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

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.

C O N T E N T S

Call to Order, Introduction of Committee - Bruce

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

Conflict of Interest Statement - Johanna Clifford,

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

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

Division of Therapeutic Biological Oncology

Products, FDA 11

Sponsor Presentations

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

Marty Huber 13

Johnson & Johnson, Ltd.

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

President, Global Regulatory Affairs 26

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

Senior Director, Clinical Team Leader, EPO, Drug

Development 33

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

Vice President, Hematology and Oncology,

Clinical Research and Global Development 47

Amgen, Inc.

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

President, Regulatory Affairs and Safety 53

- Aranesp Properties, Preclinical Observations

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

Professor of Biology and Bioengineering, MIT 58

- Aranesp Clinical Observations and Pharmaco-

vigilance Program Conclusions - David Parkinson,

M.D., Vice President, Oncology Clinical

Development 64

FDA Presentation

Harvey Luksenburg, M.D, Medical Officer, Division

of Therapeutic Biological Oncology Products, FDA 84

Open Public Hearing - [NONE]

Committee Discussion 145

Lunch 213

C O N T E N T S (Continued)

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

Acting Chair, ODAC 214

Conflict of Interest Statement - Johanna Clifford,

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

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

Division of Oncology Drug Products, FDA 218

Regulatory Background and Past FDA Approvals in

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

Officer, Division of Oncology Drug Products, FDA 225

Synopsis of FDA Colorectal Cancer Endpoints

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

Division of Medical Oncology, Allegheny General

Hospital, Pittsburgh, PA 242

Disease-Free Survival (DFS) vs. Overall Survival

(OS) as a Primary Endpoint for Adjuvant Colon

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

Cancer Center Statistics, Mayo Clinic Cancer

Center, Rochester, MN 260

Open Public Hearing 311

Committee Discussion 328

Adjourn 403

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

2 DR. CHESON: Good morning. Welcome to the

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

4 Bruce Cheson from the Lombardi Comprehensive Cancer

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

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

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

8 voluntary basis. And I am delighted to have some

9 excellent colleagues of mine on this committee

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

11 session by having everybody at the table introduce

12 themselves, starting with my friend Antonio

13 Grillo-Lopez.

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

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

16 hematologist/oncologist with the Neoplastic and

17 Autoimmune Diseases Research Institute.

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

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

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

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

22 medical oncologist and epidemiologist, and I'm a

1 professor at Emory University.

2 DR. MARTINO: Silvana Martino, medical

3 oncology, from the John Wayne Cancer Institute.

4 DR. TAYLOR: Sarah Taylor, medical

5 oncology, palliative care, University of Kansas.

6 DR. REAMAN: Gregory Reaman, pediatric

7 oncologist at the George Washington University and

8 Children's National Medical Center.

9 DR. REDMAN: Bruce Redman, medical

10 oncologist, University of Michigan.

11 MS. CLIFFORD: Johanna Clifford, FDA,

12 Executive Secretary to this meeting.

13 DR. DOROSHOW: Jim Doroshow, medical

14 oncologist, Director, Division of Cancer Treatment

15 and Diagnosis, NCI.

16 DR. GEORGE: Stephen George, Biostatistics, Duke

17 University.

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

19 oncology nurse and doctoral student at the

20 University of Texas, Medical Branch in Galveston,

21 and I'm the consumer representative.

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

1 research scientist at the Beth Israel Deaconess

2 Medical Center in Boston.

3 DR. GNECCO: Clare Gnecco. I am the

4 statistical reviewer for several of the epoetin

5 products.

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

7 medical reviewer at the Food and Drug

8 Administration.

9 DR. KEEGAN: Patricia Keegan, Division

10 Director, Division of Therapeutic Biological

11 Oncology Products.

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

13 Drug Evaluation VI, CDER, FDA.

14 DR. CHESON: Thank you.

15 Today we have an interesting series of

16 discussion, the morning of which will be a series

17 of presentations and discussions concerning safety

18 concerns associated with Aranesp from Amgen and

19 Procrit from Johnson & Johnson, both of which are

20 indicated for the treatment of anemia associated

21 with cancer chemotherapy. I was approached earlier

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

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

2 sufficient evidence that there is buzz about this,

3 and I look forward to an interesting series of

4 discussions.

5 We'll start off with opening remarks from

6 Dr. Keegan.

7 MS. CLIFFORD: Well, actually, me.

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

9 first. Johanna Clifford, the conflict of interest

10 statements.

11 MS. CLIFFORD: Thank you.

12 The following announcement addresses the

13 issue of conflict of interest with respect to this

14 meeting and is made a part of the record to

15 preclude even the appearance of such at this

16 meeting.

17 Based on the submitted agenda and

18 information provided by the participants, the

19 agency has determined that all reported interests

20 in firms regulated by the Center for Drug

21 Evaluation and Research present no potential for a

22 conflict of interest at this meeting with the

1 following exceptions:

2 Dr. Maria Rodriguez has been recused from

3 participating in all matters related to the

4 discussions of safety issues associated with

5 Aranesp and Procrit.

6 Dr. Kenneth Bauer has been granted a

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

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

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

10 $25,000.

11 Dr. John Carpenter has been granted a

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

13 an unrelated matter for the sponsor of Aranesp. He

14 is awaiting final payment of his fee that is less

15 than $5,000.

16 Dr. Otis Brawley has been granted a

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

18 his employer has a contract with the sponsor to

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

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

21 Brawley will be permitted to participate in the

22 committee's discussions; however, he will be

1 excluded from voting.

2 A copy of these waiver statements may be

3 obtained by submitting a written request to the

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

5 of the Parklawn Building.

6 Lastly, we would also like to note for the

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

8 Neoplastic and Autoimmune Diseases Research

9 Institute, is participating in this meeting as an

10 industry representative, acting on behalf of

11 regulated industry. He would like to disclose that

12 he is a scientific adviser to Chiron and receives

13 speaker fees from Wersch(ph).

14 In the event that the discussions involve

15 any other products or firms not already on the

16 agenda for which FDA participants have a financial

17 interest, the participants are aware of the need to

18 exclude themselves from such involvement, and their

19 exclusion will be noted for the record.

20 With respect to all other participants, we

21 ask in the interest of fairness that they address

22 any current or previous financial involvement with

1 any firm whose product they wish to comment upon.

2 Thank you.

3 DR. CHESON: Hearing no other comments,

4 now we'll go to Dr. Keegan.

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

6 the committee and the companies who have come

7 forward to present information about the

8 erythropoietin products, both those licensed in the

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

10 this is to review information based on the results

11 of in the context of recent findings from two

12 studies from Europe that suggested that there are

13 certain practices in the administration of

14 erythropoietin products which may raise concerns

15 for safety of the products.

16 I want to remind everyone that the

17 erythropoietin products that were approved in the

18 United States were approved as a means of treatment

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

20 period since original approval, there have been

21 investigations into alternative uses of these

22 products, looking at other benefits such as impact

1 on survival.

2 It is in that arena that two studies

3 recently conducted in Europe identified the

4 potential for some safety concerns with those

5 particular strategies. And we felt that it was

6 important at this time to review the available data

7 that both supported the original approval of

8 Aranesp and Procrit for treatment of anemia

9 associated with cancer, to review the clinical

10 trials in question conducted in Europe, and to

11 consider what additional information should be

12 obtained at this point in time to determine whether

13 or not an issue would exist with Procrit or Aranesp

14 for the treatment of anemia associated with cancer

15 and what the design of those studies should look

16 like or to hopefully rule out any problems at the

17 labeled and recommended doses for those two

18 products. So I would ask that the committee

19 carefully consider the data presented and provide

20 us with some guidance in the approach of these

21 additional studies.

22 I would like to draw your attention to the

1 fact that there are some errors in the FDA briefing

2 document, and we have provided an errata sheet that

3 will provide corrections to those errors. In

4 addition, we have revised Question 1 of the

5 questions to the committee in the first sentence,

6 and the modified questions are available as an

7 errata sheet at the table outside of this room.

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

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

10 joined by another member. If you could please

11 identify yourself and your affiliation? Turn on

12 the microphone, please. Hit the button.

13 DR. BAUER: Ken Bauer from Harvard, from

14 the VA Medical Center and Beth Israel Deaconess in

15 Boston.

16 DR. CHESON: Thank you.

17 Okay. The first presentation from a

18 sponsor will be about NeoRecormon, or epoetin beta,

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

20 name here, if you could also please introduce

21 yourself.

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

1 Huber, an oncologist with Hoffman-LaRoche.

2 Given the Advisory Committee's discussion

3 today of the safety of erythropoiesis-stimulating

4 agents in the treatment of cancer patients,

5 Hoffman-LaRoche volunteered to provide data from a

6 study that was recently published in The Lancet,

7 which we'll subsequently refer to as MF4449.

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

9 these findings, reviewing some other clinical

10 trials that have been conducted with epoetin beta.

11 Just a quick background. NeoRecormon is

12 the trade name for epoetin beta. It is a

13 recombinant human erythropoietin with a

14 well-established benefit/risk profile with more

15 than one million years of patient experience. It

16 has been available outside the United States since

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

18 approval based on patent issues. There were no

19 safety issues which prevented it from being brought

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

21 FDA. It is approved for patients with renal anemia

22 as well as oncologic indications in most of these

1 countries.

2 For the presentation today, we'd like to

3 review MF4449 focusing initially on the primary

4 study results as published in The Lancet. We will

5 also show additional analyses that were performed

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

7 clinical trial data with epoetin beta, and,

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

9 studies in which we have a long-term survival

10 follow-up.

