FOOD AND DRUG ADMINISTRATION












                          Tuesday, May 4, 2004


                               7:58 a.m.




                           Hilton Washington

                           620 Perry Parkway

                         Gaithersburg, Maryland



                        P A R T I C I P A N T S


      Committee Participants:


      Bruce D. Cheson, M.D., Acting Chairman

        [a.m. session]

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



      Otis W. Brawley, M.D.

      John T. Carpenter, Jr., M.D.

      James H. Doroshow, M.D.

      Stephen L. George, Ph.D.

      Antonio J. Grillo-Lopez, M.D.

      Pamela J. Haylock, RN

      Silvana Martino, D.O.

      Gregory H. Reaman, M.D.

      Bruce G. Redman, D.O.

      Maria Rodriguez, M.D.

      Sarah A. Taylor, M.D.


      Consultants (voting)


      For Procrit:

      Kenneth Bauer, M.D.

      Laurie Feldman, Ph.D.


      For CRC Endpoints:

      Ronelle DuBrow, M.D.

      David Kelsen, M.D., Guest Chair [p.m. session]

      Michael J. O'Connell, M.D.

      Daniel Sargent, M.D.


      Patient Representatives (voting):

      Musa Mayer, New York, New York - For Procrit


      Nancy Roach, Hood River, Oregon - For CRC Endpoints


      FDA Participants

      Clare Gnecco, Ph.D.

      Harvey Luksenburg, M.D.

      Patricia Keegan, M.D.

      Karen Weiss, M.D.

      Amna Ibrahim, M.D.

      Steven Hirschfeld, M.D., Ph.D.

      Grant Williams, M.D.

      Richard Pazdur, M.D.



                            C O N T E N T S

      Call to Order, Introduction of Committee - Bruce

      Cheson, M.D., Acting Chair, ODAC                           5


      Conflict of Interest Statement - Johanna Clifford,

      M.S., RN, Executive Secretary, ODAC                        8


      Opening Remarks - Patricia Keegan, M.D., Director,

      Division of Therapeutic Biological Oncology

      Products, FDA                                             11


      Sponsor Presentations


      NeoRecormon (epoetin beta) - Hoffman-LaRoche, Ltd.,

      Marty Huber                                               13


      Johnson & Johnson, Ltd.

       - Introduction - Robert DeLap, M.D., Ph.D., Vice

         President, Global Regulatory Affairs                   26

       - Evaluation of Studies - Peter Bowers, M.D.,

         Senior Director, Clinical Team Leader, EPO, Drug

         Development                                            33

       - Future Clinical Data - Martine George, M.D.,

         Vice President, Hematology and Oncology,

         Clinical Research and Global Development               47


      Amgen, Inc.

       - Introduction - Dawn Viveash, M.D., Vice

         President, Regulatory Affairs and Safety               53

       - Aranesp Properties, Preclinical Observations

         and EPO Receptor Biology - Harvey Lodish, Ph.D.,

         Professor of Biology and Bioengineering, MIT           58

       - Aranesp Clinical Observations and Pharmaco-

         vigilance Program Conclusions - David Parkinson,

         M.D., Vice President, Oncology Clinical

         Development                                            64


      FDA Presentation


      Harvey Luksenburg, M.D, Medical Officer, Division

      of Therapeutic Biological Oncology Products, FDA          84


      Open Public Hearing -                                 [NONE]


      Committee Discussion                                     145


      Lunch                                                    213



                      C O N T E N T S (Continued)


      Introduction of Committee - David Kelsen, M.D.,

      Acting Chair, ODAC                                       214


      Conflict of Interest Statement - Johanna Clifford,

      M.S., RN, Executive Secretary, ODAC                      216


      Opening Remarks - Richard Pazdur, M.D., Director,

      Division of Oncology Drug Products, FDA                  218


      Regulatory Background and Past FDA Approvals in

      Colorectal Cancer - Amna Ibrahim, M.D., Medical

      Officer, Division of Oncology Drug Products, FDA         225


      Synopsis of FDA Colorectal Cancer Endpoints

      Workshop - Michael O'Connell, M.D., Director,

      Division of Medical Oncology, Allegheny General

      Hospital, Pittsburgh, PA                                 242


      Disease-Free Survival (DFS) vs. Overall Survival

      (OS) as a Primary Endpoint for Adjuvant Colon

      Cancer Studies - Daniel Sargent Ph.D., Director,

      Cancer Center Statistics, Mayo Clinic Cancer

      Center, Rochester, MN                                    260


      Open Public Hearing                                      311


      Committee Discussion                                     328


      Adjourn                                                  403




  1                      P R O C E E D I N G S


  2             DR. CHESON:  Good morning.  Welcome to the


  3   Oncologic Drug Advisory Committee, May 4th.  I'm


  4   Bruce Cheson from the Lombardi Comprehensive Cancer


  5   Center.  I am the Acting Chair of the ODAC for


  6   today's session.  I do not work for, very clearly,


  7   the FDA in any way, shape, or form.  I do this on a


  8   voluntary basis.  And I am delighted to have some


  9   excellent colleagues of mine on this committee


 10   today, and I would like to start off today's


 11   session by having everybody at the table introduce


 12   themselves, starting with my friend Antonio


 13   Grillo-Lopez.


 14             DR. GRILLO-LOPEZ:  Thank you, Mr. Acting


 15   Chairman.  My name is Antonio Grillo-Lopez.  I am a


 16   hematologist/oncologist with the Neoplastic and


 17   Autoimmune Diseases Research Institute.


 18             MS. MAYER:  I am Musa Mayer.  I am the


 19   patient rep for this morning's session, and I'm a


 20   15-year breast cancer survivor from New York City.


 21             DR. BRAWLEY:  I'm Otis Brawley.  I'm a


 22   medical oncologist and epidemiologist, and I'm a




  1   professor at Emory University.


  2             DR. MARTINO:  Silvana Martino, medical


  3   oncology, from the John Wayne Cancer Institute.


  4             DR. TAYLOR:  Sarah Taylor, medical


  5   oncology, palliative care, University of Kansas.


  6             DR. REAMAN:  Gregory Reaman, pediatric


  7   oncologist at the George Washington University and


  8   Children's National Medical Center.


  9             DR. REDMAN:  Bruce Redman, medical


 10   oncologist, University of Michigan.


 11             MS. CLIFFORD:  Johanna Clifford, FDA,


 12   Executive Secretary to this meeting.


 13             DR. DOROSHOW:  Jim Doroshow, medical


 14   oncologist, Director, Division of Cancer Treatment


 15   and Diagnosis, NCI.


 16             DR. GEORGE:  Stephen George, Biostatistics, Duke


 17   University.


 18             MS. HAYLOCK:  I'm Pamela Haylock.  I'm an


 19   oncology nurse and doctoral student at the


 20   University of Texas, Medical Branch in Galveston,


 21   and I'm the consumer representative.


 22             DR. FELDMAN:  Laurie Feldman.  I'm a




  1   research scientist at the Beth Israel Deaconess


  2   Medical Center in Boston.


  3             DR. GNECCO:  Clare Gnecco.  I am the


  4   statistical reviewer for several of the epoetin


  5   products.


  6             DR. LUKSENBURG:  Harvey Luksenburg.  I'm a


  7   medical reviewer at the Food and Drug


  8   Administration.


  9             DR. KEEGAN:  Patricia Keegan, Division


 10   Director, Division of Therapeutic Biological


 11   Oncology Products.


 12             DR. WEISS:  I'm Karen Weiss, Office of


 13   Drug Evaluation VI, CDER, FDA.


 14             DR. CHESON:  Thank you.


 15             Today we have an interesting series of


 16   discussion, the morning of which will be a series


 17   of presentations and discussions concerning safety


 18   concerns associated with Aranesp from Amgen and


 19   Procrit from Johnson & Johnson, both of which are


 20   indicated for the treatment of anemia associated


 21   with cancer chemotherapy.  I was approached earlier


 22   by someone from the press who said, "How come there




  1   has been no buzz about this?"  I think this is


  2   sufficient evidence that there is buzz about this,


  3   and I look forward to an interesting series of


  4   discussions.


  5             We'll start off with opening remarks from


  6   Dr. Keegan.


  7             MS. CLIFFORD:  Well, actually, me.


  8             DR. CHESON:  Oh, excuse me.  From Johanna


  9   first.  Johanna Clifford, the conflict of interest


 10   statements.


 11             MS. CLIFFORD:  Thank you.


 12             The following announcement addresses the


 13   issue of conflict of interest with respect to this


 14   meeting and is made a part of the record to


 15   preclude even the appearance of such at this


 16   meeting.


 17             Based on the submitted agenda and


 18   information provided by the participants, the


 19   agency has determined that all reported interests


 20   in firms regulated by the Center for Drug


 21   Evaluation and Research present no potential for a


 22   conflict of interest at this meeting with the




  1   following exceptions:


  2             Dr. Maria Rodriguez has been recused from


  3   participating in all matters related to the


  4   discussions of safety issues associated with


  5   Aranesp and Procrit.


  6             Dr. Kenneth Bauer has been granted a


  7   waiver under 18 U.S.C. 208(b)(3) and 21 U.S.C.


  8   505(n) for owning stock in the parent company of


  9   the sponsor.  The stock is valued from $5,001 to


 10   $25,000.


 11             Dr. John Carpenter has been granted a


 12   waiver under 18 U.S.C. 208(b)(3) for lecturing on


 13   an unrelated matter for the sponsor of Aranesp.  He


 14   is awaiting final payment of his fee that is less


 15   than $5,000.


 16             Dr. Otis Brawley has been granted a


 17   limited waiver under 18 U.S.C. 208(b)(3) because


 18   his employer has a contract with the sponsor to


 19   study Aranesp.  The contract is less than $100,000


 20   a year.  Under the terms of the limited waiver, Dr.


 21   Brawley will be permitted to participate in the


 22   committee's discussions; however, he will be




  1   excluded from voting.


  2             A copy of these waiver statements may be


  3   obtained by submitting a written request to the


  4   agency's Freedom of Information Office, Room 12A-30


  5   of the Parklawn Building.


  6             Lastly, we would also like to note for the


  7   record that Dr. Antonio Grillo-Lopez, Chairman,


  8   Neoplastic and Autoimmune Diseases Research


  9   Institute, is participating in this meeting as an


 10   industry representative, acting on behalf of


 11   regulated industry.  He would like to disclose that


 12   he is a scientific adviser to Chiron and receives


 13   speaker fees from Wersch(ph).


 14             In the event that the discussions involve


 15   any other products or firms not already on the


 16   agenda for which FDA participants have a financial


 17   interest, the participants are aware of the need to


 18   exclude themselves from such involvement, and their


 19   exclusion will be noted for the record.


 20             With respect to all other participants, we


 21   ask in the interest of fairness that they address


 22   any current or previous financial involvement with




  1   any firm whose product they wish to comment upon.


  2             Thank you.


  3             DR. CHESON:  Hearing no other comments,


  4   now we'll go to Dr. Keegan.


  5             DR. KEEGAN:  Thank you.  I want to thank


  6   the committee and the companies who have come


  7   forward to present information about the


  8   erythropoietin products, both those licensed in the


  9   United States and two that are not.  The purpose of


 10   this is to review information based on the results


 11   of in the context of recent findings from two


 12   studies from Europe that suggested that there are


 13   certain practices in the administration of


 14   erythropoietin products which may raise concerns


 15   for safety of the products.


 16             I want to remind everyone that the


 17   erythropoietin products that were approved in the


 18   United States were approved as a means of treatment


 19   of anemia in a variety of settings that, over the


 20   period since original approval, there have been


 21   investigations into alternative uses of these


 22   products, looking at other benefits such as impact




  1   on survival.


  2             It is in that arena that two studies


  3   recently conducted in Europe identified the


  4   potential for some safety concerns with those


  5   particular strategies.  And we felt that it was


  6   important at this time to review the available data


  7   that both supported the original approval of


  8   Aranesp and Procrit for treatment of anemia


  9   associated with cancer, to review the clinical


 10   trials in question conducted in Europe, and to


 11   consider what additional information should be


 12   obtained at this point in time to determine whether


 13   or not an issue would exist with Procrit or Aranesp


 14   for the treatment of anemia associated with cancer


 15   and what the design of those studies should look


 16   like or to hopefully rule out any problems at the


 17   labeled and recommended doses for those two


 18   products.  So I would ask that the committee


 19   carefully consider the data presented and provide


 20   us with some guidance in the approach of these


 21   additional studies.


 22             I would like to draw your attention to the




  1   fact that there are some errors in the FDA briefing


  2   document, and we have provided an errata sheet that


  3   will provide corrections to those errors.  In


  4   addition, we have revised Question 1 of the


  5   questions to the committee in the first sentence,


  6   and the modified questions are available as an


  7   errata sheet at the table outside of this room.


  8             DR. CHESON:  Thank you, Dr. Keegan.


  9             Since we went around the table, we've been


 10   joined by another member.  If you could please


 11   identify yourself and your affiliation?  Turn on


 12   the microphone, please.  Hit the button.


 13             DR. BAUER:  Ken Bauer from Harvard, from


 14   the VA Medical Center and Beth Israel Deaconess in


 15   Boston.


 16             DR. CHESON:  Thank you.


 17             Okay.  The first presentation from a


 18   sponsor will be about NeoRecormon, or epoetin beta,


 19   from Hoffman-LaRoche, Ltd.  Since I don't have your


 20   name here, if you could also please introduce


 21   yourself.


 22             DR. HUBER:  Good morning.  I'm Marty




  1   Huber, an oncologist with Hoffman-LaRoche.


  2             Given the Advisory Committee's discussion


  3   today of the safety of erythropoiesis-stimulating


  4   agents in the treatment of cancer patients,


  5   Hoffman-LaRoche volunteered to provide data from a


  6   study that was recently published in The Lancet,


  7   which we'll subsequently refer to as MF4449.


  8   Additionally, we'd like to provide some context for


  9   these findings, reviewing some other clinical


 10   trials that have been conducted with epoetin beta.


 11             Just a quick background.  NeoRecormon is


 12   the trade name for epoetin beta.  It is a


 13   recombinant human erythropoietin with a


 14   well-established benefit/risk profile with more


 15   than one million years of patient experience.  It


 16   has been available outside the United States since


 17   1990.  We did not apply in the United States for


 18   approval based on patent issues.  There were no


 19   safety issues which prevented it from being brought


 20   into the United States.  It was not reviewed by the


 21   FDA.  It is approved for patients with renal anemia


 22   as well as oncologic indications in most of these




  1   countries.


  2             For the presentation today, we'd like to


  3   review MF4449 focusing initially on the primary


  4   study results as published in The Lancet.  We will


  5   also show additional analyses that were performed


  6   on this study.  We did a meta-analysis of the


  7   clinical trial data with epoetin beta, and,


  8   finally, we'll look at one of our large randomized


  9   studies in which we have a long-term survival


 10   follow-up.


 11             MF4449 was a study which was looking at an


 12   investigational use of epoetin beta.  It was


 13   looking at, Would increasing the hemoglobin with


 14   epoetin beta lead to better efficacy of


 15   radiotherapy?  This was trying to invoke


 16   radiosensitization, and could that lead to improved


 17   progression-free survival in cancer patients?  The


 18   primary endpoint was local progression-free


 19   survival.  For the rest of the study, I will refer


 20   to this as PFS, or progression-free survival.


