Thursday, January 31, 2002

8:00 a.m.













Advisors and Consultants Staff Conference Room

5630 Fishers Lane

Rockville, Maryland



Stacy Nerenstone, M.D., Chairperson

Karen M. Templeton-Somers, Ph.D., Executive



Kathy Albain, M.D. (By Videoconference)

Otis W. Brawley, M.D.

Stephen L. George, Ph.D.

David P. Kelsen, M.D. (By Teleconference)

Scott Lippman, M.D.

Jody L. Pelusi, F.N.P., Ph.D.

(Consumer Representative)

Donna Przepiorka, M.D., Ph.D.

Sara A. Taylor, M.D. (By Videoconference)


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


Philip Bonomi, M.D.

Patrick J. Loehrer, M.D.


Eugene J. Kazmierczak


Amna Ibrahim, M.D.

Richard Pazdur, M.D.

Nancy Scher, M.D.

Robert B. Temple, M.D.

Grant Williams, M.D.



Call to Order:

Stacy Nerenstone, M.D. 4

Conflict of Interest Statement:

Karen M. Templeton-Somers, Ph.D. 6

Open Public Hearing:

Ann E. Fonfa (letter) 8

NDA 21-386, Zometa (zoledronic acid for injection)

Novartis Pharmaceuticals Corporation

Sponsor Presentation


Burkhard Daldrup, Ph.D. 10

Pathophysiology of Metastatic Bone Disease

and the Role of Bisphosphonates:

Robert Coleman, M.D., FRCP 16

Zometa in Breast Cancer and Multiple Myeloma:

James Berenson, M.D. 38

Paul Gallo, Ph.D. 48

James Berenson, M.D. 52

FDA Presentation

Zometa in Breast Cancer and Multiple Myeloma:

(Study 010)

Grant Williams, M.D. 63

Questions to the Committee 78

Sponsor Presentation

Zometa in Prostate Cancer and Solid Tumors

Other than Prostate Cancer and Breast Cancer:

Matthew Smith, M.D. 102

Robert Coleman, M.D., FRCP 117


David Parkinson 129

FDA Presentation

Zometa in Prostate Cancer and Solid Tumors

Other than Prostate Cancer and Breast Cancer

(Studies 039 and 011):

Amna Ibrahim, M.D. 134

Safety Review (Studies 010, 011 and 039)

Nancy Scher, M.D. 144

Questions from the Committee 149

Introduction to the Issues 171

Committee Discussion and Vote 174


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

2 Call to Order

3 DR. NERENSTONE: I would like to welcome

4 everyone to ODAC, our 70th meeting. We still start

5 with our usual introduction of the committee.

6 Kathy, can you hear us?

7 DR. ALBAIN: Yes; I can. Good morning.

8 DR. NERENSTONE: Why don't you start with

9 the introductions. We will go around the table.

10 You are first.

11 DR. ALBAIN: Kathy Albain, medical

12 oncology, Loyola University, Chicago.

13 DR. LOEHRER: I am Pat Loehrer from

14 Indiana University.

15 DR. BONOMI: Phil Bonomi, medical

16 oncology, Rush University in Chicago.

17 DR. RAGHAVAN: Derek Raghavan, U.S.C. in

18 Los Angeles.

19 DR. GEORGE: Stephen George, Duke

20 University.

21 DR. LIPPMAN: Scott Lippman, M.D. Anderson

22 Cancer Center.

23 MR. KAZMIERCZAK: Gene Kazmierczak,

24 patient representative.

25 DR. PRZEPIORKA: Donna Przepiorka, Baylor


1 at Houston.


3 Executive Secretary to the committee, FDA.

4 DR. NERENSTONE: Stacy Nerenstone, medical

5 oncology, Hartford, Connecticut.

6 DR. BRAWLEY: Otis Brawley, medical

7 oncology, Emory University, Atlanta.

8 DR. PELUSI: Jody Pelusi, oncology nurse

9 practitioner, Phoenix Indian Medical Center and

10 consumer rep.

11 DR. SCHER: Nancy Scher, medical oncology,

12 FDA.

13 DR. IBRAHIM: Amna Ibrahim, medical

14 officer, FDA.

15 DR. WILLIAMS: Grant Williams, medical

16 team leader, FDA.

17 DR. PAZDUR: Richard Pazdur, Division

18 Director, Oncology Drugs, FDA.

19 MS. TEMPLETON-SOMERS: I would like to

20 welcome everyone to our conference room here in our

21 office. It is unusual for us to hold ODAC here but

22 this is sort of an unusual ODAC, a meeting with a

23 late addition to our schedule and so our hotel

24 choice was very limited. We apologize in advance

25 for any crowding, for the crowd, mostly, but we


1 thought it was important to get the meeting

2 scheduled in January rather than waiting for our

3 regularly scheduled meeting in late February.

4 This meeting is also ground-breaking in

5 that it represents our first steps into the world

6 of having member participation by electronic means.

7 Dr. Kathy Albain and, hopefully, Dr. Sarah Taylor

8 are participating by videoconferencing from their

9 home bases in the Midwest. Sarah may not be

10 joining us because we have heard news that Kansas

11 City has no power due to the snow storm. So even

12 electronic means are not going to get around that.

13 Kathy was saying that she might be grounded in the

14 airport, too.

15 Dr. Kelsen will be joining us from New

16 York by a combination of webcasting, by which he is

17 going to watch the proceedings, and

18 teleconferencing.

19 I am going to go right into the conflict

20 of interest.

21 Conflict of Interest Statement

22 MS. TEMPLETON-SOMERS: The following

23 announcement addresses the issue of conflict of

24 interest with respect to this meeting and is made a

25 part of record to preclude even the appearance of


1 such at this meeting.

2 Based on the submitted agenda an

3 information provided by the participants, the

4 agency has determined that all reported interests

5 in firms regulated by the Center for Drug

6 Evaluation and Research present no potential for a

7 conflict of interest at this meeting with the

8 following exceptions.

9 In accordance with 18 USC 208(b)(1), Jody

10 Pelusi, R.N., Ph.D., has been granted a waiver for

11 serving on an advisory board for a competitor and

12 for her speaking for a competitor. She receives

13 less than $10,000 a year for her participation on

14 the advisory board and from $5,000 to $10,000 a

15 year for her speaking.

16 In addition, Scott Lippman, M.D., has been

17 granted a waiver under 18 USC 208(b)(3) for his

18 consulting for a competitor on unrelated matters.

19 He receives from $10,000 to $50,000 a year for his

20 consulting.

21 A copy of these waiver statements may be

22 obtained by submitting a written request to the

23 agency's Freedom of Information Office, Room 12A-30, at the

24 Parklawn Building.

25 With respect to FDA's invited guests, Dr.


1 Philip Bonomi has a reported interest that we

2 believe should be made public to allow the

3 participants to objectively evaluate his comments.

4 Dr. Bonomi is a scientific advisor for Genentech

5 and OSI.

6 In the event that the discussions involve

7 any other products or firms not already on the

8 agenda for which FDA participants have a financial

9 interest, the participants are aware of the need to

10 exclude themselves from such involvement and their

11 exclusion will be noted for the record.

12 With respect to all other participants, we

13 ask, in the interest of fairness, that they address

14 any current or previous financial involvement with

15 any firm whose product they may wish to comment

16 upon.

17 Thank you.

18 DR. NERENSTONE: We will go now to the

19 open public hearing part and Ann E. Fonfa from the

20 Annie Appleseed Project. The letter will be read.

21 Open Public Hearing

22 MS. TEMPLETON-SOMERS: This letter is a

23 statement from Ann Fonfa of the Annie Appleseed

24 Project. "I am Ann Fonfa, a breast-cancer survivor

25 and activist, founder of the Annie Appleseed


1 Project which educates, informs, advocates and

2 raises awareness for those cancer patients, family

3 and friends interested in or using complementary

4 alternative natural therapies.

5 I have just finished giving NCI input on

6 their consumer guide for clinical trials in that

7 they show that most drugs take about fourteen years

8 to reach the approval stage. My question to this

9 body is why are we spending thousands of human

10 subject hours in constantly approving drugs that

11 are little better than the ones we cancer patients

12 already have access to.

13 There is something wrong with this entire

14 system when the best that we can do is offer a drug

15 that has just about the same safety profile, just

16 about the same response results but differs in a

17 very minor way. We patients are, therefore,

18 condemned to live out our lives, however long that

19 may be, with no real advances in treatments.

20 I resent this and I am taking this

21 opportunity to say so. Aim higher. We are all

22 tired of crawling on our hands and knees through a

23 field of broken glass. We want to leap over it

24 and, for that, we need new drugs that are different

25 and that make a real difference in our lives.


1 Thank you for your attention. If you

2 would like to find out more about our organization,

3 please go to our website,

4 www.annieappleseedproject.org.

5 FYI, I completely support the idea of

6 bisphosphonates for treatment of metastatic bone

7 disease."

8 DR. NERENSTONE: Are there any other

9 people for the open public hearing?

10 Seeing no one, then we will turn now to

11 the supplemental NDA for Zometa indicated for the

12 treatment of bone metastases in patients with

13 multiple myeloma, breast cancer, prostate cancer

14 and other solid tumors. Novartis will start with

15 their sponsor presentation.

16 NDA 21-386, Zometa (zoledronic acid for injection)

17 Novartis Pharmaceuticals Corporation

18 Introduction

19 DR. DALDRUP: Dr. Nerenstone, Dr. Pazdur,

20 Dr. Williams, members of the advisory committee,

21 FDA and guests, good morning.

22 [Slide.]

23 My name is Burkhard Daldrup. I am Global

24 Head of Drug Regulatory Affairs for Novartis

25 Oncology. On behalf of Novartis, I would like to


1 thank you for the opportunity this morning to

2 present and review our Zometa data for a new

3 indication in the treatment of bone metastases.

4 [Slide.]

5 Zometa belongs to a new class of highly

6 potent bisphosphonates. In August 2001, Zometa was

7 approved by FDA for its first indication of therapy

8 for the treatment of hypercalcemia of malignancy.

9 Zometa is currently approved for this indication in

10 more than sixty countries around the world.

11 A dossier for the treatment of bone

12 metastases was filed in July 2001 in Europe and a

13 supplemental application was also submitted in

14 August 2001 in the U.S. as well as in many other

15 countries.

16 The recommended dose is 4 milligrams

17 infused over 15 minutes administered every three to

18 four weeks. Novartis is also evaluating

19 nononcologic indications for Zometa including, at

20 this time, Paget's disease, osteoporosis and

21 rheumatoid arthritis.

22 [Slide.]

23 Specifically, we are seeking FDA approval

24 for the following proposed indication. Zometa is

25 indicated for the treatment of osteolytic,


1 osteoblastic and mixed bone metastases of solid

2 tumors and osteolytic lesions of multiple myeloma

3 in conjunction with standard antineoplastic

4 therapy.

5 [Slide.]

6 Three phase III trials form the basis of

7 this supplemental NDA. These trials are the

8 largest randomized studies ever conducted in the

9 treatment of bone metastases. Study 010 is a

10 pivotal, randomized, double-blind, double-dummy

11 study comparing Zometa to pamidronate in patients

12 with multiple myeloma and breast cancer. In this

13 study, patients were treated for thirteen months.

14 Studies 039 and 011 are pivotal,

15 randomized, double-blind, placebo-controlled

16 trials. Study 039 was conducted in patients with

17 prostate cancer over fifteen months. Study 011 was

18 conducted in patients with non-small-cell lung

19 cancer and other solid tumors over nine months.

20 The clinical program was discussed with

21 the FDA and other major health authorities from

22 around the world.

23 [Slide.]

24 The data derived from these three large

25 pivotal studies support the following clinical


1 profile for Zometa. Zometa, given at a dose of 4

2 milligrams every three to four weeks is bone

3 specific not tumor specific as Zometa shows

4 effectiveness in a broad variety of different tumor

5 types studied.

6 The clinical trials involved patients with

7 breast cancer and multiple myeloma as well as

8 patients with prostate cancer and other solid

9 tumors. Other bisphosphonates have not

10 demonstrated efficacy in these latter tumor types

11 to date.

12 [Slide.]

13 So Zometa is the first bisphosphonate

14 shown to be effective for the treatment of bone

15 metastases over a wide variety of tumor types.

16 Cumulative safety experience from all trials in the

17 treatment of bone metastases indicates that the

18 safety of Zometa at a dose of 4 milligrams infused

19 over 15 minutes is comparable with that of i.v.

20 pamidronate 90 milligrams, the current standard of

21 care for patients with multiple myeloma and breast

22 cancer.

23 The overall safety profile of Zometa is

24 supported by data from more than 3,000 patients

25 treated to date.


1 [Slide.]

2 This morning, we would like to present to

3 you detailed data on the safety and efficacy of

4 Zometa in the treatment of bone metastases. First,

5 Dr. Robert Coleman will give an overview of the

6 pathophysiology of metastatic bone disease and the

7 role of bisphosphonates. Dr. Coleman is Professor

8 of Medical Oncology at the Cancer Research Center

9 at Weston Park Hospital in Sheffield, U.K.

10 Dr. James Berenson will then present the

11 data on Zometa in the treatment of breast cancer

12 and multiple myeloma, study 010. Dr. Berenson is

13 Director of the Multiple Myeloma and Bone

14 Metastases Programs at Cedar Sinai Medical Center

15 in Los Angeles.

16 Dr. Paul Gallo, Assistant Director of

17 Biostatistics, Novartis, will provide also some

18 clarification on the statistical analysis for

19 study 010.

20 Then, after FDA's presentation and

21 discussion by the committee, Dr. Matthew Smith will

22 continue with a discussion of the role of Zometa in

23 prostate cancer. Dr. Smith is Professor of

24 Medicine at Massachusetts General Hospital, Boston,

25 and was an investigator for study 039.


1 Dr. Coleman will then return to discuss

2 the role of Zometa in the treatment of solid tumors

3 other than breast and prostate cancer, study 011.

4 Finally, Dr. David Parkinson will present

5 the overall summary and conclusions. Dr. Parkinson

6 is Vice President and Global Head for Clinical

7 Research at Novartis Oncology.

8 [Slide.]

9 In addition to the presenters for today,

10 we also have several clinical experts and advisors

11 with us who are available to help answer specific

12 questions the committee may have. Dr. John Seaman

13 will field responses to the committee's questions

14 and provide background regarding the Zometa

15 Clinical Research and Development Program. Dr.

16 Seaman in the International Team Leader for Zometa

17 at Novartis Oncology.

18 For biostatistical aspects, we have two

19 consultants in attendance, Dr. Richard Cook who is

20 an Associate Professor at the University of

21 Waterloo in Ontario, and Dr. Thomas Fleming, who is

22 Professor and Chair of the Department of

23 Biostatistics at the University of Washington in

24 Seattle.

25 Clinical experts with us today are Dr.


1 Pierre Major, medical oncologist at the Hamilton

2 Regional Cancer Center in Ontario and Associate

3 Professor at McMaster University; Dr. Joseph

4 Simeone, Professor of Radiology at Harvard Medical

5 School; and, representing the Renal Advisory Board

6 which has closely monitored the renal safety of

7 Zometa during development, Dr. Raimund Hirschberg,

8 nephrologist and Professor of Medicine at the

9 Harbor UCLA Medical Center in Torrence, California.

10 I would now like to turn the podium over

11 to Dr. Robert Coleman for an overview of the

12 pathophysiology of metastatic bone disease and the

13 role of bisphosphonates.

14 Dr. Coleman, please.

15 Pathophysiology of Metastatic Bone Diseases

16 and the Role of Bisphosphonates

17 DR. COLEMAN: Good morning.

18 [Slide.]

19 Dr. Nerenstone, members of the ODAC panel,

20 ladies and gentlemen. This morning, to provide the

21 background information to today's presentations,

22 there are really four aspects that I would like to

23 get across to the panel over the next twenty to

24 twenty-five minutes.

25 These are the clinical importance and


1 consequences of metastatic bone disease. The

2 second is the underlying pathophysiology and some

3 of the similarities that exist across the range of

4 tumor types that affect patients; thirdly, the

5 experience with previous bisphosphonates, notably

6 pamidronate, in the management of metastatic bone

7 disease; fourthly, the background information of

8 zoledronic acid in terms of its pharmacology and

9 the rationale for its dose and schedule in the

10 trials you are going to hear about.

11 [Slide.]

12 Turning first to the clinical importance

13 and prognosis of bone metastases, this slide shows

14 a number of tumors that commonly spread to bone.

15 They are listed in the order that you might

16 associate with the radiographic spectrum of disease

17 that we see on plane X-rays. In other words, at

18 the top is myeloma, typically a very lytic

19 condition. At the bottom is prostate cancer which

20 we associate more with a blastic condition. In

21 between are tumors that have a varied appearance of

22 lytic mixed and blastic.

23 This slide also shows the disease

24 prevalence in the United States and makes the point

25 that, particular for breast cancer and prostate


1 cancer, we have an enormous clinical burden to deal

2 with.

3 That is made doubly important when you

4 look at the incidence of bone metastases that

5 typically complicates advanced disease with,

6 perhaps, three-quarters or even four-fifths of

7 patients with breast cancer and prostate cancer

8 developing bone metastases during the course of

9 their illness.

10 The right-hand part of the slide shows the

11 median survival after development of bone

12 metastases and makes the point that, for many of

13 these conditions, particular breast and prostate

14 cancer, the median survival is measurable more in

15 years than in months. So this is a chronic

16 condition requiring long-term palliative therapy.

17 [Slide.]

18 The disease causes a number of very

19 important complications, very important to the

20 patient and very important to our healthcare

21 resources. The complications that we see from bone

22 metastases are shown in this slide and include

23 radiation therapy to bone, pathological fractures,

24 either of long bones or vertebral bodies,

25 hypercalcemia and malignancy, surgery to bone and,


1 in some cases, spinal-cord compression.

2 This slide is designed to try and give you

3 a feel for the proportion of patients that

4 experience these events on standard therapy. They

5 are taken from the placebo arms of randomized

6 trials that were assessing bisphosphonate use. But

7 these figures related to the placebo arms of either

8 pamidronate or Zometa trials.

9 I think they show that, across the board

10 of disease, breast, prostate and other tumors, that

11 these complications are common, perhaps three or

12 four occurring per year in a typical patient.

13 About one-third of patients with breast cancer have

14 relatively similar proportions with other diseases

15 and will require radiotherapy and a similar number

16 would experience a pathological fracture.

17 Obviously, some of the other events are

18 less common but sometimes more clinically

19 significant.

20 [Slide.]

21 Having outlined that clinical importance,

22 I want to move on to the pathophysiology. This

23 first slide is a very simplistic view of the

24 relationship between tumor cells and bone cells.

25 But it serves to make the point that osteoclast


1 activation--in other words, the acceleration of

2 bone resorption--is very important in the crosstalk

3 between tumor cells and bone.

4 Tumor cells, as most of us will know,

5 reach the target organ through the circulation and

6 are attracted to bone surface by a variety of

7 cytokines and growth factors which are probably

8 released from bone.

9 If the tumor cell possesses the right

10 machinery to produce relevant cytokines and growth

11 factors, it is able to stimulate osteoclast

12 activity, either directly or through bystander

13 cells, to resorb bone. That resorption of bone, as

14 you will see, is responsible for most of the

15 complications.

16 There is also a feedback loop where bone

17 cytokines and bone growth factors may stimulate the

18 proliferation and growth of tumor cells in the

19 biomicro environment.

20 The third mechanism that is illustrated on

21 that slide is is there a direct effect of cancer

22 cells on bone which is, perhaps, independent of the

23 osteoclast. That is an area under research but, to

24 date, it has been extremely difficult to

25 demonstrate any direct destruction of bone by tumor


1 cells in either the clinic or in animal-tumor

2 models.

3 So, to the best of our knowledge, by far,

4 the major pathway is through osteoclast activation.

5 [Slide.]

6 How does this pathway differ between what

7 you see on x-rays in osteolytic disease and what

8 you appreciate as an osteoblastic osteosclerotic

9 lesion, typical, perhaps, of prostate cancer of

10 some breast patients.

11 This slide shows that same loop of

12 osteoclast activity, both for lytic and for blastic

13 disease. The osteoclast loop is very similar for

14 both ends of the spectrum. Of course, osteoclast

15 disease is associated with excessive new bone

16 formation and there are growth factors and

17 cytokines produced by prostate cells and other

18 blastic-inducing tumors that stimulate bone

19 formation.

20 But that bone formation is probably not of

21 huge clinical importance. It is not contributing

22 greatly to the structure of the underlying bone.

23 So, across the spectrum, that osteoclast process

24 appears to be very important.

25 [Slide.]


1 That disturbance of bone-cell function

2 leads to changes in bone remodeling. Bone

3 remodeling is essential. it is going on in all of

4 us. It is essential to maintain the structural

5 integrity of bone. It is necessary to replace old

6 and fatiguing bone with replacement by new and

7 healthy bone. Usually, that process is coupled and

8 balanced; in other words, areas of bone resorption

9 are repaired in the right quantity and in the right

10 place by the various coupling signals that exist in

11 the bone microenvironment.

12 Cancer disturbs that process in a number

13 of ways. This diagram shows what we associate with

14 osteoclast disease. There are excessive numbers of

15 resorption cavities and the skeleton is unable to

16 repair that damage at a rate that maintains

17 structure integrity in either trabecular or

18 cortical bone. So, gradually, the bone thins and

19 fractures.

20 In mixed lesions, this is the appearance

21 that appears to be happening from histomorphometric

22 studies in that, yes, there is new bone formation

23 but it is in the wrong place and there is still

24 unopposed bone resorption. This process is even

25 more marked in osteosclerotic disease where there


1 are excessive amounts of new bone formation. But,

2 again, in the majority of resorption cavities, it

3 is not applied in the right place. It is laid down

4 on creascent bone surfaces and is not really

5 contributing to bone strength.

6 [Slide.]

7 How do we know that? There have been a

8 number of publications, which I don't have time to

9 go into, of histomorphometric studies of bone

10 metastases showing the importance of osteoclast

11 activity across the range of conditions. This

12 slide shows one of many studies that have looked at

13 bone markers, or bone formation and bone

14 resorption, and shows the effect of either lytic or

15 mixed or sclerotic disease on a well-known marker

16 of bone formation, alkaline phosphatase or on a

17 marker of bone resorption, the N-telopeptide, which

18 is a collagen fraction, in this case measured in

19 urine.

20 On the left is the bone formation. Of

21 course, as you would expect, bone formation is

22 massively increased in osteoblastic disease and

23 normal, or even subnormal, in lytic and mixed

24 disease.

25 What is of interest in this slide is that,


1 when we look at bone resorption, bone resorption

2 rates are massively increased in osteoblastic

3 disease. Of course, they are increased in lytic

4 disease as well but, if anything, they are even

5 more greatly increased in the osteoblastic

6 patients. So I think that gives you some

7 biochemical evidence for the importance of bone

8 resorption across the range of conditions that

9 might affect bone.

10 [Slide.]

11 As I have hinted, by and large, increased

12 bone resorption is what is responsible for the

13 problems that the patient complains of in the

14 clinic, some aspects of the pain, certainly the

15 fractures and the hypercalcemia that patients may

16 different.

17 [Slide.]

18 So, turning now to treatment. Of course,

19 we all recognize there are many treatments out

20 there for the management of these patients. Most

21 of these treatments are going to remain important

22 for the foreseeable future. Bisphosphonates, I

23 think by all of us, are seen as a complementary

24 approach. In other words, they are usually used in

25 addition to standard therapy, either endocrine or


1 chemotherapy as appropriate.

2 But, as you will see, they may reduce the

3 requirements for some other modalities, such as

4 radiation to bone, surgical intervention and,

5 perhaps, some aspects of analgesic use.

6 [Slide.]

7 The bisphosphonates are quite a large

8 class of agents and they have relatively similar

9 pharmacology in terms of their effects on bone

10 cells. This cartoon summarizes the three principal

11 mechanisms that we are aware of. Firstly, all

12 bisphosphonates bind very avidly to calcium, so

13 they bind to the bone surface and the

14 hydroxyapatite and they make it very difficult for

15 the osteoclast to adhere to that bone and resorb

16 it.

17 Secondly, they have direct effects on

18 osteoclast function and activity through

19 biochemical pathways and the indication of

20 apoptosis. Thirdly, at least myobisphosphonates

21 have the ability to affect production and

22 maturation of osteoclasts.

23 [Slide.]

24 So what is the use of bisphosphonates at

25 the moment in the conditions that we are discussing


1 today. There is a lot of uncontrolled data but I

2 am going to concentrate on the phase III

3 pamidronate studies in breast cancer, myeloma and

4 prostate cancer that are available to us.

5 These have looked at various endpoints but

6 predominantly at prevention of skeletal-related

7 events. Firstly, looking at breast cancer and

8 myeloma, there are five important studies of note,

9 four in breast cancer and one in myeloma.

10 In terms of the breast-cancer patients,

11 they really fall into two groups. The first were

12 two studies performed in Europe with doses of 45 or

13 60 milligrams of pamidronate--in other words, below

14 the current recommended dosage, which used, as an

15 endpoint, time to progression in bone assessed by

16 radiologists not involved in the study.

17 These studies did show an improvement of

18 time to progression in bone of three to four months

19 but did not show significant effects on skeletal-related

20 events at the doses used. They were then

21 followed by the better-known international trials

22 published by Theriault and colleagues and

23 Hortobagyi and colleagues which led to the

24 registration of pamidronate in this country and

25 worldwide.


1 These trials recruited breast-cancer

2 patients with at least one predominantly lytic

3 lesion plus or minus mixed or blastic lesions as

4 typically occurs in our patient population and

5 included either patients on endocrine therapy or

6 patients on chemotherapy at study entry and I think

7 showed quite clearly that pamidronate was able to

8 reduce the frequency of skeletal events, the number

9 of events per unit time and also the time to

10 skeletal events by about 10 to 13 percent.

11 In multiple myeloma, the study from

12 Berenson et al., showed similar results and led to

13 the use of pamidronate worldwide in multiple

14 myeloma again showing a significant reduction in

15 the proportion of skeletal-related events. So I

16 think there is little doubt that pamidronate works

17 in these two conditions.

18 [Slide.]

19 Let's just look at those data in a little

20 more detail, first the two pivotal breast-cancer

21 studies which have been amalgamated here as part of

22 publication from Anna Lipton and colleagues. It is

23 showing the results both at twelve months, which is

24 close to the analysis you will hear for Zometa

25 later, and at 24 months, a later follow-up


1 analysis.

2 It shows an 11 percent reduction in the

3 proportion of patients experiencing a skeletal

4 event at twelve months which increases slightly

5 more at 24 months. It is very clear from this

6 slide that the effect is quite marked in terms of

7 effects on radiation to bone and pathological

8 fractures and is maintained, or even increases, as

9 time goes by.

10 [Slide.]

11 This slides shows a similar analysis but

12 for multiple myeloma, again, a short-term analysis

13 at nine months and a follow up analysis at 21

14 months, again showing an improvement in absolute

15 terms of around 17 percent at nine months in terms

16 of the proportion of patients with skeletal events.

17 This effect is maintained out to two years

18 and includes both effects on radiation requirements

19 and fractures.

20 [Slide.]