11 MF4449 was a study which was looking at an

12 investigational use of epoetin beta. It was

13 looking at, Would increasing the hemoglobin with

14 epoetin beta lead to better efficacy of

15 radiotherapy? This was trying to invoke

16 radiosensitization, and could that lead to improved

17 progression-free survival in cancer patients? The

18 primary endpoint was local progression-free

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

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

21 This is an overview of the study design.

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

1 males with a hemoglobin less than 13, females less

2 than 12--were randomized to receive either epoetin

3 beta, 300 international units per kilogram sub-cu

4 three times weekly, or placebo in combination with

5 their radiotherapy. Then they were followed up

6 until progression or another endpoint.

7 The idea was to start them two weeks

8 before the radiotherapy, but this was not done in

9 all cases. Therefore, patients received a total of

10 either seven to nine weeks of epoetin beta maximum.

11 Epoetin beta was not continued in the follow-up

12 period.

13 An important factor in this study was how

14 the patients were stratified. As you know, head

15 and neck cancer is a very heterogeneous disease.

16 Therefore, we stratified them on the basis of tumor

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

18 stratified by resection status. Stratum 1 here was

19 patients who had had a complete resection. Stratum

20 2 was patients who had residual tumor after

21 resection. And Stratum 3 was, finally, patients

22 who received no attempt at resection and were

1 essentially treated with radiotherapy as their

2 primary therapy.

3 With regard to the population characs, the

4 details are in your briefing document, and they

5 were overall very well balanced. There were a

6 couple of exceptions we'd like to point.

7 First was smoking status. This was not

8 have a history of smoking but were they smoking at

9 the time. We believe this is relevant because we

10 know there is an interaction between active

11 cigarette smoking and radiotherapy which may

12 diminish the efficacy of radiotherapy. At

13 baseline, 53 percent of patients on placebo were

14 smoking; 66 percent in the epoetin beta group.

15 Furthermore, because the patients had had

16 surgery and then were randomized, there were

17 patients who had relapsed, even prior to

18 randomization. This was in balance, with 10

19 percent in the epoetin beta group, 7.6 percent on

20 placebo.

21 And, finally, for Stage IV TNM status,

22 there was a minimal imbalance at baseline, 72

1 percent versus 75 percent. But what you will see

2 is, as we start looking at subgroups, this

3 imbalance is magnified in an important subgroup.

4 These are the data that were shown in The

5 Lancet showing that there was a progression-free

6 survival advantage for placebo over epoetin beta.

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

8 important point here is during the first five to

9 six months, there was no difference in

10 progression-free survival. This will contrast with

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

12 We had conducted a series of secondary

13 analyses which were prospectively planned. The

14 intent of these analyses--we looked at the

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

16 robust throughout? And, also, was there

17 heterogeneity in the important subgroups?

18 Furthermore, when we looked at the

19 outcome, this inferiority of epoetin beta was very

20 much unanticipated. So this was in contrast to all

21 other clinical experience with epoetin beta. So

22 based on that, we did further additional analyses.

1 These were the planned secondary analyses to look

2 at the population robustness. What I'm showing

3 here are the Kaplan-Meiers for three populations:

4 intent to treat, radiotherapy correct, and,

5 finally, per protocol.

6 The differences between these groups are:

7 In the radiotherapy correct population, these are

8 the patients who received the radiotherapy as

9 specified in the protocol. The per protocol

10 population on the far right is not only did they

11 get the right radiotherapy, but they also got the

12 right treatment with regards to epoetin

13 beta/placebo according to dose and schedule in the

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

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

16 220.

17 What's important to notice is that as you

18 get to the purer population, the treatment effect

19 actually diminishes. This is contrary to what you

20 would expect. Normally when we do these studies

21 for robustness, we are looking to see the treatment

22 effect getting larger in the population that's

1 treated who are in per protocol. So this indicated

2 to us some lack of robustness in the data.

3 We did subgroup analysis. This is a

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

5 the categories, and these were categories we

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

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

8 baseline hemoglobin.

9 What we looked at is, to the left is

10 outcomes better with epoetin beta, and to right is

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

12 a divergence of findings on both sides of one.

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

14 of these subgroups in which there was the highest

15 relative risk, specifically Stratum 2 and they

16 hypopharynx.

17 Looking at the progression-free survival

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

19 patients who were completely resected. This is

20 Stratum 2, which were the patients who had residual

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

22 actual progression-free survival in Stratum 2

1 placebo was better than placebo with completely

2 resected patients. This goes contrary to the

3 natural history of these tumors and numerous other

4 publications. We would clearly expect that this

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

6 is there is obviously some evidence of something

7 odd about this placebo group.

8 Furthermore, when we looked into the tumor

9 site, if you look at the hypopharynx location,

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

11 treatment effect. This is placebo, epoetin beta.

12 However, all other locations there was no

13 difference in progression-free survival. So when

14 we do the subgroup analysis, the effect is

15 restricted to the hypopharyngeal population.

16 We looked further in this population, and

17 what we found was that we did have an imbalance

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

19 percent epoetin beta--within this subgroup. These

20 are the patients who did not have resection or

21 attempts at resection and were radiotherapy only.

22 Furthermore, we had an imbalance in the number of

1 patients who were in Stage IV.

2 With regards to safety, I apologize for

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

4 events, but essentially they were balanced overall:

5 65 percent placebo, 68 percent epoetin beta.

6 I would like to point out one piece of

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

8 reference to placebo 5 percent, epoetin beta 11

9 percent for vascular disorders. In this

10 terminology, vascular disorders includes

11 hypertension. What we have historically done when

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

13 of thromboembolic events. It does not include

14 hypertension. So if you see some differences in

15 numbers, this is what accounts for it

16 When we looked at thromboembolic events,

17 we saw placebo 3.5 percent, epoetin beta 5.6

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

19 more on the epoetin beta treatment group.

20 Furthermore, one of the things you may

21 have noticed in the briefing document, there was an

22 imbalance in cardiovascular deaths: 10 deaths on

1 the epoetin beta group versus 5 on placebo in the

2 cardiovascular category. Given the concerns about

3 thrombovascular events, what's important to note is

4 one epoetin beta and one placebo occurred around

5 day 50. The remaining deaths occurred after day

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

7 seven weeks, so these events are occurring well

8 after cessation of epoetin beta treatment.

9 In summary, we believe that there was a

10 heterogeneity of treatment effect across various

11 subgroups such as stratum, baseline hemoglobin,

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

13 also imbalances in important baseline

14 characteristics, smoking for the overall

15 population, as well as stage and resection status

16 for patients with tumors in the hypopharyngeal

17 location.

18 With regards to meta-analysis, this was

19 pooled results from nine controlled clinical

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

21 and hematologic tumors. We looked at tumor

22 progression, overall survival, and thromboembolic

1 events.

2 Once again this is a forest plot. What we

3 look at is better with epoetin beta, better with

4 placebo. This is the total population. These are

5 the individual studies. And then this is solid

6 versus hematologic.

7 What we saw was actually a reduction in

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

9 difference approaching significance. The remaining

10 studies are relatively consistent in that most of

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

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

13 finding for solid and hematologic tumors. In all

14 of these we saw a reduced risk of progression.

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

16 it's essentially the same for epoetin beta and

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

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

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

20 Very few deaths were noted in this study.

21 We also looked at thromboembolic events in

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

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

2 This was actually quite consistent with the

3 findings I presented from MF4449.

4 So, in summary, there was no evidence of

5 increased tumor progression in patients treated

6 with epoetin beta. There was no evidence of

7 decreased overall survival. There was a small

8 increase in the incidence of thromboembolic events:

9 6 percent of epoetin beta versus 4 percent on

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

11 looked at patient years of observation and

12 corrected for that, this difference disappeared.

13 The limitation of this meta-analysis is

14 most of these studies were relatively short in

15 duration because they were looking at endpoints

16 such transfusion or hemoglobin. Therefore, we

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

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

19 placebo-controlled study of epoetin beta in

20 patients with lymphoid malignancies. The primary

21 endpoint was transfusion-free survival, and as you

22 can see, there was a robust effect on that

1 endpoint.

2 What we did was an overall survival on

3 over 340 patients in this study. This is the

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

5 difference in overall survival between placebo and

6 epoetin beta.

7 In conclusion, the MF4449 study results

8 are inconsistent with the other epoetin beta

9 studies in oncology. We believe the most likely

10 explanation for the adverse outcomes observed in

11 MF4449 are factors independent of epoetin beta.

12 The large majority of existing data shows that

13 epoetin beta does not adversely affect tumor

14 progression or survival in cancer patients.

15 Thank you.

16 DR. CHESON: Thank you.

17 We're going to reserve questions until

18 after the FDA makes its presentation.

19 Next, Dr. DeLap from Johnson & Johnson.

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

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

22 DeLap. I'm Vice President for Regulatory Affairs

1 at Johnson & Johnson Pharmaceutical Research and

2 Development, and I will be providing a brief

3 introduction to our presentation.

4 We are pleased to be able to be here today

5 to participate in this discussion of the safety of

6 erythropoietin products in patients with cancer and

7 to present our data in support of this discussion.

8 We will not have time to summarize all of the

9 information that's been generated over the years in

10 our extensive research programs, so our

11 presentation will focus on the information that we

12 deem most relevant to today's discussion. Of

13 course, we will be pleased to elaborate further on

14 any specific points of interest.

15 Erythropoietin products are approved for

16 the treatment of anemia associated with

17 chemotherapy. Chemotherapy-associated anemia is a

18 common problem for patients with cancer, and this

19 anemia can be associated with debilitating symptoms

20 and may require transfusions of red blood cells.

21 Erythropoietic products have substantial value in

22 treating anemia and its symptoms and can

1 significantly reduce the need for transfusions.

2 This benefits individual patients and also means

3 that the units of red blood cells that are

4 collected by blood banks can serve the needs of

5 additional patients.