 21             This is an overview of the study design.


 22   Patients with head and neck cancer--and it was




  1   males with a hemoglobin less than 13, females less


  2   than 12--were randomized to receive either epoetin


  3   beta, 300 international units per kilogram sub-cu


  4   three times weekly, or placebo in combination with


  5   their radiotherapy.  Then they were followed up


  6   until progression or another endpoint.


  7             The idea was to start them two weeks


  8   before the radiotherapy, but this was not done in


  9   all cases.  Therefore, patients received a total of


 10   either seven to nine weeks of epoetin beta maximum.


 11   Epoetin beta was not continued in the follow-up


 12   period.


 13             An important factor in this study was how


 14   the patients were stratified.  As you know, head


 15   and neck cancer is a very heterogeneous disease.


 16   Therefore, we stratified them on the basis of tumor


 17   TNM Stage IV versus III.  In addition, they were


 18   stratified by resection status.  Stratum 1 here was


 19   patients who had had a complete resection.  Stratum


 20   2 was patients who had residual tumor after


 21   resection.  And Stratum 3 was, finally, patients


 22   who received no attempt at resection and were




  1   essentially treated with radiotherapy as their


  2   primary therapy.


  3             With regard to the population characs, the


  4   details are in your briefing document, and they


  5   were overall very well balanced.  There were a


  6   couple of exceptions we'd like to point.


  7             First was smoking status.  This was not


  8   have a history of smoking but were they smoking at


  9   the time.  We believe this is relevant because we


 10   know there is an interaction between active


 11   cigarette smoking and radiotherapy which may


 12   diminish the efficacy of radiotherapy.  At


 13   baseline, 53 percent of patients on placebo were


 14   smoking; 66 percent in the epoetin beta group.


 15             Furthermore, because the patients had had


 16   surgery and then were randomized, there were


 17   patients who had relapsed, even prior to


 18   randomization.  This was in balance, with 10


 19   percent in the epoetin beta group, 7.6 percent on


 20   placebo.


 21             And, finally, for Stage IV TNM status,


 22   there was a minimal imbalance at baseline, 72




  1   percent versus 75 percent.  But what you will see


  2   is, as we start looking at subgroups, this


  3   imbalance is magnified in an important subgroup.


  4             These are the data that were shown in The


  5   Lancet showing that there was a progression-free


  6   survival advantage for placebo over epoetin beta.


  7   This is follow-up from--this is month six.  An


  8   important point here is during the first five to


  9   six months, there was no difference in


 10   progression-free survival.  This will contrast with


 11   some of the other data that you will review later.


 12             We had conducted a series of secondary


 13   analyses which were prospectively planned.  The


 14   intent of these analyses--we looked at the


 15   robustness of the data--was:  Were the findings


 16   robust throughout?  And, also, was there


 17   heterogeneity in the important subgroups?


 18             Furthermore, when we looked at the


 19   outcome, this inferiority of epoetin beta was very


 20   much unanticipated.  So this was in contrast to all


 21   other clinical experience with epoetin beta.  So


 22   based on that, we did further additional analyses. 




  1   These were the planned secondary analyses to look


  2   at the population robustness.  What I'm showing


  3   here are the Kaplan-Meiers for three populations:


  4   intent to treat, radiotherapy correct, and,


  5   finally, per protocol.


  6             The differences between these groups are:


  7   In the radiotherapy correct population, these are


  8   the patients who received the radiotherapy as


  9   specified in the protocol.  The per protocol


 10   population on the far right is not only did they


 11   get the right radiotherapy, but they also got the


 12   right treatment with regards to epoetin


 13   beta/placebo according to dose and schedule in the


 14   protocol.  The n's on this, this is approximately


 15   350, this is approximately 260, and this is around


 16   220.


 17             What's important to notice is that as you


 18   get to the purer population, the treatment effect


 19   actually diminishes.  This is contrary to what you


 20   would expect.  Normally when we do these studies


 21   for robustness, we are looking to see the treatment


 22   effect getting larger in the population that's




  1   treated who are in per protocol.  So this indicated


  2   to us some lack of robustness in the data.


  3             We did subgroup analysis.  This is a


  4   forest plot.  I just oriented this slide.  This is


  5   the categories, and these were categories we


  6   normally look at in head and neck trial:  stratum,


  7   location, staging, age, gender, smoking status, and


  8   baseline hemoglobin.


  9             What we looked at is, to the left is


 10   outcomes better with epoetin beta, and to right is


 11   better with placebo.  As you can see here, there is


 12   a divergence of findings on both sides of one.


 13   What we'd like to look at today is look at a couple


 14   of these subgroups in which there was the highest


 15   relative risk, specifically Stratum 2 and they


 16   hypopharynx.


 17             Looking at the progression-free survival


 18   by stratum, this is Stratum 1, which were the


 19   patients who were completely resected.  This is


 20   Stratum 2, which were the patients who had residual


 21   tumor.  One of the things that we found was the


 22   actual progression-free survival in Stratum 2




  1   placebo was better than placebo with completely


  2   resected patients.  This goes contrary to the


  3   natural history of these tumors and numerous other


  4   publications.  We would clearly expect that this


  5   curve should be better than this.  So what we feel


  6   is there is obviously some evidence of something


  7   odd about this placebo group.


  8             Furthermore, when we looked into the tumor


  9   site, if you look at the hypopharynx location,


 10   there is a wide difference; there's a major


 11   treatment effect.  This is placebo, epoetin beta.


 12   However, all other locations there was no


 13   difference in progression-free survival.  So when


 14   we do the subgroup analysis, the effect is


 15   restricted to the hypopharyngeal population.


 16             We looked further in this population, and


 17   what we found was that we did have an imbalance


 18   with regard to Stratum 3--30 percent in placebo, 45


 19   percent epoetin beta--within this subgroup.  These


 20   are the patients who did not have resection or


 21   attempts at resection and were radiotherapy only.


 22   Furthermore, we had an imbalance in the number of




  1   patients who were in Stage IV.


  2             With regards to safety, I apologize for


  3   this slide.  This is the non-cancer-related adverse


  4   events, but essentially they were balanced overall:


  5   65 percent placebo, 68 percent epoetin beta.


  6             I would like to point out one piece of


  7   data here.  In your briefing document, there's a


  8   reference to placebo 5 percent, epoetin beta 11


  9   percent for vascular disorders.  In this


 10   terminology, vascular disorders includes


 11   hypertension.  What we have historically done when


 12   looking at these issues, we've used the definition


 13   of thromboembolic events.  It does not include


 14   hypertension.  So if you see some differences in


 15   numbers, this is what accounts for it


 16             When we looked at thromboembolic events,


 17   we saw placebo 3.5 percent, epoetin beta 5.6


 18   percent, with some--sort of slight imbalances, with


 19   more on the epoetin beta treatment group.


 20             Furthermore, one of the things you may


 21   have noticed in the briefing document, there was an


 22   imbalance in cardiovascular deaths:  10 deaths on




  1   the epoetin beta group versus 5 on placebo in the


  2   cardiovascular category.  Given the concerns about


  3   thrombovascular events, what's important to note is


  4   one epoetin beta and one placebo occurred around


  5   day 50.  The remaining deaths occurred after day


  6   100.  Remember, treatment was only for a maximum of


  7   seven weeks, so these events are occurring well


  8   after cessation of epoetin beta treatment.


  9             In summary, we believe that there was a


 10   heterogeneity of treatment effect across various


 11   subgroups such as stratum, baseline hemoglobin,


 12   age, gender, disease location, and that there were


 13   also imbalances in important baseline


 14   characteristics, smoking for the overall


 15   population, as well as stage and resection status


 16   for patients with tumors in the hypopharyngeal


 17   location.


 18             With regards to meta-analysis, this was


 19   pooled results from nine controlled clinical


 20   trials, a total of 1,409 patients, with both solid


 21   and hematologic tumors.  We looked at tumor


 22   progression, overall survival, and thromboembolic




  1   events.


  2             Once again this is a forest plot.  What we


  3   look at is better with epoetin beta, better with


  4   placebo.  This is the total population.  These are


  5   the individual studies.  And then this is solid


  6   versus hematologic.


  7             What we saw was actually a reduction in


  8   risk of progression with epoetin beta, 0.79, with a


  9   difference approaching significance.  The remaining


 10   studies are relatively consistent in that most of


 11   them are less than 1, with a couple of exceptions,


 12   but they're very close.  Also, it's a consistent


 13   finding for solid and hematologic tumors.  In all


 14   of these we saw a reduced risk of progression.


 15             For survival, we saw a risk of 0.97, so


 16   it's essentially the same for epoetin beta and


 17   placebo.  And, once again, these studies are around


 18   1.  This one study, which is a higher one of 3.39,


 19   if you notice, due to the wide confident intervals.


 20   Very few deaths were noted in this study.


 21             We also looked at thromboembolic events in


 22   this study, in this pooled study, and the control,




  1   of 609 patients, 4 percent, epoetin beta 6 percent.


  2   This was actually quite consistent with the


  3   findings I presented from MF4449.


  4             So, in summary, there was no evidence of


  5   increased tumor progression in patients treated


  6   with epoetin beta.  There was no evidence of


  7   decreased overall survival.  There was a small


  8   increase in the incidence of thromboembolic events:


  9   6 percent of epoetin beta versus 4 percent on


 10   placebo.  But what I'd like to note is when we


 11   looked at patient years of observation and


 12   corrected for that, this difference disappeared.


 13             The limitation of this meta-analysis is


 14   most of these studies were relatively short in


 15   duration because they were looking at endpoints


 16   such transfusion or hemoglobin.  Therefore, we


 17   looked at MF4467 to see what there a long-term


 18   effect on survival.  This was a double-blind,


 19   placebo-controlled study of epoetin beta in


 20   patients with lymphoid malignancies.  The primary


 21   endpoint was transfusion-free survival, and as you


 22   can see, there was a robust effect on that




  1   endpoint.


  2             What we did was an overall survival on


  3   over 340 patients in this study.  This is the


  4   Kaplan-Meier and, as you can see, there's no


  5   difference in overall survival between placebo and


  6   epoetin beta.


  7             In conclusion, the MF4449 study results


  8   are inconsistent with the other epoetin beta


  9   studies in oncology.  We believe the most likely


 10   explanation for the adverse outcomes observed in


 11   MF4449 are factors independent of epoetin beta.


 12   The large majority of existing data shows that


 13   epoetin beta does not adversely affect tumor


 14   progression or survival in cancer patients.


 15             Thank you.


 16             DR. CHESON:  Thank you.


 17             We're going to reserve questions until


 18   after the FDA makes its presentation.


 19             Next, Dr. DeLap from Johnson & Johnson.


 20             DR. DeLAP:  Dr. Cheson, members of the


 21   panel, and guests, good morning.  I'm Dr. Robert


 22   DeLap.  I'm Vice President for Regulatory Affairs




  1   at Johnson & Johnson Pharmaceutical Research and


  2   Development, and I will be providing a brief


  3   introduction to our presentation.


  4             We are pleased to be able to be here today


  5   to participate in this discussion of the safety of


  6   erythropoietin products in patients with cancer and


  7   to present our data in support of this discussion.


  8   We will not have time to summarize all of the


  9   information that's been generated over the years in


 10   our extensive research programs, so our


 11   presentation will focus on the information that we


 12   deem most relevant to today's discussion.  Of


 13   course, we will be pleased to elaborate further on


 14   any specific points of interest.


 15             Erythropoietin products are approved for


 16   the treatment of anemia associated with


 17   chemotherapy.  Chemotherapy-associated anemia is a


 18   common problem for patients with cancer, and this


 19   anemia can be associated with debilitating symptoms


 20   and may require transfusions of red blood cells.


 21   Erythropoietic products have substantial value in


 22   treating anemia and its symptoms and can




  1   significantly reduce the need for transfusions.


  2   This benefits individual patients and also means


  3   that the units of red blood cells that are


  4   collected by blood banks can serve the needs of


  5   additional patients.


  6             The safety profile of erythropoietin


  7   products has been well established in years of


  8   clinical use, both in chemotherapy-induced anemia


  9   and in other illnesses where anemia may occur.


 10   Epoetin alfa products have been the subject of may


 11   clinical studies and have been used worldwide to


 12   treat more than two million patients for this


 13   indication.


 14             In the U.S., there are two products that


 15   are labeled for treatment of patients with cancer


 16   chemotherapy-induced anemia.  These are Procrit,


 17   marketed by Ortho Biotech, a J&J company, and


 18   Aranesp, marketed by Amgen.  Procrit became


 19   available for this indication in 1993, and Aranesp


 20   became available for this indication in 2002.


 21             Products available outside of the U.S.


 22   include EPREX, an epoetin alfa product that is also




  1   marketed by J&J companies, and NeoRecormon and


  2   Aranesp.  All of these products share extensive


  3   homology with naturally occurring human


  4   erythropoietin, and all act by binding to the


  5   erythropoietin receptor with activation of


  6   downstream pathways leading to red blood cell


  7   production.


  8             Our presentation will describe a number of


  9   studies that have been done in our extensive


 10   clinical research program, and we will be talking


 11   about two different types of studies.  Studies in


 12   supportive anemia care are the studies that were


 13   used to establish the existing indication for use


 14   of these products in patients with cancer--that is,


 15   the treatment of anemia associated with cancer


 16   chemotherapy.  In this use, anemic patients are


 17   typically treated with a goal to obtain at least 1


 18   gram per deciliter rise in hemoglobin level, to


 19   raise the patient's hemoglobin to a target range


 20   that is still below normally, typically, but is


 21   sufficient to reduce the likelihood of a


 22   transfusion.




  1             Beyond correction of anemia is the term


  2   that we will be using today to describe


  3   investigational uses that have evaluated the use


  4   erythropoietin products to treat patients to higher


  5   hemoglobin target levels.  Recent studies


  6   evaluating the effect or erythropoietic agents on


  7   cancer treatment outcomes have often utilized this


  8   design.


  9             It was hypothesized that any beneficial


 10   effects of treatment with erythropoietic agents on


 11   cancer treatment outcomes might be magnified with


 12   treatment to higher hemoglobin target levels.


 13   However, some of these studies have suggested


 14   unexpected risks, including decreased survival.


 15             This has led to extensive work that is


 16   continuing at our company to better understand the


 17   observations from these studies and to ensure that


 18   patients and prescribers will continue to have all


 19   of the information necessary to support the safe


 20   and effective use of our erythropoietin alfa


 21   products.


 22             Safety data we will be presenting data are




  1   as follows:  We will first summarize data obtained


  2   in our clinical studies of epoetin alfa in


  3   supportive anemia care, which, together with the


  4   extensive clinical experience over more than a


  5   decade, support the favorable risk/benefit ratio


  6   for epoetin alfa for the existing indication.


  7             Second, we will summarize data from a


  8   number of investigational studies that have


  9   involved treatment of patients beyond correction of


 10   anemia, including indications of increased risks


 11   that have arisen in some of these studies using


 12   that treatment approach.  We remain interested in


 13   studying the effects of epoetin alfa on cancer


 14   treatment outcomes, but we have modified the


 15   hemoglobin target levels that we are using in that


 16   research.


 17             Finally, we will describe additional data


 18   that we are collecting and further research that we


 19   have currently under consideration.


 20             We look forward to the advice of the


 21   Advisory Committee today as we work to do the best


 22   possible job of planning our future activities in




  1   this area.


