DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ONCOLOGIC DRUGS ADVISORY COMMITTEE
P A R T I C I P A N T S
Bruce D. Cheson, M.D., Acting Chairman
Johanna M. Clifford, M.S., RN, BSN, Executive
Otis W. Brawley, M.D.
John T. Carpenter, Jr., M.D.
James H. Doroshow, M.D.
Stephen L. George, Ph.D.
Antonio J. Grillo-Lopez, M.D.
Pamela J. Haylock, RN
Silvana Martino, D.O.
Gregory H. Reaman, M.D.
Bruce G. Redman, D.O.
Maria Rodriguez, M.D.
Sarah A. Taylor, M.D.
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):
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
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
- Future Clinical Data - Martine George, M.D.,
Vice President, Hematology and Oncology,
Clinical Research and Global Development 47
- 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
Harvey Luksenburg, M.D, Medical Officer, Division
of Therapeutic Biological Oncology Products, FDA 84
Open Public Hearing - [NONE]
Committee Discussion 145
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
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
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
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
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.
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
6 DR. LUKSENBURG: Harvey Luksenburg. I'm a
7 medical reviewer at the Food and Drug
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
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
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
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
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
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
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
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
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
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.
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
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
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
well as oncologic indications in most of these
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
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.
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
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
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
21 And, finally, for Stage IV TNM status,
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
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
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
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
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
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.
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
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
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
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
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
see, there was a robust effect on that
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
DeLap. I'm Vice President for
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
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
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.
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
patients represented at each time point.
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
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.
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
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
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
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
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
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
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
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
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
disease progression tend to be small.
1 data show no signal that epoetin alfa is associated
2 with an adverse impact on adverse impact on tumor
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
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
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
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
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
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
19 Providing patients with a homogenous
20 chemotherapy regimen is complicated, but at least
21 three elements: the previous adjuvant
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
21 And now I would like to conclude the
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
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
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
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
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
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
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
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
binding of Aranesp, and no off-target effects were
1 seen with Aranesp or erythropoietin in toxicology
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
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
cancers. In other cases, mutation
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
erythropoietin. These individuals
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
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
possible in fixed or frozen tissues.
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
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
separate from the non-tumor cells.
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
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
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
survival in completed clinical trials.
1 finally, I'll outline a program of ongoing trials
2 involving Aranesp in different tumor treatment
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.
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
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
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
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,
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
chemotherapy. A second trial involved
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
cancer subjects. These subsets
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
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
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
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
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
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
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
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
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
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
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
stratification for disease-specific prognostic
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
both breast cancer and head and neck cancer.
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
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
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
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
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
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
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
3 And now I'd like to turn to the FDA
4 presentation, Dr. Harvey Luksenburg--who is going
5 out the door.
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
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
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
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
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
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
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.
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
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
infarction, and here are the results.
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
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
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
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
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
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
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
rate with Procrit. There was no
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
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
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
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
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
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
number of preclinical studies which have been
1 reviewed, but our selective take under the
2 literature is that there are EPO receptors which
3 are present on some tumor cell lines and on tumor
4 vasculature, meaning endothelial cells.
5 EPO has been reported in some studies to
6 inhibit apoptosis, stimulate angiogenesis,
7 stimulate endothelial cell growth, migration, and
8 proliferation, and reduce survival in some tumor
9 xenograft models.
10 Now, studies supporting the approval of
11 Procrit and Aranesp for the treatment of anemia in
12 cancer patients on chemotherapy were not designed
13 to assess the impact on tumor response, tumor
14 progression, or survival. So there's a big lacunae
15 in the information that we have for the
16 U.S.-registered EPO products. And, again, I'm
17 going to go through the two studies that utilized
18 non-U.S.-licensed EPO products and then two studies
19 which we have that have data that's useful for
20 looking at tumor progression in the U.S.-licensed
21 EPO products.
Again, just to remind you that the BEST
1 Study using EPREX, randomized, double-blind,
2 placebo-controlled, 939 patients with metastatic
3 breast cancer, first-line therapy, randomized to
4 receive EPREX or placebo for 12 months, therapy
5 started at less than 13.
6 The primary objective of this study was to
7 demonstrate superior survival at 12 months. The
8 target hemoglobin was between 12 and 14, and this
9 study, again, was stopped by the Data Monitoring
10 Committee based on the first four months of safety
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
20 In the Henke trial, again, randomized,
21 double-blind study in 351 patients with head and
neck cancer receiving concurrent chemotherapy,
1 these patients were entered if women had a
2 hemoglobin of less than 12 and men less than 13.