6 The safety profile of erythropoietin

7 products has been well established in years of

8 clinical use, both in chemotherapy-induced anemia

9 and in other illnesses where anemia may occur.

10 Epoetin alfa products have been the subject of may

11 clinical studies and have been used worldwide to

12 treat more than two million patients for this

13 indication.

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

15 are labeled for treatment of patients with cancer

16 chemotherapy-induced anemia. These are Procrit,

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

18 Aranesp, marketed by Amgen. Procrit became

19 available for this indication in 1993, and Aranesp

20 became available for this indication in 2002.

21 Products available outside of the U.S.

22 include EPREX, an epoetin alfa product that is also

1 marketed by J&J companies, and NeoRecormon and

2 Aranesp. All of these products share extensive

3 homology with naturally occurring human

4 erythropoietin, and all act by binding to the

5 erythropoietin receptor with activation of

6 downstream pathways leading to red blood cell

7 production.

8 Our presentation will describe a number of

9 studies that have been done in our extensive

10 clinical research program, and we will be talking

11 about two different types of studies. Studies in

12 supportive anemia care are the studies that were

13 used to establish the existing indication for use

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

15 the treatment of anemia associated with cancer

16 chemotherapy. In this use, anemic patients are

17 typically treated with a goal to obtain at least 1

18 gram per deciliter rise in hemoglobin level, to

19 raise the patient's hemoglobin to a target range

20 that is still below normally, typically, but is

21 sufficient to reduce the likelihood of a

22 transfusion.

1 Beyond correction of anemia is the term

2 that we will be using today to describe

3 investigational uses that have evaluated the use

4 erythropoietin products to treat patients to higher

5 hemoglobin target levels. Recent studies

6 evaluating the effect or erythropoietic agents on

7 cancer treatment outcomes have often utilized this

8 design.

9 It was hypothesized that any beneficial

10 effects of treatment with erythropoietic agents on

11 cancer treatment outcomes might be magnified with

12 treatment to higher hemoglobin target levels.

13 However, some of these studies have suggested

14 unexpected risks, including decreased survival.

15 This has led to extensive work that is

16 continuing at our company to better understand the

17 observations from these studies and to ensure that

18 patients and prescribers will continue to have all

19 of the information necessary to support the safe

20 and effective use of our erythropoietin alfa

21 products.

22 Safety data we will be presenting data are

1 as follows: We will first summarize data obtained

2 in our clinical studies of epoetin alfa in

3 supportive anemia care, which, together with the

4 extensive clinical experience over more than a

5 decade, support the favorable risk/benefit ratio

6 for epoetin alfa for the existing indication.

7 Second, we will summarize data from a

8 number of investigational studies that have

9 involved treatment of patients beyond correction of

10 anemia, including indications of increased risks

11 that have arisen in some of these studies using

12 that treatment approach. We remain interested in

13 studying the effects of epoetin alfa on cancer

14 treatment outcomes, but we have modified the

15 hemoglobin target levels that we are using in that

16 research.

17 Finally, we will describe additional data

18 that we are collecting and further research that we

19 have currently under consideration.

20 We look forward to the advice of the

21 Advisory Committee today as we work to do the best

22 possible job of planning our future activities in

1 this area.

2 Our agenda for our presentation is as

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

4 programs with Procrit, will summarize our data from

5 epoetin alfa studies that have been done for

6 supportive anemia care and investigational studies

7 that have involved treatment beyond the correction

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

9 entire hematology/oncology clinical development

10 program, will then describe future clinical data

11 relevant to this subject that we expect to have

12 from our currently ongoing studies and an

13 additional clinical study that we are considering

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

15 George will conclude our presentation.

16 We have with us today several advisors to

17 help facilitate the discussion, as noted on this

18 slide, including Drs. Jesse Berlin, Kimberly

19 Blackwell, Roger Cohen, George Demitri, Mark

20 Levine, and Brian Leyland-Jones.

21 Now I would like to introduce Dr. Peter

22 Bowers for his summary of information from our

1 clinical study database. Thank you.

2 DR. BOWERS: Dr. Cheson, committee

3 members, during the next minutes I will present a

4 summary of safety information available from

5 studies of epoetin alfa conducted in two settings:

6 supportive anemia care, our labeled indication, and

7 studies beyond correction of anemia.

8 We undertook a combined analysis of ten

9 completed randomized, double-blind,

10 placebo-controlled studies evaluating the use of

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

12 anemia care. These data from 1,976 patients

13 represent all controlled studies in this setting

14 for which we have full patient level data regarding

15 survival available. We examined mortality hazard

16 ratios for deaths during the double-blind phase

17 plus 30 days, and also tumor response and disease

18 progression information, the latter available in

19 five of the ten studies. Thrombotic vascular

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

21 also be presented.

22 Some points should be kept in mind

1 regarding these analyses. The studies represent a

2 variety of tumors, and many include mixed tumor

3 types. The studies were designed and conducted to

4 assess the impact of epoetin alfa on reducing

5 transfusion and correcting anemia. Thus, data

6 regarding survival and tumor response or disease

7 progression were collected as secondary endpoints

8 and/or for safety purposes. Additionally, the

9 study drug treatment period ranges from 12 to 24

10 weeks, plus 4 weeks follow-up.

11 These are the results from the combined

12 analysis for mortality. The chart in the center of

13 the slide displays the point estimates, the red

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

15 white horizontal bars. Unity is the dashed

16 vertical line. A point estimate less than one

17 suggests lower mortality among epoetin-treated

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

19 of the chart would favor epoetin alfa;

20 this side favors placebo.

21 Please note for the combined analysis the

22 point estimate for mortality is 0.99, shown at the

1 bottom, with a confidence interval 0.76 to 1.28.

2 This means mortality among epoetin alfa-treated

3 patients was the same as placebo patients in these

4 studies.

5 We reviewed tumor response and disease

6 progression data from the five studies where this

7 information was collected. As you can see,

8 response rates were similar between treatment

9 groups, and also as you see, disease progression

10 assessed in four studies was also similar between

11 treatment groups.

12 To summarize, the established benefits of

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

14 anemia related to cancer chemotherapy--include

15 transfusion reduction and amelioration of the

16 debilitating symptoms of anemia. An evaluation of

17 the studies in the approved indication showed no

18 signal of reduced survival and no indication of an

19 adverse impact on tumor response or disease

20 progression. Thus, the benefits of epoetin alfa

21 therapy continue to be supported by a well-defined

22 and acceptable risk profile when used for the

1 approved indication of anemia in patients receiving

2 cancer chemotherapy.

3 Now I'm going to turn to studies from

4 epoetin alfa used in settings beyond correction of

5 anemia, and before presenting the clinical data,

6 I'd like to review very briefly some key

7 preclinical findings.

8 The preclinical literature suggests a

9 potential benefit of erythropoietins on tumor

10 growth. However, there are also reports that

11 suggest the possibility of a deleterious effect.

12 Many tissues, including tumor cell lines, express

13 erythropoietin receptors. In experiments by

14 Johnson & Johnson and external groups, involving

15 more than 25 different tumor cell lines, including

16 cell lines known to express erythropoietin

17 receptor, erythropoietin did not cause tumor cell

18 proliferation. Similarly, systemic administration

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

20 units per kilogram three times per week in in vivo

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

22 did not increase tumor volume. Moreover, a

1 positive effect on tumor growth delay has been

2 observed in animal models of concurrent

3 administration of erythropoietins in chemotherapy

4 or radiation therapy.

5 There are conflicting reports regarding

6 the impact of erythropoietin on tumor cell growth.

7 Some experiments in vitro indicate increased tumor

8 cell proliferation at erythropoietin concentrations

9 5- to 100-fold greater than those achieved

10 clinically using a dose of 40,000 international

11 units.

12 Based on the balance of positive

13 preclinical data and results from Study INT-10,

14 published by Dr. Timothy Littlewood in the Journal

15 of Clinical Oncology 2001, which suggested a

16 potential positive survival impact, the company

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

18 summarized in your background briefing materials.

19 INT-76 is a large study, 939 women

20 receiving first-line chemotherapy for metastatic

21 breast cancer, with a simple design. EPREX or

22 placebo was administered weekly and continued for

1 12 months, regardless of chemotherapy changes or

2 disease progression.

3 Study drug was initiated at a hemoglobin

4 of 13 or below and titrated to maintain hemoglobin

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

6 study was survival at 12 months. Objective

7 confirmation of investigator-reported secondary

8 endpoints, including disease progression and tumor

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

10 me. Study drug treatment was discontinued at the

11 recommendation of the DSMB for the study, and at

12 that time 88 percent of the subjects had completed

13 planned study drug treatment or had been withdrawn

14 from the study. The shortest duration of treatment

15 was nine months. Blinded follow-up continued out

16 to the 12-month endpoint. Groups were generally

17 balanced with regard to prognostic factors.

18 This slide shows the Kaplan-Meier plot for

19 survival. The vertical axis is probability of

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

21 Below the horizontal axis are the numbers of

22 patients represented at each time point. White is

1 placebo, blue represents epoetin alfa. Please

2 observe the survival curves begin to diverge

3 relatively early in the course of follow-up such

4 that by month 4 the separation was near maximal,

5 and the curves continued parallel out through month

6 12.

7 The primary endpoint, survival at 12

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

9 in the placebo group, and 30 percent deaths of

10 patients in the epoetin alfa group. This

11 difference has a p value of 0.012. The hazard

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

13 1.37, the confidence interval 1.07 to 1.74.

14 In light of these unexpected results,

15 extensive analyses were undertaken by the company.

16 Post hoc analyses, including subgroup and Cox

17 modeling, were undertaken, and results of these

18 analyses should be considered exploratory and

19 interpreted cautiously. No particular subgroup was

20 identified as accounting disproportionately for

21 most of the mortality difference.

