FOOD AND DRUG ADMINISTRATION










                                VOLUME I







                        Thursday, March 3, 2005


                               8:05 a.m.



                          Gaithersberg Hilton

                           620 Perry Parkway

                         Gaithersburg, Maryland





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

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

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




      Otis W. Brawley, M.D.

      Ronald M. Bukowski, M.D.

      James H. Doroshow, M.D.

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


      Pamela J. Haylock, RN, Consumer Representative

      Maha H.A. Hussain, M.D.

      Alexandra M. Levine, M.D.

      Joanne E. Mortimer, M.D.

      Michael C. Perry, M.D.

      Gregory H. Reaman, M.D.

      Maria Rodriguez, M.D.





      Marco Amendola, M.D.

      William Bradley, M.D., Ph.D.

      Marion Couch, M.D., Ph.D.

      Ralph D'Agostino, Ph.D.

      Mark Dykewicz, M.D.

      Armando Giuliano, M.D.

      Dennis Ownby, M.D.

      Dana Smetherman, M.D.




      Eugene Kazmierczak - for Combidex and Prostate

      Cancer Endpoints




      Victor DeGruttola, Sc.D.

      Mario Eisenberger, M.D.

      Eric Klein, M.D.

      Lisa McShane, Ph.D.

      Derek Raghavan, M.D., Ph.D.

      Howard Sandler, M.D.

      Howard Scher, M.D.



                        PARTICIPANTS (Continued)


      FDA (A.M. Session)


      Zili Li, M.D., MPH

      Florence Houn, M.D.

      George Mills, M.D.

      Sally Loewke, M.D.


      PARTICIPANTS (Continued)


      FDA (P.M. Session)


      Peter Bross, M.D.

      Patricia Keegan, M.D.

      Bhupinder Mann, MBBS

      Richard Pazdur, M.D.

      Dan Shames, M.D.

      Rajeshwari Sridhara, Ph.D.

      Robert Temple, M.D.

      Grant Williams, M.D.



                            C O N T E N T S




      Call to Order and Introductions

      Silvana Martino, D.O.                                      6


      Conflict of Interest Statement

      Johanna Clifford, M.S., RN                                 9


      Opening Remarks

      George Mills, M.D.                                        11


                          Sponsor Presentation

                        Advanced Magnetics, Inc.


      Combidex, Introduction and Indication

      Mark C. Roessel                                           15


      Mechanism of Action, Combidex

      Appearance on MR Images

      Mukesh Harisinghani, M.D.                                 17


      Efficacy Data from Phase III Clinical Studies

      William Goeckeler, Ph.D.                                  29


      Safety Data from Clinical Trial

      Gerald Faich, M.D.                                        39


      Clinical Utility of Combidex and Various Cancers

      Jelle O. Barentsz, M.D.                                   46


                            FDA Presentation


      Efficacy and Safety of Combidex (NDA 21-115)

      Zili Li, M.D., MPH                                        56


      Questions from the Committee                              88


      Open Public Hearing                                      146


      Committee Discussion                                     167



                      C O N T E N T S (Continued)



                           AFTERNOON SESSION


      Call to Order and Introductions

      Maha Hussain, M.D.                                       204


      Conflict of Interest Statement

      Johanna Clifford, M.S., RN                               207


      Opening Remarks

      Richard Pazdur, M.D.                                     210


      A Regulatory Perspective of Endpoints to

      Measure Safety and Efficacy or Drugs:

      Hormone Refractory Prostate Cancer

      Bhupinder Mann, MBBS                                     216


      Towards a Consensus in Measuring Outcomes

      in New Agents for Prostate Cancer

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


      NCI Prostate Cancer Treatment Trial Portfolio

      Alison Martin, M.D.                                      261


      Toward an Endpoint for Accelerated Approval

      for Clinical Trials in Castration Resistant/

      Hormone Refractory Prostate Cancer

      Howard Scher, M.D.                                       271


      Design of Clinical Trials for Select Patients

      With a Rising PSA Following Primary Therapy

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


      Open Public Hearing                                      330


      Committee Discussion                                     333




                         P R O C E E D I N G S


                    Call to Order and Introductions


                DR. MARTINO:  Good morning, ladies and


      gentlemen. I would like to begin the meeting, if


      you would be so kind as to take your seats.


                The purpose of this morning's meeting is


      to consider a new drug application, the agent


      Combidex from Advanced Magnetics, Incorporated, a


      proposed indication for intravenous administration


      as a Magnetic Resonance Imaging contrast agent to


      assist in the differentiation of metastatic and


      non-metastatic lymph nodes in patients with


      confirmed primary cancer who are at risk for lymph


      node metastases.


                We will start the meeting by having the


      members of the panel introduce themselves, and I


      would like to begin on my left, please.


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


      Deputy Division Director for the Division of


      Medical Imaging and Radiopharmaceutical Drug




                DR. MILLS:  Good morning.  I am George




      Mills, FDA.  I am the Division Director for Medical




                DR. HOUN:  Florence Houn, Office Director,




                DR. LI:  Zili Li, Medical Team Leader,




                MR. KAZMIERCZAK:  Eugene Kazmierczak,


      Patient Consultant to FDA for prostate cancer.


                DR. BUKOWSKI:  Ron Bukowski, Medical


      Oncologist, Cleveland Clinic Foundation.


                DR. BRAWLEY:  Otis Brawley, Medical


      Oncologist and Epidemiologist, Emory University.


                DR. DOROSHOW:  Jim Doroshow, Division of


      Cancer Treatment and Diagnosis, NCI.


                DR. RODRIGUEZ:  Maria Rodriguez, Medical


      Oncologist, M.D. Anderson Cancer Center.


                DR. REAMAN:  Gregory Reaman, Pediatric


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


      and George Washington University.


                DR. MARTINO:  Silvana Martino, Medical


      Oncology, Cancer Institute Medical Group in Santa






                MS. CLIFFORD:  Johanna Clifford, Executive


      Secretary to the Oncology Drugs Advisory Committee.


                DR. HUSSAIN:  Maha Hussain, Medical


      Oncologist, University of Michigan.


                DR. PERRY:  Michael Perry, Medical


      Oncologist, Ellis Fischel Cancer Center, Columbia,




                DR. MORTIMER:  Joanne Mortimer, Medical


      Oncologist, Moores UCSD Cancer Center.


                DR. OWNBY:  Dennis Ownby, Pediatric


      Allergist at Medical College of Georgia.


                DR. D'AGOSTINO:  Ralph D'Agostino,


      Biostatistician from Boston University.




                DR. DYKEWICZ:  Mark Dykewicz, Professor of


      Internal Medicine, Allergy and Immunology, Training


      Program Director, St. Louis University.


                DR. GIULIANO:  Armando Giuliano, Surgical


      Oncologist from Los Angeles.


                DR. BRADLEY:  Bill Bradley.  I am a Neuro


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


                DR. AMENDOLA:  Marco Amendola, Professor




      of Radiology, University of Miami.


                DR. SMETHERMAN:  Dana Smetherman,


      Radiologist, Section Head of Breast Imaging,


      Oschner Clinic.


                DR. COUCH:  Marion Couch, Head and Neck


      Surgeon from the University of North Carolina.


                DR. MARTINO:  If you would all turn off


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


      the committee, please recognize that you need to


      speak into the microphone, and it only works when


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


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


                There is a reasonable amount of echo that


      I still hear in this room.  Can Audiovisual do


      anything more to clarify our sound?  Okay.


                At this point, Ms. Johanna Clifford will


      report on the Conflict of Interests.


                     Conflict of Interest Statement


                MS. CLIFFORD:  The following announcement


      addresses the issue of conflict of interest and is


      made a part of the record to preclude even the


      appearance of such at this meeting.




                Based on the submitted agenda and all


      financial interests reported by the committee


      participants, it has been determined that all


      interests in firms regulated by the Center for Drug


      Evaluation and Research present no potential for an


      appearance of a conflict of interest.


                With respect to the FDA's invited industry


      representative, we would like to disclose that Dr.


      Antonio Grillo-Lopez is participating in this


      meeting as an acting industry representative acting


      on behalf of regulated industry.  Dr. Grillo-Lopez


      is employed by Neoplastic and Autoimmune Disease




                In the event that the discussions involve


      any other products or firms not already on the


      agenda for which an FDA participant has a financial


      interest, the participants are aware of the need to


      exclude themselves from such involvement, and their


      exclusion will be noted for the record.


                With respect to all other participants, we


      ask in the interest of fairness that they address


      any current or previous financial involvement with




      any firm whose products they may wish to comment




                Thank you.




                DR. MARTINO:  Dr. Mills, if you would


      address the group.


                            Opening Remarks


                DR. MILLS:  Thank you, Dr. Martino.


                Good morning, Committee.  The sponsor of


      the application in this morning's session, Advanced


      Magnetics, requests marketing approval of Combidex


      for the proposed indication of assisting in the


      differentiation of metastatic and non-metastatic


      lymph nodes, in patients with confirmed primary


      cancer, who are at risk for lymph node metastases.


                The Agency is asked to consider an


      indication specifically for differentiating


      metastatic from non-metastatic lymph nodes with


      little restriction on the cancer type, clinical


      staging, and whether the patients have been


      previously treated.


                The Agency is in the second review cycle




      for this imaging product.  The first review cycle


      concluded with an approvable action and the sponsor


      was asked to conduct additional studies to address


      issues related to inconsistent efficacy results


      among the differential trials and to provide a


      clearer identification for the conditions of use


      for Combidex.


                In addition, the sponsors were asked to


      address safety issues related to Combidex-induced


      hypersensitivity reactions.


                In today's presentation, the sponsor will


      address these deficiency issues by using data that


      were originally submitted to the Agency, along with


      new information from a published study in the New


      England Journal of Medicine.


                The Agency's presentation today will focus


      on whether the primary analyses that were based on


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


      subjects from the European studies are adequate for


      marketing approval based on the sponsor's proposed


      indications, which reads as follows:


                "Combidex is for the intravenous




      administration as a contrast agent for use with


      MRI.  Combidex can assist in the differentiation of


      metastatic and non-metastatic lymph nodes in


      patients with confirmed primary cancer who are at


      risk for lymph node metastases."


                Today, we will be seeking comments on the


      issues related to the sample size and the adequacy


      of tumor type presentation.  We will be presenting


      the variable efficacy results by the tumor type and


      the size of the lymph nodes.


                We are seeking your opinion as to whether


      these results suggest that the variations in


      efficacy performance of Combidex are related to the


      different tumor types and to different lymph node




                Today, we are seeking your advice on how


      to better define the conditions for use for


      Combidex, assuming the validity of the efficacy


      results, so that use of Combidex can provide


      benefits to patients particularly in affecting


      patient's treatment decisions.  This point is


      particularly important given the risks of




      hypersensitivity reactions associated with




                Lastly, we will be seeking your


      recommendations on what additional data are needed


      if current data are found to be inadequate for the


      marketing approval of Combidex at this time.


                This concludes the Agency's introduction


      to the morning session.


                Thank you, Dr. Martino.


                DR. MARTINO:  Thank you.