  2             Our agenda for our presentation is as


  3   follows:  Dr. Peter Bowers, who leads our clinical


  4   programs with Procrit, will summarize our data from


  5   epoetin alfa studies that have been done for


  6   supportive anemia care and investigational studies


  7   that have involved treatment beyond the correction


  8   of anemia.  Dr. Martine George, who heads our


  9   entire hematology/oncology clinical development


 10   program, will then describe future clinical data


 11   relevant to this subject that we expect to have


 12   from our currently ongoing studies and an


 13   additional clinical study that we are considering


 14   to fill knowledge gaps in this area.  Finally, Dr.


 15   George will conclude our presentation.


 16             We have with us today several advisors to


 17   help facilitate the discussion, as noted on this


 18   slide, including Drs. Jesse Berlin, Kimberly


 19   Blackwell, Roger Cohen, George Demitri, Mark


 20   Levine, and Brian Leyland-Jones.


 21             Now I would like to introduce Dr. Peter


 22   Bowers for his summary of information from our




  1   clinical study database.  Thank you.


  2             DR. BOWERS:  Dr. Cheson, committee


  3   members, during the next minutes I will present a


  4   summary of safety information available from


  5   studies of epoetin alfa conducted in two settings:


  6   supportive anemia care, our labeled indication, and


  7   studies beyond correction of anemia.


  8             We undertook a combined analysis of ten


  9   completed randomized, double-blind,


 10   placebo-controlled studies evaluating the use of


 11   epoetin alfa, EPREX and/or Procrit, for supportive


 12   anemia care.  These data from 1,976 patients


 13   represent all controlled studies in this setting


 14   for which we have full patient level data regarding


 15   survival available.  We examined mortality hazard


 16   ratios for deaths during the double-blind phase


 17   plus 30 days, and also tumor response and disease


 18   progression information, the latter available in


 19   five of the ten studies.  Thrombotic vascular


 20   event, or TVE, data from the combined analysis will


 21   also be presented.


 22             Some points should be kept in mind




  1   regarding these analyses.  The studies represent a


  2   variety of tumors, and many include mixed tumor


  3   types.  The studies were designed and conducted to


  4   assess the impact of epoetin alfa on reducing


  5   transfusion and correcting anemia.  Thus, data


  6   regarding survival and tumor response or disease


  7   progression were collected as secondary endpoints


  8   and/or for safety purposes.  Additionally, the


  9   study drug treatment period ranges from 12 to 24


 10   weeks, plus 4 weeks follow-up.


 11             These are the results from the combined


 12   analysis for mortality.  The chart in the center of


 13   the slide displays the point estimates, the red


 14   dots, and the 95-percent confidence intervals, the


 15   white horizontal bars.  Unity is the dashed


 16   vertical line.  A point estimate less than one


 17   suggests lower mortality among epoetin-treated


 18   patients, and greater than one, higher mortality.  This side


 19   of the chart would favor epoetin alfa;


 20   this side favors placebo.


 21             Please note for the combined analysis the


 22   point estimate for mortality is 0.99, shown at the




  1   bottom, with a confidence interval 0.76 to 1.28.


  2   This means mortality among epoetin alfa-treated


  3   patients was the same as placebo patients in these


  4   studies.


  5             We reviewed tumor response and disease


  6   progression data from the five studies where this


  7   information was collected.  As you can see,


  8   response rates were similar between treatment


  9   groups, and also as you see, disease progression


 10   assessed in four studies was also similar between


 11   treatment groups.


 12             To summarize, the established benefits of


 13   epoetin alfa for supportive anemia care--that is,


 14   anemia related to cancer chemotherapy--include


 15   transfusion reduction and amelioration of the


 16   debilitating symptoms of anemia.  An evaluation of


 17   the studies in the approved indication showed no


 18   signal of reduced survival and no indication of an


 19   adverse impact on tumor response or disease


 20   progression.  Thus, the benefits of epoetin alfa


 21   therapy continue to be supported by a well-defined


 22   and acceptable risk profile when used for the




  1   approved indication of anemia in patients receiving


  2   cancer chemotherapy.


  3             Now I'm going to turn to studies from


  4   epoetin alfa used in settings beyond correction of


  5   anemia, and before presenting the clinical data,


  6   I'd like to review very briefly some key


  7   preclinical findings.


  8             The preclinical literature suggests a


  9   potential benefit of erythropoietins on tumor


 10   growth.  However, there are also reports that


 11   suggest the possibility of a deleterious effect.


 12   Many tissues, including tumor cell lines, express


 13   erythropoietin receptors.  In experiments by


 14   Johnson & Johnson and external groups, involving


 15   more than 25 different tumor cell lines, including


 16   cell lines known to express erythropoietin


 17   receptor, erythropoietin did not cause tumor cell


 18   proliferation.  Similarly, systemic administration


 19   of epoetin at doses of 20 to 2,000 international


 20   units per kilogram three times per week in in vivo


 21   models of breast, lung, and ovarian cancer in vivo


 22   did not increase tumor volume.  Moreover, a




  1   positive effect on tumor growth delay has been


  2   observed in animal models of concurrent


  3   administration of erythropoietins in chemotherapy


  4   or radiation therapy.


  5             There are conflicting reports regarding


  6   the impact of erythropoietin on tumor cell growth.


  7   Some experiments in vitro indicate increased tumor


  8   cell proliferation at erythropoietin concentrations


  9   5- to 100-fold greater than those achieved


 10   clinically using a dose of 40,000 international


 11   units.


 12             Based on the balance of positive


 13   preclinical data and results from Study INT-10,


 14   published by Dr. Timothy Littlewood in the Journal


 15   of Clinical Oncology 2001, which suggested a


 16   potential positive survival impact, the company


 17   conducted Study INT-76.  Details of this trial are


 18   summarized in your background briefing materials.


 19             INT-76 is a large study, 939 women


 20   receiving first-line chemotherapy for metastatic


 21   breast cancer, with a simple design.  EPREX or


 22   placebo was administered weekly and continued for




  1   12 months, regardless of chemotherapy changes or


  2   disease progression.


  3             Study drug was initiated at a hemoglobin


  4   of 13 or below and titrated to maintain hemoglobin


  5   in the range 12 to 14.  The primary endpoint of the


  6   study was survival at 12 months.  Objective


  7   confirmation of investigator-reported secondary


  8   endpoints, including disease progression and tumor


  9   response, were not require.  The primary--excuse


 10   me.  Study drug treatment was discontinued at the


 11   recommendation of the DSMB for the study, and at


 12   that time 88 percent of the subjects had completed


 13   planned study drug treatment or had been withdrawn


 14   from the study.  The shortest duration of treatment


 15   was nine months.  Blinded follow-up continued out


 16   to the 12-month endpoint.  Groups were generally


 17   balanced with regard to prognostic factors.


 18             This slide shows the Kaplan-Meier plot for


 19   survival.  The vertical axis is probability of


 20   survival, and the horizontal axis, time in months.


 21   Below the horizontal axis are the numbers of


 22   patients represented at each time point.  White is




  1   placebo, blue represents epoetin alfa.  Please


  2   observe the survival curves begin to diverge


  3   relatively early in the course of follow-up such


  4   that by month 4 the separation was near maximal,


  5   and the curves continued parallel out through month


  6   12.


  7             The primary endpoint, survival at 12


  8   months, was 24 percent survival--excuse me, deaths


  9   in the placebo group, and 30 percent deaths of


 10   patients in the epoetin alfa group.  This


 11   difference has a p value of 0.012.  The hazard


 12   ratio for mortality at the 12-month time point was


 13   1.37, the confidence interval 1.07 to 1.74.


 14             In light of these unexpected results,


 15   extensive analyses were undertaken by the company.


 16   Post hoc analyses, including subgroup and Cox


 17   modeling, were undertaken, and results of these


 18   analyses should be considered exploratory and


 19   interpreted cautiously.  No particular subgroup was


 20   identified as accounting disproportionately for


 21   most of the mortality difference.


 22             Additional data were collected in a




  1   retrospective blinded chart review of the medical


  2   records of all subjects in the study.  While not


  3   conclusive, the analyses in chart review, together


  4   with data from other trials, provide some


  5   hypotheses that might explain the observed survival


  6   difference.  An adverse impact of epoetin alfa on


  7   tumor proliferation is one hypothesis.  Another is


  8   imbalance in fatal thrombotic vascular events.  And


  9   we'll look at those a little further momentarily.


 10             Now, looking in detail at the cause of


 11   death data we have from INT-76, investigators


 12   captured cause of death on a case report form page


 13   with check boxes for either disease progression or


 14   other.  We looked at causes of deaths at 4 months,


 15   since most of the difference in mortality had been


 16   seen by that time point.  Investigators attributed


 17   most deaths to disease progression with a


 18   difference between the groups, as you can see on


 19   the slide.


 20             In the other category, investigators


 21   listed thrombotic vascular events, chemotherapy


 22   toxicity, again, with differences as shown.




  1             The blinded chart review suggested a


  2   somewhat higher rate of thrombotic vascular events


  3   than was reported by investigators, as you see on


  4   the bottom of the slide:  two among placebo group


  5   patients, 11 among the epoetin alfa group patients,


  6   at the 4-month time point.


  7             This suggests the possibility that


  8   thrombotic vascular events may have been underdiagnosed or


  9   -reported as a cause of death in this


 10   study and may have accounted for more of the excess


 11   deaths in the epoetin alfa arm than was


 12   appreciated.


 13             The high number of deaths within the first


 14   4 months, more so in the epoetin alfa group, may


 15   indicate that a more sick patient population than


 16   usual for a first-line metastatic breast cancer


 17   study had been enrolled.  As you can see, a greater


 18   number of deaths--as you have seen, rather, a


 19   greater number of deaths was attributed to disease


 20   progression by investigators.


 21             Further supporting the observation that


 22   the observed early differences in mortality may




  1   have resulted in substantial part from causes other


  2   than tumor proliferation, the time to disease


  3   progression curves shown here--placebo, again,


  4   white; epoetin alfa, blue--are superimposed.


  5   Response rates for the groups are similar:  46


  6   percent and 45 percent.  Thirty-eight percent of


  7   patients in the placebo group developed new


  8   lesions, whereas 30 percent of epoetin alfa


  9   patients did.  These results are not consistent


 10   with an adverse impact of epoetin alfa on tumor


 11   growth.


 12             Given that this is a large, randomized,


 13   double-blind study with unbiased, if incomplete,


 14   collection of tumor progression data, these results


 15   should be considered carefully.


 16             To summarize, in INT-76, an early survival


 17   disadvantage was observed in the treatment group.


 18   Deaths were attributed to investigators in


 19   significant part to disease progression.  However,


 20   investigator-reported disease progression and


 21   response rates were similar.  Given these


 22   inconsistencies, other potential explanations for




  1   the outcome merit consideration as well and, in


  2   particular, thrombotic vascular events may have


  3   been underdiagnosed as a cause of death in this


  4   study.


  5             Now, I'd like to turn to data from other


  6   studies using epoetin alfa in settings also beyond


  7   correction of anemia.  Here we see summarized


  8   several other studies that evaluated epoetin alfa


  9   use in these settings.  These studies are grouped


 10   to reflect status, either completed or in follow-up


 11   at the top of the chart, or discontinued in the


 12   group at the bottom of the chart.  INT-76 is


 13   included at the top for reference.


 14             As you see, the table summarizes some key


 15   details of the studies.  In general, these studies


 16   have used epoetin alfa in settings where patients


 17   are not anemic or are treated to hemoglobin levels


 18   that are somewhat or substantially higher than are


 19   needed for correction of anemia.


 20             The mortality experience is shown here.


 21   For the completed or in follow-up study, with the


 22   exception of Study INT-76, mortality is not




  1   significantly different.  The five discontinued


  2   studies represent studies stopped as a result of


  3   unplanned interim analyses of safety conducted at


  4   the company's request.  Following this review, more


  5   than 15 studies continued, some with modifications


  6   to reduce target hemoglobins.


  7             All five studies were stopped based on an


  8   unplanned analysis, and, thus, it's not possible to


  9   draw definitive conclusions other than to note


 10   unfavorable survival trends for epoetin


 11   alfa-treated patients in some of the stopped


 12   studies.  Follow-up data collection for these five


 13   studies is continuing to further understand the


 14   results.


 15             Now, let's consider the data relevant to


 16   tumor proliferation or disease response, as


 17   indicated by the endpoints shown on the slide:


 18   response rates, time to disease progression,


 19   disease-free survival, and so forth.


 20             Looking at the column on the right, the


 21   differences in outcomes related to tumor response


 22   or disease progression tend to be small.  These




  1   data show no signal that epoetin alfa is associated


  2   with an adverse impact on adverse impact on tumor


  3   growth.


  4             Turning to clinically relevant thrombotic


  5   vascular events in this same group of studies,


  6   clinically relevant thrombotic vascular events, or


  7   TVEs, are those which would be regarded by


  8   clinicians as significant and include both the


  9   venous and arterial events, but exclude such


 10   occurrences as superficial venous thrombophlebitis


 11   or catheter-related thromboses.


 12             Here I've ordered the studies by frequency


 13   of clinically relevant TVEs in the epoetin


 14   alfa-treated patients:  31 percent to 1 percent.


 15   Please note the substantial differences in the


 16   frequency of clinically relevant TVEs.


 17             Study 1015 with the greatest difference in


 18   TVE rates, 27 percent, is among the studies with


 19   the highest target hemoglobin level.


 20             In contrast to this is the frequency of


 21   TVEs in the ten studies of supportive care of


 22   anemia.  The studies are ordered by TVE frequency




  1   in the epoetin alfa group, high to low, 9 percent


  2   or lower.  In general, the absolute frequency of


  3   TVEs is substantially lower than is seen in the


  4   group of studies beyond correction of anemia.


  5   Differences between the groups are also smaller,


  6   with a negative number indicating more TVEs in


  7   placebo group patients.


  8             Overall, the odds ratio shown at the


  9   bottom of the slide is 1.55, indicating a modestly


 10   increase risk of clinically relevant TVEs in the


 11   epoetin alfa-treated patients, the confidence


 12   interval 0.96 to 2.5.


 13             In conclusion, our data indicate a


 14   favorable benefit/risk profile for epoetin alfa


 15   with no signal of tumor proliferation or adverse


 16   survival impact in settings of supportive anemia


 17   care.  In study settings using epoetin alfa beyond


 18   correction of anemia, adverse outcomes have been


 19   seen.  However, there is no clear signal suggesting


 20   an adverse effect on tumor proliferation.  There is


 21   an indication that thrombotic vascular events are


 22   more frequent in studies with higher target




  1   hemoglobin levels.  This may account for some,


  2   possibly much, of the observed survival signal.


  3             Additional data are being collected, and a


  4   new trial is under consideration.  Dr. Martine


  5   George, therapeutic area head of oncology and


  6   hematology at Johnson & Johnson PRD, will share


  7   further details with you.


        T1B                 DR. M. GEORGE:  Thank you.               8


  9             Johnson & Johnson has been studying the


 10   potential benefit of epoetin alfa in the setting of


 11   beyond correction of anemia since 1999, and our


 12   work in this area continues.  First, I will present


 13   a clinical trial design for a study considering the


 14   FDA guidance.  Then I will review with you how


 15   populated and ongoing trials could be used to


 16   address the safety questions raised.


 17             We considered several clinical trial


 18   designs according to the agency requests, and after


 19   critical analysis, we decided to select advanced


 20   breast cancer.  Our proposed clinical trial will


 21   focus on breast cancer based on the signal observed


 22   in INT-76, on the EPO receptor presence on breast




  1   tumor, which is well known, on the high incidence


  2   of the disease in the population, and also based on


  3   the need for homogeneity in terms of patient


  4   population and chemotherapy.