22 Additional data were collected in a

1 retrospective blinded chart review of the medical

2 records of all subjects in the study. While not

3 conclusive, the analyses in chart review, together

4 with data from other trials, provide some

5 hypotheses that might explain the observed survival

6 difference. An adverse impact of epoetin alfa on

7 tumor proliferation is one hypothesis. Another is

8 imbalance in fatal thrombotic vascular events. And

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

10 Now, looking in detail at the cause of

11 death data we have from INT-76, investigators

12 captured cause of death on a case report form page

13 with check boxes for either disease progression or

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

15 since most of the difference in mortality had been

16 seen by that time point. Investigators attributed

17 most deaths to disease progression with a

18 difference between the groups, as you can see on

19 the slide.

20 In the other category, investigators

21 listed thrombotic vascular events, chemotherapy

22 toxicity, again, with differences as shown.

1 The blinded chart review suggested a

2 somewhat higher rate of thrombotic vascular events

3 than was reported by investigators, as you see on

4 the bottom of the slide: two among placebo group

5 patients, 11 among the epoetin alfa group patients,

6 at the 4-month time point.

7 This suggests the possibility that

8 thrombotic vascular events may have been underdiagnosed or

9 -reported as a cause of death in this

10 study and may have accounted for more of the excess

11 deaths in the epoetin alfa arm than was

12 appreciated.

13 The high number of deaths within the first

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

15 indicate that a more sick patient population than

16 usual for a first-line metastatic breast cancer

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

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

19 greater number of deaths was attributed to disease

20 progression by investigators.

21 Further supporting the observation that

22 the observed early differences in mortality may

1 have resulted in substantial part from causes other

2 than tumor proliferation, the time to disease

3 progression curves shown here--placebo, again,

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

5 Response rates for the groups are similar: 46

6 percent and 45 percent. Thirty-eight percent of

7 patients in the placebo group developed new

8 lesions, whereas 30 percent of epoetin alfa

9 patients did. These results are not consistent

10 with an adverse impact of epoetin alfa on tumor

11 growth.

12 Given that this is a large, randomized,

13 double-blind study with unbiased, if incomplete,

14 collection of tumor progression data, these results

15 should be considered carefully.

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

17 disadvantage was observed in the treatment group.

18 Deaths were attributed to investigators in

19 significant part to disease progression. However,

20 investigator-reported disease progression and

21 response rates were similar. Given these

22 inconsistencies, other potential explanations for

1 the outcome merit consideration as well and, in

2 particular, thrombotic vascular events may have

3 been underdiagnosed as a cause of death in this

4 study.

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

6 studies using epoetin alfa in settings also beyond

7 correction of anemia. Here we see summarized

8 several other studies that evaluated epoetin alfa

9 use in these settings. These studies are grouped

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

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

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

13 included at the top for reference.

14 As you see, the table summarizes some key

15 details of the studies. In general, these studies

16 have used epoetin alfa in settings where patients

17 are not anemic or are treated to hemoglobin levels

18 that are somewhat or substantially higher than are

19 needed for correction of anemia.

20 The mortality experience is shown here.

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

22 exception of Study INT-76, mortality is not

1 significantly different. The five discontinued

2 studies represent studies stopped as a result of

3 unplanned interim analyses of safety conducted at

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

5 than 15 studies continued, some with modifications

6 to reduce target hemoglobins.

7 All five studies were stopped based on an

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

9 draw definitive conclusions other than to note

10 unfavorable survival trends for epoetin

11 alfa-treated patients in some of the stopped

12 studies. Follow-up data collection for these five

13 studies is continuing to further understand the

14 results.

15 Now, let's consider the data relevant to

16 tumor proliferation or disease response, as

17 indicated by the endpoints shown on the slide:

18 response rates, time to disease progression,

19 disease-free survival, and so forth.

20 Looking at the column on the right, the

21 differences in outcomes related to tumor response

22 or disease progression tend to be small. These

1 data show no signal that epoetin alfa is associated

2 with an adverse impact on adverse impact on tumor

3 growth.

4 Turning to clinically relevant thrombotic

5 vascular events in this same group of studies,

6 clinically relevant thrombotic vascular events, or

7 TVEs, are those which would be regarded by

8 clinicians as significant and include both the

9 venous and arterial events, but exclude such

10 occurrences as superficial venous thrombophlebitis

11 or catheter-related thromboses.

12 Here I've ordered the studies by frequency

13 of clinically relevant TVEs in the epoetin

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

15 Please note the substantial differences in the

16 frequency of clinically relevant TVEs.

17 Study 1015 with the greatest difference in

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

19 the highest target hemoglobin level.

20 In contrast to this is the frequency of

21 TVEs in the ten studies of supportive care of

22 anemia. The studies are ordered by TVE frequency

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

2 or lower. In general, the absolute frequency of

3 TVEs is substantially lower than is seen in the

4 group of studies beyond correction of anemia.

5 Differences between the groups are also smaller,

6 with a negative number indicating more TVEs in

7 placebo group patients.

8 Overall, the odds ratio shown at the

9 bottom of the slide is 1.55, indicating a modestly

10 increase risk of clinically relevant TVEs in the

11 epoetin alfa-treated patients, the confidence

12 interval 0.96 to 2.5.

13 In conclusion, our data indicate a

14 favorable benefit/risk profile for epoetin alfa

15 with no signal of tumor proliferation or adverse

16 survival impact in settings of supportive anemia

17 care. In study settings using epoetin alfa beyond

18 correction of anemia, adverse outcomes have been

19 seen. However, there is no clear signal suggesting

20 an adverse effect on tumor proliferation. There is

21 an indication that thrombotic vascular events are

22 more frequent in studies with higher target

1 hemoglobin levels. This may account for some,

2 possibly much, of the observed survival signal.

3 Additional data are being collected, and a

4 new trial is under consideration. Dr. Martine

5 George, therapeutic area head of oncology and

6 hematology at Johnson & Johnson PRD, will share

7 further details with you.

T1B DR. M. GEORGE: Thank you. 8

9 Johnson & Johnson has been studying the

10 potential benefit of epoetin alfa in the setting of

11 beyond correction of anemia since 1999, and our

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

13 a clinical trial design for a study considering the

14 FDA guidance. Then I will review with you how

15 populated and ongoing trials could be used to

16 address the safety questions raised.

17 We considered several clinical trial

18 designs according to the agency requests, and after

19 critical analysis, we decided to select advanced

20 breast cancer. Our proposed clinical trial will

21 focus on breast cancer based on the signal observed

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

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

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

3 the need for homogeneity in terms of patient

4 population and chemotherapy.

5 Furthermore, early clinical trials in

6 anemic patients have suggested a favorable outcome

7 in patients with anemia treated with erythropoietin. The

8 unfavorable outcome of INT-76 doesn't

9 preclude a potential benefit in anemic patients.

10 We are assuming a potential benefit, but

11 the trial will have to be powered to exclude a

12 negative effect, as requested by the agency.

13 The objective of the trial is simple.

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

15 outcomes in patients with metastatic breast cancer

16 receiving first-line chemotherapy.

17 The proposed clinical trial will be

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

19 will enroll patients with advanced breast cancer

20 receiving first-line chemotherapy, including taxane

21 and/or anthracyclines. Patients will be anemic at

22 entry with hemoglobin at baseline equal to or less

1 than 11 grams per deciliter before their third

2 cycle of chemotherapy. Patients will receive EPREX

3 or placebo until tumor progression, end of

4 chemotherapy, or death. The target hemoglobin

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

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

7 13 grams per deciliter.

8 The endpoints of the clinical trial will

9 be as follows: The primary endpoint will be

10 progression-free survival, and because of lack of

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

12 progression-free survival. Secondary endpoints

13 will include overall survival, thrombotic vascular

14 events, response rate, and TTP.

15 Statistical methods will include a

16 non-inferiority comparison, possibly followed by a

17 superiority test. Two thousand patients will

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

19 reduction in progression-free survival, assuming no

20 difference. If non-inferiority is demonstrated, a

21 superiority test will be done. There will be

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

1 progression-free survival.

2 There are some considerations when

3 designing the trial in which we will particularly

4 welcome your feedback. The first challenge is to

5 run a placebo-controlled trial when anemic patients

6 receive drug treatment as a standard of care.

7 Crossover of placebo patients following the

8 double-blind phase could obscure the assessment of

9 overall survival.

10 Second, functionality of the EPO receptor

11 is best addressed in fresh frozen samples.

12 Collecting samples may significantly slow down

13 patient enrollment into the trial and would delay

14 study completion. However, more preclinical

15 studies to assess ligand affinity, signal

16 transduction, and gene expression are warranted to

17 better understand the receptor and its

18 functionality.

19 Providing patients with a homogenous

20 chemotherapy regimen is complicated, but at least

21 three elements: the previous adjuvant

22 chemotherapy, the wide range of available

1 therapies, and constant innovation in therapy.

2 And, finally, this clinical trial should

3 provide an opportunity to better understand and

4 control the causes of thrombotic events.

5 In the next two to three years, as

6 depicted on the slide, we will have considerably

7 more information in the areas of tumor control and

8 survival from the tumor types where we have

9 observed a survival signal: breast cancer, head

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

11 data in carcinoma of the cervix, all in studies

12 beyond the correction of anemia.

13 In summary, we will have a significant

14 amount of additional data in the next two to three

15 years from those recently completed studies and

16 ongoing studies. This data will provide

17 significant information in various tumor types.

18 We welcome your advice and opinions on the

19 timing, design, and challenges of the proposed

20 study.

