

those were considered serious.

Four of the 12 were in the group that had

infusion stopped and then were rechallenged without

subsequent problems. The majority of these 12 had

dyspnea and flushing. There were no serious

hypotension or respiratory compromise seen in those

12 patients.

I don't mean to make much of this, but I

do show it, and it is always hazardous, and one has

to interpret data carefully when you compare one

set of data from one set of studies and labels to

another, but what I would like to do here is call

your attention to the Combidex data across the top.

The overall AE rate was 15.8 percent, the

serious AE rate was 3 per 1,000. That is those 4

cases I mentioned. If you look down in the

right-hand column just at serious AEs and compare

it to other iodinated contrast agents, both from

data in their labels and published studies, you

will see for Ultravist, that serious AE rate is 1.1

percent.

For comparators in studies done with

Ultravist, it was 0.6 percent, for Oxilan it was

1.5 percent, and for comparators to Oxilan and

studies done with it were 1.1 percent. So, this is

a basis or my basis for concluding there is not

evidence that there is increased risk of serious

adverse events comparing this drug to commonly used

iodinated contrast agents.

There is not much in the literature about

anaphylaxis in contrast agents. Here are 2 recent

studies that have been published. This is Neugut

in the Archives of Internal Medicine. His

published anaphylaxis rate done from his own

studies and across the literature was 2 per 1,000

to 10 per 1,000 or 0.22 to 1 percent. He noted

that it might be lower and most people are taking a

rate of about half that for low osmolality contrast

agents.

David Kaufman, at the Center for

Epidemiology in Boston, published this paper in

2003, and for contrast agents, this was an

international study of anaphylaxis, the observed

rate was 7 per 10,000. For nonionics, again, as I

said, 50 percent of that, about 3.5 percent, and

there was a range as you see here.

Combidex falls within or at the lower end

within that range of values.

In terms of a risk management plan for

this product, it is largely in keeping with

existing guidelines and calls for physician

education, emphasizing the need for dilution and

slow infusion obviously as a means to be able to

intervene if a reaction is occurring. The labeling

will be consistent with that, and the proposal is

to conduct targeted surveillance to gather further

data to reinforce the safety data that I have shown

you.

To summarize, then, there has been

considerable clinical exposure in the development

program. Hypersensitivity is relatively infrequent

and comparable to that of other contrast agents,

and the risk management program that I just

described is in accordance with existing

guidelines. Thank you.

Dr. Barentsz, please.

Clinical Utility of Combidex in Various Centers

DR. BARENTSZ: Madam Chairman, members of

the Committee, members of the FDA, I am an

oncologic radiologist and I have been using

Combidex MRI in more than 500 patients, and I am in

frequent contact with investigators in both the

U.S. and in Europe.

From the previous data, you have clearly

shown that this contrast agent works. A black

lymph node is normal, and a white lymph node is

abnormal. That is despite the tumors type.

Nonetheless, evaluating its clinical

utility is a lot more difficult, and for that you

need personal experience, as well as post-Phase III

studies. Based on these two, I am going to try to

show you the clinical utility and some cancer

types.

The reviewed publications were all in top

ranking journals. It was blinded post-contrast

image evaluation with gold standard histopathology,

and all those papers described a potential impact

on treatment planning.

The areas being defined where Combidex MRI

provides a significant clinical benefit were

prostate, bladder, head and neck, and breast, and I

want to address those issues with you in the next

10 minutes.

As you can see, data were collected from

almost 200 patients and almost 2,000 lymph nodes.

These are the data on sensitivity and specificity

and accuracy.

You can see that the data are highly

consistent, showing a high sensitivity,

specificity, and accuracy for all the cancers.

Now, let's start with the clinical utility

in prostate cancer. First of all, you have to

define the current strategies. Current imaging has

an insufficient sensitivity for lymph node staging,

and therefore, urologists are performing an

invasive operative surgical lymph node sampling to

detect the lymph nodes.

These techniques have limitations, only a

limited area sampled, and therefore, up to 31

percent of the positive lymph nodes are outside of

the surgical area, which have been shown by some

data recently published in the urology journals.

Furthermore, surgical sampling has a

complication rate reported to be 22 percent for the

open dissection and 5 percent for laparoscopic

dissection, including lymphocele, lymphedema, deep

venous thrombosis, pulmonary embolism, nerve

damage, and blood loss.

Because of the limitations of current

imaging technique and current staging techniques

for the lymph node dissection, these urologists are

advocating at this moment now an extended lymph

node dissection. They state that they will detect

those lymph nodes, however, this significantly

increases morbidity. The question is are the less

invasive way techniques to solve this problem.

As you can see, using the post-contrast

studies of Combidex, there is a dramatic decrease

of the number of false positives, as well as the

number of false negatives, but what is even more

important is that in our study in the New England

Journal of Medicine, in 6 percent of all the

patients, we found a small non-enlarged lymph node

which we could biopsy, and in all those patients,

we could confirm the diagnosis by image-guided

biopsy, and these patients did not undergo any

surgical dissection.

Furthermore, in 11 percent, we found lymph

nodes which were outside of the surgical field, so

they will be missed with regular surgery.

All these findings were confirmed by the

surgery because before the operation, we told the

urologists where the lymph node was, and they could

then find them.

I would like to show you two

representative cases. Here, you see a white lymph

node, metastatic, of only 7 mm in size. It is very

close to the internal iliac artery, which is

outside of the normal surgical field. In this

lymph node, we performed an image-guided biopsy

which was positive, and in this way a correct

diagnosis was being evaluated in a less invasive

manner, and this avoided inappropriate treatment.

This patient had, instead of a prostatectomy, an

androgen ablation.

In another patient, you see a lymph node

over there with a tiny white structure. You can

see it over there. This was also a lymph node

outside of the surgical field. We told our

urologist where this lymph node was located. It

was found and it was confirmed histopathologically

that this lymph node had a 1-mm metastasis.

What about bladder cancer? It is actually

the same story. In 24 percent of positive lymph

nodes, there are positive lymph nodes in 24 percent

despite negative pre-operative imaging techniques.

The presence of lymph nodes radically

changes the treatment option especially if there is

N2 and 3 node, or if there are more than 4 nodes,

so finding these lymph nodes also here is very

important.

If you perform an extended lymph node

dissection, you detect more lymph node, it will

increase survival for minimal disease, however,

also in this extended lymph node dissections, not

all lymph nodes have been sampled. Furthermore,

this increases morbidity.

These are the data in 172 lymph nodes in

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

dissection.

One representative image. This was a

patient with, on the CT scan, an enlarged 12 mm

lymph nodes, however, on the post-Combidex MRI, you

see the lymph nodes are black. This was the 12 mm

one, this was the 10 mm one, and they were normal.

In this patient, a neck dissection could have been

avoided.

Finally, breast cancer. The commonly used

staging procedure at this moment is the sentinel

lymph node staging, which has false negative

numbers of 3 to 10 percent, and is an invasive

technique, but what is even more important is that

recent data have shown that the sentinel lymph node

is the only positive lymph node in 61 percent in

patients with positive lymph nodes.

Nonetheless, these patients all undergo an

axillary lymph node dissection, and this has a high

rate of clinically significant complications.

A technique with a high negative

predictive value performed in an adjunct to the

sentinel lymph node procedure in patients with one

positive sentinel lymph node may reduce the number

of axillary lymph node dissections.

These are the published data in almost 300

patients by Michel in Switzerland, and you can see

that this technique has a high negative predictive

value.

I would like to show you one

representative case from our institution. This is

a very, very tiny primary tumor, and this was the

positive sample on lymph nodes. This lymph node is

white on Combidex, so that means metastatic, and

you can see that the second and third station lymph

nodes, that they are black, so in this patient, all

the other lymph nodes were black, which in this

case was confirmed by histopathology.

Now, to the final conclusion. I have

tried to show you some areas of clinical utility of

this contrast agent, and as soon as we get more

experience, there will be a lot more areas.

To summarize, the current techniques to

detect positive lymph nodes in prostate, bladder,

head and neck, and breast cancer have significant

limitations.

Combidex MRI shows high sensitivity and

specificity not only on the nodal basis, but also

on the patient-to-patient basis, which for a

clinician is even more important.

Therefore, Combidex MRI may reduce the

extent of surgery and morbidity, and finally,

Combidex MRI identifies additional positive lymph

nodes for biopsy or image-guided extended lymph

node dissection in this way improving the staging

of the surgeon.

Thank you.

MR. ROESSEL: Thank you. That concludes

our presentation.

Our clinical data and the clinicians I

think have shown you that Combidex is an important

diagnostic imaging tool that improves the current

practice.

Thank you. We are available for any

questions you have.

DR. MARTINO: Thank you.

At this time, I am going to ask Dr. Li to

present his view of this data, and once that is

done, we then will take questions for both the

sponsor and the FDA.

FDA Presentation

Efficacy and Safety of Combidex (NDA 21-115)

DR. LI: Dr. Martino, members of panel,

ladies and gentlemen, good morning. My name is

Zili Li. I am a medical team leader with the

Division of Medical Imaging and Radiopharmaceutical

Drug Products at FDA. I am a board-certified

physician in preventive medicine with special

training in epidemiology.

Today, I would like to share with you our

review of findings of NDA Application 21-115

Combidex.

I would like to start off by noting that

this presentation represents a collaborative effort

by a group of highly dedicated reviewers at FDA

whose names are on this list.