  5             Furthermore, early clinical trials in


  6   anemic patients have suggested a favorable outcome


  7   in patients with anemia treated with erythropoietin.  The


  8   unfavorable outcome of INT-76 doesn't


  9   preclude a potential benefit in anemic patients.


 10             We are assuming a potential benefit, but


 11   the trial will have to be powered to exclude a


 12   negative effect, as requested by the agency.


 13             The objective of the trial is simple.


 14   It's to evaluate the effects of EPO alfa on cancer


 15   outcomes in patients with metastatic breast cancer


 16   receiving first-line chemotherapy.


 17             The proposed clinical trial will be


 18   double-blind, randomized, placebo-controlled, and


 19   will enroll patients with advanced breast cancer


 20   receiving first-line chemotherapy, including taxane


 21   and/or anthracyclines.  Patients will be anemic at


 22   entry with hemoglobin at baseline equal to or less




  1   than 11 grams per deciliter before their third


  2   cycle of chemotherapy.  Patients will receive EPREX


  3   or placebo until tumor progression, end of


  4   chemotherapy, or death.  The target hemoglobin


  5   level in the study will be 12 grams per deciliter,


  6   and we'll hold the drug if the hemoglobin goes over


  7   13 grams per deciliter.


  8             The endpoints of the clinical trial will


  9   be as follows:  The primary endpoint will be


 10   progression-free survival, and because of lack of


 11   time, I won't expand on how we are going to assess


 12   progression-free survival.  Secondary endpoints


 13   will include overall survival, thrombotic vascular


 14   events, response rate, and TTP.


 15             Statistical methods will include a


 16   non-inferiority comparison, possibly followed by a


 17   superiority test.  Two thousand patients will


 18   provide 80-percent power to exclude a 15-percent


 19   reduction in progression-free survival, assuming no


 20   difference.  If non-inferiority is demonstrated, a


 21   superiority test will be done.  There will be


 22   80-percent power to detect a 15-percent gain in




  1   progression-free survival.


  2             There are some considerations when


  3   designing the trial in which we will particularly


  4   welcome your feedback.  The first challenge is to


  5   run a placebo-controlled trial when anemic patients


  6   receive drug treatment as a standard of care.


  7   Crossover of placebo patients following the


  8   double-blind phase could obscure the assessment of


  9   overall survival.


 10             Second, functionality of the EPO receptor


 11   is best addressed in fresh frozen samples.


 12   Collecting samples may significantly slow down


 13   patient enrollment into the trial and would delay


 14   study completion.  However, more preclinical


 15   studies to assess ligand affinity, signal


 16   transduction, and gene expression are warranted to


 17   better understand the receptor and its


 18   functionality.


 19             Providing patients with a homogenous


 20   chemotherapy regimen is complicated, but at least


 21   three elements:  the previous adjuvant


 22   chemotherapy, the wide range of available




  1   therapies, and constant innovation in therapy.


  2             And, finally, this clinical trial should


  3   provide an opportunity to better understand and


  4   control the causes of thrombotic events.


  5             In the next two to three years, as


  6   depicted on the slide, we will have considerably


  7   more information in the areas of tumor control and


  8   survival from the tumor types where we have


  9   observed a survival signal:  breast cancer, head


 10   and neck cancer, lung cancer, as well as some more


 11   data in carcinoma of the cervix, all in studies


 12   beyond the correction of anemia.


 13             In summary, we will have a significant


 14   amount of additional data in the next two to three


 15   years from those recently completed studies and


 16   ongoing studies.  This data will provide


 17   significant information in various tumor types.


 18             We welcome your advice and opinions on the


 19   timing, design, and challenges of the proposed


 20   study.


 21             And now I would like to conclude the


 22   Johnson & Johnson presentation.  As you have read,




  1   seen, and heard, in the supportive care of anemia


  2   we have extensive clinical experience which


  3   supports the favorable benefit/risk profile of


  4   Procrit.  We take very seriously the survival


  5   signal observed in metastatic breast cancer and


  6   head and neck cancer that occurred in studies


  7   assessing the benefit beyond the correction of


  8   anemia with two different products:  EPREX and


  9   NeoRecormon.  We have looked for and found no clear


 10   tumor proliferation signal as assessed by response


 11   rate and tumor progression.


 12             We note that TVEs account for some,


 13   potentially much, of the negative signal we have


 14   observed in those trials.  In contrast, some


 15   studies in supportive anemia suggest a potential


 16   benefit in cancer outcome, and future clinical


 17   evaluation in that setting may provide the answer


 18   to that question.


 19             In summary, Procrit provides important


 20   benefits for patients with cancer by decreasing


 21   transfusion and alleviating anemia symptoms.  We


 22   are committed to maximizing those benefits and




  1   minimizing the risks associated with its use.


  2             We look forward to working with ODAC and


  3   FDA to optimize our current and future development


  4   programs.


  5             Thank you very much for your attention.


  6             DR. CHESON:  Now we will move on to the


  7   Amgen presentations, their partners for the day.


  8   Dawn Viveash will do the introductions.


  9             DR. VIVEASH:  Good morning, members of the


 10   committee, FDA participants, ladies and gentlemen.


 11   Amgen is pleased to be here today to present data


 12   regarding the benefit and safety of Aranesp in the


 13   treatment of patients with chemotherapy-induced


 14   anemia.


 15             We have with us today a number of


 16   distinguished guests:  Dr. Jeffrey Crawford, Dr.


 17   David DeMets, Dr. John Glaspy, Dr. Harvey Lodish,


 18   Dr. Douglas Losordo, Dr. Marc Pfeffer, and Dr.


 19   Joseph Eschbach.


 20             In addition, we have a number of


 21   independent investigators who are currently


 22   conducting oncology studies with Aranesp.  These




  1   investigators are Dr. Overgaard, representing the


  2   Danish Head and Neck Cancer Study Group; Directors.


  3   Delarue and Bosley, representing the GELA Lymphoma


  4   Study Group; Dr. Nitz, representing the West German


  5   study; and Dr. Kahlert, representing the German


  6   Gynecological Oncology Study Group.


  7             I will open the presentation with a brief


  8   overview on preclinical and clinical properties of


  9   Aranesp.  There has been a change on our agenda.


 10   As you'll see, we have a different cast of


 11   presenters than is shown on the published agenda.


 12   We will have Dr. Harvey Lodish discuss considerations


 13   regarding the epoetin receptor.  His lab was


 14   the first to clone the EPO receptor.  He is


 15   professor of biology and bioengineering at MIT and


 16   is a member of the National Academy of Science.


 17   Dr. David Parkinson will describe the clinical


 18   observations with Aranesp, and he will also provide


 19   an overview of our clinical trial program.


 20             Aranesp is a distinct erythropoietic


 21   molecule.  The development of Aranesp represents


 22   the combination of over ten years of research




  1   during which time more than 450 molecules were


  2   characterized.  Aranesp is unique as a result of


  3   its novel amino acid sequence, which allows for two


  4   additional carbohydrate chains, leading to an


  5   increased negative charge and increase in molecular


  6   weight.  The terminal half-life of Aranesp is


  7   three-fold greater than epoetin, and because of its


  8   longer half-life less frequent dosing can be


  9   utilized compared to erythropoietin.


 10             Aranesp was initially approved in 2001 for


 11   the treatment of anemia associated with chronic


 12   renal failure in both dialysis and non-dialysis


 13   patients.  It was subsequently approved in July of


 14   2002 for chemotherapy-induced anemia.


 15             I'd like to highlight some relevant safety


 16   information from the package insert.  The warnings


 17   section represents prior observations from the


 18   Normal Hematocrit Study which was conducted with


 19   EPOGEN.  This was conducted in dialysis patients


 20   with pre-existing cardiovascular disease.  This


 21   section also addresses high hemoglobin, rate of


 22   rise, and mortality.




  1             The dosing guidance recommends a


  2   hemoglobin target of 12 and provides instructions


  3   for dosage adjustment to avoid excessive rate of


  4   rise of hemoglobin.


  5             The precautions section includes a


  6   statement regarding the theoretical concern of


  7   growth factor potential, and the adverse reactions


  8   section describes the thrombovascular events.


  9             You are now well aware of the findings


 10   from studies with epoetin alfa and epoetin beta and


 11   their observations regarding survival, tumor


 12   progression, and thrombotic events.  When Amgen


 13   became aware of these findings, we conducted a


 14   comprehensive review of preclinical and clinical


 15   data.


 16             The preclinical data with respect to


 17   Aranesp does not support the contention that this


 18   agent stimulates tumor growth.  Aranesp is not


 19   genotoxic.  There were not proliferative or


 20   hyperplastic signals in six-month toxicology


 21   studies.  In addition, there was no off-target


 22   binding of Aranesp, and no off-target effects were




  1   seen with Aranesp or erythropoietin in toxicology


  2   studies.


  3             In studies of tumor xenografts, one of


  4   which was performed by Dr. Blackwell from Duke


  5   University, who is present here today, there was no


  6   stimulation of tumor proliferation.  In fact, to


  7   the contrary, there was a potential beneficial


  8   effect observed when Aranesp was administered in


  9   combination with radiotherapy in some models.


 10             The clinical review includes


 11   epidemiological analysis of thrombotic events and a


 12   review of completed and ongoing Aranesp trials and


 13   also an assessment of post-marketing experience.


 14   Dr. Parkinson will review our observations from the


 15   clinical data.


 16             Based on this comprehensive review of


 17   oncology data, we did not identify any adverse


 18   survival or tumor progression signal with Aranesp.


 19   The thrombotic event rate remains consistent with


 20   that represented in the product label.


 21             One of the hypotheses that has been put


 22   forward from the signals observed in the BEST and




  1   Enhanced studies relates to the role of the EPO


  2   receptor in tumor progression.  I would like to ask


  3   Dr. Lodish to address the potential relevance of


  4   the EPO receptor on tumors and the utility of


  5   current methods to detect the receptor.


  6             Thank you, Dr. Lodish.


  7             DR. LODISH:  Thank you.


  8             To begin, I'd like to emphasize that mere


  9   detection of the EPO receptor on tumor cells--or


 10   normal cells, for that matter--does not mean that


 11   erythropoietic agents drive the oncogenic process.


 12   The EPO receptor is present at very low levels on


 13   many normal and tumor cells, but the EPO receptor


 14   does not possess any of the characteristics of an


 15   oncogenic receptor.


 16             For example, as you know, established


 17   oncogenic tyrosine kinase receptors, such as HER2


 18   or the epidermal growth factor receptor, are


 19   amplified and mutated in many types of human


 20   tumors.  Receptors can be overexpressed as many as


 21   100,000 or a million copies per cell in certain


 22   cancers.  In other cases, mutation leads to




  1   constituitive--that is, hormone


  2   independent--activation.  Both cases are


  3   transforming, are prognostic markers, and are


  4   established therapeutic targets.


  5             The situation is quite different for the


  6   EPO receptor.  With the sole exception of erythroleukemia,


  7   where EPO gene amplification has been


  8   recognized, EPO receptor amplification has not been


  9   seen in human tumors.  The presence of gene


 10   amplification into erythroleukemic cell lines


 11   illustrates that the failure to detect involvement


 12   of the EPO receptor in the vast majority of cancer


 13   samples is genuine and not simply a false negative


 14   result.  And it's my understanding that Aranesp


 15   treatment of erythroleukemia is not recommended.


 16             Importantly, there are no constituitive


 17   reactive--that is, hormone independent--EPO


 18   receptor mutants in any human or animal tumors.


 19   The one case of humans with mutations in the EPO


 20   receptor involve truncations of the cytoplasmic


 21   domain that render the receptors hypersensitive to


 22   erythropoietin.  These individuals develop




  1   polycythemia but have no increased tumor incidence.


  2             And, in conclusion, then, the EPO receptor


  3   is not known to initiate tumorigenicity or cause


  4   primary solid tumors to proliferate.  There are no


  5   known correlations of EPO receptor expression or


  6   mutation with any aspect of oncogenicity.


  7             I've also been asked to comment on


  8   methodological aspects of existing and potential


  9   assays for functional EPO receptors on primary


 10   solid tumors.  And before doing that, I'd like to


 11   point out several important aspects of EPO receptor


 12   expression on erythroid cells.


 13             First of all, over 90 percent, well over


 14   90 percent of the EPO receptors in erythroid cells


 15   are not on the cell surface.  They're in the


 16   cytoplasm on various membranes.  Erythroid cells


 17   have only 1,000 to 2,000 receptors on their


 18   surface.  Non-erythroid cells are transformed or


 19   otherwise generally have much less.  And,


 20   importantly, surface expression of the receptor


 21   requires expression of the JAK-2 protein tyrosine


 22   kinase and possibly other accessory proteins.




  1             Finally, the high-affinity receptor that


  2   is seen on erythroid cells, the signaling receptor,


  3   forms a one-erythropoietin, 2-receptor complex that


  4   initiates downstream signaling.  The low-affinity


  5   receptors that are seen on the vast majority of


  6   normal and tumor cells are low-affinity, as I said,


  7   and likely are forming a 1-erythropoietin,


  8   1-erythropoietin complex and are not signaling.


  9             Concerning the assays that one might think


 10   of for erythropoietin receptor detection in primary


 11   tumors, I'd like to point out several points.


 12   First of all, numerous publications discuss EPO


 13   receptor expression and function in tumor cell


 14   lines, but it's not clear that these translate to


 15   primary tumor samples in a clinical setting.  And,


 16   importantly, only cell surface receptors are


 17   clinically and biologically relevant.  Only these


 18   receptors can bind to erythropoietin and send


 19   signals to the inside of the cell.


 20             It's important to note that there are no


 21   measurements for functional epoetin receptors


 22   possible in fixed or frozen tissues.  Reverse




  1   transcriptase polymerase chain reaction, RT-PCR,


  2   measures RNA copies or transcripts of the EPO


  3   receptor gene.  That does not necessarily measure


  4   functional EPO receptor message and does not


  5   measure EPO receptor protein, and certainly not


  6   functional receptor.  And, importantly, these


  7   studies would require separation of the tumor cells


  8   from the other cells in the tumor.


  9             Immunohistochemistry measures erythropoietin


 10   receptors in the cytoplasm and is too


 11   insensitive to detect the minute numbers that might


 12   be expected on the surface of cells.  And,


 13   importantly, the existing antibodies, commercial or


 14   otherwise, are simply not sufficiently specific to


 15   detect EPO receptors among other background


 16   proteins.


 17             There are ways of detecting functional EPO


 18   receptors in fresh tumor biopsies, but they also


 19   present many problems.  First of all, these


 20   measurements would require fresh samples of cells


 21   and samples in which the tumor cells have been


 22   separate from the non-tumor cells.  Binding with




  1   radiolabeled EPO to cell surface receptors is


  2   possible, but it is very difficult to detect the


  3   low numbers of low-affinity receptors--and by low


  4   numbers, I mean under 1,000 receptors--present in


  5   cells.  And it's difficult to resolve the specific


  6   saturable binding to cell surface EPO receptors


  7   from the non-specific, non-saturable binding to


  8   other cell surface components.