21 As a clinician, I sometimes find it

22 difficult to assimilate proportions of patients

23 experiencing events and so I include this slide

24 which gives a flavor of the totality of events that

25 occurred in these studies and shows that about 40


1 percent of events were abolished by the addition of

2 pamidronate to underlying systemic therapy whether

3 you look at either the breast-cancer protocols or

4 the multiple-myeloma protocol.

5 You can see that it affected important

6 events like requiring surgery, requiring

7 radiotherapy and nonvertebral long-bone fractures.

8 [Slide.]

9 In addition, pamidronate and intravenous

10 bisphosphonates in general can have beneficial

11 effects on pain and analgesic consumption. This

12 slide shows this pain and analgesic results from

13 the three pivotal pamidronate trials. Of course,

14 as patients live with their cancer over a period of

15 two years or so, by and large, they deteriorate.

16 Their performance status deteriorates. They

17 require more analgesics and they have more pain.

18 But what this study shows was that the

19 addition of pamidronate slowed that deterioration

20 and reduced in increase that most patients would

21 experience in analgesic requirements. For multiple

22 myeloma, at least at the nine-month analysis, there

23 was actually a reduction in analgesia requirements

24 and pain compared to the placebo-treated patients.

25 [Slide.]


1 What about other tumors? Well, here we

2 have far fewer data with pamidronate and, indeed,

3 any other bisphosphonate prior to Zometa. As I

4 have indicated, there is biochemical and

5 histomorphometric evidence of increased bone

6 resorption with osteosclerotic metastases and there

7 are reports in the literature, somewhat anecdotal,

8 perhaps, but, nevertheless, of useful pain relief

9 from acute high-dose bisphosphonate treatment for

10 sclerotic metastases or other tumors.

11 But no previous randomized trial evidence

12 exists to date that shows a beneficial effect of

13 bisphosphonates on skeletal events.

14 [Slide.]

15 The only study that is really available to

16 present to you today is a trial that was conducted

17 with pamidronate and which has been presented in

18 abstract form which was a relatively short-term

19 study of only six months duration with a primary

20 endpoint, actually, of pain rather than skeletal

21 events. But, as far as this study can show,

22 pamidronate was unable to influence the pattern of

23 skeletal events, the number of patients who

24 experienced a skeletal event or the skeletal

25 morbidity rate.


1 So we don't have any evidence in prostate

2 cancer to date that pamidronate or any other

3 bisphosphonate is particularly useful apart from,

4 perhaps, treating pain.

5 [Slide.]

6 What about adverse-event profile of

7 bisphosphonates? In general, these are very well-tolerated

8 compounds compared to many of the things

9 that we use in oncology. Intravenous

10 bisphosphonates are associated with the acute-phase

11 response classically comprised of fever, myalgia,

12 arthralgia. There is an increased incidence of

13 anemia for uncertain reasons with bisphosphonates

14 and occasional mineral disorders such as

15 hypercalcemia and hyperphosphatemia.

16 Very importantly, there are renal effects

17 of bisphosphonates which are seen as a class effect

18 and are very much related to the dose given and

19 particularly the infusion time over which the dose

20 is administered. That is seen with cadrinate*,

21 pamidronate and almost any other intravenous

22 bisphosphonate.

23 [Slide.]

24 How does zoledronic acid differ? Well, it

25 is more potent, at least in the laboratory


1 situation, and it is more potent because of this

2 unique structure where, on the site of the PCP

3 backbone, or bone hook, is this imidazole side

4 chain with these two nitrogen atoms which increases

5 its potency above any other bisphosphonate

6 currently in development.

7 [Slide.]

8 There are a number of key preclinical

9 properties of Zometa. First, in vitro, it has been

10 shown to potently inhibit osteoclast formation and

11 bone resorption really regardless of the underlying

12 pathogenic stimulus and, in vivo, is able to

13 inhibit bone resorption in a variety of benign and

14 malignant bone-disease models, again irrespective

15 of tumor types.

16 It does this without deleterious effect on

17 bone structure in that it preserves bone

18 architecture and strength and does not inhibit bone

19 formation.

20 Interestingly and, perhaps, not of direct

21 relevance today, but Zometa also has novel effects

22 of angiogenesis and on pain and neurotransmitter

23 production. Lastly, in a number of animal models

24 where tumor cells have been inoculated into

25 animals, it has been shown that treatment with


1 bisphosphonates such as Zometa is able to reduce

2 the number and size of bone metastases and inhibit

3 much of the tumor-induced osteolysis associated

4 with those animal models.

5 [Slide.]

6 In terms of the pharmacology, Zometa is

7 very similar to other bisphosphonates. There is

8 very little protein binding or uptake by red blood

9 cells and no significant interaction with

10 cytochrome P450 metabolizing enzymes.

11 In vivo, there are similar

12 pharmacokinetics in that, after intravenous

13 administration, there is a rapid disappearance of

14 the drug from circulation and the plasma drug

15 concentrations are dose-proportional. Most of an

16 infused dose goes to bone, perhaps about 60

17 percent, and the rest is rapidly eliminated by the

18 kidney over approximately 24 hours.

19 [Slide.]

20 There have been studies of Zometa in

21 patients with renal dysfunction. This slide

22 summarizes the area under the concentration curve

23 for 24 hours of Zometa given on three occasions to

24 three different groups of patients, either with

25 normal renal function, mild impairment or moderate


1 renal dysfunction.

2 It shows that, at least down to a

3 creatinine clearance of 30, that although this is

4 associated with a small increase in AUC, it has no

5 effect on urine excretion and the increase in AUC

6 is not affected by repeated dosages. There is no

7 accumulation of the compound with time.

8 On the basis of these studies, there is no

9 indication as, indeed, there is no indication for

10 pamidronate, to dose reduce in renal impairment at

11 least down to clearance of 30 mls per minute.

12 [Slide.]

13 What about the dose and schedule for use

14 in oncology patients? Well, a lot of data has been

15 generated on phase I and phase II trials. This

16 slide summarizes findings from a phase II trial of

17 some 270 or more patients, protocol 007, where

18 Zometa was given in addition to standard therapy to

19 a population of breast cancer and myeloma patients

20 and doses of 4, 2 and 0.4 milligrams were compared

21 to pamidronate.

22 This study showed that, on a three- to

23 four-weekly schedule, that Zometa, at 2 and 4

24 milligrams, was able to produce sustained effects

25 on serum and urinary markers of bone resorption but


1 the 4 milligram dose was the most effective dose

2 tested. Skeletal events and pathological fractures

3 were reduced most by the 4 milligram dose of Zometa

4 and the 0.4 milligram dose was clearly ineffective

5 compared to the other Zometa doses or, indeed,

6 pamidronate.

7 Lastly, the time to first skeletal event

8 in the breast-cancer patients was almost two months

9 longer in the 4 milligram arm versus the 2

10 milligram dose although, being a phase II study, of

11 course it was not powered to show this as a

12 significant difference.

13 [Slide.]

14 Exploring the schedule and dose in a

15 little more detail using bone markers, this slide

16 illustrates a couple of key points. Firstly, this

17 is taken from protocol 007. It shows the

18 biochemical profiles of the three Zometa dosages,

19 0.4, 2 and 4 milligrams, and pamidronate 90 and

20 shows that there is a rapid inhibition of bone

21 resorption which reaches a maximum at around a week

22 after infusion.

23 But the red line, the 4 milligram Zometa

24 group, shows a more sustained effect with

25 persisting complete inhibition of bone resorption


1 at four weeks whereas pamidronate and the other

2 dosages are beginning to wear off by that time

3 point.

4 The right-hand side of the slide shows the

5 effects of chronic dosing where that effect of

6 inhibiting bone resorption is maintained and,

7 again, is more marked at the 4 milligram dosage

8 than it is at other dosages tested in that study

9 or, again, more marked than pamidronate.

10 [Slide.]

11 You have already heard in the introductory

12 talk that Zometa is already licensed for the

13 treatment of hypercalcemia of malignancy. This

14 slide just reminds us of the data that led to that

15 approval. This was a study in patients with

16 moderate to severe hypercalcemia of malignancy and

17 compared pamidronate 90 milligrams with Zometa at 4

18 or 8 milligrams and showed quite clearly that

19 Zometa was superior with nearly 90 percent of

20 patients achieving normocalcemia by ten days which

21 was the primary endpoint of the study, compared to

22 70 percent with pamidronate.

23 In addition, Zometa worked more quickly

24 and, of interest, there was no difference between

25 the 4 and 8 milligram dosages in this trial.


1 Clearly, these data were not available when the

2 phase III studies were generated and the protocols

3 designed. But it suggests that Zometa is superior

4 to pamidronate but there is no dose response

5 between 4 and 8 milligrams.

6 [Slide.]

7 So, to conclude my presentation, I think

8 we can all agree that metastatic bone disease is an

9 important healthcare problem in oncology and there

10 are many unmet needs for our patients in terms of

11 skeletal complications. Although the underlying

12 tumor biology is very different at the primary

13 site, when the disease gets to bone, the

14 pathophysiology is very similar in that it is

15 mediated through osteoclasts and, as far as we can

16 tell, osteoclast activation accompanies all bone

17 metastases with or without bone formation.

18 The currently available bisphosphonates

19 have a limited range of activity which I think we

20 have to say is, at the present, confined to breast

21 cancer and myeloma. Zometa is a more potent

22 inhibitor of osteoclast activity which, we believe,

23 provides a bone-specific treatment which is

24 applicable across a range of tumor types.

25 I thank you for your attention and would


1 now like to turn the podium over to Dr. Jim

2 Berenson who is going to present the first of the

3 three phase III trials, protocol 010.

4 Pathophysiology of Metastatic Bone Diseases

5 and the Role of Bisphosphonates

6 DR. BERENSON: Good morning all. Good

7 morning Dr. Nerenstone, members of the ODAC, those

8 of you who are on teleconference and

9 videoconference this morning.

10 [Slide.]

11 It is my pleasure to present to you the

12 first of three randomized double-blind studies

13 evaluating Zometa at two doses. This first study

14 involves patients with breast cancer metastatic to

15 bone and multiple myeloma with at least one lytic

16 lesion. Unlike the other studies, in this study,

17 the comparator is pamidronate since, as you heard

18 from Dr. Coleman, this has shown to be effective in

19 reducing skeletal complications in these types of

20 patients.

21 [Slide.]

22 This was a double-blind, double-dummy,

23 study involving 1648 patients who were stratified

24 prior to assignment to which drug based on *Duriei-Salmon

25 stage III patients with at least one lytic


1 lesion with myeloma and then breast-cancer patients

2 either on hormonal therapy or chemotherapy. This

3 patients had to have stage IV breast with at least

4 one either lytic, blastic or mixed lesion.

5 They could be on appropriate

6 antineoplastic therapy at baseline and this could

7 be changed at the discretion of the treating

8 physician during the trial. ECOG performance

9 status could be 0, 1 or 2 and the serum creatinine

10 at the time of study entry had to be less than or

11 equal to 3 milligrams per deciliter.

12 [Slide.]

13 The study design is shown here. This was

14 a 12-month dosing study. Pamidronate was given as

15 90 milligrams every three to four weeks over two

16 hours and then Zometa as a 4-milligram and

17 initially 8-milligram, and you will see why some of

18 those patients were changed to 4 milligrams, every

19 three to four weeks initially over five minutes and

20 amended to increase the infusion time to fifteen

21 minutes, and you will see the reasons for that

22 momentarily.

23 The duration of the study was one month

24 beyond the dosing regimen; that is, thirteen

25 months. Patients during the trial also received


1 oral vitamin D and calcium daily. This was to

2 reduce the incidence of hypocalcemia which can

3 occur with bisphosphonate use and, indeed, in this

4 study, those patients receiving pamidronate had a

5 lower incidence of hypocalcemia than that that had

6 been observed in the trials previously presented by

7 Dr. Coleman.

8 A second reason for using these two

9 medications in these patients was to reduce the

10 potential for microfractures which can occur in

11 animals as a result of bisphosphonate use with

12 increases in parathyroid hormone. This has not

13 been observed clinically, but it is a potential

14 reason to use vitamin D and calcium as well.

15 [Slide.]

16 The primary objective of the trial is

17 shown here. It was to demonstrate the efficacy of

18 Zometa through the noninferiority comparison to

19 pamidronate for the treatment of bone metastases.

20 In this trial, a margin of 8 percent with two-sided, 95-

21 percent, confidence intervals was used

22 based on the results of the prior trials that Dr.

23 Coleman presented comparing pamidronate to placebo

24 in breast-cancer patients and myeloma patients with

25 lytic bone disease.


1 We also wanted to demonstrate that the

2 safety profile of this new bisphosphonate given

3 chronically was comparable to chronic-used

4 pamidronate.

5 [Slide.]

6 The primary study endpoint is shown here.

7 It was to determine the proportion or the percent

8 of patients experiencing at least one skeletal-related event

9 not counting hypercalcemia of

10 malignancy as an event for this primary endpoint.

11 [Slide.]

12 A number of secondary endpoints were also

13 analyzed including time to first skeletal-related

14 event, the skeletal morbidity rate, and Andersen-Gill

15 multiple-event analysis which I will describe

16 momentarily. In addition, the time to first

17 skeletal-related event, skeletal morbidity rate and

18 the number of patients experiencing any skeletal

19 event was also determined, this time counting

20 hypercalcemia of malignancy as a skeletal event.

21 The pain and analgesic scores were

22 analyzed, a bone-lesion response as well. The

23 time to the progression of the patient's overall

24 disease as well as progression of their bony

25 metastasis. Then safety was analyzed including an


1 analysis of survival. Importantly, beyond the

2 thirteen months of the trial, an additional six

3 months of safety data is available and will be

4 presented for overall survival as well as changes

5 in serum creatinine in these patients.

6 [Slide.]

7 The definition of a skeletal-related event

8 is similar to that that was employed in the prior

9 trials comparing pamidronate to placebo in breast

10 and myeloma defined as the development of any new

11 pathological fracture, the development of spinal-cord

12 compression, the requirement for radiation

13 therapy for either bone pain or to treat actual or

14 impending pathological fractures or spinal-cord

15 compression, surgery to bone and, as mentioned

16 previously in some of the analyses, hypercalcemia

17 of malignancy of defined as an event.

18 [Slide.]

19 The preplanned analysis from this trial

20 was to determine, first of all, the proportion or

21 the percent of patients with at least one skeletal

22 event. This was defined as the number of patients

23 with at least one skeletal event divided by the

24 number of patients in that treatment group. The

25 time to first skeletal-related event was defined as


1 the time the patient was randomized to the

2 development of the first skeletal event and this

3 was determined in days.

4 The skeletal morbidity rate looks at the

5 number of events over time; that is, the number of

6 skeletal events divided by the time the patient is

7 on trial determined in years. The Anderson-Gill

8 method allows one to analyze multiple events over

9 time and it uses a more general model and takes

10 into account not only the time of the number of

11 events in a given period of time but the time

12 between events as well and, thus, is a more robust

13 analysis of multiple events over time in a given

14 patient.

15 [Slide.]

16 The history of the trial is shown here.

17 The initial design was to employ two doses of

18 Zometa, either 4 or 8 milligrams, initially given

19 over five minutes versus standard-dose pamidronate

20 as a 90-milligram infusion given over two hours

21 every three to four weeks for twelve months. In

22 June of 1999, because of concerns of changes in

23 creatinine in patients receiving Zometa, the

24 infusion time for Zometa was increased from five to

25 fifteen minutes.


1 In order to assure that was occurring, the

2 infusion volume was also increased from 50

3 milliliters to 100 milliliters. The following

4 year, in June of 2000, a second renal amendment was

5 made because of continuing concerns in the 8-milligram dose

6 of changes in creatinine, so all

7 those patients subsequently received 4 milligrams

8 and subsequently will be known as the 8/4 milligram

9 group.

10 In addition, renal-function monitoring was

11 begun so that, prior to each dose of Zometa within

12 a two-week period of time, the serum creatinine was

13 checked. A statistical amendment was also made

14 because of the mix in the 8-milligram dose group so

15 that the primary efficacy analysis was based on

16 comparing Zometa at 4 milligrams versus pamidronate

17 at 90 milligrams.

18 [Slide.]

19 The trial started in, as you see, the fall

20 of 1998 and concluded approximately one year ago.

21 Approximately half of the 1648 patients were

22 accrued prior to the change in the infusion time

23 from five to fifteen minutes and, indeed, nearly

24 half of these patients only received 8 milligrams

25 during the entire trial in the 8-milligram dosing


1 group.

2 The rest of the patients were accrued

3 during the subsequent six-month period of time,

4 about half of the patients. As you see, in June of

5 2000, a second renal amendment was made to change

6 8-milligram dosing patients to only receive 4. In

7 fact, those patients who were actually entered

8 after renal amendment 1, about a quarter of those

9 patients only received the 8-milligram dose.

10 The rest of the trial was completed so

11 that the last study visit occurred approximately

12 one year ago.

13 [Slide.]

14 The demographics and prognostic factors

15 among the approximately 1650 patients on this trial

16 are shown here. One can see that the mean age was

17 in the upper 50s. As you would guess, given that

18 this involved a lot of breast-cancer patients,

19 about 80 percent of the patients entered were

20 female.

21 About 85 percent were Caucasian. The

22 performance status in most cases was 0 or 1. There

23 was an approximately equal distribution of patients

24 who had breast cancer with metastatic bone disease

25 who were on chemotherapy, hormonal therapy as well


1 as those patients with myeloma who had at least one

2 lytic lesion. So, similar numbers of patients and

3 similar numbers in each arm.

4 [Slide.]

5 As one can see here, the number of

6 patients who were able to complete the study

7 therapy through twelve months of treatment and

8 additional months of follow up was about 60 percent

9 and there was an equal distribution in those

10 receiving either 4 or 8/4 Zometa versus pamidronate

11 at 90 milligrams.

12 [Slide.]

13 The reasons for early discontinuation

14 amongst approximately the 40 percent of patients

15 who did not complete the study, as you would

16 probably guess, death occurring in about 10 to 11

17 percent of patients and a similar proportion

18 throughout all three arms.

19 Adverse events also occurring with a

20 similar proportion amongst patients on Zometa 4,

21 8/4 or pamidronate at 90. Withdrawal of consent, a

22 similar proportion. And the other causes for early

23 discontinuation, again, nothing stands out. Small

24 numbers and not much difference between the arms.

25 [Slide.]


1 The primary endpoint results are shown

2 here. We are looking at the percentage of patients

3 who had at least one skeletal event by thirteen

4 months; that is, twelve months of treatment, an

5 additional month of follow up. As one can see from

6 the data, the percentage of patients having at

7 least one skeletal event by this time point is

8 quite similar across all three arms approximating

9 45 percent.

10 The red is Zometa at 4 milligrams, Zometa

11 8/4 is the blue, and the purple, here, is the

12 pamidronate arm. Importantly, as one can also see,

13 the Zometa at 4, and well remembering many in the

14 8/4 group only received 8, the percentage of

15 patients having an event is quite similar in both

16 of these two arms.

17 Now, comparison of the data shows that,

18 indeed, the primary endpoint comparing Zometa at 4

19 versus pamidronate at 90, within the 95 percent

20 confidence interval, remembering what told I said

21 earlier, we are looking for an 8 percent margin, we

22 can see here that Zometa may be as much as 7.9

23 percent better than pamidronate and as worse as 3.7

24 percent inferior. Indeed, this is well within the

25 8 percent mark that we looked at as our primary


1 endpoint in the trial.

2 Now, in order to clarify these issues

3 better in terms of interpreting a noninferiority

4 trial, from the statistical perspective, I now want

5 to bring up Dr. Paul Gallo from Novartis

6 Biostatistics.

7 DR. GALLO: Good morning.

8 [Slide.]

9 I would like to very briefly discuss some

10 issues in noninferiority trials which is a very

11 complex and quickly evolving area and their

12 implications for the interpretation of the data

13 that you have just seen.

14 A basic rationale for a noninferiority

15 trial is that if we can show sufficient

16 comparability between a new treatment and a

17 standard treatment and use historical information

18 that demonstrated how superior that standard is

19 relative to placebo, then we can infer that the new

20 treatment would have beaten placebo had there been

21 a placebo arm in the current trial.

22 In this case, the relevant historical

23 information comes from the pamidronate registration

24 trials 218 and 19. I will point to this screen to

25 the extent that I am able. I am going to summarize


1 an analysis that was done by the FDA statistical

2 reviewer and was included in the briefing document.

3 In designing study 010, we had actually

4 used a slightly different analysis, but the results

5 are not practically different so I will just

6 illustrate with this analysis to try to keep things

7 a little bit simpler.

8 In a combined analysis of data from these

9 trials, we can see that pamidronate had 13 percent

10 fewer events than placebo and the lower limit for

11 the magnitude of benefit was 7.3 percent. By

12 recent conventional practice if, in the current

13 study, we can exclude the possibility that Zometa

14 is 7.3 percent worse than pamidronate, then we can

15 claim that Zometa is effective. The number, 7.3,

16 would be called the noninferiority margin. It is

17 the potential disadvantage of Zometa that we have

18 to disprove.

19 Again, we had done a slightly different

20 analysis that led to the 8 percent margin in the

21 protocol that was previously mentioned by Dr.

22 Berenson.

23 This is a graphical illustration of what I

24 have just described, an estimated advantage for

25 pamidronate relative to placebo of 13.1 percent and


1 its confidence limits.

2 Recently, FDA personnel have proposed that

3 it may be appropriately conservative to consider

4 using an even smaller margin, in particular, half

5 of the lower confidence limit. The rationale is

6 that the current practice makes a constancy

7 assumption, namely that the standard is equally

8 effective in the current trial as it was in the

9 historical trials. In practice, we can't guarantee

10 that there are not subtle differences between the

11 historical and current trials so that the standard

12 possibly might not be as effective in the current

13 trial.

14 Achieving a stricter noninferiority

15 criterion would provide more assurance that an

16 effect is real, even allowing for some violation of

17 the constancy assumption. In our current case, the

18 conservative criterion would be a margin equal to

19 half of 7.3 percent, or 3.65 percent.

20 Now we look at the protocol 010 data,

21 specifically the primary 4-milligram dose results

22 and tie it together with the historical data by

23 lining up the pamidronate effect. We see a 2

24 percent difference advantage for Zometa with a

25 confidence limit that, in a worse case, goes as far


1 as a 3.7 percent advantage for pamidronate.

2 We can see that the conventional standard

3 of excluding 7.3 percent is safely reached. In

4 fact, these results just about achieve the proposed

5 conservative standard even though the trial was not

6 designed to be powered for such a standard which

7 was really not in existence at that time.

8 So this provides somewhat of a higher

9 level of comfort that the Zometa effect is real

10 even allowing for the possibility that, for some

11 reason, pamidronate might not be quite as effective

12 here as it was in the historical trials.

13 So, to summarize, that is the evidence for

14 the effectiveness of Zometa in this trial. We

15 estimate from the data that Zometa is just a bit

16 better than pamidronate and we know, from

17 historical trials, that pamidronate seems to be

18 quite a bit better than placebo and, in a worse

19 case, both for Zometa and for pamidronate, the

20 confidence intervals don't overlap.

21 Allowing for some violation of the

22 constancy assumption by using the newer

23 conservative standard, they still essentially don't

24 overlap.

25 Now I will turn things back to Dr.


1 Berenson to continue with the presentation of the

2 trial results.

3 DR. BERENSON: Thank you.

4 [Slide.]

5 I will continue to present the results

6 from the trial. As you see here, we are looking at

7 the specific types of skeletal events that occur

8 during the trial and the proportions, actually, are

9 quite consistent to what we observed from our

10 earlier trials comparing pamidronate to placebo.

11 Indeed, fracture and radiotherapy to bone

12 are the most frequent events. As you see here,

13 looking at all four types of events, the proportion

14 of patients having an event are quite similar in

15 the pamidronate, the Zometa 4 and 8/4 group with

16 the exception there are a smaller proportion of

17 patients who receive Zometa at 4 milligrams who are

18 actually experiencing the requirement for

19 radiotherapy to bone but the 8/4 group looks a lot

20 like pamidronate here.

21 [Slide.]

22 Indeed, the time to first skeletal-related

23 event, a secondary endpoint in the trial, as you

24 can see, these three curves are quite

25 superimposable upon one another; that is, the time


1 to first event here is approximately one year in

2 the Zometa 4, the 8/4 as well as the pamidronate

3 arm and, as you see, the hazard ratios here are

4 slightly less than 1, but do cross 1.

5 [Slide.]

6 When one looks at the number of skeletal

7 events per year, the MSR, or skeletal morbidity

8 rate, the red, again, is Zometa. The blue is

9 Zometa 8/4 and the purple is pamidronate 90. The

10 number of events per year is about 1 in the two

11 Zometa groups, a little higher with pamidronate at

12 1.4 but this is not significantly different, again

13 quite equivalent across these three arms in terms

14 of number of events per year.

15 [Slide.]

16 Now, as I mentioned earlier, another type

17 of analysis was done to look at the number of

18 events per year, not just time to first event or

19 proportional analysis of a single event. This

20 analyzes the type to each count in skeletal-related

21 event and, therefore, takes into account the

22 interval between subsequent skeletal-related events

23 in addition to just the time to the first event or

24 the number of events over time as the SMR has done.

25 So we believe this is a more robust


1 analysis. As you can see from the hazard ratios

2 here, which are less than 1, actually, the relative

3 reduction or benefit in Zometa is in the range of 9

4 to 11 percent here in terms of the Andersen-Gill

5 analysis. But, again, these do cross 1 but

6 certainly suggest equivalence of pamidronate to

7 Zometa not only in terms of time to first event and

8 number of events per year, but multiple events over

9 time as well.

10 [Slide.]

11 This slide is actually not in the handout

12 for those of you who are off-site, Drs. Taylor,

13 Albain and Kelsen, but we wanted to include it.

14 This is an exploratory analysis to determine the

15 proportion of breast-cancer patients who had an SRE

16 based on the type of bone lesion they had at the

17 time of study entry.

18 So those patients who had lytic bone

19 disease had at least one lytic lesion. The blastic

20 group only contained blastic lesions and those that

21 could not be placed in either group were considered

22 other.

23 As you see, in the lytic group, the red

24 bar, again, Zometa at 4, and the blue bar, Zometa

25 8/4, the number of patients having at least one


1 event is actually less than in pamidronate. In the

2 middle of the other group, there is a trend in the

3 other direction. The pamidronate is slightly less

4 than the other two groups.

5 On the right side, the blastic group,

6 although the Zometa 4 is lower, the Zometa 8/4

7 looks quite similar to pamidronate. So I think it

8 is very difficult to conclude from this single

9 slide whether the drug works, as you well could

10 guess, in blastic disease because the comparator

11 here is pamidronate and we have not previously

12 considered pamidronate in patients with blastic

13 disease from the trials in the mid-90's. I will

14 leave that for subsequent discussion, but I did

15 want to show that slide.

16 [Slide.]

17 Looking at disease and quality-of-life-related

18 endpoints, I will just summarize and I will

19 show you some of the data. That was very

20 comparable disease and quality-of-life-related

21 measures and changes that were demonstrated in the

22 two Zometa arms compared to the pamidronate arm;

23 that is, the time to progression of bone

24 metastasis, the time to progression of any type of

25 malignant process going on in the patients, the


1 pain analgesic score changes during the trial,

2 changes in both ECOG performance status and the

3 FACT-G global quality-of-life were quite similar

4 across these three arms.

