1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

                   ONCOLOGIC DRUGS ADVISORY COMMITTEE

 

 

 

                                VOLUME I

 

 

 

 

 

 

                        Thursday, March 3, 2005

 

                               8:05 a.m.

 

 

                          Gaithersberg Hilton

                           620 Perry Parkway

                         Gaithersburg, Maryland

                                                                 2

 

                              PARTICIPANTS

 

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

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

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

 

      COMMITTEE MEMBERS

 

      Otis W. Brawley, M.D.

      Ronald M. Bukowski, M.D.

      James H. Doroshow, M.D.

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

      Representative

      Pamela J. Haylock, RN, Consumer Representative

      Maha H.A. Hussain, M.D.

      Alexandra M. Levine, M.D.

      Joanne E. Mortimer, M.D.

      Michael C. Perry, M.D.

      Gregory H. Reaman, M.D.

      Maria Rodriguez, M.D.

 

      CONSULTANTS (VOTING)

      FOR COMBIDEX

 

      Marco Amendola, M.D.

      William Bradley, M.D., Ph.D.

      Marion Couch, M.D., Ph.D.

      Ralph D'Agostino, Ph.D.

      Mark Dykewicz, M.D.

      Armando Giuliano, M.D.

      Dennis Ownby, M.D.

      Dana Smetherman, M.D.

 

      PATIENT REPRESENTATIVE (VOTING)

 

      Eugene Kazmierczak - for Combidex and Prostate

      Cancer Endpoints

 

      CONSULTANTS

      PROSTATE CANCER ENDPOINTS

      Victor DeGruttola, Sc.D.

      Mario Eisenberger, M.D.

      Eric Klein, M.D.

      Lisa McShane, Ph.D.

      Derek Raghavan, M.D., Ph.D.

      Howard Sandler, M.D.

      Howard Scher, M.D.

                                                                 3

 

                        PARTICIPANTS (Continued)

 

      FDA (A.M. Session)

 

      Zili Li, M.D., MPH

      Florence Houn, M.D.

      George Mills, M.D.

      Sally Loewke, M.D.

 

      PARTICIPANTS (Continued)

 

      FDA (P.M. Session)

 

      Peter Bross, M.D.

      Patricia Keegan, M.D.

      Bhupinder Mann, MBBS

      Richard Pazdur, M.D.

      Dan Shames, M.D.

      Rajeshwari Sridhara, Ph.D.

      Robert Temple, M.D.

      Grant Williams, M.D.

                                                                 4

 

                            C O N T E N T S

 

                                                              Page

 

      Call to Order and Introductions

      Silvana Martino, D.O.                                      6

 

      Conflict of Interest Statement

      Johanna Clifford, M.S., RN                                 9

 

      Opening Remarks

      George Mills, M.D.                                        11

 

                          Sponsor Presentation

                        Advanced Magnetics, Inc.

 

      Combidex, Introduction and Indication

      Mark C. Roessel                                           15

 

      Mechanism of Action, Combidex

      Appearance on MR Images

      Mukesh Harisinghani, M.D.                                 17

 

      Efficacy Data from Phase III Clinical Studies

      William Goeckeler, Ph.D.                                  29

 

      Safety Data from Clinical Trial

      Gerald Faich, M.D.                                        39

 

      Clinical Utility of Combidex and Various Cancers

      Jelle O. Barentsz, M.D.                                   46

 

                            FDA Presentation

 

      Efficacy and Safety of Combidex (NDA 21-115)

      Zili Li, M.D., MPH                                        56

 

      Questions from the Committee                              88

 

      Open Public Hearing                                      146

 

      Committee Discussion                                     167

                                                                 5

 

                      C O N T E N T S (Continued)

                                                              Page

 

                           AFTERNOON SESSION

 

      Call to Order and Introductions

      Maha Hussain, M.D.                                       204

 

      Conflict of Interest Statement

      Johanna Clifford, M.S., RN                               207

 

      Opening Remarks

      Richard Pazdur, M.D.                                     210

 

      A Regulatory Perspective of Endpoints to

      Measure Safety and Efficacy or Drugs:

      Hormone Refractory Prostate Cancer

      Bhupinder Mann, MBBS                                     216

 

      Towards a Consensus in Measuring Outcomes

      in New Agents for Prostate Cancer

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

 

      NCI Prostate Cancer Treatment Trial Portfolio

      Alison Martin, M.D.                                      261

 

      Toward an Endpoint for Accelerated Approval

      for Clinical Trials in Castration Resistant/

      Hormone Refractory Prostate Cancer

      Howard Scher, M.D.                                       271

 

      Design of Clinical Trials for Select Patients

      With a Rising PSA Following Primary Therapy

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

 

      Open Public Hearing                                      330

 

      Committee Discussion                                     333

 

                                                                 6

 

                         P R O C E E D I N G S

 

                    Call to Order and Introductions

 

                DR. MARTINO:  Good morning, ladies and

 

      gentlemen. I would like to begin the meeting, if

 

      you would be so kind as to take your seats.

 

                The purpose of this morning's meeting is

 

      to consider a new drug application, the agent

 

      Combidex from Advanced Magnetics, Incorporated, a

 

      proposed indication for intravenous administration

 

      as a Magnetic Resonance Imaging contrast agent to

 

      assist in the differentiation of metastatic and

 

      non-metastatic lymph nodes in patients with

 

      confirmed primary cancer who are at risk for lymph

 

      node metastases.

 

                We will start the meeting by having the

 

      members of the panel introduce themselves, and I

 

      would like to begin on my left, please.

 

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

 

      Deputy Division Director for the Division of

 

      Medical Imaging and Radiopharmaceutical Drug

 

      Products.

 

                DR. MILLS:  Good morning.  I am George

 

                                                                 7

 

      Mills, FDA.  I am the Division Director for Medical

 

      Imaging.

 

                DR. HOUN:  Florence Houn, Office Director,

 

      FDA.

 

                DR. LI:  Zili Li, Medical Team Leader,

 

      FDA.

 

                MR. KAZMIERCZAK:  Eugene Kazmierczak,

 

      Patient Consultant to FDA for prostate cancer.

 

                DR. BUKOWSKI:  Ron Bukowski, Medical

 

      Oncologist, Cleveland Clinic Foundation.

 

                DR. BRAWLEY:  Otis Brawley, Medical

 

      Oncologist and Epidemiologist, Emory University.

 

                DR. DOROSHOW:  Jim Doroshow, Division of

 

      Cancer Treatment and Diagnosis, NCI.

 

                DR. RODRIGUEZ:  Maria Rodriguez, Medical

 

      Oncologist, M.D. Anderson Cancer Center.

 

                DR. REAMAN:  Gregory Reaman, Pediatric

 

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

 

      and George Washington University.

 

                DR. MARTINO:  Silvana Martino, Medical

 

      Oncology, Cancer Institute Medical Group in Santa

 

      Monica.

 

                                                                 8

 

                MS. CLIFFORD:  Johanna Clifford, Executive

 

      Secretary to the Oncology Drugs Advisory Committee.

 

                DR. HUSSAIN:  Maha Hussain, Medical

 

      Oncologist, University of Michigan.

 

                DR. PERRY:  Michael Perry, Medical

 

      Oncologist, Ellis Fischel Cancer Center, Columbia,

 

      Missouri.

 

                DR. MORTIMER:  Joanne Mortimer, Medical

 

      Oncologist, Moores UCSD Cancer Center.

 

                DR. OWNBY:  Dennis Ownby, Pediatric

 

      Allergist at Medical College of Georgia.

 

                DR. D'AGOSTINO:  Ralph D'Agostino,

 

      Biostatistician from Boston University.

 

 

 

                DR. DYKEWICZ:  Mark Dykewicz, Professor of

 

      Internal Medicine, Allergy and Immunology, Training

 

      Program Director, St. Louis University.

 

                DR. GIULIANO:  Armando Giuliano, Surgical

 

      Oncologist from Los Angeles.

 

                DR. BRADLEY:  Bill Bradley.  I am a Neuro

 

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

 

                DR. AMENDOLA:  Marco Amendola, Professor

 

                                                                 9

 

      of Radiology, University of Miami.

 

                DR. SMETHERMAN:  Dana Smetherman,

 

      Radiologist, Section Head of Breast Imaging,

 

      Oschner Clinic.

 

                DR. COUCH:  Marion Couch, Head and Neck

 

      Surgeon from the University of North Carolina.

 

                DR. MARTINO:  If you would all turn off

 

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

 

      the committee, please recognize that you need to

 

      speak into the microphone, and it only works when

 

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

 

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

 

                There is a reasonable amount of echo that

 

      I still hear in this room.  Can Audiovisual do

 

      anything more to clarify our sound?  Okay.

 

                At this point, Ms. Johanna Clifford will

 

      report on the Conflict of Interests.

 

                     Conflict of Interest Statement

 

                MS. CLIFFORD:  The following announcement

 

      addresses the issue of conflict of interest and is

 

      made a part of the record to preclude even the

 

      appearance of such at this meeting.

 

                                                                10

 

                Based on the submitted agenda and all

 

      financial interests reported by the committee

 

      participants, it has been determined that all

 

      interests in firms regulated by the Center for Drug

 

      Evaluation and Research present no potential for an

 

      appearance of a conflict of interest.

 

                With respect to the FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

      Antonio Grillo-Lopez is participating in this

 

      meeting as an acting industry representative acting

 

      on behalf of regulated industry.  Dr. Grillo-Lopez

 

      is employed by Neoplastic and Autoimmune Disease

 

      Research.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which an FDA participant has a financial

 

      interest, the participants are aware of the need to

 

      exclude themselves from such involvement, and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

                                                                11

 

      any firm whose products they may wish to comment

 

      upon.

 

                Thank you.

 

 

 

                DR. MARTINO:  Dr. Mills, if you would

 

      address the group.

 

                            Opening Remarks

 

                DR. MILLS:  Thank you, Dr. Martino.

 

                Good morning, Committee.  The sponsor of

 

      the application in this morning's session, Advanced

 

      Magnetics, requests marketing approval of Combidex

 

      for the proposed indication of assisting in the

 

      differentiation of metastatic and non-metastatic

 

      lymph nodes, in patients with confirmed primary

 

      cancer, who are at risk for lymph node metastases.

 

                The Agency is asked to consider an

 

      indication specifically for differentiating

 

      metastatic from non-metastatic lymph nodes with

 

      little restriction on the cancer type, clinical

 

      staging, and whether the patients have been

 

      previously treated.

 

                The Agency is in the second review cycle

 

                                                                12

 

      for this imaging product.  The first review cycle

 

      concluded with an approvable action and the sponsor

 

      was asked to conduct additional studies to address

 

      issues related to inconsistent efficacy results

 

      among the differential trials and to provide a

 

      clearer identification for the conditions of use

 

      for Combidex.

 

                In addition, the sponsors were asked to

 

      address safety issues related to Combidex-induced

 

      hypersensitivity reactions.

 

                In today's presentation, the sponsor will

 

      address these deficiency issues by using data that

 

      were originally submitted to the Agency, along with

 

      new information from a published study in the New

 

      England Journal of Medicine.

 

                The Agency's presentation today will focus

 

      on whether the primary analyses that were based on

 

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

 

      subjects from the European studies are adequate for

 

      marketing approval based on the sponsor's proposed

 

      indications, which reads as follows:

 

                "Combidex is for the intravenous

 

                                                                13

 

      administration as a contrast agent for use with

 

      MRI.  Combidex can assist in the differentiation of

 

      metastatic and non-metastatic lymph nodes in

 

      patients with confirmed primary cancer who are at

 

      risk for lymph node metastases."

 

                Today, we will be seeking comments on the

 

      issues related to the sample size and the adequacy

 

      of tumor type presentation.  We will be presenting

 

      the variable efficacy results by the tumor type and

 

      the size of the lymph nodes.

 

                We are seeking your opinion as to whether

 

      these results suggest that the variations in

 

      efficacy performance of Combidex are related to the

 

      different tumor types and to different lymph node

 

      sizes.

 

                Today, we are seeking your advice on how

 

      to better define the conditions for use for

 

      Combidex, assuming the validity of the efficacy

 

      results, so that use of Combidex can provide

 

      benefits to patients particularly in affecting

 

      patient's treatment decisions.  This point is

 

      particularly important given the risks of

 

                                                                14

 

      hypersensitivity reactions associated with

 

      Combidex.

 

                Lastly, we will be seeking your

 

      recommendations on what additional data are needed

 

      if current data are found to be inadequate for the

 

      marketing approval of Combidex at this time.

 

                This concludes the Agency's introduction

 

      to the morning session.

 

                Thank you, Dr. Martino.

 

                DR. MARTINO:  Thank you.

 

                For those of you that are new to the

 

      committee and are consulting to the committee, the

 

      final task that we will bring to you is answers to

 

      certain questions that have been posed to the

 

      committee by the FDA.  Those are in a written

 

      format and each of you should have those at your

 

      desk.

 

                They are titled as Discussion and

 

      Questions, so please recognize that it is very

 

      specifically to answer those four questions which

 

      will be the focus of the discussion at the end of

 

      this morning's presentations.

 

                                                                15

 

                At this point, I would like to ask Dr.

 

      Roessel from the company to introduce their

 

      speakers and proceed with their presentation.

 

                There will be an opportunity for questions

 

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

 

      that you hold your questions until their

 

      presentations are completed.

 

                          Sponsor Presentation

 

                        Advanced Magnetics, Inc.

 

                 Combidex, Introduction and Indication

 

                MR. ROESSEL:  Good morning.  Thank you,

 

      Madam Chairman, members of the Advisory Committee,

 

      FDA.

 

                I am Mark Roessel, Vice President of

 

      Regulatory Affairs, Advanced Magnetics.

 

                Today is an important day for us as we

 

      have been working since 1992 to bring Combidex to

 

      clinicians and cancer patients.  We are pleased to

 

      be able to show you today data from controlled

 

      clinical trials demonstrating the safety and

 

      efficacy of Combidex and the great potential it has

 

      for improving imaging in cancer patients.

 

                                                                16

 

                We have a number of distinguished

 

      consultants and speakers here today including

 

      radiologists, surgeons, oncologists, and they are

 

      available to answer any questions you may have at

 

      the end of the meeting.

 

                I want to bring your attention to the

 

      indication. It has been read twice already.  It is

 

      for a differentiation of metastatic and

 

      non-metastatic lymph nodes in cancer patients.

 

                Here is the agenda we are going to have in

 

      our presentation and the key topics.  Dr. Mukesh

 

      Harisinghani is going to show you the mechanism of

 

      action of Combidex and how it appears on MR images.

 

                Dr. William Goeckeler from Cytogen

 

      Corporation, Vice President of Cytogen, who is our

 

      marketing partner, is going to present to you data

 

      from Phase III controlled clinical trials that were

 

      designed in cooperation with the FDA for approval

 

      of the agent.

 

                Dr. Jerry Faich is going to review the

 

      safety data available, demonstrating that Combidex

 

      can be safely administered using dilution and

 

                                                                17

 

      infusion.

 

                Finally, Dr. Jelle Barentsz, a clinical

 

      investigator with Combidex, is going to review with

 

      you the clinical utility of Combidex in various

 

      cancers.

 

                Combidex is a diagnostic tool that

 

      improves the anatomic imaging that is done every

 

      day.

 

                Now, I would like to have Mukesh

 

      Harisinghani.