                For those of you that are new to the


      committee and are consulting to the committee, the


      final task that we will bring to you is answers to


      certain questions that have been posed to the


      committee by the FDA.  Those are in a written


      format and each of you should have those at your




                They are titled as Discussion and


      Questions, so please recognize that it is very


      specifically to answer those four questions which


      will be the focus of the discussion at the end of


      this morning's presentations.




                At this point, I would like to ask Dr.


      Roessel from the company to introduce their


      speakers and proceed with their presentation.


                There will be an opportunity for questions


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


      that you hold your questions until their


      presentations are completed.


                          Sponsor Presentation


                        Advanced Magnetics, Inc.


                 Combidex, Introduction and Indication


                MR. ROESSEL:  Good morning.  Thank you,


      Madam Chairman, members of the Advisory Committee,




                I am Mark Roessel, Vice President of


      Regulatory Affairs, Advanced Magnetics.


                Today is an important day for us as we


      have been working since 1992 to bring Combidex to


      clinicians and cancer patients.  We are pleased to


      be able to show you today data from controlled


      clinical trials demonstrating the safety and


      efficacy of Combidex and the great potential it has


      for improving imaging in cancer patients.




                We have a number of distinguished


      consultants and speakers here today including


      radiologists, surgeons, oncologists, and they are


      available to answer any questions you may have at


      the end of the meeting.


                I want to bring your attention to the


      indication. It has been read twice already.  It is


      for a differentiation of metastatic and


      non-metastatic lymph nodes in cancer patients.


                Here is the agenda we are going to have in


      our presentation and the key topics.  Dr. Mukesh


      Harisinghani is going to show you the mechanism of


      action of Combidex and how it appears on MR images.


                Dr. William Goeckeler from Cytogen


      Corporation, Vice President of Cytogen, who is our


      marketing partner, is going to present to you data


      from Phase III controlled clinical trials that were


      designed in cooperation with the FDA for approval


      of the agent.


                Dr. Jerry Faich is going to review the


      safety data available, demonstrating that Combidex


      can be safely administered using dilution and






                Finally, Dr. Jelle Barentsz, a clinical


      investigator with Combidex, is going to review with


      you the clinical utility of Combidex in various




                Combidex is a diagnostic tool that


      improves the anatomic imaging that is done every




                Now, I would like to have Mukesh




                     Mechanism of Action, Combidex


                        Appearance on MR Images


                DR. HARISINGHANI:  Good morning, Madam


      Chairman, members of the Committee, ladies and




                What I am going to do in the next couple


      of minutes is to review what are the current


      limitations of lymph node imaging as we practice


      radiology today, also give an overview of how


      Combidex is acting and how it allows us to


      differentiate benign from malignant lymph node, and


      then also show you some examples of how it improves




      sensitivity and specificity for nodal




                So, the question is why do we need to


      image lymph nodes, and I think one needs to


      accurately stage primary cancer, and in doing so,


      it is very important to know what the nodal status




                It is very important to know this


      information to appropriately treat the patients.


      Just to give you an example, in prostate cancer


      patients, if the nodes are found to be metastatic,


      it essentially commits the patients to non-surgical


      modes of therapy.


                We also need to get a sense of prognosis,


      and that is another factor why nodal metastases are


      important.  Again, to give you an example in


      bladder cancer, if the patient is node-positive,


      the five-year survival is way lower than if the


      patient is node-negative.


                The risk of death also increases 20


      percent with each additional node being positive.


                The current lymph node staging as is




      performed today involves non-invasive imaging


      techniques, which essentially incorporates the


      cross-sectional modalities like CT and MR, and the


      other is the invasive modes, which is essentially


      surgery, which are considered to be the gold


      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




                The example on your left is an enlarged




      node in the pelvis, which measures 18 mm and is


      rounded.  No matter which size criterion you use,


      you would label this node as malignant.


                The example on your right is a different


      patient, again a patient with a primary pelvic


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


      measures 5 mm.  Again, no matter which size


      criterion you use, you would label this node as




                But at surgery, it was exactly the


      opposite.  Thus, you can see that size criterion is


      an inaccurate yardstick by which we categorize


      nodes today.


                Morphology has been to a certain extent


      used in conjunction with size criteria


      occasionally, and one of the important morphologic


      features we rely on is presence of fatty hilum, as


      you are seeing here.


                It is said that if the node has a central


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


      we have seen from our experience that even small


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




      this patient with bladder cancer, was biopsy proven


      to be positive and having malignant cells.


                Thus, morphology, too, has its drawbacks


      and when used with size criterion, can be a




                Central necrosis is the other morphologic


      feature which has occasionally been said to be a


      very useful way to allow for diagnosing malignant


      nodes, but it is important to realize that when


      nodes become necrotic, they are enlarged beyond a


      cm, and by size criterion, you would still call


      them positive.


                Well, what about surgery, which is


      considered to be the gold standard, and I am going


      to use prostate cancer as an example, but I think


      the underlying principle can be applied or


      extrapolated to other tumors, as well.


                In prostate cancer, pelvic lymph node


      dissection accompanied by frozen section path


      examination is considered to be the gold standard.


      However, the way lymph nodes are sampled today, at


      the time of surgery in intermediate to high risk




      prostate cancer patients, the standard pelvic


      lymphadenectomy is limited.  This is because the


      surgeon only resects the low external iliac and the


      obturator group of lymph node.


                In the recent or not too recent, in an


      April 2000 study published in the Journal of


      Urology, it was shown that if the surgeon extends


      the lymphadenectomy and takes out the high external


      iliac and the internal iliac nodes, keeping all


      other risk factors the same, the incidence of lymph


      node metastases jumps from 10 to 26 percent, so you


      can see that a potential of 16 percent miss rate if


      one just follows the standard pelvic




                So, that begs that question why don't we


      do that in all the cases, because there is a


      significant morbidity that comes with that


      procedure.  Moreover, it is also important to


      realize that the frozen section analysis can also


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


      all these factors show us the limitations of how


      even when surgery is performed and nodes are




      sampled, there are some limitations.


                Here is an example of a patient who had


      underwent radical prostatectomy, and you can see


      clips where the surgeon has taken out the lymph


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


      lymphadenectomy involves, is the low external iliac


      group of lymph nodes.


                There was a small nod posteriorly in the


      pelvis that was not sampled, and the patient was


      labeled as cured. Eight months later, the patient


      shows back with that node mushrooming into a


      full-blown metastases, and this is a good example


      of how surgical sampling can sometimes be limited


      by what the surgeon can see and samples.


                Thus, there is a current need for a


      non-invasive technique that not only detects, but


      also characterizes lymph nodes with a high level of


      accuracy, not compromising sensitivity for




                It also provides a broad anatomy coverage


      which means you not only look at lymph nodes right


      next to the primary cancer, but also can look at




      lymph nodes in a broad anatomic area beyond the


      confines of the regional distribution.


                That is where I think Combidex, or the


      pharmacologic name ferumoxtran-10, is an excellent


      contrast tool that can be utilized with MR.  This


      is an iron oxide based nanoparticle with a central


      iron oxide coat and a surrounding dextran coating.


                This slide shows how the contrast acts.


      After intravenous injection, the contrast lingers


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


      blood half-life.  It gradually leaks out and then


      is transported to the lymph nodes where it binds to


      the scavenger on macrophages.  Thus, the mechanism


      of action of uptake in the normal nodes is via


      macrophages.  So, if the node is functioning


      normally and has its normal complement of


      macrophages, the contrast would then localize to


      the nodes and turn the normal area of the node




                I would like to emphasize at this point,


      two points in the mechanism of action.  One is the


      contrast is targeting the normal lymph node and




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


      node that is turning dark.


                If you have an area of tumor deposited in


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


      normal functioning macrophages and that area would


      show lack of uptake and continue to stay bright.


                Another important point to remember is


      that this mechanism of action is independent of


      which primary cancer affects the node, and, hence,


      the lack of uptake would be present no matter which


      tumor deposit is present within the lymph node.


                This slide is just to show the technique


      that we use.  Any conventional 1.5 MR system that


      exists today in the community, independent of


      vendor platform, can be used for imaging the MR


      with Combidex, and these are the sequences, again


      nothing fancy, just regular bread and butter




                We can do post-processing, which can


      provide for elegant ways of communicating the


      information, but these are not essential for making


      the diagnosis.




                So, let me show you an example of how the


      Combidex acts in real life.  This is a patient who


      has a known pelvic malignancy.  There are two lymph


      nodes in the groin.  Both are hyper-intense or


      bright on the pre-contrast.


                Twenty-four hours after injection of


      Combidex, you can see the medial node is turning


      homogeneously dark, and that is the node that is


      benign.  The node to the right shows lack of


      uptake, and that means that it's infiltrated with


      cancer and, hence, it is not taking up the




                Let me show you some examples of how


      Combidex scanning improves sensitivity in detecting


      metastases in small lymph nodes.


                This is a patient with prostate cancer


      undergoing staging.  The yellow arrows point to two


      very small nodes next to the external iliac vein.


      Again, by size criterion, you would never call


      these nodes positive.


                On the pre-Combidex scan, you can see


      these two nodes are hyper-intense, and 24 hours




      later after Combidex, the inferior one is turning


      homogeneously dark.  It means that that is benign.


      The one which is pointed by the red arrow shows


      lack of uptake, and that is the one which is


      malignant, which was proven at the time of surgery.


                This is a patient with breast cancer.


      Again, the patient is lying prone.  Here is the


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


      at the axilla.  Again, there are two very small


      nodes in the axilla pointed by the yellow and the


      red arrow, measuring between 3 to 4 mm.


                After giving Combidex, the superior one is


      turning dark as outlined by the yellow arrow, the


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


      update, indicating it's malignant and again proven


      with surgery.


                So, I have shown you how Combidex improves


      sensitivity in different types of primary cancers.


      It is equally important to have enhanced


      specificity, which means if the node is enlarged,


      you need to accurately diagnose it as benign or






                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






                Thank you


             Efficacy Data from Phase III Clinical Studies


                DR. GOECKELER:  Good morning.  I am going


      to review in the next few minutes the efficacy data


      in support of the proposed indication.  The studies


      I will be discussing were designed to evaluate the


      ability of Combidex to improve the differentiation


      of metastatic from non-metastatic lymph nodes,


      particularly in the post-contrast setting.


                To do this, we compare the parameters of


      sensitivity and specificity in both the pre- and


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


      which was conducted in cooperation with the FDA,


      provided for multiple primary tumor types and


      independent blinded evaluations of image sets with


      histopathologic confirmation of the imaging data.


                I think it is worth taking just a step


      back to say that all the imaging data that you will


      be presented this morning by the sponsor involves


      histopathologic confirmation at the individual node


      level, which is a significant undertaking.


                So, in reviewing the efficacy data, I will




      first go over quickly the blind read procedures


      that were used in conducting the analysis of this


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


      studies, talk a little bit about data from


      publication in the New England Journal of Medicine


      that investigated the agent in this application,


      and finally, close by looking at how this


      improvement in differentiation at the nodal level


      impacts clinical nodal staging.


                So, first, the blinded read procedure, and


      there are a number of blinded reads that were


      carried out in each of the clinical studies, so I


      will try to explain the terminology and the


      sequence in which they were conducted.