5 [Slide.]

6 Now, first looking at the data for

7 disease-related endpoints here, in the top part

8 here, we are looking at the time to the progression

9 of the bone disease measured in days. You can see,

10 it is quite similar across all three arms

11 approximating six months. Now, secondly, looking

12 at the time to the progression of the patient's

13 malignancy, again, the numbers are quite similar

14 although slightly shorter for pamidronate but

15 reassuredly show in terms of the two Zometa arms.

16 The Zometa, it looks quite similar. It

17 certainly doesn't look worse than pamidronate in

18 terms of the progression of the patient's

19 underlying malignancy.

20 [Slide.]

21 Here we are showing the data for quality-of-life

22 endpoints and I will summarize by telling

23 you that brief pain inventory score changes,

24 analgesic scores, ECOG performance changes, FACT-G

25 total-score changes and, again, here we are looking


1 at the change from the baseline to either end of

2 study or last measurement, were not significantly

3 different from Zometa at 4, Zometa at 8/4, compared

4 to pamidronate although those patients, over time,

5 in terms of pain, did improve pain within each arm,

6 just not different between the arms.

7 [Slide.]

8 So here is a summary of the efficacy data

9 from the trial. On the left side, we are looking,

10 again, at the percent of patients who had at least

11 one skeletal event by thirteen months, twelve

12 months of therapy, one month of additional follow

13 up, and the numbers are strikingly quite similar,

14 44, 46 and 46.

15 The time to first skeletal-related event,

16 hazard ratio less than 1, crosses 1, again

17 consistent with equivalence of this drug in terms

18 of efficacy to standard-dose pamidronate. The mean

19 SMR--as I mentioned earlier, the SMRs were around 1

20 for the two Zometa arms, slightly higher in the

21 pamidronate arm, 1.4, but not significantly

22 different.

23 Looking at multiple events over time in a

24 little different matter, as I mentioned earlier, by

25 Andersen-Gill analysis, the hazard ratios, in fact,


1 are less than 1, again cross 1. So, overall, the

2 results of this trial in terms of efficacy

3 certainly suggest comparable efficacy of this new

4 drug to pamidronate in reducing skeletal

5 complications in these patients.

6 [Slide.]

7 Now let's turn our attention to the safety

8 data from this trial. The primary cause of death

9 during the trial or within one month after study

10 drug termination is shown here. As you could

11 guess, the most common cause, of course, would be

12 the underlying malignancy in approximately 8 to 10

13 percent of patients throughout all three of these

14 arms.

15 Other causes which were less common,

16 including respiratory, cardiac and infectious

17 causes, certainly are similar across all three arms

18 and the other less common causes, as you can see,

19 the numbers quite small and quite similar across

20 three arms, very reassuring.

21 [Slide.]

22 Now, overall survival was obviously looked

23 at as well. As you can see, in this trial, in

24 those patients again with breast cancer metastatic

25 to bone and myeloma with at least one lytic lesion,


1 the survival was approximately 800 days in all

2 three arms, strikingly similar in the Zometa 4, 8/4

3 and pamidronate arms with p-values that are very

4 high and much above 0.05.

5 [Slide.]

6 The incidence of adverse events that

7 occurred in at least 15 percent of patients in one

8 of the arms is shown here regardless of whether we

9 believed it was related to the study drug. You see

10 a lot of white here indicating that there were very

11 similar proportions of patients in all three arms

12 having these events with the exception of the

13 yellow, pyrexia, a known side effect with the first

14 or second administration of bisphosphonates, about

15 5 percent more common in the Zometa arms and,

16 indeed, anorexia, really for unknown reasons, a

17 little bit more than 5 percent than the pamidronate

18 in the 4-milligram arm. But there are a lot, as

19 you see, of adverse events we looked at.

20 [Slide.]

21 Now, importantly, the incidence of anemia

22 has been shown to be higher with chronic

23 administration of pamidronate in the previously

24 done trials comparing pamidronate to placebo in

25 breast-cancer on chemotherapy and myeloma patients


1 with at least one lytic lesion.

2 Although, there was some incidence of

3 anemia, it was less than 6 percent in all treatment

4 groups and was not different between the treatment

5 groups as well. Of probably more importance, the

6 use of packed red blood-cell transfusions and

7 exogenous erythropoietin support was not different

8 between the treatment arms as well.

9 Electrolyte and mineral adverse events,

10 mentioned previously in Dr. Coleman's talk which

11 occurs with pamidronate occasionally, this

12 incidence was quite uncommon in all treatment

13 groups. The most common events with the Zometa at

14 the 4-milligram dose were hypophosphatemia, low

15 potassium or high potassium, but these were

16 uncommon.

17 [Slide.]

18 Now, the definition of serum creatinine

19 used to monitor these patients following renal

20 amendment 2 was a serum creatinine that was normal

21 at baseline and then increased by 0.5 milligrams

22 per deciliter. A serum creatinine that was

23 abnormal at baseline and increased by more than 1

24 milligram per deciliter or a doubling of serum

25 creatinine from the number that was available at


1 study entry.

2 If the serum creatinine was increased by

3 any of these three determinations, it was decided

4 to hold the dose until it returned to 10 percent of

5 the baseline serum level.

6 [Slide.]

7 This is a rather complex slide but an

8 important one. Turning our attention, first of

9 all, to the top half of the slide, this is the

10 number of patients who had no increase of serum

11 creatinine and, again, the definitions I showed you

12 in the previous slide, before we changed the

13 infusion time from five to fifteen minutes.

14 The purple line represents patients on

15 pamidronate. The two Zometa curves in red and

16 light blue, as you can see, are lower lines

17 suggesting that, indeed, before the amendment

18 change was made, a slowing of infusion time, there

19 was an increased risk of creatinines going up in

20 patients on Zometa in the 4 or 8/4 group.

21 Following the amendment change, shown in

22 the bottom half of the slide, and, again, about

23 half of the patients accrued at that time, one can

24 see a disappearance of the increased risk of renal

25 problems or creatinine rises in those patients who


1 were receiving Zometa at 4 over fifteen minutes;

2 that is, the dark red and the purple curves are

3 superimposable, hazard ratio there at 1.012.

4 But we continue to observe problems in the

5 8-milligram dose when given over fifteen minutes in

6 the light blue with a hazard ratio over 2 and a

7 quite significant p-value suggesting continued

8 problems. Importantly, as I mentioned earlier,

9 nearly half of the patients who were on the 8-milligram dose

10 prior to the fifteen-minute infusion

11 time change only received that dose, about 21

12 percent of patients following that change.

13 [Slide.]

14 Now, let's look at the data globally in

15 terms of significant NCI grade 3 and 4 serum

16 creatinine changes. After the fifteen-minute

17 amendment was changed, only those patients

18 enrolled, again that was about half of the 1648,

19 803, and one can see grade 3 problems only in one

20 patient at Zometa at 4, no grade 4s, and, as you

21 can see, slightly more in the Zometa 8/4s at six

22 grade 3s and one grade 4, again, necessitating the

23 change in those patients from 8 to 4.

24 In the pamidronate, in fact, there were

25 more events here of grade 3 and grade 4 than Zometa


1 at 4.

2 [Slide.]

3 So the safety summary that I have just

4 outlined tells that when you give Zometa at a 4-milligram

5 i.v. dose over fifteen minutes every

6 three to four weeks, the safety profile, including

7 changes in creatinine, is quite comparable to

8 intravenously administered pamidronate at

9 90 milligrams over two hours.

10 [Slide.]

11 Indeed, an overall summary of this trial

12 would tell us that Zometa at 4 milligrams over

13 fifteen minutes given every three to four weeks

14 demonstrates comparable safety and efficacy as

15 noninferiority design in this trial to standard

16 dose pamidronate at 90 milligrams over 120 minutes

17 in treating bone metastasis of all types in

18 patients in breast cancer, in lytic bone disease,

19 in multiple myeloma.

20 DR. NERENSTONE: Thank you very much. We

21 are going to go right to the FDA presentation for

22 review of the study 010. Then we are going to

23 leave the clarifying questions to both the sponsor

24 and the FDA until after the FDA presentation.

25 FDA Presentation


1 Zometa in Breast Cancer and Multiple Myeloma

2 (Study 010)

3 DR. WILLIAMS: Dr. Nerenstone, members of

4 ODAC, it is my pleasure to begin the FDA

5 presentation of this application.

6 [Slide.]

7 I want to break from protocol a little.

8 You are welcome to interrupt me if I am on wrong

9 slide. Otherwise, we will wait until the end.

10 [Slide.]

11 First, I would like to recognize the FDA

12 review team. The FDA clinical review team worked

13 hard to review this large complicated application.

14 This slide recognizes the members of that team.

15 Debra Vause led us as project manager. Five

16 medical and statistical reviewers helped prepare

17 the information for this meeting. Medical

18 reviewers included myself for study 010, Dr. Amna

19 Ibrahim for studies 011 and 039, Dr. Nancy Scher

20 for the safety data from these studies and Dr.

21 Richard Pazdur, our Division Director.

22 The statistical review of study 010 was

23 performed by Dr. Ning Li for study 010. For 011

24 and 039 was Dr. Raji Sridhara. And the statistical

25 team leader is Dr. Gang Chen. All of the reviewers


1 will be available for questions and discussion.

2 [Slide.]

3 This is the outline of my presentation.

4 First, I will present an overview and then a

5 regulatory framework followed by discussion of the

6 FDA findings from study 010 and myeloma and breast

7 cancer. The latter will include a discussion of

8 the noninferiority trial design, results and

9 examination of assumptions.

10 [Slide.]

11 As a reminder, this is the proposed Zometa

12 indication; treatment of osteolytic, osteoblastic

13 and mixed bone metastases of solid tumors and

14 osteolytic of multiple myeloma. These are in

15 conjunction with standard antineoplastic therapy.

16 [Slide.]

17 The FDA reviews the Zometa from a

18 regulatory perspective as well as from a scientific

19 perspective. The FDA requirement to demonstrate

20 efficacy dates to a 1962 amendment to the Federal

21 Food, Drug and Cosmetic Act which required

22 substantial evidence of efficacy from adequate and

23 well-controlled investigations.

24 Usually, this means evidence from multiple

25 clinical trials but very impressive and robust


1 results from a single multicenter trial has

2 sometimes been accepted. An important question you

3 will be considering during your deliberations will

4 be whether these trials meet the regulatory

5 efficacy requirement.

6 You will be asked this for each of the

7 different indications that correspond to the

8 different trials. You might find that one of the

9 trials is so impressive that it supports approval

10 withput any support from the other trials or you

11 may find that, while a single trial is not

12 convincing enough to stand alone, you find the

13 results of one of the other trials to be supportive

14 also.

15 It is a matter of both science and of

16 judgment whether the results of the different

17 trials support each other. This is a fitting topic

18 for ODAC and we invite your advice.

19 [Slide.]

20 At the planning stage, both FDA and

21 Novartis assumed that some sharing of information

22 between tumor types was reasonable. For example,

23 breast cancer and myeloma were combined in a single

24 study. For each indication, only single studies

25 were planned. Finally, multiple different solid-tumor types


1 were lumped together in the single

2 study 011.

3 Of course, these general assumptions were

4 made without having the results in hand. The

5 questions before ODAC concern specifics. Now, with

6 the result in hand, there may be unanticipated

7 questions. This often seems to happen in clinical

8 trials in the real world. So we need your advice

9 whether these assumptions are still reasonable in

10 light of the clinical-trial data.

11 [Slide.]

12 In the next two slides, I want to discuss

13 the skeletal-related event analyses used in these

14 studies. Evaluating efficacy by measuring cancer-patient

15 morbidity is difficult and there is no

16 perfect endpoint. Patients suffering from cancer

17 often drop out early from studies either from

18 death, side effects of treatment of from other

19 cancer problems not captured by the endpoint.

20 Historically, in evaluating bisphosphonate

21 treatment of cancer metastatic to bone, FDA has

22 emphasized two very closely related endpoints;

23 first, the proportion of patients entering the

24 study who have a documented event and, second, the

25 time to skeletal-related event.


1 In studies of bisphosphonate, the results

2 from these two analyses usually go hand in hand and

3 this should not be surprising. Both use exactly

4 the same skeletal events. The first analysis

5 describes the number of patients with at least one

6 event and the second uses the additional

7 information of event timing.

8 During FDA analysis of these studies,

9 questions arose regarding which of the two

10 different endpoints was preferred.

11 [Slide.]

12 However, both endpoints share serious

13 problems. That problem is dropouts. Some patients

14 who drop out may subsequently have an event and

15 this is not counted. This would lead to an

16 underestimation of the event frequency in the

17 proportions analysis.

18 Furthermore, patients may drop out because

19 of symptoms of an impending event and that event is

20 not documented as such. This would lead to a

21 phenomenon known as informative censoring,

22 something that would violate assumptions of the

23 time-to-event analysis. This analysis assumes that

24 censoring occurs in a random manner.

25 These analyses share the problem of


1 competing risks, simultaneous risk of cancer-related

2 problems such as death and the risk of

3 having a skeletal event. With both endpoints,

4 there is likely to be bias in estimating the true

5 effect of the drug. This bias could affect how

6 accurately we describe the benefit of the drug but

7 this bias should apply equally and in the same

8 direction to both arms.

9 Because this study is blinded, neither

10 analysis should introduce bias between the study

11 arms. So a significant p-value for either endpoint

12 might be viewed as valid evidence that efficacy has

13 been demonstrated. I am sure that ODAC's Dr.

14 George and the FDA statisticians will be glad to

15 discuss this point further during this afternoon's

16 discussion.

17 So I believe we should view these two

18 closely-related endpoints with a bit more

19 flexibility than we might otherwise in evaluating

20 primary and secondary endpoints. Novartis'

21 prespecified endpoint was the proportion of

22 patients having an event. The FDA's statisticians

23 preferred analysis, this time to SRE.

24 As you have observed in these trials,

25 results were sometimes statistically significant


1 for one endpoint but not for the other.

2 [Slide.]

3 Each of the clinical trials raised one or

4 more important questions which I will summarize in

5 the following three slides. For study 010 in

6 breast cancer and myeloma, we note that it was a

7 single study of noninferiority design. Due to the

8 inherent weakness of noninferiority studies, we

9 usually expect results from two such studies or

10 additional evidence from studies of a different

11 design.

12 The question for ODAC, do the totality of

13 the data in the NDA provide support for this

14 indication. We believe they do and we invite your


16 [Slide.]

17 In prostate cancer, the 4-milligram Zometa

18 arm shows convincing results for both the primary

19 and secondary event endpoints. The 8-milligram arm

20 shows no statistical difference from placebo. Two

21 questions arise; first, considering both arms of

22 the study, how convincing are these data that

23 Zometa, 4 milligrams, is effective?

24 Second, prostate cancer produces blastic

25 bone metastasis. In considering the efficacy of


1 Zometa in prostate cancer, is it reasonable to also

2 consider evidence of Zometa efficacy from studies

3 of lytic bone metastases from other cancers?

4 Finally, after you consider all of the

5 evidence in the NDA, we will ask you whether the

6 regulatory efficacy requirement has been satisfied

7 for Zometa and prostate cancer; that is, is there

8 substantial evidence of efficacy from adequate and

9 well-controlled investigations?

10 [Slide.]

11 In patients with other solid tumors, the

12 4-milligram arm was statistically better than

13 placebo in time to skeletal-related event but not

14 by the proportions analysis. The 8-milligram

15 Zometa arm was statistically better than placebo in

16 both analyses. FDA believes the data are

17 convincing, that the population studied in this

18 trial received a benefit from Zometa.

19 However, the population studied was

20 heterogeneous composed of patients with many

21 different tumor types. The question we want you to

22 consider is whether these data support approval for

23 treatment of all individual patients with all types

24 of other solid tumors.

25 [Slide.]


1 Now, we will turn to study 010. As you

2 have heard, study 010 was an international

3 multicenter stratified double-blind study that

4 randomized patients to Zometa 4 milligrams, Zometa

5 8 milligrams or Aredia 90 milligrams i.v. every

6 three to four weeks for twelve months.

7 Randomization was stratified by center and

8 three disease strata; myeloma, breast cancer

9 treated with hormones and breast cancer treated

10 with chemotherapy. In this trial, the efficacy of

11 Zometa was determined by a noninferiority

12 comparison to Aredia.

13 [Slide.]

14 First, a few comments about design.

15 First, the design of this study assumes that data

16 from the bisphosphonate efficacy in bone metastases

17 and myeloma and breast cancer can be combined and

18 analyzed together.

19 Then a few comments about the inferiority

20 design. Here are listed several different points

21 or several different steps in the noninferiority

22 analysis. I think Novartis did a nice job of

23 presenting that. First, you estimate the

24 historical Aredia effect size versus placebo. Then

25 you compare Zometa and Aredia in the current study.


1 You determine Zometa efficacy by showing that a

2 reasonable fraction of the Aredia effect size is

3 proven for Zometa using statistical methodology.

4 Finally, you evaluate the constancy assumption.

5 There is much discussion and research

6 regarding the best methodology for performing

7 noninferiority analyses. In this case, because

8 only a single noninferiority trial was submitted,

9 FDA used a conservative method, the two 95 percent

10 confidence interval method which I will describe.

11 I think, again, Novartis has touched on this so I

12 will be brief.

13 [Slide.]

14 As you have seen, the slide summarized the

15 efficacy of Aredia showing the 13.1 percent

16 difference from historical trials. In the

17 submission, Novartis had centered on the 13.1

18 percent as the effect size. In the FDA's more

19 conservative analysis, we have used the 7.3 percent

20 lower confidence interval.

21 [Slide.]

22 Then, there is a comparison between Aredia

23 and Zometa, as you see, a 44 percent event rate on

24 the Zometa arm versus 46 percent on the Aredia arm.

25 [Slide.]


1 Although the estimate from these data

2 favors Aredia by 2 percent, again, the method used

3 a conservative limit of the confidence interval to

4 estimate the Zometa effect at 3.7 percent. By the

5 FDA analysis, using the effect size of historical

6 estimate of 7.3 percent and the worst-case estimate

7 of Zometa effect at 3.7 percent, we calculated 49

8 percent retention of the Aredia effect versus

9 placebo in sort of a worst-case analysis.

10 [Slide.]

11 A critical assumption of making

12 conclusions from noninferiority trials is this

13 constancy assumption. This requires a

14 determination that active control drug, Aredia,

15 would have shown efficacy versus placebo in the

16 current clinical-trial setting.

17 Potential problems that could challenge

18 this constancy assumption include different study

19 populations in the historical study compared to the

20 current study, changes in supportive care and also

21 study conduct could affect this assumption. Sloppy

22 trial conduct could obscure differences and make it

23 easier to win than a noninferiority analysis.

24 [Slide.]

25 Important differences were found between


1 the current and historical studies. Compared to

2 the Aredia versus placebo studies, more patients on

3 study 010 had a short time since diagnosis of bone

4 metastases. More patients had a history of a

5 previous skeletal-related events. In breast

6 cancer, more patients had no lytic bone lesions.

7 [Slide.]

8 So FDA used a couple of approaches to

9 evaluate the importance of these historical

10 differences. First, retrospective analysis of the

11 estimates of Aredia versus placebo data showed that

12 the Aredia effect appeared even greater in patients

13 with a short time since diagnosis of bone

14 metastases and in patients with a history of

15 previous skeletal-related event.

16 Therefore, enrichment of the study

17 population with these patients should, if anything,

18 increase the sensitivity of the study.

19 [Slide.]

20 The question of whether the active control

21 Aredia is effective in breast-cancer patients

22 without lytic lesions, however, cannot be directly

23 examined in by an historical Aredia versus placebo

24 study because only patients with lytic lesions were

25 entered. One can examine Zometa efficacy in the


1 subgroup of study 010 who had lytic disease. Such

2 a subgroup analysis of study 010 comparing Zometa

3 versus Aredia and breast-cancer patients with lytic

4 bone lesions did not suggest a lack of Zometa

5 efficacy here.

6 As this slide shows, it suggested a

7 noninferiority trend in favor of Zometa.

8 [Slide.]

9 Another concern was that Aredia might have

10 been effective in decreasing certain types of

11 skeletal-related events such as fractures but that

12 the current study had few such events. This

13 possibility was evaluated and the types of

14 skeletal-related events found most commonly in the

15 historical Aredia trials were similar to those seen

16 in study 010. Most were fractures and radiation

17 therapy to bone.

18 [Slide.]

19 So these are the FDA conclusions from the

20 study. Study 010 is a single study of

21 noninferiority design demonstrating efficacy of

22 Zometa for patients with bone lesions of myeloma

23 and breast cancer. We believe other data from

24 studies 011 and 039 are supportive and they

25 collectively meet the regulatory requirement for


1 substantial evidence of efficacy for well-controlled

2 investigations for the treatment of

3 myeloma and breast cancer.

4 We look forward to your discussion and

5 your advice.

6 Than you. Both the medical reviewers and

7 the statistical group will be available for

8 clarifying questions in the table along with the

9 company and then, this afternoon, we will also be

10 here for the discussion.

11 DR. TEMPLETON-SOMERS: We would like to

12 check and see if Dr. Albain and Dr. Kelsen and

13 maybe Dr. Taylor are on line.

14 DR. KELSEN: David Kelsen in New York.

15 DR. TEMPLETON-SOMERS: Kathy, are you

16 there, too?

17 DR. ALBAIN: Yes; I am here.

18 DR. TEMPLETON-SOMERS: Is there any chance

19 that Sarah made it through the snow storm?

20 DR. TAYLOR: I'm here.

21 DR. TEMPLETON-SOMERS: Good. We are glad

22 to see you. How is the weather there?

23 DR. TAYLOR: There are a lot of trees down

24 and a lot of ice.

25 DR. NERENSTONE: Now we see you, Sarah.


1 Welcome. We were afraid we wouldn't get to you

2 today, or you wouldn't get to us.

3 I am going to open in now for questions

4 from the committee.

5 Questions from the Committee

6 DR. NERENSTONE: I want to remind

7 everybody that we really want to stay focused on

8 just factual questions and don't want to open up

9 for discussion. We will have lots of time for that

10 later.

11 Questions from the committee for either

12 Novartis or FDA? Dr. George?

13 DR. GEORGE: I have a question about the

14 original design, the rationale behind having two

15 doses and what the objective of the study was of

16 that. Was there a feeling that there might be a

17 dose-response kind of effect or was it simply to

18 have two different doses, both of which would be

19 compared independently to the placebo--well, all of

20 these studies had the same question.

21 DR. NERENSTONE: Would whoever comes up to

22 the podium please identify himself.

23 DR. SEAMAN: Good morning. I am Dr. John

24 Seaman from Novartis. I worked on all the Aredia

25 submissions and also the Zometa submission. Going


1 back to the historical reason for the 8-milligram

2 and the 4-milligram being included in this trial,

3 it was basically done because, when we did our

4 phase I trial, we saw markers of bone resorption

5 being suppressed to a great extent with the 8-milligram dose

6 versus the 4.

7 We had gone all the way up to a 16-milligram dose

8 and saw no increase in the

9 suppression so we felt that, using that surrogate

10 marker as and endpoint, we should go a bit higher

11 to see if we had better efficacy.

12 Unfortunately, we didn't have the data

13 from the hypercalcemia trials to show there was an

14 equivalent efficacy in terms of 8 and 4 when we got

15 that trial started.

16 DR. NERENSTONE: Dr. George

17 DR. GEORGE: Just a quick follow up. The

18 reason I am asking is to try to determine what your

19 mind set was. Did you anticipate that you could

20 have had a situation where there is a reversal;

21 that is, that the 4 looks effective not the 8 and

22 vice-versa. How would you have interpreted that?

23 In other words, were you looking at a dose-response

24 kind of thing or were you really just going to

25 compare them as if they are two treatments, two


1 placebo, and see--

2 DR. SEAMAN: We were looking to see if we

3 were going to get a dose response, we would have a

4 better response rate.

5 DR. NERENSTONE: Dr. Raghavan?

6 DR. RAGHAVAN: I really do understand all

7 the flaws of retrospective subset analysis but one

8 of the things that has puzzled me is some of the

9 inconsistencies between the 4 and the 8/4. So,

10 recognizing all the flaws of doing a subset

11 analysis post hoc, do you have any information you

12 can share with us about the absolutely pure 8-milligram

13 group dissecting out the post-fiddling

14 dose reduction time change? Do you have any data

15 that give the same sort of endpoints that you

16 looked at the for the global group taking out just

17 the 8-milligram doses, pure 8-milligram doses?

18 DR. SEAMAN: Unfortunately, we don't have

19 any 8-milligram-dose-alone efficacy.

20 DR. NERENSTONE: I have a question along

21 those same lines. It seems to me that, according

22 to the presentation that the 8-milligram dose had a

23 higher incidence of renal problems and, therefore,

24 the doses were held until the creatinine came back

25 down to normal.


1 Can you give us a feeling for how many

2 doses were held and how long and is there a

3 possibility that what happened is that, instead of

4 8-milligram dosing every three to four weeks, you

5 had a number of patients who got 8-milligram dosing

6 every six to eight weeks?

7 I agree with Derek that there is some

8 inconsistency in the data and I was just wondering

9 if you have any other thoughts about that?

10 DR. SEAMAN: Why don't I turn this over to

11 Dr. Raimund Hirschberg who is from UCLA and was a

12 member of our renal advisory board that actually

13 looked at every piece of this data and let him

14 answer that for you.

15 DR. HIRSCHBERG: At the time, in June of

16 2000 when this second amendment which included this

17 creatinine sort of flag point, at this same time,

18 the 8-milligram dose was discontinued so this could

19 not have kicked in with the 8-milligram dose. It

20 excluded each other.

21 DR. TEMPLE: I didn't see a noninferiority

22 analysis of the 8-milligram, 8/4, dose. Did you do

23 that? I mean, in some sense, it is a replication

24 of the other or could be taken as. Obviously, we

25 know the rates were equal, but did you do a similar


1 analysis?

2 DR. SEAMAN: I will have Dr. Bee-Lian

3 Chen, our statistician, answer that. We did do a

4 8/4 analysis. This is Dr. Bee-Lian Chen from

5 Novartis.

6 DR. CHEN: My name is Bee-Lian Chen. I am

7 the project statistician for the project. I may

8 answer the question too quick in terms of

9 noninferiority. It is based on extensive analysis

10 as done by FDA and internally by Novartis. But

11 when we performed the analysis for the study

12 report, we pretty much paralleled the comparison,

13 the 4-milligram versus Aredia 90 milligrams and 8-milligram

14 versus Aredia 90 milligrams.

15 Basically, we have the confidence interval

16 based on the study 010 results. But, in terms of

17 extensive analysis performed with the

18 noninferiority details, we didn't do that.

19 DR. TEMPLE: The main result you report is

20 that you have pretty close to 50 percent retention

21 of a conservatively estimated effect of

22 pamidronate. It certainly is conservative to say 8

23 percent is the lower bound. That is the lower

24 bound of the 95 percent confidence interval. That

25 is not the typical result. That is an extremely


1 low result for pamidronate.

2 So, granting that it is conservative, you

3 then do your analysis and you show the difference

4 between the two treatments has a worst-case bound

5 of almost the same as half of that effect. Fine.

6 So you must have some idea what the upper bound for

7 the 8/4 group is and be able to say with some idea

8 what percent retention of the pamidronate effect

9 you have in that group.