 

                     Mechanism of Action, Combidex

 

                        Appearance on MR Images

 

                DR. HARISINGHANI:  Good morning, Madam

 

      Chairman, members of the Committee, ladies and

 

      gentlemen.

 

                What I am going to do in the next couple

 

      of minutes is to review what are the current

 

      limitations of lymph node imaging as we practice

 

      radiology today, also give an overview of how

 

      Combidex is acting and how it allows us to

 

      differentiate benign from malignant lymph node, and

 

      then also show you some examples of how it improves

 

                                                                18

 

      sensitivity and specificity for nodal

 

      characterization.

 

                So, the question is why do we need to

 

      image lymph nodes, and I think one needs to

 

      accurately stage primary cancer, and in doing so,

 

      it is very important to know what the nodal status

 

      is.

 

                It is very important to know this

 

      information to appropriately treat the patients.

 

      Just to give you an example, in prostate cancer

 

      patients, if the nodes are found to be metastatic,

 

      it essentially commits the patients to non-surgical

 

      modes of therapy.

 

                We also need to get a sense of prognosis,

 

      and that is another factor why nodal metastases are

 

      important.  Again, to give you an example in

 

      bladder cancer, if the patient is node-positive,

 

      the five-year survival is way lower than if the

 

      patient is node-negative.

 

                The risk of death also increases 20

 

      percent with each additional node being positive.

 

                The current lymph node staging as is

 

                                                                19

 

      performed today involves non-invasive imaging

 

      techniques, which essentially incorporates the

 

      cross-sectional modalities like CT and MR, and the

 

      other is the invasive modes, which is essentially

 

      surgery, which are considered to be the gold

 

      standard today.

 

                When one talks of the non-invasive

 

      cross-sectional modalities for staging lymph nodes,

 

      the predominant yardstick by which we differentiate

 

      benign from malignant lymph nodes is the size

 

      criterion, and this is what we use.

 

                If the node is oval and less than 10 mm in

 

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

 

      size, we label the node as benign.

 

                In contrast, if the node is oval and

 

      greater than 10 mm, or is rounded and greater than

 

      8 mm, we label the node as malignant.

 

                So, let's apply the size criterion to

 

      these two individuals.  These are two different

 

      patients, both have obtained a CT scan for staging

 

      purposes.

 

                The example on your left is an enlarged

 

                                                                20

 

      node in the pelvis, which measures 18 mm and is

 

      rounded.  No matter which size criterion you use,

 

      you would label this node as malignant.

 

                The example on your right is a different

 

      patient, again a patient with a primary pelvic

 

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

 

      measures 5 mm.  Again, no matter which size

 

      criterion you use, you would label this node as

 

      benign.

 

                But at surgery, it was exactly the

 

      opposite.  Thus, you can see that size criterion is

 

      an inaccurate yardstick by which we categorize

 

      nodes today.

 

                Morphology has been to a certain extent

 

      used in conjunction with size criteria

 

      occasionally, and one of the important morphologic

 

      features we rely on is presence of fatty hilum, as

 

      you are seeing here.

 

                It is said that if the node has a central

 

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

 

      we have seen from our experience that even small

 

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

 

                                                                21

 

      this patient with bladder cancer, was biopsy proven

 

      to be positive and having malignant cells.

 

                Thus, morphology, too, has its drawbacks

 

      and when used with size criterion, can be a

 

      problem.

 

                Central necrosis is the other morphologic

 

      feature which has occasionally been said to be a

 

      very useful way to allow for diagnosing malignant

 

      nodes, but it is important to realize that when

 

      nodes become necrotic, they are enlarged beyond a

 

      cm, and by size criterion, you would still call

 

      them positive.

 

                Well, what about surgery, which is

 

      considered to be the gold standard, and I am going

 

      to use prostate cancer as an example, but I think

 

      the underlying principle can be applied or

 

      extrapolated to other tumors, as well.

 

                In prostate cancer, pelvic lymph node

 

      dissection accompanied by frozen section path

 

      examination is considered to be the gold standard.

 

      However, the way lymph nodes are sampled today, at

 

      the time of surgery in intermediate to high risk

 

                                                                22

 

      prostate cancer patients, the standard pelvic

 

      lymphadenectomy is limited.  This is because the

 

      surgeon only resects the low external iliac and the

 

      obturator group of lymph node.

 

                In the recent or not too recent, in an

 

      April 2000 study published in the Journal of

 

      Urology, it was shown that if the surgeon extends

 

      the lymphadenectomy and takes out the high external

 

      iliac and the internal iliac nodes, keeping all

 

      other risk factors the same, the incidence of lymph

 

      node metastases jumps from 10 to 26 percent, so you

 

      can see that a potential of 16 percent miss rate if

 

      one just follows the standard pelvic

 

      lymphadenectomy.

 

                So, that begs that question why don't we

 

      do that in all the cases, because there is a

 

      significant morbidity that comes with that

 

      procedure.  Moreover, it is also important to

 

      realize that the frozen section analysis can also

 

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

 

      all these factors show us the limitations of how

 

      even when surgery is performed and nodes are

 

                                                                23

 

      sampled, there are some limitations.

 

                Here is an example of a patient who had

 

      underwent radical prostatectomy, and you can see

 

      clips where the surgeon has taken out the lymph

 

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

 

      lymphadenectomy involves, is the low external iliac

 

      group of lymph nodes.

 

                There was a small nod posteriorly in the

 

      pelvis that was not sampled, and the patient was

 

      labeled as cured. Eight months later, the patient

 

      shows back with that node mushrooming into a

 

      full-blown metastases, and this is a good example

 

      of how surgical sampling can sometimes be limited

 

      by what the surgeon can see and samples.

 

                Thus, there is a current need for a

 

      non-invasive technique that not only detects, but

 

      also characterizes lymph nodes with a high level of

 

      accuracy, not compromising sensitivity for

 

      specificity.

 

                It also provides a broad anatomy coverage

 

      which means you not only look at lymph nodes right

 

      next to the primary cancer, but also can look at

 

                                                                24

 

      lymph nodes in a broad anatomic area beyond the

 

      confines of the regional distribution.

 

                That is where I think Combidex, or the

 

      pharmacologic name ferumoxtran-10, is an excellent

 

      contrast tool that can be utilized with MR.  This

 

      is an iron oxide based nanoparticle with a central

 

      iron oxide coat and a surrounding dextran coating.

 

                This slide shows how the contrast acts.

 

      After intravenous injection, the contrast lingers

 

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

 

      blood half-life.  It gradually leaks out and then

 

      is transported to the lymph nodes where it binds to

 

      the scavenger on macrophages.  Thus, the mechanism

 

      of action of uptake in the normal nodes is via

 

      macrophages.  So, if the node is functioning

 

      normally and has its normal complement of

 

      macrophages, the contrast would then localize to

 

      the nodes and turn the normal area of the node

 

      dark.

 

                I would like to emphasize at this point,

 

      two points in the mechanism of action.  One is the

 

      contrast is targeting the normal lymph node and

 

                                                                25

 

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

 

      node that is turning dark.

 

                If you have an area of tumor deposited in

 

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

 

      normal functioning macrophages and that area would

 

      show lack of uptake and continue to stay bright.

 

                Another important point to remember is

 

      that this mechanism of action is independent of

 

      which primary cancer affects the node, and, hence,

 

      the lack of uptake would be present no matter which

 

      tumor deposit is present within the lymph node.

 

                This slide is just to show the technique

 

      that we use.  Any conventional 1.5 MR system that

 

      exists today in the community, independent of

 

      vendor platform, can be used for imaging the MR

 

      with Combidex, and these are the sequences, again

 

      nothing fancy, just regular bread and butter

 

      sequences.

 

                We can do post-processing, which can

 

      provide for elegant ways of communicating the

 

      information, but these are not essential for making

 

      the diagnosis.

 

                                                                26

 

                So, let me show you an example of how the

 

      Combidex acts in real life.  This is a patient who

 

      has a known pelvic malignancy.  There are two lymph

 

      nodes in the groin.  Both are hyper-intense or

 

      bright on the pre-contrast.

 

                Twenty-four hours after injection of

 

      Combidex, you can see the medial node is turning

 

      homogeneously dark, and that is the node that is

 

      benign.  The node to the right shows lack of

 

      uptake, and that means that it's infiltrated with

 

      cancer and, hence, it is not taking up the

 

      Combidex.

 

                Let me show you some examples of how

 

      Combidex scanning improves sensitivity in detecting

 

      metastases in small lymph nodes.

 

                This is a patient with prostate cancer

 

      undergoing staging.  The yellow arrows point to two

 

      very small nodes next to the external iliac vein.

 

      Again, by size criterion, you would never call

 

      these nodes positive.

 

                On the pre-Combidex scan, you can see

 

      these two nodes are hyper-intense, and 24 hours

 

                                                                27

 

      later after Combidex, the inferior one is turning

 

      homogeneously dark.  It means that that is benign.

 

      The one which is pointed by the red arrow shows

 

      lack of uptake, and that is the one which is

 

      malignant, which was proven at the time of surgery.

 

                This is a patient with breast cancer.

 

      Again, the patient is lying prone.  Here is the

 

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

 

      at the axilla.  Again, there are two very small

 

      nodes in the axilla pointed by the yellow and the

 

      red arrow, measuring between 3 to 4 mm.

 

                After giving Combidex, the superior one is

 

      turning dark as outlined by the yellow arrow, the

 

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

 

      update, indicating it's malignant and again proven

 

      with surgery.

 

                So, I have shown you how Combidex improves

 

      sensitivity in different types of primary cancers.

 

      It is equally important to have enhanced

 

      specificity, which means if the node is enlarged,

 

      you need to accurately diagnose it as benign or

 

      malignant.

 

                                                                28

 

                So, here is a patient with bladder cancer.

 

      You have an enlarged node measuring 20 mm, and this

 

      was labeled as malignant on the contrast-enhanced

 

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

 

      Post-Combidex, it turns homogeneously dark

 

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

 

                Another example of enhanced specificity,

 

      again a patient with prostate cancer.  The two

 

      yellow arrows point to enlarged obturator nodes,

 

      again labeled malignant based on the size

 

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

 

      turning homogeneously dark, and these turned out to

 

      be reactive enlarged nodes or reactive benign nodes

 

      in the pelvis.

 

                As you can see, by improving the

 

      sensitivity and specificity in these patients, one

 

      can provide for improved clinical staging, and then

 

      also provide for better surgical planning and

 

      better radiation therapy and image-guided

 

      intervention planning.  Some of these points will

 

      be highlighted later by my colleague, Dr. Jelle

 

      Barentsz.

 

                                                                29

 

                Thank you

 

             Efficacy Data from Phase III Clinical Studies

 

                DR. GOECKELER:  Good morning.  I am going

 

      to review in the next few minutes the efficacy data

 

      in support of the proposed indication.  The studies

 

      I will be discussing were designed to evaluate the

 

      ability of Combidex to improve the differentiation

 

      of metastatic from non-metastatic lymph nodes,

 

      particularly in the post-contrast setting.

 

                To do this, we compare the parameters of

 

      sensitivity and specificity in both the pre- and

 

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

 

      which was conducted in cooperation with the FDA,

 

      provided for multiple primary tumor types and

 

      independent blinded evaluations of image sets with

 

      histopathologic confirmation of the imaging data.

 

                I think it is worth taking just a step

 

      back to say that all the imaging data that you will

 

      be presented this morning by the sponsor involves

 

      histopathologic confirmation at the individual node

 

      level, which is a significant undertaking.

 

                So, in reviewing the efficacy data, I will

 

                                                                30

 

      first go over quickly the blind read procedures

 

      that were used in conducting the analysis of this

 

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

 

      studies, talk a little bit about data from

 

      publication in the New England Journal of Medicine

 

      that investigated the agent in this application,

 

      and finally, close by looking at how this

 

      improvement in differentiation at the nodal level

 

      impacts clinical nodal staging.

 

                So, first, the blinded read procedure, and

 

      there are a number of blinded reads that were

 

      carried out in each of the clinical studies, so I

 

      will try to explain the terminology and the

 

      sequence in which they were conducted.

 

                All the blinded reads were carried out

 

      with the readers blinded to clinical, demographic,

 

      and pathologic information, and the cases were

 

      presented in random order.

 

                The readers were first presented with the

 

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

 

      images alone, made an assessment on size based.

 

                You will also see that in some of the

 

                                                                31

 

      slides called an MRI-based diagnosis, and then the

 

      reader made a second assessment based solely on the

 

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

 

      skill.  In that subjective evaluation, the reader

 

      was allowed to use any criteria they thought was

 

      appropriate in differentiating metastatic from

 

      non-metastatic lymph nodes.

 

                Following those readings, the readers were

 

      presented with the post-contrast images and carried

 

      out an evaluation of the post-contrast side by side

 

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

 

      paired evaluation.  The prospective primary

 

      endpoint in each of the Phase III studies was a

 

      comparison of the paired evaluation with the

 

      pre-contrast size-based evaluation at the nodal

 

      level.

 

                Next, a period of about two weeks to

 

      eliminate a recall bias was allowed, and then the

 

      readers were presented, again in random order, with

 

      the post-contrast only images, and then made an

 

      assessment based only on the post-contrast image,

 

      which is called the post-contrast evaluation.

 

                                                                32

 

                Post-contrast images, there were reading

 

      guidelines developed to assist the reader in

 

      evaluating the nodal post-contrast images.  They

 

      were prospectively developed and finalized before

 

      the blinded read.  Thus, the Phase III blind read

 

      of images is a valid assessment of nodal images

 

      across a wide range of cancers.

 

                This is the study population in the three

 

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

 

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

 

      Journal.  The number of patients dosed and the

 

      number of patients with histopathology is not

 

      always the same since eventually, not all patients

 

      go to surgery for things that happen in the

 

      intervening time between the imaging session and

 

      the treatment of the patients.

 

                This outlines the number of lymph nodes

 

      that were evaluated in the various studies both

 

      pre- and post-contrast and a breakdown of where

 

      those lymph nodes resided by anatomic region in the

 

      various cancers.

 

                So, right into the Phase III study, in the

 

                                                                33

 

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

 

      pre-contrast evaluations, both the size and the

 

      subjective base, we see a high pre-contrast

 

      sensitivity and a low pre-contrast specificity,

 

      whereas, in the post-contrast evaluation, the

 

      paired evaluation, what we see is sensitivity

 

      remains high at 96 percent, but specificity is

 

      significantly improved, and the improvement in

 

      specificity was statistically significant over both

 

      of the pre-contrast reads and for both of the

 

      blinded readers.

 

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

 

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

 

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

 

      pre-contrast analysis, sensitivity was low and

 

      specificity was high, so sort of just the opposite

 

      of what was seen in the EU study.

 

                In the subjective evaluation, we see that

 

      the subjective reader's assessment resulted in a

 

      very high sensitivity, but the tradeoff for that

 

      increase in sensitivity was a large decrease in

 

      specificity.

 

                                                                34

 

                So, the pre-contrast reads had either high

 

      sensitivity or high specificity, but not both.  In

 

      the post-contrast reads, you will see that

 

      sensitivity was high and specificity was high, so

 

      we had a combination of high sensitivity and high

 

      specificity.

 

                You will also note that in the post-only

 

      read, in which the only image that was available

 

      was the post-contrast image, resulted in the

 

      highest level of imaging performance and the

 

      greatest level of consistency.