                All the blinded reads were carried out


      with the readers blinded to clinical, demographic,


      and pathologic information, and the cases were


      presented in random order.


                The readers were first presented with the


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


      images alone, made an assessment on size based.


                You will also see that in some of the




      slides called an MRI-based diagnosis, and then the


      reader made a second assessment based solely on the


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


      skill.  In that subjective evaluation, the reader


      was allowed to use any criteria they thought was


      appropriate in differentiating metastatic from


      non-metastatic lymph nodes.


                Following those readings, the readers were


      presented with the post-contrast images and carried


      out an evaluation of the post-contrast side by side


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


      paired evaluation.  The prospective primary


      endpoint in each of the Phase III studies was a


      comparison of the paired evaluation with the


      pre-contrast size-based evaluation at the nodal




                Next, a period of about two weeks to


      eliminate a recall bias was allowed, and then the


      readers were presented, again in random order, with


      the post-contrast only images, and then made an


      assessment based only on the post-contrast image,


      which is called the post-contrast evaluation.




                Post-contrast images, there were reading


      guidelines developed to assist the reader in


      evaluating the nodal post-contrast images.  They


      were prospectively developed and finalized before


      the blinded read.  Thus, the Phase III blind read


      of images is a valid assessment of nodal images


      across a wide range of cancers.


                This is the study population in the three


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


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


      Journal.  The number of patients dosed and the


      number of patients with histopathology is not


      always the same since eventually, not all patients


      go to surgery for things that happen in the


      intervening time between the imaging session and


      the treatment of the patients.


                This outlines the number of lymph nodes


      that were evaluated in the various studies both


      pre- and post-contrast and a breakdown of where


      those lymph nodes resided by anatomic region in the


      various cancers.


                So, right into the Phase III study, in the




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


      pre-contrast evaluations, both the size and the


      subjective base, we see a high pre-contrast


      sensitivity and a low pre-contrast specificity,


      whereas, in the post-contrast evaluation, the


      paired evaluation, what we see is sensitivity


      remains high at 96 percent, but specificity is


      significantly improved, and the improvement in


      specificity was statistically significant over both


      of the pre-contrast reads and for both of the


      blinded readers.


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


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


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


      pre-contrast analysis, sensitivity was low and


      specificity was high, so sort of just the opposite


      of what was seen in the EU study.


                In the subjective evaluation, we see that


      the subjective reader's assessment resulted in a


      very high sensitivity, but the tradeoff for that


      increase in sensitivity was a large decrease in






                So, the pre-contrast reads had either high


      sensitivity or high specificity, but not both.  In


      the post-contrast reads, you will see that


      sensitivity was high and specificity was high, so


      we had a combination of high sensitivity and high




                You will also note that in the post-only


      read, in which the only image that was available


      was the post-contrast image, resulted in the


      highest level of imaging performance and the


      greatest level of consistency.


                If we take a look for just a minute at


      this discrepancy between the two pre-contrast


      reads, where one had high sensitivity and low


      specificity, and the other was the opposite, if we


      look at the false diagnoses that occurred in these


      various blinded readings, and we look at false


      diagnoses as a percentage of the total, we see that


      the percentage of false diagnoses for both of the


      pre-contrast reads is relatively the same.


                What we see is that in the subjective


      readers' diagnosis with the readers subjectively




      overreading to try to account for the known low


      sensitivity of the size-based analysis, we see a


      very large percentage of false positive reads that


      occur in the subjective readings, whereas, in the


      post-contrast reads, we see a decreased percentage


      of false reads with the lowest and most consistent


      data again in the post-only read.


                This is the data broken out by body


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


      and breast, we saw large increases in sensitivity


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


      maintaining specificity which overall resulted in


      the increase in accuracy.


                In the pelvis and abdomen, we had more


      moderate levels of increase in both sensitivity and


      specificity, the net effect of which is that the


      increase in accuracy in the pelvis and abdomen is


      virtually identical to what one sees in both the


      head and neck and the breast.


                One region that was a little bit different


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


      moderate, small increases in both sensitivity and




      specificity, and we believe this has to do with


      limitations of anatomic imaging in this particular


      body region, and not differential uptake or


      performance of the contrast agent.


                So, turning now to the data published in


      the New England Journal of Medicine, and I think


      this data is important supplemental data that can


      help us understand better some of the differences


      that were seen particularly in the pre-contrast


      reads in the Phase III studies and also can help us


      learn a little bit more about the performance of


      the agent in different size nodes.


                So, this is a study carried out in


      prostate cancer patients at two centers, one in the


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


      There was a centralized independent blinded read


      with histopathologic confirmation of data.


                So, to address some of the issues that I


      just mentioned, I am going to go through the data


      in a little bit of a sequential order.


                First, with regard to the issue of the


      discrepancies in the pre-contrast evaluations and




      also to look at the issue of the effect of nodal


      size on the performance of the contrast agent, what


      you see is as you move across these three studies,


      the distribution of nodes categorized as either


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


      appropriate cut point because as Dr. Harisinghani


      said earlier, that is the point at which we


      differentiate a malignant from a non-malignant




                We see that as we move from the EU to the


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


      proportion of large nodes are greater than 10 mm in


      the yellow, goes from about three-quarters to about


      a third to only 7 percent in the New England


      Journal study.


                We see in the pre-contrast size-based


      sensitivities and specificities, we see that the


      sensitivities and specificities largely track with


      the nodal size.  That is, in studies where there


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


      sensitivity in the pre-contrast evaluation in the


      green bars, which decreases as the proportion of




      large nodes in the study decreases.


                Conversely, as in the purple bars, we see


      that as the percentage of small nodes increases,


      then, the specificity increases also.


                So, finally, in the post-contrast data,


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


      the performance of the agent on the size of


      distribution of the nodes in the study.  We have


      high sensitivity and specificity regardless of the


      distribution of the lymph node sizes that were in


      those studies.


                Finally, just a word about clinical nodal


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


      clinical nodal staging where we could collapse the


      nodal stage in its simplest form to where patients


      were either node positive, node negative, or




                What we see here is a comparison of the


      clinical nodal stage that was assigned based on the


      images compared to the eventual pathologic stage,


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


      post-paired to the post, the percent where the




      agreement was correct increases, the percent where


      it's incorrect decreases, and the percentage that


      could not be staged also decreases.


                So, to sum up, there are two prospective


      Phase III studies.  The pre-contrast evaluations in


      these studies show a characteristic tradeoff of


      sensitivity for specificity. Post-contrast


      evaluations show high sensitivity and high


      specificity, which results in an overall


      improvement in accuracy.


                The improved lymph node differentiation


      improved clinical staging.  The supporting data


      from the New England Journal publication showed


      high sensitivity and specificity in a population of


      largely small lymph nodes.


                Finally, these data collectively


      demonstrate the efficacy of Combidex in


      differentiating metastatic from non-metastatic


      lymph nodes.


                Thank you.  Now, Dr. Faich will review the


      safety data.


                    Safety Data from Clinical Trial




                DR. FAICH:  I am Jerry Faich.  Good


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


                What I would like to do rather briefly is


      review the amount of exposure data that has been


      obtained for Combidex, discuss and show you the


      pattern of adverse events that have occurred, make


      a few comparisons with other agents, and then


      discuss the proposed risk management plan for the




                In total, 2,061 subjects have been dosed


      with Combidex.  Of these, and I would like to


      emphasize this and explain it, 131 received bolus


      injection.  This was in the process of developing


      or exploring the utility of the product for liver


      scanning, which required a bolus injection.  That


      indication and mode of administration has been




                The remaining patients, the remaining


      1,930 patients were dosed with dilution and


      infusion either in 50 ml or 100 ml saline, and


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


      who got the 100 ml dilution.




                For the proposed indication and mode of


      distribution, there were 1,236 patients in the NDA


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


      dilution over 30 minutes.


                This shows you on the left-hand side the


      rate of adverse events in the bolus injection 30


      percent, in the middle 17 percent for 50 ml


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


      100 ml dilution showing a clear dose-response


      relationship in terms of adverse events, and this


      is indeed why the 100 ml dilution has been focused




                It needs to be said that during the bolus


      injection studies, there was one anaphylactic death


      that occurred immediately.  That and the need to


      use bolus injection for liver scanning is what led


      to dropping the pursuit of that indication.


                This shows you in the 1,236 patients the


      pattern and rates of adverse events, you can see


      going from vasodilation at 3.4 percent, rash, back


      pain, pruritus, urticaria, et cetera, overall


      totaling these 15.8 percent.




                I would simply like to emphasize that


      nearly all of these were mild, transient, and




                Within the 1,236 core patients, 5.6


      percent had adverse events from that prior list


      that could be called hypersensitivity events.


      Mainly these were vasodilation.  It included 24


      patients, however, who had more than one symptom


      from that list.


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


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


      adverse event rate is no greater than that found in


      labeling for nonionic iodinated contrast media,


      which ranges from 0.6 to 1.5 percent, and I will


      show you that in a moment.


                There were no life-threatening


      anaphylactic/anaphylactoid reactions at the


      proposed dose and method of administration.


                In terms of immediate adverse events,


      immediate hypersensitivity adverse events can, of


      course, be controlled in large part by stopping the


      infusion.  The most common reaction, as I noted,




      was flushing.


                Thirty-six patients had infusion stopped


      and restarted, that is, these patients were


      rechallenged.  Only two of them could not tolerate


      the rechallenge and were discontinued.  The


      remaining 36 went on to complete their procedure.


                Put a slightly different way, 94 percent


      of all immediate hypersensitivity reactions


      occurred within the first 5 minutes after dosing.


      Most hypersensitivity reactions, as I indicated,


      were mild to moderate in intensity.


                At the proposed dose and method of


      administration, out of the 4 serious AEs, 2 were


      classified as immediate hypersensitivity reactions


      using the FDA definition.  That translates to a


      rate of 1.6 per 1,000.


                In terms of anaphylactoid reactions, again


      using an FDA definition of affecting two body


      systems, there were 12 such patients at the


      proposed dose and method of administration.  Two of


      those were considered serious.


                Four of the 12 were in the group that had




      infusion stopped and then were rechallenged without


      subsequent problems.  The majority of these 12 had


      dyspnea and flushing.  There were no serious


      hypotension or respiratory compromise seen in those


      12 patients.


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


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


      to interpret data carefully when you compare one


      set of data from one set of studies and labels to


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


      your attention to the Combidex data across the top.


                The overall AE rate was 15.8 percent, the


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


      cases I mentioned. If you look down in the


      right-hand column just at serious AEs and compare


      it to other iodinated contrast agents, both from


      data in their labels and published studies, you


      will see for Ultravist, that serious AE rate is 1.1




                For comparators in studies done with


      Ultravist, it was 0.6 percent, for Oxilan it was


      1.5 percent, and for comparators to Oxilan and




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


      a basis or my basis for concluding there is not


      evidence that there is increased risk of serious


      adverse events comparing this drug to commonly used


      iodinated contrast agents.