21 And now I would like to conclude the

22 Johnson & Johnson presentation. As you have read,

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

2 we have extensive clinical experience which

3 supports the favorable benefit/risk profile of

4 Procrit. We take very seriously the survival

5 signal observed in metastatic breast cancer and

6 head and neck cancer that occurred in studies

7 assessing the benefit beyond the correction of

8 anemia with two different products: EPREX and

9 NeoRecormon. We have looked for and found no clear

10 tumor proliferation signal as assessed by response

11 rate and tumor progression.

12 We note that TVEs account for some,

13 potentially much, of the negative signal we have

14 observed in those trials. In contrast, some

15 studies in supportive anemia suggest a potential

16 benefit in cancer outcome, and future clinical

17 evaluation in that setting may provide the answer

18 to that question.

19 In summary, Procrit provides important

20 benefits for patients with cancer by decreasing

21 transfusion and alleviating anemia symptoms. We

22 are committed to maximizing those benefits and

1 minimizing the risks associated with its use.

2 We look forward to working with ODAC and

3 FDA to optimize our current and future development

4 programs.

5 Thank you very much for your attention.

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

7 Amgen presentations, their partners for the day.

8 Dawn Viveash will do the introductions.

9 DR. VIVEASH: Good morning, members of the

10 committee, FDA participants, ladies and gentlemen.

11 Amgen is pleased to be here today to present data

12 regarding the benefit and safety of Aranesp in the

13 treatment of patients with chemotherapy-induced

14 anemia.

15 We have with us today a number of

16 distinguished guests: Dr. Jeffrey Crawford, Dr.

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

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

19 Joseph Eschbach.

20 In addition, we have a number of

21 independent investigators who are currently

22 conducting oncology studies with Aranesp. These

1 investigators are Dr. Overgaard, representing the

2 Danish Head and Neck Cancer Study Group; Directors.

3 Delarue and Bosley, representing the GELA Lymphoma

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

5 study; and Dr. Kahlert, representing the German

6 Gynecological Oncology Study Group.

7 I will open the presentation with a brief

8 overview on preclinical and clinical properties of

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

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

11 presenters than is shown on the published agenda.

12 We will have Dr. Harvey Lodish discuss considerations

13 regarding the epoetin receptor. His lab was

14 the first to clone the EPO receptor. He is

15 professor of biology and bioengineering at MIT and

16 is a member of the National Academy of Science.

17 Dr. David Parkinson will describe the clinical

18 observations with Aranesp, and he will also provide

19 an overview of our clinical trial program.

20 Aranesp is a distinct erythropoietic

21 molecule. The development of Aranesp represents

22 the combination of over ten years of research

1 during which time more than 450 molecules were

2 characterized. Aranesp is unique as a result of

3 its novel amino acid sequence, which allows for two

4 additional carbohydrate chains, leading to an

5 increased negative charge and increase in molecular

6 weight. The terminal half-life of Aranesp is

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

8 longer half-life less frequent dosing can be

9 utilized compared to erythropoietin.

10 Aranesp was initially approved in 2001 for

11 the treatment of anemia associated with chronic

12 renal failure in both dialysis and non-dialysis

13 patients. It was subsequently approved in July of

14 2002 for chemotherapy-induced anemia.

15 I'd like to highlight some relevant safety

16 information from the package insert. The warnings

17 section represents prior observations from the

18 Normal Hematocrit Study which was conducted with

19 EPOGEN. This was conducted in dialysis patients

20 with pre-existing cardiovascular disease. This

21 section also addresses high hemoglobin, rate of

22 rise, and mortality.

1 The dosing guidance recommends a

2 hemoglobin target of 12 and provides instructions

3 for dosage adjustment to avoid excessive rate of

4 rise of hemoglobin.

5 The precautions section includes a

6 statement regarding the theoretical concern of

7 growth factor potential, and the adverse reactions

8 section describes the thrombovascular events.

9 You are now well aware of the findings

10 from studies with epoetin alfa and epoetin beta and

11 their observations regarding survival, tumor

12 progression, and thrombotic events. When Amgen

13 became aware of these findings, we conducted a

14 comprehensive review of preclinical and clinical

15 data.

16 The preclinical data with respect to

17 Aranesp does not support the contention that this

18 agent stimulates tumor growth. Aranesp is not

19 genotoxic. There were not proliferative or

20 hyperplastic signals in six-month toxicology

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

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

1 seen with Aranesp or erythropoietin in toxicology

2 studies.

3 In studies of tumor xenografts, one of

4 which was performed by Dr. Blackwell from Duke

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

6 stimulation of tumor proliferation. In fact, to

7 the contrary, there was a potential beneficial

8 effect observed when Aranesp was administered in

9 combination with radiotherapy in some models.

10 The clinical review includes

11 epidemiological analysis of thrombotic events and a

12 review of completed and ongoing Aranesp trials and

13 also an assessment of post-marketing experience.

14 Dr. Parkinson will review our observations from the

15 clinical data.

16 Based on this comprehensive review of

17 oncology data, we did not identify any adverse

18 survival or tumor progression signal with Aranesp.

19 The thrombotic event rate remains consistent with

20 that represented in the product label.

21 One of the hypotheses that has been put

22 forward from the signals observed in the BEST and

1 Enhanced studies relates to the role of the EPO

2 receptor in tumor progression. I would like to ask

3 Dr. Lodish to address the potential relevance of

4 the EPO receptor on tumors and the utility of

5 current methods to detect the receptor.

6 Thank you, Dr. Lodish.

7 DR. LODISH: Thank you.

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

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

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

11 erythropoietic agents drive the oncogenic process.

12 The EPO receptor is present at very low levels on

13 many normal and tumor cells, but the EPO receptor

14 does not possess any of the characteristics of an

15 oncogenic receptor.

16 For example, as you know, established

17 oncogenic tyrosine kinase receptors, such as HER2

18 or the epidermal growth factor receptor, are

19 amplified and mutated in many types of human

20 tumors. Receptors can be overexpressed as many as

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

22 cancers. In other cases, mutation leads to

1 constituitive--that is, hormone

2 independent--activation. Both cases are

3 transforming, are prognostic markers, and are

4 established therapeutic targets.

5 The situation is quite different for the

6 EPO receptor. With the sole exception of erythroleukemia,

7 where EPO gene amplification has been

8 recognized, EPO receptor amplification has not been

9 seen in human tumors. The presence of gene

10 amplification into erythroleukemic cell lines

11 illustrates that the failure to detect involvement

12 of the EPO receptor in the vast majority of cancer

13 samples is genuine and not simply a false negative

14 result. And it's my understanding that Aranesp

15 treatment of erythroleukemia is not recommended.

16 Importantly, there are no constituitive

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

18 receptor mutants in any human or animal tumors.

19 The one case of humans with mutations in the EPO

20 receptor involve truncations of the cytoplasmic

21 domain that render the receptors hypersensitive to

22 erythropoietin. These individuals develop

1 polycythemia but have no increased tumor incidence.

2 And, in conclusion, then, the EPO receptor

3 is not known to initiate tumorigenicity or cause

4 primary solid tumors to proliferate. There are no

5 known correlations of EPO receptor expression or

6 mutation with any aspect of oncogenicity.

7 I've also been asked to comment on

8 methodological aspects of existing and potential

9 assays for functional EPO receptors on primary

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

11 point out several important aspects of EPO receptor

12 expression on erythroid cells.

13 First of all, over 90 percent, well over

14 90 percent of the EPO receptors in erythroid cells

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

16 cytoplasm on various membranes. Erythroid cells

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

18 surface. Non-erythroid cells are transformed or

19 otherwise generally have much less. And,

20 importantly, surface expression of the receptor

21 requires expression of the JAK-2 protein tyrosine

22 kinase and possibly other accessory proteins.

1 Finally, the high-affinity receptor that

2 is seen on erythroid cells, the signaling receptor,

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

4 initiates downstream signaling. The low-affinity

5 receptors that are seen on the vast majority of

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

7 and likely are forming a 1-erythropoietin,

8 1-erythropoietin complex and are not signaling.

9 Concerning the assays that one might think

10 of for erythropoietin receptor detection in primary

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

12 First of all, numerous publications discuss EPO

13 receptor expression and function in tumor cell

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

15 primary tumor samples in a clinical setting. And,

16 importantly, only cell surface receptors are

17 clinically and biologically relevant. Only these

18 receptors can bind to erythropoietin and send

19 signals to the inside of the cell.

20 It's important to note that there are no

21 measurements for functional epoetin receptors

22 possible in fixed or frozen tissues. Reverse

1 transcriptase polymerase chain reaction, RT-PCR,

2 measures RNA copies or transcripts of the EPO

3 receptor gene. That does not necessarily measure

4 functional EPO receptor message and does not

5 measure EPO receptor protein, and certainly not

6 functional receptor. And, importantly, these

7 studies would require separation of the tumor cells

8 from the other cells in the tumor.

9 Immunohistochemistry measures erythropoietin

10 receptors in the cytoplasm and is too

11 insensitive to detect the minute numbers that might

12 be expected on the surface of cells. And,

13 importantly, the existing antibodies, commercial or

14 otherwise, are simply not sufficiently specific to

15 detect EPO receptors among other background

16 proteins.

17 There are ways of detecting functional EPO

18 receptors in fresh tumor biopsies, but they also

19 present many problems. First of all, these

20 measurements would require fresh samples of cells

21 and samples in which the tumor cells have been

22 separate from the non-tumor cells. Binding with

1 radiolabeled EPO to cell surface receptors is

2 possible, but it is very difficult to detect the

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

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

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

6 saturable binding to cell surface EPO receptors

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

8 other cell surface components.