 

                If we take a look for just a minute at

 

      this discrepancy between the two pre-contrast

 

      reads, where one had high sensitivity and low

 

      specificity, and the other was the opposite, if we

 

      look at the false diagnoses that occurred in these

 

      various blinded readings, and we look at false

 

      diagnoses as a percentage of the total, we see that

 

      the percentage of false diagnoses for both of the

 

      pre-contrast reads is relatively the same.

 

                What we see is that in the subjective

 

      readers' diagnosis with the readers subjectively

 

                                                                35

 

      overreading to try to account for the known low

 

      sensitivity of the size-based analysis, we see a

 

      very large percentage of false positive reads that

 

      occur in the subjective readings, whereas, in the

 

      post-contrast reads, we see a decreased percentage

 

      of false reads with the lowest and most consistent

 

      data again in the post-only read.

 

                This is the data broken out by body

 

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

 

      and breast, we saw large increases in sensitivity

 

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

 

      maintaining specificity which overall resulted in

 

      the increase in accuracy.

 

                In the pelvis and abdomen, we had more

 

      moderate levels of increase in both sensitivity and

 

      specificity, the net effect of which is that the

 

      increase in accuracy in the pelvis and abdomen is

 

      virtually identical to what one sees in both the

 

      head and neck and the breast.

 

                One region that was a little bit different

 

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

 

      moderate, small increases in both sensitivity and

 

                                                                36

 

      specificity, and we believe this has to do with

 

      limitations of anatomic imaging in this particular

 

      body region, and not differential uptake or

 

      performance of the contrast agent.

 

                So, turning now to the data published in

 

      the New England Journal of Medicine, and I think

 

      this data is important supplemental data that can

 

      help us understand better some of the differences

 

      that were seen particularly in the pre-contrast

 

      reads in the Phase III studies and also can help us

 

      learn a little bit more about the performance of

 

      the agent in different size nodes.

 

                So, this is a study carried out in

 

      prostate cancer patients at two centers, one in the

 

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

 

      There was a centralized independent blinded read

 

      with histopathologic confirmation of data.

 

                So, to address some of the issues that I

 

      just mentioned, I am going to go through the data

 

      in a little bit of a sequential order.

 

                First, with regard to the issue of the

 

      discrepancies in the pre-contrast evaluations and

 

                                                                37

 

      also to look at the issue of the effect of nodal

 

      size on the performance of the contrast agent, what

 

      you see is as you move across these three studies,

 

      the distribution of nodes categorized as either

 

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

 

      appropriate cut point because as Dr. Harisinghani

 

      said earlier, that is the point at which we

 

      differentiate a malignant from a non-malignant

 

      node.

 

                We see that as we move from the EU to the

 

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

 

      proportion of large nodes are greater than 10 mm in

 

      the yellow, goes from about three-quarters to about

 

      a third to only 7 percent in the New England

 

      Journal study.

 

                We see in the pre-contrast size-based

 

      sensitivities and specificities, we see that the

 

      sensitivities and specificities largely track with

 

      the nodal size.  That is, in studies where there

 

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

 

      sensitivity in the pre-contrast evaluation in the

 

      green bars, which decreases as the proportion of

 

                                                                38

 

      large nodes in the study decreases.

 

                Conversely, as in the purple bars, we see

 

      that as the percentage of small nodes increases,

 

      then, the specificity increases also.

 

                So, finally, in the post-contrast data,

 

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

 

      the performance of the agent on the size of

 

      distribution of the nodes in the study.  We have

 

      high sensitivity and specificity regardless of the

 

      distribution of the lymph node sizes that were in

 

      those studies.

 

                Finally, just a word about clinical nodal

 

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

 

      clinical nodal staging where we could collapse the

 

      nodal stage in its simplest form to where patients

 

      were either node positive, node negative, or

 

      indeterminate.

 

                What we see here is a comparison of the

 

      clinical nodal stage that was assigned based on the

 

      images compared to the eventual pathologic stage,

 

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

 

      post-paired to the post, the percent where the

 

                                                                39

 

      agreement was correct increases, the percent where

 

      it's incorrect decreases, and the percentage that

 

      could not be staged also decreases.

 

                So, to sum up, there are two prospective

 

      Phase III studies.  The pre-contrast evaluations in

 

      these studies show a characteristic tradeoff of

 

      sensitivity for specificity. Post-contrast

 

      evaluations show high sensitivity and high

 

      specificity, which results in an overall

 

      improvement in accuracy.

 

                The improved lymph node differentiation

 

      improved clinical staging.  The supporting data

 

      from the New England Journal publication showed

 

      high sensitivity and specificity in a population of

 

      largely small lymph nodes.

 

                Finally, these data collectively

 

      demonstrate the efficacy of Combidex in

 

      differentiating metastatic from non-metastatic

 

      lymph nodes.

 

                Thank you.  Now, Dr. Faich will review the

 

      safety data.

 

                    Safety Data from Clinical Trial

 

                                                                40

 

                DR. FAICH:  I am Jerry Faich.  Good

 

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

 

                What I would like to do rather briefly is

 

      review the amount of exposure data that has been

 

      obtained for Combidex, discuss and show you the

 

      pattern of adverse events that have occurred, make

 

      a few comparisons with other agents, and then

 

      discuss the proposed risk management plan for the

 

      product.

 

                In total, 2,061 subjects have been dosed

 

      with Combidex.  Of these, and I would like to

 

      emphasize this and explain it, 131 received bolus

 

      injection.  This was in the process of developing

 

      or exploring the utility of the product for liver

 

      scanning, which required a bolus injection.  That

 

      indication and mode of administration has been

 

      dropped.

 

                The remaining patients, the remaining

 

      1,930 patients were dosed with dilution and

 

      infusion either in 50 ml or 100 ml saline, and

 

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

 

      who got the 100 ml dilution.

 

                                                                41

 

                For the proposed indication and mode of

 

      distribution, there were 1,236 patients in the NDA

 

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

 

      dilution over 30 minutes.

 

                This shows you on the left-hand side the

 

      rate of adverse events in the bolus injection 30

 

      percent, in the middle 17 percent for 50 ml

 

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

 

      100 ml dilution showing a clear dose-response

 

      relationship in terms of adverse events, and this

 

      is indeed why the 100 ml dilution has been focused

 

      on.

 

                It needs to be said that during the bolus

 

      injection studies, there was one anaphylactic death

 

      that occurred immediately.  That and the need to

 

      use bolus injection for liver scanning is what led

 

      to dropping the pursuit of that indication.

 

                This shows you in the 1,236 patients the

 

      pattern and rates of adverse events, you can see

 

      going from vasodilation at 3.4 percent, rash, back

 

      pain, pruritus, urticaria, et cetera, overall

 

      totaling these 15.8 percent.

 

                                                                42

 

                I would simply like to emphasize that

 

      nearly all of these were mild, transient, and

 

      self-limited.

 

                Within the 1,236 core patients, 5.6

 

      percent had adverse events from that prior list

 

      that could be called hypersensitivity events.

 

      Mainly these were vasodilation.  It included 24

 

      patients, however, who had more than one symptom

 

      from that list.

 

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

 

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

 

      adverse event rate is no greater than that found in

 

      labeling for nonionic iodinated contrast media,

 

      which ranges from 0.6 to 1.5 percent, and I will

 

      show you that in a moment.

 

                There were no life-threatening

 

      anaphylactic/anaphylactoid reactions at the

 

      proposed dose and method of administration.

 

                In terms of immediate adverse events,

 

      immediate hypersensitivity adverse events can, of

 

      course, be controlled in large part by stopping the

 

      infusion.  The most common reaction, as I noted,

 

                                                                43

 

      was flushing.

 

                Thirty-six patients had infusion stopped

 

      and restarted, that is, these patients were

 

      rechallenged.  Only two of them could not tolerate

 

      the rechallenge and were discontinued.  The

 

      remaining 36 went on to complete their procedure.

 

                Put a slightly different way, 94 percent

 

      of all immediate hypersensitivity reactions

 

      occurred within the first 5 minutes after dosing.

 

      Most hypersensitivity reactions, as I indicated,

 

      were mild to moderate in intensity.

 

                At the proposed dose and method of

 

      administration, out of the 4 serious AEs, 2 were

 

      classified as immediate hypersensitivity reactions

 

      using the FDA definition.  That translates to a

 

      rate of 1.6 per 1,000.

 

                In terms of anaphylactoid reactions, again

 

      using an FDA definition of affecting two body

 

      systems, there were 12 such patients at the

 

      proposed dose and method of administration.  Two of

 

      those were considered serious.

 

                Four of the 12 were in the group that had

 

                                                                44

 

      infusion stopped and then were rechallenged without

 

      subsequent problems.  The majority of these 12 had

 

      dyspnea and flushing.  There were no serious

 

      hypotension or respiratory compromise seen in those

 

      12 patients.

 

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

 

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

 

      to interpret data carefully when you compare one

 

      set of data from one set of studies and labels to

 

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

 

      your attention to the Combidex data across the top.

 

                The overall AE rate was 15.8 percent, the

 

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

 

      cases I mentioned. If you look down in the

 

      right-hand column just at serious AEs and compare

 

      it to other iodinated contrast agents, both from

 

      data in their labels and published studies, you

 

      will see for Ultravist, that serious AE rate is 1.1

 

      percent.

 

                For comparators in studies done with

 

      Ultravist, it was 0.6 percent, for Oxilan it was

 

      1.5 percent, and for comparators to Oxilan and

 

                                                                45

 

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

 

      a basis or my basis for concluding there is not

 

      evidence that there is increased risk of serious

 

      adverse events comparing this drug to commonly used

 

      iodinated contrast agents.

 

                There is not much in the literature about

 

      anaphylaxis in contrast agents.  Here are 2 recent

 

      studies that have been published.  This is Neugut

 

      in the Archives of Internal Medicine.  His

 

      published anaphylaxis rate done from his own

 

      studies and across the literature was 2 per 1,000

 

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

 

      that it might be lower and most people are taking a

 

      rate of about half that for low osmolality contrast

 

      agents.

 

                David Kaufman, at the Center for

 

      Epidemiology in Boston, published this paper in

 

      2003, and for contrast agents, this was an

 

      international study of anaphylaxis, the observed

 

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

 

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

 

      there was a range as you see here.

 

                                                                46

 

                Combidex falls within or at the lower end

 

      within that range of values.

 

                In terms of a risk management plan for

 

      this product, it is largely in keeping with

 

      existing guidelines and calls for physician

 

      education, emphasizing the need for dilution and

 

      slow infusion obviously as a means to be able to

 

      intervene if a reaction is occurring.  The labeling

 

      will be consistent with that, and the proposal is

 

      to conduct targeted surveillance to gather further

 

      data to reinforce the safety data that I have shown

 

      you.

 

                To summarize, then, there has been

 

      considerable clinical exposure in the development

 

      program.  Hypersensitivity is relatively infrequent

 

      and comparable to that of other contrast agents,

 

      and the risk management program that I just

 

      described is in accordance with existing

 

      guidelines.  Thank you.

 

                Dr. Barentsz, please.

 

            Clinical Utility of Combidex in Various Centers

 

                DR. BARENTSZ:  Madam Chairman, members of

 

                                                                47

 

      the Committee, members of the FDA, I am an

 

      oncologic radiologist and I have been using

 

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

 

      frequent contact with investigators in both the

 

      U.S. and in Europe.

 

                From the previous data, you have clearly

 

      shown that this contrast agent works.  A black

 

      lymph node is normal, and a white lymph node is

 

      abnormal.  That is despite the tumors type.

 

                Nonetheless, evaluating its clinical

 

      utility is a lot more difficult, and for that you

 

      need personal experience, as well as post-Phase III

 

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

 

      show you the clinical utility and some cancer

 

      types.

 

                The reviewed publications were all in top

 

      ranking journals.  It was blinded post-contrast

 

      image evaluation with gold standard histopathology,

 

      and all those papers described a potential impact

 

      on treatment planning.

 

                The areas being defined where Combidex MRI

 

      provides a significant clinical benefit were

 

                                                                48

 

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

 

      want to address those issues with you in the next

 

      10 minutes.

 

                As you can see, data were collected from

 

      almost 200 patients and almost 2,000 lymph nodes.

 

      These are the data on sensitivity and specificity

 

      and accuracy.

 

                You can see that the data are highly

 

      consistent, showing a high sensitivity,

 

      specificity, and accuracy for all the cancers.

 

                Now, let's start with the clinical utility

 

      in prostate cancer.  First of all, you have to

 

      define the current strategies.  Current imaging has

 

      an insufficient sensitivity for lymph node staging,

 

      and therefore, urologists are performing an

 

      invasive operative surgical lymph node sampling to

 

      detect the lymph nodes.

 

                These techniques have limitations, only a

 

      limited area sampled, and therefore, up to 31

 

      percent of the positive lymph nodes are outside of

 

      the surgical area, which have been shown by some

 

      data recently published in the urology journals.

 

                                                                49

 

                Furthermore, surgical sampling has a

 

      complication rate reported to be 22 percent for the

 

      open dissection and 5 percent for laparoscopic

 

      dissection, including lymphocele, lymphedema, deep

 

      venous thrombosis, pulmonary embolism, nerve

 

      damage, and blood loss.

 

                Because of the limitations of current

 

      imaging technique and current staging techniques

 

      for the lymph node dissection, these urologists are

 

      advocating at this moment now an extended lymph

 

      node dissection.  They state that they will detect

 

      those lymph nodes, however, this significantly

 

      increases morbidity.  The question is are the less

 

      invasive way techniques to solve this problem.

 

                As you can see, using the post-contrast

 

      studies of Combidex, there is a dramatic decrease

 

      of the number of false positives, as well as the

 

      number of false negatives, but what is even more

 

      important is that in our study in the New England

 

      Journal of Medicine, in 6 percent of all the

 

      patients, we found a small non-enlarged lymph node

 

      which we could biopsy, and in all those patients,

 

                                                                50

 

      we could confirm the diagnosis by image-guided

 

      biopsy, and these patients did not undergo any

 

      surgical dissection.

 

                Furthermore, in 11 percent, we found lymph

 

      nodes which were outside of the surgical field, so

 

      they will be missed with regular surgery.

 

                All these findings were confirmed by the

 

      surgery because before the operation, we told the

 

      urologists where the lymph node was, and they could

 

      then find them.

 

                I would like to show you two

 

      representative cases. Here, you see a white lymph

 

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

 

      close to the internal iliac artery, which is

 

      outside of the normal surgical field.  In this

 

      lymph node, we performed an image-guided biopsy

 

      which was positive, and in this way a correct

 

      diagnosis was being evaluated in a less invasive

 

      manner, and this avoided inappropriate treatment.

 

      This patient had, instead of a prostatectomy, an

 

      androgen ablation.

 

                In another patient, you see a lymph node

 

                                                                51

 

      over there with a tiny white structure.  You can

 

      see it over there.  This was also a lymph node

 

      outside of the surgical field.  We told our

 

      urologist where this lymph node was located.  It

 

      was found and it was confirmed histopathologically

 

      that this lymph node had a 1-mm metastasis.

 

                What about bladder cancer?  It is actually

 

      the same story.  In 24 percent of positive lymph

 

      nodes, there are positive lymph nodes in 24 percent

 

      despite negative pre-operative imaging techniques.