  9             Proliferation of tumor cells in culture


 10   and response to EPO is also not practical for the


 11   simple reason that, as you know, fresh tumor cells


 12   generally are not viable in culture.  In my view,


 13   the only assay that would detect functional EPO


 14   receptors in tumor cells--or, for that matter,


 15   other types of cells--involve EPO-induced


 16   activation of downstream signaling proteins as


 17   measured by, say, phosphorylation of the


 18   erythropoietin receptor, the JAK-2 kinase, other


 19   signaling proteins.  These are complicated assays


 20   that require, as do the others, on the order of ten


 21   million cells per assay.  The cells, again, must


 22   have been purified from other cells, and in




  1   non-erythroid cells, these immuno-precipitation


  2   Western blot analyses are quite insensitive and


  3   have a very low signal-to-background ratio.


  4             So, in conclusion, there are no presently


  5   available assays suitable for routine measurement


  6   of functional erythropoietin receptors on primary


  7   solid human tumors.  Development of such assays


  8   will take years, and it's unclear to me what form


  9   these assays might ultimately take.


 10             I now turn the podium over to Dr.


 11   Parkinson, who will discuss the clinical


 12   observations.


 13             DR. PARKINSON:  Good morning.  Thank you,


 14   Dr. Lodish.


 15             Outlined are the clinical observations


 16   which I will discuss relevant to this morning's


 17   meeting.  After briefly reviewing some of the


 18   benefits associated with the treatment of anemia,


 19   I'll present the results of Amgen's studies of the


 20   risk of thrombotic events in association with


 21   erythropoietins.  Next I'll present the analysis of


 22   survival in completed clinical trials.  And,




  1   finally, I'll outline a program of ongoing trials


  2   involving Aranesp in different tumor treatment


  3   settings.


  4             Together, these trials have power to


  5   detect a safety signal far smaller than those which


  6   have been discussed already this morning.  We


  7   believe this represents a responsible and credible


  8   approach to definitively resolving the questions


  9   raise in this morning's meeting.


 10             With regard to the cancer indication,


 11   today we're here primarily to consider risks.  But


 12   no meaningful discussion of risk can occur in the


 13   absence of a consideration of benefit.  Anemia,


 14   which translates in patients with cancer into the


 15   important symptom of fatigue, is a highly prevalent


 16   comorbidity which significantly affects the quality


 17   of life in patients with cancer.  Without


 18   erythropoietic protein therapy, 90 percent of


 19   cancer patients undergoing chemotherapy will have


 20   some level of anemia, and some 40 to 60 percent of


 21   those patients will require transfusions.


 22             Historically, chemotherapy-related anemia




  1   has been treated with transfusion, with its


  2   attendant inconveniences and risks.  Not only is


  3   fatigue common in cancer patients, but fatigue as a


  4   symptom is rated by the majority of patients to be


  5   more important even than pain.


  6             The left side of this panel shows the


  7   hematopoietic response indication correction of


  8   anemia by Aranesp therapy.  Portrayed to the right


  9   is the significant decrease in the rate of


 10   transfusion with Aranesp therapy utilizing dosing


 11   intervals extending as far as three weeks.


 12             Extensive literature suggests the


 13   association of this anemia correction with improved


 14   fatigue and other quality-of-life scores.


 15   Recognition by the oncology community of the


 16   importance of anemia and the benefits of its


 17   treatment with erythropoietic proteins have led to


 18   the production of independent, evidence-based


 19   treatment guidelines.  These include treatment


 20   algorithms and desirable upper levels for


 21   hemoglobin.


 22             These evidence-based guidelines have been




  1   incorporated by Amgen into our current trials and


  2   analyses.  Furthermore, treatment recommendations


  3   in the product label are consistent with these


  4   guidelines.


  5             We'll now present the results of our


  6   evaluation of thrombotic events in patients with


  7   cancer.  First of all, it's well established that


  8   patients with cancer have a higher background rate


  9   of thrombotic events.  A full description of the


 10   epidemiology of these events in patients with


 11   cancer is outlined in our briefing document.  We


 12   have extensively reviewed that.


 13             The increased risk of thrombotic events


 14   with Aranesp therapy is represented in the adverse


 15   events section of the Aranesp label, as has already


 16   been discussed by Dr. Viveash.  But we proactively


 17   initiated a reevaluation of thrombotic event


 18   experience within Aranesp clinical trials--these


 19   are 11 completed trials as of late last


 20   year--involving more than 1,800 Aranesp-treated


 21   subjects relative to more than 400 placebo-treated


 22   subjects.




  1             On this slide, we see that our own Amgen


  2   analysis of the Medstat Claims database reflecting


  3   patients treated primarily with erythropoietin alfa


  4   also shows an increased risk of thrombotic events


  5   with epoetin alfa therapy.  This analysis is


  6   consistent with the Cochran meta-analysis involving


  7   cancer patients receiving either erythropoietin


  8   alfa or beta, presented by Bohlius, et al., at the


  9   December American Society of Hematology meeting,


 10   the relative risks of thrombotic events in our


 11   study and the Bohlius study being 1.4 and 1.55,


 12   respectively.


 13             We'll now show you our analysis of


 14   survival in completed clinical trials.


 15             We identified four suitable randomized,


 16   double-blind, placebo-controlled trials.  Two of


 17   these, involving more than 600 patients, had


 18   long-term follow-up and with 360 events allow us to


 19   carefully evaluate Aranesp's effect on survival.


 20   One trial was conducted in lung cancer and included


 21   anemic patients beginning platinum-based


 22   chemotherapy.  A second trial involved patients




  1   with five different lymphoid malignancies.  In this


  2   trial, Aranesp therapy was initiated when patients


  3   became anemic.  Finally, Amgen conducted a pooled


  4   analysis involving these two trials and two


  5   additional controlled trials comprising more


  6   heterogeneous patient populations.


  7             The first of the studies, in lung cancer,


  8   is represented on this slide.  More than 300


  9   patients with either small-cell or non-small-cell


 10   lung cancer beginning platinum-based chemotherapy


 11   were randomized to weekly Aranesp or placebo.  The


 12   relatively homogeneous patient population, the fact


 13   that most patients were beginning chemotherapy, and


 14   the long-term follow-up make the study very


 15   appropriate for survival analysis.  Seventy percent


 16   of these patients have been followed until death.


 17             On this slide, we see the results of this


 18   study in lung cancer.  There is no evidence of any


 19   decrease in progression-free survival with Aranesp.


 20   In the Amgen briefing document, we've provided a


 21   breakdown of small-cell and non-small-cell lung


 22   cancer subjects.  These subsets behave similarly.




  1             This slide shows similar results for


  2   overall survival.  The sample size of the trial and


  3   the number of observed deaths were appropriate to


  4   detect reduced survival of the magnitude seen in


  5   the BEST and Enhanced or Henke trials.  Yet there


  6   is evidence for any negative survival influence


  7   with Aranesp therapy.


  8             Trial 161, this lymphoid malignancy trial,


  9   differs from the lung cancer trial, as I've


 10   indicated, since patients with multiple lymphoid


 11   tumor types were eligible, and these patients could


 12   be randomized anytime during the course of


 13   chemotherapy.  In this study, 344 patients with one


 14   of five different lymphoid malignancies with


 15   chemotherapy-induced anemia were randomized to


 16   receive either weekly Aranesp or placebo.  The


 17   distribution of the different malignancies is


 18   outlined here.


 19             The slide illustrates the baseline


 20   characteristics of the patients in the lymphoid


 21   malignancy trial.  The study, while it did include


 22   long-term follow-up, was again designed to study




  1   anemia.  As a consequence, patients were not


  2   stratified for malignancy-specific prognostic


  3   factors.  This led by chance, as you can see, to


  4   patients with the worse prognosis for both


  5   non-Hodgkin's lymphoma and chronic lymphocytic


  6   leukemia to be assigned to the Aranesp arm.


  7             This slide indicates the trial result.  We


  8   see on this slide no evidence for a significant


  9   decrease in progression-free survival.  The hazard


 10   ratio, which is adjusted for disease type, stage,


 11   and IPI score, is greater than 1 but the confidence


 12   interval extends below 1.  We continue to follow


 13   these patients.


 14             On this slide, we observe no convincing


 15   evidence for a significant decrease in overall


 16   survival in association with Aranesp therapy.


 17   Again, the hazard ratio is above 1, but the


 18   confidence interval extends below 1.  We've


 19   presented data on individual lymphoid malignancy


 20   subset in the briefing document.


 21             I will now review the pooled analyses for


 22   these completed trials.




  1             As previously noted, two other randomized,


  2   double-blind, placebo-controlled short trials with


  3   short-term follow-up were considered to be


  4   appropriate for the pooled analysis and to


  5   contribute particularly to the study of the early


  6   part of the survival curve which seemed to be so


  7   important in the BEST trial results, as you've


  8   heard.


  9             On this slide are demonstrated the number


 10   of patients and the breakdown by tumor type of the


 11   patients contributing to this pooled analysis with


 12   cumulative follow-up involved.  Combined, these


 13   trials provide more than a 80-percent power to


 14   detect an effect on survival of the magnitude seen


 15   in the BEST and Enhanced trials.


 16             I'll now review results starting with


 17   progression-free survival.


 18             Portrayed here is the progression-free


 19   survival in the overall pooled analysis.  Note here


 20   that the time scale extends to 16 weeks and that


 21   the progression-free survival percent extends from


 22   80 to 100.  We've magnified the scale.  The hazard




  1   ratio is close to 1, and there is no evidence of an


  2   effect of Aranesp on progression-free survival


  3   during this period.


  4             On this slide, we again see no evidence


  5   for a negative overall survival influence in


  6   association with Aranesp therapy.  In addition, as


  7   shown in our briefing document, the long-term


  8   follow-up from this pooled data set is a hazard


  9   ratio of approximately 1.  The confidence interval


 10   for that analysis extends from 0.8 to 1.2, which


 11   excludes an effect of the size seen in the BEST and


 12   Enhanced trials.


 13             I will now review the analysis by tumor


 14   type.


 15             On this slide, I portray the


 16   progression-free survival results of the pooled


 17   analysis by tumor type.  No clear association is


 18   observed between progression-free survival and


 19   tumor type.  Results are similar with respect to


 20   overall survival.


 21             Here we find an association with improved


 22   progression-free survival and overall survival is




  1   observed with respect to achieving an on-study rise


  2   in hemoglobin of 1 gram per deciliter or more over


  3   14 days.  These hazard ratios are 0.51 and 0.43,


  4   respectively, with the indicated confidence


  5   intervals.


  6             Note that a similar association is found


  7   with improved progression-free survival and overall


  8   survival with respect to achieving an on-study


  9   hemoglobin of greater than or equal to 13 grams per


 10   deciliter.


 11             In summary, our more recent analyses have


 12   confirmed the appropriateness of the Aranesp


 13   prescribing information with respect to thrombotic


 14   event rate.  In an evaluation of data from over


 15   1,100 patients randomized to placebo-controlled


 16   oncology trials with Aranesp, we found nearly


 17   identical survival and progression-free survival


 18   with Aranesp and placebo.  We believe that our


 19   detailed examination confirms the safety profile of


 20   Aranesp and that the benefit/risk ratio remains


 21   favorable and warrants continued examination of


 22   potential beneficial effects on survival.




  1             I will now review a program of ongoing


  2   trials involving Aranesp in different tumor


  3   treatment settings.  We believe this group of


  4   trials represents a robust approach to ultimately


  5   resolving the questions raised in this meeting.


  6   The trials to be described were initiated, I should


  7   point out, because of evidence regarding the


  8   positive potential benefits of anemia treatment on


  9   patient survival.  Outlined here are the relevant


 10   preclinical and clinical observations providing the


 11   rationale for these trials.


 12             On particular note at the bottom is the


 13   Cochran meta-analysis with a favorable relative


 14   risk and a conclusion by the authors that more


 15   trials to explore this finding were merited.


 16             On the next several slides are outlined


 17   the Amgen-sponsored and the four independent


 18   investigator-initiated and  -conducted studies.


 19   The Amgen response to the information from the BEST


 20   and Enhanced trials has already been described by


 21   Dr. Viveash, including our formal review of all


 22   ongoing clinical trials involving Aranesp being




  1   conducted worldwide.


  2             One of our goals in this review was to


  3   identify clinical trials in which the design, the


  4   size, and the patient population would be


  5   particularly informative with respect to answering


  6   the kinds of questions that we're dealing with


  7   today.  We identified five such trials--one


  8   Amgen-sponsored and four utilizing Aranesp but


  9   being conducted by independent investigators.  All


 10   of these studies are randomized and controlled.


 11   One trial is itself double-blind and


 12   placebo-controlled.  The other four clinical trials


 13   involve randomization to Aranesp or no epoetin.  In


 14   these trials, Aranesp treatment is administered


 15   proximate to the time of chemotherapy and not for


 16   the full duration of follow-up.  These studies


 17   include long-term follow-up with collection of


 18   predefined progression and survival endpoints.  In


 19   addition, of course, the studies will capture


 20   thrombotic and cardiovascular events.  Each study


 21   includes homogeneous populations with


 22   stratification for disease-specific prognostic




  1   variables.


  2             One question posed by the FDA relates to


  3   the feasibility and appropriateness of conducting


  4   placebo-controlled studies.  You will note that, as


  5   I've indicated, one of our studies includes


  6   placebo-controlled design.  While these studies are


  7   currently ongoing in Europe, we can report that we


  8   are successfully accruing patients to a


  9   placebo-controlled trial of Aranesp in


 10   chemotherapy-induced anemia in the United States if


 11   that's relevant to your deliberations.


 12             In fact, it is our opinion that controlled


 13   studies are essential in certain situations and


 14   that it is feasible to conduct such studies in the


 15   United States.


 16             On this slide, we also indicate that the


 17   number of patients for each tumor type and the


 18   total number of patients for these five trials


 19   being over 3,500.  We believe that there is


 20   particular value to an approach which incorporates


 21   a range of tumors with robust numbers of patients


 22   in both breast cancer and head and neck cancer.  I




  1   will now review each study design in detail.


  2             Portrayed here is the Amgen-sponsored,


  3   double-blind, placebo-controlled study.  Six


  4   hundred patients with newly diagnosed extensive


  5   small-cell lung cancer will be randomized to


  6   combination chemotherapy with Aranesp or placebo.


  7   As you can see, endpoints include survival, and


  8   this trial has accrued more than 200 patients to


  9   date.  I'd like to point out again that this trial


 10   is placebo-controlled.


 11             The first independent


 12   investigator-conducted trial which I will discuss


 13   is the neoadjuvant breast cancer trial being


 14   conducted by the German Gynecologic Oncology Group.


 15   Seven hundred patients with diagnosed breast cancer


 16   will be randomized to dose-intense or standard


 17   chemotherapy with a secondary randomization to


 18   Aranesp or observation.  Following induction


 19   chemotherapy, surgery will be conducted.  Endpoints


 20   are as listed; follow-up is long term.


 21             By the nature of this patient population


 22   and by the nature of the study design and




  1   investigator intent with Amgen support, tumor


  2   tissue is being collected and stored.  The trial


  3   has accrued more than 400 patients, half of the


  4   projected total accrual.  An interim analysis of


  5   the experience in the first 200 patients will take


  6   place in the next several weeks.


  7             The second investigator-initiated study is


  8   the adjuvant breast cancer study being conducted by


  9   the West German Study Group.  After definitive


 10   surgery, the projected 1,000 patients will be


 11   randomized to center-specific adjuvant chemotherapy


 12   with or without Aranesp.  Endpoints are as listed,


 13   and this trial has recently initiated accrual.