10 DR. CHEN: The FDA statistician--

11 DR. TEMPLE: Or we do; right.


13 DR. LI: Ning Li, FDA. Actually we did

14 the 930 analysis for the 8-milligram arm under--the

15 committee members who got the FDA briefing package

16 can find the analysis on page 68, in the

17 statistical review.

18 Essentially, the result is comparable to

19 the 4 milligrams for study 010. The only

20 difference is the percentage of retention is lower.

21 It is about 20, 20.5, percent rather than the 49

22 percent as in the 4-milligram arm, so still

23 demonstrating the 20 percent efficacy compared to

24 placebo according to our analysis.

25 DR. TEMPLE: Can I just make one


1 observation? Dr. Gallo said that the reason that

2 you do this 50 percent is to support the constancy

3 assumption. This will be discussed later but that

4 is incorrect. You evaluate the constancy on its

5 own. You make your best guess. There is no way to

6 really do it.

7 The preservation of effect is a clinical

8 judgment; that is, how much of the effect of the

9 control agent must you have. After all, this is a

10 situation in which you are so sure the control

11 agent has an effect that you are not allowing

12 yourself to use a placebo.

13 So we customarily ask--this is well-established--

14 how reassured are we that the effect

15 of the control is present. Arbitrarily, completely

16 arbitrarily, we have often said something like 50

17 percent, but we don't stick to that. So it is of

18 some interest that the second group didn't have as

19 strong support that it retained at least 50

20 percent. But, again, this is a very conservative

21 analysis and we know that. We have used much less

22 conservative analyses and presented them to this

23 committee.

24 DR. NERENSTONE: Dr. Przepiorka?

25 DR. PRZEPIORKA: A question about the


1 study population, if I can. What percentage of the

2 patients had hypercalcemia at the time of

3 enrollment in the study and what percentage

4 actually received vitamin D and calcium, as Dr.

5 Berenson indicated in one of his slides, throughout

6 the study?

7 DR. SEAMAN: Can I get a little

8 clarification what percentage in terms of entry

9 into the trial or occurred during the course of

10 trial?

11 DR. PRZEPIORKA: At the time of entry.

12 DR. SEAMAN: No one had hypercalcemia.

13 That was an exclusion criteria for entering the

14 trial and everyone was to receive calcium and oral

15 vitamin D during the course of the trial.

16 DR. PRZEPIORKA: 10 percent of the

17 patients withdraw consent. Is there any sense for

18 why?

19 DR. SEAMAN: It probably has mostly to do

20 with the patient population. We looked at that and

21 went back and looked at our old Aredia trials and

22 determined that basically these patients are

23 progressing and they just don't want to come back

24 and talk to some of our investigators, and they

25 felt the same thing. They just withdrew consent.


1 They were terminal and just stopped coming. It is

2 much higher in our subsequent trials you will see

3 today.

4 DR. NERENSTONE: Dr. George

5 DR. GEORGE: I have a question about the

6 constancy assumption in the 010 trial. In

7 particular, most of what was presented--I guess all

8 that was presented today had to do with breast

9 cancer and myeloma sort of together, but one sort

10 of piece of indirect evidence about the constancy

11 assumption would be to look at the Aredia, just the

12 proportion who had SREs historically compared to

13 what happened in this trial.

14 In the myeloma group, it looked much lower

15 in the past. The percentage of patients with SREs

16 in the NDA studies was much lower than on the 010

17 trial in contrast with the breast cancer which was

18 very similar, almost identical, in fact, remarkably

19 similar. Do you have any explanation for this

20 little tidbit because the issue might be, of

21 course, that the effect on this new trial is you

22 are doing a noninferiority to something that is not

23 any different than placebo. Do you have any reason

24 for that?

25 DR. SEAMAN: You are correct, and Dr. Dirk


1 Reitsma, who is a clinical research physician and

2 has been working with me for the last fifteen years

3 with Aredia and Zometa will answer that question.

4 DR. REITSMA: Good morning. My name is

5 Dirk Reitsma. I am a research physician with

6 Novartis Oncology Development. It is actually a

7 very interesting observation that you brought up.

8 It appears, as you say, in contrast to the breast-cancer

9 trials that, in the multiple-myeloma trials,

10 there are more events.

11 I will show you that.

12 [Slide.]

13 This slide shows you the proportion of

14 patients having any SRE contrasting the previous

15 trial in pamidronate with the multiple-myeloma

16 patients on top, study 012, and Zometa study 010 on

17 the bottom. The two lines to look at are the top

18 line in the old study 012, the pamidronate 90

19 milligrams, and the bottom line, pamidronate 90

20 milligrams in study 010.

21 What you see is the difference at the very

22 beginning between 010 and 025. What you also see

23 is that these programs behave in much the same way.

24 If you go across from three to twelve months, it is

25 10 to 21 to 24 to 38. In the bottom line, it is,


1 again, a big jump in the beginning, 25 to 40, and a

2 leveling off of the accrual of events.

3 Now, that is odd and I think the clue to

4 that is on the next slide.

5 [Slide.]

6 What you see here is the demographic and

7 some prognostic variables, specifically age, which

8 is the same all the way across for both trials.

9 The old pamidronate trial is on the left and the

10 study 010 is on the right.

11 If you look at the bottom line, I think that is the

12 clue to what was happening and it was shown already

13 by Dr. Berenson,

14 I believe, where you see the longer median

15 time from diagnosis to visit 2 in the previous

16 trial compared to now, what happened was, in the

17 meantime, Aredia was approved for treatment.

18 People realized that once these people had a bone

19 disease, they needed to get treatment.

20 The puzzling bit about that is why would

21 they have more fractures at that point. So the

22 hypothesis becomes that the event rate in patients

23 being diagnosed with multiple myeloma is initially

24 driven by that cohort of lesions they have when

25 they come untreated into the trial, bearing in mind


1 that a lot of the breast-cancer patients at that

2 point would already have been on treatment for

3 other metastases unlike multiple myeloma which

4 present with bone disease.

5 So, if I can have the next slide.

6 [Slide.]

7 The way to look at that would be to look

8 at time between diagnosis and getting into the

9 trial and how that affected the event rate. Here

10 you see, on the top again, the old pamidronate

11 trial of multiple myeloma and, on the right, that

12 column that says, "with pathologic fractures," you

13 see that split out by patients that had had their

14 diagnosis within six months and patients that had

15 their diagnosis longer than that.

16 You see that it is true that those

17 patients do, indeed, have a higher event rate with

18 a recent diagnosis. So that would say, indeed,

19 before the treatment kicks in and the chemotherapy,

20 they have events. So you see, basically, the same

21 thing in a slightly different cut of the data from

22 the current trial 010 on the bottom of the slide.

23 Again, if you look across, starting at

24 three months, you see the patients that just came

25 into the trial had a higher rate of 21 compared to


1 15 if they had been diagnosed previously by which

2 time chemotherapy would have kicked in in a lot of

3 patients. After that, you see a fairly similar

4 behavior in both groups.

5 DR. NERENSTONE: Dr. Loehrer?

6 DR. LOEHRER: I just have a couple of

7 questions because I can't remember. In the

8 original pamidronate studies, did everyone get

9 vitamin D and calcium?

10 DR. SEAMAN: No. In the original

11 pamidronate trials, not everyone got vitamin D and

12 calcium.

13 DR. LOEHRER: That impact, in terms of

14 this therapy, then, it is a couple of different

15 variables compared to the historical controls; is

16 that right?

17 DR. SEAMAN: I think it had a major impact

18 on particularly electrolyte and mineral imbalances

19 in terms of the amount of vitamin D and calcium

20 that was given. It wasn't even the minimum daily

21 requirement that we would take on a daily basis.

22 DR. LOEHRER: One of the things Dr.

23 Berenson mentioned, and I kind of skipped through

24 this and I wasn't sure, is, in the skeletal-related

25 events, it was said, actually, that hypercalcemia


1 was included in terms of their criteria yet he said

2 it was used sparingly. It is not clear how this

3 hypercalcemia was actually included in these

4 incidents of skeletal-related events.

5 DR. SEAMAN: The analysis that we have

6 done and presented here today did not included

7 hypercalcemia of malignancy. Either Grant or

8 myself can answer the question regarding why we

9 don't include it, but, in essence, we didn't

10 include it because we know bisphosphonates work in

11 hypercalcemia and we thought that that was not an

12 important endpoint and not including it was

13 probably appropriate.

14 DR. LOEHRER: Just two more questions.

15 One is, there were four renal deaths in the 8-milligram

16 dosage. Can you explain, were those

17 part--were they drug related or incidental, do you

18 think?

19 DR. SEAMAN: There were renal deaths in

20 this trial. Mainly, they were myeloma patients.

21 In every case, there was underlying pathophysiology

22 and drugs that were on board that you couldn't sort

23 out whether it was being caused by the drug or the

24 disease.

25 DR. LOEHRER: Just finally, just again a


1 comment, on Dr. Coleman's slide because there are

2 some people in the audience who are not necessarily

3 sophisticated and who may be more stockholders, but

4 when one looks at, for example, the incidence of

5 the various malignancies on a second slide for

6 bladder cancer, for example, one might suspect, if

7 you would be real excited and multiple 40 percent

8 by 582,000 and think this is how many patients are

9 going to be candidates for receiving this drug, the

10 fallacy of that, actually, is that, at autopsy, for

11 example, that 40 percent of the patients have it.

12 8 percent of bladder cancer patients, for example,

13 are going to survive without having metastatic

14 disease. So, I think, just to clarify those

15 issues. The same with the other malignancies.

16 DR. SEAMAN: Okay.

17 DR. NERENSTONE: I would like to ask Dr.

18 Kelsen, Dr. Albain or Dr. Taylor if they have any

19 questions for either our sponsor or the FDA.

20 DR. TAYLOR: I don't at this point.

21 DR. ALBAIN: I have a question or two.

22 This is Kathy. I have a question regarding the

23 systemic therapy status at the time of study entry.

24 In particular, were these patients already on some

25 stable type of chemotherapy or hormonal therapy or


1 were they newly progressing and just started on a

2 new systemic therapy because, certainly, in breast

3 cancer and, to some degree, in myeloma, the

4 systemic therapy could significantly reduce

5 skeletal-related as well as visceral events.

6 So, could you comment on that first and

7 then I have a follow-up to that.

8 DR. SEAMAN: The answer to that first

9 question is that patients entered the trial on

10 appropriate antineoplastic therapy and that meant

11 that they could have started anywhere from the last

12 year to the last two to three weeks prior to

13 entering the trial. So it is a whole host of

14 patients that are coming in at a variety of times

15 during the course of the disease.

16 DR. ALBAIN: Do you have any data on how

17 often the therapy was changed during the course of

18 the trial for each of the subsets, the chemotherapy

19 and the hormonal subset?

20 DR. SEAMAN: Yes. Just a second and we

21 will find that. Can I have this slide up? This is

22 for multiple myeloma, how many regimen changes were

23 done during the course of the trial.

24 [Slide.]

25 You can see that around 6 percent stayed


1 on the same therapy they entered and 6 percent of

2 the patients went to greater than five changes.

3 The vast majority had between one and two changes

4 during the course of the study.

5 DR. ALBAIN: I can't read that.

6 DR. SEAMAN: Oh; I'm sorry. I apologize.

7 DR. ALBAIN: The difference between the

8 three arms; was there any difference among the

9 arms?

10 DR. SEAMAN: Not really when you look at

11 the proportion of patients having changes in their

12 chemotherapy in the myeloma, it is very similar

13 depending on whether they had one, two or three

14 changes or up to five changes.

15 DR. ALBAIN: Do you have this data for

16 breast-cancer chemotherapy?

17 DR. SEAMAN: Yes.

18 [Slide.]

19 The next slide displayed on this slide--I

20 know you can't see it. I apologize--the breast-cancer

21 chemotherapy changes and the breast-cancer

22 hormonal changes. In the course of the trial for

23 the breast-cancer chemotherapy changes, there were

24 no changes in terms of entering the trial, only

25 around 1 to 3 percent of the patients.


1 The vast majority had one to two changes--around

2 30 percent had one to two changes in their

3 chemotherapy regimen and they were equivalent

4 across the treatment groups. In terms of their

5 hormonal therapies, the vast majority here, in

6 terms of changes, occurred only once. Around 40 to

7 50 percent of the patients had a change in their

8 hormonal therapy during the course of the trial and

9 twice in between, 25 and 32 percent of patients

10 having a change in their hormonal therapy.

11 DR. ALBAIN: One last question. Could you

12 comment on the study-treatment duration of twelve

13 months. Do you have any data, perhaps not from

14 this trial, but from the pamidronate trials on

15 longer durations and toxicity beyond for those

16 patients doing well at twelve months?

17 DR. SEAMAN: This trial was initially

18 designed to not only have a twelve-month core in

19 terms of looking at the overall efficacy and safety

20 of Zometa versus pamidronate but also has an

21 extension which will close the last patient, last

22 visit, within the next few months and will be

23 subject to another supplemental NDA next year for

24 long-term data.

25 In the pamidronate trials, we have data up


1 to 24 months for breast cancer and 21 months for

2 myeloma. There is no difference in the overall

3 safety profiles that we could see that would occur

4 at a later date. One of the things that was of

5 concern, there may have been a few more renal

6 events in the myeloma patient population in

7 protocol 012, the original Aredia trial, but it

8 wasn't clear to us, and still is not clear to us,

9 if that was probably the disease and not the drug.

10 DR. ALBAIN: Thank you very much.

11 DR. NERENSTONE: Dr. Taylor, did you have

12 a question for us?

13 DR. TAYLOR: Just to clarify, then, we

14 don't really know how many patients were on second-

15 or third-line chemotherapy when they came into the

16 trial?

17 DR. SEAMAN: I don't know, at trial entry,

18 how many were on second-line or third-line

19 chemotherapy. I know how many changes were taking

20 place during the course of the trial.

21 DR. TAYLOR: In the pamidronate data, over

22 that two-year period, can you tell if there was

23 continued reduction in skeletal events?

24 DR. SEAMAN: I'm sorry; I couldn't hear

25 you.


1 DR. TAYLOR: Was there continued reduction

2 in skeletal events over the 24-month period of time

3 with the pamidronate?

4 DR. SEAMAN: Yes. In the pamidronate

5 trials, you saw a continued effect on skeletal-related

6 events for the 24-month breast-cancer data

7 and the 21-month myeloma data.

8 DR. TAYLOR: Thank you.

9 DR. NERENSTONE: Dr. Przepiorka?

10 DR. PRZEPIORKA: The difference between

11 the pamidronate and placebo was actually, according

12 to the data here, somewhat smaller than at the

13 twelve-month mark. Do you have any preliminary

14 data from the current trial regarding time to

15 skeletal-related events after twelve months?

16 DR. SEAMAN: No. That is the subject of

17 the studies that we are closing down now in terms

18 of the extension. We will have that data within

19 the next year.

20 DR. COLEMAN: Dr. Pelusi?

21 DR. PELUSI: Two questions. One is,

22 either in your historical data or in your current

23 studies, do you see any difference in ethnic

24 minorities in terms of response to bisphosphonates

25 at all because it seemed like the majority of


1 people accrued to the current studies were mostly

2 Caucasian patients?

3 DR. SEAMAN: That is even more true for

4 the original Aredia trials but I will share with

5 you what we have from these trials so you can make

6 your own judgment. As you said, the sample sizes

7 here are small.

8 Could I have the slide up, 43, please?

9 [Slide.]

10 As I said, the sample sizes are small in

11 terms of other types of races, whether it be black

12 or other, as we captured them. But you can see, in

13 protocol 010, again with pamidronate control trial,

14 that around 29 percent of the patients in the

15 Zometa 4-milligram treatment arm had an SRE and

16 around 30 percent of the pamidronate arm.

17 In protocol 011, around 27 percent had an

18 SRE in the Zometa treatment arm and 33 percent in

19 the placebo arm. More importantly, in protocol

20 039, the prostate-cancer patient population which

21 has a problem in terms of the number of blacks

22 having it and now progressive seems to be in the

23 black patient population.

24 There is a 17 percentage of the patients

25 having an SRE in the 4-milligram arm for Zometa and


1 a 42 percent for placebo, which is quite high.

2 But, again, remembering the n's are small in all

3 these trials.

4 DR. PELUSI: My last question would relate

5 to your quality-of-life assessments. Were the

6 quality-of-life assessments done in general for

7 quality of life or was it specifically looking at

8 quality of life as related to skeletal events?

9 DR. SEAMAN: Unfortunately, there are no

10 quality-of-life tools for skeletal-related events.

11 The ones we used were, as you saw, FACT-G and ECOG

12 performance status. That is the best we could do

13 at that time. There still is nothing that I am

14 aware of.

15 DR. PELUSI: I don't think there is but I

16 guess the point that I was trying to just kind of

17 bring up to our awareness is, as we are looking at

18 some of these endpoints, is do we really ask the

19 question, what do these skeletal-related events do

20 in terms of function and being able to look at what

21 are the goals for some of the patients.

22 Thank you.

23 DR. SEAMAN: I am in agreement.

24 DR. NERENSTONE: Dr. Raghavan?

25 DR. RAGHAVAN: This is directed, actually,


1 to Dr. Williams. It may be that I misunderstood

2 your statistician in the reference to pages 67 and

3 68. Did any of the twelve inquiring minds in your

4 team with the n equals 300 patients that had 8

5 milligrams to look at the early phase of the trial?

6 300 patients got through the phase I part of the

7 trial. That is not a subset selection, really,

8 because they were just being left alone until they

9 ran into renal problems.

10 It is actually kind of interesting to look

11 at the whole global day's presentation, stuff we

12 have had in advance, this dichotomy between 8, 8/4

13 and 4. It would expect, Grant, you or one of the

14 group would have played with the numbers.

15 DR. WILLIAMS: Thanks. Now, who all do

16 you include in this?

17 DR. RAGHAVAN: I would say the twelve

18 inquiring minds that you listed. I wouldn't leave

19 anybody out, so I counted very carefully.

20 DR. WILLIAMS: I think our approach

21 basically was to consider that the 8-milligram arm

22 really was an 8-milligram arm. If you start

23 looking at the times when they were accrued and how

24 many doses they received, there is a very small

25 number of doses and many patients received only 8


1 milligrams.

2 So, from an efficacy standpoint, I think

3 it is a complete study. Dr. Ibrahim has done

4 analyses in her studies and in mine that they

5 basically received the same numbers of doses of

6 something and most of them were 8 milligrams. We

7 looked carefully to see if we could find the

8 evidence that there was a problem with that arm and

9 we just didn't see it.

10 I think if you accept the results, I think

11 we would feel that they would have to be more by

12 chance than anything else.

13 DR. SRIDHARA: I am Rajeshwari Sridhara.

14 The study was reviewed by Ling Li, but if you refer

15 to the statistical review on page 19, you get some

16 sense of what was going on. As Grant said, it was

17 not possible for us to look at how many doses each

18 received or whether they received exactly 8 or 4,

19 but it tells you, over a period of time, how the

20 events were occurring. So that gives you some

21 sense of what was happening between 4 and 8.

22 It gives you about the 4. Everything

23 about 8 is in the appendix. It is on page 19.

24 That is for the 4 milligrams, how the events were

25 happening.


1 DR. NERENSTONE: Are there any other

2 questions?

3 What I would like to do then is for us to

4 take a break. I would like to be back at 10:45,

5 please.

6 [Break.]

7 DR. NERENSTONE: If the sponsor would like

8 to start their presentation on Zometa in the

9 prostate cancer and solid tumors other than

10 prostate cancer and breast cancer.

11 Sponsor Presentation

12 Zometa in Prostate Cancer and Solid Tumors

13 Other than Prostate Cancer and Breast Cancer

14 DR. SMITH: Thank you. I am Matthew

15 Smith. I am an assistant professor of medicine at

16 Harvard Medical School and a medical oncologist at

17 Massachusetts General Hospital. I was a

18 participant in study 039. Good morning.

19 [Slide.]

20 My first task is to introduce two double-blind

21 placebo-controlled randomized trials of

22 Zometa in patients with bone metastases, protocol

23 039 for men with metastatic prostate cancer and

24 protocol 011 for patients with solid tumors other

25 than prostate cancer or breast cancer.


1 After introducing all studies, I will

2 present the efficacy and safety data for protocol

3 039. Dr. Robert Coleman will then present the

4 efficacy and safety data for protocol 011.

5 [Slide.]

6 The objective of the protocols was to

7 demonstrate that Zometa is superior to placebo for

8 the treatment of bone metastases.

9 [Slide.]

10 The primary endpoint for each study was

11 defined as the proportion of patients experiencing

12 any skeletal-related event, or SRE, not including

13 hypercalcemia of malignancy.

14 [Slide.]

15 The secondary study endpoints included

16 time to first SRE, skeletal morbidity rate and

17 Andersen-Gill multiple-event analysis. Secondary

18 analyses were also performed considering these

19 outcomes including hypercalcemia of malignancy.

20 Other secondary endpoints include pain and

21 analgesic scores, bone-lesion response, time to

22 progression of disease and safety including

23 survival.

24 Six months of additional survival in

25 serum-creatinine data were included in the 120-day


1 safety update.

2 [Slide.]

3 SREs were defined as pathological

4 fractures, spinal-cord compression, radiation

5 therapy to treat bone pain or to treat or prevent

6 pathological fractures or spinal-cord compression

7 or surgery to bone. In protocol 039, for men with

8 prostate cancer, the definition of SREs also

9 included change in antineoplastic therapy for bone

10 pain.

11 Hypercalcemia of malignancy was not

12 included in the definition of SREs for the primary

13 efficacy analyses but was included for some of the

14 secondary analyses.

15 [Slide.]

16 These are the preplanned analyses terms.

17 They were defined in the same manner as protocol

18 010.

19 [Slide.]

20 The original study design randomly

21 assigned patients to treatment with Zometa 4 or 8

22 milligrams or placebo administered as a five-minute

23 infusion. Two renal safety amendments address

24 concerns about renal safety. In June, 1999, renal

25 amendment 1 increased the infusion time from five


1 to fifteen minutes and increased the volume from 50

2 to 100 milliliters.

3 In June, 2000, renal amendment 2 switched

4 the 8-milligram dose to 4 milligrams and all

5 subjects assigned to the 8-milligram dose will be

6 termed the 8/4 group to indicate this change.

7 Renal amendment 2 also introduced monitoring of

8 renal function with measurement of serum creatinine

9 within two weeks before each dose.

10 Before unblinding of the data, a

11 statistical amendment defined the primary efficacy

12 analysis based on the comparison of the Zometa 4-milligram

13 group versus placebo.

14 [Slide.]

15 This figure illustrates the time lines for

16 the renal amendments in patient accrual. In

17 protocol 039, for men with prostate cancer, 368 of

18 648 men were accrued before renal amendment 1. In

19 protocol 011, for patients with solid tumors other

20 than breast cancer or prostate cancer, 195 of 773

21 patients were accrued before renal amendment 1.

22 Both studies completed accrual before

23 renal amendment 2 and treatment and follow up

24 continued through January, 2001. Notably, most

25 patients completed or discontinued the study before


1 renal amendment 2 and, as a result, as you have

2 already heard, three-quarters of the patients

3 assigned to the Zometa 8/4 group received only the

4 8-milligram dose.

5 [Slide.]

6 Next, I will summarize the design,

7 efficacy and safety data for protocol 039.

8 [Slide.]

9 Protocol 039 included men with progressive

10 metastatic prostate cancer. Requirements for study

11 entry included radiographic documentation of bone

12 metastases, rising serum PSA, baseline serum

13 testosterone concentration in the castrate range,

14 no strong opiate analgesics, ECOG performance

15 status of 0, 1 or 2, serum creatinine less than 3

16 and appropriate neoplastic therapy at study entry.

17 [Slide.]

18 Subjects were stratified according to the

19 presence or absence of distant metastases at the

20 time of initial diagnosis with prostate cancer. As

21 in the prior studies, all patients received

22 supplemental vitamin D and calcium and Zometa was

23 administered every three weeks for fifteen months.

24 [Slide.]

25 The groups were well balanced in most


1 baseline demographic and prognostic factors. The

2 mean age was 71 to 72 years. Approximately 10

3 percent of the men were black. Most men had an

4 ECOG performance status of 0 or 1. Median PSA at

5 study entry was 61 to 89 and both Zometa groups had

6 higher median PSA values than the placebo group.

7 [Slide.]

8 Patient dispositions by group are shown

9 here. As expected for this population of older men

10 with metastatic prostate cancer, about one-third of

11 men in each group completed fifteen months of

12 treatment. The Zometa 4-milligram group had the

13 highest rate of study completion.

14 [Slide.]

15 This table shows the reasons for early

16 discontinuation. Discontinuation due to an

17 unsatisfactory therapeutic effect was more common

18 in the placebo group than the Zometa groups. Rates

19 of early discontinuation for other reasons were

20 similar for all groups. These data are similar to

21 the historical results of placebo-controlled trials

22 of pamidronate in breast cancer.

23 [Slide.]

24 The primary efficacy analysis is shown in

25 this figure. 44 percent of men in the placebo


1 group experienced one or more SREs by fifteen

2 months. In both Zometa groups, the proportion of

3 men with an SRE was less than the placebo group.

4 The primary efficacy analysis was positive.

5 33 percent of men in the Zometa 4-milligram group

6 experienced an SRE. This improvement was

7 statistically significant compared to placebo and

8 the p-value for that comparison is 0.021.

9 Notably, the improvement in the Zometa 4-milligram

10 group remained significant even when

11 fractures were excluded as an SRE. 38 percent of

12 men in the Zometa 8/4 milligram groups experienced

13 and SRE although this improvement compared to

14 placebo did not reach statistical significance.

15 Thus, while the primary efficacy analysis of the

16 Zometa 4-milligram group was positive, the results

17 from the 8/4 group raised two important questions.

18 [Slide.]

19 First, why was no dose effect observed?

20 The doses of Zometa, as you have already heard,

21 were chosen based on early dose-finding studies

22 and, as Dr. Robert Coleman has nicely introduced,

23 Zometa targets the osteoclasts. NTX is a

24 biochemical marker of osteoclast function and

25 approximately 70 percent inhibition was achieved in


1 both Zometa groups, 4 and 8/4, and this inhibition

2 was maintained throughout the duration of the

3 study.

4 So, with maximum target inhibition in the

5 Zometa 4-milligram group, it is not surprising that

6 no dose effect was observed.

7 [Slide.]

8 The second question, how should the

9 results of the Zometa 8/4 milligram group be

10 interpreted relative to the positive primary

11 efficacy analysis in the 4-milligram group? This

12 is a revised slide.

13 We attempted to address this issue in a

14 combined analysis of both Zometa groups compared to

15 placebo. As you recall, the proportion of men with

16 an SRE in each Zometa group was less than the

17 placebo group. In this combined analysis, SREs

18 were reduced from 44 percent in the placebo-treated

19 group to 36 percent in the combined Zometa groups.

20 This risk reduction was significant compared to

21 placebo. The p-value for this comparison was

22 0.041.

23 I would also like to add that the

24 treatment effect observed, even in this combined

25 analysis, compares quite favorably with the


1 original pivotal placebo-controlled trials of

2 pamidronate in breast cancer.

3 The efficacy of Zometa across a spectrum

4 of skeletal-related events further supports the

5 effectiveness of Zometa in metastatic prostate

6 cancer.