 

                The presence of lymph nodes radically

 

      changes the treatment option especially if there is

 

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

 

      so finding these lymph nodes also here is very

 

      important.

 

                If you perform an extended lymph node

 

      dissection, you detect more lymph node, it will

 

      increase survival for minimal disease, however,

 

      also in this extended lymph node dissections, not

 

      all lymph nodes have been sampled. Furthermore,

 

      this increases morbidity.

 

                These are the data in 172 lymph nodes in

 

                                                                52

 

      58 patients from a Radiology paper, and it has been

 

      shown that in normal-sized lymph nodes, 10 out of

 

      12 were detected using Combidex MRI, and this

 

      information was crucial for the surgeon to find

 

      these lymph nodes, and they were removed.

 

                Most important areas, also head and neck.

 

      The survival rates depends on whether the tumor has

 

      metastasis in lymph nodes or not.  Therefore, the

 

      status of cervical lymph nodes is vital for the

 

      choice of therapy.

 

                Twenty-five percent of positive lymph

 

      nodes are found despite negative preoperative

 

      imaging techniques like contrast CT or

 

      ultrasound-guided biopsy.  Why?  Because these

 

      lymph nodes are below normal size criteria.  They

 

      are only 5 to 10 mm in size.

 

                Because of the fact that these lymph nodes

 

      do not show up with imaging, head and neck surgeons

 

      perform commonly a radical neck dissection, which

 

      causes a very severe cosmetic deformity and has a

 

      very high complication rate, in literature reported

 

      up to 54 percent.

 

                                                                53

 

                The data from Mack, et al. in Radiology

 

      show a very high sensitivity and negative

 

      predictive value, and furthermore, what is more

 

      important, if you look on a patient level, they

 

      were able to make an accurate diagnosis in 26 out

 

      of 27 patients, and what is the most important

 

      thing is that this information would have resulted

 

      in reduced extent of surgery in 26 percent of these

 

      patients, so avoiding an aggressive neck

 

      dissection.

 

                One representative image.  This was a

 

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

 

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

 

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

 

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

 

      In this patient, a neck dissection could have been

 

      avoided.

 

                Finally, breast cancer.  The commonly used

 

      staging procedure at this moment is the sentinel

 

      lymph node staging, which has false negative

 

      numbers of 3 to 10 percent, and is an invasive

 

      technique, but what is even more important is that

 

                                                                54

 

      recent data have shown that the sentinel lymph node

 

      is the only positive lymph node in 61 percent in

 

      patients with positive lymph nodes.

 

                Nonetheless, these patients all undergo an

 

      axillary lymph node dissection, and this has a high

 

      rate of clinically significant complications.

 

                A technique with a high negative

 

      predictive value performed in an adjunct to the

 

      sentinel lymph node procedure in patients with one

 

      positive sentinel lymph node may reduce the number

 

      of axillary lymph node dissections.

 

                These are the published data in almost 300

 

      patients by Michel in Switzerland, and you can see

 

      that this technique has a high negative predictive

 

      value.

 

                I would like to show you one

 

      representative case from our institution.  This is

 

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

 

      positive sample on lymph nodes.  This lymph node is

 

      white on Combidex, so that means metastatic, and

 

      you can see that the second and third station lymph

 

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

 

                                                                55

 

      the other lymph nodes were black, which in this

 

      case was confirmed by histopathology.

 

                Now, to the final conclusion.  I have

 

      tried to show you some areas of clinical utility of

 

      this contrast agent, and as soon as we get more

 

      experience, there will be a lot more areas.

 

                To summarize, the current techniques to

 

      detect positive lymph nodes in prostate, bladder,

 

      head and neck, and breast cancer have significant

 

      limitations.

 

                Combidex MRI shows high sensitivity and

 

      specificity not only on the nodal basis, but also

 

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

 

      clinician is even more important.

 

                Therefore, Combidex MRI may reduce the

 

      extent of surgery and morbidity, and finally,

 

      Combidex MRI identifies additional positive lymph

 

      nodes for biopsy or image-guided extended lymph

 

      node dissection in this way improving the staging

 

      of the surgeon.

 

                Thank you.

 

                MR. ROESSEL:  Thank you.  That concludes

 

                                                                56

 

      our presentation.

 

                Our clinical data and the clinicians I

 

      think have shown you that Combidex is an important

 

      diagnostic imaging tool that improves the current

 

      practice.

 

                Thank you.  We are available for any

 

      questions you have.

 

                DR. MARTINO:  Thank you.

 

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

 

      present his view of this data, and once that is

 

      done, we then will take questions for both the

 

      sponsor and the FDA.

 

                            FDA Presentation

 

              Efficacy and Safety of Combidex (NDA 21-115)

 

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

 

      ladies and gentlemen, good morning.  My name is

 

      Zili Li.  I am a medical team leader with the

 

      Division of Medical Imaging and Radiopharmaceutical

 

      Drug Products at FDA.  I am a board-certified

 

      physician in preventive medicine with special

 

      training in epidemiology.

 

                Today, I would like to share with you our

 

                                                                57

 

      review of findings of NDA Application 21-115

 

      Combidex.

 

                I would like to start off by noting that

 

      this presentation represents a collaborative effort

 

      by a group of highly dedicated reviewers at FDA

 

      whose names are on this list.

 

                Combidex is an MR contrast agent.  The

 

      proposed clinical dose is 2.6 milligram iron per

 

      kilo of body weight.

 

                Of three methods of administration which

 

      has been used in the clinical development program,

 

      the sponsor select the dilution in 100 cc with the

 

      slow infusion over 30 minutes of a standard measure

 

      of administration.

 

                The other two methods, particularly the

 

      direct injection, is no longer being proposed.

 

                This slide summarized the indication that

 

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

 

      one more time--that Combidex can assist in the

 

      differentiation of metastatic and non-metastatic

 

      lymph nodes in patients with confirmed primary

 

      cancer who are at risk for lymph node metastases.

 

                                                                58

 

                I would like to draw your attention to the

 

      fact that this is a broad indication.  If granted,

 

      this agent can be used for almost all cancers

 

      regardless of type, size, clinical stage, whether

 

      patient has been previously treated with drug,

 

      biologic, radiation, or surgery.

 

                One objective of today's presentation is

 

      to show you why the Agency has concerns for such a

 

      wide or broad indication given the level of

 

      efficacy and safety observed from clinical trials.

 

                To support this indication, the sponsor

 

      submit one U.S. and three European Phase III

 

      studies.  In addition, sponsor also ask Agency to

 

      consider data from a published article in the New

 

      England Journal of Medicine.

 

                For the safety, the sponsor submitted a

 

      safety data adverse event profile in particular

 

      from approximately 2,000 individuals who received

 

      Combidex from multiple clinical studies.

 

                I would like to make a remark on this New

 

      England Journal of Medicine article.  This study is

 

      pooled analysis from two ongoing clinical studies. 

 

                                                                59

 

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

 

      other study is non-IND study and in Europe.

 

                The clinical investigators themselves took

 

      initiative to combine 40 cancer patients from each

 

      original study to form the basis for this New

 

      England Journal of Medicine study.  At this time,

 

      however, it is unclear to us how those 80 patients

 

      were selected, and more important, after repeat

 

      requests, the sponsor is not able to provide us the

 

      original source document which included pre-defined

 

      statistical plan, blind reader evaluation manual,

 

      and original copy of blind readers' evaluation of

 

      the medical imaging.

 

                For that reason, the Agency cannot

 

      conclude this study was conducted in compliance

 

      with the Federal regulations pertaining new drug

 

      application.  For that reason, we are not able to

 

      consider this study as adequate and well-controlled

 

      study.

 

                However, the Agency do agree that the

 

      cases present in this article may demonstrate some

 

      potential the benefit of the use of Combidex in a

 

                                                                60

 

      clinical setting.

 

                I also would like to draw your attention,

 

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

 

      got update from sponsor yesterday.  This study is

 

      closed at this time. Roughly, they have 220

 

      patients enrolled including 91 prostate cancer and

 

      34 bladder cancer patients.

 

                Although the original protocol require all

 

      the pathology confirmation and MR imaging for all

 

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

 

      how many patients for this study will have both

 

      information available for a meaningful analysis for

 

      efficacy if such analysis is needed.

 

                Now, I would like to first highlight the

 

      differences between sponsor and the Agency's final

 

      conclusion regarding efficacy and for safety.

 

                As far as for the efficacy, the sponsor

 

      believes the non-contrast MR agent only offer high

 

      sensitivity or high specificity, but not both.  The

 

      advantage of this Combidex is its ability to offer

 

      both high sensitivity and specificity consistently

 

      regardless type of cancer or size of the lymph

 

                                                                61

 

      node.

 

                At this time, the Agency is not able to

 

      draw such a conclusion because of the

 

      generalizability and validity issues we are going

 

      to show you in the later presentation, and also in

 

      the later presentation, we are going to show some

 

      preliminary evidence which may suggest the

 

      performance of Combidex may vary by size or type of

 

      cancer.

 

                For the safety, sponsor acknowledge that

 

      Combidex is associated with hypersensitivity

 

      reaction, however, their emphasis is that no death

 

      or life-threatening AEs are associated with the

 

      proposed clinical method of administration.  That

 

      is the dilution with the slow infusion.

 

                Also, I just noticed in the sponsor's

 

      presentation is new to us that they make a claim

 

      that this agent's safety profile is equivalent to

 

      the iodinated contrast agent.  I believe in your

 

      briefing document, they also made a claim that

 

      serious adverse event with the Combidex is only

 

      one-third of that iodinated contrast agent.

 

                                                                62

 

                Our position is that dilution and slow

 

      infusion are not entirely free, and also we

 

      disagree that the Combidex, the safety profile

 

      resemble that of iodinated contrast agent.

 

                This slide highlights the issues we are

 

      going to bring to the panel today.  For the

 

      efficacy, we are going to talk about sample size.

 

      We are going to talk about representation of

 

      different tumor types in the clinical study.

 

                We are also going to talk about impact of

 

      study inclusion/exclusion criteria.  Later, the

 

      last one, we are going to talk about develop use of

 

      Combidex imaging guidance, which was the major

 

      issue in our briefing documentation to you.

 

                For safety, we are going to talk about the

 

      hypersensitivity reaction.  We are also going to

 

      make a comparison with iodinated contrast agent.

 

                Then, we are going to follow up with the

 

      discussion of risk-benefit ratio, including the

 

      sponsor's proposed risk management plan and our

 

      emphasis on the need to understand, to define the

 

      conditions of use for this product.

 

                                                                63

 

                From the sponsor's presentation, it was

 

      stated that total 152 U.S. patients and 181

 

      patients from a European study received Combidex

 

      injection, however, what was not apparent on their

 

      slide was the number of patients who were actually

 

      included in the primary analysis.  What we are

 

      showing you is, because there are two different

 

      blind readers, so they may see the different people

 

      different, so the number may vary slightly.

 

                For the U.S. study, there is only 64

 

      percent of original total population were actually

 

      involved in the final analysis.  For the European

 

      studies, the number varies from zero, 16 percent,

 

      roughly 20 percent to 41 percent.  It only

 

      represent a small proportion of the patients who

 

      originally received the Combidex.

 

                I need to make a clarification for the

 

      study with zero participation.  This is a breast

 

      cancer study.  You probably read our briefing

 

      document.  The original statistical plan for the

 

      European study is on the patient basis.  It is

 

      totally different from what they did here.  So, for

 

                                                                64

 

      that reason, the individual nodal level analysis

 

      was never performed, so those people cannot include

 

      in their primary analysis and consistent with U.S.

 

      statistical plan.

 

                The small number of patients or small

 

      proportion of patients included in the primary

 

      analysis create two dilemmas for us.  The first, we

 

      need to understand whether the estimate we got from

 

      this population is applicable to entire population.

 

                The second one is because of the small

 

      number of patients, we want to ensure that the

 

      patients included in the analysis more represent

 

      the cancer patient distribution in the United

 

      States.

 

                This is the second issue we would like to

 

      bring to your attention.

 

                Based on the statistic provided by

 

      American Cancer Society, it is estimated this year,

 

      2005, there is going to be 1.4 million new cancer

 

      diagnosed.  The left two column showed you the rank

 

      of the top 10 cancers and also showed their

 

      percentage distribution in the United States.  I

 

                                                                65

 

      need to mention that lymphoma or leukemia are not

 

      included in this table.

 

                On the right two columns show the number

 

      of patients and their distribution for each type of

 

      cancer included in the primary analysis.  I would

 

      like to bring your attention to the fact they have

 

      two readers.  In this slide, we pick the highest

 

      number in this table.

 

                You probably noticed that the majority of

 

      patients come from head and neck, which is ranked

 

      roughly number 6 in the frequency distribution, and

 

      also you probably noticed that prostate cancer

 

      being the number one in the United States.  There

 

      is only 5 patients from the United States and 5

 

      patients from Europe was included in the primary

 

      analysis, and the highest number each category is

 

      only in here is 37.

 

                Also, I need to remind you that for

 

      European study, the sponsor showed you the majority

 

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

 

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

 

      there is no nodes like the 10 mm for the European

 

                                                                66

 

      study for this population, particularly this head

 

      and neck what I referred to.

 

                So, you probably will ask why that so many

 

      patients are not included in the primary analysis.

 

      I would like to bring your attention to the fact

 

      the primary analysis was conduct at the nodal

 

      level, so the target lymph nodes, which should be

 

      included in the analysis, is represented here, the

 

      large circle here, is all the lymph nodes

 

      visualized by site investigators.

 

                When patient enrolled, when they take MR,

 

      site investigator looked at the MR to circle the

 

      node they see on those MR images.  That should form

 

      the basis for primary analysis.  However, not all

 

      the nodes was able to match with pathology, so you

 

      drop some nodes right over there.

 

                Then, when you present the same images,

 

      the unmarked images to blinded reader, the blinded

 

      reader may not pick up the same nodes the original

 

      investigator picked in the first place, so you drop

 

      some nodes over there.

 

                Then, for the comparison purpose, because

 

                                                                67

 

      they want to compare the post-images with the

 

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

 

      identified on both end, so for that reason, you

 

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

 

      nodes included in the analysis is much smaller than

 

      the nodes originally seen by site investigator

 

      initially.

 

                This table actually show you the

 

      deposition of how the nodes got lost with each

 

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

 

      patients.  The first row showed you number of nodes

 

      originally visualized by the site investigator,

 

      which should form the basis for primary analysis -

 

      371, 834, 333, and 234.

 

                This row showed you what percentage of

 

      those nodes have matched pathology, and this row,

 

      the final one, showed you what number, how many

 

      nodes were actually included in the primary

 

      analysis.  You can see it is roughly from 3

 

      percent, 6 percent, to 45 percent of nodes was

 

      originally seen is included in the primary

 

      analysis.

 

                                                                68

 

                The fundamental assumption for this

 

      clinical development program is that the

 

      performance of Combidex should be independent from

 

      the type of cancer and the size of lymph nodes.

 

      That was why originally that was allowed for

 

      different cancer patients included in the one

 

      study.

 

                However, if you look at this performance

 

      of Combidex, by different type of cancer, you will

 

      see, first, this is the sensitivity slide.  You

 

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

 

      to 100 depending on the site of primary cancer, and

 

      the 95 percent of the lower boundary could go as

 

      low as 55 percent.