Combidex is an MR contrast agent. The

proposed clinical dose is 2.6 milligram iron per

kilo of body weight.

Of three methods of administration which

has been used in the clinical development program,

the sponsor select the dilution in 100 cc with the

slow infusion over 30 minutes of a standard measure

of administration.

The other two methods, particularly the

direct injection, is no longer being proposed.

This slide summarized the indication that

had been proposed by the sponsor--I will go over

one more time--that Combidex can assist in the

differentiation of metastatic and non-metastatic

lymph nodes in patients with confirmed primary

cancer who are at risk for lymph node metastases.

I would like to draw your attention to the

fact that this is a broad indication. If granted,

this agent can be used for almost all cancers

regardless of type, size, clinical stage, whether

patient has been previously treated with drug,

biologic, radiation, or surgery.

One objective of today's presentation is

to show you why the Agency has concerns for such a

wide or broad indication given the level of

efficacy and safety observed from clinical trials.

To support this indication, the sponsor

submit one U.S. and three European Phase III

studies. In addition, sponsor also ask Agency to

consider data from a published article in the New

England Journal of Medicine.

For the safety, the sponsor submitted a

safety data adverse event profile in particular

from approximately 2,000 individuals who received

Combidex from multiple clinical studies.

I would like to make a remark on this New

England Journal of Medicine article. This study is

pooled analysis from two ongoing clinical studies.

One is U.S. IND study, is under sponsor's IND. The

other study is non-IND study and in Europe.

The clinical investigators themselves took

initiative to combine 40 cancer patients from each

original study to form the basis for this New

England Journal of Medicine study. At this time,

however, it is unclear to us how those 80 patients

were selected, and more important, after repeat

requests, the sponsor is not able to provide us the

original source document which included pre-defined

statistical plan, blind reader evaluation manual,

and original copy of blind readers' evaluation of

the medical imaging.

For that reason, the Agency cannot

conclude this study was conducted in compliance

with the Federal regulations pertaining new drug

application. For that reason, we are not able to

consider this study as adequate and well-controlled

study.

However, the Agency do agree that the

cases present in this article may demonstrate some

potential the benefit of the use of Combidex in a

clinical setting.

I also would like to draw your attention,

say a few words about this U.S. IND study. We just

got update from sponsor yesterday. This study is

closed at this time. Roughly, they have 220

patients enrolled including 91 prostate cancer and

34 bladder cancer patients.

Although the original protocol require all

the pathology confirmation and MR imaging for all

the patients, at this time it is not clear to us

how many patients for this study will have both

information available for a meaningful analysis for

efficacy if such analysis is needed.

Now, I would like to first highlight the

differences between sponsor and the Agency's final

conclusion regarding efficacy and for safety.

As far as for the efficacy, the sponsor

believes the non-contrast MR agent only offer high

sensitivity or high specificity, but not both. The

advantage of this Combidex is its ability to offer

both high sensitivity and specificity consistently

regardless type of cancer or size of the lymph

node.

At this time, the Agency is not able to

draw such a conclusion because of the

generalizability and validity issues we are going

to show you in the later presentation, and also in

the later presentation, we are going to show some

preliminary evidence which may suggest the

performance of Combidex may vary by size or type of

cancer.

For the safety, sponsor acknowledge that

Combidex is associated with hypersensitivity

reaction, however, their emphasis is that no death

or life-threatening AEs are associated with the

proposed clinical method of administration. That

is the dilution with the slow infusion.

Also, I just noticed in the sponsor's

presentation is new to us that they make a claim

that this agent's safety profile is equivalent to

the iodinated contrast agent. I believe in your

briefing document, they also made a claim that

serious adverse event with the Combidex is only

one-third of that iodinated contrast agent.

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.

statistical plan.

The small number of patients or small

proportion of patients included in the primary

analysis create two dilemmas for us. The first, we

need to understand whether the estimate we got from

this population is applicable to entire population.

The second one is because of the small

number of patients, we want to ensure that the

patients included in the analysis more represent

the cancer patient distribution in the United

States.

This is the second issue we would like to

bring to your attention.

Based on the statistic provided by

American Cancer Society, it is estimated this year,

2005, there is going to be 1.4 million new cancer

diagnosed. The left two column showed you the rank

of the top 10 cancers and also showed their

percentage distribution in the United States. I

need to mention that lymphoma or leukemia are not

included in this table.

On the right two columns show the number

of patients and their distribution for each type of

cancer included in the primary analysis. I would

like to bring your attention to the fact they have

two readers. In this slide, we pick the highest

number in this table.

You probably noticed that the majority of

patients come from head and neck, which is ranked

roughly number 6 in the frequency distribution, and

also you probably noticed that prostate cancer

being the number one in the United States. There

is only 5 patients from the United States and 5

patients from Europe was included in the primary

analysis, and the highest number each category is

only in here is 37.

Also, I need to remind you that for

European study, the sponsor showed you the majority

nodes are larger than 10 mm. Actually, in reality,

all 37 patients have a node larger than 10 mm, so

there is no nodes like the 10 mm for the European

study for this population, particularly this head

and neck what I referred to.

So, you probably will ask why that so many

patients are not included in the primary analysis.

I would like to bring your attention to the fact

the primary analysis was conduct at the nodal

level, so the target lymph nodes, which should be

included in the analysis, is represented here, the

large circle here, is all the lymph nodes

visualized by site investigators.

When patient enrolled, when they take MR,

site investigator looked at the MR to circle the

node they see on those MR images. That should form

the basis for primary analysis. However, not all

the nodes was able to match with pathology, so you

drop some nodes right over there.

Then, when you present the same images,

the unmarked images to blinded reader, the blinded

reader may not pick up the same nodes the original

investigator picked in the first place, so you drop

some nodes over there.

Then, for the comparison purpose, because

they want to compare the post-images with the

pre-images, you can only do analysis on the nodes

identified on both end, so for that reason, you

have a few nodes drop again, so by the end, the

nodes included in the analysis is much smaller than

the nodes originally seen by site investigator

initially.

This table actually show you the

deposition of how the nodes got lost with each

process. In the U.S. study, this is the number of

patients. The first row showed you number of nodes

originally visualized by the site investigator,

which should form the basis for primary analysis -

371, 834, 333, and 234.

This row showed you what percentage of

those nodes have matched pathology, and this row,

the final one, showed you what number, how many

nodes were actually included in the primary

analysis. You can see it is roughly from 3

percent, 6 percent, to 45 percent of nodes was

originally seen is included in the primary

analysis.

The fundamental assumption for this

clinical development program is that the

performance of Combidex should be independent from

the type of cancer and the size of lymph nodes.

That was why originally that was allowed for

different cancer patients included in the one

study.

However, if you look at this performance

of Combidex, by different type of cancer, you will

see, first, this is the sensitivity slide. You

will see in the U.S. trial, the variation from 76

to 100 depending on the site of primary cancer, and

the 95 percent of the lower boundary could go as

low as 55 percent.

Only if you are willing to accept

assumption that Combidex performance is independent

of sites, you get 83 percent performance with the

lower boundary 73. That is exactly the reason why

the Agency was so worried about small lymph nodes,

small size, because from this table we really don't

know whether it's a variation because of the random

event, or if it truly reflects the different

performance of Combidex among the different type of

cancers.

This is the same table for the

specificity, which again challenge assumption

whether the Combidex, the performance should be

considered or accepted independent from the type of

cancers.

You notice depending on the different

sites, the specificity vary from 44 to 91, and with

the lower bound, can go as low as 21 percent. The

significance of the two slides is that with dose

variation we will have a very hard time to

understand what is appropriate performance

characteristic of this Combidex-enhanced MR

contrast agent, and if indeed the performance are

different, if this drug is approved for all the

cancers, this information may be misused by the

clinician to make their clinical judgment.

The next issue is about study

inclusion/exclusion criteria. I will go very fast.

Basically, for this study, the people who received

treatment, chemotherapy or radiation therapy in the

past 6 months was excluded.

Actually, in reality, when you look at the

people included in the primary analysis, I don't

think any of them had any prior treatment, so

mainly this database, we believe, if valid, only

applied to people who are newly diagnosed patients.

This is issue about development of a

clinical MR imaging guidance. Why is this imaging

guidance so important? It is because for the

radiation to use this contrast agent, you need to

have a standard way to interpret imaging. So, we

work with sponsor to ask them to come with the

guidance.

So, this actually, the clinical trial is

actually to validate the guidance for this validity

and usefulness, however, originally, from the NDA

submission, it appeared to suggest this guidance

was developed and validated from the same database.

That is the U.S. database. That was a big concern

for us because basically, if that is true, that

destroyed independence of this guidance themself.

Later on when we spoke to sponsor, they

provided us a revised statement. Basically, the

guidance was developed by use of Phase II images,

it is not Phase III.

Sponsor's consultant, when she developed

this guidance, she did look at the 16 cases from

Phase III trials, however, no pathology was

provided, and also, there was a statement that

there is no more changes for the guidance after

review of Phase III data.

To support their statement, sponsor did

submit original soft document to FDA for our

verification. We also had extensive discussion

with their consultant to recall what happening on

that day for the development of a Combidex imaging

guidance.

All we conclude at this time is that,

first, we do not have definitive evidence to

absolutely exclude the probability that Phase III

data has no impact in this guidance development,

however, the evidence provided by the sponsor is

consistent with this revised statement, therefore,

at this time, we decided not to pursue this issue

any further unless there is new evidence emerge.