7 [Slide.]

8 This figure shows SREs by type and

9 treatment group. For all groups, the most common

10 types of SREs were radiation to bone and fractures.

11 The risk of these and other events were

12 consistently lower in the Zometa group than in the

13 placebo group.

14 [Slide.]

15 Kaplan-Meier estimates of time to first

16 SRE are shown here. The median time to first SRE

17 was 321 days in the placebo group. The median

18 time to first SRE was longer in each of the Zometa

19 groups. After 420 days, the median time to first

20 SRE was not yet reached in the Zometa 4-milligram

21 group and this improvement in time to first SRE is

22 statistically significant. The p-value is 0.011.

23 [Slide.]

24 SREs were also analyzed as events per year

25 or skeletal morbidity rate. The SMR was lower in


1 both Zometa groups than in the placebo group.

2 Compared to placebo, the SMR in the Zometa 4-milligram was

3 decreased by 46 percent. This

4 improvement, again, was significant.

5 [Slide.]

6 Andersen-Gill multiple-event analyses were

7 performed to provide a robust evaluation of the

8 changes in event rate over time. Compared to

9 placebo, the hazard ratios for each of the Zometa

10 groups were less than 1. The risk reduction in the

11 Zometa 8/4 group was 15 percent. The risk

12 reduction in the Zometa 4-milligram group was

13 36 percent and significant compared to placebo.

14 [Slide.]

15 This is a new slide. As an exploratory

16 analysis, we also evaluated the proportion of men

17 with an SRE based on the radiographic

18 classification of bone lesions. Bone lesions were

19 classified as lytic, blastic or mixed. For this

20 analysis, men were defined as members of the lytic

21 subset if they had one or more lytic lesion

22 regardless of whether they had many other blastic

23 metastases.

24 They were classified as the blastic subset

25 if they had exclusively blastic lesions and other


1 if they could not be defined in either the lytic or

2 blastic subset. For all, the lytic, blastic and

3 other subsets, the Zometa groups had fewer events

4 than the placebo group. This consistent treatment

5 effect can be clearly seen in the blastic and other

6 subsets.

7 The result in the lytic subset is a bit

8 more varied where you do a more dramatic treatment

9 effect in the 4-milligram group but I would also

10 point out that few patients were in this subset and

11 this is subject to more random variation.

12 Again, while this subset analysis has

13 limitations, it suggests that Zometa is effective

14 in prostate cancer across the spectrum of

15 radiographic classifications of lesions.

16 [Slide.]

17 Here we see disease-related endpoints.

18 The time to progression of bone lesions and time to

19 disease progression were similar for all the

20 groups.

21 [Slide.]

22 At study completion, changes in analgesic

23 scores, ECOG performance status and FACT-G total

24 scores were similar for all groups. Pain scores

25 increased from baseline for all groups. The


1 increases in pain scores were attenuated in both

2 Zometa groups. Compared to the placebo group, the

3 relative improvements in pain scores were

4 significant at all time points for the Zometa 8/4

5 group and at three and nine months for the Zometa

6 4-milligram group.

7 [Slide.]

8 This table summarizes the efficacy data

9 for Zometa in men with prostate cancer. Compared

10 to placebo, both Zometa groups showed improvements

11 in the proportion of men with any SRE, time to

12 first SRE, mean SMR and multiple-event analysis

13 hazard ratios.

14 For the Zometa 4-milligram group, the

15 improvements in each of these outcomes were

16 statistically significant. Collectively, the

17 efficacy data showed that Zometa decreases skeletal

18 complications in men with metastatic prostate

19 cancer.

20 [Slide.]

21 The safety data for protocol 039 is

22 summarized in the next few slide.

23 [Slide.]

24 Causes of death during the trial or within

25 28 days of drug termination were similar for all


1 groups. As expected for this patient population,

2 chance of progression was the most common cause of

3 death for all groups.

4 [Slide.]

5 There were no statistically significant

6 differences in overall survival between the groups.

7 The median survival in the Zometa 4-milligram group

8 was about three months longer than the placebo

9 group. The p-value for this comparison was 0.087.

10 [Slide.]

11 This slide summarizes the common adverse

12 events. Events that occurred at least 5 percent

13 more often than placebo are highlighted in yellow.

14 Events that occurred at least 5 percent less often

15 than placebo are highlighted in green. Adverse

16 events related to intravenous bisphosphonates

17 including pyrexia and myalgias were more common in

18 the Zometa groups. Bone pain was less common in

19 the Zometa 4-milligram group than in the other

20 groups.

21 [Slide.]

22 Grade 3 or grade 4 anemia occurred in less

23 than 10 percent of men in all the groups. Grade 3

24 or 4 anemia was more common in the Zometa 8/4 group

25 than in the other two groups. Blood transfusion


1 and treatment with erythropoietin were somewhat

2 more common in the Zometa groups than placebo.

3 Grade 3 or 4 hypocalcemia was observed in

4 less than 2 percent of patients in all groups.

5 Grade 3 or 4 hypermagnesemia and hypophosphatemia

6 were more common in the Zometa groups than placebo

7 although no patient experienced symptoms related to

8 these mineral changes.

9 [Slide.]

10 This slide shows NCI grade 3 and 4 serum

11 creatinine changes after renal amendment 1. For

12 men randomized to the study after renal amendment

13 1, there were no grade 4 changes in serum

14 creatinine in any of the groups. Grade 3 changes

15 in serum creatinine were uncommon but a few more

16 events were observed in the Zometa groups than in

17 the placebo group.

18 [Slide.]

19 This slide shows Kaplan-Meier estimates of

20 the first increase in serum creatinine. It follows

21 the same format at Dr. Berenson's talk and serum

22 creatinine increase was defined in the same manner

23 as protocol 011.

24 Patients randomized prior to renal

25 amendment 1 are shown in the upper panel. Patients


1 randomized after renal amendment 1 are shown in the

2 lower panel. Before renal amendment 1 the risk of

3 serum creatinine increase was significantly higher

4 in the Zometa groups. Compared to placebo, the

5 hazard ratios for the Zometa 4-milligram group and

6 8/4 groups were 2.0 and 4.0 respectively.

7 After renal amendment 1, excess risk of

8 serum creatinine increase was markedly reduced in

9 the Zometa 8/4 group. The excess risk was nearly

10 eliminated in the Zometa 4-milligram group with a

11 hazard ratio of 1.1. These results highlight the

12 success of fifteen-minute infusion time in

13 improving the renal-safety profile.

14 [Slide.]

15 The safety data indicate that Zometa is

16 well tolerated. Adverse events associated with

17 bisphosphonates were more common in the Zometa

18 groups than placebo. The renal-safety profile of

19 Zometa 4-milligrams over fifteen minutes is similar

20 to placebo in men with prostate cancer.

21 [Slide.]

22 Collectively, the protocol 039 data

23 indicate that Zometa decreases complications in men

24 with prostate cancer and bone metastases.

25 Thank you for your attention. Dr. Robert


1 Coleman will now present the efficacy and safety

2 data for protocol 011.

3 DR. COLEMAN: Good morning again.

4 [Slide.]

5 It is my pleasure to present the third of

6 these randomized clinical trials and to focus on

7 the data in protocol 011 which included solid

8 tumors other than prostate cancer or breast cancer

9 in a placebo-controlled trial.

10 Dr. Matthew Smith has already given you

11 the definitions for the endpoints. He has also

12 highlighted the renal safety changes and how that

13 affected the recruitment times. So I am going to

14 go straight into the trial design which is shown on

15 this slide.

16 [Slide.]

17 These patients had to have histological

18 confirmation of advanced malignancy from a tumor

19 other than prostate or breast cancer and had to

20 have radiographic evidence of at least one bone

21 metastasis. On entry into the study, they were

22 allowed to be on appropriate antineoplastic therapy

23 and this therapy could be changed as was

24 appropriate during the study period.

25 They had to have reasonable renal function


1 with a serum creatinine below 3 milligrams per

2 deciliter and they had to be of ECOG performance

3 status 0, 1 or 2.

4 [Slide.]

5 Prior to randomization, patients were

6 stratified into two groups, either non-small-cell

7 lung cancer or all other solid tumors which

8 included some 20 different primary-tumor types.

9 The most common are shown here, being renal-cell

10 cancer, small-cell lung cancer, carcinomas of

11 unknown primary type, bladder and colorectal.

12 As for protocol 011 and protocol 039, all

13 patients received supplemental vitamin D and

14 calcium. The dose and dosing regimens were as

15 defined in the protocol 039 study, namely patients

16 received Zometa at 4 or 8, as you have heard

17 subsequently reduced to 4 milligrams, or placebo as

18 a five-minute infusion initially subsequently

19 amended to fifteen minutes. This was given on a

20 three-weekly basis.

21 Because of the short survival prospects of

22 these patients, the endpoint was chosen to be at

23 nine months after eight infusions.

24 [Slide.]

25 The demographics and prognostic factors


1 for protocol 011 are shown on this slide. The mean

2 age was similar at around 60 in all three treatment

3 groups. About two thirds were male. Some 90

4 percent were Caucasian with other ethnic groups

5 relatively infrequently represented. Around 80

6 percent were of apparently good performance status,

7 with a performance status of 0 or 1 on the ECOG

8 scale and had reasonable quality of life with a

9 FACT-G score of around 70 with 100 being

10 performance quality.

11 You can see that the stratification

12 resulted in about one-half of patients entered into

13 the study having a diagnosis of non-small-cell lung

14 cancer and the other half being the other solid

15 tumors. Because of the stratification, they were

16 well-balanced between the three treatment arms.

17 [Slide.]

18 As a reflection of the poor prognosis of

19 these patients, only 25 percent of patients

20 completed study therapy out to nine months which

21 means that three-quarters withdrew from the study

22 therapy due to various reasons which will be shown

23 on a subsequent slide. However, where possible,

24 patients were followed after therapy

25 discontinuation until the nine-month endpoint.


1 [Slide.]

2 This slide summarizes those reasons for

3 early discontinuation. The most common cause was

4 death, nearly always due to the underlying

5 malignancy. Next were adverse events. Again, most

6 of these were adverse events associated with that

7 malignancy rather than the treatments being

8 administered. And just under 20 percent withdrew

9 their consent. Again, this was usually due to

10 deteriorating performance status and the

11 difficulties of attending for regular infusion

12 therapies.

13 The other reasons for withdrawal are

14 relatively uncommon and are listed on this slide

15 and show no differences between the three treatment

16 groups.

17 [Slide.]

18 I will now take you to the results and the

19 primary efficacy analysis which you will recall was

20 the proportion of patients experiencing and SRE.

21 Also, on this slide, is the time to first SRE for

22 the three treatment groups.

23 On the left-hand panel, you see the

24 proportion of patients experiencing one or more

25 events. It was 44 percent in the placebo arm which


1 was reduced to 38 percent in the Zometa 4

2 milligrams but with a p-value which did not reach

3 significance of 0.127. For the 8-milligram dose,

4 it was 35 percent which did reach significance with

5 a p-value of 0.023.

6 However, on the right-hand side is the

7 time-to-first-event analysis which, as we have

8 already heard from Dr. Williams, is the preferred--or the

9 statistician's preferred analysis of these

10 data and takes into account the fact that many

11 patients drop out due to death and other reasons,

12 and that is not well-reflected in the time to first

13 SRE analysis--I'm sorry; in the percent of patients

14 analysis.

15 In the time to first SRE analysis, it is

16 clear that both treatments are working with an

17 extension in time to first SRE for approximately

18 two to three months and a difference of about 10

19 percent which appears three months into therapy and

20 persists out to at least eight months, as shown on

21 this graph.

22 So, in this analysis, both dosages show

23 significant improvements over placebo with p-values

24 of 0.023 and 0.034 for the 4-milligram and the 8-milligram

25 groups respectively.


1 [Slide.]

2 As you have seen before, here is a slide

3 showing the individual components which may cut the

4 SREs. There is a reduction for both Zometa groups

5 in terms of radiation therapy to bone, a reduction,

6 although less marked, in fractures and, as you

7 would expect with infrequent events, little change

8 in terms of surgery to bone or spinal-cord

9 compression rates.

10 [Slide.]

11 As with the other studies, skeletal

12 morbidity rates were calculated and analyzed. This

13 slide shows that the skeletal morbidity rate for

14 placebo was 2.5 and was reduced to 2.24 in the

15 Zometa 4-milligram arm which did not quite reach

16 significance at 0.069 and was significantly reduced

17 to 1.55 in the 8-milligram treatment arm.

18 [Slide.]

19 As for the other protocols, an Andersen-Gill

20 multiple-event analysis was performed. The

21 main reason for this is to look at the possible

22 differences between the strata as well as the

23 differences between the treatment arms.

24 You can see that the hazard ratio, looking

25 at the 4-milligram data, is very similar for non-small-cell


1 lung-cancer patients as it is for other

2 solid tumors with approximately 27 percent risk

3 reduction. For the Zometa 8/4 milligrams, overall,

4 there is a 32 percent risk reduction with an

5 apparent increased efficacy in lung cancer than in

6 other solid tumors but the numbers, obviously, are

7 relatively small in this subset analysis.

8 [Slide.]

9 This slide, like in the previous

10 presentations, has been added and I am sorry for

11 the people who are not on site who don't have

12 access to this slide, but it shows the breakdown of

13 SREs in terms of the radiographic appearances of

14 their lesions on study entry. So, as before, there

15 is a group of patients with at least one lytic

16 lesion plus-or-minus other types throughout the

17 skeleton. They are labeled as lytic, a group with

18 only blastic disease, labeled as blastic, and a

19 group that fall between those two extremes, labeled

20 other.

21 The slides shows that in the lytic

22 metastases, there is a reduction in favor of both

23 treatment arms compared to placebo. There is also

24 a reduction in the blastic patients. The group in

25 the middle, the other patients, there is no obvious


1 change and we would suggest that that is more to do

2 with classification of radiographic subtypes than a

3 biological underlying reason for why that group

4 show no difference from placebo.

5 [Slide.]

6 Turning now to disease-related endpoints,

7 time to progression in bone and time to progression

8 of the overall disease is shown here in days. In

9 comparing the 4-milligram arm to placebo, there was

10 no difference in time to progression in bone or

11 overall progression. There is a suggestion with

12 the 8-milligram dose that bone progression is

13 delayed from 109 to 238 days.

14 [Slide.]

15 As with the other studies, a number of

16 quality-of-life-related issues were assessed.

17 These included the brief pain inventory score,

18 analgesic scores, ECOG performance status and the

19 FACT-G quality-of-life assessment.

20 Between the three treatment arms, there

21 were no significant differences in these quality-of-life

22 endpoints. In other words, pain was little

23 changed through the nine-month period. Analgesia

24 increased slightly. There was approximately a 1.0

25 increase in performance status and a small decline


1 in quality of life, but no discernible or

2 statistically significant differences between the

3 Zometa arms and placebo.

4 [Slide.]

5 So, to summarize the efficacy, as we have

6 seen before, the four different analyses, the

7 proportion with a skeletal-related event, the time

8 to first event, the skeletal-morbidity rate and the

9 Andersen-Gill analysis, the results are positive

10 for all analyses for the 8-milligram dosage and are

11 statistically significant for the time to first SRE

12 in the 4-milligram dosage group.

13 We would, therefore, conclude that Zometa

14 is the first bisphosphonate to demonstrate efficacy

15 in decreasing skeletal complications in this broad

16 range of solid tumors.

17 [Slide.]

18 Finally, the safety analysis from protocol

19 011.

20 [Slide.]

21 This slide shows the primary cause of

22 death during the trial or within 28 days after

23 study-drug termination. The most frequent cause of

24 death was the underlying malignancy followed by

25 respiratory complications which is, perhaps, not


1 surprising for a population of non-small-cell lung-cancer

2 patients.

3 The other causes of death were infrequent

4 and are very similar between the treatment groups

5 with renal and urinary causes of death being very

6 unusual.

7 [Slide.]

8 Here is the Kaplan-Meier plot for

9 survival. There is no significant difference

10 between any of the three treatment arms with a

11 median survival of just six months.

12 [Slide.]

13 Here is a similar slide to the one you

14 have seen before of adverse events occurring in

15 more than 15 percent of patients. There are very

16 few events that are more frequent in the Zometa-treated

17 arms. In particular, in this trial, the

18 acute-phase reactions were unusual and did not

19 appear on this slide. There was a slight reduction

20 in bone pain as an adverse event in the Zometa-treated

21 patients and odd increases in nausea,

22 dyspnea and headache of uncertain reasons in the

23 Zometa 4-milligram treatment arm.

24 [Slide.]

25 In terms of hematology, electrolyte and


1 mineral changes, anemia incidence was low at less

2 than 5 percent for all treatment groups but was

3 slightly higher in the Zometa-treated cohorts.

4 However, the use of red blood cells and

5 erythropoietin was similar for all treatment

6 groups.

7 Electrolyte and mineral adverse events

8 were uncommon with an instance of hypercalcemia of

9 less than 2 percent for all treatment groups, but

10 there was a higher incidence of hyperphosphatemia

11 in Zometa-treated groups although this was not of

12 any clinical significance and related symptoms were

13 not reported.

14 [Slide.]

15 This slide shows the NCI grade 3 and 4

16 serum-creatinine changes in the patients enrolled

17 after the fifteen minutes of measurement. It shows

18 firstly that grade 3 and 4 changes are rare, at

19 around 1 percent, 1 to 2 percent, and there was no

20 difference in these severe events between the

21 Zometa arms and the placebo arm.

22 [Slide.]

23 You have seen this kind of analysis

24 before. It is the Kaplan-Meier estimate of first

25 serum-creatinine increase with the top panel


1 showing the Kaplan-Meier estimate before the

2 infusion-time amendment and the bottom panel the

3 same sort of plot after the fifteen-minute infusion

4 change.

5 The top part of the panel shows that both

6 Zometa arms were associated with an increased risk

7 of renal dysfunction with a hazard ratio of 3.8 for

8 Zometa 4 and 2.9 for Zometa 8. After the

9 amendment, there is a substantial reduction in the

10 hazard ratio for both treatment arms although some

11 increased risk persists over and above placebo with

12 the hazard ratio for the 4-milligram arm being 1.6

13 with a p-value of 0.0228.

14 [Slide.]

15 So, to summarize the safety, adverse

16 events commonly associated with bisphosphonates

17 such as hyperphosphatemia and anemia were reported

18 more frequently in the Zometa-treated groups. The

19 risk of renal deterioration was moderately higher

20 in the Zometa 4-milligram treatment group even at

21 the fifteen-minute infusion than it was in the

22 placebo group.

23 [Slide.]

24 I would, therefore, conclude, in overall

25 summary, that Zometa is the first bisphosphonate to


1 demonstrate efficacy in decreasing skeletal

2 complications across this broad range of solid

3 tumors affecting bone and that Zometa, when given

4 at a dose of 4 milligrams over fifteen minutes has

5 an acceptable safety profile which is probably very

6 similar to the safety profile of intravenous

7 pamidronate, 90 milligrams.

8 Thank you very much for your attention. I

9 will now pass over the podium to the next speaker,

10 Dr. David Parkinson.

11 Conclusions

12 DR. PARKINSON: Thank you, Rod. I am

13 David Parkinson from Novartis Clinical Research.

14 [Slide.]

15 Before I summarize and conclude the

16 Novartis part of the presentation today, we wanted

17 to take this opportunity to thank the hundreds of

18 investigators and research staff at literally

19 hundreds of sites in thirty countries around the

20 world. We also wanted to express our appreciation

21 to the more than 3000 patients who have contributed

22 to these studies.

23 [Slide.]

24 We believe that the problems which are

25 being addressed here today are, in fact, extremely


1 important to cancer patients. As you have heard

2 from Dr. Coleman earlier, the consequences of bone

3 metastases are very serious events in the lives of

4 cancer patients. Current therapy is clearly

5 inadequate to meet to clinical needs of this broad

6 population.

7 The reason we began this very large and

8 complex clinical program is that we had significant

9 preclinical data suggesting the superior potency of

10 Zometa in inhibiting osteoclast activity when one

11 compared that activity with the entire range of

12 other bisphosphonates, pamidronate included.

13 The current treatment program, therefore,

14 was designed to test the efficacy of Zometa across

15 a broad range of tumors beyond the areas where we

16 knew the pamidronate was effective.

17 [Slide.]

18 We have presented here, this morning, data

19 from three large international controlled double-blind and,

20 in the case of protocol 010, double-dummy randomized

21 clinical trials. As I have

22 indicated, these trials have included more than

23 3000 patients with breast cancer, myeloma, prostate

24 cancer and the range of other solid tumors.

25 To reemphasize what you have heard, this


1 is the largest clinical-trial program ever

2 conducted to evaluate the efficacy and safety of

3 bisphosphonates in patients with cancer metastatic

4 to bone.

5 [Slide.]

6 Our initial experience with this agent

7 showed that, with higher doses and/or with shorter

8 infusion times, renal events occurred which were

9 characteristic of those associated with all other

10 intravenous bisphosphonates. But we believe we

11 have shown you that, by increasing the infusion

12 time to fifteen minutes and by using the 4-milligram dose of

13 Zometa, the renal-safety profile

14 does not differ from that of pamidronate.

15 Furthermore, the safety profile is

16 consistent for other adverse events, other

17 toxicities, with that similarly typically seen with

18 other intravenous bisphosphonates.

19 [Slide.]

20 With respect to efficacy, going across the

21 range of tumors, we believe that we have shown that

22 the effectiveness of Zometa as compared to

23 pamidronate has been reliably established in

24 preplanned analyses, as you have heard, of the

25 range of the skeletal-related events with this


1 noninferiority design that we have talked so much

2 about.

3 [Slide.]

4 Furthermore, in the range of solid tumors,

5 we believe that there is consistent benefit across

6 the range of skeletal-related-event analysis with a

7 relative reduction of 14 percent in the proportion

8 of patients having skeletal-related events.

9 Importantly, we see an extension of the median time

10 to this first event by more than two months. That

11 represents a 27 percent reduction in relative risk

12 in a very poor-prognosis patient population, as you

13 have just seen.

14 This is the first clinical trial

15 demonstration of bisphosphonate benefit in these

16 patient populations.

17 [Slide.]

18 Prostate cancer, protocol 039, we believe

19 represents a clear demonstration of efficacy, both

20 in terms of the 25 percent relative reduction of

21 SREs as well as with the extension of the time to

22 first SRE by, in this case, more than 100 days

23 representing a 33 percent relative risk reduction

24 as compared to placebo.

25 Again, this is the first demonstration of


1 such benefit in patients with prostate cancer and

2 an important addition, we submit, to the therapy of

3 prostate-cancer patients.

4 [Slide.]

5 To conclude, we have confirmed the

6 activity, we believe, of Zometa in breast cancer

7 and myeloma. We have demonstrated extension of

8 that clinical benefit to the range of other tumors.

9 We believe that the consistency of this efficacy is

10 an important characteristic of the drug, that it

11 extends across all three trials, across multiple

12 tumor types and with multiple endpoints.

13 Furthermore, the efficacy is observed in

14 patients with bone lesions ranging from osteolytic

15 to osteoblastic in radiological appearance.

16 Importantly, this efficacy is observed with a

17 safety profile similar to that to pamidronate and

18 with a much more convenient administration time.

19 We thank you for your attention this

20 afternoon--still this morning--and look forward to

21 further discussions.

22 Thank you.

23 DR. NERENSTONE: Thank you. We will now

24 go on to the FDA presentation.

25 FDA Presentation


1 Zometa in Prostate Cancer and Solid Tumors

2 Other than Prostate Cancer and Breast Cancer

3 (Studies 010, 011 and 039)

4 DR. IBRAHIM: Good morning. I am Amna

5 Ibrahim and I will be discussing the issues related

6 to the efficacy of two trials. The first trial to

7 be discussed with be in prostate-cancer patients.

8 This will be followed by a discussion of the solid-tumor

9 trial.

10 [Slide.]

11 This is the first indication for a

12 bisphosphonate for prostate-cancer patients. As

13 already pointed out by Dr. Williams, the main issue

14 for the prostate-cancer study is the lack of

15 concordance in the 4- and 8-milligram arms of the

16 prostate-cancer trial.

17 The critical questions for the study are

18 considering both the 4-milligram and the 8-milligram arms,

19 how convincing is the prostate-cancer trial. Can the data

20 from other studies

21 provide support?

22 [Slide.]

23 The overview of my presentation on

24 efficacy of the prostate-cancer study will be as

25 follows. We will go through the study results and


1 some of the exploratory analysis. Then there can

2 be several reasons to explain the lack of

3 concordance in the two Zometa arms such as baseline

4 imbalances and large numbers of early

5 discontinuations.

6 I will represent to you the division's

7 conclusions regarding the possibility of baseline

8 imbalances. No impact of early discontinuations

9 could be found on the result of the primary

10 endpoint. At the end, a summary of the issues will

11 be presented.

12 [Slide.]

13 This slide illustrates the protocol-specified

14 primary endpoint; that is, proportion of

15 patients with at least one SRE. The second column

16 from the left shows the proportion of patients with

17 at least one SRE. The third and fourth columns

18 give the p-value and confidence intervals.

19 33 percent of patients in the 4-milligram

20 arm had at least one SRE. This was statistically

21 better than placebo with a p-value of 0.021. 38

22 percent and 44 percent of the patients in the 8-milligram

23 and placebo arm, respectively, had at

24 least one SRE. These were not statistically

25 different from each other. The p-value was 0.222.


1 [Slide.]

2 We had similar results for time to first

3 event. The 4-milligram arm is better than placebo

4 statistically with a p-value of 0.009 whereas the

5 8-milligram arm is no different statistically from

6 placebo with a p-value of 0.541. The median time

7 to first event was not reached for the 4-milligram

8 arm. There was a trend towards improvement for

9 8 milligrams. This is lack of concordance between

10 the results of the two Zometa arms. The lower dose

11 of the 4-milligram arm appears to be effective

12 where as the higher dose of 8-milligram arm does

13 not demonstrate efficacy.

14 [Slide.]

15 This slide shows hazard ratios of the

16 comparison of each Zometa arm versus placebo in the

17 two studies I am presenting. Study 011, in red,

18 illustrates the hazard ratio in the solid-tumor

19 trial the discussion of which will follow the

20 prostate-cancer trial. Then, in green, you can see

21 the hazard ratios for the prostate-cancer trial,

22 that is trial 039.

23 The point estimates for the hazard ratios

24 and the 95 percent confidence interval were less

25 than 1 for the 4-milligram arm. The point estimate


1 for 8 milligrams was 0.912. The upper end of the

2 95 percent confidence interval of hazard ratio was

3 over 1 at 1.226.

4 [Slide.]

5 The secondary endpoints shown here showed

6 no statistical difference across the three arms of

7 the study.

8 [Slide.]

9 The next three slides present to you

10 analyses that were not prespecified and are

11 exploratory in nature.

12 [Slide.]

13 When the results of the two Zometa arms

14 are pooled together, the p-value for time to first

15 SRE was borderline at 0.06. The point estimate of

16 the hazard ratio was 0.781 with the upper end of

17 the 95 percent confidence interval as 1.01.

18 Looking at the proportion of patients with any

19 first event, the p-value was 0.04. The point

20 estimate for the difference of proportions was -0.08.

21 [Slide.]