 

                Only if you are willing to accept

 

      assumption that Combidex performance is independent

 

      of sites, you get 83 percent performance with the

 

      lower boundary 73.  That is exactly the reason why

 

      the Agency was so worried about small lymph nodes,

 

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

 

      know whether it's a variation because of the random

 

      event, or if it truly reflects the different

 

                                                                69

 

      performance of Combidex among the different type of

 

      cancers.

 

                This is the same table for the

 

      specificity, which again challenge assumption

 

      whether the Combidex, the performance should be

 

      considered or accepted independent from the type of

 

      cancers.

 

                You notice depending on the different

 

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

 

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

 

      significance of the two slides is that with dose

 

      variation we will have a very hard time to

 

      understand what is appropriate performance

 

      characteristic of this Combidex-enhanced MR

 

      contrast agent, and if indeed the performance are

 

      different, if this drug is approved for all the

 

      cancers, this information may be misused by the

 

      clinician to make their clinical judgment.

 

                The next issue is about study

 

      inclusion/exclusion criteria.  I will go very fast.

 

      Basically, for this study, the people who received

 

      treatment, chemotherapy or radiation therapy in the

 

                                                                70

 

      past 6 months was excluded.

 

                Actually, in reality, when you look at the

 

      people included in the primary analysis, I don't

 

      think any of them had any prior treatment, so

 

      mainly this database, we believe, if valid, only

 

      applied to people who are newly diagnosed patients.

 

                This is issue about development of a

 

      clinical MR imaging guidance.  Why is this imaging

 

      guidance so important?  It is because for the

 

      radiation to use this contrast agent, you need to

 

      have a standard way to interpret imaging.  So, we

 

      work with sponsor to ask them to come with the

 

      guidance.

 

                So, this actually, the clinical trial is

 

      actually to validate the guidance for this validity

 

      and usefulness, however, originally, from the NDA

 

      submission, it appeared to suggest this guidance

 

      was developed and validated from the same database.

 

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

 

      for us because basically, if that is true, that

 

      destroyed independence of this guidance themself.

 

                Later on when we spoke to sponsor, they

 

                                                                71

 

      provided us a revised statement.  Basically, the

 

      guidance was developed by use of Phase II images,

 

      it is not Phase III.

 

                Sponsor's consultant, when she developed

 

      this guidance, she did look at the 16 cases from

 

      Phase III trials, however, no pathology was

 

      provided, and also, there was a statement that

 

      there is no more changes for the guidance after

 

      review of Phase III data.

 

                To support their statement, sponsor did

 

      submit original soft document to FDA for our

 

      verification.  We also had extensive discussion

 

      with their consultant to recall what happening on

 

      that day for the development of a Combidex imaging

 

      guidance.

 

                All we conclude at this time is that,

 

      first, we do not have definitive evidence to

 

      absolutely exclude the probability that Phase III

 

      data has no impact in this guidance development,

 

      however, the evidence provided by the sponsor is

 

      consistent with this revised statement, therefore,

 

      at this time, we decided not to pursue this issue

 

                                                                72

 

      any further unless there is new evidence emerge.

 

                The second issue we are having, which I

 

      will present was included in our briefing document,

 

      is in the European study, this guidance, the core

 

      instrument actually was not used by the blinded

 

      reader.  The blinded reader was using a different

 

      guidance to make their diagnosis.

 

                At this time, the sponsor is not able to

 

      provide any documentation for us to understand

 

      which method or who actually do the translation

 

      from this guidance and to this one.  Actually, the

 

      question we are having for the committee,

 

      especially for people expert in MR imaging, is

 

      whether the similarity or correlation between these

 

      two guidance is so great, the Agency should not

 

      worry about who did it and with all this

 

      documentation.

 

                Now, I would like to switch to the safety

 

      side of Combidex evaluation.  I will focus my

 

      presentation in Combidex-induced hypersensitivity

 

      reaction.

 

                There is one case hypersensitivity-related

 

                                                                73

 

      death in a clinical development program.  This is a

 

      70-year-old male with history of allergy to

 

      contrast, who received undiluted direct injection

 

      and developed hypersensitivity reaction immediately

 

      after injection and become unresponsive.

 

                At the clinical site, however, there were

 

      no appropriate personnel or emergency response

 

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

 

      arrived, they delivered CPR and epinephrine.  When

 

      the patient get to the hospital, patient was

 

      pronounced dead approximately 35 minutes after this

 

      injection.  An autopsy revealed no MI or PE, and

 

      they conclude this is a Combidex-related

 

      anaphylactic shock.

 

                I would like to make two points here.

 

      This injection is no longer being used.  The second

 

      one, we are really concerned about the lack of

 

      appropriate personnel for emergency situations

 

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

 

      effective, there is many free-standing clinical

 

      imaging centers around the country, so we need to

 

      have a way to ensure this drug to be used

 

                                                                74

 

      appropriately.  That is with assumption that if

 

      this study is valid and the drug is safe.

 

                This table shows the distribution of the

 

      safety database or number of patients by

 

      administration and by the dose.  There are a total

 

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

 

      patients received proposed clinical dose, 131

 

      patients received bolus injection.  Those three

 

      groups will form the comparison for our next few

 

      slides.

 

                This slide shows the rate and severe

 

      hypersensitivity reactions by the three different

 

      subgroups I just mentioned to you.  For the

 

      clinical proposed dose, the rate of

 

      hypersensitivity reaction is 5.3.  For direct

 

      injection, it is 6.1.

 

                I would like to let you know that in your

 

      briefing document, this number is slightly higher

 

      because we just discovered some computer error, so

 

      made correction on this slide.

 

                People may define the severity

 

      differently, so we use few indicators to give you a

 

                                                                75

 

      range of severity, so you can pick which one is

 

      appropriate for you.  The first one is death.  The

 

      second one is serious events, which was the event

 

      that meet the regulatory definition for serious

 

      adverse event.

 

                The next one is hypersensitivity involve

 

      at least two body systems.  The next one is the

 

      patient was treated with antihistamine.  The last

 

      one is the patient treated with steroid.  Most of

 

      them are IV steroid.

 

                If you look at this population, there is

 

      no deaths.  There is two cases the sponsor point to

 

      you meet the definition of serious event.  There is

 

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

 

      percent, of people treated with antihistamine, and

 

      1.5 percent of people need IV steroids.

 

                This slide outline the presenting symptoms

 

      of hypersensitivity reactions.  We work extensively

 

      with our internal expert at FDA.  We define

 

      hypersensitivity reaction with the following three

 

      groups of symptoms.

 

                First, is skin reaction.  The second group

 

                                                                76

 

      with the respiratory difficulty with cardiovascular

 

      symptoms together.  The third one with the facial,

 

      laryngeal, and general edema.  This table show the

 

      distribution of the patient presentation.

 

                You will notice the majority of patients

 

      present with skin symptoms, however, this slide

 

      does show that direct injection, they may associate

 

      with a high percentage of people with more severe

 

      symptoms.

 

                This is a slide I would like to bring to

 

      your attention with a comparison with iodinated

 

      contrast agent. The sponsor told you that there

 

      were 4 cases serious AE happened in the clinical

 

      program.  That was an incorrect statement.  In

 

      reality, there was 29 serious events happened in

 

      the clinical program.

 

                The reason for include there, because the

 

      25 cases, the Agency do not consider is drug

 

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

 

      analysis.

 

                In the comparator, iodinated contrast

 

      agents in their Table 9 safety presentation, they

 

                                                                77

 

      are including all SAEs regardless whether drug

 

      related, so that is we believe incorrect

 

      comparison.  So, that is why the number of events

 

      in Combidex group is smaller than the iodinated

 

      group.

 

                This table, we focus on the

 

      hypersensitivity reaction between Combidex and the

 

      iodinated contrast agent.  If you read the labels,

 

      three labels which have clinical data for iodinated

 

      contrast agents, totaled together there are 4,545

 

      patients received iodinated contrast agent.  There

 

      is no death happening.  For Combidex, there is 1

 

      death of all the people receive Combidex.  There is

 

      zero out of 1,000 who has clinical dose.

 

                For the serious AE, which is associated

 

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

 

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

 

      cases for the clinical proposed dose.

 

                Also, the last one, the column, we show

 

      the percent distribution of those symptoms suggests

 

      hypersensitivity reaction, you can see the rate is

 

      quite different, the relative risk is quite

 

                                                                78

 

      different.  We do not want to draw definite

 

      conclusion over here because we understand the

 

      population are different, but at least this table

 

      do not support this two rate are comparable.

 

                When you talk about whether the drug is

 

      appropriate for populations, you basically talk

 

      about the risk-benefit ratios.  From the sponsor's

 

      presentation, they believe the best way to manage

 

      to get a best ratio is to focus on the risks.  I

 

      will show you their risk management slides later.

 

                From our end, we believe from the safety

 

      data we have at this time, this drug is definitely

 

      associated with hypersensitivity reaction.

 

      Although we have not observed serious event, more

 

      serious event including death in the proposed

 

      clinical dose, our level of assurance is limited by

 

      the number of patients involved in that group of

 

      patients who received the clinical dose.

 

                At this time, we are only able to say that

 

      the death-related hypersensitivity reaction

 

      probably will now be higher than 1 out of 400 or

 

      500 people based on data. Anything beyond that,

 

                                                                79

 

      that is purely speculation without any data.

 

                Sponsor present to you their risk

 

      management program.  I rearranged our slides.

 

      Basically, they say if we provided dilution and

 

      slow infusion, and educate physicians to the

 

      labeling and to the targeting academic center, they

 

      should be able to adequately address the safety

 

      issue.

 

                We believe this is item we need to discuss

 

      to implement, and also we believe that with

 

      uncertainty with those severe events with this

 

      Combidex administration, when you focus on the

 

      issues, enhance the benefit of this drug to the

 

      appropriate population.

 

                We need to better understand actually the

 

      performance of Combidex by different type of tumor

 

      and the nodal size, because we have preliminary

 

      evidence those performance may vary.  Also, we need

 

      to define appropriate patient population or

 

      condition for use, that the use of Combidex, the

 

      benefit will outweigh the risk, potential risk.

 

                This is a table to support our preliminary

 

                                                                80

 

      conclusion that performance of Combidex may vary by

 

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

 

      cancer.  This analysis actually was conducted by

 

      sponsor.  We didn't make any modification to their

 

      slides.  We just presented their slides, their

 

      result to you.

 

                On the top is for the nodes less than 10

 

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

 

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

 

      sensitivity from their clinical database is between

 

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

 

      percent.

 

                For the nodes larger than 10, the

 

      sensitivity is 93, 98 for different readers, and 56

 

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

 

      point estimator.  We have not put 95 percent lower

 

      boundary yet.

 

                If we put in the boundary, this number

 

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

 

      there is interaction between size and type of tumor

 

      because so small nodes that was included in the

 

      primary analysis would not allow us to do a further

 

                                                                81

 

      analysis.

 

                This table showed you the prevalence of

 

      nodes being positive by size of lymph nodes.  Why

 

      this information is important is because the

 

      sponsor showed you the positive predictive value

 

      and the negative predictive value in their

 

      presentation.

 

                To better understand that positive and

 

      negative predictive value, you not only need to

 

      understand the performance, that is, sensitivity

 

      and specificity of agent, you also need to know the

 

      prior probability that the prevalence of this node

 

      being positive before you give a drug.

 

                This data collected from their studies,

 

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

 

      the MR imaging measurement, so we have to use the

 

      pathology measurement as a surrogate over here.

 

      For nodes less than 10, the prevalence range from

 

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

 

      than 10 mm, the probability that the nodes be

 

      cancer-positive range from 10 to 20 percent from

 

      this data.

 

                                                                82

 

                If the nodes are more than 10 mm, then,

 

      the probability from 34 to 60 percent depending on

 

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

 

      variations.

 

                Also, you probably reviewed the New

 

      England Journal of Medicine.  From their study, the

 

      percentage is even higher.  They got 75 percent of

 

      people for the nodes larger than 10 has a cancer.

 

                So, how are we going to put all this

 

      information together to understand or to help us to

 

      understand the value of Combidex to help physicians

 

      in their patient care decisionmaking, or for any

 

      other benefit that they believe is good for

 

      patients?

 

                I will present to you the predictive

 

      values of a positive or negative Combidex test.  I

 

      will go over slowly with you.  For the lymph nodes

 

      less than 10 mm, the sensitivity is 68, the

 

      specificity is 80.  We make this assumption.  This

 

      has not been demonstrated by data yet, because the

 

      lymph nodes, the number are too small, but we

 

      assume if this is what we observed.

 

                                                                83

 

                The prevalence tell you what is the

 

      probability  the nodes is cancer, whether they are

 

      cancer-positive nodes before you give Combidex.

 

      The positive predictive value really tell you after

 

      you give Combidex, and if you get a positive

 

      result, what is the probability that node is

 

      metastatic at that time.

 

                The negative predictive value tell you if

 

      you gave Combidex, and the result is negative, what

 

      is the probability that node is negative.

 

                We look at different scenarios.  If the

 

      prevalence is 1, based on data or based on your

 

      suspicion, the clinical knowledge, if you are

 

      thinking the node, the probability of metastasis is

 

      only 1 percent, based on this performance, even

 

      Combidex is positive, the probability that nodes

 

      being positive is only 3 percent, so the people

 

      should make their own judgment this kind of

 

      improvement where they have clinical implication or

 

      values to help you to make decision to the patient

 

      care.

 

                When the prevalence get into 10, 25

 

                                                                84

 

      percent, you see big changes here in the

 

      probability, and this probably will getting higher

 

      if sensitivity and specificity get improved, which

 

      means that after you get a Combidex test, these

 

      nodes more likely become cancer.  You may go ahead

 

      to biopsy that one to confirm your suspicion.

 

                However, the positive predictive value is

 

      not that high enough, so we believe with this

 

      probability or likelihood, you will never make

 

      final diagnosis based on the Combidex positive

 

      result only, so most likely you will go to biopsy

 

      to confirm it.

 

                So, we do believe for nodes less than 10,

 

      there might be potential values for Combidex if

 

      performance is constantly demonstrated to help

 

      physicians to select nodes for further evaluation,

 

      to help patients to make some decision.

 

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

 

      already heard from sponsor for those nodes, most

 

      physicians will already consider is metastatic

 

      cancer, so for those nodes more than 10, most

 

      likely you will proceed with biopsy anyway without

 

                                                                85

 

      Combidex.

 

                The question you probably can ask yourself

 

      in that scenario is if I get negative results from

 

      Combidex, is that going to prevent me from going to

 

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

 

      the answer can vary depending on what is the

 

      pre-probability, how likely that nodes being

 

      positive before you give Combidex.

 

                Before Combidex, if the probabilities are

 

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

 

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

 

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

 

      my previous presentation, the probability already

 

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

 

      if you get a negative result, you only get 80

 

      percent assurance that the node is negative.  You

 

      still have 20 percent probability the nodes become

 

      positive, so maybe in that scenario, most

 

      physicians probably would still go ahead to do a

 

      biopsy for nodes even Combidex is negative.

 

                So, for that reason, we are seeking your

 

      advice to see how we can understand the values of

 

                                                                86

 

      Combidex for nodes more than 10 mm for helping

 

      patients.

 

                Also, where you would emphasize what my

 

      assumption here is based on the performance and

 

      which we believe has not constantly demonstrated

 

      from a clinical development program.