The second issue we are having, which I

will present was included in our briefing document,

is in the European study, this guidance, the core

instrument actually was not used by the blinded

reader. The blinded reader was using a different

guidance to make their diagnosis.

At this time, the sponsor is not able to

provide any documentation for us to understand

which method or who actually do the translation

from this guidance and to this one. Actually, the

question we are having for the committee,

especially for people expert in MR imaging, is

whether the similarity or correlation between these

two guidance is so great, the Agency should not

worry about who did it and with all this

documentation.

Now, I would like to switch to the safety

side of Combidex evaluation. I will focus my

presentation in Combidex-induced hypersensitivity

reaction.

There is one case hypersensitivity-related

death in a clinical development program. This is a

70-year-old male with history of allergy to

contrast, who received undiluted direct injection

and developed hypersensitivity reaction immediately

after injection and become unresponsive.

At the clinical site, however, there were

no appropriate personnel or emergency response

available, so they have to call 911. When the EMT

arrived, they delivered CPR and epinephrine. When

the patient get to the hospital, patient was

pronounced dead approximately 35 minutes after this

injection. An autopsy revealed no MI or PE, and

they conclude this is a Combidex-related

anaphylactic shock.

I would like to make two points here.

This injection is no longer being used. The second

one, we are really concerned about the lack of

appropriate personnel for emergency situations

especially if this drug is found to be valid, safe,

effective, there is many free-standing clinical

imaging centers around the country, so we need to

have a way to ensure this drug to be used

appropriately. That is with assumption that if

this study is valid and the drug is safe.

This table shows the distribution of the

safety database or number of patients by

administration and by the dose. There are a total

of 2,061 patients exposed to Combidex, 1,236

patients received proposed clinical dose, 131

patients received bolus injection. Those three

groups will form the comparison for our next few

slides.

This slide shows the rate and severe

hypersensitivity reactions by the three different

subgroups I just mentioned to you. For the

clinical proposed dose, the rate of

hypersensitivity reaction is 5.3. For direct

injection, it is 6.1.

I would like to let you know that in your

briefing document, this number is slightly higher

because we just discovered some computer error, so

made correction on this slide.

People may define the severity

differently, so we use few indicators to give you a

range of severity, so you can pick which one is

appropriate for you. The first one is death. The

second one is serious events, which was the event

that meet the regulatory definition for serious

adverse event.

The next one is hypersensitivity involve

at least two body systems. The next one is the

patient was treated with antihistamine. The last

one is the patient treated with steroid. Most of

them are IV steroid.

If you look at this population, there is

no deaths. There is two cases the sponsor point to

you meet the definition of serious event. There is

13 cases that involve two body systems, 27, or 2.4

percent, of people treated with antihistamine, and

1.5 percent of people need IV steroids.

This slide outline the presenting symptoms

of hypersensitivity reactions. We work extensively

with our internal expert at FDA. We define

hypersensitivity reaction with the following three

groups of symptoms.

First, is skin reaction. The second group

with the respiratory difficulty with cardiovascular

symptoms together. The third one with the facial,

laryngeal, and general edema. This table show the

distribution of the patient presentation.

You will notice the majority of patients

present with skin symptoms, however, this slide

does show that direct injection, they may associate

with a high percentage of people with more severe

symptoms.

This is a slide I would like to bring to

your attention with a comparison with iodinated

contrast agent. The sponsor told you that there

were 4 cases serious AE happened in the clinical

program. That was an incorrect statement. In

reality, there was 29 serious events happened in

the clinical program.

The reason for include there, because the

25 cases, the Agency do not consider is drug

related, therefore, we didn't include it in our

analysis.

In the comparator, iodinated contrast

agents in their Table 9 safety presentation, they

are including all SAEs regardless whether drug

related, so that is we believe incorrect

comparison. So, that is why the number of events

in Combidex group is smaller than the iodinated

group.

This table, we focus on the

hypersensitivity reaction between Combidex and the

iodinated contrast agent. If you read the labels,

three labels which have clinical data for iodinated

contrast agents, totaled together there are 4,545

patients received iodinated contrast agent. There

is no death happening. For Combidex, there is 1

death of all the people receive Combidex. There is

zero out of 1,000 who has clinical dose.

For the serious AE, which is associated

with the Combidex, this is zero over here, and you

have 6 cases out of 2,000 for all doses, you have 2

cases for the clinical proposed dose.

Also, the last one, the column, we show

the percent distribution of those symptoms suggests

hypersensitivity reaction, you can see the rate is

quite different, the relative risk is quite

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,

that is purely speculation without any data.

Sponsor present to you their risk

management program. I rearranged our slides.

Basically, they say if we provided dilution and

slow infusion, and educate physicians to the

labeling and to the targeting academic center, they

should be able to adequately address the safety

issue.

We believe this is item we need to discuss

to implement, and also we believe that with

uncertainty with those severe events with this

Combidex administration, when you focus on the

issues, enhance the benefit of this drug to the

appropriate population.

We need to better understand actually the

performance of Combidex by different type of tumor

and the nodal size, because we have preliminary

evidence those performance may vary. Also, we need

to define appropriate patient population or

condition for use, that the use of Combidex, the

benefit will outweigh the risk, potential risk.

This is a table to support our preliminary

conclusion that performance of Combidex may vary by

type, by size of nodes, in addition of the type of

cancer. This analysis actually was conducted by

sponsor. We didn't make any modification to their

slides. We just presented their slides, their

result to you.

On the top is for the nodes less than 10

mm, the bottom row is for nodes larger than 10 mm.

You can see for the nodes less than 10 mm, the

sensitivity from their clinical database is between

67, 66 percent, and the specificity is 80 to 78

percent.

For the nodes larger than 10, the

sensitivity is 93, 98 for different readers, and 56

and 71. This, I would remind you, this is just a

point estimator. We have not put 95 percent lower

boundary yet.

If we put in the boundary, this number

could even be lower. We also don't know whether

there is interaction between size and type of tumor

because so small nodes that was included in the

primary analysis would not allow us to do a further

analysis.

This table showed you the prevalence of

nodes being positive by size of lymph nodes. Why

this information is important is because the

sponsor showed you the positive predictive value

and the negative predictive value in their

presentation.

To better understand that positive and

negative predictive value, you not only need to

understand the performance, that is, sensitivity

and specificity of agent, you also need to know the

prior probability that the prevalence of this node

being positive before you give a drug.

This data collected from their studies,

and for nodes less than 10, because we don't have

the MR imaging measurement, so we have to use the

pathology measurement as a surrogate over here.

For nodes less than 10, the prevalence range from

10 to 21 percent, which means if you see nodes less

than 10 mm, the probability that the nodes be

cancer-positive range from 10 to 20 percent from

this data.

If the nodes are more than 10 mm, then,

the probability from 34 to 60 percent depending on

different study. We still don't know why there is

variations.

Also, you probably reviewed the New

England Journal of Medicine. From their study, the

percentage is even higher. They got 75 percent of

people for the nodes larger than 10 has a cancer.

So, how are we going to put all this

information together to understand or to help us to

understand the value of Combidex to help physicians

in their patient care decisionmaking, or for any

other benefit that they believe is good for

patients?

I will present to you the predictive

values of a positive or negative Combidex test. I

will go over slowly with you. For the lymph nodes

less than 10 mm, the sensitivity is 68, the

specificity is 80. We make this assumption. This

has not been demonstrated by data yet, because the

lymph nodes, the number are too small, but we

assume if this is what we observed.

The prevalence tell you what is the

probability the nodes is cancer, whether they are

cancer-positive nodes before you give Combidex.

The positive predictive value really tell you after

you give Combidex, and if you get a positive

result, what is the probability that node is

metastatic at that time.

The negative predictive value tell you if

you gave Combidex, and the result is negative, what

is the probability that node is negative.

We look at different scenarios. If the

prevalence is 1, based on data or based on your

suspicion, the clinical knowledge, if you are

thinking the node, the probability of metastasis is

only 1 percent, based on this performance, even

Combidex is positive, the probability that nodes

being positive is only 3 percent, so the people

should make their own judgment this kind of

improvement where they have clinical implication or

values to help you to make decision to the patient

care.

When the prevalence get into 10, 25

percent, you see big changes here in the

probability, and this probably will getting higher

if sensitivity and specificity get improved, which

means that after you get a Combidex test, these

nodes more likely become cancer. You may go ahead

to biopsy that one to confirm your suspicion.

However, the positive predictive value is

not that high enough, so we believe with this

probability or likelihood, you will never make

final diagnosis based on the Combidex positive

result only, so most likely you will go to biopsy

to confirm it.

So, we do believe for nodes less than 10,

there might be potential values for Combidex if

performance is constantly demonstrated to help

physicians to select nodes for further evaluation,

to help patients to make some decision.

Let's look at nodes more than 10 mm. You

already heard from sponsor for those nodes, most

physicians will already consider is metastatic

cancer, so for those nodes more than 10, most

likely you will proceed with biopsy anyway without

Combidex.

The question you probably can ask yourself

in that scenario is if I get negative results from

Combidex, is that going to prevent me from going to

a biopsy. Here is the result. As I showed you,

the answer can vary depending on what is the

pre-probability, how likely that nodes being

positive before you give Combidex.

Before Combidex, if the probabilities are

low, then, you get a pretty high assurance if you

get an accurate result, it is going to be a true

and accurate result, however, as you will see, in

my previous presentation, the probability already

got up to 75 percent or 60 percent. In that range,

if you get a negative result, you only get 80

percent assurance that the node is negative. You

still have 20 percent probability the nodes become

positive, so maybe in that scenario, most

physicians probably would still go ahead to do a

biopsy for nodes even Combidex is negative.