                There is not much in the literature about


      anaphylaxis in contrast agents.  Here are 2 recent


      studies that have been published.  This is Neugut


      in the Archives of Internal Medicine.  His


      published anaphylaxis rate done from his own


      studies and across the literature was 2 per 1,000


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


      that it might be lower and most people are taking a


      rate of about half that for low osmolality contrast




                David Kaufman, at the Center for


      Epidemiology in Boston, published this paper in


      2003, and for contrast agents, this was an


      international study of anaphylaxis, the observed


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


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


      there was a range as you see here.




                Combidex falls within or at the lower end


      within that range of values.


                In terms of a risk management plan for


      this product, it is largely in keeping with


      existing guidelines and calls for physician


      education, emphasizing the need for dilution and


      slow infusion obviously as a means to be able to


      intervene if a reaction is occurring.  The labeling


      will be consistent with that, and the proposal is


      to conduct targeted surveillance to gather further


      data to reinforce the safety data that I have shown




                To summarize, then, there has been


      considerable clinical exposure in the development


      program.  Hypersensitivity is relatively infrequent


      and comparable to that of other contrast agents,


      and the risk management program that I just


      described is in accordance with existing


      guidelines.  Thank you.


                Dr. Barentsz, please.


            Clinical Utility of Combidex in Various Centers


                DR. BARENTSZ:  Madam Chairman, members of




      the Committee, members of the FDA, I am an


      oncologic radiologist and I have been using


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


      frequent contact with investigators in both the


      U.S. and in Europe.


                From the previous data, you have clearly


      shown that this contrast agent works.  A black


      lymph node is normal, and a white lymph node is


      abnormal.  That is despite the tumors type.


                Nonetheless, evaluating its clinical


      utility is a lot more difficult, and for that you


      need personal experience, as well as post-Phase III


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


      show you the clinical utility and some cancer




                The reviewed publications were all in top


      ranking journals.  It was blinded post-contrast


      image evaluation with gold standard histopathology,


      and all those papers described a potential impact


      on treatment planning.


                The areas being defined where Combidex MRI


      provides a significant clinical benefit were




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


      want to address those issues with you in the next


      10 minutes.


                As you can see, data were collected from


      almost 200 patients and almost 2,000 lymph nodes.


      These are the data on sensitivity and specificity


      and accuracy.


                You can see that the data are highly


      consistent, showing a high sensitivity,


      specificity, and accuracy for all the cancers.


                Now, let's start with the clinical utility


      in prostate cancer.  First of all, you have to


      define the current strategies.  Current imaging has


      an insufficient sensitivity for lymph node staging,


      and therefore, urologists are performing an


      invasive operative surgical lymph node sampling to


      detect the lymph nodes.


                These techniques have limitations, only a


      limited area sampled, and therefore, up to 31


      percent of the positive lymph nodes are outside of


      the surgical area, which have been shown by some


      data recently published in the urology journals.




                Furthermore, surgical sampling has a


      complication rate reported to be 22 percent for the


      open dissection and 5 percent for laparoscopic


      dissection, including lymphocele, lymphedema, deep


      venous thrombosis, pulmonary embolism, nerve


      damage, and blood loss.


                Because of the limitations of current


      imaging technique and current staging techniques


      for the lymph node dissection, these urologists are


      advocating at this moment now an extended lymph


      node dissection.  They state that they will detect


      those lymph nodes, however, this significantly


      increases morbidity.  The question is are the less


      invasive way techniques to solve this problem.


                As you can see, using the post-contrast


      studies of Combidex, there is a dramatic decrease


      of the number of false positives, as well as the


      number of false negatives, but what is even more


      important is that in our study in the New England


      Journal of Medicine, in 6 percent of all the


      patients, we found a small non-enlarged lymph node


      which we could biopsy, and in all those patients,




      we could confirm the diagnosis by image-guided


      biopsy, and these patients did not undergo any


      surgical dissection.


                Furthermore, in 11 percent, we found lymph


      nodes which were outside of the surgical field, so


      they will be missed with regular surgery.


                All these findings were confirmed by the


      surgery because before the operation, we told the


      urologists where the lymph node was, and they could


      then find them.


                I would like to show you two


      representative cases. Here, you see a white lymph


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


      close to the internal iliac artery, which is


      outside of the normal surgical field.  In this


      lymph node, we performed an image-guided biopsy


      which was positive, and in this way a correct


      diagnosis was being evaluated in a less invasive


      manner, and this avoided inappropriate treatment.


      This patient had, instead of a prostatectomy, an


      androgen ablation.


                In another patient, you see a lymph node




      over there with a tiny white structure.  You can


      see it over there.  This was also a lymph node


      outside of the surgical field.  We told our


      urologist where this lymph node was located.  It


      was found and it was confirmed histopathologically


      that this lymph node had a 1-mm metastasis.


                What about bladder cancer?  It is actually


      the same story.  In 24 percent of positive lymph


      nodes, there are positive lymph nodes in 24 percent


      despite negative pre-operative imaging techniques.


                The presence of lymph nodes radically


      changes the treatment option especially if there is


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


      so finding these lymph nodes also here is very




                If you perform an extended lymph node


      dissection, you detect more lymph node, it will


      increase survival for minimal disease, however,


      also in this extended lymph node dissections, not


      all lymph nodes have been sampled. Furthermore,


      this increases morbidity.


                These are the data in 172 lymph nodes in




      58 patients from a Radiology paper, and it has been


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


      12 were detected using Combidex MRI, and this


      information was crucial for the surgeon to find


      these lymph nodes, and they were removed.


                Most important areas, also head and neck.


      The survival rates depends on whether the tumor has


      metastasis in lymph nodes or not.  Therefore, the


      status of cervical lymph nodes is vital for the


      choice of therapy.


                Twenty-five percent of positive lymph


      nodes are found despite negative preoperative


      imaging techniques like contrast CT or


      ultrasound-guided biopsy.  Why?  Because these


      lymph nodes are below normal size criteria.  They


      are only 5 to 10 mm in size.


                Because of the fact that these lymph nodes


      do not show up with imaging, head and neck surgeons


      perform commonly a radical neck dissection, which


      causes a very severe cosmetic deformity and has a


      very high complication rate, in literature reported


      up to 54 percent.




                The data from Mack, et al. in Radiology


      show a very high sensitivity and negative


      predictive value, and furthermore, what is more


      important, if you look on a patient level, they


      were able to make an accurate diagnosis in 26 out


      of 27 patients, and what is the most important


      thing is that this information would have resulted


      in reduced extent of surgery in 26 percent of these


      patients, so avoiding an aggressive neck




                One representative image.  This was a


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


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


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


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


      In this patient, a neck dissection could have been




                Finally, breast cancer.  The commonly used


      staging procedure at this moment is the sentinel


      lymph node staging, which has false negative


      numbers of 3 to 10 percent, and is an invasive


      technique, but what is even more important is that




      recent data have shown that the sentinel lymph node


      is the only positive lymph node in 61 percent in


      patients with positive lymph nodes.


                Nonetheless, these patients all undergo an


      axillary lymph node dissection, and this has a high


      rate of clinically significant complications.


                A technique with a high negative


      predictive value performed in an adjunct to the


      sentinel lymph node procedure in patients with one


      positive sentinel lymph node may reduce the number


      of axillary lymph node dissections.


                These are the published data in almost 300


      patients by Michel in Switzerland, and you can see


      that this technique has a high negative predictive




                I would like to show you one


      representative case from our institution.  This is


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


      positive sample on lymph nodes.  This lymph node is


      white on Combidex, so that means metastatic, and


      you can see that the second and third station lymph


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




      the other lymph nodes were black, which in this


      case was confirmed by histopathology.


                Now, to the final conclusion.  I have


      tried to show you some areas of clinical utility of


      this contrast agent, and as soon as we get more


      experience, there will be a lot more areas.


                To summarize, the current techniques to


      detect positive lymph nodes in prostate, bladder,


      head and neck, and breast cancer have significant




                Combidex MRI shows high sensitivity and


      specificity not only on the nodal basis, but also


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


      clinician is even more important.


                Therefore, Combidex MRI may reduce the


      extent of surgery and morbidity, and finally,


      Combidex MRI identifies additional positive lymph


      nodes for biopsy or image-guided extended lymph


      node dissection in this way improving the staging


      of the surgeon.


                Thank you.


                MR. ROESSEL:  Thank you.  That concludes




      our presentation.


                Our clinical data and the clinicians I


      think have shown you that Combidex is an important


      diagnostic imaging tool that improves the current




                Thank you.  We are available for any


      questions you have.


                DR. MARTINO:  Thank you.


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


      present his view of this data, and once that is


      done, we then will take questions for both the


      sponsor and the FDA.


                            FDA Presentation


              Efficacy and Safety of Combidex (NDA 21-115)


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


      ladies and gentlemen, good morning.  My name is


      Zili Li.  I am a medical team leader with the


      Division of Medical Imaging and Radiopharmaceutical


      Drug Products at FDA.  I am a board-certified


      physician in preventive medicine with special


      training in epidemiology.


                Today, I would like to share with you our




      review of findings of NDA Application 21-115




                I would like to start off by noting that


      this presentation represents a collaborative effort


      by a group of highly dedicated reviewers at FDA


      whose names are on this list.


                Combidex is an MR contrast agent.  The


      proposed clinical dose is 2.6 milligram iron per


      kilo of body weight.


                Of three methods of administration which


      has been used in the clinical development program,


      the sponsor select the dilution in 100 cc with the


      slow infusion over 30 minutes of a standard measure


      of administration.


                The other two methods, particularly the


      direct injection, is no longer being proposed.


                This slide summarized the indication that


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


      one more time--that Combidex can assist in the


      differentiation of metastatic and non-metastatic


      lymph nodes in patients with confirmed primary


      cancer who are at risk for lymph node metastases.




                I would like to draw your attention to the


      fact that this is a broad indication.  If granted,


      this agent can be used for almost all cancers


      regardless of type, size, clinical stage, whether


      patient has been previously treated with drug,


      biologic, radiation, or surgery.


                One objective of today's presentation is


      to show you why the Agency has concerns for such a


      wide or broad indication given the level of


      efficacy and safety observed from clinical trials.


                To support this indication, the sponsor


      submit one U.S. and three European Phase III


      studies.  In addition, sponsor also ask Agency to


      consider data from a published article in the New


      England Journal of Medicine.


                For the safety, the sponsor submitted a


      safety data adverse event profile in particular


      from approximately 2,000 individuals who received


      Combidex from multiple clinical studies.


                I would like to make a remark on this New


      England Journal of Medicine article.  This study is


      pooled analysis from two ongoing clinical studies. 




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


      other study is non-IND study and in Europe.


                The clinical investigators themselves took


      initiative to combine 40 cancer patients from each


      original study to form the basis for this New


      England Journal of Medicine study.  At this time,


      however, it is unclear to us how those 80 patients


      were selected, and more important, after repeat


      requests, the sponsor is not able to provide us the


      original source document which included pre-defined


      statistical plan, blind reader evaluation manual,


      and original copy of blind readers' evaluation of


      the medical imaging.


                For that reason, the Agency cannot


      conclude this study was conducted in compliance


      with the Federal regulations pertaining new drug


      application.  For that reason, we are not able to


      consider this study as adequate and well-controlled




                However, the Agency do agree that the


      cases present in this article may demonstrate some


      potential the benefit of the use of Combidex in a




      clinical setting.