22 Individual SREs may be evaluated in

23 several ways with pros and cons existing for each

24 method. This graph has been reproduced from the


1 sponsor's briefing package. It represents the

2 proportion of patients with the individual types of

3 SRE. This was not the prespecified analysis.

4 Each type of SRE such as radiation

5 fracture or any other SRE was counted the first

6 time it occurred in that patient regardless of the

7 number of times it occurred subsequently. In this

8 method, an event of a pathological fracture which

9 resulted in surgery and radiation would show up in

10 three different categories.

11 [Slide.]

12 Can we rely on evidence from other trials

13 in the NDA for blastic metastases? Can we draw

14 support from the results of the breast-cancer and

15 myeloma study or from the other solid-tumor study?

16 This graph presents the findings in a subgroup of

17 patients in the solid-tumor trial. It gives the

18 proportion of patients with any SRE in patients in

19 whom metastasis was blastic at baseline.

20 There were a total of 133 patients in the

21 solid-tumor study with blastic only met at

22 baseline. 42 of them were in the 4-milligram arm,

23 51 in the 8-milligram arm and 40 in the placebo

24 arm. Eleven and fifteen patients in the 4-milligram and 8-

25 milligram arms and 14 patients in


1 the placebo had any SREs. No conclusions can be

2 drawn regarding effect of Zometa from the solid-tumor study

3 due to the subgroup analysis and the

4 relatively small number of patients.

5 Does literature provide support for the

6 efficacy of a bisphosphonate in prostate cancer?

7 There were no large randomized trials published for

8 the effect of bisphosphonate in prostate cancer for

9 SREs.

10 Does any other study provide support of a

11 bisphosphonate in prostate cancer? Novartis showed

12 a slide on the effect of Aredia on proportions of

13 patients with SREs in Aredia and placebo. Their

14 conclusion was that no effect was demonstrated.

15 This data has not been submitted to FDA for

16 analysis.

17 [Slide.]

18 We did not detect any baseline imbalances

19 in the three arms. Prior SREs, baseline PSAs and

20 the analgesic scores were important prognostic

21 factors for both arms. In the multivariate Cox

22 regression model, however, these factors did not

23 alter the overall time to first SRE results. The

24 4-milligram arm remained significantly better than

25 placebo. The 8-milligram arm was, again, not


1 statistical different from placebo.

2 [Slide.]

3 Early discontinuations were not the reason

4 for the discordant results of the two treatment

5 arms. Early dropouts ranged from 62 to 72 percent

6 in the three arms by the end of the fifteen months.

7 The number of infusions administered were similar

8 at three months implying an equal number of

9 patients treated. However, the number of SREs were

10 already diverging by three months.

11 [Slide.]

12 Both proportions of patients with SRE and

13 time to first SRE for the 4-milligram arm were

14 significantly better than placebo. There was no

15 difference statistically for both these endpoints

16 between the 8-milligram arm and placebo.

17 [Slide.]

18 As you have heard, the 8-milligram arm was

19 dropped from the trial due to safety reasons. It

20 may be argued that the 8-milligram arm should be

21 ignored completely. This guidance states that,

22 when considering a single multicenter trial, all

23 available data should be examined to either support

24 or undercut reliance on a single multicenter trial.

25 [Slide.]


1 Another guidance states that support may

2 be drawn from another trial if the other trial was

3 conducted in a disease considered to be

4 biologically similar to the trial in question.

5 Since this is a first indication for an

6 osteoblastic tumor, we will be interested in your

7 opinion to this question; are osteoblastic lesions

8 biologically similar to osteolytic lesions.

9 [Slide.]

10 I will conclude the presentation on the

11 prostate-cancer trial by the summary of issues.

12 Considering both the 4-milligram and 8-milligram

13 arms, how convincing is study 039? This is the

14 first indication of a bisphosphonate for a

15 predominantly osteoblastic disease. Can support be

16 drawn from other trials? Is there substantial

17 evidence to support efficacy of the 4-milligram

18 arm?

19 [Slide.]

20 The next discussion will be on the solid-tumor

21 trial.

22 [Slide.]

23 As with the previous presentation, primary

24 endpoint results will be presented. This will be

25 followed by issues raised because of the


1 heterogeneity of the patient population. SREs may

2 be affected by the concurrent therapy and issues

3 dealing with chemotherapy will be presented. At

4 the end, the summary of issues of this trial will

5 be discussed.

6 [Slide.]

7 38 percent of patients in the 4-milligram

8 arm of Zometa had at least one SRE which was

9 statistical no different to the 44 percent of

10 patients in the placebo arm. The 8-milligram arm

11 showed a statistical improvement over placebo. The

12 4-milligram arm, in this study, did not prove

13 statistically significant superiority over placebo

14 in the protocol-specified primary endpoint.

15 [Slide.]

16 This slide presents the FDA preferred

17 endpoint of time to first SRE. In these patients,

18 the was a 67-day improvement over placebo in time

19 to first SRE in the 4-milligram arm of Zometa. It

20 should be noted that this improvement occurred in a

21 group of patients who had a median survival of less

22 than seven months.

23 [Slide.]

24 This slide shows an exploratory analysis

25 where the results of both Zometa arms were pooled


1 together. The p-value for time to first event was

2 0.01. The hazard ratios were less than 1 for point

3 estimate as well as 95 percent confidence interval.

4 The p-value for the proportions of patients with

5 any SRE was 0.03.

6 [Slide.]

7 The population included in this trial is

8 heterogeneous. Different tumor types have a

9 varying predilection for the metastases to bone.

10 The different tumor types may have a variable

11 behavior in the bone. Lastly, there may be a

12 potentially variable response to Zometa in the

13 diverse tumor types in the study.

14 [Slide.]

15 This slide is meant to show the tumor

16 types included in the study. They were fairly

17 evenly balanced except for the renal-cell-cancer

18 patients that was slightly more in the 4-milligram

19 arm.

20 [Slide.]

21 SREs may be affected by response to

22 chemotherapy. Prior chemotherapy treatment was not

23 recorded. However, the study was blinded and

24 randomized and it is likely that it does not impact

25 on the study results.


1 [Slide.]

2 Summarizing the other solid-tumor trial,

3 there was no statistical difference for the 4-milligram arm

4 for the protocol-specified endpoint.

5 There was substantial evidence for the 4-milligram

6 arm for time to first SRE and there was substantial

7 efficacy for the 8-milligram arm in both endpoints;

8 that is, proportion of patients with any SRE and

9 for time to first event.

10 [Slide.]

11 Issues of the other solid-tumor trial.

12 There was a heterogenous population. Is there

13 substantial evidence to support efficacy of the 4-milligram

14 arm? If yes, should Zometa be approved

15 for all solid tumors?

16 Thank you. Dr. Nancy Scher will now

17 present to you the safety data.

18 Safety Data

19 (Studies 010, 011 and 039)

20 DR. SCHER: Good morning.

21 [Slide.]

22 I am Dr. Nancy Scher and I will discuss

23 the safety analysis of the three trials.

24 [Slide.]

25 Early in the course of the bone-metastases


1 trials, renal safety became a concern when three

2 patients were reported with acute renal failure.

3 The protocol was amended to improve safety. The

4 infusion time was increased from five to fifteen

5 minutes. The Zometa 8-milligram dose was decreased

6 to 4 milligrams and, as you heard, this became the

7 8/4 milligram arm of each study.

8 Serum-creatinine monitoring was required

9 before each dose. Zometa was to be held for renal

10 deterioration as previously defined and resumed

11 when the creatinine was within 10 percent of

12 baseline.

13 [Slide.]

14 This table shows renal deterioration by

15 baseline creatinine for the breast and myeloma

16 patients who were randomized after fifteen-minute

17 infusion amendment. The first row shows the number

18 of percentage of patients with normal baseline

19 creatinine who developed renal deterioration

20 according to treatment arm. The second row shows

21 patients with abnormal baseline creatinine. The

22 third row shows the outcome for all patients.

23 The percent renal deterioration was

24 similar for Zometa 4-milligram and Aredia. Renal

25 deterioration occurred in patients with normal and


1 with abnormal baseline creatinine. The renal

2 effects seem dose-dependent for Zometa 8 arm

3 compared to the 4-milligram arm.

4 [Slide.]

5 For this Aredia-controlled study of

6 patients with multiple myeloma and breast cancer,

7 the incidence of adverse events was similar for

8 Zometa and Aredia. Slightly more patients in both

9 Zometa arms had a greater than 25 percent from

10 baseline decrease in hemoglobin. The incidence of

11 renal-function deterioration was greater for Zometa

12 4 than for Aredia prior to the fifteen-minute

13 infusion amendment, as you have heard.

14 Post-amendment, the incidence was similar

15 for Zometa 4 and Aredia. The time to first renal

16 deterioration was similar by Kaplan Meier analysis.

17 [Slide.]

18 This table shows renal deterioration by

19 baseline creatinine for prostate-cancer patients

20 who were randomized following the fifteen-minute

21 infusion amendment. The incidence of renal

22 deterioration was slightly higher for Zometa 4 than

23 placebo. For the entire group and for patients

24 with normal creatinine, rows 1 and 3, the effect

25 was greater with Zometa 8.


1 Perhaps the small number of patients with

2 abnormal baseline creatinine in the Zometa 4 group

3 exaggerates the adverse effect in this arm compared

4 with placebo and even compared with Zometa 8.

5 [Slide.]

6 This table shows renal deterioration by

7 baseline creatinine for patients with solid tumors

8 excluding prostate and breast cancer who were

9 randomized following the fifteen-minute infusion

10 amendment. The incidence of renal deterioration

11 was greater for Zometa 4 than placebo, both for

12 patients with normal and abnormal renal function.

13 In this study, the effect was similar for

14 the 4- and 8-milligram treatment arms.

15 [Slide.]

16 For the two placebo-controlled studies,

17 adverse events previously reported to be associated

18 with bisphosphonates such as fever, arthralgias,

19 electrolyte and mineral abnormalities were more

20 common with Zometa than placebo, as was anemia. As

21 you heard, there was no increase in grade 3 or 4

22 hematologic events. The incidence of renal-function

23 deterioration was greater for Zometa 4

24 than for placebo. This incidence tended to

25 increase over time with duration of therapy.


1 [Slide.]

2 Our overall conclusions are that Zometa 4-

3 milligrams when given intravenously over fifteen

4 minutes every three or four weeks has an acceptable

5 safety profile. It is more toxic than placebo but

6 comparable in safety profile to Aredia.

7 Renal events occurred in patients with

8 normal and abnormal renal function. Particular

9 caution is indicated for patients with abnormal

10 renal function. Patients with creatinine greater

11 than 3 were excluded from the current trials.

12 Zometa is excreted unchanged by the kidneys

13 resulting in an effectively higher exposure for

14 patients with renal dysfunction. Serum creatinine

15 monitoring is appropriate in patients with normal

16 as well as abnormal renal function.

17 I would like to thank you for your

18 attention. We will be available at the table for

19 questions of clarification now and we will be

20 present for the discussion after lunch.

21 DR. NERENSTONE: Thank you very much. I

22 will open it up to questions for the committee. I

23 want to remind everyone that we are going to have

24 time afterwards for discussion of the issues.

25 Right now, I really wanted it to be specifically


1 questions and clarifications.

2 Questions from the Committee

3 DR. NERENSTONE: I would like to start by

4 asking Dr. Scher, when you say that you recommend

5 monitored serum creatinine in all patients, how

6 often do you think that that is necessary; before

7 every treatment, every two or three treatments?

8 DR. SCHER: I feel that the conservative

9 answer would be to model the conduct of the trials

10 after the renal amendments. So that would be to

11 monitor the creatinine prior to each dose.

12 DR. NERENSTONE: Other questions? Dr.

13 George?

14 DR. GEORGE: I have a question about the

15 intent-to-treat analysis or approach taken. There

16 were, in both of these studies, a large number of

17 discontinuations prior to the scheduled end of the

18 study. There was one brief mention that an attempt

19 was made to follow these patients for the primary

20 endpoints. Is there evidence on that point? How

21 many of these that were discontinued, in fact, were

22 followed through the period and how many were just--did that

23 discontinuation mean that no further

24 observation was possible?

25 DR. SEAMAN: As in any oncology trial,


1 there were a lot of dropouts, as you said, as you

2 might expect. We have taken into consideration and

3 have done analysis in terms of the three trials to

4 take into consideration whether they dropped out

5 from death or dropped out otherwise. I will gladly

6 show you that information.

7 Let's take a look at 080.

8 [Slide.]

9 If you take into consideration--let's take

10 a look at protocol 011 first and you take into

11 consideration both death and dropouts and look at

12 the time to the first skeletal-related event, you

13 can see the median time still reaches significance

14 for the Zometa 4-milligram group versus placebo

15 with the median time around 127 days for the Zometa

16 4 group and 85 for placebo.

17 Can I have the next slide, please, 081.

18 [Slide.]

19 Let's look at protocol 010 with the same

20 sort of scrutiny in terms of taking deaths and

21 dropouts. You can see, again, the median time to

22 the first SRE is around 312 days for Zometa 4-milligram and

23 252 days for the pamidronate 90

24 milligram. The p-value here is 0.099.

25 [Slide.]


1 Finally, for protocol 039, which is the

2 next slide, protocol 042, you can see here, again,

3 taking dropouts and deaths into consideration and

4 looking at the time to the first SRE, we still

5 maintain the significance of 4-milligram treatment

6 group over placebo with the median time being

7 around 337 days for the Zometa 4-milligram group

8 and placebo, 221.

9 Grant?

10 DR. WILLIAMS: This occurred to me, too,

11 and I know I asked for an analysis from Novartis

12 and they supplied one about how many--you were

13 supposed to monitor events after going off the drug

14 but it wasn't clear how many of those events

15 actually happened. It was really relatively few.

16 So if I were to redesign the study, I would

17 probably not try to do that because it was a very

18 sketchy collection of data thereafter, I think.

19 But looking with and without, it didn't

20 seem to make a difference. There were so few

21 events that were collected after going off drug

22 that it didn't seem to make a difference whether

23 you included or excluded them.

24 DR. NERENSTONE: Dr. George, was your

25 question answered?


1 DR. GEORGE: Not completely. Let me just

2 state it. We will come back to in the discussion

3 because this is an important issue with respect to

4 what these estimates are of percentage of patients

5 with these events. But, just to be clear, what you

6 showed me there was you assumed any dropout was the

7 same as an SRE at that time.

8 What I was really asking about was, among

9 those dropouts, and I think, Grant, maybe had

10 answered it, it was very rare after a dropout to

11 actually be able to observe what happened between

12 then and the end of the study.

13 DR. SEAMAN: That is correct, because of

14 the patient population.

15 DR. NERENSTONE: Dr. Przepiorka?

16 DR. PRZEPIORKA: Can you clarify, please,

17 for patients who did develop an SRE, did they stay

18 on study drug?

19 DR. SEAMAN: Yes; they did. They stayed

20 on study drug and we continued to follow them and

21 they continued to be treated.

22 DR. PRZEPIORKA: Was there any difference

23 in second, third, fourth or multiple SREs between

24 the treatment arms?

25 DR. SEAMAN: That was the Andersen-Gill


1 multiple-event analysis. Basically, you could see

2 from protocols 011 and 039, they were positive.

3 DR. PRZEPIORKA: Has anyone looked at a

4 hazard plot? We have looked at the rate per year,

5 but patients were restaged at multiple times during

6 the year and the Kaplan-Meier plots seem to drop at

7 three months and a little at six and more at nine

8 months. I was just wondering if there was any

9 point where the hazard for SREs actually plateaued

10 out for all three lines and you have lost the

11 effect of the drug.

12 DR. SEAMAN: No. I am looking at my

13 biostatistician. We didn't do a hazard plot like

14 that.

15 DR. PRZEPIORKA: Do you know how long

16 bisphosphonates stay in the bone?

17 DR. SEAMAN: Yes. From preclinical animal

18 models, they stay in the bone for at least a year

19 after they had received one dose. But that doesn't

20 mean they are pharmacologically active. What

21 happens is the bone is remodeled. It is covered

22 over and an osteoclast buries in exactly that same

23 site where the bisphosphonate is present. It is

24 not reactivated.

25 DR. NERENSTONE: Mr. Kazmierczak?


1 MR. KAZMIERCZAK: Gene Kazmierczak. I am

2 a prostate-cancer patient. Both the sponsor and

3 the FDA seem to agree that, when you consider time

4 to the first SRE, that the results in study 011, in

5 both arms of the study, the 4 and 8/4, show a

6 significant improvement from the standpoint of time

7 to the first SRE.

8 When you look at 039, the 4-milligram arm

9 doesn't show any significance with regard to

10 improvement in time--or does; pardon me--but the 8

11 doesn't. You did do an analysis that lumped the 4

12 and the 8 together with regard to numbers of SREs

13 but you didn't do that for time to the first SRE.

14 I noticed by your chart that, when you look at time

15 to the first SRE in the 8/4 arm, it wasn't

16 significant.

17 Maybe you could explain why.

18 DR. SEAMAN: I think the FDA medical

19 reviewer did do an analysis of the time to the

20 first SRE and maybe she can answer that. I think

21 it is significant but let her explain.

22 DR. SRIDHARA: It is barely significant at

23 0.06. But, you know, this is exploratory and how

24 we interpret this p-value is questionable. We are

25 doing multiple analyses and we are not adjusting


1 for all of this multiple testing. So it is not

2 correct to be comparing it to 0.05 and say that

3 this is borderline or any of those. It was just an

4 exploratory analysis.

5 The other thing is, your question, if I

6 understand correctly, we saw that there was no

7 difference in 8 milligrams versus placebo but how

8 come, when we combine together, we saw some

9 difference. That is simply a matter of power and

10 you are putting the two together and, therefore,

11 even a smaller difference you can detect by doing a

12 larger study.

13 DR. NERENSTONE: Dr. Pelusi.

14 DR. PELUSI: When Dr. Smith was talking, I

15 just needed some clarification in terms of

16 inclusion into the prostate study. You had on your

17 slide, on page 5, that individuals who were not on

18 strong opioids could be included. I guess I have a

19 few questions about that since many of our patients

20 would be using strong opioids and why the decision

21 was made to--what the definition is of a strong

22 opiate--why the decision was made not to include

23 them and if, in the course of their disease, they

24 required them, did they go off study or were they

25 allowed to take strong opioids?


1 DR. SMITH: So the definition of a strong

2 opioid was anything stronger than codeine. So that

3 part is easy. Why they were excluded if they

4 needed more pain medicines, that was simply an

5 attempt to define an homogenous patient population.

6 There can be, certainly, variability. That was the

7 basis for doing so.

8 Patients were not removed from the study

9 if they subsequently required narcotics. As you

10 can imagine, many of these men did.

11 DR. NERENSTONE: Dr. Bonomi?

12 DR. BONOMI: Did you collect serial PSA

13 levels in the prostate study?

14 DR. SEAMAN: Yes; we did. Would you like

15 to see them? Could we have that?

16 [Slide.]

17 These are the median PSA levels for the 4,

18 8/4 and placebo treatment groups over the time

19 course of the study, over the fifteen-month time

20 course of the study. As you can see, they start at

21 the baseline like you saw in the '80s or '60s and,

22 as they progressed, so did their PSA values. We

23 also looked to see was it preceded in terms of were

24 their PSA values elevated prior to their overall

25 progression and the answer is yes.


1 DR. BONOMI: One other follow-up on that.

2 The baselines are different, too. Are those

3 differences significant?

4 DR. SEAMAN: We did go and take a look at

5 that information to see if it had an impact on

6 whether or not they were having more progressive

7 disease in terms of their bone disease, and that

8 was not significant when we looked at that.

9 DR. NERENSTONE: Dr. Lippman?

10 DR. LIPPMAN: I think that the question

11 Mr. Kazmierczak was getting at and maybe we can

12 discuss this more later, is do you have any

13 suggestions why, in terms of biologic plausibility

14 or statistical, why the higher dose would be less

15 effective than the 4, why the 8/4 was not

16 significant and the 4 was.

17 DR. NERENSTONE: I think I am going to

18 take the chair's prerogative and say that we are

19 going to leave that for discussion and stick to the

20 questions of specific--for clarification for the

21 FDA and the sponsor because I think that will come

22 up in the discussion. I think it is going to be a

23 question.

24 Dr. Loehrer?

25 DR. LOEHRER: Actually, in September last


1 year, there was a New England Journal of Medicine

2 article that looked at pamidronate in patients with

3 prostate cancer increasing bone-mineral density. I

4 guess I would challenge you, and maybe the

5 inquiring minds that Derek had, in the prostate-cancer

6 population, the challenge was does Zometa

7 work in terms of blastic metastases.

8 In reality, is it actually a population of

9 patients with osteoporosis. So, putting it, framed

10 in that way, particularly in the patients with

11 prostate cancer, there was no control or at least

12 could you give me the analysis of the time on

13 hormonal therapy prior to going on study and the

14 analysis from that. Similarly, I guess we can go

15 back to the myeloma patients in terms of

16 corticosteroid use and the duration of

17 corticosteroid use prior to going on study.

18 Or, thirdly, was there a subgroup of

19 patients that had bone-mineral density done that

20 would show us that there weren't any imbalances in

21 any of the arms here?

22 DR. SEAMAN: I am going to turn this over

23 to Dr. Matthew Smith who actually wrote the paper

24 in NEJM.

25 DR. SMITH: Thank you for the question.


1 It can be answered in several ways. First, the

2 time from diagnosis to study entry was similar

3 across all the groups. I will see if we can pull

4 up the data on prior hormonal therapy. I am not

5 sure of that, but if we have it, we will certainly

6 present it to you.

7 Bone-mineral density cannot be reliably

8 measured in men with metastatic prostate cancer,

9 period. So the bone-mineral-density measurements

10 would be unreliable in this setting.

11 The question you raise though is have we

12 done something useful in addition to preventing

13 osteoporosis or have we done more than that and

14 prevented disease-related complications, as I

15 understand your question. So the way I asked this

16 question to be looked at and I presented in my

17 talk, but it was a bullet point, was if you look at

18 the primary efficacy analysis for the 4 group and

19 you take out all the fractures, the comparison with

20 placebo remains significant. So I think this is

21 the best way to address the issue of have you done

22 more than treat osteoporosis.

23 I think that analysis says you have. If

24 you look, also, at the other analysis, looking at

25 the type of events that you prevent, you prevent


1 radiation therapy to bone. You prevent other kinds

2 of problems that are separate from osteoporosis.

3 DR. LOEHRER: Could you, again, assure me,

4 then? I am looking for imbalances between the

5 groups and duration of hormonal therapy which we

6 know can predict for more problems with

7 osteoporosis. So what were the differences between

8 the groups with respect to duration of hormonal

9 therapy prior to going on study?

10 DR. SMITH: John, do we have that data?

11 DR. SEAMAN: No; we don't. Unfortunately,

12 we don't have the data.

13 DR. SMITH: I can tell you that the time

14 from diagnosis was similar. We don't have the data

15 for duration of prior hormonal therapy. But I

16 think, again, looking at the clinical endpoint,

17 fractures, if you take them out, the primary

18 efficacy analysis for the 4 group remains

19 significant compared to placebo.

20 DR. LOEHRER: Just to clarify. Can you

21 get fractures from osteoporosis?

22 DR. SMITH: That is the concern, that

23 osteoporosis leads to fractures. Osteoporosis is

24 typically defined by a bone-mineral-density

25 criteria. But the reason we are concerned about


1 that is that it increases the risk of fractures.

2 So, if you take the clinical outcome due to

3 osteoporosis out of the equation, you still have

4 benefit in the Zometa 4 group in the primary

5 efficacy analysis.

6 DR. NERENSTONE: Dr. Kelsen, Dr. Albain or

7 Dr. Taylor, any questions for the sponsor or for

8 the FDA?

9 Hearing none, Dr. Brawley?

10 DR. BRAWLEY: With Dr. Smith there, can we

11 have the last slide that was shown, the one with

12 the PSAs?

13 [Slide.]

14 I just want to clarify. The PSA rise over

15 time for the 8/4 group whereas it was relatively

16 stable for the placebo and 4 group. Am I reading

17 that correctly?

18 DR. SMITH: I will ask for a clarification

19 on how the analyses were done but you have to

20 realize that, as you got out further, you don't

21 have repeated measurements. So the further you go

22 out on this line, the fewer measurements you have

23 maintained. Remember, only about a third of the

24 patients completed treatment at fifteen months.

25 So, once you get out--the second half of this


1 panel, there is not a lot of time measurement.

2 So I would interpret the large separation

3 that you see in the right-hand side of this figure

4 very cautiously.

5 Does that answer your question, Dr.

6 Brawley?

7 DR. BRAWLEY: Yes. I think it is about

8 the best answer I am going to get right now.

9 DR. NERENSTONE: Dr. Raghavan?

10 DR. RAGHAVAN: Matt, coming back to the

11 point that I think Pat Loeher was trying to get at,

12 one of the issues that I think we do need to try to

13 get a handle on is the level of selection of the

14 patient population. When you look at the patients

15 with prostate cancer, the mean or median weights

16 were around 82 kilograms. These are, by and large,

17 relatively chubby patients with prostate cancer.

18 The length of time from presentation to

19 hitting the study is relatively long. I think it

20 is perfectly sound to have a homogenous population

21 so that is not the question. I think you have

22 achieved that. But my question is do you have a

23 concern that you have subselected out the best

24 patients so that you are not answering the question

25 in the context of killing bad, aggressive prostate


1 cancer.

2 These look like pretty good actors. I

3 just wondered, does this tell us something about

4 the group of patients where this may have a role to

5 play?

6 DR. SMITH: That is a great question. I

7 want to make a couple of comments. First, their

8 survival would argue against being great actors.

9 The medical survival was about one year. It is

10 pretty bad. It is actually worse than most

11 published phase II studies of chemotherapy for

12 hormone-refractory disease.

13 The second issue of weight I think

14 probably reflects the fact that many of these men

15 have been on hormone therapy for a long time, so

16 you lose lean body mass but you gain fat mass and

17 increase weight. So I think their apparent weights

18 overrepresented their vigor.

19 DR. NERENSTONE: Dr. Raghavan, go ahead.

20 DR. RAGHAVAN: Just a point of

21 clarification. Isn't it true, though, that you

22 have got heterogeneity of chemotherapy patients. I

23 think if I read the entry criteria correctly, you

24 have people who are and who are not on

25 chemotherapy. So that would argue against what you


1 just said for duration.

2 DR. SMITH: Let me clarify that. Prior

3 chemotherapy was excluded. So, if you had prior

4 chemotherapy, you were excluded. You could go onto

5 chemotherapy during the course of the trial but if

6 you had been on chemotherapy, you couldn't, then,

7 enter the trial.

8 DR. NERENSTONE: Any further questions

9 from the committee? Dr. Albain?

10 DR. ALBAIN: I have a question and also

11 Dr. Kelsen did. There was something wrong with our

12 audio feed. It has now been corrected. My

13 question has to do with the pathophysiology of bone

14 metastases and non-small-cell lung cancer in

15 particular and wondering if there is any data that

16 would indicate that the dose response for the

17 bisphosphonate might differ than in the hormone-dependent

18 malignancies of breast or prostate,

19 getting at this issue in the other solid tumors and

20 in lung, in particular, the higher dose seemed to

21 better.

22 So is there anything in the

23 pathophysiology of the process?