So, for that reason, we are seeking your

advice to see how we can understand the values of

Combidex for nodes more than 10 mm for helping

patients.

Also, where you would emphasize what my

assumption here is based on the performance and

which we believe has not constantly demonstrated

from a clinical development program.

So, based on everything I present today is

we believe or the data seem to suggest that

Combidex may not have a value for people with a low

risk, that patients with lymph nodes larger than

10, the value may be limited, and also this cannot

be substituted for the confirmation. Also, we

believe there probably is not a good surveillance

of the recurrence of cancer, because that

population was not studied.

This list and go on and on, and very long,

so that is why we are really concerned with the

general indication. So, the key question we ask

ourself, we are seeking your advice is how the

Combidex result will really benefit to patients.

We don't want to leave you a wrong

impression that FDA do not care about knowing the

nodes, whether positive or not, we care greatly,

however, there is non-contrast agent available. We

try to understand what is additional value with

Combidex to bring it to the table in addition to

the non-contrast agent.

We also understand this test cannot be

used as confirmatory test, so we try to understand

what role this will play to help a physician help

their patients.

We also understand this drug may associate

with the potential, the risk, so we want to make

clear the use of this drug in appropriate

populations, the benefit with risk.

In the later discussion with the sponsor,

sponsor proposes four types of cancer which might

benefit, that Combidex may have a beneficial effect

to the patient, and they also presented those

cancers in their presentation.

For the prostate cancer first, I said

earlier the Agency do believe for nodes less than

10, Combidex may have a potential value, however,

we are struggling with the fact there is only 5

patients from U.S., 5 patients from the European

study included in the primary analysis, and the

estimate is so unstable from the data I just showed

you, we just have no clear understanding what is

the true performance of the Combidex for that

population.

Also, the same concern applied to bladder

cancer, breast cancer, and in less degree to head

and neck cancer, because they have more patients,

but I would like to bring your attention again for

head and neck cancer, most of nodes in European

trial, actually, all the nodes in European trial is

more than 10.

So, with that, I will conclude my

presentation. Thank you very much for your

attention. We are looking forward for your

guidance to help us to determine the efficacy and

safety of this product.

DR. MARTINO: Thank you, Dr. Li.

Questions from the Committee

DR. MARTINO: At this point, I will turn

to the committee and give you the opportunity to

ask questions both of the sponsor, as well as of

the FDA. As you do that, please raise your hand.

Your name will be taken down, and I will call on

you as we go around, so please don't yell out, we

will acknowledge you in turn.

I would like to ask the first question. I

would like the sponsor to make it clearer to me how

they actually looked at the MRIs. I am still not

entirely clear what they did first, what they did

second, and who, in fact, were the radiologists,

were they a specific group of radiologists, were

there any radiologists, please clarify those issues

for me.

DR. GOECKELER: Let me start by saying the

question with regard to who made the diagnoses, the

order in which that was done was shown in the

slides, so that the pre-contrasts were done first,

and those diagnoses were committed to. Then, there

was the paired, and then after some time there was

the post-only.

In terms of who did that, are you

referring to the specific specialty of the

radiologist involved?

DR. MARTINO: No, I am trying to figure

out did you have two radiologists that looked at

all of the films, did you have 100 radiologists? I

am trying to understand that element.

DR. GOECKELER: I will address that, thank

you.

For the U.S. Phase III trial, there were

two blinded radiologists each independently, and

the data has been reported both for each individual

reader or, as reported today, is the average of the

two readers.

DR. MARTINO: Can you also clarify to me

what the task of the radiologist was? I know you

have shown it, but I need it clear in my own mind

what was the charge given to them at each of these

interventions?

DR. GOECKELER: I am going to ask Mark

Roessel to speak to that issue a little bit in

terms of how the radiologists, what they were

actually asked to do on each of the blinded reads.

MR. ROESSEL: The blinded readers were

given training and given the guidelines to evaluate

lymph nodes, but they weren't given any direction.

The nodes were not marked on the images, so they

saw the pre-contrast images and any nodes they

identified, they circled, and they made a

diagnosis.

Then, on the paired evaluation, they did

the same thing. They circled the nodes. But the

nodes were not pre-identified on the images. The

FDA, when we designed the blind read, told us that

if we circled the nodes that we had pathology on,

that that would bias the readers, so the images

weren't marked, and then they did the same with the

post alone, they circled the nodes, put an arrow,

and gave their diagnosis.

Does that answer the question?

DR. MARTINO: It does. What constituted

the denominator for pathology, then, it was the

node as seen post-contrast?

DR. GOECKELER: Well, as Dr. Li indicated

on his slide, one of the reasons that these

patients and nodes drop out along the way is that

the two readings were done on unmarked images, and

then the nodes were also taken out just according

to standard surgical procedures.

So, then, after all those readings were

done, and then the readings had to be matched to

the pathology, so in order to be evaluable at the

end of all that, the node had to be read on both

the pre-contrast image and then identified and read

on the post-contrast image, and then it had to have

pathology.

So, when you impose those sequential

conditions for unmarked images, that is why some of

the nodes fall out along the way.

DR. MARTINO: So, then, it was, in fact,

the same node. The node had to have been seen on

non-contrast, also seen on contrast, and pathology

done. That, then, constituted the denominator. Am

I clear on that?

DR. GOECKELER: Yes, ma'am.

DR. MARTINO: Dr. D'Agostino.

DR. D'AGOSTINO: I have a couple of

questions, first, of the sponsor, and then Dr. Li.

If you look at Slide 9 on the sponsor's

presentation, this is page 5 of the handout.

DR. GOECKELER: Is it possible to get that

slide?

MR. ROESSEL: Yes.

DR. D'AGOSTINO: It was the sponsor's

presentation, I am sorry, the efficacy analysis.

DR. GOECKELER: Could you help us with the

title, what it says on the slide?

DR. D'AGOSTINO: Slide 9 is Nodal

Analysis, U.S., Phase III.

DR. GOECKELER: Is this the slide you are

referring to?

DR. D'AGOSTINO: Yes. I guess I was

surprised that there were no confidence intervals

given as the presentation was made. Later on, the

FDA presentation did have some confidence

intervals.

What I am interested in, in this here, is

how big were these confidence intervals if you

looked at, say, the post-contrasts and compared

them with the pre-contrasts for the paired, I mean

certainly the sensitivity doesn't change or they

would overlap.

Is there a real differentiation between

the specificity or are the confidence intervals so

large that it gets blurred?

DR. GOECKELER: I believe we have a slide

that has the data with the confidence--if not, I

can obtain it, and if someone could pull that data

for me, I can provide it to you. I don't have it

sitting right here this minute. I believe it was

in either the briefing book or if someone could

pull the data.

If you give me just a minute, I can

provide you the answer to that question. Perhaps

we could take another one.

DR. D'AGOSTINO: The other question is,

you know, the second question that follows is, as

you go to the body regions, which is Slide 11 in

this sheet here, how do you make a statement or

what kind of statement can be made from the

statistics point of view, and then hopefully from a

substantive point of view, that it makes sense to

pool these different body regions, because it seems

to me in terms of the questions that are asked

later on, if we go to particular body regions, it

has to be such a small number of nodes involved,

and such a small number of subjects, that the

inferences are really going to be almost

impossible.

So, is there an argument, and I haven't

heard it, that says you can, in fact, combine these

body regions?

DR. GOECKELER: I am going to ask a couple

of the clinicians that routinely image these

patients, but, first of all, you will recall from

Dr. Harisinghani's talk in the beginning that the

mechanism of action of the drug depends on, not a

primary tumor, but a physical process of

displacement of macrophages within a lymph node.

So, the study was designed with a variety

of primary tumors based on the way the imaging

agent acts in terms of imaging lymph nodes.

Mukesh, would you like to comment on that

further?

Well, with regard to the specific body

regions, then, the study obviously was carried out

in a mixed populations of patients, and I think

that obviously, if you start splitting out a large

number of subgroups, the confidence intervals for

any given subgroup increase.

I think that looking at the study as a

whole, which was designed to evaluate the premise

of differentiation of lymph nodes, obviously, that

occurred. With regard to the subgroups, I think

what is important is that there are consistent

trends amongst those subgroups based on the

mechanism of action of the drug.

DR. D'AGOSTINO: Moving on, I have just a

couple more questions, I obviously don't want to

tie up everything here.

In terms of the post-contrast, we were

told in the last presentation that not all the

nodes were actually used because you want to have a

pre- and a post, but there were nodes that were

there.

Was any analysis done on the nodes that

didn't enter into the post?

DR. GOECKELER: Yes, there was a separate

analysis that was done called the "blinded

overread." It is not one of the ones that I

described to you, but it involved a much higher

percentage of the total nodes.

So, it was again a blinded reading of the

nodes, and there was histopathologic correlation of

the data at the nodal level for each of the

readings, and I can show you--

DR. D'AGOSTINO: Yes, it would be nice to

see what the sensitivity and specificity was.

DR. GOECKELER: --what happened in those.

Can you first show the data in terms of

the numbers of patients that were evaluated both in

the unmarked images and in the blinded overread?

These are the numbers that were evaluated

by each reader in the blinded overread, and you can

see, based on the various reads, the number of

nodes that were read and for which there was

histopathologic confirmation for each reader and in

each diagnosis.