 14             The diffuse large-cell lymphoma study


 15   conducted by the French, Belgian, and Swiss GELA,


 16   is outlined here.  More than 600 patients will be


 17   randomized to 14- or 21-day monoclonal antibody


 18   CHOP(?) chemotherapy treatment regimens.  These


 19   patients are secondarily randomized to Aranesp or


 20   supportive transfusion.  Endpoints are as listed;


 21   long-term follow-up is involved.  This trial has


 22   recently initiated accrual.




  1             The head and neck cancer study being


  2   conducted by the Danish Head and Neck Cancer Study


  3   Group is outlined here to test the hypothesis that


  4   anemia contributes to radiotherapy failure.  A


  5   projected 600 patients with head and neck cancer


  6   are randomized to radiotherapy alone or to Aranesp


  7   with long-term follow-up.  The principal


  8   investigator is Professor Overgaard, a


  9   well-recognized authority in the field of tumor


 10   oxygenation and radiation therapy.  More than 260


 11   patients have already been accrued to this trial.


 12             In response to the Henke and Enhanced


 13   trial results, the investigators have conducted an


 14   interim analysis for safety.  We are informed that


 15   this trial is proceeding.


 16             On this slide, the five clinical trials


 17   are outlined with respect to the tumor types


 18   involves, projected and current accrual, and the


 19   detectable differences from the expected control


 20   arm results.  Individually, these trials will


 21   accrue between 600 and 1,000 patients and have


 22   power to detect absolute differences in survival




  1   between 7 and 11 percent.  Note that these studies


  2   are ongoing outside of the United States, but we


  3   believe the findings should absolutely be


  4   applicable to United States practice.


  5             This slide shows the statistical power of


  6   the individual trials to detect an increase in the


  7   risk of death.  Each of these trials has reasonable


  8   power to detect a hazard ratio of 1.4 or 1.5.  Even


  9   if the true hazard ratio is as low as 1.2, there is


 10   a greater than 85-percent chance that at least one


 11   of these trials will result in a statistically


 12   significant difference.


 13             On this slide is outlined the projected


 14   accrual over time to these trials and the expected


 15   cumulative patient years of follow-up.  Including


 16   all five ongoing studies, more than 3,500 patients


 17   will be randomized in trial settings in which the


 18   influence of Aranesp on survival can be compared.


 19             This slide shows the power of a


 20   meta-analysis illustrated in yellow of all five


 21   trials.  This analysis will have high power to


 22   detect a true hazard ratio as small as 1.15, which




  1   is far smaller than that observed in the BEST and


  2   Enhanced trials.


  3             Also shown on this graph in the purple is


  4   the power of the meta-analysis of the neoadjuvant


  5   and adjuvant breast cancer studies, a total of


  6   1,700 breast cancer patients.  This analysis will


  7   have 80-percent power to detect a true hazard ratio


  8   as small as 1.32.


  9             So on this slide, I've summarized the


 10   strengths of the ongoing clinical trials


 11   activities.  As I've discussed, these include


 12   design elements which involve either double-blind,


 13   placebo-controlled, or Aranesp versus epoetin


 14   elements, with predefined survival or tumor


 15   progression endpoints.  I'd like to emphasize this


 16   in view of the agency's first question.


 17             While it is true that these trials are all


 18   being conducted ex-U.S., we would point out that it


 19   is entirely possible to conduct placebo-controlled


 20   trials in the United States.  These ongoing trials


 21   cross multiple tumor types with approximately 1,700


 22   breast cancer patients and 600 head and neck cancer




  1   patients.  The cumulative meta-analyses of 3,500


  2   patients will provide robust power for assessment


  3   of survival outcomes in this program.


  4             Of note, these studies have already


  5   accrued close to 900 patients.  These studies


  6   include careful safety monitoring, and the AGO


  7   breast cancer trial incorporates tissue collection


  8   to enable appropriate correlative biological


  9   studies.


 10             In conclusion, we've outlined the known


 11   and potential benefits of therapy with Aranesp.  We


 12   have found no adverse effects on tumor progression


 13   or survival to date in our Aranesp clinical trials.


 14   To the contrary, evidence exists for potential


 15   benefit from erythropoietic protein therapy, both


 16   in the settings of cancer and other conditions.


 17             It is our position that this potential


 18   benefit should be studies, but that such studies


 19   must be carried out responsibly, with carefully


 20   designed and executed trials.


 21             Thank you very much.


        T2A                 DR. CHESON:  I would like to thank the            





  1   sponsors for their very clear and on-time


  2   presentations.


  3             And now I'd like to turn to the FDA


  4   presentation, Dr. Harvey Luksenburg--who is going


  5   out the door.


  6             [Laughter.]


  7             DR. CHESON:  Harvey, come back, please.


  8   And for those of you who are standing against the


  9   side wall, if you would please, for fire safety


 10   reasons, stand in the back or you'll have to be


 11   asked to leave the room.


 12             DR. LUKSENBURG:  Dr. Cheson, members of


 13   the committee, ladies and gentlemen, I'm Harvey


 14   Luksenburg.  I'm a clinical reviewer at the Food


 15   and Drug Administration, and I would just like to


 16   start off by noting that I am but a member of a


 17   team of very talented individuals who put in a


 18   tremendous amount of work in putting together the


 19   data which we'll be presenting today.


 20             Now, two large randomized studies in


 21   cancer patients on chemotherapy plus or minus EPO


 22   have shown shorter overall survival, shorter




  1   progression-free survival, and an increased


  2   incidence of thrombotic and cardiovascular events


  3   in the groups assigned to receive erythropoietins.


  4             The erythropoietin products used in these


  5   two studies are not licensed in the U.S.  They are


  6   NeoRecormon, epoetin beta, manufactured by


  7   Hoffman-LaRoche, and EPREX, epoetin alfa, would is


  8   manufactured by Ortho Biologics.  Both of these


  9   studies used a treatment strategy to achieve a


 10   hemoglobin greater than 12 grams per deciliter,


 11   which is higher than that recommended in the


 12   labeling for U.S.-licensed products.


 13             The clinical trials for U.S.-licensed EPO


 14   products were not designed to assess the impact on


 15   response rate, with one exception--the N93 study,


 16   which I'll describe momentarily; they were not


 17   designed to look at in a systematic way time to


 18   progression or progression-free survival; and they


 19   were not designed to look at overall survival.


 20             Now, the goals of my talk are four-fold.


 21   First of all, I'll try to give some justification


 22   of why the FDA feels that the safety issues




  1   observed with EPREX and NeoRecormon, the


  2   non-U.S.-licensed EPOs, may also apply to


  3   U.S.-licensed products.  In addition, I will review


  4   results of trials with EPREX and NeoRecormon, the


  5   non-U.S.-licensed products, regarding the safety


  6   concerns.  Thirdly, I will review data available


  7   regarding safety from trials of EPOGEN/Procrit and


  8   Aranesp, the U.S.-licensed trials, and finally will


  9   try to come agreement on the design of future


 10   studies regarding these safety issues.


 11             Now, the three safety issues which I'm


 12   going to be discussing are, first of all, an


 13   increased risk of thrombotic and cardiovascular


 14   adverse events, an increased risk of tumor


 15   progression in patients receiving EPO products, and


 16   poorer survival in groups of patients receiving EPO


 17   products.


 18             Just the cast of characters.  Recombinant


 19   EPO products which are currently U.S.-licensed are


 20   epoetin alfa manufactured by Amgen and marketed


 21   under the name of EPOGEN; the same drug


 22   manufactured by Amgen and marketed as Procrit by




  1   Ortho Biotech; and darbepoetin alfa, or Aranesp,


  2   manufactured and marketed by Amgen.


  3             The EPO products which are not licensed in


  4   the U.S. are epoetin alfa, or EPREX, manufactured


  5   by Ortho Biologics; Epoetin beta, NeoRecormon,


  6   manufactured by Hoffman-LaRoche.


  7             Now, the FDA considers all these products


  8   members of the same product class, and, thus, these


  9   evolving safety issues are assumed to apply to all


 10   products unless adequate and well-controlled trials


 11   demonstrate otherwise.


 12             The differences between these products are


 13   as follows:  epoetin alfa and beta have the same


 14   amino acid sequence, but they differ in


 15   glycosylation.  Aranesp differs in the amino acid


 16   sequence (5) and in the degree of glycosylation.


 17             The similarities are meaningful.  All


 18   these exert their principal clinical effect by


 19   binding to the erythropoietin receptor.  All these


 20   products have similar pharmacodynamic effects when


 21   they're used at recommended dosages.  And there's a


 22   similar toxicity profile across all of these




  1   products with the exception of pure red cell


  2   aplasia, which has been seen thus far only in


  3   EPREX.


  4             Now, target hemoglobin, the labels for


  5   EPOGEN/Procrit and Aranesp have dosage guidelines


  6   based on safety data from registration studies


  7   performed in patients with chronic renal failure.


  8   Just to quote what is written on the current


  9   labels, for EPOGEN/Procrit, "The suggested target


 10   hematocrit range is between 30 and 36 percent."


 11   For Aranesp, "The dose should be adjusted for each


 12   patient to achieve and maintain a target hemoglobin


 13   not to exceed 12 g/dL."


 14             In addition, for rapid increase in


 15   hemoglobin greater than 1 gm per deciliter, or four


 16   points in hematocrit, in any two-week period, the


 17   dose should be reduced.  And the product should be


 18   held if the hemoglobin is greater than 13 until the


 19   hemoglobin falls less than or equal to 12 grams per


 20   deciliter and re-start the dose at 25 percent below


 21   the previous dose.


 22             Now, the first safety issue which I'd like




  1   to discuss is that of an increased incidence of


  2   thrombotic and cardiovascular adverse events.  This


  3   is a road map, and I'll show this slide several


  4   more times, and for each safety issue--thrombotic


  5   events, tumor progression, overall survival--I'm


  6   going to discuss only one study done in renal


  7   patients, the Normal Hematocrit Study.  These in


  8   yellow are the studies done in non-U.S.-licensed


  9   EPO, and the studies in pink are the studies done


 10   in U.S.-licensed EPO products.  An "x" means that


 11   there's data available for evaluation for each of


 12   these safety concerns.


 13             Now, the licensing studies for


 14   EPOGEN/Procrit and Aranesp demonstrated that


 15   there's a baseline risk of thrombotic and


 16   cardiovascular adverse events at their labeled


 17   target hemoglobin, that is, between 10 and 12 grams


 18   per deciliter.


 19             A study which dramatically showed the


 20   potential adverse effects of increasing the


 21   hemoglobin was the so-called Normal Hematocrit


 22   Study, first author Besarab, published in the New




  1   England Journal in 1998.  The idea behind this


  2   study was that patients with chronic renal failure


  3   on dialysis who had clinical evidence of cardiac


  4   disease could do better clinically if they had


  5   their hemoglobin raised from the nominal low 30


  6   range to a higher hematocrit, around 40.  And so


  7   1,200 patients with chronic renal failure on


  8   dialysis with clinical evidence of congestive heart


  9   failure or ischemic heart disease, they were all on


 10   EPOGEN at baseline and maintaining a hematocrit of


 11   between 27 and 33 percent.


 12             Now, both arms received EPOGEN, but they


 13   were randomized to different treatment strategies.


 14   One was randomized to achieve a higher hematocrit,


 15   around 42, plus or minus 3.  This was called the


 16   so-called normal hematocrit group.  The other arm


 17   maintained the lower hematocrit group, as was


 18   customary in practice, around 30 percent.  This was


 19   called the low hematocrit group.


 20             This study had a composite primary


 21   endpoint of either death or non-fatal myocardial


 22   infarction, and here are the results.  In the




  1   normal hematocrit group, there's an increased


  2   incidence of death, 30 percent, versus 34 percent


  3   in the low hematocrit group.  There's an increased


  4   risk of non-fatal myocardial infarction, 3.1


  5   percent in the normal hematocrit group, versus 2.3


  6   percent in the low hematocrit group.  And there was


  7   an increased risk of vascular access thrombosis, 39


  8   percent in the normal hematocrit group versus 29


  9   percent in the low hematocrit group.


 10             Here's a graph showing the increased


 11   probability of death in the normal hematocrit


 12   group, death or myocardial infarction in the normal


 13   hematocrit group, and in the low hematocrit group.


 14   This goes out to about 30 months.


 15             Now, when I talk about target hemoglobin,


 16   a target hemoglobin is only a target, and many


 17   patients don't achieve that target.  However--and


 18   this has been seen in both the renal studies and in


 19   the oncology studies--it's the dosing strategy, it


 20   is the idea of pushing the dose of the


 21   erythropoietin to a higher level in order to try to


 22   attain the target hemoglobin.  However, we've seen




  1   in all these studies that the adverse event signals


  2   seem to occur in the group assigned to the dosage


  3   strategy aimed at the target hemoglobin, despite


  4   whether they attained that hemoglobin or not.


  5             Now, the next studies I want to discuss


  6   are the BEST and the Henke studies.  These are the


  7   studies done in oncology patients using


  8   non-U.S.-licensed erythropoietins.  And, again, I'm


  9   just talking about thrombotic events.


 10             The Breast Cancer Erythropoietin Trial, or


 11   the BEST Trial, used EPREX.  This was a randomized,


 12   double-blind, placebo-controlled trial in 939


 13   patients with metastatic breast cancer who were


 14   receiving first-line therapy.  They received EPREX


 15   or placebo for 12 months, and the therapy was not


 16   started until the hemoglobin was less than 13.


 17             The primary objective of this study was to


 18   demonstrate superior survival at 12 months.  The


 19   target hemoglobin, again, was higher than what is


 20   on the label, between 12 and 14, and this study was


 21   stopped by an Independent Data Monitoring Committee


 22   based on the first four months of safety data.




  1             At four months, there was an increase


  2   incidence of fatal thrombotic and cardiovascular


  3   events.  In the EPREX arm, it was 2.3 percent; in


  4   the placebo arm, it was 0.4 percent.


  5             The next trial that got our attention was


  6   published in The Lancet last October by Henke and


  7   his colleagues, and it used NeoRecormon, or epoetin


  8   beta.  This was a randomized, double-blind,


  9   placebo-controlled trial in 351 patients with head


 10   and neck cancer who were receiving concurrent


 11   radiation therapy.  All these patients were anemic,


 12   less than 12 grams per deciliter in women, less


 13   than 13 grams per deciliter in men.


 14             The primary objective in this trial was to


 15   demonstrate superior locoregional progression-free


 16   survival.  The target hemoglobin was less than or


 17   equal to 14 in women and less than or equal to 15


 18   in men.


 19             Now, the incidence of cardiovascular and


 20   thrombotic events was higher in the epoetin beta


 21   arm, 11 percent, versus placebo--this included


 22   hypertension, hemorrhage, venous thrombosis,




  1   pulmonary embolism, and stroke.  In addition, the


  2   incidence of patients who died of cardiac disorders


  3   not otherwise specified was 5 percent in the


  4   epoetin beta group versus 3 percent in the placebo


  5   group.


  6             Next, still in the thrombotic events


  7   column, I'm going to discuss the studies we have


  8   available to us on the U.S.-licensed epoetin


  9   products.


 10             The registration studies for Procrit


 11   consisted of pooled analyses of six multicenter,


 12   randomized, double-blind, placebo-controlled


 13   studies constituting a total of 131 patients.  They


 14   had various primary cancers.  Three of these


 15   studies consisted of patients receiving


 16   platinum-containing chemotherapy and three of them


 17   consisted of patients receiving


 18   non-platinum-containing chemotherapy.  All these


 19   patients were anemic, and the primary endpoint was


 20   proportion of patients transfused.  There were no


 21   progression-free survival or survival endpoints


 22   incorporated in these studies.