                I also would like to draw your attention,


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


      got update from sponsor yesterday.  This study is


      closed at this time. Roughly, they have 220


      patients enrolled including 91 prostate cancer and


      34 bladder cancer patients.


                Although the original protocol require all


      the pathology confirmation and MR imaging for all


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


      how many patients for this study will have both


      information available for a meaningful analysis for


      efficacy if such analysis is needed.


                Now, I would like to first highlight the


      differences between sponsor and the Agency's final


      conclusion regarding efficacy and for safety.


                As far as for the efficacy, the sponsor


      believes the non-contrast MR agent only offer high


      sensitivity or high specificity, but not both.  The


      advantage of this Combidex is its ability to offer


      both high sensitivity and specificity consistently


      regardless type of cancer or size of the lymph






                At this time, the Agency is not able to


      draw such a conclusion because of the


      generalizability and validity issues we are going


      to show you in the later presentation, and also in


      the later presentation, we are going to show some


      preliminary evidence which may suggest the


      performance of Combidex may vary by size or type of




                For the safety, sponsor acknowledge that


      Combidex is associated with hypersensitivity


      reaction, however, their emphasis is that no death


      or life-threatening AEs are associated with the


      proposed clinical method of administration.  That


      is the dilution with the slow infusion.


                Also, I just noticed in the sponsor's


      presentation is new to us that they make a claim


      that this agent's safety profile is equivalent to


      the iodinated contrast agent.  I believe in your


      briefing document, they also made a claim that


      serious adverse event with the Combidex is only


      one-third of that iodinated contrast agent.




                Our position is that dilution and slow


      infusion are not entirely free, and also we


      disagree that the Combidex, the safety profile


      resemble that of iodinated contrast agent.


                This slide highlights the issues we are


      going to bring to the panel today.  For the


      efficacy, we are going to talk about sample size.


      We are going to talk about representation of


      different tumor types in the clinical study.


                We are also going to talk about impact of


      study inclusion/exclusion criteria.  Later, the


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


      Combidex imaging guidance, which was the major


      issue in our briefing documentation to you.


                For safety, we are going to talk about the


      hypersensitivity reaction.  We are also going to


      make a comparison with iodinated contrast agent.


                Then, we are going to follow up with the


      discussion of risk-benefit ratio, including the


      sponsor's proposed risk management plan and our


      emphasis on the need to understand, to define the


      conditions of use for this product.




                From the sponsor's presentation, it was


      stated that total 152 U.S. patients and 181


      patients from a European study received Combidex


      injection, however, what was not apparent on their


      slide was the number of patients who were actually


      included in the primary analysis.  What we are


      showing you is, because there are two different


      blind readers, so they may see the different people


      different, so the number may vary slightly.


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


      percent of original total population were actually


      involved in the final analysis.  For the European


      studies, the number varies from zero, 16 percent,


      roughly 20 percent to 41 percent.  It only


      represent a small proportion of the patients who


      originally received the Combidex.


                I need to make a clarification for the


      study with zero participation.  This is a breast


      cancer study.  You probably read our briefing


      document.  The original statistical plan for the


      European study is on the patient basis.  It is


      totally different from what they did here.  So, for




      that reason, the individual nodal level analysis


      was never performed, so those people cannot include


      in their primary analysis and consistent with U.S.


      statistical plan.


                The small number of patients or small


      proportion of patients included in the primary


      analysis create two dilemmas for us.  The first, we


      need to understand whether the estimate we got from


      this population is applicable to entire population.


                The second one is because of the small


      number of patients, we want to ensure that the


      patients included in the analysis more represent


      the cancer patient distribution in the United




                This is the second issue we would like to


      bring to your attention.


                Based on the statistic provided by


      American Cancer Society, it is estimated this year,


      2005, there is going to be 1.4 million new cancer


      diagnosed.  The left two column showed you the rank


      of the top 10 cancers and also showed their


      percentage distribution in the United States.  I




      need to mention that lymphoma or leukemia are not


      included in this table.


                On the right two columns show the number


      of patients and their distribution for each type of


      cancer included in the primary analysis.  I would


      like to bring your attention to the fact they have


      two readers.  In this slide, we pick the highest


      number in this table.


                You probably noticed that the majority of


      patients come from head and neck, which is ranked


      roughly number 6 in the frequency distribution, and


      also you probably noticed that prostate cancer


      being the number one in the United States.  There


      is only 5 patients from the United States and 5


      patients from Europe was included in the primary


      analysis, and the highest number each category is


      only in here is 37.


                Also, I need to remind you that for


      European study, the sponsor showed you the majority


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


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


      there is no nodes like the 10 mm for the European




      study for this population, particularly this head


      and neck what I referred to.


                So, you probably will ask why that so many


      patients are not included in the primary analysis.


      I would like to bring your attention to the fact


      the primary analysis was conduct at the nodal


      level, so the target lymph nodes, which should be


      included in the analysis, is represented here, the


      large circle here, is all the lymph nodes


      visualized by site investigators.


                When patient enrolled, when they take MR,


      site investigator looked at the MR to circle the


      node they see on those MR images.  That should form


      the basis for primary analysis.  However, not all


      the nodes was able to match with pathology, so you


      drop some nodes right over there.


                Then, when you present the same images,


      the unmarked images to blinded reader, the blinded


      reader may not pick up the same nodes the original


      investigator picked in the first place, so you drop


      some nodes over there.


                Then, for the comparison purpose, because




      they want to compare the post-images with the


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


      identified on both end, so for that reason, you


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


      nodes included in the analysis is much smaller than


      the nodes originally seen by site investigator




                This table actually show you the


      deposition of how the nodes got lost with each


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


      patients.  The first row showed you number of nodes


      originally visualized by the site investigator,


      which should form the basis for primary analysis -


      371, 834, 333, and 234.


                This row showed you what percentage of


      those nodes have matched pathology, and this row,


      the final one, showed you what number, how many


      nodes were actually included in the primary


      analysis.  You can see it is roughly from 3


      percent, 6 percent, to 45 percent of nodes was


      originally seen is included in the primary






                The fundamental assumption for this


      clinical development program is that the


      performance of Combidex should be independent from


      the type of cancer and the size of lymph nodes.


      That was why originally that was allowed for


      different cancer patients included in the one




                However, if you look at this performance


      of Combidex, by different type of cancer, you will


      see, first, this is the sensitivity slide.  You


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


      to 100 depending on the site of primary cancer, and


      the 95 percent of the lower boundary could go as


      low as 55 percent.


                Only if you are willing to accept


      assumption that Combidex performance is independent


      of sites, you get 83 percent performance with the


      lower boundary 73.  That is exactly the reason why


      the Agency was so worried about small lymph nodes,


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


      know whether it's a variation because of the random


      event, or if it truly reflects the different




      performance of Combidex among the different type of




                This is the same table for the


      specificity, which again challenge assumption


      whether the Combidex, the performance should be


      considered or accepted independent from the type of




                You notice depending on the different


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


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


      significance of the two slides is that with dose


      variation we will have a very hard time to


      understand what is appropriate performance


      characteristic of this Combidex-enhanced MR


      contrast agent, and if indeed the performance are


      different, if this drug is approved for all the


      cancers, this information may be misused by the


      clinician to make their clinical judgment.


                The next issue is about study


      inclusion/exclusion criteria.  I will go very fast.


      Basically, for this study, the people who received


      treatment, chemotherapy or radiation therapy in the




      past 6 months was excluded.


                Actually, in reality, when you look at the


      people included in the primary analysis, I don't


      think any of them had any prior treatment, so


      mainly this database, we believe, if valid, only


      applied to people who are newly diagnosed patients.


                This is issue about development of a


      clinical MR imaging guidance.  Why is this imaging


      guidance so important?  It is because for the


      radiation to use this contrast agent, you need to


      have a standard way to interpret imaging.  So, we


      work with sponsor to ask them to come with the




                So, this actually, the clinical trial is


      actually to validate the guidance for this validity


      and usefulness, however, originally, from the NDA


      submission, it appeared to suggest this guidance


      was developed and validated from the same database.


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


      for us because basically, if that is true, that


      destroyed independence of this guidance themself.


                Later on when we spoke to sponsor, they




      provided us a revised statement.  Basically, the


      guidance was developed by use of Phase II images,


      it is not Phase III.


                Sponsor's consultant, when she developed


      this guidance, she did look at the 16 cases from


      Phase III trials, however, no pathology was


      provided, and also, there was a statement that


      there is no more changes for the guidance after


      review of Phase III data.


                To support their statement, sponsor did


      submit original soft document to FDA for our


      verification.  We also had extensive discussion


      with their consultant to recall what happening on


      that day for the development of a Combidex imaging




                All we conclude at this time is that,


      first, we do not have definitive evidence to


      absolutely exclude the probability that Phase III


      data has no impact in this guidance development,


      however, the evidence provided by the sponsor is


      consistent with this revised statement, therefore,


      at this time, we decided not to pursue this issue




      any further unless there is new evidence emerge.


                The second issue we are having, which I


      will present was included in our briefing document,


      is in the European study, this guidance, the core


      instrument actually was not used by the blinded


      reader.  The blinded reader was using a different


      guidance to make their diagnosis.


                At this time, the sponsor is not able to


      provide any documentation for us to understand


      which method or who actually do the translation


      from this guidance and to this one.  Actually, the


      question we are having for the committee,


      especially for people expert in MR imaging, is


      whether the similarity or correlation between these


      two guidance is so great, the Agency should not


      worry about who did it and with all this




                Now, I would like to switch to the safety


      side of Combidex evaluation.  I will focus my


      presentation in Combidex-induced hypersensitivity




                There is one case hypersensitivity-related




      death in a clinical development program.  This is a


      70-year-old male with history of allergy to


      contrast, who received undiluted direct injection


      and developed hypersensitivity reaction immediately


      after injection and become unresponsive.


                At the clinical site, however, there were


      no appropriate personnel or emergency response


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


      arrived, they delivered CPR and epinephrine.  When


      the patient get to the hospital, patient was


      pronounced dead approximately 35 minutes after this


      injection.  An autopsy revealed no MI or PE, and


      they conclude this is a Combidex-related


      anaphylactic shock.


                I would like to make two points here.


      This injection is no longer being used.  The second


      one, we are really concerned about the lack of


      appropriate personnel for emergency situations


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


      effective, there is many free-standing clinical


      imaging centers around the country, so we need to


      have a way to ensure this drug to be used




      appropriately.  That is with assumption that if


      this study is valid and the drug is safe.


                This table shows the distribution of the


      safety database or number of patients by


      administration and by the dose.  There are a total


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


      patients received proposed clinical dose, 131


      patients received bolus injection.  Those three


      groups will form the comparison for our next few




                This slide shows the rate and severe


      hypersensitivity reactions by the three different


      subgroups I just mentioned to you.  For the


      clinical proposed dose, the rate of


      hypersensitivity reaction is 5.3.  For direct


      injection, it is 6.1.


                I would like to let you know that in your


      briefing document, this number is slightly higher


      because we just discovered some computer error, so


      made correction on this slide.