 

                So, based on everything I present today is

 

      we believe or the data seem to suggest that

 

      Combidex may not have a value for people with a low

 

      risk, that patients with lymph nodes larger than

 

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

 

      be substituted for the confirmation.  Also, we

 

      believe there probably is not a good surveillance

 

      of the recurrence of cancer, because that

 

      population was not studied.

 

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

 

      so that is why we are really concerned with the

 

      general indication. So, the key question we ask

 

      ourself, we are seeking your advice is how the

 

      Combidex result will really benefit to patients.

 

                We don't want to leave you a wrong

 

      impression that FDA do not care about knowing the

 

                                                                87

 

      nodes, whether positive or not, we care greatly,

 

      however, there is non-contrast agent available.  We

 

      try to understand what is additional value with

 

      Combidex to bring it to the table in addition to

 

      the non-contrast agent.

 

                We also understand this test cannot be

 

      used as confirmatory test, so we try to understand

 

      what role this will play to help a physician help

 

      their patients.

 

                We also understand this drug may associate

 

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

 

      clear the use of this drug in appropriate

 

      populations, the benefit with risk.

 

                In the later discussion with the sponsor,

 

      sponsor proposes four types of cancer which might

 

      benefit, that Combidex may have a beneficial effect

 

      to the patient, and they also presented those

 

      cancers in their presentation.

 

                For the prostate cancer first, I said

 

      earlier the Agency do believe for nodes less than

 

      10, Combidex may have a potential value, however,

 

      we are struggling with the fact there is only 5

 

                                                                88

 

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

 

      study included in the primary analysis, and the

 

      estimate is so unstable from the data I just showed

 

      you, we just have no clear understanding what is

 

      the true performance of the Combidex for that

 

      population.

 

                Also, the same concern applied to bladder

 

      cancer, breast cancer, and in less degree to head

 

      and neck cancer, because they have more patients,

 

      but I would like to bring your attention again for

 

      head and neck cancer, most of nodes in European

 

      trial, actually, all the nodes in European trial is

 

      more than 10.

 

                So, with that, I will conclude my

 

      presentation.  Thank you very much for your

 

      attention.  We are looking forward for your

 

      guidance to help us to determine the efficacy and

 

      safety of this product.

 

                DR. MARTINO:  Thank you, Dr. Li.

 

                      Questions from the Committee

 

                DR. MARTINO:  At this point, I will turn

 

      to the committee and give you the opportunity to

 

                                                                89

 

      ask questions both of the sponsor, as well as of

 

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

 

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

 

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

 

      will acknowledge you in turn.

 

                I would like to ask the first question.  I

 

      would like the sponsor to make it clearer to me how

 

      they actually looked at the MRIs.  I am still not

 

      entirely clear what they did first, what they did

 

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

 

      were they a specific group of radiologists, were

 

      there any radiologists, please clarify those issues

 

      for me.

 

                DR. GOECKELER:  Let me start by saying the

 

      question with regard to who made the diagnoses, the

 

      order in which that was done was shown in the

 

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

 

      and those diagnoses were committed to.  Then, there

 

      was the paired, and then after some time there was

 

      the post-only.

 

                In terms of who did that, are you

 

      referring to the specific specialty of the

 

                                                                90

 

      radiologist involved?

 

                DR. MARTINO:  No, I am trying to figure

 

      out did you have two radiologists that looked at

 

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

 

      am trying to understand that element.

 

                DR. GOECKELER:  I will address that, thank

 

      you.

 

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

 

      two blinded radiologists each independently, and

 

      the data has been reported both for each individual

 

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

 

      two readers.

 

                DR. MARTINO:  Can you also clarify to me

 

      what the task of the radiologist was?  I know you

 

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

 

      what was the charge given to them at each of these

 

      interventions?

 

                DR. GOECKELER:  I am going to ask Mark

 

      Roessel to speak to that issue a little bit in

 

      terms of how the radiologists, what they were

 

      actually asked to do on each of the blinded reads.

 

                MR. ROESSEL:  The blinded readers were

 

                                                                91

 

      given training and given the guidelines to evaluate

 

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

 

      The nodes were not marked on the images, so they

 

      saw the pre-contrast images and any nodes they

 

      identified, they circled, and they made a

 

      diagnosis.

 

                Then, on the paired evaluation, they did

 

      the same thing.  They circled the nodes.  But the

 

      nodes were not pre-identified on the images.  The

 

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

 

      if we circled the nodes that we had pathology on,

 

      that that would bias the readers, so the images

 

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

 

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

 

      and gave their diagnosis.

 

                Does that answer the question?

 

                DR. MARTINO:  It does.  What constituted

 

      the denominator for pathology, then, it was the

 

      node as seen post-contrast?

 

                DR. GOECKELER:  Well, as Dr. Li indicated

 

      on his slide, one of the reasons that these

 

      patients and nodes drop out along the way is that

 

                                                                92

 

      the two readings were done on unmarked images, and

 

      then the nodes were also taken out just according

 

      to standard surgical procedures.

 

                So, then, after all those readings were

 

      done, and then the readings had to be matched to

 

      the pathology, so in order to be evaluable at the

 

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

 

      the pre-contrast image and then identified and read

 

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

 

      pathology.

 

                So, when you impose those sequential

 

      conditions for unmarked images, that is why some of

 

      the nodes fall out along the way.

 

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

 

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

 

      non-contrast, also seen on contrast, and pathology

 

      done.  That, then, constituted the denominator.  Am

 

      I clear on that?

 

                DR. GOECKELER:  Yes, ma'am.

 

                DR. MARTINO:  Dr. D'Agostino.

 

                DR. D'AGOSTINO:  I have a couple of

 

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

 

                                                                93

 

                If you look at Slide 9 on the sponsor's

 

      presentation, this is page 5 of the handout.

 

                DR. GOECKELER:  Is it possible to get that

 

      slide?

 

                MR. ROESSEL:  Yes.

 

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

 

      presentation, I am sorry, the efficacy analysis.

 

                DR. GOECKELER:  Could you help us with the

 

      title, what it says on the slide?

 

                DR. D'AGOSTINO:  Slide 9 is Nodal

 

      Analysis, U.S., Phase III.

 

                DR. GOECKELER:  Is this the slide you are

 

      referring to?

 

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

 

      surprised that there were no confidence intervals

 

      given as the presentation was made.  Later on, the

 

      FDA presentation did have some confidence

 

      intervals.

 

                What I am interested in, in this here, is

 

      how big were these confidence intervals if you

 

      looked at, say, the post-contrasts and compared

 

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

 

                                                                94

 

      certainly the sensitivity doesn't change or they

 

      would overlap.

 

                Is there a real differentiation between

 

      the specificity or are the confidence intervals so

 

      large that it gets blurred?

 

                DR. GOECKELER:  I believe we have a slide

 

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

 

      can obtain it, and if someone could pull that data

 

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

 

      sitting right here this minute.  I believe it was

 

      in either the briefing book or if someone could

 

      pull the data.

 

                If you give me just a minute, I can

 

      provide you the answer to that question.  Perhaps

 

      we could take another one.

 

                DR. D'AGOSTINO:  The other question is,

 

      you know, the second question that follows is, as

 

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

 

      this sheet here, how do you make a statement or

 

      what kind of statement can be made from the

 

      statistics point of view, and then hopefully from a

 

      substantive point of view, that it makes sense to

 

                                                                95

 

      pool these different body regions, because it seems

 

      to me in terms of the questions that are asked

 

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

 

      has to be such a small number of nodes involved,

 

      and such a small number of subjects, that the

 

      inferences are really going to be almost

 

      impossible.

 

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

 

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

 

      body regions?

 

                DR. GOECKELER:  I am going to ask a couple

 

      of the clinicians that routinely image these

 

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

 

      Dr. Harisinghani's talk in the beginning that the

 

      mechanism of action of the drug depends on, not a

 

      primary tumor, but a physical process of

 

      displacement of macrophages within a lymph node.

 

                So, the study was designed with a variety

 

      of primary tumors based on the way the imaging

 

      agent acts in terms of imaging lymph nodes.

 

                Mukesh, would you like to comment on that

 

      further?

 

                                                                96

 

                Well, with regard to the specific body

 

      regions, then, the study obviously was carried out

 

      in a mixed populations of patients, and I think

 

      that obviously, if you start splitting out a large

 

      number of subgroups, the confidence intervals for

 

      any given subgroup increase.

 

                I think that looking at the study as a

 

      whole, which was designed to evaluate the premise

 

      of differentiation of lymph nodes, obviously, that

 

      occurred. With regard to the subgroups, I think

 

      what is important is that there are consistent

 

      trends amongst those subgroups based on the

 

      mechanism of action of the drug.

 

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

 

      couple more questions, I obviously don't want to

 

      tie up everything here.

 

                In terms of the post-contrast, we were

 

      told in the last presentation that not all the

 

      nodes were actually used because you want to have a

 

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

 

      there.

 

                Was any analysis done on the nodes that

 

                                                                97

 

      didn't enter into the post?

 

                DR. GOECKELER:  Yes, there was a separate

 

      analysis that was done called the "blinded

 

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

 

      described to you, but it involved a much higher

 

      percentage of the total nodes.

 

                So, it was again a blinded reading of the

 

      nodes, and there was histopathologic correlation of

 

      the data at the nodal level for each of the

 

      readings, and I can show you--

 

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

 

      see what the sensitivity and specificity was.

 

                DR. GOECKELER:  --what happened in those.

 

                Can you first show the data in terms of

 

      the numbers of patients that were evaluated both in

 

      the unmarked images and in the blinded overread?

 

                These are the numbers that were evaluated

 

      by each reader in the blinded overread, and you can

 

      see, based on the various reads, the number of

 

      nodes that were read and for which there was

 

      histopathologic confirmation for each reader and in

 

      each diagnosis.

 

                                                                98

 

                DR. D'AGOSTINO:  Do you have the

 

      sensitivity and specificity?

 

                DR. GOECKELER:  Can you show me the data

 

      on false diagnoses in this, because that

 

      essentially relates to, and we can go back then?

 

      If you have a slide on sensitivity and specificity,

 

      I think you do.

 

                This is the data on the false diagnoses

 

      that occurred in the larger reading population.

 

      You can see the trends are largely the same as we

 

      saw before, about 15 percent with the post-contrast

 

      reads, and 25 percent are slightly higher.

 

                We did see a higher variability between

 

      blinded readers and the blinded overread for the

 

      individual readers.

 

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

 

      the sensitivity and the specificity and the

 

      confidence intervals.

 

                DR. GOECKELER:  Do you have the

 

      sensitivity and specificity?  Get me the numbers,

 

      so that I can just provide them.

 

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

 

                                                                99

 

      back to it.

 

                DR. GOECKELER:  I can give you the

 

      numbers, and I can tell you that the trends are

 

      very--

 

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

 

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

 

                My last question is that you did a lymph

 

      node as the unit of analysis.  There is still the

 

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

 

      know about the nodes, but in other activities, when

 

      you are looking at the same subject, and you are

 

      taking different specimens, and so forth, they tend

 

      to be correlated.

 

                So, if you did a person analysis, what

 

      would you do with the person, what would you say

 

      about the person?  Your sample size is greatly

 

      reduced.  Are there still your inferences?

 

                DR. GOECKELER:  Yes, the analyses were

 

      also carried out at the patient level, so we have

 

      the same data for each of the analyses pre- and

 

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

 

      ask for a slide one more time.

 

                                                               100

 

                DR. D'AGOSTINO:  Maybe they can produce it

 

      later on, the confidence intervals around some of

 

      these things I am talking about.

 

                DR. GOECKELER:  No, actually, I think they

 

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

 

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

 

      in sensitivity and specificity at the nodal level

 

      translated through to the patient level also.

 

                Here we go.  But this is nodes less than

 

      or greater.

 

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

 

      point estimates, but the confidence intervals, what

 

      are you actually saying about the individual, how

 

      much confidence you have.

 

                DR. MARTINO:  Dr. Hussain.

 

                DR. HUSSAIN:  I have a question to the

 

      sponsor, and it strictly relates to the study

 

      design, because I am still not clear about really

 

      what the design was, so starting with the

 

      eligibility criteria, how were the patients

 

      characterized, were there standardized surgery, and

 

      was the surgery required each time if it was

 

                                                               101

 

      prostate or breast or bladder or head and neck, to

 

      actually do the same template or do beyond what is

 

      normally needed?

 

                And understanding that my specialty, and I

 

      am a gyn-oncologist, that there are certain

 

      prognostic features that will make you feel or

 

      believe that the patient has a high probability of

 

      a lymph node positivity, say, in prostate cancer if

 

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

 

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

 

      because in this patient you would think, based on

 

      clinical criteria only, without even imaging, that

 

      those are very high odds of having this patient

 

      have lymph node positivity.

 

                So, with all that taken into account, and

 

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

 

      done the appropriate studies, which is accounting

 

      for the subpopulations as having adequate head and

 

      neck patients, adequate breast patients, adequate

 

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

 

      conclusions from that?

 

                And final question, and maybe I didn't see

 

                                                               102

 

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

 

      was compared to what?

 

                DR. GOECKELER:  Let me take a couple of

 

      those and then refer some of those to other people

 

      who are more directly involved.

 

                With regard to the comparison, the primary

 

      comparator was the paired evaluation as compared to

 

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

 

      those were the prospectively designed endpoints for

 

      the Phase III studies.

 

                With regard to the treatment of the

 

      patients and how it was decided which nodes would

 

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

 

      that.  That varied a little bit as Dr. Barentsz

 

      said between the Phase III studies and what Dr.

 

      Barentsz presented in the post-Phase III studies.

 

      So, Mark.

 

                MR. ROESSEL:  In the Phase III studies,

 

      the entry criteria were patients who had a known

 

      primary, who were scheduled for either surgery or

 

      biopsy, and who had suspicion of metastatic disease

 

      spread to lymph nodes.

 

                                                               103

 

                There was no direction as to what the

 

      surgery or biopsy procedures would be.  It was just

 

      based on the clinical investigator.

 

                DR. GOECKELER:  The standard of practice

 

      at the institution.

 

                MR. ROESSEL:  Does that answer the

 

      question?

 

                DR. HUSSAIN:  I guess what I am asking is

 

      was it the sense of the treating physicians, or

 

      were there guidelines that said if you had this

 

      size tumor, this kind of risk?

 

                MR. ROESSEL:  No, there were no--

 

                DR. HUSSAIN:  So, this was left random to

 

      the person enrolling the patient based on their gut

 

      feeling whether the patient have--

 

                MR. ROESSEL:  There were no guidelines

 

      given.  The entry criteria were just that, patients

 

      with a known primary who were scheduled to have

 

      surgery or biopsy, so that we could get

 

      pathological confirmation of nodal status.

 

                DR. GOECKELER:  Did you have another

 

      question, Dr. Hussain, about risk stratification

 

                                                               104

 

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

 

      speak to that with regard to relative risk and some

 

      of the models and selection of patients who might

 

      be most appropriate for treatment.

 

                DR. ROACH:  In the sponsor's indication,

 

      it specified that patients who were at risk for

 

      nodal involvement, so the clinical use for this

 

      agent in patients with prostate cancer would be

 

      patients at intermediate and high risk disease for

 

      whom we have data from randomized trials that

 

      demonstrates that treating the nodes is beneficial,

 

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

 

      of the nodes as possible.

 

                So, this agent would be useful for

 

      identifying where the nodes are located and allow

 

      us to reduce the morbidity of giving radiotherapy

 

      in patients with prostate cancer.