3 The primary objective was to demonstrate superior
4 locoregional progression-free survival. The target
5 hemoglobin was less than or equal to 14 in women or
6 less than or equal to 15 in men.
7 For locoregional progression-free survival
8 as the primary endpoint, the relative risk was 1.62
9 favoring placebo, and the lower bound or the
10 95-percent confidence interval was greater than 1,
11 with a highly significant p value.
12 For locoregional progression, again, the
13 relative risk was 1.69 favoring placebo and the
14 lower bound of the 95-percent confidence interval
15 was greater than 1, with a significant p value.
16 Study N93, the post-marketing study which
17 looked at small-cell carcinoma, this was a
18 randomized, double-blind, non-inferiority study
19 which was intended to enroll 400 patients who were
20 receiving first-line therapy.
21 The primary endpoint, again, was objective
response rate after three cycles of chemotherapy to
1 rule out a 15-percent decrement in the overall
2 response rate in the Procrit arm. No target
3 hemoglobin was determined. The Procrit dose was
4 reduced for hemoglobins greater than or equal to
5 16, and the study was terminated at 225 patients
6 out of a projected 400 for poor enrollment.
7 This study was not designed to assess the
8 impact on time to progression, and survival was a
9 secondary endpoint, and there was no formal
10 hypothesis testing.
11 The results showed that for the placebo
12 group the overall response rate was 67 percent; for
13 the Procrit group it was 72 percent. The
14 95-percent confidence interval around the observed
15 difference had a lower bound of minus 6 percent.
16 So even though this study met its intended
17 objective despite the early termination, it was
18 able to exclude a difference of greater than 15
20 The Aranesp Oncology Registration Study, a
21 randomized, double-blind, 320 patients with
non-small-cell and small-cell lung cancer all
1 receiving platinum chemotherapy and all of whom
2 were anemic.
3 The primary endpoint was a transfusion
4 endpoint. The Aranesp was held for hemoglobins
5 greater than 14 in women and 15 in men.
6 The median progression-free survival was
7 five months in the Aranesp group and four months in
8 the placebo group. This study, again, was not
9 designed to assess the impact on progression-free
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
relative risk for locoregoinal progression-free
1 survival favored placebo, 1.62.
2 The tumor stimulation studies without a
3 signal, the Procrit group, the post-marketing
4 commitment in small-cell carcinoma of the lung, the
5 overall response rate was 72 percent in the Procrit
6 group versus 67 percent in the placebo group. The
7 Aranesp Oncology Registration trial, the median
8 progression-free survival, four months for Aranesp,
9 five months for placebo.
10 And, finally, I'd like to discuss the data
11 we have concerning poorer survival in patients
12 randomized to receiving erythropoietins.
13 Again, I'll be discussed the data we have
14 on the BEST trial and the Henke trial as well as
15 the U.S.-licensed erythropoietins.
16 Just to remind you once again, the breast
17 cancer study, 939 patients with metastatic breast
18 cancer, randomized to receive EPO or--EPREX or
19 placebo for 12 months, and the primary objective of
20 this trial was to demonstrate superior survival at
21 12 months. The target hemoglobin was between 12
14, and this study was stopped by the
1 Independent Data Monitoring Committee based on four
2 months safety data.
3 The estimated 12-month survival was 70
4 percent in the EPO group and 76 percent in the
5 placebo group. The relative risk of death was 1.4
6 favoring the placebo group, and the lower bound of
7 the 95-percent confidence interval was greater than
8 1, with a p value of 0.12.
9 Here are the curves for the first 12
10 months, which was the primary endpoint. This is
11 the placebo group on top, and here is the EPREX
13 In the Henke Study, again, 351 patients
14 with head and neck cancer getting radiation
15 therapy. The erythropoietin product used was
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
group--was 605 days in the NeoRecormon group versus
1 928 days in the placebo group.
2 Study N93, the post-marketing commitment
3 done in patients with small-cell carcinoma of the
4 lung, again, this study was not designed to assess
5 an impact on survival. The median survival was
6 10.5 months in the Procrit group and 10.4 months in
7 the placebo group. The overall mortality rate was
8 92 percent in the Procrit group versus 88 percent
9 in the placebo group.
10 And here are the curves. The dotted line
11 is the placebo group. The sold line is the Procrit
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.
And this is the placebo arm here, and here
1 is the Aranesp arm. This is one year, two years.