9 Proliferation of tumor cells in culture

10 and response to EPO is also not practical for the

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

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

13 the only assay that would detect functional EPO

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

15 other types of cells--involve EPO-induced

16 activation of downstream signaling proteins as

17 measured by, say, phosphorylation of the

18 erythropoietin receptor, the JAK-2 kinase, other

19 signaling proteins. These are complicated assays

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

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

22 have been purified from other cells, and in

1 non-erythroid cells, these immuno-precipitation

2 Western blot analyses are quite insensitive and

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

4 So, in conclusion, there are no presently

5 available assays suitable for routine measurement

6 of functional erythropoietin receptors on primary

7 solid human tumors. Development of such assays

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

9 these assays might ultimately take.

10 I now turn the podium over to Dr.

11 Parkinson, who will discuss the clinical

12 observations.

13 DR. PARKINSON: Good morning. Thank you,

14 Dr. Lodish.

15 Outlined are the clinical observations

16 which I will discuss relevant to this morning's

17 meeting. After briefly reviewing some of the

18 benefits associated with the treatment of anemia,

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

20 risk of thrombotic events in association with

21 erythropoietins. Next I'll present the analysis of

22 survival in completed clinical trials. And,

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

2 involving Aranesp in different tumor treatment

3 settings.

4 Together, these trials have power to

5 detect a safety signal far smaller than those which

6 have been discussed already this morning. We

7 believe this represents a responsible and credible

8 approach to definitively resolving the questions

9 raise in this morning's meeting.

10 With regard to the cancer indication,

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

12 no meaningful discussion of risk can occur in the

13 absence of a consideration of benefit. Anemia,

14 which translates in patients with cancer into the

15 important symptom of fatigue, is a highly prevalent

16 comorbidity which significantly affects the quality

17 of life in patients with cancer. Without

18 erythropoietic protein therapy, 90 percent of

19 cancer patients undergoing chemotherapy will have

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

21 those patients will require transfusions.

22 Historically, chemotherapy-related anemia

1 has been treated with transfusion, with its

2 attendant inconveniences and risks. Not only is

3 fatigue common in cancer patients, but fatigue as a

4 symptom is rated by the majority of patients to be

5 more important even than pain.

6 The left side of this panel shows the

7 hematopoietic response indication correction of

8 anemia by Aranesp therapy. Portrayed to the right

9 is the significant decrease in the rate of

10 transfusion with Aranesp therapy utilizing dosing

11 intervals extending as far as three weeks.

12 Extensive literature suggests the

13 association of this anemia correction with improved

14 fatigue and other quality-of-life scores.

15 Recognition by the oncology community of the

16 importance of anemia and the benefits of its

17 treatment with erythropoietic proteins have led to

18 the production of independent, evidence-based

19 treatment guidelines. These include treatment

20 algorithms and desirable upper levels for

21 hemoglobin.

22 These evidence-based guidelines have been

1 incorporated by Amgen into our current trials and

2 analyses. Furthermore, treatment recommendations

3 in the product label are consistent with these

4 guidelines.

5 We'll now present the results of our

6 evaluation of thrombotic events in patients with

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

8 patients with cancer have a higher background rate

9 of thrombotic events. A full description of the

10 epidemiology of these events in patients with

11 cancer is outlined in our briefing document. We

12 have extensively reviewed that.

13 The increased risk of thrombotic events

14 with Aranesp therapy is represented in the adverse

15 events section of the Aranesp label, as has already

16 been discussed by Dr. Viveash. But we proactively

17 initiated a reevaluation of thrombotic event

18 experience within Aranesp clinical trials--these

19 are 11 completed trials as of late last

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

21 subjects relative to more than 400 placebo-treated

22 subjects.

1 On this slide, we see that our own Amgen

2 analysis of the Medstat Claims database reflecting

3 patients treated primarily with erythropoietin alfa

4 also shows an increased risk of thrombotic events

5 with epoetin alfa therapy. This analysis is

6 consistent with the Cochran meta-analysis involving

7 cancer patients receiving either erythropoietin

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

9 December American Society of Hematology meeting,

10 the relative risks of thrombotic events in our

11 study and the Bohlius study being 1.4 and 1.55,

12 respectively.

13 We'll now show you our analysis of

14 survival in completed clinical trials.

15 We identified four suitable randomized,

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

17 these, involving more than 600 patients, had

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

19 carefully evaluate Aranesp's effect on survival.

20 One trial was conducted in lung cancer and included

21 anemic patients beginning platinum-based

22 chemotherapy. A second trial involved patients

1 with five different lymphoid malignancies. In this

2 trial, Aranesp therapy was initiated when patients

3 became anemic. Finally, Amgen conducted a pooled

4 analysis involving these two trials and two

5 additional controlled trials comprising more

6 heterogeneous patient populations.

7 The first of the studies, in lung cancer,

8 is represented on this slide. More than 300

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

10 lung cancer beginning platinum-based chemotherapy

11 were randomized to weekly Aranesp or placebo. The

12 relatively homogeneous patient population, the fact

13 that most patients were beginning chemotherapy, and

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

15 appropriate for survival analysis. Seventy percent

16 of these patients have been followed until death.

17 On this slide, we see the results of this

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

19 decrease in progression-free survival with Aranesp.

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

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

22 cancer subjects. These subsets behave similarly.

1 This slide shows similar results for

2 overall survival. The sample size of the trial and

3 the number of observed deaths were appropriate to

4 detect reduced survival of the magnitude seen in

5 the BEST and Enhanced or Henke trials. Yet there

6 is evidence for any negative survival influence

7 with Aranesp therapy.

8 Trial 161, this lymphoid malignancy trial,

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

10 indicated, since patients with multiple lymphoid

11 tumor types were eligible, and these patients could

12 be randomized anytime during the course of

13 chemotherapy. In this study, 344 patients with one

14 of five different lymphoid malignancies with

15 chemotherapy-induced anemia were randomized to

16 receive either weekly Aranesp or placebo. The

17 distribution of the different malignancies is

18 outlined here.

19 The slide illustrates the baseline

20 characteristics of the patients in the lymphoid

21 malignancy trial. The study, while it did include

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

1 anemia. As a consequence, patients were not

2 stratified for malignancy-specific prognostic

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

4 patients with the worse prognosis for both

5 non-Hodgkin's lymphoma and chronic lymphocytic

6 leukemia to be assigned to the Aranesp arm.

7 This slide indicates the trial result. We

8 see on this slide no evidence for a significant

9 decrease in progression-free survival. The hazard

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

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

12 interval extends below 1. We continue to follow

13 these patients.

14 On this slide, we observe no convincing

15 evidence for a significant decrease in overall

16 survival in association with Aranesp therapy.

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

18 confidence interval extends below 1. We've

19 presented data on individual lymphoid malignancy

20 subset in the briefing document.

21 I will now review the pooled analyses for

22 these completed trials.

1 As previously noted, two other randomized,

2 double-blind, placebo-controlled short trials with

3 short-term follow-up were considered to be

4 appropriate for the pooled analysis and to

5 contribute particularly to the study of the early

6 part of the survival curve which seemed to be so

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

8 heard.

9 On this slide are demonstrated the number

10 of patients and the breakdown by tumor type of the

11 patients contributing to this pooled analysis with

12 cumulative follow-up involved. Combined, these

13 trials provide more than a 80-percent power to

14 detect an effect on survival of the magnitude seen

15 in the BEST and Enhanced trials.

16 I'll now review results starting with

17 progression-free survival.

18 Portrayed here is the progression-free

19 survival in the overall pooled analysis. Note here

20 that the time scale extends to 16 weeks and that

21 the progression-free survival percent extends from

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

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

2 effect of Aranesp on progression-free survival

3 during this period.

4 On this slide, we again see no evidence

5 for a negative overall survival influence in

6 association with Aranesp therapy. In addition, as

7 shown in our briefing document, the long-term

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

9 ratio of approximately 1. The confidence interval

10 for that analysis extends from 0.8 to 1.2, which

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

12 Enhanced trials.

13 I will now review the analysis by tumor

14 type.

15 On this slide, I portray the

16 progression-free survival results of the pooled

17 analysis by tumor type. No clear association is

18 observed between progression-free survival and

19 tumor type. Results are similar with respect to

20 overall survival.

21 Here we find an association with improved

22 progression-free survival and overall survival is

1 observed with respect to achieving an on-study rise

2 in hemoglobin of 1 gram per deciliter or more over

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

4 respectively, with the indicated confidence

5 intervals.

6 Note that a similar association is found

7 with improved progression-free survival and overall

8 survival with respect to achieving an on-study

9 hemoglobin of greater than or equal to 13 grams per

10 deciliter.

11 In summary, our more recent analyses have

12 confirmed the appropriateness of the Aranesp

13 prescribing information with respect to thrombotic

14 event rate. In an evaluation of data from over

15 1,100 patients randomized to placebo-controlled

16 oncology trials with Aranesp, we found nearly

17 identical survival and progression-free survival

18 with Aranesp and placebo. We believe that our

19 detailed examination confirms the safety profile of

20 Aranesp and that the benefit/risk ratio remains

21 favorable and warrants continued examination of

22 potential beneficial effects on survival.

1 I will now review a program of ongoing

2 trials involving Aranesp in different tumor

3 treatment settings. We believe this group of

4 trials represents a robust approach to ultimately

5 resolving the questions raised in this meeting.

6 The trials to be described were initiated, I should

7 point out, because of evidence regarding the

8 positive potential benefits of anemia treatment on

9 patient survival. Outlined here are the relevant

10 preclinical and clinical observations providing the

11 rationale for these trials.

12 On particular note at the bottom is the

13 Cochran meta-analysis with a favorable relative

14 risk and a conclusion by the authors that more

15 trials to explore this finding were merited.

16 On the next several slides are outlined

17 the Amgen-sponsored and the four independent

18 investigator-initiated and -conducted studies.

