1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

                   ONCOLOGIC DRUGS ADVISORY COMMITTEE

 

 

 

 

 

 

                          Tuesday, May 4, 2004

 

                               7:58 a.m.

 

 

 

                           Hilton Washington

                           620 Perry Parkway

                         Gaithersburg, Maryland

                                                                 2

 

                        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

        Secretary

 

      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.

                                                                 3

 

                            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

                                                                 4

 

                      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

 

                                                                 5

 

  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

 

                                                                 6

 

  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

 

                                                                 7

 

  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

 

                                                                 8

 

  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

 

                                                                 9

 

  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

 

                                                                10

 

  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

 

                                                                11

 

  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

 

                                                                12

 

  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

 

                                                                13

 

  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

 

                                                                14

 

  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

 

                                                                15

 

  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

 

                                                                16

 

  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

 

                                                                17

 

  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

 

                                                                18

 

  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. 

 

                                                                19

 

  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

 

                                                                20

 

  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

 

                                                                21

 

  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

 

                                                                22

 

  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

 

                                                                23

 

  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

 

                                                                24

 

  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,

 

                                                                25

 

  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

 

                                                                26

 

  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

 

                                                                27

 

  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

 

                                                                28

 

  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

 

                                                                29

 

  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.

 

                                                                30

 

  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

 

                                                                31

 

  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

 

                                                                32

 

  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

 

                                                                33

 

  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

 

                                                                34

 

  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

 

                                                                35

 

  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

 

                                                                36

 

  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

 

                                                                37

 

  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

 

                                                                38

 

  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

 

                                                                39

 

  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

 

                                                                40

 

  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.

 

                                                                41

 

  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

 

                                                                42

 

  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

 

                                                                43

 

  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

 

                                                                44

 

  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

 

                                                                45

 

  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

 

                                                                46

 

  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

 

                                                                47

 

  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

 

                                                                48

 

  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

 

                                                                49

 

  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

 

                                                                50

 

  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

 

                                                                51

 

  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,

 

                                                                52

 

  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

 

                                                                53

 

  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

 

                                                                54

 

  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

 

                                                                55

 

  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.

 

                                                                56

 

  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

 

                                                                57

 

  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

 

                                                                58

 

  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

 

                                                                59

 

  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

 

                                                                60

 

  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.

 

                                                                61

 

  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

 

                                                                62

 

  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

 

                                                                63

 

  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

 

                                                                64

 

  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,

 

                                                                65

 

  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

 

                                                                66

 

  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

 

                                                                67

 

  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.

 

                                                                68

 

  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

 

                                                                69

 

  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.

 

                                                                70

 

  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

 

                                                                71

 

  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.

 

                                                                72

 

  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

 

                                                                73

 

  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

 

                                                                74

 

  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.

 

                                                                75

 

  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

 

                                                                76

 

  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

 

                                                                77

 

  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

 

                                                                78

 

  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

 

                                                                79

 

  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.

 

                                                                80

 

  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

 

                                                                81

 

  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

 

                                                                82

 

  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

 

                                                                83

 

  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            

22

 

                                                                84

 

  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

 

                                                                85

 

  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

 

                                                                86

 

  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

 

                                                                87

 

  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

 

                                                                88

 

  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

 

                                                                89

 

  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

 

                                                                90

 

  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

 

                                                                91

 

  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

 

                                                                92

 

  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.

 

                                                                93

 

  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,

 

                                                                94

 

  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.

 

                                                                95

 

  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;

 

                                                                96

 

  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.

 

                                                                97

 

  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

 

                                                                98

 

  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.

 

                                                                99

 

  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

 

                                                               100

 

  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

 

                                                               101

 

  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,

 

                                                               102

 

  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

 

                                                               103

 

  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

 

                                                               104

 

  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

 

                                                               105

 

  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

 

                                                               106

 

  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

 

                                                               107

 

  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

 

                                                               108

 

  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

 

                                                               109

 

  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,

 

                                                               110

 

  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

 

                                                               111

 

  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? 

 

                                                               112

 

  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.

 

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  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

 

                                                               114

 

  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

 

                                                               115

 

  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

 

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  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

 

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  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

 

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  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,

 

                                                               119

 

  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

 

                                                               120

 

  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

 

                                                               121

 

  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.

 

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  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

 

                                                               123

 

  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

 

                                                               124

 

  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

 

                                                               125

 

  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

 

                                                               126

 

  1   were important therapeutic questions to ask.

 

  2             You know, we can go into as much

 

  3   detail--there are actually investigators here from