2 And so, just to summarize the studies we
3 had in which there was a survival signal, the BEST
4 Study, metastatic breast cancer, the 12-month
5 survival rate, the primary endpoint, poorer
6 survival in the EPREX group, 70 percent, versus 76
7 percent in the placebo group, p value of 0.12. In
8 the Henke Study using NeoRecormon, the median
9 overall survival not significant but a trend, 605
10 days for NeoRecormon versus 928 days with placebo.
11 The studies that we have without a
12 survival signal, the N93 Study, post-marketing
13 study in small-cell carcinoma of the lung, 10.5
14 months in the Procrit group versus 10.4 months in
15 the placebo group. The Aranesp Oncology
16 Registration Study, ten months in the Aranesp group
17 versus eight months in the placebo group.
18 So, to summarize, two large, multicenter
19 studies--the BEST Study and the Henke Study--which
20 were designed to show superior survival or
21 progression-free survival, instead demonstrated an
increased risk of thrombotic and cardiovascular
1 events, a shorter progression-free survival, and a
2 shorter overall survival. Both of these studies
3 used a treatment strategy to achieve hemoglobin
4 levels greater than or equal to 12.
5 The multicenter, placebo-controlled trials
6 using Procrit and Aranesp, the U.S.-licensed
7 erythropoietins, were smaller in size; they were
8 not designed to assess the impact on
9 progression-free survival or overall survival.
10 Their treatment strategy varied: Procrit was held
11 in the N93 Study for hemoglobin greater than
12 14--the label recommends 12--and in the Aranesp
13 study it was held for greater than 14 in women or
14 greater than 15 in men.
15 So, to conclude, we have these evolving
16 safety concerns. They cannot be dismissed. The
17 current dosing recommendations we feel are adequate
18 to minimize the risk of thrombotic events.
19 However, there is insufficient information
20 concerning overall survival and progression-free
21 survival for U.S.-licensed products at approved
doses to assess these risks.
Amgen, Ortho Biotech,
1 and the FDA have agreed on the need for further
2 studies to investigate these safety issues.
3 Now, the FDA recommends certain elements
4 that should be components of all current and future
5 studies which will be done to investigate these
6 safety issues. First of all, there should be a
7 homogeneous primary tumor type. There should be
8 homogeneous chemotherapy or radiotherapy regimes.
9 The studies should be designed to detect clinically
10 meaningful decrements in response rate,
11 progression-free survival, and survival. There
12 should be prespecified definitions of
13 cardiovascular and thrombotic events. And there
14 should be Data Safety Monitoring Committee
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.
And I think that is the end of my
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.
Any other questions from the committee?
1 Any comments from the committee? Dr. Martino?
2 DR. MARTINO: I'm reminded of a quote from
3 Enrico Fermi, which goes as follows: "Before I
4 came here, I was confused on this topic. Now I'm
5 still confused, but at a somewhat higher level."
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
growth may occur, if, in fact, it does.
1 DR. CHESON: Dr. DeLap?
2 DR. DeLAP: Yes, I'd like to ask Dr.
3 Francis Farrell to address that question. Dr.
4 Farrell is head of our preclinical program for this
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
maximal serum dose a patient would get with 40 IUs
1 per kg dose, which is approximately two units per
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
close as you can get to a rodent model to human
1 model. We've also looked at CT26, which is a
2 colorectal model.
3 So, very briefly, our experiments have
4 looked at tumor proliferation using Key 67, tumor
5 growth using biodimensional tumor volume. We've
6 also looked at micro-vessel density, and I think
7 the best experiment is we've actually looked at in
8 vivo angiogenesis using a dorsal window fold where
9 you can actually measure vascular development in
10 the mammary carcinoma model. And I will say that
11 we've looked at erythropoietin in close to 16
12 mammary carcinomas and have failed to see any
13 effect on tumor growth, tumor proliferation, or
14 tumor angiogenesis. Obviously the in vivo
15 angiogenesis models involve a small number, about
16 25 animals, because those are difficult experiments
17 to do.
18 We've also looked at darbepoetin using
19 similar models in both R3230 and CT26 that was
20 alluded to the Aranesp presentation, and using
21 biodimensional models in over 200 animals with
R3230 tumors have failed to see effect on tumor
1 growth, tumor proliferation, and angiogenesis
2 measured by micro-vessel density.
3 So I agree with Dr. Farrell that this
4 really needs to be studied further in in vivo tumor
5 models because the interaction between tumor
6 endothelial cells, that's really the only way to
7 study it as opposed to studying endothelial cells
8 or tumor cells separately in cell culture models.