DR. D'AGOSTINO: Do you have the

sensitivity and specificity?

DR. GOECKELER: Can you show me the data

on false diagnoses in this, because that

essentially relates to, and we can go back then?

If you have a slide on sensitivity and specificity,

I think you do.

This is the data on the false diagnoses

that occurred in the larger reading population.

You can see the trends are largely the same as we

saw before, about 15 percent with the post-contrast

reads, and 25 percent are slightly higher.

We did see a higher variability between

blinded readers and the blinded overread for the

individual readers.

DR. D'AGOSTINO: It would be nice to see

the sensitivity and the specificity and the

confidence intervals.

DR. GOECKELER: Do you have the

sensitivity and specificity? Get me the numbers,

so that I can just provide them.

DR. D'AGOSTINO: Again, maybe we can come

back to it.

DR. GOECKELER: I can give you the

numbers, and I can tell you that the trends are

very--

DR. D'AGOSTINO: I think it would be very

helpful, but I don't want to tie it up here.

My last question is that you did a lymph

node as the unit of analysis. There is still the

subject, and sometimes in other activities, I don't

know about the nodes, but in other activities, when

you are looking at the same subject, and you are

taking different specimens, and so forth, they tend

to be correlated.

So, if you did a person analysis, what

would you do with the person, what would you say

about the person? Your sample size is greatly

reduced. Are there still your inferences?

DR. GOECKELER: Yes, the analyses were

also carried out at the patient level, so we have

the same data for each of the analyses pre- and

post-contrast at the patient level. I am going to

ask for a slide one more time.

100

DR. D'AGOSTINO: Maybe they can produce it

later on, the confidence intervals around some of

these things I am talking about.

DR. GOECKELER: No, actually, I think they

have it. I will tell you and then the slide will

be up here in just a second, that the trends we saw

in sensitivity and specificity at the nodal level

translated through to the patient level also.

Here we go. But this is nodes less than

or greater.

DR. D'AGOSTINO: It is really not only the

point estimates, but the confidence intervals, what

are you actually saying about the individual, how

much confidence you have.

DR. MARTINO: Dr. Hussain.

DR. HUSSAIN: I have a question to the

sponsor, and it strictly relates to the study

design, because I am still not clear about really

what the design was, so starting with the

eligibility criteria, how were the patients

characterized, were there standardized surgery, and

was the surgery required each time if it was

101

prostate or breast or bladder or head and neck, to

actually do the same template or do beyond what is

normally needed?

And understanding that my specialty, and I

am a gyn-oncologist, that there are certain

prognostic features that will make you feel or

believe that the patient has a high probability of

a lymph node positivity, say, in prostate cancer if

a guy comes in with a T2 disease, PSA of 50, and a

Gleason score, say, of 9, was that accounted for,

because in this patient you would think, based on

clinical criteria only, without even imaging, that

those are very high odds of having this patient

have lymph node positivity.

So, with all that taken into account, and

if it's not, why not, and what is wrong with having

done the appropriate studies, which is accounting

for the subpopulations as having adequate head and

neck patients, adequate breast patients, adequate

lung patients, and so on, to try to make some

conclusions from that?

And final question, and maybe I didn't see

102

it, but what actually was the Phase III trial, what

was compared to what?

DR. GOECKELER: Let me take a couple of

those and then refer some of those to other people

who are more directly involved.

With regard to the comparison, the primary

comparator was the paired evaluation as compared to

the size-based evaluation on pre-contrast. So,

those were the prospectively designed endpoints for

the Phase III studies.

With regard to the treatment of the

patients and how it was decided which nodes would

be sampled, I am going to ask Mark to comment on

that. That varied a little bit as Dr. Barentsz

said between the Phase III studies and what Dr.

Barentsz presented in the post-Phase III studies.

So, Mark.

MR. ROESSEL: In the Phase III studies,

the entry criteria were patients who had a known

primary, who were scheduled for either surgery or

biopsy, and who had suspicion of metastatic disease

spread to lymph nodes.

103

There was no direction as to what the

surgery or biopsy procedures would be. It was just

based on the clinical investigator.

DR. GOECKELER: The standard of practice

at the institution.

MR. ROESSEL: Does that answer the

question?

DR. HUSSAIN: I guess what I am asking is

was it the sense of the treating physicians, or

were there guidelines that said if you had this

size tumor, this kind of risk?

MR. ROESSEL: No, there were no--

DR. HUSSAIN: So, this was left random to

the person enrolling the patient based on their gut

feeling whether the patient have--

MR. ROESSEL: There were no guidelines

given. The entry criteria were just that, patients

with a known primary who were scheduled to have

surgery or biopsy, so that we could get

pathological confirmation of nodal status.

DR. GOECKELER: Did you have another

question, Dr. Hussain, about risk stratification

104

and predictive of--I am going to ask Dr. Roach to

speak to that with regard to relative risk and some

of the models and selection of patients who might

be most appropriate for treatment.

DR. ROACH: In the sponsor's indication,

it specified that patients who were at risk for

nodal involvement, so the clinical use for this

agent in patients with prostate cancer would be

patients at intermediate and high risk disease for

whom we have data from randomized trials that

demonstrates that treating the nodes is beneficial,

and that, in fact, it is important to treat as many

of the nodes as possible.

So, this agent would be useful for

identifying where the nodes are located and allow

us to reduce the morbidity of giving radiotherapy

in patients with prostate cancer.

DR. MARTINO: Dr. Levine.

DR. LEVINE: I have several questions.

First of all, for the sponsor, are you asking that

the individual, that the patient would have two

different MRI scans, in other words, your

105

indication is based on the post-read, so that means

that you are asking that patients are now going to

have a pre- and a post-MRI? So, that was one

question.

My second question, what was in those

benign nodes? You know, there are infiltrative

diseases of nodes, TB, MAC, et cetera. What were

those benign nodes, and what kinds of benign

conditions, in fact, fulfill your requirements for

benign?

Number 3. This is kind of a funny one,

but how did you know that the correct node was

actually taken out? Did you do an MRI scan after

surgery to know that you really took the right node

out?

DR. GOECKELER: Let me ask, in terms of

the matching, since Dr. Harisinghani has been

involved in a number of these studies, how that is

done.

The first part of the question dealt

with--I am sorry?

DR. LEVINE: Is the company requesting

106

that the patient have two different--no, not two

different reads--two different MRI scans?

DR. GOECKELER: Two different images,

yeah.

DR. LEVINE: And who pays for that?

DR. GOECKELER: In the conduct of the

clinical studies, that was required, because the

primary endpoint was the comparison of a

pre-contrast and a post-contrast read, and I am

going to let the radiologists comment upon how they

read these scans and how they match the nodes in

the clinical studies.

DR. LEVINE: That actually wasn't the

question. The question is if this compound is

licensed, are you asking that the patient be sent

to MRI scan twice?

DR. HARISINGHANI: And the answer is yes,

the patient will require two scans pre- and after

contrast administration, and in terms of being able

to correlate the nodes specifically to the areas on

how we know that surgically, we are right, it is an

arduous and a difficult task, and for that reason,

107

we have developed exquisite anatomic maps to which

we map the nodes when we read these out, and the

surgeons then correlate them to fix the anatomic

landmarks, which could be the vessels or bony

landmarks, and that is how they figure out where

the nodes lie.

DR. LEVINE: All right. Another question

was the character of the reactive lymph nodes, what

were they?

DR. HARISINGHANI: The benign enlarged

lymph nodes ranged in etiology. Most of them are

reactive nodes, not pointing to any specific

etiology for the so-called reactive lymph nodes,

but we had occasional cases of sarcoidosis.

I must say there were no caseating

tuberculosis at least in the trials that I have

been involved. I am not sure of the general trend,

but the benign nodes mainly were reactive and

enlarged.

DR. LEVINE: And the sarcoid case

fulfilled your criteria as benign, as well?

DR. HARISINGHANI: Yes, that was the case

108

I showed earlier in the presentation where it

behaved like a reactive lymph node.

DR. LEVINE: Have you guys done a cost

analysis of the efficacy of this approach given the

fact that you are going to do two MRI scans, is

there a cost analysis perhaps?

DR. HARISINGHANI: We have not formally

studied this in the States, but Dr. Barentsz's

group in the Netherlands has actually published

their results on cost saving.

Do you want to comment on that?

DR. GOECKELER: Also, just let me comment

that although two separate imaging sessions were

required in the clinical trials, because of the way

that clinical trials were conducted, different

investigators in the post-Phase III setting

interpret pre and post different ways, and Dr.

Barentsz can comment on that also.

DR. BARENTSZ: I would like to comment on

the first question first, about cost. We recently

published a paper in European Radiology in which

we, based on the sensitivity and specificity data,

109

did do a calculation and analysis on the health

care perspective.

If you are including this technique, it

will save, in Europe, 2,000 euros per patient, but

that is I think not the most important thing. The

most important thing, it saves also morbidity.

That was not taken in account in that study.

To reflect on the pre- and post-contrast,

as among radiologists there are some discussions

going on, at this moment, with some newer

techniques, you are able to make a sequence which

is insensitive to iron, so you can tell the machine

"Iron Off," and you can tell immediately after

that, "Switch on Iron," and that will substitute

for the pre-contrast examination.

Nonetheless, to start in the initial phase

for new readers to get some experience, it is

advised to use both of those examinations pre and

post. I am performing now and studying in the

Netherlands, in foreign patients in prostate

cancer, a multi-sound study only doing the post

just by having insensitive and sensitive sequence.