24 DR. SEAMAN: I will bring Dr. Robert

25 Coleman up to talk to that.


1 DR. COLEMAN: Robert Coleman. I am not

2 aware of any specific data that have looked at

3 marker changes in lung-cancer patients and compared

4 them to prostate-cancer patients, so it is a good

5 question but I am not aware of any data in the

6 literature to answer it and I don't think we have

7 an analysis of marker changes by disease type. We

8 have marker changes cut in other ways, but not by

9 disease type.

10 So I am sorry, I don't think I can answer

11 your question.

12 DR. ALBAIN: Hopefully, we can get that

13 data down the road. To follow up regarding the

14 lung patients, is there any further analysis of use

15 of systemic chemotherapy in this group? We saw a

16 bullet go by that probably there were no imbalances

17 due to the randomization, but how many of these

18 patients were not being treated with systemic

19 chemotherapy versus were? Do you have that data?

20 DR. SEAMAN: We are looking it up right

21 now. I think we do have that data. Just a second.

22 We have the one prior to. How about, do we have

23 the one after?

24 [Slide.]

25 These are the types of chemotherapy. I


1 don't think you can see these so I will read them

2 to you. The vast majority of patients were

3 receiving chemotherapy, around 75 percent,

4 carboplatin being the number-one agent, paclitaxel

5 second, gemcitabine and cisplatin followed by that.

6 So they were receiving, in 75 percent of the cases,

7 some sort of chemotherapy for solid tumors.

8 You need to know about non-small-cell lung

9 cancer also; correct?

10 DR. ALBAIN: Correct. If you have it.

11 DR. SEAMAN: That was for everything. I'm

12 sorry. I will take that back. If we could go back

13 to the previous slide. That was for all patients.

14 That includes not only non-small-cell lung cancer

15 but it also includes all the other cell and tumors

16 during the course of the trial. I don't think we

17 have it broken down specifically for non-small-cell

18 lung cancer.

19 DR. ALBAIN: Do you have it by subsequent

20 change in regimen like you did for the other

21 studies?

22 DR. SEAMAN: Yes; I do. Slide 17.

23 [Slide.]

24 In the non-small-cell lung cancer, we

25 broke it down by strata in this. About 16 to 20


1 percent of the patients stayed on their original

2 regimen. Between 30 and 40 percent of the

3 patients, up to 50 percent of the patients, changed

4 at least one time up to twice for the non-small-cell lung

5 cancer.

6 In other solid tumors, it is about 30

7 percent of the patients stayed on their original

8 regimen and then 40 percent changed once and around

9 12 to 20 percent of the patients changed at least

10 twice.

11 DR. ALBAIN: Could the camera be moved so

12 I could see the placebo column, please?

13 DR. SEAMAN: Yes.

14 DR. ALBAIN: Thank you.

15 DR. NERENSTONE: Kathy, your question was

16 answered?

17 DR. ALBAIN: Yes. I just couldn't read

18 the placebo column. It was off-screen. I can see

19 it now. Thank you.

20 DR. NERENSTONE: Dr. Kelsen?

21 DR. KELSEN: Thank you. This may have

22 been answered. I may have missed it when some of

23 the audio was lost, but, in trying to get a better

24 understanding as to why, in study 039, there was

25 benefit to the lower dose of Zometa but not as


1 apparent benefit to the higher dose.

2 In the briefing book, it indicates that

3 Aredia was also studied in prostate cancer and

4 failed to show benefit. Could you give us any

5 data? Was there a similar trend toward benefit

6 that didn't reach statistical significance? Was

7 there a complete absence of benefit? Was there any

8 reason to suspect that osteoblastic lesions really

9 are more resistant to bisphosphonate therapy?

10 DR. SEAMAN: In the study that was

11 conducted in the prostate-cancer trial with

12 pamidronate, when we looked at the data from there,

13 we could not detect a benefit in skeletal-related

14 episodes. However, that was not the primary-efficacy

15 endpoint in this trial. The primary

16 efficacy endpoint was sized for pain.

17 It may be a reflection of the design of

18 the trial in terms of the inclusion criteria, but

19 we certainly did not see a benefit from the 90

20 milligram treatment group compared to placebo in

21 that trial.

22 DR. KELSEN: Thank you.

23 DR. NERENSTONE: Any other questions from

24 the committee? Dr. Przepiorka?

25 DR. PRZEPIORKA: Just to clarify about the


1 quality-of-life indicators, please. If you could

2 just summarize--if what I am summarizing, let me

3 say, it is true that there is no difference in the

4 quality-of-life indicator, or the change in

5 quality-of-life indicators, between the 4-milligram

6 arm and placebo for the prostate-cancer trial and

7 the solid-tumor trial?

8 DR. SEAMAN: That's correct.

9 DR. PRZEPIORKA: There is no difference in

10 three of the four indicators for the breast cancer

11 myeloma trial and, actually, the Aredia arm fared

12 better in some of the subscales for the FACT-G

13 trial?

14 DR. SEAMAN: That's correct. But you

15 should make sure you look at that FACT-G scale with

16 some concern because that change, when you look at

17 the literature, is probably not clinically relevant

18 in terms of the numbers you are seeing there. It

19 also should be remembered that we would not expect

20 to see a difference between the three active

21 controls in this sort of study in protocol 010.

22 DR. NERENSTONE: Dr. Ibrahim?

23 DR. IBRAHIM: Just a clarification for

24 study 011. It will be difficult to look at any one

25 individual strata. It would be difficult because


1 there were small-cell patients in the non-small-cell

2 stratum. There were several small-cell

3 patients, small-cell lung-cancer patients, who were

4 there. So it will be difficult to--an intent-to-treat

5 analysis will be different from the actual

6 fact. It could be.

7 DR. NERENSTONE: Thank you.

8 Right now, it is 12:15, for those of us in

9 Washington. We are going to break for forty-five

10 minutes and return at 1 o'clock. So, our people at

11 remote areas, it will be a forty-five minute break.

12 Thank you.

13 [Whereupon, at 12:15 p.m., the proceedings

14 were recessed, to reconvene at 1:00 p.m., this same

15 day.]


1 A F T E R N O O N P R O C E E D I N G S

2 [1:00 p.m.]

3 DR. NERENSTONE: Dr. Williams, if you

4 would like to start us off.

5 Introduction to the Issues

6 DR. WILLIAMS: To begin this afternoon's

7 session, I will briefly introduce the questions

8 that we have prepared. You should have a copy of

9 the questions in your packet. You will probably

10 want to refer to them.

11 On the first page, you will find two

12 tables that summarize the Zometa efficacy findings.

13 These will be useful as a reference as we proceed.

14 The first table summarizes the

15 noninferiority study of Zometa versus Aredia in

16 breast cancer and myeloma. The second table

17 summarizes the two placebo-controlled studies, one

18 in prostate cancer and the other in solid tumors.

19 [Slide.]

20 Results from both of the critical

21 skeletal-related events analyses are listed here,

22 the proportions analysis, as presented in the third

23 column, followed by the estimated treatment

24 difference and the 95 percent confidence intervals

25 within that difference.


1 A negative number here is an estimate that

2 favors the Zometa arm. The sixth column provides

3 the hazard ratio for time to first skeletal-related

4 event and then the confidence intervals. In this

5 analysis, a number less than 1 is an estimate that

6 favors Zometa. P-values are included for each

7 analysis.

8 As I discussed earlier, each of these

9 clinical trials suggests one or more important

10 questions which I will summarize again in the next

11 three slides. For study 010 in breast cancer and

12 myeloma, we note that it is a single study of

13 noninferiority design. The question for ODAC is do

14 the totality of the data in the NDA provide support

15 for this indication.

16 [Slide.]

17 In prostate cancer, the 4-milligram Zometa

18 arm shows convincing results for both the primary

19 and secondary skeletal-related endpoints. The 8-milligram

20 arm shows no statistical difference from

21 placebo. Again, two questions arise. First,

22 considering both of the arms of the study, how

23 convincing are these data that Zometa 4 milligrams

24 is effective.

25 Second, prostate cancer produces blastic


1 bone metastases. When considering the efficacy of

2 Zometa in prostate cancer, is it reasonable to also

3 consider evidence of Zometa efficacy from studies

4 of lytic bone metastases from other cancers?

5 [Slide.]

6 In patients with other solid tumors, the

7 4-milligram Zometa arm was statistical better than

8 placebo in time to skeletal-related event but not

9 by the proportions analysis. The 8-milligram

10 Zometa arm was statistical better than placebo in

11 both analyses. FDA believes that these data are

12 convincing for the populations studied and received

13 benefit. However, the population was

14 heterogeneous. We want you to consider whether

15 these data support approval for the treatment of

16 all individual patients with all types of other

17 solid tumors.

18 [Slide.]

19 For each of these studies, we want you,

20 then, to put on the regulatory hat with us--if we

21 have one in your size. You have to check with

22 Stacy--and determine whether the data collectively

23 meet the regulatory standard for demonstrating

24 efficacy, substantial evidence from adequate and

25 well-controlled investigations.


1 As I noted earlier, this means evidence

2 from multiple clinical trials--it usually means

3 evidence from multiple clinical trials--but very

4 impressive and robust results from a single

5 multicenter trial sometimes have been accepted.

6 You may find that one of these trials is

7 so impressive that it supports approval without any

8 support from another trial or you may find that,

9 while a single trial is not convincing alone, you

10 find the results of another study to be supportive.

11 We look forward to your advice on these

12 matters.

13 DR. NERENSTONE: Thank you.

14 I am going to open the discussion now to

15 the committee members. Just to check, Dr. Albain,

16 can you hear us?

17 DR. ALBAIN: Yes; I can.

18 DR. NERENSTONE: Dr. Taylor, are you

19 there?

20 DR. TAYLOR: Yes; I can hear you.

21 DR. NERENSTONE: Dr. Kelsen, are you with

22 us?

23 DR. KELSEN: Yes; I am.

24 Committee Discussion and Vote

25 DR. NERENSTONE: Does anyone on the


1 committee have any questions? Actually, let's have

2 some comments now. We are opening it up for

3 discussion.

4 Dr. Lippman, I know that you had some

5 comments that I think are very important to open up

6 the discussion.

7 DR. LIPPMAN: I think that my comments

8 were asked by subsequent people on the committee

9 and answered so I don't have anything else to add

10 to that. I think the issue of the 8/4 versus 4, we

11 have heard all that we will know about that issue.

12 DR. NERENSTONE: I think that is an issue

13 that is still a little problematic. Thinking about

14 that, which is why is there not consistency in all

15 the arms, I agree with Dr. Lippman that it seems

16 like the sponsor has not really been able to

17 adequately give us data about why, or explain why,

18 it might be not consistent. It may be that they

19 don't have the data.

20 Does the FDA have any thoughts about why

21 there might be some inconsistency?

22 DR. WILLIAMS: We certainly looked to find

23 some source of the problem. In my opinion, if you

24 are looking for an excuse to explain, say, the drug

25 works and why we find these things, the trials were


1 designed at 80 percent power. You expect one in

2 five studies to be negative. I think the power of

3 these studies was probably even less than that,

4 getting the final effect size.

5 Depending on which analysis you see, you

6 see trends in favor, and we don't see anything

7 against. So my opinion is that, if the drug works

8 and we have these results, it is probably chance.

9 DR. PAZDUR: One of the things I would

10 like to bear in on this is we should look at the

11 totality of data that is coming and not simply the

12 clinical trials. One of the things that I urged

13 the company to reiterate at this time, or people in

14 their own minds to think of, is the pathophysiology

15 of the disease, any potential differences in

16 osteoblastic or osteolytic lesions, especially with

17 the interaction of the bisphosphonates.

18 Would one expect from the underlying

19 disease process and the mechanism of action of the

20 bisphosphonates that one should see a difference in

21 osteoblastic and osteolytic disease. Perhaps the

22 company could address this again for the committee

23 because, really, it isn't just the clinical trials.

24 It is the totality of evidence that we must look

25 at.


1 DR. SEAMAN: I am Dr. John Seaman from

2 Novartis. I would like the slide with the

3 information regarding all the trials that we have

4 done with Zometa for hypercalcemia in bone

5 metastases, et cetera.

6 [Slide.]

7 This slide depicts all the results of

8 trials done in terms of Zometa in a malignant

9 indication. On the left-hand side, you will see

10 the Zometa hypercalcemia data in regards to the

11 response rates for Zometa, 4-milligrams and 8

12 milligrams, versus pamidronate. These are in

13 patients with bone metastases because they are

14 probably a more reasonable patient population to

15 look at because humoral is somewhat different.

16 As you can see, the proportion of patients

17 having a response to Zometa in these treatment

18 groups are somewhat variable. You see a 90 percent

19 response for the Zometa 4-milligram treatment

20 group, and 84 percent response for the 8/4 and a 80

21 percent response for pamidronate.

22 That is somewhat consistent when you look

23 across the three trials that we have done in terms

24 of bone metastases. There is a reflection that you

25 see responses in terms of efficacy for prostate


1 cancer and for other solid tumors include non-small-cell

2 lung cancer that is somewhat different

3 when you look at the treatment groups.

4 If you look at the 4-milligram treatment

5 group, for example, in the prostate-cancer patient

6 population, there is a 33 percentage of patients

7 having an SRE. For the 4-milligram group, it is

8 around 38 percent. They are both reducing the

9 portion of patients having an SRE although the 8/4

10 does not reach significance.

11 Somewhat of a different pattern sort of

12 shows up in terms of the protocol 010 where the 8-milligram

13 group is a bit more successful in having

14 less SREs, 35 percent, and 38 percent in the 4-milligram

15 treatment group.

16 Then you see, even in the other trials

17 where we have seen noninferiority, you see

18 variability in the data that you are looking at.

19 Our feeling is the totality of data supports the

20 fact that Zometa works across all these tumor types

21 in terms of what is going on.

22 I think this is the first time we have an

23 opportunity to look at all the results for all the

24 trials we have done in a malignant setting with

25 patients who have bone metastases.


1 DR. NERENSTONE: Thank you.

2 Dr. George?

3 DR. GEORGE: With respect to this issue of

4 whether the results are contradictory, or the 4 and

5 8 business, it seems to me, in looking at all this,

6 to try to synthesize it some, the obvious thing

7 that I would do is just pool those results. If you

8 had a situation--if your model ahead of time is

9 that you can't come up with the plausible

10 biological reasons why the 8 would produce a worse

11 control in terms of the primary endpoint, then a

12 sound statistical procedure is to sort of, in these

13 restricted inference procedures--is to pool the

14 data, to pool them and say, "This is the best

15 estimate we can do of what the effect is."

16 I would do that on all these studies, if

17 you want to try to get a handle on what that effect

18 size really is. I think that is important because

19 we have been focusing on a lot of the--we look at

20 these confidence intervals but the effect size is

21 really a key issue.

22 I like to think in terms of the number-needed-to-

23 treat analyses. If the effect size is

24 really, say, 8 percent like it seems to be in one

25 of these, then the number needed to treat is 12,


1 12.5, to be precise, or something like you have to

2 treat twelve or thirteen patients to reduce one SRE

3 in one patient. The other eleven or twelve are

4 treated for nothing--well, maybe not nothing, but

5 at least with respect to the primary endpoint, that

6 is what happens.

7 So then you have to assess is it worth it

8 in that sense. So that is the way I tend to think

9 of it. In other words, whether you do a formal

10 pooling, just add them together, or pool them some

11 other way, I think it is important to do that.

12 That is the only way you can make sense of it.

13 But I have a fundamental point I wanted to

14 address concerning--it is sort of a technical point

15 but I think it is important with respect to what it

16 is we are estimating. There have been two

17 analyses, types of analyses, presented here with

18 respect to the primary endpoint in the first event

19 that occurs.

20 One is just simply the percentage of SREs

21 that are observed in the specified time frame. The

22 other is the time to that event. Now, there is a

23 problem with both of these. It boils down to the

24 fact--or it relates to the fact that you are in an

25 area of a lot of competing risks. So what I would


1 have really like to have seen is something like

2 cumulative-incidence kinds of curves.

3 Just to be clear, if you look at the

4 percentage of events, the percentage of SREs that

5 occur in this time frame, if you had no censoring

6 at all, then those percentages would give you the

7 same as the cumulative incidence. But, when you

8 have censoring, they give you the wrong answer.

9 They give you something different.

10 The answer you are getting when you look

11 at those percentages of SREs is too low. It is too

12 low. The cumulative incidence would actually be

13 higher. On the other hand, if you do the time to

14 the event and you censor the competing events,

15 which I think is what was done on both the FDA's

16 and the sponsor's analysis, then you get something

17 that is too high.

18 So that is why you get this discrepancy.

19 Maybe it is true that, if you did something else,

20 if you did something like this cumulative

21 incidence, that you would get the same qualitative

22 answer but it is not guaranteed. So I don't know

23 what that answer is. I would have liked to have

24 seen that.

25 If you have already done it--


1 DR. SEAMAN: We have done it

2 DR. GEORGE: Then that would be

3 interesting to see.

4 [Slide.]

5 DR. SEAMAN: Here is the cumulative

6 incidence rate of SREs in all patients for the 4,

7 8/4 and pamidronate treatment group in terms of

8 median time to first SRE. You can see that it is

9 very similar in terms of the median time being

10 around 397 days with the 4, 373 for the 8/4 and 370

11 for the 90 milligram.

12 DR. WILLIAMS: Could you clarify? Is that

13 patients or all events, patients within event?

14 When you say cumulative incidence rate, does that

15 mean to the first event in a patient or all events?

16 DR. SEAMAN: It is the first-

17 DR. GEORGE: And do you have the same

18 thing for the other--

19 DR. SEAMAN: Can I see the next slide,

20 Slide 11?

21 [Slide.]

22 You can see that we have maintained the

23 significance there with the median time, 314 not

24 reached for the 8/4 and 185.

25 DR. GEORGE: Remind me; where was the time


1 point? If you do something vertically here--I just

2 forgot the time that you looked at.

3 DR. SEAMAN: Nine months is the endpoint

4 DR. GEORGE: Nine months?

5 DR. SEAMAN: Yes.

6 [Slide.]

7 And then for 039, again, the cumulative

8 incidence for 4-milligram treatment.

9 DR. GEORGE: So, trying to assimilate this

10 quickly, qualitatively, you get the same results;

11 is that correct?

12 DR. SEAMAN: Correct.

13 DR. SCHER: Excuse me. To me, it looks

14 like the top two, the 8 and the placebo, seem to be

15 running together.

16 DR. SEAMAN: It looks like exactly what we

17 had if you look at the time to first SRE in that

18 039 data. They are running together the opposite

19 way.

20 DR. BRAWLEY: That is consistent with the

21 PSA data that was shown earlier as well for the

22 8/4.

23 DR. SEAMAN: Matt wants to address that a

24 bit more. We talked about it a bit during the

25 break and maybe he could say a little bit more


1 about that because we were talking about the 8/4

2 data a bit during the break, too, when we looked at

3 the data and talked a bit.

4 DR. SMITH: I wish I could, with

5 certainty, explain the difference between the 4 and

6 8/4 group in the prostate study. I don't think it

7 is possible. So I think an honest attempt has been

8 made and a thoughtful review by the FDA

9 statisticians have done so.

10 I think about it in the following way. It

11 is not just about reaching significance. It is

12 also about the treatment effect. I like what Dr.

13 George has said which is, if you think there is the

14 possibility of imbalances or chance effect, then

15 hold it against the drug and lump the less

16 favorable arm in with the more favorable arm.

17 If you do that analysis, you have a 20

18 percent relative reduction--not absolute reduction,

19 but 20 percent relative reduction in SREs in the

20 combined 4 and 8/4 group compared to placebo. That

21 is statistically significant.

22 By the way, that is exactly the same

23 treatment effect you see in the pivotal placebo-controlled

24 trials of pamidronate in breast cancer

25 with 24 months follow up. You lump 18 and 19. So


1 breast-cancer patients with bone metastases treated

2 with either chemotherapy or endocrine therapy, if

3 you lump the studies together, at 24 months, you

4 have about a 20 percent reduction in risk, relative

5 reduction in risk.

6 So I think the treatment effect in

7 prostate cancer is quite comparable to that you see

8 in metastatic breast cancer. In the pooled

9 analysis, trying to correct for any possible

10 imbalances, you do maintain statistical

11 significance with the primary effectiveness

12 analysis.

13 I think there have been a lot of

14 thoughtful attempts to provide other explanations,

15 possible imbalances and such. When you do that, it

16 does move the 8/4 group closer to statistical

17 significance. It doesn't reach it. I am not sure

18 what else could be done.

19 DR. NERENSTONE: Dr. Lippman?

20 DR. LIPPMAN: I would just like to

21 clarify, Stacy, your comment. My question wasn't

22 meant to be negative. It wasn't meant to be that

23 the company couldn't explain it. I actually asked

24 when the FDA presented. People that have really

25 pored over this data and tortured it, I was just


1 trying to see if they had any sense of some of

2 imbalances or thoughts that made it kind of--or

3 people that know more about bone metastases than I

4 do, if there was biological plausibility for this.

5 Certainly, in other areas, higher doses

6 are not always better. Clearly, the 4-milligram is

7 the cleanest arm and that data was convincing. The

8 8/4 shows the same trend, although it is not

9 significant. So, again, I would just like to

10 reiterate what Grant says. I can accept the fact

11 that this was a chance finding. The totality of

12 the data are very consistent.

13 I didn't mean--I thought the way you

14 phrased it might have a sense that I was not happy

15 with the answer or negative in any sense. I just

16 was trying to see if people who looked at the data

17 more closely had any other insight.

18 DR. BONOMI: Maybe I am missing something,

19 but when we looked at the curves, when you showed

20 the PSA levels, it was higher at baseline and it

21 went higher throughout the study and that would

22 suggest that their disease wasn't being controlled

23 and that they were a worse group of patients.

24 DR. SMITH: I incompletely answered Dr.

25 Raghavan's question about survival.


1 If you could bring up the overall survival

2 slide. I think it is 28.

3 I misspoke by saying their median survival

4 was about a year. It is, in fact, a bit longer

5 than that. There were differences none of which

6 reached statistical significance but there were

7 differences in their survival.

8 I need the Kaplan-Meier survival curves,

9 Slide 28 from my presentation.

10 [Slide.]

11 So the median survival in placebo was

12 about fifteen months, 469 days. It was worse in

13 Zometa, 8/4, 418, and best in Zometa 4. So there

14 was trend towards better survival in 4 and the

15 worst arm was the 8/4.

16 Now, in all of the other studies, we have

17 looked at survival basically overlapped. So, if

18 you look at overall survival, maybe as another way

19 of thinking about potential imbalances, and

20 recognize that we don't have a better explanation.

21 I am trying to provide a reasonable explanation

22 here.

23 If you look at that and say, this is an

24 integrated way of looking at prognostic factors,

25 perhaps this is the explanation. My guess is if


1 you pooled the survival for the 4 and 8/4, it

2 looked exactly like placebo.

3 DR. NERENSTONE: Dr. Albain, did you have

4 a question?


6 DR. NERENSTONE: Dr. Temple?

7 DR. TEMPLE: I wanted to ask Steve how

8 much explanation of these kinds of differences is

9 needed. The power of these studies isn't infinite.

10 The p-values for the most favorable results are

11 fairly close to 0.05. If the true difference is

12 what it was in that study, your chance of

13 replicating it on another study is only modest, at

14 best.

15 So is there anything here to explain

16 except that the effect isn't very big?

17 DR. GEORGE: I would say no. I think the

18 results here are pretty clear, if you are trying to

19 get my conclusion ahead of time. It is pretty

20 clear. The way I get them is to pool those results

21 together. I see attenuation of the effect of the

22 most extreme one because I think it is probably

23 random variation. I haven't heard any other

24 plausible reason.

25 I have heard some things thrown out that


1 might have contributed but there is no real good

2 evidence that there is anything there. So it is

3 fairly straightforward for me in that sense.

4 DR. NERENSTONE: I just wanted to ask--or

5 talk to Dr. Williams. I think that three of the

6 studies are pretty--to my mind, the answers are

7 pretty--or two of the studies-- are pretty clear.

8 But, going back to the solid tumor, which is a

9 little bit more of a hodgepodge of studies, and

10 some concern about the heterogeneity of the patient

11 population, I guess, from a clinical point of view,

12 I would look at the statistical numbers there.

13 There, of interest, is that the p-values

14 are significant; that is, the p-values for the

15 Zometa 4 milligrams in the time to first SRE, which

16 is your preferred analysis, was significant at the

17 0.02 level and both the difference in the

18 proportion as well as the time to first SRE are

19 significant for the 8-milligram.

20 The argument about heterogeneity of the

21 patient population, I think, is important. Again,

22 if you postulated that perhaps there would be a

23 difference of what it is doing or how tumor types

24 are going to act on the bone, and if they didn't

25 have a significant p-value, that would be raised.


1 The fact that these are significant, in my

2 mind, suggests that the mechanism either is the

3 same or is affected in the same positive way. To

4 my thinking, I don't have a problem with that. I

5 think, from a clinical point of view, to have a

6 phase III trial in metastatic cervix cancer to the

7 bone is not going to happen and, in fact, this data

8 suggests that those patients would benefit from

9 this kind of treatment.

10 I just wanted to open this up to the

11 committee because I think is the most problematic

12 study.

13 Dr. Lippman?

14 DR. LIPPMAN: Again, this gets at what

15 Rick raised. From what I have heard, and not being

16 an expert on bone physiology, it seems as thought

17 the pathophysiology of the lytic and blastic

18 lesions, the aspect is similar. Unless there is

19 really a biological reason to think that it is

20 different, I think it may be reasonable to include

21 them all as one for the reasons you mentioned, and

22 Stacy, that it is really not going to be practical

23 or possible to do single-site definitive trials.

24 So there would have to be some real

25 biologic reason not to, and I haven't heard that.


1 DR. NERENSTONE: Dr. Temple.

2 DR. TEMPLE: As Grant said, we always

3 wonder how quickly to generalize any putative

4 common mechanism. Anybody can make up a mechanism,

5 you know, and it will always be plausible because

6 they wouldn't offer anything silly. So the

7 question is how much replication, how much

8 verification, do you need.

9 As Grant said, the division thought, well,

10 you have got prostate, you have got breast, you

11 have got a variety of solid tumors. That is

12 getting to the point where you might consider this

13 to be a generalizable finding. That is obviously

14 one of the things we want to ask everybody, how

15 plausible that seems, plus all the other data from

16 drugs in the class. You bring all of that.

17 DR. NERENSTONE: Dr. Przepiorka?

18 DR. PRZEPIORKA: I think there is a lot of

19 data to suggest that statistically we are seeing

20 something. But I guess the question on the table

21 is is there substantial evidence to support

22 approvals for these indications. We are clearly

23 not treating the primary cancer, and the survival

24 statistics pretty much show that we are not

25 treating the primary cancer.


1 The quality-of-life indicators demonstrate

2 no benefit for the drug. The median time to SREs

3 are the same in the breast-cancer trials so you

4 can't really say anything since that is an

5 equivalency trial. But, for the solid-tumor trial,

6 the reduction of median time to SRE is only two

7 months. So the question is, in the clinic, is that

8 going to make a difference.

9 The point reduction in SREs at nine months

10 or one year, I have heard conflicting data and it

11 wasn't on the slide, is 8 percent. Is 8 percent

12 enough to really say that this is substantial

13 clinical evidence for a benefit for these patients?