  1             The incidence of thrombotic and


  2   cardiovascular events in the pooled data was 12


  3   percent in the placebo group and 3 percent in the


  4   Procrit group.


  5             A post-marketing commitment study done


  6   after the approval of EPOGEN/Procrit for the


  7   oncology indication asked the question whether


  8   giving Procrit along with chemotherapy for


  9   small-cell carcinoma of the lung would have a


 10   potential adverse effect on the tumor's response to


 11   chemotherapy.  This was a randomized, double-blind,


 12   placebo-controlled, non-inferiority study which was


 13   intended to enroll 400 patients with small-cell


 14   carcinoma of the lung who were receiving first-line


 15   therapy and their baseline hemoglobin was less than


 16   14.  So these patients did not necessarily have to


 17   be anemic.


 18             The primary endpoint, as I mentioned, was


 19   the objective response rate, CR plus PR, after


 20   three cycles of chemotherapy to rule out a


 21   decrement of 15 percent in the overall response


 22   rate with Procrit.  There was no target hemoglobin;




  1   however, the Procrit dose was reduced if the


  2   hemoglobin exceeded 16 grams per deciliter.  The


  3   study, however, was terminated because of poor


  4   accrual at 224 patients.


  5             Now, the incidence of thrombotic and


  6   vascular events in this study--we did review the


  7   data after 224 patients--in the Procrit group was


  8   22 percent and in the placebo group was 23 percent.


  9   However, the definition of thrombotic and vascular


 10   events included chest pain, not otherwise


 11   specified, as well as all the other well-known


 12   clinical entities.  So we subtracted chest pain and


 13   came up with these figures:  for the Procrit group,


 14   the incidence of thrombotic/vascular events went to


 15   14 percent, and in the placebo group, it was 9.5


 16   percent.


 17             The Aranesp Oncology Registration Study


 18   was a randomized, double-blind, placebo-controlled


 19   study in 320 patients with both small-cell and


 20   non-small-cell lung cancer, all of who were


 21   receiving platinum-containing chemotherapy.  All


 22   these patients were anemic.




  1             The primary endpoint, again, was a


  2   transfusion endpoint, the proportion of patients


  3   transfused between week 5 and week 12 or the end of


  4   the treatment period.  The dosage guidelines were


  5   that Aranesp was to be held for hemoglobin of


  6   greater than or equal to 14 in women and for


  7   greater than or equal to 15 in men.


  8             The incidence of thrombotic events in this


  9   study was 5 percent in the Aranesp group and 3


 10   percent in the placebo group.


 11             So, to summarize the studies for the


 12   thrombotic/cardiovascular events so far, in the


 13   studies in which a signal was detected, the Normal


 14   Hematocrit Study done in patients with chronic


 15   renal failure, the incidence of non-fatal


 16   myocardial infarction, 3.1 percent in the normal


 17   hematocrit group versus 2.3 percent in the low


 18   hematocrit group.  An increased incidence of


 19   vascular access thrombosis, 39 percent in the


 20   normal hematocrit group versus 29 percent in the


 21   low hematocrit group.  In the BEST Study, done in


 22   939 patients with metastatic breast cancer, there




  1   was an increased risk of fatal thrombotic events in


  2   the arm randomized to receive EPREX, 2.3 percent,


  3   versus 0.4 percent in the placebo arm.


  4             In the Henke Study in head and neck cancer


  5   and the patients were randomized to receiving


  6   epoetin beta, or NeoRecormon, or placebo, there was


  7   also an increased risk of cardiovascular and


  8   thrombotic events, 11 percent in the epoetin beta


  9   group versus 5 percent in the placebo group.


 10             In the thrombotic and vascular events


 11   studies that didn't have a signal, the Procrit


 12   pooled studies, 3 percent in the Procrit group


 13   versus 12 percent in the placebo group.  The N93


 14   study in small-cell carcinoma of the lung, 22


 15   percent Procrit versus 23 percent placebo.  We put


 16   an asterisk next to this because after we


 17   subtracted the non-specific chest pain, we did find


 18   that there was an increased risk of


 19   thrombotic/vascular events in the Procrit group.


 20   And, finally, the Aranesp Oncology Registration


 21   Study, 5 percent incidence in the Aranesp group


 22   versus 3 percent in the placebo group.




  1             Now, in September 2003, three


  2   placebo-controlled clinical trials in oncology


  3   patients in which one arm received EPO to target a


  4   higher hemoglobin were terminated because of


  5   unexpected rates of thrombotic events in the EPO


  6   arm.


  7             Briefly, to summarize these studies, in


  8   one, the primary cancer was small-cell carcinoma of


  9   the lung; the target hemoglobin was between 14 and


 10   16; the incidence of thrombovascular events, TVE,


 11   was 34 percent in the EPREX group versus 6 percent


 12   in the placebo group.  The second study, patients


 13   who had cervical cancer, the target hemoglobin was


 14   between 13 and 14; the incidence of TVE, 16 percent


 15   in the Procrit group, versus 5 percent in the


 16   placebo group.  And the third study, gastric or


 17   rectal carcinoma, target hemoglobin 14 or 15; the


 18   incidence of TVE, 24 percent in the Procrit group


 19   versus 6 percent in the placebo group.


 20             Now, the next safety issue I'd like to


 21   discuss is that of tumor progression.  There are a


 22   number of preclinical studies which have been




  1   reviewed, but our selective take under the


  2   literature is that there are EPO receptors which


  3   are present on some tumor cell lines and on tumor


  4   vasculature, meaning endothelial cells.


  5             EPO has been reported in some studies to


  6   inhibit apoptosis, stimulate angiogenesis,


  7   stimulate endothelial cell growth, migration, and


  8   proliferation, and reduce survival in some tumor


  9   xenograft models.


 10             Now, studies supporting the approval of


 11   Procrit and Aranesp for the treatment of anemia in


 12   cancer patients on chemotherapy were not designed


 13   to assess the impact on tumor response, tumor


 14   progression, or survival.  So there's a big lacunae


 15   in the information that we have for the


 16   U.S.-registered EPO products.  And, again, I'm


 17   going to go through the two studies that utilized


 18   non-U.S.-licensed EPO products and then two studies


 19   which we have that have data that's useful for


 20   looking at tumor progression in the U.S.-licensed


 21   EPO products.


 22             Again, just to remind you that the BEST




  1   Study using EPREX, randomized, double-blind,


  2   placebo-controlled, 939 patients with metastatic


  3   breast cancer, first-line therapy, randomized to


  4   receive EPREX or placebo for 12 months, therapy


  5   started at less than 13.


  6             The primary objective of this study was to


  7   demonstrate superior survival at 12 months.  The


  8   target hemoglobin was between 12 and 14, and this


  9   study, again, was stopped by the Data Monitoring


 10   Committee based on the first four months of safety


 11   data.


 12             At four months, there was a twofold


 13   increase in the incidence of disease progression.


 14   It was 6 percent in the EPREX group and 3 percent


 15   in the placebo group.


 16             At four months, there was 2.5-fold


 17   increase in early mortality.  It was 8.7 percent in


 18   the EPREX group versus 3.4 percent in the placebo


 19   group.


 20             In the Henke trial, again, randomized,


 21   double-blind study in 351 patients with head and


 22   neck cancer receiving concurrent chemotherapy,




  1   these patients were entered if women had a


  2   hemoglobin of less than 12 and men less than 13.


  3   The primary objective was to demonstrate superior


  4   locoregional progression-free survival.  The target


  5   hemoglobin was less than or equal to 14 in women or


  6   less than or equal to 15 in men.


  7             For locoregional progression-free survival


  8   as the primary endpoint, the relative risk was 1.62


  9   favoring placebo, and the lower bound or the


 10   95-percent confidence interval was greater than 1,


 11   with a highly significant p value.


 12             For locoregional progression, again, the


 13   relative risk was 1.69 favoring placebo and the


 14   lower bound of the 95-percent confidence interval


 15   was greater than 1, with a significant p value.


 16             Study N93, the post-marketing study which


 17   looked at small-cell carcinoma, this was a


 18   randomized, double-blind, non-inferiority study


 19   which was intended to enroll 400 patients who were


 20   receiving first-line therapy.


 21             The primary endpoint, again, was objective


 22   response rate after three cycles of chemotherapy to




  1   rule out a 15-percent decrement in the overall


  2   response rate in the Procrit arm.  No target


  3   hemoglobin was determined.  The Procrit dose was


  4   reduced for hemoglobins greater than or equal to


  5   16, and the study was terminated at 225 patients


  6   out of a projected 400 for poor enrollment.


  7             This study was not designed to assess the


  8   impact on time to progression, and survival was a


  9   secondary endpoint, and there was no formal


 10   hypothesis testing.


 11             The results showed that for the placebo


 12   group the overall response rate was 67 percent; for


 13   the Procrit group it was 72 percent.  The


 14   95-percent confidence interval around the observed


 15   difference had a lower bound of minus 6 percent.


 16   So even though this study met its intended


 17   objective despite the early termination, it was


 18   able to exclude a difference of greater than 15


 19   percent.


 20             The Aranesp Oncology Registration Study, a


 21   randomized, double-blind, 320 patients with


 22   non-small-cell and small-cell lung cancer all




  1   receiving platinum chemotherapy and all of whom


  2   were anemic.


  3             The primary endpoint was a transfusion


  4   endpoint.  The Aranesp was held for hemoglobins


  5   greater than 14 in women and 15 in men.


  6             The median progression-free survival was


  7   five months in the Aranesp group and four months in


  8   the placebo group.  This study, again, was not


  9   designed to assess the impact on progression-free


 10   survival.


 11             And here are the curves.  This is the


 12   placebo group here.  Here is the Aranesp group.


 13   Here is a year, two years.


 14             So, just to summarize, the data we have on


 15   tumor stimulation, first the studies in which a


 16   signal was detected.  The BEST Study, EPREX,


 17   metastatic breast cancer, at four months an


 18   increased risk of deaths due to disease progression


 19   being 6 percent in the EPREX group versus 3 percent


 20   in the placebo group.  In the Henke Study, head and


 21   neck carcinoma using NeoRecormon, EPO B, the


 22   relative risk for locoregoinal progression-free




  1   survival favored placebo, 1.62.


  2             The tumor stimulation studies without a


  3   signal, the Procrit group, the post-marketing


  4   commitment in small-cell carcinoma of the lung, the


  5   overall response rate was 72 percent in the Procrit


  6   group versus 67 percent in the placebo group.  The


  7   Aranesp Oncology Registration trial, the median


  8   progression-free survival, four months for Aranesp,


  9   five months for placebo.


 10             And, finally, I'd like to discuss the data


 11   we have concerning poorer survival in patients


 12   randomized to receiving erythropoietins.


 13             Again, I'll be discussed the data we have


 14   on the BEST trial and the Henke trial as well as


 15   the U.S.-licensed erythropoietins.


 16             Just to remind you once again, the breast


 17   cancer study, 939 patients with metastatic breast


 18   cancer, randomized to receive EPO or--EPREX or


 19   placebo for 12 months, and the primary objective of


 20   this trial was to demonstrate superior survival at


 21   12 months.  The target hemoglobin was between 12


 22   and 14, and this study was stopped by the




  1   Independent Data Monitoring Committee based on four


  2   months safety data.


  3             The estimated 12-month survival was 70


  4   percent in the EPO group and 76 percent in the


  5   placebo group.  The relative risk of death was 1.4


  6   favoring the placebo group, and the lower bound of


  7   the 95-percent confidence interval was greater than


  8   1, with a p value of 0.12.


  9             Here are the curves for the first 12


 10   months, which was the primary endpoint.  This is


 11   the placebo group on top, and here is the EPREX


 12   group.


 13             In the Henke Study, again, 351 patients


 14   with head and neck cancer getting radiation


 15   therapy.  The erythropoietin product used was


 16   NeoRecormon.


 17             The relative risk of death was 1.4


 18   favoring placebo; the lower bound of the 95-percent


 19   confidence interval was greater than 1.  The median


 20   overall survival was not different, but there's a


 21   trend toward poorer survival in the NeoRecormon


 22   group--was 605 days in the NeoRecormon group versus




  1   928 days in the placebo group.


  2             Study N93, the post-marketing commitment


  3   done in patients with small-cell carcinoma of the


  4   lung, again, this study was not designed to assess


  5   an impact on survival.  The median survival was


  6   10.5 months in the Procrit group and 10.4 months in


  7   the placebo group.  The overall mortality rate was


  8   92 percent in the Procrit group versus 88 percent


  9   in the placebo group.


 10             And here are the curves.  The dotted line


 11   is the placebo group.  The sold line is the Procrit


 12   group.


 13             The Aranesp Oncology Registration trial,


 14   320 patients with lung cancer receiving


 15   platinum-containing chemotherapy.  This study was


 16   not designed to assess the impact on survival.


 17             The median overall survival was ten months


 18   in the Aranesp group and eight months in the


 19   placebo group.  The overall mortality rate, 14


 20   percent in the Aranesp group, and 12 percent in the


 21   placebo group.


 22             And this is the placebo arm here, and here




  1   is the Aranesp arm.  This is one year, two years.


  2             And so, just to summarize the studies we


  3   had in which there was a survival signal, the BEST


  4   Study, metastatic breast cancer, the 12-month


  5   survival rate, the primary endpoint, poorer


  6   survival in the EPREX group, 70 percent, versus 76


  7   percent in the placebo group, p value of 0.12.  In


  8   the Henke Study using NeoRecormon, the median


  9   overall survival not significant but a trend, 605


 10   days for NeoRecormon versus 928 days with placebo.


 11             The studies that we have without a


 12   survival signal, the N93 Study, post-marketing


 13   study in small-cell carcinoma of the lung, 10.5


 14   months in the Procrit group versus 10.4 months in


 15   the placebo group.  The Aranesp Oncology


 16   Registration Study, ten months in the Aranesp group


 17   versus eight months in the placebo group.


 18             So, to summarize, two large, multicenter


 19   studies--the BEST Study and the Henke Study--which


 20   were designed to show superior survival or


 21   progression-free survival, instead demonstrated an


 22   increased risk of thrombotic and cardiovascular




  1   events, a shorter progression-free survival, and a


  2   shorter overall survival.  Both of these studies


  3   used a treatment strategy to achieve hemoglobin


  4   levels greater than or equal to 12.


  5             The multicenter, placebo-controlled trials


  6   using Procrit and Aranesp, the U.S.-licensed


  7   erythropoietins, were smaller in size; they were


  8   not designed to assess the impact on


  9   progression-free survival or overall survival.


 10   Their treatment strategy varied:  Procrit was held


 11   in the N93 Study for hemoglobin greater than


 12   14--the label recommends 12--and in the Aranesp


 13   study it was held for greater than 14 in women or


 14   greater than 15 in men.


 15             So, to conclude, we have these evolving


 16   safety concerns.  They cannot be dismissed.  The


 17   current dosing recommendations we feel are adequate


 18   to minimize the risk of thrombotic events.


 19   However, there is insufficient information


 20   concerning overall survival and progression-free


 21   survival for U.S.-licensed products at approved


 22   doses to assess these risks.  Amgen, Ortho Biotech,




  1   and the FDA have agreed on the need for further


  2   studies to investigate these safety issues.