                People may define the severity


      differently, so we use few indicators to give you a




      range of severity, so you can pick which one is


      appropriate for you.  The first one is death.  The


      second one is serious events, which was the event


      that meet the regulatory definition for serious


      adverse event.


                The next one is hypersensitivity involve


      at least two body systems.  The next one is the


      patient was treated with antihistamine.  The last


      one is the patient treated with steroid.  Most of


      them are IV steroid.


                If you look at this population, there is


      no deaths.  There is two cases the sponsor point to


      you meet the definition of serious event.  There is


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


      percent, of people treated with antihistamine, and


      1.5 percent of people need IV steroids.


                This slide outline the presenting symptoms


      of hypersensitivity reactions.  We work extensively


      with our internal expert at FDA.  We define


      hypersensitivity reaction with the following three


      groups of symptoms.


                First, is skin reaction.  The second group




      with the respiratory difficulty with cardiovascular


      symptoms together.  The third one with the facial,


      laryngeal, and general edema.  This table show the


      distribution of the patient presentation.


                You will notice the majority of patients


      present with skin symptoms, however, this slide


      does show that direct injection, they may associate


      with a high percentage of people with more severe




                This is a slide I would like to bring to


      your attention with a comparison with iodinated


      contrast agent. The sponsor told you that there


      were 4 cases serious AE happened in the clinical


      program.  That was an incorrect statement.  In


      reality, there was 29 serious events happened in


      the clinical program.


                The reason for include there, because the


      25 cases, the Agency do not consider is drug


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




                In the comparator, iodinated contrast


      agents in their Table 9 safety presentation, they




      are including all SAEs regardless whether drug


      related, so that is we believe incorrect


      comparison.  So, that is why the number of events


      in Combidex group is smaller than the iodinated




                This table, we focus on the


      hypersensitivity reaction between Combidex and the


      iodinated contrast agent.  If you read the labels,


      three labels which have clinical data for iodinated


      contrast agents, totaled together there are 4,545


      patients received iodinated contrast agent.  There


      is no death happening.  For Combidex, there is 1


      death of all the people receive Combidex.  There is


      zero out of 1,000 who has clinical dose.


                For the serious AE, which is associated


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


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


      cases for the clinical proposed dose.


                Also, the last one, the column, we show


      the percent distribution of those symptoms suggests


      hypersensitivity reaction, you can see the rate is


      quite different, the relative risk is quite




      different.  We do not want to draw definite


      conclusion over here because we understand the


      population are different, but at least this table


      do not support this two rate are comparable.


                When you talk about whether the drug is


      appropriate for populations, you basically talk


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


      presentation, they believe the best way to manage


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


      will show you their risk management slides later.


                From our end, we believe from the safety


      data we have at this time, this drug is definitely


      associated with hypersensitivity reaction.


      Although we have not observed serious event, more


      serious event including death in the proposed


      clinical dose, our level of assurance is limited by


      the number of patients involved in that group of


      patients who received the clinical dose.


                At this time, we are only able to say that


      the death-related hypersensitivity reaction


      probably will now be higher than 1 out of 400 or


      500 people based on data. Anything beyond that,




      that is purely speculation without any data.


                Sponsor present to you their risk


      management program.  I rearranged our slides.


      Basically, they say if we provided dilution and


      slow infusion, and educate physicians to the


      labeling and to the targeting academic center, they


      should be able to adequately address the safety




                We believe this is item we need to discuss


      to implement, and also we believe that with


      uncertainty with those severe events with this


      Combidex administration, when you focus on the


      issues, enhance the benefit of this drug to the


      appropriate population.


                We need to better understand actually the


      performance of Combidex by different type of tumor


      and the nodal size, because we have preliminary


      evidence those performance may vary.  Also, we need


      to define appropriate patient population or


      condition for use, that the use of Combidex, the


      benefit will outweigh the risk, potential risk.


                This is a table to support our preliminary




      conclusion that performance of Combidex may vary by


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


      cancer.  This analysis actually was conducted by


      sponsor.  We didn't make any modification to their


      slides.  We just presented their slides, their


      result to you.


                On the top is for the nodes less than 10


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


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


      sensitivity from their clinical database is between


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




                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






                This table showed you the prevalence of


      nodes being positive by size of lymph nodes.  Why


      this information is important is because the


      sponsor showed you the positive predictive value


      and the negative predictive value in their




                To better understand that positive and


      negative predictive value, you not only need to


      understand the performance, that is, sensitivity


      and specificity of agent, you also need to know the


      prior probability that the prevalence of this node


      being positive before you give a drug.


                This data collected from their studies,


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


      the MR imaging measurement, so we have to use the


      pathology measurement as a surrogate over here.


      For nodes less than 10, the prevalence range from


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


      than 10 mm, the probability that the nodes be


      cancer-positive range from 10 to 20 percent from


      this data.




                If the nodes are more than 10 mm, then,


      the probability from 34 to 60 percent depending on


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




                Also, you probably reviewed the New


      England Journal of Medicine.  From their study, the


      percentage is even higher.  They got 75 percent of


      people for the nodes larger than 10 has a cancer.


                So, how are we going to put all this


      information together to understand or to help us to


      understand the value of Combidex to help physicians


      in their patient care decisionmaking, or for any


      other benefit that they believe is good for




                I will present to you the predictive


      values of a positive or negative Combidex test.  I


      will go over slowly with you.  For the lymph nodes


      less than 10 mm, the sensitivity is 68, the


      specificity is 80.  We make this assumption.  This


      has not been demonstrated by data yet, because the


      lymph nodes, the number are too small, but we


      assume if this is what we observed.




                The prevalence tell you what is the


      probability  the nodes is cancer, whether they are


      cancer-positive nodes before you give Combidex.


      The positive predictive value really tell you after


      you give Combidex, and if you get a positive


      result, what is the probability that node is


      metastatic at that time.


                The negative predictive value tell you if


      you gave Combidex, and the result is negative, what


      is the probability that node is negative.


                We look at different scenarios.  If the


      prevalence is 1, based on data or based on your


      suspicion, the clinical knowledge, if you are


      thinking the node, the probability of metastasis is


      only 1 percent, based on this performance, even


      Combidex is positive, the probability that nodes


      being positive is only 3 percent, so the people


      should make their own judgment this kind of


      improvement where they have clinical implication or


      values to help you to make decision to the patient




                When the prevalence get into 10, 25




      percent, you see big changes here in the


      probability, and this probably will getting higher


      if sensitivity and specificity get improved, which


      means that after you get a Combidex test, these


      nodes more likely become cancer.  You may go ahead


      to biopsy that one to confirm your suspicion.


                However, the positive predictive value is


      not that high enough, so we believe with this


      probability or likelihood, you will never make


      final diagnosis based on the Combidex positive


      result only, so most likely you will go to biopsy


      to confirm it.


                So, we do believe for nodes less than 10,


      there might be potential values for Combidex if


      performance is constantly demonstrated to help


      physicians to select nodes for further evaluation,


      to help patients to make some decision.


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


      already heard from sponsor for those nodes, most


      physicians will already consider is metastatic


      cancer, so for those nodes more than 10, most


      likely you will proceed with biopsy anyway without






                The question you probably can ask yourself


      in that scenario is if I get negative results from


      Combidex, is that going to prevent me from going to


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


      the answer can vary depending on what is the


      pre-probability, how likely that nodes being


      positive before you give Combidex.


                Before Combidex, if the probabilities are


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


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


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


      my previous presentation, the probability already


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


      if you get a negative result, you only get 80


      percent assurance that the node is negative.  You


      still have 20 percent probability the nodes become


      positive, so maybe in that scenario, most


      physicians probably would still go ahead to do a


      biopsy for nodes even Combidex is negative.


                So, for that reason, we are seeking your


      advice to see how we can understand the values of




      Combidex for nodes more than 10 mm for helping




                Also, where you would emphasize what my


      assumption here is based on the performance and


      which we believe has not constantly demonstrated


      from a clinical development program.


                So, based on everything I present today is


      we believe or the data seem to suggest that


      Combidex may not have a value for people with a low


      risk, that patients with lymph nodes larger than


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


      be substituted for the confirmation.  Also, we


      believe there probably is not a good surveillance


      of the recurrence of cancer, because that


      population was not studied.


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


      so that is why we are really concerned with the


      general indication. So, the key question we ask


      ourself, we are seeking your advice is how the


      Combidex result will really benefit to patients.


                We don't want to leave you a wrong


      impression that FDA do not care about knowing the




      nodes, whether positive or not, we care greatly,


      however, there is non-contrast agent available.  We


      try to understand what is additional value with


      Combidex to bring it to the table in addition to


      the non-contrast agent.


                We also understand this test cannot be


      used as confirmatory test, so we try to understand


      what role this will play to help a physician help


      their patients.


                We also understand this drug may associate


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


      clear the use of this drug in appropriate


      populations, the benefit with risk.


                In the later discussion with the sponsor,


      sponsor proposes four types of cancer which might


      benefit, that Combidex may have a beneficial effect


      to the patient, and they also presented those


      cancers in their presentation.


                For the prostate cancer first, I said


      earlier the Agency do believe for nodes less than


      10, Combidex may have a potential value, however,


      we are struggling with the fact there is only 5




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


      study included in the primary analysis, and the


      estimate is so unstable from the data I just showed


      you, we just have no clear understanding what is


      the true performance of the Combidex for that




                Also, the same concern applied to bladder


      cancer, breast cancer, and in less degree to head


      and neck cancer, because they have more patients,


      but I would like to bring your attention again for


      head and neck cancer, most of nodes in European


      trial, actually, all the nodes in European trial is


      more than 10.


                So, with that, I will conclude my


      presentation.  Thank you very much for your


      attention.  We are looking forward for your


      guidance to help us to determine the efficacy and


      safety of this product.


                DR. MARTINO:  Thank you, Dr. Li.


                      Questions from the Committee


                DR. MARTINO:  At this point, I will turn


      to the committee and give you the opportunity to




      ask questions both of the sponsor, as well as of


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


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


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


      will acknowledge you in turn.


                I would like to ask the first question.  I


      would like the sponsor to make it clearer to me how


      they actually looked at the MRIs.  I am still not


      entirely clear what they did first, what they did


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


      were they a specific group of radiologists, were


      there any radiologists, please clarify those issues


      for me.


                DR. GOECKELER:  Let me start by saying the


      question with regard to who made the diagnoses, the


      order in which that was done was shown in the


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


      and those diagnoses were committed to.  Then, there


      was the paired, and then after some time there was


      the post-only.


                In terms of who did that, are you


      referring to the specific specialty of the




      radiologist involved?


                DR. MARTINO:  No, I am trying to figure


      out did you have two radiologists that looked at


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


      am trying to understand that element.


                DR. GOECKELER:  I will address that, thank




                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




                DR. GOECKELER:  I am going to ask Mark


      Roessel to speak to that issue a little bit in


      terms of how the radiologists, what they were


      actually asked to do on each of the blinded reads.


                MR. ROESSEL:  The blinded readers were




      given training and given the guidelines to evaluate


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


      The nodes were not marked on the images, so they


      saw the pre-contrast images and any nodes they


      identified, they circled, and they made a




                Then, on the paired evaluation, they did


      the same thing.  They circled the nodes.  But the


      nodes were not pre-identified on the images.  The


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


      if we circled the nodes that we had pathology on,


      that that would bias the readers, so the images


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


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


      and gave their diagnosis.