14 I would like to hear anybody else's

15 comments about that, too.

16 DR. NERENSTONE: Dr. George

17 DR. GEORGE: I am not going to address

18 clinically whether it is, but it relates to what I

19 mentioned earlier about the--if it is true. Let's

20 just assume, for the moment, that 8 percent is the

21 true difference. I mean, really, if you give this

22 agent, you will get 8 percent less SREs in the time

23 frame specified. That is the main thing you are

24 looking at. We are not considering all the other

25 endpoints right now.


1 That means that you have to treat twelve

2 or so patients in order to get that one benefit.

3 So eleven are not getting any benefit, in that

4 sense. They might be getting something else if

5 there is some other benefit, but I didn't see any

6 other benefit.

7 So what you are getting is those eleven

8 patients or so were getting treated with something

9 that is not doing them any good. So, is it worth

10 it? I don't know regulatory--

11 DR. PAZDUR: Could I clarify something,

12 Donna? When you are talking about significance

13 here or substantial evidence, what you are really

14 talking about is is this of clinical importance or

15 clinical significance.

16 The way, really, the questions were raised

17 and what we were thinking of is more substantial

18 evidence of a drug effect. There are, really, two

19 kind of separate issues, perhaps. One is does it

20 make sense from a clinical point of view this two

21 months or whatever, X months, may be. That is a

22 clinical question.

23 The other one is substantial evidence, is

24 that reproducible, is it a reliable statistical

25 point of view. So there are two kind of different


1 issues come into play here, I think.

2 DR. NERENSTONE: Dr. Przepiorka?

3 DR. PRZEPIORKA: I was actually thinking

4 about that in the same way as well because,

5 clearly, if the effect is so marginal, a second

6 study may not show a benefit at all.

7 DR. NERENSTONE: The sponsor would like to

8 say something.

9 DR. SEAMAN: I think if you take into

10 consideration the 8 percent, that is probably

11 correctly, if you are just counting the first

12 event. But, if you wouldn't mind, let me show you

13 all the events, if you count all the events. The

14 only way you can look at that is in a multiple-event

15 analysis.

16 It is not in any of your slides, but let

17 me just give you an idea how many events occurred

18 in this patient population over the course of the

19 trial and just give you the numerical numbers.

20 May I have those slides?

21 If you remember back to Dr. Coleman's

22 slide where he showed the hundreds and hundreds of

23 events that took over the 24 month period. Let's

24 take a look at what we saw, too. That 8 percent is

25 just a first event, whether it be proportion or--


1 [Slide.]

2 This is for protocol 010. During the

3 course of that thirteen-month evaluation, there

4 were 808 SREs in terms of Zometa 4 and pamidronate

5 at 849. These are the types of things that took

6 place during that time frame. So it is

7 substantial. It is pretty similar to what we are

8 seeing. So we are just talking about an 8 percent

9 reduction.

10 Now, we don't have a placebo group in this

11 but let's look at the next set of slides for 011

12 and 039.

13 [Slide.]

14 You can see, again, here, that, over that

15 nine-month time frame, there are a number of these

16 events occurring in the placebo treatment group,

17 quite a few, 275, if you included hypercalcemia.

18 You were just counting that first event. In each

19 treatment group, you are having an impact. In the

20 treatment group, you are seeing an impact on that.

21 [Slide.]

22 Finally, in protocol 039, again you see

23 that there are a substantial number of events we

24 are not counting. So there are a whole host of

25 other events that we are taking into consideration.


1 If you look at the multiple-event analysis

2 in terms of protocol 011 and protocol 039, it is a

3 25 to 27 percent reduction in these events rates.

4 DR. NERENSTONE: I think, Donna, one of

5 your questions is more a more philosophical one,

6 which is how meaningful clinically is this drug. I

7 think no one who treats patients is going to say

8 this is a home run but it probably is a small

9 improvement.

10 Certainly, for those of us who treat a lot

11 of breast-cancer patients, showing that Zometa is

12 not worse--and you might want to debate that--but

13 is probably not worse than pamidronate, getting

14 patients out in fifteen minutes rather than two

15 hours definitely is going to add to their quality

16 of life and the patients will tell you that. And

17 that is a big deal.

18 So that study, in itself, I think, as much

19 as we don't like "me, too" drugs, does provide an

20 advantage, just on the basis of that alone.

21 MR. KAZMIERCZAK: I would agree with that.

22 Fifteen minutes instead of two hours certainly does

23 make a difference when you are a patient. I agree.

24 DR. NERENSTONE: Dr. Temple?

25 DR. TEMPLE: Of course, if the effect


1 isn't worth anything, you can avoid the fifteen

2 minutes and the two hours.

3 It is worth remembering that if you look

4 at the absolute percent difference--I mean, there

5 is a constant debate about this and Steve is trying

6 to do this, how many people do you have to treat to

7 benefit anybody. In some settings, hypertension

8 and things like that, we are accustomed to looking

9 at the percent reduction in bad events when the

10 actual reduction might be only 1 or 2 percent per

11 year. But that is because the events are

12 considered so very bad.

13 In these, I guess not all of the events

14 are really horrible, but some of them probably are.

15 So it is worth at least considering the hazard-ratio part of

16 it, too, which gives you some sense

17 of the relative reduction in the nasty events and

18 which shows a larger effect, obviously, than the

19 absolute reduction of roughly double.

20 DR. NERENSTONE: Dr. George?

21 DR. GEORGE: Just as follow up. Actually,

22 I don't know if it was addressed here. Maybe

23 someone knows it. Grant, I think, mentioned

24 something about it earlier. The endpoint, the SRE,

25 is a very heterogeneous collection of events, some


1 of which are treatment driven and some of which are

2 biologically based.

3 I have been just assuming that this is a

4 widely accepted endpoint in this area, but what is

5 the genesis of this endpoint?

6 DR. WILLIAMS: I am sure Dr. Seaman could

7 comment on this too, but, as I recall, the company

8 developed this endpoint for the Aredia trials and

9 certainly, we were involved. The basic idea was to

10 try to capture the very different kinds of

11 morbidity that seemed to be about of the same

12 significance. There was a big debate, do you put

13 hypercalcemia on here, and we steadfastly said no,

14 that this is something different, of a different

15 nature, that you could treat later.

16 I think that, as it happened, the bone

17 events ended up being a little different than we

18 expected. I think we were probably thinking about

19 long-bone fractures and it ended up being a lot of

20 compression fractures, of less significance,

21 perhaps, than we initially anticipated.

22 But I think we really have come to think

23 of the radiation therapy to bone to be a reasonable

24 sort of an integrator of what--a physician, I don't

25 think, just willy-nilly, goes out and puts the


1 patient in for a course of radiation therapy that

2 ended in a blinded trial where they don't know

3 which arm is getting which.

4 They are making that commitment usually

5 for something significant. So, even though they

6 are different in nature, we felt like they were

7 about of the same significance and I think we felt

8 comfortable over the past seven or eight years,

9 perhaps, with this event.

10 I don't know that it has been used

11 anywhere outside of the regulatory environment.

12 DR. NERENSTONE: Dr. George

13 DR. GEORGE: Along those lines, the

14 consistency of these studies, if you look at this

15 first page you gave us, if you do that pooling that

16 I was talking about across the treatments, it is

17 really remarkable that the proportion of patients

18 with an SRE, it would 36 percent in the treated

19 group pooled in the prostate-cancer study, in the

20 placebo, 44 percent.

21 In the solid tumors, the lung cancer and

22 others, exactly the same thing, with a different

23 time period but in different kinds of events and

24 patterns. But, overall, you get precisely the same

25 point estimates. That is with that 8 percent


1 effect.

2 DR. NERENSTONE: Dr. Bonomi?

3 DR. BONOMI: From a clinical perspective,

4 if you prevent one patient out of twelve from

5 having severe pain or from having a pathologic

6 fracture, I think that is very clinically relevant.

7 Even though we can't pick it up in the quality of

8 life, all the patients are in one pool, that really

9 has a huge impact on the quality of life, if you

10 have terrible pain. Certainly, if you have a

11 fracture, it is much worse.

12 DR. NERENSTONE: Dr. Raghavan?

13 DR. RAGHAVAN: I would like to change

14 gears just a little bit. It comes back to Matt

15 Smith's late response to my question. You know,

16 one of the things that I think is important--because one

17 senses there is a consensus around the

18 table that these are relatively straightforward

19 decisions. It is the fine tuning that we are

20 spending the time on.

21 So I, with that in mind, took the liberty

22 of looking at the package insert. It does strike

23 me that, in the context of prostate cancer, for

24 someone who does see a lot of prostate cancer and

25 bad prostate cancer that is aggressive, as a


1 clinician, I am not sure that I know where this

2 drug should find its place.

3 I think everything that has been said

4 about reducing the pain for patients is true. I

5 think it is good to do that, but I am not sure that

6 what I have heard today will tell me how to apply

7 it in clinical practice. So, if it does happen

8 that this gets approval, I would say to the FDA,

9 you want to spend some time with the company

10 looking at the development of the package insert

11 and getting the wording right.

12 We know that people tend to telescope from

13 meetings such as this. I could imagine that there

14 could be tens of thousands of patients who have

15 radical prostatectomies who go on this straight

16 away "to prevent bone complications."

17 We know that people use drugs in strange

18 ways. Now, even within the context of what we have

19 heard, I am absolutely convinced that a very good

20 thing to be is--I mean, it is not a good thing to

21 be stuck with prostate cancer, but it seems to get

22 into this trial is a good thing because every arm

23 has good survival.

24 I think what that really tells us is it is

25 a very heterogenous group. In the real world, the


1 median survival for prostate cancer is short.

2 Skeletal-related events occur more commonly than

3 even in the placebo-treated group here. It

4 probably means the doctors have managed them well.

5 I don't take that away from the treating team, but

6 I do think there is case selection, as I said

7 before.

8 Median weight seems to be--well, half the

9 patients have a weight between 80 and 130

10 kilograms. That is pretty big for a patient with

11 prostate cancer. There is not a lot of anemia.

12 There is not a lot of hydronephrosis. There are

13 not a lot of the things that you would expect to

14 see. So what I think we have got in the definition

15 of patients going into the trial is a mix of people

16 who have had a bit of chemotherapy for a range of

17 reasons.

18 People are on hormones, off hormones, and

19 so on. So, while I don't think that detracts from

20 the importance of the product, I think the FDA is

21 going to need to spend some time on the package

22 insert. It may well behoove the company to look at

23 sets of patients like those who present with more

24 significant symptoms than require codeine only.

25 The vast majority of patients with


1 prostate cancer and bone metastases have severe

2 pain and major problems. So I think they have

3 picked a good group, which is fine, but in the

4 further development of the drug, it might be nice

5 to encourage them to look at some of the tougher

6 cases.

7 DR. NERENSTONE: Dr. Loeher?

8 DR. LOEHER: I just want to echo what

9 Derek said. I mean, a nice clean study which would

10 have answered a lot of questions is primary

11 treatment of hormonal-sensitive patients to do

12 orchi-activity or do LHR-antagonist with or without

13 this. Then you would be able to get removal out of

14 these variables and find out exactly how to do

15 that. So I would encourage the company to pursue

16 that.

17 The other question I had, I guess along

18 that line, and picking up on what Donna said, is

19 what is the subset of patients that are going to

20 benefit. Do we need to treat all of these people

21 or can we identify them? The question I have, and

22 I don't understand curves and stuff, but you had

23 this urinary telopeptide-creatinine ratio. Is this

24 useful in terms of predicting who will respond and

25 who will not respond in terms of outcome?


1 DR. SEAMAN: I will have Rob Coleman

2 answer that who is very familiar with a lot of the

3 things that have been done over the years and it is

4 somewhat in its infancy.

5 DR. COLEMAN: Rob Coleman. Most of the

6 data with N-telopeptides is actually from the

7 breast-cancer literature. It is a small series so

8 it is difficult to add a lot of weight to it, but

9 it seems that what we should be trying to do is

10 normalize bone resorption. The way we measure that

11 is, obviously, with one of these bone markers.

12 There are some patients who you won't

13 normalize bone resorption even with a

14 bisphosphonate for reasons that are not very well

15 explained. So I think we do have to look at trying

16 to use the markers to pick out those patients who

17 are unresponsive because, clearly, bisphosphonates

18 are not a panacea. They are an improvement but

19 they are not a panacea.

20 Trying to use the markers to predict who

21 is going to respond in the first place--for

22 instance, if you have absolutely normal bone

23 resorption, why add in the bone-resorption-inhibitor on top?

24 So there may be people who you

25 don't need to treat or there may be people who are


1 resistant and our hope is that the markers will

2 sort this out

3 Obviously, there is as huge database of

4 information that will be analyzed over the coming

5 months to try and dissect that out, but that is the

6 theory behind it. But there isn't a sort of

7 internationally approved set of response criteria

8 that we could use as of today.

9 DR. NERENSTONE: Other comments from the

10 committee? Dr. Kelsen?

11 DR. KELSEN: No; I have no more comments

12 at this point.

13 DR. NERENSTONE: Dr. Albain?

14 DR. ALBAIN: Yes. I wondered if we could

15 have a little bit of discussion about the labeling

16 in renal function and what--

17 DR. NERENSTONE: We are losing you, Kathy.

18 Hold on just a minute. Try again.

19 DR. ALBAIN: I wondered if we could have a

20 little discussion about the labeling and the

21 pretreatment renal function as well as monitoring.

22 Are we going to recommend that this not be given

23 for creatinine clearances less than 30 or could we

24 have a little more discussion about that?

25 DR. WILLIAMS: We are having discussions


1 internally on that matter. I don't think we have

2 made up our mind what to recommend. Certainly,

3 this is renally excreted and there seems to be a

4 relationship between the creatinine and toxicity

5 and AUC and toxicity. But whether or not you would

6 recommend treatment outside of the range of the

7 study, that is still a point for debate, I think.

8 We probably won't have that debate here.

9 DR. NERENSTONE: Any other questions, Dr.

10 Albain?

11 DR. ALBAIN: Just thinking, when we give

12 pamidronate, as a rule, in practice, we don't

13 routinely--or many places do not get a serum

14 creatinine before each dose. What we have seen

15 today would seem to indicate that you probably

16 should as much as you should with this agent.

17 Is that going to be a strong suggestion

18 that it be done? It was alluded to during the

19 presentations. How necessary is that?

20 DR. SCHER: I think you are right that

21 initially the nephrotoxic nature of pamidronate was

22 not that obvious as imparted to us clinicians,

23 which it was at the time. I can't make a comment

24 on that label at this point but, as Grant said, the

25 exact labeling of this drug will be under


1 discussion. Clearly, we will be recommending, if

2 Zometa is approved, that creatinine be closely

3 monitored and there will be some comment on level

4 of renal function. But that has to be discussed

5 further.

6 DR. ALBAIN: Just to follow that up a

7 little bit further because these patients routinely

8 will be just coming in including visits for the

9 agent without physician input on each and every

10 dose. If we follow the guidelines of the clinical

11 trial for Zometa, it is a lot more involved.

12 You hold it. You wait until it decreases

13 to a certain fraction, et cetera. So it may change

14 the national practice standards of how we give

15 these agents based on what you decide.

16 DR. NERENSTONE: To follow that up, are

17 you going to recommend the vitamin D and calcium

18 which, I guess, all patients on these studies go on

19 and was sort of news to me.

20 DR. WILLIAMS: We generally do put in the

21 label the way it is done in the study. We have a

22 noninferiority study which seemed very similar with

23 the amount of toxicity to Aredia. We just happen

24 to have the sponsor for Aredia here in the same

25 room. I would think that we would generally want


1 that label to be pretty similar regarding this.

2 DR. NERENSTONE: Dr. Kelsen, did you have

3 any questions?

4 DR. KELSEN: No additional questions.

5 DR. NERENSTONE: Dr. Taylor, do you have

6 any questions?

7 DR. TAYLOR: Not right now.

8 DR. NERENSTONE: I will take that as a no.

9 Dr. Lippman?

10 DR. LIPPMAN: I just wanted to bring up

11 again, just to make sure we brought some closure,

12 albeit with, maybe, not the perfect answers, but

13 FDA, Bob, everyone raised the issue of the blastic

14 versus lytic. It came up again in Pat's questions

15 about can we dissect who would respond or not.

16 Since one might have thought that the biggest

17 predictor might have been whether it is blastic or

18 lytic and that doesn't seem to be the case, is

19 there any more discussion? I think Bob left it

20 with, well, you can always come up with biologic

21 plausibility.

22 I think we have heard one mechanism. We

23 haven't heard any others that would dispute it and

24 we see results in the two tables, Grant, that you

25 put on this page which show very similar results in


1 prostate and the others.

2 So I don't know that we have any

3 information or anything else to say that it

4 shouldn't be used in both. I just don't know.

5 Have we resolved that? Because it is one of the

6 major questions that you raised and one of the

7 questions on the sheet. Is there anything that you

8 want to discuss?

9 DR. WILLIAMS: You have heard the

10 evidence, preclinical and clinical. It is your

11 discussion.

12 DR. PAZDUR: Perhaps you will resolve it

13 with your vote.

14 DR. NERENSTONE: Dr. George

15 DR. GEORGE: Along those lines, one other

16 issue I haven't completely resolved in my own mind

17 is the myeloma data with respect to the first study

18 because the main thing that concerns me about that

19 still is that difference with the Aredia effect--not the

20 effect because we don't have a placebo, but

21 the Aredia results--in the new study and the old.

22 It is sort of indirect evidence that there is not a

23 constancy here but--maybe very indirect, but there

24 were some prognostic factors that seemed to be

25 different.


1 But I am still a little worried about

2 that. After saying I favor pooling generally, now

3 I am sort of backtracking a little bit, got a

4 little worried about the fact that breast cancer

5 seems very clear, clear-cut. That is nice. And

6 the myeloma, I am wondering whether that evidence

7 is really there strong enough.

8 [Slide.]

9 The only thing I could think to do was to

10 try to find patients that were similar within the

11 old trial and see what estimate effect we had. It

12 seemed to be, if anything, greater. So that is all

13 I could think to do to examine that question. It

14 seemed to be clear that they were a more aggressive

15 disease and one could wonder is it so aggressive

16 that we are going to have no effect on it.

17 But, in looking back at similar patients

18 with what appeared to be more aggressive disease,

19 earlier time since diagnosis, the effect seemed, if

20 anything, more, the Aredia versus placebo effect.

21 So I think that is about all we could do.

22 DR. NERENSTONE: Dr. Raghavan?

23 DR. RAGHAVAN: I would like to respond to

24 Scott Lippman's question. I think that it is only

25 one trial but the differences are actually quite


1 compelling, not withstanding the caveats that I put

2 in, in prostate cancer. That really is an

3 absolutely blastic-metastasis-dominated disease. I

4 think they showed it somewhere in the stuff we have

5 looked at today that there were a tiny proportion

6 of mixed sclerotic and lytic.

7 But, for practical purposes, prostate

8 cancer, in the board questions, comes up. You see

9 a picture of blastic metastasis. So I was pretty

10 impressed with the prostate as a paradigm of

11 blastic disease so it didn't leave me feeling too

12 uncomfortable about that issue.

13 DR. NERENSTONE: Dr. Lippman?

14 DR. LIPPMAN: I think that was sort of the

15 point, that we have sort of the biologic

16 plausibility, the only mechanism that we have. And

17 we have consistent clinical results that also

18 support efficacy. So, again, I don't know that we

19 have anything else to resolve it, but there is no

20 other data to have to suggest that isn't active in

21 that setting.

22 DR. NERENSTONE: Mr. Kazmierczak?

23 MR. KAZMIERCZAK: I guess I would have

24 been a participant in your clinical trial if I

25 could because I am a patient with a rising PSA


1 right now. I hope I am one of the one in twelve.

2 One in twelve is certainly better than none in

3 twelve. Thank you.

4 DR. NERENSTONE: If we could turn now to

5 the questions. We have all seen the first page. I

6 am not going to go over that.

7 For new drug approval, substantial

8 evidence of efficacy from adequate and well-controlled

9 investigations is required. Evidence

10 from multiple clinical trials is usually submitted

11 but robust results from a single multicenter trial

12 have been accepted.

13 We are going to consider whether the

14 results from trials fulfill the regulatory

15 requirement. So the first study we are going to

16 look at is study 010 in breast cancer and myeloma.

17 In that study, 44 percent of Aredia patients had an

18 SRE on study versus 46 percent of Zometa patients.

19 Using the conservative two-95-percent-confidence-

20 interval method, the FDA calculates that

21 Zometa retains at least 49 percent of Aredia's

22 efficacy demonstrated historically in comparison to

23 placebo.

24 The first question, do other studies, 011

25 and 039, provide supportive evidence for Zometa's


1 efficacy in breast cancer and myeloma.

2 DR. SEAMAN: The numbers are reversed, 44

3 for Zometa, for Aredia 46 percent.

4 DR. NERENSTONE: Okay. Thank you. So it

5 is 46 percent of the Aredia and 44 percent for

6 Zometa. I am going to have to see a show of hands

7 and then I will ask for our participants at the

8 remote locations by name. So, first we are going

9 to go around the table. Do the other studies

10 provide supportive evidence for Zometa's efficacy

11 in breast cancer and myeloma?

12 Dr. Kelsen?

13 DR. KELSEN: Yes.

14 DR. NERENSTONE: Dr. Albain?

15 DR. ALBAIN: Yes.

16 DR. NERENSTONE: Dr. Taylor?

17 DR. TAYLOR: Yes.

18 DR. NERENSTONE: Dr. Raghavan?


20 DR. NERENSTONE: Dr. George

21 DR. GEORGE: Yes.

22 DR. LIPPMAN: Yes.

23 MR. KAZMIERCZAK: Not being a clinician, I

24 will abstain.





3 DR. PELUSI: Yes.

4 DR. NERENSTONE: It is ten yes and one

5 abstention.

6 Part b; is there substantial evidence from

7 adequate and well-controlled investigations of

8 Zometa, 4 milligrams, efficacy in breast cancer and

9 myeloma?

10 Dr. Kelsen?

11 DR. KELSEN: Yes.

12 DR. NERENSTONE: I'm sorry; first of all,

13 are there any other comments from the committee?

14 Okay.

15 Dr. Kelsen?

16 DR. KELSEN: Yes.

17 DR. NERENSTONE: Dr. Albain?

18 DR. ALBAIN: Yes.

19 DR. NERENSTONE: Dr. Taylor?

20 DR. TAYLOR: Yes.

21 DR. NERENSTONE: Dr. Raghavan?


23 DR. NERENSTONE: Dr. George

24 DR. GEORGE: Yes.

25 DR. NERENSTONE: You can now go around the


1 table. I don't have to call your name.






7 DR. PELUSI: Yes.

8 DR. NERENSTONE: Eleven yes.

9 The next page. Study 039 in prostate

10 cancer. Zometa studies 010 and 011 have evaluated

11 Zometa efficacy in predominantly lytic metastases.

12 Can results from these studies provide supportive

13 evidence for Zometa's efficacy in prostate cancer

14 which produces predominantly blastic bone

15 metastases? Further comments from the committee?

16 I think we have talked about this.

17 Dr. Kelsen, do you want to start us?

18 DR. KELSEN: Yes; I will say yes.

19 DR. NERENSTONE: Dr. Albain?

20 DR. ALBAIN: Yes.

21 DR. NERENSTONE: Dr. Taylor?

22 DR. TAYLOR: Yes.


24 DR. GEORGE: Yes.

25 DR. LIPPMAN: Yes.






5 DR. PELUSI: Yes.

6 DR. NERENSTONE: Eleven yes.

7 Part b; is there substantial evidence of

8 Zometa, 4 milligrams, efficacy in prostate cancer

9 from adequate and well-controlled investigations?

10 Any further comments?

11 Dr. Kelsen, you are doing such a good job.

12 Would you like to start?

13 DR. KELSEN: Yes.

14 DR. NERENSTONE: Dr. Albain?

15 DR. ALBAIN: Yes.

16 DR. NERENSTONE: Dr. Taylor?

17 DR. TAYLOR: Yes.


19 DR. GEORGE: Yes.

20 DR. LIPPMAN: Yes.


22 DR. PRZEPIORKA: Unfortunately, I have to

23 say no. The reason I have to say no is because, as

24 was pointed out, there may be a difference between

25 the patient groups because of the survival


1 difference in the Zometa, 4-milligram, dose so I am

2 not sure I could actually draw this conclusion as

3 much as I would like to.


5 DR. BRAWLEY: For 4 milligrams, yes.

6 DR. PELUSI: Yes.

7 DR. NERENSTONE: The vote is ten yes and

8 one no.

9 For study 011 in other solid tumors.

10 Analysis from both the 4-milligram and 8-milligram

11 Zometa arms of study 011 support the efficacy of

12 Zometa. Do you agree with FDA that these results

13 provide substantial evidence of Zometa, 4

14 milligrams, efficacy in the population studied?

15 Any comments?

16 Dr. Kelsen?

17 DR. KELSEN: Yes.

18 DR. NERENSTONE: Dr. Albain?

19 DR. ALBAIN: Yes.

20 DR. NERENSTONE: Dr. Taylor?

21 DR. TAYLOR: Yes.


23 DR. GEORGE: Yes.

24 DR. LIPPMAN: Yes.

25 MR. KAZMIERCZAK: I abstain.





4 DR. PELUSI: Yes.

5 DR. NERENSTONE: Ten yes and one

6 abstention.

7 The sponsor's proposed indication includes

8 "treatment of osteolytic, osteoblastic and mixed

9 bone metastases of solid tumors." This indication

10 infers treatment as indicated for patients with

11 bone metastases from all solid tumors irrespective

12 of the primary tumor. Do you agree with this

13 proposed indication?

14 Further comments? Dr. Loehrer?

15 DR. LOEHRER: I have some concerns about

16 how this may be used for prostate cancer, patients

17 who are not hormone refractory who have bone mets

18 may get primary hormonal therapy and do extremely

19 well. The way this indication is listed, it goes

20 beyond what the studies were designed.

21 DR. WILLIAMS: This is actually referring

22 just to the other solid-tumor group, but we will

23 take that into consideration when we are thinking

24 about the prostate indication.

25 DR. NERENSTONE: Other comments? For the


1 vote, Dr. Kelsen?

2 DR. KELSEN: Yes.

3 DR. NERENSTONE: Dr. Albain?

4 DR. ALBAIN: Yes.

5 DR. NERENSTONE: Dr. Taylor?

6 DR. TAYLOR: Yes.


8 DR. GEORGE: Yes.





13 DR. BRAWLEY: Yes.

14 DR. PELUSI: Yes.

15 DR. NERENSTONE: Eleven yes.

16 There is a last sentence. Please provide

17 suggestions for wording of the indication section

18 or the clinical-trials section of the Zometa

19 labeling with regard to this issue.

20 Do you have enough discussion now?

21 DR. WILLIAMS: Yes. It wasn't clear where

22 the discussion would go, whether you were going to

23 say, "all solid tumors except," this or that. But

24 I think you have addressed that.

25 DR. NERENSTONE: I would like to thank


1 everybody for their attendance. We will meet again

2 at the end of February, February 27.

3 Thank you.

4 DR. TEMPLETON-SOMERS: Thank you Kathy,

5 Sarah and David for pioneering for us. Thanks.

6 [Whereupon, at 2:00 p.m., the meeting was

7 adjourned.]