  3             Now, the FDA recommends certain elements


  4   that should be components of all current and future


  5   studies which will be done to investigate these


  6   safety issues.  First of all, there should be a


  7   homogeneous primary tumor type.  There should be


  8   homogeneous chemotherapy or radiotherapy regimes.


  9   The studies should be designed to detect clinically


 10   meaningful decrements in response rate,


 11   progression-free survival, and survival.  There


 12   should be prespecified definitions of


 13   cardiovascular and thrombotic events.  And there


 14   should be Data Safety Monitoring Committee


 15   oversight.


 16             We also recommend the determination of


 17   expression and ligand affinity of EPO receptor on


 18   specific primary tumor types, preferably through


 19   the analysis of clinical tissue specimens or


 20   through pre-existing tissue repositories


 21   representing common tumor types.


 22             And I think that is the end of my




  1   presentation.


  2             DR. CHESON:  Thank you, Dr. Luksenburg.


  3             It's now time for questions from the


  4   committee to either the sponsor or Dr. Luksenburg.


  5   I'd like to start, while all the people are coming


  6   up, with questions for Dr. Luksenburg.  On your


  7   various slides, Harvey, when you're talking about


  8   studies with signals, you mean with negative


  9   signals, since there are a number of studies with


 10   positive signals, including one of the ones on your


 11   slide, 98-0297, with the ten- versus eight-month


 12   survival in favor of the erythropoietin compound,


 13   right?  So when you say with signal, you're


 14   referring to negative signal in your slides.


 15             DR. LUKSENBURG:  Yes.


 16             DR. CHESON:  Okay.


 17             DR. KEEGAN:  I would point out that the


 18   one that you're referring to as having the positive


 19   signal is actually not significantly different.


 20             DR. CHESON:  I know, but neither are some


 21   of the others.


 22             Any other questions from the committee? 




  1   Any comments from the committee?  Dr. Martino?


  2             DR. MARTINO:  I'm reminded of a quote from


  3   Enrico Fermi, which goes as follows:  "Before I


  4   came here, I was confused on this topic.  Now I'm


  5   still confused, but at a somewhat higher level."


  6             [Laughter.]


  7             DR. MARTINO:  And I'm not sure who I want


  8   to sort of address this to, but whoever of you


  9   thinks you have an answer, I'd appreciate it.


 10             It occurs to me that looking at the tumor


 11   tissue itself to see if it has receptors certainly


 12   is reasonable if it's doable.  Simultaneous to


 13   that, it is likely that the mechanism, if there is


 14   any by which tumors grow, may not be by direct


 15   involvement of the tumor cell itself, but may be


 16   through some other mechanism.  One of those, you


 17   know, is what it might do to the vascular system


 18   and neovascularization.


 19             Is there some way to look at that


 20   parameter?  Because some of us think that that may


 21   be the more likely mechanism by which tumor cell


 22   growth may occur, if, in fact, it does.




  1             DR. CHESON:  Dr. DeLap?


  2             DR. DeLAP:  Yes, I'd like to ask Dr.


  3   Francis Farrell to address that question.  Dr.


  4   Farrell is head of our preclinical program for this


  5   area.


  6             DR. FARRELL:  Thanks for the excellent


  7   question.  Francis Farrell, Johnson & Johnson.


  8             We feel that your idea does have credence.


  9   Although we don't feel that the receptor on tumor


 10   cells is functional, there is enough preclinical


 11   data to show that EPO does have an effect on


 12   endothelial cell function, including some papers


 13   showing that EPO binds to endothelial cells.  There


 14   have been some studies showing some chemotaxis with


 15   EPO on endothelial cells.  There's also been some


 16   data that aortic ring formation can be formed.


 17             The only caveat with these experiments,


 18   though, are that high doses of EPO are actually


 19   used to see this effect.  And in one publication,


 20   the dose used was actually 50 units per ml, which


 21   would be very high compared to what the clinical


 22   maximal serum dose a patient would get with 40 IUs




  1   per kg dose, which is approximately two units per


  2   ml.


  3             So to answer your question, though, I


  4   think better preclinical modeling and xenograft


  5   models where you could actually look at vascular


  6   density, micro-vessel formation, I think are


  7   warranted, and that would be the direction that we


  8   would go in.


  9             DR. DeLAP:  If I could ask your


 10   indulgence, we also have Dr. Kimberly Blackwell


 11   here who could also contribute to this point, I


 12   think, as a consultant, if we have a minute.


 13             DR. CHESON:  Please.  That would be fine.


 14             DR. BLACKWELL:  Hi.  I'm Kim Blackwell


 15   from Duke University.


 16             I, like the questioner, had some interest


 17   in was this tumor effect, was it endothelial cell


 18   effect, and we've embarked on a number of


 19   preclinical modeling, now with well over 500


 20   animals that we've looked at, both in R3230, which


 21   is an ER-positive mammary carcinoma line.  So it's


 22   as close as you can get to a rodent model to human




  1   model.  We've also looked at CT26, which is a


  2   colorectal model.


  3             So, very briefly, our experiments have


  4   looked at tumor proliferation using Key 67, tumor


  5   growth using biodimensional tumor volume.  We've


  6   also looked at micro-vessel density, and I think


  7   the best experiment is we've actually looked at in


  8   vivo angiogenesis using a dorsal window fold where


  9   you can actually measure vascular development in


 10   the mammary carcinoma model.  And I will say that


 11   we've looked at erythropoietin in close to 16


 12   mammary carcinomas and have failed to see any


 13   effect on tumor growth, tumor proliferation, or


 14   tumor angiogenesis.  Obviously the in vivo


 15   angiogenesis models involve a small number, about


 16   25 animals, because those are difficult experiments


 17   to do.


 18             We've also looked at darbepoetin using


 19   similar models in both R3230 and CT26 that was


 20   alluded to the Aranesp presentation, and using


 21   biodimensional models in over 200 animals with


 22   R3230 tumors have failed to see effect on tumor




  1   growth, tumor proliferation, and angiogenesis


  2   measured by micro-vessel density.


  3             So I agree with Dr. Farrell that this


  4   really needs to be studied further in in vivo tumor


  5   models because the interaction between tumor


  6   endothelial cells, that's really the only way to


  7   study it as opposed to studying endothelial cells


  8   or tumor cells separately in cell culture models.


  9             DR. VIVEASH:  I'd like to ask Dr. Losordo


 10   to make some comments relating to this issue.


 11             DR. CHESON:  Please.


 12             DR. LOSORDO:  I'm Dr. Losordo from Tufts


 13   University and St. Elizabeth's Medical Center in


 14   Boston.  My expertise is actually in cardiovascular


 15   where we've been studying actually the stimulation


 16   of angiogenesis for various ischemic disorders.


 17   And that experience I think has bearing here


 18   because the patient population that we study, which


 19   is generally aged and, therefore, it is somewhat


 20   higher risk for cancer than the general population,


 21   forces us to analyze the potential risk of


 22   stimulating angiogenesis in those patients in




  1   various in vivo models.  And so as a result of our


  2   work primarily using VEG-F to stimulate


  3   neovascularization of ischemic tissue, we've also


  4   conducted studies analyzing the impact of


  5   stimulating angiogenesis in that context on tumor


  6   vascularization and tumor progression by implanting


  7   tumors into animals and then stimulating


  8   angiogenesis by exogenous administration of


  9   angiogenic cytokines and have found, in fact,


 10   interestingly, that the angiogenesis that's


 11   stimulated is very context-dependent, meaning that


 12   in the region where angiogenesis seems to be


 13   deficient, for example, in the myocardium or the


 14   lower extremity where we've induced ischemia, the


 15   exogenous cytokine can stimulate and improve


 16   perfusion of that tissue.  While the tumor itself


 17   regresses under the influence of chemotherapy, the


 18   vascularity of the tumor does not change at all.


 19             And so what we've learned in a number of


 20   studies, and that would now include also studies in


 21   which we're using progenitor cells from the bone


 22   marrow or peripheral circulation, to also augment




  1   neovascularization of ischemic tissue, and in those


  2   instances either stimulating the release of those


  3   progenitor cells from the marrow or directly


  4   implanting them into ischemic tissue also does not


  5   influence tumor progression.


  6             So I would say that at the same time the


  7   study of these things is of great interest and


  8   something that we'll likely do and continue to do


  9   in the context of generating safety data for


 10   ongoing clinical studies.  However, it also seems


 11   to me that all those preclinical studies, while


 12   generating interesting science, will not trump the


 13   sort of clinical trial data that's being generated


 14   and continuing to be generated, which I think will


 15   influence patients and clinicians to a far greater


 16   degree.


 17             DR. CHESON:  Thank you.


 18             Are there any other investigators who


 19   would like to comment on this particular topic?


 20             [No response.]


 21             DR. CHESON:  Okay.  We can move on then.


 22   Other questions from the panel?  Dr. George,




  1   please.


  2             DR. GEORGE:  I have a question for Dr.


  3   Luksenburg.  That was a very thorough presentation,


  4   but I was a little puzzled by the way it was


  5   presented with respect to studies that showed a


  6   signal, those that didn't show a signal, and I was


  7   left trying to do my own mental meta-analysis of


  8   things to try to get some bottom line there.


  9             Did you do such things?  Or can you help


 10   us out in that way?


 11             DR. LUKSENBURG:  No, we didn't.  We


 12   obviously reviewed data which had come in over a


 13   number of years, and much of this data was from


 14   registration studies which were a few years old,


 15   and we looked, as did the sponsors, for evidence


 16   of--we looked at the data that was there for


 17   overall survival and progression-free survival.


 18   But since the studies were not designed to look at


 19   that, we, you know, just--we took the data as it


 20   was.  We did not do any meta-analyses.


 21             In general, our stance is that the studies


 22   that are valuable are studies--except for




  1   thrombotic/cardiovascular disease, the studies that


  2   will provide the best quality data for overall


  3   survival, progression-free survival, time to tumor


  4   progression, are those with homogeneous tumor


  5   populations.  And it's really difficult to do


  6   meta-analyses with variegated tumor populations.


  7             DR. CHESON:  Dr. Keegan, did you want to


  8   make a comment?


  9             DR. KEEGAN:  Yes.  Actually, that was one


 10   of our concerns with several of the meta-analyses


 11   presented, that it's trying to put the data in


 12   there in a way that--and take studies that weren't


 13   intended to look at these events and provide


 14   information.  And I think the quality of many of


 15   the studies included in the meta-analysis are not


 16   the same in terms of what information they can give


 17   you on progression-free survival or on overall


 18   survival simply because of the heterogeneity and


 19   the lack of control.  So that, you know, I think if


 20   we were to choose to select the studies, we would


 21   try and find studies that were actually designed to


 22   look at these endpoints and have the qualities that




  1   we are recommending further.


  2             DR. GEORGE:  Just a quick follow-up.  I


  3   certainly agree with respect to some of those


  4   endpoints, but survival should be a clear one.


  5             DR. KEEGAN:  I think when you look at some


  6   of those studies--and many of them are fairly small


  7   studies, and they enrolled any patient with any


  8   tumor at any stage in their treatment.  It might


  9   tell us something about transfusion rates.  That's


 10   what they were intended to do.  But they weren't


 11   really intended to give us a good comparison of


 12   impact on tumors.  These studies were really done


 13   in a manner not well designed to assess impact on


 14   tumor, just given all the incredible variables so


 15   much more important in terms of impact on survival


 16   and time to progression.


 17             Presumably, if there had been thousands of


 18   patients, all of those variables would probably


 19   have been evened out.  But most of the studies, as


 20   you look at them, are not particularly large, with


 21   the exception of the ones that we tried to


 22   highlight.




  1             DR. CHESON:  Are you satisfied with that


  2   answer, Dr. George?


  3             DR. GEORGE:  Yes.


  4             DR. CHESON:  Okay.  Ms. Mayer?


  5             MS. MAYER:  As I understand it, FDA is


  6   coming to ODAC not to ask us to assess if there is


  7   any level of risk associated with these products,


  8   but given that there may be a level of risk, to


  9   look at what kinds of clinical trials need to be


 10   done.  And I'm wondering since the data doesn't


 11   seem to be conclusive, since there are different


 12   perspectives, if it's useful for us to continue to


 13   try to assess what we know already from the trials.


 14   It's just a question, I guess a clarification of


 15   what our task is.


 16             DR. KEEGAN:  I think you're right in


 17   saying that if we thought we knew the answer, we


 18   wouldn't be asking you to reinterpret the data for


 19   us.  I think we're saying that we don't think it's


 20   been definitively assessed and could we seek some


 21   guidance on how to really address this question.


 22             DR. CHESON:  And the way I see it is we're




  1   being asked to do one of several things:  one,


  2   decide if the data are of sufficient concern; two,


  3   if they are of sufficient concern, are additional


  4   studies warranted; and, three, if additional


  5   studies are warranted, are those the studies that


  6   are already ongoing, as clearly elucidated by Dr.


  7   Parkinson and his colleagues.


  8             Dr. Bauer, please?


  9             DR. BAUER:  Yes, maybe I could just follow


 10   up on that point, because some of the studies we've


 11   heard presented clearly are driven by safety


 12   concerns in terms of showing safety, but, you know,


 13   as I understand the studies that are being


 14   proposed, there's really a desire to show improved


 15   survival.  And I guess we haven't heard a great


 16   deal about the rationale really in terms of showing


 17   survival.  I think we know about effects on


 18   radiotherapy and tumor oxygenation.  We also know


 19   some of the high hematocrits targeted there clearly


 20   are detrimental and a desire in all the studies


 21   going forward to keep the hematocrit below certain


 22   specified levels.  I guess I would like to hear




  1   more about really the rationale for really at this


  2   point believing that there really will be improved


  3   progression-free survival with the use of some of


  4   these erythropoietic stimulating agents, or


  5   survival overall, especially given the clear


  6   detrimental effect, albeit it small, in terms of


  7   thrombosis.


  8             DR. CHESON:  I think that most of these


  9   are probably non-inferiority trials, if I'm not


 10   mistaken.  They just don't want to show that there


 11   is a negative effect.


 12             Dr. Parkinson, since you were reviewing


 13   all those articles, would you like to comment on


 14   that, please?


 15             DR. PARKINSON:  Dr. Bauer, you're correct


 16   in that we did not spend a lot of time talking


 17   about the rationales.  The time was short.


 18   Sponsors were many.


 19             There is a wealth of preclinical evidence


 20   which I think there are a number of people who


 21   could discuss in more detail.  There is a


 22   significant amount of clinical evidence.  I




  1   referred to the Cochran meta-analysis, independent


  2   analysis conducted, as you're aware, by the Cochran


  3   group, which was considered to be suggestive


  4   enough--not definitive, but suggestive enough to


  5   warrant further trials.  I mention that because I


  6   think it's important.  It's dissociated from any


  7   product-related.


  8             We've shown you and you've seen from other


  9   sponsors quite interesting suggestions of patient


 10   benefit in a number of defined settings, both of


 11   radiotherapy and chemotherapy.  Additionally, the


 12   trials that I described which were not


 13   Amgen-sponsored were initiated by independent


 14   investigators based on their own independent


 15   assessment of preclinical and clinical data


 16   designed to test particular hypotheses, which are


 17   actually superiority hypotheses.  These were not


 18   trials designed to look for negative survival


 19   signals with erythropoietins.  These were trials


 20   designed to look for benefit based on--we won't


 21   give you our assessment of the literature--their


 22   assessment of the literature and what they believed




  1   were important therapeutic questions to ask.


  2             You know, we can go into as much


  3   detail--there are actually investigators here from