                Does that answer the question?


                DR. MARTINO:  It does.  What constituted


      the denominator for pathology, then, it was the


      node as seen post-contrast?


                DR. GOECKELER:  Well, as Dr. Li indicated


      on his slide, one of the reasons that these


      patients and nodes drop out along the way is that




      the two readings were done on unmarked images, and


      then the nodes were also taken out just according


      to standard surgical procedures.


                So, then, after all those readings were


      done, and then the readings had to be matched to


      the pathology, so in order to be evaluable at the


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


      the pre-contrast image and then identified and read


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




                So, when you impose those sequential


      conditions for unmarked images, that is why some of


      the nodes fall out along the way.


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


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


      non-contrast, also seen on contrast, and pathology


      done.  That, then, constituted the denominator.  Am


      I clear on that?


                DR. GOECKELER:  Yes, ma'am.


                DR. MARTINO:  Dr. D'Agostino.


                DR. D'AGOSTINO:  I have a couple of


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




                If you look at Slide 9 on the sponsor's


      presentation, this is page 5 of the handout.


                DR. GOECKELER:  Is it possible to get that




                MR. ROESSEL:  Yes.


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


      presentation, I am sorry, the efficacy analysis.


                DR. GOECKELER:  Could you help us with the


      title, what it says on the slide?


                DR. D'AGOSTINO:  Slide 9 is Nodal


      Analysis, U.S., Phase III.


                DR. GOECKELER:  Is this the slide you are


      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




                What I am interested in, in this here, is


      how big were these confidence intervals if you


      looked at, say, the post-contrasts and compared


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




      certainly the sensitivity doesn't change or they


      would overlap.


                Is there a real differentiation between


      the specificity or are the confidence intervals so


      large that it gets blurred?


                DR. GOECKELER:  I believe we have a slide


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


      can obtain it, and if someone could pull that data


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


      sitting right here this minute.  I believe it was


      in either the briefing book or if someone could


      pull the data.


                If you give me just a minute, I can


      provide you the answer to that question.  Perhaps


      we could take another one.


                DR. D'AGOSTINO:  The other question is,


      you know, the second question that follows is, as


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


      this sheet here, how do you make a statement or


      what kind of statement can be made from the


      statistics point of view, and then hopefully from a


      substantive point of view, that it makes sense to




      pool these different body regions, because it seems


      to me in terms of the questions that are asked


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


      has to be such a small number of nodes involved,


      and such a small number of subjects, that the


      inferences are really going to be almost




                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






                Well, with regard to the specific body


      regions, then, the study obviously was carried out


      in a mixed populations of patients, and I think


      that obviously, if you start splitting out a large


      number of subgroups, the confidence intervals for


      any given subgroup increase.


                I think that looking at the study as a


      whole, which was designed to evaluate the premise


      of differentiation of lymph nodes, obviously, that


      occurred. With regard to the subgroups, I think


      what is important is that there are consistent


      trends amongst those subgroups based on the


      mechanism of action of the drug.


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


      couple more questions, I obviously don't want to


      tie up everything here.


                In terms of the post-contrast, we were


      told in the last presentation that not all the


      nodes were actually used because you want to have a


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




                Was any analysis done on the nodes that




      didn't enter into the post?


                DR. GOECKELER:  Yes, there was a separate


      analysis that was done called the "blinded


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


      described to you, but it involved a much higher


      percentage of the total nodes.


                So, it was again a blinded reading of the


      nodes, and there was histopathologic correlation of


      the data at the nodal level for each of the


      readings, and I can show you--


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


      see what the sensitivity and specificity was.


                DR. GOECKELER:  --what happened in those.


                Can you first show the data in terms of


      the numbers of patients that were evaluated both in


      the unmarked images and in the blinded overread?


                These are the numbers that were evaluated


      by each reader in the blinded overread, and you can


      see, based on the various reads, the number of


      nodes that were read and for which there was


      histopathologic confirmation for each reader and in


      each diagnosis.




                DR. D'AGOSTINO:  Do you have the


      sensitivity and specificity?


                DR. GOECKELER:  Can you show me the data


      on false diagnoses in this, because that


      essentially relates to, and we can go back then?


      If you have a slide on sensitivity and specificity,


      I think you do.


                This is the data on the false diagnoses


      that occurred in the larger reading population.


      You can see the trends are largely the same as we


      saw before, about 15 percent with the post-contrast


      reads, and 25 percent are slightly higher.


                We did see a higher variability between


      blinded readers and the blinded overread for the


      individual readers.


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


      the sensitivity and the specificity and the


      confidence intervals.


                DR. GOECKELER:  Do you have the


      sensitivity and specificity?  Get me the numbers,


      so that I can just provide them.


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




      back to it.


                DR. GOECKELER:  I can give you the


      numbers, and I can tell you that the trends are




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


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


                My last question is that you did a lymph


      node as the unit of analysis.  There is still the


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


      know about the nodes, but in other activities, when


      you are looking at the same subject, and you are


      taking different specimens, and so forth, they tend


      to be correlated.


                So, if you did a person analysis, what


      would you do with the person, what would you say


      about the person?  Your sample size is greatly


      reduced.  Are there still your inferences?


                DR. GOECKELER:  Yes, the analyses were


      also carried out at the patient level, so we have


      the same data for each of the analyses pre- and


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


      ask for a slide one more time.




                DR. D'AGOSTINO:  Maybe they can produce it


      later on, the confidence intervals around some of


      these things I am talking about.


                DR. GOECKELER:  No, actually, I think they


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


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


      in sensitivity and specificity at the nodal level


      translated through to the patient level also.


                Here we go.  But this is nodes less than


      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




      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




      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.




                There was no direction as to what the


      surgery or biopsy procedures would be.  It was just


      based on the clinical investigator.


                DR. GOECKELER:  The standard of practice


      at the institution.


                MR. ROESSEL:  Does that answer the




                DR. HUSSAIN:  I guess what I am asking is


      was it the sense of the treating physicians, or


      were there guidelines that said if you had this


      size tumor, this kind of risk?


                MR. ROESSEL:  No, there were no--


                DR. HUSSAIN:  So, this was left random to


      the person enrolling the patient based on their gut


      feeling whether the patient have--


                MR. ROESSEL:  There were no guidelines


      given.  The entry criteria were just that, patients


      with a known primary who were scheduled to have


      surgery or biopsy, so that we could get


      pathological confirmation of nodal status.


                DR. GOECKELER:  Did you have another


      question, Dr. Hussain, about risk stratification




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


      speak to that with regard to relative risk and some


      of the models and selection of patients who might


      be most appropriate for treatment.


                DR. ROACH:  In the sponsor's indication,


      it specified that patients who were at risk for


      nodal involvement, so the clinical use for this


      agent in patients with prostate cancer would be


      patients at intermediate and high risk disease for


      whom we have data from randomized trials that


      demonstrates that treating the nodes is beneficial,


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


      of the nodes as possible.


                So, this agent would be useful for


      identifying where the nodes are located and allow


      us to reduce the morbidity of giving radiotherapy


      in patients with prostate cancer.


                DR. MARTINO:  Dr. Levine.


                DR. LEVINE:  I have several questions.


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


      the individual, that the patient would have two


      different MRI scans, in other words, your




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


      that you are asking that patients are now going to


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




                My second question, what was in those


      benign nodes?  You know, there are infiltrative


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


      those benign nodes, and what kinds of benign


      conditions, in fact, fulfill your requirements for




                Number 3.  This is kind of a funny one,


      but how did you know that the correct node was


      actually taken out? Did you do an MRI scan after


      surgery to know that you really took the right node




                DR. GOECKELER:  Let me ask, in terms of


      the matching, since Dr. Harisinghani has been


      involved in a number of these studies, how that is




                The first part of the question dealt


      with--I am sorry?


                DR. LEVINE:  Is the company requesting




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


      different reads--two different MRI scans?


                DR. GOECKELER:  Two different images,




                DR. LEVINE:  And who pays for that?


                DR. GOECKELER:  In the conduct of the


      clinical studies, that was required, because the


      primary endpoint was the comparison of a


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


      going to let the radiologists comment upon how they


      read these scans and how they match the nodes in


      the clinical studies.


                DR. LEVINE:  That actually wasn't the


      question.  The question is if this compound is


      licensed, are you asking that the patient be sent


      to MRI scan twice?


                DR. HARISINGHANI:  And the answer is yes,


      the patient will require two scans pre- and after


      contrast administration, and in terms of being able


      to correlate the nodes specifically to the areas on


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


      arduous and a difficult task, and for that reason,




      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




                DR. LEVINE:  And the sarcoid case


      fulfilled your criteria as benign, as well?


                DR. HARISINGHANI:  Yes, that was the case




      I showed earlier in the presentation where it


      behaved like a reactive lymph node.


                DR. LEVINE:  Have you guys done a cost


      analysis of the efficacy of this approach given the


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


      there a cost analysis perhaps?


                DR. HARISINGHANI:  We have not formally


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


      group in the Netherlands has actually published


      their results on cost saving.


                Do you want to comment on that?


                DR. GOECKELER:  Also, just let me comment


      that although two separate imaging sessions were


      required in the clinical trials, because of the way


      that clinical trials were conducted, different


      investigators in the post-Phase III setting


      interpret pre and post different ways, and Dr.


      Barentsz can comment on that also.


                DR. BARENTSZ:  I would like to comment on


      the first question first, about cost.  We recently


      published a paper in European Radiology in which


      we, based on the sensitivity and specificity data,




      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.




                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




      metastatic disease?


                DR. GOECKELER:  Let me make sure I


      understand.  In terms of obtaining them in surgery




                DR. MORTIMER:  Actually, reviewing them


      histologically, so to make an analogy of sentinel


      node mapping, the sentinel node is immunostained.


                DR. GOECKELER:  I think I understand.  The


      histology was reviewed without knowledge of the


      image findings.  So, they didn't analyze those


      particular nodes any different than they did any


      other nodes that were in the study.


                DR. MORTIMER:  And it was just H and E


      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




      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




      going to have problems.


                DR. MARTINO:  Dr. Brawley.


                DR. BRAWLEY:  There are a couple of


      statements that were made in the FDA presentation


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




                The first is of 152 and 181 patients who


      received Combidex in the U.S. and the European


      studies, a third of patients were censored from the


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


      censored from the European study, and not included


      in the primary analysis.


                I would like your response to that, and


      then I have a couple others.


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


      with regard to the European studies, as I think


      someone indicated at the beginning, the European


      studies themselves were initially carried out by


      the European sponsor with different endpoints, so


      they were analyzing patients at the patient and


      group and nodal level.


                So, in those studies initially, there was




      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




      European studies.


                DR. BRAWLEY:  A couple more follow-up




                I am told that there are only 5 prostate


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


      the primary analysis.  Is that true?


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


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


      Phase III studies, the purpose of the studies was


      to investigate the ability of the agent to


      differentiate nodes, malignant from non-malignant.