 

                DR. MARTINO:  Dr. Levine.

 

                DR. LEVINE:  I have several questions.

 

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

 

      the individual, that the patient would have two

 

      different MRI scans, in other words, your

 

                                                               105

 

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

 

      that you are asking that patients are now going to

 

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

 

      question.

 

                My second question, what was in those

 

      benign nodes?  You know, there are infiltrative

 

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

 

      those benign nodes, and what kinds of benign

 

      conditions, in fact, fulfill your requirements for

 

      benign?

 

                Number 3.  This is kind of a funny one,

 

      but how did you know that the correct node was

 

      actually taken out? Did you do an MRI scan after

 

      surgery to know that you really took the right node

 

      out?

 

                DR. GOECKELER:  Let me ask, in terms of

 

      the matching, since Dr. Harisinghani has been

 

      involved in a number of these studies, how that is

 

      done.

 

                The first part of the question dealt

 

      with--I am sorry?

 

                DR. LEVINE:  Is the company requesting

 

                                                               106

 

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

 

      different reads--two different MRI scans?

 

                DR. GOECKELER:  Two different images,

 

      yeah.

 

                DR. LEVINE:  And who pays for that?

 

                DR. GOECKELER:  In the conduct of the

 

      clinical studies, that was required, because the

 

      primary endpoint was the comparison of a

 

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

 

      going to let the radiologists comment upon how they

 

      read these scans and how they match the nodes in

 

      the clinical studies.

 

                DR. LEVINE:  That actually wasn't the

 

      question.  The question is if this compound is

 

      licensed, are you asking that the patient be sent

 

      to MRI scan twice?

 

                DR. HARISINGHANI:  And the answer is yes,

 

      the patient will require two scans pre- and after

 

      contrast administration, and in terms of being able

 

      to correlate the nodes specifically to the areas on

 

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

 

      arduous and a difficult task, and for that reason,

 

                                                               107

 

      we have developed exquisite anatomic maps to which

 

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

 

      surgeons then correlate them to fix the anatomic

 

      landmarks, which could be the vessels or bony

 

      landmarks, and that is how they figure out where

 

      the nodes lie.

 

                DR. LEVINE:  All right.  Another question

 

      was the character of the reactive lymph nodes, what

 

      were they?

 

                DR. HARISINGHANI:  The benign enlarged

 

      lymph nodes ranged in etiology.  Most of them are

 

      reactive nodes, not pointing to any specific

 

      etiology for the so-called reactive lymph nodes,

 

      but we had occasional cases of sarcoidosis.

 

                I must say there were no caseating

 

      tuberculosis at least in the trials that I have

 

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

 

      but the benign nodes mainly were reactive and

 

      enlarged.

 

                DR. LEVINE:  And the sarcoid case

 

      fulfilled your criteria as benign, as well?

 

                DR. HARISINGHANI:  Yes, that was the case

 

                                                               108

 

      I showed earlier in the presentation where it

 

      behaved like a reactive lymph node.

 

                DR. LEVINE:  Have you guys done a cost

 

      analysis of the efficacy of this approach given the

 

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

 

      there a cost analysis perhaps?

 

                DR. HARISINGHANI:  We have not formally

 

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

 

      group in the Netherlands has actually published

 

      their results on cost saving.

 

                Do you want to comment on that?

 

                DR. GOECKELER:  Also, just let me comment

 

      that although two separate imaging sessions were

 

      required in the clinical trials, because of the way

 

      that clinical trials were conducted, different

 

      investigators in the post-Phase III setting

 

      interpret pre and post different ways, and Dr.

 

      Barentsz can comment on that also.

 

                DR. BARENTSZ:  I would like to comment on

 

      the first question first, about cost.  We recently

 

      published a paper in European Radiology in which

 

      we, based on the sensitivity and specificity data,

 

                                                               109

 

      did do a calculation and analysis on the health

 

      care perspective.

 

                If you are including this technique, it

 

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

 

      that is I think not the most important thing.  The

 

      most important thing, it saves also morbidity.

 

      That was not taken in account in that study.

 

                To reflect on the pre- and post-contrast,

 

      as among radiologists there are some discussions

 

      going on, at this moment, with some newer

 

      techniques, you are able to make a sequence which

 

      is insensitive to iron, so you can tell the machine

 

      "Iron Off," and you can tell immediately after

 

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

 

      for the pre-contrast examination.

 

                Nonetheless, to start in the initial phase

 

      for new readers to get some experience, it is

 

      advised to use both of those examinations pre and

 

      post.  I am performing now and studying in the

 

      Netherlands, in foreign patients in prostate

 

      cancer, a multi-sound study only doing the post

 

      just by having insensitive and sensitive sequence.

 

                                                               110

 

                Also, if you have looked at the data of

 

      the sponsor, you can see that if you do the

 

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

 

      Perhaps you can comment on that also, Mukesh.

 

                DR. HARISINGHANI:  I think, as Dr.

 

      Barentsz alluded to, for initial training purposes

 

      you need both scans.  Once the individual is

 

      trained, then, yes, with the existing technology,

 

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

 

      Then, it would be possible that you could just do

 

      the post-contrast study.

 

                MR. ROESSEL:  If I might add, because we

 

      need to be clear about labeling for this, as the

 

      sponsor, the proposed labeling, the proposed

 

      package insert does not specify that you have to do

 

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

 

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

 

                DR. MORTIMER:  I wonder if the sponsor

 

      could clarify the management of the lymph nodes.

 

      Were the lymph nodes just handled in a routine

 

      fashion?  Were those nodes that were suspicious

 

      handled in any different manner to ensure micro

 

                                                               111

 

      metastatic disease?

 

                DR. GOECKELER:  Let me make sure I

 

      understand.  In terms of obtaining them in surgery

 

      or--

 

                DR. MORTIMER:  Actually, reviewing them

 

      histologically, so to make an analogy of sentinel

 

      node mapping, the sentinel node is immunostained.

 

                DR. GOECKELER:  I think I understand.  The

 

      histology was reviewed without knowledge of the

 

      image findings.  So, they didn't analyze those

 

      particular nodes any different than they did any

 

      other nodes that were in the study.

 

                DR. MORTIMER:  And it was just H and E

 

      slicing and--

 

                DR. GOECKELER:  Right.

 

                DR. MARTINO:  Dr. Perry.

 

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

 

      point number 2 about inadequate representation of

 

      tumor types, I don't think the sponsor ever

 

      attempted to try to do all sorts of tumor types.

 

      For many kinds of cancers, this methodology is not

 

      necessary.  For melanoma, as an example, we have

 

                                                               112

 

      other staging systems or imaging systems that are

 

      quite sufficient.

 

                So, I think it is an unfair criticism to

 

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

 

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

 

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

 

      and I don't think that is an appropriate criticism

 

      of the sponsor.

 

                For the sponsor, when it comes to

 

      education should this product be approved, I think

 

      you are focusing on the wrong market.  I think if

 

      you put the emphasis on physician education, you

 

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

 

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

 

      not the physician.

 

                I don't know any physician that I have

 

      ever seen administer a contrast agent.  Perhaps

 

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

 

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

 

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

 

      educated and make sure that they give it the right

 

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

 

                                                               113

 

      going to have problems.

 

                DR. MARTINO:  Dr. Brawley.

 

                DR. BRAWLEY:  There are a couple of

 

      statements that were made in the FDA presentation

 

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

 

      them.

 

                The first is of 152 and 181 patients who

 

      received Combidex in the U.S. and the European

 

      studies, a third of patients were censored from the

 

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

 

      censored from the European study, and not included

 

      in the primary analysis.

 

                I would like your response to that, and

 

      then I have a couple others.

 

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

 

      with regard to the European studies, as I think

 

      someone indicated at the beginning, the European

 

      studies themselves were initially carried out by

 

      the European sponsor with different endpoints, so

 

      they were analyzing patients at the patient and

 

      group and nodal level.

 

                So, in those studies initially, there was

 

                                                               114

 

      nodal matching predominantly only amongst the large

 

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

 

      to recall that these studies were all done seven or

 

      eight years ago now, it was felt that the matching

 

      could be better done on those large nodes, and I

 

      think that is why there is a disproportionate

 

      number of large nodes in the European studies.

 

                After the studies were done, the sponsor

 

      met with the FDA and agreed that they could take

 

      data that was acquired at the individual node level

 

      in those studies and analyze it in a blinded read

 

      through the same sort of matching procedures, using

 

      the same sort of analyses that were carried out for

 

      the U.S. study.

 

                So, one of the consequences of that is

 

      that there were a large number of nodes removed

 

      from those patients that weren't matched on a

 

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

 

      number of nodes, and the numbers that were

 

      originally--and then the ones that were eventually

 

      matched up by two blinded readers and then had

 

      pathology, it's a smaller percentage in the

 

                                                               115

 

      European studies.

 

                DR. BRAWLEY:  A couple more follow-up

 

      questions.

 

                I am told that there are only 5 prostate

 

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

 

      the primary analysis.  Is that true?

 

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

 

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

 

      Phase III studies, the purpose of the studies was

 

      to investigate the ability of the agent to

 

      differentiate nodes, malignant from non-malignant.

 

                I think that when you move on to--and

 

      obviously, you can subset that a lot of different

 

      ways, either by body region or individual tumor, or

 

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

 

      certain categories will be large or small, and the

 

      confidence intervals will react accordingly.

 

                I think that that is why, when we turn to

 

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

 

      Combidex improved the ability to differentiate

 

      malignant from non-malignant lymph nodes.

 

                I think that as Dr. Li indicated and as we

 

                                                               116

 

      indicated, when you move on to the question of

 

      where does that provide a clinical benefit, the

 

      tumors that we presented on were ones where not

 

      only we believe there is a clinical benefit, but

 

      also that there was supplemental data post-Phase

 

      III, not only on imaging performance, which you saw

 

      in the slides that Dr. Barentsz provided, but also

 

      on how that imaging performance impacted on

 

      clinical utility.

 

                DR. BRAWLEY:  So, you are trying to

 

      convince the committee that this drug is safe,

 

      effective, and efficacious in prostate cancer with

 

      a series of 10 prostate cancer patients.

 

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

 

      argument about the risk-benefit solely on those 10.

 

      I think we have to look at some of the additional

 

      supplemental data that is available from other

 

      places, such as the publications in the New England

 

      Journal and other places.

 

                DR. BRAWLEY:  I have also heard that

 

      certain source documents, including a pre-defined

 

      statistical plan, blinded reader manual, the

 

                                                               117

 

      original copy of the blinded reader efficacy

 

      evaluation, were not available to the Food and Drug

 

      Administration.

 

                I would like you to respond to that

 

      allegation.

 

                DR. GOECKELER:  Well, I think that there

 

      have been some questions raised about the exact

 

      sequences of events in which the nodal imaging

 

      guidelines were developed and finalized, and I

 

      addressed that on one of the slides that I

 

      presented from the sponsor's perspective.  The

 

      guidelines were finalized prior to any blind

 

      reader, availability of blind read data.  Mark, if

 

      you would like to expand on that.

 

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

 

      answering a different question.  I think the

 

      question was about the prospective plan being

 

      available for the New England Journal of Medicine

 

      article.  Is that correct?

 

                DR. BRAWLEY:  That's correct.

 

                MR. ROESSEL:  The material that was

 

      published in the New England Journal of Medicine

 

                                                               118

 

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

 

      independently of the sponsor. Two clinical

 

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

 

      got together and took 40 patients from trials that

 

      they were conducting and did a blinded read.

 

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

 

      was done independent of us, on their own

 

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

 

      don't have from them a prospective statistical plan

 

      or prospective plan for conducting that blind read.

 

                We do have that for our Phase III studies,

 

      of course, for our clinical studies.

 

                DR. BRAWLEY:  Let me just say

 

      parenthetically that that is an acceptable answer,

 

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

 

      want to criticize this company, Advanced Magnetics

 

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

 

      Magnetics, and I do want the news media to listen

 

      to this.

 

                In my last four years here, I have seen

 

      some companies come before this committee, and some

 

      companies submit data to the FDA, and what is done

 

                                                               119

 

      is sort of slight of hand, with selection biases in

 

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

 

      point that a particular drug or a particular agent

 

      works, and we have to be very, very careful

 

      whenever we look at data to understand exactly what

 

      the source of the data is and the validity of the

 

      data, and most importantly, the selection biases of

 

      the patients going into the data before we can make

 

      a decision.

 

                That is a point that has been missed

 

      repeatedly in a number of newspaper editorials

 

      about drug approval recently, so that is the basis

 

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

 

      acceptable answer, and again I want to state I

 

      don't want to at all impugn your company.

 

                Last question.  I heard that a patient

 

      died getting this contrast agent.  I thought I

 

      heard that the patient got the contrast agent in a

 

      facility that was not able to treat an allergic

 

      reaction.

 

                Is that true?

 

                DR. GOECKELER:  Mark, you can comment on

 

                                                               120

 

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

 

      comment on sort of the guidelines and regulations

 

      regarding what those sorts of facilities are

 

      required to have.

 

                MR. ROESSEL:  The facility in question was

 

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

 

      qualifications for doing clinical trials that

 

      equipment was available to treat any reactions that

 

      occurred.  They did have emergency equipment, which

 

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

 

      available.  Apparently, they didn't choose to use

 

      it.

 

                DR. BRAWLEY:  That, too, is an acceptable

 

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

 

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

 

      make a comment?

 

                DR. HOUN:  Yes, just to clarify when a

 

      sponsor obtains right of reference to studies to

 

      support their application, they have to be able to

 

      provide to FDA access to underlying data to provide

 

      the basis of the report of the investigation.

 

                This did not happen with the New England

 

                                                               121

 

      Journal study, and also just as a reference to the

 

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

 

      terms of the numbers of people enrolled, just in

 

      previous approvals for ProstaScint, prostate cancer

 

      only imaging drug, there were 152 people entered

 

      into the analysis only with prostate cancer, and

 

      there were 183 that were followed for the open

 

      label efficacy study.

 

                When we did NeoTec, a lung cancer

 

      detection for non-small cell lung cancer, there

 

      were 228 entered into the analyses.  When we

 

      approved PET-FDG, that got a broad indication for

 

      all kinds of cancers.  There were 1,311 people

 

      entered into the analyses.

 

                DR. MARTINO:  Dr. Reaman.

 

                DR. REAMAN:  Just a question again about

 

      the eligibility criteria, and I guess to somewhat

 

      follow up on the issue of selection bias.

 

                You stated that any patient with cancer

 

      who was at risk for developing lymph node

 

      metastases were eligible for this study, and they

 

      were eligible based on whether or not they were

 

                                                               122

 

      going to then have either a biopsy or a surgical

 

      procedure.

 

                So, how was the decision as to whether

 

      they were going to have surgery or a biopsy

 

      procedure made, by equivocal or positive

 

      radiographic studies before they were entered on

 

      this study, or did they have palpable adenopathy?

 

      Other than the breast cancer patients in the

 

      sentinel node biopsy, I am still not satisfied that

 

      this isn't a selected population.

 

                DR. GOECKELER:  I will ask Mark to expand

 

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

 

      verify, that the image findings, the post-contrast

 

      image findings could not play a role, and were not

 

      available to the physicians in making those

 

      assessments.