110

Also, if you have looked at the data of

the sponsor, you can see that if you do the

post-read only, it gives a very good result.

Perhaps you can comment on that also, Mukesh.

DR. HARISINGHANI: I think, as Dr.

Barentsz alluded to, for initial training purposes

you need both scans. Once the individual is

trained, then, yes, with the existing technology,

we can then, as he said, switch on and switch off.

Then, it would be possible that you could just do

the post-contrast study.

MR. ROESSEL: If I might add, because we

need to be clear about labeling for this, as the

sponsor, the proposed labeling, the proposed

package insert does not specify that you have to do

a pre-contrast image and a post-contrast image.

DR. MARTINO: Dr. Mortimer, you are next.

DR. MORTIMER: I wonder if the sponsor

could clarify the management of the lymph nodes.

Were the lymph nodes just handled in a routine

fashion? Were those nodes that were suspicious

handled in any different manner to ensure micro

111

metastatic disease?

DR. GOECKELER: Let me make sure I

understand. In terms of obtaining them in surgery

or--

DR. MORTIMER: Actually, reviewing them

histologically, so to make an analogy of sentinel

node mapping, the sentinel node is immunostained.

DR. GOECKELER: I think I understand. The

histology was reviewed without knowledge of the

image findings. So, they didn't analyze those

particular nodes any different than they did any

other nodes that were in the study.

DR. MORTIMER: And it was just H and E

slicing and--

DR. GOECKELER: Right.

DR. MARTINO: Dr. Perry.

DR. PERRY: A comment for Dr. Li. Your

point number 2 about inadequate representation of

tumor types, I don't think the sponsor ever

attempted to try to do all sorts of tumor types.

For many kinds of cancers, this methodology is not

necessary. For melanoma, as an example, we have

112

other staging systems or imaging systems that are

quite sufficient.

So, I think it is an unfair criticism to

say, when they set out to study four tumor types,

that they didn't do all the tumor types. I don't

think that is--that is a cheap shot in my opinion,

and I don't think that is an appropriate criticism

of the sponsor.

For the sponsor, when it comes to

education should this product be approved, I think

you are focusing on the wrong market. I think if

you put the emphasis on physician education, you

are really going to miss the mark by a long shot.

It is really the tech who gives the medicine, it's

not the physician.

I don't know any physician that I have

ever seen administer a contrast agent. Perhaps

it's different in Europe or in other locations, but

if it is, I would like to know that, but it seems

to me it is the techs who are going to need to be

educated and make sure that they give it the right

way, and if you focus on the physicians, you are

113

going to have problems.

DR. MARTINO: Dr. Brawley.

DR. BRAWLEY: There are a couple of

statements that were made in the FDA presentation

that I would like to get the sponsor's response to

them.

The first is of 152 and 181 patients who

received Combidex in the U.S. and the European

studies, a third of patients were censored from the

U.S. study, and two-thirds of patients were

censored from the European study, and not included

in the primary analysis.

I would like your response to that, and

then I have a couple others.

DR. GOECKELER: Yes, sir. First of all,

with regard to the European studies, as I think

someone indicated at the beginning, the European

studies themselves were initially carried out by

the European sponsor with different endpoints, so

they were analyzing patients at the patient and

group and nodal level.

So, in those studies initially, there was

114

nodal matching predominantly only amongst the large

nodes because it was felt at the time, and you have

to recall that these studies were all done seven or

eight years ago now, it was felt that the matching

could be better done on those large nodes, and I

think that is why there is a disproportionate

number of large nodes in the European studies.

After the studies were done, the sponsor

met with the FDA and agreed that they could take

data that was acquired at the individual node level

in those studies and analyze it in a blinded read

through the same sort of matching procedures, using

the same sort of analyses that were carried out for

the U.S. study.

So, one of the consequences of that is

that there were a large number of nodes removed

from those patients that weren't matched on a

node-by-node level. So, if you look at the gross

number of nodes, and the numbers that were

originally--and then the ones that were eventually

matched up by two blinded readers and then had

pathology, it's a smaller percentage in the

115

European studies.

DR. BRAWLEY: A couple more follow-up

questions.

I am told that there are only 5 prostate

cancer patients from the U.S. and 5 from Europe in

the primary analysis. Is that true?

DR. GOECKELER: Yes, that's true, and one

of the reasons, if you look at both the U.S. and EU

Phase III studies, the purpose of the studies was

to investigate the ability of the agent to

differentiate nodes, malignant from non-malignant.

I think that when you move on to--and

obviously, you can subset that a lot of different

ways, either by body region or individual tumor, or

any number of other ways, and if you do that,

certain categories will be large or small, and the

confidence intervals will react accordingly.

I think that that is why, when we turn to

the issue--and I think those studies did show that

Combidex improved the ability to differentiate

malignant from non-malignant lymph nodes.

I think that as Dr. Li indicated and as we

116

indicated, when you move on to the question of

where does that provide a clinical benefit, the

tumors that we presented on were ones where not

only we believe there is a clinical benefit, but

also that there was supplemental data post-Phase

III, not only on imaging performance, which you saw

in the slides that Dr. Barentsz provided, but also

on how that imaging performance impacted on

clinical utility.

DR. BRAWLEY: So, you are trying to

convince the committee that this drug is safe,

effective, and efficacious in prostate cancer with

a series of 10 prostate cancer patients.

DR. GOECKELER: Well, I wouldn't make the

argument about the risk-benefit solely on those 10.

I think we have to look at some of the additional

supplemental data that is available from other

places, such as the publications in the New England

Journal and other places.

DR. BRAWLEY: I have also heard that

certain source documents, including a pre-defined

statistical plan, blinded reader manual, the

117

original copy of the blinded reader efficacy

evaluation, were not available to the Food and Drug

Administration.

I would like you to respond to that

allegation.

DR. GOECKELER: Well, I think that there

have been some questions raised about the exact

sequences of events in which the nodal imaging

guidelines were developed and finalized, and I

addressed that on one of the slides that I

presented from the sponsor's perspective. The

guidelines were finalized prior to any blind

reader, availability of blind read data. Mark, if

you would like to expand on that.

MR. ROESSEL: I am sorry, I think you are

answering a different question. I think the

question was about the prospective plan being

available for the New England Journal of Medicine

article. Is that correct?

DR. BRAWLEY: That's correct.

MR. ROESSEL: The material that was

published in the New England Journal of Medicine

118

article, as Dr. Li really nicely showed, was done

independently of the sponsor. Two clinical

investigators, one in Europe and one in the U.S.,

got together and took 40 patients from trials that

they were conducting and did a blinded read.

We don't have, as the sponsor, again, it

was done independent of us, on their own

initiative, I think is the way Dr. Li put it, we

don't have from them a prospective statistical plan

or prospective plan for conducting that blind read.

We do have that for our Phase III studies,

of course, for our clinical studies.

DR. BRAWLEY: Let me just say

parenthetically that that is an acceptable answer,

I understand that answer, but I need, and I don't

want to criticize this company, Advanced Magnetics

at all, I definitely don't want to impugn Advanced

Magnetics, and I do want the news media to listen

to this.

In my last four years here, I have seen

some companies come before this committee, and some

companies submit data to the FDA, and what is done

119

is sort of slight of hand, with selection biases in

terms of choosing patients, to try to make one's

point that a particular drug or a particular agent

works, and we have to be very, very careful

whenever we look at data to understand exactly what

the source of the data is and the validity of the

data, and most importantly, the selection biases of

the patients going into the data before we can make

a decision.

That is a point that has been missed

repeatedly in a number of newspaper editorials

about drug approval recently, so that is the basis

for my question. You, sir, you did give me an

acceptable answer, and again I want to state I

don't want to at all impugn your company.

Last question. I heard that a patient

died getting this contrast agent. I thought I

heard that the patient got the contrast agent in a

facility that was not able to treat an allergic

reaction.

Is that true?

DR. GOECKELER: Mark, you can comment on

120

the facility, and I am going to ask Dr. Bettmann to

comment on sort of the guidelines and regulations

regarding what those sorts of facilities are

required to have.

MR. ROESSEL: The facility in question was

a free-standing MRI unit. We made sure in our site

qualifications for doing clinical trials that

equipment was available to treat any reactions that

occurred. They did have emergency equipment, which

I think is what you asked me, they did have it

available. Apparently, they didn't choose to use

it.

DR. BRAWLEY: That, too, is an acceptable

answer, I just want to go on the record as saying.

DR. MARTINO: Dr. Houn, did you want to

make a comment?

DR. HOUN: Yes, just to clarify when a

sponsor obtains right of reference to studies to

support their application, they have to be able to

provide to FDA access to underlying data to provide

the basis of the report of the investigation.

This did not happen with the New England

121

Journal study, and also just as a reference to the

committee, FDA didn't mean to give a cheap shot in

terms of the numbers of people enrolled, just in

previous approvals for ProstaScint, prostate cancer

only imaging drug, there were 152 people entered

into the analysis only with prostate cancer, and

there were 183 that were followed for the open

label efficacy study.

When we did NeoTec, a lung cancer

detection for non-small cell lung cancer, there

were 228 entered into the analyses. When we

approved PET-FDG, that got a broad indication for

all kinds of cancers. There were 1,311 people

entered into the analyses.

DR. MARTINO: Dr. Reaman.

DR. REAMAN: Just a question again about

the eligibility criteria, and I guess to somewhat

follow up on the issue of selection bias.