9 DR. VIVEASH: I'd like to ask Dr. Losordo
10 to make some comments relating to this issue.
11 DR. CHESON: Please.
12 DR. LOSORDO: I'm Dr. Losordo from Tufts
13 University and St. Elizabeth's Medical Center in
14 Boston. My expertise is actually in cardiovascular
15 where we've been studying actually the stimulation
16 of angiogenesis for various ischemic disorders.
17 And that experience I think has bearing here
18 because the patient population that we study, which
19 is generally aged and, therefore, it is somewhat
20 higher risk for cancer than the general population,
21 forces us to analyze the potential risk of
stimulating angiogenesis in those patients in
1 various in vivo models. And so as a result of our
2 work primarily using VEG-F to stimulate
3 neovascularization of ischemic tissue, we've also
4 conducted studies analyzing the impact of
5 stimulating angiogenesis in that context on tumor
6 vascularization and tumor progression by implanting
7 tumors into animals and then stimulating
8 angiogenesis by exogenous administration of
9 angiogenic cytokines and have found, in fact,
10 interestingly, that the angiogenesis that's
11 stimulated is very context-dependent, meaning that
12 in the region where angiogenesis seems to be
13 deficient, for example, in the myocardium or the
14 lower extremity where we've induced ischemia, the
15 exogenous cytokine can stimulate and improve
16 perfusion of that tissue. While the tumor itself
17 regresses under the influence of chemotherapy, the
18 vascularity of the tumor does not change at all.
19 And so what we've learned in a number of
20 studies, and that would now include also studies in
21 which we're using progenitor cells from the bone
marrow or peripheral circulation, to also augment
1 neovascularization of ischemic tissue, and in those
2 instances either stimulating the release of those
3 progenitor cells from the marrow or directly
4 implanting them into ischemic tissue also does not
5 influence tumor progression.
6 So I would say that at the same time the
7 study of these things is of great interest and
8 something that we'll likely do and continue to do
9 in the context of generating safety data for
10 ongoing clinical studies. However, it also seems
11 to me that all those preclinical studies, while
12 generating interesting science, will not trump the
13 sort of clinical trial data that's being generated
14 and continuing to be generated, which I think will
15 influence patients and clinicians to a far greater
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.
Other questions from the panel?
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
that are valuable are studies--except for
1 thrombotic/cardiovascular disease, the studies that
2 will provide the best quality data for overall
3 survival, progression-free survival, time to tumor
4 progression, are those with homogeneous tumor
5 populations. And it's really difficult to do
6 meta-analyses with variegated tumor populations.
7 DR. CHESON: Dr. Keegan, did you want to
8 make a comment?
9 DR. KEEGAN: Yes. Actually, that was one
10 of our concerns with several of the meta-analyses
11 presented, that it's trying to put the data in
12 there in a way that--and take studies that weren't
13 intended to look at these events and provide
14 information. And I think the quality of many of
15 the studies included in the meta-analysis are not
16 the same in terms of what information they can give
17 you on progression-free survival or on overall
18 survival simply because of the heterogeneity and
19 the lack of control. So that, you know, I think if
20 we were to choose to select the studies, we would
21 try and find studies that were actually designed to
look at these endpoints and have the qualities that
1 we are recommending further.
2 DR. GEORGE: Just a quick follow-up. I
3 certainly agree with respect to some of those
4 endpoints, but survival should be a clear one.
5 DR. KEEGAN: I think when you look at some
6 of those studies--and many of them are fairly small
7 studies, and they enrolled any patient with any
8 tumor at any stage in their treatment. It might
9 tell us something about transfusion rates. That's
10 what they were intended to do. But they weren't
11 really intended to give us a good comparison of
12 impact on tumors. These studies were really done
13 in a manner not well designed to assess impact on
14 tumor, just given all the incredible variables so
15 much more important in terms of impact on survival
16 and time to progression.
17 Presumably, if there had been thousands of
18 patients, all of those variables would probably
19 have been evened out. But most of the studies, as
20 you look at them, are not particularly large, with
21 the exception of the ones that we tried to
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.
DR. CHESON: And the way I see it
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
specified levels. I guess I would
like to hear
1 more about really the rationale for really at this
2 point believing that there really will be improved
3 progression-free survival with the use of some of
4 these erythropoietic stimulating agents, or
5 survival overall, especially given the clear
6 detrimental effect, albeit it small, in terms of
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
significant amount of clinical evidence.
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
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
assessment of the literature and what they believed
1 were important therapeutic questions to ask.
2 You know, we can go into as much
3 detail--there are actually investigators here from