19 The Amgen response to the information from the BEST

20 and Enhanced trials has already been described by

21 Dr. Viveash, including our formal review of all

22 ongoing clinical trials involving Aranesp being

1 conducted worldwide.

2 One of our goals in this review was to

3 identify clinical trials in which the design, the

4 size, and the patient population would be

5 particularly informative with respect to answering

6 the kinds of questions that we're dealing with

7 today. We identified five such trials--one

8 Amgen-sponsored and four utilizing Aranesp but

9 being conducted by independent investigators. All

10 of these studies are randomized and controlled.

11 One trial is itself double-blind and

12 placebo-controlled. The other four clinical trials

13 involve randomization to Aranesp or no epoetin. In

14 these trials, Aranesp treatment is administered

15 proximate to the time of chemotherapy and not for

16 the full duration of follow-up. These studies

17 include long-term follow-up with collection of

18 predefined progression and survival endpoints. In

19 addition, of course, the studies will capture

20 thrombotic and cardiovascular events. Each study

21 includes homogeneous populations with

22 stratification for disease-specific prognostic

1 variables.

2 One question posed by the FDA relates to

3 the feasibility and appropriateness of conducting

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

5 I've indicated, one of our studies includes

6 placebo-controlled design. While these studies are

7 currently ongoing in Europe, we can report that we

8 are successfully accruing patients to a

9 placebo-controlled trial of Aranesp in

10 chemotherapy-induced anemia in the United States if

11 that's relevant to your deliberations.

12 In fact, it is our opinion that controlled

13 studies are essential in certain situations and

14 that it is feasible to conduct such studies in the

15 United States.

16 On this slide, we also indicate that the

17 number of patients for each tumor type and the

18 total number of patients for these five trials

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

20 particular value to an approach which incorporates

21 a range of tumors with robust numbers of patients

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

1 will now review each study design in detail.

2 Portrayed here is the Amgen-sponsored,

3 double-blind, placebo-controlled study. Six

4 hundred patients with newly diagnosed extensive

5 small-cell lung cancer will be randomized to

6 combination chemotherapy with Aranesp or placebo.

7 As you can see, endpoints include survival, and

8 this trial has accrued more than 200 patients to

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

10 is placebo-controlled.

11 The first independent

12 investigator-conducted trial which I will discuss

13 is the neoadjuvant breast cancer trial being

14 conducted by the German Gynecologic Oncology Group.

15 Seven hundred patients with diagnosed breast cancer

16 will be randomized to dose-intense or standard

17 chemotherapy with a secondary randomization to

18 Aranesp or observation. Following induction

19 chemotherapy, surgery will be conducted. Endpoints

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

21 By the nature of this patient population

22 and by the nature of the study design and

1 investigator intent with Amgen support, tumor

2 tissue is being collected and stored. The trial

3 has accrued more than 400 patients, half of the

4 projected total accrual. An interim analysis of

5 the experience in the first 200 patients will take

6 place in the next several weeks.

7 The second investigator-initiated study is

8 the adjuvant breast cancer study being conducted by

9 the West German Study Group. After definitive

10 surgery, the projected 1,000 patients will be

11 randomized to center-specific adjuvant chemotherapy

12 with or without Aranesp. Endpoints are as listed,

13 and this trial has recently initiated accrual.

14 The diffuse large-cell lymphoma study

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

16 is outlined here. More than 600 patients will be

17 randomized to 14- or 21-day monoclonal antibody

18 CHOP(?) chemotherapy treatment regimens. These

19 patients are secondarily randomized to Aranesp or

20 supportive transfusion. Endpoints are as listed;

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

22 recently initiated accrual.

1 The head and neck cancer study being

2 conducted by the Danish Head and Neck Cancer Study

3 Group is outlined here to test the hypothesis that

4 anemia contributes to radiotherapy failure. A

5 projected 600 patients with head and neck cancer

6 are randomized to radiotherapy alone or to Aranesp

7 with long-term follow-up. The principal

8 investigator is Professor Overgaard, a

9 well-recognized authority in the field of tumor

10 oxygenation and radiation therapy. More than 260

11 patients have already been accrued to this trial.

12 In response to the Henke and Enhanced

13 trial results, the investigators have conducted an

14 interim analysis for safety. We are informed that

15 this trial is proceeding.

16 On this slide, the five clinical trials

17 are outlined with respect to the tumor types

18 involves, projected and current accrual, and the

19 detectable differences from the expected control

20 arm results. Individually, these trials will

21 accrue between 600 and 1,000 patients and have

22 power to detect absolute differences in survival

1 between 7 and 11 percent. Note that these studies

2 are ongoing outside of the United States, but we

3 believe the findings should absolutely be

4 applicable to United States practice.

5 This slide shows the statistical power of

6 the individual trials to detect an increase in the

7 risk of death. Each of these trials has reasonable

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

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

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

11 of these trials will result in a statistically

12 significant difference.

13 On this slide is outlined the projected

14 accrual over time to these trials and the expected

15 cumulative patient years of follow-up. Including

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

17 will be randomized in trial settings in which the

18 influence of Aranesp on survival can be compared.

19 This slide shows the power of a

20 meta-analysis illustrated in yellow of all five

21 trials. This analysis will have high power to

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

1 is far smaller than that observed in the BEST and

2 Enhanced trials.

3 Also shown on this graph in the purple is

4 the power of the meta-analysis of the neoadjuvant

5 and adjuvant breast cancer studies, a total of

6 1,700 breast cancer patients. This analysis will

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

8 as small as 1.32.

9 So on this slide, I've summarized the

10 strengths of the ongoing clinical trials

11 activities. As I've discussed, these include

12 design elements which involve either double-blind,

13 placebo-controlled, or Aranesp versus epoetin

14 elements, with predefined survival or tumor

15 progression endpoints. I'd like to emphasize this

16 in view of the agency's first question.

17 While it is true that these trials are all

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

19 is entirely possible to conduct placebo-controlled

20 trials in the United States. These ongoing trials

21 cross multiple tumor types with approximately 1,700

22 breast cancer patients and 600 head and neck cancer

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

2 patients will provide robust power for assessment

3 of survival outcomes in this program.

4 Of note, these studies have already

5 accrued close to 900 patients. These studies

6 include careful safety monitoring, and the AGO

7 breast cancer trial incorporates tissue collection

8 to enable appropriate correlative biological

9 studies.

10 In conclusion, we've outlined the known

11 and potential benefits of therapy with Aranesp. We

12 have found no adverse effects on tumor progression

13 or survival to date in our Aranesp clinical trials.

14 To the contrary, evidence exists for potential

15 benefit from erythropoietic protein therapy, both

16 in the settings of cancer and other conditions.

17 It is our position that this potential

18 benefit should be studies, but that such studies

19 must be carried out responsibly, with carefully

20 designed and executed trials.

21 Thank you very much.

T2A DR. CHESON: I would like to thank the

1 sponsors for their very clear and on-time

2 presentations.

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

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

5 out the door.

6 [Laughter.]

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

8 And for those of you who are standing against the

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

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

11 asked to leave the room.

12 DR. LUKSENBURG: Dr. Cheson, members of

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

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

15 and Drug Administration, and I would just like to

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

17 team of very talented individuals who put in a

18 tremendous amount of work in putting together the

19 data which we'll be presenting today.

20 Now, two large randomized studies in

21 cancer patients on chemotherapy plus or minus EPO

22 have shown shorter overall survival, shorter

1 progression-free survival, and an increased

2 incidence of thrombotic and cardiovascular events

3 in the groups assigned to receive erythropoietins.

4 The erythropoietin products used in these

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

6 NeoRecormon, epoetin beta, manufactured by

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

8 manufactured by Ortho Biologics. Both of these

9 studies used a treatment strategy to achieve a

10 hemoglobin greater than 12 grams per deciliter,

11 which is higher than that recommended in the

12 labeling for U.S.-licensed products.

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

14 products were not designed to assess the impact on

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

16 which I'll describe momentarily; they were not

17 designed to look at in a systematic way time to

18 progression or progression-free survival; and they

19 were not designed to look at overall survival.

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

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

22 of why the FDA feels that the safety issues

1 observed with EPREX and NeoRecormon, the

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

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

4 results of trials with EPREX and NeoRecormon, the

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

6 concerns. Thirdly, I will review data available

7 regarding safety from trials of EPOGEN/Procrit and

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

9 try to come agreement on the design of future

10 studies regarding these safety issues.

11 Now, the three safety issues which I'm

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

13 increased risk of thrombotic and cardiovascular

14 adverse events, an increased risk of tumor

15 progression in patients receiving EPO products, and

16 poorer survival in groups of patients receiving EPO

17 products.

18 Just the cast of characters. Recombinant

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

20 epoetin alfa manufactured by Amgen and marketed

21 under the name of EPOGEN; the same drug

22 manufactured by Amgen and marketed as Procrit by

1 Ortho Biotech; and darbepoetin alfa, or Aranesp,

2 manufactured and marketed by Amgen.

3 The EPO products which are not licensed in

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

5 by Ortho Biologics; Epoetin beta, NeoRecormon,

6 manufactured by Hoffman-LaRoche.

7 Now, the FDA considers all these products

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

9 evolving safety issues are assumed to apply to all

10 products unless adequate and well-controlled trials

11 demonstrate otherwise.

12 The differences between these products are

13 as follows: epoetin alfa and beta have the same

14 amino acid sequence, but they differ in

15 glycosylation. Aranesp differs in the amino acid

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

17 The similarities are meaningful. All

18 these exert their principal clinical effect by

19 binding to the erythropoietin receptor. All these

20 products have similar pharmacodynamic effects when

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

22 similar toxicity profile across all of these

1 products with the exception of pure red cell

2 aplasia, which has been seen thus far only in

3 EPREX.

4 Now, target hemoglobin, the labels for

5 EPOGEN/Procrit and Aranesp have dosage guidelines

6 based on safety data from registration studies

7 performed in patients with chronic renal failure.