                I think that when you move on to--and


      obviously, you can subset that a lot of different


      ways, either by body region or individual tumor, or


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


      certain categories will be large or small, and the


      confidence intervals will react accordingly.


                I think that that is why, when we turn to


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


      Combidex improved the ability to differentiate


      malignant from non-malignant lymph nodes.


                I think that as Dr. Li indicated and as we




      indicated, when you move on to the question of


      where does that provide a clinical benefit, the


      tumors that we presented on were ones where not


      only we believe there is a clinical benefit, but


      also that there was supplemental data post-Phase


      III, not only on imaging performance, which you saw


      in the slides that Dr. Barentsz provided, but also


      on how that imaging performance impacted on


      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




      original copy of the blinded reader efficacy


      evaluation, were not available to the Food and Drug




                I would like you to respond to that




                DR. GOECKELER:  Well, I think that there


      have been some questions raised about the exact


      sequences of events in which the nodal imaging


      guidelines were developed and finalized, and I


      addressed that on one of the slides that I


      presented from the sponsor's perspective.  The


      guidelines were finalized prior to any blind


      reader, availability of blind read data.  Mark, if


      you would like to expand on that.


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


      answering a different question.  I think the


      question was about the prospective plan being


      available for the New England Journal of Medicine


      article.  Is that correct?


                DR. BRAWLEY:  That's correct.


                MR. ROESSEL:  The material that was


      published in the New England Journal of Medicine




      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




      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




                Is that true?


                DR. GOECKELER:  Mark, you can comment on




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


      comment on sort of the guidelines and regulations


      regarding what those sorts of facilities are


      required to have.


                MR. ROESSEL:  The facility in question was


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


      qualifications for doing clinical trials that


      equipment was available to treat any reactions that


      occurred.  They did have emergency equipment, which


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


      available.  Apparently, they didn't choose to use




                DR. BRAWLEY:  That, too, is an acceptable


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


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


      make a comment?


                DR. HOUN:  Yes, just to clarify when a


      sponsor obtains right of reference to studies to


      support their application, they have to be able to


      provide to FDA access to underlying data to provide


      the basis of the report of the investigation.


                This did not happen with the New England




      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




      going to then have either a biopsy or a surgical




                So, how was the decision as to whether


      they were going to have surgery or a biopsy


      procedure made, by equivocal or positive


      radiographic studies before they were entered on


      this study, or did they have palpable adenopathy?


      Other than the breast cancer patients in the


      sentinel node biopsy, I am still not satisfied that


      this isn't a selected population.


                DR. GOECKELER:  I will ask Mark to expand


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


      verify, that the image findings, the post-contrast


      image findings could not play a role, and were not


      available to the physicians in making those




                So, the physicians did not have any


      post-contrast image findings on which to base that


      assessment of whether the patient then went on to


      surgery or biopsy.  It was done based on the normal


      clinical information that would be available to


      make that decision for every other patient.




                DR. REAMAN:  So, radiographic studies


      weren't part of the clinical information?


                DR. GOECKELER:  Well, I think that the


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


      MRI pre-contrast, but no post-contrast image




                DR. MARTINO:  Dr. Bradley.


                DR. BRADLEY:  I have a couple of questions


      maybe for the authors of the New England Journal


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


                How did you select those 40 and 40


      patients from a group that was 3 times larger?  I


      mean selection bias kind of comes to mind, but what


      selection criteria did you use?


                DR. HARISINGHANI:  It is 3 times larger


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


      consecutive patients who were scheduled to undergo


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


      European site.


                They were of the intermediate and


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


      of the patient selection.




                DR. BRADLEY:  And then a follow-up


      question.  You showed some very nice images of very


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


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


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


      know you are comparing the same nodes pre and post,


      particularly not for you, but for the chest where


      you have respiratory artifact?


                DR. BARENTSZ:  In our New England Journal


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


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


      performed a combination of sequences which


      visualized the anatomy and also a sequence which


      visualizes the iron, and based on also a 3D


      sequence which we performed, we were able to


      compare the pre and post and exactly locate the


      lymph nodes where they were, so we could make a


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


                Also, we located the nodes in relation to


      the vessels.  So, I agree with you that


      localization and the location of lymph nodes is


      very important.




                DR. BRADLEY:  So, the slice location of


      3-mm slices was accurate, looking at the other




                DR. BARENTSZ:  Absolutely.


                DR. BRADLEY:  A follow-up question.  On


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


      15 percent false positive and false negative, we


      have talked a little bit about what might cause a


      false positive.  What about false negative, any


      thoughts, did you do an analysis of why they were


      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




      agent?  Is it so sensitive that a gradient echo at


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


      having read all of this, that that was also where


      you had your single death, is that correct?


                DR. GOECKELER:  I am going to have to ask


      Mark or Paula to comment on the specific imaging


      equipment.  Please recall that the death was in a


      liver imaging study, not in a lymph node imaging




                DR. BRADLEY:  Right.  I saw the physician


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


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


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


                MR. ROESSEL:  We tried to include in the


      Phase III clinical studies, we didn't specify the


      imager to be used. There was no requirement for it


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


      Agency with the information on the types of imaging


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


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


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


                DR. BRADLEY:  Just to follow up, was the




      0.2 Hitachi also where the death occurred?


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


                DR. MARTINO:  Ladies and gentlemen, we are


      running short of our allotted time, but I


      appreciate these questions as important, and that


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


      part of the meeting.


                That being said, I would ask those of you


      asking the subsequent questions, please be sure


      that your questions are necessary to your thinking


      about the efficacy and the approval of this agent,


      and are not just purely for your perhaps


      intellectual curiosity.


                Dr. Giuliano.


                DR. GIULIANO:  I am a surgeon, Dr.


      Martino.  We have limited intellectual curiosity,


      so my--


                DR. MARTINO:  I know.




                DR. GIULIANO:  Therefore, my questions


      will be brief.  But I am struggling as a surgeon


      through these documents.  We say the surgical




      procedure was not altered, the post-enhancement


      images were not available.


                How did you instruct the surgeon to remove


      the Combidex abnormal enhanced lymph node?  He or


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


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


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


      surgical bias because as any surgeon knows, it is


      easier to find a positive node than a negative




                In addition, using the node-by-node


      analysis, what happens with nodes not seen on MR


      that are removed?  For example, if this agent did


      not alter your surgical operation, the patient with


      a prostatectomy may have had a pelvic lymph node


      dissection, and there was one node that had been


      identified on your preoperative images or an


      axillary dissection for breast cancer, and there


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




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


      to be seen on the image, had to evaluated




      histopathologically, and they correlated, let's say


      they were both negative, what if all of the


      remaining nodes were positive or one of the


      remaining nodes was positive, how was that dealt


      with statistically or in your presentation?  I


      could not understand that.


                DR. GOECKELER:  I will ask Dr. Anzai to


      talk about the nodal matching and how those nodes


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


      in the identification of those nodes.


                DR. ANZAI:  I am the radiologist involved


      in Phase II and III clinical trials.  Your comment


      is absolutely right.  This was the hardest trial


      that we ever had in Radiology, that I personally


      have to have images going to OR when the patient is


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


      make stitches on a certain anatomical level.


                For example, a head and neck radiology, I


      have to ask the surgeon to make stitches on the


      submandibular--this is the jugular vein, so in


      between this lymph node is the lymph node that I am


      seeing in imaging, and it was very labor intensive.




                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




                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




      require evaluation on unmarked images to avoid bias


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


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


      identify the same nodes every time they read.


                That is why you see some of the nodes or


      the numbers dropping off at every level.  We tried


      to address that in part by looking at another read


      that involved the blinded overread, which are a


      much larger percentage of the nodes.


                DR. GIULIANO:  Maybe I wasn't very clear


      about that.  My question is if the labeled node


      from the operating room is the one identified on


      the MR, and histologically evaluated, and is


      positive or negative or whatever the correlation


      is, but other nodes that were not seen are


      positive, was that counted as a false negative or


      was that not counted because the other nodes were


      not seen on MR?


                DR. GOECKELER:  No, the primary analysis


      was at the nodal level, so those numbers that were


      presented were at the nodal level.  There were


      other analyses the data tracked very closely at the




      patient level where you can look at the patient


      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




      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




                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




      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




      is extremely high.


                That means the number you are missing is


      extremely low, and that current threshold, our


      urologist advises, but I would like also to have


      one of the urologists to speak on that.  That is


      very important clinical information which may


      actually decrease the number of lymph node




                If you have a positive lymph node, it


      always must be confirmed histopathologically.  If


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


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


      to tell the urologist the node is down there, and


      he can remove it.


                Perhaps the urologists can make also some


      clinical remark on that.  Comment about the


      clinical use, how this technique can be applied,


      what will you do if you have a negative MR


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


      positive lymph node.


                DR. KALINER:  Well, first of all, any


      information that I give as a clinician, first of




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


      George Washington University, and recently joined


      Cytogen as the Vice President of Medical Affairs,


      so I have a lot of experience in surgery and




                Any information I can get that helps me


      identify whether there is more extensive disease or


      not is extremely important with these patients.


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


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


      unless it is somebody that is intermediate to high


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


      stratified by risk to begin with.


                So, this is somebody that has a negative


      Combidex scan, we still would perform the lymph


      node dissection, but if there was a reason to look


      in an extended area, which we know pathologically


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




                On the other hand, if we did find


      something ahead of time, we may be able to


      eliminate doing an invasive procedure by performing




      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




      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




      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




      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




                Were any of these patients given




                DR. PAGE:  I believe none were.  Mark,


      correct me if I am wrong there.  Some were given


      steroids, of course, some were given albuterol in


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


      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






                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




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


      back to what Dr. Brawley touched on about why was


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


      the reaction couldn't be treated appropriately.


                I think the answer is simply that there


      are, the American College of Radiology has very


      clearly stated that contrast should not be injected


      where there isn't equipment to treat reactions that


      are potentially fatal and where there aren't people


      who are ACLS trained.


                So, you started by saying it's not an


      indictment against the sponsor, I think perhaps


      it's an indictment against clinical radiology.


      There is no question that patients should be


      treated appropriately, there is no question that


      the appropriate treatment is known.  It is a matter


      of linking those two.


                I think that is a question that sort of is


      unfortunately way beyond Combidex.


                DR. MARTINO:  Thank you.


                Dr. Rodriguez.  For the rest of you, there


      is only three of you.  Please be brief and






                DR. RODRIGUEZ:  I just want to be very


      clear about one issue.  One of the committee


      members previously said that the company obviously


      did not intend this product to be used in all




                As I read the application or in this


      proposed indication, however, it is worded exactly


      the same in both the FDA presentation and the


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


      differentiation of metastatic and non-metastatic


      lymph nodes in patients with confirmed primary


      cancer who are at risk for lymph node metastases.


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


      requesting that the FDA approve this product for


      broad application in all malignancies?


                DR. MARTINO:  I will take a yes or no


      answer to that.  That is all that is necessary in


      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




      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




      disposition of the patient.


                A yes or no from the sponsor would be




                DR. GOECKELER:  There were a lot of


      questions. First of all, with regard to the body


      regions, those weren't combined.  The data sets


      were for the entire populations. They were


      subgrouped out after the fact.