You stated that any patient with cancer

who was at risk for developing lymph node

metastases were eligible for this study, and they

were eligible based on whether or not they were

122

going to then have either a biopsy or a surgical

procedure.

So, how was the decision as to whether

they were going to have surgery or a biopsy

procedure made, by equivocal or positive

radiographic studies before they were entered on

this study, or did they have palpable adenopathy?

Other than the breast cancer patients in the

sentinel node biopsy, I am still not satisfied that

this isn't a selected population.

DR. GOECKELER: I will ask Mark to expand

on that, but I believe it's the case, and Mark can

verify, that the image findings, the post-contrast

image findings could not play a role, and were not

available to the physicians in making those

assessments.

So, the physicians did not have any

post-contrast image findings on which to base that

assessment of whether the patient then went on to

surgery or biopsy. It was done based on the normal

clinical information that would be available to

make that decision for every other patient.

123

DR. REAMAN: So, radiographic studies

weren't part of the clinical information?

DR. GOECKELER: Well, I think that the

pre-contrast, you know, you could have a CT or an

MRI pre-contrast, but no post-contrast image

findings.

DR. MARTINO: Dr. Bradley.

DR. BRADLEY: I have a couple of questions

maybe for the authors of the New England Journal

article, following up on a question by Dr. Li.

How did you select those 40 and 40

patients from a group that was 3 times larger? I

mean selection bias kind of comes to mind, but what

selection criteria did you use?

DR. HARISINGHANI: It is 3 times larger

now, but it wasn't then. The selection was

consecutive patients who were scheduled to undergo

radical prostatectomy both at the U.S. and at the

European site.

They were of the intermediate and

high-risk category, I must admit to that in terms

of the patient selection.

124

DR. BRADLEY: And then a follow-up

question. You showed some very nice images of very

small nodes, one of you, or positive nodes. With

5-mm cuts, and no way of guaranteeing that you are

in the same place for the second scan, how do you

know you are comparing the same nodes pre and post,

particularly not for you, but for the chest where

you have respiratory artifact?

DR. BARENTSZ: In our New England Journal

paper, we used 3-mm cuts in the obturator plane,

and we used 5-mm cuts in the axial plane. We

performed a combination of sequences which

visualized the anatomy and also a sequence which

visualizes the iron, and based on also a 3D

sequence which we performed, we were able to

compare the pre and post and exactly locate the

lymph nodes where they were, so we could make a

very accurate match on the 3-mm and 5-mm images.

Also, we located the nodes in relation to

the vessels. So, I agree with you that

localization and the location of lymph nodes is

very important.

125

DR. BRADLEY: So, the slice location of

3-mm slices was accurate, looking at the other

anatomy?

DR. BARENTSZ: Absolutely.

DR. BRADLEY: A follow-up question. On

the 15 percent--this may not be for you guys--but

15 percent false positive and false negative, we

have talked a little bit about what might cause a

false positive. What about false negative, any

thoughts, did you do an analysis of why they were

false negative?

DR. HARISINGHANI: I think there are two

issues here at least from our study. I would let

Bill answer for the general part, but the false

negatives are mainly as we are talking of nodes

which are smaller than 5 mm, then, the current

resolution of our scanner only enables us to be

confident at a certain level, and that could

account for the false negative reads.

DR. BRADLEY: Then, one final question for

the sponsor. Why did you choose a 0.2T Hitachi

when this is clearly a magnetic susceptibility

126

agent? Is it so sensitive that a gradient echo at

0.2 shows you what you see at 1.5? Also, I suspect,

having read all of this, that that was also where

you had your single death, is that correct?

DR. GOECKELER: I am going to have to ask

Mark or Paula to comment on the specific imaging

equipment. Please recall that the death was in a

liver imaging study, not in a lymph node imaging

study.

DR. BRADLEY: Right. I saw the physician

of record on that, who happens to own a bunch of

low-field magnets in Ohio. I am just wondering if

it is the same case. But why include a 0.2 at all?

MR. ROESSEL: We tried to include in the

Phase III clinical studies, we didn't specify the

imager to be used. There was no requirement for it

to be a 1.5T or 0.2T. The fact is we provided the

Agency with the information on the types of imaging

equipment used, and I think most of them were 1.5T,

the vast majority. It was a very, very small, I

think one or two that used 0.2T in the studies.

DR. BRADLEY: Just to follow up, was the

127

0.2 Hitachi also where the death occurred?

MR. ROESSEL: That, I don't know.

DR. MARTINO: Ladies and gentlemen, we are

running short of our allotted time, but I

appreciate these questions as important, and that

is why I am giving you a little more time in this

part of the meeting.

That being said, I would ask those of you

asking the subsequent questions, please be sure

that your questions are necessary to your thinking

about the efficacy and the approval of this agent,

and are not just purely for your perhaps

intellectual curiosity.

Dr. Giuliano.

DR. GIULIANO: I am a surgeon, Dr.

Martino. We have limited intellectual curiosity,

so my--

DR. MARTINO: I know.

[Laughter.]

DR. GIULIANO: Therefore, my questions

will be brief. But I am struggling as a surgeon

through these documents. We say the surgical

128

procedure was not altered, the post-enhancement

images were not available.

How did you instruct the surgeon to remove

the Combidex abnormal enhanced lymph node? He or

she had to know what that node was, where it was.

It had to be labeled as such. So, on a

node-by-node analysis, I think that introduces a

surgical bias because as any surgeon knows, it is

easier to find a positive node than a negative

node.

In addition, using the node-by-node

analysis, what happens with nodes not seen on MR

that are removed? For example, if this agent did

not alter your surgical operation, the patient with

a prostatectomy may have had a pelvic lymph node

dissection, and there was one node that had been

identified on your preoperative images or an

axillary dissection for breast cancer, and there

are one or two nodes, and 15 or 20 nodes were

removed.

If you look at the 1 or 2 nodes, which had

to be seen on the image, had to evaluated

129

histopathologically, and they correlated, let's say

they were both negative, what if all of the

remaining nodes were positive or one of the

remaining nodes was positive, how was that dealt

with statistically or in your presentation? I

could not understand that.

DR. GOECKELER: I will ask Dr. Anzai to

talk about the nodal matching and how those nodes

were identified, and how imaging was or wasn't used

in the identification of those nodes.

DR. ANZAI: I am the radiologist involved

in Phase II and III clinical trials. Your comment

is absolutely right. This was the hardest trial

that we ever had in Radiology, that I personally

have to have images going to OR when the patient is

in operating site, and we have to ask a surgeon to

make stitches on a certain anatomical level.

For example, a head and neck radiology, I

have to ask the surgeon to make stitches on the

submandibular--this is the jugular vein, so in

between this lymph node is the lymph node that I am

seeing in imaging, and it was very labor intensive.

130

Many of the radiologists have to be in the

OR with this graph, and the surgeon to identify,

correctly identify those lymph nodes on imaging, or

lymph node in a patient, so the pathologist would

identify this is the exact lymph node that we saw

in imaging.

That is why the sample size was so small,

because we have to have a certain confidence that

the imaging on the lymph node is matched with final

pathology. That is why the size of the lymph node

that is seen in all the cancer patients are small,

but this is such a labor intensive study, but we

did as much as possible to correlate imaging on a

lymph node with surgical pathology by being in the

OR.

The second question for statistics, maybe

Mark can comment.

DR. GOECKELER: I think that the issues

that have just been identified by Dr. Anzai and

others are the ones that account for the analysis

that Dr. Li showed, where you start out with a

large number of nodes and then if you are going to

131

require evaluation on unmarked images to avoid bias

in the reading of the data, then, you lose some

nodes along the way, because the readers don't all

identify the same nodes every time they read.

That is why you see some of the nodes or

the numbers dropping off at every level. We tried

to address that in part by looking at another read

that involved the blinded overread, which are a

much larger percentage of the nodes.

DR. GIULIANO: Maybe I wasn't very clear

about that. My question is if the labeled node

from the operating room is the one identified on

the MR, and histologically evaluated, and is

positive or negative or whatever the correlation

is, but other nodes that were not seen are

positive, was that counted as a false negative or

was that not counted because the other nodes were

not seen on MR?

DR. GOECKELER: No, the primary analysis

was at the nodal level, so those numbers that were

presented were at the nodal level. There were

other analyses the data tracked very closely at the

132

patient level where you can look at the patient

level also.

DR. GIULIANO: Thank you.

DR. MARTINO: Does that answer your

question, Dr. Giuliano, because I am not sure that

it did.

DR. ANZAI: Let me add one thing. I think

your question that the lymph node that not

identified on the MRI, how do we handle that. I

think a nodal level correlation, we didn't look at

those lymph nodes were pretty not pre-identified by

imaging, but a patient level analysis, if, for

example, MRI showed all the normal lymph node, but

pathology somehow find one positive lymph node that

not identified MRI, I think that was considered to

be false negative.

DR. GIULIANO: Perhaps you could share

that patient analysis, would that be appropriate,

Dr. Martino?

DR. MARTINO: Well, to be honest with you,

I think at this point you are going to have to make

your decision realizing that the data that you need

133

perhaps are not presented to you right now. I

think that may be one of the issues.

Dr. Bukowski.

DR. BUKOWSKI: I am trying to understand

the efficacy and benefits of this approach, and

there was a statement made that there is a decrease

in morbidity when you apply this particular

product.