8 Just to quote what is written on the current

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

10 hematocrit range is between 30 and 36 percent."

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

12 patient to achieve and maintain a target hemoglobin

13 not to exceed 12 g/dL."

14 In addition, for rapid increase in

15 hemoglobin greater than 1 gm per deciliter, or four

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

17 dose should be reduced. And the product should be

18 held if the hemoglobin is greater than 13 until the

19 hemoglobin falls less than or equal to 12 grams per

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

21 the previous dose.

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

1 to discuss is that of an increased incidence of

2 thrombotic and cardiovascular adverse events. This

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

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

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

6 going to discuss only one study done in renal

7 patients, the Normal Hematocrit Study. These in

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

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

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

11 there's data available for evaluation for each of

12 these safety concerns.

13 Now, the licensing studies for

14 EPOGEN/Procrit and Aranesp demonstrated that

15 there's a baseline risk of thrombotic and

16 cardiovascular adverse events at their labeled

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

18 per deciliter.

19 A study which dramatically showed the

20 potential adverse effects of increasing the

21 hemoglobin was the so-called Normal Hematocrit

22 Study, first author Besarab, published in the New

1 England Journal in 1998. The idea behind this

2 study was that patients with chronic renal failure

3 on dialysis who had clinical evidence of cardiac

4 disease could do better clinically if they had

5 their hemoglobin raised from the nominal low 30

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

7 1,200 patients with chronic renal failure on

8 dialysis with clinical evidence of congestive heart

9 failure or ischemic heart disease, they were all on

10 EPOGEN at baseline and maintaining a hematocrit of

11 between 27 and 33 percent.

12 Now, both arms received EPOGEN, but they

13 were randomized to different treatment strategies.

14 One was randomized to achieve a higher hematocrit,

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

16 so-called normal hematocrit group. The other arm

17 maintained the lower hematocrit group, as was

18 customary in practice, around 30 percent. This was

19 called the low hematocrit group.

20 This study had a composite primary

21 endpoint of either death or non-fatal myocardial

22 infarction, and here are the results. In the

1 normal hematocrit group, there's an increased

2 incidence of death, 30 percent, versus 34 percent

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

4 risk of non-fatal myocardial infarction, 3.1

5 percent in the normal hematocrit group, versus 2.3

6 percent in the low hematocrit group. And there was

7 an increased risk of vascular access thrombosis, 39

8 percent in the normal hematocrit group versus 29

9 percent in the low hematocrit group.

10 Here's a graph showing the increased

11 probability of death in the normal hematocrit

12 group, death or myocardial infarction in the normal

13 hematocrit group, and in the low hematocrit group.

14 This goes out to about 30 months.

15 Now, when I talk about target hemoglobin,

16 a target hemoglobin is only a target, and many

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

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

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

20 is the idea of pushing the dose of the

21 erythropoietin to a higher level in order to try to

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

1 in all these studies that the adverse event signals

2 seem to occur in the group assigned to the dosage

3 strategy aimed at the target hemoglobin, despite

4 whether they attained that hemoglobin or not.

5 Now, the next studies I want to discuss

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

7 studies done in oncology patients using

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

9 just talking about thrombotic events.

10 The Breast Cancer Erythropoietin Trial, or

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

12 double-blind, placebo-controlled trial in 939

13 patients with metastatic breast cancer who were

14 receiving first-line therapy. They received EPREX

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

16 started until the hemoglobin was less than 13.

17 The primary objective of this study was to

18 demonstrate superior survival at 12 months. The

19 target hemoglobin, again, was higher than what is

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

21 stopped by an Independent Data Monitoring Committee

22 based on the first four months of safety data.

1 At four months, there was an increase

2 incidence of fatal thrombotic and cardiovascular

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

4 the placebo arm, it was 0.4 percent.

5 The next trial that got our attention was

6 published in The Lancet last October by Henke and

7 his colleagues, and it used NeoRecormon, or epoetin

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

9 placebo-controlled trial in 351 patients with head

10 and neck cancer who were receiving concurrent

11 radiation therapy. All these patients were anemic,

12 less than 12 grams per deciliter in women, less

13 than 13 grams per deciliter in men.

14 The primary objective in this trial was to

15 demonstrate superior locoregional progression-free

16 survival. The target hemoglobin was less than or

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

18 in men.

19 Now, the incidence of cardiovascular and

20 thrombotic events was higher in the epoetin beta

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

22 hypertension, hemorrhage, venous thrombosis,

1 pulmonary embolism, and stroke. In addition, the

2 incidence of patients who died of cardiac disorders

3 not otherwise specified was 5 percent in the

4 epoetin beta group versus 3 percent in the placebo

5 group.

6 Next, still in the thrombotic events

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

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

9 products.

10 The registration studies for Procrit

11 consisted of pooled analyses of six multicenter,

12 randomized, double-blind, placebo-controlled

13 studies constituting a total of 131 patients. They

14 had various primary cancers. Three of these

15 studies consisted of patients receiving

16 platinum-containing chemotherapy and three of them

17 consisted of patients receiving

18 non-platinum-containing chemotherapy. All these

19 patients were anemic, and the primary endpoint was

20 proportion of patients transfused. There were no

21 progression-free survival or survival endpoints

22 incorporated in these studies.

1 The incidence of thrombotic and

2 cardiovascular events in the pooled data was 12

3 percent in the placebo group and 3 percent in the

4 Procrit group.

5 A post-marketing commitment study done

6 after the approval of EPOGEN/Procrit for the

7 oncology indication asked the question whether

8 giving Procrit along with chemotherapy for

9 small-cell carcinoma of the lung would have a

10 potential adverse effect on the tumor's response to

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

12 placebo-controlled, non-inferiority study which was

13 intended to enroll 400 patients with small-cell

14 carcinoma of the lung who were receiving first-line

15 therapy and their baseline hemoglobin was less than

16 14. So these patients did not necessarily have to

17 be anemic.

18 The primary endpoint, as I mentioned, was

19 the objective response rate, CR plus PR, after

20 three cycles of chemotherapy to rule out a

21 decrement of 15 percent in the overall response

22 rate with Procrit. There was no target hemoglobin;

1 however, the Procrit dose was reduced if the

2 hemoglobin exceeded 16 grams per deciliter. The

3 study, however, was terminated because of poor

4 accrual at 224 patients.

5 Now, the incidence of thrombotic and

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

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

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

9 However, the definition of thrombotic and vascular

10 events included chest pain, not otherwise

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

12 clinical entities. So we subtracted chest pain and

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

14 the incidence of thrombotic/vascular events went to

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

16 percent.

17 The Aranesp Oncology Registration Study

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

19 study in 320 patients with both small-cell and

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

21 receiving platinum-containing chemotherapy. All

22 these patients were anemic.

1 The primary endpoint, again, was a

2 transfusion endpoint, the proportion of patients

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

4 the treatment period. The dosage guidelines were

5 that Aranesp was to be held for hemoglobin of

6 greater than or equal to 14 in women and for

7 greater than or equal to 15 in men.

8 The incidence of thrombotic events in this

9 study was 5 percent in the Aranesp group and 3

10 percent in the placebo group.

11 So, to summarize the studies for the

12 thrombotic/cardiovascular events so far, in the

13 studies in which a signal was detected, the Normal

14 Hematocrit Study done in patients with chronic

15 renal failure, the incidence of non-fatal

16 myocardial infarction, 3.1 percent in the normal

17 hematocrit group versus 2.3 percent in the low

18 hematocrit group. An increased incidence of

19 vascular access thrombosis, 39 percent in the

20 normal hematocrit group versus 29 percent in the

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

22 939 patients with metastatic breast cancer, there

1 was an increased risk of fatal thrombotic events in

2 the arm randomized to receive EPREX, 2.3 percent,

3 versus 0.4 percent in the placebo arm.

4 In the Henke Study in head and neck cancer

5 and the patients were randomized to receiving

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

7 also an increased risk of cardiovascular and

8 thrombotic events, 11 percent in the epoetin beta

9 group versus 5 percent in the placebo group.

10 In the thrombotic and vascular events

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

12 pooled studies, 3 percent in the Procrit group

13 versus 12 percent in the placebo group. The N93

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

15 percent Procrit versus 23 percent placebo. We put

16 an asterisk next to this because after we

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

18 that there was an increased risk of

19 thrombotic/vascular events in the Procrit group.

20 And, finally, the Aranesp Oncology Registration

21 Study, 5 percent incidence in the Aranesp group

22 versus 3 percent in the placebo group.

1 Now, in September 2003, three

2 placebo-controlled clinical trials in oncology

3 patients in which one arm received EPO to target a

4 higher hemoglobin were terminated because of

5 unexpected rates of thrombotic events in the EPO

6 arm.

7 Briefly, to summarize these studies, in

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

9 the lung; the target hemoglobin was between 14 and

10 16; the incidence of thrombovascular events, TVE,

11 was 34 percent in the EPREX group versus 6 percent

12 in the placebo group. The second study, patients

13 who had cervical cancer, the target hemoglobin was

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

15 in the Procrit group, versus 5 percent in the

16 placebo group. And the third study, gastric or

17 rectal carcinoma, target hemoglobin 14 or 15; the

18 incidence of TVE, 24 percent in the Procrit group

19 versus 6 percent in the placebo group.

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

21 discuss is that of tumor progression. There are a

22 number of preclinical studies which have been

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.

113

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

116

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

117

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

118

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.

122

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

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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

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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

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1 were important therapeutic questions to ask.

2 You know, we can go into as much

3 detail--there are actually investigators here from