 

                So, the physicians did not have any

 

      post-contrast image findings on which to base that

 

      assessment of whether the patient then went on to

 

      surgery or biopsy.  It was done based on the normal

 

      clinical information that would be available to

 

      make that decision for every other patient.

 

                                                               123

 

                DR. REAMAN:  So, radiographic studies

 

      weren't part of the clinical information?

 

                DR. GOECKELER:  Well, I think that the

 

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

 

      MRI pre-contrast, but no post-contrast image

 

      findings.

 

                DR. MARTINO:  Dr. Bradley.

 

                DR. BRADLEY:  I have a couple of questions

 

      maybe for the authors of the New England Journal

 

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

 

                How did you select those 40 and 40

 

      patients from a group that was 3 times larger?  I

 

      mean selection bias kind of comes to mind, but what

 

      selection criteria did you use?

 

                DR. HARISINGHANI:  It is 3 times larger

 

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

 

      consecutive patients who were scheduled to undergo

 

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

 

      European site.

 

                They were of the intermediate and

 

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

 

      of the patient selection.

 

                                                               124

 

                DR. BRADLEY:  And then a follow-up

 

      question.  You showed some very nice images of very

 

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

 

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

 

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

 

      know you are comparing the same nodes pre and post,

 

      particularly not for you, but for the chest where

 

      you have respiratory artifact?

 

                DR. BARENTSZ:  In our New England Journal

 

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

 

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

 

      performed a combination of sequences which

 

      visualized the anatomy and also a sequence which

 

      visualizes the iron, and based on also a 3D

 

      sequence which we performed, we were able to

 

      compare the pre and post and exactly locate the

 

      lymph nodes where they were, so we could make a

 

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

 

                Also, we located the nodes in relation to

 

      the vessels.  So, I agree with you that

 

      localization and the location of lymph nodes is

 

      very important.

 

                                                               125

 

                DR. BRADLEY:  So, the slice location of

 

      3-mm slices was accurate, looking at the other

 

      anatomy?

 

                DR. BARENTSZ:  Absolutely.

 

                DR. BRADLEY:  A follow-up question.  On

 

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

 

      15 percent false positive and false negative, we

 

      have talked a little bit about what might cause a

 

      false positive.  What about false negative, any

 

      thoughts, did you do an analysis of why they were

 

      false negative?

 

                DR. HARISINGHANI:  I think there are two

 

      issues here at least from our study.  I would let

 

      Bill answer for the general part, but the false

 

      negatives are mainly as we are talking of nodes

 

      which are smaller than 5 mm, then, the current

 

      resolution of our scanner only enables us to be

 

      confident at a certain level, and that could

 

      account for the false negative reads.

 

                DR. BRADLEY:  Then, one final question for

 

      the sponsor.  Why did you choose a 0.2T Hitachi

 

      when this is clearly a magnetic susceptibility

 

                                                               126

 

      agent?  Is it so sensitive that a gradient echo at

 

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

 

      having read all of this, that that was also where

 

      you had your single death, is that correct?

 

                DR. GOECKELER:  I am going to have to ask

 

      Mark or Paula to comment on the specific imaging

 

      equipment.  Please recall that the death was in a

 

      liver imaging study, not in a lymph node imaging

 

      study.

 

                DR. BRADLEY:  Right.  I saw the physician

 

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

 

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

 

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

 

                MR. ROESSEL:  We tried to include in the

 

      Phase III clinical studies, we didn't specify the

 

      imager to be used. There was no requirement for it

 

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

 

      Agency with the information on the types of imaging

 

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

 

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

 

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

 

                DR. BRADLEY:  Just to follow up, was the

 

                                                               127

 

      0.2 Hitachi also where the death occurred?

 

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

 

                DR. MARTINO:  Ladies and gentlemen, we are

 

      running short of our allotted time, but I

 

      appreciate these questions as important, and that

 

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

 

      part of the meeting.

 

                That being said, I would ask those of you

 

      asking the subsequent questions, please be sure

 

      that your questions are necessary to your thinking

 

      about the efficacy and the approval of this agent,

 

      and are not just purely for your perhaps

 

      intellectual curiosity.

 

                Dr. Giuliano.

 

                DR. GIULIANO:  I am a surgeon, Dr.

 

      Martino.  We have limited intellectual curiosity,

 

      so my--

 

                DR. MARTINO:  I know.

 

                [Laughter.]

 

                DR. GIULIANO:  Therefore, my questions

 

      will be brief.  But I am struggling as a surgeon

 

      through these documents.  We say the surgical

 

                                                               128

 

      procedure was not altered, the post-enhancement

 

      images were not available.

 

                How did you instruct the surgeon to remove

 

      the Combidex abnormal enhanced lymph node?  He or

 

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

 

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

 

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

 

      surgical bias because as any surgeon knows, it is

 

      easier to find a positive node than a negative

 

      node.

 

                In addition, using the node-by-node

 

      analysis, what happens with nodes not seen on MR

 

      that are removed?  For example, if this agent did

 

      not alter your surgical operation, the patient with

 

      a prostatectomy may have had a pelvic lymph node

 

      dissection, and there was one node that had been

 

      identified on your preoperative images or an

 

      axillary dissection for breast cancer, and there

 

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

 

      removed.

 

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

 

      to be seen on the image, had to evaluated

 

                                                               129

 

      histopathologically, and they correlated, let's say

 

      they were both negative, what if all of the

 

      remaining nodes were positive or one of the

 

      remaining nodes was positive, how was that dealt

 

      with statistically or in your presentation?  I

 

      could not understand that.

 

                DR. GOECKELER:  I will ask Dr. Anzai to

 

      talk about the nodal matching and how those nodes

 

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

 

      in the identification of those nodes.

 

                DR. ANZAI:  I am the radiologist involved

 

      in Phase II and III clinical trials.  Your comment

 

      is absolutely right.  This was the hardest trial

 

      that we ever had in Radiology, that I personally

 

      have to have images going to OR when the patient is

 

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

 

      make stitches on a certain anatomical level.

 

                For example, a head and neck radiology, I

 

      have to ask the surgeon to make stitches on the

 

      submandibular--this is the jugular vein, so in

 

      between this lymph node is the lymph node that I am

 

      seeing in imaging, and it was very labor intensive.

 

                                                               130

 

                Many of the radiologists have to be in the

 

      OR with this graph, and the surgeon to identify,

 

      correctly identify those lymph nodes on imaging, or

 

      lymph node in a patient, so the pathologist would

 

      identify this is the exact lymph node that we saw

 

      in imaging.

 

                That is why the sample size was so small,

 

      because we have to have a certain confidence that

 

      the imaging on the lymph node is matched with final

 

      pathology.  That is why the size of the lymph node

 

      that is seen in all the cancer patients are small,

 

      but this is such a labor intensive study, but we

 

      did as much as possible to correlate imaging on a

 

      lymph node with surgical pathology by being in the

 

      OR.

 

                The second question for statistics, maybe

 

      Mark can comment.

 

                DR. GOECKELER:  I think that the issues

 

      that have just been identified by Dr. Anzai and

 

      others are the ones that account for the analysis

 

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

 

      large number of nodes and then if you are going to

 

                                                               131

 

      require evaluation on unmarked images to avoid bias

 

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

 

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

 

      identify the same nodes every time they read.

 

                That is why you see some of the nodes or

 

      the numbers dropping off at every level.  We tried

 

      to address that in part by looking at another read

 

      that involved the blinded overread, which are a

 

      much larger percentage of the nodes.

 

                DR. GIULIANO:  Maybe I wasn't very clear

 

      about that.  My question is if the labeled node

 

      from the operating room is the one identified on

 

      the MR, and histologically evaluated, and is

 

      positive or negative or whatever the correlation

 

      is, but other nodes that were not seen are

 

      positive, was that counted as a false negative or

 

      was that not counted because the other nodes were

 

      not seen on MR?

 

                DR. GOECKELER:  No, the primary analysis

 

      was at the nodal level, so those numbers that were

 

      presented were at the nodal level.  There were

 

      other analyses the data tracked very closely at the

 

                                                               132

 

      patient level where you can look at the patient

 

      level also.

 

                DR. GIULIANO:  Thank you.

 

                DR. MARTINO:  Does that answer your

 

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

 

      it did.

 

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

 

      your question that the lymph node that not

 

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

 

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

 

      those lymph nodes were pretty not pre-identified by

 

      imaging, but a patient level analysis, if, for

 

      example, MRI showed all the normal lymph node, but

 

      pathology somehow find one positive lymph node that

 

      not identified MRI, I think that was considered to

 

      be false negative.

 

                DR. GIULIANO:  Perhaps you could share

 

      that patient analysis, would that be appropriate,

 

      Dr. Martino?

 

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

 

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

 

      your decision realizing that the data that you need

 

                                                               133

 

      perhaps are not presented to you right now.  I

 

      think that may be one of the issues.

 

                Dr. Bukowski.

 

                DR. BUKOWSKI:  I am trying to understand

 

      the efficacy and benefits of this approach, and

 

      there was a statement made that there is a decrease

 

      in morbidity when you apply this particular

 

      product.

 

                Can you help me understand what the

 

      implications are?  Are you implying that there will

 

      not be a need for surgery if there is an identified

 

      positive node, or that there will be then a

 

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

 

      likelihood of being able to biopsy the small nodes

 

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

 

      techniques not only at academic centers, but

 

      centers elsewhere?

 

                DR. BARENTSZ:  You raise a very good

 

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

 

      our New England Journal paper, which is different

 

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

 

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

 

                                                               134

 

      allowed to include data which were obtained from

 

      the Combidex MRI into clinical practice.

 

                So, that paper shows better the real

 

      clinical effect of what this contrast agent can do.

 

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

 

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

 

      communication with the surgeon where the node is,

 

      is very important.

 

                Mukesh and I, we started by making some

 

      nice schemes, which have been used by the surgeon,

 

      and sometimes we, well, we went to the surgery

 

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

 

      the surgeon, and we asked our surgeon how this

 

      scan, how did this really change his management,

 

      did that decrease the extent of surgery.

 

                Actually, the black nodes, they are

 

      normal, and if you have a high sensitivity and a

 

      high negative predictive value, but if you have

 

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

 

      the New England Journal, both on the patient and as

 

      on the nodal level, that means that the risk after

 

      an MRI, that the patient has a negative lymph node

 

                                                               135

 

      is extremely high.

 

                That means the number you are missing is

 

      extremely low, and that current threshold, our

 

      urologist advises, but I would like also to have

 

      one of the urologists to speak on that.  That is

 

      very important clinical information which may

 

      actually decrease the number of lymph node

 

      dissections.

 

                If you have a positive lymph node, it

 

      always must be confirmed histopathologically.  If

 

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

 

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

 

      to tell the urologist the node is down there, and

 

      he can remove it.

 

                Perhaps the urologists can make also some

 

      clinical remark on that.  Comment about the

 

      clinical use, how this technique can be applied,

 

      what will you do if you have a negative MR

 

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

 

      positive lymph node.

 

                DR. KALINER:  Well, first of all, any

 

      information that I give as a clinician, first of

 

                                                               136

 

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

 

      George Washington University, and recently joined

 

      Cytogen as the Vice President of Medical Affairs,

 

      so I have a lot of experience in surgery and

 

      urology.

 

                Any information I can get that helps me

 

      identify whether there is more extensive disease or

 

      not is extremely important with these patients.

 

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

 

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

 

      unless it is somebody that is intermediate to high

 

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

 

      stratified by risk to begin with.

 

                So, this is somebody that has a negative

 

      Combidex scan, we still would perform the lymph

 

      node dissection, but if there was a reason to look

 

      in an extended area, which we know pathologically

 

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

 

      that.

 

                On the other hand, if we did find

 

      something ahead of time, we may be able to

 

      eliminate doing an invasive procedure by performing

 

                                                               137

 

      a biopsy or perhaps a laparoscopic lymph node

 

      dissection as opposed to an open procedure.  There

 

      are a variety of ways to look at doing that.

 

                Any way that I can get more information to

 

      help prevent an invasive procedure when it is not

 

      necessary is extremely important.

 

                DR. MARTINO:  Dr. Dykewicz.

 

                DR. DYKEWICZ:  I have two questions

 

      regarding safety and adverse events.  The first is

 

      whether slowing the rate of the infusion as

 

      proposed will really reduce the risk of

 

      hypersensitivity reactions.

 

                In the sponsor's presentation, there was

 

      data presented showing that the number of adverse

 

      events were reduced with the use of that

 

      administration method, but, of course, adverse

 

      events could include both hypersensitivity and

 

      non-hypersensitivity events.

 

                Hypersensitivity events are the ones that

 

      are potentially going to lead to fatalities, so

 

      that is where I have my greatest concern.

 

                The FDA analysis was that the overall risk

 

                                                               138

 

      in severity of hypersensitivity reactions was

 

      actually not reduced, and they presented one data

 

      on Slide 21, Presenting Symptoms of

 

      Hypersensitivity Reactions, that showed that at

 

      least in terms of urticaria, the rate even

 

      increased with slowing the infusion rate from 63

 

      percent with the bolus to 85 percent.

 

                Some of this I think is probably just a

 

      result of the signal of having a relatively smaller

 

      population with the bolus group, but from the

 

      standpoint of the sponsor, are you of the belief

 

      that the slower infusion rate will significantly

 

      reduce the risk of hypersensitivity reactions?

 

                DR. GOECKELER:  I think the issues are

 

      related to risk and management, and I am going to

 

      ask Dr. Page to speak to that, please.

 

                DR. PAGE:  The most telling data about

 

      this are to look, not at all hypersensitivity

 

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

 

      iron product, so that the notion is that any

 

      exposure in the bloodstream is likely to cause some

 

      activation of mediators, so you are going to see

 

                                                               139

 

      some flush.

 

                So I would contend that the notion of

 

      hypersensitivity is probably too broad.  That is

 

      what we are looking at, it is a hypersensitivity

 

      reaction, and in that sense, I agree with the

 

      statement that it is not clear that dilution will

 

      reduce rates of hypersensitivity, but I believe the

 

      data show convincingly that they will reduce severe

 

      both all AEs, as well as hypersensitivity AEs.

 

                In the case of bolus, there were 3 serious

 

      adverse events out of 131 patients.  That is a rate

 

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

 

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

 

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

 

      order difference in the rate of severe adverse

 

      events.  That is one piece of information.

 

                The other is we know that in patients who

 

      are having an immediate hypersensitivity reaction,

 

      you can turn off the infusion, the reaction goes

 

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

 

      not only the accrued rate of all the reactions.

 

      The real question is severe, and the reason is can

 

                                                               140

 

      you intervene.

 

                DR. DYKEWICZ:  The second question, which

 

      actually dovetails with that, and a question that

 

      Dr. Brawley had asked about earlier, is the acute

 

      treatment of the serious hypersensitivity

 

      reactions.

 

                Were any of these patients given

 

      epinephrine?

 

                DR. PAGE:  I believe none were.  Mark,

 

      correct me if I am wrong there.  Some were given

 

      steroids, of course, some were given albuterol in

 

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

 

      epinephrine given.

 

                DR. DYKEWICZ:  Well, this is no indictment

 

      specifically of the sponsor, but for discussion

 

      later, I would raise the point that the treatment

 

      of choice for a serious hypersensitivity reaction

 

      would be epinephrine.

 

                DR. PAGE:  And would you say that is true

 

      if there was no hypotension and on cessation of

 

      infusion, and there is no acute respiratory

 

      compromise?

 

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                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.