Can you help me understand what the

implications are? Are you implying that there will

not be a need for surgery if there is an identified

positive node, or that there will be then a

percutaneous biopsy done, and, if so, what is the

likelihood of being able to biopsy the small nodes

that you are referring to, less than 10 mm, using

techniques not only at academic centers, but

centers elsewhere?

DR. BARENTSZ: You raise a very good

point, and I would like to address a little bit to

our New England Journal paper, which is different

from the Phase III study in that way, that in the

New England Journal paper, we were able to--we were

134

allowed to include data which were obtained from

the Combidex MRI into clinical practice.

So, that paper shows better the real

clinical effect of what this contrast agent can do.

So, if we found an extra node, we were allowed to

tell to the surgeon, and I again agree with you,

communication with the surgeon where the node is,

is very important.

Mukesh and I, we started by making some

nice schemes, which have been used by the surgeon,

and sometimes we, well, we went to the surgery

room. So, we added the information of the MRI for

the surgeon, and we asked our surgeon how this

scan, how did this really change his management,

did that decrease the extent of surgery.

Actually, the black nodes, they are

normal, and if you have a high sensitivity and a

high negative predictive value, but if you have

both very high, as what we obtained in our paper in

the New England Journal, both on the patient and as

on the nodal level, that means that the risk after

an MRI, that the patient has a negative lymph node

135

is extremely high.

That means the number you are missing is

extremely low, and that current threshold, our

urologist advises, but I would like also to have

one of the urologists to speak on that. That is

very important clinical information which may

actually decrease the number of lymph node

dissections.

If you have a positive lymph node, it

always must be confirmed histopathologically. If

it's large, 7 mm, 6 mm, or 10 mm, you can do that

by image-guided biopsy. If it's smaller, you have

to tell the urologist the node is down there, and

he can remove it.

Perhaps the urologists can make also some

clinical remark on that. Comment about the

clinical use, how this technique can be applied,

what will you do if you have a negative MR

Combidex, what will you do if I am saying it's a

positive lymph node.

DR. KALINER: Well, first of all, any

information that I give as a clinician, first of

136

all, I am a urologist for the last 16 years at

George Washington University, and recently joined

Cytogen as the Vice President of Medical Affairs,

so I have a lot of experience in surgery and

urology.

Any information I can get that helps me

identify whether there is more extensive disease or

not is extremely important with these patients.

So, in the case, if I have a negative Combidex

scan, first of all, I wouldn't do a Combidex scan

unless it is somebody that is intermediate to high

risk, as many of these patients were, so they are

stratified by risk to begin with.

So, this is somebody that has a negative

Combidex scan, we still would perform the lymph

node dissection, but if there was a reason to look

in an extended area, which we know pathologically

does occur, then, that scan can help guide us to do

that.

On the other hand, if we did find

something ahead of time, we may be able to

eliminate doing an invasive procedure by performing

137

a biopsy or perhaps a laparoscopic lymph node

dissection as opposed to an open procedure. There

are a variety of ways to look at doing that.

Any way that I can get more information to

help prevent an invasive procedure when it is not

necessary is extremely important.

DR. MARTINO: Dr. Dykewicz.

DR. DYKEWICZ: I have two questions

regarding safety and adverse events. The first is

whether slowing the rate of the infusion as

proposed will really reduce the risk of

hypersensitivity reactions.

In the sponsor's presentation, there was

data presented showing that the number of adverse

events were reduced with the use of that

administration method, but, of course, adverse

events could include both hypersensitivity and

non-hypersensitivity events.

Hypersensitivity events are the ones that

are potentially going to lead to fatalities, so

that is where I have my greatest concern.

The FDA analysis was that the overall risk

138

in severity of hypersensitivity reactions was

actually not reduced, and they presented one data

on Slide 21, Presenting Symptoms of

Hypersensitivity Reactions, that showed that at

least in terms of urticaria, the rate even

increased with slowing the infusion rate from 63

percent with the bolus to 85 percent.

Some of this I think is probably just a

result of the signal of having a relatively smaller

population with the bolus group, but from the

standpoint of the sponsor, are you of the belief

that the slower infusion rate will significantly

reduce the risk of hypersensitivity reactions?

DR. GOECKELER: I think the issues are

related to risk and management, and I am going to

ask Dr. Page to speak to that, please.

DR. PAGE: The most telling data about

this are to look, not at all hypersensitivity

reactions, which again tended to be--this is an

iron product, so that the notion is that any

exposure in the bloodstream is likely to cause some

activation of mediators, so you are going to see

139

some flush.

So I would contend that the notion of

hypersensitivity is probably too broad. That is

what we are looking at, it is a hypersensitivity

reaction, and in that sense, I agree with the

statement that it is not clear that dilution will

reduce rates of hypersensitivity, but I believe the

data show convincingly that they will reduce severe

both all AEs, as well as hypersensitivity AEs.

In the case of bolus, there were 3 serious

adverse events out of 131 patients. That is a rate

of 2.5 percent. In the case of diluted, there was,

in fact, only 4 out of 1,200, and, of course, that

is a rate on the order of 0.3, so there is a log

order difference in the rate of severe adverse

events. That is one piece of information.

The other is we know that in patients who

are having an immediate hypersensitivity reaction,

you can turn off the infusion, the reaction goes

away, and you can restart the infusion. So, it is

not only the accrued rate of all the reactions.

The real question is severe, and the reason is can

140

you intervene.

DR. DYKEWICZ: The second question, which

actually dovetails with that, and a question that

Dr. Brawley had asked about earlier, is the acute

treatment of the serious hypersensitivity

reactions.

Were any of these patients given

epinephrine?

DR. PAGE: I believe none were. Mark,

correct me if I am wrong there. Some were given

steroids, of course, some were given albuterol in

one case. As far as I recall, there was no

epinephrine given.

DR. DYKEWICZ: Well, this is no indictment

specifically of the sponsor, but for discussion

later, I would raise the point that the treatment

of choice for a serious hypersensitivity reaction

would be epinephrine.

DR. PAGE: And would you say that is true

if there was no hypotension and on cessation of

infusion, and there is no acute respiratory

compromise?

141

DR. DYKEWICZ: Potentially, yes. Studies

have shown that in anaphylaxis, delay in the

administration of emerging anaphylaxis is

associated with an increased fatality rate.

Obviously, this requires some clinical

judgment depending upon the clinical presentation

of the patient, but I would say that, in general,

if you have patients with serious hypersensitivity

reactions, that none have received any epinephrine,

that is sad in my opinion as an allergist.

But again, this is nothing specific for

the sponsor of this agent. I think it is

reflective of the standard of care generally.

DR. GOECKELER: Dr Bettmann.

DR. BETTMANN: I wanted to comment as a

clinical radiologist. I think your point is very

well taken. My recollection of the data are that

the only patient that was given epinephrine was the

one patient who died, and that patient was given in

a very delayed fashion, so it was inappropriate.

Again speaking as a clinical radiologist,

it gets to the point of who treats these reactions

142

and how, and how are they trained, and that gets

back to what Dr. Brawley touched on about why was

the study done, that one fatality, in a place where

the reaction couldn't be treated appropriately.

I think the answer is simply that there

are, the American College of Radiology has very

clearly stated that contrast should not be injected

where there isn't equipment to treat reactions that

are potentially fatal and where there aren't people

who are ACLS trained.

So, you started by saying it's not an

indictment against the sponsor, I think perhaps

it's an indictment against clinical radiology.

There is no question that patients should be

treated appropriately, there is no question that

the appropriate treatment is known. It is a matter

of linking those two.

I think that is a question that sort of is

unfortunately way beyond Combidex.

DR. MARTINO: Thank you.

Dr. Rodriguez. For the rest of you, there

is only three of you. Please be brief and

143

succinct.

DR. RODRIGUEZ: I just want to be very

clear about one issue. One of the committee

members previously said that the company obviously

did not intend this product to be used in all

malignancies.

As I read the application or in this

proposed indication, however, it is worded exactly

the same in both the FDA presentation and the

sponsor, and it states that it is to assist in the

differentiation of metastatic and non-metastatic

lymph nodes in patients with confirmed primary

cancer who are at risk for lymph node metastases.

So, to the sponsor, are you, in fact,

requesting that the FDA approve this product for

broad application in all malignancies?

DR. MARTINO: I will take a yes or no

answer to that. That is all that is necessary in

my mind.

DR. RODRIGUEZ: That is all I need.

DR. GOECKELER: The indication was based

on the Phase III clinical trials. I think the FDA

144

and the sponsor --well, that is the indication that

is being sought, yes.

DR. MARTINO: Thank you.

DR. D'Agostino. Succinct and brief.

DR. D'AGOSTINO: I will be very brief.

Just to go back to some of the questions I raised

earlier in here, it seems to me, and the sponsor

can say yes or no, that what we are dealing with is

trying to evaluate efficacy based on not all the

subjects available, not all the nodes available, if

there is differences between the pre and post in

terms of sensitivity and specificity, it is

basically on a per-node basis. It is not based on

per type, body region, and it is not based on a

per-person basis.

I don't see any justification for

combining the body regions by statistical criteria.

I didn't see anything on what happened to the nodes

that weren't in the paired analysis, and I think on

the per-patient basis, you have such a small number

of patients, that we probably don't have any

significance on sensitivity, specificity, and

145

disposition of the patient.

A yes or no from the sponsor would be

interesting.

DR. GOECKELER: There were a lot of

questions. First of all, with regard to the body

regions, those weren't combined. The data sets

were for the entire populations. They were

subgrouped out after the fact.